AP384A - Inhibition of the replication of HIV and related viruses using thiourea derivative compounds or salts thereof. - Google Patents

Inhibition of the replication of HIV and related viruses using thiourea derivative compounds or salts thereof. Download PDF

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Publication number
AP384A
AP384A APAP/P/1992/000412A AP9200412A AP384A AP 384 A AP384 A AP 384A AP 9200412 A AP9200412 A AP 9200412A AP 384 A AP384 A AP 384A
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AP
ARIPO
Prior art keywords
thiourea
ethyl
pyridyl
substituted
thiazolyl
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APAP/P/1992/000412A
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AP9200412A0 (en
Inventor
Peter Thomas Lind
Jr John Michael Morin
Rolf Noreen
Robert John Ternansky
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Medivir Ab
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Priority to APAP/P/1995/000723A priority Critical patent/AP388A/en
Publication of AP9200412A0 publication Critical patent/AP9200412A0/en
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Publication of AP384A publication Critical patent/AP384A/en

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    • A—HUMAN NECESSITIES
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/17—Amides, e.g. hydroxamic acids having the group >N—C(O)—N< or >N—C(S)—N<, e.g. urea, thiourea, carmustine
    • A—HUMAN NECESSITIES
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
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    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
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    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
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    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
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    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
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    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
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    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C07D249/10—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D277/62—Benzothiazoles
    • C07D277/68—Benzothiazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
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Abstract

Method of aids, inhibition of the replication of hiv by contacting hiv with a compound of the formula-(see file)

Description

COMPOUNDS AND-METHQPS FQR INHIBITION QF
HIV AND RELATED VIRUSES This application is a continuation-in-part of application serial No. 07/739,927, filed on August 2, 1991.
Eisld-af ..the invention
The present invention relates to compounds and
0 pharmaceutically acceptable salts thereof and processes for treating infections by HIV and related viruses and/or the treatment of Acquired Immune Deficiency Syndrome (AIDS). This invention also relates to pharmaceutical compositions containing the compounds and the method of use of the
5 present compounds alone or in combination with other agents, for the treatment and inhibition of AIDS and viral infection from HIV.
Background qL the InvenLion
A retrovirus designated Human Immunodeficiency Virus (HIV) is believed to be the causative agent of the complex disease termed Acquired Immune Deficiency Syndrome (AIDS) and is a member of the lentivirus family of retroviruses (M. A. Gonda, F. Wong-Staal NR. C. Gallo,
Sequence Homology and Morphological Similarity of HTLV III and Visna Virus, A Pathogenic Lentivirus*, Science. 227,
173, (1985); and P. Sonigo and N. Alizon, et al.,
Nucleotide Sequence of the Visna Lentivirus: Relationship
0 to the AIDS Virus, Cell. 42, 369, (1985)). The HIV virus
X-8571A
-2as or referred to as LAV, HTLV-III, or ARV, and is now designated by HIV-1. Other closely related variants of HIV-1 include HIV-2 and SIV (simian immunodeficiency virus), and mutants thereof.
The complex disease AIDS includes progressive destruction of the immune system and degeneration of the central and peripheral nervous system. The HIV virus appears to preferentially attack helper T-cells (Tlymphocytes or 0KT4-bearing T-cells) and also other human cells, e.g., certain cells within the brain. The helper Tcells are invaded by the virus and the T-cell becomes an HIV virus producer. The helper T-cells are quickly destroyed and their number in the human being is depleted to such an extent that the body's B-cells as well as other T-cells normally stimulated by helper T-cells no longer function normally or produce sufficient lymphokines and antibodies to destroy the invading virus or other invading microbes.
While the HIV virus does not necessarily cause death per se, it does cause the human's immune system to be so severely depressed that the human falls prey to various other diseases such as herpes, Pneumocistis carinii. toxoplasmosis, cytomegalovirus, Kaposi's sarcoma, and Epstein-Barr virus related lymphomas among others. These secondary infections are separately treated using other medications as is conventional. Early during infection, humans with HIV virus seem to live on with little or no symptoms, but have persistent infections. Later in the disease, humans suffer mild immune system depression with various symptoms such as weight loss, malaise, fever, and
APΟ Ο Ο 384
Χ-8571Α-3persistent generalized lymphadenopathy syndrome (PGL) and AIDS related complex (ARC) and develop into AIDS.
In all cases, those infected with the AIDS virus are believed to be persistently infective to others.
Further, AIDS and AIDS related complex is after some time fatal.
A description of the mechanism by which the virus infects its host is given in an article by R. Yarchoan, and S. Broder, ‘Development of Antiretroviral
0 Therapy for the Acquired Immunodeficiency Syndrome and
Related Disorders’, NSW England Journal .ΡΪ. 316, 557-564· (February 26, 1987).
Considerable efforts are being directed toward the control of HIV by means of inhibition of the reverse
5 transcriptase of HIV, required for replication of the virus. (V. Merluzzi et al., Inhibition of the HIV-1 Replication by a Nonnucleoside Reverse Transcriptase Inhibitor’, Science. 25, 1411 (1990)). For example, a currently used therapeutic compound, AZT, is an inhibitor of the viral reverse transcriptase (U.S. Patent No.
4,724,232). Unfortunately, many of the known compounds suffer from toxicity problems, lack of bioavailability or are short lived in vivo, viral resistance, or combinations thereof.
Therefore it is an object of the invention to provide compounds and pharmaceutically acceptable salts thereof· to inhibit and/or treat HIV and AIDS.
Another object of the present invention is to provide therapeutic formulations that are of value in the
X-8571A
-4treatment or inhibition of the acquired immune deficiency syndrome.
Another object is to provide methods for the inhibition and/or treatment of infection by HIV and the resulting acquired immune deficiency syndrome.
Other objects, features, and advantages will become apparent to those skilled in the art from the following description and claims.
Description of the Invention
The present invention provides compounds useful for the inhibition and/or treatment of HIV and AIDS, either as compounds, pharmaceutically acceptable salts, pharmaceutical composition ingredients, whether or not in combination with other anti-virals, immunomodulators, antibiotics, or vaccines. Methods of treating or inhibiting AIDS, methods of inhibiting replication of HIV, and methods of treating or inhibiting HIV in humans are also disclosed.
The compounds used in the methods of the present invention are those of the formula (IA) below
S
R,-N-C-N-R, (IA)
I I *4 Rl in which Ri is a stable saturated or unsaturated, substituted or unsubstituted, 3 to 8 membered organic
AP Ο Ο Ο ό 8 4
Χ-8571Α
-5monocyclic ring having 0 to 4 hetero atoms selected from S, 0, and N; or Ri is a stable, saturated or unsaturated, substituted or unsubstituted, 7 to 10 membered organic bicyclic ring having 0 to 5 hetero atoms selected from S,
0, and N;
R2 is a group of the formula
Rs-C-CI I
Rfl Rq wherein R5 is Ri as defined above; or R5 is a group of the formula (RlO)y-Xwherein y is 1 or 2; X is N, S, O and Rio is R1 as defined; or Rio is hydrogen, Ci~Cg alkyl, C2~Cg alkenyl, or C2~Cg alkynyl; or R5 is hydrogen, halo, cyano, carboxy, amino, thio, hydroxy, C1-C4 alkoxy, Ci-Cg alkyl, C2-C8 alkenyl, C2-C8 alkynyl, or C2-C8 alkenoxy;
Rg, R7, R8, and R9 are independently C3-C8 cycloalkyl, hydrogen, Ci~Cg alkyl, C2-Cg alkenyl, C2~Cg alkynyl, halo, amino, nitro, cyano, C1-C5 alkoxy, hydroxy, carboxy, hydroxymethyl, aminomethyl, carboxymethyl, C1-C4 alkylthio, C1-C4 alkanoyloxy, carbamoyl, or a halo substituted Ci-Cg alkyl; or two of which, along with the carbons to which they are attached, combine to form a stable, saturated or unsaturated, substituted or unsubstituted, 3 to 7 membered organic monocylic ring having 0 to 4 hetero atoms selected from S, 0, or N; or Rg and R8, or R7 and Rg, along with the carbon to which they
X-8571A·
-6are attached, form a stable, saturated or unsaturated, substituted or unsubstituted, 3 to 7 membered organic monocylic ring having 0 to 4 hetero atoms selected from S,
0, or N;
R3 and R4 are independently hydrogen, hydroxy, Ci-Cg alkyl, C2-C6 alkenyl, C2-C6 alkynyl, amino, cyano, nitro, C1-C5 alkoxy, carboxy, hydroxymethyl, aminomethyl, carboxymethyl, C1-C4 alkylthio, C1-C4 alkanoyloxy, halosubstituted (Ci-Cg)alkyl, or carbamoyl; or salts thereof;
or compounds of the formula ·
S
II 13\ /c\ / n Ν N
(IB)
R,< (CH2)n wherein n is 0 to 4;
Z is y;=Y or
Y is 0 or S;
RH is of the formula /CH2 *16
AP Ο Ο Ο 3 8 4
Χ-8571Α
-7Rl4 is a stable saturated or unsaturated, substituted or unsubstituted, 3 to 8 membered organic monocyclic ring having 0 to 4 hetero atoms selected from S, 0, and N; or
Rl4 is a stable, saturated or unsaturated, substituted 5 or unsubstituted, 7 to 10 membered organic bicyclic ring having 0 to 5 hetero atoms selected from S, 0, and N; or
Rl4 is a group of the formula (RlO)y-Xwherein y is 1 or 2; X is N, S, O and Rio is a stable 1 0 saturated or unsaturated, substituted or unsubstituted, 3 to 8 membered organic monocyclic ring having 0 to 4 hetero atoms selected from S, O, and N; or Rio is a stable, saturated or unsaturated, substituted or unsubstituted, 7 to 10 membered organic bicyclic ring having 0 to 5 hetero atoms selected from S, O, and N; or Rio is hydrogen, C1-C6 alkyl, C2~Cg alkenyl, or C2~Cg alkynyl; or
Rl4 is hydrogen, halo, cyano, carboxy, amino, thio, hydroxy, C1-C4 alkoxy, C1-C6 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, or C2-C8 alkenoxy;
R15 and Ri6 are independently C3-C8 cycloalkyl, hydrogen, C1-C6 alkyl, C2-C6 alkenyl, halo, amino, nitro, cyano, C1-C5 alkoxy, hydroxy, carboxy, hydroxymethyl, aminomethyl, carboxymethyl, C1-C4 alkylthio, C1-C4 alkanoyloxy, carbamoyl, or a halo substituted C1-C6 alkyl;
R12 is hydrogen, hydroxy, C1-C6 alkyl, C2-C6 alkenyl, amino, cyano, nitro, C3.-C5 alkoxy, carboxy, hydroxymethyl, aminomethyl, carboxymethyl, C1-C4 alkylthio, C1-C4 alkanoyloxy, halo-substituted (Ci-C6)alkyl, or carbamoyl;
Rl3 is a stable saturated or unsaturated, substituted or unsubstituted, 3 to 8 membered organic monocyclic ring
X-8571A
-8Rl3 is a stable, saturated or unsaturated, substituted or unsubstituted, 7 to 10 membered organic bicyclic ring having 0 to 5 hetero atoms selected from S, 0, and N; or
R13 is Rn as defined; or salts thereof.
The invention further encompasses compounds of the formula
S
wherein n is 0 to 4;
Z is \=Y or ^ch2 / Z wherein Y is S or 0;
Rll is of the formula
5
wherein R14 is cyclo(C3-C8)alkyl, cyclo (C3~Cg) alkenyl; isothiazolyl, substituted isothiazolyl, tetrazolyl, substituted tetrazolyl, triazolyl, substituted triazolyl, pyridyl, substituted pyridyl, imidazolyl, substituted
AP Ο Ο Ο 3 8 4
Χ-8571Α
-9substituted naphthyl, benzoxazolyl, substituted benzoxazolyl, benzimidazolyl, substituted benzimidazolyl,thiazolyl, substituted thiazolyl, oxazolyl, substituted oxazolyl, benzothiazolyl, substituted benzothiazolyl, pyrazinyl, substituted pyrazinyl, pyridazinyl, substituted pyridazinyl, thiadiazolyl, substituted thiadiazolyl, benzotriazolyl, substituted benzotriazolyl, pyrrolyl, substituted pyrrolyl, indolyl, substituted indolyl, benzothienyl, substituted benzothienyl, thienyl, substituted thienyl, benzofuryl, substituted benzofuryl, furyl, substituted furyl, quinolinyl, substituted quinolinyl, isoquinolinyl, substituted isoquinolinyl, pyrazolyl, and substituted pyrazolyl; or
Rl4 is a group of the formula (RlO)y-Xwherein y is 1 or 2; X is N, S, or 0, and
RlO is cyclo(C3-C8)alkyl, cyclo (C3-C8) alkenyl;
isothiazolyl, substituted isothiazolyl, tetrazolyl, substituted tetrazolyl, triazolyl, substituted triazolyl, pyridyl, substituted pyridyl, imidazolyl, substituted imidazolyl, phenyl, substituted phenyl, naphthyl, substituted naphthyl, benzoxazolyl, substituted benzoxazolyl, benzimidazolyl, substituted benzimidazolyl,thiazolyl, substituted thiazolyl, oxazolyl, substituted oxazolyl, benzothiazolyl, substituted benzothiazolyl, pyrazinyl, substituted pyrazinyl, pyridazinyl, substituted pyridazinyl, thiadiazolyl, substituted thiadiazolyl, benzotriazolyl, substituted
0 benzotriazolyl, pyrrolyl, substituted pyrrolyl, indolyl, substituted indolyl, benzothienyl, substituted
X-8571A
-10benzothienyl, thienyl, substituted thienyl, benzofuryl, substituted benzofuryl, furyl, substituted furyl, quinolinyl, substituted quinolinyl, isoquinolinyl, substituted isoquinolinyl, pyrazolyl, and substituted pyrazolyl; or
Rl4 is halo, cyano, carboxy, amino, thio, hydroxy, C1-C4 alkoxy, C2-C8 alkonyl, C2-C8 alkynyl, or C2C8 alkenoxy;
Rl2 is hydrogen, hydroxy, C1-C6 alkyl, C2-C6 10 alkenyl, amino, cyano, nitro, C1-C5 alkoxy, carboxy, hydroxymethyl, aminomethyl, carboxymethyl, C3.-C4 alkylthio, C1-C4 alkanoyloxy, halo substituted C1-C6 alkyl, or carbamoyl; and R13 is cyclo(C3-C8)alkyl, cyclo (C3-C8) alkenyl;
5 isothiazolyl, substituted isothiazolyl, tetrazolyl, substituted tetrazolyl, triazolyl, substituted triazolyl, pyridyl, substituted pyridyl, imidazolyl, substituted imidazolyl, phenyl, substituted phenyl, naphthyl, substituted naphthyl, benzoxazolyl, substituted
0 benzoxazolyl, benzimidazolyl, substituted benz imidazolyl, thiazolyl, substituted thiazolyl, oxazolyl, substituted oxazolyl, benzothiazolyl, substituted benzothiazolyl, pyrazinyl, substituted pyrazinyl, pyridazinyl, substituted pyridazinyl, thiadiazolyl, substituted thiadiazolyl, benzotriazolyl, substituted benzotriazolyl, pyrrolyl, substituted pyrrolyl, indolyl, substituted indolyl, benzothienyl, substituted benzothienyl, thienyl, substituted thienyl, benzofuryl, substituted benzofuryl, furyl, substituted furyl,
0 quinolinyl, substituted quinolinyl, isoquinolinyl.___
AP Ο Ο Ο 3 8 4
Χ-8571Α
-11substituted isoquinolinyl, pyrazolyl, and substituted pyrazolyl;
or R13 is Rn as defined;
Rl5 and Rig are independently C3-C3 cycloalkyl, hydrogen, C1-C6 alkyl, C2-C6 alkenyl, halo, amino, nitro, cyano, C1-C5 alkoxy, hydroxy, carboxy, hydroxymethyl, aminomethyl, carboxymethyl, C1-C4 alkylthio, C1-C4 alkanoyloxy, carbamoyl, or halo substituted (C1-C6)alkyl; and salts thereof, with the proviso that R12 is not hydrogen when R15 and Rig are both hydrogen, R14 is phenyl, Rl3 is phenyl, Z is and n is O.
The invention also encompasses compounds of the formula
S
II
R,-N-C-N-R, (IA)
I I r4 r, in which Ri is a stable saturated or unsaturated, substituted or unsubstituted, 3 to 8 membered organic monocyclic ring having 0 to 4 hetero atoms selected from S, O, and N; or Ri is a stable, saturated or unsaturated, substituted or unsubstituted, 7 to 10 membered organic bicyclic ring having 0 to 5 hetero atoms selected from S, 0, and N;
R2 is a group of the formula
X-8571A
-12μ..
JJ_
K5 j c
Rfl R<j wherein R5 is Ri as defined above; or R5 is a group of the 5 formula (RlO)y-Xwherein y is 1 or 2; X is N, S, O and Rio is Ri as defined; or Rio is hydrogen, Ci-Cg alkyl, C2~Cg alkenyl,or C2-Cg alkynyl; or R5 is hydrogen, Ci~Cg alkyl, halo, cyano, carboxy, amino, thio, hydroxy, C1-C4 alkoxy, C2-C8 alkenyl, C2-C8 alkynyl, or C2 to Cg alkenoxy;
Rg and R7 are independently C3-C8 cycloalkyl, hydrogen, Ci-Cg alkyl, C2~Cg alkenyl, C2~Cg alkynyl, halo, amino, nitro, cyano, C1-C5 alkoxy, hydroxy, carboxy, hydroxymethyl, aminomethyl, carboxymethyl, C1-C4 alkylthio, C1-C4 alkanoyloxy, carbamoyl, or a halo substituted Cj-Cg alkyl;
R8 and Rg, along with the carbons to which they are attached, combine to form a stable, saturated or
0 unsaturated, substituted or unsubstituted, 3 to 7 membered organic monocylic ring having 0 to 4 hetero atoms selected from S, O, or N;
R3 and R4 are independently hydrogen, hydroxy, Ci-Cg alkyl, C2~Cg alkenyl, C2~Cg alkynyl, amino, cyano, nitro, C1-C5 alkoxy, carboxy, hydroxymethyl, aminomethyl, carboxymethyl, C1-C4 alkylthio, C1-C4 alkanoyloxy, halosubstituted (Ci~Cg)alkyl, or carbamoyl; or salts thereof.
AP Ο Ο Ο 3 β 4
Χ-8571Α -13The invention also encompasses compounds of the formula
S
II
R,-N-C-N-R, (IA)
I I
Ri wherein Ri is cyclo(C3-C8)alkyl, cyclo (C3-C8) alkenyl; isothiazolyl, substituted isothiazolyl, tetrazolyl, substituted tetrazolyl, triazolyl, substituted triazolyl,
0 pyridyl, substituted pyridyl, imidazolyl, substituted imidazolyl, phenyl, substituted phenyl, naphthyl, substituted naphthyl, benzoxazolyl, substituted benzoxazolyl, benzimidazolyl, substituted benzimidazolyl,thiazolyl, substituted thiazolyl, oxazolyl,
5 substituted oxazolyl, benzothiazolyl, substituted benzothiazolyl, pyrazinyl, substituted pyrazinyl, pyridazinyl, substituted pyridazinyl, thiadiazolyl, substituted thiadiazolyl, benzotriazolyl, substituted benzotriazolyl, pyrrolyl, substituted pyrrolyl, indolyl, substituted indolyl, benzothienyl, substituted benzothienyl, thienyl, substituted thienyl, benzofuryl, substituted benzofuryl, furyl, substituted furyl, quinolinyl, substituted guinolinyl, isoquinolinyl, substituted isoquinolinyl, pyrazolyl, and substituted
5 pyrazolyl;
R2 is a group of the formula
X-8571A
-14R6 *7
Rs Rq wherein R5 is pyridyl, substituted pyridyl, phenyl, substituted phenyl, naphthyl, substituted naphthyl, cyclohexenyl, benzyl, or R5 is a group of the formula (RlO)y-Xwherein y is 1 or 2; X is N, S, O and Rio is Ri as defined; or Rio is hydrogen, Ci-Cg alkyl, C2-Cg alkenyl, or C2-C6 alkynyl;or R5 is hydrogen, C1-C6 alkyl, halo, cyano, carboxy, amino, thio, hydroxy, C1-C4 alkoxy, C2-C8 alkenyl, C2-C8 alkynyl, or C2 to Cs alkenoxy;
R6, R7. r8< and R9 are independently C3-C8 cycloalkyl, hydrogen, C1-C6 alkyl, C2-Cg alkenyl, C2-C6 alkynyl, halo, amino, nitro, cyano, C1-C5 alkoxy, hydroxy, carboxy, hydroxymethyl, aminomethyl, carboxymethyl, C1-C4 alkylthio, C1-C4 alkanoyloxy, carbamoyl, or a halosubstituted C1-C6 alkyl; or R6 and Rs, or R7 and Rg, along with the carbon to which they are attached, form a stable, saturated or unsaturated, substituted or unsubstituted, 3
0 to 7 membered organic monocylic ring having 0 to 4 hetero atoms selected from S, 0, or N;
R3 and R4 are independently hydrogen, hydroxy, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, amino, cyano, nitro, C1-C5 alkoxy, carboxy, hydroxymethyl, aminomethyl, carboxymethyl, C1-C4 alkylthio, C1-C4 alkanoyloxy, halosubstituted C1-C6 alkyl; or carbamoyl; or salts thereof, with the proviso that when
AP Ο Ο Ο 3 8 4 r·
Χ-8571Α -15Rl is pyridyl or pyridyl monosubstituted with halogen, hydroxy, Ci-Cg alkyl, or Ci~C6 alkoxy; and
R3 and R4 are hydrogen; and R6, R7, Rq, and R9 are hydrogen;
R5 is not non-substituted phenyl.
When referring to the above as formula (I), it is understood to encompass formulae (IA) and (IB). It should also be understood that when the term HIV is used, it includes HIV-1, components, mutant variations, subtypes,
0 and serotypes thereof, and related viruses, components, mutant variations, subtypes, and serotypes thereof. When the term inhibit· is used, its ordinary meaning is intended, which is to prohibit, hold in check, or discourage, and is not to be construed to be limited to a
5 particular process, procedure, or mechanism of action.
The terms stable, saturated or unsaturated, substituted or unsubstituted, 3 to 8 membered, or 3 to 7 membered organic monocyclic ring having 0 to 4 hetero atoms selected from S, O, and N include those wherein the nitrogen and sulfur hetero atoms are optionally oxidized, and the nitrogen hetero atom optionally quaternized. The substituted ring may have 1-8 substituents independently selected from aryl, substituted aryl, halo, C1-C6 alkyl, C1-C5 alkoxy, C2-C6 alkenyl, C2-C8 alkynyl, C2-C8 alkenoxy, amino, nitro, cyano, carboxy, hydroxymethyl, aminomethyl, carboxymethyl, C1-C4 alkylthio, hydroxy, C1-C4 alkanoyloxy, carbamoyl, halo-substituted C1-C6 alkyl, a group of the formula
-SO2RX
0 wherein Rx is C1-C6 alkyl, aryl, substituted aryl, or
X-8571A
-16O
II
-C-Rx wherein Rx is as defined above.
The term ‘stable, saturated or unsaturated, substituted or unsubstituted, 7 to 10 membered organic bicyclic rings having 0 to 5 hetero atoms selected from S, 0, and N* includes those wherein the nitrogen and sulfur hetero atoms are optionally oxidized, and the nitrogen hetero atom(s) optionally quaternized. The bicyclic rings may be substituted 1 to 8 times, the substituents independently selected from those above listed for the. ' monocyclic rings.
Examples of such monocyclic and bicyclic rings are cyclo(C3-C8)alkyl, cyclo(C3-C8)alkenyl; isothiazolyl, substituted isothiazolyl, tetrazolyl, substituted tetrazolyl, triazolyl, substituted triazolyl, pyridyl, substituted pyridyl, imidazolyl, substituted imidazolyl, phenyl, substituted phenyl, naphthyl, substituted naphthyl, benzoxazolyl, substituted benzoxazolyl, benzimidazolyl, substituted benzimidazolyl,thiazolyl, substituted thiazolyl, oxazolyl, substituted oxazolyl, benzothiazolyl, substituted benzothiazolyl, pyrazinyl, substituted pyrazinyl, pyridazinyl, substituted pyridazinyl, thiadiazolyl, substituted thiadiazolyl, benzotriazolyl, substituted benzotriazolyl, pyrrolyl, substituted pyrrolyl, indolyl, substituted indolyl, benzothienyl, substituted benzothienyl, thienyl, substituted thienyl, benzofuryl, substituted benzofuryl, furyl, substituted furyl, quinolinyl, substituted quinolinyl, isoquinolinyl,
AP Ο Ο Ο 3 8 4
Χ-8571Α -17substituted isoquinolinyl, pyrazolyl, and substituted pyrazolyl. Other examples of such ring systems may be found in J. Fletcher, 0. Dermer, R. Fox, Nomenclature of Organic Compounds, pp. 20-63 (1974), and in the Examples herein.
The term Ci-C6 alkyl includes such groups as methyl, ethyl, n-propyl, isopropyl, n-butyl, s-butyl, tbutyl, n-pentyl, n-hexyl, 3-methylpentyl, and the like.
The term halo and halogen refer to chloro,
0 bromo, fluoro, and iodo.
C1-C5 alkoxy refers to those groups such as methoxy, ethoxy, propoxy, t-butoxy, and the like.
C2-C6 alkenyl refers to those groups such as vinyl, l-propene-2-yl, l-butene-4-yl, 1-pentene-5-yl, 11 5 butene-l-yl, and the like.
•C1-C4 alkylthio refers to those groups such as methylthio, ethylthio, t-butylthio, and the like.
•C1-C4 alkanoyloxy refers to those groups such as acetoxy, propionoxy, formyloxy, butyryloxy, and the
0 like.
The term C2-Ce alkenoxy includes groups such as ethenyloxy, propenyloxy, iso-butoxy ethenyl, and the like.
The term C2-C8 alkynyl includes groups such as ethyny1, propynyl, pentynyl, butynyl, and the like.
The term halo-substituted C1-C6 alkyl includes alkyls substituted 1, 2, or 3 times by a halogen, including groups such as trifluoromethyl, 2-dichloroethyl, 3,3difluoropropyl, and the like.
The term aryl includes 3 to 8 membered stable saturated or unsaturated organic monocyclic rings having 0 to 4 hetero atoms selected from S, O, and N; and 7 to 10
X-8571A
-18membered organic stable, saturated or unsaturated, bicyclic rings having 0 to 5 hetero atoms selected from S, 0, N; both of which may be substituted by halo, Ci-Cg alkyl, CjC5 alkoxy, C2-C6 alkenyl, amino, nitro, cyano, carboxy, hydroxymethyl, aminomethyl, carboxymethyl, C1-C4 alkylthio, hydroxy, C1-C4 alkanoyloxy, carbamoyl, or halo-substituted C1-C6 alkyl.
The following are preferred compounds.
N- (2-phenethyl) -Ν' - (2-thiazolyl) thiourea
N-(2-phenethyl)-Ν' -(2-(4-methyl)thiazolyl]thiourea N-(2-phenethyl)-Ν'-(2-(4,5-dimethyl)thiazolyl]thiourea N-(2-phenethyl)-Ν’ -[2-(4-cyano)thiazolyl]thiourea N-(2-phenethyl)-Ν' -[2-(41 5 trifluoromethyl)thiazolyl]thiourea
N-(2-phenethyl)-Ν' -(2-benzothiazolyl) thiourea N-(2-phenethyl)-Ν' -[2-(6fluoro)benzothiazolyl]thiourea
N-(2-phenethyl)-Ν' -[2-(6-chloro)pyrazinyl]thiourea
0 N- (2-phenethyl) -N’ - (2 - (4-ethyl) thiazolyl] thiourea
N-(2-phenethyl)-Ν'-(2-(4-(3pyridyl)thiazolyl)]thiourea
N-(2-phenethyl)-Ν'-(2-(4-(3nitrophenyl)thiazolyl)]thiourea
5 N- (2-phenethyl) -Ν' - (2-pyridyl) thiourea
N-(2-phenethyl)-N'-[2- (6-bromo) pyridyl]thiourea N-(2-phenethyl)-Ν' -[2-(6-chloro)pyridyl]thiourea N-(2-phenethyl)-Ν' -[2-(6-methyl)pyridyl]thiourea N-(2-phenethyl)-N'-[2- (5-methyl) pyridyl]thiourea
0 N- (2-phenethyl) -Ν' - (2- (6tri fluoromethyl) pyridyl]thiourea N- (2-phenethyl)-Ν' -[2-(5trifluoromethyl)pyridyl]thiourea
N-(2-phenethyl)-Ν' -(2-(6-ethyl)pyridyl]thiourea
5 N- (2-phenethyl) -Ν' - [2 - (5-ethyl)pyridyl] thiourea
N-(2-phenethyl)-Ν' -[2-(6-bromo)pyrazinyl]thiourea N- (2-phenethyl)-Ν' -[(3-(6-bromo)pyridazinyl)]thiourea N-(2-phenethyl)-Ν' -[2-(6-cyano)pyridyl]thiourea N-(2-phenethyl)-Ν' -(2-(5-cyano)pyridyl]thiourea
0 N- (2-phenethyl) -Ν' - [2 - (5-cyano)pyrazinyl] thiourea
N-(2-phenethyl)-Ν' -(2-(6-cyano)pyrazinyl]thiourea
AP Ο Ο Ο 3 8 4
Χ-8571Α
-19Ν-(2-phenethyl)-Ν’ -(2-[1,3,4-thiadiazoyl]) thiourea Ν-(2-phenethyl)-Ν' -(2-benzimidazolyl)thiourea Ν-(2-phenethyl)-Ν' -(2-imidazolyl)thiourea Ν-(2-(2-methoxyphenyl)ethyl)-Ν' - (2-thiazolyl)thiourea
N-(2-(2-methoxyphenyl)ethyl)-Ν' -[2-(4methyl)thiazolyl]thiourea
N-(2- (2-methoxyphenyl)ethyl)-N'-[2-(4,5dimethyl) thiazolyl] thiourea
N-(2- (2-methoxyphenyl) ethyl)-N'- (210 benzothiazolyl) thiourea
N-(2-(2-methoxyphenyl)ethyl)-Ν' -[2-(6fluoro)benzothiazolyl]thiourea
N-(2- (2-methoxyphenyl) ethyl)-N'-[2-{6chloro) pyrazinyl] thiourea
N- (2 - (2 -methoxyphenyl) ethyl )-N'-[2-(4-(3pyridyl) thiazolyl) ] thiourea
N-(2- (2-methoxyphenyl)ethyl)-N'-[2-(4-{3nitrophenyl)thiazolyl)]thiourea
N-(2 - (2-methoxyphenyl) ethyl)-N'- (2-pyridyl) thiourea 2 0 N- (2- (2-methoxyphenyl) ethyl) -N* - [2- (6bromo) pyridyl]thiourea
N-(2-(2-methoxyphenyl) ethyl)-N’-[2-(6chloro)pyridyl]thiourea
N-(2-(2-methoxyphenyl)ethyl)-Ν'-[2-(62 5 methyl) pyridyl] thiourea
N-(2- (2-methoxyphenyl) ethyl)-N'-[2- (5methyl)pyridyl]thiourea
N-'{2- (2-methoxyphenyl) ethyl) -Ν' - [2- (6tri f luoromethyl) pyridyl ] thiourea
0 N- (2- (2-methoxyphenyl) ethyl) -Ν' - [2- (5tri fluoromethyl) pyridyl ] thiourea
N-(2-(2-methoxyphenyl)ethyl)-Ν' -(2-(6ethyl) pyridyl ] thiourea
N-(2-(2-methoxyphenyl)ethyl)-Ν' -[2-(53 5 ethyl) pyridyl] thiourea
N- (2- (2-methoxyphenyl) ethyl) -Ν' - [2 - (6bromo) pyrazinyl ] thiourea
N- (2- (2-methoxyphenyl) ethyl) -Ν' - [ (3- (6bromo)pyridazinyl) ] thiourea
0 N- (2 - (2-methoxyphenyl) ethyl) -Ν' - [2 - (6cyano) pyridyl]thiourea
N-(2-(2-methoxyphenyl)ethyl)-Ν' -[2-(5cyano) pyridyl]thiourea
N-(2-(2-methoxyphenyl)ethyl)-Ν' -[2-(54 5 cyano) pyrazinyl] thiourea
X-8571A
-2045
N- (2-(2-methoxyphenyl)ethyl)-N'-[2-(6cyano)pyrazinyl]thiourea
N-(2-(2-methoxyphenyl)ethyl)-Ν' -[(3-(6cyano)pyridazinyl)]thiourea
N-(2 - (2-methoxyphenyl) ethyl)-Ν'-(2-(1,3,4thiadiazoyl]) thiourea
N-(2-(2-methoxyphenyl)ethyl)-N*-(2benzimidazolyl) thiourea
N- (2- (2-methoxyphenyl) ethyl) -N‘ - (2-imidazolyl) thiourea 10 N- (2- (3-methoxyphenyl) ethyl) -Ν' - (2-thiazolyl)thiourea
N-(2- (3-methoxyphenyl) ethyl)-N'-[2-{4methyl)thiazoly1) thiourea
N-(2- (3-methoxyphenyl) ethyl)-N'-[2-(4,5dimethyl)thiazolyl]thiourea
N- (2 - (3-methoxyphenyl) ethyl) -Ν' -(2benzothiazolyl)thiourea
N-(2- (3-methoxyphenyl) ethyl)-N'-[2- (6fluoro)benzothiazolyl]thiourea
N-(2-(3-methoxyphenyl)ethyl)-Ν' -(2-(620 chloro)pyrazinyl]thiourea
N-(2- (3-methoxyphenyl) ethyl)-Ν'-(2-(4-(3pyridyl)thiazolyl)]thiourea
N-(2-(3-methoxyphenyl)ethyl)-Ν' -(2-(4-(3nitrophenyl)thiazolyl)]thiourea
5 N- {2 - (3 -methoxyphenyl) ethyl) -N · - (2 -pyridyl) thiourea
N-(2- (3-methoxyphenyl) ethyl) -N'-[2- (6bromo) pyridyl]thiourea
N-(2- (3-methoxyphenyl) ethyl)-N'-[2- (6chloro) pyridyl]thiourea
0 N- (2 - (3 -methoxyphenyl) ethyl) -N' - [ 2 - (6 methyl) pyridyl]thiourea
N-(2-(3-methoxyphenyl)ethyl)-Ν' -[2-(5methy1) pyridyl]thiourea
N-(2-(3-methoxyphenyl)ethyl)-Ν' -[2-(63 5 trifluoromethyl)pyridyl]thiourea
N-(2-(3-methoxyphenyl)ethyl)-Ν' -(2-(5trifluoromethyl)pyridyl]thiourea
N-(2- (3-methoxyphenyl) ethyl)-N'-[2-{6ethyl) pyridyl]thiourea
0 N- (2 - (3 -methoxyphenyl) ethyl) -N' - [ 2 - (5 ethyl) pyridyl]thiourea
N-(2-(3-methoxyphenyl) ethyl)-Ν' -[2-(6bromo)pyrazinyl]thiourea
N-(2- (3-methoxyphenyl) ethyl)-N'-[(3- (6 bromo)pyridazinyl)]thiourea
AP Ο Ο Ο 3 8 4
Χ-8571Α
-21Ν- (2-(3-methoxyphenyl) ethyl)-Ν' -[2-(6cyano)pyridyl]thiourea
N- (2-(3-methoxyphenyl) ethyl)-N'-[2-(5cyano)pyridyl]thiourea
N- (2-(3-methoxyphenyl) ethyl)-N'-[2-(5cyano)pyrazinyl]thiourea
N- (2-(3-methoxyphenyl)ethyl)-Ν' -[2 - (6cyano)pyrazinyl]thiourea
N- (2- (3-methoxyphenyl) et hy 1) -N' - [(3-(610 cyano)pyridazinyl) ] thiourea
N- (2- (3-methoxyphenyl) ethyl)-Ν'-(2-(1,3,4thiadiazoyl]) thiourea
N- (2-(3-methoxyphenyl)ethyl)-Ν' -(2benzimidazolyl)thiourea
N- (2-(3-methoxyphenyl)ethyl)-Ν' -(2-imidazolyl)thiourea
N- (2- (4-methoxyphenyl)ethyl)-Ν' -(2-thiazolyl)thiourea N- (2- (4-methoxyphenyl) ethyl)-N'-[2- (4 methyl)thiazoly1]thiourea
N- (2-(4-methoxyphenyl)ethyl)-N’-[2-(4,52 0 dimethyl) thiazolyl] thiourea
N- (2-(4-methoxyphenyl)ethyl)-Ν' -[2-(4cyano)thiazolyl]thiourea
N-(2-(4-methoxyphenyl)ethyl)-Ν'-(2 - (4trifluoromethyl)thiazolyl]thiourea
5 N- (2- (4 -methoxyphenyl) ethyl)-N'- (2benzothiazolyl)thiourea
N- (2-(4-methoxyphenyl)ethyl)-Ν' -[2-(6fluoro)benzothiazolyl]thiourea
N- (2 -{4-methoxyphenyl) ethyl)-N'-[2- (63 0 chloro)pyrazinyl] thiourea
N- (2-(4-methoxyphenyl) ethyl)-Ν' -[2-(4ethy1)thiazolyl]thiourea
N- (2-(4-methoxyphenyl)ethyl)-Ν' -(2-(4-(3pyridyl)thiazolyl)]thiourea
5 N- (2-(4-methoxyphenyl) ethyl)-N'-(2-(4-(3nitropheny1)thiazolyl)]thiourea
N- (2- (4-methoxyphenyl) ethyl)-N'- (2-pyridyl) thiourea N- (2-(4-methoxyphenyl) ethyl)-N'-(2-{6bromo)pyridyl]thiourea
0 N- (2 - (4-methoxyphenyl) ethyl) -Ν' - [2 - (5bromo) pyridyl]thiourea
N-(2-(4-methoxyphenyl) ethyl)-Ν' -[2 - (6chloro) pyridyl]thiourea
X-8571A l-' . V ’’ i i-\
-22N-(2- (4-methoxyphenyl) ethyl)-N'-[2- (6methyl) pyridyl]thiourea
N-(2 - (4-methoxyphenyl)ethyl)-Ν' -[2-(5methyl) pyridyl]thiourea
N- (2- (4-methoxyphenyl) ethyl)-N'- (2 - (6trifluoromethyl)pyridyl]thiourea
N-(2 - (4-methoxyphenyl) ethyl)-N’-[2-(5trifluoromethyl) pyridyl]thiourea
N- (2 - (4-methoxyphenyl)ethyl)-Ν' -[2-(610 ethyl) pyridyl] thiourea
N- (2 - (4-methoxyphenyl)ethyl)-Ν' -(2-(5ethyl)pyridyl]thiourea
N- (2- (4-methoxyphenyl) ethyl)-N'-[2-(5chloro)pyrazinyl]thiourea
N- (2- (4-methoxyphenyl) ethyl)-N'-[2-(6bromo)pyrazinyl]thiourea
N-(2 - (4-methoxyphenyl) ethyl)-N'-[2- (5bromo)pyrazinyl]thiourea
N- (2 - (4-methoxyphenyl) ethyl)-Ν' -[(3-(620 bromo)pyridazinyl)]thiourea
N- (2 - (4-methoxyphenyl)ethyl)-Ν' -[(3-(6chloro)pyridazinyl)]thiourea
N- (2 - (4-methoxyphenyl)ethyl)-Ν' -[2-(6cyano)pyridyl]thiourea
5 N- (2 - (4-methoxyphenyl) ethyl)-N'-[2- (5 cyano) pyridyl]thiourea
N-(2 - (4-methoxyphenyl)ethyl)-Ν' - [2 - (5cyano)pyrazinyl]thiourea
N- (2 - (4-methoxyphenyl) ethyl)-Ν' -[2-(63 0 cyano)pyrazinyl] thiourea
N- (2 - (4-methoxyphenyl) ethyl)-Ν' -[ (3-(6cyano)pyridazinyl)]thiourea
N- (2 - (4-methoxyphenyl) ethyl)-N'-(2-(l,3,4thiadiazoyl]) thiourea
5 N- (2- (4 -methoxyphenyl) ethyl)-N’- (2benzimidazolyl)thiourea
N-(2-(4-methoxyphenyl) ethyl)-Ν' -(2-imidazolyl) thiourea N-(2- (2-ethoxyphenyl)ethyl)-Ν' -(2-thiazolyl)thiourea N- (2 - (2-ethoxyphenyl)ethyl)-Ν' -[2-(44 0 methyl) thiazolyl] thiourea
N- (2 - (2-ethoxyphenyl)ethyl)-Ν' -[2-(4,5dimethyl)thiazolyl]thiourea
N-(2-(2-ethoxyphenyl)ethyl)-Ν' - (2benzothiazolyl)thiourea
5 N- (2- (2-ethoxyphenyl) ethyl) -Ν' - [2- (6-
AP Ο Ο Ο 3 8 4
Χ-8571Α
-23Ν- (2-(2-ethoxyphenyl)ethyl)-Ν' -[2-(6chloro)pyrazinyl]thiourea
Ν- (2 - (2-ethoxyphenyl)ethyl)-Ν'-(2-(4-(3pyridy1)thiazolyl)]thiourea
N- (2 - (2-ethoxyphenyl)ethyl)-N'-[2-(4-(3nitrophenyl)thiazolyl)]thiourea
N- (2-(2-ethoxyphenyl)ethyl)-Ν' - (2-pyridyl) thiourea N-(2-(2-ethoxyphenyl) ethyl)-Ν' -[2-(6bromo) pyridyl]thiourea
N- (2 - (2-ethoxyphenyl) ethyl) -Ν' -[2-(6chloro)pyridyl]thiourea
N-(2-(2-ethoxyphenyl)ethyl)-Ν' - [2-(6methyl) pyridyl]thiourea
N-(2 - (2-ethoxyphenyl)ethyl)-Ν' -[2-(515 methyl) pyridyl] thiourea
N-(2-(2-ethoxyphenyl)ethyl)-Ν' -[2-(6tri fluoromethyl) pyridyl]thiourea
N-(2-(2-ethoxyphenyl)ethyl)-Ν' -[2-(5trifluoromethyl) pyridyl]thiourea
0 N- (2 - (2-ethoxyphenyl) ethyl) -Ν' - [2 - (6ethy1) pyridyl]thiourea
N-(2-(2-ethoxyphenyl)ethyl)-Ν' -(2-(5ethyl) pyridyl]thiourea
N-(2-(2-ethoxyphenyl)ethyl)-Ν' - [2-(62 5 bromo) pyrazinyl] thiourea
N-(2-(2-ethoxyphenyl)ethyl)-N'-[(3-(6bromo)pyridazinyl) ]thiourea
N-(2-(2-ethoxyphenyl)ethyl)-Ν' -[2-(6cyano) pyridyl]thiourea
0 N- (2 - (2-ethoxyphenyl) ethyl) -Ν' - [2- (5cyano) pyridyl]thiourea
N-(2-(2-ethoxyphenyl)ethyl)-Ν' -(2-(5cyano)pyrazinyl]thiourea
N-(2-(2-ethoxyphenyl)ethyl)-Ν' -[2-(63 5 cyano) pyrazinyl ] thiourea
N-(2-(2-ethoxyphenyl)ethyl)-N’-[(3-(6cyano)pyridazinyl)]thiourea
N-(2-(2-ethoxyphenyl)ethyl)-N'-(2-[l,3,4thiadiazoyl]) thiourea
0 N- (2 - (2-ethoxyphenyl) ethyl) -Ν' -(2benzimidazolyl)thiourea
N-(2-(2-ethoxyphenyl)ethyl)-Ν' -(2-imidazolyl) thiourea N-(2-(2-methylphenyl)ethyl)-Ν' -(2-thiazolyl)thiourea N-(2 - (2-methylphenyl)ethyl)-Ν' -[2-(44 5 methyl) thiazolyl ] thiourea
V
X-8571A
-24N-(2-(2-methylphenyl)ethyl)-Ν’ -(2-(4,5dimethyl)thiazolyl]thiourea
N-(2 - (2-methylphenyl) ethyl)-N’- (2 benzothiazolyl) thiourea
N-(2-(2-methylphenyl)ethyl)-Ν' -(2-(6fluoro)benzothiazolyl]thiourea
N-(2-(2-methylphenyl)ethyl)-Ν' -(2-(6chloro)pyrazinyl]thiourea
N-(2-(2-methylphenyl)ethyl)-Ν'-(2-(4-(31 0 pyridyl)thiazolyl)]thiourea
N-(2-(2-methylphenyl)ethyl)-Ν'-(2-(4-(3nitrophenyl)thiazolyl)]thiourea
N-(2-(2-methylphenyl)ethyl)-Ν' -(2-pyridyl) thiourea N-(2-(2-methylphenyl)ethyl)-Ν' -[2-(615 bromo) pyridyl] thiourea
N-(2-(2-methylphenyl)ethyl)-N'-[2- (5chloro)pyridyl]thiourea
N-(2-(2-methylphenyl)ethyl)-Ν' -[2-(6methyl) pyridyl]thiourea
0 N- (2- (2-methylphenyl) ethyl) -Ν' - [2 - (5methyl) pyridyl ] thiourea
N-.(2- (2-methylphenyl) ethyl) -N' - (2- tetri fluoromethyl) pyridyl]thiourea
N-(2-(2-methylphenyl)ethyl)-Ν' -[2-(52 5 trifluoromethyl) pyridyl]thiourea
N-(2-(2-methylphenyl)ethyl)-Ν' -[2-(6ethy1) pyridyl]thiourea
N-(2-(2-methylphenyl)ethyl)-Ν' -(2-(5ethyl) pyridyl]thiourea
0 N- (2 - (2 -methylphenyl) ethyl )-N'-[2- (6bromo)pyrazinyl]thiourea
N- (2-(2-methylphenyl)ethyl)-N‘-[(3-(6bromo)pyridazinyl)]thiourea
N- (2- (2-methylphenyl) ethyl)-N'- (2 - (6 3 5 cyano) pyridyl] thiourea
N-(2-(2-methylphenyl)ethyl)-N'-(2-(5cyano)pyridyl]thiourea
N- (2-{2-methylphenyl) ethyl)-N'-[2 - (5cyano)pyrazinyl]thiourea
0 N- (2 - (2-methylphenyl) ethyl) -N'-(2~(6cyano)pyrazinyl]thiourea
N-(2-(2-methylphenyl)ethyl)-N'-[(3-(6cyano)pyridazinyl)]thiourea
AP Ο Ο Ο 3 8 4
Χ-8571Α
-26Ν-(2- (3 -methylphenyl) ethyl )-Ν'-[2-(5chloro)pyrazinyl]thiourea
N- (2- (3-methylphenyl) ethyl) -N'-[2-(6bromo)pyrazinyl]thiourea
N- (2 - (3-methylphenyl) ethyl) -Ν' -[2-(5bromo) pyrazinyl ] thiourea
N- (2 - (3-methylphenyl) ethyl) —Ν’—((3-(6bromo)pyridazinyl)]thiourea
N- {2 - (3 -methylphenyl) ethyl)-N'-[(3-{6chloro)pyridazinyl)]thiourea
N- (2- (3-methylphenyl) ethyl) -Ν' - [2- (6cyano) pyridyl]thiourea
N- (2 - (3 -methylphenyl) ethyl )-N' - (2 - (5cyano)pyridyl]thiourea
N-'(2- (3-methylphenyl) ethyl) -Ν' -[2-(5cyano)pyrazinyl]thiourea
N- (2 - (3-methylphenyl) ethyl) -Ν' -[2-(6cyano) pyrazinyl ] thiourea
N- (2 - (3-methylphenyl) ethyl) -N'-[(3-(6cyano)pyridazinyl)]thiourea
N- (2 - (3-methylphenyl) ethyl) -Ν' - (2-(1,3,4thiadiazoyl]) thiourea
N- (2 - (3-methylphenyl) ethyl) -Ν' - (2benzimidazolyl)thiourea
N- (2- (3-methylphenyl) ethyl) -Ν' - (2-imidazolyl) thiourea N- (2- (2-fluorophenyl)ethyl) -Ν' - (2-thiazolyl) thiourea N- (2- (2-fluorophenyl) ethyl) -Ν' - [2- (4methyl)thiazolyl]thiourea
N- (2- (2-fluorophenyl) ethyl) -Ν' -[2-(4,5dimethyl)thiazolyl]thiourea
N- (2 - (2-fluorophenyl) ethyl) -Ν' -(2benzothiazolyl)thiourea
N-(2- (2-fluorophenyl)ethyl)-Ν' -[2-(6fluoro)benzothiazolyl]thiourea
N-(2- (2-fluorophenyl)ethyl)-Ν' - (2- (6chloro)pyrazinyl]thiourea
N-.{2- (2-fluorophenyl) ethyl) -Ν' - [2- (4- (3pyridyl) thiazolyl) ] thiourea
N-(2- (2-fluorophenyl)ethyl)-Ν' -[2- (4- (3 nitrophenyl)thiazolyl)]thiourea
N- (2- (2-fluorophenyl) ethyl) -Ν' - (2-pyridyl) thiourea N- (2 - (2-fluorophenyl) ethyl) -Ν' -[2-(6bromo) pyridyl]thiourea
N-(2- (2-fluorophenyl)ethyl)-Ν'-[2-(6chloro) pyridyl] thiourea
X-8571A
-27N- (2 - (2-fluoropheny1) ethyl)-N' -[2 - (6methyl) pyridyl]thiourea
N- (2 - (2-fluoropheny1) ethyl)-N’-[2 - (5methyl) pyridyl]thiourea
N- (2 - (2-fluorophenyl)ethyl)-Ν' -[2-tetri fluoromethyl ) pyridyl]thiourea
N- (2- (2-fluoropheny1) ethyl)-N'-[2-(5tri fluoromethyl) pyridyl]thiourea
N- (2-{2-fluorophenyl) ethyl)-N'-[2 - (610 ethyl)pyridyl] thiourea
N- (2- (2-fluorophenyl) ethyl) -N'-[2 - (5 ethyl) pyridyl]thiourea
N- (2- (2 -fluorophenyl) ethyl)-N* -[2 - (6bromo)pyrazinyl]thiourea
N- (2- (2-f luorophenyl) ethyl) -Ν' - [ (3- (6bromo)pyridazinyl)]thiourea
N-(2 - (2-fluorophenyl) ethyl)-N‘-[2 - (6cyano) pyridyl]thiourea
N-(2 - (2-fluorophenyl) ethyl)-N'-[2 - (52 0 cyano) pyridyl] thiourea
N- (2 - (2-fluorophenyl) ethyl)-N'-[2 - (5cyano)pyrazinyl]thiourea
N-.(2- (2-fluorophenyl) ethyl) -Ν' -(2-(6cyano)pyrazinyl]thiourea
5 N- (2 - (2-fluorophenyl) ethyl) -Ν' - [ (3-(6cyano)pyridazinyl)]thiourea
N- (2- (2-fluorophenyl)ethyl)-Ν' -(2-[1,3,4thiadiazoyl]) thiourea
N- (2- (2-fluorophenyl) ethyl)-N' -{23 0 benzimidazolyl) thiourea
N- (2- (2-fluorophenyl)ethyl) -N' - (2-imidazolyl) thiourea N- (2-(2,6-difluorophenyl) ethyl)-Ν' -(2-(4,5dimethyl)thiazolyl]thiourea
N- (2-(2,6-difluorophenyl)ethyl)-Ν' -(23 5 benzothiazolyl) thiourea
N- (2 - (2,6-difluorophenyl) ethyl)-Ν' -[2-(6fluoro)benzothiazolyl]thiourea
N- (2-(2,6-difluorophenyl) ethyl)-N'-[2-(6chloro)pyrazinyl]thiourea
0 N- (2 - (2,6-dif luorophenyl) ethyl) -N'-[2-(4-(3pyridyl)thiazolyl)]thiourea
N- (2-(2,6-difluorophenyl)ethyl)-N'-[2- (4- (3nitrophenyl)thiazolyl)]thiourea
N- (2-(2,6-difluorophenyl)ethyl)-N'-[2-(64 5 chloro)pyridyl] thiourea
AP Ο Ο Ο 3 8 4
Χ-8571Α
-28Ν-(2-(2,6-difluorophenyl) ethyl)-Ν' -[2-(6methyl) pyridyl]thiourea
N-(2 - (2,6-difluorophenyl)ethyl)-N’-(2-(6trifluoromethyl) pyridyl)thiourea
N-(2 - (2,6-difluorophenyl)ethyl)-N'-[2-(6ethyl)pyridyl)thiourea
N-(2- (2,6-difluorophenyl) ethyl)-Ν' -[2-(6bromo)pyraz iny1) thiourea
N-(2-(2,6-difluorophenyl) ethyl)-Ν' -[(3-(61 0 bromo)pyridazinyl)) thiourea
N-(2-(2,6-difluorophenyl) ethyl)-N'-[2-(6cyano)pyridyl)thiourea
N-(2-(2,6-difluorophenyl) ethyl)-N'-[2-(5cyano)pyrazinyl)thiourea
N- (2 - (2,6-difluorophenyl) ethyl) -N* - [2 - (6cyano)pyraz iny1) thiourea
N-(2-(2,6-difluorophenyl)ethyl)-Ν' - ((3-(6cyano)pyridazinyl)) thiourea
N-(2-(2,6-difluorophenyl) ethyl)-Ν'-(2-(1,3,42 0 thiadiazoyl)) thiourea
N-(2-(2,6-difluorophenyl)ethyl)-Ν' -(2benzimidazolyl)thiourea
N-(2-(2,6-difluorophenyl)ethyl)-Ν’ -(2imidazoly1) thiourea
5 N- (2- (2-fluoro-6-methoxyphenyl) ethyl) -Ν' - (2thiazolyl) thiourea
N-(2-(2-fluoro-6-methoxyphenyl) ethyl)-Ν’ — [2-(4methyl)thiazolyl]thiourea
N-(2- (2-fluoro-6-methoxyphenyl)ethyl)-Ν’ -(2-(4,53 0 dimethyl) thiazolyl) thiourea
N-'(2- (2-fluoro-6-methoxyphenyl) ethyl) -Ν' - (2benzothiazolyl) thiourea
N-(2- (2-fluoro-6-methoxyphenyl)ethyl)-Ν' -[2-(6fluoro)benzothiazoly1]thiourea
5 N- (2- (2-f luoro-6-methoxyphenyl) ethyl) -N'-(2-(6chloro)pyrazinyl)thiourea
N-(2-(2-fluoro-6-methoxyphenyl)ethyl)-Ν'-(2-(4-(3pyridyl)thiazolyl)) thiourea
N- (2- (2-fluoro-6-methoxyphenyl) ethyl)-N'-[2- (4- (34 0 nitrophenyl)thiazolyl)) thiourea
N-(2-(2-fluoro-6-methoxyphenyl)ethyl)-Ν' -(2pyridyl)thiourea
N-(2-(2-fluoro-6-methoxyphenyl) ethyl)-Ν' -[2-(6bromo)pyridyl)thiourea
N- (2- (2-f luoro-6-methoxyphenyl) ethyl) -Ν' - [2- (6chloro)pyridyl]thiourea
X-8571A
-29N- (2-(2-fluoro-6-methoxyphenyl)ethyl)-Ν' -[2-(6methy1) pyridyl]thiourea
N- (2-(2-fluoro-6-methoxyphenyl)ethyl)-Ν' -[2-(5methy1) pyridyl]thiourea
N-(2-(2-fluoro-6-methoxyphenyl)ethyl)-Ν' -[2-(6trifluoromethyl) pyridyl]thiourea
N-(2-(2-fluoro-6-methoxyphenyl)ethyl)-Ν' -(2-(5trifluoromethyl) pyridyl]thiourea
N-(2-(2-fluoro-6-methoxyphenyl)ethyl)-Ν' -[2-(61 0 ethyl) pyridyl]thiourea
N-(2-(2-fluoro-6-methoxyphenyl)ethyl)-Ν' -[2-(5ethyl) pyridyl]thiourea
N-(2-(2-fluoro-6-methoxyphenyl)ethyl)-Ν' -[2-(6bromo)pyraz inyl]thiourea
5 N-(2-(2-fluoro-6-methoxyphenyl)ethyl)-N'-[(3-(6bromo)pyridazinyl)]thiourea
N-(2-(2-fluoro-6-methoxyphenyl)ethyl)-Ν' -[2-(6cyano) pyridyl]thiourea
N-(2-(2-fluoro-6-methoxyphenyl)ethyl)-Ν' -[2-(52 0 cyano) pyridyl ] thiourea
N-(2 - (2 -fluoro-6-methoxyphenyl) ethyl) -N'-[2 - (5cyano)pyrazinyl]thiourea
N-(2-(2-fluoro-6-methoxyphenyl)ethyl)-Ν' -[2-(6cyano)pyrazinyl]thiourea
N-(2-(2-fluoro-6-methoxyphenyl)ethyl)-Ν' -[(3-(6cyano)pyridazinyl)]thiourea
N-(2-(2-fluoro-6-methoxyphenyl)ethyl)-N'-(2-[l,3,4thiadiazoyl]) thiourea
N-(2-(2-fluoro-6-methoxyphenyl)ethyl) -Ν' - (23 0 benzimidazolyl) thiourea
N-(2-(2-fluoro-6-methoxyphenyl)ethyl)-Ν' - (2imidazolyl)thiourea
N-(2-(2-fluoro-6-ethoxyphenyl)ethyl)-Ν' -(2thiazolyl) thiourea
5 N- (2 - (2-fluoro-6-ethoxyphenyl) ethyl) -Ν' -[2-(4methyl)thiazolyl]thiourea
N-(2 -(2-fluoro-6-ethoxyphenyl) ethyl)-N'-[2-(4,5dimethyl)thiazolyl]thiourea
N-(2-(2-fluoro-6-ethoxyphenyl)ethyl) -Ν' - (24 0 benzothiazolyl) thiourea
N-(2-(2-fluoro-6-ethoxyphenyl) ethyl)-Ν' -[2-(6fluoro)benzothiazolyl]thiourea
N-(2-(2-fluoro-6-ethoxyphenyl)ethyl)-Ν' -(2-(6chloro)pyrazinyl]thiourea
N-(2-(2-fluoro-6-ethoxyphenyl)ethyl)-Ν’-(2-(4-(3-
AP Ο Ο Ο 3 8 4
Χ-8571Α
-30Ν- (2- (2-fluoro-6-ethoxyphenyl)ethyl)-N'-[2-(4-(3nitrophenyl)thiazolyl,]thiourea
N- (2- (2-fluoro-6-ethoxyphenyl)ethyl)-Ν' -(2pyridyl) thiourea
N- (2- (2-fluoro-6-ethoxyphenyl) ethyl)-N'-[2-(6bromo)pyridyl]thiourea
N-(2-(2-fluoro-6-ethoxyphenyl)ethyl) -Ν' -[2- (6 chloro)pyridyl)thiourea
N- (2- (2-fluoro-6-ethoxyphenyl) ethyl)-Ν' -[2- ( >10 methyl) pyridyl] thiourea
N- (2- (2-fluoro-6-ethoxyphenyl)ethyl)-Ν' -[2-,5methy1) pyridyl]thiourea
N- (2- (2-fluoro-6-ethoxyphenyl)ethyl) -Ν' -(7.-(6trifluoromethy1)pyridyl]thiourea
N- (2 - (2-f luoro-6-ethoxyphenyl) ethyl )-Ν' - 2-(5trifluoromethyl) pyridyl]thiourea
N- (2-(2-fluoro-6-ethoxyphenyl)ethyl)-N' (2-(6ethyl) pyridyl]thiourea
N-(2-(2-fluoro-6-ethoxyphenyl)ethyl)-l·'' - [2 - (52 0 ethyl)pyridyl] thiourea
N- (2-(2-fluoro-6-ethoxyphenyl)ethyl)- Ν' -[2-(6bromo)pyrazinyl]thiourea
N- (2 - (2-fluoro-6-ethoxyphenyl) ethyl’ -Ν' -[(3-(6bromo)pyridazinyl)]thiourea
5 N- (2 - (2-f luoro-6-ethoxyphenyl) ethyl.) -Ν' - [2 - (6cyano) pyridyl]thiourea
N- (2- (2-fluoro-6-ethoxyphenyl)eth.1)-Ν' -[2-(5cyano) pyridyl]thiourea
N-(2-(2-fluoro-6-ethoxyphenyl)ethyl) -Ν' - [2-(53 0 cyano)pyrazinyl] thiourea
N- (2- (2-fluoro-6-ethoxyphenyl)ethyl)-Ν' -[2-(6cyano)pyrazinyl]thiourea
N-(2-(2-fluoro-6-ethoxyphenyl ethyl)-Ν' - ( (3-(6cyano)pyridazinyl)]thiourea
5 N- (2- (2-fluoro-6-ethoxypheny_)ethyl)-Ν'-(2-(1,3,4thiadiazoyl)) thiourea
N- (2 - (2-f luoro-6-ethoxypher.yl) ethyl) -Ν' - (2benzimidazolyl)thiourea
N- (2- (2-fluoro-6-ethoxyphenyl)ethyl) -Ν' -(24 0 imidazolyl) thiourea
N- (2- (2,3,5,6-tetrafluorophenyl)ethyl)-Ν' -(2thiazolyl) thiourea
N- (2-(2,3,5,6-tetrafluorophenyl)ethyl)-Ν' -[2-(4methyl)thiazolyl]thiourea
5 N- (2- (2,3,5,6-tetraflu- rophenyl) ethyl) -Ν' - (2 - (4,5dimethyl)thiazolyl]thiourea
X-8571A
-31N- (2-(2,3,5,6-tetrafluorophenyl)ethyl)-Ν' -(2-(4cyano)thiazolyl]thiourea
N-(2-(2,3,5,6-tetrafluorophenyl)ethyl)-Ν'- [2- (4trifluoromethyl)thiazolyl) thiourea
N-(2-(2,3,5,6-tetrafluorophenyl)ethyl)-Ν' -(2benzothiazolyl)thiourea
N- (2-(2,3,5,6-tetrafluorophenyl)ethyl)-Ν' - [2- (6fluoro)benzothiazolyl]thiourea
N-(2-(2,3,5,6-tetrafluorophenyl)ethyl)-Ν' - [2- (610 chloro)pyrazinyl]thiourea
N- (2- (2,3,5,6-tetrafluorophenyl)ethyl)-Ν' -[2-(4ethy1)thiazolyl]thiourea
N- (2-(2,3,5,6-tetrafluorophenyl)ethyl)-Ν' -[2- (4- (3pyridyl)thiazolyl)) thiourea
N-(2-(2,3,5,6-tetrafluorophenyl)ethyl)-Ν'-(2-(4-(3nitrophenyl)thiazolyl)]thiourea
N-(2-(2,3,5,6-tetrafluorophenyl)ethyl)-Ν' - (2pyridyl)thiourea
N-(2-(2,3,5,6-tetrafluorophenyl)ethyl)-Ν' - [2 - (62 0 bromo) pyridyl] thiourea
N- (2-(2,3,5,6-tetrafluorophenyl)ethyl)-Ν' -[2- (5bromo) pyridyl]thiourea
N- (2-(2,3,5,6-tetrafluorophenyl)ethyl)-Ν' -[2-(6chloro)pyridyl]thiourea
N-(2-(2,3,5,6-tetrafluorophenyl) ethyl) -Ν' -[2 - (5chloro)pyridyl]thiourea
N- (2- (2,3,5,6-tetrafluorophenyl)ethyl)-Ν' - [2 - (6methyl)pyridyl]thiourea
N-(2-(2,3,5,6-tetrafluorophenyl)ethyl)-Ν' — (2-(53 0 methyl)pyridyl] thiourea
N- (2-(2,3,5,6-tetrafluorophenyl)ethyl)-N' — (2—(6 — trifluoromethyl) pyridyl] thiourea
N- (2- (2,3,5,6-tetrafluorophenyl)ethyl)-Ν' -(2-(5trif luoromethy 1) pyridyl] thiourea
N-(2-(2,3,5,6-tetrafluorophenyl) ethyl)-Ν' -[2-(6ethyl)pyridyl]thiourea
N-(2-(2,3,5,6-tetrafluorophenyl)ethyl)-Ν' -[2-(5ethyl)pyridyl]thiourea
N- (2-(2,3,5,6-tetrafluorophenyl)ethyl)-Ν' -[2-(54 0 chloro )pyrazinyl] thiourea
N- (2-(2,3,5,6-tetrafluorophenyl)ethyl)-N' — [2- (6bromoJpyrazinyl]thiourea
N- (2- (2,3,5,6-tetrafluorophenyl)ethyl)-Ν' -(2-(5bromo)pyrazinyl]thiourea
N-(2-(2,3,5,6-tetrafluorophenyl)ethyl)-N'-((3-(6bromo)pyridazinyl)]thiourea
AP000384
X-8571A
-32N- (2- (2,3,5,6-tetrafluorophenyl)ethyl)-Ν' -[(3- (6chlorolpyridazinyl)]thiourea
N- (2 - (2,3,5,6-tetrafluorophenyl)ethyl)-N’-[2-(6cyano)pyridyl)thiourea
N-(2-(2,3,5,6-tetrafluorophenyl) ethyl)-Ν' -(2-(5cyano)pyridyl]thiourea
N-(2-(2,3,5,6-tetrafluorophenyl)ethyl)-Ν' -(2-(5cyano)pyrazinyl]thiourea
N-(2-(2,3,5,6-tetrafluorophenyl)ethyl)-N'-(2-(610 cyano)pyrazinyl ] thiourea
N-(2-(2,3,5,6-tetrafluorophenyl)ethyl)-Ν’ - ((3-(6-cyano)pyridazinyl)]thiourea
N-(2-(2,3,5,6-tetrafluorophenyl)ethyl)-Ν’-(2-(1,3,4thiadiazoyl]) thiourea
N- (2- (2,3,5,6-tetrafluorophenyl) ethyl) -Ν' - (2benzimidazolyl)thiourea
N-(2-(2,3,5,6-tetrafluorophenyl)ethyl)-Ν' -(2imidazolyl)thiourea
N-(2-(2-chlorophenyl)ethyl)-N*-(2-thiazolyl)thiourea
0 N- (2 - (2-chlorophenyl) ethyl) -Ν' - [2- (4methyl)thiazolyl) thiourea
N-(2-(2-chlorophenyl)ethyl)-Ν' -(2-(4,5dimethyl)thiazolyl]thiourea
N-(2-(2-chlorophenyl)ethyl)-Ν' -(225 benzothiazolyl)thiourea
N-(2-(2-chlorophenyl)ethyl)-Ν' -[2-(6fluoro)benzothiazolyl]thiourea
N-(2-(2-chlorophenyl)ethyl)-Ν' -[2-(6chloro)pyrazinyl]thiourea
0 N- (2 - {2-chlorophenyl) ethyl) -Ν’-(2-(4-(3pyridyl)thiazolyl)]thiourea
N- (2-{2-chlorophenyl) ethyl)-N'-[2- (4- (3 nitrophenyl)thiazolyl)]thiourea
N-(2-(2-chlorophenyl)ethyl)-Ν' -(2-pyridyl)thiourea
5 N- (2 - (2-chlorophenyl) ethyl) -N'-(2-(6bromo)pyridyl]thiourea
N-(2-(2-chlorophenyl)ethyl)-Ν' - [2- (6chloro)pyridyl]thiourea
N-(2-(2-chlorophenyl)ethyl)-Ν' - [2-(64 0 methyl)pyridyl] thiourea
N- (2-(2-chlorophenyl)ethyl)-Ν' -[2-(5methyl) pyridyl]thiourea
N- (2-(2-chlorophenyl)ethyl)-Ν' -(2-(6tri fluoromethyl) pyridyl]thiourea
5 N- (2 - (2-chlorophenyl) ethyl) -Ν' - [2 - (5tri fluoromethyl) pyridyl]thiourea
Χ-8571Α
-33Ν-·(2- (2-chlorophenyl) ethyl) -Ν' -(2-(6ethyl)pyridyl]thiourea
N-(2-(2-chlorophenyl) ethyl)-Ν' -(2-(5ethyl)pyridyl]thiourea
N-(2-(2-chlorophenyl) ethyl)-Ν' -(2-(6bromo)pyrazinyl]thiourea
N-(2-(2-chlorophenyl) ethyl)-Ν' -[(3-(6bromo)pyridazinyl)]thiourea
N-(2-(2-chlorophenyl)ethyl)-Ν' -[2-(610 cyano)pyridyl]thiourea
N-(2-(2-chlorophenyl) ethyl)-N’-[2-(5cyano)pyridyl]thiourea
N-(2-(2-chlorophenyl)ethyl)-Ν' -(2-(5cyano)pyrazinyl]thiourea
N- (2- (2-chlorophenyl) ethyl) -N' - [2- (6cyano)pyrazinyl ] thiourea
N-(2-(2-chlorophenyl) ethyl)-Ν' -[(3-(6cyano)pyridazinyl)]thiourea
N-(2-(2-chlorophenyl) ethyl)-Ν'-(2-(1,3,42 0 thiadiazoyl]) thiourea
N-(2-(2-chlorophenyl) ethyl)-Ν' -(2benzimidazolyl) thiourea
N- (2- (2-chlorophenyl) ethyl) -Ν' - (2-imidazolyl) thiourea N- (2- (3-chlorophenyl) ethyl) -Ν' - (2-thiazolyl) thiourea
5 N- (2 - (3 -chlorophenyl) ethyl)-N'-[2 - (4 methyl)thiazolyl]thiourea
N-(2 - (3-chlorophenyl) ethyl)-N'-[2-(4,5dimethyl)thiazolyl]thiourea
N-(2-(3-chlorophenyl)ethyl)-Ν' -(23 0 benzothiazolyl) thiourea
N-(2- (3-chlorophenyl) ethyl)-N'-[2- (6fluoro)benzothiazolyl]thiourea
N-(2-(3-chlorophenyl)ethyl)-Ν' -(2-(6chloro)pyrazinyl]thiourea
5 N- (2- (3-chlorophenyl) ethyl) -N' - [ 2 - (4 - (3 pyridyl)thiazolyl)]thiourea
N-(2-(3-chlorophenyl)ethyl)-N'-[2- (4- (3nitrophenyl)thiazolyl)]thiourea
N- (2- (3-chlorophenyl) ethyl) -Ν' - (2-pyridyl) thiourea
0 N- (2 - (3-chlorophenyl) ethyl) -N* — [2- (6bromo) pyridyl]thiourea
N-(2-(3-chlorophenyl)ethyl)-N'-[2 -{6 chloro) pyridyl]thiourea
N-(2-(3-chlorophenyl)ethyl)-Ν' -(2-(64 5 methyl)pyridyl] thiourea
AP Ο Ο Ο 3 8 4
Χ-8571Α
-34Ν- (2-(3-chlorophenyl) ethyl)-Ν' -(2-(5methyl)pyridyl]thiourea
Ν-(2 -{3-chlorophenyl) ethyl) -N'-[2 - (6 tri fluoromethyl) pyridyl]thiourea
N- (2-(3-chlorophenyl)ethyl)-N’-[2-(5trifluoromethyl) pyridyl]thiourea
N-(2-(3-chlorophenyl)ethyl)-N’-[2-(6ethyl)pyridyl]thiourea
N-(2-(3-chlorophenyl)ethyl)-Ν' -[2-(510 ethyl) pyridyl] thiourea
N- (2-(3-chlorophenyl)ethyl)-N’-[2-(6bromo)pyrazinyl]thiourea
N- (2 -{3-chlorophenyl) ethyl)-N’-((3-(6bromo)pyridazinyl)]thiourea
N- (2 - (3 -chlorophenyl) ethyl) -N' - (2 - (6cyano) pyridyl]thiourea
N-(2 - (3-chlorophenyl) ethyl)-N'-[2-(5cyano)pyridyl]thiourea
N-(2-(3-chlorophenyl)ethyl)-Ν' -[2-(52 0 cyano)pyrazinyl] thiourea
N- (2-(3-chlorophenyl)ethyl)-Ν' -[2-(6cyano)pyrazinyl]thiourea
N-(2-(3-chlorophenyl) ethyl)-Ν' -[(3-(6cyano)pyridazinyl)]thiourea
5 N-(2- (3-chlorophenyl) ethyl)-N'-(2-[l,3,4thiadiazoyl]) thiourea
N-(2-(3-chlorophenyl)ethyl)-Ν' -(2benzimidazolyl)thiourea
N- (2-(3-chlorophenyl)ethyl)-Ν' -(2-imidazolyl) thiourea
0 N- (2 - {1-cyclohexenyl) ethyl) -Ν' - (2- (4,5dimethyl)thiazolyl]thiourea
N-(2-(1-cyclohexenyl) ethyl)-Ν' - (2benzothiazolyl)thiourea
N- (2-(1-cyclohexenyl)ethyl)-Ν' -[2-(63 5 f luoro) benzothiazoly 1 ] thiourea
N- (2-(1-cyclohexenyl)ethyl)-Ν' -(2-(6chloro)pyrazinyl] thiourea
N- (2-(1-cyclohexenyl)ethyl)—N' — [ 2 — (4 - (3 pyridyl)thiazolyl)]thiourea
0 N- (2 - (1-cyclohexenyl) ethyl) -N'-[2-(4-(3nitrophenyl)thiazolyl)]thiourea
N- (2-(1-cyclohexenyl)ethyl)-Ν' -[2-(6bromo)pyridyl]thiourea
N-(2-(1-cyclohexenyl)ethyl)-Ν'-(2-(64 5 chloro)pyridyl] thiourea
Χ-8571Α'
-35Ν- (2-(1-cyclohexenyl)ethyl)-Ν’-[2-(6methyl)pyridyl]thiourea
N-(2-(1-cyclohexenyl)ethyl)-Ν' -(2-(6trifluoromethyl) pyridyl]thiourea
N-(2 - (1-cyclohexenyl) ethyl)-N'-[2-(6ethyl)pyridyl]thiourea
N-(2-(1-cyclohexenyl)ethyl)-Ν’ -[2-(6bromo)pyrazinyl]thiourea
N-(2-(1-cyclohexenyl) ethyl)-N‘-((3-(610 bromo)pyridazinyl) ] thiourea
N- (2-(1-cyclohexenyl)ethyl)-N*-[2-(6cyano)pyridyl]thiourea
N-(2-(1-cyclohexenyl)ethyl)-Ν' -[2-(6cyano)pyraz iny1]thiourea
N- (2 - (1-cyclohexenyl) ethyl )-N‘-(2-(l,3,4thiadiazoyl]) thiourea
N-.(2- (1-cyclohexenyl) ethyl)-Ν' -(2benzimidazolyl) thiourea
M-(2- (1-cyclohexenyl)ethyl)-Ν' -(2-imidazolyl) thiourea 2 0 N-(2-(2-naphthyl) ethyl) -Ν' -(2-thiazolyl)thiourea
N- (2-(2-naphthyl)ethyl)-Ν' -(2-(4methyl)thiazolyl]thiourea
N-(2-(2-naphthyl)ethyl)-N'-[2-(4,5dimethyl)thiazolyl]thiourea
5 N- (2 - (2-naphthyl) ethyl) -Ν' - [2- (4cyano)thiazolyl]thiourea
N-(2-(2-naphthyl)ethyl)-Ν' - [2-(4trifluoromethyl)thiazolyl]thiourea
N-(2 - (2-naphthyl) ethyl)-N1 - (2-benzothiazolyl) thiourea
0 N- (2 - (2-naphthyl) ethyl) -Ν' - [2 - (6fluoro)benzothiazolyl]thiourea
N-(2-(2-naphthyl)ethyl)-Ν' - [2 - (6chloro)pyrazinyl]thiourea
N-(2-(2-naphthyl)ethyl)-Ν’ - [2-(43 5 ethyl) thiazolyl ] thiourea
N-(2-(2-naphthyl)ethyl)-N‘-(2-(4-(3pyridyl)thiazolyl)]thiourea
N-(2-(2-naphthyl)ethyl)-Ν'-(2-(4-(3nitrophenyl)thiazolyl)]thiourea
0 N- (2- (2-naphthyl) ethyl) -N' - (2-pyridyl) thiourea
N-(2-(2-naphthyl) ethyl)-Ν' -(2-(6bromo)pyridyl]thiourea
N-(2-(2-naphthyl)ethyl)-Ν' -[2-(5bromo) pyridyl]thiourea
5 N- (2- (2-naphthyl) ethyl) -Ν' - [2 - (6-
AP Ο Ο Ο 3 8 4
Χ-8571Α
-36Ν-(2-(2-naphthyl)ethyl)-Ν' -[2-(5chloro) pyridyl]thiourea
N-'(2- (2-naphthyl) ethyl) -Ν' -(2-(6methyl) pyridyl]thiourea
N-(2-(2-naphthyl)ethyl)-N’-[2-(5methyl) pyridyl]thiourea
N- (2-(2-naphthyl)ethyl)-Ν'-[2-(6trifluoromethyl)pyridyl]thiourea
N- (2-(2-naphthyl)ethyl)-N'-[2-(50 trifluoromethyl) pyridyl]thiourea
N- (2- (2-naphthyl) ethyl)-N·-[2- (6ethyl) pyridyl]thiourea
N-(2-(2-naphthyl)ethyl)-N'-[2-(5ethyl)pyridyl]thiourea
N- (2-(2-naphthyl)ethyl)-N’-[2-(5chloro)pyrazinyl]thiourea
N-(2-(2-naphthyl)ethyl)-Ν' -(2-(6bromo)pyrazinyl]thiourea
N-(2-(2-naphthyl)ethyl)-Ν' -[2-(50 bromo)pyrazinyl]thiourea
N-(2-(2-naphthyl)ethyl)-N'-((3-(6bromo)pyridazinyl)]thiourea
N-(2-(2-naphthyl)ethyl)-Ν' -[(3-(6chloro)pyridazinyl)]thiourea
N-(2-(2-naphthyl)ethyl)-N'-[2-(6cyano)pyridyl]thiourea
N-(2-(2-naphthyl)ethyl)-N'-[2-(5cyano)pyridyl]thiourea
N-(2-(2-naphthyl)ethyl)-Ν' -(2-(50 cyano)pyrazinyl]thiourea
N-(2-(2-naphthyl)ethyl)-N'-[2-(6cyano)pyrazinyl]thiourea
N-(2-(2-naphthyl)ethyl)-Ν' -[(3-(6cyano)pyridazinyl)]thiourea
N-(2-(2-naphthyl)ethyl)-N'-(2-[l,3,4thiadiazoyl]) thiourea
N-(2-(2-naphthyl) ethyl)-Ν' -(2-benzimidazolyl) thiourea N-(2-(2-naphthyl) ethyl)-Ν' -(2-imidazolyl)thiourea N-(2-(2,5-dimethoxyphenyl) ethyl)-N*-(20 thiazolyl) thiourea
N-(2-(2,5-dimethoxyphenyl)ethyl)-N'-[2- (4methyl)thiazolyl]thiourea
N-(2-(2,5-dimethoxyphenyl)ethyl)-Ν' -[2-(4,5dimethyl)thiazolyl]thiourea 5 N-(2- (2,5-dimethoxyphenyl) ethyl)-N'- (2benzothiazolyl)thiourea
X-8571A
-37N-(2-(2,5-dimethoxyphenyl)ethyl)-Ν' -[2-(6fluoro)benzothiazolyl]thiourea
N-(2-(2,5-dimethoxyphenyl)ethyl)-Ν' -(2-(6chloro)pyrazinyl]thiourea
N-(2 - (2,5-dimethoxyphenyl) ethyl)-N'-(2-(4-(3pyridyl)thiazolyl)]thiourea
N-(2-(2,5-dimethoxyphenyl) ethyl)-N*-(2-(4-(3nitrophenyl)thiazolyl)]thiourea
N- (2-(2,5-dimethoxyphenyl) ethyl)-Ν' -(210 pyridyl) thiourea
N-(2-(2,5-dimethoxyphenyl)ethyl)-Ν' -(2- (6bromo) pyridyl]thiourea
N-(2-(2,5-dimethoxyphenyl)ethyl)-N'-(2-(6chloro)pyridyl]thiourea
N- (2 - (2,5-dimethoxyphenyl) ethyl) -N‘ - [2 - (5chloro) pyridyl]thiourea
N-(2-(2,5-dimethoxyphenyl)ethyl)-Ν' -(2 - (6methyl) pyridyl]thiourea
N-(2-(2,5-dimethoxyphenyl)ethyl,-Ν' -(2-(520 methyl)pyridyl] thiourea
N-(2-(2,5-dimethoxyphenyl) ethyl)-Ν' -(2-(6trifluoromethyl)pyridyl]thiourea
N-(2-(2,5-dimethoxyphenyl)ethyl)-N'-[2-(5trifluoromethyl) pyridyl]thiourea
5 N- (2 - (2,5-dimethoxyphenyl) ethyl) -Ν’—(2-(6ethy1) pyridyl]thiourea
N-(2-(2,5-dimethoxyphenyl)ethyl)-N'-[2-(5ethyl)pyridyl]thiourea
N-(2-(2,5-dimethoxyphenyl)ethyl,-Ν' -(2-(63 0 bromo) pyrazinyl] thiourea
N-(2-(2,5-dimethoxyphenyl,ethyl)-Ν' -((3-(6bromo)pyridazinyl)]thiourea
N-(2-(2,5-dimethoxyphenyl)ethyl)—N' — [2- {6cyano) pyr idyl] thiourea
5 N- (2- (2,5-dimethoxyphenyl, ethyl) -Ν' -[2-(5cyano) pyridyl]thiourea
N-(2-(2,5-dimethoxyphenyl)ethyl)-Ν' -[2-(5cyano)pyrazinyl]thiourea
N-(2-(2,5-dimethoxyphenyl)ethyl)-Ν' -(2-(64 0 cyano) pyrazinyl ] thiourea
N-(2-(2,5-dimethoxyphenyl) ethyl)-N'-[(3-(6cyano)pyridazinyl)]thiourea
N-(2 -(2,5-dimethoxyphenyl) ethyl)-N'-(2-(l,3,4thiadiazoyl]) thiourea
5 N-(2 - (2,5-dimethoxyphenyl) ethyl,-N'- (2 benzimidazolyl)thiourea
AP Ο Ο Ο 3 8 4
Χ-8571Α
-38Ν-(2-(2,5-dimethoxyphenyl)ethyl)-Ν' -(2imidazolyl) thiourea
Ν- (2-(2-azidophenyl)ethyl)-Ν' -(2-thiazolyl)thiourea N- (2-(2-azidophenyl)ethyl)-Ν' -[2-(45 methyl)thiazolyl]thiourea
N-(2-(2-azidophenyl)ethyl)-Ν' -[2-(4,5dimethyl)thiazolyl]thiourea
N- (2-(2-azidophenyl)ethyl)-Ν'-[2-(4cyano)thiazolyl]thiourea
N- (2 - (2-azidophenyl) ethyl) -Ν' -[2-(4tri fluoromethyl) thiazolyl] thiourea
N- (2- (2-azidophenyl)ethyl)-N' - (2benzothiazolyl) thiourea
N- (2-(2-azidophenyl)ethyl)-Ν'-[2-(61 5 fluoro)benzothiazolyl]thiourea
N- (2 - (2-azidophenyl) ethyl)-N'-[2-(6chloro)pyrazinyl]thiourea
N- (2-(2-azidophenyl) ethyl)-Ν' -[2-(4ethyl)thiazolyl]thiourea
0 N- (2 - (2-azidophenyl) ethyl) -N'-[2-(4-(3pyridyl)thiazolyl)]thiourea
N- (2-(2-azidophenyl)ethyl)-Ν'-[2-(4-(3nitrophenyl)thiazolyl)3 thiourea
N- (2- (2-azidophenyl) ethyl) -Ν' - (2-pyridyl) thiourea
N- (2 - (2-azidophenyl) ethyl)-N*-[2-(6bromo)pyridyl]thiourea
N-(2-(2-azidophenyl) ethyl)-Ν' -[2-(5bromo)pyridyl]thiourea
N- (2 - (2-azidophenyl)ethyl)-Ν'-[2-(63 0 chloro)pyridyl] thiourea
N- (2-(2-azidophenyl) ethyl)-N* -[2-(5chloro) pyridyl]thiourea
N-(2-(2-azidophenyl)ethyl)-Ν' -[2-(6methyl)pyridyl]thiourea
5 N- (2- (2-azidophenyl)ethyl) -N'-[2-(5methyl)pyridyl]thiourea
N-(2-(2-azidophenyl)ethyl)-Ν' -[2-(6trifluoromethyl) pyridyl]thiourea
N-{2-(2-azidophenyl)ethyl)-Ν' -[2-(54 0 trifluoromethyl)pyridyl]thiourea
N- (2-(2-azidophenyl)ethyl)-N’-[2-(6ethy1) pyridyl]thiourea
N- (2-(2-azidophenyl)ethyl)-Ν' -[2-(5ethyl) pyridyl]thiourea
5 N- (2- (2-azidophenyl) ethyl) -Ν' - [2 - (5chloro)pyrazinyl]thiourea
X-8571A
-39'I
N-(2- (2-azidophenyl)ethyl)-N‘-[2-(6bromo)pyrazinyl]thiourea
N-(2-(2-azidophenyl)ethyl)-Ν' -(2-(5bromo)pyrazinyl]thiourea
N-(2-(2-azidophenyl) ethyl)-N'-[(3-(6bromo)pyridazinyl)]thiourea
N-(2 - (2-azidophenyl)ethyl)-Ν’ - ((3-(6chloro)pyridazinyl)]thiourea
N- (2- (2-azidophenyl)ethyl)-Ν' -(2-(610 cyano) pyr idyl] thiourea
N- (2 - (2-azidophenyl) ethyl) -Ν' -(2-(5cyano) pyridyl] thiourea
N- (2 - (2-azidophenyl) ethyl) -N'-[2-(5cyano)pyrazinyl]thiourea
N- (2- (2-azidophenyl)ethyl)-N'-[2-(6cyano)pyrazinyl]thiourea
N-(2 - (2-azidophenyl)ethyl)-Ν' - ((3-(6cyano)pyridazinyl)]thiourea
N-(2-(2-azidophenyl)ethyl)-N'-(2-(1,3,42 0 thiadiazoyl] ) thiourea
N- (2- (2-azidophenyl) ethyl) -Ν' -(2benzimidazolyl) thiourea
N-(2 - (2-azidophenyl)ethyl)-Ν' -(2-imidazolyl)thiourea N-(2 - (2,3,4-trifluorophenyl)ethyl)-Ν' - (22 5 thiazolyl) thiourea
N-(2- (2,3,4-trifluorophenyl)ethyl)-Ν' -(2-(4methy 1)thiazolyl]thiourea
N- (2 - (2,3,4-trifluorophenyl)ethyl)-Ν' -(2 - (4,5dimethyl)thiazolyl]thiourea
0 N- (2- (2,3,4-trif luorophenyl) ethyl) -Ν' - (2 - (4cyano)thiazolyl]thiourea
N-(2- (2,3,4-trifluorophenyl) ethyl)-N'-(2-(4trifluoromethyl)thiazolyl]thiourea
N-(2 - (2,3,4-trifluorophenyl) ethyl)-Ν' - (23 5 benzothiazolyl) thiourea
N-(2- (2,3,4-trifluorophenyl) ethyl)-N'-(2-(6fluoro)benzothiazolyl]thiourea
N-(2-(2,3,4-trifluorophenyl)ethyl)-Ν' - [2- (6chloro)pyrazinyl]thiourea
0 N- (2- (2,3,4-trif luorophenyl) ethyl) -Ν' - [2- (4ethyl)thiazolyl]thiourea
N-(2- (2,3,4-trifluorophenyl)ethyl)-N'-[2- (4- (3pyridyl)thiazolyl)]thiourea
N-(2- (2,3,4-trifluorophenyl)ethyl)-N'-(2-(4-(34 5 nitrophenyl)thiazolyl)]thiourea
AP Ο Ο Ο 3 β 4
-40X-8571A
Ν-(2-(2,3,4-trifluorophenyl) ethyl)-Ν' - (2pyridyl)thiourea
Ν-(2- (2,3,4-trifluorophenyl)ethyl)-N'-[2-(6bromo)pyridyl]thiourea
N-(2-(2,3,4-trifluorophenyl) ethyl)-N’-[2-(5bromo) pyridyl]thiourea
N- (2-(2,3. 4-trifluorophenyl) ethyl)-Ν' -[2-(6chloro)pyridyl]thiourea
N-(2-(2,3,4-trifluorophenyl) ethyl)-Ν' -[2-(51 0 chloro) pyridyl]thiourea
N-(2- (2,3,4-trifluorophenyl)ethyl)-Ν' -(2-(6methyl)pyridyl]thiourea
N-(2-(2,3,4-trifluorophenyl)ethyl)-Ν'-[2-(5methy1) pyridyl]thiourea
N- (2 - (2,3,4-trif luorophenyl) ethyl )-N'-[2-(6trifluoromethyl) pyridyl]thiourea
N-(2-(2,3,4-trifluorophenyl) ethyl)-N'-[2- (5trifluoromethyl) pyridyl]thiourea
N- (2 - (2,3,4-trifluorophenyl) ethyl)-N'-[L-(62 0 ethyl) pyridyl] thiourea
N- (2-(2,3,4-trifluorophenyl)ethyl)-Ν' -.2-(5ethyl) pyridyl]thiourea
N-(2-(2,3,4-trifluorophenyl) ethyl)-N'-[2-(5chloro)pyrazinyl]thiourea
N-(2-(2,3,4-trifluorophenyl)ethyl)-N'-[2-(6bromo)pyrazinyl]thiourea
N- (2-(2,3,4-trifluorophenyl)ethyl)-N’-[2-(5bromo)pyrazinyl]thiourea
N-(2-(2,3,4-trifluorophenyl)ethyl)-N'-[(3-(630 bromo)pyridazinyl) ]thiourea
N- (2- (2,3,4-trifluorophenyl)ethyl)-Ν' -[(3-(6chloro)pyridazinyl)]thiourea
N- (2 - (2,3,4-trifluorophenyl)ethyl)-N'-[2-(6cyano)pyridyl]thiourea
5 N- (2- (2,3,4-trif luorophenyl) ethyl) -Ν' -[2-(5cyano)pyridyl]thiourea
N- (2-(2,3,4-trifluorophenyl) ethyl)-N’-[2-(5cyano)pyrazinyl]thiourea
N-(2-(2,3,4-trifluorophenyl)ethyl)-Ν' -[2-(64 0 cyano) pyrazinyl ] thiourea
N-(2-(2,3,4-trifluorophenyl)ethyl)-Ν' -[(3-(6cyano)pyridazinyl)]thiourea
N-(2-(2,3,4-trifluorophenyl) ethyl)-N'-(2-[l,3,4thiadiazoyl]) thiourea
5 N-(2-(2,3,4-trifluorophenyl) ethyl)-Ν' -(2-
t
X-8571A
-41N-(2-(2,3,4-trifluorophenyl) ethyl)-N'- (2imidazolyl) thiourea
N-(2-(2-fluoro-6-chlorophenyl) ethyl)-Ν' -(2thiazolyl) thiourea
N-(2-(2-fluoro-6-chlorophenyl)ethyl)-N’-[2-(4methyl)thiazolyl]thiourea
N-(2-(2-fluoro-6-chlorophenyl)ethyl)-Ν' -(2-(4,5dimethyl)thiazolyl]thiourea
N-(2-(2-fluoro-6-chlorophenyl)ethyl)-Ν' -(210 benzothiazolyl) thiourea
N-(2-(2-fluoro-6-chlorophenyl)ethyl)-Ν' -(2-(6fluoro)benzothiazolyl]thiourea
N-(2-(2-fluoro-6-chlorophenyl)ethyl)-Ν' -[2-(6chloro)pyrazinyl]thiourea
N-(2-(2-fluoro-6-chlorophenyl)ethyl)-Ν' -[2-(4- (3pyridyl)thiazolyl)]thiourea
N-(2-(2-fluoro-6-chlorophenyl)ethyl)-Ν'-(2-(4-(3nitrophenyl)thiazolyl)]thiourea
N-(2-(2-fluoro-6-chlorophenyl)ethyl)-Ν' -(22 0 pyridyl) thiourea
N-(2-(2-fluoro-6-chlorophenyl)ethyl)-Ν' -(2-(6bromo)pyridyl]thiourea
N-(2-(2-fluoro-6-chlorophenyl)ethyl)-Ν' -[2-(6chloro) pyridyl]thiourea
5 N- (2 - (2-fluoro-6-chlorophenyl) ethyl) -Ν' -[2-(6methyl)pyridyl] thiourea
N-(2-(2-fluoro-6-chlorophenyl)ethyl)-Ν' -(2-(5methy1) pyridyl]thiourea
N-(2 - (2-fluoro-6-chlorophenyl)ethyl)-Ν' -(2-(63 0 trifluoromethyl)pyridyl]thiourea
N-(2-(2-fluoro-6-chlorophenyl)ethyl)-Ν' -[2-(5trifluoromethyl)pyridyl]thiourea
N-(2-(2-fluoro-6-chlorophenyl)ethyl)-Ν' -(2-(6ethy1) pyridyl]thiourea
5 N- (2- (2-f luoro-6-chlorophenyl) ethyl) -N'-[2-(5ethyl)pyridyl]thiourea
N-(2-(2-fluoro-6-chlorophenyl)ethyl)-Ν' -[2-(6bromo)pyrazinyl]thiourea
N-(2-(2-fluoro-6-chlorophenyl)ethyl)-Ν' -[(3-(64 0 bromo)pyridazinyl) ] thiourea
N-(2-(2-fluoro-6-chlorophenyl)ethyl)-Ν' -(2-(6cyano)pyridyl]thiourea
N-(2 -(2-fluoro-6-chlorophenyl)ethyl)-N'-[2-(5cyano)pyridyl]thiourea
5 N- (2 - (2-f luoro-6-chlorophenyl) ethyl) -Ν' - [2 - (5-
APOOO384
X-8571A
-42N-(2-(2-fluoro-6-chlorophenyl) ethyl)-N*-[2-(6cyano)pyrazinyl]thiourea
N-(2-(2-fluoro-6-chlorophenyl)ethyl)-Ν' - ((3-(6cyano!pyridazinyl)]thiourea
N- (2- (2-fluoro-6-chlorophenyl)ethyl) -Ν'-(2-(1,3,4thiadiazoyl]) thiourea
N-(2-(2-fluoro-6-chlorophenyl) ethyl)-Ν' - (2benzimidazolyl)thiourea
N-(2-(2-fluoro-6-chlorophenyl)ethyl)-N’-(20 imidazolyl)thiourea
N-(2-(2,6-dimethoxyphenyl)ethyl)-Ν' -(2thiazolyl) thiourea
N-(2-(2,6-dimethoxyphenyl)ethyl)-Ν' -(2-(4methyl)thiazolyl]thiourea
N-(2-(2,6-dimethoxyphenyl) ethyl)-N'-[2 - (4,5dimethyl)thiazolyl]thiourea
N-(2-(2,6-dimethoxyphenyl)ethyl)-Ν' -(2benzothiazoly1) thiourea
N-(2-(2,6-dimethoxyphenyl)ethyl)-Ν' -[2 - (60 fluoro)benzothiazolyl]thiourea
N-(2-(2,6-dimethoxyphenyl)ethyl)-Ν' - (2- (6chloro)pyrazinyl]thiourea
N-(2-(2,6-dimethoxyphenyl)ethyl)-N'-[2- (4- (3pyridyl)thiazolyl)]thiourea
N- (2-(2,6-dimethoxyphenyl) ethyl)-N'-[2-(4-(3nitrophenyl)thiazolyl)]thiourea
N-(2-(2,6-dimethoxyphenyl)ethyl)-N'-(2pyridyl) thiourea
N-(2-(2,6-dimethoxyphenyl)ethyl)-N’-[2 - (60 bromo)pyridyl]thiourea
N-(2-(2,6-dimethoxyphenyl)ethyl)-Ν' -[2-(6chloro) pyridyl]thiourea
N-(2-(2,6-dimethoxyphenyl)ethyl)-Ν' -(2- (6methyl) pyridyl]thiourea
N-(2-(2,6-dimethoxyphenyl)ethyl)-Ν' -(2-(5methyl) pyridyl]thiourea
N-(2-(2,6-dimethoxyphenyl)ethyl)-Ν' -[2-(6tri fluoromethyl) pyridyl]thiourea
N-(2-(2,6-dimethoxyphenyl)ethyl)-Ν' - (2 - (50 trifluoromethyl)pyridyl]thiourea
N-(2-(2,6-dimethoxyphenyl)ethyl)-Ν' -[2 - (6ethyl) pyridyl]thiourea
N-(2-(2,6-dimethoxyphenyl)ethyl)-Ν' -(2-(5ethyl)pyridyl]thiourea
N-(2-(2,6-dimethoxyphenyl)ethyl)-N'-[2-(6bromo)pyrazinyl]thiourea
X-8571A
-43N- (2 - (2,6-dimethoxyphenyl)ethyl)-Ν' -[(3-(6bromo)pyridazinyl)]thiourea
N- (2-(2,6-dimethoxyphenyl)ethyl)-Ν' - [2 - (6cyano) pyridyl]thiourea
N- (2 - (2,6-dimethoxyphenyl)ethyl)-Ν' -(2-(5cyano) pyridyl]thiourea
N- (2- (2,6-dimethoxyphenyl)ethyl)-Ν' - [2-(5cyano)pyrazinyl]thiourea
N-(2-(2,6-dimethoxyphenyl) ethyl)-Ν' -(2-(6cyano)pyrazinyl]thiourea
N- (2- (2,6-dimethoxyphenyl) ethyl)-Ν' -[(3-(6cyano)pyridazinyl)]thiourea
N-(2-(2,6-dimethoxyphenyl) ethyl)-N'- (2-(1,3,4thiadiazoyl]) thiourea
N- (2- (2,6-dimethoxyphenyl)ethyl)-Ν' -(2benzimidazolyl)thiourea
N- (2-(2,6-dimethoxyphenyl)ethyl)-Ν' - (2imidazoly1) thiourea
N- (2-(2,3,6-trichlorophenyl) ethyl)-N'-(2thiazolyl) thiourea
N- (2-(2,3,6-trichlorophenyl) ethyl)-Ν' - (2-(4methyl)thiazolyl]thiourea
N- (2-(2,3,6-trichlorophenyl) ethyl)-N'-[2-(4,5dimethyl)thiazolyl]thiourea
N- (2-(2,3,6-trichlorophenyl) ethyl)-Ν' -(2-(4cyano)thiazolyl]thiourea
N- (2-(2,3,6-trichlorophenyl) ethyl)-N' — [2-(4trifluoromethyl)thiazolyl]thiourea
N- (2-(2,3,6-trichlorophenyl)ethyl)-Ν' -(2benzothiazolyl) thiourea
N- (2-(2,3,6-trichlorophenyl) ethyl)-Ν' - (2-(6fluoro)benzothiazolyl]thiourea
N-'(2- (2,3,6-trichlorophenyl) ethyl) -Ν' -[2-(6chloro)pyrazinyl]thiourea
N- (2-(2,3,6-trichlorophenyl)ethyl)-Ν' - [2-(4ethyl)thiazolyl]thiourea
N- (2- (2,3,6-trichlorophenyl) ethyl)-N'-[2-(4-(3pyridyl)thiazolyl)]thiourea
N-(2-(2,3,6-trichlorophenyl)ethyl)-Ν' - (2-(4-(3nitrophenyl)thiazolyl)]thiourea
N- (2-(2,3,6-trichlorophenyl) ethyl) -Ν' - (2pyridyl) thiourea
N-(2-(2,3,6-trichlorophenyl) ethyl)-N' - [2 - (6bromo) pyridyl]thiourea
N-(2-(2,3,6-trichlorophenyl)ethyl)-Ν' - [2- (5bromo) pyridyl]thiourea
AP Ο Ο Ο 3 8 4
Χ-8571Α-44Ν-(2-(2,3, 6-trichlorophenyl)ethyl)-Ν' -[2-(6chloro)pyridyl]thiourea
Ν-(2-(2,3,6-trichlorophenyl) ethyl)-Ν' -(2-(5chloro) pyridyl]thiourea
N-(2-(2,3,6-trichlorophenyl) ethyl)-Ν' -[2-(6methyl) pyridyl]thiourea
N-(2- (2,3,6-trichlorophenyl) ethyl)-Ν' -[2-(5methyl) pyridyl]thiourea
N-(2-(2,3,6-trichlorophenyl) ethyl)-Ν' -(2-(61 0 trifluoromethyl, pyridyl]thiourea
N-(2- (2,3,6-trichlorophenyl) ethyl)-Ν' -[2-(5trifluoromethyl) pyridyl]thiourea
N-(2-(2,3,6-trichlorophenyl)ethyl)-Ν' -[2-(6ethyl) pyridyl]thiourea
N-(2-(2,3,6-trichlorophenyl) ethyl)-Ν' -[2-(5ethyl) pyridyl]thiourea
N-(2- (2,3 ,6-trichlorophenyl) ethyl)-Ν' -[2-(5chloro)pyrazinyl]thiourea
N-(2-(2,3,6-trichlorophenyl) ethyl)-Ν' -(2-(620 bromo)pyrazinyl]thiourea
N-(2- (2,3,6-trichlorophenyl)ethyl)-Ν' -[2-(5bromo)pyrazinyl]thiourea
N-(2-(2,3,6-trichlorophenyl)ethyl)-N'-((3-(6bromo)pyridazinyl)]thiourea
5 N- (2- (2,3,6-trichlorophenyl) ethyl) -Ν' - [ (3- (6chloro)pyridazinyl)]thiourea
N-(2-(2,3,6-trichlorophenyl)ethyl)-N'-[2-(6cyano)pyridyl]thiourea
N-(2-(2,3,6-trichlorophenyl)ethyl)-Ν' -[2-(53 0 cyano) pyridyl] thiourea
N-(2-(2,3,6-trichlorophenyl)ethyl)-N’-[2-(5cyano)pyrazinyl)thiourea
N-(2-(2,3,6-trichlorophenyl) ethyl)-Ν' -[2 - (6cyano)pyrazinyl]thiourea
5 N- (2 - (2,3,6-trichlorophenyl) ethyl) -Ν' - [ (3-(6cyano)pyridazinyl)]thiourea
N-(2- (2,3,6-trichlorophenyl) ethyl)-N'-(2-[l,3,4thiadiazoyl]) thiourea
N-(2-(2,3,6-trichlorophenyl) ethyl)-Ν' -(24 0 benzimidazolyl) thiourea
N-(2-(2,3,6-trichlorophenyl) ethyl)-Ν' -(2imidazoly1) thiourea
N-(2 - (2,6-dichlorophenyl) ethyl)-Ν' - (2thiazolyl) thiourea
5 N- (2 - (2,6-dichlorophenyl} ethyl) -N' - [2- (4-
X-8571A
-4520
Ν-(2-(2,6-dichlorophenyl) ethyl)-Ν' -(2-(4,5dimethyl)thiazolyl]thiourea
N- (2- (2,6-dichlorophenyl) ethyl)-Ν' -(2benzothiazolyl) thiourea
N-(2-(2,6-dichlorophenyl) ethyl)-Ν' -[2-(6fluoro)benzothiazolyl]thiourea
N- (2 - (2,6-dichlorophenyl) ethyl)-N'-(2 - (6chloro)pyrazinyl]thiourea
N- (2-(2,6-dichlorophenyl) ethyl) —N'- (2- (4- (3pyridyl)thiazolyl)]thiourea
N- (2-(2,6-dichlorophenyl) ethyl)-N’-[2-(4-(3nitrophenyl)thiazolyl)]thiourea
N- (2 - (2,6-dichlorophenyl) ethyl)-N'- (2-pyridyl) thiourea N-(2-(2,6-dichlorophenyl) ethyl) -N'-[2- (6bromo)pyridyl]thiourea
N-(2-(2,6-dichlorophenyl) ethyl) -N' - (2 - (6chloro)pyridyl]thiourea
N-(2 - (2,6-dichlorophenyl)ethyl)-Ν' -[2-(6methyl) pyridyl]thiourea
N- (2 - (2,6-dichlorophenyl)ethyl)-Ν' -(2-(5methy1) pyridyl]thiourea
N- {2-(2,6-dichlorophenyl) ethyl)-N*-[2-(6trifluoromethyl) pyridyl]thiourea
N- (2-(2,6-dichlorophenyl) ethyl)-Ν' -(2- (5tri fluoromethyl) pyridyl]thiourea
N-.(2 - (2,6-dichlorophenyl) ethyl) -Ν' -(2-(6ethyl) pyridyl]thiourea
N-(2-(2,6-dichlorophenyl) ethyl)-Ν' -(2-(5ethyl)pyridyl]thiourea
N-(2-(2,6-dichlorophenyl) ethyl)-N'-[2-(6bromo)pyrazinyl]thiourea
N-(2-(2,6-dichlorophenyl) ethyl)-N'-[(3-(6bromo)pyridazinyl)]thiourea
N-(2-(2,6-dichlorophenyl)ethyl)-Ν' -(2-(6cyano)pyridyl]thiourea
N-(2-(2,6-dichlorophenyl)ethyl)-Ν' -(2-(5cyano)pyridyl]thiourea
N-(2-(2,6-dichlorophenyl) ethyl)-N'-[2-(5cyano)pyrazinyl]thiourea
N-(2-(2,6-dichlorophenyl)ethyl)-Ν' -[2-(6cyano)pyrazinyl]thiourea
N-(2-(2,6-dichlorophenyl)ethyl)-Ν' - ((3-(6cyano)pyridazinyl)]thiourea
N-(2-(2,6-dichlorophenyl)ethyl)-Ν' -(2-(1,3,4thiadiazoyl]) thiourea
5
AP Ο Ο Ο 3 8 4
Χ-8571Α
-46Ν- (2-(2,6-dichlorophenyl)ethyl)-Ν’ -(2benzimidazolyl) thiourea
Ν- (2- (2,6-dichlorophenyl) ethyl)-Ν'- (2imidazolyl) thiourea
Ν- (2-(2,3,5-trichlorophenyl) ethyl)-Ν' -(2thiazoly1) thiourea
N- (2- (2,3,5-trichlorophenyl) ethyl)-Ν' -(2- (4methyl)thiazolyl]thiourea
N- (2-(2,3,5-trichlorophenyl) ethyl)-N'-[2-(4,510 dimethyl) thiazolyl] thiourea
N-(2-(2,3,5-trichlorophenyl)ethyl)-Ν' -(2-(4cyano)thiazolyl]thiourea
N- (2- (2,3,5-trichlorophenyl) ethyl)-Ν' -[2- (4trifluoromethyl)thiazolyl]thiourea
N- (2 - (2,3,5-trichlorophenyl) ethyl) -Ν' - (2benzothiazolyl) thiourea
N- (2- (2,3,5-trichlorophenyl)ethyl)-Ν' -[2-(δί luoro) benzothiazolyl] thiourea
N- (2-(2,3,5-trichlorophenyl) ethyl)-Ν' -[2 - (62 0 chloro)pyrazinyl] thiourea
N- (2-(2,3,5-trichlorophenyl)ethyl)-Ν' -(2-(4ethyl)thiazolyl]thiourea
N- (2-(2,3,5-trichlorophenyl) ethyl)-N'-[2-(4-(3pyridyl)thiazolyl)]thiourea
5 N- (2 - (2,3,5-trichlorophenyl) ethyl) -N'-[2-(4-(3nitrophenyl)thiazolyl)]thiourea
N- (2 - (2,3,5-trichlorophenyl) ethyl) -N' - (2pyridyl) thiourea
N- (2- (2,3,5-trichlorophenyl)ethyl)-Ν' -[2-(63 0 bromo) pyridyl] thiourea
N- (2 - (2,3,5-trichlorophenyl)ethyl)-Ν' -(2-(5bromo) pyridyl]thiourea
N-(2-(2,3,5-trichlorophenyl)ethyl)-Ν' -[2 - (6chloro)pyridyl]thiourea
5 N- (2- (2,3,5-trichlorophenyl)ethyl)-Ν' -[2-(5chloro)pyridyl]thiourea
N-(2-(2,3,5-trichlorophenyl)ethyl)-Ν' -[2- (6methyl)pyridyl]thiourea
N- (2-(2,3,5-trichlorophenyl)ethyl)-N’-[2 - (54 0 methyl) pyridyl ] thiourea
N- (2-(2,3,5-trichlorophenyl)ethyl)-Ν' -[2-(6tri fluoromethyl) pyridyl]thiourea
N- (2- (2,3,5-trichlorophenyl)ethyl)-Ν' -[2-(5trifluoromethyl) pyridyl]thiourea
5 N- (2- (2,3,5-trichlorophenyl) ethyl)-Ν' -[2-(6ethyl) pyridyl]thiourea
X-8571A
-47Ν- (2-(2,3,5-trichlorophenyl)ethyl)-Ν' -[2-(5ethyl)pyridyl]thiourea
N- (2 - (2,3,5-trichlorophenyl) ethyl)-N'-(2-(5chloro)pyrazinyl]thiourea
N-(2-(2,3,5-trichlorophenyl) ethyl)-Ν' -(2-(6bromo)pyrazinyl]thiourea
N- (2-(2,3,5-trichlorophenyl)ethyl)-N‘-(2-(5bromo)pyrazinyl]thiourea
N-(2-(2,3,5-trichlorophenyl)ethyl)-N'- ((3 - (610 bromo) pyridazinyl) ] thiourea
N- (2- (2,3,5-trichlorophenyl)ethyl)-N'-[(3-(6chloro)pyridazinyl)]thiourea
N- (2-(2,3,5-trichlorophenyl)ethyl)-Ν' -[2-(6cyano)pyridyl]thiourea
N- (2-(2,3,5-trichlorophenyl) ethyl)-N‘-[2 - (5cyano)pyridyl]thiourea
N-(2-(2,3,5-trichlorophenyl)ethyl)-Ν' -[2-(5cyano)pyrazinyl]thiourea
N-(2- (2,3,5-trichlorophenyl)ethyl)-Ν' -[2-(62 0 cyano)pyrazinyl] thiourea
N- (2 - (2,3,5-trichlorophenyl) ethyl)-Ν' - ((3- (6cyano)pyridazinyl)) thiourea
N- (2 - (2,3,5-trichlorophenyl)ethyl)-N‘-(2-(1,3,4thiadiazoyl]) thiourea
5 N-(2-(2,3,5-trichlorophenyl)ethyl)-Ν' -(2benzimidazolyl) thiourea
N-(2-(2,3,5-trichlorophenyl)ethyl)-Ν' -(2imidazolyl) thiourea
N-(2-(3,5-dichlorophenyl)ethyl)-Ν' -(23 0 thiazolyl) thiourea
N-(2-(3,5-dichlorophenyl)ethyl)-Ν' -[2-(4methyl)thiazolyl]thiourea
N-(2-(3,5-dichlorophenyl)ethyl)-Ν' -[2- (4,5dimethyl)thiazolyl]thiourea
5 N- (2 - (3,5 -dichlorophenyl) ethyl) -N' - [ 2 - (4 cyano)thiazolyl]thiourea
N- (2-(3,5-dichlorophenyl)ethyl)-Ν' -(2 - (4trifluoromethyl)thiazolyl]thiourea
N- (2 - (3,5-dichlorophenyl)ethyl)-Ν' -(24 0 benzothiazolyl) thiourea
N- (2-(3,5-dichlorophenyl)ethyl)-Ν' -(2-{6fluoro)benzothiazolyl]thiourea
N-(2 - (3,5-dichlorophenyl) ethyl)-N'- (2 - (6 chloro)pyrazinyl]thiourea
5 N- (2 - (3,5-dichlorophenyl) ethyl) -Ν' - [2 - (4ethyl) thiazolyl ] thiourea
AP Ο Ο Ο 3 8 4
-48X-8571A
Ν- (2 - (3,5-dichlorophenyl) ethyl)-Ν'-(2-(4-(3pyridyl)thiazolyl)]thiourea
Ν-(2- (3,5-dichlorophenyl) ethyl)-Ν' -(2-(4-(3nitrophenyl)thiazolyl)]thiourea
N- (2- (3,5-dichlorophenyl) ethyl) -N‘ - (2-pyridyl) thiourea
N-(2- (3,5-dichlorophenyl) ethyl)-N'- (2 - (6 bromo)pyridyl]thiourea
N-(2-(3, 5-dichlorophenyl)ethyl)-N'-(2-(5bromo)pyridyl]thiourea
N-(2-(3,5-dichlorophenyl)ethyl)-Ν' -[2-(6chloro)pyridyl]thiourea
N-(2-(3,5-dichlorophenyl)ethyl)-Ν' -(2-(5chloro) pyridyl]thiourea
N-(2-(3,5-dichlorophenyl)ethyl)-Ν' -[2-(615 methyl) pyridyl ] thiourea
N-(2-(3,5-dichlorophenyl)ethyl)-Ν' -(2-(5methyl) pyridyl]thiourea
N-(2-(3,5-dichlorophenyl) ethyl)-N'-(2-{6tri fluoromethyl) pyridyl]thiourea
0 N- (2 - (3,5-dichlorophenyl) ethyl) -Ν' - [2- (5tri fluoromethyl) pyridyl]thiourea
N-(2-(3,5-dichlorophenyl)ethyl)-N'-[2-(6ethyl) pyridyl]thiourea
N-(2-(3,5-dichlorophenyl)ethyl)-Ν' -[2-(52 5 ethyl)pyridyl] thiourea
N-(2-(3,5-dichlorophenyl)ethyl)-Ν' -(2-(5chloro)pyrazinyl]thiourea
N-(2-(3,5-dichlorophenyl)ethyl)-Ν' -(2-(6bromo)pyrazinyl]thiourea
0 N- (2 - (3,5-dichlorophenyl) ethyl) -Ν' - (2 - (5bromo)pyrazinyl]thiourea
N-(2-(3,5-dichlorophenyl)ethyl)-Ν' - ((3-(6bromo)pyridazinyl)]thiourea
N-(2-(3,5-dichlorophenyl)ethyl)-Ν' - I (3-(63 5 chloro)pyridazinyl) ] thiourea
N-(2-(3,5-dichlorophenyl)ethyl)-Ν' -(2-(6cyano) pyridyl]thiourea
N-(2-(3,5-dichlorophenyl)ethyl)-Ν' -[2-(5cyano) pyridyl]thiourea
0 N- (2 - (3,5-dichlorophenyl) ethyl) -N' - (2- (5cyano)pyrazinyl]thiourea
N-(2-(3,5-dichlorophenyl)ethyl)-Ν'-[2-(6cyano)pyrazinyl]thiourea
\ ,
X-8571A
-49N-(2 -{3,5-dichlorophenyl)ethyl)-Ν'-(2-(1,3,4thiadiazoyl]) thiourea
N-(2-(3,5-dichlorophenyl) ethyl)-Ν' -(2benzimidazolyl) thiourea
N-(2-(3,5-dichlorophenyl) ethyl)-N*-(2imidazoly1) thiourea
N-(2-(3-fluorophenyl) ethyl)-Ν' -(2-thiazolyl) thiourea N-(2- (3 -fluorophenyl) ethyl)-N'-[2 - (4 methyl)thiazolyl]thiourea
N- (2 - (3 - fluorophenyl) ethyl )-N'-[2-(4,5dimethyl)thiazolyl]thiourea
N-'{2- (3-fluorophenyl) ethyl) -Ν' -(2benzothiazolyl) thiourea
N-(2-(3-fluorophenyl)ethyl)-Ν' -[2-(61 5 fluoro)benzothiazolyl]thiourea
N-(2-(3-fluorophenyl) ethyl)-Ν' -(2-(6chloro)pyrazinyl]thiourea
N-(2- (3 -fluorophenyl) ethyl)—N'-[2-(4-(3pyridyl)thiazolyl)]thiourea
0 N- (2 - (3-f luorophenyl) ethyl )-N'-[2-(4-{3nitrophenyl)thiazolyl)]thiourea
N-(2-(3-fluorophenyl) ethyl)-Ν' - (2-pyridyl) thiourea N-(2-(3-fluorophenyl)ethyl)-Ν' -(2-(6bromo)pyridyl]thiourea
5 N- (2 - (3-f luorophenyl) ethyl) -Ν' - [2- (6chloro) pyridyl]thiourea
N-(2-(3-fluorophenyl)ethyl)-Ν' -[2-(6methyl) pyridyl]thiourea
N-(2-(3-fluorophenyl)ethyl)-Ν' -[2-(53 0 methyl)pyridyl] thiourea
N-(2-(3-fluorophenyl)ethyl)-Ν' -[2-tetri fluoromethyl ) pyridyl]thiourea
N-(2-(3-fluorophenyl) ethyl)-Ν'-(2-(5trifluoromethyl) pyridyl]thiourea
N-(2-(3-f luorophenyl) ethyl )-N’-[2 - (6ethyl)pyridyl]thiourea
N-(2-(3-fluorophenyl)ethyl)-Ν' -(2-(5ethy1) pyridyl]thiourea
N-(2-(3-fluorophenyl)ethyl)-Ν' -[2-(64 0 bromo)pyrazinyl] thiourea
N-(2-(3-fluorophenyl) ethyl)-N'-((3-(6bromo)pyridazinyl)]thiourea
N-(2-(3-fluorophenyl) ethyl)-N’- (2 - (6cyano)pyridyl]thiourea
5 N- (2 - (3- fluorophenyl) ethyl)-N'-[2-(5cyano)pyridyl]thiourea
AP Ο Ο Ο 3 8 4
Χ-8571Α
-50Ν-(2- (3-fluorophenyl) ethyl)-Ν'-[2-(5cyano)pyrazinyl]thiourea
N-(2-(3-fluorophenyl)ethyl)-N'- (2- (6cyano)pyrazinyl]thiourea
N-(2- (3-fluorophenyl)ethyl)-N'-[(3-(6cyano)pyridazinyl)]thiourea
N-(2 - (3-fluorophenyl)ethyl)-N’-(2-11,3,4thiadiazoyl]) thiourea
N-(2-(3-fluorophenyl)ethyl)-Ν' -(210 benzimidazolyl) thiourea
N-(2- (3-fluorophenyl)ethyl)-Ν' -(2-imidazolyl)thiourea N- (2- (2,4 -dimethoxyphenyl) ethyl) -N' - (2thiazolyl)thiourea
N- (2 - (2,4-dimethoxyphenyl)ethyl)-Ν' -[2-(41 5 methyl)thiazolyl]thiourea
N-(2- (2,4-dimethoxyphenyl) ethyl)-N'- (2 - (4,5dimethyl)thiazolyl]thiourea
N- (2 - (2,4-dimethoxyphenyl) ethyl) -N* - [2 - (4cyano) thiazolyl ] thiourea
0 N- (2- (2,4-dimethoxyphenyl) ethyl) -Ν' -(2-(4trifluoromethyl)thiazolyl]thiourea
N- (2 - (2,4 -dimethoxyphenyl) ethyl) -N' - (2 benzothiazolyl) thiourea
N- (2 - (2,4-dimethoxyphenyl) ethyl) -Ν' - [2- (62 5 fluoro)benzothiazolyl]thiourea
N- (2 - (2,4-dimethoxyphenyl) ethyl) -Ν' -[2 - (6chloro)pyrazinyl]thiourea
N- (2 - (2,4 -dimethoxyphenyl) ethyl) -N' - [ 2 - (4 ethyl)thiazolyl]thiourea
0 N- (2 - (2,4 -dimethoxyphenyl) ethyl )-N'-[2-(4-(3pyridy1)thiazolyl)]thiourea
N-(2-(2,4-dimethoxyphenyl)ethyl)-N'- (2- (4- (3nitrophenyl)thiazolyl)]thiourea
N- (2 - (2,4-dimethoxyphenyl)ethyl) -Ν' - (23 5 pyridyl) thiourea
N- (2 - (2,4-dimethoxyphenyl)ethyl) -N'-[2-(6bromo) pyridyl] thiourea
N- (2 - (2,4-dimethoxyphenyl) ethyl) -Ν' - [2 - (5bromo) pyridyl]thiourea
0 N- (2 - (2,4-dimethoxyphenyl) ethyl )-Ν' -(2-(6chloro) pyridyl] thiourea
N-(2 - (2,4-dimethoxyphenyl) ethyl) -Ν' -(2-(5chloro)pyridyl]thiourea
N- (2 - (2,4-dimethoxyphenyl) ethyl) -Ν' - (2 - (64 5 methyl) pyridyl] thiourea
AP Ο Ο Ο 3 8 4
X-857ΙΑ
-51Ν-(2-(2,4-dimethoxyphenyl) ethyl)-Ν' -[2-(5methy1) pyridyl]thiourea
Ν-(2 - (2,4-dimethoxyphenyl) ethyl)-Ν'-[2- (6 tri fluoromethyl) pyridyl] thiourea
N- (2 - (2,4-dimethoxyphenyl) ethyl) -Ν' -[2-(5tri fluoromethyl) pyridyl ] thiourea
N-(2-(2,4-dimethoxyphenyl)ethyl)-Ν' -[2-(6ethyl) pyridyl]thiourea
N- (2-(2,4-dimethoxyphenyl) ethyl) -Ν' - [2- (51 0 ethyl) pyridyl]thiourea
N- (2- (2,4-dimethoxyphenyl) ethyl) -Ν' - [2- (5chloro) pyrazinyl] thiourea
N-(2-(2,4-dimethoxyphenyl)ethyl)—Ν' — [2 — (6 — bromo)pyrazinyl]thiourea
N- (2- (2,4 -dimethoxyphenyl) ethyl )-N'-(2-(5bromo) pyrazinyl] thiourea
N-(2- (2,4-dimethoxyphenyl)ethyl)-Ν' - ((3-(6bromo)pyridazinyl) ] thiourea
N- (2 - (2,4-dimethoxyphenyl) ethyl) -Ν' - [ (3-(62 0 chloro) pyridazinyl) ] thiourea
N- (2 - (2,4 -dimethoxyphenyl) ethyl) -N' - [ 2 - {6 cyano) pyridyl]thiourea
N- (2- (2,4-dimethoxyphenyl) ethyl) -Ν' - [2- (5cyano)pyridyl]thiourea
5 N- (2- (2,4-dimethoxyphenyl) ethyl) -Ν' - (2- (5cyano)pyrazinyl]thiourea
N- (2- (2,4-dimethoxyphenyl)ethyl) -Ν' -(2- (6cyano)pyrazinyl]thiourea
N- (2- (2,4-dimethoxyphenyl) ethyl) -Ν' - [ (3-(63 0 cyano)pyridazinyl) ] thiourea
N- (2- (2,4-dimethoxyphenyl) ethyl) -Ν' - (2- (1,3,4thiadiazoyl]) thiourea
N- (2 - (2,4-dimethoxyphenyl) ethyl) -Ν' - (2benzimidazolyl)thiourea
5 N- (2- (2, 4-dimethoxyphenyl) ethyl) -Ν' - (2imidazolyl)thiourea
N-((4-methyl)-3-pentenyl]-Ν' -(2-thiazolyl) thiourea N- ((4-methyl)-3-pentenyl]-Ν' -(2-(4methyl)thiazolyl]thiourea 40 N- [ (4-methyl) -3-pentenyl] -Ν' - [2- (4,5dimethyl) thiazolyl] thiourea
N-[(4-methyl)-3-pentenyl]-Ν' -(2-(4cyano)thiazolyl]thiourea
X-8571A
-52N- [ (4-methyl)-3-pentenyl]-Ν' - (2benzothiazolyl)thiourea
N-[(4-methyl)-3-pentenyl]-Ν' -(2-(6f luoro)benzothiazolyl] thiourea
N-( (4-methyl)-3-pentenyl]-N'-[2-(6chloro) pyrazinyl] thiourea
N- [ (4-methyl)-3-pentenyl]-Ν' -[2-(4ethyl)thiazolyl]thiourea
N- ((4-methyl)-3-pentenyl]-Ν' -(2-(4-(310 pyridyl) thiazolyl) ] thiourea
N-.((4-methyl) -3-pentenyl] -N’ - [2- {4- (3nitrophenyl) thiazolyl) ] thiourea
N-((4-methyl)-3-pentenyl]-Ν' - (2-pyridyl)thiourea N- [(4-methyl)-3-pentenyl]-Ν' -(2-(61 5 bromo)pyridyl]thiourea
N- [ (4-methyl) -3 -pentenyl] -Ν' - [2 - (5bromo) pyridyl]thiourea
N- [ (4-methyl)-3-pentenyl]-Ν' -(2-(6chloro)pyridyl]thiourea
0 N- ( (4-methyl) -3 -pentenyl] -N'-[2-(5chloro)pyridyl]thiourea
N-[(4-methyl)-3-pentenyl]-Ν' -[2-(6methy1) pyridyl]thiourea
N- [ (4-methyl)-3-pentenyl]-Ν' -(2-(52 5 methyl) pyridyl]thiourea
N-[(4-methyl)-3-pentenyl]-Ν' -(2-(6tr if luorome thyl) pyr idyl] thiourea
N- [ {4-methyl)-3-pentenyl] -N' - [ 2 - (5 trif luoromethyl)pyridyl] thiourea
0 N- ( (4-methyl) -3-pentenyl] -Ν' -[2-(6ethyl)pyridyl]thiourea
N- [ (4-methyl) -3-pentenyl] -Ν' - [2- (5ethyl) pyridyl]thiourea
N- ( (4-methyl) -3-pentenyl] -Ν' -(2- (53 5 chloro)pyrazinyl] thiourea
N- [ (4-methyl)-3-pentenyl]-Ν' -(2-(6bromo)pyrazinyl]thiourea
N-[(4-methyl) -3-pentenyl]-N'-[2-(5bromo)pyrazinyl]thiourea
0 N- [ (4-methyl) -3-pentenyl] -N'-[(3-{6bromo)pyridazinyl)]thiourea
N-((4-methyl)-3-pentenyl]-N' -((3-(6chloro)pyridazinyl)]thiourea
N-[(4-methyl)-3-pentenyl]-Ν' -(2-(6-
AP Ο Ο Ο 3 8 4
Χ-8571Α
-53Ν-[(4-methyl)-3-pentenyl]-Ν' -[2-(5cyano) pyridyl]thiourea
Ν-((4-methyl)-3-pentenyl]-N'-(2-(5cyano)pyrazinyl]thiourea
N-((4-methyl)-3-pentenyl]-Ν' -(2-(6cyano)pyrazinyl]thiourea
N-[(4-methyl)-3-pentenyl]-N*-[(3-(6cyano)pyridazinyl)]thiourea
N-((4-methyl)-3-pentenyl]-N'-(2-[l,3,410 thiadiazoyl] ) thiourea
N-[(4-methyl)-3-pentenyl]-Ν' -(2benzimidazolyl)thiourea
N-[(4-methyl)-3-pentenyl]-Ν' -(2-imidazolyl)thiourea N-(2-cis-phenylcyclopropyl)-Ν' -(2-(415 methyl) thiazolyl] thiourea
N-(2-cis-phenylcyclopropyl)-Ν' -(2-(4,5dimethyl)thiazolyl]thiourea
N-(2-cis-phenylcyclopropyl)-Ν' - (2benzothiazolyl) thiourea
N- (2-cis-phenylcyclopropyl) -Ν' - (2- (6fluoro)benzothiazolyl]thiourea
N-(2-cis-phenylcyclopropyl)-N*-[2-(6chloro)pyrazinyl]thiourea
N-(2-cis-phenylcyclopropyl)-Ν' -(2-(4-(32 5 pyridyl) thiazolyl) ] thiourea
N- (2-cis-phenylcyclopropyl)-N'-[2-(4-(3nitrophenyl)thiazolyl)]thiourea
N-(2-cis-phenylcyclopropyl)-Ν' -(2- (6bromo) pyridyl]thiourea
0 N- (2-cis-phenylcyclopropyl) -Ν' -(2-(6chloro)pyridyl]thiourea
N-(2-cis-phenylcyclopropyl)-Ν' -(2-(6methyl)pyridyl]thiourea
N- (2-cis-phenylcyclopropyl)-Ν' -(2-(63 5 trifluoromethyl)pyridyl]thiourea
N-(2-cis-phenylcyclopropyl)-Ν' -(2-(6ethyl)pyridyl]thiourea
N-(2-cis-phenylcyclopropyl)-Ν' -(2-(6bromo)pyrazinyl]thiourea
0 N- (2-cis-phenylcyclopropyl) -Ν' - [2- (6cyano) pyridyl]thiourea
N-(2-cis-phenylcyclopropyl)-Ν' -[2-(5cyano)pyrazinyl]thiourea
X-8571A
-54N- (2-cis-phenylcyclopropyl)-Ν'-((3-(6cyano)pyridazinyl)]thiourea
N-(2-cis-phenylcyclopropyl) -Ν' - (2- [1,3,4thiadiazoyl]) thiourea
N- (2-cis-phenylcyclopropyl)-Ν' -(2benzimidazolyl)thiourea
N- (2-cis-phenylcyclopropyl)-Ν' - (2-imidazolyl) thiourea N- [ (2-methyl)-2-(2,6-dichlorophenyl)ethyl]-Ν' -(2thiazoly1) thiourea
N- [ (2-methyl) -2- (2,6-dichlorophenyl)ethyl] -Ν' -(2- (4methy1)thiazolyl]thiourea
N-[(2-methyl)-2-(2,6-dichlorophenyl)ethyl]-Ν' -[2- (4,5dimethy1)thiazolyl]thiourea
N-[(2-methyl)-2-(2,6-dichlorophenyl) ethyl]-Ν' -[2 - (415 cyano) thiazolyl] thiourea
N- ((2-methyl)-2-(2,6-dichlorophenyl) ethyl]-Ν' -[2-(4tri fluoromethyl) thiazolyl ] thiourea
N- [ (2-methyl)-2-(2,6-dichlorophenyl)ethyl]-Ν' -(2benzothiazolyl)thiourea
0 N- [(2-methyl)-2-(2,6-dichlorophenyl)ethyl]-Ν' -(2-(6fluoro)benzothiazolyl]thiourea
N-((2-methyl)-2-(2,6-dichlorophenyl)ethyl]-Ν' -[2- (6chloro)pyrazinyl]thiourea
N-[(2-methyl)-2-(2,6-dichlorophenyl)ethyl]-Ν' -[2- (42 5 ethyl) thiazolyl] thiourea
N- [ (2-methyl) -2- (2,6-dichlorophenyl) ethyl] -Ν' -(2-(4(3-pyridyl) thiazolyl) ] thiourea
N- [ (2-methyl) -2- (2,6-dichlorophenyl) ethyl] -Ν' - [2- (4(3 -nitrophenyl) thiazolyl) ] thiourea
0 N-[ (2-methyl) -2- (2,6-dichlorophenyl)ethyl] -Ν' - (2pyridyl) thiourea
N- [ (2-methyl) -2-(2,6-dichlorophenyl)ethyl] -Ν' - [2 - (6bromo) pyridyl]thiourea
N- [ (2-methyl)-2-(2,6-dichlorophenyl)ethyl]-Ν' -(2-(53 5 bromo) pyridyl]thiourea
N- [ (2-methyl) -2-(2,6-dichlorophenyl) ethyl] -Ν' - [2 - (6chloro) pyridyl]thiourea
N-[(2-methyl)-2-(2,6-dichlorophenyl)ethyl]-N’-(2- (5chloro)pyridyl]thiourea
0 N- [ (2-methyl)-2-(2,6-dichlorophenyl)ethyl]-N*-[2 - (6methy1) pyridyl]thiourea
N- [ (2-methyl)-2-(2,6-dichlorophenyl)ethyl]-Ν' -[2-(5methy1) pyridyl]thiourea
N-[(2-methyl)-2-(2,6-dichlorophenyl)ethyl]-N*-(2- (6-
AP Ο Ο Ο 3 8
-554
X-8571A
Ν-((2-methyl)-2-(2,6-dichlorophenyl)ethyl]-Ν' -[2-(5trif luoromethyDpyridyl]thiourea
N-((2-methyl)-2-(2,6-dichlorophenyl) ethyl]-N'-[2- (6ethyl) pyridyl]thiourea
N-((2-methyl)-2-(2,6-dichlorophenyl)ethylJ-Ν' -(2-(5ethyl)pyridyl]thiourea
N-((2-methyl)-2-(2,6-dichlorophenyl)ethyl]-Ν' -(2-(5chloro)pyrazinyl]thiourea
N-((2-methyl)-2-(2,6-dichlorophenyl) ethyl]-Ν' - (2-(610 bromo) pyrazinyl] thiourea
N- [(2-methyl)-2-(2,6-dichlorophenyl) ethyl]-N‘-(2-(5bromo)pyrazinyl]thiourea
N-[(2-methyl)-2-(2,6-dichlorophenyl)ethyl]-Ν' - ((3-(6bromo)pyridazinyl)]thiourea
N-[(2-methyl)-2-(2,6-dichlorophenyl)ethyl]-Ν' - ((3-(6chloro)pyridazinyl)]thiourea
N-((2-methyl)-2-(2,6-dichlorophenyl)ethyl]-N’-(2-(6cyano) pyridyl]thiourea
N-[(2-methyl)-2-(2,6-dichlorophenyl)ethyl]-N*-(2-(52 0 cyano) pyridyl] thiourea
N- ((2-methyl) -2-(2,6-dichlorophenyl) ethyl] -Ν' -(2-(5cyano)pyrazinyl]thiourea
N-[(2-methyl)-2-(2,6-dichlorophenyl)ethyl]-Ν'-(2-(6cyano)pyrazinyl]thiourea
5 N- [(2-methyl)-2-(2,6-dichlorophenyl)ethyl]-Ν’ - ((3-(6cyano)pyridazinyl)]thiourea
N-[(2-methyl)-2-(2,6-dichlorophenyl)ethyl]-Ν' -(2(1,3,4-thiadiazoyl]) thiourea
N-[(2-methyl)-2-(2,6-dichlorophenyl)ethyl] -Ν' -(23 0 benzimidazolyl) thiourea
N-[(2-methyl)-2-(2,6-dichlorophenyl) ethyl]-N'- (2imidazolyl)thiourea
N—((2,2-dimethyl)-2-(2-fluoro-6-chlorophenyl)ethyl]Ν' -(2-thiazolyl)thiourea
N-((2,2-dimethyl)-2-(2-fluoro-6-chlorophenyl)ethyl]Ν' -[2-(4-methyl)thiazolyl)thiourea
N-[(2,2-dimethyl)-2-(2-fluoro-6-chlorophenyl)ethyl]Ν' -[2-(4,5-dimethyl)thiazolyl]thiourea
N-((2,2-dimethyl)-2-(2-fluoro-6-chlorophenyl) ethyl]4 0 Ν' - [2- (4-cyano) thiazolyl] thiourea
N-((2,2-dimethyl)-2-(2-fluoro-6-chlorophenyl)ethyl]Ν' -(2-(4-trifluoromethyl)thiazolyl]thiourea
N-((2,2-dimethyl)-2-(2-fluoro-6-chlorophenyl)ethyl]Ν' -(2-benzothiazolyl)thiourea
N-[(2,2-dimethyl)-2-(2-fluoro-6-chlorophenyl)ethyl]N'- (2- (6 - fluoro)benzothiazolyl]thiourea
Χ-8571Α
-56Ν-[(2,2-dimethy1)-2-(2-fluoro-6-chlorophenyl)ethyl]Ν' -[2-(6-chloro)pyrazinyl]thiourea
N-((2,2-dimethyl)-2-(2-fluoro-6-chlorophenyl)ethyl]Ν' - [2-(4-ethyl)thiazolyl]thiourea
N-[(2,2-dimethyl)-2-(2-fluoro-6-chlorophenyl)ethyl]Ν' - (2-(4-(3-pyridyl)thiazolyl)]thiourea
N-[(2,2-dimethyl)-2-(2-fluoro-6-chlorophenyl, ethyl]Ν'—[2-(4-(3-nitrophenyl)thiazolyl)]thiourea
N-((2,2-dimethyl)-2-(2-fluoro-6-chlorophenyl)ethyl]10 Ν' - (2-pyridyl) thiourea
N-[(2,2-dimethyl,-2-(2-fluoro-6-chlorophenyl)ethyl]Ν' -(2-(6-bromo)pyridyl]thiourea
N-[(2,2-dimethyl)-2-(2-fluoro-6-chlorophenyl,ethyl]Ν' -[2-(5-bromo)pyridyl]thiourea
N- ( (2,2-dimethyl) -2- (2-f luoro-6-chlorophenyl) ethyl] Ν' - [2-(6-chloro)pyridyl]thiourea
N-[(2,2-dimethyl)-2-(2-fluoro-6-chlorophenyl)ethyl]Ν' -(2-(5-chloro)pyridyl]thiourea
N-[(2,2-dimethyl,-2-(2-fluoro-6-chlorophenyl)ethyl]2 0 Ν' - [2 - (6-methyl)pyridyl] thiourea
N-((2,2-dimethyl)-2-(2-fluoro-6-chlorophenyl)ethyl]Ν' -[2-(5-methyl)pyridyl]thiourea
N-[(2,2-dimethyl)-2-(2-fluoro-6-chlorophenyl)ethyl]N'-[2-(6-trifluoromethyl) pyridyl]thiourea
N-[(2,2-dimethyl)-2-(2-fluoro-6-chlorophenyl)ethyl]Ν' -[2-(5-trifluoromethyl)pyridyl]thiourea
N-((2,2-dimethyl)-2-(2-fluoro-6-chlorophenyl)ethyl]Ν' -[2-(6-ethyl)pyridyl]thiourea
N-[(2,2-dimethyl)-2-(2-fluoro-6-chlorophenyl)ethyl]3 0 N'-[2 -(5-ethyl, pyridyl]thiourea
N-[(2,2-dimethyl)-2-(2-fluoro-6-chlorophenyl)ethyl]Ν' -[2-(5-chloro)pyrazinyl]thiourea
N-[(2,2-dimethyl)-2-(2-fluoro-6-chlorophenyl)ethyl]Ν' -[2-(6-bromo)pyrazinyl]thiourea
5 N- [ (2,2-dimethyl)-2- (2-fluoro-6-chlorophenyl)ethyl] Ν' -(2-(5-bromo)pyrazinyl]thiourea
N-[(2,2-dimethyl)-2-(2-fluoro-6-chlorophenyl)ethyl]Ν' - ((3-(6-bromo)pyridazinyl)]thiourea
N-((2,2-dimethyl)-2-(2-fluoro-6-chlorophenyl)ethyl]4 0 Ν' - [ (3--(6-chloro) pyridazinyl) ] thiourea
N- [ (2,2-dimethyl) -2- (2-f luoro-6-chlorophenyl) ethyl] Ν' -(2-(6-cyano)pyridyl]thiourea
N- [(2,2-dimethyl)-2-(2-fluoro-6-chlorophenyl)ethyl] Ν' -[2-(5-cyano)pyridyl]thiourea
N-((2,2-dimethyl)-2-(2-fluoro-6-chlorophenyl)ethyl]-
AP Ο Ο Ο 3 8 4
Χ-8571Α
-57Ν-[(2,2-dimethyl)-2-(2-fluoro-6-chlorophenyl)ethyl]Ν*-(2-(6-cyano)pyrazinyl)thiourea
N-[(2,2-dimethyl)-2-(2-fluoro-6-chlorophenyl) ethyl]N' - [(3-(6-cyano)pyridazinyl)]thiourea
N-[(2,2-dimethyl)-2-(2-fluoro-6-chlorophenyl)ethyl]Ν' -(2-[1,3,4-thiadiazoyl]) thiourea
N- [(2,2-dimethyl )-2-(2-fluoro-6-chlorophenyl) ethyl]N‘ -(2-benzimidazolyl)thiourea
N-[(2,2-dimethyl)-2-(2-fluoro-6-chlorophenyl)ethyl]10 Ν'- (2-imidazolyl) thiourea
N- [2-(2-pyridyl)ethyl]-Ν'-(2-(4,5dimethyl)thiazolyl]thiourea
N- [2- (2-pyridyl) ethyl]-N’- (2-benzothiazoly1) thiourea N-[2-(2-pyridyl)ethyl]-Ν' -[2-(61 5 fluoro)benzothiazoly1]thiourea
N- [2-(2-pyridyl)ethyl]—N’ — [2 — (6 — chloro)pyrazinyl]thiourea
N-(2-(2-pyridyl)ethyl]-N*-(2-(4-(3pyridy1)thiazolyl)]thiourea
0 N- [ 2 - (2 -pyridyl) ethyl ]-Ν'-(2-(4-(3nitrophenyl)thiazolyl)]thiourea
N-[2-(2-pyridyl)ethyl]-Ν' -[2-(6bromo)pyrazinyl]thiourea
N-(2-(2-pyridyl)ethyl]-Ν' -[2-(6-cyano)pyridyl]thiourea
5 N- [2-(2-pyridyl)ethyl]-Ν' -[2-(6cyano)pyrazinyl]thiourea
N- [2-(2-pyridyl)ethyl]-Ν' - (2-(1,3,4thiadiazoyl]) thiourea
N-[2-(2-pyridyl)ethyl]-Ν' -(2-benzimidazolyl)thiourea
0 N- [2- (2-pyridyl) ethyl]-N'- (2-imidazolyl) thiourea
N- [2-(2-(6-methoxy)pyridyl)ethyl]-Ν' -(2-(4,5dimethyl)thiazolyl]thiourea
N- [2-(2-(6-methoxy)pyridyl)ethyl]-Ν' -(2benzothiazolyl)thiourea
N-[2-(2-(6 -methoxy) pyridyl) ethyl ] -N' - [ 2 - (6 fluoro)benzothiazolyl]thiourea
N-[2-(2-(6-methoxy)pyridyl)ethyl]-N’-[2- (6chloro)pyrazinyl]thiourea
N- [2-(2-(6-methoxy)pyridyl)ethyl]-N'-[2- (4- (34 0 pyridyl)thiazolyl)]thiourea
N- [2-(2-(6-methoxy)pyridyl)ethyl]-N'-[2 - (4 - (3 nitrophenyl)thiazolyl)]thiourea
N- [2-(2-(6-methoxy)pyridyl)ethyl]-Ν' -[2-(6bromo)pyridyl]thiourea
N-[2-(2-(6-methoxy)pyridyl)ethyl]-Ν' -[2-(6-
X-8571A
-58N-(2-(2-(6-methoxy)pyridyl)ethyl]-Ν' -(2-(6methy1) pyridyl]thiourea
N- [2-(2-(6-methoxy)pyridyl)ethyl]-Ν' -(2-(6trifluoromethyl) pyridyl]thiourea
N- [2-(2-(6-methoxy)pyridyl)ethyl]-Ν'-[2-(6ethy1) pyridyl]thiourea
N- [2-(2-(6-methoxy)pyridyl)ethyl]-Ν' -[2-(5ethy1) pyridyl]thiourea
N- [2- (2-(6-methoxy)pyridyl)ethyl]-Ν' -[2-(610 bromo) pyrazinyl] thiourea
N- (2-(2-(6-methoxy)pyridyl) ethyl)-Ν' - ((3-(6bromo)pyridazinyl)) thiourea
N- [2- (2-(6-methoxy)pyridyl)ethyl]-Ν' -(2-(6cyano) pyridyl]thiourea
N- (2 - (2 - (6-methoxy)pyridyl) ethyl] -Ν' -(2-(5cyano)pyridyl]thiourea
N- (2-(2-(6-methoxy)pyridyl)ethyl]-Ν' -(2-(5cyano)pyrazinyl]thiourea
N- [2 - (2-(6-methoxy)pyridyl)ethyl]-Ν' -(2-(62 0 cyano)pyrazinyl] thiourea
N- (2 - (2- (6-methoxy) pyridyl) ethyl]-N'-((3-(6cyano)pyridazinyl)]thiourea
N- [2-(2-(6-methoxy)pyridyl)ethyl]-N'-(2-(l,3,4thiadiazoyl]) thiourea
5 N- (2- (2-(6-methoxy)pyridyl)ethyl]-Ν' - (2benzimidazolyl) thiourea
N- (2-(2-(6-methoxy)pyridyl)ethyl]-Ν' -(2imidazolyl) thiourea
N- [2-(2-(6-ethoxy)pyridyl)ethyl]-Ν' -(2-(4,53 0 dimethyl)thiazolyl]thiourea
N- [2-(2-(6-ethoxy)pyridyl)ethyl]-Ν' -(2benzothiazolyl)thiourea
N-[2-(2-(6-ethoxy)pyridyl)ethyl]-Ν' -[2-(δί luoro) benzothiazolyl] thiourea
5 N- (2-(2-(6-ethoxy)pyridyl)ethyl]-Ν' -[2-(6chloro)pyrazinyl]thiourea
N- [2-(2-(6-ethoxy)pyridyl)ethyl]-Ν'-(2-(4-(3pyridyl)thiazolyl)]thiourea
N- (2-(2-(6-ethoxy)pyridyl)ethyl]-N'-[2-(4-(34 0 nitrophenyl)thiazolyl)]thiourea
N- [2 - (2-(6-ethoxy)pyridyl)ethyl]-Ν' -(2-(6bromo) pyridyl]thiourea
N- [2-(2-(6-ethoxy)pyridyl)ethyl]-Ν' -(2-(6chloro) pyridyl]thiourea
5 N- [2 - (2 - (6-ethoxy)pyridyl) ethyl] -Ν' - [2 - (6methy1) pyridyl]thiourea
AP Ο Ο Ο 3 8 4
Χ-8571Α
-59Ν-[2-(2-(6-ethoxy)pyridyl)ethyl]-N’-[2-(6trifluoromethyl) pyridyl]thiourea
N-[2-(2-(6-ethoxy)pyridyl)ethyl]-N’-[2-(6ethyl) pyridyl]thiourea
N-[2-(2-(6-ethoxy)pyridyl)ethyl]-Ν' -(2-(5ethyl) pyridyl]thiourea
N-[2-(2-(6-ethoxy)pyridyl)ethyl]-Ν' -(2-(6bromo)pyrazinyl]thiourea
N-(2- (2- (6-ethoxy)pyridyl)ethyl]-N'-[(3-(610 bromo)pyridazinyl) ] thiourea
N-[2-(2- (6-ethoxy)pyridyl)ethyl]-Ν' -[2-(6cyano)pyridyl]thiourea
N-[2-(2- (6-ethoxy)pyridyl)ethyl]-Ν'-[2-(5cyano)pyraz iny1]thiourea
N- [2 - (2- (6-ethoxy)pyridyl) ethyl] -N'-[2-(6cyano)pyrazinyl]thiourea
N- [2- (2- (6-ethoxy)pyridyl)ethyl]-N'-[(3-(6cyano)pyridazinyl)]thiourea
N-[2 - (2-(6-ethoxy)pyridyl)ethyl]-N'-(2-[l,3,42 0 thiadiazoyl]) thiourea
N-[2-(2-(6-ethoxy)pyridyl)ethyl]-Ν' -(2benzimidazolyl)thiourea
N-[2-(2-(6-ethoxy)pyridyl)ethyl]-N*-(2imidazolyl)thiourea
5 N- [2- (2 - (6-f luoro)pyridyl) ethyl] -Ν' -[2-(4,5dimethyl)thiazolyl]thiourea
N-[2-(2-(6-fluoro)pyridyl)ethyl]-Ν' -(2benzothiazolyl)thiourea
N-[2-(2-(6-fluoro)pyridyl)ethyl]-Ν' -[2-(63 0 fluoro)benzothiazolyl]thiourea
N-[2-(2-(6-fluoro)pyridyl)ethyl]-Ν' -[2-(6chloro)pyrazinyl]thiourea
N-[2-(2-(6-fluoro)pyridyl)ethyl]-Ν'-(2-(4-(3pyridyl)thiazolyl)]thiourea
5 N- [2- (2 - (6-fluoro)pyridyl) ethyl] -Ν' -(2-(4-(3nitrophenyl)thiazolyl)]thiourea
N-(2-(2-(6-fluoro)pyridyl)ethyl]-Ν' -[2-(6bromo) pyridyl]thiourea
N-[2- (2- (6-fluoro)pyridyl)ethyl]-Ν' -[2-(64 0 chloro)pyridyl] thiourea
N- [2 - (2-(6-fluoro)pyridyl) ethyl]-Ν' -[2-(6methy1)pyridyl]thiourea
N-[2-(2 - (6-fluoro)pyridyl)ethyl]-Ν' -[2-(6tri fluoromethyl) pyridyl]thiourea
5 N- [2 - (2 - (6-fluoro)pyridyl) ethyl] -Ν' - [2 - (6bromo)pyrazinyl]thiourea
X-8571A
-60N-(2-(2 - (6-fluoro)pyridyl)ethyl]-Ν' - [(3-(6bromo)pyridazinyl)]thiourea
N-(2 - (2- (6-fluoro)pyridyl)ethyl]-Ν' -(2-(6cyano) pyridyl]thiourea
N-(2-(2-(6-fluoro)pyridyl)ethyl]-Ν' -(2-(5cyano)pyrazinyl]thiourea
N-[2-(2-(6-fluoro)pyridyl)ethyl]-Ν' -[2-(6cyano)pyrazinyl]thiourea
N-[2-(2-(6-fluoro)pyridyl)ethyl]-N‘-[(3-(610 cyano) pyridazinyl) ] thiourea
N-[2-(2-(6-fluoro)pyridyl)ethyl]-N‘-(2-(1,3,4thiadiazoyl]) thiourea
N-(2-(2 - (6-fluoro)pyridyl)ethyl]-N‘-(2benzimidazolyl)thiourea
N- [2-(2- (6-fluoro)pyridyl)ethyl]-N‘ -(2imidazolyl)thiourea
N-(2-(2-(5-fluoro)pyridyl)ethyl]-N‘-(2thiazolyl)thiourea
N-[2-(2-(5-fluoro)pyridyl)ethyl]-Ν' -[2-(42 0 methyl) thiazolyl] thiourea
N-[2-(2-(5-fluoro)pyridyl)ethyl]-N*-(2-(4,5dimethyl)thiazolyl]thiourea
N-[2-(2-(5-fluoro)pyridyl)ethyl]-N'-(2-(4cyano)thiazolyl]thiourea
5 N-.(2- (2- (5-fluoro)pyridyl) ethyl] -N'-[2-(4trifluoromethyl)thiazolyl]thiourea
N- [2-(2-(5-fluoro)pyridyl)ethyl]-Ν' -(2benzothiazolyl)thiourea
N-(2-(2-(5-fluoro)pyridyl)ethyl]-Ν' -(2-(63 0 fluoro)benzothiazolyl]thiourea
N-(2-(2-(5-fluoro)pyridyl)ethyl]-N‘-(2-(6chloro)pyrazinyl]thiourea
N-[2-(2-(5-fluoro)pyridyl)ethyl]-N*-[2-(4ethyl)thiazolyl]thiourea
5 N- [2 - (2- (5-f luoro) pyridyl) ethyl] -Ν'-(2-(4-(3pyridy1)thiazolyl)]thiourea
N-[2-(2-(5-fluoro)pyridyl)ethyl]-Ν'-(2-(4-(3nitrophenyl)thiazolyl,]thiourea
N-[2-(2-(5-fluoro)pyridyl)ethyl]-Ν' -(240 pyridyl)thiourea
N-(2-(2-(5-fluoro)pyridyl)ethyl]-Ν'-(2-(6bromo) pyridyl]thiourea
N-[2-(2-(5-fluoro)pyridyl)ethyl]-N‘-[2-(5bromo) pyridyl]thiourea
AP Ο Ο Ο 3 8 4
Χ-8571Α
-61Ν- (2 - (2-(5-fluoro)pyridyl)ethyl]-Ν' -(2-(5chloro) pyridyl]thiourea
N-[2-(2-(5-fluoro)pyridyl)ethyl]-Ν' -[2-(6methyl)pyridyl]thiourea
N- (2 - (2- (5-fluoro)pyridyl)ethyl]-N'-[2-(5methyl)pyridyl]thiourea
N- (2 - (2-(5-fluoro)pyridyl)ethyl]-N*-(2-(6tri fluoromethyl) pyridyl]thiourea
N- (2 - (2-(5-fluoro)pyridyl)ethyl]-Ν’—(2-(51 0 tri fluoromethy1) pyridyl]thiourea
N- (2 - (2-(5-fluoro)pyridyl)ethyl]-Ν' -(2-(6ethyl)pyridyl]thiourea
N- (2 - (2 - (5-fluoro)pyridyl)ethyl]-Ν' -[2-(5ethyl) pyridyl]thiourea
N- [2 - (2 - (5-fluoro)pyridyl)ethyl]-N'-[2-(5chloro)pyrazinyl]thiourea
N- (2 - (2-(5-fluoro)pyridyl)ethyl]-N'-[2-(6bromo)pyrazinyl]thiourea
N- [2-(2-(5-fluoro)pyridyl) ethyl]-Ν' -[2-(52 0 bromo) pyrazinyl] thiourea
N- [2-(2 - (5-fluoro)pyridyl)ethyl]-Ν’-[(3-(6bromo)pyridazinyl)]thiourea
N- [2 - (2 - (5-fluoro)pyridyl)ethyl]-N*- ((3-(6chloro)pyridazinyl)]thiourea
5 N- [2 - (2 - (5-f luoro) pyridyl) ethyl] -N'-(2-(6cyano)pyridyl]thiourea
N- [2 - (2 - (5-fluoro)pyridyl)ethyl]-N'-[2-(5cyano)pyridyl]thiourea
N- [2 - (2-(5-fluoro)pyridyl)ethyl]-Ν' -[2-(53 0 cyano) pyrazinyl] thiourea
N-(2-(2-(5-fluoro)pyridyl)ethyl]-N·-(2-(6cyano)pyraz iny1]thiourea
N-[2- (2 - (5-fluoro)pyridyl)ethyl]-Ν' -[(3-(6cyano)pyridazinyl)) thiourea
5 N- (2- (2- (5-fluoro)pyridyl) ethyl] -Ν' - (2- (1,3,4thiadiazoyl]) thiourea
N-[2-(2-(5-fluoro)pyridyl)ethyl]-N’-(2benzinidazolyl)thiourea
N- (2-(2-(5-fluoro)pyridyl)ethyl]-Ν' -(240 imidazolyl)thiourea
N- (2-(2-(4-fluoro)pyridyl)ethyl]-Ν' -(2thiazolyl) thiourea
N-[2-(2-(4-fluoro)pyridyl)ethyl]-N*-(2-(4-
X-8571A
-62N- [2-(2-(4-fluoro)pyridyl) ethyl]-N'-(2-(4cyano)thiazolyl]thiourea
N-[2-(2-(4-fluoro)pyridyl)ethyl]-Ν' -(2-(4trifluoromethyl)thiazolyl]thiourea
N-(2-(2-(4-fluoro)pyridyl)ethyl]-Ν' -(2benzothiazolyl) thiourea
N- [2-(2-(4-fluoro)pyridyl) ethyl]-Ν' -(2-(6fluoro)benzothiazolyl]thiourea
N-(2-(2-(4-fluoro)pyridyl)ethyl]-Ν' -(2-(610 chloro)pyrazinyl] thiourea
N-(2-(2-(4-fluoro)pyridyl)ethyl]-Ν' -[2-(4ethy1)thiazolyl]thiourea
N-(2-(2-(4-fluoro)pyridyl)ethyl]-N'-(2-(4-(3pyridyl)thiazolyl)]thiourea
N- [2- (2 - (4-fluoro) pyr idyl) ethyl] -N'-(2-(4-(3nitrophenyl)thiazolyl)]thiourea
N-(2-(2-(4-fluoro)pyridyl)ethyl]-Ν' -(2pyridyl) thiourea
N- [2- (2-(4-fluoro)pyridyl)ethyl]-Ν' -[2-(62 0 bromo)pyridyl] thiourea
N- (2 - (2-(4-fluoro)pyridyl)ethyl]-N'-(2-(5bromo) pyridyl] thiourea
N- (2-(2-(4-fluoro)pyridyl)ethyl]-N'- (2-{6chloro)pyridyl]thiourea
5 N- [2-(2-(4-fluoro)pyridyl)ethyl]-Ν' -(2-(5chloro) pyridyl]thiourea
N- (2-(2-(4-fluoro)pyridyl)ethyl]-Ν' -(2-(6methy1) pyridyl]thiourea
N-(2-(2-(4-fluoro)pyridyl)ethyl]-Ν' -[2-(53 0 methyl)pyridyl] thiourea
N- (2-(2-(4-fluoro)pyridyl)ethyl]-Ν' -[2-(6trifluoromethyl) pyridyl]thiourea
N- [2-(2-(4-fluoro)pyridyl)ethyl]-Ν' -[2-(5tri fluoromethyl) pyridyl]thiourea
5 N- (2 - (2 - (4-f luoro)pyridyl) ethyl] -Ν' - [2 - (6ethyl) pyridyl]thiourea
N- (2-(2-(4-fluoro)pyridyl)ethyl]-Ν' -[2-(5ethyl) pyridyl]thiourea
N- [2-(2-(4-fluoro)pyridyl)ethyl]-Ν' -(2-(54 0 chloro) pyrazinyl] thiourea
N-.(2- (2 - (4-f luoro)pyridyl) ethyl] -Ν' - (2- (6bromo)pyrazinyl]thiourea
N-[2-(2-(4-fluoro)pyridyl)ethyl]—Ν'—(2—(5— bromo)pyrazinyl]thiourea
5 N- [2- (2 - (4-f luoro)pyridyl) ethyl] -Ν' - ( (3-(6-
AP Ο Ο Ο 3 8 4
-63X-8571A
Ν-[2-(2-(4-fluoro)pyridyl)ethyl]-Ν’ - ((3-(6chloro)pyridazinyl)]thiourea
N-(2-(2-(4-fluoro)pyridyl)ethyl]-N'-[2-(6cyano)pyridyl]thiourea
N-(2-(2-(4-fluoro)pyridyl)ethyl]-N'-[2-(5cyano)pyridyl]thiourea
N- (2-(2-(4-fluoro)pyridyl)ethyl]-Ν' -(2-(5cyano)pyrazinyl]thiourea
N-(2-(2-(4-fluoro)pyridyl) ethyl]-Ν' -(2-(610 cyano) pyrazinyl] thiourea
N- [2-(2-(4-fluoro)pyridyl) ethyl]-Ν' - [(3-(6cyano)pyridazinyl)]thiourea
N-[2-(2-(4-fluoro)pyridyl) ethyl]-Ν'-(2-(1,3,4thiadiazoyl]) thiourea
N- (2 - (2- (4-f luoro) pyridyl) ethyl] -Ν' -(2benzimidazolyl) thiourea
N-[2-(2-(4-fluoro)pyridyl)ethyl]-Ν' -(2imidazolyl)thiourea
N- (2 - (2-(3-fluoro)pyridyl)ethyl]-Ν' -(22 0 thiazolyl) thiourea
N-(2-(2-(3-fluoro)pyridyl)ethyl]-Ν' -[2-(4methyl)thiazolyl]thiourea
N- [2 - (2-(3-fluoro)pyridyl)ethyl]-Ν' -[2-(4,5dimethyl)thiazolyl]thiourea
5 N-[2-(2- (3-f luoro)pyridyl) ethyl] -Ν' - (2benzothiazolyl)thiourea
N-(2-(2-(3-fluoro)pyridyl)ethyl]-N'-[2-(6fluoro)benzothiazolyl]thiourea
N-(2-(2-(3-fluoro)pyridyl)ethyl]-Ν' -[2-(63 0 chloro) pyrazinyl] thiourea
N-[2-(2-(3-fluoro)pyridyl)ethyl]-N'-(2-(4-(3pyridyl)thiazolyl)]thiourea
N-[2-(2-(3-fluoro)pyridyl)ethyl]-N'-[2- (4- (3nitrophenyl)thiazolyl)]thiourea
5 N- (2 - (2 - (3-f luoro )pyr idyl) ethyl] -Ν' - (2pyridyl) thiourea
N-[2-(2-(3-fluoro)pyridyl)ethyl]-N'-(2-(6bromo)pyridyl]thiourea
N-(2-(2-(3-fluoro)pyridyl)ethyl]-Ν' -[2-(64 0 chloro)pyridyl] thiourea
N-(2-(2-(3-fluoro)pyridyl)ethyl]-Ν' -(2-(6methy1)pyridyl]thiourea
N-(2-(2-(3-fluoro)pyridyl)ethyl]-Ν' -(2-(5methyl) pyridyl]thiourea
5 N- [2 - (2 - (3-fluoro)pyridyl) ethyl] -Ν' -(2 - (6trifluoromethyl) pyridyl]thiourea
X-8571A
-64N-[2-(2-(3-fluoro)pyridyl)ethyl]-N’-[2-(5trifluoromethyl) pyridyl]thiourea
N-[2 - (2-(3-fluoro)pyridyl)ethyl]-N’-[2-(6ethyl) pyridyl]thiourea
N-[2 - (2 - (3-fluoro)pyridyl)ethyl]-Ν' -[2-(5ethyl)pyridyl)thiourea
N-[2-(2-(3-fluoro)pyridyl) ethyl]-Ν’ -[2-(6bromo)pyrazinyl]thiourea
N- [2- (2-(3-fluoro)pyridyl)ethyl]-Ν' -[(3-(610 bromo)pyridazinyl) ] thiourea
N-(2- (2- (3-fluoro)pyridyl)ethyl]-Ν' -(2-(6cyano) pyridyl]thiourea
N-[2-(2-(3-fluoro)pyridyl)ethyl]-Ν' -[2-(5cyano) pyridyl]thiourea
N-[2 - (2- (3-fluoro)pyridyl)ethyl]-Ν' -(2-(5cyano)pyrazinyl]thiourea
N-[2 - (2 - (3-fluoro)pyridyl)ethyl]-Ν' -(2-(6cyano) pyrazinyl ] thiourea
N-[2 - (2- (3-fluoro)pyridyl)ethyl]-N’-[(3-(62 0 cyano) pyridazinyl) ] thiourea
N-[2 - (2- (3-fluoro)pyridyl)ethyl]-Ν' -(2-(1,3,4thiadiazoyl]) thiourea
N-[2 - (2- (3-fluoro)pyridyl)ethyl]-Ν' -(2benzimidazolyl, thiourea
5 N- [2 - (2 - (3-f luoro)pyridyl) ethyl] -N’-(2imidazoly1) thiourea
N-[2 - (2-(6-chloro)pyridyl)ethyl]-Ν' - (2thiazoly1) thiourea
N-[2 - (2 - (6-chloro(pyridyl)ethyl]-Ν' -[2-(43 0 methyl) thiazolyl] thiourea
N-[2 - (2 - (6-chloro) pyridyl) ethyl]-N'- (2 - (4,5dimethyl)thiazolyl]thiourea
N-[2- (2- (6-chloro)pyridyl) ethyl]-Ν' -(2benzothiazolyl)thiourea
5 N- [2 - (2 - (6-chloro)pyridyl) ethyl] -Ν' -(2 - (6fluoro)benzothiazolyl]thiourea
N-[2-(2-(6-chloro)pyridyl)ethyl]-Ν' -(2-{6chloro)pyrazinyl]thiourea
N-[2 - (2 - (6-chloro)pyridyl) ethyl]-N'-[2-(4-(34 0 pyridyl) thiazolyl) ] thiourea
N-(2-(2-(6-chloro)pyridyl)ethyl]-N'-[2-(4-(3nitrophenyl)thiazolyl)]thiourea
N-(2 - (2- (6-chloro)pyridyl) ethyl]-Ν' -(2pyridyl) thiourea
5 N- [2 - (2- (6-chloro)pyridyl) ethyl] -Ν' - (2 - (6bromo) pyridyl]thiourea
AP Ο Ο Ο 3 8 4
:.-857ΐΑ
-65Ν-[2-(2-(6-chloro)pyridyl)ethyl]-Ν' -[2-(6chloro) pyridyl]thiourea
N-(2 - (2-(6-chloro) pyridyl)ethyl]-Ν' -[2-(6methyl) pyridyl]thiourea
N-[2-(2-(6-chloro)pyridyl)ethyl]-Ν' -(2-(5methyl) pyridyl]thiourea
N-[2-(2-(6-chloro)pyridyl)ethyl]-Ν' -[2-tetri fluoromethyl) pyridy 1 ] thiourea
N-[2-(2-(6-chloro)pyridyl)ethyl]-Ν' -[2-(51 0 trifluoromethyl)pyridyl)thiourea
N-[2 - (2-(6-chloro)pyridyl)ethyl]-Ν' -(2-(6ethyl) pyridyl]thiourea
N-[2-(2-(6-chloro)pyridyl)ethyl]-Ν' -(2-(5ethy1) pyridyl]thiourea
N-[2-(2-(6-chloro)pyridyl) ethyl]-Ν' -[2-(6bromo)pyrazinyl)thiourea
N-[2 - (2-(6-chloro)pyridyl)ethyl]-Ν' - ((3-(6bromo)pyridazinyl)]thiourea
N-[2-(2-(6-chloro)pyridyl)ethyl]-Ν' -(2-(62 0 cyano) pyridyl] thiourea
N-[2-(2-(6-chloro)pyridyl)ethyl]-Ν' -[2-(5cyano)pyridyl]thiourea
N-(2-(2-(6-chloro)pyridyl)ethyl]-Ν' -[2-(5cyano)pyrazinyl]thiourea
N- (2- (2-(6-chloro)pyridyl) ethyl] -Ν' - (2- (6cyano)pyrazinyl]thiourea
N-[2-(2-(6-chloro)pyridyl)ethyl]-Ν' -[(3-(6cyano)pyridazinyl)]thiourea
N-[2-(2-(6-chloro)pyridyl)ethyl]-N'-(2-[l,3,43 0 thiadiazoyl]) thiourea
N-[2-(2-(6-chloro)pyridyl)ethyl]-N* -(2benzimidazolyl) thiourea
N-(2-(2-(6-chloro)pyridyl)ethyl]-Ν' -(2imidazolyl)thiourea
N-[2- (2-(5-chloro) pyridyl) ethyl] -Ν'-(2thiazolyl) thiourea
N-[2-(2-(5-chloro)pyridyl)ethyl]-Ν' -[2-(4methyl)thiazolyl]thiourea
N- (2 - (2-(5-chloro)pyridyl)ethyl]-Ν' -[2-(4,54 0 dimethyl) thiazolyl] thiourea
N-'[2- (2- (5-chloro)pyridyl) ethyl] -Ν' - [2- (4cyano)thiazolyl]thiourea
N-(2-(2-(5-chloro)pyridyl)ethyl)-N’-[2-(4trifluoromethyl)thiazolyl]thiourea
X-8571A
-66:(
Ν- [2 - (2-(5-chloro)pyridyl)ethyl]-Ν' -[2-(6fluoro)benzothiazolyl]thiourea
N- [2 - (2-(5-chloro)pyridyl)ethyl]-Ν' -[2-(6chloro)pyrazinyl]thiourea
N-’(2- (2 - (5-chloro)pyridyl) ethyl] -Ν' -[2-(4ethyl)thiazolyl]thiourea
N- (2- (2-(5-chloro)pyridyl)ethyl]-Ν'- (2-(4-(3pyridyl)thiazolyl)]thiourea
N- (2- (2- (5-chloro) pyridyl) ethyl ]-Ν'-(2-(4-(31 0 nitrophenyl)thiazolyl)]thiourea
N- (2-(2-(5-chloro)pyridyl)ethyl]-N'-(2pyridyl) thiourea
N- [2- (2-(5-chloro)pyridyl)ethyl]-Ν' -[2-(6bromo) pyridyl]thiourea
N- [2 - (2 - (5-chloro)pyridyl) ethyl] -Ν' -(2-(5bromo)pyridyl]thiourea
N-(2 - (2-(5-chloro)pyridyl)ethyl]-Ν' -(2-(6chloro) pyridyl]thiourea
N- [2 - (2- (5-chloro)pyridyl) ethyl] -Ν' -[2-(52 0 chloro) pyridyl]thiourea
N- (2-(2-(5-chloro)pyridyl)ethyl]-Ν' - [2-(6methy1) pyridyl]thiourea
N- (2- (2- (5-chloro)pyridyl) ethyl] -N* - (2- (5methyl) pyridyl]thiourea
5 N- [2 - (2 - (5-chloro)pyridyl) ethyl] -Ν' - [2 - (6tri fluoromethyl) pyridyl]thiourea
N-[2- (2- (5-chloro)pyridyl)ethyl]-Ν' -(2-(5tri fluoromethyl) pyridyl]thiourea
N- [2- (2 - (5-chloro)pyridyl) ethyl] -Ν' - (2 - (63 0 ethyl) pyridyl] thiourea
N- (2- (2- (5-chloro)pyridyl) ethyl]-Ν' -(2-(5ethyl) pyridyl]thiourea
N- [2-(2-(5-chloro)pyridyl)ethyl]-Ν' - (2-(5chloro)pyrazinyl]thiourea
N- (2-(2-(5-chloro)pyridyl)ethyl]-N’-(2-(6bromo)pyrazinyl]thiourea
N- [2-(2-(5-chloro)pyridyl)ethyl]-Ν' - (2-(5bromo)pyrazinyl]thiourea
N- [2-(2-(5-chloro)pyridyl)ethyl]-Ν' -[(3-(60 bromo)pyridazinyl)]thiourea
N- (2 - (2-(5-chloro)pyridyl)ethyl]-Ν' - [ (3-(6chloro)pyridazinyl)]thiourea
N- [2-(2-(5-chloro)pyridyl)ethyl]-Ν' -[2 - (6cyano) pyridyl]thiourea
N-[2-(2-(5-chloro)pyridyl)ethyl]-N* -(2-(5cyano) pyridyl]thiourea
AP Ο Ο Ο 3 8 4
Χ-8571Α
-67Ν-[2-(2-(5-chloro)pyridyl) ethyl]-Ν' -[2-(5cyanoJpyrazinyl]thiourea
N-(2-(2- (5-chloro)pyridyl)ethyl]-Ν' -[2-(6cyano)pyrazinyl]thiourea
N- [2 - (2- (5-chloro)pyridyl) ethyl]-N'-((3-(6cyano)pyridazinyl)]thiourea
N- (2 - (2- (5-chloro)pyridyl)ethyl]-N'-(2-(1,3,4thiadiazoyl]) thiourea
N- (2 - (2- (5-chloro)pyridyl) ethyl]-Ν' -(210 benzimidazolyl)thiourea
N-[2-(2-(5-chloro)pyridyl)ethyl]-Ν' -(2imidazoly1) thiourea
N-(2-(2-(4-chloro)pyridyl) ethyl]-Ν' - (2thiazoly1) thiourea
N- (2 - (2 - (4-chloro) pyr idyl) ethyl] -Ν' - (2- (4methy1)thiazolyl]thiourea
N- (2-(2-(4-chloro)pyridyl)ethyl]-Ν' -[2-(4,5dimethy1)thiazolyl]thiourea
N-[2 - (2-(4-chloro)pyridyl)ethyl]-Ν' -[2- (42 0 cyano) thiazolyl] thiourea
N-(2 - (2 - (4-chloro)pyridyl)ethyl]-Ν' -12 - (4tri fluoromethy1)thiazolyl]thiourea
- N-[2-(2-(4-chloro)pyridyl)ethyl)-Ν' - (2benzothiazolyl)thiourea
5 N- (2 - (2 - (4-chloro)pyridyl) ethyl) -Ν' -[2-(6f luoro)benzothiazolyl] thiourea
N-(2-(2-(4-chloro) pyridyl)ethyl]-Ν' -(2-(6chloro)pyrazinyl]thiourea
N- (2 - (2 - (4-chloro)pyridyl)ethyl]-Ν' -(2-(43 0 ethyl) thiazolyl] thiourea
N-[2-(2-(4-chloro)pyridyl)ethyl]-N*-(2-(4-(3pyridyl) thiazolyl) ] thiourea
N- (2- (2 - (4-chloro)pyridyl)ethyl]-Ν'-(2-(4-(3nitrophenyl) thiazolyl) ] thiourea
5 N- [2- (2-(4-chloro)pyridyl)ethyl]-N*- (2pyridyl) thiourea
N-(2 - (2-(4-chloro)pyridyl)ethyl]-Ν' -(2- (6bromo) pyridyl]thiourea
N-(2 - (2 - (4-chloro)pyridyl)ethyl]-Ν' -(2-(54 0 bromo)pyridyl] thiourea
N-(2 - (2-(4-chloro)pyridyl)ethyl]-Ν' -(2-(6chloro)pyridyl]thiourea
N-(2 - (2- (4-chloro)pyridyl)ethyl]-N‘-(2-(5chloro)pyridyl]thiourea
X-8571A
-68N-[2-(2-(4-chloro)pyridyl)ethyl]-Ν' -[2- (5methy1) pyridyl]thiourea
N-[2-(2-(4-chloro)pyridyl)ethyl]-Ν' -[2-(6trifluoromethyl) pyridyl]thiourea
N-[2-(2-(4-chloro)pyridyl)ethyl]-Ν' -[2-(5trifluoromethyl)pyridyl] thiourea
N-(2-(2-(4-chloro)pyridyl)ethyl]-Ν' -[2-(6ethy1) pyridyl]thiourea
N-[2-(2-(4-chloro)pyridyl)ethyl]-Ν' -[2-(510 ethyl)pyridyl] thiourea
N- [2-(2-(4-chloro)pyridyl)ethyl]-Ν' -(2-(5chloro)pyrazinyl]thiourea
N-(2-(2-(4-chloro)pyridyl)ethyl]-Ν' -(2-(6bromo)pyrazinyl]thiourea
N- [2 - (2 - (4-chloro) pyr idyl) ethyl] -Ν' - [2- (5bromo)pyra z inyl]thiourea
N-[2-(2-(4-chloro)pyridyl)ethyl]-Ν' - ((3- (6bromo)pyridazinyl)]thiourea
N- [2-(2-(4-chloro)pyridyl)ethyl]-Ν' -[(3-(620 chloro)pyridazinyl)]thiourea
N-[2-(2-(4-chloro)pyridyl)ethyl]-Ν' -[2-(6cyano) pyridyl]thiourea
N-(2-(2-(4-chloro)pyridyl)ethyl]-Ν' -[2-(5cyano) pyridyl]thiourea
5 N- [2 - (2 - (4-chloro) pyr idyl) ethyl] -Ν' -(2-(5cyano)pyrazinyl]thiourea
N-(2-(2-(4-chloro)pyridyl)ethyl]-Ν' -[2-(6cyano)pyrazinyl]thiourea
N-(2-(2-(4-chloro)pyridyl)ethyl]-N‘-[(3 -{63 0 cyano) pyridazinyl) ] thiourea
N- (2- (2 - (4-chloro) pyr idyl) ethyl] -N'-(2-(l,3,4thiadiazoyl]) thiourea
N-[2- (2-(4-chloro)pyridyl)ethyl]-Ν' -(2benzimidazolyl)thiourea
5 N- (2 - (2 - (4-chloro) pyr idyl) ethyl] -Ν' -(2imidazolyl) thiourea
N-(2-(2-(3-chloro)pyridyl)ethyl]-Ν' -(2thiazolyl) thiourea
N-[2 - (2-(3-chloro)pyridyl)ethyl]-Ν' -[2-(44 0 methyl) thiazolyl] thiourea
N-(2-(2-(3-chloro)pyridyl)ethyl]-Ν' -(2-(4,5dimethyl)thiazolyl]thiourea
N-(2-(2-(3-chloro)pyridyl)ethyl]-Ν' -[2-(4cyano)thiazolyl]thiourea
5 N- (2 - (2- (3-chloro)pyridyl) ethyl] -Ν' - (2 - (4trifluoromethyl)thiazolyl]thiourea
AP Ο Ο Ο 3 8 4
Χ-8571Α
-69Ν- (2 - (2- (3-chloro)pyridyl) ethyl] -Ν' - (2benzothiazolyl)thiourea
Ν- (2 - (2 - (3-chloro)pyridyl) ethyl] -Ν' -(2-(6fluoro)benzothiazolyl]thiourea
N- (2-(2-(3-chloro)pyridyl)ethyl)-Ν' -[2-(6chloro)pyrazinyl]thiourea
N- [2 - (2 - (3-chloro)pyridyl) ethyl] -Ν' -(2-(4ethyl)thiazolyl]thiourea
N-(2-(2-(3-chloro)pyridyl)ethyl]-Ν' -(2-(4-(310 pyridyl)thiazolyl)]thiourea
N- [2-(2-(3-chloro)pyridyl)ethyl]-N'-(2-(4-(3nitrophenyl)thiazolyl)]thiourea
N- (2- (2- (3-chloro)pyridyl) ethyl] -Ν' - (2pyridyl) thiourea
N- (2 - (2- (3-chloro)pyridyl) ethyl] -Ν' -(2-(6bromo) pyridyl]thiourea
N- (2-(2-(3-chloro)pyridyl)ethyl]-Ν' -(2-(5bromo) pyridyl]thiourea
N-(2-(2-(3-chloro)pyridyl)ethyl]-Ν' -(2-(62 0 chloro)pyridyl] thiourea
N- (2 - (2 - (3-chloro)pyridyl) ethyl] -Ν' - (2 - (5chloro) pyridyl]thiourea
N- [2- (2- (3-chloro)pyridyl)ethyl] -Ν' - (2- (6methy1) pyridyl]thiourea
5 N- (2- (2 - (3-chloro)pyridyl) ethyl] -Ν' - (2 - (5methy1) pyridyl]thiourea
N- [2-(2-(3-chloro)pyridyl)ethyl)-Ν' -(2-(6tri f luoromethyl) pyr idyl ] thiourea
N- (2-(2-(3-chloro)pyridyl) ethyl]-Ν' -(2-(53 0 trifluoromethyl)pyridyl]thiourea
N- (2-(2-(3-chloro)pyridyl)ethyl]-N’-(2-(6ethyl) pyridyl]thiourea
N- (2-(2-(3-chloro)pyridyl)ethyl]-Ν' -(2-(5ethy1) pyridyl]thiourea
5 N- (2- (2- (3-chloro)pyridyl) ethyl] -Ν' - [2- (5chloro)pyrazinyl]thiourea
N- [2- (2- (3-chloro)pyridyl) ethyl] -Ν' - [2- (6bromo) pyrazinyl]thiourea
N- (2-(2-(3-chloro)pyridyl)ethyl]-Ν' -(2-(54 0 bromo) pyrazinyl] thiourea
N- (2-(2-(3-chloro)pyridyl) ethyl]-Ν' - ((3-(6bromo)pyridazinyl)]thiourea
N- [2-(2 - (3-chloro)pyridyl)ethyl]-Ν' - ((3-(6chloro)pyridazinyl)]thiourea
5 N- (2 - (2 - (3-chloro)pyridyl) ethyl] -Ν' - [2- (6cyano) pyridyl ] thiourea
l· V Λ ν u
X-8571A
-70N- [2 - (2-(3-chloro)pyridyl)ethyl]-Ν' -[2-(5cyano)pyridyl]thiourea
N-(2-(2-(3-chloro)pyridyl) ethyl]-N'-[2-(5cyano)pyrazinyl]thiourea
N-[2-(2-(3-chloro)pyridyl)ethyl]-Ν'-(2-(6cyano)pyrazinyl]thiourea
N- [2-(2-(3-chloro)pyridyl)ethyl]-Ν' - ((3-(6cyano)pyridazinyl)]thiourea
N-(2-(2-(3-chloro)pyridyl)ethyl]-N'-(2-[l,3,41 0 thiadiazoyl]) thiourea
N-[2-(2-(3-chloro)pyridyl)ethyl]-Ν' -(2benzimidazolyl)thiourea
N-.[2- {2- (3-chloro)pyridyl)ethyl] -Ν' - (2imidazoly1) thiourea
N-[2-(2-(5 -methoxy- 6 - f luoro) pyridyl) ethyl ]-N'- (2thiazolyl) thiourea
N- [2 - (2-(5-methoxy-6-fluoro)pyridyl)ethyl]-Ν' -[2-(4methyl)thiazolyl]thiourea
N-[2-(2-(5-methoxy-6-fluoro)pyridyl)ethyl]-Ν' -[2-(4,52 0 dimethyl) thiazolyl] thiourea
N- [2- (2-(5-methoxy-6-fluoro)pyridyl)ethyl]-Ν' -(2-(4cyano)thiazolyl]thiourea
N-[2- (2-(5-methoxy-6-fluoro)pyridyl)ethyl]-Ν' -(2-(4trifluoromethyl)thiazolyl]thiourea
5 N- [2 - (2-(5-methoxy-6-fluoro)pyridyl,ethyl]-Ν' -(2benzothiazolyl)thiourea
N- (2- (2-(5-methoxy-6-fluoro)pyridyl)ethyl)-N‘-(2-(6fluoro)benzothiazolyl]thiourea
N-[2-(2-(5-methoxy-6-fluoro)pyridyl)ethyl]-N'-(2-(63 0 chi oro) pyraz iny 1 ] thiourea
N- [2- (2-(5-methoxy-6-fluoro)pyridyl)ethyl]-Ν' -[2-(4ethy1)thiazolyl]thiourea
N-[2-(2-(5-methoxy-6-fluoro)pyridyl)ethyl]-Ν' -[2-(4(3-pyridyl)thiazolyl)]thiourea
5 N-[2-(2-(5-methoxy-6-fluoro,pyridyl)ethyl]-Ν' -[2-(4(3-nitrophenyl)thiazolyl)]thiourea
N- [2- (2-(5-methoxy-6-fluoro)pyridyl)ethyl]-Ν' -(2pyridyl) thiourea
N- [2- (2- (5-methoxy-6-fluoro) pyridyl) ethyl]-N'- (2- (64 0 bromo) pyridyl) thiourea
N- (2- (2-(5-methoxy-6-fluoro)pyridyl,ethyl]-Ν' -[2-(5bromo) pyridyl]thiourea
N-(2-(2-(5-methoxy-6-fluoro)pyridyl)ethyl]-Ν' -[2-(6chloro) pyridyl]thiourea
5 N- [2- (2 - (5-methoxy-6-fluoro)pyridyl) ethyl] -Ν' - [2 - (5chloro)pyridyl]thiourea
AP Ο Ο Ο 3 8 4
Χ-8571Α
-71Ν- (2- (2-(5-methoxy-6-fluoro)pyridyl) ethyl]-Ν' -[2-(6methy1) pyridyl]thiourea
N-[2- (2-(5-methoxy-6-fluoro)pyridyl) ethyl]-N'-[2-(5methy1) pyridyl]thiourea
N-(2 - (2-(5-methoxy-6-fluoro)pyridyl) ethyl]-N'-[2-(6trif luoromethyl Jpyridyl] thiourea
N- (2- (2- (5-methoxy-6-fluoro) pyr idyl, ethyl] -Ν' - [2- (5tri f luoromethyl) pyridyl ] thiourea
N- (2- (2-(5-methoxy-6-fluoro)pyridyl) ethyl]-Ν' -[2-(610 ethyl) pyridyl] thiourea
N-(2-(2-(5-methoxy-6-fluoro)pyridyl) ethyl]-Ν' -[2-(5ethyl) pyridyl] thiourea
N-[2- (2-(5-methoxy-6-fluoro)pyridyl)ethyl]-Ν' -[2-(5chloro) pyrazinyl ] thiourea
N- [2 - (2 - (5-methoxy-6-fluoro) pyridyl) ethyl] -N'-[2-(6bromo) pyrazinyl] thiourea
N- [2 - (2 - (5-methoxy-6-fluoro)pyridyl) ethyl] -Ν' -[2-(5bromo)pyrazinyl]thiourea
N-(2 - (2-(5-methoxy-6-fluoro)pyridyl) ethyl]-Ν' - [(3-(62 0 bromo) pyridazinyl) ] thiourea
N-[2 - (2-(5-methoxy-6-fluoro)pyridyl)ethyl]-Ν' -[(3-(6chloro,pyridazinyl) ]thiourea
N- [2- (2-(5-methoxy-6-fluoro)pyridyl)ethyl]-Ν' -(2-(6cyano) pyridyl ] thiourea
N- [ 2 - (2 - (5 -methoxy- 6-f luoro) pyridyl) ethyl ] -N' - (2 - (5 cyano) pyridyl ] thiourea
N- (2 - (2- (5-methoxy-6-fluoro) pyridyl) ethyl] -Ν' -(2-(5cyano) pyrazinyl ] thiourea
N- [2- (2- (5-methoxy-6-f luoro) pyridyl) ethyl] -Ν' -(2-(63 0 cyano) pyrazinyl] thiourea
N-[2-(2-(5-methoxy-6-fluoro)pyridyl)ethyl]-Ν' - ((3-(6cyano) pyridazinyl) ] thiourea
N- (2- (2- (5-methoxy-6-f luoro)pyridyl) ethyl] -Ν' - (2[1,3,4-thiadiazoyl]) thiourea
5 N- [2- (2- (5-methoxy-6-f luoro)pyridyl) ethyl] -Ν' - (2benzimidazolyl)thiourea
N-[2- (2-(5-methoxy-6-fluoro,pyridyl)ethyl]-Ν' -(2imidazolyl) thiourea
N-[2- (2-(3-methoxy-6-fluoro)pyridyl) ethyl]-Ν' -(24 0 thiazolyl) thiourea
N- [2 - (2 - (3-methoxy-6-f luoro)pyridyl)ethyl] -Ν' -(2-(4,5dimethyl)thiazolyl]thiourea
N- [2- (2 - (3-methoxy-6-fluoro) pyridyl) ethyl] -Ν' - (2benzothiazolyl) thiourea
5 N- (2 - (2 - (3-methoxy-6-fluoro) pyridyl, ethyl] -Ν' -(2-(6 f luoro) benzothiazolyl ] thiourea
X-8571A
-72Ν-[2-(2-(3-methoxy-6-fluoro)pyridyl)ethyl]-Ν' -[2-(6chloro)pyrazinyl]thiourea
N-[2-(2-(3-methoxy-6-fluoro)pyridyl)ethyl]-Ν' -(2-(4(3-pyridyl)thiazolyl)]thiourea
N-[2-{2-(3-methoxy-6-fluoro)pyridyl)ethyl]-Ν' -(2-(4(3-nitrophenyl)thiazolyl)]thiourea
N-(2-(2-(3-methoxy-6-fluoro)pyridyl)ethyl]-Ν'-[2-(6bromo)pyridyl]thiourea
N-[2-(2-(3-methoxy-6-fluoro)pyridyl)ethyl]-Ν' -(2-(61 0 chloro) pyridyl]thiourea
N-[2-(2-(3-methoxy-6-fluoro)pyridyl)ethyl]-N*-(2-(6methy1) pyridyl]thiourea
N-[2-(2-(3-methoxy-6-fluoro)pyridyl)ethyl]-Ν' -[2-(5methyl) pyridyl]thiourea
N- [2- (2-(3-methoxy-6-fluoro)pyridyl)ethyl] -N* - (2- (6trifluoromethyl) pyridyl]thiourea
N-[2-(2-(3-methoxy-6-fluoro)pyridyl)ethyl] -Ν' -(2-(5tri fluoromethyl) pyridyl]thiourea
N-[2-(2-(3-methoxy-6-fluoro)pyridyl)ethyl]-Ν'-[2-(62 0 ethyl) pyridyl] thiourea
N-[2-(2-(3-methoxy-6-fluoro)pyridyl)ethyl]-Ν' -(2-(5ethy1) pyridyl]thiourea
N-[2-(2-(3-methoxy-6-fluoro)pyridyl)ethyl]-Ν' -(2-(6bromo)pyrazinyl]thiourea
5 N- [2- (2 - (3-methoxy-6-f luoro)pyridyl) ethyl) -Ν' - [ (3- (6bromo)pyridazinyl)]thiourea
N-[2-(2-(3-methoxy-6-fluoro) pyridyl)ethyl]-Ν'-(2-(6cyano)pyridyl]thiourea
N—(2-(2-(3-methoxy-6-fluoro)pyridyl)ethyl]-Ν' -[2-(53 0 cyano) pyridyl] thiourea
N-[2-(2-(3-methoxy-6-fluoro)pyridyl)ethyl]-Ν' -(2-(5cyano)pyrazinyl]thiourea
N-[2-(2-(3-methoxy-6-fluoro)pyridyl)ethyl]-Ν' -[2-(6cyano)pyrazinyl]thiourea
5 N-(2-(2-(3-methoxy-6-fluoro)pyridyl)ethyl]-Ν' - ((3-(6cyano)pyridazinyl)]thiourea
N-[2-(2-(3-methoxy-6-fluoro)pyridyl)ethyl]-Ν' -(2(1,3,4-thiadiazoyl]) thiourea
N-(2-(2-(3-methoxy-6-fluoro) pyridyl) ethyl]-Ν' -(240 benzimidazolyl) thiourea
N-(2-(2-(3-methoxy-6-fluoro)pyridyl)ethyl]-N*-(2imidazolyl)thiourea
N-[2-(2-(6-methoxy-3-fluoro) pyridyl) ethyl]-Ν' -(2thiazolyl) thiourea
5 N- [2 - (2- (6-methoxy-3-fluoro) pyridyl) ethyl] -Ν' - (2 - (4methy1)thiazolyl]thiourea
AP Ο Ο Ο 3 8 4
Χ-8571Α
-73Ν- [2- (2- (6-methoxy-3-fluoro)pyridyl)ethyl]-Ν' -(2- (4,5dimethy1)thiazolyl]thiourea
N-(2-{2- (6-methoxy-3 -fluoro) pyridyl) ethyl]-N'-[2- (4 cyano)thiazolyl]thiourea
N-[2-(2-(6-methoxy-3-fluoro)pyridyl) ethyl]-Ν' -[2- (4trifluoromethy1)thiazolyl ] thiourea
N-[2-(2-(6-methoxy-3-fluoro)pyridyl)ethyl]-Ν' -(2benzothiazolyl) thiourea
N-[2-(2-(6-methoxy-3-fluoro)pyridyl) ethyl]-Ν' -(2-(61 0 fluoro)benzothiazolyl]thiourea
N-(2-(2-(6-methoxy-3-fluoro)pyridylJethyl]-Ν' -(2-(6chloro)pyrazinyl]thiourea
N-(2-(2-(6-methoxy-3-fluoro)pyridyl)ethyl]-Ν' -(2-(4ethyl)thiazolyl]thiourea
N-[2- (2-(6-methoxy-3-fluoro)pyridyl,ethyl]-Ν' -(2-(4(3-pyridyl)thiazolyl)]thiourea
N-[2-(2-(6-methoxy-3-fluoro)pyridyl,ethyl]-Ν' -[2-(4(3-nitrophenyl)thiazolyl)]thiourea
N-(2- (2- (6-methoxy-3-fluoro) pyridyl) ethyl,-N'- (220 pyridyl) thiourea
N-[2-(2-(6-methoxy-3-fluorojpyridyl,ethyl]-N'-[2-(6bromo)pyridyl]thiourea
N-[2-(2-(6-methoxy-3-fluoro)pyridyl)ethyl]-Ν' -[2-(5bromo) pyridyl]thiourea
5 N-(2-(2-(6-methoxy-3-fluoro)pyridyl)ethyl]-Ν' -(2-(6chloro)pyridyl]thiourea
N-[2-(2-(6-methoxy-3-fluoro)pyridylJethyl]-Ν' -(2-(5chloro)pyridyl]thiourea
N-[2- (2-(6-methoxy-3-fluoro)pyridyl,ethyl]-Ν' - (2- (63 0 methyl) pyridyl] thiourea
N- [2- (2- (6-methoxy-3-fluoro) pyridyl) ethyl]-N‘- (2- (5methyl)pyridyl]thiourea
N-(2-(2-(6-methoxy-3-fluoro)pyridyl)ethyl]-Ν' -[2-(6trifluoromethyl) pyridyl]thiourea
N-(2-(2-(6-methoxy-3-fluoro)pyridylJethyl]-N'-[2-(5trifluoromethyl)pyridyl]thiourea
N-[2- (2-(6-methoxy-3-fluoro,pyridyl)ethyl]-Ν' -(2-(6ethyl) pyridyl]thiourea
N- [2- (2-(6-methoxy-3-fluoro,pyridyl,ethyl]-Ν' -[2-(54 0 ethyl)pyridyl] thiourea
N-[2-(2-(6-methoxy-3-fluoro,pyridyl,ethyl]-Ν' -(2-(5chloro,pyrazinyl]thiourea
N-(2-(2-(6-methoxy-3-fluoro,pyridyl)ethyl]-Ν' -[2-(6bromo)pyrazinyl]thiourea
N-[2-(2-(6-methoxy-3-fluoro)pyridyl,ethyl]-Ν' -[2-(5bromo, pyrazinyl ] thiourea
X-8571A
-74N-[2-(2-(6-methoxy-3-fluoro)pyridyl)ethyl]-Ν' -[(3-(6bromo)pyridazinyl)]thiourea
N-[2-(2-(6-methoxy-3-fluoro)pyridyl)ethyl]-N’ - [(3-(6chloro)pyridazinyl)]thiourea
N-[2-(2-(6-methoxy-3-fluoro)pyridyl)ethyl]-N’-[2-(6cyano) pyridyl]thiourea
N-(2-(2-(6-methoxy-3-fluoro)pyridyl)ethyl]-Ν' -[2-(5cyano)pyridyl]thiourea
N-(2-(2-(6-methoxy-3-fluoro)pyridyl)ethyl]-Ν' -[2-(510 cyano) pyrazinyl] thiourea
N-[2-(2-(6-methoxy-3-fluoro)pyridyl)ethyl]-Ν' -(2- 16cyano)pyrazinyl]thiourea
N-[2-(2-(6-methoxy-3-fluoro)pyridyl)ethyl]-Ν' - ((3-(6cyano)pyridazinyl)]thiourea
5 N-[2-(2-(6-methoxy-3-fluoro)pyridyl)ethyl]-Ν' -(2[1,3,4-thiadiazoyl]) thiourea
N-[2-(2-(6-methoxy-3-fluoro)pyridyl)ethyl]-Ν' - (2benzimidazolyl)thiourea
N-[2-(2-(6-methoxy-3-fluoro)pyridyl)ethyl]-Ν' -(22 0 imidazolyl) thiourea
N-[2-(2-(5-ethoxy-6-fluoro)pyridyl)ethyl]-Ν' -(2thiazolyl) thiourea
N-[2-(2-(5-ethoxy-6-fluoro)pyridyl)ethyl]-Ν' - [2- (4methyl)thiazolyl]thiourea
5 N- [2- (2 - (5-ethoxy-6-f luoro)pyridyl) ethyl] -N' - [2- (4,5dimethyl)thiazolyl]thiourea
N-[2-(2-(5-ethoxy-6-fluoro)pyridyl)ethyl]-Ν' -(2benzothiazolyl)thiourea
N-[2-(2-(5-ethoxy-6-fluoro)pyridyl)ethyl]-Ν' -[2-(63 0 fluoro)benzothiazolyl]thiourea
N-[2-(2-(5-ethoxy-6-fluoro)pyridyl)ethyl]-Ν' -(2-(6chloro)pyrazinyl]thiourea
N-[2-(2-(5-ethoxy-6-fluoro)pyridyl)ethyl]-Ν'-(2-(4-(3pyridyl)thiazolyl)]thiourea
5 N- [2- (2 - (5-ethoxy-6-fluoro) pyridyl) ethyl] -Ν'-(2-(4-(3nitrophenyl)thiazolyl)]thiourea
N-[2-(2-(5-ethoxy-6-fluoro)pyridyl)ethyl]-Ν' -(2pyridyl) thiourea
N-[2-(2-(5-ethoxy-6-fluoro)pyridyl)ethyl]-Ν' -[2-(64 0 bromo) pyridyl] thiourea
N-[2-(2-(5-ethoxy-6-fluoro)pyridyl)ethyl]-Ν' -[2-(6chloro)pyridyl]thiourea
N-[2-(2-(5-ethoxy-6-fluoro)pyridyl)ethyl]-Ν'-[2- (6methyl) pyridyl]thiourea
5 N- [2- (2 - (5-ethoxy-6-f luoro) pyridyl) ethyl] -Ν' - [2- (5-
Χ-8571Α
-75Ν-[2 - (2-(5-ethoxy-6-fluoro)pyridyl)ethyl]-Ν' -[2-(6trifluoromethyl) pyridyl]thiourea
N-[2- (2-(5-ethoxy-6-fluoro)pyridyl)ethyl]-N*-[2-(5trifluoromethyl)pyridyl]thiourea
N-[2 - (2-(5-ethoxy-6-fluoro)pyridyl) ethyl]-N'-[2-(6ethyl) pyridyl]thiourea
N-[2-(2-(5-ethoxy-6-fluoro)pyridyl)ethyl]-Ν' -[2-(5ethyl)pyridyl]thiourea
N-[2-(2-(5-ethoxy-6-fluoro)pyridyl)ethyl]-Ν' -[2-(610 bromo) pyrazinyl ] thiourea
N-12-(2-(5-ethoxy-6-fluoro)pyridyl,ethyl]-Ν' -((3-(6^ bromo)pyridazinyl)]thiourea
N- [2- (2- (5-ethoxy-6-fluoro)pyridyl) ethyl]—N'-[2-(6 — cyano) pyridyl]thiourea
N-[2-(2-(5-ethoxy-6-fluoro)pyridyl)ethyl]-Ν' -[2-(5cyano) pyridyl]thiourea
N-[2-(2-(5-ethoxy-6-fluoro)pyridyl)ethyl]-N’-(2-(5cyano)pyrazinyl]thiourea
N-[2-(2-(5-ethoxy-6-fluoro)pyridyl)ethyl]-Ν' -[2-(62 0 cyano )pyraz inyl ] thiourea
N-(2- (2 - (5-ethoxy-6-fluoro)pyridyl)ethyl]-Ν' -[(3-(6cyano)pyridazinyl)]thiourea
Ν-Λ2- (2-(5-ethoxy-6-fluoro)pyridyl)ethyl]-N'-(2[1,3,4-thiadiazoyl]) thiourea
5 N- (2- (2 - (5-ethoxy-6-fluoro) pyr idyl) ethyl] -N'-(2benzimidazolyl)thiourea
N- [2-(2- (5-ethoxy-6-fluoro)pyridyl)ethyl]-Ν' -(2imidazolyl) thiourea
N- [2- (2- (3-ethoxy-6-fluoro)pyridyl)ethyl]-Ν' -(23 0 thiazolyl) thiourea
N-[2-(2-(3-ethoxy-6-fluoro)pyridyl,ethyl]-Ν' -[2-(4methyl,thiazolyl]thiourea
N-[2-(2-(3-ethoxy-6-fluoro)pyridyl)ethyl]-Ν' -[2-(4,5dimethyl)thiazolyl]thiourea
5 N- (2- (2- (3-ethoxy-6-f luoro)pyridyl) ethyl] -Ν' - (2benzothiazolyl)thiourea
N- [2- (2-(3-ethoxy-6-fluoro)pyridyl)ethyl]-N’-[2-(6fluoro)benzothiazolyl]thiourea
N-[2-(2-(3-ethoxy-6-fluoro)pyridyl)ethyl)-Ν' -[2-(64 0 chloro)pyrazinyl] thiourea
N-[2-(2-(3-ethoxy-6-fluoro)pyridyl)ethyl]-Ν' -(2-(4-(3pyridyl)thiazolyl)]thiourea
N-[2-(2-(3-ethoxy-6-fluoro)pyridyl)ethyl]-N'- (2- (4- (3nitrophenyl)thiazolyl)]thiourea
N- [2- (2- (3-ethoxy-6-fluoro)pyridyl) ethyl] -Ν' - (2pyridyl) thiourea
X-8571A
-76N-[2 -(2-(3-ethoxy-6-fluoro)pyridyl) ethyl]-N'-[2-(6bromo)pyridyl]thiourea
N-(2-(2- (3-ethoxy-6-fluoro)pyridyl)ethyl]-Ν' -(2-(6chloro)pyridyl]thiourea
N-[2-(2-(3-ethoxy-6-fluoro)pyridyl) ethyl]-Ν' -(2-(6methyl) pyridyl]thiourea
N-[2-(2-¢3-ethoxy-6-fluoro)pyridyl)ethyl]-N'-(2-(5methyl) pyridyl]thiourea
N-[2-(2-(3 - ethoxy-6-fluoro)pyridyl)ethyl]-Ν' -[2-(61 0 trifluoromethyl!pyridyl]thiourea
N-[2-(2-(3-ethoxy-6-fluoro)pyridyl)ethyl]-Ν’—[2-(5trifluoromethyl) pyridyl]thiourea
N-[2-(2-(3-ethcxy-6-fluoro)pyridyl)ethyl]-Ν' -[2-(6ethyl) pyridyl]thiourea
N-'(2- (2 - (3-ethoxy-6-fluoro)pyridyl)ethyl]-N*—[2—(5ethyl)pyridyl]thiourea
N-(2-(2-(3-ethoxy-6-fluoro)pyridyl)ethyl]-Ν' -(2- (6bromo) pyrazinyl]thiourea
N-[2-(2-(3-ethoxy-6-fluoro)pyridyl)ethyl]-Ν' - ((3-(620 bromo)pyridazinyl)]thiourea
N-(2-(2-(3-ethoxy-6-fluoro)pyridyl)ethyl]-Ν' -[2-(6cyano)pyridyl]thiourea
N-(2-(2-(3-ethoxy-6-fluoro)pyridyl)ethyl]-Ν'-(2-(5cyano)pyridyl]thiourea
N-(2-(2-(3 - ethoxy-6-fluoro) pyridyl) ethyl] -Ν' -[2-(5cyano)pyrazinyl]thiourea
N-[2-(2-(3-ethoxy-6-fluoro)pyridyl)ethyl]-N'-[2-(6cyano)pyrazinyl]thiourea
N-(2-(2-(3-ethoxy-6-fluoro)pyridyl)ethyl)-Ν' - ((3-(63 0 cyano)pyridazinyl!]thiourea
N-(2-(2-(3-ethoxy-6-fluoro)pyridyl)ethyl]-Ν' -(2(1,3,4-thiadiazoyl]) thiourea
N-(2-(2-(3-ethoxy-6-fluoro,pyridyl)ethyl]-Ν' -(2benzimidazolyl) thiourea
5 N- [2- (2- (3-ethoxy-6-fluoro)pyridyl)ethyl] -Ν' - (2imidazoly 1) thiourea
N-.(2- (2 - (6 - ethoxy-3-fluoro)pyridyl) ethyl] -Ν' - (2thiazolyl) thiourea
N-[2-(2-(6-ethoxy-3-fluoro)pyridyl)ethyl]-Ν' -[2-(44 0 methyl) thiazolyl ] thiourea
N-[2-(2-(6-etncxy-3-fluoro)pyridyl)ethyl]-Ν' -[2-(4,5dimethyl)thiazolyl]thiourea
N-[2-(2-(6-ethoxy-3-fluoro)pyridyl)ethyl]-Ν' -(2-(4cyano)thiazolyl]thiourea
5 N- (2- (2- (6-ethoxy-3-fluoro)pyridyl) ethyl] -Ν' - [2 - (4trifluoromethyl)thiazolyl]thiourea
BAD ORIGINAL
AP Ο Ο Ο 3 8 4
Χ-8571Α
-77Ν- [2-(2-(6-ethoxy-3-fluoro)pyridyl)ethyl]-Ν’ -(2benzothiazolyl) thiourea
N- [2- (2-(6-ethoxy-3-fluoro)pyridyl,ethyl]-Ν' -[2-(6fluoro)benzothiazolyl]thiourea
N- (2-(2-(6-ethoxy-3-fluoro)pyridyl)ethyl] -Ν' -[2-(6chloro)pyrazinyl]thiourea
N-[2-(2-(6-ethoxy-3-fluoro)pyridyl)ethyl]-Ν' -(2-(4ethyl)thiazolyl]thiourea
N-[2-(2-(6-ethoxy-3-fluoro)pyridyl)ethyl]-Ν' -(2-(4-(31 0 pyridyl)thiazolyl)]thiourea
N-[2-(2-(6-ethoxy-3-fluoro)pyridyl)ethyl]-Ν' -(2-(4-(3nitrophenyl)thiazolyl)]thiourea
N- (2-(2-(6-ethoxy-3-fluoro)pyridyl)ethyl]-Ν' -(2pyridyl)thiourea
N- (2- (2- (6-ethoxy-3-fluoro)pyridyl) ethyl] -Ν' - (2- (6bromo) pyridyl]thiourea
N- (2-(2-(6-ethoxy-3-fluoro)pyridyl)ethyl]-Ν' -(2-(5bromo) pyridyl]thiourea
N-(2-(2-(6-ethoxy-3-fluoro)pyridyl)ethyl]-Ν' -(2-(62 0 chloro)pyridyl] thiourea
N- (2-(2-(6-ethoxy-3-fluoro)pyridyl) ethyl)-Ν' -(2-(5chloro) pyridyl) thiourea
N- (2-(2-(6-ethoxy-3-fluoro)pyridyl)ethyl]-Ν' -[2-(6methyl) pyridyl]thiourea
5 N- [2- (2- (6-ethoxy-3-fluoro)pyridyl) ethyl] -Ν' - [2- (5methyl)pyridy1]thiourea
N-[2-(2-(6-ethoxy-3-fluoro)pyridyl)ethyl]-Ν' -[2-tetri fluoromethyl) pyridyl ] thiourea
N- [2- (2- (6-ethoxy-3-fluoro)pyridyl) ethyl] -Ν' -(2- (53 0 tri f luoromethyl) pyridyl] thiourea
N-[2-(2-(6-ethoxy-3-fluoro)pyridyl)ethyl]-Ν' -[2-(6ethyl) pyridyl]thiourea
N-[2-(2-(6-ethoxy-3-fluoro)pyridyl)ethyl]-Ν' -(2-(5ethy1) pyridyl]thiourea
5 N- [2- (2- (6-ethoxy-3-fluoro)pyridyl) ethyl] -Ν' -(2- (5chloro)pyrazinyl]thiourea
N- (2-(2-(6-ethoxy-3-fluoro)pyridyl)ethyl]-N'-(2-(6bromo)pyrazinyl]thiourea
N- [2- (2- (6-ethoxy-3-fluoro)pyridyl) ethyl] -Ν' - [2- (54 0 bromo) pyrazinyl] thiourea
N- [2-(2-(6-ethoxy-3-fluoro)pyridyl)ethyl]-N'-((3-(6bromo)pyridazinyl)]thiourea
N-[2-(2-(6-ethoxy-3-fluoro)pyridyl)ethyl]-Ν' - ((3-(6chloro)pyridazinyl)]thiourea
X-8571A
-7820
Ν-(2-(2-(6-ethoxy-3-fluoro)pyridyl)ethyl]-Ν' -[2-(5cyano) pyridyl]thiourea
N-[2-(2-{6-ethoxy-3-fluoro)pyridyl)ethyl]-Ν' -[2-(5cyano)pyrazinyl]thiourea
N-[2-(2-(6-ethoxy-3-fluoro)pyridyl)ethyl]-Ν' -(2-(6cyano)pyrazinyl]thiourea
N- [2-(2-(6-ethoxy-3-fluoro)pyridyl)ethyl]-Ν' - ((3-(6cyano)pyridazinyl)]thiourea
N-[2-(2-(6-ethoxy-3-fluoro)pyridyl)ethyl]-Ν' -(2[1,3,4-thiadiazoyl]) thiourea
N-[2-(2-(6-ethoxy-3-fluoro)pyridyl)ethyl]-N'-(2benzimidazolyl)thiourea
N-[2-(2-(6-ethoxy-3-fluoro)pyridyl)ethyl]-Ν' -(2imidazolyl) thiourea
N-[2-(5,6-fluoro)pyridyl)ethyl]-Ν' -(2thiazolyl) thiourea
N-[2-(5,6-fluoro)pyridyl)ethyl]-N'-[2-(4methyl)thiazolyl]thiourea
N-[2-(5,6-fluoro)pyridyl)ethyl]-N·-[2-(4,5dimethyl)thiazolyl) thiourea
N-[2-(5,6-fluoro)pyridyl)ethyl]-Ν' -(2-(4cyano)thiazolyl]thiourea
N-[2-(5,6-fluoro)pyridyl)ethyl]-N'-[2-(4trifluoromethyl)thiazolyl]thiourea
N-[2-(5,6-fluoro)pyridyl)ethyl]-Ν'-(2benzothiazolyl)thiourea
N-[2-(5,6-fluoro)pyridyl)ethyl]-Ν' -(2-(6fluoro)benzothiazolyl]thiourea
N—[2-(5,6-fluoro)pyridyl)ethyl]-N‘-[2-(6chloro)pyrazinyl]thiourea
N-[2-(5,6-fluoro)pyridyl)ethyl]-Ν' -(2-(4ethyl)thiazolyl]thiourea
N-[2-(5,6-fluoro)pyridyl)ethyl]-N'-[2-(4-(3pyridyl)thiazolyl)]thiourea
N-[2-(5,6-fluoro)pyridyl)ethyl]-Ν' -(2-(4-(3nitrophenyl,thiazolyl)]thiourea
N-[2-(5,6-fluoro)pyridyl)ethyl]-Ν' -(2-pyridyl)thiourea N-[2-(5,6-fluoro)pyridyl)ethyl]-Ν' -[2-(6bromo)pyridyl]thiourea
N-[2-(5,6-fluoro)pyridyl)ethyl]-Ν' -[2-(5bromo) pyridyl]thiourea
N-[2-(5,6-fluoro)pyridyl)ethyl]-Ν' -[2-(6chloro)pyridyl]thiourea
N-[2-(5,6-fluoro)pyridyl)ethyl]-Ν' -[2-(5chloro)pyridyl]thiourea
AP Ο Ο Ο 3 8 4
Χ-8571Α
-79Ν-(2-(5,6-fluoro)pyridyl)ethyl]-Ν' -[2-(6methyl) pyridyl]thiourea
N-[2-(5,6-fluoro)pyridyl)ethyl]-N'-[2-(5methyl)pyridyl]thiourea
N- [2-(5,6-fluoro)pyridyl)ethyl]-N*-[2-(6tri fluoromethyl)pyridyl]thiourea
N-[2-(5,6-fluoro)pyridyl)ethyl]-Ν' -[2-(5tri fluoromethyl) pyridyl]thiourea
N- (2-(5,6-fluoro)pyridyl) ethyl]-N'-[2-(610 ethyl) pyridyl] thiourea
N-(2 - (5,6-fluoro)pyridyl)ethyl]-Ν' -[2-(5ethyl) pyridyl]thiourea
N- (2 - (5,6-fluoro)pyridyl)ethyl]-Ν' -[2-(5chloro)pyrazinyl]thiourea
N- [2 - (5,6-fluoro)pyridyl) ethyl] -N'-(2-(6bromo)pyrazinyl]thiourea
N-[2-(5,6-fluoro)pyridyl)ethyl]-Ν' -[2-(5bromo)pyrazinyl]thiourea
N-(2-(5,6-fluoro)pyridyl)ethyl]-Ν' - ((3-(620 bromo)pyridazinyl) ] thiourea
N- [2 - (5,6-fluoro)pyridyl)ethyl]-Ν' -[(3-(6chloro)pyridazinyl)]thiourea
N- [2 - (5,6-fluoro)pyridyl)ethyl]-Ν' -(2-(6cyano) pyridyl]thiourea
5 N- (2 - (5,6-f luoro) pyridyl) ethyl] -Ν' - [2 - (5cyano) pyridyl ] thiourea
N-[2 - (5,6-fluoro)pyridyl)ethyl]-Ν' -[2-(5cyano)pyrazinyl]thiourea
N- [2- (5,6-fluoro)pyridyl)ethyl]-Ν' -[2-(63 0 cyano) pyrazinyl] thiourea
N-[2 - (5,6-fluoro)pyridyl)ethyl]-N'-({3-(6cyano)pyridazinyl)]thiourea
N- [2- (5,6-fluoro)pyridyl)ethyl]-N'-(2-[l,3,4thiadiazoyl]) thiourea
5 N- (2 - (5,6-f luoro) pyridyl) ethyl] -Ν' - (2benzimidazolyl)thiourea
N-[2-(5,6-fluoro)pyridyl)ethyl]-Ν' -(2imidazolyl)thiourea
N-[2-(2-(5,6-difluoro)pyridyl)ethyl]-Ν' -(24 0 thiazolyl) thiourea
N-[2- (2-(5,6-difluoro)pyridyl)ethyl]-Ν' -(2-(4methyl)thiazolyl]thiourea
N-[2-(2-(5,6-difluoro)pyridyl)ethyl]-Ν' -[2-(4,5dimethyl)thiazolyl]thiourea
5 N- [2- (2 - (5,6-dif luoro) pyr idyl) ethyl] -Ν' - [2 - (4-
X-8571A
-80N- [2-(2-(5,6-difluoro)pyridyl)ethyl]-Ν' -[2-(4trif luoromethyl) thiazolyl] thiourea
N- [2 - (2 - (5,6-dif luoro)pyridyl) ethyl]-N’-(2benzothiazolyl)thiourea
N- [2 - (2 - (5,6-difluoro)pyridyl)ethyl] -Ν' -[2-(6f luoro) benzothiazolyl ] thiourea
N- [2- (2 - (5,6-di fluoro (pyridyl) ethyl] -N*-[2-(6chloro) pyrazinyl]thiourea
N- (2- (2 - (5,6-difluoro)pyridyl)ethyl] -Ν' -[2-(41 0 ethyl)thiazolyl]thiourea
N-[2 - (2 - (5,6-difluoro(pyridyl(ethyl]-N'- (2-{4- (3pyridyl) thiazolyl) ] thiourea
N- [2 - (2 - (5,6-dif luoro) pyridyl) ethyl] -Ν'-[2 -(4-(3nitrophenyl) thiazolyl) ] thiourea
N-[2-(2-(5,6-di fluoro) pyridyl) ethyl] -Ν' -(2pyridyl) thiourea
N- [2 - (2 - (5,6-dif luoro) pyridyl) ethyl] -N*-[2-(6bromo) pyridyl]thiourea
N- [2- (2- (5,6-difluoro(pyridyl)ethyl]-N’ - [2- (520 bromo)pyridyl]thiourea
N-[2- (2- (5,6-dif luoro) pyridyl (ethyl] -Ν' -(2-(6chloro)pyridyl]thiourea
N- [2- (2 - (5,6-di fluoro) pyr idyl) ethyl] -N'-(2-(5chloro)pyridyl]thiourea
N-[2-(2-(5,6-dif luoro) pyridyl) ethyl] -N'-(2-(6methy1)pyridyl]thiourea
N- [2- (2 - (5,6-di fluoro) pyr idyl) ethyl] -Ν' - [2 - (5methy1) pyridyl]thiourea
N-[2-(2-(5,6-difluoro)pyridyl)ethyl]-Ν'-(2- (63 0 tri fluoromethyl) pyridyl] thiourea
N- (2 - (2 - (5,6-difluoro)pyridyl) ethyl] -N’-[2-(5t r i f luoromethyl) pyridyl ] thiourea
N- [2- (2 - (5,6-dif luoro) pyridyl) ethyl] -Ν' -[2-(6ethyl) pyridyl]thiourea
N-[2-(2-(5,6-dif luoro) pyr idyl) ethyl] -Ν' - [2 - (5ethy1) pyridyl]thiourea
N- [2- (2 - (5,6-dif luoro) pyridyl) ethyl] -Ν' - [2 - (5chloro)pyrazinyl]thiourea
N- [2 - (2 - (5,6-dif luoro (pyridyl) ethyl] -Ν' - [2 - (64 0 bromo) pyraz inyl] thiourea
N- [2 - (2 - (5,6-dif luoro) pyridyl) ethyl ]-Ν' -[2-(5bromo)pyrazinyl]thiourea
N-.[2- (2- (5,6-difluoro)pyridyl)ethyl] -Ν' - ( (3- (6bromo)pyridazinyl)]thiourea
N-[2-(2-(5,6-dif luoro) pyridyl) ethyl] -Ν' - [ (3-(6chloro)pyridazinyl)]thiourea
AP Ο Ο Ο 3 8 4
Χ-8571Α
-81Ν-[2-(2-(5,6-difluoro)pyridyl)ethyl]-N'-[2-(6cyano)pyridyl J thiourea
N-(2- (2 - (5,6-difluoro)pyridyl,ethyl]-Ν'-[2-(5cyano) pyridyl]thiourea
N-(2-(2-(5,6-difluoro)pyridyl)ethyl]-N*-[2-(5cyano)pyrazinyl]thiourea
N-(2-(2-(5,6-difluoro)pyridyl)ethyl]-Ν'-[2-(6cyano)pyrazinyl]thiourea
N-[2-(2-(5,6-difluoro)pyridyl)ethyl]-Ν' -( (3-(610 cyano)pyridazinyl) ] thiourea
N-[2-(2-(5,6-difluoro)pyridyl)ethyl]-Ν'-(2-(1,3,4thiadiazoyl]) thiourea
N-[2-(2-(5,6-difluoro)pyridyl)ethyl]-Ν' -(2benzimidazolyl)thiourea
N-[2-(2-(5,6-di fluoro) pyr idyl) ethyl] -Ν' -(2imidazolyl)thiourea
N-[2-(2-(3,6-difluoro)pyridyl)ethyl]-Ν' -(2thiazolyl) thiourea
N-[2 - (2 - (3,6-difluoro)pyridyl)ethyl]-Ν' -(2 - (42 0 methyl)thiazolyl]thiourea
N-[2 - (2-(3,6-difluoro)pyridyl)ethyl]-Ν'-(2-(4,5dimethyl)thiazolyl]thiourea
N-(2-(2-(3,6-difluoro) pyridyl)ethyl]-N*-(2benzothiazolyl)thiourea
N-[2-(2-(3,6-dif luoro) pyridyl) ethyl] -Ν' -(2-(6fluoro)benzothiazolyl]thiourea
N-[2-(2-(3,6-difluoro)pyridyl)ethyl]-Ν' -(2-(6chloro)pyrazinyl]thiourea
N-(2 - (2- (3,6-difluoro)pyridyl)ethyl]-Ν' -(2-(4-(33 0 pyridyl) thiazolyl) ] thiourea
N-(2-(2-(3,6-difluoro)pyridyl)ethyl]-Ν' -(2-(4-(3nitrophenyl)thiazolyl)]thiourea
N-[2 - (2-(3,6-difluoro)pyridyl,ethyl]-Ν' -(2pyridyl, thiourea
N-(2-(2-(3,6-dif luoro) pyridyl) ethyl] -Ν' -(2-(6bromo) pyridyl]thiourea
N-[2- (2-(3,6-difluoro)pyridyl)ethyl]-N*-(2-(6chloro) pyridyl]thiourea
N-[2-(2-(3,6-difluoro)pyridyl)ethyl]-Ν' -(2 - (64 0 methyl, pyridyl] thiourea
N-(2-(2-(3,6-difluoro)pyridyl)ethyl]-Ν' -(2-(5methyl)pyridyl]thiourea
N-[2-(2-(3,6-difluoro)pyridyl)ethyl]-Ν' -(2-(6-
X-8571A
-82N- [2 - (2- (3,6-difluoro)pyridyl)ethyl]-Ν' -[2-(6ethyl) pyridyl]thiourea
N-(2-(2 - (3,6-difluoro)pyridyl)ethyl]-N*-[2-(5ethy1) pyridyl]thiourea
N-[2-(2 - (3,6-difluoro)pyridyl)ethyl]-Ν' -[2-(6bromo)pyrazinyl]thiourea
N-[2-(2-(3,6-difluoro)pyridyl)ethyl]-Ν' - ((3-(6bromo)pyridazinyl)]thiourea
N-[2-(2-(3,6-difluoro)pyridyl)ethyl]-Ν' -[2-(61 0 cyano) pyridyl]thiourea
N-[2-(2-(3,6-difluoro)pyridyl)ethyl]-Ν' -[2-(5cyano) pyridyl]thiourea
N-T2-(2-(3,6-difluoro)pyridyl)ethyl]-Ν' -[2-(5cyano)pyrazinyl]thiourea
N-[2-(2-(3,6-difluoro)pyridyl)ethyl]-Ν' -[2-(6cyano)pyraz iny1]thiourea
N-[2-(2-(3,6-difluoro)pyridyl)ethyl]-Ν' -[(3-(6cyano)pyridazinyl)]thiourea
N-[2-(2-(3,6-difluoro)pyridyl)ethyl]-Ν' -(2-(1,3,420 thiadiazoyl]) thiourea
N-[2-(2-(3,6-difluoro)pyridyl)ethyl]-Ν' -(2benzimidazolyl)thiourea
N-[2-(2-(3,6-difluoro)pyridyl)ethyl]-N*-(2imidazoly1) thiourea
N- [2- (2 - (5,6-dichloro) pyridyl) ethyl] -Ν’ -(2thiazolyl) thiourea
N-[2-(2-(5,6-dichloro)pyridyl)ethyl]-Ν' -[2-(4methyl)thiazolyl]thiourea
N-[2-(2-(5,6-dichloro)pyridyl)ethyl]-Ν' -[2-(4,53 0 dimethyl) thiazolyl] thiourea
N-[2-(2-(5,6-dichloro)pyridyl)ethyl]-Ν' -[2-(4cyano)thiazolyl]thiourea
N-[2-(2-(5,6-dichloro)pyridyl)ethyl]-Ν' -(2-(4tri fluoromethyl)thiazolyl]thiourea
5 N- [2-(2-(5,6-dichloro)pyridyl)ethyl]-N*-(2benzothiazolyl)thiourea
N-(2-(2-(5,6-dichloro)pyridyl)ethyl]-Ν' -(2-(6fluoro)benzothiazolyl]thiourea
N-[2-(2-(5,6-dichloro)pyridyl)ethyl]-Ν' -[2-(64 0 chloro) pyrazinyl] thiourea
N-[2-(2-(5,6-dichloro)pyridyl)ethyl]-Ν' -[2-(4ethy1)thiazolyl]thiourea
N-[2-(2-(5,6-dichloro)pyridyl)ethyl]-N*-(2-(4-(3pyridyl)thiazolyl)]thiourea
N-[2-(2-(5,6-dichloro)pyridyl)ethyl]-Ν' - (2-(4-(3-
AP Ο Ο Ο 3 8 4
Χ-8571Α
-83Ν-(2-(2-(5,6-dichloro)pyridyl) ethyl]-Ν*-(2pyridy1) thiourea
Ν-(2-(2-(5,6-dichloro)pyridyl)ethyl]-N'-(2-(6bromo)pyridyl]thiourea
N-(2-(2-(5,6-dichloro)pyridyl)ethyl]-Ν' -[2-(5bromo)pyridyl]thiourea
N-[2-(2-(5,6-dichloro)pyridyl)ethyl]-Ν' -(2-(6chloro)pyridyl]thiourea
N-[2-(2-(5,6-dichloro)pyridyl)ethyl]-N*-[2-(510 chloro)pyridyl]thiourea
N-[2-(2-(5,6-dichloro)pyridyl)ethyl]-Ν' -(2-(6methyl) pyridyl]thiourea
N-[2-(2-(5,6-dichloro)pyridyl)ethyl]-Ν' -[2-(5methyl) pyridyl]thiourea
N-[2 - (2 - (5,6-dichloro)pyridyl)ethyl]-N‘-[2-(6trifluoromethyl) pyridyl]thiourea
N-[2-(2-(5,6-dichloro)pyridyl)ethyl]-N*-[2-(5trifluoromethyl)pyridyl]thiourea
N-[2-(2 - (5,6-dichloro)pyridyl)ethyl]-N‘-[2-(620 ethyl)pyridyl]thiourea
N-(2-(2-(5,6-dichloro)pyridyl)ethyl]-Ν’ -[2-(5ethyl) pyridyl]thiourea
N-[2-(2-(5,6-dichloro)pyridyl) ethyl]-Ν' -[2-(5chloro)pyrazinyl]thiourea
N-[2-(2-(5,6-dichloro) pyridyl) ethyl] -Ν' -[2-(6bromo) pyrazinyl]thiourea
N-[2-(2-(5,6-dichloro)pyridyl)ethyl]-Ν' -(2-(5bromo)pyrazinyl]thiourea
N-[2-(2-(5,6-dichloro)pyridyl)ethyl]-Ν' -[(3-(63 0 bromo)pyridazinyl)]thiourea
N-[2-(2-(5,6-dichloro)pyridyl)ethyl]-Ν' -((3-(6chloro)pyridazinyl)]thiourea
N-[2-(2-(5,6-dichloro)pyridyl)ethyl]-Ν' -(2-(6cyano)pyridyl]thiourea
N-[2-(2-(5,6-dichloro)pyridyl)ethyl]-Ν' -[2-(5cyano) pyridyl]thiourea
N-[2-(2-(5,6-dichloro)pyridyl)ethyl]-N'-[2-(5cyano)pyrazinyl]thiourea
N-[2-(2-(5,6-dichloro)pyridy1)ethyl]-N*-(2-(640 cyano)pyrazinyl]thiourea
N-[2-(2-(5,6-dichloro)pyridyl)ethyl]-N* - [(3-(6cyano,pyridazinyl)]thiourea
Ν-12 - (2- (5,6-dichloro) pyridyl) ethyl]-Ν'-(2-(1,3,4thiadiazoyl]) thiourea
5 N-[2-(2-(5,6-dichloro)pyridyl)ethyl]-Ν' -(2-
X-8571A
-84N-[2 - (2 - (5,6-dichloro) pyridyl) ethyl]-N’- (2imidazoly1) thiourea
N-[2-(2-(3,6-dichloro,pyridyl, ethyl] -Ν’ - (2thiazolyl) thiourea
N-[2-(2-(3,6-dichloro)pyridyl)ethyl)-Ν' -[2-(4methy1)thiazolyl]thiourea
N-[2-(2-(3,6-dichloro)pyridyl)ethyl)-Ν' -[2-(4,5dimethyl)thiazolyl]thiourea
N-(2-(2-(3,6-dichloro)pyridyl)ethyl)-Ν' -(2- (41 0 cyano)thiazolyl)thiourea
N-[2-(2-(3,6-dichloro)pyridyl)ethyl]-N'-[2-(4trifluoromethyl)thiazolyl]thiourea
N-(2-(2-(3,6-dichloro)pyridyl)ethyl]-Ν' -(2benzothiazolyl)thiourea
N-[2-(2-(3,6-dichloro) pyridyl) ethyl] -Ν' -[2-(6fluoro)benzothiazolyl]thiourea
N-[2-(2-(3,6-dichloro)pyridyl)ethyl]-Ν' -[2-(6chloro)pyrazinyl]thiourea
N-[2-(2-(3,6-dichloro)pyridyl)ethyl]-Ν' -(2- (42 0 ethyl) thiazolyl] thiourea
N-[2-(2-(3,6-dichloro)pyridyl)ethyl]-N'-[2-(4-(3pyridyl)thiazolyl)]thiourea
N-[2-(2 - (3,6-dichloro)pyridyl)ethyl]-N'-[2-(4-(3nitrophenyl)thiazolyl)]thiourea
N-[2-(2-(3,6-dichloro) pyridyl) ethyl] -Ν' - (2pyridyl)thiourea
N-[2-(2-(3,6-dichloro)pyridyl)ethyl]-Ν' - [2 - (6bromo) pyridyl]thiourea
N-[2-(2-(3,6-dichloro,pyridyl)ethyl]-Ν' - [2- (53 0 bromo) pyridyl] thiourea
N-[2-(2-(3,6-dichloro)pyridyl)ethyl]-Ν' -[2-(6chloro)pyridyl]thiourea
N-[2-(2-(3,6-dichloro)pyridyl)ethyl]-Ν' -[2-(5chloro)pyridyl]thiourea
N-[2-(2-(3,6-dichloro) pyridyl) ethyl] -Ν' - [2 - (6methy 1) pyridyl ] thiourea
N-[2-(2-(3,6-dichloro)pyridyl)ethyl]-Ν' -[2-(5methy1) pyridyl]thiourea
N-[2-(2-(3,6-dichloro)pyridyl)ethyl]-Ν' -[2-(64 0 tri fluoromethyl) pyridyl]thiourea
N-[2-(2-(3,6-dichloro)pyridyl)ethyl]-Ν' -[2-(5tri fluoromethyl) pyridyl]thiourea
N-[2-(2-(3,6-dichloro)pyridyl)ethyl]-Ν' -[2 - (6ethyl) pyridyl]thiourea
Χ-8571Α
ΑΡ Π π ο 3 8 4
-85Ν-[2-(2-(3,6-dichloro)pyridyl)ethyl]-Ν' -[2-(5chloro)pyrazinyl]thiourea
N- (2 - (2-(3,6-dichloro)pyridyl)ethyl]-N'-[2-(6bromo)pyrazinyl]thiourea
N- (2- (2 - (3,6-dichloro)pyridyl)ethyl]-Ν' -(2-(5bromo)pyrazinyl]thiourea
N- (2 - (2 - (3,6-dichloro)pyridyl)ethyl]-Ν' - ((3-(6bromo)pyridazinyl)]thiourea
N- [2- (2 - (3 ,6-dichloro)pyridyl)ethyl]-Ν' -[(3-(610 chloro)pyridazinyl) ] thiourea
N-[2-(2-(3,6-dichloro)pyridyl)ethyl]-N'-[2-(6cyano)pyridyl]thiourea
N-(2-(2-(3,6-dichloro)pyridyl)ethyl]-Ν' -(2-(5cyano)pyridyl]thiourea
N-[2-(2-(3,6-dichloro) pyridyl) ethyl] -Ν' -(2-(5cyano)pyraziny1]thiourea
N- [2- (2-(3,6-dichloro)pyridyl)ethyl]-Ν' -[2-(6cyano)pyrazinyl]thiourea
N- [2- (2-(3,6-dichloro)pyridyl)ethyl]-Ν' -[(3-(62 0 cyano) pyridazinyl) ] thiourea
N-[2-(2-(3,6-dichloro)pyridyl)ethyl]-Ν' - (2-(1,3,4thiadiazoyl]) thiourea
N- [2- (2-(3,6-dichloro)pyridyl) ethyl]-N*-(2benzimidazolyl)thiourea
5 N- [2- (2- (3,6-dichloro)pyridyl)ethyl] -Ν' -(2imidazoly1) thiourea
N- [2- (cis-2-pyridyl)cyclopropyl]-Ν'-(2thiazolyl) thiourea
N- [2- (cis-2-pyridyl)cyclopropyl]-Ν' -[2-(43 0 methyl) thiazolyl ] thiourea
N- [2-(cis-2-pyridyl)cyclopropyl]-Ν' -[2- (4,5dimethyl)thiazolyl]thiourea
N-[2-(cis-2-pyridyl)cyclopropyl]-Ν' -(2benzothiazolyl)thiourea
5 N-'[2- (cis-2-pyridyl) cyclopropyl] -Ν' - (2- (6fluoro)benzothiazolyl]thiourea
N- (2-(cis-2-pyridyl)cyclopropyl]-Ν' -(2-(6chloro)pyrazinyl]thiourea
N- [2 - (cis-2-pyridyl)cyclopropyl]-N'-[2-(4-(34 0 pyridyl) thiazolyl) ] thiourea
N- [2- (cis-2-pyridyl)cyclopropyl)-Ν' -[2-(4-(3nitrophenyl)thiazolyl)]thiourea
N- [2 - (cis-2-pyridyl)cyclopropyl]-Ν' -[2-(6bromo) pyridyl]thiourea
5 N- [2- (cis-2-pyridyl)cyclopropyl] -Ν' - [2-(6chloro) pyridyl]thiourea
X-8571A
-> ;· Λ - . £
-86Ν- [2-(cis-2-pyridyl)cyciopropyl]-Ν' -[2-(6methy1) pyridyl]thiourea
N-[2-(cis-2-pyridyl)cyciopropyl]-Ν' -[2-(6tri fluoromethyl) pyridyl]thiourea
N-[2-(cis-2-pyridyl)cyciopropyl]-Ν' -[2-(6ethyl) pyridyl]thiourea
N-(2-(cis-2-pyridyl)cyciopropyl]-Ν' -[2-(6bromo)pyraz inyl]thiourea
N-[2-(cis-2-pyridyl)cyciopropyl]-Ν' -[(3-(6bromo)pyridazinyl)]thiourea
N-[2-(cis-2-pyridyl)cyciopropyl]-N'-[2-(6cyano) pyridyl]thiourea
N-[2-(cis-2-pyridyl)cyciopropyl]-Ν' -[2-(5cyano) pyridyl]thiourea
N-[2-(cis-2-pyridyl)cyciopropyl]-Ν' -(2- (5cyano)pyrazinyl]thiourea
N-[2-(cis-2-pyridyl)cyciopropyl]-Ν' -[2-(6cyano)pyrazinyl]thiourea
N-.[2- (cis-2-pyridyl)cyciopropyl] -Ν' -[ (3-(6cyano)pyridazinyl)]thiourea
N-[2-(cis-2-pyridyl)cyciopropyl]-N'-(2-(l,3,4thiadiazoyl]) thiourea
N-[2-(cis-2-pyridyl)cyciopropyl]-Ν' - (2benzimidazolyl)thiourea
N-[2-(cis-2-pyridyl)cyciopropyl]-Ν' -(2imidazoly1) thiourea
N-[2-(cis-2-(6-fluoro)pyridyl,cyciopropyl]-Ν' -(2thiazolyl) thiourea
N-(2-(cis-2-(6-fluoro)pyridyl)cyciopropyl]-Ν' -(2-idmethyl )thiazolyl]thiourea
N-[2-(cis-2-(6-fluoro)pyridyl)cyciopropyl]-Ν' -[2-(4,5 dimethyl)thiazolyl]thiourea
N-[2-(cis-2-(6-fluoro)pyridyl)cyciopropyl]-Ν' -(2benzothiazolyl)thiourea
N-(2-(cis-2-(6-fluoro)pyridyl)Cyciopropyl]-Ν' -[2-(6fluoro)benzothiazolyl]thiourea
N-[2-(cis-2-(6-fluoro)pyridyl)cyciopropyl]-Ν' -(2-(6chloro)pyrazinyl]thiourea
N-[2-(cis-2-(6-fluoro)pyridyl)cyciopropyl]-Ν' -[2-(4(3-pyridyl)thiazolyl)]thiourea
N-[2-(cis-2-(6-fluoro,pyridyl,cyciopropyl]-Ν' -[2-(4{3-nitropheny1)thiazolyl)]thiourea
N-[2-(cis-2-(6-fluoro)pyridyl)cyciopropyl]-Ν' -[2-(6bromo, pyridyl]thiourea
N-(2-(cis-2-(6-fluoro)pyridyl)cyciopropyl]-Ν' -[2-(6chloro)pyridyl]thiourea
AP 0 0 0 3 8 4
X-8571A
-87N-[2-(cis-2-(6-fluoro)pyridyl)cyclopropyl]-Ν' -[2-(6methy1) pyridyl]thiourea
N-[2-(cis-2-(6-fluoro)pyridyl)cyclopropyl]-Ν' -(2-(6tri fluoromethyl) pyridyl]thiourea
N-'[2- (cis-2- (6-fluoro)pyridyl)cyclopropyl] -N* -(2-(5trifluoromethyl)pyridyl]thiourea
N-(2-(cis-2-(6-fluoro)pyridyl)cyclopropyl]-Ν'-(2-(6ethyl)pyridyl]thiourea
N- (2-(cis-2-(6-fluoro)pyridyl)cyclopropyl]-Ν' -(2-(510 ethyl) pyridyl] thiourea
N-[2-(cis-2-(6-fluoro)pyridyl)cyclopropyl]-Ν' -(2-(6bromo)pyrazinyl]thiourea
N-[2-(cis-2-(6-fluoro)pyridyl)cyclopropyl]-Ν' - [(3-(6bromo)pyridazinyl)]thiourea
N-(2-(cis-2-(6-fluoro)pyridyl)cyclopropyl]-N'-(2-(6cyano)pyridyl]thiourea
N-(2-(cis-2-(6-fluoro)pyridyl)cyclopropyl]-Ν' -(2-(5cyano) pyridyl]thiourea
N-[2-(cis-2-(6-fluoro)pyridyl)cyclopropyl]-Ν' -(2-(52 0 cyano) pyrazinyl] thiourea
N-[2-(cis-2-(6-fluoro)pyridyl)cyclopropyl]-Ν' -(2-(6cyano)pyrazinyl]thiourea
N- [2-(cis-2-(6-fluoro)pyridyl)cyclopropyl]-Ν' - ((3-(6cyano)pyridazinyl)]thiourea
5 N- (2-(cis-2-{6-fluoro)pyridyl)cyclopropyl]-Ν' -(2[1,3,4-thiadiazoyl]) thiourea
N-(2-(cis-2-(6-fluoro)pyridyl)cyclopropyl]-N*-(2benzimidazolyl)thiourea
N- (2-(cis-2-(6-fluoro)pyridyl)cyclopropyl]-Ν' -(23 0 imidazolyl)thiourea
N-(2-(cis-2-(6-chloro)pyridyl)cyclopropyl]-Ν' -(2thiazolyl) thiourea
N-(2-(cis-2-<6-chloro)pyridyl)cyclopropyl]-N‘-(2-(4methyl)thiazolyl]thiourea
5 N- (2-(cis-2-(6-chloro)pyridyl)cyclopropyl]-Ν' -(2-(4,5dimethyl)thiazolyl]thiourea
N-[2-(cis-2-(6-chloro)pyridyl)cyclopropyl]-N*-(2- (4cyano)thiazolyl]thiourea
N-(2-(cis-2-(6-chloro)pyridyl)cyclopropyl]-Ν' -[2-(44 0 trifluoromethyl)thiazolyl]thiourea
N-(2-(cis-2-(6-chloro)pyridyl)cyclopropyl]-Ν' -(2benzothiazolyl)thiourea
N-[2-(cis-2-(6-chloro)pyridyl)cyclopropyl]-Ν' -[2-(6f luoro) benzothiazolyl ] thiourea
5 N-(2-(cis-2-(6-chloro)pyridyl)cyclopropyl]-Ν' -(2-(6-
X-8571A
-88N- [2- (cis-2- (6-chloro)pyridyl) cyclopropyl] -Ν' -(2-(4ethyl)thiazolyl]thiourea
N-[2-(cis-2-(6-chloro)pyridyl)cyclopropyl]-Ν' -[2-(4(3-pyridyl)thiazolyl)]thiourea
N-[2-(cis-2-(6-chloro)pyridyl)cyclopropyl]-Ν' -[2-(4(3-nitrophenyl)thiazolyl)]thiourea
N-[2-(cis-2-(6-chloro)pyridyl)cyclopropyl]-Ν' -(2pyridyl) thiourea
N-(2-(cis-2-(6-chloro)pyridyl)cyclopropyl]-Ν' -[2-(610 bromo) pyr idyl] thiourea
N- [2- (cis-2 - (6-chloro) pyr idyl) cyclopropyl] -Ν' -[2-(5bromo)pyridyl]thiourea
N-[2-(cis-2-(6-chloro)pyridyl)cyclopropyl]-Ν' -[2-(6chloro) pyridyl]thiourea
N-[2-(cis-2-(6-chloro)pyridyl)cyclopropyl]-Ν' -[2-(5chloro)pyridyl]thiourea
N-(2-(cis-2-(6-chloro)pyridyl) cyclopropyl]-Ν' - [2-(6methy1) pyridyl]thiourea
N-[2-(cis-2-(6-chloro)pyridyl)cyclopropyl]-Ν' -[2-(52 0 methyl) pyr idyl] thiourea
N-[2-(cis-2-(6-chloro)pyridyl)cyclopropyl3-N' - [2- tetri f luoromethyl) pyr idyl ] thiourea
N-(2-(cis-2-(6-chloro)pyridyl)cyclopropyl]-Ν' -[2-(5trifluoromethyl) pyridyl]thiourea
5 N-[2-(cis-2-(6-chloro)pyridyl)cyclopropyl]-Ν' -[2-(6ethyl) pyridyl]thiourea
N-(2-(cis-2-(6-chloro)pyridyl)cyclopropyl]-Ν' -[2-(5ethy1) pyridyl]thiourea
N-(2-(cis-2-(6-chloro)pyridyl)cyclopropyl]-Ν' -[2-(53 0 chloro) pyrazinyl] thiourea
N-[2-(cis-2-(6-chloro)pyridyl)cyclopropyl]-Ν' -[2-(6bromo)pyrazinyl]thiourea
N-[2-(cis-2-(6-chloro)pyridyl)cyclopropyl]-Ν' -[2-(5bromo)pyrazinyl]thiourea
5 N- (2- (cis-2 - (6-chloro) pyr idyl) cyclopropyl] -Ν' - [ (3-(6bromo)pyridazinyl)]thiourea
N-[2-(cis-2-(6-chloro)pyridyl)cyclopropyl]-Ν' -[(3-(6chloro)pyridazinyl)]thiourea
N-[2-(cis-2-(6-chloro)pyridyl)cyclopropyl]-Ν' -[2-(64 0 cyano) pyr idyl ] thiourea
N-(2-(cis-2-(6-chloro)pyridyl)cyclopropyl]-N’-[2-(5cyano)pyridyl]thiourea
N-[2-(cis-2-(6-chloro)pyridyl)cyclopropyl]-N'-[2-(5cyano)pyrazinyl]thiourea
5 N- [2- (cis-2- (6-chloro)pyridyl) cyclopropyl] -Ν' -(2-(6cyano)pyrazinyl]thiourea
AP Ο Ο Ο 3 8 4
Χ-8571Α
-89Ν-[2-(cis-2-(6-chloro)pyridyl)cyclopropyl] -Ν' - ((3-(6cyano)pyridazinyl)]thiourea
N-[2-(cis-2-(6-chloro)pyridyl)cyclopropyl]-N'-(2[1,3,4-thiadiazoyl]) thiourea
N-[2-(cis-2-(6-chloro)pyridyl)cyclopropyl]-Ν' -(2benzimidazolyl) thiourea
N-[2-(cis-2-(6-chloro)pyridyl)cyclopropyl]-Ν' -(2imidazoly1, thiourea
N-[2-(cis-2-(6-methoxy)pyridyl)cyclopropyl]-Ν' - (210 thiazolyl) thiourea
N- [2-(cis-2-(6-methoxy)pyridyl)cyclopropyl]-Ν' -[2- (4methy1)thiazolyl]thiourea
N-[2-(cis-2-(6-methoxy)pyridyl)cyclopropyl)-Ν' -(2(4,5-dimethyl)thiazolyl]thiourea
N-[2-(cis-2-(6-methoxy)pyridyl)cyclopropyl]-Ν' - (2benzothiazolyl)thiourea
N-[2-(cis-2-(6-methoxy)pyridyl)cyclopropyl]-Ν' -[2- (6fluoro)benzothiazolyl]thiourea
N-[2-(cis-2-(6-methoxy)pyridyl)cyclopropyl]-Ν' -[2-(62 0 chloro) pyrazinyl] thiourea
N- [2- (cis-2- (6-methoxy)pyridyl)cyclopropyl] -N* - [2- (4(3-pyridyl)thiazolyl)]thiourea
N- [2- (cis-2-(6-methoxy)pyridyl)cyclopropyl]-Ν' -[2-(4(3-nitrophenyl)thiazolyl)]thiourea
5 N-[2-(cis-2-(6-methoxy)pyridyl)cyclopropyl]-Ν' -(2pyridyl)thiourea
N-[2-(cis-2-(6-methoxy)pyridyl)cyclopropyl]-Ν' -[2- (6bromo) pyridyl]thiourea
N-[2-(cis-2-(6-methoxy,pyridyl)cyclopropyl]-Ν' -[2-(63 0 chloro) pyridyl]thiourea
N-[2-(cis-2-(6-methoxy)pyridyl)cyclopropyl]-Ν' -[2- (6methy1) pyridyl]thiourea
N-[2-(cis-2-(6-methoxy)pyridyl)cyclopropyl]-N'-[2- (5methy1) pyridyl]thiourea
5 N- (2- (cis-2- (6-methoxy)pyridyl)cyclopropyl] -Ν' - [2- tetri fluoromethyl ) pyridyl]thiourea
N-(2 - (cis-2-(6-methoxy)pyridyl)cyclopropyl)-N'-[2-(5tri fluoromethyl) pyridyl]thiourea
N-[2-(cis-2-(6-methoxy)pyridyl) cyclopropyl]-Ν' -[2 - (64 0 ethyl) pyridyl] thiourea
N-[2- (cis-2-(6-methoxy)pyridyl)cyclopropyl]-Ν' -[2-(5ethyl) pyridyl]thiourea
N-[2-(cis-2-(6-methoxy)pyridyl)cyclopropyl]-Ν' -[2- (6bromo)pyrazinyl)thiourea
N-(2- (cis-2- (6-methoxy)pyridyl)cyclopropyl] -Ν' - [ (3-(6-
X-8571A
-90N- [2-(cis-2-(6-methoxy) pyridyl, cyclopropyl]-Ν' -[2-(6cyano)pyridyl]thiourea
N- [2-(cis-2-(6-methoxy)pyridyl}cyclopropyl]-Ν’ -[2-(5cyano)pyridyl]thiourea
N-[2-(cis-2-(6-methoxy)pyridyl)cyclopropyl]-N‘-(2-(5cyano)pyrazinyl]thiourea
N-[2-(cis-2-(6-methoxy)pyridyl)cyclopropyl]-Ν' -[2-(6cyano)pyrazinyl]thiourea
N-(2-(cis-2-(6-methoxy)pyridyl)cyclopropyl]-Ν' -[(3-(610 cyano) pyridazinyl) ] thiourea
N-(2-(cis-2-(6-methoxy)pyridyl)cyclopropyl]-Ν' -(2[1,3,4-thiadiazoyl]) thiourea
N-[2-(cis-2-(6-methoxy)pyridyl,cyclopropyl]-Ν' -(2benzimidazolyl)thiourea
N-[2-(cis-2 - (6-methoxy) pyr idyl) cyclopropyl] -Ν' -(2imidazolyl)thiourea
N-[2-(cis-2-(6-ethoxy)pyridyl)cyclopropyl]-Ν' -(2thiazolyl)thiourea
N-[2-(cis-2-(6-ethoxy)pyridyl)cyclopropyl]-Ν' -[2-(42 0 methyl) thiazolyl] thiourea
N-(2-(cis-2-(6-ethoxy)pyridyl)cyclopropyl]-Ν' -[2-(4,5dimethyl)thiazolyl]thiourea
N-[2-(cis-2-(6-ethoxy)pyridyl,cyclopropyl]-Ν' -(2benzothiazolyl)thiourea
N-[2-(cis-2 - (6-ethoxy) pyridyl) cyclopropyl] -Ν' -[2-(6fluoro)benzothiazolyl]thiourea
N- [2-(cis-2-(6-ethoxy)pyridyl)cyclopropyl]-Ν' -[2-(6chloro)pyrazinyl]thiourea
N- [2-(cis-2-(6-ethoxy)pyridyl)cyclopropyl]-Ν' -[2-(43 0 (3-pyridyl) thiazolyl) ] thiourea
N-[2-(cis-2-(6-ethoxy) pyridyl)cyclopropyl]-N' — [2-(4(3-nitrophenyl)thiazolyl)]thiourea
N-[2-(cis-2-(6-ethoxy)pyridyl)cyclopropyl]-Ν' -(2pyridyl) thiourea
5 N-(2-(cis-2- (6-ethoxy)pyridyl)cyclopropyl]-N'-[2-(6bromo) pyridyl]thiourea
N-[2-(cis-2-(6-ethoxy)pyridyl)cyclopropyl]-Ν' -[2-(6chloro) pyridyl]thiourea
N-[2-(cis-2-(6-ethoxy)pyridyl)cyclopropyl]-Ν' -[2-(64 0 methyl)pyridyl] thiourea
N-[2-(cis-2-(6-ethoxy,pyridyl) cyclopropyl]-Ν' -[2-(5methyl) pyridyl]thiourea
N-[2-(cis-2-(6-ethoxy)pyridyl)cyclopropyl]-Ν' -[2-tetri fluoromethyl ) pyridyl]thiourea
5 N-[2-(cis-2-(6-ethoxy)pyridyl)cyclopropyl]-Ν' -[2-(5-
AP Ο Ο Ο 3 8 4
Χ-8571Α
-91Ν-[2-(cis-2-(6-ethoxy)pyridyl)cyclopropyl]-Ν' -(2-(6ethyl)pyridyl]thiourea
N-(2-(cis-2-(6-ethoxy)pyr idyl)cyclopropyl]-Ν' -(2-(5ethyl) pyridyl]thiourea
N-(2-(cis-2-(6-ethoxy)pyridyl)cyclopropyl]-N'-[2-(6bromo)pyrazinyl]thiourea
N-(2-(cis-2-(6-ethoxy)pyridyl)cyclopropyl]-N’-[(3-(6bromo)pyridazinyl)]thiourea
N-(2-(cis-2-(6-ethoxy)pyr idyl)cyclopropyl]-Ν' -[2-(610 cyano) pyr idyl] thiourea
N-(2-(cis-2-(6-ethoxy)pyridyl)cyclopropyl]-Ν' -(2-(5cyano) pyridyl]thiourea
N- (2-(cis-2-(6-ethoxy)pyridyl)cyclopropyl]-Ν' -(2- (5cyano)pyrazinylJ thiourea
N-(2-(cis-2-(6-ethoxy)pyridyl)cyclopropyl]-Ν'-[2-(6cyano)pyrazinyl]thiourea
N-[2-(cis-2-(6-ethoxy)pyridyl)cyclopropyl]-Ν' -[(3-(6cyano)pyridazinyl)]thiourea
N-[2-(cis-2-(6-ethoxy)pyridyl)cyclopropyl]-Ν'-(22 0 [1,3,4-thiadiazoyl]) thiourea
N-[2-(cis-2-(6-ethoxy)pyridyl)cyclopropyl]-Ν' -(2benzimidazolyl)thiourea
N-[2-(cis-2-(6-ethoxy)pyridyl)cyclopropyl]-Ν' -(2imidazolyl) thiourea
5 N- [2 - (2-[1,3-pyrimidyl] ) ethyl] -Ν' -(2thiazolyl) thiourea
N-[2-(2-[1,3-pyrimidyl]) ethyl)-N’-(2-(4methyl)thiazolyl]thiourea
N-(2-(2-[1,3-pyrimidyl]) ethyl]-Ν' -(2-(4,53 0 dimethyl) thiazolyl] thiourea
N-(2-(2-(1,3-pyrimidyl]) ethyl]-N*-[2-(4cyano)thiazolyl]thiourea
N- [2-{2-[1,3-pyrimidy1]) ethyl]-N'-[2- (4 trifluoromethyl)thiazolyl]thiourea
N-(2-(2-(1,3-pyrimidyl] ) ethyl] -N'-(2benzothiazolyl)thiourea
N-[2-(2-[1,3-pyrimidyl]) ethyl]-N*-(2-(6fluoro)benzothiazolyl]thiourea
N- [2-(2-[1,3-pyrimidyl]) ethyl]-Ν' -(2-(64 0 chloro) pyrazinyl] thiourea
N-[2-(2-(1,3-pyrimidyl]) ethyl]-Ν' -(2-(4ethyl)thiazolyl]thiourea
N- [2-(2-[1,3-pyrimidyl]) ethyl]-N'- (2- (4- (3pyridyl)thiazolyl)]thiourea
5 N- (2 - (2- [1,3-pyrimidyl]) ethyl) -N' - [2- (4- (3-
X-8571A
-92r< /·
N- [2- (2-[1,3-pyrimidyl]) ethyl] -Ν'-(2-pyridyl) thiourea N- [2-(2-[1,3-pyrimidyl]) ethyl]-Ν’ -[2-(6bromo)pyridyl]thiourea
N-[2-(2-[1,3-pyrimidyl]) ethyl]-Ν' -[2-(55 bromo)pyridyl]thiourea
N- (2 - (2-(1,3-pyrimidyl]) ethyl]-N‘-[2-(6chloro)pyridyl]thiourea
N- [2-(2-[1,3-pyrimidyl]) ethyl]-N‘-[2-(5chloro)pyridyl]thiourea
N-(2-(2-(1,3-pyrimidyl] ) ethyl] -Ν’ - [2- (6methy1) pyridyl]thiourea
N- (2 - (2-[1,3-pyrimidyl]) ethyl]-Ν' -[2-(5methyl) pyridyl]thiourea
N- (2-(2-[1,3-pyrimidyl]) ethyl]-Ν' -[2-(61 5 trifluoromethyl)pyridyl]thiourea
N- [2 - (2-[1,3-pyrimidyl]) ethyl]-Ν' -[2-(5trifluoromethyl) pyridyl]thiourea
N- [2 - (2-[1,3-pyrimidyl]) ethyl]-Ν' -[2-(6ethyl)pyridyl]thiourea
0 N- [2 - (2- [ 1,3-pyrimidyl ] ) ethyl] -Ν' - (2 - (5ethyl) pyridyl]thiourea
N-.{2- (2-(1,3-pyrimidyl] ) ethyl] -Ν' -[2-(5chloro)pyrazinyl]thiourea
N- [2 - (2-[1,3-pyrimidyl]) ethyl]-N'-(2-(62 5 bromo) pyrazinyl ] thiourea
N- [2 - (2-[1,3-pyrimidyl]) ethyl]-Ν' -[2-(5bromo)pyrazinyl]thiourea
N- [2 - (2-(1,3-pyrimidyl]) ethyl]-Ν' - ((3-(6bromo)pyridazinyl)]thiourea
N-[2-(2-(1,3 -pyrimidyl]) ethyl] -Ν' - [ (3-(6chloro)pyridazinyl)]thiourea
N-[2-(2-[1,3-pyrimidyl]) ethyl]-N'-[2-(6cyano)pyridyl]thiourea
N- [2 - (2-[1,3-pyrimidyl]) ethyl]-Ν' -(2-(53 5 cyano) pyr idyl] thiourea
N- [2 - (2-[1,3-pyrimidyl]) ethyl]-Ν' -[2-(5cyano)pyrazinyl]thiourea
N- [2 - (2-[1,3-pyrimidyl]) ethyl] -Ν' -(2-(6cyano)pyrazinyl]thiourea
N-[2-(2-(1,3-pyrimidyl] ) ethyl] -Ν' - [ (3-(6cyano)pyridazinyl)]thiourea
N-[2-(2-[1,3-pyrimidyl]) ethyl]-N'- (2-[1,3,4thiadiazoyl]) thiourea
N-[2 - (2-[1,3-pyrimidyl]) ethyl]-N*-(24 5 benzimidazolyl) thiourea
AP Ο Ο Ο 3 8 4
-93X-8571A
Ν- (2-(2- (1,3-pyrimidyl]) ethyl]-Ν' -(2imidazoly1) thiourea
Ν- (2 - (2-pyrazinyl]ethyl]-Ν' -(2-thiazolyl)thiourea N-[2-(2-pyrazinyl]ethyl]-Ν' -[2-(45 methyl)thiazolyl]thiourea
N- [2-(2-pyrazinyl]ethyl]-Ν' -(2-(4,5dimethyl)thiazolyl]thiourea
N-[2-(2-pyrazinyl]ethyl]-N*- [2 - (4cyano)thiazolyl]thiourea 10 N- [2 - (2-pyrazinyl] ethyl] -Ν' - [2 - (4trifluoromethyl)thiazolyl]thiourea
N- [2- (2-pyrazinyl]ethyl] -Ν' - (2-benzothiazolyl) thiourea N- [2-(2-pyrazinyl]ethyl]-Ν' -(2-(6fluoro)benzothiazolyl]thiourea 15 N- [2- (2-pyrazinyl] ethyl] -Ν' -[2-(6chloro)pyrazinyl]thiourea
N- [2-(2-pyrazinyl]ethyl]-Ν' -[2-(4ethyl)thiazolyl]thiourea
N-(2-(2-pyrazinyl]ethyl]-Ν' -(2-(4- (32 0 pyridyl) thiazolyl) ] thiourea
N- [2 - (2-pyrazinyl] ethyl] -N* -(2-(4-(3nitropheny1)thiazolyl)]thiourea
N- (2-(2-pyrazinyl]ethyl]-Ν’ -(2-pyridyl)thiourea N- [2-(2-pyrazinyl]ethyl]-N’-(2-(62 5 bromo) pyridyl] thiourea
N-[2-(2-pyrazinyl]ethyl]-Ν' - (2 - (5bromo) pyridyl]thiourea
N-12-(2-pyrazinyl]ethyl]-N'-(2-(6ohloro)pyridyl]thiourea
0 N- (2 - (2-pyrazinyl] ethyl] -Ν' -(2-(5chlcro)pyridyl]thiourea
N- [2-(2-pyrazinyl]ethyl]-N'-[2-(6methyl,pyridyl]thiourea
N-[2-(2-pyrazinyl]ethyl]-Ν' -[2 - (53 5 methyl)pyridyl] thiourea
N-(2-(2-pyrazinyl]ethyl]-Ν' - (2 - (6trifluoromethyl) pyridyl]thiourea
N- [2-(2-pyrazinyl]ethyl]-N*-[2-(5trifluoromethyl) pyridyl]thiourea
0 N- (2 - (2-pyrazinyl]ethyl] -Ν' - [2 - (6ethyl) pyridyl]thiourea
N- [2-(2-pyrazinyl]ethyl]-N'-(2-(5ethvl) pyridyl]thiourea
N- [2-(2-pyrazinyl]ethyl]-Ν' -(2-(5-
X-8571A
-94N- (2-(2-pyrazinyl]ethyl]-Ν' -[2-(6bromo)pyrazinyl]thiourea
N- [2-(2-pyrazinyl]ethyl]-Ν' -[2-(5bromo)pyrazinyl]thiourea
N-[2-(2-pyrazinyl]ethyl]-Ν' -[(3-(6bromo)pyridazinyl)]thiourea
N- [2-(2-pyrazinyl]ethyl]-Ν' - ((3-(6chloro)pyridazinyl)]thiourea
N-[2-(2-pyrazinyl]ethyl]-Ν' -(2-(610 cyano)pyridyl]thiourea
N- [2-(2-pyrazinyl]ethyl]-N'-[2-(5cyano)pyridyl]thiourea
N-(2-(2-pyrazinyl]ethyl]-Ν' -[2-(5cyano)pyrazinyl]thiourea
N-[2-(2-pyrazinyl]ethyl]-Ν' -[2-(6cyano)pyrazinyl]thiourea
N-(2-(2-pyrazinyl]ethyl]-Ν' -[(3-(6cyano)pyridazinyl)]thiourea
N-[2-(2-pyrazinyl]ethyl]-Ν'-(2-(1,3,42 0 thiadiazoyl]) thiourea
N-[2-(2-pyrazinyl]ethyl]-Ν' -(2-benzimidazolyl)thiourea N-[2-(2-pyrazinyl]ethyl]-Ν' -(2-imidazolyl) thiourea N- [2-(3-pyridazinyl)ethyl]-Ν' - (2-thiazolyl) thiourea N-[2-(3-pyridazinyl)ethylj-Ν' -[2-(42 5 methyl)thiazolyl]thiourea
N-[2-(3-pyridazinyl)ethyl]-N'-[2-(4,5dimethyl)thiazolyl]thiourea
N-[2-(3-pyridazinyl)ethyl]-Ν' -(2-(4cyano)thiazolyl]thiourea
0 N- [2 - (3-pyridazinyl) ethyl] -Ν' -[2-(4trifluoromethyl)thiazolyl]thiourea
N- (2-(3-pyridazinyl,ethyl]-Ν' -(2benzothiazolyl,thiourea
N- [2-(3-pyridazinyl)ethyl]-Ν' -[2-(63 5 fluoro)benzothiazolyl]thiourea
N- [2-(3-pyridazinyl)ethyl]-Ν' -[2-(6chloro)pyrazinyl]thiourea
N-[2-(3-pyridazinyl)ethyl]-Ν' -[2-(4ethy1)thiazolyl]thiourea
0 N- [2- (3-pyr idaz inyl) ethyl] -N'-(2-(4-(3pyridyl)thiazolyl)]thiourea
N- (2-(3-pyridazinyl)ethyl)-Ν'-(2-(4-(3nitrophenyl)thiazolyl)]thiourea
N-(2-(3-pyridazinyl)ethyl]-Ν' -(2-pyridyl)thiourea
5 N- [2 - (3-pyridazinyl)ethyl] -Ν' -[2-(6bromo)pyridyl]thiourea
AP Ο Ο ο 3 8 4
Χ-8571Α
-95Ν-(2-(3-pyridazinyl)ethyl]-Ν*-[2-(5bromo)pyridyl]thiourea
N-(2-(3-pyridazinyl)ethyl]-Ν' -(2-(6chloro) pyridyl]thiourea
N-(2-(3-pyridazinyl)ethyl]-Ν' -[2-(5chloro) pyridyl]thiourea
N-[2-(3-pyridazinyl)ethyl]-Ν' -(2-(6methyl) pyridyl]thiourea
N-(2-(3-pyridazinyl) ethyl]-Ν' -(2-(50 methyl)pyridyl]thiourea
N-(2-(3-pyridazinyl)ethyl]-Ν' -(2-(6tri fluoromethy1) pyridyl]thiourea
N-[2-(3-pyridazinyl)ethyl]-Ν' -(2-(5trifluoromethyl) pyridyl]thiourea
N-(2-(3-pyridazinyl)ethyl]-N'-(2-(6ethyl) pyridyl]thiourea
N-[2-(3-pyridazinyl)ethyl]-Ν' -[2-(5ethyl) pyridyl]thiourea
N-(2-(3-pyridazinyl)ethyl]-Ν' - [2- (50 chloro)pyrazinyl]thiourea
N-[2-(3-pyridazinyl)ethyl]-Ν' -[2-(6bromo)pyrazinyl]thiourea
N- [2-(3-pyridazinyl)ethyl]-Ν' -(2-(5bromo)pyrazinyl]thiourea
N-(2-(3-pyridazinyl)ethyl]-Ν' - ((3-(6bromo)pyridazinyl)]thiourea
N-(2-(3-pyridazinyl)ethyl]-Ν’ -((3-(6chloro)pyridazinyl)]thiourea
N-[2-(3-pyridazinyl)ethyl]-Ν' -(2-(60 cyano)pyridyl]thiourea
N-(2-(3-pyridazinyl)ethyl]-Ν' -(2-(5cyano)pyridyl]thiourea
N-[2-(3-pyridazinyl)ethyl]-N‘-(2-(5cyano)pyrazinyl]thiourea
N-(2-(3-pyridazinyl)ethyl]-Ν' -(2-(6cyano)pyrazinyl]thiourea
N-[2-(3-pyridazinyl) ethyl]-Ν' -[(3-(6cyano)pyridazinyl)]thiourea
N-(2-(3-pyridazinyl)ethyl]-N'-(2-[l,3,40 thiadiazoyl]) thiourea
N-(2-(3-pyridazinyl) ethyl]-Ν' -(2benzimidazolyl)thiourea
N-(2-(3-pyridazinyl) ethyl]-Ν' -(2-imidazolyl)thiourea N-(2-(2,6-difluoro-3-methoxyphenyl)ethyl)-N*-(25 thiazolyl) thiourea
X-8571A
-96N- (2-(2,6-difluoro-3-methoxyphenyl)ethyl]-Ν' -[2-(4met’nyl) thiazolyl] thiourea
N-[2-(2,6-difluoro-3-methoxyphenyl)ethyl]-N'-[2-(4,5dimethyl)thiazolyl]thiourea
N-[2-(2,6-difluoro-3-methoxyphenyl) ethyl]-Ν' -[2-(4cyano)thiazolyl]thiourea
N-.[2- (2,6-dif luoro-3-methoxyphenyl) ethyl] -Ν' - (2- (4tri fluoromethyl)thiazolyl]thiourea
N-[2-(2,6-difluoro-3-methoxyphenyl)ethyl]-Ν' - (210 benzothiazolyl) thiourea
N-[2-(2,6-difluoro-3-methoxyphenyl,ethyl]-Ν' -[2-(6fluoro)benzothiazolyl]thiourea
N-[2-(2,6-difluoro-3-methoxyphenyl)ethyl]-Ν' -[2-(6chloro)pyrazinyl]thiourea
N-[2-(2,6-difluoro-3-methoxyphenyl)ethyl]-Ν'-[2-(4ethyl)thiazolyl]thiourea
N-[2-(2,6-difluoro-3-methoxyphenyl)ethyl]-Ν' -[2-(4-(3pyridyl)thiazolyl,]thiourea
N-[2-(2,6-difluoro-3-methoxyphenyl)ethyl]-Ν' -[2-(4-(32 0 nitrophenyl)thiazolyl)]thiourea
N-[2-(2,6-difluoro-3-methoxyphenyl)ethyl]-Ν' -(2pyridyl)thiourea
N-[2-(2,6-difluoro-3-methoxyphenyl)ethyl]-Ν' -[2-(6bromo)pyridyl]thiourea
5 N- (2-(2,6-difluoro-3-methoxyphenyl)ethyl]-Ν' -[2-(6chloro)pyridyl]thiourea
N-(2-(2,6-difluoro-3-methoxyphenyl)ethyl]-Ν' -[2-(5chloro) pyridyl]thiourea
N-[2-(2,6-difluoro-3-methoxyphenyl)ethyl]-Ν' -[2-(63 0 methyl,pyridyl] thiourea
N-[2-(2,6-difluoro-3-methoxyphenyl)ethyl]-Ν' -(2-(5methyl) pyridyl]thiourea
N-[2-(2,6-difluoro-3-methoxyphenyl)ethyl]-Ν' -[2-(6tri fluoromethyl) pyridyl]thiourea
5 N- (2 - (2,6-dif luoro-3-methoxyphenyl) ethyl] -Ν' -[2-(5tri fluoromethyl) pyridyl]thiourea
N-[2-(2,6-difluoro-3-methoxyphenyl)ethyl]-Ν' -(2-(6ethyl) pyridyl]thiourea
N-[2-(2,6-difluoro-3-methoxyphenyl)ethyl]-Ν' -[2-(54 0 ethyl)pyridyl] thiourea
N-[2-(2,6-difluoro-3-methoxyphenyl)ethyl]-Ν' -(2-(5chloro)pyrazinyl]thiourea
N-[2-(2,6-difluoro-3-methoxyphenyl)ethyl]-Ν' -[2-{6bromo)pyrazinyl]thiourea
5 N- [2- (2,6-difluoro-3-methoxyphenyl) ethyl] -Ν' -(2-(5-
AP Ο Ο Ο 3 8 4
Χ-8571Α
-97Ν- [2- (2 ,6-difluoro-3-methoxyphenyl)ethyl]-Ν'-[2 -< 3 -[6 bromo]pyridazinyl)]thiourea
II- [2- (2,6- dif luoro-3-methoxyphenyl) ethyl] -N' - [2- (3 - [ 6chloro;pyridazinyl)]thiourea
N-[2- (2,6-difluoro-3-methoxyphenyl)ethyl]-Ν' -[2- (6cyano)pyridyl]thiourea
N- [2 - (2,6-difluoro-3-methoxyphenyl)ethyl]-Ν'-[2-(5cyano) pyridyl]thiourea
N-(2 -(2,6-difluoro-3-methoxyphenyl) ethyl]-Ν' -[2-(510 cyano) pyrazinyl ] thiourea
N-[2-(2,6-difluoro-3-methoxyphenyl)ethyl]-N’-[2-(6cyano)pyrazinyl]thiourea
M- [2- (2,6-difluoro-3-methoxyphenyl)ethyl]-N'-[2-(3-[6cyano]pyridazinyl)]thiourea
5 N-[2-(2,6-difluoro-3-methoxyphenyl) ethyl]-Ν' -(2[1,3,4-thiadiazoyl]) thiourea
M-[2- (2,6-difluoro-3-methoxyphenyl)ethyl]-Ν' - (2benzimidazolyl) thiourea
M-[2- (2,6-dif luoro-3-methoxyphenyl) ethyl] -Ν' -(22 0 imidazolyl) thiourea
M- (2 - (2,6 - dif luoro-3 - ethoxyphenyl) ethyl] -N‘ - (2thiazclyl) thiourea
N- [2- (2,6-dif luoro-3-ethoxyphenyl) ethyl] -N’-[2- (4methyl·thiazolyl]thiourea
5 M-[2 -ί 2,6-difluoro-3-ethoxyphenyl) ethyl]-N'-[2-(4,5dimethyl)thiazolyl]thiourea
M- [2 - 12,6-dif luoro-3-ethoxyphenyl) ethyl] -Ν' -(2-(4cyano)thiazolyl]thiourea
N- (2- (2,6-difluoro-3-ethoxyphenyl)ethyl]-Ν' -(2-(43 0 trifluoromethyl)thiazolyl]thiourea
N- [2 - (2,6-dif luoro-3-ethoxyphenyl) ethyl] -N* - (2benzothiazolyl) thiourea
N-[2 - (2,6-difluoro-3-ethoxyphenyl) ethyl]-Ν' - [2 - (6fluoro)benzothiazolyl]thiourea
5 N- [2 - (2,6-dif luoro-3-ethoxyphenyl) ethyl] -Ν' -(2-(6chloro)pyrazinyl]thiourea
N-[2- f 2,6-dif luoro-3-ethoxyphenyl) ethyl] -N'-[2- (4ethyl)thiazolyl]thiourea
N- [2- (2,6-dif luoro-3-ethoxyphenyl) ethyl] -Ν' -[2- (4- (34 0 pyridyl) thiazolyl) ] thiourea
N- [2 - (2,6-dif luoro-3-ethoxyphenyl) ethyl] -Ν' - [2 - (4 - (3nitropneny1)thiazolyl)]thiourea
N-(2-(2,6-difluoro-3-ethoxyphenyl)ethyl]-Ν' - (2pyridyl) thiourea
5 N- [2- (2,6-dif luoro-3-ethoxyphenyl) ethyl] -Ν' - [2 - (6-
X-8571A
-98N-(2-(2,6-difluoro-3-ethoxyphenyl)ethyl]-N*-(2-(5bromo) pyridyl]thiourea
N-[2-(2,6-difluoro-3-ethoxyphenyl) ethyl]-N*-[2-(6chloro)pyridyl]thiourea
N-[2-(2,6-difluoro-3-ethoxyphenyl) ethyl]-N’-(2-(5chloro)pyridyl]thiourea
N-(2-(2,6-difluoro-3-ethoxyphenyl)ethyl]-Ν’ -(2-(6methy1) pyridyl]thiourea
N-[2-(2,6-difluoro-3-ethoxyphenyl)ethyl]-Ν' -[2-(51 0 methyl) pyridyl]thiourea
N-[2-(2,6-difluoro-3-ethoxyphenyl)ethyl]-Ν' -[2-(6trifluoromethyl)pyridyl]thiourea
14-(2-(2,6-difluoro-3-ethoxyphenyl)ethyl]-Ν' -[2-(5tri fluoromethyl) pyridyl]thiourea
N-(2-(2,6-difluoro-3-ethoxyphenyl)ethyl]-Ν' -[2-(6ethy1) pyridyl]thiourea
N-[2-(2,6-difluoro-3-ethoxyphenyl)ethyl]-Ν' -(2-(5ethyl) pyridyl]thiourea
N-[2-(2,6-difluoro-3-ethoxyphenyl)ethyl]-Ν' -(2-(52 0 chloro) pyrazinyl] thiourea
N-[2-(2,6-difluoro-3-ethoxyphenyl)ethyl]-Ν' -[2-(6bromo)pyrazinyl]thiourea
N-[2-(2,6-difluoro-3-ethoxyphenyl)ethyl]-Ν' -(2-(5bromo)pyrazinyl]thiourea
5 N- [2 - (2,6-di fluoro-3-ethoxyphenyl) ethyl] -N'-[2-(3-[6bromo]pyridazinyl)]thiourea
N-[2-(2,6-difluoro-3-ethoxyphenyl)ethyl]-Ν' -(2-(3-(6chloro]pyridazinyl)]thiourea
N-[2-(2,6-difluoro-3-ethoxyphenyl)ethyl]-Ν' -(2-(630 cyano)pyridyl]thiourea
N-[2-(2,6-difluoro-3-ethoxyphenyl)ethyl]-N’-[2-(5cyano) pyridyl]thiourea
N-[2-(2,6-difluoro-3-ethoxyphenyl)ethyl]-Ν' -[2-(5cyano)pyrazinyl]thiourea
5 N-[2-(2,6-difluoro-3-ethoxyphenyl) ethyl]-Ν' -(2-(6cyano)pyrazinyl]thiourea
N-[2-(2,6-difluoro-3-ethoxyphenyl)ethyl]-N'-[2-(3-[6cyano]pyridazinyl)]thiourea
N-[2 -(2,6-difluoro-3-ethoxyphenyl)ethyl]-N'-(2-[l,3,44 0 thiadiazoyl]) thiourea
N-[2-(2,6-difluoro-3-ethoxyphenyl)ethyl]-Ν' -(2benzimidazolyl) thiourea
N-[2-(2,6-difluoro-3-ethoxyphenyl)ethyl]-Ν' -(2-
AP Ο Ο ο 3 8 4
Χ-8571Α
-99Ν-[2-(2,6-difluoro-4-methoxyphenyl) ethyl]-Ν’ -[2-(4methyl)thiazolyl]thiourea
N-(2-(2,6-difluoro-4-methoxyphenyl)ethyl]-Ν' -(2-(4,5dimethyl)thiazolyl]thiourea
N-[2-(2,6-difluoro-4-methoxyphenyl) ethyl]-Ν' -(2-(4cyano)thiazolyl]thiourea
N-[2-(2,6-difluoro-4-methoxyphenyl, ethyl]-Ν' -(2-(4trifluoromethyl)thiazolyl]thiourea
N-(2-(2,6-difluoro-4-methoxyphenyl)ethyl]-Ν' -(210 benzothiazolyl) thiourea
N-[2-(2,6-difluoro-4-methoxyphenyl)ethyl]-Ν' -(2-(6f luoro)benzothiazolyl]thiourea
N-[2-(2,6-difluoro-4-methoxyphenyl)ethyl]-Ν' -[2-(6chloro)pyrazinyl]thiourea
N-(2-(2,6-difluoro-4-methoxyphenyl)ethyl]-Ν' -[2-(4ethyl)thiazolyl]thiourea
N-[2-(2,6-difluoro-4-methoxyphenyl)ethyl]-N'-[2- (4- (3pyridyl)thiazolyl,]thiourea
N-[2-(2,6-difluoro-4-methoxyphenyl)ethyl]-N'-[2-(4-(32 0 nitrophenyl)thiazolyl)]thiourea
N-[2-(2,6-difluoro-4-methoxyphenyl)ethyl]-Ν' -(2pyridyl) thiourea
N-[2-(2,6-difluoro-4-methoxyphenyl)ethyl]-Ν' -(2-(6bromo) pyridyl]thiourea
5 N-[2-(2,6-difluoro-4-methoxyphenyl)ethyl]-Ν' -(2-(5bromo) pyridyl]thiourea
N-[2-(2,6-difluoro-4-methoxyphenyl)ethyl]-Ν' -[2-(6chloro) pyridyl]thiourea
N-[2-(2,6-difluoro-4-methoxyphenyl)ethyl]-Ν' -[2-(530 chloro)pyridyl]thiourea
N-[2-(2,6-difluoro-4-methoxyphenyl)ethyl]-Ν' -[2-(6methy 1) pyridyl]thiourea
N-(2-(2,6-difluoro-4-methoxyphenyl) ethyl]-Ν' -(2-(5methyl) pyridyl]thiourea
5 N-[2-(2,6-difluoro-4-methoxyphenyl) ethyl]-Ν' -[2-(6tri fluoromethyl)pyridyl]thiourea
N-[2-(2,6-difluoro-4-methoxyphenyl)ethyl]-Ν' -[2-(5tri fluoromethyl) pyridyl]thiourea
N-[2-(2,6-difluoro-4-methoxyphenyl)ethyl]-Ν' -[2-(64 0 ethyl) pyridyl] thiourea
N-[2-(2,6-difluoro-4-methoxyphenyl)ethyl]-Ν' -[2-(5ethyl) pyridyl]thiourea
N-[2-(2,6-difluoro-4-methoxyphenyl)ethyl]-Ν' -(2-(5chloro)pyrazinyl]thiourea
5 N-[2-(2,6-difluoro-4-methoxyphenyl,ethyl]-Ν' -(2-(6bromo)pyrazinyl]thiourea
X-8571A
-100N-(2-(2,6-difluoro-4-methoxyphenyl, ethyl]-N' - (2- (5fcromo)pyrazinyl]thiourea
N-(2-(2,6-difluoro-4-methoxyphenyl)ethyl]-N‘-(2-(3-[6bromo]pyridazinyl)(thiourea
N-[2-(2,6-difluoro-4-methoxyphenyl)ethyl]-N'-[2-(3-[6chloro]pyridazinyl)(thiourea
N-[2-(2,6-difluoro-4-methoxyphenyl)ethyl]-N*-[2-(6cyano)pyridyl]thiourea
N-[2-(2,6-difluoro-4-methoxyphenyl) ethyl]-Ν'-[2- (510 cyano) pyridyl ] thiourea
N-[2- (2,6-difluoro-4-methoxyphenyl)ethyl]-Ν' -[2-(5cyano)pyrazinyl]thiourea
N-[2-(2,6-difluoro-4-methoxyphenyl)ethyl]-Ν' -[2-(6cyanc)pyrazinyl]thiourea
N-[2-(2,6-difluoro-4-methoxyphenyl)ethyl]-N'-[2-(3-[6cyano]pyridazinyl)(thiourea
N-[2-(2,6-difluoro-4-methoxyphenyl)ethyl]-Ν' - (2[1,3,4-thiadiazoyl]) thiourea
N-[2-(2,6-difluoro-4-methoxyphenyl)ethyl]-Ν' -(22 0 benzimidazolyl) thiourea
N- [2-(2,6-difluoro-4-methoxyphenyl) ethyl] -Ν' - (2imidazolyl) thiourea
N-[2-(2,6-difluoro-4-ethoxyphenyl)ethyl]-Ν' - (2thiazolyl) thiourea
5 Ii- [2- (2,6-di fluoro-4-ethoxyphenyl) ethyl] -Ν' -[2-(4methyl)thiazolyl]thiourea
N-[2-(2,6-difluoro-4-ethoxyphenyl)ethyl]-Ν' -(2-(4,5dimethyl)thiazolyl]thiourea
N-[2-(2,6-difluoro-4-ethoxyphenyl)ethyl]-Ν' -(2- (43 0 cyano) thiazolyl ] thiourea
N-(2-(2,6-difluoro-4-ethoxyphenyl)ethyl]-Ν' -(2-(4trifluoromethyl)thiazolyl]thiourea
N-(2-(2,6-difluoro-4-ethoxyphenyl)ethyl]-Ν' - (2benzothiazolyl)thiourea
5 N-[2-(2,6-difluoro-4-ethoxyphenyl)ethyl)-Ν' -[2-(6fluoro)benzothiazolyl]thiourea
N-.[2- (2,6-difluoro-4-ethoxyphenyl) ethyl] -Ν' - [2- (6chioro,pyrazinyl]thiourea
N-(2-(2,6-difluoro-4-ethoxyphenyl) ethyl]-Ν' -[2- (44 0 ethyl) thiazolyl ] thiourea
H-[2- (2,6-difluoro-4-ethoxyphenyl) ethyl]-N'-[2-(4-(3pyridyl)thiazolyl)]thiourea
N-[2-(2,6-difluoro-4-ethoxyphenyl)ethyl]-Ν' -[2- (4- (3nitrophenyl)thiazolyl)]thiourea
AP Ο Ο Ο 3 8 4
Χ-8571Α
-101Ν-(2-(2,6-difluoro-4-ethoxyphenyl) ethyl] -Ν’-(2-(6bromo) pyridyl] thiourea
N-[2-(2,6-difluoro-4-ethoxyphenyl)ethyl]-Ν' -(2-(5bromo) pyridyl]thiourea
N-[2-(2,6-difluoro-4-ethoxyphenyl) ethyl]-Ν'-[2-(6chloro) pyridyl]thiourea
N- [2- (2,6-difluoro-4-ethoxyphenyl) ethyl] -N* -(2-(5chloro) pyridyl]thiourea
N- [2- (2,6-difluoro-4-ethoxyphenyl) ethyl] -Ν' -(2-(61 0 methyl) pyridyl ] thiourea
N- [2 - (2,6-difluoro-4-ethoxyphenyl) ethyl] -Ν' -(2-(5methyl) pyridyl]thiourea
N-(2- (2,6-difluoro-4-ethoxyphenyl)ethyl] -Ν' -(2-(6tri fluoromethyl) pyridyl]thiourea
5 N-[2-(2,6-difluoro-4-ethoxyphenyl)ethyl]-N'-(2-(5trifluoromethyl) pyridyl]thiourea
N- (2- (2,6-difluoro-4-ethoxyphenyl)ethyl] -Ν' -(2- (6ethyl) pyridyl]thiourea
N- (2- (2,6-difluoro-4-ethoxyphenyl) ethyl] -Ν' -(2- (52 0 ethyl) pyridyl ] thiourea
N- [2- (2,6-dif luoro-4-ethoxyphenyl) ethyl] -Ν' - (2- (5cnloro)pyrazinyl]thiourea
N-(2-(2,6-difluoro-4-ethoxyphenyl)ethyl]-Ν' -(2 - (6bromo)pyrazinyl]thiourea
5 N- [2- (2,6-dif luoro-4-ethoxyphenyl) ethyl] -Ν' - (2- (5bromo)pyrazinyl]thiourea
N- [2- (2,6-difluoro-4-ethoxyphenyl) ethyl] -Ν' -(2- (3-(6bromo] pyridazinyl) ]thiourea
N- (2- (2,6-dif luoro-4-ethoxyphenyl) ethyl] -Ν' - (2- (3-(63 0 chloro]pyridazinyl) ] thiourea
N- (2 - (2,6-difluoro-4-ethoxyphenyl)ethyl] -Ν' - (2- (6cyano) pyridyl]thiourea
N- (2- (2,6-difluoro-4-ethoxyphenyl) ethyl) -Ν' - (2- (5cyano) pyridyl]thiourea
5 N- (2- (2,6-difluoro-4-ethoxyphenyl) ethyl] -Ν' - (2- (5cyano) pyrazinyl ] thiourea
N- (2-(2,6-difluoro-4-ethoxyphenyl) ethyl] -N* - (2- (6cyano) pyrazinyl ] thiourea
N- (2- (2,6-difluoro-4-ethoxyphenyl)ethyl] -Ν' - (2- (3-(64 0 cyano] pyridazinyl) ] thiourea
N- (2- (2,6-difluoro-4-ethoxyphenyl) ethyl] -Ν' -(2-(1,3,4thiadiazoyl]) thiourea
N- (2- (2,6-dif luoro-4-ethoxyphenyl) ethyl] -Ν' - (2benzimidazolyl)thiourea
5 N- (2- (2,6-difluoro-4-ethoxyphenyl)ethyl] -N* -(2imidazolyl)thiourea
X-8571A
-102N-[2-(2-(3-ethoxy)pyridyl)ethyl]-Ν' -(2-(5bromo) pyridyl]thiourea
N-[2- (2-(3-methoxy)pyridyl)ethyl]-Ν' -(2-(5bromo) pyridyl]thiourea
N-(2-phenethyl)-N*-[2-(3-ethyl)pyridyl]thiourea
N-(2- (2,6-difluorophenyl)ethyl]-Ν' -(3-(6methoxy·) pyridazinyl ] thiourea
N-[2-(2,6-difluoro-3-N-methylcarboxamidephenyl)ethyl]Ν' -(2-(5-bromo)pyridyl]thiourea 10 N- (2- (2-fluoro-6-chlorophenyl) ethyl] -Ν' -(2thiazolyl) thiourea
N-[2-(2-pyridyl)ethyl]-Ν' -(2-{5-nitro)pyridyl]thiourea N-[2-(3-bromo-6-methoxyphenyl)ethyl]-Ν' - (2thiazolyl) thiourea (±)N-(2-((2,6-difluorophenyl) -2- (methyl) ] ethyl] -Ν' - (2thiazolyl) thiourea
N- [2- (3-ethoxyphenyl) ethyl] -Ν' - (2-thiazolyl) thiourea N- (2- (3-bromo-6-ethoxyphenyl) ethyl] -Ν' - (2thiazolyl) thiourea
0 N- (2- (cis- (2-fluoro)phenyl) cyclopropyl] -Ν' - (2thiazolyl) thiourea
N-[2 - (3- (2-fluoro)pyridyl)ethyl]-Ν' -[2-(5bromo) pyridyl]thiourea (±)N-(cis-2-(3-chlorophenyl)cyclopropyl]-Ν' -(2-(52 5 chloro) pyridyl] thiourea (±)N-(cis-2- (3-fluorophenyl)cyclopropyl]-Ν' -[2-(5chloro) pyridyl]thiourea
N- [2- (2-vinyl)phenethyl] -Ν' -(2-(5bromo) pyridyl]thiourea
0 N-[2- (3-vinyl)phenethyl]-N'-[2- (5bromo) pyridyl]thiourea
N-(2- (3-methoxycarbonyl)phenethyl]-Ν' -[2-(5bromo)pyr idyl]thiourea
N-(2- (5,6-dimethylbenzotriazolyl)ethyl]-Ν'-[2-(53 5 bromo) pyridyl] thiourea
N-[2-(1-cyclohexenyl)ethyl]-Ν' -[2-(5,6-dichloro-4azabenzimidazolyl)]thiourea
N-[2- (2,3-difluoro-6-methoxyphenyl)ethyl]-Ν' -[2-(5bromo) pyridyl]thiourea (±)N-[cis-2- (4-methylphenyl)cyclopropyl]-Ν' -[2-(5chloro)pyridy1]thiourea (±)N-[cis-2-(2-fluorophenyl)cyclopropyl]-Ν' -[2-(5chloro)pyridyl]thiourea (±)N- [cis-2-(3-cyanophenyl)cyclopropyl]-Ν' -(2-(5-
Χ-8571Α
AP ο Ο Ο 3 8 4
-103(±)Ν-(cis-2-(2,6-difluoro-3-cyanophenyl) cyclopropyl]Ν' -[2-(5-chloro)pyridyl]thiourea (±)-cis-N-(3,4-benzo-cis-bicyclo-[3.1.0]-hexen-6-yl)Ν' -[2-(5-chloro)pyridyl]thiourea
N-[2-(3-ethynylphenyl)ethyl]-Ν'-[2-(5bromo) pyridyl]thiourea
N-(2-(2,5-diethoxyphenyl)ethyl]-Ν' -(2-(5bromo)pyridyl]thiourea
N-(2- (2-methoxyphenyl) ethyl]-N' -[4- (61 0 aminopyrimidinyl)]thiourea
N-[2-(2-methoxyphenyl) ethyl]-N'-(4pyrimidinyl)thiourea (±)N-[2-(cis-2-pyridyl)]-Ν' -[2-(3pyridazinyl)]thiourea (±)N- [2 - (cis-2-pyridyl) ] -N' - [2- (3 - (6methyl)pyridazinyl)]thiourea .
(±)N-[2-(cis-2-pyridyl)]-Ν' -(2-pyrazinyl)]thiourea (±)N-(2-(cis-2-pyridyl)]-N'-[2-(5methyl)pyrazinyl)]thiourea (±)N-[2-(cis-2- (3-f luoro) pyridyl) ] -Ν' - [2 - (3pyridazinyl)]thiourea (±)N-[2-(cis-2-(3-fluoro)pyridyl)]-Ν'-(2-(3-(6methyl)pyridazinyl)]thiourea (±)N-(2-(cis-2-(3-fluoro)pyridyl)]-Ν' -(225 pyrazinyl)]thiourea (±)N-(2-(cis-2-(3-fluoro)pyridyl)]-N*-[2-(5methyl)pyrazinyl)]thiourea
N-(2-cis-phenylcyclopropyl)-Ν' -(2-(3pyridazinyl,]thiourea
0 N- (2-cis-phenylcyclopropyl) -N'-[2-(3-(6methyl) pyridazinyl) ] thiourea
N-(2-cis-phenylcyclopropyl)-N·- (2-pyrazinyl)]thiourea N-(2-cis-phenylcyclopropyl)-Ν' -[2-(5methy1)pyrazinyl)]thiourea
5 N- [2- (cis-2-fluorophenyl)cyclopropyl) ]-Ν' -(2-(3pyridazinyl)]thiourea
N-(2-(cis-2-fluorophenyl)cyclopropyl)]-N’-(2-(3-(6methyl)pyridazinyl)]thiourea
N-[2-(cis-2-fluorophenyl)cyclopropyl)]-Ν' -(24 0 pyrazinyl)]thiourea
N-(2-(cis-2-fluorophenyl)cyclopropyl)]-Ν' - (2-(5methyl,pyrazinyl)]thiourea
N-(2-(cis-2,6-difluorophenyl)cyclopropyl)]-N'-[2- (3pyridazinyl)]thiourea
5 N-[2-(cis-2,6-difluorophenyl)cyclopropyl)]-Ν' -[2-(3-
X-8571A
-104N-(2- (cis-2,6-difluorophenyl)cyclopropyl)]-N’~(2pyrazinyl)]thiourea
N-[2- (cis-2,6-difluorophenyl)cyclopropyl)]-Ν’ -[2-(5methyl)pyrazinyl)]thiourea
N-(2-(cis-3-methoxyphenyl)cyclopropyl)]-N'-[2-(3pyridaziny1)]thiourea
N- [2- (cis-3-methoxyphenyl) cyclopropyl) ]-Ν'-(2-(3-(6methyl)pyridazinyl)]thiourea
N- (2- (cis-3-methoxyphenyl)cyclopropyl) ] -Ν' -(21 0 pyrazinyl)]thiourea
N-[2- (cis-3-methoxyphenyl)cyclopropyl)]-N'-(2- (5methyl)pyrazinyl)]thiourea
AP Ο Ο Ο 3 8 4
Χ-8571Α
-105The following are more preferred compounds.
N- (2-phenethyl)-N‘-[2-(5-bromo)pyridyl]thiourea 5 N-(2-phenethyl)-Ν' -[2-(5-chloro)pyridyl]thiourea
N-(2-phenethyl)-N*-(2-(5-chloro)pyrazinyl]thiourea N- (2-phenethyl) -N*-(2- (5-bromo)pyrazinyl] thiourea N- (2-phenethyl)-Ν' -((3-(6-chloro)pyridazinyl)]thiourea N- (2 - (2-methoxyphenyl) ethyl)-N'-[2- (50 chloro)pyrazinyl]thiourea
N-(2 - (2-methoxyphenyl) ethyl)-Ν' -(2 - (5bromo)pyrazinyl]thiourea
N-(2-(2-methoxyphenyl) ethyl)-Ν' - ((3-(6chloro)pyridazinyl)]thiourea ί 5 N-(2-(3-methoxyphenyl)ethyl)-N'-[2-{5chloro)pyrazinyl]thiourea
N-(2- (3-methoxyphenyl)ethyl)-Ν' -[2-(5bromo)pyrazinyl]thiourea
N-(2- (3-methoxyphenyl) ethyl)-N'-[(3-(6:0 chloro)pyridazinyl)]thiourea
N-(2- (2-ethoxyphenyl)ethyl)-Ν' -[2-(4cyano)thiazolyl]thiourea
N-(2-(2-ethoxyphenyl)ethyl)-Ν' -[2-(4trifluoromethyl)thiazolyl]thiourea 15 N-(2 - (2-ethoxyphenyl)ethyl)-Ν'-[2-(4ethy1)thiazolyl]thiourea
N- (2-(2-ethoxyphenyl)ethyl)-N'-[2-(5chloro)pyrazinyl]thiourea
N-(2- (2-ethoxyphenyl) ethyl)-N'-[2 - (50 bromo)pyrazinyl]thiourea
N-(2 - (2-ethoxyphenyl)ethyl)-Ν' -((3-(6chloro)pyridazinyl)]thiourea
N-(2- (2-methylphenyl) ethyl,-N'- (2 - (4cyano)thiazolyl]thiourea
N-(2 - (2-methylphenyl) ethyl) -N ’ - [ 2 - (4 trifluoromethyl)thiazolyl]thiourea
N-(2- (2-methylphenyl) ethyl) -N' - (2- (4 ethyl)thiazolyl]thiourea
N-(2- (2-methylphenyl) ethyl)-N'-[2 - (50 bromo)pyridyl]thiourea
N-(2 - (2-methylphenyl) ethyl)-N'- (2 - (6chloro) pyridyl]thiourea
N-(2- (2-methylphenyl) ethyl) -N' - (2 - (5chloro)pyrazinyl]thiourea
N- (2*- (2-methylphenyl) ethyl) -Ν' - (2- (5bromo)pyrazinyl]thiourea
X-8571A
-106N-(2-(2-methylphenyl)ethyl)-N’-((3-(6chioro)pyridazinyl)]thiourea
N-(2-(2-fluorophenyl)ethyl)-Ν' -(2-(4cyano)thiazolyl]thiourea
N-(2-(2-fluorophenyl) ethyl)-Ν' -[2-(4trifluoromethyl)thiazolyl]thiourea
N-(2-(2-fluorophenyl) ethyl)-Ν' -[2-(4ethyi)thiazolyl]thiourea
N-(2-(2-fluorophenyl)ethyl)-Ν' -(2-(510 bromo)pyridyl]thiourea
N-(2 - (2-fluorophenyl) ethyl)-N'-[2-(5chloro)pyridyl]thiourea
N-(2-(2-fluorophenyl) ethyl)-Ν' -[2-(5chlcrc)pyrazinyl]thiourea
N- (2 - (2-f luorophenyl) ethyl) -N'-[2-(5bromo)pyrazinyl]thiourea
N-(2-(2-fluorophenyl)ethyl)-Ν' - [(3-(6chloro)pyridazinyl)]thiourea
N-(2-(2,6-difluorophenyl)ethyl)-Ν' -(22 0 thiazolyl) thiourea
N-(2-(2,6-difluorophenyl) ethyl)-N'-(2-(4methyl)thiazolyl]thiourea
N-(2-(2,6-difluorophenyl)ethyl)-Ν' - (2-pyridyl)thiourea N-(2-(2,6-difluorophenyl) ethyl)-Ν' -[2-(625 bromo)pyridyl]thiourea
N-(2-(2,6-difluorophenyl) ethyl)-N'-[2-(5methyl) pyridyl]thiourea
N-(2-(2,6-difluorophenyl)ethyl)-Ν' -[2-(5trifluoromethyl)pyridyl]thiourea
0 N- (2 - (2,6-dif luorophenyl) ethyl) -N'-[2-(5ethy1) pyridyl]thiourea
N-(2 -(2,6-difluorophenyl)ethyl)-N’-[2-(5chloro)pyrazinyl]thiourea
N-(2-(2,6-difluorophenyl) ethyl)-N'-(2-(53 5 cyano) pyridyl] thiourea
N-(2-(2-fluoro-6-methoxyphenyl)ethyl)-Ν' -[2-(4cyano)thiazolyl]thiourea
N-(2-(2-fluoro-6-methoxyphenyl)ethyl)-N’-[2-(4trifluoromethyl)thiazolyl]thiourea
0 N- (2- (2-fluoro-6-methoxyphenyl) ethyl) -Ν' - (2 - (4ethyl)thiazolyl]thiourea
N-(2-(2-fluoro-6-methoxyphenyl)ethyl)-Ν' -[2-(5chloro)pyrazinyl]thiourea
N-(2-(2-fluoro-6-methoxyphenyl)ethyl)-Ν' -(2-(54 5 bromo)pyrazinyl]thiourea
AP Ο Ο Ο 3 8 4
-107X-8571A
Ν-(2-(2-fluoro-6-methoxyphenyl,ethyl,-Ν' -[(3-(6chloro)pyridazinyl)]thiourea
N- (2-(2-fluoro-6-ethoxyphenyl)ethyl)-Ν' -[2-(4cyano)thiazolyl]thiourea
N- (2-(2-fluoro-6-ethoxyphenyl)ethyl)-Ν' -(2-(4tri fluoromethyl)thiazolyl]thiourea
N-(2-(2-fluoro-6-ethoxyphenyl)ethyl)-Ν' -(2-(4ethy1)thiazolylJ thiourea
N- (2-(2-fluoro-6-ethoxyphenyl)ethyl)-N'-(2-(510 bromo)pyridyl]thiourea
N-(2-(2-fluoro-6-ethoxyphenyl)ethyl)-Ν'-(2-(5chloro) pyridyl]thiourea
N- (2-(2-fluoro-6-ethoxyphenyl)ethyl)-Ν' -(2-(5chloro)pyrazinyl]thiourea
5 N-(2-(2-fluoro-6-ethoxyphenyl)ethyl)-N’-(2-(5bromo)pyrazinyl]thiourea
N-(2-(2-fluoro-6-ethoxyphenyl)ethyl,-Ν'-((3-(6chloro,pyridazinyl)]thiourea
N- (2 - (2-chlorophenyl, ethyl,-N'- (2-{42 0 tri f luoromethyl, thiazolyl ] thiourea
N- (2-(2-chlorophenyl)ethyl)-N*-(2-(5chlorc)pyrazinyl]thiourea
N- (2-(2-chlorophenyl)ethyl)-Ν' - [2- (5bromo,pyrazinyl]thiourea
N- (2- (2-chlorophenyl)ethyl)-Ν'- ((3-(6chloro)pyridazinyl)]thiourea
N- (2-(3-chlorophenyl)ethyl)-Ν' -(2-(4tri fluoromethyl) thiazolyl] thiourea
N- (2-(3-chlorophenyl)ethyl)-N*-(2-(53 0 chloro,pyrazinyl] thiourea
N- (2-(3-chlorophenyl)ethyl)-Ν' - (2-(5bromo)pyrazinyl]thiourea
N- (2-(3-chlorophenyl)ethyl)-N'-((3-(6chloro)pyridazinyl) ] thiourea
5 N- (2- (1-cyclohexenyl)ethyl) -N* - (2-thiazolyl) thiourea
N- (2-(1-cyclohexenyl,ethyl)-Ν' -[2-(4methy1)thiazolyl]thiourea
N- (2- (1-cyclohexenyl) ethyl) -Ν' - {2-pyridyl) thiourea N- (2- (1-cyclohexenyl) ethyl) -Ν' -(2-(54 0 methyl) pyridyl] thiourea
N- (2-(1-cyclohexenyl)ethyl)-N'-[2-(5t ri f luoromethyl, pyridyl J thiourea
N-(2- (1-cyclohexenyl) ethyl) -Ν' - (2- (5ethy1)pyridyl]thiourea
5 N- (2-(1-cyclohexenyl)ethyl)-Ν' - (2-(5-
I
X-8571A
-108» *!
N- (2- (1-cyclohexenyl) ethyl) -N'-[2-(5bromo)pyrazinyl]thiourea
N- (2 - (1-cyclohexenyl, ethyl) -Ν' -[2-(5cyano) pyridyl]thiourea
N- (2 - (1-cyclohexenyl) ethyl) -N'-[2-(5cyano)pyrazinyl]thiourea
N- (2 - (1-cyclohexenyl) ethyl) -Ν' - [ (3-(6cyano)pyridazinyl)]thiourea
N- (2 - (2,5-dimethoxyphenyl, ethyl)-Ν' -[2-(410 cyano) thiazolyl] thiourea
N- (2 - (2,5-diraethoxyphenyl, ethyl) -Ν' -[2-(4trif luoromethyl, thiazolyl ] thiourea
N- (2 - (2,5-dimethoxyphenyl) ethyl) —Ν' — (2-(4ethyl) thiazolyl ] thiourea
N- (2 - (2,5-dimethoxyphenyl) ethyl) -Ν' -[2-(5bromo)pyridyl]thiourea
N- (2 - (2,5-dimethoxyphenyl) ethyl) -Ν' - ( (3 - (6chloro)pyridazinyl)]thiourea
N- (2- (2-f luoro-6-chlorophenyl) ethyl) -Ν' -(2-(42 0 cyano) thiazolyl ] thiourea
N- (2- (2-fluoro-6-chlorophenyl) ethyl) -Ν' - [2 - (4trifluoromethyl)thiazolyl]thiourea
N- (2- (2-f luoro-6-chlorophenyl) ethyl, -Ν' -(2-(4ethyl) thiazolyl ] thiourea
5 N- (2- (2-fluoro-6-chlorophenyl)ethyl) -N'-[2- (5bromo) pyridyl]thiourea
N- (2- (2-fluoro-6-chlorophenyl)ethyl) -N'-[2- (5chloro) pyridyl ] thiourea
N- (2- (2-f luoro-6-chlorophenyl) ethyl, -Ν' - [2- (53 0 chloro) pyrazinyl] thiourea
N- (2- (2-fluoro-6-chlorophenyl) ethyl) -Ν' -(2- (5bromo) pyrazinyl ] thiourea
N- (2- (2-fluoro-6-chlorophenyl) ethyl)-Ν' -[(3-(6chloro)pyridazinyl) ] thiourea
5 N- (2 - (2,6-dimethoxyphenyl) ethyl) -Ν' - [2 - (4cyano) thiazolyl ] thiourea
N- (2-(2,6-dimethoxyphenyl) ethyl) -Ν' - [2- (4trifluoromethyl) thiazolyl] thiourea
N- (2-(2,6-dimethoxyphenyl)ethyl) -Ν' - [2- (44 0 ethyl) thiazolyl] thiourea
N- (2-(2,6-dimethoxyphenyl) ethyl) -Ν' -(2- (5bromo) pyridyl]thiourea
N- (2- (2,6-dimethoxyphenyl) ethyl) -Ν' - [2 - (5chloro) pyridyl ] thiourea
5 N- (2 - (2,6-dimethoxyphenyl) ethyl) -Ν' - [2 - (5chl or o) pyrazinyl ] thiourea
AP Ο Ο Ο 3 8 4
Χ-8571Α
-109Ν- (2-(2,6-dimethoxyphenyl)ethyl)-Ν*-[2-(5bromo)pyrazinyl]thiourea
Ν- (2- (2,6-dimethoxyphenyl)ethyl)-Ν' -[(3-(6chloro)pyridazinyl)]thiourea
N- (2- (2,6-dichlorophenyl) ethyl)-N'-[2- (4cyano)thiazolyl]thiourea
N- (2-(2,6-dichlorophenyl)ethyl)-Ν' -[2 - (4trifluoromethyl)thiazolyl]thiourea
N- (2-(2,6-dichlorophenyl)ethyl)-Ν' -[2-(41 0 ethyl)thiazolylJ thiourea
N- (2-(2,6-dichlorophenyl)ethyl)-Ν' -[2-(5bromo)pyridyl]thiourea
N-(2-(2,6-dichlorophenyl)ethyl)-N'-[2-(5chloro)pyridyl]thiourea
N- (2 - (2,6-dichlorophenyl) ethyl) -Ν' -(2-(5chloro)pyrazinyl]thiourea
N- (2 - (2,6-dichlorophenyl) ethyl)-N'-[2-{5bromo)pyrazinyl]thiourea
N- (2-(2,6-dichlorophenyl)ethyl)-Ν' -[(3-(62 0 chloro)pyridazinyl)]thiourea
N- (2 - (3-fluorophenyl)ethyl)-N'-[2-(4cyano)thiazolyl]thiourea
N- (2 - (3-fluorophenyl)ethyl)-Ν' -(2-(4trifluoromethyl)thiazolyl)thiourea
5 N- (2 - (3-f luorophenyl) ethyl) -Ν' - (2- (4ethyl)thiazolyl]thiourea
N- (2-(3-fluorophenyl)ethyl)-Ν' -(2-(5bromo)pyridyl]thiourea
N- (2-(3-fluorophenyl)ethyl)-Ν' -(2- (53 0 chloro) pyridyl] thiourea
N- (2- (3-fluorophenyl)ethy1)-Ν' -[2-(5chloro)pyrazinyl]thiourea
N- (2-(3-fluorophenyl)ethyl)-Ν' -(2-(5bromo)pyrazinyl]thiourea
5 N- (2- (3-fluorophenyl)ethyl)-Ν' -[(3-(6chloro)pyridazinyl)]thiourea
N- (2-cis-phenylcyclopropyl)-Ν' -(2-thiazolyl)thiourea N-(2-cis-phenylcyclopropyl)-Ν' -(2-(4cyano)thiazolyl]thiourea
0 N- (2-cis-phenylcyclopropyl) -Ν' - [2- (4tri fluoromethyl)thiazolylJ thiourea
N- (2-cis-phenylcyclopropyl)-Ν' -12-(5methy1) pyridyl]thiourea
N- (2-cis-phenylcyclopropyl)-Ν' -[2- (445 ethyl)thiazolyl)thiourea
N-(2-cis-phenylcyclopropyl)-Ν' -(2-pyridyl)thiourea
ό t
X-8571A
-110N-(2-cis-phenylcyclopropyl)-Ν'-[2-(5trifluoromethyl) pyridyl]thiourea
N-(2-cis-phenylcyclopropyl)-Ν' -[2-(5ethyl)pyridyl]thiourea
N-(2-cis-phenylcyclopropyl)-Ν' -(2-(5- ’ chloro,pyrazinyl]thiourea
N-(2-cis-phenylcyclopropyl)-N'-(2-(5bromo)pyrazinyl]thiourea
N-(2-cis-phenylcyclopropyl,-Ν' -[(3-(610 bromo)pyridazinyl)]thiourea
N-(2-cis-phenylcyclopropyl)-Ν' - ((3-(6chloro)pyridazinyl,]thiourea
N-(2-cis-phenylcyclopropyl)-Ν' -(2-(5cyano)pyridyl]thiourea
N-[2- (2-pyridyl, ethyl]-N'- (2-thiazolyl) thiourea
N-[2-(2-pyridyl)ethyl]-Ν'-(2-(4methyl)thiazolyl]thiourea
N-(2- (2-pyridyl) ethyl]-N·- (2- (4cyano)thiazolyl]thiourea 20 N-[2-(2-pyridyl) ethyl]-N'-(2-(4trifluoromethyl)thiazolyl]thiourea
N-[2- (2-pyridyl) ethyl]-N'- (2- (4ethyl)thiazolyl]thiourea
N-[2 - (2-pyridyl) ethyl]-N- (2-pyridyl) thiourea
5 N- [2- (2-pyridyl) ethyl] -Ν' - [2- (6-bromo) pyr idyl] thiourea
N-[2- (2-pyridyl) ethyl]-N'-[ 2- (6chloro) pyridyl]thiourea
N-(2-(2-pyridyl)ethyl]-Ν' -(2-(6methyl) pyridyl]thiourea
0 N- [2 - (2-pyridyl) ethyl] -Ν' -(2-(5methy1) pyridyl]thiourea
N-[2-(2-pyridyl)ethyl]-Ν' -(2-(6tri fluoromethy1) pyridyl]thiourea
N- [2- (2-pyridyl) ethyl] -N' - [2- (6-ethyl) pyridyl] thiourea
N-[2-(2-pyridyl)ethyl]-Ν'-[2-(5chloro)pyrazinyl]thiourea
N-(2-{2-pyridyl) ethyl] -N ‘ - [ 2 - (5 bromo)pyrazinyl]thiourea
N-[2-(2-pyridyl)ethyl]-Ν' -[ (3-(64 0 bromo) pyridazinyl) ] thiourea
N-[2-(2-pyridyl)ethyl]-Ν' - ( (3-(6chloro)pyridazinyl)]thiourea
N—[2- (2-pyridyl) ethyl] -Ν' -(2- (5-cyano)pyridyl] thiourea N-[2 - (2-pyridyl) ethyl]-N'-[2 - (5-
AP Ο Ο Ο 3 8 4
Χ-8571Α
-111Ν- (2 - (2-pyridyl) ethyl] -Ν' - [ (3-(6cyano)pyridazinyl)]thiourea
N- [2-(2- (6-methoxy)pyridyl) ethyl] -Ν' -(2thiazolyl) thiourea
N- [2- (2 - (6-methoxy)pyridyl) ethyl] -Ν' - [2 - idmethyl )thiazolyl]thiourea
N- [2 - (2- (6-methoxy)pyridyl) ethyl] -Ν' - [2- (4cyano)thiazolyl]thiourea
N- [2 - (2 - (6-methoxy) pyr idyl, ethyl] -Ν' - (2 - (410 trifluoromethyl,thiazolyl]thiourea
N- [2 - (2 - (6-methoxy)pyridyl) ethyl] -Ν’ - [2- (4ethyl)thiazolyl]thiourea
N- [2- (2- (6-methoxy)pyridyl) ethyl] -Ν' - (2pyridyl) thiourea
N- [2 - (2- (6-methoxy)pyridyl) ethyl] -N'-(2-(5methyl)pyridyl]thiourea
N- (2- (2- {6-methoxy) pyr idyl) ethyl) -N ' -[2-(5tri fluoromethyl) pyridyl] thiourea
N- (2- (2- (6-methoxy)pyridyl) ethyl] -Ν' - (2- (52 0 chloro) pyrazinyl] thiourea
N- (2 - (2 - (6-methoxy)pyridyl) ethyl] -N'-[2-(5bromo)pyrazinyl]thiourea
N- [2- (2- (6-methoxy)pyridyl) ethyl] -Ν' - ( (3- (6chloro)pyridazinyl,]thiourea
5 N- (2 - (2- (6-ethoxy)pyridyl) ethyl] -Ν' - (2thiazolyl) thiourea
N- [2- (2- (6-ethoxy) pyridyl) ethyl] -Ν' -(2- idmethyl )thiazolyl]thiourea
N- [2 - (2 - (6-ethoxy)pyridyl)ethyl] -Ν' - [2 - (43 0 cyano) thiazolyl] thiourea
N- [2- (2- (6-ethoxy)pyridyl) ethyl] -N* - (2- (4trif luoromethyl) thiazolyl] thiourea
N-(2-(2-(6-ethoxy) pyridyl) ethyl]-Ν'-(2-(4ethy1)thiazolyl) thiourea
5 N- [2- (2- (6-ethoxy)pyridyl)ethyl] -Ν' - (2pyridyl)thiourea
N- (2 - (2 - (6-ethoxy)pyridyl) ethyl] -Ν' -(2-(5methy1) pyridyl]thiourea
N- [2- (2- (6-ethoxy)pyridyl) ethyl] -Ν' - (2- (54 0 trif luoromethyl) pyridyl] thiourea
N- (2 - (2 - (6-ethoxy) pyr idyl) ethyl] -N'-[2-(5chloro)pyrazinyl]thiourea
N- (2 - (2 - (6-ethoxy)pyridyl) ethyl] -Ν' - [2 - (5bromo)pyrazinyl]thiourea
5 N- (2 - (2- (6-ethoxy)pyridyl) ethyl] -Ν' - ( (3-(6chloro)pyridazinyl)]thiourea
Χ-8571Α +-112Ν-[2-(2-(6-ethoxy)pyridyl)ethyl]-Ν' -(2-(5cyano) pyridyl]thiourea
N-[2-(2-(6-fluoro)pyridyl)ethyl]-Ν' -(2thiazolyl) thiourea
N- [2- (2-(6-fluoro)pyridyl)ethyl]-Ν' -(2-(4methy1)thiazolyl]thiourea
N- (2-(2-(6-fluoro)pyridyl)ethyl]-Ν' -(2-(4cyano)thiazolyl]thiourea
N-[2-(2-(6-fluoro)pyridyl)ethyl]-Ν' -(2-(41 0 trifluoromethyl)thiazolyl]thiourea
N-[2 - (2-(6-fluoro)pyridyl)ethyl]-Ν' -[2-(4ethyl)thiazolyl]thiourea
N- [2-(2-(6-fluoro)pyridyl)ethyl]-Ν' -(2pyridyl)thiourea
N-[2-(2-(6-fluoro)pyridyl)ethyl]-Ν' -[2-(5methyl)pyridyl]thiourea
N- (2- (2-(6-fluoro)pyridyl)ethyl]-Ν' -[2-(5tri fluoromethyl) pyridyl]thiourea
N- [2-(2-(6-fluoro)pyridyl)ethyl]-Ν' -[2-(62 0 ethyl)pyridyl] thiourea
N- [2 - (2-(6-fluoro)pyridyl)ethyl]-Ν' -[2-(5ethyl)pyridyl]thiourea
N- [2-(2-(6-fluoro)pyridyl)ethyl]-Ν' -(2-(5chloro}pyrazinyl]thiourea
5 N- [2 - (2- (6-fluoro)pyridyl) ethyl] -Ν' -(2-(5bromo)pyrazinyl]thiourea
N- (2- (2-(6-fluoro)pyridyl)ethyl]-Ν' - ((3-(6chloro)pyridazinyl)]thiourea
N-(2-(2-(6-fluoro)pyridyl)ethyl]-Ν' -[2-(53 0 cyano) pyridyl] thiourea
N-[2-(2-(3-fluoro)pyridyl)ethyl]-Ν' -[2-(4cyano)thiazolyl]thiourea
N-[2-(2-(3-fluoro)pyridyl)ethyl]-Ν' -(2-(4tri fluoromethyl)thiazolyl]thiourea
5 N-.[2- (2 - (3-f luoro)pyridyl) ethyl] -Ν' - [2 - (4ethyl)thiazolyl]thiourea
N-(2-(2-(3-fluoro)pyridyl)ethyl]-N'-(2-(5chloro)pyrazinyl]thiourea
N-[2-(2-(3-fluoro)pyridyl)ethyl]-Ν' -[2-(54 0 bromo)pyrazinyl]thiourea
N-[2-(2-(3-fluoro)pyridyl)ethyl]-Ν' -[(3-(6chloro)pyridazinyl)]thiourea
N-[2-(2-(6-chloro)pyridyl)ethyl]-Ν' -[2-(4cyano)thiazolyl]thiourea
AP Ο Ο Ο 3 8 4
Χ-8571Α
-113Ν-[2-(2-(6-chloro,pyridyl,ethyl]-Ν' -[2-(4ethyl)thiazolyl]thiourea
N-[2-(2-(6-chloro)pyridyl)ethyl]-N’-[2-(5chloro)pyrazinyl]thiourea
N-(2-(2-(6-chloro)pyridyl)ethyl]-N'-[2-(5bromo)pyrazinyl]thiourea
N-[2-(2-(6-chloro)pyridyl)ethyl]-Ν' -[(3-(6chloro)pyridazinyl)]thiourea
N-(2-(2-(3-methoxy-6-fluoro)pyridyl) ethyl]-Ν' -[2-(410 methyl)thiazolyl]thiourea
N-[2-(2-(3-methoxy-6-fluoro)pyridyl)ethyl] -Ν' - [2-(4cyano)thiazolyl]thiourea
N-(2-(2-(3-methoxy-6-fluoro,pyridyl)ethyl]-Ν' -[2-(4trifluoromethyl)thiazolyl]thiourea
N- (2 - (2- (3-methoxy-6-f luoro) pyridyl, ethyl] -N'-[2-(4ethyl)thiazolyl]thiourea
N- [2- (2 - (3 -methoxy-6-fluoro,pyridyl) ethyl] -Ν' - (2pyridyl,thiourea
N-(2-(2-(3-methoxy-6-fluoro)pyridyl)ethyl]-Ν' -[2-(52 0 chloro)pyrazinyl] thiourea
N- (2- (2 - (3-methoxy-6-f luoro)pyridyl) ethyl] -Ν' -[2-(5bromo)pyrazinyl]thiourea
N- [2 - (2 - (3-methoxy-6-f luoro) pyridyl) ethyl ] -Ν' - ( (3-(6chloro)pyridazinyl)]thiourea
5 N- (2- (2 - (5-ethoxy-6-f luoro,pyridyl, ethyl] -Ν' -[2-(4cyano) thiazolyl ] thiourea
N- (2 - (2 - (5-ethoxy-6-fluoro)pyridyl) ethyl] -Ν' - [2- (4trifluoromethyl)thiazolyl]thiourea
N-(2-(2-(5-ethoxy-6-fluoro)pyridyl,ethyl] -Ν' -[2-(43 0 ethyl) thiazolyl] thiourea
N-[2-(2-(5-ethoxy-6-fluoro)pyridyl)ethyl]-Ν' -(2-(5chloro,pyrazinyl]thiourea
N- (2- (2 - (5-ethoxy-6-fluoro)pyridyl)ethyl] -N'-[2-(5bromo)pyrazinyl]thiourea
5 N- (2- (2- (5-ethoxy-6-fluoro)pyridyl)ethyl] -Ν' -((3-(6chloro)pyridazinyl)]thiourea
N- [2- (2- (3-ethoxy-6-f luoro)pyridyl)ethyl] -Ν' - [2- (4cyano)thiazolyl]thiourea
N-[2-(2-(3-ethoxy-6-fluoro)pyridyl)ethyl] -N’-[2-(440 trif luoromethyl) thiazolyl) thiourea
N-[2-(2-(3-ethoxy-6-fluoro,pyridyl)ethyl] -Ν' -[2-(4ethyl)thiazolyl]thiourea
X-8571A
-114N- [2- (2- (3-ethoxy-6-fluoro)pyridyl) ethyl] -Ν' -((3-(6chloro)pyridazinyl) ]thiourea
N- [2 - (2 - (3,6-dif luoro)pyridyl)ethyl] -Ν' - [2 - (4cyano) thiazolyl ] thiourea
N- [2 - (2 - (3,6-dif luoro) pyridyl) ethyl ] -N' - (2 - (4 trif luoromethy 1) thiazolyl] thiourea
N- [2- (2- (3,6-dif luoro) pyridyl) ethyl] -N‘ - (2- (4ethyl) thiazolyl ] thiourea
N- [2- (2 - (3,6-dif luoro) pyridyl) ethyl] -N‘ - (2 - (510 chloro) pyrazinyl] thiourea
N- [2 - (2- (3 ,6-dif luoro) pyridyl) ethyl ] -N' - [ 2 - (5 bromo)pyrazinyl] thiourea
N- (2- (2- (3,6-di fluoro) pyr idyl) ethyl] -Ν' - ((3-(6chloro)pyridazinyl) ] thiourea
N- [2- (cis-2-pyridyl) cyclopropyl] -N'-(2-(4cyano) thiazolyl] thiourea
N- [2 - (cis-2-pyridyl) cyclopropyl] -Ν' - (2 - (4tri fluoromethyl) thiazolyl] thiourea
N- [2 - (cis-2-pyridyl) cyclopropyl) -Ν' -(2-(42 0 ethyl) thiazolyl] thiourea
N- [2- (cis-2-pyridyl) cyclopropyl] -Ν' - (2pyridyl) thiourea
N- [2 - (cis-2-pyridyl)cyclopropyl] -Ν' - [2 - (5methy 1) pyridyl ] thiourea
5 N- [2 - (cis-2-pyridyl) cyclopropyl] -N'-(2-(5tri fluoromethyl) pyridyl ] thiourea
N- (2 - (cis-2-pyridyl) cyclopropyl] -Ν' - (2 - (5ethyl) pyridyl]thiourea
N- [2 - (cis-2-pyridyl) cyclopropyl] -Ν' - [2 - (53 0 chloro)pyrazinyl] thiourea
N- (2- (cis-2-pyridyl)cyclopropyl] -Ν' - [2- (5bromo) pyrazinyl ] thiourea
N- (2- (cis-2-pyridyl) cyclopropyl] -Ν' - [ (3- (6chloro)pyridazinyl) ] thiourea
5 N- (2- (cis-2- (6-f luoro) pyridyl) cyclopropyl] -Ν' - [2- (4cyano) thiazolyl ] thiourea
N- (2- (cis-2 - (6-f luoro)pyridyl) cyclopropyl] -N'-[2-(4trifluoromethyl) thiazolyl]thiourea
N-(2-(cis-2- (6-f luoro)pyridyl)cyclopropyl] -Ν' - [2- (44 0 ethyl) thiazolyl] thiourea
N- (2- (cis-2- (6-f luoro)pyridyl) cyclopropyl] -N'-(2pyridyl)thiourea
N- [2 - (cis-2 - (6-f luoro)pyridyl) cyclopropyl] -Ν' - (2 - (5methy1) pyridyl]thiourea
5 N- (2- (cis-2 - (6-f luoro)pyridyl) cyclopropyl] -Ν' - [2 - (5-
AP Ο Ο Ο 3 8 4
-115X-8571A
Ν- (2-(cis-2-(6-fluoro)pyridyl)cyclopropyl]-Ν' -(2-(5bromo)pyrazinyl]thiourea
N-[2-(cis-2-(6-fluoro)pyridyl)cyclopropyl]-N'-((3-(6chloro)pyridazinyl)]thiourea
N- [2- (cis-2- (6-methoxy)pyridyl)cyclopropyl] -Ν' - [2- (4cyano)thiazolyl]thiourea
N- (2- (cis-2- (6-methoxy)pyridyl) cyclopropyl] -Ν' - (2- (4tri fluoromethyl)thiazolyl]thiourea
N- [2- (cis-2- (6-methoxy)pyridyl)cyclopropyl] -Ν' - [2- (410 ethyl) thiazolyl] thiourea
N- [2- (cis-2- (6-methoxy) pyr idyl) cyclopropyl] -Ν' - [2-{5chloro)pyrazinyl]thiourea
N- (2- (cis-2- (6-methoxy)pyridyl) cyclopropyl] -Ν' -(2-(5bromo)pyrazinyl]thiourea
N- (2 - (cis-2 - (6-methoxy)pyridyl) cyclopropyl] -Ν' - [ (3-(6chloro)pyridazinyl)]thiourea
N- [2-(cis-2-(6-ethoxy)pyridyl)cyclopropyl]-Ν'-(2 - (4cyano)thiazolyl]thiourea
N- [2-(cis-2-(6-ethoxy)pyridyl)cyclopropyl]-Ν' -[2-(42 0 trifluoromethyl)thiazolyl]thiourea
N- [2-(cis-2-(6-ethoxy)pyridyl)cyclopropyl]-Ν' -(2-(4ethyl,thiazolyl]thiourea
N- [2-(cis-2-(6-ethoxy)pyridyl)cyclopropyl]-N'-(2-(5chloro)pyrazinyl]thiourea
N-[2-(cis-2-(6-ethoxy)pyridyl)cyclopropyl]-Ν' -(2-(5bromo)pyrazinyl]thiourea
N-[2-(cis-2-(6-ethoxy)pyridyl)cyclopropyl]-Ν' -[(3-(6chloro)pyridazinyl)]thiourea
The following are most preferred compounds.
N- (2-(2-methoxyphenyl) ethyl)-Ν' -(2-(4cyano)thiazolyl]thiourea
5 N- (2 - (2 -methoxyphenyl) ethyl )-N'-[2- (4 trifluoromethyl)thiazolyl]thiourea
N- (2-(2-methoxyphenyl)ethyl)-Ν' -(2-(4ethyl)thiazolyl]thiourea
N-(2-(2-methoxyphenyl)ethyl)-N’-(2-(54 0 bromo)pyridyl] thiourea
N- (2- (2-methoxyphenyl) ethyl)-N'-[2- (5chloro) pyridyl]thiourea
N- (2-(3-methoxyphenyl)ethyl)-Ν' -[2-(4cyano)thiazolyl]thiourea
X-8571A
-116N-(2 - (3-methoxyphenyl) ethyl) -N'-[2 - (4 trifluoromethyl)thiazolyl]thiourea
N-(2 - (3-methoxyphenyl) ethyl)-N'- (2 -{4 ethyl)thiazolyl]thiourea
N-(2 - (3 -methoxypheny1) ethyl)-N’-[2 - (5 bromo) pyridyl]thiourea
N- (2-(3-methoxyphenyl)ethyl)-Ν' -[2-(5chloro)pyridyl]thiourea
N-(2-(2-ethoxyphenyl)ethyl) -Ν' - [2- (510 bromo) pyridyl] thiourea
N- (2-(2-ethoxyphenyl) ethyl)-Ν' -[2-(5chloro)pyridyl]thiourea
N-(2-(2,6-difluorophenyl) ethyl)-Ν' -[2-(4cyano)thiazolyl]thiourea
N- (2- (2,6-difluorophenyl)ethyl) -Ν' - [2- (4trifluoromethyl)thiazolyl]thiourea
N-(2-(2,6-difluorophenyl)ethyl)-Ν' -[2-(4ethyl)thiazolyl]thiourea
N- {2-(2,6-difluorophenyl)ethyl)-Ν' -[2-(52 0 bromo)pyridyl] thiourea
N-(2-(2,6-difluorophenyl)ethyl)-Ν' -[2-(5chloro)pyridyl]thiourea
N-(2-(2,6-difluorophenyl)ethyl)-Ν' -[2-(5bromo)pyrazinyl]thiourea
5 N- (2 - (2,6-dif luorophenyl) ethyl) -Ν' - ( (3-(6chloro)pyridazinyl)]thiourea
N-(2-(2-fluoro-6-methoxyphenyl)ethyl)-Ν' -(2-(5bromo)pyridyl]thiourea
N-(2-(2-fluoro-6-methoxyphenyl)ethyl)-Ν' -[2-(53 0 chloro)pyridyl] thiourea
N- (2-(2-chlorophenyl)ethyl)-Ν' -[2-(4cyano)thiazolyl]thiourea
N- (2- (2-chlorophenyl) ethyl)-N'-[2- (4ethyl)thiazolyl]thiourea
5 N- (2 - (2-chlorophenyl) ethyl) -Ν' - [2 - (5bromo) pyridyl]thiourea
N-(2-(2-chlorophenyl)ethyl)-Ν' -[2-(5chloro) pyridyl]thiourea
N-(2-(3-chlorophenyl)ethyl)-Ν' -[2-(44 0 cyano) thiazolyl] thiourea
N-(2-(3-chlorophenyl)ethyl)-Ν' -[2-(4ethy1)thiazolyl]thiourea
N-(2-(3-chlorophenyl)ethyl)-Ν' - [2- (5bromo)pyridyl]thiourea
5 N- (2 - (3-chlorophenyl) ethyl) -Ν' - [2 - (5-
AP Ο Ο Ο 3 8 4
Χ-8571Α
-117Ν-(2-(1-cyclohexenyl)ethyl?-Μ·-[2- (4cyano)thiazolyl]thiourea
Ν-(2-(1-cyclohexenyl) ethyl)-N’-[2-(4trifluoromethyl)thiazolyl]thiourea
N-(2-(1-cyclohexenyl)ethyl)-Ν'-(2-(4ethyl)thiazolyl]thiourea
N-(2-(1-cyclohexenyl) ethyl)-N1-(2-(5bromo) pyridyl]thiourea
N-(2-(1-cyclohexenyl)ethyl)-Ν' -[2-(510 chloro)pyridyl]thiourea
N-(2-(1-cyclohexenyl)ethyl)-Ν' -((3-(6chloro)pyridazinyl)]thiourea
N-(2-(2,5-dimethoxyphenyl) ethyl)-Ν' -(2-(5chloro)pyrazinyl]thiourea
N- (2 - (2,5-dimethoxyphenyl ) ethyl)-Ν' -[2-(5bromo)pyrazinyl]thiourea
N-(2-cis-phenylcyclopropyl)-Ν' -(2-(5bromo) pyridyl]thiourea
N-(2-cis-phenylcyclopropyl)-Ν' -(2-(52 0 chloro)pyridyl] thiourea
N-[2-(2-pyridyl)ethyl]-Ν' -[2- (5-bromo)pyridyl]thiourea N-[2-(2-pyridyl) ethyl]-N'-[2- (5chloro)pyridyl)thiourea
N-[2-(2-pyridyl) ethyl]-N’-[2-(52 5 trifluorornethyl)pyridyl]thiourea
N-[2-(2-pyridyl)ethyl]-Ν' - [2- (5-ethyl)pyridyl]thiourea N-[2-(2-pyridyl)ethyl]-Ν' -(2-(5methyl) pyridyl]thiourea
N-[2-(2-(6-methoxy)pyridyl) ethyl]-Ν' -(2-(53 0 bromo) pyr idyl] thiourea
N-[2-(2-{6-methoxy)pyridy1) ethyl]-Ν' -[2-(5chloro)pyridyl]thiourea
N-[2-(2-(6-ethoxy)pyridyl)ethyl]-Ν' -[2-(5bromo) pyridyl]thiourea
5 N- [2 - (2 - (6-ethoxy)pyridyl) ethyl] -Ν' - (2 - (5chloro) pyridyl]thiourea
N-[2-(2-(6-fluoro)pyridyl) ethyl]-N'-[2-(5bromo)pyridyl]thiourea
N-[2-(2-(6-fluoro)pyridyl) ethyl]-Ν' -(2-(54 0 chloro) pyridyl] thiourea
N-[2-(2-(3-fluoro)pyridyl)ethyl]-Ν' -[2-(5bromo)pyridyl]thiourea
N-[2-(2-(3-fluoro)pyridyl) ethyl]-N'-[2-(5chloro)pyridyl]thiourea
5 N- (2 - (2- (6-chloro)pyridyl) ethyl] -Ν' - [2- (5bromo)pyridyl]thiourea
ι' 5
Ζλ
X-8571A
-118Ν- [2-(2-(6-chloro)pyridyl)ethyl]-Ν' -(2-(5chloro) pyridyl]thiourea
N-(2-(2-(3-methoxy-6-fluoro)pyridyl)ethyl]-Ν' -(2-(5bromo) pyridyl]thiourea
N-[2-(2-(3-methoxy-6-fluoro)pyridyl)ethyl]-Ν' -(2-(5chloro) pyridyl]thiourea
N-(2-(2-(5-ethoxy-6-fluoro)pyridyl)ethyl]-Ν' -[2-(5bromo) pyridyl]thiourea
N-[2-(2-(5-ethoxy-6-fluoro)pyridyl)ethyl]-Ν' -(2-(50 chloro) pyridyl 3 thiourea
N-(2-(2-(3-ethoxy-6-fluoro)pyridyl)ethyl]-Ν' -[2-(5bromo)pyridyl]thiourea
N-[2-(2-(3-ethoxy-6-fluoro)pyridyl)ethyl]-Ν' -[2-(5chloro)pyridyl]thiourea
N-(2-(2-(3,6-difluoro)pyridyl)ethyl]-Ν' -(2-(5bromo) pyridyl]thiourea
N-(2 - (2-(3,6-difluoro)pyridyl)ethyl]-Ν' -[2-(5chloro) pyridyl]thiourea
N-[2-{cis-2-pyridyl)cyclopropyl]-Ν' -(2-(50 bromo)pyridyl]thiourea
N- (2-(cis-2-pyridyl)cyclopropyl]-Ν' -(2-(5chloro) pyridyl]thiourea
N-[2-(cis-2-(6-fluoro)pyridyl)cyclopropyl]-Ν' -(2-(5bromo) pyridyl]thiourea
N-[2-(cis-2-(6-fluoro)pyridyl)cyclopropyl]-N*-(2-(5chloro) pyridyl]thiourea
N-(2-(cis-2-(6-methoxy)pyridyl)cyclopropyl]-Ν' -(2-(5bromo) pyridyl]thiourea
N-(2-(cis-2-(6-methoxy)pyridyl)cyclopropyl]-Ν' -(2-(50 chloro) pyridyl]thiourea
N-(2-(cis-2-(6-ethoxy)pyridyl)cyclopropyl]-Ν' -(2-(5bromo) pyridyl]thiourea
N-[2-(cis-2-(6-ethoxy)pyridyl)cyclopropyl]-Ν' -(2-(5chloro) pyridyl]thiourea
N—[2-(2,6-difluoro-3-methoxyphenyl)ethyl]-Ν' -(2-(5bromo) pyridyl]thiourea
Especially preferred is N-(2-(2-pyridyl)ethyl]N'-(2-(5-bromo)pyridyl]thiourea, and its hydrochloride salt.
As mentioned above, the invention includes pharmaceutically acceptable salts of the compounds defined by the above formula (I). Although generally neutral, a
AP Ο Ο Ο 3 β 4
Χ-8571Α -119particular compound of this invention can possess a sufficiently acidic, a sufficiently basic, or both, functional groups, and accordingly react with any of a number of nontoxic inorganic bases, and nontoxic inorganic and organic acids, to form a pharmaceutically acceptable salt. Acids commonly employed to form acid addition salts are inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid and the like, and organic acids such as p-toluene sulfonic, methanesulfonic acid, oxalic acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid, and the like. Examples of such pharmaceutically acceptable salts thus are the sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate,
5 monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate, hexyne-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, g-hydroxybutyrate, glycollate, tartrate, methanesulfonate, propanesulfonate, naphthalene-l-sulfonate, naphthalene-2-sulfonate, mandelate and the like. Preferred pharmaceutically acceptable acid addition salts are those formed with mineral acids such as hydrochloric acid and hydrobromic acid, and those formed with organic acids such as maleic acid and methanesulfonic
Χ-8571Α
-120Base addition salts include those derived from inorganic bases, such as ammonium or alkali or alkaline earth metal hydroxides, carbonates, bicarbonates, and the like. Such bases useful in preparing the salts of this invention thus include sodium hydroxide, potassium hydroxide, ammonium hydroxide, potassium bicarbonate, calcium hydroxide, calcium carbonate, and the like.
The pharmaceutically acceptable salts of the invention are typically formed by reacting a compound as
0 defined with an equimolar or excess amount of acid or base. The reactants are generally combined in a mutual solvent such as diethyl ether or benzene, for acid addition salts, or water or alcohols for base addition salts, and the salts normally precipitate out of solution within about one hour
5 to about ten days and can be isolated by filtration or other conventional methods. The salts of the compounds of the invention will convert to the compound per se after administration and are thus prodrugs. All prodrugs are administered in an amount sufficient to generate an effective amount of the compound to contact the virus and interact with it (e.g. inhibit replication thereof).
The compounds of the present invention also include racemates, racemic mixtures, and individual enantiomers or diastereomers. All asymmetric forms,
5 individual isomers and combinations thereof are within the scope of the present invention.
As noted, the optically active diastereomers of the compounds of Formula 1 are considered part of this invention and such optically active isomers may be prepared
0 from their respective optically active precursors by the procedures described herein, or by resolving the racemic
AP Ο Ο Ο 3 8 4
Χ-8571Α
-121mixtures. The resolution can be carried out in the presence of a resolving agent, by chromatography, by repeated crystallization or by some combination of these techniques which are known to those skilled in the art.
Further details regarding resolutions can be found in
Jacques, et al., Enantiomers, Racemates, and Resolutions, John Wiley & Sons 1981.
The compounds of the present invention, or their precursors, are prepared using procedures known to those of ordinary skill in art. More particularly, the compounds of Formula (1) are prepared according to the procedures shown below in Schemes I, II, and III, and as described following the Schemes.
(3) f,
X-8571A
-122In Scheme I, a derivative of isothiocyanate (1) is reacted with an amino group (2) in approximately 1:1 molar ratio, in an inert organic solvent such as N,Ndimethyl formamide and stirred at an appropriate temperature of between about 0-150°C for a period of time between about 1 and 72 hours. The time and temperature used depends upon the reactivity of the individual reagents. The product (3) may be isolated by conventional techniques.
Scheme ..II
(3)
Scheme II is run under the same general reaction conditions as Scheme I.
AP Ο Ο Ο 3 8 4
Χ-8571Α
-123Scheme, .III
r5—c—c—n—c—NRi
Rfl R9 R4 R,
Scheme III is a process analogous to that described in J. Ora, Chem. ,Vol. 49, 4123 (1984) herein incorporated by reference.
The compounds employed as initial starting materials in the synthesis of the compounds of* this invention are well known and, to the extent not commercially available, are readily synthesized by standard procedures commonly employed by those or ordinary skill in the art.
Other teaching for preparing the compounds of the invention may be found in Organic Synthesis, 15, 69 (1965); Synthesis, 202 (1974); Journal of the American Chem, Society, 22, 1236 (19 57),- and Organic Synthesis, 22. 69, (1940), and Synthesis. May 1983, p. 391, incorporated herein by reference.
Tests with the above compounds of Formula 1 have indicated activity as inhibitors of HIV. While not being bound by theory, it is believed that the compounds act as
X-8571A -124' ft ίreverse transcriptase inhibitors, and thereby act to inhibit replication of the virus.
The following is a description of the test systems used in analyzing compounds in effectiveness against HIV.
Tests A, B, C, and D (XTT)
MT4 cells in a medium of RPMI 1640, 5% FCS, penicillin/streptomycin are adjusted to 2x10^ cells/ml and seeded into microplates (96 wells/plate) 100 ml cell suspension/well giving 2xl04 cells/well. The compound to be tested is made into a 10 mg/ml mixture in DMSO and stored at -20°C. The compound in DMSO is diluted with medium containing 10% DMSO in a 10-fold dilution series to give 1 mg/ml, 10 mg/ml, and 100 mg/ml solutions. Further
5 dilutions to 400, 40, 4 and 0.4 mg/ml are made in medium containing microplates. Fifty ml of the 400, 40, and 4 mg/ml are transferred to the cell-containing microplates with a multi-channel pipette (final concentration: 100,
10, and 1 mg/ml). Finally, 50 ml of virus suspension is added to each well (with a repetitive Eppendorf* multipipett). Each plate has at least six wells with the following: (Test A: HIV virus; Test B: HIV(II) virus; Test
C: SIV virus; Test D: No virus]; with no drug (virus control) and six wells without virus (medium control). The plate is put into a plastic bag and incubated for six days in CO2 atmosphere. To each well in the plate is added 50 ml of XTT ( (2,3-bis[2-methoxy-4-nitro-5-sulfophenyl]-5[ (phenylamino) carbonyl]-2H-tetrazolium hydroxide), (1 mg/ml 0.01-0.02 mM N-metyl-phenazonium methosulfate). After six
0 hours of incubation in CO2 atmosphere the plates are
Χ-8571Α
AP ο Ο Ο 3 8 4
-125vortex. Optical densities are determined at a wavelength of 450 nm and a reference wavelength of 650 nm. The percent reduction of cytotoxocity caused by the virus infection is calculated as follows:
OD450 compound - OD450 inf cells _ x 100
OD450 uninf cells - OD450 inf cells
Tests E, F, G, H {HIV-IRT, HIV-2RT, SIVRT, no virus)
MT-4/H9-cells are adjusted to 2x10^ cels/ml medium (RPMI 1640, 5% FCS, penicillin/streptomycin) and seeded into microplates (96 wells/plate) 100 ml cell suspension/well giving 2 x 10^ cells/well. The compound to be tested is made 10 mg/ml in DMSO = stock solution (stored at -20°C). The compound dissolved in DMSO is diluted 25 times in medium to give 400 mg/ml. Further dilutions to 40 mg/ml and 4 mg/ml are made in microplates.
ml of the dilutions 400 mg/ml, 40 mg/ml and
4mg/ml are transferred to the cell-containing microplate with a multichannel pipette. (Final concentration: 100, 10 and 1 mg/ml).
Finally 50 ml of virus suspension is added to each well (with a repetitive Eppendorf multipett). [Test
5 E-HIV-1; Test F-HIV-2; Test G-SIV; Test H-no virus].
Each plate has at least four wells with virus but no drug (virus control) and two wells without virus (medium control) . The plate is put into a plastic bag to avoid evaporation and incubated for six days in CO23 0 atmosphere. 10 ml supernatant from each well is
X-8571A . ? η γ, ο π α
-126microplate to which 40 ml VDB, (50 mM Tris-HCl pH = 7.6, 35 mM KCl, 4 mM DTT, 1 mM EDTA, 1.3% Triton X-100), have been added to each well. The addition of 50 ml RT-reaction mix, (10 ml culture supernatant, 40 ml VDB and 50 ml reaction mixture giving a final concentration of: 100 mM Tris-HCl pH = 7.6, 100 mM KCl, 4 mM MgCl2, 4 mM DTT, 275 mg/ml BSA/ml, 5 mg (rA)n(dT) 12-18/ml and 0.3 mM 3H dTTP (specific activity 18.000 cpm/pmol)) gives a final volume of 100 ml/well. After 60 minutes of incubation the whole assay
0 volume is transferred by use of a cell harvester to a filter mat prewetted with 5% TCA. The filter is washed in 5% TCA and rinsed once in ethanol. After drying the filter mat at 60°C for 30 min. each filter (96/mat) is punched out and put into counting vials 2 ml of scintillation fluid is
5 added and the samples are counted (1 min) or the whole filter mat is put into a plastic bag, 10 ml of scintillation fluid is added and the filter mat is counted in a Beckman Betaplate counter. Percent reduction of RT activity is determined by comparing RT activity for virus
0 control with the RT activity measured for each dilution of the compound.
Test I (HIVRT (rAdt))
The compounds were tested for direct inhibitory
5 activity on HIV-RT in a volume of 100 ml recombinant HIV-RT (diluted in virus disruption buffer to give 200.000 cpm).
100 mM Tris-HCl pH 7.6, 100 mM KCl, 4 mM MgCl2, mM DTT, 275 mg/ml BSA, 0.5 mg (rA)n(dT)12-18 and 0.3 mM ^H-=dTTP (specific activity 18.000 cpm/mol). After 60
0 minutess of incubation 40 ml in duplicate were spotted on
AP Ο Ο Ο 3 8 4
Χ-8571Α
-127discs in ethanol they were dried and counted in scintillation fluid.
The following Tables illustrate activities of compounds in the above-described tests. The numbers represent % inhibition. *
X-8571A
-128
Table.. Al s
lesr 100 μα/ml 10. . US 1 μα/ml 0 J.....uo/ml
A - 99 41 13
A 100 100 2
A 48 100 80 4
A -. 70 62 8
A 58 100 78 4
A 64 98 77 0
D 45 33 18 31
B 50 28 48 0
B 20 84 0 10
B 0 0 0 19
C 6 0 0
C 9 75 0 0
C 22 40 8 0
C 65 17 2 1
E 99 99 99 10
E 99 99 99 1
F 95 57 75 43
F 86 76 79 43
AP Ο Ο Ο 3 8 4
Χ-8571Α
-129Table Α2
£1 issr 1U0... uaZml IQ.-Uq/nd 1., uaZiQl iLl-Ho/nil
-ϊχ a CF-, 66 24 100 -
A 4 16 75 62
• A 31 31 84 84
B D 68 75 46 0
C 43 5 11 9
I 73 73 63
I - 75 75 68
E 97 96 97 98
B F 96 98 95 56
B 19 38 100 21
—¢1 N C(CH3)3 0 9 0 0
a T - 15 8 8
r
X-8571A
30Iablg..A2.J.gantinuedI,
El Test 100 .uq/rcl 10.uq/mi L.ug/ml 0.1 ua/ml
SV CH3 X N ch3 A 99 85 71 -
H A 100 88 6 7
D 0 0 -
« I — 38 39 34
• c 0 1 0
a E 94 91 23 1
F 93 61 92 1
B 85 100 100 13
-4S1 A Ν -X , CN 0 0 63 -
a A 0 0 51 84
a D 93 70 53 0
a C 0 2 5 11
a I — 94 93 72
a I - 95 95 73
a E 98 98 98 99
a F 96 94 91 67
a B 0 0 90 74
AP Ο Ο Ο 3 8 4
-131X-8571A lakle. Α2 Icoptinued].
El jTesi. 1Q. .uq/ml I iw/ml Ώ-.1 UQ/ml
A 0 w* 0 0 0 -
» I - 13 1 1
Al A a 18 0 0 -
a I 1 1 1
A>/ 30 0 0 -
a I - 1 1 1
X-8571A
-132Table A2 (continued)
Ei xesi 100 ua/ml IQ-HO/ml 1 ug/ml 0..l uo/ml
—1 Ό A 30 51 32 -
A 14 65 46
S^C i jHt9 33 0 0 -
a I - 1 1 . 1
o A 0 25 0 -
M I — 16 16 1
-O“ A 0 67 17 -
I - 35 29 4
AP Ο Ο Ο 3 8 4
Χ-8571Α
-133lafelg_,A2. (continued).
Ει TEST lQO ugZml 10 UQ/mi l.ug/ml Q.l μα/ml
-F A - 41 5 0
A 0 32 5 w.
Cl A 0 52 0 -
• I 50 31 5
A - 22 0 3
-Q-c°2 nBu A 0 0 0
Ό A 6 2 0 -
-o A 22 23 0 -
I - 6 12 5
X-8571A
-134η ,
Hal
Table,a2-(continued)
El 1E£1 100..U3/jnl 10. U2/ml 1 Jl.q/jnl 0.,1 ug/ml
Ν—λ CH, 100 64 42 -
M I - 9 15 9
B 100 27 0
a C 0 0 0
-O A N=/ 100 100 4 -
a I - 36 27 1
a c 100 20 2 —
N^, —( 1 A \-N 10 0 0 -
-ZS ff N-N 45 27 11 -
a I — 14 14 12
a c 15 8 5 •
a D 0 33 33 15
AP Ο Ο Ο 3 8 4
Χ-8571Α
-135Table Α2.. (.continued!
El. TES1 100 ua/ml 10 ua/ml 1 μσ/ml 0.1 Ua/ml
-er N-N CH3 a 20 38 3 -
1 I * 18 21 1
s jch:ch3 a _< I nn 17 7 0 -
I 11 53 12
M I — 17 9 12
-cl N'N I - 14 14 12
A 100 100 100
fl C 0 17 0
fl B 96 57 100
<4 * Cl 100 100 94 -
A 38 49 37
B 26 16 8
B 100 60 55 -
X-8571A
-136Table A2 (continued)
El TEST 100 ug/ml 10.. Ug/ml 1 .ug/ml £,.1 jig/ml
-0 N , A - 0 0 0
1 A — 0 0 0
“0 A 0 0 0 -
1 I - 38 8 1
— A 0 71 0 —
A - 7 10 3
I - 10 12 7
X-8571A
APΟ 00 3 8 4
-137lable. JXL. (continued).
El TEST 100 μα/ml 10 μα/ml 1 μα/ml 0.1 μα/ml
~λΧ) a 100 100 63 -
D 23 27 32
« C 8 1 0
tt I 40 36 39
• A 41 99 53 0
V E 95 96 77 1
« F 96 84 87 1
B 50 100 99 17
ch3 50 28 8
I - 24 J 12 12
X-8571A j ' MA
-138T.able,.A2 ...Icontir,
Ei TEST 100 Lia/ml 10 „a/ml 1 ua/ml 0.1 ua/ml
X Cl 100 19 4
E 97 8 11
F 93 72 6 1
B 36 100 22 18
I * 1 6 9
c 17 2 0
G 8' 1 1
OCH2CHj A 33 5 0
1 I - 8 5 1
APΟ Ο Ο 384
Χ-8571Α
-139Table Α2 (continued)
Il TEST 100 μσ/ml 10 μσ/ml 1 Lio/ml 0.1 ua/ml
„ ,C1 άΧΧ α 68 63 0 -
Α 49 67 0
Ε 96 51 1
« F 98 79 1 —
« I - 18 18 12
Η Β 27 67 9 24
• C 21 0 0
Β G 90 12 1
-<σ'> 100 100 100 -
• Α 100 100 100
Β Α 100 100 100
D 0 28 5
« C 19 5 2
a I - 39 38 33
Β Ε 95 16 51 1
F 97 62 77 4
Η Β 93 12 40 4
Α 72 21 3 -
X-8571A
-140Table.Al s
H
Ex TEST 100 ua/ml 10 μσ/ml 1 ua/ml 0.1 ua/ml
θ A - 0 0 0
A - 0 0 25
0 1 A 0 0 0
/-y A —N NMe v y 0 0 0
r~y —N 0 A — 9 13 0
AP Ο Ο Ο 3 8 4
-141X-8571A
Table Α4
Η Η
£5 TEST 100 Lia/ml 10 uo/ml 1 ua/ml 0.lUa/ml
MeO—Ζ Α MeOZ 0 54 4 -
a A 0 58 44
-Ο- . 73 79 5 -
a A 71 93 22
F 100 100 100 -
a A 16 52 98
a I - 92 77 43
Χ-8571Α
-142Table Α4 (continued)
Bs TEST 100 uc/ml 10 ua/ml 1 uc/ml 0.1 Uc/ml
Q- * ΟΟΗς 100 100 96 -
B 100 91 100
• C 0 5 0 -
I - 33 30 12
AP Ο Ο Ο 3 8 4
Χ-8571Α
-143Table-AS s
i'
I 'J ί· Η Μ.
X-8571A
-144Table A5 (continued)
Su El 3. TEST 100 1
ck2pi-.-pci Ac A 18 3 5 __
CH2Ph Ph A 100 16 2
a C 100 12 0
a a D 3 0 0 —
a a A 99 12 0 *
a a E 98 63 41 •
a a F 95 1 33 42
a a B 80 48 37 24
CH2Ph CH2Ph A 100 46 0
a a a 100 29 4 -
a a E 98 9 1
a a F 98 59 1 1
a a B 58 100 35 0
a a C 100 20 2
a a G 93 1 1
CH2Ph-p-OH H A - 0 0 0
CH2Ph-p-OH Ph A - 34 4 1
CH2Ph-p-OH Ph A 99 19 44
. a B 100 12 0
• a C 100 28 6 -
AP 0 0 0 3 8 4
X-8571A -145A feature of this invention also disclosed is a method of administering to a human in need thereof the compounds of the invention or their pharmaceutically acceptable salts to treat or inhibit HIV/AIDS, to inhibit the replication of the HIV/AIDS virus in infected human cells and to inhibit AIDS from developing in humans infected with the HIV/AIDS virus or carrying antibodies to the HIV/AIDS virus.
The present invention also discloses the compounds of the invention and their salts for use in the treatment of the condition referred to above, as well as the use of such compounds in the preparation of pharmaceutical formulations for the treatment of such conditions.
In general for the treatment as described above, a suitable effective dose of the compound or its pharmaceutically acceptable salt will be in the range of 0.5 to 250 rag per kilogram bodyweight of recipient per day. Administration may be by any suitable route including oral, rectal, nasal, topical (including buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous and intradermal) administration. It will be appreciated that the preferred route may vary with, for example, the condition, age, and weight of the recipient.
The administered ingredients may be used as a therapy in conjunction with other therapeutic agents, (other anti-virals, anti-bacterials, compounds useful for preventing resulting secondary or contemporaneous afflictions associated with HIV/AIDS) such as AZT, ddl, ddC, 9-( (2-hydroxy-1-(hydroxymethyl) ethoxy]methyl]guanine.
,» ί-S
X-8571A
-1469- (2-hydroxyethoxymethyl)guanine (acyclovir), 2-amino-9- (2hydroxyethoxymethyl) purine, suramin, ribavarin, antimoniotungstate (HPA-23), interferon, e.g., a interferon, interleukin II, and phosphonoformate (Foscarnet) or in conjunction with other immune modulators including bone marrow or lymphocyte transplants or other medications such as levamisol or thymosin which would increase lymphocyte numbers and/or function as is appropriate.
For example, in an evaluation of the combination of AZT and a compound of the formula
Η H a synergistic effect was observed. The combination was evaluated against HIV-l in CEM cells using the technique of Prichard and Shipman (Antiviral Research, 14, 181-206 (1990)). The peak of synergy was observed at 0.5 pg/ml of the compound of the formula above and 0.005 pg/ml of AZT.
While it is possible for the administered ingredients to be administered alone, it is preferable to present them as part of a pharmaceutical formulation. The formulations of the present invention comprise at least one administered ingredient, as above-defined together with one or more acceptable carriers thereof and optionally other therapeutic ingredients. The carrier(s) must be
AP Ο Ο Ο 3 8 4
Χ-8571Α
-24713C-NMR (CDCI3 + DMSO-dg) δ 178, 162, 141, 137, 127, 125, 124, 111, 46, 29 PPM.
iH-NMR (CDCI3 + DMSO-dg) δ 3.3 ppm (t), 3.9 ppm (m), 6.85 ppm (d), 6.90 ppm (m), 7.20 ppm (d), 7.25 ppm (d) .
Example 116
N-(2-(2-fluoro-6-chloro)phenethvl)-Ν' -(2-thiazolvl)thioqrea
2-Chloro-6-fluorophenylacetonitrile (2.5 g, 14.7 mmol) was dissolved in 30 ml diethyl ether. Lithium aluminium hydride (1.5 g) was added in small portions over a period of 10 minutes. The mixture was then heated to reflux for 15 minutes. After cooling to room temperature,
1.5 ml water, 1.5 ml aqueous sodium hydroxide, and 4 ml water was added slowly. The ether solution containing the product 2-chloro-6-fluorophenethylamine was decanted off and the solvent was removed in vacuo.
The amine formed was condensed with the product of Example 103 using the method as described in Examples 104 and 105 to give 270 mg of the titled product after recrystallization from ethanol.
^-H-NMR (DMSO-d6) δ 3.1 ppm (t), 3.85 ppm (m) , 7.1 ppm (d) , 7.15-7.30 ppm (m), 7.40 ppm (d).
Example. 117
Μ.-.Ϊ2-.(3-Methoxy) -Phenethyl.) -Ν' - (2-thiazolvl) thiourea
In a manner analogous to Example 105, the product of Example 103 was condensed with 3methoxyphenethylamine to give the titled product.
AP ο Ο ο 3 8 4
Χ-8571Α -248^-H-NMR (DMSO-dg) 8 2.9 (t, Ph, CH2 , 2H) , 3.75 (s, OCH3,
3H), 3,9 (q, CH2N, 2H), 6.8 (mult. 0 and ρ, 4H), 7.1 (d, thiazole, IH), 7.2 (t, m, IH), 7.4 (d, thiazole, IH).
Example 118
N-(2-Phenethvl)-N1 -f2-(5-methvl)pvridvl1 thiourea
A stirred solution of 2-phenethyl isothiocyanate (1.63 g, 10 mmol, 1.5 mL) and 2-amino-5-methylpyridine (1.08 g, 10 mmol) in N-methylpyrrolidinone (20 mL) was heated to 125°C. After 16.5 h, the reaction was cooled to room temperature and poured into ethyl acetate. The organic phase was washed with water (4x) and brine. The organic layer was dried over sodium sulfate, filtered and concentrated. The solid obtained was purified by flash chromatography on silica gel (2% ethyl acetate/dichloromethane) to provide 2.01 g of the titled product (74%) . This material was recrystallized from ethyl acetate/hexanes to provide 1.72 g of titled product as a white crystalline solid:
mp 153-154°C; IR (KBr,cm'1) 3235, 2939, 1613, 1559, 1534, 1493, 1300, 1188;
ςΗ NMR (300 MHZ, DMSO-dg·) δ 11.56 (br S, IH) , 10.42 (s, IH) ,
7.84 (d, J=1.3 Hz, IH), 7.52 (dd, , J=8.5, 2.1 Hz, IH), 7.31
7.16 (m, 5H), 6.99 (d, J=8.5 Hz, IH), 3. 82-3 . .75 (m, 2H) ,
25 2.87 (t, J=7.0 Hz, 2H), 2.16 (s, 3H) ;
MS (FD) m/e 271 (M+);
UV (EtOH) 298nm (ε= 14080), 268nm (ε=21638), 248nm (ε= 15905), 201nm (ε= 18504).
Anal. Calcd for C15H17N3S: C, 66.39; H, 6.31; N, 15.48.
AP Ο Ο Ο 3 8 4
Χ-8571Α
-249Example 119
N-Methvl-N- (2-phenethyl)-Ν1-(2-thiazolvl)thiourea
In a manner analogous to Example 105, the product of Example 103 was condensed with N-methyl5 phenethylamine, to give the titled product.
1H-NMR (DMSO-dg) δ2.9 (t, PhCH2,2H) , 3.2 (s,NCH3,3H) 4.0 (t, CH2N,2H), 6.8 (d,thiazole,IH), 7.2(m, thiazole,IH), 7.3(mult.,CgH5,5H)
Example 120
N-. (2 -Indanyl) -N' - (2: -thiazglylLEhiPurga
In a manner analogous to Example 105, the product of Example 103 was condensed with 2indanylamine, to give the titled product.
^-H-NMR (DMSO-d6) 52.4 (q, CH2 , 2H) , 3.3 (q, CH2 , 2H) ,
4.8 (q, CHN, IH), 7.0 (d, thiazole, IH), 7.1-7.3 (mult., C5H4, 4H), 7.4 (d, thiazole, IH).
Example 121
N-.(2-(2-Azido) -phenethyl) -Ν' - (2-thiazolvl) thiourea
2-Aminophenethylalcohol (Aldrich) (0.8 g, 5.8 mmol) was dissolved in 15 ml H2O at 0°C. Trifluoroacetic acid (1.2 ml) was added. Sodium nitrite (0.41 g, 0.6 mmol) dissolved in cold water (2.0 ml) was added. The solution was stirred at 0°C for 10 minutes.
Lithium azide (0.59 g, 12 mmol) in water (2.0 ml) was added slowly. The solution was brought up to ambient temperature. The solution was extracted with diethyl ether (3 x 50 ml), the organic phase was washed with 1 N HCl (aq.) (2 x 20 ml), dried with Na2SC>4, filtered and evaporated.
AP 0 0 0 3 8 4
X-8571A
-150buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. The formulations may be presented in unit-dose or multidose containers, for example, sealed ampules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, or example water for injections, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules, and tablets of the kind previously described.
Preferred unit dosage formulations are those containing a daily dose or unit, daily sub-dose, as herein above recited, or an appropriate fraction thereof, of the administered ingredient.
The antiviral compounds of Formula I can be used as surface disinfectants. Solutions containing as little as 0.1 percent by weight of the antiviral compound maybe effective for disinfecting purposes. Preferably, such solutions also can contain a detergent or other cleansing agent. The solutions maybe useful for disinfecting objects such as glassware, dental and surgical instruments, and surfaces such as walls, floors, and tables in areas where maintenance of sterile conditions is important, for example., hospitals, food-preparation areas, and the like.
In practicing the method for treating or inhibiting HIV and/or AIDS, the antiviral can be administered in a single daily dose or in multiple doses per day. The treatment regime may require administration over extended periods of time, e.g., for several days or
X-8571A
-151for several months or years. The amount administered per dose or the total amount administered will depend on such factors as the nature and severity of the infection, the age and general health of the patient, the tolerance of both the patient and the microorganism or microorganisms involved in the infection to the antiviral compound.
The following formulation examples represent specific pharmaceutical formulations employing compounds comprehended by the present method. The formulations may employ as active compounds any of the compounds of Formula I or a pharmaceutically acceptable salt thereof. The examples are illustrative only and are not intended to limit the scope of the invention in any way.
Formulation 1
Hard gelatin capsules are prepared using the following ingredients:
Quantity (mo/capsule)
Compound 1250
Starch dried 200
Magnesium stearate 10
The above ingredients are mixed and filled into
AP Ο Ο Ο 3 8 4
Χ-8571Α -152Formulation 2
A tablet formula is prepared using the
ingredients below: Ouantitv (ma/tablet)
Compound 250
Cellulose, microcrystalline 400
Silicon dioxide, fumed 10
Stearic acid 5
Magnesium stearate 10
The components are blended and compressed to form tablets each weighing 675 mg.
Formulation 3
An aerosol solution is prepared containing the 15 following components:
Compound 0.25
Ethanol 29.75
Propellant 22 70.00 (Chlorodifluoromethane)
The active compound is mixed with ethanol and the mixture added to a portion of the propellant 22, cooled to -30°C and transferred to a filling device. The required amount is then placed in a stainless steel container and diluted with the remainder of the propellant. The valve
X-8571A
-153Formulation 4
Tablets each containing 60 mg of active ingredient are made up as follows:
* f.
Compound 60 mg
Starch 45 mg
Microcrystalline cellulose 35 mg
Polyvinylpyrrolidone (as 10% solution in water) 4 mg
Sodium carboxymethyl starch 4.5 mg
Magnesium stearate 0.5 mg
Talc 1 mg
The active ingredient, starch and cellulose are passed through a No. 45 mesh U.S. sieve and mixed thoroughly. The solution of polyvinylpyrrolidone is mixed with the resultant powders which are then passed through a No. 14 mesh U.S. sieve. The granules so produced are dried at 40°-60°C and passed through a No. 18 mesh U.S. sieve.
The sodium carboxymethyl starch, magnesium stearate and talc, previously passed through a No. 60 mesh U.S. sieve, are then added to the granules which, after mixing, are compressed on a tablet machine to yield tablets each weighing 150 mg.
Formulation .5.
Capsules each containing 80 mg of medicament are made as follows:
Compound 80 mg
Starch 59 mg
Microcrystalline cellulose 59 mg
Silicone fluid 2 mg
AP Ο Ο Ο 3 8 4
Χ-8571Α -154The active ingredient, cellulose, starch and magnesium stearate are blended, passed through a No. 45 mesh U.S. sieve, and filled into hard gelatin capsules in 200 mg quantities.
Earmulation £
Suppositories each containing 225 mg of medicament are made as follows:
Compound 225 mg
Saturated fatty acid glycerides 2 mg
The active ingredient is passed through a No. 60 mesh U.S. sieve and suspended in the saturated fatty acid glycerides previously melted using the minimum heat necessary. The mixture is then poured into a suppository mold of nominal 2 g capacity and allowed to cool.
Fcnnulation. 7.
As intravenous formulation is prepared as follows:
Compound 100 mg
Isotonic saline 1000 ml
The solution of the above ingredients is administered intravenously at a rate of 1 ml/minute to a mammal in need of treatment.
It should be understood that in addition to the ingredients particularly mentioned above the formulations of this invention may include other agents conventional in the art having regard to the type of formulation in
,Ί Λ
X-8571A
-155The following examples further illustrate the compounds of the present invention and methods for the synthesis. The examples are not intended to be limiting to the scope of the invention in any respect and should not be so construed.
Examples and Procedures
The following are experimentals illustrating methods for preparing the compounds of the invention.
Example 1
N-(2-Phenethyl)-N‘-f2-(1.3.4-thiadiazolvl)1 thiourea
A solution of 2-phenethyl isothiocyanate (3.26 g, 20 mmol, 3.0 mL) and 2-amino-l,3,4-thiadiazole (2.02 g, 20 mmol) in N,N-dimethylformamide (50 mL) was heated to 100°C. After 68 h, the reaction was cooled to room temperature and poured into ethyl acetate. The organic phase was washed with IN hydrochloric acid, saturated sodium bicarbonate solution, and water. The organic layer was filtered and the solid obtained (2.24 g) triturated with ethyl acetate to provide 1.9 g (36%) of the title
AP 0 0 0 3 8 4
X-8571A
-156mp 210-211.5°C;
IR (KBr, cm'1) 3320, 2924, 2869, 2685, 1645, 1543, 1453, 1384, 1344, 1278, 762, 749, 700, 650;
!h NMR (300 MHz, DMSO-dg) 6 12.35 (br S, IH), 8.92 (s, IH) ,
8.78 (br s, IH), 7.38-7.18 (m, 5H), 3.84-3.72 (m, 2H), 2.92 (t, J=6 Hz, 2H);
MS (FD) m/e 264 (M+);
UV (EtOH) 277nm, 253nm, 205nm.
Anal. Calcd for C11H12N4S2:
Theory: C, 49.98; H, 4.57; N, 21.19.
Found: C, 50.07; H, 4.66; N, 21.48.
Example 2
N-(2-Phenethvl)-Ν'-L4.5-dimethvl-(2-thiazolvl)) thiourea
2-Amino-4,5-dimethylthiazole hydrochloride (3.3 g, 20 mmol) was slurried with methylene chloride and shaken with saturated sodium bicarbonate solution. The layers were separated and the aqueous washed with methylene chloride (2x). The combined organics were dried over magnesium sulfate, filtered and concentrated. To the resulting solid was added 2-phenethyl isothiocyanate (3.26 g, 20 mmol, 3.0 mL) and W,N-dimethylformamide (50 mL). The resulting
X-8571A
-157was cooled to room temperature and poured into ethyl acetate. The organic phase was washed with IN hydrochloric acid, saturated sodium bicarbonate solution, and water (2x). The organic layer was filtered and the solid obtained (3.9 g) recrystallized from ethyl acetate to provide 3.3 g (57%) of the title product: mp 186-7°C;
IR (KBr, cm-1) 3166, 3022, 1523, 1502, 1289, 1215, 737,'
695;
!h NMR (300 MHz, DMSO-dg) δ 11.42 (br s, IH), 9.83 (br s,
IH), 7.36-7.16 (m, 5H), 3.86-3.73 (m, 2H), 2.91 (t, J=7 Hz, 2H), 2.19 (s, 3H,, 2.08 (s, 3H) ;
MS (FD) m/e 291 (M+);
UV (EtOH) 298nm (6=17987), 257nm (6=9939), 204nm (6=20802).
Anal. Calcd for C14H3.7N3S2:
Theory: C, 57.70; H, 5.80; N, 14.42.
Found: C, 57.41; H, 5.85; N, 14.39.
Example 3
N-f2-(4-Methvl)-1-phenethvll-N*-(2-thiazolvl) thiourea
A solution of 2-(4-methylphenethyl) isothiocyanate (820 mg, 4.6 mmol) and 2-aminothiazole (565 mg, 5.65 mmol) in N,N-dimethylformamide (15 mL) was heated
AP Ο Ο Ο 3 8 4
Χ-8571Α
-158to 100°C. After 20.5 h, the reaction was cooled to room temperature and poured into ethyl acetate. The organic phase was washed with IN hydrochloric acid (2x), saturated sodium bicarbonate solution, and brine. The organic layer was dried over magnesium sulfate, filtered and concentrated. The solid obtained (1.1 g) was purified by flash chromatography on silica gel (1% ethyl acetate in methylene chloride) to provide 570 mg (45%) of the titled compound. A sample was recrystallized from ethyl acetate:
mp 132-3°C;
IR (KBr, cm-1) 3168, 2990, 1560, 1513, 1166, 808, 705;
!h NMR (300 MHz, DMSO-d6) δ 11.62 (br s, IH), 9.69 (br s, IH), 7.36 (d, J=4 Hz, IH), 7.20-7.06 (m, 5H) , 3.83-3.73 (m, 2H), 2.87 (t, J=7 Hz, 2H), 2.30 (s, 3H);
MS (FD) m/e 277 (M+);
UV (EtOH) 288nm (€=18773), 257nm (ε=11948), 212nm (e=14509).
Anal. Calcd for C13H15N3S2:
Theory: C, 56.29; H, 5.45; N, 15.15.
Found: C, 56.55; H, 5.52; N, 15.04.
X-8571A
-159A solution of 2-phenethyl isothiocyanate (3.26 g, 20 mmol, 3.0 mL) and 2-aminopyridine (1.90 g, 20 mmol) in N,N-dimethylformamide (50 mL) was heated to 100°C. After
4 h, the reaction was cooled to room temperature and poured into ethyl acetate. The organic solution was washed with water {3x). The organic layer was dried over sodium sulfate, filtered and concentrated. The resulting white solid was recrystallized from ethyl acetate to provide 1.86 g (36%) of the titled product: mp 153-154°C;
IR (KBr, cm’1) 3232, 1536, 1477, 1319, 775;
2H NMR (300 MHz, CDCI3) δ 11.72 (br s, IH) , 8.59 (br s,
IH), 7.97 (d, J=4.2 Hz, IH) , 7.64{dt, J=1.7,8.2 Hz, IH) ,
15 7.37-7.26 (m, 5H), 6.92 (dd. J=7.2,5.1 Hz, IH), 6.74 (d.
J=8.2 Hz, IH) , 4.06 (m. J=6.8 Hz, 2H), 3.04 (t, J=6.9 Hz,
2H) ;
MS (FD) m/e 257 (M+) ;
UV (EtOH) 293nm (6=12040), 266nm (6=12961), 247nm (6=11912) 20 202nm (6=12963).
Anal. Calcd for C14H15N3S:
Theory: C, 65.35; H, 5.87; N, 16.33.
Χ-8571Α
AP ο Ο Ο 3 8 4
-160-
Α solution of 2-phenethyl isothiocyanate (3.26 g, 20 mmol, 3.0 mL) and 4-aminopyridine (1.92 g, 20 mmol) in N,N-dimethylformamide (50 mL) was heated to 100°C. After
4.5 h, the reaction was cooled to room temperature and poured into ethyl acetate. The organic solution was washed with water (2x) and brine. The organic layer was dried over sodium sulfate, filtered and concentrated. The oil obtained was purified by flash chromatography on silica gel (5% methanol in ethyl acetate to 10% methanol in ethyl acetate). This material was recrystaiiized from ethyl acetate yielding 1.85g (36%) of the title product: mp 154.5°C;
IR (KBr, cm-1) 3142, 1579, 1518, 1328, 1276, 750;
1h NMR .(300 MHz, CDCI3) δ 8.42 (dd, J=l,5 Hz, 2H) , 7.94 (br s, IH), 7.39-7.23 (m, 5H), 6.81 (d, J=5 Hz, 2H), 6.38 (br s, IH), 3.99 (m, J=6 Hz, 2H) , 3.02 (t, J=6 Hz, 2H) :
MS (FD) m/e 258 (M+1);
UV (EtOH) 281nm (ε=16486), 255nm (€=21182), 208nm (£=25744).
Anal. Calcd for C14H15N3S:
Theory: C, 65.34; H, 5.87; N, 16.33.
X-8571A
-161Example 6
N- (2-ph.enethvl)-Ν'- f2-(6-fl.uoro) -benzothiazolyl 1 thiourea
A solution of 2-phenethyl isothiocyanate (3.26 g, 20 mmol, 3.0mL) and 2-amino-6-fluoro-benzothiazole (3.36 g, 20 mmol) in dimethylsulfoxide (10 mL) was heated to
150°C. After 5 h, the reaction was cooled to room temperature and filtered. The filtrate was poured into ethyl acetate, washed with water (5x) and brine (2x). The organic layer was concentrated and recrystallized from ethyl acetate to provide 729.5 mg (11%) of the titled product:
mp 212-213°C;
IR (KBr, cm1) 3175, 3025, 1561, 1534, 1461, 1249, 1215;
!h NMR (300 MHz, CDCI3) δ 11.81 (br s, IH), 9.83 (br s,
IH), 7.77 (dd, J=8.7, 2.4 Hz, IH), 7.52 (br s, IH), 7.3120 7.15 (m, 6H), 3.79 (m, 2H,, 2.90 (t, J=6.6 Hz, 2H);
MS (FD) m/e 331 (M+);
UV (EtOH) 310nm, 289nm, 245nm, 208nm, 201nm.
AP Ο Ο Ο 3 8 4
Χ-8571Α
-162Anal. Calcd for C16H14N3S2F:
Theory: C, 57.98; H, 4.26; N, 12.68.
Found: C, 57.74; H, 4.39; N, 12.53.
Example., 7
N-(2-ohenethvl)-Ν' -f2-(4-phenvl-5-tetradecvll-thiazolvn
Phiaurea
A solution of 2-phenethyl isothiocyanate (3.26 g, 20 mmol, 3 mL) and 2-amino-4-phenyl-5-tetradecylthiazole (7.45 g, 20 mmol) in Ν,Ν-dimethylformamide (50 mL) was heated to 100°C. After 24 h, the reaction was cooled to room temperature and poured into ethyl acetate. The organic solution was washed with IN hydrochloric acid, saturated sodium bicarbonate solution, water (3x) and brine. The organic layer was dried over sodium sulfate, filtered and concentrated. The material was recrystallized from ethyl acetate (once) and hexanes (once) to provide
4.93 g (46%) of the title product:
X-8571A ·? π r, q
-163-
IR (KBr, cm1) 3166, 3022, 2915, 1850, 1574, 1523 , 1502,
1215, 695; ςΗ NMR (300 MHz, CDCI3) δ 10.87 (br s, IH), 9.28 (br s,
IH) , 7.55-7.16 (m, 10H), 4.00-3.95 (m, 2H), 2.99 (t, J=7
5 Hz, 2H), 2.79 (t, J=9Hz, 2H), 1.65-1.00 (m, 24H), 0.86 (t.
J=6 Hz, 3H);
MS (FD) m/e 535 (M+) ;
UV (EtOH) 299nm (ε=19199), 261nm (ε=17809), 203nm (ε=31542) . Anal. Calcd for C32H45N3S2:
Theory: C, 71.73; H, 8.46; N, 7.84.
Found: C, 71.93; H, 8.75; N, 7.92.
Example 8
N-f2-(3.4-dimethoxv)-phenethyl)-Ν'-(2-thiazolyl) thiourea
A solution of 2-(3,4-dimethoxyphenethyl) isothio-cyanate (0.52 g, 2.33 mmol) and 2-aminothiazole (233 mg, 2.33 mmol) in N,N-dimethylformamide (10 mL) was heated to 100°C. After 24 h, the reaction was cooled to room temperature and poured into ethyl acetate. The organic, solution was washed with IN hydrochloric acid, saturated sodium bicarbonate solution, water (3x) and
AP Ο Ο Ο 3 8 4
X-8571A
-164brine. The organic layer was dried over sodium sulfate, filtered and concentrated. The oil was recrystallized from toluene to provide 129mg (17%) of the title product: mp 139°C;
IR (KBr', cm’1) 3168, 3112, 3013, 1572, 1550, 1516, 1461,
1263, 1237, 1183;
!h NMR (300 MHz, DMSO-d6) 5 11.55 (br s, IH), 9.80-9.62 (br s, IH). 7.35 (m, IH), 7.15 (br s, IH), 6.90-6.75 (m, 3H), 3.80-3.70 (m, 2H), 3.72 (s, 6H), 2.84 (t, J=6 Hz, 2H);
MS (FD) m/e 323 (M+);
UV (EtOH, 287nm (ε=21678), 258nm (€=11828), 228nm (€=11401), 205nm (€=36669).
Anal. Calcd for C14H17N3O2S2:
Theory: C, 51.99; H, 5.30; N, 12.99.
Found: C, 51.96; H, 5.51; N, 13.02.
X-8571A
-165Exampls, -2
N-(2-phenethvl)-N' -Γ2-(4-(4-bromophenvl))thiazolvll thiourea
A solution of 2-phenethyl isothiocyanate (3.26 g, 20 mmol, 3 mL) and 2-amino-4-(4-bromophenyl)thiazole (5.15 g, 20 mmol) in N,N-dimethylformamide (50 mL) was heated to 100eC. After 65 h, the reaction was cooled to room temperature and poured into ethyl acetate. The organic solution was washed with IN hydrochloric acid, saturated sodium bicarbonate solution, water (3x) and brine. The organic layer contained as solid which was filtered. The filtrate was dried over sodium sulfate, filtered and concentrated and added to the filtered solid. The combined material was recrystallized from ethyl acetate to provide 12.04 g (24%) of the title product: mp 215.5-216.5°C;
IR (KBr, cm'1) 3166, 3022, 1574, 1523, 1502, 737, 695;
AP Ο Ο Ο 3 8 4
X-857ΙΑ
-1661η NMR (300 MHz , DMS0-C?6) δ 11.70 (br s, 1Η) , 9.40 (br S, IH) , 7.74-7.54 (m, 5H) , 7.36-7.18 (m, 5H) , 3.90-3.81 (m,
2H), 2.96 (t, J=6 Hz, 2H);
MS (FD) m/e 419 (M+l);
UV (EtOH) 287nm (£=28740), 268nm (£=24574), 246nm (£=18009), 203nm (£=35813).
Anal. Calcd for Ci8Hl6N3S2Br:
Theory: C, 51.68; H, 3.86; N, 10.04.
Found: C, 51.39; H, 3.77; N, 9.77.
Example IQ
N-i 2-.(4-Chloro) -phenethvlL-N'.- (2-thiazolyl) thiourea
A solution of 2-(4-chloro)-phenethyl isothiocyanate (657 mg, 3.3 mmol) and 2-aminothiazole (335 mg, 3.3 mmol) in Ν,Ν-dimethylformamide (10 mL) was heated o
to 100c. After 20.5 h, the reaction was cooled to room 20 temperature and poured into ethyl acetate. The organic solution was washed with IN hydrochloric acid, saturated sodium bicarbonate solution, and water (3x). The organic
X-8571A
-167t·.
concentrated. The material was recrystallized from ethyl acetate (2x) to provide 136 mg (14%) of title product: mp 154-155°C;
IR (KBr, cm'1) 3090, 2991, 1561, 1515, 1490, 1176;
TH NMR .(300 MHz, DMSO-dg) δ 11.58 (br s, IH), 9.78-9.60 (br s, IH), 7.40-7.28 (m, 5H) , 7.12 (br s, IH), 3.81-3.72 (m, 2H), 2.92 (t, J=6 Hz, 2H);
MS (FD) m/e 297 (M+);
UV (EtOH) 289nm (£=19572), 257nm (£=12071), 220nm (£=15393), 10 202nm (£=22079).
Anal. Calcd for C12H12N3S2CI:
Theory: C, 48.40; H, 4.06; N, 14.11.
Found: C, 48.17; H, 4.02; N,13.83.
Example 11
N- (2-Phenethyl.) -Ν'..-1.2--£4^-5-dihvdro) thiazolyl) thiourea
H
g, 10 mmol, 1.5 mL) and 2-amino-4,5-dihydrothiazole (1.02 g, 10 mmol) in dimethylsulfoxide (10 mL) was heated to
AP Ο Ο Ο 5 8 4
Χ-8571Α
-168temperature and poured into ethyl acetate. The organic phase was washed with IN hydrochloric acid (2x), water (4x), and brine. The organic layer was dried over sodium sulfate, filtered and concentrated. The solid obtained was recrystallized from ethyl acetate to provide 1.48 g (56%, of title product as a white crystalline solid. A sample was recrystallized a second time from ethyl acetate: rap 132-134°C;
IR (KBr, cm-1) 3161, 3027, 2945, 2862, 1630, 1574, 1552,
1221, 1033;
!h NMR (300 MHZ, CDCI3) δ 11.11 (br s, IH), 8.36 (s, IH,,
7.32-7.14 (m, 5H), 4.05-3.97 (m, 2H), 3.90-3.83 (m, 2H),
3.30-3.22 (m, 2H) , 2.94 (t, J=7.1 Hz, 2H,;
MS (El) m/e 265 (M+);
UV (EtOH) 269nm (£=18349), 206nm (£=18745,.
Anal. Calcd for C12H15N3S2:
Theory: C, 54.31; H, 5.70; N, 15.83.
Found: C, 54.36; H, 5.66; N, 15.78.
Example 12
- Phenethyl) (4-methvlthiazolvl) 1 thiourea
X-8571A
-169A solution of 2-phenethyl isothiocyanate (1.63 g, 10 mmol, 1.5 mL), 2-amino-4-methylthiazole hydrochloride (1.51 g, 10 mmol) and Ν,Ν-diisopropylethylamine (1.29 g, 10 mmol, 1.74 mL) in dimethylsulfoxide (10 mL) was heated to
100eC. After 21 h, the reaction was cooled to room temperature and poured into ethyl acetate. The organic phase was washed with IN hydrochloric acid, saturated sodium bicarbonate solution, water (3x), and brine. The organic layer was dried over sodium sulfate, filtered and concentrated. The solid obtained was purified by flash chromatography on silica gel (1% ethyl acetate in dichloromethane), followed by recrystallization from ethyl acetate to provide 1.05 g (38%) of the title product as a very light green crystalline solid:
mp 190-192°C;
IR (KBr, cm-1) 3456, 3169, 3084, 3024, 1565, 1533, 1506, 1214;
ΧΗ NMR (300 MHZ, CDCI3) δ 10.92 (s, 1H) , 10.08 (s, 1H),
7.33-7.20 (m, 5H), 6.31 (s, 1H), 4.04-3.98 (m, 2H), 3.01 (t, J=6.9 Hz, 2H), 2.17 (s, 3H);
MS (El)' m/e 277 (M+) ;
UV (EtOH) 293nm (ε=18119), 258nm (£=10137), 204nm (£=18979). Anal. Calcd. for C13H15N3S2:
Theory: C, 56.29; H, 5.45; N, 15.15.
Found: C, 56.53; H, 5.53; N, 15.18.
AP Ο Ο Ο 3 8 4
Χ-8571Α
-170Εχ ample 13,
Ν- (2-Phenethvl) -Ν' -12-£4-ίethvlglvoxylateithiazolyl) 1 thipur&a
A solution of 2-phenethyl isothiocyanate (3.26 g, 20 mmol, 3.0 mL) and ethyl 2-amino-4-thiazoleglyoxylate (4.0 g, 20 mmol) in dimethylsulfoxide (20 mL) was heated to 110°C. After 68 h, the reaction was cooled to room temperature and poured into ethyl acetate. The organic phase was washed with IN hydrochloric acid, water (5x), and brine. The organic layer was dried over sodium sulfate, filtered and concentrated. The solid obtained was purified by flash chromatography on silica gel (10% ethyl acetate in dichloromethane) and treated with decolorizing carbon to provide 2.37 g (33%) of the title product as a light yellow solid. · A sample was recrystallized from ethyl acetate: mp 168-169°C;
IR (KBr, cm1) 3174, 3029, 1724, 1685, 1558, 1530, 1215,
AP Ο Ο Ο 3 8 4
-171X-8571A
Ih NMR (300 MHZ, CDCI3) δ 10.67 (s, IH), 8 .21 (s, IH) ,
7.34-7.17 (m, 5H), 4.39 (g, J=7.1 Hz, 2H), 3.96-3 .85 (m,
2H) , 3.09-2.93 (m, 2H), 1.40 (t, J=7.1 Hz, 3H) ;
MS (FD) m/e 363 (M+);
UV (EtOH) 284nm (£=18549), 255nm (£=17141), 204nm (£=23447
Anal. Calcd for C16H17N3O3S2:
Theory: C, 52.87; H, 4.71; N, 11.56.
Found: C, 53.08; H, 4.80; N, 11.55.
ιο Example., 14
Μ- (2-Phenethyl) rN‘. τ ί 2 - (5,6-dime.thylhenzQthiazplvl 11 thiourea s
A solution of 2-phenethyl isothiocyanate (3.26 g, 20 mmol, 3.0 mL) and 2-amino-5,6-dimethylbenzothiazole (3.57 g, 20 mmol) in Ν,Ν-dimethyl-formamide (50 mL) was heated to 100 C. After 24 h, the reaction was cooled to room temperature and poured into ethyl acetate, with formation of a precipitate. The organic phase was washed with IN hydrochloric acid, saturated sodium bicarbonate solution, water (2x) and brine. The organic layer was filtered and the solid obtained (3.0 g) triturated with 20% ethanol in ethyl acetate to provide 2.91 g (43%) of the
X-8571A
-17210
IR (KBr, cm-1) 3178, 3047, 1557, 1530, 1462, 1254, 1220; NMR (300 MHZ, DMSO-dtf) δ 11.69 (s, IH) , 10.30 (s, IH),
7.55 (s, IH), 7.35-7.16 (m, 6H), 3.80-3.73 (m, 2H), 2.90 (t, J=7.0 Hz, 2H), 2.25 (s, 3H), 2.23 (s, 3H);
MS (El) m/e 341 (M+);
UV (EtOH) 307nm, 253nm, 204nm.
Anal. Calcd for C18H19N3S2:
Theory; C, 63.31; H, 5.61; N, 12.31.
Found: C, 63.15; H, 5.63; N, 12.14.
Example 15
N-(2-Phenethyl)-Ν' -Γ2-(6-methoxybenzothiazolvl)) thiourea
A solution of 2-phenethyl isothiocyanate (3.26 g, 20 mmol, 3.0 mL) and 2-amino-6-methoxybenzothiazole (3.60 g, 20 mmol) in N,N-dimethylformamide (50 mL) was heated to 100°C. After 16 h, the reaction was cooled to room temperature and poured into ethyl acetate. The organic phase was washed with IN hydrochloric acid, saturated sodium bicarbonate solution, water (3x) and brine. The organic layer was filtered to provide 550 mg of the title product. The filtrate was concentrated and the
AP Ο Ο Ο 3 8 4
Χ-8571Α
-173resulting solid recrystaiiized from ethyl acetate to provide, another 830 mg of the title product. Total yield: 1.38 g (20%) of the title product as a fluffy white solid: mp 217-218°C;
IR (KBr, cm1) 3182, 3050, 1556, 1534, 1473, 1437, 1221,
1055;
XH NMR (300 MHZ, CDCI3) δ 10.99 (s, IH) , 9.29 (s, IH) , 7.46-6.99 (m, 8H), 4.12-4.06 (m, 2H), 3.86 (s, 3H), 3.08 (t, J=6.8 Hz, 2H);
MS (FD) m/e 343 (M+) ;
UV (EtOH) 312nm (£=22725), 251nm (£=11152), 204nm (£=26183). Anal. Calcd for C17H17N3OS2:
Theory: C, 59.45; H, 4.99; N, 12.23.
Found: C, 59.21; H, 4.97; N, 12.19.
03CN
Example 16
2-JUninot,4-CYanQthiazgle
EEPQ
Ethyl l,2-dihydro-2-ethoxy-lquinolinecarboxylate (6.68 g, 27.0 mmol) was added to a solution of ethyl [2-(tritylamino)thiazol-4-yl]-(Z)hydroxyiminoacetate (11.46 g, 26.7 mmol) in N,N-dimethylformamide (100 mL) and stirred for 6 h at room temperature.
The reaction was poured into ethyl acetate, washed with IN hydrochloric acid (2x), water (3x) and brine, dried over sodium sulfate, filtered and concentrated. The resulting
X-8571A
-174mL) , treated with triethylsilane (12.44 g, 107 mmol, 17 mL) and trifluoroacetic acid (25 mL) and stirred for 2.5 h at room temperature. The reaction was concentrated in vacuo. dissolved in ethyl acetate, washed with saturated sodium bicarbonate solution and brine, dried over sodium sulfate, filtered and concentrated. The solid obtained was purified by flash chromatography on silica gel (1:1 ethyl acetate and hexanes) to provide 2.75 g (82%) of the title product as a white solid:
mp 154-156°C;
IR (KBr, cm1) 3416, 3291, 3118, 2234, 1638, 1547, 1315, 1108;
!h NMR (300 MHZ, CDCI3) δ 7.23 (s, IH), 5.19 (br s, 2H);
MS (FD) m/e 125 (M+);
UV (EtOH) 278nm (e=4359), 235nm (e=4047), 210nm (e=16728).
Anal. Calcd for C4H3N3S:
Theory: C, 38.39; H, 2.42; N, 33.57.
Found: C, 38.65; H, 2.46; N, 33.24.
Example 17
N- (3-Phenvlpropvl) -Ν' -(2-thiazolvl) thiourea
AP Ο Ο Ο 3 8 4
Χ-8571Α
-175Α solution of 3-phenylpropyl isothiocyanate (500 mg, 2.82 mmol) and 2-aminothiazole (300 mg, 3.0 mmol) in Ν,Ν-dimethylformamide (10 mL) was heated to 100°C. After 20 h, the reaction was cooled to room temperature and poured into ethyl acetate. The organic phase was washed with IN hydrochloric acid, water (3x), and brine. The organic layer was dried over sodium sulfate, filtered and concentrated. The solid obtained was purified by flash chromatography on silica gel (1% ethyl acetate in dichloromethane) and then recrystallized from ethyl acetate to provide 129 mg of the title product. A second crop was recrystallized from 1:1 ethyl acetate/hexanes to provide another 110 mg of the title product. Total yield of the title product: 239 mg (30%) as an off-white solid. A sample was recrystallized again from ethyl acetate: mp 126.5-127.5°C;
IR (KBr, cm-1) 3166, 3022, 1574, 1523, 1502, 1215, 1166;
!h NMR (300 MHZ, CDCI3) δ 10.88 (s, IH) , 10.42 (s, IH) , 7.37-7.15 (m, 6H), 6.82 (d, J=3.6 Hz, IH) , 3.82-3.71 (m,
2H), 2.74 (t, J=7.7 Hz, 2H), 2.12-2.01 (m, 2H) ;
MS (FD) rn/e 277 (M+);
UV (EtOH) 288nm (e=19598), 256nm (e=11329), 206nm (e=19259).
Anal. Calcd for C13H15N3S2:
Theory: C, 56.29; H, 5.45; N, 15.15.
Χ-8571Α
-176Example 18
Ν- (2-Phen£thvll_-N' -f2- (6-ethQxybenzothiazolvl) 1 thiourea
A solution of 2-phenethyl isothiocyanate (3.26 g, 20 mmol, 3.0 mL, and 2-amino-6-ethoxy-benzothiazole (3.88 g, 20 mmol) in N,N-dimethylformamide (50 mL) was heated to 100°C. After 20 h, the reaction was cooled to room temperature and poured into ethyl acetate. The organic phase was washed with IN hydrochloric acid, saturated sodium bicarbonate solution, water (3x) and brine. The organic layer was dried over sodium sulfate, filtered and concentrated. The solid obtained was recrystallized from ethyl acetate to provide 649 mg (9%) of the title product as a tan solid: mp 204-205°C;
IR (KBr, cm-1) 3166, 3022, 1574, 1523, 1502, 1435, 1215;
!h NMR (300 MHZ, CDCI3) δ 11.01 (s, IH), 9.77 (s, IH) , 7.43-6.95 (m, 8H), 4.08-4.01 (m, 4H), 3.06 (t, J=6.6 Hz,
2H), 1.43 (t, J=6.8 Hz, 3H);
AP Ο Ο Ο 3 β 4
X-857ΙΑ -177UV (EtOH) 312nm (e=23035), 251nm (e=11355), 2O4nro (e=26891).
Anal. Calcd for C18H19N3OS2:
Theory: C, 60.48; H, 5.36; N, 11.75.
Found: C, 60.21; H, 5.10; N, 11.52.
Example 12
-J2^14 iXert-butyl thiazpIyJ. )2 -thiourea
g, 20 mmol, 3.0 mL) and 2-amino-4-tert-butylthiazole (3.13 g, 20 mmol) in N,N-dimethylformamide (50 mL) was heated to o
100 C. After 64 h, the reaction was cooled to room 15 temperature and poured into ethyl acetate. The organic phase was washed with IN hydrochloric acid, saturated sodium bicarbonate solution, water (2x) and brine. The organic layer was dried over sodium sulfate, filtered and concentrated. The solid obtained was recrystallized from ethyl acetate to provide 2.98 g (47%) of the title product as an off-white crystalline solid:
mp 173,5-175°C;
X-8571A
-178IR (KBr, cm1) 3173, 2960, 1576, 1514, 1465, 1348, 1204, 1098;
1H NMR (300 MHZ, CDCI3) δ 11.14 (s, IH), 10.26 (s, IH),
7.31-7.18 (m, 5H), 6.33 (s, IH) , 4.05-3.99 (m, 2H), 3.04 (t, J=7.1 Hz, 2H), 1.14 (s, 9H) ;
MS (FD) m/e 319 (M+);
UV (EtOH) 292nm (e=20804), 257nm (e=10502), 203nm (e=19085) .
Anal. Calcd for C16H21N3S2:
Theory: C, 60.15; H, 6.63; N, 13.15.
Found: C, 59.95; H, 6.66; N, 13.15.
Example 20
N-(2-Phenethvl)-N*-f2-(4-trifluoromethvlthiazolvl)1 15 thiourea
A solution of 2-phenethyl isothiocyanate (3.26 20 g, 20 mmol, 3.0 mL) and 2-amino-4-trifluoromethylthiazole (3.84 g, 22.8 mmol) in N,N-dimethyl-formamide (50 mL) was o
heated to 100 C. After 20 h, the reaction was cooled to room temperature and poured into ethyl acetate. The organic
AP Ο Ο Ο 3 8 4
-179X-8571A brine. The organic layer was dried over sodium sulfate, filtered and concentrated. The solid obtained was recrystallized from 1:1 ethyl acetate/hexanes to provide 846 mg (13%) of the title product as a white solid:
mp 162-163°C;
IR (KBr, cm1) 3166, 3033, 1562, 1516, 1469, 1242, 1126; Ih NMR (300 MHZ, CDCI3) δ 10.49 (s, IH), 10.31 (s, IH),
7.33-7.19 (m, 6H), 4.01-3.95 (m, 2H), 3.02 (t, J=6.9 Hz, 2H) ;
MS (FD) m/e 331 (M+);
UV (EtOH) 286nm (e=14352), 258nm (e=14149), 205nm (e=24571).
Anal. Calcd for Ci3Hi2F3N3S2‘
Theory: C, 47.12; H, 3.65; N, 12.68.
Found: C, 47.34; H, 3.85; N, 12.72.
A solution of 2-phenethyl isothiocyanate (3.26
X-8571A
-18020 mmol) in Ν,Ν-dimethyl formamide (50 mL) was heated to 100°C. After 20 h, the reaction was cooled to room temperature and poured into ethyl acetate. The organic phase was washed with IN hydrochloric acid and brine (3x) .
The organic layer was dried over sodium sulfate, filtered and concentrated. The solid obtained was purified by flash chromatography on silica gel (1% ethyl acetate in dichloromethane) and then recrystallized twice from ethyl acetate to provide 606 mg (14%) of the title product as an off-white crystalline solid: mp 104.5-105.5°C;
IR (KBr, cm-1) 3284, 1536, 1452, 1347, 901;
1h NMR (300 MHZ, CDCI3) 5 7.33-7.19 (m, 5H) , 5.37 (br s,
IH), 3.93-3.87 (m, 2H), 3.16 (s, 6H), 2.93 (t, J=6.8 Hz,
2H);
MS (FD) m/e 208 (M+);
UV (EtOH) 242nm (£=12899), 210nra (£=21286).
Anal. Calcd for C11H16N2S:
Theory: C, 63.42; H, 7.74; N, 13.45.
Found: C, 63.39; H, 7.80; N, 13.67.
AP Ο Ο Ο 3 θ 4
Χ-8571Α
-181Examplfi 22
M-J2-Ehenyethyl]-zN.' -J Zz-lArgyanathiAzalYll,., .thiourea
A solution of 2-phenethyl isothiocyanate (3.26 g, 20 mmol, 3.0 mL) and 2-amino-4-cyanothiazole (2.50 g, 20 mmol) in N,N-dimethylformamide (50 mL) was heated to 100°C. After 20 h, the reaction was cooled to room temperature and poured into ethyl acetate. The organic phase was washed with saturated sodium bicarbonate solution, water (3x), and brine. The organic layer was dried over sodium sulfate, filtered and concentrated. The solid obtained was purified by flash chromatography on silica gel (1% ethyl acetate in dichloromethane) and then recrystallized from 1:1 ethyl acetate/hexanes to provide 132 mg of the title product (2%) as a white solid:
mp 169-170°C;
IR (KBr, cm-1) 3166, 3022, 1574, 1523, 1502, 1215, 1166;
!h NMR (300 MHZ, CDCI3) δ 10.88 (s, IH), 10.09 (s, IH) ,
7.50 (s, IH), 7.39-7.23 (m, 5H), 4.00-3.93 (m, 2H), 3.02 (t, J=6.9 Hz, 2H);
MS (FD) m/e 288 (M+);
X-8571A
-182Anal. Calcd for C13H12N4S2:
Theory: C, 54.14; H, 4.19; N, 19.43.
Found: C, 54.04; H, 4.23; N, 19.73.
Example 23
N-(2-Phenethvl)-N‘-2-f4-(4-pyridvl)-thiazolvll thiourea
2-Amino-4-(4-pyridyl)thiazole hydrobromide1'2 was slurried with methylene chloride and shaken with saturated sodium bicarbonate solution. The layers were separated and the aqueous washed with methylene chloride and ethyl acetate. The combined organic layers were concentrated. To the solid (l.Og, 5.6 mmol) was added 215 phenethyl isothiocyanate (0.91 g, 5.6 mmol, 0.83mL) in N,Ndimethylformamide (12.5 mL) . The resulting suspension was heated to 100°C. After 20.5 h, the reaction was cooled to room temperature and poured into ethyl acetate. The organic phase was washed with water (4x) and brine. The organic layer was dried over sodium sulfate, filtered and
AP Ο Ο Ο 3 8 4
Χ-8571Α
-183ethyl acetate (3χ) to provide 133 mg (7%) of the title product: mp 196.5*C;
IR (KBr, cm1) 3250, 2939, 1723, 1604, 1506, 1223, 670,
664;
XH NMR (300 MHz, DMSO-d6) δ 11.72 (s, 1H) , 9.21 (br s, 1H) , 8.54 (d, J=6 Hz, 2H), 7.82 (s, 1H), 7.63 (d, J=6 Hz, 2H),
7.30-7.15 (m, 5H), 3.84-3.77 (m, 2H), 2.89 (t, J=7 Hz, 2H); MS (FD) m/e 340 (M+);
HRMS (FAB) m/e (M+) calcd 341.0895, obs 341.0909;
UV (EtOH) 294nm (£=23935), 231nm (£=16356), 203nm (£=25793).
(1) Nielsen, A.T. and Platt, E.N. Heterocyclic Chem.,
1969, vol 6 p 896.
(2) Brown, Cowden, Grigg, Kavulak Aust. J. Chem. 1980, 33,
ΙΑ
X-8571A
-184Exampl.fi 24
Κ-_(2-ohenethvl 1-Ν' - (2- (4-14-biphenvl) -thiazolyl 1 thiourea
A solution of 2-phenethyl isothiocyanate (0.82 g, 5 mmol, 0.75 mL) and 2-amino-4-(4-biphenyl)thiazole (1.26 g, 5 mmol) in N,N-dimethylformamide (12.5 mL) was heated to 100°C. After 19.5 h, the reaction was cooled to room temperature and poured into ethyl acetate. The organic solution was washed with IN hydrochloric acid. The mixture was filtered and the filtrate was separated and the organic phase washed with saturated sodium bicarbonate solution, water (4x) and brine. The organic layer was dried over sodium sulfate, filtered and concentrated. The material was purified by flash chromatography on silica gel (1% ethyl acetate in dichloromethane to 2% ethyl acetate in dichloromethane) to provide 372 mg of the title product (18%). .The yellow solid was recrystallized from ethyl acetate:
AP Ο Ο Ο 3 8 4
X-857ΙΑ
-185IR (KBr, cm-1) 3437, 3172, 3029, 1570, 1553, 1511, 1211, 1060, 738;
1Η NMR (300 MHz, DMSO-de) d 11.72 (s, IH) , 9.54 (br s, IH),
7.86-7.80 (m, 2H), 7.78-7.68 (m, 4H), 7.58 (s, IH), 7,525 7.44 (m, 2H), 7.41-7.35 (m, IH) , 7.34-7.29 (m, 4H,, 7.277.20 (m, IH), 3.92-3.84 (m, 2H), 2.98 (t, J=3 Hz, 2H) ;
MS (FD) m/e 415 (M+);
UV (EtOH) 293nm, 212nm.
Anal. Calcd for C24H21N3S2:
Theory: C, 69.36; H, 5.09; N, 10.11.
Found: C, 69.08; H, 5.10; N, 9.99.
Example 25
N- (2-Phenethyl)-Ν'-2-Γ4- (1-(1-ethvoxvcarbonlvl)-(3-115 butoxvcar bonv Ime thoxy) imino)-thiazolyll thiourea
X-8571A
-186Γ; Λ Γ'
2-Amino-4-(1-(1-ethoxycarbonyl,-(3-t-butoxycarbony Imethoxy) imino)thiazole (2.64 g, 8 mmol) and 2phenethyl isothiocyanate (1.31 g, 8 mmol, 1.2 mL) in Ν,Νdime thyl formamide (20 mL) were heated to 100°C. After 24 h, the reaction was cooled to room temperature and poured into ethyl acetate. The organic phase was washed with IN hydrochloric acid, saturated sodium bicarbonate solution, water (3x) and brine. The organic layer was dried over sodium sulfate, filtered and concentrated. The resulting solid was triturated with ethyl acetate to provide 801 mg (20%) of the title product: mp 188.5eC;
IR (KBr, cm-1) 3293, 2975, 1749, 1594, 1543, 1453, 1382, 1231, 1154, 1054, 748, 698;
XH NMR (300 MHz, DMSO-dg) d 11.85 (s, IH), 8.46 (br S,1H), 7.29-7.17 (m, 5H) , 4.59 (s, 2H), 4.31-4.24 (q, J=7.1 Hz, 2H) , 3.70-3.64 (m, 2H), 2.82 (t, J=7.1 Hz, 2H), 1.36 (s, 9H) , 1.23 (t, J= 7.1 Hz, 3H);
MS (FD) m/e 492 (M+);
UV (EtOH) 292nm, 257nm (£=16356), 203nm.
Anal. Calcd for C22H28N4O5S2:
Theory: C, 53.64; H, 5.73; N, 11.37.
Found: C, 53.67; H, 5.83; N, 11.34.
Example 26
N- (2-Phenethyl L-N.1 -2-14:J;TbutyI-5-meth¥lLhiazgly.l,l. thiQ.ui-ea
AP Ο Ο Ο 3 8 4
-187X-8571A
2-Amino-4-t-butyl-5-methylthiazole (1.87 g, 11 mmol) and 2-phenethyl isothiocyanate (1.80 g, 11 mmol, 1.64 mL) in Ν,Ν-dimethylformamide (25 mL) were heated to 100°C.
After 18.5 h, the reaction was cooled to room temperature and poured into ethyl acetate. The organic phase was washed with IN hydrochloric acid, saturated sodium bicarbonate solution, water (3x) and brine. The organic layer was dried over sodium sulfate, filtered and concentrated. The resulting solid was triturated with ether to provide 1.02 g (28%) of the title product: mp 153-153.5*C;
IR (KBr, cm1) 3171, 2966, 1474, 1534, 1510, 1455, 1346, 1221, 1186, 755, 704;
:H NMR (300 MHz, DMSO-d6) δ 11.28 (BR S, IH) , 9.90 (BR S,
IH) , 7.28-7.14 (Μ, 5H) , 3.78-3.34 (Μ, 2H), 2.84 (T, J=7 Hz, 2H) , 2.27 (s, 3H), 1.16 (s, 9H);
MS (FD) m/e 333 (M+);
UV (EtOH) 297nm (€=19835), 257nm (€=9954), 202nm (€=21059).
Anal. Calcd for C17H23N3S2:
Theory: C, 61.22; H, 6.95; N, 12.60.
Found: C, 61.42; H, 6.92; N, 12.55.
£X3IQ&l£_22
N-A2 -FheagXbYl] -N' - J5 r, mathYlr. 12 r 11,.3., 4 τ thiadiazolyl) II
LhiQur.ea
A solution of 2-amino-5-methyl 1,3,4-thiadiazole (2.30 g, 20 mmol) and 2-phenethyl isothiocyanate (3.26 g, mmol', 3.0 mL) in Ν,Ν-dimethylformamide (50 mL) was heated to 100°C for 18 h. The reaction was cooled to room
X-8571A
-188resultant solid was crystallized from ethyl acetate to provide 1.86 g (33%) of the title product as a white solid: IR (KBr, cm1) 3323, 3031, 1640, 1540, 1444, 1385, 781,
697, 652;
1H NMR (300 MHz, DMSO-d6) 6 12.4 (br s, IH), 8.75 (br s, IH), 7.4-7.2 (m, 5H) , 3.85-3.75 (m, 2H), 2.9 (t, J=7 Hz,
2H), 2.54 (s, 3H);
MS (FD) m/e 278 (M+);
UV (EtOH) 280nm (ε=10188), 253nm (ε=11849), 205nm (ε=19724).
Example 28
N- (2-P-henethvl) -N1 -(2-Pvrimidinvl) thiourea
A solution of 2-aminopyrimidine (1.90 g, 20 mmol) and 2-phenethyl isothiocyanate (3.26 g, 20 mmol, 3.0 mL) in Ν,Ν-dimethylformamide (50 mL) was heated to 120°C for 40 h. The reaction was cooled to room temperature and the solvent was removed in vacuo. The resultant solid was recrystallized twice from ethyl acetate to provide 0.90 g (17%) of the title product as white needles:
IR (KBr, cm1) 3325, 1588, 1524, 1434, 1415, 1333, 1228,
1154, 797;
!h NMR (300 MHz, DMSO-dg) δ 11.25 (br s, IH), 10.65 (br s, IH), 8.6 (d, J=5 HZ, 2H) 7.4-7.2 (m, 6H) , 3.85-3.75 (m,
2H), 2.9 (t, J=7 Hz, 2H);
MS (FD) m/e 258 (M+);
UV (EtOH) 286nm (ε=17644), 267nm (ε=15834), 244nm (ε=12312), 205nm (ε=21839) .
Anal. Calcd for C13H14N4S:
Theory: C, 60.44; H, 5.46; N, 21.69.
ΑΡΟΟΟ384
Χ-8571Α
-189Example...2i
Ν- (2-Phenethy II τΝ-'.-12..--(4-. (4-chlQrophenyl) thiazolyl? 1 thiourea
A solution of 2-phenethyl isothiocyanate (0.77 5 g, 4.75 mmol) and 2-amino-4-(4-chlorophenyl)thiazole (1.0 g, 4.75 mmol) in Ν,Ν-dimethylformamide (10 mL) was heated to 120°C 20 h. The solvent was removed in vacuo. The resultant solid was recrystallized from ethyl acetate to provide 0.30 g (17%) of the title product as a yellow solid:
IR (KBr, cm'1) 3176, 3029, 1579, 1515, 1231, 737, 698;
!h NMR (300 MHz, DMSO-άζ) 5 11.70 (br s, IH), 9.40 (br s, IH), 7.74-7.54 (m, 5H) , 7.36-7.18 (m, 5H) , 3.9-3.8 (m, 2H),
2.96 (t, J=6 Hz, 2H);
MS (FD) m/e 373 (M+);
UV (EtOH) 273nm (6=35089), 247nm (6=21894), 202nm (6=22213). Anal. Calcd for C18H16N3S2CI:
Theory: C, 57.82; H, 4.31; N, 11.24.
Found: C, 57.55; H, 4.24; N, 11.26.
Example 3Q
NrL2-phenethyl) -N2.-J2-J6-chloro)benzothiazolvll thiourea
A solution of 2-phenethyl isothiocyanate (3.26 g, 20 mmol) and 2-amino-6-chlorobenzothiazole (3.69 g, 20 mmol) in Ν,Ν-dimethylformamide (50 mL) was heated to 120ec for 24 h. The solvent was removed in vacuo. The resultant solid was recrystallized from ethyl acetate to provide 3.68 g (53%) of the title product as a white solid:
IR (KBr, cm-1) 3165f 3021, 1574, 1522, 1501, 1289, 1215;
Ih NMR (300 MHz, CDCI3) δ 12.0 (br s, IH), 9.8 (br s, IH),
*1Μ
X-8571A
-190MS (FD) m/e 347 (M+);
UV (EtOH) 304nm, 292nm, 248nm, 220nm, 205nm.
Example 31
N- (2-Phene.thvl) -Ν'- f 5-ethvl- f2- (1.3.4-thiadiazolvl) 1) thiourea
A solution of 2-amino-5-ethyl-l,3,4-thiadiazole (2.58 g, 20 mmol) and 2-phenethyl isothiocyanate (3.26 g, mmol, 3.0 mL) in N,N-dimethylformamide (50 mL) was heated to 120°C for 8 h. The reaction was cooled to room temperature and the solvent was removed in vacuo. The resultant solid was crystallized from ethyl acetate to provide 2.45 g (33%) of the title product as a white solid: IR (KBr, cm-1) 3317, 1645, 1536, 1448, 1384, 783, 693, 651;
NMR (300 MHz, DMSO-d6> δ 12.4 (br s, IH) , 8.75 (br s,
IH), 7.4-7.2 (m, 5H), 3.85-3.75 (m, 2H) , 3.0-2.8 (m, 4H) ,
1.25 (t, J=7 Hz, 3H);
MS (FD) m/e 292 (M+);
UV (EtOH) 281nm (€=13028), 253nm (€=13615), 206nm (€=23674).
Example 32
NrI2.rFhenethvll-N.l- iA-chlorophenvll thiourea
A solution of 4-chloroaniline (2.55 g, 20 mmol) and 2-phenethyl isothiocyanate (3.26 g, 20 mmol, 3.0 mL) in
N,N-dimethylformamide (50 mL) was heated to 120°C for 18 h.
The reaction was cooled to room temperature and the solvent was removed in vacuo. The resultant solid was crystallized from ethyl acetate to provide 1.50 g (26%) of the title product, as a yellow solid:
AP Ο Ο Ο 3 8 4
Χ-8571Α -191IR (KBr, cm-1) 3166, 3021, 1523, 1501, 1289, 1079, 802,
737, 695;
!η NMR (300 MHz, DMS0-d6) δ 9.6 (br s, IH), 7.9 (br s, IH),
7.5-7.2- (m, 9H), 3.8-3.65 (m, 2H), 3.0-2.8 (t, J=7 Hz, 2H) ;
MS (FD) m/e 290 (M+);
UV (EtOH) 270nm (ε=14107), 247nm (8=18128), 206nm (8=27795). Anal. Calcd for C15H15N2SCI:
Theory: C, 61.95; H, 5.20; N, 9.63.
Found: C, 62.19; H, 5.46; N, 9.87.
Example 33
N- (2-Phenethyl) -N· -f3-chlorophenvl] - thiourea
A solution of 3-chloroaniline (2.55 g, 20 mmol) and 2-phenethyl isothiocyanate (3.26 g, 20 mmol, 3.0 mL) in
N,N-dimethylformamide (50 mL) was heated to 120°C for 20 h.
The reaction was cooled to room temperature and the solvent was removed in vacuo. The resultant yellow oil was purified by HPLC on silica gel to provide 0.95 g (16%) of the title product as a white solid:
IR (KBr, cm1) 3310, 1591, 1542, 1495;
ΣΗ NMR (300 MHz, DMSO-dg) δ 9.85 (br s, IH), 7.9 (br s,
IH), 7.65-7.2 (m, 9H), 3.8-3.65 (m, 2H), 3.0-2.8 (t, J=7 Hz, 2H);
MS (FD) m/e 290 (M+);
UV (EtOH) 250nm (8=17296), 209nm (8=29630).
Anal. Calcd for C15H15N2SCI:
Theory: C, 61.95; H, 5.20; N, 9.63. Found: C, 61.65; H, 5.44; N, 9.84.
Χ-8571Α
-192Example. ,34
Ν- (n-Propvl)-Ν' - f2-thiazovn thiourea A solution of 2-aminothiazole (2.0 g, 20 mmol) and n-propyl isothiocyanate (2.0 g, 20 mmol) in N,N5 dimethylformamide (50 mL) was heated to 120°C for 20 h.
The reaction was cooled to room temperature and the solvent was removed in vacuo. The resultant yellow oil was recrystallized twice from ethyl acetate to provide 0.42 g (10%) of the title product as a white solid:
IR (KBr, cm-1) 3179, 1556, 1514, 1471, 680;
!h NMR (300 MHz, DMSO-c?6) δ 11.55 (br s, IH), 9.7 (br s,
IH), 7.4 (d, J=5 Hz, IH), 7.1 (d, J=5 Hz, IH), 3.5 (m, 2H) ,
1.6 (m, 2H), 0.95 (t, J=7 Hz, 3H);
MS (FD) m/e 201 (M+);
UV (EtOH) 288nm (€=19469), 256nm (€=10151), 202nm (€=11550). Anal. Calcd for C7H11N3S2:
Theory: C, 41.77; H, 5.51; N, 20.87.
Found: C, 42.02; H, 5.61; N, 20.93.
Example 35
N-(2-phenethvl) -Ν'-12-¢4,5.6,7-tetrahvdrobenzothiazolvl)1 thiourea
A solution of 2-phenethyl isothiocyanate (1.63 g, 10 mmol) and 2-amino-4,5,6,7-tetrahydrobenzothiazole (1.54 g, 10 mmol) in Ν,Ν-dimethyl formamide (25 mL) was heated to 120°C for 48 h. The solvent was removed in vacuo. The resultant solid was recrystallized from ethyl acetate to provide 0.32 g (11%) of the title product as a white solid:
IR (KBr, cm1) 3165, 3021, 2923, 1601, 1529, 1501, 1261,
AP Ο Ο Ο 3 8 4
Χ-8571Α -193*Η NMR (300 MHz, DMS0-c?6) δ 11.5 (br s, 1Η) , 10.0 (br s, IH), 7.4-7.2 (m, 5H), 3.85 (m, 2H) , 2.95 (t, J=7 Hz, 2H),
2.6-2.4 (m, 4H), 1.75 (m, 4H);
MS (FD) m/e 317 (M+);
UV (EtOH) 299nm (6=11440), 258nm (6=6011), 207nm (6=10579).
Example.. 36
N- (2-phenethyl) -Ν' - f.2.tbenzgthiazplyl1 thiourea
A solution of 2-phenethyl isothiocyanate (3.26 g, 20 mmol, 3.0 mL) and 2-aminobenzothiazole (3.0 g, 20 mmol) in toluene (50 mL) was heated to reflux. After 5 h, the reaction was cooled to room temperature and poured into ethyl acetate, washed with water, IN aqueous HCI, water, saturated sodium bicarbonate, and brine. The organic layer was concentrated and the residue recrystallized from ethyl acetate to provide 1.8 g (29%) of the title product: mp 203-207°C;
IR (KBr, cm1) 3181, 3045, 1697, 1557, 1523, 1451, 1440,
1244, 749;
1H NMR (300 MHZ, CDCl3/DMSO-d6) δ 11.7 (br s , IH), 10.6 (br
s, IH), 7.8-7.2 (m, 9H), 3.95 (m, 2H) , 3.05 (t, J= 7 Hz,
2H) t
MS (FD) m/e 313 (M+);
UV (EtOH) 300nm (6=24241), 207 nm (6=28964).
Anal. Calcd for C16H15N3S2:
Theory: C, 61.31; H, 4.82; N, 13.41.
.1
X-8571A
-194Examole 37
Mr .i2r.phene.thvl·) -N2- (4-methvl)benzothiazolyl 1 thiourea
A solution of 2-phenethyl isothiocyanate (3.26 g, 20 mmol, 3.0 mL) and 2-amino-4-methylbenzothiazole (3.3 g, 20 mmol) in toluene (50 mL) was heated to reflux. After 5 h, the reaction was cooled to room temperature and poured into ethyl acetate, washed with water, IN aqueous HCl, water, saturated sodium bicarbonate, and brine. The organic layer was concentrated and the residue recrystallized from ethyl acetate to provide 1.68 g (26%) of the title product: mp 185-188°C;
IR (KBr, cm1) 3170, 3024, 1571, 1525, 1219, 767, 742, 698; lH NMR (300 MHz, CDCI3/DMSO-dg) δ 11.4 (br s, IH) , 10.9 (br s, IH), 7.6-7.1 (m, 8H), 4.05 (m, 2H), 3.05 (t, J=7 Hz,
2H), 2.37 (s, 3H);
MS (FD) m/e 327 (M+);
UV (EtOH) 303nm (6=27416), 204 nm (6=30294).
Anal. Calcd for C17H17N3S2:
Theory: C, 62.35; H, 5.23; N, 12.83.
Found: C, 62.56; H, 5.37; N, 12.77.
Example 38
N- (2-phenethyl)-N'-f2- (4-methoxv) benzothiazolyl1 thiourea
A solution of 2-phenethyl isothiocyanate (3.26 25 g, 20 mmol, 3.0 mL) and 2-amino-4-methoxybenzothiazole (3.2 g, 20 mmol) in Ν,Ν-dimethylformamide (20 mL) was heated at 115°C for 24 h. The reaction was cooled to room temperature, poured into ethyl acetate, washed with water,
IN aqueous HCl, water, saturated sodium bicarbonate, and
AP Ο Ο Ο 3 8 4
-195X-8571A recrystallized from ethyl acetate to provide 0.97 g (14%) of the title, product: mp 205-207°C;
IR (KBr, αη-1) 3165, 3021, 1574, 1522, 1215, 736, 695, 655; 5 NMR (300 MHz, DMSO-dg) 8 12.4 (br s, 1H) , 9.9 (br s,
1H), 7.6-7.0 (m, 8H), 3.9 (s, 3H), 3.85 (m, 2H) , 2.95 (t, J=7 Hz, 2H);
MS (FD) m/e 343 (M+) ;
UV (EtOH) 293nm (6=20046), 248 nm (6=15731), 210 nm (6=38172).
Example 3?
N-(2-phenethvl)-Ν'- f 2-(4-chloro)benzothiazolyl) thiourea
A solution of 2-phenethyl isothiocyanate (3.26 g, 20 mmol, 3.0 mL) and 2-amino-4-chlorobenzothiazole (3.7 g, 20 mmol) in N, N-dimethyl formamide (20 mL) was heated at 115eC for 24 h. The reaction was cooled to room temperature, poured into ethyl acetate, washed with water, IN aqueous HCl, water, saturated sodium bicarbonate, and brine. The organic layer was concentrated and the residue recrystallized from ethyl acetate to provide 2.56 g (37%) of the title product:
mp 216-217°C;
IR (KBr, αη-1) 3166, 2940, 1568, 1527, 766, 733, 673;
1H NMR (300 MHz, DMSO-dg) δ 12.2 (br s, 1H) , 9.3 (br s,
1H) , 7.6-7.0 (m, 8H), 3.85 (m, 2H), 2.95 (t, J=7 Hz, 2H);
MS (FD) m/e 347 (M+);
UV (EtOH) 301nm (6=20231), 249 nm (6=17615), 211 nm (6=31440).
X-857ΙΑ
-196Example 4Q
Ν-(2-Phenethyl)-N‘-f3-(1.2.4-triazolvl)1 thiourea
A solution of 3-amino-l,2,4-triazole (1.70 g, 20 mmol) and 2-phenethyl isothiocyanate (3.26 g, 20 mmol, 3.0 mL) in N,N-dimethylformamide (20 mL) was heated to 115°C for 24 h. The reaction was cooled to room temperature, poured into ethyl acetate, washed with water, IN aqueous HCl, water, saturated sodium bicarbonate, and brine. The organic layer was concentrated and the residue recrystallized from ethyl acetate to provide 0.99 g (20%) of the title product: mp 160-162°C;
IR (KBr, cm-1) 3160, 3061, 2872, 977, 743, 681; 1581, 1535, 1467, 1167,
15 1H NMR (300 MHz, DMSO-C?6) δ 13.9 (br s, IH), 10.85 (br s,
IH) , 10.0 (br s, IH), 7.4-7.2 (m, (t, J=7 Hz, 2H) ; MS (FD) m/e 247 (M+); 6H), 3.85 (m, 2H), 2.95
20 UV (EtOH) 261nm (£=21785), 229 nm (£=17437) . Anal. Calcd for C11H13N5S: (£=11918) , 206 nm
Theory: C, 53.42 H, 5.30; N, 28.32.
Found: C, 53.69; H, 5.50; N, 28.07.
Example.,., 41
N- (2-Phenethvl) -N‘ -(3-quinolinyn thiourea
A solution of 3-aminoquinoline (2.90 g, 20 mmol) and 2-phenethyl isothiocyanate (3.26 g, 20 mmol, 3.0 mL) in N, N-dimethylformamide (20 mL) was heated to 90°C for 72 h.
The reaction was cooled to room temperature, poured into
AP 0 0 0 3 8 4
X-8571A
-197saturated sodium bicarbonate, and brine. The organic layer was concentrated and the residue recrystallized from ethyl acetate· to provide 3.62 g (59%) of the title product: mp 162-164°C;
IR (KBr, cm1) 3143, 1537, 1493, 1350, 1283, 1239, 749,
705;
1H NMR (300 MHz, DMSO-dg) δ 9.9 (br s, IH), 8.87 (d, J=4 Hz), IH), 8.35 (br s, IH), 8.0 (d, J=8 Hz, IH) , 7.9 (d, J=8 Hz, IH), 7.7-7.2 (m, 8H), 3.8 (m, 2H), 2.95 (t, J=7 Hz,
2H) ;
MS (FD) m/e 308 (M+);
UV (EtOH) 331nm (€=5945), 257nm (€=27215), 247nm (€=28319), 212 nm (€=37613).
Example 42
N- (2rPhenethvl) -N_‘ -12- (4-methvl)pyrimidine! thiourea
A solution of 2-aminopyrimidine (1.90 g, 20 mmol) and 2-phenethyl isothiocyanate (3.26 g, 20 mmol, 3.0 mL) in Ν, N- dimethyl formamide (20 mL) was heated to 115°C for 24 h. The reaction was cooled to room temperature, poured into ethyl acetate, washed with water, IN aqueous HCI, water, saturated sodium bicarbonate, and brine. The organic layer was concentrated and the residue recrystallized from ethyl acetate to provide 1.21 g (22%) of the title product: mp 174-176°C;
IR (KBr, cm1) 3184, 3034, 1561, 1409, 1344, 1291, 1165, 1030, 836, 792;
1H NMR (300 MHz, DMSO-dg) 6 11.3 (br S, IH) , 10.45 (br S, IH), 8.4 (d, J=5 Hz, 2H) 7.4-7.2 (m, 5H), 7.0 (d, J=5 Hz, IH), 3.85-3.75 (m, 2H) , 2.9 (t, J=7 Hz, 2H), 2.3 (s, 3H);
X-8571A
-198MS (FD) m/e 272 (M+);
UV (EtOH) 274nm (€=25263), 248nm (€=15528), 203nm (€=17107). Anal. Calcd for C14H16N4S:
Theory: C, 61.74; H, 5.92; N, 20.57.
Found: C, 61.44; H, 6.11; N, 20.38.
Example.,.43
N-(2-phenethyl)-N‘-f2-(4-(4-fluorophenyl))thiazolyl) thiourea
A solution of 2-phenethyl isothiocyanate (1.63 g, 10 mmol), triethylamine (1.01 g, 10 mmol), and 2-amino4-(4-fluorophenyl)thiazole hydroiodide (3.2 g, 10 mmol) in N,N-dimethylformamide (20 mL) was heated to 100°C for 24 h. The reaction was cooled to room temperature, poured into ethyl acetate, washed with water, IN aqueous HCl, water, saturated sodium bicarbonate, and brine. The organic layer was concentrated and the residue recrystallized from ethyl acetate to provide 1.06 g (30%) of the title product: mp 224-228°C;
IR (KBr, cm-1) 3178, 3030, 1553, 840, 737, 670;
1H NMR (300 MHz, DMSO-dg) δ 11.70 (br s, IH), 9.50 (br s, IH), 7.8-7.2 (m, 10H), 3.90-3.81 (m, 2H), 2.95 (t, J=6 Hz, 2H) ;
MS (FD) m/e 357 (M+);
UV (EtOH, 282nm (€=15755), 264nm (€=17277), 239nm (€=13046), 209nm (€=18271).
Anal. Calcd for Ci8Hl6N3S2F:
Theory: C, 60.42; H, 4.48; N, 11.74.
Found: C, 60.79; H, 4.48; N, 11.63.
AP Ο Ο Ο 3 8 4
Χ-8571Α
-199Example 44
Ν- (2-Phenethvl)-Ν'-(2-(4-thiazolvlacetic acid! thiourea methyl ester
A solution of 2-phenethyl isothiocyanate (0.82 5 g, 5 mmol) and 2-aminothiazoleacetic acid methyl ester (0.85 g, 5 mmol) in A7,N-dimethylfonnamide (20 mL) was heated to 100°C for 72 h, the reaction was cooled to room temperature and poured into ethyl acetate, washed with water, IN aqueous HCl, water, saturated sodium bicarbonate, and brine. The organic layer was concentrated and the residue recrystallized from ethyl acetate to provide 0.52 g (31%) of the title product:
mp 125-127°C;
IR (KBr, cm1) 3168, 3085, 1740, 1557, 1524, ;
1h NMR (300 MHz, DMSO-d6) δ 11.6 (br s, IH), 9.4 (br s,
IH), 7.4-7.2 (m, 5H), 6.85 (s, IH), 3.8 (m, 2H), 3.65 (s,
2H) , 3.6 (S, 3H), 2.9 (t, J=7 Hz, 2H);
MS (FD, m/e 335 (M+);
UV (EtOH, 291nm (€=19133), 258nm (€=10917), 202nm (€=21433).
Anal. Calcd for C15H17N3S2O2:
Theory: C, 53.71; H, 5.11; N, 12.53.
Found: C, 53.96; H, 5.16; N, 12.79.
Example 45
N-_L2-phenethyl) -NL- L2-thiazolyl) thiourea
A solution of 2-phenethyl isothiocyanate (7.5 g,
45.9 mmol) and 2-aminothiazole (4.6 g, 45.9 mmol) in N,Ndimethylformamide (100 mL) was heated at 115°C for 12 h.
The reaction was cooled to room temperature, poured into ethyl acetate, washed with water, IN aqueous HCl, water,
X-8571A
-200·< ί was concentrated and the residue recrystaiiized twice from ethyl acetate to provide 5.7 g (47%) of the title product: IR (KBr, cm-1) 3187, 3033, 2978, 1569, 1515, 1470, 1454, 1216, 1170, 1063;
!η NMR (300 MHz, DMSO-άζ) δ 11.6 (br s, IH), 9.7 (br s,
IH) , 7.4-7.2 (m, 6H), 7.1 (d, J=3 Hz, IH), 3.8 (m, 2H), 2.9 (t, J=7 Hz, 2H);
MS (FD) m/e 263 (M+);
UV (EtOH) 288nm (£=19656), 257 nm (£=11658), 203 nm 10 (£=20054).
Anal. Calcd for C12H13N3S2:
Theory: C, 54.72 H, 4.97; N, 15.95.
Found: C, 54.63; H, 5.02; N, 15.85.
Example 46
N-(2-fl-cvclohexenvllethvl)-N1-f2-thiazolvl1 thiourea
A solution of 2-(1-cyclohexenyl)ethyl isothiocyanate' (3.3 g, 20 mmol) and 2-aminothiazole (2.0 g, 20 mmol) in Ν,Ν-dimethylfonnamide (20 mL) was heated at 100°C for 24 h. The reaction was cooled to room temperature, poured into ethyl acetate, washed with water, IN aqueous HCl, water, saturated sodium bicarbonate, and brine. The organic layer was concentrated and the residue recrystaiiized from ethyl acetate to provide 2.66 g (50%) of the title product: mp 147-148°C;
IR (KBr, cm1) 3170, 3118, 2989, 1566, 1513, 1180, 706;
XH NMR (300 MHz, EMSO-dg) δ 11.6 (br s, IH), 9.7 (br s,
IH), 7.38 (d, J=3 Hz, 1Η), 7.1 (d, J=3 Hz, 1Η), 5.45 (br s,
IH), 3.65 (m, 2H), 2.25 (t, J=7 Hz, 2H), 1.9 (m, 4H), 1.5 (m, 4H);
AP Ο Ο Ο 3 8 4
Χ-8571Α
-201MS (FD) m/e 267 (Μ+);
UV (EtOH) 288nm (£=19663), 256 run (£=10534), 201 nm (£=14819) .
Anal. Calcd for C3.2H13N3S2:
Theory: C, 53.89 H, 6.41; N, 15.71.
Found: C, 54.15; H, 6.52; N, 15.84.
Example. <2
N-(2-phenethvl)-N1-f2-(4-thiazolvlacetic acidl thiourea ethyl .ester
A solution of 2-phenethyl isothiocyanate (3.62 g, 20 mmol) and 2-aminothiazoleacetic acid ethyl ester (3.72 g, 20 mmol) in Ν,Ν-dimethyl formamide (20 mL) was heated to 100°C for 24 h, the reaction was cooled to room temperature and poured into ethyl acetate, washed with water, IN aqueous HCl, water, saturated sodium bicarbonate, and brine. The organic layer was concentrated and the residue was purified by HPLC on silica gel to provide 1.7 g (24%) of the title product:
mp 80-83°C;
IR (KBr, cm-1) 3184, 3109, 1730, 1580, 704, ;
*H NMR (300 MHz, DMSO-d6) δ 11.6 (br s, IH), 9.4 (br s,
IH), 7.4-7.2 (m, 5H), 6.85 (s, IH), 4.1 (q, J=7 Hz, 2H) ,
3.8 (m, 2H), 3.65 (s, 2H), 2.9 (t, J=7 Hz, 2H), 1.2 (t, J=7
Hz, 3H);
MS (FD) m/e 349 <M+);
UV (EtOH) 291nm (£=15025), 250nm (£=10893), 203nm (£=24071). Anal. Calcd for C3.6H19N3S2O2:
Theory: C, 54.99; H, 5.48; N, 12.02.
Found: C, 55.24; H, 5.62; N, 11.96.
X-8571A
-202Εχample 48
Nz_C2-phenethyl) -Ν’ - i2-(4c.thiazolvlacetic acidl thiourea
A solution of N-(2-phenethyl)-Ν'-[2-(4thiazolylacetic acid] thiourea ethyl ester (0.7 g, 2.0 mmol) and IN NaOH (2.5 mL, 2.5 mmol) in 50 mL of 1/1 acetonitrile-water was stirred at room temperature for 24
h. The reaction was poured into ethyl acetate and washed with saturated sodium bicarbonate. The aqueous layer was acidified to pH 2 with IN HCl and extracted with ethyl acetate. The organic extracts were washed with brine and concentrated. The residue was crystallized from ethyl acetate to provide 0.29 g (45%) of the title product: mp 188-190°C;
IR (KBr, cm-1) 3200-2800 (br), 1659, 1586, 1377, 671, ;
TH NMR (300 MHz, DMSO-dg) δ 12.0 (br s, 2H), 9.6 (br s,
IH), 7.4-7.2 (m, 5H), 6.85 (s, IH), 3.8 (m, 2H) , 3.65 (s.
2H) , 2.9 (t, J=7 Hz, 2H);
MS (FD) m/e 322 (M+);
UV (EtOH) 291nm (£=19464), 257nm 1 [£=10601) , , 202nm (£=20396)
Anal. Calcd for C14H15N3S2O2 :
Theory: C, 52.32; H, 4.70; N, 13.07.
Found: C, 52.58; H, 4.88; N, 13.34.
Example 49 tbclbenzvl)-N* - [2_-thiazolyl) thiourea A solution of benzyl isothiocyanate (1.5 g, 10 mmol) and 2-aminothiazole (1.0 g, 10 mmol) in N,N-dimethyl formamide (25 mL) was heated at 100°C for 12 h. The reaction was cooled to room temperature, poured into ethyl acetate, washed with water, IN aqueous HCl, water,
AP Ο Ο Ο 3 8 4
Χ-8571Α
-203saturated sodium bicarbonate, and brine. The organic layer was concentrated and the residue recrystallized twice from ethyl acetate to provide 1.15 g (46%) of the title product: mp 165-167°C;
IR (KBr, αη1) 3171, 3038, 1560, 1509, 1451, 1183, 972,
691;
1H NMR (300 MHz, DMSO-dg) δ 11.7 (br s, IH), 9.9 (br s,
IH), 7.4-7.2 (m, 6H), 7.05 (d, J=3 Hz, IH), 4.8 (m, 2H);
MS (FD) m/e 249 (M+);
UV (EtOH) 289nm (6=19103), 257 nm (6=12196), 204 nm (6=21328).
Anal. Calcd for C11H11N3S2:
Theory: C, 52.99 H, 4.47; N, 16.85.
Found: C, 53.09; H, 4.50; N, 16.77.
Example -5Ω
N- (2-Phenethvl) -N* -(2-pvrazinvl). thiourea A solution of 2-aminopyrazine (1.90 g, 20 mmol) and 2-phenethyl isothiocyanate (3.26 g, 20 mmol, 3.0 mL) in 20 N, N-dimethylformamide (50 mL) was heated to 100°C for 17 h.
The reaction was cooled to room temperature, poured into ethyl acetate, washed with water, IN aqueous HCl, water, saturated sodium bicarbonate, and brine. The organic layer was concentrated and the residue recrystallized twice from ethyl acetate to provide 0.95 g (18%) of the title product: mp 142-143°C;
IR (KBr, cm-1·) 3181, 3049, 1606, 1533, 1472, 1314, 1221,
862, 725;
1H NMR (300 MHz, DMSO-dg) δ 11.02 (br s, IH), 10.95 (br s,
X-8571A
-204-
IH), 7.4-7.2 (m, 5H) , 3.85-3.75 (m, 2H), 2.9 (t, J=7 Hz,
2H) t
MS (FD) m/e 258 (M+) ;
UV (EtOH) 318nm (6=10579), 263nm (6=17922), 202nm (6=15887)
Anal. Calcd for C13H14N4S:
Theory : C, 60.44; H, 5.46; N, 21.69.
Found: C, 60.45; H, 5.63; N, 22.02.
Exairole. 51
Ν-(2-Phenethyl)-Ν' -(3-pvrazolvl) thiourea A solution of 3-aminopyrazole (1.66 g, 20 mmol) and 2-phenethyl isothiocyanate (3.26 g, 20 mmol, 3.0 mL) in N, N-dimethylformamide (50 mL) was heated to 100°C for 18.5 h. The reaction was cooled to room temperature, poured into ethyl acetate, washed with water, IN aqueous HCl, water, saturated sodium bicarbonate, and brine. The organic layer was concentrated and the residue recrystallized twice from ethyl acetate to provide 2.38 g (48%) of the title product:
mp 142-144°C;
IR (KBr, cm1) 3397, 3207, 3078, 1576, 1537, 1255, 1182,
751;
*H nmr (300 MHz, DMSO-dg) δ 12.4 (br s, IH) , 10.35 (br s, IH), 9.85 (br s, IH), 7.6 (s, IH), 7.4-7.2 (m, 5H) , 5.83 (s, IH), 3.75 (m, 2H), 2.85 (t, J=7 Hz, 2H);
MS (FD) m/e 246 (M+);
UV (EtOH) 264nm (6=21473), 204nm (6=17842).
Anal. Calcd for Ci2H14N4S:
Theory: C, 58.51; H, 5.73; N, 22.74.
Found: C, 58.80; H, 5.83; N, 23.00.
APO 00 3 8 4
X-8571A
-205Example 52
Preparation of N-(2-Phenethvl)-Ν'-(phenv 33 ..thiaur&a
A solution of aniline (1.86 g, 2Q mmol) and 25 phenethyl isothiocyanate (3.26 g, 20 mmol, 3.0 mL) in Ν,Νdimethylformamide (50 mL) was heated to 100°C for 18 h.
The reaction was cooled to room temperature, poured into ethyl acetate, washed with water, IN aqueous HCl, water, saturated sodium bicarbonate, and brine. The organic layer was concentrated and the residue recrystallized from ethyl ether/hexanes to provide 2.88 g (56%) of the title product: mp 102-104°C;
IR (KBr, cm1) 3375, 1592, 1542, 1493, 1250, 1000, 695;
!h NMR (300 MHz, CDCI3) δ 7.85 (br s, IH), 7.5-7.0 (m,
10Η), 6.0 (br s, IH), 3.9 (m, 2Η), 2.9 (t, J=7 Hz, 2Η) ;
MS (FD) m/e 256 (M+);
UV (EtOH) 248nm (£=15081), 206nm (ε=25573).
Anal. Calcd for C15H16N2S:
Theory: C, 70.28; H, 6.29; N, 10.93.
Found: C, 70.14; H, 6.37; N, 10.97.
Example 53
N- (ethvl)-Ν' -(2-thiazolvl) thiourea A solution of ethyl isothiocyanate (1.74 g, 20 mmol) and 2-aminothiazole (2.0 g, 20 mmol) in Ν,Ν-dimethylformamide (50 mL) was heated at 100°C for 23 h. The reaction was cooled to room temperature, poured into ethyl acetate, washed with water, IN aqueous HCl, water, saturated sodium bicarbonate, and brine. The organic layer was concentrated and the residue recrystallized twice from
X-8571A
-206mp 135-136°C;
IR (KBr, cm1) 3165, 3021, 1574, 1501, 1435, 1366, 1215, 1179, 695;
1H NMR (300 MHz, DMSO-dg) δ 10.4 (br S, 2H), 7.4 (d, J=3 5 Hz, IH) , 6.8 (d, J=3 Hz, IH), 3.7 (m, 2H), 1.4 (t, J=7 Hz,
3H) ;
MS (FD) m/e 187 (M+) ;
UV (EtOH) 287nm (8=19544), 256 nm (8=10213), 202 nm (8=11588) .
Anal. Calcd for CgHgN3S2:
Theory: C, 38.48 H, 4.84; N, 22.44.
Found: C, 38.71; H, 4.92; N, 22.66.
Example 54
N-(2-Phenethyl)-Ν'-(2-chlorophenvl) thiourea
A solution of 2-chloroaniline (2.55 g, 20 mmol) and 2-phenethyl isothiocyanate (3.26 g, 20 mmol, 3.0 mL) in N, N-dimethylformamide (50 mL) was heated to 100°C for 17 h. The reaction was cooled to room temperature, poured into ethyl acetate, washed with water, IN aqueous HCl, water, saturated sodium bicarbonate, and brine. The organic layer was concentrated and the residue was purified by HPLC on silica gel to provide 1.18 g (20%) of the title product as a white solid:
IR (KBr, cm-1) 3378, 3167, 1540, 1499, 1470, 1250, 1060,
758, 685;
!h NMR (300 MHz, DMSO-dg) δ 7.55 (br s, IH), 7.5-7.2 (m,
9H), 5.9 (br s, IH), 3.9 (m, 2H), 2.9 (t, J=7 Hz, 2H) ;
MS (FD) rn/e 290 (M+);
UV (EtOH) 245nm (8=16042), 209nm (8=29276).
AP 0 0 0 3 8 4
X-8571A -207Anal. Calcd for C15H15N2SCI:
Theory: C, 61.95; H, 5.20; N, 9.63.
Found: C, 61.69; H, 5.28; N, 9.84.
Example 55
HrfbenzyP-N'-J2- (5-chloro)thiazolyl] thiourea
A solution of benzyl isothiocyanate (3.0 g, 20 mmol) and 2-amino-5-chlorothiazole (2.69 g, 20 mmol) in Ν,Ν-dimethylformamide (25 mL) was heated at 100°C for 20 h. The reaction was cooled to room temperature, poured into ethyl acetate, washed with water, IN aqueous HCl, water, saturated sodium bicarbonate, and brine. The organic layer was concentrated and the residue purified by HPLC on silica gel to provide 0.86 g (15%) of the title product: mp 162-164’C;
IR (KBr, cm1) 3154, 3003, 2958, 1588, 1515, 1421, 1231, 1192, 726;
NMR (300 MHz, DMSO-dg) 58.8 (br s, IH), 7.45 (s IH),
7.4-7.2 (m, 5H), 4.7 (m, 2H); MS (EI) m/e 283 (M+); UV (EtOH, 295nm (€=6457), 259 nm (€=5741), 208 nm (€=11042)
Example 56
N.- i3--PhenvlDrogvll -N, -f2- (5-chloro) thiazolyl 1 thiourea
A solution of 3-phenylpropyl isothiocyanate (3.54 g, 20 mmol) and 2-amino-5-chlorothiazole (2.69 g, 20 mmol) in Ν,Ν-dimethylformamide (50 mL) was heated to 100°C. After 18 h, the reaction was cooled to room temperature, poured into ethyl acetate, washed with water, IN aqueous HCl, water, saturated sodium bicarbonate, and brine. The organic layer was concentrated and the residue purified by
X-8571A
-208HPLC on silica gel to provide 0.29 g (5%) of the title product: mp 121-130eC;
IR (KBr, cm1) 3160, 3100, 2949, 1565, 1517, 1493, 698;
1H NMR (300 MHZ, DMSO-dg) 6 10.8 (s, 1H), 8.5 (br s, 1H) ,
7.4 (s, 1H), 7.3 (m, 5H), 3.5 (m, 2H), 2.6 (t, J=7.7 Hz,
2H), 1.8 (m, 2H);
MS (FD) m/e 311 (M+);
UV (EtOH) 295nm (£=14069), 259nm (£=12092), 205nm (£=27316).
Anal. Calcd for C13H14N3S2CI:
Theory: C, 50.07; H, 4.52; N, 13.47.
Found: C, 50.17; H, 4.51; N, 13.42.
Example 57
N-(2-Phenethvl)-Ν' -(5-tetrazovl) thiourea
A solution of 5-aminotetrazole monohydrate (2.06 g, 20 mmol) and 2-phenethyl isothiocyanate (3.26 g, 20 mmol, 3.0 mL) in Ν,Ν-dimethylformamide (50 mL) was heated to 100°C for 21 h. The reaction was cooled to room temperature, poured into ethyl acetate, washed with water,
IN aqueous HCl, water, saturated sodium bicarbonate, and brine. The organic layer was concentrated and the residue recrystallized twice from ethyl acetate to provide 0.59 g (12%) of impure title product:
mp 161-177°C;
IR (KBr, cm-1) 3451, 3235, 3148, 1547, 1511, 1169, 697;
1H NMR (300 MHz, DMSO-dg) δ 10.8 (s, 1H), 10.4 (m, 1H) , 8.6 (br s, 1H), 7.2-7.0 (m, 5H) , 3.8 (m, 2H), 2.8 (t, J=7 Hz,
2H) ;
MS (FD) m/e 248 (M+) ;
UV (EtOH) 258nm (£=13630), 234nm (£=15631), 204nm (£=15594).
AP Ο Ο Ο 3 β 4
Χ-8571Α
-209Example--5£
Ν- (2-phenethyl) -Ν' -i2-(4-methvl-5-acetvlkthiazolvl] thiourea
A solution of 2-phenethyl isothiocyanate (1.14 g, 7 mmol) and 2-amino-4-methyl-5-acetylthiazole (1.09 g, 7 mmol) in Ν,Ν-dimethylformamide (50 mL) was heated at 100°C for 23 h. The reaction was cooled to room temperature, poured into ethyl acetate, washed with water, IN aqueous
HCl, water, saturated sodium bicarbonate, and brine. The organic layer was concentrated and the residue recrystallized twice from ethyl acetate to provide 0.21 g (9%)- of the title product:
IR (KBr, cm-1) 3314, 3060, 1694, 1610, 1555, 1507, 1372,
1233, 980, 667;
!η NMR (300 MHZ, DMSO-d$) 8 12.5(br s, IH), 8.8 (br s, IH),
7.4-7.2 (m, 5H), 3.8 (m, 2H) , 2.9 (t, J=7 Hz, 2H) 2.4 (s,
3H), 2.3 (s, 3H);
MS (FD) m/e 319 (M+);
UV (EtOH) 319nm (£=16944), 230 nm (£=13216), 201 nm (£=18476) .
Example. 59.
N---(2-Phenethvl)-N'-f2-(6-chloro)pyrazinvn thiourea
A solution of 2-amino-6-chloropyrazine (2.59 g, mmol) and 2-phenethyl isothiocyanate (3.26 g, 20 mmol,
3.0 mL) in Ν,Ν-dimethylformamide (50 mL) was heated to 100°C for 35 h. The reaction was cooled to room temperature, poured into ethyl acetate, washed with water,
IN aqueous HCl, water, saturated sodium bicarbonate, and
X-8571A
-210purified by HPLC on silica gel to provide 0.23 g (4%) of the title product: mp 194-195°C;
IR (KBr, cm’1) 3171, 2932, 1575, 1517, 1465, 1359, 1270,
1169, 707;
!h NMR (300 MHz, DMSO-d6) 5 11.2 (s, IH) , 10.2 (br S, IH),
8.5 (s, IH), 8.3 (s, IH), 7.4-7.2 (m, 5H) , 3.85-3.75 (m,
2H), 2.9 (t, J=7 Hz, 2H);
MS (FD) m/e 292 (M+);
UV (EtOH) 328nm (€=12858), 265nm (€=17945), 201nm (€=17746).
Example ¢0
N- (2-phenbutvl)-Ν' - f 2-thiazolvn thiourea A solution of 2-phenbutyl isothiocyanate (3.8 g,
20 mmol) and 2-aminothiazole (2.0 g, 20 mmol) in N,Ndimethyl-formamide (50 mL) was heated at 100°C for 26 h.
The reaction was cooled to room temperature, poured into ethyl acetate, washed with water, IN aqueous HCl, water, saturated sodium bicarbonate, and brine. The organic layer was concentrated and the residue recrystallized from ethyl ether to provide 2.3 g (39%) of the title product: mp 105-107°C
IR (KBr, cm-1) 3171, 2932, 1575, 1517, 1465, 1359, 1169, 1064, 707;
25 !h NMR (300 MHz, DMSO-d6) δ 11.5 (br s, IH) , 9.7 (br s, IH), 7.4-7.1 (m, 7H) , 3.6 (m, 2H), 2.6 (m, 2H), 1.6 (m,
4H) ;
MS (FD) m/e 291 (M+);
UV (EtOH) 288nm (€=19013), 256 nm (€=10681), 203 nm
AP Ο Ο Ο 3 β 4
-211X-8571A
Anal. Calcd for C14H17N3S2:
Theory: C, 57.70; H, 5.88; N, 14.42.
Found: C, 57.60; H, 6.08; N, 14.56.
Example,61
N- (2-Phenethyl) -Ν' - Γ2-(4- (3-nitro)phenvllthiazolv-n.
thiourea
A solution of 2-phenethyl isothiocyanate (0.74 g, 4.5 mmol) and 2-amino-4-[(3-nitro)phenyl]-thiazole (1.0 g, 4.5 mmol) in Ν,Ν-dimethylformamide (50 mL) was heated to 100°C for 120 h. The reaction was cooled to room temperature, poured into ethyl acetate, washed with water, IN aqueous HCi, water, saturated sodium bicarbonate, and brine. The organic layer was concentrated and the residue purified by HPLC on silica gel to provide 0.07 g (4%) of the title product: mp 192-196°C;
IR (KBr, cm'1) 3165, 3023, 1571, 1517, 1352, 1217, 1166;
!h NMR (300 MHz, DMSO-d6) δ 11.7 (br s, IH) , 9.0 (br s,
IH), 8.6 (s, IH), 8.2 (m, 2H), 7.75 (s, IH), 7.6 (t, J=6 Hz, IH), 7.4-7.2 (m, 5H), 3.8 (m, 2H), 2.95 (t, J=6 Hz,
2H) ;
MS (FD) m/e 384 (M+);
UV (EtOH) 286nm (6=21349), 264nm (6=22766), 237nm (6=18307), 202nm (6=28514).
Anal. Calcd for C18H16N4S2O2:
Theory: C, 56.23; H, 4.19; N, 14.57.
_______ Found: C, 56.12; H, 4.24; N, 14.47.
X-8571A
-21210
Example 62
Nr In-Propyl) -N’ - r2-_(5-chlorothiazovl) 1 thiourea
A solution of 2-amino-5-chlorothiazole (2.69 g, 20 mmol) and n-propyl isothiocyanate (2.0 g, 20 mmol) in Ν', N-dimethylformamide (50 mL) was heated to 100°C for 19 h. The reaction was cooled to room temperature, poured into ethyl acetate, washed with water, IN aqueous HCl, water, saturated sodium bicarbonate, and brine. The organic layer was concentrated and the residue purified by HPLC on silica gel to provide 0.17 g (4%) of the title product: mp 128-133°C;
IR (KBr, cnT1) 3170, 2958, 1560, 1487, 1187, 691;
!κ NMR (300 MHz, DMSO-dg) δ 11.5 (br s, IH) , 8.4 (br s,
IH), 7. 4 (s IH), 3.4 (m, 2H), 1.6 (m, 2H), 0.95 (t, J=7 Hz,
3K) ;
MS (FD) m/e 235 (M+) ;
UV (EtOH) 294nm (€=12928), 259nm (€=10257), 204nm (€=16979) .
Anal. Calcd for C7H10N3S2CI:
Theory: C, 35.66; H, 4.28; N, 19.82. Found: C, 35.85; H, 4.19; N, 19.78.
Example 63
N- (2-Phenethyl)-N'-Γ2-(4-(2'.2'-diphenvl-2'cvano)ethvl)thiazovll thiourea
A solution of 2-amino(4-(2',2,-diphenyl-2'cyano)ethyl)thiazole (0.91 g, 3 mmol) and 2-phenethyl isothiocyanate (0.49 g, 3 mmol) in N,N-dimethylformamide (50 mL) was heated to 100°C for 91 h. The reaction was cooled to room temperature, poured into ethyl acetate, washed with water, IN aqueous HCl, water, saturated sodium bicarbonate, and brine. The organic layer was concentrated
AP Ο Ο Ο 3 8 4
Χ-8571Α
-21310 and the residue purified by HPLC on silica gel to provide
0.28 g (20%) of the title product:
IR (KBr, cm'1) 3179, 3024, 2238, 1562, 1250, 698;
!h NMR (300 MHz, OMSO-d^) δ 11.5 (s, IH) , 10.4 (br S, IH) ,
7.5-7.2 (m, 15H), 6.6 (s, IH), 3.85 (s, 2H), 3.8 (m, 2H),
2.8 (t, J=7 Hz, 2H);
MS (FD) m/e 468 (M+);
UV (EtOH) 292nm (£=12023), 259nm (£=5862), 202 nm (£=25516). Anal. Calcd for C27H24N4S2:
Theory: C, 69.20; H, 5.16; N, 11.95.
Found: C, 69.05; H, 5.33; N, 11.76.
Example 64
M- (2-fl-cvclohexenvllethvl)-N* -f2-benzothiazolvll thiourea
A solution of 2-(1-cyclohexenyl)ethyl isothiocyanate (3.3 g, 20 mmol) and 2-aminobenzothiazole (3.0 g, mmol) in N, N-dimethylf ormamide (50 mL) was heated at 100°C for 17.5 h. The reaction was cooled to room temperature, poured into ethyl acetate, washed with water,
IN aqueous HCI, water, saturated sodium bicarbonate, and brine. The organic layer was concentrated and the residue recrystallized from ethyl acetate to provide 2.57 g (40%) of the title product:
mp 185-186°C;
IR (KBr, cm'1) 3179, 3044, 2921, 2830, 1556, 1523, 1441, 1196;
^-H NMR (300 MHz, DMSO-dg) d 11.8 (br s, IH) , 10.2 (br s, IH), 8.0-7.2 (m, 4H), 5.45 (s, IH), 3.65 (m, 2H) , 2.3 (t, J=7 Hz, 2H), 1.9 (m, 4H) , 1.5 (m, 4H);
MS (FD) m/e 317 (M+);
UV (EtOH) 287nm (£=20679), 201 nm (£=25939).
X-8571A
-214Anal. Calcd for C16H19N3S2:
Theory: C, 60.53; H, 6.03; N, 13.24.
Found: C, 60.29; H, 5.94; N, 13.49.
Example 65
N-12-phenethyl) -N‘ -12- (4-ethvl)thiazolvll thiourea
A solution of 2-phenethyl isothiocyanate (1.63 g, 10 mmol) and 2-amino-4-ethylthiazole (1.28 g, 10 mmol) in N,N-dimethylformamide (50 mL, was heated at 100°C for 23
h. The reaction was cooled to room temperature, poured into ethyl acetate, washed with water, IN aqueous HCl, water, saturated sodium bicarbonate, and brine. The organic· layer was concentrated and the residue recrystallized from ethyl acetate to provide 0.84 g (29%) of the title product:
mp 145-146°C;
IR (KBr, cm-1) 3199, 3049, 2962, 1591, 1275, 685;
1H NMR (300 MHz, DMSO-d6) δ 11.5 (br s, IH), 9.8 (br s,
IH, , 7.4-7.2 (m, 5H), 6.6 (s, IH), 3.8 (m, 2H), 2.9 (t, J=7
20 Hz, 2H), 2.45 (q, J=7 Hz, 2H) , 1.1 (t, J=7 Hz, 3H);
MS (FD) m/e 291 (M+) ;
UV (EtOH, 292nm (€=193 82) , 257 nm (€=10 362) , 202 nm
(€=20282).
Anal. Calcd for C14H17N3S2:
25 Theory: C, 57.70; H, 5.88; N, 14.42
Found: C, 57.47; H, 5.91; N, 14.51
Example 66 l^l.(2-benzothiazolvl)thiocarbamovn imidazole 30 A solution of 1,1'-thiocarbonyldiimidazole (8.9
AP Ο Ο Ο 3 8 4
Χ-8571Α
-215acetonitrile (125 mL) was stirred at room temperature for 20 h. The resulting precipitate was collected by filtration to provide 5.75 g (44%) of the title product:
IR (KBr, cm'1) 3199, 3049, 2962, 1628, 1461, 738;
!h NMR (300 MHZ, DMSO-dg) δ 8.85 (S, IH) , 8.1 (br s, IH), 7.9-7.0 (m, 6H);
MS (FD) m/e 261 (M+);
UV (EtOH) 366nm (£=13072), 305 nm (£=11556), 213 nm (£=35893).
Anal. Calcd for C11H8N4S2:
Theory: C, 50.75; H, 3.10; N, 21.52.
Found: C, 50.50; H, 3.02; N, 21.49.
Example 67
N-f2-(2-chlorophenvl)ethvl)-Ν' -ί2-benzothiazolvll thiourea
A solution of l-[(2-benzothiazolyl)thiocarbamoyl) imidazole (2.1 g, 8 mmol) and 2-(2chlorophenyl)-ethylamine (1.25 g, 8 mmol) in N, Ν'dimethyl formamide (30 mL) was stirred at 100°C for 1.5 h, the reaction was cooled to room temperature and the solvent removed in vacuo. The residue was crystallized from ethyl acetate to provide 1.6 g (57%) of the title product:
IR (KBr, cm-1) 3181, 3050, 1587, 1527, 1231, 753;
ΧΗ NMR (300 MHz, DMSO-dg) δ 11.9 (br s, IH), 10.0 (br s,
IH), 7.8-7.2 (m, 8H), 3.95 (m, 2H) , 3.1 (t, J=7 Hz, 2H);
MS (FD) m/e 347 (M+);
UV (EtOH) 301nm (£=23050), 202 nm (£=30924).
X-8571A
-216Example 68
N- F2- (3-chlorophenvl)ethvl)-Ν' - f 2-benzothiazolvn thiourea
A solution of 1-[(2-benzothiazolyl)thiocarbamoyl] imidazole (1.04 g, 4 mmol) and 2-(35 chlorophenyl) ethylamine (0.63 g, 4 mmol) in Ν,Νdimethylformamide (15 mL) was stirred at 100°C for 1 h, the reaction was cooled to room temperature and the solvent removed in vacuo. The residue was crystallized from ethyl acetate'to provide 0.88 g (63%) of the title product:
IR (KBr, cm-1) 3180, 2997, 1569, 1527, 1209, 755;
^H NMR (300 MHz, DMSO-dg) δ 11.9 (br s, IH) , 10.1 (br s,
IH), 7.8-7.2 (m, 8H) , 3.9 (m, 2H), 3.0 (t, J=7 Hz, 2H) ;
MS (FD) m/e 347 (M+);
UV (EtOH) 301nm (6=25367), 202 nm (6=31735).
Anal. Calcd for CigHi4N3S2Cl:
Theory: C, 55.24; H, 4.06; N, 12.08.
Found: C, 55.05; H, 4.05; N, 12.03.
Examplfi-6.9
N- f2- (4-chlorophenvl)ethvl)-N1-r2-benzothiazolvn thiourea
A solution of 1-[(2-benzothiazolyl) thiocarbamoyl] imidazole (1.04 g, 4 mmol) and 2-(4chlorophenyl)ethylamine (0.63 g, 4 mmol) in Ν,Ndimethylformamide (15 mL) was stirred at 100°C for 1 h, the reaction was cooled to room temperature and the solvent removed in vacuo. The residue was crystallized from ethyl acetate to provide 0.89 g (64%) of the title product:
IR (KBr, cm1) 3180, 2997, 1569, 1527, 1257, 755;
!h NMR (300 MHz, DMSO-dg) δ 12.0 (br s, IH), 10.0 (br s,
IH) , 7.9-7.2 (m, 8H), 3.85 (m, 2H), 2.95 (t, J=7 Hz, 2H) ;
_MS (FD) m/e 347 (M+);_
AP Ο Ο Ο 3 8 4
Χ-8571Α -217UV (EtOH) 301nm (£=25731), 218nm (£=29376), 202 nm (£=28033) .
Anal. Calcd for C16H14N3S2CI:
Theory: C, 55.24; H, 4.06; N, 12.08.
Found: C, 55.27; H, 4.02; N, 12.10.
Example 70
N.-f2 - (2-methoxyphenyl) ethvl 1 -N'_-f2-benzothiazolvn thiourea
A solution of 1-[(2-benzothiazolyl)10 thiocarbamoyl) imidazole (1.04 g, 4 mmol) and 2-(2methoxyphenyl)ethylamine (0.62 g, 4 mmol) in N,Ndimethylformamide (15 mL, was stirred at 100°C for 1 h, the reaction was cooled to room temperature and the solvent removed in vacuo. The residue was crystallized from ethyl acetate to provide 0.9 g (66%, of the title product:
IR (KBr, cm-1) 3180, 1672, 1539, 1437, 1202, 1137, 783;
1H NMR (300 MHz, DMSO-de) δ 12.0 (br s, IH), 10.0 (br s,
IH), 7.9-7.0 (m, 8H), 3.85 (m, 2H,, 3.75 (s, 3H), 2.9 (t,
J=7 Hz, 2H);
MS (FD) m/e 343 <M+);
UV (EtOH, 301nm (£=25894), 218nm (£=28357), 202 nm (£=32552) .
Anal. Calcd for C17H17N3OS2:
Theory: C, 59.45; H, 4.99; N, 12.23.
Found: C, 59.70; H, 5.01; N, 11.99.
Example 71
N--12.- (3-methoxvphenvl) ethvll -N1 - f2-benzothiazolvn thiourea
A solution of 1-[(2-benzothiazolyl) -
X-8571A
-218methoxyphenyl) ethyl-amine (0.62 g, 4 mmol) in N,Ndimethylformamide (15 mL) was stirred at 100°C for 1 h, the reaction was cooled to room temperature and the solvent removed in vacuo. The residue was crystallized from ethyl acetate to provide 0.77 g (56%) of the title product:
IR (KBr, cm'1) 3180, 1670, 1543, 1479, 1205, 1136, 718;
1H NMR (300 MHz, DMSO-dg) δ 11.9 (br s, IH) , 10.05 (br s, IH), 7.9-6.8 (m, 8H), 3.87 (m, 2H), 3.75 (s, 3H), 2.95 (t, J=7 Hz, 2H);
MS (FD) m/e 343 (M+);
UV (EtOH) 301nm (£=24893), 216nm (£=28250), 203 nm (£=33504) .
Anal. Calcd for C17H17N3OS2 ··
Theory: C, 59.45; H, 4.99; N, 12.23.
Found: C, 59.36; H, 5.02; N, 12.00.
Example 72
N- F2- (4-methoxvphenvl)ethvll-Ν' -^-benzothiazolyl] thiourea
A solution of 1-[(2-benzothiazolyl) 20 thiocarbamoyl] imidazole (1.04 g, 4 mmol) and 2-(4methoxyphenyl)ethylamine (0.62 g, 4 mmol) in N,Ndimethylformamide (15 mL) was stirred at 100°C for 1 h, the reaction was cooled to room temperature and the solvent removed in vacuo. The residue was crystallized from ethyl acetate to provide 0,85 g (62%) of the title product:
IR (KBr, cm-1) 3162, 1610, 1572, 1255, 1208, 1106, 761;
^H NMR (300 MHz, DMSO-dg) δ 11.9 (br s, IH) , 10.05 (br s, IH), 7.9-6.8 (m, 8H), 3.85 (m, 2H), 3.75 (s, 3H), 2.9 (t,
J=7 Hz, 2H);
AP Ο 0 Ο 3 8 4
-219X-8571A
UV (EtOH) 301nm (€=22113), 218nm (€=23878), 201 nm (€=28098) .
Anal. Calcd for C17H17N3OS2:
Theory: C, 59.45; H, 4.99; N, 12.23.
Found: C, 59.33; H, 5.06; N, 12.04.
Example 73
1--.J (2τ flu dimethyl Lthiazolyl) thiocarbamovl1 imidazole
A solution of 1,1'-thiocarbonyldiimidazole (1.8 g, 10 mmol), 2-amino-4,5-dimethylthiazole hydrochloride (1.65 g, 10 mmol) and triethylamine (1.01 g, 10 mmol) in acetonitrile (40 mL) was stirred at room temperature for 7
h. The solvent was removed in vacuo to afford crude of the title product as a yellow solid used in the next step without purification.
Example 74
K.T.12-- (,2^chlorophenyll ethvl] -Ν' -f2- (4, 5-dimethvl) thiazolyl 1
Phiaurea
A solution of 1-[ (2-[4,5-dimethyl]thiazolyl) thio-carbamoyl] imidazole (10 mmol) and 2-(2-chlorophenyl)ethylamine (1.55 g, 10 mmol) in N,ΛΓ-dimethylformamide (30 mL, was stirred at 90°C for 1 h. The reaction was cooled to room temperature, poured into ethyl acetate, washed with water, IN aqueous HCl, water, saturated sodium bicarbonate, and brine. The organic layer was concentrated and the residue recrystallized from ethyl acetate to provide 2.1 g
X-8571A
-2201h NMR (300 MHz, DMSO-dg) δ 11.45 (br s, IH), 9.75 (br s, IH), 7.5-7.2 (m, 4H), 3.85 (m, 2H), 3.05 (t, J=7 Hz, 2H),
2.2 (s, 3H), 2.05 (s, 3H) ;
MS (FD) m/e 325 (M+);
UV (EtOH) 297nm (£=9209), 257nm (£=5133), 201 nm (£=14635).
Example 75
N- f 2- (3-chlorophenvl)ethvlI-N' -f2-(4.5-dimethvl)thiazolyl1 thiourea
A solution of 1-[(2-[4,5-dimethyl]thiazolyl) thio-carbamoyl] imidazole (10 mmol) and 2-(3-chlorophenyl) ethylamine (1.55 g, 10 mmol) in N, N-dimethylformamide (30 mL) was- stirred at 90°C for 1 h. The reaction was cooled to room temperature, poured into ethyl acetate, washed with water, IN aqueous HCl, water, saturated sodium bicarbonate, and brine. The organic layer was concentrated and the residue recrystaiiized from ethyl acetate to provide 2.2 g (67%) of the title product:
IR (KBr, cm1) 3182, 3018, 1584, 1549, 1511, 1215, 788;
!h NMR (300 MHz, DMSO-dg) δ 11.45 (br s, IH), 9.8 (br s,
IH) , 7.4-7.2 (m, 4H), 3.85 (m, 2H) , 2.9 (t, J=7 Hz, 2H),
2.2 (s, 3H), 2.05 (s, 3H);
MS (FD) m/e 325 (M+);
UV (EtOH) 297nm (£=6543), 257nm (£=3650).
Anal. Calcd for C14H15N3S2CI:
Theory: C, 51.60; H, 4.95; N, 12.89.
Found: C, 51.73; H, 4.99; N, 13.16.
Χ-8571Α
APΟ Ο Ο 384
-221Example .76
Ν-Γ2- (2-methoxyphenvl)ethyn-N'-f2- (4,5-dimethvllthiazolYl!
thiourea
A solution of 1-[(2-[4,5-dimethyl]thiazolyl) thio-carbamoyl] imidazole (47) (10 mmol) and 2-(2methoxyphenyl)ethylamine (1.51 g, 10 mmol) in N,Ndimethylformamide (30 mL) was stirred at 90°C for 1 h. The reaction was cooled to room temperature, poured into ethyl acetate, washed with water, IN aqueous HCl, water, saturated sodium bicarbonate, and brine. The organic layer was concentrated and the residue recrystallized from ethyl acetate to provide 1.9 g (65%) of the title product: mp 178-180°C;
IR (KBr, cm-1) 3175, 2998, 1598, 1495, 1213, 760, 707;
Th NMR (300 MHz, DMSO-d6) d 11.4 (br s, IH), 9.75 (br s,
IH) , 7.25-6.8 (m, 4H), 3.8 (s, 3H) , 3.78 (m, 2H), 2.87 (t, J=7 Hz, 2H), 2.2 (s, 3H), 2.05 (s, 3H);
MS (FD). m/e 321 (M+) ;
UV (EtOH) 297nm (£=18573), 258nm (£=10587), 202 nm (£=28862).
Anal. Calcd for C15H19N3OS2:
Theory: C, 56.04; H, 5.96; N, 13.09.
Found; C, 56.29; H, 6.19; N, 13.27.
Example 77
-13-methoxvphenvl)ethyl1-Ν' - Γ2- (4,5-dimethyl) thiazolyll thiourea
A solution of 1-[(2-[4,5-dimethyl]thiazolyl) thiocarbamoyl] imidazole (10 mmol) and 2-(330 methoxyphenyl)ethylamine (1.51 g, 10 mmol) in N,N-
X-8571A
-222reaction was cooled to room temperature, poured into ethyl acetate, washed with water, IN aqueous HCl, water, saturated sodium bicarbonate, and brine. The organic layer was concentrated and the residue recrystallized from ethyl acetate to provide 2.2 g (69%) of the title product:
mp 146-148°C;
IR (KBr, cm-1) 3179, 3035, 1587, 1551, 1214, 701, 682;
XH NMR (300 MHz, OMSO-dfi) δ 11.45 (br s, IH), 9.8 (br s,
IH), 7.25-6.8 (m, 4H), 3.8 (m, 2H), 3.75 (s, 3H), 2.85 (t,
J=7 Hz, 2H), 2.2 (s, 3H) , 2.05 (s, 3H);
MS (FD) m/e 321 (M+);
UV (EtOH) 297nm (£=16992), 258nm (£=9639), 202 nm (£=27993). Anal. Calcd for C15H19N3OS2:
Theory: C, 56.04; H, 5.96; N, 13.09.
Found: C, 56.01; H, 5.96; N, 13.30.
Example 7a
N-f2-(4-methoxvphenvl)ethvl!-N‘ - f2- (4.5-dimethvl)thiazolyl) thiourea
A solution of 1-[(2-[4,5-dimethyl]thiazolyl) thiocarbamoyl] imidazole (10 mmol) and 2-(4methoxyphenyl)ethylamine (1.51 g, 10 mmol) in Ν,Νdimethyl formamide (30 mL) was stirred at 90°C for 1 h. The reaction was cooled to room temperature, poured into ethyl acetate, washed with water, IN aqueous HCl, water, saturated sodium bicarbonate, and brine. The organic layer was concentrated and the residue recrystallized from ethyl acetate to provide 2.2 g (69%) of the title product: mp 178-180°C;
IR (KBr, cm*1) 3174, 3024, 1590, 1552, 1214, 688;
AP Ο Ο Ο 3 8 4
Χ-8571Α
-223!η NMR (300 MHz, DMSO-dg) δ 11.45 (br s, 1Η), 9.8 (br s,
1Η), 7.2(d, J=8 Hz. 2H), 6.85 (d, J=8 Hz, 2H), 3.78 (m,
2H) , 3.75 (s, 3H), 2.85 (t, J=7 Hz, 2H), 2.2 (s, 3H), 2.05 (S, 3H);
MS (FD) m/e 321 (M+);
UV (EtOH) 297nm (6=8102), 258nm (6=4813), 223 nm (6=6614).
Example 75,
N- (2-phenethyl)-Ν' - (5-f3-methvll isothiazolvD -thiourea
A solution of 2-phenethyl isothiocyanate (3.26 g, 20 mmol, 3.0 mL) and 5-amino-3-methylisothiazole (3.0 g, 20 mmol) in N,N-dimethylformamide (30 mL) was heated at 100°C 24 h, the reaction was cooled to room temperature and poured into ethyl acetate, washed with water, IN aqueous
HCl, water, saturated sodium bicarbonate, and brine. The organic layer was concentrated and the residue recrystallized from ethyl acetate to provide 5.5 g (100%) of the title product:
mp 213-216°C;
IR (KBr, cm’1) 3188, 2744, 1593, 1525, 1495, 1423, 1313, 1248, 829, 777, 752, 705, 670, 522;
!h NMR (300 MHz, DMSO-dg) δ 9.3 (br s, IH) , 7.4-7.2 (m,
5H), 6.85 (br s, IH), 3.7(m, 2H), 2.9 (t, J=7 Hz, 2H), 2.45 (s, 3H);
MS (FD) rn/e 278 (M+) ;
UV (EtOH) 286nm (6=12263), 247 nm (6=14257), 206 nm (6=27381) .
X-8571A
-224Example 8Ώ
1-1 (2-f.6-fluoro)benzothiazolyl) thiocarbamovΠ imidazole
A solution of 1,11-thiocarbonyldiimidazole (17.8 g, 100 mmol) and 2-amino-6-fluorobenzothiazole (16.8 g, 100 mmol) in acetonitrile (700 mL) was stirred at room temperature for 20 h, then at 40°C for 6 h. The resulting precipitate was collected by filtration to provide 19.5 g (70%) of the title product:
IR (KBr, cm-1) 3200, 3050, 2558, 1595, 1560, 1461, 1331,
10 1216, 1088, 1040, 948, 740, 648, 627;
!η NMR (300 MHz, DMSO-dg) δ 12.0 (br s, IH), 8.85 (s, IH),
8.1 (br s, IH), 7.9-7.0 (m, 4H) ;
MS (FD) m/e 279 (M+H);
UV (EtOH) 364nm (8=7372), 306 nm (8=13593), 213 nm (8=31325).
Anal. Calcd for C11H7N4S2F:
Theory: C, 47.47; H, 2.54; N, 20.13.
Found: C, 47.72; H, 2.66; N, 20.09.
Example 81
N-f 2- (2-chlQrophenvl) ethvll-Ν'- (2-f 6-fluoro)benzothiazolyl)
Lhipurea
A solution of 1-[ (2-[6-fluoro]benzothiazolyl) thio-carbamoyl] imidazole (2.1 g, 8 mmol) and 2-(2-chloro25 phenyl) ethylamine (1.25 g, 8 mmol) in N, N-dimethylformamide (30 mL) was stirred at 100°C for 1.5 h, the reaction was cooled to room temperature and the solvent removed in vacuo. The residue was crystallized from ethyl acetate to provide 1.6 g (57%) of the title product:
AP Ο Ο Ο 3 8 4
Χ-8571Α
-225IR (KBr, cm'1) 3166, 3014, 1560, 1538, 1460, 1217, 1198, 853;
ΤΗ NMR (300 MHz, DMSO-dg) d 11.6 (br s, 1H) , 9.8 !br s,
1H), 7.9-7.2 (m, 7H), 3.9 (m, 2H) , 3.1 (t, J=7 Hz, 2H);
MS (FD) m/e 365 (M+);
UV (EtOH) 301nm (£=22535), 216nm (£=27344), 201 nm (£=28624) .
Anal. Calcd for CigHi3N3S2ClF:
Theory: C, 52.53; H, 3.58; N, 11.49.
Found: C, 52.79; H, 3.72; N, 11.76.
Example 82
M-.I2- (3-chlorophenvl)ethvl] -Ν' - (2- f 6-fluorolbenzothiazolyl) thiourea
A solution of 1-[(2-(6-fluoro]benzothiazolyl)thiocarbamoyl] imidazole (2.1 g, 8 mmol) and 2-(3chlorophenyl)ethylamine (1.25 g, 8 mmol) in Ν,Ν-dimethylformamide (30 mL) was stirred at 100°C for 1.5 h, the reaction was cooled to room temperature and the solvent removed in vacuo. The residue was crystallized from ethyl acetate to provide 1.6 g (57%) of the title product:
: mp 193-194°C;
IR (KBr, cm-1) 3171, 3015, 1557, 1526, 1460, 1229, 1201, 866;
1H NMR (300 MHz, DMSO-dg) d 11.9 (br s, 1H) , 9.9 (br s,
1H), 7.9-7.2 (m, 7H), 3.85 (m, 2H), 3.0 (t, J=7 Hz, 2H);
MS (FD) m/e 365 (M+);
UV (EtOH) 301nm (£=24232), 2l7nm (£=30020), 201 nm (£=31875).
X-8571A
-226Anal. Calcd for C16H13N3S2CIF:
Theory: C, 52.53; H, 3.58; N, 11.49.
Found: C, 52.50; H, 3.67; N, 11.38.
Example 83 tL--l-2-.i4-chlproDhenyl-) ethvl]-N' - (2- f6-fluorolbenzothiazolyl) thiourea
A solution of 1-[(2-[6-fluoro]benzothiazolyl)thio-carbamoyl] imidazole (2.1 g, 8 mmol) and 2-(4-chloro10 phenyl)ethylamine (1.25 g, 8 mmol) in Ν,Ν-dimethylformamide (30 mL) was stirred at 100°C for 1.5 h, the reaction was cooled to room temperature and the solvent removed in vacuo. The residue was crystallized from ethyl acetate to provide 1.6 g (57%) of the title product:
: mp 217-218°C;
IR (KBr, cm’1) 3168, 3033, 1559, 1532, 1491, 1462, 1230,
1143, 809;
1H NMR (300 MHz, DKSO-c?6) d 11.85 (br s, IH), 9.8 (br s, IH), 7.9-7.2 (m, 7H), 3.85 (m, 2H), 2.95 (t, J=7 Hz, 2H);
MS (FD) m/e 365 (M+);
UV (EtOH) 301nm (ε=24527), 220nm (ε=31031).
Anal. Calcd for C16H13N3S2CIF:
Theory: C, 52.53; H, 3.58; N, 11.49.
Found: C, 52.80; H, 3.70; N, 11.34.
Example 84
N- f 2- (2-methoxvpheny1)ethvl1-N’- (2-f 6fluoroibenzothiazolyl) thiourea A solution of 1-[(2-[6-fluoro]benzothiazolyl) 30 thiocarbamoyl] imidazole (2.1 g, 8 mmol) and 2-(2-methoxyphenyl)ethylamine (1.25 g, 8 mmol) in N,N-dimethylformamide
AP Ο Ο Ο 3 8 4
Χ-8571Α
-227(30 mL) was stirred at 100°C for 1.5 h, the reaction was cooled to room temperature and the solvent removed in vacuo. The residue was crystallized from ethyl acetate to provide 1.6 g (57%) of the title product:
: mp 208-209°C;
IR (KBr, cm1) 3168, 3034, 1561, 1536, 1462, 1242, 1198, 852;
-H NMR (300 MHz, DMSO-C?6) d 11.85 (br s, IH) , 9.8 (br s, IH), 7.9-7.0 (m, 7H), 3.85 (m, 2H), 3.8 (s, 3H), 2.9 (t,
J=7 Hz, 2H);
MS (FD) rn/e 361 (M+);
UV (EtOH) 300nm (6=24273), 218nm (6=28369), 201 nm (6=34036).
Anal. Calcd for C17H16N3OS2CF:
Theory: C, 56.49; H, 4.46; N, 11.63.
Found: C, 56.56; H, 4.59; N, 11.66.
Example 35
N- r2- (3-methoxvphenvl)ethvl1-N'- (2 -f 6 20 llusrplhsnzpthiazglyl) thiQurea
A solution of 1-[(2-(6-fluoro]benzothiazolyl)thiocarbamoyl] imidazole (2.1 g, 8 mmol) and 2-(3-methoxyphenyl) ethylamine (1.25 g, 8 mmol) in N, N-dimethy If ormamide (30 mL) was stirred at 100°C for 1.5 h, the reaction was cooled to room temperature and the solvent removed in vacuo. The residue was crystallized from ethyl acetate to provide 1.6 g (57%) of the title product:
mp 190-192°C;
IR (KBr, cm'1) 3050, 1536, 1460, 1302,1221, 1060, 674;
Χ-8571Α
-2281H NMR (300 MHz, DMSO-<?6) d 11.9 (br s, IH) , 9.9 (br s,
IH), 7.9-7.0 (m, 7H), 3.85 (m, 2H), 3.75 (s, 3H, , 2.95 (t, J=7 Hz, 2H);
MS (FD, m/e 361 (M+);
UV (EtOH) 301nm (£=24608), 218nm (£=28535), 201 nm (£=37337).
Anal. Calcd for C17H16N3OS2CF:
Theory: C, 56.49; H, 4.46; N, 11.63.
Found: C, 56.21; H, 4.54; N, 11.40.
Example,, 86.
N- f 2-(4 -methoxvphenvl) ethvl 1 -N’ - (2- f 6fluorolbenzothiazolyl) thiourea A solution of 1-[ (2-[6-fluoro]benzothiazolyl) 15 thio-carbamoyl] imidazole (54) (2.1 g, 8 mmol) and 2-(4methoxy-phenyl)ethylamine (1.25 g, 8 mmol) in Ν,Νdimethylformamide (30 mL) was stirred at 100°C for 1.5 h, the reaction was cooled to room temperature and the solvent removed in vacuo. The residue was crystallized from ethyl acetate to provide 1.6 g (57%) of the title product:
: mp 203-204.5°C;
IR (KBr, cm-1) 3001, 1561, 1539, 1458, 1251, 860, 818;
XH NMR (300 MHz, OMSO-de) d 11.85 (br s, IH) , 9.85 (br s, IH), 7.9-6.9 (m, 7H), 3.85 (m, 2H), 3.75 (s, 3H), 2.9 (t,
J=7 Hz,. 2H) ;
MS (FD) m/e 361 (M+);
UV (EtOH) 301nm (£=23562), 222 nm (£=28328).
Anal. Calcd for C17H16N3OS2CF:
Theory: C, 56.49; H, 4.46; N, 11.63.
Found: C, 56.70; H, 4.42; N, 11.79.
AP Ο Ο Ο 3 8 4
Χ-8571Α
-229Exampis .87 l-f (2-f 5-chloro 1 thiazolyl·) thiocarbamovl 1 imidazole
A solution of 1,1'-thiocarbonyldiimidazole (25 5 g, 140 mmol) and 2-amino-5-chlorothiazole (18.8 g, 140 mmol) in acetonitrile (300 mL) was stirred at room temperature for 23 h. The resulting precipitate was collected by filtration to provide 21.2 g (62%) of the title product:
!h NMR (300 MHz, DMSO-dg) δ 9.5 (s, IH), 8.2 (s, IH) , 7.6 (S, IH) , 7.5 (S, IH) ;
MS (FD) m/e 176 (M+-C3H3N2).
Example 88
N.-12.-12rchLorQDhenvl) ethvll -Ν' -f2-(5-chloro) thiazolyl 1.
thiourea
A solution of 1-[(2-[5-chloro]thiazolyl)thiocarbamoyl] imidazole (0.68 g, 2.8 mmol) and 2-(2-chlorophenyl)ethylamine (0.43 g, 2.8 mmol) in N,N20 dimethylformamide (15 mL) was stirred at 100°C for 1 h.
The reaction was cooled to room temperature, poured into ethyl acetate, washed with water, IN aqueous HCl, water, saturated sodium bicarbonate, and brine. The organic layer was concentrated and the residue recrystallized from ethyl acetate to provide 0.68 g (73%) of the title product: mp 172-174°C;
IR (KBr, cm1) 3318, 2873, 1606, 1526, 1513, 1436, 1351, 1237, 747;
1H NMR (300 MHz, DMSO-dg) δ 10.7 (br s, IH) , 8.5 (br s,
IH), 7.4 (s, IH), 7.4-7.2 (m, 4H) , 3.8 (m, 2H) , 2.9 (t, J=7
X-8571A
-230MS (FD) m/e 331 (M+) ;
UV (EtOH) 295nm (€=11804), 259 nm (€=10397), 202 nm (€=27067).
Anal. Calcd for C12H11N3S2CI2:
Theory: C, 43.38; H, 3.34; N, 12.65.
Found: C, 43.61; H, 3.57; N, 12.57.
Example, 82
N-f2-(3-chlorophenvl)ethyn-N1-f2-(5-chloro)thiazolyl) thiourea
A solution of 1-[(2-[5-chloro]thiazolyl)thiocarbamoyl] imidazole (1.22 g, 5 mmol) and 2-(3-chlorophenyl)ethylamine (0.78 g, 5 mmol) in N,N-dimethylformamide (20 mL) was stirred at 100°C for 1 h. The reaction was cooled to room temperature, poured into ethyl acetate, washed with water, IN aqueous HCl, water, saturated sodium bicarbonate, and brine. The organic layer was concentrated and the residue reorystallized from ethyl ether to provide 0.9 g (54%) of the title product:
mp 154-155°C;
IR (KBr, cm-1) 3178, 3044, 1557, 1520, 1458, 1346, 1196,
784, 755;
!h NMR (300 MHz, OMSO-άζ) δ 11.6 (br s, IH), 8.4 (br s,
IH), 7.4 (s, IH), 7.4-7.2 (m, 4H) , 3.7 (m, 2H), 2.8 (t, J=7
Hz, 2H);
MS (FD) m/e 331 (M+) ;
UV (EtOH) 296nm (€=14281), 259 nm (€=12090), 205 nm (€=29809) .
AP Ο Ο Ο 3 8 4
Χ-8571Α'
-231Example 9Q
Ν-.Γ2- i4-chlQCQPheny.lJethyll-N,...7-f2z (5.T.£hloro) thiazolyl 1 thiourea
A solution of 1-[(2-[5-chloro]thiazolyl)thiocar5 bamoyl] imidazole (1.22 g, 5 mmol) and 2-(4-chlorophenyl) ethylamine (0.78 g, 5 mmol) in N, N-dimethylformamide (20 mL) was stirred at 100°C for 1 h. The reaction was cooled to room temperature, poured into ethyl acetate, washed with water, IN aqueous HCI, water, saturated sodium bicarbonate, and brine. The organic layer was concentrated and the residue recrystallized from ethyl acetate to provide 1.1 g (66%) of the title product:
mp 178-180®C;
IR (KBr, cm-1) 3180, 2927, 1610, 1536, 1492, 1325, 1256,
1181, 1088, 1014, 811, 747, 643, 508;
NMR (300 MHz, DMSO-dg) δ 11.6 (br S, IH), 8.4 (br s,
IH), 7.4 (s, IH), 7.32 (d, J=8 Hz, 2H), 7.22 (d, J=8 Hz,
2H), 3.7 (m, 2H), 2.8 (t, J=7 Hz, 2H);
MS (FD) m/e 331 (M+) ;
UV (EtOH) 295nm (€=13675), 259 nm (€=12330), 202 nm (€=27524) .
Anal. Calcd for C12H11N3S2CI2:
Theory: C, 43.38; H, 3.34; N, 12.65.
X-8571A
-232Example. 31
H--..(2- (l-methvl) -2-Pvrrolylethvl)-N‘-(2-thiazolyl)thiourea
An isothiocyanate of 2-(2-aminoethyl)-1methylpyrrole was prepared according to Ann 657, 104-107 (1962). Iji-NMR (CDCI3) 6 2.95 (t, 2H) , 3.55 (s, IH), 3.65 (t, 2H), 5.9-5.95 (m, IH,, 6.05 (t, IH), 6.55 (t, IH). This isothiocyanate was dissolved in DMF (4 ml). To this solution was added 200 mg (2 mmol, of 2-aminothiazole and the solution was heated at 100°C for about 16 h. EtOAc was added and the organic phase was washed with sat. NH4CIsolution and brine. After drying (Na2SO4,, the product was purified on a silica gel column, using EtOAc/Hexane 1:1, as eluent. This gave almost pure titled product.
Recrystallization from toluene/hexanes gave 150 mg of the titled product.
Mp: 183-184°C (dec).
1H-NMR (DMSO-dg) δ 2.86 (t, 2H), 3.55 (s, 3H), 3.75 (q,
2H), 5.85-5.90 (m, 2H,, 6.62 (s, IH) , 7.09 (d, IH) , 7.36 id, IH) , 9.74 (broad s, IH), 11.65 (broad s, IH).
13C-NMR (DMSO-dg) δ 25.03, 33.31, 43.92, 106.24, 106.31, 112.03, 121.55, 129.33, 136.71, 161.68, 178.25.
Example 92
N-(2-il-Diperazinvlethvl))-N1-(2-thiazolyl) thiourea
1.78 g Thiocarbonyldiimidazole (10 mmol) was added to a solution of 1.29 g 1-(2-aminoethyl)piperazine (10 mmol) in 5 ml methylene chloride at 0°C. The reaction mixture was warmed to room temperature, and stirred for 30 minutes. The methylene chloride was evaporated, and 40 ml dimethylformamide together with 10.01 g 2-aminothiazole were added. The mixture was stirred 17 h at 100°C. The
AP Ο Ο Ο 3 8 4
Χ-8571Α
-233product was purified by chromatography on a silica gel column eluted with mixtures of methanol and chloroform. Crystallization of the salt with oxalic acid gave further purification.
^H-NMR (oxalate in D2O): 2.8-3.7 ppm (m), 6.75 ppm (d), 7.1 ppm (d).
Example .,.93
N-(2 - (2-chloro)phenethyl)-N‘-(2-thiazolvl)thiourea
Thiocarbonyldiimidazolide (980 mg, 5.5 mmole) was dissolved in 20 ml methylene chloride. To the solution was added dropwise 2-chlorophenethylamine (0.69 ml, 5 mmole) in 20 ml methylene chloride at 0°C. After reaction for 30 min at 0°C, it was wanned up to room temperature, and then concentrated to small volume in vacuo. To the residue was added 20 ml DMF and 2-aminothiazole (700 mg, 7 mmole). It was kept at 100°C for 3 hours. After cooling to room temperature, it was poured into 1 N HCl solution (100 ml) and extracted with ethyl acetate (2 x 100 ml); the organic phase was washed with brine and dried over magnesium sulfate. The solution was concentrated in vacuo and separated by silica gel column chromatography. Yield = 440 mg (30%) .
^H-NMR {CDCI3) 57.38-7.17 (m, 5H, ClPh, thiazol) 6.81 (d,
J = 3.7 Hz, IH, thiazole), 4,02 (q, J = 7Hz, 2H, CH2NH),
3.17 (t, J = 7.1 Hz, CH2).
13C-NMR (CDCI3) 5177.5 (C=S), 161 (thiazol), 137.5 (thiazol), 136.0 (ClPh), 134.1 (ClPh), 131.1 (ClPh), 129.5 (ClPh), 128.0 (ClPh) and 126.7 (ClPh) 111.1 (thiazol), 44.8 (CH2) and 32.3 (CH2).
X-8571A
-234Example 94
Ν- (2.- (2-metboxy)phenethyl) -_N' - (2-thiazolvl) thiourea
To a solution of 1.8 g (10 mmol) 1,1'thiocarbonyldiimidazole in CH2CI2 (30 ml) at C°C was added
1.46 ml (10 mmol) of 2-methoxyphenethylamine. The solution was then stirred for 1 hour. After the addition of hexane, the reaction mixture was filtered and evaporated. The residue was dissolved in DMF (8 ml) and 1.0 g (10 mmol) 210 aminothiazole (Merck) was added, heated at 100°C for about 16 h. diluted HCl-solution were added.
The reaction mixture was Thereafter, EtOAc and
The organic phase was separated and washed with diluted HCl-solution, sat. NH4CIsolution and water (x 2), respectively. After drying over Na2SO4, the product was purified on a silica gel column, using hexanes/EtOAc (2:1) as eluent, to give 0.77 g crude product. Recrystallization from toluene gave 0.54 g of still crude titled product. A final purification was achieved by the use of a AI2O3 column eluted with CHCI3 (containing 0.5% EtOH) as the eluent. This gave 85 mg of the titled product.
Mp: 126.0-127.5°C.
1H-NMR (CDCI3) δ 3.03 (t, 2H), 3.82 (s, 3H), 3.96 (q, 2H) , 6.79-6.93 (m, 3H) , 7.20-7.26 (m, 3H), 10.35 (broad s, IH) , 10.73 (broad s, IH).
13C-NMR (CDCI3) δ 29.59, 45.69, 55.19, 110.22, 110.97, 120.40, 126.75, 127.96, 130.78, 137.72, 157.62, 161.58, 177.34.
Example 95
N- (2-(4-fluoro)phenethyl)-N1- (2 tXhiazolyJ.) thiourea
In a manner analogous to Example 94, using 4fluorophenethylamine, the titled product resulted.
AP Ο Ο Ο 3 8 4
Χ-8571Α -235Analyses: Calculated: C 51.22, Η 4.30, Ν 14.93. Found: C 51.0, Η 4.35, Ν 14.8.
Mp: 124.5-126.0°C.
^H-NMR (CDCI3) δ 3.0 (t, 3H), 4.0 (q, 3H), 6.86 (d, IH),
7.0-7.3 (m, 5H).
13C-NMR (CDCI3) δ 34.05, 46.82, 111.35, 115.38 (d, 20, 130.39 (d, 20, 134.20 (d, 1C), 137.46, 161.74 (d, 1C), 161.83, 177.52.
Example 96
N-(2- (4-nitro)phenethvl)-N'- (2-thiazolyl) thiourea
In a manner analogous to Example 93, using 4nitrophenethylamine, the titled product resulted.
!h-NMR (CDCI3) δ 8.17 (d, J = 8.6 Hz, 2H, O2NPh), 7.45 (d,
J = 8.6 Hz, 2H, O2NPh), 7.21 (d, J = 3.7 Hz, IH, thiazole),
6.84 (d, J = 3.7 Hz, IH, thiazole), 4.01 (q, J = 5.7 Hz,
2H, CH2NH), 3.15 (t, J = 7.2 Hz, 2H, CH2 ) .
13C-NMR (CDCI3 + CD3OD) δ 179 (C=S), 161 (thiazole), 146.4 (O2NPh), 136.9 (thiazole), 129 (O2NPh), 123.4 (O2NPh),
111.1 (thiazole), 45.3 (CH2), 34.3 (CH2).
Example,97
M-12^14-amino.) phenethyll--N2-.12-thiazolyl) thiourea
The titled product was prepared by reduction of 25 the product from Example 96 with iron and hydrochloric acid using the literature procedure (Vogel, Textbook of Practical Organic Chemistry. 4th ed., p.657, Longman 1978). !h-NMR (CDCI3) 6 7.23 (d, J = 3.8 Hz, IH, thiazole), 7.07 (d, J = 8.3 Hz, 2H, H2NPh), 6.79 (d, J = 3.7 Hz, IH, thiazole), 6.65 (d, J = 8.3 Hz, 2H, H2NPh), 3.91 (q, 2H,
CH2NH), 2.91 (t, J = 7.1 Hz. 2H, CH2).
X-857ΙΑ
-23613c-nmr (CDC13 + CD3OD) 6 177 (C=S), 161 (thiazole), 144 (H2NPh), 137.3 (thiazole), 129.5 (H2NPh), 128.6 (H2NPh),
115.4 <H2NPh), 110.9 (thiazole), 46.7 (CH2), 33.6 (CH2).
Example 98
N- C2- (4-methoxy). Phenethyl) -N‘ - (2-thiazolvl) thiourea
In a manner analogous to Example 93, using 4methoxyphenethylamine, the titled product resulted.
^-H-NMR (CDCI3) 8 7.22-7.18 (t, 3H, MeOPh and thiazole),
6.85 (d, J = 8.5 Hz, 2 H, MeOPh), 6.81 (d, J = 3.7 Hz, 1 H, thiazole), 3.94 (q, J = 7.1 Hz, 2 H, CH2NH), 3.79 (s, 3H, MeO), 2.96 (t, J = 7.1 Hz, 2H, CH2).
13C-NMR (CDCI3) δ 177.3 (C=s), 161.6 (thiazole) 158.2 (MeOPh), 137.4 (thiazole), 130.4 (MeOPh), 129.7 (MeOPh),
113.8 (MeOPh), 111.0 (thiazole), 55.1 (MeO), 47.0 (CH2),
33.8 (CH2).
£xant£l.e„ 21
N-(2- (4-±vdrQxy)EhenethvU-N· - (2-thiazolvl) thiourea
The titled product was prepared by treatment of the product of Example 98 with iodotrimethyl silane in dichloroethane according to literature procedure (H. Sakurai, Synthesis. p. 740, 1979) (Example 97).
1H-NMR (CDCI3) δ 7.22 (d, J = 3.6 Hz, IH, thiazole), 7.14 (d. J = 8.4 Hz, 2H, HOPh), 6.81-6.77 (t, 2H, thiazole,
HOPh), 3.94 (q, 2H, CH2NH2), 2.94 (t, J = 7.2 Hz, 2H, CH2). 13C-NMR (CDCI3) δ 177.4 (C=S), 161.4 (thiazole), 154.1 (HOPh), 137.6 (thiazole), 130.5 (HOPh), 129.9 (HOPh), 115.3 (HOPh), 110.9 (thiazole), 47.1 (CH2), 33.7 (CH2).
AP Ο Ο Ο 3 8 4
Χ-8571Α -237Example 1Q.Q
Ν- (2 - (4-bromo)phenethyl)-Ν' -(2-thiazolvl)thiaurea
In a manner analogous to Example 93, using 4bromophenethylamine, the titled product resulted.
iH-NMR (CDCl3 + CD3OD) δ 7.43 (d, J = 6.4 Hz, 2 H, BrPh),
7.22 (d, J = 3.6 Hz, 1 H, thiazole), 7.15 (d, J = 6.3 Hz, 2 H, BrPh), 6.83 (d, J = 3.7 Hz, 1 H, thiazole), 3.95 (t, J =
7.1 Hz, 2H, CH2NH), 2.94 (t, J = 7 Hz, 2H, CH2).
13C-NMR (CDCI3 + CD3OD) δ 177.5 (C=S), 161.5 (thiazole),
137.4 (thiazole), 131.5 (BrPh), 130.5 (BrPh), 120.3 (BrPh),
111.1 (thiazole), 46.2 (CH2), 34.0 (CH2).
Example 101
N-(2-(1-pjperidinyl)ethvl)-N‘-(2-thiazolvl)thiourea 15 In a manner analogous to Example 93, using 1piperidinylethylamine, the titled product resulted.
^H-NMR (CDCI3) δ 7.32 (d, J = 3.7 Hz, 1 H, thiazole), 6.84 (d, J = 3.7 Hz, IH, thiazole), 3.80 (t, 2H, CH2NH), 2.62 (t, J = 6.4 Hz, 2H, CH2), 2.48 (m, 2H, pip), 1.62 (m, 2H, pip), 1.46 (m, IH, pip).
13C-NMR (CDCI3 + CD3OD): 177.3 (C=S), 161 (thiazole), 137.3 (thiazole), 111.1 (thiazole), 56.1 (CH2), 54.1 (pip), 42.2 (CH2), 25.6 (pip), 24.0 (pip).
Example 102
N.-12-mprphQlinpethYl) -N,‘ - (2-xhiazolylltiiiffiur.ea
In a manner analogous to Example 91, using morpholinoethylamine, the title product resulted.
X-8571A
-2381H-NMR (250 MHz, CDCI3) δ 7.38 (d, IH, CH=CH), 6.86 (d, IH, CH=CH), 3.82 (q, 2H, CH2-NH), 3.86-3.71 (m, 4H, CH2O-CH2), 2.67 (t, 2H,CH2-N (ring)), 2.62-2.52 (m, 4H, ch2-n-ch2).
13C-NMR (250 MHz, CDCI3) δ 178, 163, 138, 112, 67, 57, 53, 42.
Mp: 150.5 - 151.5°C.
Example.. 1Q3
1-(2-Aminothiazole)-1'-imidazole thiocarbonvl
8.90 g Thiocarbonyldiimidazole (50 mmole) and
5.0 g 2-aminothiazole (50 mmole) was added to 50 ml acetonitrile. The mixture was heated to 40°C, and stirred for 2 hours at this temperature. The mixture was cooled to
0°C, and the solid was filtrated off, and washed with 300 ml cold acetonitrile. The yield of pure product after drying was 9.7 g (46 mmole).
Elemental anal: Found; C=39.3, H=2.8, N=26.2; Calc: C=40.0, H=2.87, N=26.6.
1-H-NMR (250 MHz, DMSO) δ 8.68 (s, IH, N=CH-N) , 7.97 (s, IH,
N-CH=CH-N), 7.76 (d, IH, S-CH=CH-N), 7.33 (d, IH, S-CH=CHN) , 7.08 (S, IH, N-CH=CH-N).
Example 1Q4
N-(2-Phenethvl)-N*-Γ2-(6-hvdroxv)pyridyl! thiourea
A stirred solution of phenethyl isothiocyanate (1.63 g, 10 mmol, 1.5 mL) and 2-amino-6-hydroxypyridine (1.10 g, 10 mmol) in N-methylpyrrolidinone (20 mL) was heated to 100°C. After 87.25 h, the reaction was cooled to
APO00384
X-8571A
-239phase was washed with water (4x) and brine. The organic layer was dried over sodium sulfate, filtered and concentrated. The solid obtained was purified by flash chromatography on silica gel (10% ethyl acetate/dichloromethane to 15% ethyl acetate), followed by trituration with ethyl acetate to provide 1.15 g of the titled product (42%) as an off-white solid:
mp 19 6-197°C;
IR (KBr, cm-1, 2937, 1668, 1595, 1475, 1428, 1365, 1219,
1158, 1023;
^H NMR (300 MHZ, DMSO-dg) δ 11.49 (br s, IH) , 10.82 (s, IH) ,
10.33 (s, IH), 7.52 (t, J=7.9 Hz, IH) , 7.25-7.14 (m, 5H) ,
6.53 (d, J=7.9 Hz, IH), 6.19 (d, J=8.0 Hz, IH), 3.80-3.73 (m, 2H,, 2.92 (t, J=7.7 Hz, 2H) ;
MS (FD, m/e 273 (M+);
UV (EtOH) 305nm (£= 20692), 262nm (£= 13737), 247nm (ε= 18743), 203nm (£=19201).
Anal. Calcd for Ci4H15N3OS: C, 61.52; H, 5.53; N, 15.37. Found: C, 61.73; H, 5.72; N, 15.57.
Examcl.fi .IQ 5
H-(2-12maphthvl) ethvl) -N1 - (2-thiazolyl) thiourea
2-Naphthalenethylamine (256 mg, 1.5 mmole) and the product from Example 103 (400 mg, 1.9 mmole) was suspended in DMF (5 ml) . The reaction mixture was heated to 110°C and it became a clear solution in a few minutes. After 1 hour, the reaction mixture was cooled to room temperature, and 20 ml methylene chloride was added. The organic solution was washed successively with 0.5 N HCl solution (70 ml), brine (50 ml) and water (50 ml). The organic solution was dried over magnesium sulfate, and then
X-8571A
-240dried in vacuo. The product was purified by silica gel column chromatography (chloroform/cyclohexane = 1/1 v/v). Yield = 324 mg (69%).
Ιη-NMR (CDC13) δ 7.82-7.39 (m, 7H, naph), 6.98 (d, J = 3.6
Hz, IH, thiazol), 6.73 (d, J = 3.1 Hz, IH, thiazol), 4.07 (q, J = 7 Hz, 2H, CH2NH), 3.28 (t, J = 7 Hz, 2H, CH2). 13C-NMR (CDCI3+CD3OD) δ 177 (C=S), 161 (thiazol), 137 (thiazol), 134.5 (naph), 133.6 (naph), 131.7 (naph), 128.5 (naph), 127.2 (naph), 126.8 (naph), 125.9 (naph), 125.5 (naph), 125.2 (naph), 123.6 (naph), 110.9 (thiazol), 45.8 (CH2), 31.7 (CH).
Example 106
EL· 11--(4-pentenvll-Ν' - (2-thiazolvl) thiourea 15 A mixture of 4-pentenol (3.04 g, 35.3 mmole), pyridine (2.79 g, 35.3 mmole) and 25 ml diethyl ether was cooled to -60°C. Trifluoromethanesulfonic anhydride (10 g,
35.4 mmol) was added dropwise at -60°C (5 min). The reaction was heated slowly (30 min) to room temperature, and the salt formed was filtered off.
The filtrate was added dropwise to a mixture of ml diethyl ether and 30 ml liquid ammonia kept at ca -30°C. The ammonia was evaporated while the remaining solution was allowed to reach room temperature. The ether solution was extracted with 10 ml 10 M aqueous sodium hydroxide. Distillation at atmosphere pressure gave 4pentenylamine (2.35 g, 27.6 mmole).
0.85 g (10 mmole) of this amine was condensed with 2.1 g of the product of Example 103 using the method as described in Example 105. Crystallization from a mixture of n-hexane and toluene gave pure product.
AP Ο Ο Ο 3 8 4
Χ-8571Α -241l-H-NMR (CDCI3) δ 1.85 ppm (m), 2.20 ppm (m) , 3.7 ppm (m),
5.0-5.15 ppm (m), 5.75-5.95 ppm (m), 6.85 ppm (d), 7.30 ppm (d) .
13C-NMR (CDCI3) δ 177, 162, 137, 137, 116, 111, 45, 31, 28 5 ppm.
Example IP?
N-i2-¢3-trifluoromethyl)phenethyl)-N·-(2-thiazolvl)thiourea
In a manner analogous to Example 106, using 110 trifluoromethyl-3-ethanolbenzene, the titled product resulted.
^H-NMR (CDCI3) δ 3.0 (t, PhCH2, 2H) , 4.0 (q, CH2N, 2H) , 6.8 (d, thiazole, IH), 7.2 (d, thiazole, IH), 7.4-7.6 (mult, o, m and ρ, 4H).
Example 1P.8.
N-(cis-3-Hexenvl))-Ν' -(2-thiazolvl)thiourea
In a manner analogous to Example 106, using 3cis-hexenol, the titled product resulted.
!h-NMR (CDCI3) δ 7.30 (d, J = 3.9 Hz, 1 H, thiazol), 6.83 (d, J = 3.8 Hz, IH, thiazole), 5.56 and 5.40 (m, 2H, H-C=CH), 3.75 (q, 2H, CH2NH), 2.47 (q, 2H, CH2), 2.09 (ρ, 2H, CH2), 0.95 (t, J = 5.4 Hz, 3H, CH3).
13C-NMR (CDCI3) δ 177 (C=S), 161 (thiazole), 137.5 (thiazole), 134.8 (C=C), 124.6 (C=C), 111.0 (thiazole),
45.4 (CH2NH), 26.3 (CH2), 20.6 (CH2), 14.1 (CH3).
X-8571A
-242Example 1Q9
Ν- (2- (l-naphthvlkethvl)-N’.- (2-thiazolyl) thiourea
In a manner analogous to Example 106, using (1naphthyl)-2-ethanol, the titled product resulted.
XH-NMR (CDCI3 + CD3OD) δ 8.24-7.40 (m, 7H, naph), 7.16 (d,
J = 3.7 Hz, IH, thiazole), 6.80 (d, J = 3.7 Hz, IH, thiazole), 4.10 (t, J = 7.5 Hz, 2H, CH2NH), 3.49 (t, J =
7.5 Hz, 2H, CH2).
Example 110
N- (2-(2-fluoro)-phenethyl)-Ν' -(2-thiazolvl)thiourea
In a manner analogous to Example 106, using 1fluoro-2-ethanolbenzene, the titled product resulted.
1H-NMR (CDCI3) 57.28-7.03 (m, 5H, thiazole, FPh), 6.81 (d,
J = 3.8 Hz, IH, thiazole), 3.99 (q, J = 7.1 Hz, 2H, CH2NH),
3.08 (t, J = 7 Hz, 2H, CH2,.
13C-NMR (CDCI3) δ 178 (C=S), 161 (thiazole), 137.4 (thiazole), 131 (d, C-F coupling, FPh), 128 (d, C-F coupling, FPh), 124 (FPh), 115.4 (FPh), 115 (FPh), 111 (thiazole), 45.3 (CH2), 28.1 (CH2).
Example 111
N-(2-(2-trifluoromethvl)phenethyl)-Ν' - (2-thiazolvllthiourea
In a manner analogous for Example 106, using 125 trifluoromethyl-2-ethanolbenzene, the title product resulted.
^-H-NMR (CDCI3) δ 7.66 (d, IH, TFMPh), 7.51 (m, 2H, TFMPh), 7.34 (m, IH, TFMPh), 7.26 (d, J = 3.6 Hz, IH, thiazole), 6.84 (d, J = 3.8 Hz, IH, thiazole), 3.99 (q, J = 6.3 Hz,
30_2H, CH2NH), 3.23 (t, J = 7.6 Hz, 2H, CH2) .
AP Ο Ο Ο 3 8 4
Χ-8571Α
-24313C-NMR (CDCI3) δ 177.7 (C=S) , 161.5 (thiazole), 137.6 (thiazole), 136.9 (TFMPh), 131.8 (TFMPh), 131.6 (TFMPh),
129 (q, C-F coupling, CF3), 126.6 (TFMPh), 125.9 (d,
TFMPh), 111.1 (thiazole), 46.3 (CH2), 31.4 (CH2).
Example 112
N-N-(3-pentvnvl)-Ν' -(2-thiazolvl)thiourea
The starting material, 3-pentynylamine, was synthesized from 3-pentyn-l-ol.
3-Pentvnvlamine
Trifluoromethanesulfonic anhydride (4.0 ml; 23.8 mmol) was added to a solution of 3-pentyn-l-ol (2.0 g; 23.8 mmol) and pyridine (1.92 ml; 23.8 mmol) in diethyl ether (50 ml) at -45°C. The mixture was stirred for 15 min at the same temperature and filtered cold into diethyl ether (—10 ml) saturated with NH3 at -45°C with stirring. The precipitate was washed with cold diethyl ether. The reaction mixture was stirred at RT for 3 h and evaporated to give yellow crystals (2.0 g, 36 %) as a salt of 320 pentynylamine and trifluoromethane sulfonic acid.
3H-NMR (250 MHz, D2O) 6 3.12 (t, 2H, CH2-NH+3), 2.55 (m,
2H, CH2-C=C), 178 (t, 3H,CH3-CsC).
13C-NMR (250 MHz, D2O) δ 126, 83, 77, 41, 20, 5.
The titled product was then prepared in a manner analogous to Example 106.
!h-NMR (250MHz, CDCI3) 07.33 (d, IH, CH=CH), 6.87 (d, IH, CH=CH) , 3.86 (q, 2H, CH2-NH) , 2.56 (tt, 2H, CH2-OC) , 1.81 (t, 3H,CH3-CsC).
13C-NMR (250 MHz, CDCI3) δΐ78, 162, 138, 111, 45, 19, 4.
Mp: 118.5-119.5°C.
X-8571A
-244EXSIDDlS_llI
3-(2-Phenethyl)r2-thioxQ-l,2,3,4-tetrahvdroouinazoline
2-Nitrobenzaldehyde (10.0 g, 66 mmol) and 2phenylethylamine (8.3 ml, 66 mmol) was dissolved in acetonitrile (200 ml). pH was adjusted to 6.0 with acetic acid.
Sodium cyanoborohydride (4.15 g, 66 mol) was added in small portions. The solution was stirred 40 min. The solution was diluted with water (400 ml) and extracted with ether.
Acid-base partitioning [aq. HCl, NH4OH (aq.)] and evaporation gave an oil. The oil was suspended in water (200 ml) and iron dust (10 g, 180 mmol) was added.
The mixture was heated to reflux and HCl (cone. aq.) (10 ml) was slowly added. Reflux was continued for 40 minutes.
The solution was cooled, basified with sodium hydroxide 40 % (aq.) to pH 14. The solution was stirred with toluene (700 ml) and filtered through a pad of celite.
Acid-base partitioning [(HCl (a.q.) NH4OH (a.q.)] and evaporation afforded an oil. The oil was dissolved in acetonitrile (20 ml) and N,N-thiocarbonyldiimidazole (0.7 g, 6.6 mmol) was added. The solution was stirred for 78 hours at ambient temperature, heated to 75°C for 40 minutes and evaporated. The residue was purified by flash-chromatography on silica gel by elution with ethyl acetate-cyclohexane (1:3). The product crystallized spontaneously from the pure fractions forming long needles. 1H-NMR (CDCI3) 5 3.0 (t, PhCH2, 2H), 4.1 (t, PhCH2£h2N'
2H), 4.4 (S, PhCH2N, 2H), 6.7-7.5 (mult., C6H5, CgH4, 9H),
8.7 (Broad singlet NH, 1H).
AP Ο Ο Ο 3 8 4
Χ-8571Α
-245ExamEl£_lil
Ν-τ 12-Phenethyl) -Ν' - ί2- ί3-methyl·) -pyridYLLxhigui.ea
A stirred solution of 2-phenethyl isothiocyanate (1.63 g. 10 mmol, 1.5 mL) and 2-amino-3-methyIpyridine (1.08 g, 10 mmol) in N-methylpyrrolidinone (20 mL) was heated to 100°C. After 16.5 h, the reaction was cooled to room temperature and poured into ethyl acetate. The organic phase was washed with water (4x) and brine. The organic layer was dried over sodium sulfate, filtered and concentrated. The solid obtained was purified by flash chromatography on silica gel (2% ethyl acetate/dichloromethane) to provide 1.77 g of the titled product (65%). This material was recrystaiiized from ethyl acetate/hexanes to provide 878 mg of the titled product as a pale yellow crystalline solid:
mp 82-84°C; IR (KBr, cm’1) 3430, 2945, 1594, 1555, 1454, 1268, 1243, 1161;
XH NMR (300 MHZ, DMSO-dg) δ 11.62 (br s, IH) , 8.66 (s, IH) ,
7.90 (d·, J=4.1 Hz, IH) , 7.59 (d, J=7.2 Hz, IH) , 7.28-7.15 (m, 5H), 6.96 (dd, J=7.4, 5.0 Hz, IH) , 3.84-3.78 (m, 2H) ,
2.89 (t, J=7.0 Hz, 2H), 2.23 (s, 3H);
MS (FD) m/e 271 (M+) ; UV (EtOH) 293nm (£= 17290), ‘265nm (£= 14634), 244nm (£=16338), 202nm (£=19784).
Anal. Calcd for C15H17N3S: C, 66.39; H, 6.31; N, 15.48.
Found: C. 66.66; H, 6.32; N, 15.73.
Example 115
N- (2- (2-thienvl) ethvl) -Ν' - (2-thiazolvl) thiourea
6.4 g 2-(2-thienyl)ethanol (50 mmoles) was dissolved in 50 ml diethyl ether together with 3.95 g pyridine (50 mmoles) .
X-8571A
-246The mixture was cooled to -30°C, and 5.7 g methanesulfonylchloride (50 mmoles) was added dropwise under stirring. The reaction mixture was then heated and kept at reflux temperature for 30 minutes. The mixture was then cooled to room temperature and filtered. The filtrate was transferred to an autoclave together with 100 ml of a solution of ammonia in methanol (saturated at 0°C). The autoclave was sealed and heated to 150°C for 17 hours. The solvent, was removed by evaporation in vacuo, and 100 ml 5 M sodium hydroxide in water was added. The mixture was extracted twice with 100 ml methylene chloride to give a solution of 2-(2-thienyl)ethylamine together with some secondary amine.
The pure primary amine was obtained by fractional crystallization from methanol of the salts with oxalic acid, followed by addition of aqueous sodium hydroxide and extraction with methylene chloride.
500 mg of the pure 2-(2-thienyl)ethylamine (3.93 mmole) was added to a solution of 800 mg thiocarbonyl20 diimidazole (4.5 mmole) in 5 ml methylene chloride at 0°C.
The mixture was stirred at 0°C for 15 minutes, and then 1 hour at 20°C. The solvent was removed in vacuo, and 5 ml dimethylformamide and 500 mg 2-aminothiazole was added.
This mixture was allowed to react 17 hours at 110°C. After evaporation of solvent in vacuo 100 ml ethyl acetate was added, and the mixture was heated to 50°C. The warm mixture was washed twice with 20 ml 1 M HCl, and once with 20 ml H2O. Evaporation of solvent to a small volume gave crystals of the desired product. Recrystaliization twice
AP Ο Ο Ο 3 8 4
Χ-8571Α
-24713c-NMR (CDC13 + DMSO-dg) δ 178, 162, 141, 137, 127, 125, 124, 111, 46, 29 PPM.
iH-NMR (CDCI3 + DMSO-dg) δ 3.3 ppm (t), 3.9 ppm (m) , 6.85 ppm (d), 6.90 ppm (m), 7.20 ppm (d), 7.25 ppm (d).
Example 11,6
EL· {2-(2-£luprPr6-chlprpIphenethYll.-N:- (2-thigzQ.LYlIthiP.uree
2-Chloro-6-fluorophenylacetonitrile (2.5 g, 14.7 mmol) was dissolved in 30 ml diethyl ether. Lithium aluminium hydride (1.5 g) was added in small portions over a period of 10 minutes. The mixture was then heated to reflux for 15 minutes. After cooling to room temperature,
1.5 ml water, 1.5 ml aqueous sodium hydroxide, and 4 ml water was added slowly. The ether solution containing the product 2-chloro-6-fluorophenethylamine was decanted off and the solvent was removed in vacuo.
The amine formed was condensed with the product of Example 103 using the method as described in Examples 104 and 105 to give 270 mg of the titled product after recrystallization from ethanol.
iH-NMR (DMSO-d6) δ 3.1 ppm (t) , 3.85 ppm (m) , 7.1 ppm (d) , 7.15-7.30 ppm (m), 7.40 ppm (d).
Example 117
Ef-12.z (3-Methoxy) -phenethyl) -Ν' - (2-thiazolvl) thiourea
In a manner analogous to Example 105, the product of Example 103 was condensed with 3-
X-8571A
-248!h-NMR (DMSO-dg) δ 2.9 (t, Ph, CH2, 2H) , 3.75 (S, OCH3,
3H) , 3,9 (q, CH2N, 2H), 6.8 (mult. 0 and ρ, 4H), 7.1 (d, thiazole, IH) , 7.2 (t, m, IH) , 7.4 (d, thiazole, IH).
Example 118
N-(2-Phenethyl)-N1 -f2-(5-methvl)pvridvl1 thiourea
A stirred solution of 2-phenethyl isothiocyanate (1.63 g, 10 mmol, 1.5 mL) and 2-amino-5-methylpyridine (1.08 g, 10 mmol) in N-methylpyrrolidinone (20 mL) was heated to 125°C. After 16.5 h, the reaction was cooled to room temperature and poured into ethyl acetate. The organic phase was washed with water (4x) and brine. The organic layer was dried over sodium sulfate, filtered and concentrated. The solid obtained was purified by flash chromatography on silica gel (2% ethyl acetate/dichloromethane) to provide 2.01 g of the titled product (74%). This material was recrystallized from ethyl acetate/hexanes to provide 1.72 g of titled product as a white crystalline solid:
mp 153-154°C; IR (KBr,cm1) 3235, 2939, 1613, 1559, 1534, 1493, 1300, 1188;
XH NMR (300 MHZ, DMSO-dg) δ 11.56 (br s, IH), 10.42 (s, IH) ,
7.84 (d, J=1.3 Hz, IH), 7.52 (dd, J=8.5, 2.1 Hz, IH), 7.31
7.16 (m, 5H), 6.99 (d, J=8.5 Hz, IH), 3. 82-3. .75 (m, 2H),
25 2.87 (t, J=7.0 Hz, 2H), 2.16 (s, 3H);
MS (FD) m/e 271 (M+);
UV (EtOH) 298nm (ε= 14080), 268nm (ε=21638), 248nm (ε= 15905), 201nm (ε= 18504).
Anal. Calcd for CjsHivNaS: C, 66.39; H, 6.31; N, 15.48. 30 Found: C, 66.33; H, 6.26; N, 15.33.
AP Ο Ο Ο 3 8 4
Χ-8571Α
-249Example 11a
N-Methvl-N- (2-phenethvl) -Ν’ - (2-thiazolvl) thiourea
In a manner analogous to Example 105, the product of Example 103 was condensed with N-methyl5 phenethylamine, to give the titled product.
1H-NMR (DMSO-dg) 82.9 (t,PhCH2,2H), 3.2 (s,NCH3,3H) 4.0 (t, CH2N,2H), 6.8 (d,thiazole,IH), 7.2(m, thiazole,IH) , 7.3(mult.,CgH5,5H) io Example 120
N-(2-Indanvl)-Ν' -(2♦-thiazolyl)thiourea
In a manner analogous to Example 105, the product of Example 103 was condensed with 2indanylamine, to give the titled product.
1H-NMR (DMSO-d6) 82.4 (q, CH2, 2H) , 3.3 (q, CH2, 2H) ,
4.8 (q, CHN, IH), 7.0 (d, thiazole, 1H), 7.1-7.3 (mult., CgH4, 4H), 7.4 (d, thiazole, IH).
Example 121 η- (2-12-Azido).-phenethyl).-N* - (2-thiazolvl) thio.ur_ea
2-Aminophenethylalcohol (Aldrich) (0.8 g, 5.8 mmol) was dissolved in 15 ml H2O at 0°C. Trifluoroacetic acid (1.2 ml) was added. Sodium nitrite (0.41 g, 0.6 mmol) dissolved in cold water (2.0 ml) was added. The solution was stirred at 0°C for 10 minutes.
Lithium azide (0.59 g, 12 mmol) in water (2.0 ml) was added slowly. The solution was brought up to ambient temperature. The solution was extracted with diethyl ether (3 x 50 ml), the organic phase was washed with 1 N HCl (aq.) (2 x 20 ml), dried with Na2SO4, filtered and evaporated.
X-8571A
-250The residue was dissolved in dichloromethane (20 ml) under a nitrogen atmosphere. The solution was cooled to -10°C and ethyldiisopropylamine (1.1 ml, 6.4 mmol) was added.
Trifluoromethanesulfonic anhydride (0.87 ml,
5.17 mmol) was added dropwise. The solution was stirred at 0° for 20 minutes and then added to a solution of NH3 (g) in methanol (50 ml sat. at 0°C) under vigouros stirring. The solution was stirred for 40 minutes at ambient temperature. The solution was diluted with water (100 ml) and extracted with dichloromethane (2 x 50 ml). Acid-base partitioning [NH4OH (aq)-HCl (aq)[ and evaporation gave 2-azidophenethylamine.
In a manner analogous to Examples 104 and
105, the product of Example 103 was condensed with 2azidophenethylamine, to give the titled product.
!h-NMR (DMSO-d6) δ 2.9 (t, PhCH2, 2H, , 3.8 (q, CH2N,
2H), 7.0-7.4 (m, Ph-o, m, p, thiazole, 6H).
Example 122
IL·,, L2.-tlL^EluQrQ) phenethyl) -N‘ -.(2,.-thiazplYl) thiourea
In a manner analogous to Example 105, the product of Example 103 was condensed with 3fluorophenethylamine to give the titled product.
^H-NMR (DMSO-d6) δ 2.9 (t, PhCH2, 2H), 3.8 (q, CH2N,
2H), 7.0-7.4 (m, Ph-o,m,p, thiazole, 6H).
AP Ο Ο Ο 3 8 4
-251X-8571A
Example. 123
Ν- (2- (Benzenesulfonamide-4-ethvl)) -Ν' -2.2.-.
thiazQlylJ.thiQ.ur.ea
In a manner analogous to Example 105, the 5 product of Example 103 was condensed with 4-(2aminoethyl)benzenesulfonamide to give the titled product.
Th-NMR(DMSO-de) δ 3.Oft), 3.8(m), 7.1(d), 7.35(m), 7.45(d), 7.80(d).
13C-NMR (EMSO-dg) 6 178, 162, 143, 142, 137, 129, 126, 112, 45, 34.
Example ..124
-..(^ATfiimethQxy.) pheae£hyl,)--H' - ¢.2 -thiazolyl) thiourea
In a manner analogous to Example 105, the product of Example 103 was condensed with 3,4dimethoxyphenethylamine to give the titled product. Τη-NMR (DMSO-dg-CDCl3) 62.95 (t), 3.70 (t), 3,85 (s),
3.90 (si, 6.80 (s), 6.90 (d), 7.40 (d).
Example 125
M- (PhenyJ.pr.gpaa-l-ol-2-yl) -Ν' - (2-thiazQlylI..thiourea
In a manner analogous to Example 105, the product of Example 103 was condensed with norephedrine to give the titled product.
Th-NMR (DMSO-dg) δ 0.95 (d), 4.25 (m), 4.95 (d), 7.1-7.5 (m) .
X-8571A
-252Example 126
Ν-(2-(2-FVridvl) ethvl)-Ν'- (2-thiazolvl) thiourea
In a manner analogous to Example 105, the product of Example 103 was condensed with 2-(25 aminoethyl)pyridine to give the titled product.
XH-NMR (DMSO-d6) 6 3.1 (t), 4.0 (m) , 7.1 (d), 7.2-7.4 (m), 7.7 (m), 8.5 (d), 9.8 (s), 11.7 (s) .
Example 127
N- 12-(2.,5-Dimethoxv)phenethyl)-N' -(2-thiazolvl)thiourea
In a manner analogous to Example 105, the product of Example 103 was condensed with 2,6dimethoxyphenethylamine to give the titled product. !h-NMR (CDCI3) 53.00 (t), 3.73 (s), 3.77 (s), 3.97 (m),
6.70-6.85 (m), 7.24 (d), 10.80 (s).
13C-NMR (CDCI3) δ 177, 162, 153, 152, 138, 128, 117,
112, 111, 111, 56, 56, 46, 30.
Example 128
M--(lr. L2.-:phenylJ propanylL-H:..-. (2-thiazQlyll thiourea
In a manner analogous to Example 105, the product of Example 103 was condensed with l-amino-2phenylpropane to give the titled product.
1h-NMR ,(DMSO-d6) δ 1.20 (d), 3.13 (q) , 3.70 (t) , 7.09 (d), 7.20-7.50 (m).
Broad peaks δ 8.14, 9.33, 9.75 and 10.57.
AP Ο Ο Ο 3 8 4
Λ
Χ-8571Α
-253Examoie 129
Ν-(2-(3-Indol)ethvl)-Ν' -(2-thiazolvl) thiourea
In a manner analogous to Example 105, the product of Example 103 was condensed with tryptamine to give the titled product.
^-H-NMR (CDCI3 + CD3OD) δ 7.68-7.06 (m, 6H, indole, thiazole), 6.84 (d, J = 3.7 Hz, IH, thiazole), 4.02 (t,
J = 7 Hz, 2H, CH2NH), 3.16 (t, J = 6.9 Hz, 2H, CH2 ) . 13C-NMR (CDCI3 + CD3OD) δ 177 (thiazole), 161 (thiazole), 137 (thiazole), 136 (indole), 127 (indole),
123 (indole), 121 (indole), 118 (indole), 117 (indole), 111 (thiazole), 110 (indole), 109 (indole), 46 (CH2), 26 (CH2).
Example 130 (2^hy.d£Qxye£hQxyJ ethyl L-Ν' -. (2-thiazolyl 1,thiourea
In a manner analogous to Example 105, the product of Example 103 was condensed with 2-(2aminoethoxy) ethanol to give the titled product.
1h-NMR (CDCI3} δ 7.34 (d, J = 3.4 Hz, IH, thiazole),
6.84 (d, J = 3.4 Hz, IH, thiazole), 3.96 (t, J = 4.9 Hz, 2H, CH2NH), 3.76 (m, 4H, CH2), 3.66 (t, J = 4.3 Hz, 2H, CH2) .
13C-NMR (CDCI3) δ 177.4 (C=S), 161.8 (thiazole), 137.5 25 (thiazole), 111.2 (thiazole), 72.1, 68.4, 61.5, 44.9.
Example 131
Hr.(2.7, (5-NitxQpYrid-:2-yl) Ami noe thyl 1.-J1(2 -.
thiazolyl) thiourea
In a manner analogous to Example 105, the product of Example 103 was condensed with 2-(230
Χ-8571Α
-254aminoethy1amino)-5-nitropyridine to give the titled product.
1H-NMR (CDCI3 + CD3OD) δ 8.95 (d, 1H, pyr), 8.12 (dd,
IH, pyr), 7.26 (d, J = 3.8 Hz, IH, thiazole), 6.86 (d, J = 3.8 Hz, IH, thiazole), 6.52 (d, IH, pyr), 3.99 (t, 2H,
CH2NH), 3.78 (t, 2H, CH2).
Example, 132
N-12-(l-MethvlPvrrolid-2-vl)ethvl)-N’-(210 thiazolyl) thiourea
In a manner analogous to Example 105, the product of Example 103 was condensed with 2-(2aminoethyl)-1-methylpyrrolidine to give the titled product.
1H-NMR (CDCI3) δ 7.32 (d, J = 4 Hz, IH, thiazole), 6.83 (d, J = 3.6 Hz, IH, thiazole), 3.78 (q, 2H, CH2NH), 3.08 (m, IH, NCH(CH2)2), 2.34 (s, 3H, N-CH3), 2.16 (m, 2H, NCH2), 2.01 (m, 2H, CH2), 1.7 (m, 4H, pyr).
13C-NMR (CDCI3) δ 177 (C=S), 161 (thiazole), 137.5 (thiazole), 111.1 (thiazole), 64.1 (pyr), 57.1 (pyr),
43.1 (CH2), 40.6 (CH2), 32.1 (pyr), 30.3 (pyr), 22.2 (pyr)·
Example 133 ν- (2- (2,4t£>ichlQrp).phenethyl).-N'.r.(2..-thiazQlYl) thipurea In a manner analogous to Example 105, the product of Example 103 was condensed with 2,4-dichlorophenethylamine to give the titled product.
1h-NMR (CDCI3 + CD3OD) δ 7.40 (d, IH, thiazole), 7.41 (s, IH, DClPh), 7.24 (m, 2H, DClPh), 6.87 (d, IH,
AP 0 0 0 3 8 4
X-8571A
-255Example.134
M-.il, 1- (2 -p-hvdroxvphenvl) methoxycarbQpylg.thV-11-M! - L2thiazolvl thiourea
In a manner analogous to Example 105, the product of Example 103 was condensed with tyrosine methylester to give the titled product.
iH-NMR (CDC13) δ 7.25 (d, J = 3.3 Hz, IH, thiazole), 7.02 (d, J = 8.2 Hz, 2H, Tyr), 6.82 (d, J = 3.4 Hz, IH, thiazole), 6.74 (d, J = 8.2 Hz, 2H, Tyr), 5.29 (t, IH, CH), 3.73 (s, 3H, CH3), 3.19 (d, 2H, CH2).
13C-NMR- (CDC13) δ 177.4 (C=S), 171.5 (CO2Me), 161.2 (thiazole), 155.4 (Tyr), 136.9 (thiazole), 130.0 (Tyr),
126.2 (Tyr), 115.0 (Tyr), 111.1 (thiazole), 59.0 (CH) ,
51.9 (CH3), 36.4 (CH2).
Example 135
1-(2-Thiazolyl)-4-(p-hvdroxvbenzvl)-2-thiohvdantoin
The titled product was obtained as a by product during the preparation of the product described in Example 134.
^H-NMR (CDCI3 + CD30D, δ 7.78 (d, IH, thiazole), 7.50 (d, IH, thiazole), 7.07 (d, 2H, Tyr), 6.78 (d, 2H, Tyr),
4.50 (t, IH, CH), 3.15 (m, 2H, CH2).
Example 136
Mrl2-trans-phenylcvclopropyl)-N‘-2-(thiazolyl)thiourea
In a manner analogous to Example 105 the product of Example 103 was condensed with trans-2phenylcyclopropylamine to give the titled product.
X-8571A
-2561H-NMR (CDCI3 + CD3OD) δ 7.32 (d, J = 3.8 Hz, 1H, thiazole), 7.23 (m, 5H, Ph), 3.38 (m, 1H, CHNH), 2.27 (m, 1H, CH), 1.91 (m, 2H, CH2).
13C-NMR (CDCI3 + CD3OD) δ 179.2 (C=S), 161.7 (thiazole),
139.8 (Ph), 137.3 (thiazole), 128.2 (Ph), 126.5 (Ph), 126.0 (Ph), 111.2 (thiazole), 36.1 (CH), 35.1 (CH), 16.1 (CH2).
Example 137
N-(4-Methyl-3-pentenvl)-N‘- (2-thiazolvl) thiourea
The starting material, 4-methyl-3-pentenylamine, was prepared from 5-bromo-2-methyl-2-pentene.
-Bentepylaming
L1N3 (1 g, 20 mmol) was added to a solution of 5-bromo-2-methyl-2-pentene (1.63 g, 10 mmol) in 5 ml DMF. The solution was stirred at room temperature for two days. The reaction mixture was poured into a mixture of hexanes and sat. NH^l-solution. The organic phase was washed with sat. NH^l-solution, brine and water.
After drying, the solvent was removed and the crude azide was reacted with L1AIH4 (380 mg, 10 mmol) in ether at 0°C. After 2 h the reaction was quenched by the addition of 380 μΐ H2O, 380 μΐ 15 % NaOH-solution and 1.14 ml H2O, respectively. After filtration the solvent was evaporated and the residue was distilled in vacuo to give 0.42 g of the title amine.
B.p. 50°C/40 mm.
1H-NMR (CDCI3) δ 1.5 (broad s, 2K), 1.60 (d, 3H), 1.70
AP Ο Ο Ο 3 8 4
Χ-8571Α -25713C-NMR (CDC13) 5 17.70, 18.39, 25.66, 32.22, 42.03, 121.64, 133.50.
In a manner analogous to Example 105, the 5 product of Example 103 was condensed with 4-methyl-3pentenylamine to give the titled product.
Mp: 87.5-88.5°C.
Analyses: Calculated: C 49.76, H 6.26, N 17.41. Found: C
49.35, H 6.20, N 17.15.
1H-NMR (CDC13) 6 1.65 (s, 3H) , 1.75 (s, 3H), 2.40 (q,
2H), 3.73 (q, 2H), 5.1-5.25 (m, IH), 6.83 (d, IH), 7.29
(d, IH).
13C-NMR (CDC13) δ 17.93, 25.88, 27.31, 45.54, 111.22,
120.40, 135.10, 137.51, 161.94, 177.21.
Example 138
EL--lIXaaszl-.hexenyI) -N1.- i2,-thiazglxll£higurea
The starting material, trans-3-hexenvlamine. was prepared from trans-3-hexen-l-ol.
Trans.? 3. ch.ex.envlamine
To a stirred solution of trans-3-hexen-l-ol (5.0 g, 0.050 mol), Et3N (7.65 ml, 0.055 mol) and CH2C12 (70 ml) at -30°C was added 4.33 ml (0.055 mol) methanesulfonyl chloride. The solution was stirred at about -20°C for 2 h. After addition of CH2C12, the organic phase was washed with sat. NaHCO3 solution, sat. NH4Cl-solution and water, dried <Na2SC>4) and concentrated in vacuo. This gave a crude mesylate which was dissolved in DMF (30 ml) and LiN3 (5 g, 100 mmol)
X-8571A
-258was added. The reaction mixture was stirred overnight and poured into a mixture of ether and brine. The ether phase was washed with brine (x 2) and dried (Na2SO4>.
The ether solution was concentrated to about 100 ml and 5 cooled to 0°C, whereafter 1.9 g (50 mmol) of LiAlH4 was added. After 1 h the reaction was quenched with 1.9 ml H2O, 1.9 ml 15 % NaOH-solution and 5.7 ml H2O, respectively. After filtration, the solvent was evaporated and the residue was distilled in vacuo to give 2.35 g of the titled amine.
B.p. 3 4°C/20 mm 1H-NMR (CDCI3) δ 0.92-1.05 (m, 3H), 1.75 (broad s, 2H),
1.95-2.20 (m, 4H) , 2.68-2.75 (m, 2H), 5.27-5.63 (m, 2H). 13C-NMR (CDCI3) δ 13.80, 25.55, 36.62, 41.56, 126.10,
134.48.
In a manner analogous to Example 105, the product of Example 103 was condensed with trans-3hexenylamine to give the titled product.
Mp: 116.0-117.0°C .
Analyses: Calculated: C 49.76, H 6.26, N 17.41. Found: C
49.6, H 6.3, N 17.4.
iH-NMR (CDCI3) δ 0.98 (t, 3H), 2.0-2.1 (m, 2H), 2.41 (q, 2H), 3.76 (q, 2H), 5.4-5.7 (m, 2H), 6.83 (d, IH), 7.29 (d, IH), 10.8 (broad s, IH) , 11.35 (broad s, IH).
13C-NMR. (CDCI3) δ 13.72, 25.65, 45.42, 111.25, 124.97, 135.56, 137.50, 161.95, 177.14.
AP Ο Ο Ο 3 8 4
-259X-8571A
Example .12$
Ν-f2-fCvclo-2-penten-l-vl)ethvll-Ν' - (2thiazQlyJJ thiourea
The starting material 2-(cyclo-2-penten-l5 yl)ethylamine was prepared from 2-cyclopenten-l-yl acetic acid.
2.r(CYclo-2-penten-J--yll.athylamiQ.e
2-Cyclopenten-l-ylacetic acid (5 ml, 0.042 mol) was dissolved in ether (100 ml). L1AIH4 (2.4 g,
0.063 mol) was added in portions. After the addition, the reaction mixture was stirred for 2 h at room temperature. The reaction mixture was quenched with 2.4 g H2O, 2.4 g 15 % NaOH-solution and 7.2 ml H2O, respectively. Filtration and evaporation of the solvent gave 4.45 g of crude 2-(cyclo-2-penten-l-yl) ethanol.
This alcohol was transformed to the title amine by a procedure analogous to Example 138.
l-H-NMR (CDCI3) δ 1.4-1.8 (m, 4H) , 2.0-2.15 (m, IH, , 2.220 2.4 (m, 3H), 2.6-2.8 (m, 3H) , 5.6-5.8 (m, 2H) .
13C-NMR (CDCI3) δ 29.68, 31.78, 40.00, 40.64, 42.97, 130.29, 134.61.
In a manner analogous to Example 105, the product of Example 103 was condensed with 2-(cyclo-2penten-l-yl)ethylamine to give the titled product.
Mp: 139.0-140.0°C.
Analyses: Calculated: C 52.14, H 5.97, N 16.58. Found: C 52.20, H 6.05, N 16.35.
X-8571A
-260iH-NMR (CDCI3) δ 1.42-1.58 (m, IH), 1.62-1.92 (m, 2H), 2.06-2.45 (m, 3H) , 2.72-2.86 (m, IH), 3.71-3.84 (m, 2H> , 5.70-5.80 (m, 2H) , 6.85 (d, IH), 7.32 (d, IH) , 10.9 (broad s, IH), 10.95 (broad s, IH).
13C-NMR (CDCI3) δ 29.71, 32.01, 34.77, 43.23, 44.31,
111.15, 131.19, 134.13, 137.66, 161.99, 177.28.
Example 140
N-(2-. (trans-3-pentenvl))-Ν' -(2-thiazolvl)thiourea 10 The starting material trans-3-penten-l-ol was prepared by reduction of 3-pentyn-l-ol with lithium aluminium hydride in refluxing tetrahydrofuran and the titled product was then prepared in a manner analogous to Examples 106 and 112.
iH-NMR (250 MHz, CDCI3) δ 7.28 (d, IH, CH=CH), 6.83 (d,
IH, CH=CH), 5.66-5.38 (m, 2H, trans-CH=CH), 3.67 (q, 2H, CH2-NH), 2.37 (q, 2H, CH2-CH=CH) , 1.72 (dd, 3H, CH=CHCH3) .
13C-NMR (250 MHz, CDCI3) δ 177, 162, 138, 129, 127, 111, 20 46, 32, 18.
Mp: 129-129.5°C.
Anal. Calcd. for C9H13N3S2: C, 47.5; H, 5.7; N, 18.5. Found: C, 47.9; H, 5.8; N, 17.8.
Example 141
N-(2-(cis-3-pentenvl))-Ν' -(2-thiazolvl)thiourea
The starting material cis-3-penten-l-ol was prepared by reduction of 3-pentyn-l-ol with hydrogen in acetone at about 5 psi for 20 minutes using palladium on
AP Ο Ο Ο 3 8 4
Χ-8571Α -261the titled product was then prepared in a manner analogous to Examples 106 and 112.
^H-NMR (250 MHz, CDCI3) 67.30 (d, IH, CH=CH) , 6.83 (d,
IH, CH=CH) , 5.73-5.34 (m, 2H, cis-CH=CH) , 3.76 (q, 2H,
CH2-NH), 2.48 (q, 2H, CH=CH-CH2), 1.66 (d, 3H,CH=CHCH3) .
13C-NMR (250 MHz, CDCI3) δ 177, 162, 138, 127, 126, 111, 45, 26.
Mp: 76.5°C.
Example 142
H.-.(2- (2-Methyl k-chene-thvlt-N' - (2-thiazolyl 1 thiourea
The starting material 1-methylphenethanol was prepared by reduction of o-tolylacetic acid with lithium aluminium hydride in refluxing tetrahydrofuran and the titled product was then prepared analogous to Examples 106 and 112.
Mp: 143-144OC.
Example 143
N- (2- (3.4,.5-trimethoxv)phenethvl) -Ν' - (2thiazolvl). thiourea
The starting material 2-(3,4,5-trimethoxy) phenethylamine was prepared by reduction of 3,4,525 trimethoxyphenylacetonitrile with cobalt chloride and sodium borohydride, according to the general method described by L.S. Heinzman in J, Am. Chem, Soc, 104. p. 6801 (1982).
3,4,5-Trimethoxybenzonitrile (965 mg, 5 mmole) and cobalt chloride (2,37 g, 10 mmole) were dissolved in methanol (70 ml) . To the solution was added sodium
X-8571A
-262borohydride (1.89 g, 50 mmole). After 3 hours, the reaction mixture was filtered through celite, and concentrated to small volume. It was then taken up in chloroform and extracted with IN HCl (100 ml). The organic phase was discarded. The aqueous solution was basified with aqueous ammonia, and extracted with chloroform. The organic phase was dried over magnesium sulfate, and dried in vacuo to yield 2-(3,4,5trimethoxy)phenethylamine (427 mg).
ί-Η-ΝΜΚ (CDCI3) 5 6.58 (s, 2H, TMPh), 3.85 (m, 8H, 2 x MeO, CH2), 3.82 (s, 3H, OMe), 3.80 (m, 2H, CH2).
The titled product was then prepared analogous to Example 105.
iH-NMR (CDCI3) δ 7.26 (d, IH, thiazole), 6.85 (d, IH, thiazole), 6.64 (s, 2H, TMPh), 4.84 (d, J = 5.7 Hz, 2H, CH2NH),'3.86 (m, 11H, CH2, MeO).
13C-NMR (CDCI3) δ 177 (C=S), 161 (thiazole), 153 (TMPh),
138 (TMPh), 137 (thiazole), 132 (TMPh), 111 (thiazole), 20 104.8 (TMPh), 61 (MeO), 56.1 (MeO), 53 (CH2), 50 (CH2).
Example 144
N- (2-(2,4-Difluoro)phenethyl)-Ν' -(2-thiazolvl) thiourea
In a manner analogous to Example 143, using 25 2,4-difluorophenylacetonitrile, the titled product resulted.
l-H-NMR (CDCI3) δ 7.26 (m, IH, DFPh) , 7.20 (d, IH, thiazole), 6.80 (d, IH, thiazole), 6.75 (m, 2H, DFPh), 3.85 (q, 2H, CH2NH), 3.04 (t, 2H, CH2).
AP Ο Ο Ο 3 8 4 /'S,
Χ-8571Α
-263Example 145
Ν- (2- (2,6-Difluoro)phenethyl) -Ν' - (2-thiazplv.il thiourea
In a manner analogous to Example 143, using
2,6-dif luorophenylacetonitrile, the titled product resulted.
^-H-NMR (CDCI3) δ 7.23 (d, J = 3.8 Hz, IH, thiazole),
7.26-7.12 (m, IH, DFPh) , 6.86 (m, 2H, DFPh) , 6.81 (d, J = 3.6 Hz, IH, thiazole), 3.96 (q, 2H, CH2NH), 3.11 (t, J = 7 Hz, CH2).
13C-NMR (CDCI3) 6 177 (C=S), 164 and 159 (dd, C-F coupling, DFPh), 162 (thiazole), 137 (thiazole), 128 (m, C-F coupling, DFPh), 111 (thiazole), 110.8 (d, C-F coupling, DFPh), 44.5 (CH2), 21.6 (CH2).
Example 146
N-(2-(3,4-Methvlenedioxy)phenethyl)-Nl-(2-thiazolyll .thiourea
In a manner analogous to Example 143, using 3,4-methylenedioxyphenylacetonitrile, the titled product resulted.
^H-NMR (CDCI3) δ 7.24 (d, IH, thiazole), 6.80 (m, 3H,
Ph, thiazole), 6.74 (s, IH, Ph), 5.93 (s, 2H, OCH2O),
3.94 (q, 2H, CH2NH), 2.93 (t, 2H, CH2).
13c-NMR (CDCI3) 6177.3 (C=S), 161.6 (thiazole), 148 (Ph), 146 (Ph), 137.4 (thiazole), 132.1 (Ph), 111.1 (thiazole), 109.2 (Ph), 108.2 (Ph), 100.7 (OCH2O), 47.0 (CH2), 34.4 (CH2).
X-8571A
-264 Example 147
M--i2-,{4-Tr,i£.luorgmaPhyllEhenethYl)zNl-r (.2thiazolvl) thiourea
In a manner analogous to Example 143, using 5 4-trifluoromethylphenylacetonitrile, the titled product resulted.
iH-NMR (CDCI3 + CD3OD) 8 7.57 (d, J = 8.3 Hz, 2H,
TFMPh), 7.40 (d, J = 8.3 Hz, 2H, TFMPh), 7.19 (d, J =
3.7 Hz, IH, thiazole), 6.83 (d, J = 3.7 Hz, IH, thiazole), 3.95 (t, J = 7.2 Hz, 2H, CH2NH), 3.08 (t, 2H, CH2) .
Example 148 .IRS) -N-(2-Methyl-2- (2,6.,7di£luoxQlphenethyD-?Ml z.il15 thiazQlylJXhiourea
2,6-Difluorobenzyl cyanide (1.24 ml, 10 mmole) was reacted with sodium hydride (360 mg, 12 mmole) in THF (5 ml) for 2 hour. Then iodomethane was added to the reaction mixture. After 30 min, the reaction mixture was worked up and the product was isolated by silica gel column chromatography. Yield 985 mg (59 %) .
1h-NMR {CDCI3) δ (Mixture of two stereoisomers) 7.28 (m,
IH, DFPh) , 6.98 (m, 2H, DFPh) , 4.26 (m, 1Η, CH) , 1.69 and 1.66 (2 x s, 3H, CH3).
In a manner analogous to Example 143, using 2methyl-2-(2,6-difluoro)phenethylamine, the titled product resulted.
AP Ο Ο Ο 3 8 4
Χ-8571Α
-265^H-NMR (CDCI3) δ R and S stereomixture), 7.12 (m, 2H, DFPh, thiazole), 6.85 (t, 2H, DFPh), 6.77, 6.76, 6.75,
6.74 (2d, J = 3.6 Hz, IH, thiazole), 4.11 {ro, IH, CH) , 4.05-3.65 (m, 2H, CH2), 1.45, 1.42, (2s, 3H, CH3).
Example 149
N-(2- (2-Bromo)-phenethyl)-Ν' -(2-thiazolvl) thiourea
In a manner analogous to Example 143, using
2-bromophenylacetonitrile, the titled product resulted.
1H-NMR (DMSO-dg) δ 2.9 (t, PhCH2, 2H), 3.05 (t, PhCH2, 2H), 3.8 (q, CH2N, 2H), 7.1 (d, thiazole, IH), 7.15-7.6 (mult, o, m, p, thiazole, 5H).
Example ,15Q
N-(2-(l-Phenvl-l-cvclopropane)ethvl)-Ν' - (2thia&olYl),thiourea
In a manner analogous to Example 116, using 1phenyl-l-cyclopropanecarbonitrile, the titled product resulted.
iH-NMR (CDCI3) δ 1.0 (d), 3.8 (d), 6.9 (d), 7.2 - 7.4 (m), 7.9, 9.5 (NH).
Example. 151
H.-12- ¢2.6-BlmethoxYl.phen£,thYll-^li.r-i2·-: thiazolyl·) Phiourea 25 The starting material 2,6-dimethoxyphenethylamine was prepared from 2,6-dimethoxybenzaldehyde. Reaction with nitromethane according to the procedure described in Vogel, Textbook of Practical Organic Chemistry, p. 176 (Longman 1978, 4th Ed.)
Χ-8571Α
-266g, 5.3 mmole) was dissolved in diethyl ether/tetrahydrofuran (2:1, 200 ml) and lithium aluminium hydride (0.5 g, 13 mmol) was added in small portions. The mixture was refluxed for 120 minutes and then treated with 0.6 ml H2O, 0.6 ml 15 % NaOH (aq) and
1.8 ml H2O. The mixture was filtered and purified by acid-base partitioning (NH4OH (aq) HCl dil. (aq)) and evaporated. The crude product 2,6dimethoxyphenethylamine was pure enough to be used 10 directly in the following reaction where it was condensed with the product of Example 103, in a manner analogous to Example 105, to give the titled product. iH-NMR (DMSO-dg) δ 2.9 (t, PhCH2, 2H) , 3,7 (q, CH2N,
2H) , 3.8 (s, OCH3, 6H), 6.7 (d, ο, 2H), 7.1 (d, thiazole, IH) , 7.2 (t, p, IH), 7.3 (d, thiazole, IH)).
N- (2- (3,5t£iBfi,thaxy )ph.enethyl.)nl!l.l-n.(.,thiazolyl) thiourea
In a manner analogous to Example 151 the 20 product of Example 103 was condensed with 3,5dimethoxyphenethylamine, obtained from 3,5dimethoxybenzaldehyde, to result in the titled product. iH-NMR (DMSO-dg) δ 2.8 (t, PhCH2, 2H) , 3.65 (s, OCH3, 6H) , 3.7 (q, CH2N, 2H), 6.3 (t, ρ, IH), 6.4 (t, ο, 2H),
7.1 (d, thiazole, IH) , 7.3 (d, thiazole, IH).
Md2 --13,. 5 -Ci.chlox.Q,)phengthyIl-M,1r.l2„-thiazoly.l) thiourea
In u manner analogous to Example 151, the 30 product of Example 103 vas condensed with 3,5-
Bad
ORIGINAL
AP Ο Ο Ο 3 8 4
Χ-8571Α -267dichlorophenethylamine, obtained from 3,5dichlorobenzaldehyde.
3H-NMR (DMSO-dg) δ 2.9 (t, PhCH2, 2H), 3.8 (q, CH2N,
2H), 7.1 (d, thiazole, IH), 7.3 (mult, o and ρ, 3H), 7.4 (d, thiazole, IH).
Example .154
N-(2-(2.5-Dichloro-6-hvdroxv)phenethvl)-Ν' -(2thiazQlvlJ rhi.auxsa
In a manner analogous to Example 151, the product of Example 103 was condensed with 2,5-dichloro6-hydroxyphenethylamine, obtained from 2,5-dichloro-6hydroxybenzaldehyde.
l-H-NMR (CDCI3) δ 3.0 (t, PhCH2, 2H) , 3.9 (q, CH2N, 2H) ,
6.9 (d, ο, IH), 7.1 (d, thiazole, IH), 7.2 (d, p, IH),
7.3 (d, thiazole, IH).
Example.155
N-(2.3.6-Trichloro)Phenethyl)-Ν' -(2-thiazolvl)thiourea
In a manner analogous to Example 151, the product of Example 103, was condensed with 2,3,6trichlorophenethylamine, obtained from 2,3,6trichlorobenzaldehyde.
3H-NMR (DMSO-dg) δ 3.3 (t, PhCH2, 2H), 3.4 (q, CH2N,
2H), 7.1 (d, thiazole, IH), 7.4 (d, thiazole, IH), 7.57.5 (mult., m and ρ, 2H).
X-857ΙΑ
-268Example 156
Ν-(2-(2,3,4-Trifluoro)Phenethyl) -Ν' - (2thiazplyl·)thiourea
In a manner analogous to Example 151, the 5 product of Example 103 was condensed with 2,3,4trifluorophenethylamine, obtained from 2,3,4trifluorobenzaldehyde, to result in the titled product. 1H-NMR (CDCl3) 5 3.0 (t, PhCH2, 2H) , 4.0 (q, CH2N, 2H),
6.8 (d, thiazole, 2H), 6.85-7.0 (mult., m and ο, 2H),
7.2 (d, thiazole, IH).
Example 157
Ur.L2-(2,3.5-Trichlorp),phenethyl) -Ν' - (2thiazolvl) thiourea
In a manner analogous to Example 151, the product of Example 103 was condensed with 2,3,5trichlorophenethylamine, obtained from 2,3,5trichlorobenzaldehyde.
^H-NMR (DMSO-dg) 5 3.05 (t, PhCH2, 2H), 3.9 (q, CH2N,
2H), 7.1 (d, thiazole, IH,, 7.4 (d, thiazole, IH), 7.5 (d, o, IH), 7.7 (d, p, IH).
Example 158
N- (2- (2.4-Dimethoxy)Phenethyl) -N' - (2-thiazolvl) thiourea
In a manner analogous to Example 151, the product of Example 103 was condensed with 2,4-dimethoxyphenethylamine, obtained from 2,4-dimethoxybenzaldehyde.
AP Ο Ο Ο 3 8 4
-269X-8571A iH-NMR (CDCI3 + CD3OD) δ 7.23 (d, J = 3.6 Hz, IH, thiazole), 7.10 (d, J = 7.8 Hz, IH, DMPh), 6.81 (d, 3.6 Hz, IH, thiazole), 6.44 (s, IH, DMPh), 6.42 (d, IH, DMPh), 3.87 (t, 2H, CH2NH), 3.80 (s, 3H, OMe), 3.79 (S,
3H, OMe), 2.94 (t, 2H, CH2 ) .
13C-NMR (CDCI3 + CD3OD) δ 177.3 (C=S), 161.6 (thiazole),
159.7 (DMPh), 158.4 (DMPh), 137.5 (thiazole), 130.9 (DMPh) ,· 119.1 (DMPh), 110.9 (thiazole), 103.8 (DMPh), 99.3 (DMPh), 55.3 (OMe), 55.1 (OMe), 45.5 (CH2), 28.7 (CH2).
Example 159
M,--(2-12,.J,-DiniethoxY)phsngthYl.L..7JL'·- i2--Lhi.azQlyl).thiQurga
In a manner analogous to Example 151, the product of Example 103 was condensed with 2,3-dimethoxyphenethylamine, obtained from 2,3-dimethoxybenzaldehyde. iH-NMR (CDCI3) δ 7.23 (d, J = 3.7 Hz, IH, thiazole),
7.02-6.83 (m, 3H, DMPh), 6.79 (d, J = 3.6 Hz, IH, thiazole), 3.99 (q, J = 8.9 Hz, 2H, CH2NH), 3.87 (s, 3H,
OMe), 3.86 (s, 3H, OMe), 3.05 (t, 2H, CH2).
13C-NMR (CDCI3) δ 177.3 (C=S), 161.6 (thiazole), 152.6 (DMPh), 147.3 (DMPh), 137.3 (thiazole), 132 (DMPh),
123.7 (DMPh), 122.2 (DMPh), 110.9 (thiazole), 110.8 (DMPh), 60.6 (OMe), 55.5 (OMe), 45.8 (CH2), 28.9 (CH2).
Example 160
3,5,6rTetjafluQro)phenethvl) -Ν' -(2thiasplvl.) thiourea
In a manner analogous to Example 151, the
X-8571A
-270tetrafluorophenethylamine, obtained from 2,3,5,6tetrafluorobenzaldehyde.
1H-NMR (CDCI3 + CD3OD) δ 7.24 (d, J = 3 Hz, IH, thiazole), 6.98 (m, H-F coupling, IH, TFPh), 6.83 (d, J 5 = 3 Hz, IH, thiazole), 3.99 (t, J = 6.8 Hz, 2H, CH2NH),
3.18 (t, J = 6.9 Hz, 2H, CH2).
13C-NMR(CDC13) 6l78.2(C=S), 161.5(thiazole),
147.6(m,TFPh), 143.6(m,TFPh), 137.3(thiazole),
117.6(t,TFPh), 111.1(thiazole), 104.3(t,TFPh),
53.3(CH2), 43.7(CH2).
Example 161
N- (2- (2-Methoxy ? 5-bromo ^pheneThYll-JT.- (2τ.
thiazolylLthiourea
In a manner analogous to Example 151, the product of Example 103 was condensed with 2-methoxy-5bromophenethylamine, obtained from 2-methoxy-5bromobenzaldehyde.
1H-NMR (CDCI3) δ 7.34 (m, 3H, MBPh and thiazole), 6.81 (d, J = 3.6 Hz, IH, thiazole), 6.72 (d, J = 8.4 Hz, IH,
MBPh), 3.95 (q, 2H, CH2NH), 3.79 (s, 3H, OMe), 2.98 (t, J = 6.8 Hz, 2H, CH2).
Example..-162
H7-12r.(2-Etho2iyl,pheiie-thYl,} -N‘-r L2-.thi.azolyll thiourea
In a manner analogous to Example 151, the product of Example 103, was condensed with 2ethoxyphenethylamine, obtained from 2-ethoxybenzaldehyde.
AP Ο Ο Ο 3 8 4
Χ-8571Α
-271^H-NMR (250 MHz, CDCI3) δ 7.37-7.16 (m, 2Η, arom.), 7.22 (d, 1H, CH=CH), 6.91-6.78 (m, 2H, arom), 6.78 (d, 1H, CH=CH), 4.07-3.93 (2xq, 2x2H, CH2-NH, CH2-O), 3.04 (t,
2H, Ph-CH2), 1.42 (t, 3H, OCH2CH3).
13C-NMR (250 MHz, CDCI3) δ 178, 162, 157, 138, 131, 128, 127, 120, 111, 111, 63, 46, 30, 15.
Mp: 140°C.
Anal. Calcd. for C14H17N3OS2: C, 54.6; H, 5.5; N, 13.7. Found: C, 54.4; H, 5.6; N, 13.3:
Example,163
N-12ri2,3.riDichlpro)phenetIiyJJ-N:t(2-thiazglyl} thigyrea
In a manner analogous to Example 151, the product of Example 103 was condensed with 2,3-dichloro15 phenethylamine, obtained from 2,3-dichlorobenzaldehyde.
^H-NMR (250 MHz, DMSO) δ 7.55 (d, 1H, CH=CH) , 7.42-7.32 (m, 3H, arom), 7.12 (d, 1H, CH=CH), 3.86 (q, 2H, CH2NH), 3.12 (t, 2H, Ph-CH2).
13C-NMR (250 MHz, DMSO) δ 178, 162, 138, 130, 129, 128,
112, 44, 33.
Example.., 16,1
N.rl 2τ i.4,-,chlQ£gph£py-ll ethyl]-N,1.-i2---ilx^.-JJ.meghYl) thiazplyl 1.
A solution of 1-[(2-[4,5-dimethyl]thiazolyl) thiocarbamoyl] imidazole (10 mmol) and 2-(4chlorophenyl)ethylamine (1.55 g, 10 mmol) in Ν,Νdimethylformamide (30 mL) was stirred at 90°C for 1 h. The reaction was cooled to room temperature, poured into ethyl acetate, washed with water, IN aqueous HCl, water,
X-8571A
-272was concentrated and the residue recrystallized from ethyl acetate to provide 2.44 g (75%) of the titled product.
IR (KBr, cm'1) 3170, 3024, 1550, 1510, 1260, 1212, 708;
!h NMR (300 MHz, DMSO-dg) δ 11.45 (br s, IH) , 9.8 (br s,
IH), 7.35 (d, J=8 Hz, 2H), 7.3 (d, J=8 Hz, 2H), 3.8 (m,
2H), 2.85 (t, J=7 Hz, 2H), 2.2 (s, 3H), 2.05 (s, 3H) ;
MS (FD) rn/e 326 (M+);
UV (EtOH) 297nm (e=17467), 257nm (e=10021), 219nm (e=16075, 201nm (e=22380)).
Anal. Calcd for Ci4HigN3S2Cl:
Theory: C, 51.60; H, 4.95; N, 12.89.
Found: C, 51.70; H, 5.07; N, 13.08.
Example 165
1-f (S-napLhQ.ll.x.llUiia^glYlixhlPPaibampYn imidazole
A solution of 1,11-thiocarbonyldiimidazole (1.8 g, 20 mmol) and 2-aminonaptho[1,2]thiazole (2.0 g, 20 mmol) in acetonitrile (150 mL) was stirred at 65°C for 24 h. The resulting precipitate was collected by filtration to provide 1.69 g (46%) of the titled product.
IR (KBr, cm1) 3148, 2670, 1465, 736;
lH NMR (300 MHZ, DMSO-dg) δ 9 .2 (s, IH) 8.85 (s, IH), 8.65
(d, J=8 Hz, IH), )8.2 (br s. IH) , 8.0-7.3 (m, 5H);
MS (FD). m/e 309 (M+-H);
25 UV (EtOH) 383nm (£=8297), 244 nm (£=15160), 226 nm
(£=17126) .
Anal. Calcd for C15H10N4S2:
Theory: C, 58.04; H, 3.25; N, 18.05.
Found: C, 58.13; H, 3.21; N, 18.03.
AP Ο Ο Ο 3 8 4 ι
Χ-8571Α -273Example .1.66
Ν- f 2-phenylethyl) -Ν' - f 2-naptho ί 1,.2 l thla-Z-OlvD thiourea
A solution of 1-[ (2-naptho[1,2]thiazolyl) thiocarbamoyl] imidazole (1.6 g, 5 mmol) and 25 phenylethylamine (0.62 g, 5.2 mmol) in Ν,Νdimethyl formamide (20 mL) was stirred at 90°C for 1 h, the reaction was cooled to room temperature and the solvent removed in vacuo. The residue was crystallized from ethyl acetate to provide 1.5 g (82%) of the titled product:
IR (KBr, cm'1) 3171, 3027, 1581, 1521, 1213, 695;
1h nmr (300 MHz, DMSO-d6) δ 11.7 (br s, IH) , 9.9 (br s,
IH), 8.25 (d, J=8 Hz, IH), 8.0 (d, J=8 Hz, 2H) , 7.8 (d, J=8 Hz, IH), 7.6-7.2 (m, 7H), 3.95 (m, 2H), 3.05 (t, J=7 Hz,
2H) ;
MS (FD)· m/e 364 (M+);
UV (EtOH) 340nm (€=23922), 325nm (€=19262), 313nm (€=20808), 245nm (€=39665), 209 nm (€=36141).
Anal. Calcd for C20H17N3S2:
Theory: C, 66.09; H, 4.71; N, 11.56.
Found: C, 65.86; H, 4.84; N, 11.48.
Example 167.
1-f(2-f4-methyl)thiazolyl) thiocarbamovl) imidazole
A solution of 1,1'-thiocarbonyldiimidazole (13.37 g, 75 mmol) and 2-amino-4-methylthiazole (8.55 g, mmol) in acetonitrile (150 mL) was stirred at room temperature for 24 h. The resulting precipitate was collected by filtration to provide 14.22 g (85%) of the titled product:
IR (KBr; cm’1) 3179, 2558, 1455, 1217, 737;
X-8571A
-274!h NMR (300 MHz, DMSO-dg) δ 8.55 (s, IH) 7.9 (s, IH), 7.05 (s, IH), ), 6.9 (s, IH), 2.3 (s, 3H);
MS (FD) m/e 224 (M+-H);
UV (EtOH) 359nm (£=10749), 291 nm (£=8720), 202 nm 5 (£=20498).
Anal. Calcd for C8H8N4S2:
Theory: C, 42.84; H, 3.59; N, 24.98.
Found: C, 42.90; H, 3.54; N, 24.89.
Example 168
N-(2-ri-cvclohexenvllethvl)-Ν'-f2-(4-methvl)thiazolyl1 thiourea
A solution of 1-[ (2-[4-methyl]thiazolyl) thiocarbamoyl] imidazole (2.24 g, 10 mmol) and 2-(115 cyclohexenyl)ethylamine (1.25 g, 10 mmol) in N,Ndimethylformamide (25 mL) was stirred at 90°C for 4 h, the reaction was cooled to room temperature and the solvent removed in vacuo. The residue was crystallized from ethyl acetate to provide 2.4 g (86%) of the titled product:
IR {KBr; cm’1) 3177, 2918, 1565, 1505, 1202, 717;
3H NMR (300 MHz, DMSO-dg) δ 11.55 (br s, IH), 9.85 (br s, IH), 6.65 (s, IH), 5.45 (s, IH), 3.65 (m, 2H), 2.25 (m,
5H). 1.9 (m, 4H), 1.55 (m, 4H);
MS (FD) m/e 281 (M+);
UV (EtOH) 291nm (£=19178), 257nm (£=9837), 201 nm (£=16247). Anal. Calcd for C13H19N3S2:
Theory: C, 55.48; H, 6.80; N, 14.93.
_Found: C, 55.40; H, 6.82; Ν, 14.7 7.
AP Ο Ο Ο 3 8 4 'Λ
Χ-8571Α -275Example .163.
Ν- f 2- (2-chlorophenvl)-ethvl-L-N_'-I2- i4im£thvU-thiazolyl 1 thioursa
A solution of 1-[(2-[4-methyl]thiazolyl) thiocarbamoyl] imidazole (2.24 g, 10 mmol) and 2-(2chlorophenyl)ethylamine (1.56 g, 10 mmol) in Ν,Νdimethyl formamide (25 mL) was stirred at 90°C for 1.5 h, the reaction was cooled to room temperature and the solvent removed in vacuo. The residue was crystallized from ethyl acetate to provide 2.4 g (77%) of the titled product:
IR (KBr, cm*1) 3163, 3012, 1584, 1214, 754, 706;
!h NMR (300 MHz, DMSO-dg) δ 11.6 (br s, IH), 9.8 (br s,
IH), 7.5-7.2 (m, 4H), 6.65 (s, IH), 3.85 (m, 2H), 3.05 (t, J=7 Hz, 2H), 2.2 (S, 3H);
MS (FD) m/e 311 (M+);
UV (EtOH) 292nm (£=18641), 257nm (£=10471), 202 nm (£=24729) .
Anal. Calcd for C13H14N3S2CI:
Theory: C, 50.07; H, 4.52; N, 13.47.
Found: C, 49.99; H, 4.56; N, 13.45.
Example 170
Ν-Γ2-(3-chlorophenvl)ethyn-N‘-Γ2-(4-methvl)thiazolyl)
LhiPU££a
A solution of 1-((2-[4-methyl]thiazolyl) thiocarbamoyl] imidazole (2.24 g, 10 mmol) and 2-(3chlorophenyl)ethylamine (1.56 g, 10 mmol) in Ν,N- * dimethylformamide (25 mL) was stirred at 90°C for 1.5 h, the reaction was cooled to room temperature and the solvent removed in vacuo. The residue was crystallized from ethyl acetate to provide 2.67 g (86%) of the titled product:
X-8571A
-276IR (KBr, cm'1) 3171, 3016, 1581, 1214, 761, 713;
Th NMR (300 MHz, DMSO-d6) δ 11.6 (br s, IH), 9.85 (br s,
IH), 7.4-7.2 (m, 4H), 6.65 (s, IH), 3.85 (m, 2H), 2.95 (t, J=7 Hz, 2H), 2.2 (s, 3H);
MS (FD) m/e 311 (M+);
UV (EtOH) 293nm (£=18976), 257nm (£=10523), 202 nm (£=27048).
Anal. Calcd for C13H14N3S2CI:
Theory: C, 50.07; H, 4.52; N, 13.47.
Found: C, 49.94; H, 4.48; N, 13.37.
Example 171
N-f2-(4-chlorophenvllethvll-N1-f2-(4-methvl)thiazolyll thiourea
A solution of 1-((2-[4-methyl]thiazolyl) thiocarbamoyl] imidazole (2.24 g, 10 mmol) and 2-(4chlorophenyl)ethylamine (1.56 g, 10 mmol) in N,Ndimethylformamide (25 mL) was stirred at 90°C for 1.5 h, the reaction was cooled to room temperature and the solvent removed in vacuo. The residue was crystallized from ethyl acetate to provide 2.52 g (81%) of the titled product:
IR (KBr, cml) 3170, 3022, 1562, 1215, 744, 709;
Th NMR (300 MHz, DMSO-d6) δ 11.6 (br s, IH), 9.85 (br s,
IH) , 7.38 (d, J=8 Hz,, 2H) , 7.30 (d, J=8 Hz, , 2H), 6.65 (s,
IH) , 3.8 (m, 2H), 2.9 (t. J=7 Hz, 2H), 2.18 (s, 3H);
MS (FD) m/e 311 (M+);
UV (EtOH) 292nm (£=16470), 257nm (£=9506), 219nm (£=13695),
201 nm (£=20563 ) .
AP Ο Ο Ο 3 8 4 η
Χ-8571Α -277Anal. Calcd for Ci3H14N3S2Cl:
Theory: C, 50.07; H, 4.52; N, 13.47.
Found: C, 49.94; H, 4.55; N, 13.58.
Example 172
N- f2- (2-methoxvphenvl)ethvΠ-Ν' - f 2-.( 4-methyl).thiazolvll thiourea
A solution of 1-[(2-[4-methyl]thiazolyl) thiocarbamoyl] imidazole(2.24 g, 10 mmol) and 2-(210 methoxyphenyl)ethylamine (1.51 g, 10 mmol) in Ν,Νdimethylformamide (25 mL) was stirred at 90°C for 2 h, the reaction was cooled to room temperature and the solvent removed in vacuo. The residue was crystallized from ethyl acetate to provide 2.2 g (73%) of the titled product:
IR (KBr, cm1) 3173, 3024, 1568, 1246, 1206, 750, 694;
XH NMR (300 MHz, DMSO-dg) 5 11.55 (br s, IH), 9.85 (br s, IH), 7.2-6.8 (m, 4H), 6.65 (s, IH) , 3.75 (m, 5H) , 2.9 (t, J=7 Hz, 2H), 2.18 (s, 3H);
MS (FD) m/e 307 (M+);
UV (EtOH) 291nm (6=18637), 259nm (6=10786), 202 nm (6=25565).
Anal. Calcd for C14H17N3OS2:
Theory: C, 54.70; H, 5.57; N, 13.67.
Found: C, 54.68; H, 5.50; N, 13.46.
Example 173
H-12t i3-meth.QXYDhenvlj.ethv.Ll -Ν' - J 2-JA-methvl) thiazolvll .thiourea
A solution of 1-((2-[4-methyl]thiazolyl) thiocarbamoyl] imidazole(2.24 g, 10 mmol) and 2-(3methoxyphenyl)ethylamine (1.51 g, 10 mmol) in N,N-
X-8571A
-278dimethylformamide (25 mL) was stirred at 90°C for 3.5 h, the reaction was cooled to room temperature and the solvent removed in vacuo. The residue was crystallized from ethyl acetate to provide 2.73 g (89%) of the titled product:
IR (KBr, cm1) 3170, 3029, 1586, 1213, 749, 691;
3H NMR (300 MHz, DMSO-dg) δ 11.55 (br s, IH), 9.9 (br s,
IH), 7.2-6.8 (m, 4H), 6.65 (s, IH), 3.8 (m, 2H), 3.72 (s,
3H), 2.85 (t, J=7 Hz, 2H), 2.18 (s, 3H);
MS (FD) m/e 307 (M+>;
UV (EtOH) 292nm (£=16935), 258nm (£=9604), 202 nm (£=27197). Anal. Calcd for C14H17N3OS2:
Theory: C, 54.70; H, 5.57; N, 13.67.
Found: C, 54.97; H, 5.58; N, 13.60.
Example 174
N- f 2- (4-methoxvphenvl)ethvl)-N‘- 12-(4-methvl)thiazolyl1 thiourea
A solution of 1-((2-[4-methyl]thiazolyl) thiocarbamoyl] imidazole (2.24 g, 10 mmol) and 2-(420 methoxyphenyl)ethylamine (1.51 g, 10 mmol) in N,Ndimethylformamide (25 mL) was stirred at 90°C for 3 h, the reaction was cooled to room temperature and the solvent removed in vacuo. The residue was crystallized from ethyl acetate to provide 2.35 g (76%) of the titled product:
IR (KBr., cm’1) 3171, 3009, 1565, 1511 , 1218, 720, 514;
iH NMR (300 MHz, DMSO-dg) δ 11.55 (br s, IH), 9.9 (br s,
IH) , 7.2 (d, J=8 Hz, 2H), 6.9 (d, J=8 Hz, 2H) , 6. 65 (s,
IH) , 3.8 (m, 2H), 3.75 (s, 3H), 2 .85 (t, J=7 Hz, 2H), 2.18
(S, 3H) ;
MS (FD) m/e 307 (M+);
APO 00 3 8 4
X-8571A -279UV (EtOH) 292nm (€=18700), 258nm (€=11165), 223nm (€=14043), 201 nm (€=25520).
Anal. Calcd for C14H17N3OS2:
Theory: C, 54.70; H, 5.57; N, 13.67.
Found: C, 54.62; H, 5.55; N, 13.69.
Example.175
N-f2 - (4-.methvlphenv2) ethvl 1-Ν'- f2 - (4-methvl) thiazolvll thiourea
A solution of 2-(4-methylphenyl)ethyl isothiocyanate (1.0 g, 5.64 mmol) and 2-amino-4methylthiazole (0.644 g, 5.64 mmol) in N,Ndime thy If ormamide (20 mL) was heated to 90°C for 24 h. The solvent was removed in vacuo. The resultant solid was recrystallized from ethyl acetate to provide 0.67 g (41%) of the titled product as a white solid:
IR (KBr, cm'l) 3170, 3020, 1562, 1507, 1203, 986;
1h NMR (300 MHz, DMSO-d6) δ 11.55 (br s, IH), 9.9 (br s,
IH), 7.18 (d, J=8 Hz, 2H), 7.18 (d, J=8 Hz, 2H), 6.65 (s,
IH), 3.8 (m, 2H), 2.85 (t, J=7 Hz, 2H), 2.26 (s, 3H), 2.18 (S, 3H);
MS (FD) m/e 291 (M+);
UV (EtOH) 292nm (€=18863), 257nm (€=10889), 202 nm (€=21164).
Anal. Calcd for C14H17N3S2:
Theory: C, 57.70; H, 5.88; N, 14.42.
Found: C, 57.83; H, 5.90; N, 14.36.
X-8571A
-280Examp 16..176
Μ-(2-(2-methoxvphenvl)ethvll-Ν'-f2-(5-chloro)thiazolvll thiourea
A solution of 1-( (2-(5-chloro)thiazolyl) 5 thiocarbamoyl] imidazole (1.22 g, 5.0 mmol) and 2-(2methoxyphenyl)ethylamine (0.77 g, 5.0 mmol) in N,Ndimethylformamide (20 mL) was stirred at 90°C for 2 h. The reaction was cooled to room temperature, poured into ethyl acetate, washed with water, IN aqueous HCl, water, saturated sodium bicarbonate, and brine. The organic layer was concentrated and the residue recrystallized from ethyl acetate to provide 0.86 g (53%) of the titled product: mp 152-156°C;
IR (KBr, cm'1) 3313, 2835, 1608, 1527, 1514, 1441, 1352,
1244, 1040;
XH NMR (300 MHz, DMSO-c?6) δ 11.55 (br s, IH) , 8.4 (br s, IH), 7.4 (s, IH), 7.2-6.8 (m, 4H), 3.74 (s, 3H), 3.68 (m, 2H), 2.8 (t, J=7 Hz, 2H);
MS (FD) m/e 327 (M+);
UV (EtOH) 295nm (£=14366), 261 nm (£=12558), 203 nm (£=31267).
Example 177
Ν-.Γ2-(3-methoxvphenvl)ethvll-Ν'-(2-(5-chloro)thiazolvll thiourea
A solution of 1-[(2-[5-chloro]thiazolyl)thiocarbamoyl] imidazole (1.22 g, 5.0 mmol) and 2-(3methoxyphenyl)ethylamine (0.77 g, 5.0 mmol) in Ν,Ndimethylformamide (20 mL) was stirred at 90°C for 2 h. The reaction was cooled to room temperature, poured into ethyl acetate, washed with water, IN aqueous HCl, water,
AP Ο Ο Ο 3 8 4
Χ-8571Α
-281saturated sodium bicarbonate, and brine. The organic layer was concentrated and the residue recrystallized from ethyl acetate to provide 0.86 g (53%) of the titled product: mp 106-107°C;
IR (KBr, cm-1) 3334, 2826, 1611, 1517, 1332, 1259, 1156, 1051, 777;
1H NMR (300 MHz, DMSO-dg) δ 11.6 (br ε, IH) , 8.4 (br s,
IH), 7.4 (s, IH) , 7.18 (m, IH) , 6.77 (m, 3H) . 3.7 (m, 5H) ,
2.8 (t, J=7 Hz, 2H) ;
MS (FD) m/e 327 (M+) ;
UV (EtOH) 295nm (£=13695), 260 nm (£=11987), 203 nm (£=32295).
Anal. Calcd for C13H14N3OS2CI:
Theory: C, 47.63; H, 4.30; N, 12.81.
Found: C, 47.75; H, 4.41; N, 12.65.
Example, 17g
Ν-Γ2-(4-methoxvphenvl)ethvl)-Ν’ -(2-(5-chloro)thiazolyl) .thiourea
A solution of 1-[(2-[5-chloro]thiazolyl) thiocarbamoyl) imidazole (1.22 g, 5.0 mmol) and 2-(4methoxyphenyl) ethylamine (0.77 g, 5.0 mmol) in N,Ndimethylformamide (20 mL) was stirred at 90°C for 2 h. The reaction was cooled to room temperature, poured into ethyl acetate, washed with water, IN aqueous HCl, water, saturated sodium bicarbonate, and brine. The organic layer was concentrated and the residue recrystallized from ethyl acetate’ to provide 1.2 g (74%) of the titled product: mp 156-158°C;
IR (KBr, cm-1) 3315, 2934, 1601, 1511, 1320, 1243, 1180,
X-8571A
-282!η NMR (300 MHz, DMSO-dg) 6 11.6 (br s, IH), 8.4 (br s,
IH) , 7.4 (s, IH), 7.1 (d, J=8 Hz, 2H), 6.8 (d, J=8 Hz, 2H), 3.67 (s, 3H), 3.63 (m, 2H), 2.7 (t, J=7 Hz, 2H);
MS (FD) m/e 327 (M+);
UV (EtOH) 295nm (€=13569), 260 nm (€=12490), 223 nm (€=18432), 202 nm (€=28264).
Anal. Calcd for C13H14N3OS2CI:
Theory: C, 47.63; H, 4.30; N, 12.81.
Found: C, 47.59; H, 4.34; N, 12.53.
Example,,-!?. 9
N- f 2 - (1-cvclohexenvl)ethvl1-N'-f 2- (5-chloro)thiazolyl1 thiourea
A solution of 1-[(2-[5-chloro]thiazolyl) 15 thiocarbamoyl] imidazole (1.22 g, 5.0 mmol) and 2-(1cyclohexenyl)ethylamine (0.645 g, 5.0 mmol) in N,Ndimethylformamide (20 mL) was stirred at 90°C for 2 h. The reaction was cooled to room temperature, poured into ethyl acetate, washed with water, IN aqueous HCl, water, saturated sodium bicarbonate, and brine. The organic layer was concentrated and the residue recrystallized from methylene chloride to provide 0.83 g (55%) of the titled product:
mp 145-147 °C;
25 IR (KBr, cm-1) 3167, 2929, 1564, 1488, 1230, 1183, 1098,
1030, 685;
iH NMR (300 MHz, DMSO-dg) δ 11.6 (br s, IH), 8.4 (br s,
IH), 7.4 (S, IH), 5.4 (s, IH), 3.5 (m, 2H), 2.15 (t, J=7
Hz, 2H,, 1.9 (m, 4H), 1.5 (m, 4H) ;
MS (FD) m/e 301 (M+);
AP000384
Χ-8571Α
-283UV (EtOH) 295nm (£=14231), 259 nm (£=11275), 204 nm (£=20953).
Anal. Calcd for C12H16N3S2CI:
Theory: C, 47.75; H, 5.34; N, 13.92.
Found: C, 47.90; H, 5.47; N, 14.21.
Example ,180.
5-Benzyl-3=Dhenyl^2-thiohvdantoin A solution of DL-phenylalanine (1.65 g, 10 mmol), methyl N-phenyldithiocarbamate (1.85 g, 10 mmol), and triethylamine (1.4 mL, 10 mmol) in ethanol (30 mL) was heated at reflux for 5 h, the mixture was cooled to room temperature and the solvent removed in vacuo. The residue was dissolved in ethyl acetate, washed with IN aqueous HCl and water. The organic layer was concentrated and the residue recrystallized form ethanol to provide 2.48 g (88%) of the titled product:
mp 187-189°C;
MS (FD) m/e 282 (M+).
Example 181 l-f(2-f5-bromo) thiazolyl)thiocarbamovll imidazole
A solution of 1,1 *-thiocarbonyldiimidazole (9.9 g, 50 mmol) and 2-amino-5-bromothiazole (8.95 g, 50 mmol) in acetonitrile (200 mL) was stirred at 50°C for 24 h. The resulting precipitate was collected by filtration to provide 5.38 g (37%) of the titled product:
ΧΗ NMR (300 MHz, DMSO-dg) δ 9.3 (s, IH) , 8.25 (s, IK), 7.63 (s, IH), 7.43 (s, IH) ;
MS (FD) m/e 288, 290 (M+).
X-8571A
-284Example 182
Rr L2..-L2-chlorophenyl)ethvl 1-N'- f2-(5-bromo) thiazolvll thiourea
A solution of 1-[(2-[5-bromo]thiazolyl)5 thiocarbamoyl] imidazole (0.72 g, 2.5 mmol) and 2-(2chlorophenyl)ethylamine (0.40 g, 2.5 mmol) in N,Ndimethylformamide (15 mL) was stirred at 100 °C for 1 h.
The reaction was cooled to room temperature, poured into ethyl acetate, washed with water, IN aqueous HCl, water, saturated sodium bicarbonate, and brine. The organic layer was concentrated and the residue purified by chromatography on silica gel to provide 0.06 g (5%) of the titled product: IR (KBr, cm1) 3318, 2926, 1562, 1512, 1257, 1177, 1052, 749, 687;
!h NMR (300 MHz, DMSO-c?6) δ 11.6 (br s, IH) , 8.4 (br s,
IH) , 7.4-7.0 (m, 5H), 3.8 (m, 2H), 2.9 (t, J=7 Hz, 2H);
MS (FD) m/e 375, 377 (M+);
UV (EtOH) 291nm (£=15522), 258 nm (£=11594), 202 nm (£=28572) .
Example. 183
N--I2-- (3-rchlorophenvl)ethvl1 -N1 -(2- (5-bromo) thiazolyl 1 .thiourea
A solution of 1-[(2-[5-bromo]thiazolyl) 25 thiocarbamoyl] imidazole (0.72 g, 2.5 mmol) and 2-(3chlorophenyl)ethylamine (0.40 g, 2.5 mmol) in N,Ndimethylformamide (15 mL) was stirred at 100°C for 1 h.
The reaction was cooled to room temperature, poured into ethyl acetate, washed with water, IN aqueous HCl, water, saturated sodium bicarbonate, and brine. The organic layer was concentrated and the residue purified by chromatography
AP Ο Ο Ο 3 8 4
Χ-8571Α -285οη silica gel to provide 0.36 g (38%) of the titled product:
mp 141-145 °C;
IR (KBr, cm'1) 3168, 3019, 1568, 1514, 1331, 1251, 1189,
787, 686;
ΣΗ NMR (300 MHz, DMSO-dg) δ 11.6 (br s, IH) , 8.4 (br s,
IH), 7.44 (s, IH), 7.4-7.2 (m, 4H) , 3.7 (m. 2H) , 2.8 (t,
J=7 Hz, 2H);
MS (FD) m/e 377, 379 (M+) ;
UV (EtOH) 296nm (6=10140), 259 nm (6=8392), 201 nm (6=23984).
Example 18.4
N- (2.-..(4 rchlorophenvl) ethvl 1-N-?_(2 - (5-bromo) thiazolyl 1 is thiourea
A solution of 1-[ (2-(5-bromo]thiazolyl)thiocarbamoyl] imidazole (0.72 g, 2.5 mmol) and 2-(4chlorophenyl,ethylamine (0.40 g, 2.5 mmol) in N,Ndimethylformamide (15 mL) was stirred at 100°C for 1 h.
The reaction was cooled to room temperature, poured into ethyl acetate, washed with water, IN aqueous HCl, water, saturated sodium bicarbonate, and brine. The organic layer was concentrated and the residue purified by chromatography on silica gel to provide 0.32 g (34%) of the titled product:
mp 147-150°C;
IR (KBr, cm1) 3170, 3020, 1608, 1507, 1348, 1180, 745,
642;
1H NMR (300 MHz, DMSO-dg) δ 11.6 (br s, IH), 8.4 (br s,
IH), 7.44 (s, IH), 7.3 (d, J=8 Hz, 2HJ, 7.2 (d, J=8 Hz,
X-8571A
-286MS (FD) m/e 377, 379 (M+);
UV (EtOH) 296nm (£=14604), 259 nm (£=12656), 201 nm (£=28845) .
Example 185
N-f 2- (2-methoxyphenvl) ethvll-Ν'- f2- (5-bromo)thiazolyl1 thiourea
A solution of 1-[(2-(5-bromo]thiazolyl)thiocarbamoyl] imidazole (0.72 g, 2.5 mmol) and 2-(210 methoxyphenyl)ethylamine (0.41 g, 2.5 mmol) in Ν,Νdimethylformamide (15 mL) was stirred at 100 °C for 1 h.
The reaction was cooled to room temperature, poured into ethyl acetate, washed with water, IN aqueous HCl, water, saturated sodium bicarbonate, and brine. The organic layer was concentrated and the residue purified by chromatography on silica gel to provide 0.38 g (41%) of the titled product;
IR (KBr, cm-1) 3164, 2960, 1563, 1513, 1241, 1182, 1030, 757, 682;
!h NMR (300 MHz, CMSO-de) δ 11.6 (br s, IH), 8.4 (br s,
IH), 7.43 (s, IH), 7.4-7.0 (m, 4H), 3.73 (s, 3H), 3.7 (m,
2H), 2.9 (t, J=7 Hz, 2H);
MS (FD) m/e 371, 373 (M+);
UV (EtOH) 291nm (£=16746), 261 nm (£=13112), 202 nm (£=31492).
AP Ο Ο Ο 3 8 4
Χ-8571Α -287Example 186
Ν-12-i3rme.thoxyphe.nyl) ethyl.]-:N' -J2.-.i^.brom.o) thiazolyll thiourea
A solution of 1-[(2-[5-bromojthiazolyl)5 thiocarbamoyl] imidazole (0.72 g, 2.5 mmol) and 2-(3methoxyphenyliethylamine (0.41 g, 2.5 mmol) in N,Nd ime thyl formamide (15 mL) was stirred at 100°C for 1 h. The reaction was cooled to room temperature, poured into ethyl acetate, washed with water, IN aqueous HCl, water, saturated sodium bicarbonate, and brine. The organic layer was concentrated and the residue purified by chromatography on silica gel to provide 0.53 g (57%) of the titled product-:
IR (KBr, cm’1) 3174, 1558, 1510, 1339, 1238, 1175, 1041,
785. 688;
Th NMR (300 MHz, DMSO-dg) δ 11.6 (br s, IH), 8.4 (br s,
IH), 7.44 (s, IH), 7.3-6.8 (m, 4H), 3.7 (s, 3H), 3.7 (m,
2H), 2.9 (t, J=7 Hz, 2H);
MS (FD) m/e 371, 373 (M+);
uv (EtOH) 294nm (£=15068), 260 nm (£=12248), 202 nm (£=35594) .
Example. 187
N-.f.2- (IzmethoxYPhenvl) ethvl! -N1 - f2- (5-bromo) thiazolyll ihienrea.
A solution of 1-[(2-[5-bromo]thiazolyl)thiocarbamoyl] imidazole (0.72 g, 2.5 mmol) and 2-(3methoxyphenyl)ethylamine (0.41 g, 2.5 mmol) in N,Ndimethylformamide (15 mL) was stirred at 100°C for 1 h. The reaction was cooled to room temperature, poured into ethyl
X-8571A
-288saturated sodium bicarbonate, and brine. The organic layer was concentrated and the residue purified by chromatography on silica gel to provide 0.42 g (45%) of the titled product':
IR (KBr, cm1) 3170, 1558, 1512, 1343, 1246, 1163, 1082,
824;
NMR (300 MHz, DMSO-de) δ 11.6 (br s, IH), 8.4 (br s,
IH), 7.44 (s, 1Η), 7.1 (d, J=8 Hz, 2Η), 6.8 (d, J=8 Hz,
2H) , 3.67 (s, 3H), 3.63 (m, 2H), 2.9 (t, J=7 Hz, 2H) ;
MS (FD) m/e 371, 373 (M+);
UV (EtOH) 295nm (8=15314), 260 nm (8=13349), 222 nm (8=19619), 202 nm (8=30379).
Example 188
N-f2-(l-cvclohexenvl)ethvll-N*-f2- (5-bromo)thiazolvll ihiourea
A solution of 1-[(2-[5-bromo]thiazolyl) thiocarbamoyl] imidazole (0.72 g, 2.5 mmol) and 2-(1cyclohexenyl) ethylamine (0.32 g, 2.5 mmol) in N,N20 dimethylformamide (15 mL) was stirred at 100°C for 1 h.
The reaction was cooled to room temperature, poured into ethyl acetate, washed with water, IN aqueous HCl, water, saturated sodium bicarbonate, and brine. The organic layer was concentrated and the residue recrystallized from methylene chloride to provide 0.157 g (18%) of the titled product:
IR (KBr, cm1) 3170, 2928, 1559, 1510, 1478, 1344, 1228, 1182, 1096, 834;
1H NMR (300 MHz, DMSO-dg) δ 11.6 (br s, IH), 8.3 (br s,
IH), 7.4 (s, IH), 5.4 (s, IH), 3.5 (m, 2H), 2.15 (t, J=7 Hz, 2H), 1.9 (m, 4H), 1.5 (m, 4H);
AP 0 0 0 3 8 4
X-8571A
-289MS (FD) m/e 345, 347 (M+);
UV (EtOH) 295nm (£=15533), 259 nm (£=11792), 201nm (£=21261) .
Anal. Calcd for Ci2Hi6N3S2Br:
Theory: C, 41.62; H, 4.66; N, 12.13.
Found: C, 41.87; H, 4.91; N, 12.21.
Example, 189
N- f2- (l-Cvclohexenyl)ethvlJ--N, - Γ2- (5-bromo)pyridvll io thiourea
A stirred solution of 2-(1-cyclohexenyl)ethyl isothiocyanate (1.67 g, 10 mmol) and 2-amino-5bromopyridine (1.73 g, 10 mmol) in N-methylpyrrolidinone (20 mL) was heated to 100°C. After 17 h, the reaction was cooled to room temperature and poured into ethyl acetate. The organic phase was washed with IN hydrochloric acid, water (2x) and brine. The organic layer was dried over sodium sulfate, filtered and concentrated. .The solid obtained was purified by recrystallization from ethyl acetate to provide 1.08 g of the titled product (32%) as an off-white crystalline solid:
mp 166-167°C; IR (KBr, cm’1) 3159, 2927, 1595, 1561, 1531, 1475, 1310, 1228, 1092; 1H NMR (300 MHZ, DMSO-dg) δΐΐ. 09 (br s, IH),' 10.64 (s, IH), 8.20 (d, J=2.4 Hz, IH), 7.93 (dd,
J=8.9, 2.4 Hz, IH), 7.09 (d, J=9.0 Hz, IH), 5.47 (s, IH),
3.62-3.58 (m, 2H), 2.19 (t, J=6.7 Hz, 2H), 2.00-1.90 (m,
4H), 1.55-1.44 (m, 4H); MS (FD) m/e 339 (M+), 341 (M+2); UV (EtOH) 305nm (£=14037), 274nm (£=25281).
Anal. Calcd for Ci4Hi8BrN3S: C, 49.42; H, 5.33; N, 12.35.
Found: C, 49.22; H, 5.28; N, 12.32.
X-8571A
-290Examole 190
H- (2-iPhenethvl) -Ν ’ -1.2 - (4 -methyl) pvridvl 1 thiourea
A stirred solution of 2-phenethyl isothiocyanate (1.63 g, 10 mmol, 1.5 mL) and 2-amino-4-methylpyridine (1.08 g, 10 mmol) in N-methylpyrrolidinone (20 mL) was heated to 100eC. After 16.75 h, the reaction was cooled to room temperature and poured into ethyl acetate. The organic phase was washed with IN hydrochloric acid, water (3x) and brine. The organic layer was dried over sodium sulfate,
1C filtered and concentrated. The solid obtained was purified by recrystallization from ethyl acetate/hexanes to provide 1.69 g of the titled product (62%) as a white crystalline solid:
mp 151-153°C; IR (KBr, cm1) 3225, 1616, 1534, 1486, 1313,
1192, 1037;
!h NMR (300 MHZ, DMSO-dg) δ 11.72 (br s, IH) , 10.42 (s, IH) ,
7.87 (d. J=5.3 Hz, IH), 7.31-7.15 (m. 5H) , 6.88 (s, IH) ,
6.80 (d, J=5.2 Hz, IK), 3.81-3.76 (m, 2H) , 2.88 (t, J=7.0
Hz, 2H) , 2.20 (s, 3H); MS (FD) m/e 271 (M+) t
UV (EtOH) 290nm (£= 15080), 266pm (£= 15528), 247nm (ε= 13132), 202nm (£=21819).
Anal. Calcd for C15H17N3S: C, 66.38; H, 6.31; N, 15.48. Found: C, 66.09; H, 6.34; N, 15.71.
Example 191
N- (2-Phenethvl) -N’ - (2.-14,6-dimethyl)pvridvl1 thiourea
A stirred solution of 2-phenethyl isothiocyanate (1.63 g, 10 mmol, 1.5 mL) and 2-amino-4,6-dimethylpyridine (1.22 g, 10 mmol) in N-methylpyrrolidinone (20 mL) was heated to 100*C. After 16 h, the reaction was cooled to
AP Ο Ο Ο 3 8 4 η
Χ-8571Α -291phase was washed with IN hydrochloric acid, water (3x) and brine. The organic layer was dried over sodium sulfate, filtered and concentrated. The solid obtained was purified by recrystaliization from ethyl acetate/hexanes to provide
1.81 g of the titled product (63%) as an off-white crystalline solid:
mp 165-167°C; IR (KBr, cm'1) 3219, 1618, 1543, 1342, 1215; *Η NMR (300 MHZ, DMSO-dg) δ 11.83 (br s, IH) , 10.35 (s, IH) , 7.25-7.16 (m, 5H), 6.69 (s, IH) , 6.63 (s, IH), 3.88-3.82 (m, 2H), 2.89 (t, J=6.8 Hz, 2H) , 2.14 (s, 3H), 2.09 (s,
3H); MS (FD) m/e 285 (M+) ;
UV (EtOH) 294nm (€=17405), 266nm (€= 15904), 247nm (e= 14348), 203nm (€=23896).
Anal. Calcd for C^H^^S: C, 67.33; H, 6.71; N, 14.72.
Found: C, 67.11; H, 6.63; N, 14.71.
Example.192
Hrl2.-fh£afit,hYlI-N-' rl 2 r 13-hydroxy) pyridyl 1,. thiourea
A stirred solution of 2-phenethyl isothiocyanate (1.63 g, 10 mmol, 1.5 mL) and 2-amino-3-hydroxypyridine (1.10 g, 10 mmol) in N-methylpyrrolidinone (20 mL) was heated to 100°C. After 65.5 h, the reaction was cooled to room temperature and poured into ethyl acetate. The organic phase was washed with IN hydrochloric acid, water (3x) and brine. The organic layer was dried over sodium sulfate, filtered and concentrated. The solid obtained was purified by flash chromatography on silica gel (5% ethyl acetate/dichloromethane to 10% ethyl acetate) to provide
1.51 g of the titled product (55%). This material was recrystallized from ethyl acetate to provide 1.05 g of the titled product as an off-white crystalline solid:
X-8571A
-292mp 168-169°C;
IR (KBr, cm1) 3377, 1613, 1561, 1534, 1347, 1288, 1152;
NMR (300 MHZ, DMSO-df) 511.43 (br S, IH) , 10.94 (s, IH) ,
8.32 (s, IH), 7.54-7.52 (m, IH), 7.28-7.14 (m, 6H), 6.905 6.86 (m, IH) , 3.84-3.77 (m, 2H) , 2.90 (t, J=7.0 Hz, 2H) ;
MS (FD) m/e 273 (M+,;
UV (EtOH) 309nm (6= 17349), 261nm (6= 11851), 245nm (6= 17252), 204nm (6= 23596).
Anal. Calcd for C14H15N3OS: C, 61.51; H, 5.53; N, 15.37.
Found: C, 61.46; H, 5.52; N, 15.35.
Example 193
N- f 2- (2-Methoxvphenvl) ethvl 1 -N' - f 2- (5-bromo) pyridyll thiourea
A stirred solution of N-(thioimidazoyl)-2-(2methoxyphenyl)ethyl amine (2.61 g, 10 mmol) and 2-amino-5bromopyridine (1.73 g, 10 mmol) in Ν,Ν-dimethylformamide (25 mL) was heated to 90eC. After 65 h, the reaction was cooled to room temperature and poured into ethyl acetate.
The organic phase was washed with IN hydrochloric acid (2x) , water (2x) and brine. The organic layer was dried over sodium sulfate, filtered and concentrated. The solid obtained was purified by recrystallization from ethyl acetate to provide 1.78 g of the titled product (49%) as an off-white crystalline solid: mp 147-148°C;
IR (KBr, cm’1) 3224, 1596, 1530, 1492, 1459, 1229, 1191, 1038;
X-8571A
AP Ο Ο Ο 3 8 4
-293NMR (300 MHZ, DMSO-d$) δ 11.10 (br s, IH) , 10.63 (s, IH) ,
8.11 (d', J=2.3 Hz, IH) , 7.90 (dd, J=8.9, 2.6 Hz, IH) , 7.217.16 (m, 2H), 7.06 (d, J=8.9 Hz, IH) , 6.94-6.83 (m, 2H) , 3.78-3.73 (m, 2H) , 3.72 (s, 3H), 2.86 (t, J=6.8 Hz, 2H) ;
MS (FD) m/e 365 (M+), 367 (M+2);
UV (EtOH) 305nm (£=13279), 274nm (£=26971), 202nm (£=
28527) .
Anal. Calcd for Ci5Hi6BrN3OS: C, 49.19; H, 4.40; N, 11.47. Found: C, 48.97; H, 4.36; N, 11.66.
1C
Example ,194
N- f 2- (2 -Chlorophenvl) ethvl Ί -N' - f 2 - (5 -bromo) pvtidvl) thiourea
A stirred solution of N-(thioimidazoyl)-2-(215 chlorophenyl)ethyl amine (2.65 g, 10 mmol) and 2-amino-5bromopyridine (1.73 g, 10 mmol) in Ν,Ν-dimethylformamide (20 mL)'was heated to 90eC. After 64.75 h, the reaction was cooled to room temperature and poured into ethyl acetate. The organic phase was washed with water (4x) and brine. The organic layer was dried over sodium sulfate, filtered and concentrated. The solid obtained was purified by recrystallization from ethyl acetate/hexanes to provide
1.52 g of the titled product (41%) as a tan crystalline solid:
mp 160-161°C;
IR (KBr, cm-1) 3220, 1594, 1562, 1534, 1474, 1338, 1222, 1165, 1088;
X-8571A
-294NMR (300 MHZ, DMSO-d6) δ 11.16 (br S, IK) , 10.69 (s, IH) ,
8.15 (d, J=2.2 Hz, IH) , 7.93 (dd, J=8. .9, 2.4 Hz, IH), 7.41
7.38 (m, 2H) , 7.28- -7.23 (m, 2H), 7.08 (d, J=8.9 Hz, IH),
3.86- 3.80 (m, 2H), 3.04 (t, J=6.9 Hz, 2H) ;
MS (FD) m/e 369 (M+), 371 (M+2);
UV (EtOH) 306nm (€=14321), 275nm (€=24813), 257nm (ε= 16728), 201nm (€=27700).
Anal. Calcd for Ci4Hi3BrClN3S: C, 45.36; H, 3.53; N, 11.33. Found; C, 45.13; H, 3.60; N, 11.17.
Example 195
N-(2-Phenethyl)-Ν' -f2-(4-n-propvl)thiazolvll thiourea
A stirred solution of 2-phenethyl isothiocyanate (1.38 g, 8.44 mmol, 1.26 mL) and 2-amino-4-n-propylthiazole (1.2 g, 8.44 mmol) in N-methylpyrrolidinone (20 mL) was heated to 100’c. After 17 h, the reaction was cooled to room temperature and poured into ethyl acetate. The organic phase was washed with IN hydrochloric acid (2x) , water (2x) and brine. The organic layer was dried over sodium sulfate, filtered and concentrated. The solid obtained was purified by recrystallization from ethyl acetate/hexanes to provide 1.39 g of the titled product (54%) as a yellow crystalline solid:
mp 135-137°C;
IR (KBr, cm’1) 3175, 3027, 1562, 1529, 1507, 1216;
1h NMR (300 MHZ, DMSO-d€) δ 11.50 (br s, IH) , 9.93 (br s,
IH), 7.29-7.15 (m, 5H), 6.60 (s, IH), 3.79-3.73 (m, 2H), 2.85 (t, J=6.9 Hz, 2H) , 2.40 (t, J=7.4 Hz, 2H), 1.53-1.41 (m, 2H), 0.82 (t, J=7.3 Hz, 3H);
AP Ο Ο Ο 3 8 4
Ο
Χ-8571Α -295UV (EtOH) 292nm (€=19216), 257nm (€= 10283), 202nm (ε= 20314).
Anal. Calcd for C15H19N3S2: C, 58.98; H, 6.27; N, 13.76. Found: C, 59.17; H, 6.08; N, 13.55.
Example. ,19.6
N- (2-Phenethyl)-N1 - (2-(.3,5-dichloro) pyridvl 1 thiourea
A stirred solution of 2-phenethyl isothiocyanate (1.63 g, 10 mmol, 1.5 mL) and 2-amino-3,5-dichloropyridine (3.26 g, 20 mmol) in N-methylpyrrolidinone (20 mL) was heated to 125eC. After 16.5 h, the reaction was cooled to room temperature and poured into ethyl acetate. The organic phase was washed with water (5x) and brine. The organic layer was dried over sodium sulfate, filtered and concentrated. The solid obtained was purified by flash chromatography on silica gel (20% hexanes/dichloromethane) and then recrystallized from ethyl acetate/hexanes to provide 581 mg of the titled product (18%) as a white crystalline solid:
mp 102-104°C;
IR (KBr, cm’1) 3409, 3040, 1560, 1508, 1429, 1147, 1057; bR NMR (300 MHZ, DMSO-dg) δ 10.66 (s, IH) , 8.71 (s, IH) ,
8.27 (d, J=2.2 Hz, IH), 8.12 (d, J=2.2 Hz, IH) , 7.32-7.19 (m, 5H), 3.82-3.76 (m, 2H) , 2.90 (t, J=7.1 Hz, 2H) ;
MS (FD) m/e 325 (M+), 327 (M+2);
UV (EtOH) 311nm (€=8820), 276nm (€= 16571), 257nm (€=
13676) , 203nm (€=19245) .
Anal. Calcd for Ci4Hi3Cl2N3S: C, 51.54; H, 4.02; N, 12.88. Found: C, 51.32; H, 4.12; N, 12.69.
X-8571A
-29 6Example 19?
El·- (2-Phenethvl)-Ν'-f2-(4-n-butvl)thiazolyl) thiourea
A stirred solution of 2-phenethyl isothiocyanate (1.63 g, 10 mmol, 1.5 mL) and 2-amino-4-n-butylthiazole (1.56 g, 10 mmol) in N-methylpyrrolidinone (20 mL) was heated to lOO’c. After 16.5 h, the reaction was cooled to room temperature and poured into ethyl acetate. The organic phase was washed with IN hydrochloric acid (2x), water (2x) and brine. The organic layer was dried over sodium sulfate, filtered and concentrated. The solid obtained was purified by recrystallization from ethyl acetate/hexanes to provide 1.63 g of the titled product (51%) as a yellow crystalline solid:
mp 100-102’C;
IR (KBr, cm-1) 3027, 1560, 1529, 1262, 1212;
1H NMR (300 MHZ, DMSO-dg) 611.52 (br s, IH) , 9.89 (br s,
IH) , 7.29-7.15 (m. 5H), 6.59 (s, IH), 3.79- -3.73 (m, 2H),
2.86 (t, J=6.9 Hz, 2H), 2.45- -2.40 (m, 2H) , 1.50 -1.40 (m,
2H) , 1.29-1.19 (m, 2H), 0.84 (t, J=7.3 Hz, 3H) ;
MS (FD) ro/e 319 (M+ ) ;
UV (EtOH) 292nm (£= 19193), 258nm (£= 10262), 203nm (£= 20024) .
Anal. Calcd for C16H21N3S2: C, 60.15; H, 6.62; N, 13.15. Found: C, 59.86; H, 6.62; N, 12.99.
Example 198
Ν-Γ2-(l-Cvclohexenyllethvll-N·-Γ2-(4-n-propvl)thiazolyl) thiourea
A stirred solution of 2-(1-cyclohexenyl)ethyl 30 isothiocyanate (1.67 g, 10 mmol) and 2-amino-4-npropylthiazole (1.42 g, 10 mmol) in N-methylpyrrolidinone
AP Ο Ο Ο 3 8 4 ο
Χ-8571Α -297(20 mL) was heated to 100eC. After 40.5 h, the reaction was cooled to room temperature and poured into ethyl acetate. The organic phase was washed with IN hydrochloric acid (2x) , water (2x) and brine. The organic layer was dried over sodium sulfate, filtered and concentrated. The solid obtained was purified by recrystallization from ethyl acetate/hexanes to provide 1.26 g of the titled product (41%) as a yellow crystalline solid:
mp 152-153°C;
IR (KBr, cm’1) 3175, 2930, 1561, 1529, 1507, 1203;
l-H NMR (300 MHZ, DMSO-dg) δ 11.49 (br s, IH) , 9.90 (br s,
IH), 6.63 (s, IH), 5.42 (s, IH), 3.60-3.54 (m, 2H), 2.492.45 (m, 2H), 2.16 (t, J=6.5 Hz, 2H) , 1.95-1.88 (m, 4H) , 1.60-1.43 (m, 6H), 0.84 (t, J=7.3 Hz, 3H);
MS (FD) m/e 309 (M+);
UV (EtOH) 292nm, 257nm, 201nm.
Anal. Calcd for C15H23N3S2: C, 58.21; H, 7.49; N, 13.58. Found: C, 58.29; H, 7.58; N, 13.37.
Example 199
1^12-λ l-Cyclohexeriyl) ethvl Ί-Ν' -f2-(4-n-butvl)thiazolyl) thiaurea
A stirred solution of 2-(1-cyclohexenyl)ethyl isothiocyanate (1.67 g, 10 mmol) and 2-amino-4-n25 butylthiazole (1.56 g, 10 mmol) in N-methylpyrrolidinone (20 mL) was heated to 100*C. After 18 h, the reaction was cooled to room temperature and poured into ethyl acetate. The organic phase was washed with IN hydrochloric acid (2x) , water (2x) and brine. The organic layer was dried over sodium sulfate, filtered and concentrated. The solid obtained was purified by recrystallization from ethyl
X-8571A
-298acetate/hexanes to provide 1.02 g of the titled product (32%) as a yellow crystalline solid: mp 92-94°C;
IR (KBr, cm'1) 3174, 2927, 1583, 1532, 1507, 1466, 1203; 5 J-H NMR (300 MHZ, DMSO-dg) δ 11.73 (br s, IH) , 10.14 (br s,
IH) , 6.86 (s, IH), 5.65 (s, IH) , 3.83-3.78 (m, 2H), 2.75-
2.70 (m, 2H), 2.42-2.38 (m, 2H) , 2.18-2.10 (m, 4H), 1.81-
1.65 (m, 6H), 1.55-1.43 (m, 2H) , 1.08 (t, J=7.3 Hz, 3H) ;
MS (FD) m/e 323 (M+);
UV (EtOH) 292nm (€= 19266), 257nm (€=9555), 2Clnm (ε=
15788).
Anal. Calcd for Ci6H25N3S2: C, 59.40; H, 7.79; N, 12.99. Found: C, 59.56; H, 7.94; N, 13.00.
Example 200
Ν- Γ2- (1-Cvclohexenvl) ethvl 1 -Ν' - f2- (4-i-propvl) thiazolyl 1 .thiourea
A stirred solution of 2-(1-cyclohexenyl)ethyl isothiocyanate (1.67 g, 10 mmol) and 2-amino-4-i20 propylthiazole (1.42 g, 10 mmol) in W-methylpyrrolidinone (20 mL) was heated to 100’c. After 15.75 h, the reaction was cooled to room temperature and poured into ethyl acetate. The organic phase was washed with IN hydrochloric acid (2x), water (2x) and brine. The organic layer was dried over sodium sulfate, filtered and concentrated. The solid obtained was purified by recrystallization from ethyl acetate/hexanes to provide 1.01 g of the titled product (33%) as a pale yellow crystalline solid:
mp 110-112°C;
IR (KBr, cm'1) 3164, 2936, 1562, 1525, 1463, 1321, 1214;
AP Ο Ο Ο 3 8 4 η
Χ-8571Α -299ΧΗ NMR (300 MHZ, DMSO-dg) δ 11.50 (br S, 1Η) , 9.84 (br s,
IH), 6.61 is, IH), 5.41 (s, IH) , 3.61-3.55 tin, 2H>, 2.322.76 (m, IH), 2.17 (t, J=6.4 Hz, 2H), 1.94-1.88 tin, 4H5 ,
1.56-1.41 (m, 4H) , 1.14 (d, J=6.8 Hz, 6H) ;
MS (FD) ’ m/e 309 (M+) ;
UV (EtOH) 291nm (6= 202495, 256nm (6= 9969), 201nm (6=
15880).
Anal. Calcd for Ci5H23N3S2: C, 58.21; H, 7.49; N, 13.58. Found: C, 58.50; H, 7.63; N, 13.38.
Example 201
N-(2-Phenethyl)..-11/.-(2- (4-i-propvl)thiazolyl1 thiourea
A stirred solution of 2-phenethyl isothiocyanate (1.63 g, 10 mmol, 1.5 mL) and 2-amino-4-i-propyl thia zole (1.42 g, 10 mmol) in N-methylpyrrolidinone (20 mL) was heated to 100°C. After 17 h, the reaction was cooled to room temperature and poured into ethyl acetate. The organic phase was washed with N/10 hydrochloric acid (2x), water (2x) and brine. The organic layer was dried over sodium sulfate, filtered and concentrated. The solid obtained was purified by recrystallization from ethyl acetate/hexanes to provide 1.42 g of the titled product (46%) as a yellow crystalline solid:
mp 155-156°C;
IR (KBr, cm1) 3172, 2962, 1581, 1525, 1467, 1350, 1290, 1210;
3H NMR (300 MHZ, DMSO-dg) δ 11.52 (br s, IH), 9.89 (br s,
IH), 7.29-7.14 (m, 5H), 6.58 (s, IH) , 3.80-3.74 tin, 2H) , 2.87 (t, J=6.9 Hz, 2H), 2.76-2.71 (m, IH), 1.07 (d, J=6.8
Hz, 6H) ;
X-8571A
-300MS (FD) m/e 305 (M+);
UV (EtOH) 292nm (£= 19882), 257nm (£= 10580), 203nm (ε=
20047).
Anal. Calcd for C15H19N3S2: C, 58.98; H, 6.27; N, 13.76.
Found: C, 58.95; H, 6.39; N, 13.72.
Example 202
M-12-Phenethyl)-Ν'-Ϊ2-((4-qlvoxvlic acid)thiazolyl)1 thiourea
A solution of N-(2-phenethyl)-N'-(2-((4ethylglyoxylate)thiazolyl)] thiourea (1.30 g, 3.58 mmol) in ethanol (3 0 mL) was treated with IN sodium hydroxide and heated to reflux. After 1 h, the reaction was cooled to room temperature, diluted with water and washed wtih ethyl acetate (2x). The aqueous layer was acidified to pH 1 with hydrochloric acid and extracted with dichloromethane (2x). The organic layers were combined, washed with brine, dried over sodium sulfate, filtered and concentrated. The solid obtained was purified by triturating with ethyl acetate to yield 390 mg of the titled product (32%) as a light brown solid:
mp >170°C (d);
IR (KBr, cm-1) 3024, 1705, 1669, 1565, 1323, 1146;
^-H NMR (300 MHZ, DMSO-άζ) δ 12.2 (br s, IH) , 9.07 (s, IH) ,
8.01 (s, IH), 7.28-7.14 (m, 5H), 3.71-3.64 (m, 2H), 2.84 (t, J=7.3 Hz, 2H);
MS (FD) m/e 336 (M+1);
HRMS (FAB) m/e (M+1) calcd 336.0477, obs 336.0474;
UV (EtOH) 284nm (£=17301), 203nm (£=18110).
AP Ο Ο Ο 3 8 4
-301X-8571A
Example 2Q3
Ν- (2-Phenethyll -Hl.-f,2.-.i4-7methQxybgnzQ,thiaz.Q,lyl) 1 thiourea
A solution of 2-phenethyl isothiocyanate {3.26 g, 20 mmol, 3.0 mL) and 2-amino-4-methoxybenzothiazole (3.60 g, 20 mmol) in N,N-dimethylformamide (50 mL) was heated to 100°C. After 64 h, the reaction was cooled to room temperature and poured into ethyl acetate. The organic phase was washed with IN hydrochloric acid, saturated sodium bicarbonate solution, water (2x), and brine. The organic layer was filtered directly to provide 3.87 g of the titled product (56%) as a white solid: mp 209-211°C;
IR (KBr, cm-1) 3171, 2938, 1570, 1527, 1331, 1191, 1044;
NMR (300 MHZ, DMSO-dg) δ 11.88 (s, IH) , 9.86 (s, IH) ,
7.49-6.93 (m, 8H), 3.86 (s, 3H), 3.77-3.70 (m, 2H), 2.89 (t, J=7.1 Hz, 2H);
MS (FD) m/e 343 (M+);
HRMS (FAB) m/e (M+l) calcd 344.0891, obs 344.0884;
UV (EtOH) 290nm, 248nm, 210nm.
Example 2Q4
Nc. 12 r-Phenethyl.) -N.‘ -.12- LLS-ttrii luoromethyl ).,-1,3 ,..4 ?.
thiadiazolyl)) thiourea
A solution of 2-phenethyl isothiocyanate (3.26 g, 20 mmol, 3.0 mL) and 2-amino-5-trifluoromethyl-1,3,4thiadiazole (3.38 g, 20 mmol) in N,N-dimethylformamide (50 mL) was heated to 100°C. After 40 h, the reaction was cooled to room temperature and poured into ethyl acetate. The organic phase was washed with water (3x) and brine (2x). The organic layer was dried over sodium sulfate,
X-8571A
-302by flash chromatography on silica gel (5% ethyl acetate in dichloromethane) and then recrystallized from ethyl acetate to provide 171 mg of the titled product (3%) as a white solid:
mp 212-213°C;
IR {KBr, cm-1) 3336, 2788, 1629, 1534, 1494, 1398, 1327, 1148, 1038;
ΧΗ NMR (300 MHZ, DMSO-dg) δ 12.6 (br s, IH), 8.51 (s, IH),
7.30-7.15 (m, 5H) , 3.73-3.66 (m, 2H), 2.85 (t, J=7.3 Hz,
2H);
MS (FD) m/e 332 (M+) ;
UV (EtOH) 322nm (£=5240), 261nm (£= 11025), 204nm (£=28776). Anal. Calcd for C12H11F3N4S2: C, 43.36; H, 3.34; N, 16.86. Found: C, 43.20; H, 3.44; N, 16.86.
Example 205
N-(2-Phenethvl)-Ν' -Γ2- ((4-carboxvlic acid)thiazolyl)1 thiourea
A solution of N-(2-phenethyl)-Ν'-[2-(420 cyano)thiazolyl] thiourea (250 mg, 0.867 mmol) in glacial acetic acid (10 mL) and 5N hydrochloric acid (10 mL) was heated to reflux. After 16 h, the reaction was cooled to room temperature, diluted with acetonitrile and concentrated to dryness (2x). The solid obtained was purified by flash chromatography on silica gel (2% acetic acid in ethyl acetate) and then recrystallized from methanoi/ethyl acetate to provide 13 mg of the titled product. The mother liquor was concentrated and triturated with ethyl acetate to provide another 34 mg of the titled product, for a total yield of 47 mg (18%) as a white solid: mp >230°C;
AP Ο Ο Ο 3 8 4
Γ\
Χ-8571Α. -303IR (KBr,cm1) 3275, 1603, 1531, 1394, 1268;
Η NMR (300 MHZ, DMSO-dtf) δ 7.26-7.14 (m, 6Η) , 3.71-3.65 (m, 2Η) , 2.87 (t, J=7.2 Hz, 2H);
MS (FD) m/e 307 (M+);
HRMS (FAB) m/e (M+l) calcd 309.0527, obs 309.0528;
UV (EtOH) 288nm, 260nm, 206nm.
Example 2Q6
N-L2-ll-Cyclohexenvl) ethvl) -Ν' - f2- (6-fluorobenzothiazolvl 11 10 thiourea
A solution of 2-(1-cyclohexenyl)ethyl isothiocyanate (1.66 g, 9.93 mmol) and 2-amino-6fluorobenzothiazole (1.67 g, 9.93 mmol) in dimethyl sulfoxide (10 mL) was heated to 125°C. After 20 h, the reaction was cooled to room temperature and poured into ethyl acetate. The organic phase was washed with IN hydrochloric acid, water (3x), and brine. The organic layer was dried over sodium sulfate, filtered and concentrated. The solid obtained was purified by flash chromatography on silica gel (1% ethyl acetate in dichloromethane) and then recrystallized from ethyl acetate to provide 1.04 g of the titled product (31%) as a yellow crystalline solid: mp 200-201°C;
IR (KBr, cm’1) 3451, 3177, 3044, 2924, 2832, 1560, 1533,
1462, 1215, 1198;
^•H NMR (300 MHZ, CDCl3)6 10.83 (s, IH) , 10.33 (br s, IH) , 7.61-7.56 (m, IH), 7.41-7.37 (m, IH), 7.17-7.10 (m, IH) ,
5.65 (s, IH), 3.87-3.81 (m, 2H), 2.38 (t, J=6.5 Hz, 2H) , 2.03-2.00 (m, 4H), 1.67-1.52 (m, 4H);
X-8571A
-304UV (EtOH) 301nm, 218nm, 201nm.
Anal. Calcd for C16H18FN3S2: C, 57.29; H, 5.41; N, 12.53. Found: C, 57.58; H, 5.44; N, 12.42.
Example 2Q7
N-- (2-Phenethvl)-N1 -f2-(5-chlorothiazolvl) 1 thiourea
2-Amino-5-chlorothiazole hydrochloride (1.71 g, mmol) was slurried with dichloromethane and shaken with a slight excess of sodium hydroxide solution. The layers were separated and the aqueous washed with dichloromethane. The combined organics were dried over sodium sulfate, filtered and concentrated. To the resulting solid was added 2-phenethyl isothiocyanate (1.63 g, 10 mmol, 1.5 mL) and N-methyl-pyrrolidinone (20 mL). The resulting solution was heated to 100°C. After 20 h, the reaction was cooled to room temperature and poured into ethyl acetate. The organic phase was washed with IN hydrochloric acid, water (4x), and brine. The organic layer was dried over sodium sulfate, filtered and concentrated. The solid obtained was purified by flash chromatography on silica gel (2% ethyl acetate in dichloromethane) and then recrystallized twice from 1:1 ethyl acetate/hexanes to provide 187 mg of the titled product (6%) as a light brown crystalline solid: mp 163-164°C;
IR (KBr, cm1) 3312, 3028, 2925, 1607, 1527, 1513, 1438, 1377, 1348, 1314, 1026;
1H NMR (300 MHZ, DMSO-dg-) δ 11.60 (br s, IH) , 8.41 (s, IH) , 7.39 (s, IH), 7.30-7.15 (m, 5H) , 3.70-3.63 (m, 2H), 2.82 (t, J=7.2 Hz, 2H);
MS (FD) m/e 297 (M+), 299 (M+2);
UV (EtOH) 296nm (8=14487) , 260nm (8=12442) , 206nm (8=27427) .
AP Ο Ο Ο 3 8 4
S-\
Χ-8571Α -305Anal. Calcd for C12H12CIN3S2: C, 48.40; H, 4.06; N, 14.11. Found; C, 48.40; H, 4.16; N, 13.85.
Example,208
Ν- Γ2 - (1-Cvclohexenvl) ethvll -Ν' - 12- (.(,4 τ txi£luor.Qmethy 1) thiazolyl 11 thiourea
A solution of 2-(1-cyclohexenyl)ethyl isothiocyanate (1.67 g, 10 mmol) and 2-amino-4trifluoromethylthiazole (1.68 g, 10 mmol) in N10 methylpyrrolidinone (20 mL) was heated to 125°C. After 20 h, the reaction was cooled to room temperature and poured into ethyl acetate. The organic phase was washed with IN hydrochloric acid (2x) , water (3x), and brine. The organic layer was dried over sodium sulfate, filtered and concentrated. The solid obtained was purified by flash chromatography on silica gel (1% ethyl acetate in dichloromethane) and then recrystallized from 1:1 ethyl acetate/hexanes to provide 139 mg of the titled product (4%) as an off-white solid:
mp 153-154°C;
IR (KBr,cm'1) 3168, 2932, 1562, 1513, 1472, 1438, 1219, 1175, 1081;
3H NMR (300 MHZ, DMSO-dg) δ 11.95 (s, IH) , 8.21 (s, IH) ,
7.71 (s, IH), 5.41 (s, IH), 3.55-3.49 (m, 2H), 2.14 (t,
J=6.7 Hz, 2H), 1.93-1.83 (m, 4H), 1.56-1.41 (m, 4H);
MS (FD) m/e 335 (M+) ;
HRMS (FAB) m/e (M+l) calcd 336.0816, obs 336.0842;
UV (EtOH) 285nm (£=15215), 258nm (£=12868), 203nm (£=20271).
X-8571A
-306Example 2Q9
N-f 2- (2-chlorophenv1)ethvl1-N1 - ί 2 - ((4 trifluoromethyl)thiazolyl)1 thiourea A solution of 2-(2-chlorophenyl) ethyl amine (1.56 g, 10 mmol,1.41 mL) and N-(thioimidazoyl)-2-amino-4trifluoromethylthiazole (3.0 g, 10.8 mmol) in Ν,Νdimethylformamide (20 mL) was heated to 90-100°C. After 2 h, the reaction was cooled to room temperature and poured into ethyl acetate. The organic phase was washed with IN hydrochloric acid (2x), water (2x), and brine. The organic layer was dried over sodium sulfate, filtered and concentrated. The solid obtained was purified by flash chromatography on silica gel (1% ethyl acetate in dichloromethane) and then recrystallized from 1:1 ethyl acetate/hexanes to provide 870 mg of the titled product (24%) as a white crystalline solid: mp 187-188°C;
IR (KBr,cm-1) 3169, 3018, 1569, 1512, 1245, 1220, 1154, 1133, 1080;
1HNMR (300 MHZ, DMSO-dg) δ 11.92 (s, IH) , 8.32 (S, IH) ,
7.71 (s, IH), 7.41-7.22 (m, 4H) , 3.76-3.69 (m, 2H) , 2.97 (t, J=7.1 Hz, 2H);
MS (FD) m/e 365 (M+) ;
UV (EtOH) 285nm (£=13758) , 257nm (£=14164) , 202nm (£=30204 ) .
Anal. Calcd for C13H11F3CIN3S2: C, 42.68; H, 3.03; N,
11.49. Found: C, 42.82; H, 3.14; N, 11.68.
AP Ο Ο Ο 3 8 4
Χ-8571Α -307Examp 1. €-.2.,10
Ν-f 2- (4-Chlorophenvl)ethvl1-Ν'-f 2 - ((4 trifluoromethvl)thiazolyl)1 thiourea A solution of 2-(4-chlorophenyl)ethyl amine (1.56 g, 10 mmol, 1.40 mL) and N-(thioimidazoyl)-2-amino-4trifluoromethylthiazole (3.0 g, 10.8 mmol) in Ν,Νdimethylformamide (20 mL) was heated to 90-100°C. After 2 h, the reaction was cooled to room temperature and poured into ethyl acetate. The organic phase was washed with IN hydrochloric acid (2x), water (2x), and brine. The organic layer was dried over sodium sulfate,, filtered and concentrated. The solid obtained was purified by flash chromatography on silica gel (1% ethyl acetate in dichloromethane) and then recrystallized from 1:1 ethyl acetate/hexanes to provide 570 mg of the titled product (16%) as a white crystalline solid: mp 196-197°C;
IR (KBr, cm1) 3167, 3021, 1562, 1516, 1469, 1445, 1184, 1173, 1126, 1083;
IH NMR (300 MHZ, DMSO-dg) δ 11.91 (S, IH), 8.27 (s, IH) ,
7.71 (s, IH), 7.32 (d, J=8.4 Hz, 2H), 7.23 (d, J=8.4 Hz,
2H), 3.72-3.65 (m, 2H), 2.83 (t, J=7.0 Hz, 2H) ;
MS (FD) m/e 365 (M+);
UV (EtOH) 286nm (6=113 09) , 257nm (6=11445) , 202nm (6=21815 ) .
Anal. Calcd for C13H11F3CIN3S2: C, 42.68; H, 3.03; N,
11.49. Found: C, 42.87; H, 3.05; N, 11.46.
X-8571A
-308Examcle 211
Ν- f2-(3-Chlorophenvl)ethvll-Ν1 -f2-((4trifluoromethyl)thiazolyl)1 thiourea A solution of 2-(3-chlorophenyl)ethyl amine (1.56 g, 10 mmol, 1.40 mL) and N-(thioimidazoyl)-2-amino-4trifluoromethylthiazole (3.0 g, 10.8 mmol) in Ν,Νdimethylformamide (20 mL) was heated to 90-100°C. After 2 h, the reaction was cooled to room temperature and poured into ethyl acetate. The organic phase was washed with IN hydrochloric acid (2x), water (2x), and brine. The organic layer was dried over sodium sulfate, filtered and concentrated. The solid obtained was purified by flash chromatography on silica gel (1% ethyl acetate in dichloromethane) and then recrystallized from 1:1 ethyl acetate/hexanes to provide 407 mg of the titled product (11%) as a white crystalline solid: mp 159-160°C;
IR (KBr, cm-1) 3176, 3017, 1567, 1517, 1224, 1133, 1080;
1H NMR (300 MHZ, DMSO-dg) δ 11.93 (s, 1H) , 8.28 (s, 1H) ,
7.72 (s, 1H), 7.33-7.17 (m, 4H), 3.73-3.67 (m, 2H), 2.85 (t, J=7.0 Hz, 2H);
MS (FD) m/e 365 (M+), 367 (M+2);
UV (EtOH) 285nm (£=14175), 257nm (£=14293), 202nm (£=31514). Anal. Calcd for C13H11F3CIN3S2: C, 42.68; H, 3.03; N,
11.49. Found: C, 42.72; H, 3.09; N, 11.79.
Example 212
N- f2-(2-Methoxvphenvl)ethvll-N1 -f2-((4trifluoromethyl)thiazolyl)1 thiourea
A solution of 2-(2-methoxyphenyl)ethyl amine (1.51 g, 10 mmol, 1.46 mL) and N-(thioimidazoyl)-2-amino-4-
APO 0 0 3 8 4
X-8571A
-309trifluoromethylthiazole (3.0 g, 10.8 mmol) in Ν,Νdimethyl formamide (20 mL) was heated to 90-100°C. After 2 h, the reaction was cooled to room temperature and poured into ethyl acetate. The organic phase was washed with IN hydrochloric acid (2x), water (2x), and brine. The organic layer was dried over sodium sulfate, filtered and concentrated. The solid obtained was purified by flash chromatography on silica gel (2% ethyl acetate in dichloromethane) and then reorystallized from 1:1 ethyl acetate/hexanes to provide 872 mg of the titled product (24%) as a white crystalline solid: mp 184-184.5°C;
IR (KBr, cm'1) 3168, 2973, 1571, 1514, 1244, 1221, 1168, 1127, 1077;
i-H NMR -(300 MHZ, DMSO-dg·) δ 11.'β7 (s, IH) , 8.24 (s, IH) ,
7.71 (s, IH), 7.18-7.10 (m, 2H) , 6.94-6.82 (m, 2H), 3.74 (s, 3H), 3.68-3.61 (m, 2H), 2.80 (t, J=7.0 Hz, 2H);
MS (FD) m/e 361 (M+);
UV (EtOH) 280nm (€=16781), 259nm (€=15202) , 203nm (€=32863) .
Anal. Calcd for C14H14F3N3OS2: C, 46.53; H, 3.90; N, 11.63. Found: C, 46.52; H, 3.94; N, 11.52.
Example 213
N-f 2 - (3-MethQxyph.envl) ethvl 1-Ν' - f 2 - ((425 trifluoromethyl)thiazolyl)1 thiourea
A solution of 2-(3-methoxyphenyl)ethyl amine (1.51 g, 10 mmol, 1.45 mL) and N-(thioimidazoyl)-2-amino-4trifluoromethylthiazole (3.0 g, 10.8 mmol) in N,Ndimethylformamide (20 mL) was heated to 90-100°C. After 2 h, the reaction was cooled to room temperature and poured into ethy/ acetate. The organic phase was washed with IN
X-8571A
-310hydrochloric acid (2x), water (2x), and brine. The organic layer was dried over sodium sulfate, filtered and concentrated. The solid obtained was purified by flash chromatography on silica gel (2% ethyl acetate in dichloromethane) and then recrystallized from 1:1 ethyl acetate/hexanes to provide 1.32 g of the titled product (36%) as a white solid:
mp 139-14O°C;
IR (KBr, cm4) 3215, 3018, 1598, 1582, 1544, 1490, 1299,
1242, 1180, 1081;
1H NMR (300 MHZ, DMSO-dg) δ 11.93 (s, IH) , 8.26 (s, IH) ,
7.71 (s, IH), 7.18 (t, J=8.0 Hz, IH), 6.79-6.74 (m, 3H) , 3.73-3.66 (m, 2H), 3.69 (s, 3H), 2.80 (t, J=7.0 Hz, 2H) ;
MS (FD) m/e 361 (M+);
UV (EtOH) 281nm (€=15384), 258nm (€=14389), 202nm (€=35020).
Anal. Calcd for C14H14F3N3OS2: C, 46.53; H, 3.90; N, 11.63. Found: C, 46.76; H, 3.91; N, 11.52.
Example 214
N- f2-(4-Methoxvphenvl)ethvl)-Ν' -(2-((4triflupromethvl)thiazolyl) 1 thiourea
A solution of 2-(4-methoxyphenyl) ethyl amine (1.51 g, 10 mmol, 1.46 mL) and N-(thioimidazoyl)-2-amino-4trifluoromethylthiazole (3.0 g, 10.8 mmol) in N,N25 dimethylformamide (20 mL) was heated to 90-100°C. After 2 h, the reaction was cooled to room temperature and poured into ethyl acetate. The organic phase was washed with IN hydrochloric acid (2x), water (2x), and brine. The organic layer was dried over sodium sulfate, filtered and concentrated. The solid obtained was purified by flash chromatography on silica gel (2% ethyl acetate in
AP Ο Ο Ο 3 8 4
Χ-8571Α -311dichloromethane) and then recrystaiiized from 1:1 ethyl acetate/hexanes to provide 893 mg of the titled product (25%) as a white crystalline solid:
mp 169-170°C;
IR (KBr, cm'1) 3173, 3025, 1565, 1515, 1240, 1181, 1127,
1083;
NMR (300 MHZ, DMSO-dg) δ 11.90 (s, IH), 8.26 (S, IH),
7.71 (s, IH), 7.12 (d, J=8.5 Hz, 2H), 6.83 (d, J=8.5 Hz, 2H), 3.67 (s, 3H), 3.67-3.61 (m, 2H), 2.76 (t, J=7.1 Hz,
2H);
MS (FD) m/e 361 (M+) ;
UV (EtOH) 284nm (£=15865), 258nm (£=14872), 224nm (£=16821), 201nm (£=29323) .
Anal. Calcd for C14H14F3N3OS2: C, 46.53; H, 3.90; N, 11.63. 15 Found: C, 46.70; H, 3.89; N, 11.50.
Example 215
N- f.2- (l-Cvclohexenvl)ethvl)-N* -f2- ((4,5dimethvl)thiazolyl)1 thiourea
2-Amino-4,5-dimethylthiazole hydrochloride (1.65 g, 10 mmol) was slurried with dichloromethane and shaken with a mixture of sodium hydroxide/saturated sodium bicarbonate solution. The organics were washed with brine, dried over sodium sulfate, filtered and concentrated. To the resulting solid was added 2-(1-cyclohexenyl) ethyl isothiocyanate (1.67 g, 10 mmol) and N-methylpyrrolidinone (20 mL) . The resulting solution was heated to 105° C. After 20 h, the reaction was cooled to room temperature and poured into ethyl acetate. The organic phase was washed with IN hydrochloric acid (2x), water (2x) , and brine. The organic layer was dried over sodium sulfate, filtered and_
X-8571A
-312concentrated. The solid obtained was purified by recrystallization from 2:1 ethyl acetate/hexanes to provide 1.57 g of the titled product (53%) as a light yellow crystalline solid:
mp 162-164°C;
IR (KBr, cm-1) 3170, 2917, 1583, 1554, 1514, 1433, 1325, 1255, 1215;
1H NMR (300 MHZ, DMSO-dg) 5 11.35 (s, IH) , 9.83 (br s, IH) ,
5.43 (s, IH), 3.58-3.52 (m, 2H), 2.17-2.11 (m, 5H), 2.07 (s, 3H), 1.94-1.89 (m, 4H) , 1.57-1.44 (m, 4H);
MS (FD) m/e 295 (M+);
UV (EtOH) 297nm (£=18557), 256nm (£=9443), 201nm (£=16880). Anal. Calcd for C14H21N3S2: C, 56.91; H, 7.16; N, 14.22. Found: C, 57.10; H, 7.28; N, 14.36.
Examplg 216
N- f2- (3-Ethoxv-4^methoxvphenvl)ethvll-Ν' -(2-thiazolvl)
PhiQurea
A solution of 2-(3-ethoxy-4-methoxyphenyl) ethyl amine (1.00 g, 5.12 mmol) and N-(thioimidazoyl)-2aminothiazole (1.08 g, 5.12 mmol) in Ν,Ν-dimethylformamide (20 mL) was heated to 90-100°C. After 16 h, the reaction was cooled to room temperature and poured into ethyl acetate. The organic phase was washed with IN hydrochloric acid (2x), water (2x), and brine. The organic layer was dried over sodium sulfate, filtered and concentrated. The solid obtained was purified by recrystallization from dichloromethane/ethyl acetate to provide 471 mg of the titled product (27%) as an off-white solid:
mp 150-152°C;
AP Ο Ο Ο 3 8 4
Χ-8571Α -313IR (KBr, cm'1) 3176, 3112, 3040, 1575, 1514, 1469, 1261, 1235, 1140, 1042;
^Η NMR (300 MHZ, DMSO-dg) δ 11.51 (s, IH) , 9.73 (br s, IH) ,
7.28 (d, J=3.6 Hz, 1 H), 7.07 (s, IH), 6.90-6.78 (m, 2H) ,
6.72 (d, J=8.2 Hz, IH), 4.00-3.88 (m, 2H), 3.80-3.67 (m,
5H), 2.76 (t, J=6.9 Hz, 2H), 1.25 (t, J=6.9 Hz, 3H);
MS (FD) m/e 337 (M+);
UV (EtOH) 287nm (€=21828), 259nm (€=11770), 205nm (€=35881). Anal. Calcd for C15H19N3O2S2: C, 53.39; H, 5.67; N, 12.45.
Found: C, 53.10; H, 5.64; N, 12.22.
Example 217
N- f 2 - (3-Methoxy-4-isopropoxvphenyl) ethvl I-N ' 7l2rtiiiazQly-U thiourea
A solution of 2-(3-methoxy-4-isopropoxyphenyl) ethyl amine (1.00 g, 4.78 mmol) and N{thioimidazoyl)-2-aminothiazole (1.00 g, 4.78 mmol) in N,NdimethyIformamide (20 mL) was heated to 90-95°C. After 24 h, the reaction was cooled to room temperature and poured into ethyl acetate. The organic phase was washed with IN hydrochloric acid (2x), water (2x), and brine. The organic layer was dried over sodium sulfate, filtered and concentrated. The solid obtained was purified by recrystallization from ethyl acetate to provide 891 mg of the titled product (53%) as yellowish needles. A sample was recrystallized a second time from ethyl acetate: mp 140-141°C;
IR (KBr, cm1) 3165, 2971, 1560, 1516, 1466, 1266, 1182,
X-8571A
-314!h NMR (3 00 MHZ, DMSO-dg) δ 11.53 (s, IH) , 9.71 (br S, IH) ,
7.28 (d, J=3.6 Hz, IH), 7.06 (s, IH), 6.84-6.81 (m, 2H)
6.71-6.68 (m, IH), 4.45 -4.37 (m, IH), 3.74-3.66 (m, 5H)
2.77 (t, J=7.0 Hz, 2H), 1.17 (d, J=6.0 Hz, 6H);
MS (FD) m/e 351 (M+) ;
UV (EtOH) 286nm, 258nm, 204nm
Anal. Calcd for C16H21N3O2S2: C, 54.68; H, 6.02; N, 11.96. Found: C, 54.79; H, 6.11; N, 12.21.
Example 218
N-f2-(3.4-dichlorophenvl)ethvll-N‘- (2-thiazolvl1.thiourea
2-(3, 4-Dichlorophenyl)ethyl amine hydrochloride (1.00 g, 4.41 mmol) was slurried in dichioromethane and shaken with a slight excess of sodium hydroxide solution.
The layers were separated and the organics were dried over sodium sulfate, filtered and concentrated. N(thioimidazoyl)-2-aminothiazole (928 mg, 4.41 mmol) and N,N-dimethylformamide (20 mL) were added to the resulting oil. This solution was heated to 90-100°C. After 18 h, the reaction was cooled to room temperature and poured into ethyl acetate. The organic phase was washed with IN hydrochloric acid (2x), water (2x), and brine. The organic layer was dried over sodium sulfate, filtered and concentrated. The solid obtained was purified by flash chromatography on silica gel (2% ethyl acetate/dichloromethane) to provide 1.0 g of 3 (68%) as a white solid. This solid was recrystallized from ethyl acetate to provide 700 mg of the titled product as a white crystalline solid:
mp 159.5-160°C;
AP Ο Ο Ο 3 8 4
Χ-8571Α
-315IR (KBr, cm1) 3175, 1577, 1515, iH NMR (300 MHZ, DMSO-dg) δΐΐ.55
7.54-7.48 (m, 2H), 7.30-7.21 <m, 3.70 (m, 2H), 2.87 (t, J=6.9 Hz, MS (FD) m/e 331 (M+);
UV (EtOH) 289nm (€=19623) , 265nm
1472, 1328, 1190, 1029; (s, IH), 9.63 (br s, IH) ,
2H), 7.06 (s, IH), 3.772H) ;
(€=11818), 204nm (€=36059).
Anal. Calcd for C12H11CI2N3S2: C, 43.38; H, 3.34; N, 12.65.
Found: C, 43.14; H, 3.36; N, 12.63.
Example. ...219
N- f2- (2-methvl-3-trifluoromethylphenyl) ethyl! -N1 - (2thiazolyl). ..thiourea
2- (2-Methyl-3-trifluoromethylphenyl)ethyl amine hydrochloride (1.00 g, 4.17 mmol) was slurried in dichloromethane and shaken with a slight excess of sodium hydroxide solution. The layers were separated and the organics were dried over magnesium sulfate, filtered and concentrated. N- (thioimidazoyl)-2-aminothiazole (877 mg,
4.17 mmol) and N, N-dimethyl formamide (20 mL) were added to the resulting oil. This solution was heated to 90-100°C.
After 65 h, the reaction was cooled to room temperature and poured into ethyl acetate. The organic phase was washed with IN hydrochloric acid (2x), water, and brine. The organic layer was dried over sodium sulfate, filtered and concentrated. The solid obtained was purified by flash chromatography on silica gel (2% ethyl acetate/dichloromethane) and then recrystallized from ethyl acetate (1st crop) or 1:1 ethyl acetate/hexanes (2nd crop) to provide 581 mg of the titled product (40%) as a white solid:
X-8571A
-316mp 158-159°C;
IR (KBr,cm'1) 3178, 3130, 2994, 1566, 1514, 1473, 1321, 1161, 1120;
NMR (300 MHZ, DMSO-dg) δ 11.60 (S, IH) , 9.76 (br S, IH) ,
7.52-7.47 (m, 2H) , 7.33-7.28 (m, 2H), 7.07 (s, IH), 3.753.68 (m, 2H), 2.98 (t, J=7.4 Hz, 2H), 2.40 (s, 3H);
MS (FD) m/e 345 (M+) ;
UV (EtOH) 289nm (£=19176) , 258nm (£=11507) , 203nm (£=21953 ) . Anal. Calcd for C14H14F3N3S2: C,48.68; H,4.08; N,12.16.
Found: C,48.89; H,4.06; N,12.14.
Example 22Q
N-f2- (3-(3,3,3-trifluoro)propvlohenvl)ethvll-N'- (2th iaz o 1 y.1 ) ...xhi gur ea
2-(3- (3,3,3-trifluoro)propylphenyl)ethyl amine tosylate (1.00 g, 2.57 mmol) was slurried in dichloromethane and shaken with a slight excess of sodium hydroxide solution. The layers were separated and the aqueous was extracted with dichlororaethane. The combined organics were dried over magnesium sulfate, filtered and concentrated. N-(thioimidazoyl)-2-aminothiazole (540 mg, 2.57 mmol) and N,N-dimethylformamide (20 mL) were added to the resulting oil. This solution was heated to 90-95°C.
r
After 1 h, the reaction was cooled to room temperature and poured into ethyl acetate. The organic phase was washed with IN hydrochloric acid (2x), water (2x), and brine. The organic layer was dried over sodium sulfate, filtered and concentrated. The solid obtained was purified by _recrystallization from 40% ethyl acetate/hexanes to provide
AP Ο Ο Ο 3 8 4 η
Χ-8571Α -317508 mg of the titled product (55%) as an off-white crystalline solid: mp 138-139°C;
IR (CHCI3, cm-1·) 3192, 3058, 2979, 1567, 1514, 1259, 1139;
NMR (300 MHZ, DMSO-dg) δ 11.53 (s, IH) , 9.73 (hrs, IH) ,
7.29-7.06 (m, 6H), 3.75-3.69 (m, 2H), 2.83 (t, J=7.0 Hz,
2H), 2.77-2.71 (m, 2H), 2.57-2.45 (m, 2H);
MS (FD) m/e 359 (M+) ;
UV (EtOH) 288nm (£=19255) , 257nm (£=11152) , 203nm (£=21782) .
Anal. Calcd for C15H16F3N3S2: C, 50.13; H, 4.45; N, 11.69. Found: C, 50.36; H, 4.45; N, 11.46.
Example 221
N- (2-(l-Cvclohexenvl) ethvl)-N* - f2-pvridvn thiourea
A solution of 2-(1-cyclohexenyl) ethyl isothiocyanate (1.67 g, 10 mmol) and 2-aminopyridine (941 mg, 10 mmol) in W-methylpyrrolidinone (20 mL) was heated to 100°C. After 16.5 h, the reaction was cooled to room temperature and poured into ethyl acetate. The organic phase was washed with water (4x) and brine. The organic layer was dried over sodium sulfate, filtered and concentrated. The solid obtained was purified by · recrystallization from ethyl acetate to provide 1.31 g of the titled product (50%) as a white crystalline solid:
mp 153-155°C;
IR (KBr, cm-1) 3219, 2921, 1605, 1569, 1537, 1481, 1319, 1235, 1181, 1092;
X-8571A -318^-H NMR (300 MHZ, DMSO-dg) δ 11.55 (S, IH) , 10.47 (s, IH) , 8.09 (d, J=3.9 Hz, IH) , 7.74-7.68 (m, IH) , 7.09 (d, J = 8.3 Hz, IH), 7.00-6.96 (m, IH), 5.47 (s, IH) , 3.65-3.59 (m,
2H), 2.19 (t, J=6.6 Hz, 2H), 1.94-1.90 (m, 4H), 1.55-1.43 (m, 4H);
MS (FD) m/e 261 (M+);
UV (EtOH) 292nm (8=15926), 265nm (8=17724), 247nm (8=15198). Anal. Calcd for C14H19N3S: C, 64.33; H, 7.33; N, 16.08. Found: C, 64.12; H, 7.33; N, 15.89.
Example 222
N- (2-phenethv-l)^N'_- f 2- (5-bromo) pvridvl I thiourea
A solution of 2-phenethyl isothiocyanate (1.63 g, 10 mmol, 1.5 'mL) and 2-amino-5-bromopyridine (1.73 g, 10 mmol) in N-methylpyrrolidinone (20 mL) was heated to 100°C.
After 22 h, the reaction was cooled to room temperature and poured into ethyl acetate. The organic phase was washed with IN hydrochloric acid (2x), water (2x) and brine. The organic layer was dried over sodium sulfate, filtered and concentrated. The solid obtained was purified by recrystallization from ethyl acetate/hexanes to provide
1.20 g of the titled product (36%) as a white crystalline solid:
mp 160-162°C;
IR (KBr, cm*1) 3028, 1595, 1559, 1531, 1475, 1311, 1228, 1092;
1H NMR (300 MHZ, DMSO-dg) δ 11.16 (s, IH) , 10.65 (s, IH) ,
8.11 (d, J=2.1 Hz, IH), 7.93-7.90 (m, IH), 7.29-7.18 (m,
5H), 7.05 (d, J=8.8 Hz, IH), 3.82-3.77 (m, 2H), 2.88 (t,
J=7.0 Hz, 2H);
AP Ο Ο Ο 3 8 4
Χ-8571Α -319MS (FD) m/e 335 (Μ+), 337 (M+2);
UV (EtOH) 305nm (6=14171) , 275nm (6=24881) , 201nm (6=21601) . Anal. Calcd for Ci4Hi4BrN3S: C, 50.01; H, 4.20; N, 12.50. Found: C, 49.93; H, 4.19; N, 12.52.
Example 223
N- f 2- (1-Cvclohexenvl) ethvll-N* -(2 - (5-cvano).pyridvl) thiourea
A stirred solution of 2-(1-cyclohexenyl)ethyl isothiocyanate (1.36 g, 8.14 mmol) and 2-amino-5cyanopyridine (0.97 g, 8.14 mmol) in N-methylpyrrolidinone (20 mL) was heated to 100°C. After 5 days, the reaction was cooled to room temperature and poured into EtOAc. The organic phase was washed with H2O (4x) and brine. The organic layer was dried over Na2SO4, filtered and concentrated. The solid obtained was purified by flash chromatography on silica gel (2% EtOAc/CH2Cl2), followed by recrystallization with EtOAc/hexanes to provide 78 mg of the titled product (3%) as an off-white solid:
mp 195-197°C;
IR (KBr, cm1) 2927, 2224, 1605, 1570, 1533, 1487, 1369, 1228, 1165;
1H NMR '(300 MHZ, DMSO-dg) δ 11.17 (br s, IH) , 10.96 (s,
IH), 8.57 (d, J=1.9 Hz, IH) , 8.12 (dd, J=8.8, 2.1 Hz, IH),
7.20 (d, J=8.8 Hz, IH), 5.47 (s, IH) , 3.66-3.59 (m, 2H) ,
2.20 (t, J=6.6 Hz, 2H), 1.94-1.89 (m, 4H), 1.54-1.43 (m,
4H) ;
MS (FD) m/e 286 (M+);
UV (EtOH) 308nm, 202nm.
Anal. Calcd for C15H18N4S: C, 62.91; H, 6.34; N, 19.56. Found: C, 62.70; H, 6.42; N, 19.42.
Χ-8571Α
-32010
Example 224
NrJ2-Phenethvl) .-211-712- (4- (4-biphenvl) thiazolyl 1 thiourea
A solution of 2-phenethyl isothiocyanate (0.82 g, 5 mmol, 0.75 mL) and 2-amino-4-(4-biphenyl)thiazole (1.26 g, 5 mmol) in Ν,Ν-dimethylformamide (12.5 mL) was heated to 100°C. After 19.5 h, the reaction was cooled to room temperature and poured into ethyl acetate. The organic solution was washed with IN hydrochloric acid. The mixture was filtered and the filtrate was separated and the organic phase washed with saturated sodium bicarbonate solution, water (4x) and brine. The organic layer was dried over sodium sulfate, filtered and concentrated. The material was purified by flash chromatography on silica gel (1% ethyl acetate in dichloromethane to 2% ethyl acetate in dichloromethane) to provide 372 mg of the titled product (18%). The yellow solid was recrystallized from ethyl acetate:
mp 208.5-209’C;
IR (KBr, cm*1) 3437, 3172, 3029, 1570, 1553, 1511, 1211,
1060, 738;
!h NMR (300 MHz, DMSO-dg) δ 11.72 7.86-7.80 (m, 2H), 7.78-7.68 (m, 7.44 (m, 2H), 7.41-7.35 (m, IH), 7.20 (m, IH), 3.92-3.84 (m, 2H), MS (FD) m/e 415 (M+);
UV (EtOH) 293nm, 212nm.
(s, IH) , 9.54 (br s, IH) , 4H), 7.58 (s, IH), 7,527.34-7.29 (m, 4H), 7.272.98 (t, J=3 Hz, 2H);
Anal. Calcd for C24H21N3S2: C, 69.36; H, 5.09; N, 10.11. Found: . C, 69.08; H, 5.10; N, 9.99.
AP Ο Ο Ο 3 8 4
Χ-8571Α
-321Example, 225.
Ν- (2-Phenethvl) -Ν1 -2-Γ4-(4-pvridvl) thiazolylthiourea
2-Amino-4-(4-pyridyl)thiazole hydrobromide was slurried with methylene chloride and shaken with saturated sodium bicarbonate solution. The layers were separated and the aqueous washed with methylene chloride and ethyl acetate. The combined organic layers were concentrated. To the solid (1.0 g, 5.6 mmol) was added 2-phenethyl isothiocyanate (0.91 g, 5.6 mmol, 0.83mL) in N,N10 dimethylformamide (12.5 mL). The resulting suspension was heated to 100°C. After 20.5 h, the reaction was cooled to room temperature and poured into ethyl acetate. The organic phase was washed with water (4x) and brine. The organic layer was dried over sodium sulfate, filtered and concentrated. The resulting solid was recrystallized from ethyl acetate (3x) to provide 133 mg (7%) of the titled product:
mp 196.5°C;
IR (KBr·, cm’1) 3250, 2939, 1723, 1604, 1506, 1223, 670,
664;
Ih NMR (300 MHz, DMSO-dg) δ 11.72 (s, IH), 9.21 (br s, IH),
8.54 (d, J=6 Hz, 2H) , 7.82 (s, IH) , 7.63 (d, J=6 Hz, 2.H) ,
7.30-7.15 (m, 5H), 3.84-3.77 (m, 2H), 2.89 (t, J=7 Hz, 2H); MS (FD) m/e 340 (M+);
HRMS (FAB) m/e (M+) calcd 341.0895, obs 341.0905;
_UV (EtOH) 294nm (£=23935), 231nm (£=16356), 203nm (£=25793 K
X-8571A
-322Example 226
Nri2-Phenethyl)-Ν'-2-Γ4-(1-(1-ethvoxvcarbonvl)-(3-tbutoxycarbonylmethoxv)imino)thiazolyll thiourea
2-Amino-4-{1-(1-ethoxycarbony1)-(3-tbutoxycarbonylmethoxy)imino)thiazole (2.64 g, 8 mmol) and 2-phenethyl isothiocyanate (1.31 g, 8 mmol, 1.2 mL) in N,N~ dimethylformamide (20 mL) were heated to 100°C. After 24 h, the reaction was cooled to room temperature and poured into ethyl acetate. The organic phase was washed with IN hydrochloric acid, saturated sodium bicarbonate solution, water (3x) and brine. The organic layer was dried over sodium sulfate, filtered and concentrated. The resulting solid was triturated with ethyl acetate to provide 801 mg (20%) of the titled product:
mp 188.5°C;
IR (KBr, cm’1) 3293, 2975, 1749, 1594, 1543, 1453, 13S2, 1231, 1154, 1054, 748, 698;
Th NMR (300 MHZ, DMSO-dg) δ 11.85 (s, IH), 8.46 (br s,lH), 7.29-7.17 (m, 5H), 4.59 (s, 2H), 4.31-4.24 (q, J=7.1 Hz,
2H) , 3.70-3.64 (m, 2H) , 2.82 (t, J=7.1 Hz, 2H), 1.36 (s,
9H), 1.23 (t, J= 7.1 Hz, 3H);
MS (FD) m/e 492 (M+);
UV (EtOH) 292nm, 257nm (e=16356), 203nm.
Anal. Calcd for C22H28N4O5S2: C, 53.64; H, 5.73; N, 11.37. Found: C, 53.67; H, 5.83; N, 11.34.
Example 227
N-(2-Phenethyl)-Ν' -2-f4-t-butvl-5-methvlthiazolyl) thiourea
2-Amino-4-t-butyl-5-methylthiazole (1.87 g, 11 mmol) and 2-phenethyl isothiocyanate (1.80 g, 11 mmol, 1.64 mL) in N, N-dimethylformamide (25 mL) were heated to 100°C.
AP Ο Ο Ο 3 8 4
Χ-8571Α
-323After 18.5 h, the reaction was cooled to room temperature and poured into ethyl acetate. The organic phase was washed with IN hydrochloric acid, saturated sodium bicarbonate solution, water (3x) and brine. The organic layer was dried over sodium sulfate, filtered and concentrated. The resulting solid was triturated with ether to provide 1.02 g (28%) of the titled product:
mp 153-153.5°C;
IR (KBr, cm-1, 3171, 2966, 1474, 1534, 1510, 1455, 1346,
1221, 1186, 755, 704;
iH NMR (300 MHz, DMSO-d6> δ 11.28 (BR S, IH) , 9.90 (BR S,
IH), 7.28-7.14 (Μ, 5H), 3.78-3.34 (Μ, 2H), 2.84 (T, J=7 Hz, 2H), 2.27 (s, 3H), 1.16 (ε, 9H) ;
MS (FD) m/e 333 (M+);
UV (EtOH) 297nm (£=19835), 257nm (£=9954), 202nm (£=21059). Anal. Calcd for C3.7H23N3S2: C, 61.22; H, 6.95; N, 12.60. Found: C, 61.42; H, 6.92; N, 12.55.
Example.2,28
N-¢2-Phenethyl) -N1 -2-Γ4-(4-bromophenvl)-S-ethvlthiazolvll xhipurea
2-Amino-4- (4-bromophenyl) - 5-ethylthiazole (848 mg, 3 mmol) and 2-phenethyl isothiocyanate (490 mg, 3 mmol,
0.45 mL) in N,N-dimethylformamide (7.5 mL) were heated to
100°C. After 22.5 h, the reaction was cooled to room temperature and poured into ethyl acetate. The organic phase was washed with IN hydrochloric acid, saturated sodium bicarbonate solution, water (3x) and brine. The organic layer was dried over sodium sulfate, filtered and
30_ concentrated. The resulting solid was recrystallized from
X-8571A
-324 ethyl acetate and toluene to provide 146 mg (11%) of the titled product: mp 169-170°C;
IR (KBr, cm1) 3169, 3025, 2969, 2930, 1581, 1558, 1520,
1234, 1168, 1009;
TH NMR (300 MHz, DMSO-dg) δ 11.54 (s, IH), 9.40 (br s, IH), 7.57 (d, J=8.3 Hz, 2H), 7.36 (d, J=8.3 Hz, 2H) , 7.21-7.14 (m, 5H), 3.75-3.73 (m, 2H), 2.87-2.82 (m, 2H), 2.80 (q, J=7.8 Hz, 2H), 1.17 (t, J=7.8 Hz, 3H);
MS (FD) m/e 445 (M+), 447 (M+2);
UV (EtOH) 291nm, 263nm, 237nm, 203nm.
Anal. Calcd for C20H20BrN3s2 ·’ C, 53.81; H, 4.52; N, 9.41; Found: C, 53.71; H, 4.61; N, 9.39.
Example 229
N-(2-phenethvl)-Ν' -f2-pvridinof2.3-dlthiazolyl thiourea
A solution of 2-phenethyl isothiocyanate (1.33 g, 8.13 mmol, 1.21 mL) and 2-aminopyridion[2,3-d]thiazole (1.23 g, 8.13 mmol) in Ν,Ν-dimethylformamide (15 mL) was heated to 105°C. After 46.5 h, the reaction was cooled to room temperature and poured into ethyl acetate. The organic solution was washed with water (6x) and brine. The organic layer was dried over sodium sulfate, filtered and concentrated. The material was purified by flash chromatography on silica gel (5% ethyl acetate in dichloromethane to 10% ethyl acetate in dichloromethane) to provide 330 mg of the titled product (13%). The white powder was recystallized from ethyl acetate:
mp 202-202.5°C;
IR (KBr, cm1) 3445, 3171, 3025, 1565, 1551, 1510, 1382,
1201, 1150;
AP 0 0 0 3 8 4
-325X-8571A ifi NMR (300 MHz, DMSO-d6> δ 11.91 (br s. IH) , 9.76 (br s, IH) , 8.37 (m, IH), 7.88 (m, IH) , 7.43 (dd, J= 3 and 6 Hz, IH), 7.33-7.20 (m, 5H), 3.82-3.79 (m, 2H), 2.89 (t, J=7 Hz, 2H) ;
MS (FAB) m/e 315 (M+l);
•JV (EtOH) 312nm (6=22468), 211nm (6=19194).
Anal. Calcd for C15H3.4N4S2: C, 57.30; H, 4.49; N, 17.82. Found: C, 57.20; H, 4.49; N, 17.66.
Example 230
N- (2-Phenethyl) -Ν' -ί2-(3-ethvl)pyridyl)thiourea
A) 2-t-Butoxvcarbonvlamino-3-ethvlpvridine
2-t-Butoxycarbonylaminopyridine (10 g, 51.5 nmol) was dissolved in tetrahydrofuran (80 mL) , and cooled to -78° C. N-butyllithium (80 mL of 1.49 M in hexanes,
120 mmol) was added dropwise over a period of 1 h. After stirring for an additional 15 min at -78°C and then for 2.5 hours at -10°C, the solution was then recooled back down to -7 8°C and iodoethane (77.2 mmol, 6.18 mL) was added cropwise over a period of 15 min via syringe. The solution vas allowed to warm to room temperature. The reaction was cuenched with 100 mL of a saturated ammonium chloride and extracted with ethyl acetate (3x). The organic layers were collected, dried over magnesium sulfate, and concentrated. The resulting solid was purified by flash chromatography on silica gel (25% ethyl acetate/hexanes) to provide the 4.9 g (43%) of the titled product as a light brown solid: mp 101-102°C;
IR (KBr,cm-1, 3174, 2968, 1725, 1594, 1519, 1442, 1278,
1249, 1156;
X-8571A
-326*Η NMR (300 MHZ, DMSO-dg) δ 8.98 (S, 1 Η) , 8.17 (m, IH) , 7.61 (m, IH), 7.15 (m, IH) , 2.52 (q, J=7.5 Hz, 2H) , 1.39 (s, 9H) , 1.08 (t, J=7.5 Hz, 3H) ;
MS (FD) m/e 222 (M+);
UV (EtOH) 270nm (ε= 4398), 223nm (ε= 6745).
Anal. Calcd for C12H18N2O2: C, 64.84; H, 8.16; N, 12.60. Found: C, 64.91; H, 8.34; N, 12.42.
B) Preparation of 3-Ethvl-2-aminopvridine.
2-t-Butoxycarbonylamino-3-ethylpyridine (4.9 g, 19.8 mmol) was dissolved in 90 ml of 3N HCl/Acetic acid and stirred for two hours. The sloution was neutralized with 2N NaOH to pH 7 and then extracted with ethyl acetate (2x 400 ml). The organics were dried over magnesium sulfate and concentrated giving 2.3 g (95%) of a yellowish solid. This solid was used in the next reaction without further purification.
C) N-(2-Phenethyl)-N’-ί2-(3-ethyl)pyridyl)thiourea
A solution of phenethyl isothiocyanate (3.61 g,
18.8 mmol, 3.3 mL) and 2-amino-3-ethylpyridine (2.3 g, 18.8 mmol) in N, N-dimethylformamide (20 mL) was stirred at 90S5°C for 3 h. The solution was cooled to room temperature, poured into ethyl acetate (150 mL), and washed with 0. IN hydrochloric acid (2x), water (3x), and brine. The organics were dried over sodium sulfate, filtered, and concentrated. The resulting solid was purified by flash chromatography on silica gel (1.5% ethyl acetate/dichloromethane) and then recrystallized (30% ethyl
AP Ο Ο Ο 3 8 4
Χ-8571Α -327acetate/ hexanes) to give 1.1 g (21%) of the titled product as a white solid : mp 57-58°C;
IR (KBr, cm-1) 3433, 2932, 1561, 1516, 1452, 1433, 1328,
1237, 760;
1H NMR (3 00 MHZ, DMSO-dg) δ 11.58 (br S, IH) , 8.66 (s, IH) , 7.92-7.90 (m, IH), 7.6-7.58 (m, IH), 7.30-7.15 (m, 5H), 7.02-6.98 (m, IH) , 3.83-3.77 (m, 2H), 2.89 (t, J=6 Hz, 2H), 2.64 (q, J=7.5 Hz, 2H), 1.09 (t, J=7.5 Hz, 3 H);
MS (FD) m/e 285 (M+);
UV (EtOH) 293nm (ε= 16632), 265nm (£= 14930), 244nm (£=
16594), 202nm (£=21127) .
Anal. Calcd for C16H19N3S: C, 67.33; H, 6.71; N, 14.72. Found: C, 67.17; H, 6.88; N, 14.51.
Example 231
N-(2-Phenethvl)-Ν' -(2-(3-bromo)pyridvll thiourea
A) 2-t-ButQxycarbonvlamino-3-bromopvridine
2-t-Butoxycarbonylaminopyridine (10 g, 51.5 mmol) was dissolved in tetrahydrofuran (80 mL), and cooled to -78° C . N-butyllithium (120 mmol, 80 mL of 1.49 M in hexanes) was added dropwise over a period of 1 h . After stirring for an additional 15 min at -78°C and then for 2.5 h at -10°C, the solution was recooled back down to -78°C and 1,2-dibromoethane (77.2 mmol, 6.65 mL) was added dropwise over a period of 15 min via syringe. The solution was allowed to warm to room temperature. The reaction was quenched with 100 mL of saturated ammonium chloride and was extracted with ethyl acetate (3x). The organic layers were _____________collected, dried over magnesium sulfate, filtered, and
X-8571A-328concentrated. The resulting solid was purified by flash chromatography on silica gel (25% ethyl acetate/hexanes) giving 4.5 g (32%) of the titled product as a light brown solid:
mp 120-121°C;
IR (KBr, on'1) 3191, 2980, 1729, 1521, 1442, 1365, 1272, 1166, 1032;
1H NMR (300 MHZ, DMSO-dg) δ 9.28 (s, IH) , 8.34 (m, IH) , 8.05 (m, IH), 7.15 (m, IH), 1.39 (s, 9H) ;
MS (FD) m/e 272 (M+), 274 (M+2);
UV (EtOH) 280nm (e= 4047) , 230nm (ε= 9067) , 204nm (ε= 16385) .
B) Preparation .of 3-Brom.o-2-aminopvridine.
3-Bromo-2-t-butoxycarbonylaminopyridine (3.8 g,13.9 mmol) was dissolved up in 70 ml of 3N HCl/ Acetic acid and stirred for two hours. The solution was neutralized with 2N NaOH to pH 7 and then extracted with ethyl acetate (3x 300 ml). The organics were dried over magnesium sulfate and concentrated giving a brown oil.
This was put on vacuum overnight giving 2.4 g (100%) solid crystals. This was used in the next reaction without further purification:
mp 57-59’C;
1H NMR (300 MHZ, DMSO-dg) δ 7.9 (m,lH), 7.65 (m,IH), 6.56.4 (m,lH), 6.2-6.1(s, 2H).
C) N-(2-Phenethvl)-N'-f2-(3-bromo!pvridvl1 thiourea
A solution of phenethyl isothiocyanate (1.89g, 11.6 mmol, 1.73 mL) and 2-amino-3-bromopyridine (2.0 g,
11.6 mmol) in Ν,Ν-dimethylformamide was stirred at 90-95°C for 3 h. The solution was cooled to room temperature,
AP 0 0 0 3 8 4
X-8571A
-329poured into ethyl acetate (150 mL), and washed with 0. IN hydrochloric acid (2x) , water (3x), and brine. The organics were dried over sodium sulfate, filtered, and concentrated. The resulting solid was purified by flash chromatography on silica gel (30% ethyl acetate/hexanes) to yield 0.5 g (13%) of the titled product as a white solid: mp 95-9 6°C;
IR (KBr, cm1) 3403, 3021, 1591, 1564, 1548, 1514, 1435, 1150, 750, 700;
NMR (300 MHZ, DMSO-dg) δ 11.2 (s, IH) , 8.45 (S, IH) , 8.13-8.06 (m, 2H), 7.29-7.18 (m, 5H) , 7.04-7.0 (m, IH),
3.86-3.8 (m, 2H), 2.91 (t, J=6 Hz, 2H) ;
MS (FD) rn/e 335 (M+), 337 (M+2);
UV (EtOH) 298nm (e= 13404) , 272nm (e= 16029 ) , 250nm (ε= 17186) , 203nm (€=22974) .
Anal. Calcd for Cl4Hl4N3S2Br: C, 50.01; H, 4.20; N, 12.50. Found: C, 49.77; H, 4.21; N, 12.37.
Example 232
Ni (4-Erpn)o,phgngt,hy-l),-N:,.-J2.- (4-gthvll.th.iaz.g-lYl,Kh,iQurg^ .,
4-BromophenethyIamine hydrochloride (1 g, 4.22 mmol) was slurried with dichloromethane and water. Sodium hydroxide (0.17g, 4.22 mmol) dissolved in water was added to this mixture and stirred. The organics were separated, washed with brine, dried over sodium sulfate, filtered, and concentrated. The resulting solid was added to N(thioimidazoyl)-2-amino-4-ethylthiazole (1.0 g, 4.22 mmol) in Ν,Ν-dimethyl-formamide (20 mL) and stirred for 3 h at 90-95°C. The solution was cooled to room temperature and added to 150 mL of ethyl acetate, washed with 0.1N hydrochloric acid (2x), water (3x), and brine. The
X-8571A
-330organics were dried over sodium sulfate, filtered, and concentrated. The solid was recrystallized (50% ethyl acetate/ hexanes) providing 0.7 g (45%) of the titled product as a yellow solid :
mp 156-157°C;
IR (KBr, cm'1) 2963, 1560, 1527, 1259, 1212, 1011, 802,
743 ;
NMR (300 MHZ, CDCI3) δ 10.94 (br s, 1H), 9.77 (br s,
1H), 7.41 (d, J=8.3 Hz, 2H), 7.24 (d, J=8.2 Hz, 2H), 6.33 (s, 1H) , 4.03-3.97 (m, 2H), 2.97 (t, J=6.8 Hz, 2H), 2.49 (q, J=7.5 Hz, 2H), 1.13 (t, J=7.5 Hz, 3H);
MS (FD) m/e 369 (M+), 371 (M+2);
UV (EtOH) 292nm (ε= 10803 ) , 257nm (ε= 6300) .
Anal. Calcd for Cl4Hi6N3SBr: C, 45.41; H, 4.35; N, 11.35. Found: C, 45.53; H, 4.42; N, 11.49.
Example 233
N-(3-Phenoxvphenethvl)-N‘-f2-(4-ethvl)thiazolvll thiourea
3-Phenoxyphenethylamine hydrochloride (1.0 g,
4.0 mmol) was slurried with dichloromethane and water. Sodium hydroxide (0.16 g, 4.0 mmol) dissolved in water was added and stirred. The organics were separated, washed with brine, dried over sodium sulfate, filtered, and concentrated. The resulting solid was added to N(thioimidazoyl)-2-amino-4-ethylthiazole (1.0 g, 4.22 mmol) in Ν,Ν-dimethyl-formamide (20 mL) and stirred for 3 h at 90-95°C. The solution was cooled to room temperature, added to 150 mL of ethyl acetate and washed with 0. IN hydrochloric acid (2x), water (3x), and brine. The organics were dried over sodium sulfate, filtered, and concentrated. The oil was put on vacuum overnight and
AP 0 0 0 3 8 4
X-8571A
-331recrystallized (50% ethyl acetate / hexanes) providing 0.6 g (42%) of the titled product as a white solid : mp 124°C;
IR (KBr, cm-1) 3177, 2966, 1563, 1534, 1509, 1491, 1446, 1349, 1287, 1260, 1218, 1158, 773;
XH NMR (300 MHZ, CDCl3)6l0.99 (br s, IH) , 9.87 (br s, IH) ,
7.31-7.23 (m, 3H), 7.09-6.84 (m, 6H), 6.32 (s, IH), 4.033.97 (m, 2H), 2.99 (t, J=6.8 Hz, 2H), 2.53 (q, J=7.5 Hz,
2H), 1.14 (t, J=7.5 Hz, 3H) ;
MS (FD) m/e 383 (M+);
UV (EtOH) 293nm (ε= 19262) , 258nm (ε= 11356) , 205nm (ε= 37212) . Anal. Calcd for C20H21N3OS2: C, 62.63; H, 5.52; N, 10.96. Found: C, 62.69; H, 5.61; N, 11.06.
Example,234
M,-..(2-Nitrophenethvl .(4-ethyl) thiazQlyUtJxtQursa
2-Nitrophenethylamine tosylate (0.97g, 3.0 mmol) was slurried with dichioromethane and water. Sodium hydroxide (0.12 g, 3 mmol) dissolved in water was added and stirred. The organics were separated, washed with brine, dried over sodium sulfate, filtered, and concentrated. The resulting solid was added to N-(thioimidazoyl)-2-amino-4ethylthiazole [BK8-6TT-074] (0.71 g, 3 mmol) in N,Ndimethylformamide (20 mL) and stirred for 3 h at 90-95°C. The solution was allowed to cool to room temperature and then was added to 150 mL of ethyl acetate and washed with 0.1N hydrochloric acid (2x), water (3x), and brine. The organics were dried over sodium sulfate, filtered, and concentrated. The solid was recrystallized (50% ethyl acetate/ hexanes) providing 0.5g (54%) of the titled product as a white solid :
X-8571A
-332mp 132-133°C;
IR (KBr, cm’1) 3171, 2966, 1586, 1531, 1509, 1341, 1215;
!h NMR (300 MHZ, CDCI3) 511.06 (br s, lH) , 9.76 (br s, IH) ,
7.98 (d, J=8.1 Hz, IH), 7.56-7.35 (m, 3H), 6.35 (s, IH),
4.13-4.02 (m, 2H), 3.33 (t, J=7 Hz, 2H) , 2.56 (q, J=7.4 Hz,
2H) , 1.16 (t, J=7.4 Hz, 3H);
MS (FD) m/e 336 (M+) ;
UV (EtOH) 292nm (ε= 20546) , 258nm (ε= 14748) , 203nm (ε= 24932) . Anal. Calcd for C14H15N4O2S2: C, 49.98; H, 4.79; N, 16.65. Found: C, 49.95; H, 4.86; N, 16.59.
Example 225
Ν-Γ6-(2-Phenvlbenzoxazole))ethvl)-Ν'-J 2ethvlthiazolyllthiourea
2-(6-(2-phenylbenzoxazole)] ethylamine hydrochloride (0.88 g, 3.2 mmol) was slurried with dichloromethane and water. Sodium hydroxide (0.13 g, 3.2 mmol) dissolved in water was added and stirred. The organics were separated, washed with brine, dried over sodium sulfate, filtered, and concentrated. The resulting solid was added to N-(thioimidazoyl)-2-amino-4ethylthiazole (0.71 g, 3 mmol) in N,N-dimethylformamide (20 mL) and stirred for 3 h at 90-95°C. The solution was cooled to room temperature, added to 150 mL of ethyl acetate and washed with 0.1N hydrochloric acid (2x), water (3x), and brine. The organics were dried over sodium sulfate, filtered, and concentrated. The solid was recrystallized (50% ethyl acetate/ hexanes) providing 0.64 g (49%) of the titled product as a white solid :
mp 183°C;
AP 0 0 0 3 8 4
X-8571A
-333 IR (KBr, cm1) 3178, 3035, 1578, 1533, 1506, 1253, 1214, 701;
^H NMR (300 MHZ, CDCI3) δ 10. 96 (br s, IH), 9.7 (br s, IH),
8.25-8.21 (m, 2H), 7.69 (d, J=8.1 Hz, IH) , 7.53 -7.4S (m,
4H), 7.29 (m, IH), 6.28 (s, IH), 4.13 -4.06 (m, 2H), 3.17
(t, J=6.6 Hz, 2H), 2.39 (q. J=7.5 Hz, 2H) , 1.0 (t, J=7.5
Hz, 3H);
MS (FD) m/e 408 (M+);
UV (EtOH) 294nm (£=12603) , 201nm (e= 14517) .
Anal. Calcd for C21H20N4OS2: C, 61.74; H, 4.93; N, 13.71. Found: C, 61.99; H, 5.18; N, 13.85.
Example 236
N- (2-PhenpxYPhgnethyn-N'r [.2-(ethyl) thiazolyl 1 thiourea
2-Phenoxyphenethylamine hydrochloride (0.97 g,
3.9 mmol) was slurried with dichloromethane and water. Sodium hydroxide (0.13 g, 3.9 mmol) dissolved in water was added and stirred. The organics were separated, washed with brine, dried over sodium sulfate, filtered, and concentrated. The resulting solid was added to N(thioimidazoyl)-2-amino-4-ethylthiazole (0.929 g, 3.9 mmol) in Ν,Ν-dimethylformamide (20 mL) and stirred for 3 h at 9095°C. The solution was cooled to room temperature, added to 150 mL of ethyl acetate and washed with 0.1N hydrochloric acid (2x), water (3x), and brine. The organics were dried over sodium sulfate, filtered, and concentrated. The resulting solid was recrystallized (50% ethyl acetate/ hexanes) providing 0.73 g (49%) of the titled product as a white solid :
mp 168°C;
X-8571A
-334IR (KBr, cm-1) 3168, 3013, 1581, 1532, 1487, 1237, 1209,
53;
1H NMR (300 MHZ, CDCl3)6l0.93 (br s, IH), 9.67 (br s, IH),
7.35-7.24 (m, 3H), 7.21-7.16 (m, IH) , 7.08-7.02 (m, 2H), 6.94-6.86 (m, 3H), 6.31 (s, IH), 4.05-4.0 (m, 2H), 3.05 (t, J=6.9 Hz, 2H), 2.5 (q, J=7.5 Hz, 2H), 1.12 (t, J=7.5 Hz,
3H) ;
MS (FD) m/e 383 (M+);
UV (EtOH) 292nm (£= 19052) , 258nm (ε= 11450) , 204nm (£= 38534 ) . Anal. Calcd for C20H21N3OS2: C, 62.63; H, 5.52; N, 10.96. Found: C, 62.91; H, 5.67; N, 11.22.
Example,237
N-f f(4-methvi-2-thiazolyl)aminolthioxomethy1I-DLphenylalanine methyl ester A solution of 1-[(2-[4-methyl]thiazolyl) thiocarbamoyl] imidazole (0.45 g, 5.0 mmol) and DLphenylalanine methyl ester hydrochloride (0.43 g, 2.0 mmol) in N,N-dimethylformamide (50 mL) was heated at 110'C for 12 h. The reaction was cooled to room temperature, solvent removed under reduced pressure, recrystallized from ethyl ether-hexanes to provide 118 mg (18%) of the titled product:
mp 131-132’C;
IR (KBr, cm-1) 3179, 3027, 1578, 1579, 1533,1224;
^•H NMR (300 MHz, DMSO-dg) δ 11.80 ( br s, IH) , 10.20 (br s, IH), 7.20-7.38 (m, 5H), 6.63 (s, IH), 5.10 (q, IH), 3.63 (s, 3H), 3.03-3.22 (m, 2H), 2.12 (s, 3H);
MS (FD) m/e 335(M+);
UV (EtOH) 294nm (£=18428) , 257nm (£=9852 ) , 202nm (£=21796) .
AP Ο Ο Ο 3 8 4
Χ-8571Α
-335Anal. Calcd for C15H17N3O2S2: C, 53.71; H, 5.11; N, 12.53. Found: C, 53.47; H, 5.11; N, 12.75.
Example 238 .(+-) -3- (4-jr,ethYl.-2c-thiaz,Ql¥ll-5- (phenvlmethvl) -2-thioxo-l·:
imidazolidinone
A solution of N-[[(4-methyl-2thiazolyl)amino]thioxomethyl]-DL-phenylalanine methyl ester (0.94 g, 2.80 mmol) and p-toluene sulfonic acid hydrate (0.20 g 1.05 mmol) in toluene (80 mL) was refluxed with a
Dean-Stark trap for 24 h. The reaction was cooled to room temperature, solvent removed under reduced pressure, residue taken up in ethyl acetate, washed with saturated sodium bicarbonate and saturated sodium chloride, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting product was recrystallized from ethyl acetate-hexanes to provide 216.1 mg (25%) of the titled product:
mp 169-171’C;
IR (KBr, cm-1) 3i53/ 177gf 1539f 12qo, 1195, 744, 303;
l-H NMR (300 MHz, DMSO-dg) δ 10.85 ( s, IH) , 7.40 (d, IH) , 7.30(m, 3H), 7.11(m, 2H), 4.83 (t, IH), 3.50 (d, 2H),
2.35 (s, 3H);
MS (FD) m/e 303(M+);
UV(EtOH) 265nm (8=16902) , 203nm (8=17971) .
Anal. Calcd for Cl4Hi3N3OS2: C, 55.42; H,4.32; N,13.85. Found: C,55.63; H, 4.45; N, 13.91.
X-8571A
-336Example 239
N-f(2-thiazolvlamino)thioxomethvl)-DL-phenvIalanine methvl gjs.ter
A solution of 1-[(2-thiazolyl) thiocarbamoyl] imidazole (4.21 g, 20.0 mmol) and DL-phenylalanine methyl ester hydrochloride (4.31 g, 20.0 mmol) in Ν,Νdimethylformamide (150 mL) was heated at 90‘C for 3 h. The reaction was cooled to room temperature, solvent removed under reduced pressure, recrystalllized from ether-hexanes to provide 3.26 g (51%) of the titled product:
IR (KBr, cm-1) 3184, 3029, 1735 1569, 1510, 1223,1189 ;
^H NMR (300 MHz, DMSO-dg) δ 11.90 (s, IH) , 7.40 (d, IH) , 7.20-7.38 (m, 5H), 7.17 (d, IH), 5.30 (q, IH), 3.63 (s,
3H), 3.02-3.22 (m, 2H);
MS (FD) m/e 321(M+);
UV (EtOH) 291nm (£=18235), 255 nm (£=10773), 202nm (£=20575). Anal. Calcd for C14H15N3O2S2: C, 52.31; H, 4.70; N, 13.07. Found: C, 52.24; H, 4.61; N, 13.18.
Example 240
DL-5-(phenvlmethvl)-3-(2-thiazolvl)-2-thioxo-4thiazolidinone
A solution of N-[(2-thiazolylamino)thioxomethyl]DL-phenylalanine methyl ester (0.47 g, 2.23 mmol) and p25 toluene' sulfonic acid hydrate (0.20 g 1.05 mmol) in toluene (50 mL) was refluxed with a Dean-Stark trap for 12 h. The reaction was cooled to room temperature, solvent removed under reduced pressure, residue taken up in ethyl acetate, washed with saturated sodium bicarbonate and saturated sodium chloride, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting product
AP 0 0 0 3 8 4
X-8571A
-337was recrystallized from ethyl ether-hexanes to provide 0.243g (58%) of the titled product: mp 164-165‘C;
IR (KBr, cm-1) 3099, 2985, 2873, 1775,1532, 1440, 1398, 1329, 1251, 1208, 737 ;
iH NMR (300 MHz, DMSO-dg) δ 10.90 ( s, IH) , 7.83 (d, IH) , 7.80 (d, IH), 7.50 (m, 3H), 7.20 (m, 2H), 4.90 (t, IH),
3.17 (d, 2H);
MS (FD) m/e 289(M+);
UV (EtOH) 264nm (€=16108) , 202nm (€=17275) .
Anal. Calcd for C13H11N3OS2: C, 53.96; H, 3.83; N,14.52. Found: C,54.22; H, 3.96; N, 14.30.
Example 243N-f(2-benzothiazolvlamino) thioxomethvll-DL-phenvlalanine
A solution of 1-[(2-benzothiazolyl) thiocarbamoyl] imidazole (1.30 g, 5.0 mmol) and DLphenylalanine methyl ester hydrochloride (1.08 g, 5.0 mmol) in N,JV-dimethylformamide (50 mL) was heated at 90’C for 3 h. The reaction was cooled to room temperature, solvent removed under reduced pressure, recrystalllized from ethyl ether-hexanes to provide 1.31 g (70%) of the titled product:
mp 168-169‘C; IR (KBr, cm-1) 3168, 3030, 1732, 1548, 1525, 1206,1193;
1H NMR (300 MHz, DMSO-dg) 6 10.30 (br S, IH) , 7.88 (d, IH) , 7.62 (d, IH), 7.32 (t, IH) , 7.20-7.29 (m, 6H), 5.18 (q,
IH), 3.70 (s, 3H), 3.22 (m, 2H);
MS (FD)' m/e 371 (M+) ;
UV (EtOH) 303nm (€=25329), 247 nm (€=12095), 203nm (€=28990).
X-8571A
-338Anal. Calcd for Ci8H17N3O2S2: C, 58.20; H, 4.61; N, 11.31. Found: C, 58.19; H, 4.70; N, 11.30.
Example 242
DL-3-(2-benzothiazolyl)-5-(phenvlmethvl)-2-thioxo-4thiazoliflinone
A solution of N-[(2benzothiazolylamino)thioxomethyl]-DL-phenylalanine methyl ester (1.0 g, 2.69 mmol) and p-toluene sulfonic acid hydrate (0.20 g 1.05 mmol) in toluene (80 mL) was refluxed with a Dean-Stark trap for 36 h. The reaction was cooled to room temperature, solvent removed under reduced pressure, residue taken up in ethyl acetate, washed with saturated sodium bicarbonate and saturated sodium chloride, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting product was recrystallized from ethyl acetate-hexanes to provide 74.9 mg (8%) of the titled product:
mp 187-189‘C;
IR (KBr, cm1) 3250, 1766, 1522, 1489;
i-H NMR (300 MHz, OMSO-άζ) 5 11.00 (s, IH) , 8.18 (d, IH) ,
8.02 (d, IH), 7.08-8.00 (m, 2H), 7.37 (m, 3H), 7.23 (d,
2H), 4.97 (t, IH), 3.18 (d, 2H);
MS (FD) m/e 339(M+);
UV (EtOH) 300nm (£=73 55) , 265nm (£=19454) , 217nm (£=26558 ), 203nm (£=31150) .
Anal. Calcd for C17H13N3OS2: C, 60.16; H,3.86; N,12.38. Found: C, 60.33; H, 4.14; N, 12.25.
AP Ο Ο Ο 3 8 4
Χ-8571Α
-339Ν- f ί (6-fluoro-2-benzothiazolvl)amino1thioxomethvn-DLBheaylalanine methyL-esS-gx
A solution of 1-( (2-[6-fluoro] benzothiazolyl) thiocarbamoyl] imidazole (1.40 g, 5.0 mmol) and DLphenylalanine methyl ester hydrochloride (1.08 g, 5.0 mmol) in N, N-dimethylf ormamide (175 mL) was heated at 90 °C for 3 h. The reaction was cooled to room temperature, solvent removed under reduced pressure, recrystalllized from ethyl ether-hexanes to provide 900 mg (46%) of the titled product:
iH NMR (300 MHz, DMSO-dg) δ 10.03 (br s, IH) , 7.82 (q, IH) , 7.60 (m, IH), 7.20-7.32 (m, 6H) , 5.10 (q, IH) , 3.63 (s,
3H), 3.20 (t, 2H); MS (FD) m/e 389 (M+).
Example, 2.4 4
EL.--3.^i6-fluoro-2rhenzQ-thiazQlvl1 -5-(phenvlmethvl)-2-thioxo4.-imi,dazQlidinpne
A solution of N-[[(6-fluoro-2benzothiazolyl) amino] thioxomethyl] -DL-phenylalanine methyl ester (0.90 g, 2.31 mmol) and p-toluene sulfonic acid hydrate (0.20 g 1.05 mmol) in toluene (80 mL) was refluxed with a Dean-Stark trap for 48 h. The reaction was cooled to room temperature, solvent removed under reduced pressure, residue taken up in ethyl acetate, washed with saturated sodium bicarbonate and saturated sodium chloride, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting product was recrystallized from ethyl ether-hexanes to provide 251mg (31%) of the titled product:
Χ-8571Α
-340in mp 223-224‘C;
IR (KBr, cm’1) 3173, 1767, 1538, 1453, 1388, 1267;
1H NMR (300 MHz, DMSO-dg) δ 11.02 (s, IH), 8.00-8.12 (m,
2H), 7.40-7.50 (m, IH), 7.20-7.39 (m, 5H), 4.97 (t, IH) ,
3.20 (d, 2H);
MS (FD) m/e 357(M+);
UV (EtOH) 265nm (£=15680), 223nm (£=19505), 201nm (£=23665). Anal. Calcd for C17H12FN3OS2: C, 57.13; H,3.38; N,11.76. Found: 0,56.89; H, 3.43; N, 11.60.
Example 2.15
N-f ί(4.5-dimethvl-2-thiazolyl) amino]thioxomethvl 1-DLphenvlalanine methvl ester A solution of 1-[(2-[4,5-dimethyl]thiazolyl) thiocarbamoyl] imidazole (1.80 g, 7.5 mmol) and DLphenylalanine methyl ester hydrochloride (1.60 g, 7.5 mmol) in Ν,Ν-dimethylformamide (50 mL) was heated at 90’C for 4 h. The reaction was cooled to room temperature, solvent removed under reduced pressure, recrystalllized from ether20 hexanes to provide 1.91 g (72%) of the titled product:
IR (KBr, cm’1) 3178, 3029, 1756, 1552, 1505, 1219 ;
!h NMR (300 MHz, DMSO-dg) δ 11.65 (br s, IH), 7.20-7.38 (m, 5H), 5.10 (q, IH), 3.65 (s, 3H), 3.05-3.21 (m, 2H) , 2.20 (s, 3H), 2.08 (s, 3H);
MS (FD) rn/e 349(M+) ;
UV (EtOH) 300nm (£=17248), 257 nm (£=9202), 203nm (£=22444). Anal. Calcd for C16H19N3O2S2: c, 54.99; H, 5.48; N, 12.02. Found: C, 55.16; H, 5.57; N, 12.01.
AP Ο 0 0 3 8 4
X-8571A
-341Ex ample. 24 £ dl-3- (4,5-dimethvI-2-thiazolyl) -5- (phenvlmethyll-.2_-thiooxo4-imidazolidinone A solution of N-(4,5-dimethyl-25 thiazolyl)amino]thioxomethyl]-DL-phenylalanine (1.00 g,
2.86 mmol) and p-toluene sulfonic acid hydrate (0.20 g,
1.05 mmol! in toluene (50 mL) was refluxed with a DeanStark trap for 48 h. The reaction was cooled to room temperature, solvent removed under reduced pressure, residue taken up in ethyl acetate, washed with saturated sodium bicarbonate and saturated sodium chloride, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting product was recrystallized from ethyl ether-hexanes to provide 0.545 g (60%) of the titled product:
mp 205-207’C;
IR (KBr, cm'1) 3161, 1783, 1527, 1287, 1164;
!h NMR (300 MHz, DMSO-dg) δ 10.80 (s, IH) , 7.30 (m, 3H) ,
7.20 (m, 2H), 4.83 (t, IH), 3.10 (d, 2H), 2.32 (s, 3H),
2.21 (s, 3H) ) ;
MS (FD) m/e 317 (M+);
UV (EtOH) 266nm (£=16921), 201 nm (£=17995).
Anal. Calcd for C15H15N3OS2: C, 56.76; H, 4.76; N, 13.24. Found: C, 56.53; H, 4.94; N, 13.49.
Example 247
Ν-Ll (4-cvano-2-thiazolyl)amino!thioxomethyl)-PLphenvlalanine methyl ester A solution of 1-[(2-[4-cyano]thiazolyl) thiocarbamoyl] imidazole (1.76 g, 7.5 mmol) and DLphenylalanine methyl ester hydrochloride (1.62 g, 7.5 mmol)
X-8571A
-342in Ν,Ν-dimethylformamide (50 mL) was heated at 90°C for 5 h. The reaction was cooled to room temperature, solvent removed under reduced pressure, recrystallized from ethyl ether-hexanes to provide 1.42 g (55%) of the titled product:
IR (KBr, cm’1) 3011, 2220, 1742, 1672, 1586,1455, 1372;
1H NMR (300 MHz, DMSO-dg) 6 7.12-7.38 (m, 5H) , 7.40 (s, IH) , 5.05 (q, IH), 3.63 (s, 3H), 3.03-3.22 (m, 2H); MS (FD) m/e 346 (M+);
UV (EtOH)287nm (ε=7404 ) , 257nm (ε=12260), 206nm (€=30014).
Example 248
DL-3-(4-cvano-2-thiazolyl)-5-(phenvlmethvl)-2-thioxo-4imidazolidinone A solution of N-[[(4-cyano-2thiazolyl) amino]thioxomethyl]-DL-phenylalanine methyl ester (1.42 g, 4.10 mmol) and p-toluene sulfonic acid hydrate (0.20 g 1.05 mmol) in toluene (80 mL) was refluxed with a Dean-Stark trap for 24 h. The reaction was cooled to room temperature, solvent removed under reduced pressure, residue taken up in ethyl acetate, washed with saturated sodium bicarbonate and saturated sodium chloride, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting product was recrystallized from ethyl ether-hexanes to provide 170.1 mg (10%) of the titled product:
mp 214-216’C; IR (KBr, cm’1) 3294, 3092, 2246, 1781, 1505, 1381, 1325, 1244;
!h NMR (300 MHz, DMSO-dg) δ 11.08 (s, IH) , 8.90 (S, IH) , 7.22-7.80 (m, 3H), 7.20-7.22 (m, 2H), 4.83 (t, IH) , 3.17 (d, 2H);
AP Ο Ο Ο 3 8 4
Χ-8571Α
-343MS (FD) m/e 314(M+);
UV (EtOH) 259nm (6=15097) , 205nm (6=26419) .
Anal. Calcd for C14H10N4OS2: C, 53.49; H, 3.21; N,17.82. Found: C, 53.75; H, 3.43; N, 17.62.
Ν- I f (4-trifluoromethvl-2-thiazolyl)aminol thioxomethyl]-DLphxnylalanine methyl· esxsr A solution of 1-[(2-[4-trifluoromethyl]thiazolyl) thiocarbamoyl] imidazole (1.60 g, 5.8 mmol) and DLphenylalanine methyl ester hydrochloride (1.24 g, 5.8 mmol) in N, N-dimethylformamide (50 mL) was heated at 90‘C for 5h. The reaction was cooled to room temperature, solvent removed under reduced, recrystallized ethyl ether-hexanes to provide 2.22 g (99%) of the titled product:
IR (CHCI3, cm-1) 3000, 1744, 1672,1554, 1523, 1226;
1H NMR (300 MHz, DMSO-d6) δ 8.64 (d, IH) , 7.82 (s, IH) , 7.21-7.38 (m, 3H), 7.19-7.21 (d, 2H), 5.05 (q, IH), 3.63 (s, 3H), 3.02-3.22 (m, 2H);
MS (FD) m/e 389(M+);
UV (EtOH) 287nm (6=11327) , 256nm (6=11674) , 203nm (6=24532) . Anal. Calcd for C15H14F3N3O2S2: C, 46.27; H, 3.62; N,
10.79. Found: C, 46.55; H, 3.57; N, 11.06.
Example 250
EL.-_3-nL4-trifluoromethyl-2-thiazolyl) -5- (phenylmethyl) -230 thioxo-4-imidazolidinone
X-8571A
-344A solution of N-[[(4-trifluoromethyl-2thiazolyl)amino]thioxomethyl]-DL-phenylalanine methyl ester(2.09 g, 5.38 mmol) and p-toluene sulfonic acid hydrate (0.20 g 1.05 mmol) in toluene (80 mL) was refluxed with a Dean-Stark trap for 48 h. The reaction was cooled to room temperature, solvent removed under reduced pressure, residue taken up in ethyl acetate, washed with saturated sodium bicarbonate and saturated sodium chloride, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting product was recrystallized from ethyl ether-hexanes to provide 1.01 g (53%) of the titled product:
mp 187-189'C;
IR (CHCI3, cm'1) 3431, 3008, 1782, 1495, 1369, 1328, 1242, 1178, 1149, 1085;
1H NMR (300 MHz, DMSO-dg) δ 11.02 (s, IH), 8.59 (s, IH), 7.22-7.80 (m, 3H), 7.20-7.22 (m, 2H), 4.83 (t, IH), 3.17 (d, 2H);
MS (FD) m/e 357 (MA);
UV (EtOH) 263nm (6=13898) , 202nm (6=19355) .
Anal. Calcd for C14H10F3N3OS2: C, 47.05; H,2.82; N,11.76. Found: C,47.33; H, 2.86; N, 11.67.
Example 251
N- i2-flt.eyc.lghexenYlIethYl) -Ν'-[2,·:ί$-^ΓΡΡΡ)ργ.Γΐ^ίηγ11
A solution of 2-(1-cyclohexenyl) ethyl isothiocyanate (1.67 g, 10 mmol) and 2-amino-6bromopyridine (1.73 g, 10 mmol) in Ν,Ν-dimethylformamide (100 mL) was heated at 100'C for 96 h. The reaction was cooled to room temperature, solvents removed under reduced
AP 0 0 0 3 8 4
X-8571A -345pressure, taken up in ethyl acetate washed with IN HCl.
The organic layer was concentrated and the residue purified by HPLC (elution with hexanes-EtOAc) to afford 70.1 mg (2.1%) of the titled product:
mp 174-175'C;
IR (CHCI3, cm1) 2936, 1592, 1512, 1448, 1203 ;
^•Η NMR (300 MHz, DMSO-ας) 8 10.79 (s,lH), 10.65 (m, IH) ,
7.70 (t, IH), 7.28 (d, IH) , 7.19 (d, IH), 5.60 (s, IH),
3.70 (q, 2H), 2.23 (t, 2H) , 1.95 (s, 4H), 1.62-1.42 (m, 4H) t
MS (FD) m/e 341 (M+);
UV (EtOH) 303nm (£=19786), 269nm (ε=18279) , 252nm (ε=18006), 201nm (€=17992) .
Anal. Calcd for Ci4Hi8BrN3S: C, 49.42 H, 5.33; N, 12.35. Found: C, 49.69; H, 5.36; N, 12.09.
Example ?52
Nr (2-Jl-cyclohexen-yJJ-ethvI)-N‘ - f (4-isopropvl)pvridinvn
Phigurea
A solution of 2-(1-cyclohexenyl)ethyl isothiocyanate (0.36 g, 2.2 mmol) and 2-amino-4isopropyIpyridine (0.36 g, 2.2 mmol) in N,Ndimethylformamide (20 mL) was heated at 100'C for 96 h.
The reaction was cooled to room temperature, solvents removed under reduced pressure, taken up in ethyl acetate, washed with IN aqueous HCl. The organic layer was concentrated and the residue purified by HPLC (elution with hexanes-EtOAc) to afford 169 mg (5.6%) of the titled product:
mp 105-106‘C;
IR (KBr, cm1) 3215, 2931, 1614 1556, 1534, 1487, 1199;
X-8571A
-346-
!η NMR (300 MHz, DMSO-d6) δ 11.65 (t, IH), 10.40 (s, IH),
8.30 (d, IH), 7.20 (s, IH), 6.93 (d, IH), 5.52 (s, IH),
3.63 (q, 2H), 2.80 (m, IH), 2.22 (t, 2H), 1.95 (m, 4H), ,
1.62-1.42 (m, 4H) , 1.18 (d, 6H) ;
MS (FD) m/e 303 (M+);
UV (EtOH) 290nm (£=17565) , 266nm (£=18863 ) , 247nm (£=15125) , 203nm(£=23091) .
Anal. Calcd for C17H25N3S: C, 67.28;H, 8.30; N, 13.85. Found: C, 67.55; H, 8.48; N, 13.94.
Example 252.
N- (2-fl-cvclohexenvllethvl)-N'-,-(2-(6methvlthiolbenzothiazolyl1 thiourea
A solution of 2-(1-cyclohexenyl)ethyl isothiocyanate (1.67g, 10 mmol) and 2-amino-6methylthiobenzothiazole (1.96 g, 10 mmol) in Ν,Νdimethylformamide (20 mL) was heated at 100*C for 96 h.
The reaction was cooled to room temperature, a precipitate formed, ’ collected, washed with ethyl acetate to provide
1.22 g (54%) of the titled product:
mp 186-187*C;
IR (KBr, cm'1) 3171, 3036, 2918, 1548, 1522, 1251, 1214;
!h NMR (300 MHz, DMSO-d6) δ 11.82 (br s, IH) , 10.20 (br s, IH), 7.88 (s, IH), 7.6-7.5 (m, IH), 7.4-7.3 (q, IH), 5.55 (s, IH) , 3.67 (q, 2H), 2.4 (s, 3H), 2.25 (t, 2H), 1.95 (s, 4H), 1.62-1.42 (m, 4H);
MS (FD) m/e 363 (M+);
UV (EtOH) 318nm (£=14538), 256 nm (£=6742), 224nm (£=13749), 201 nm (£=11940) .
AP Ο Ο Ο 3 8 4
Χ-8571Α
-347Anal. Calcd for C17H21N3S3: C, 56.16; H, 5.82; N, 11.56. Found: C, 56.40; H, 5.94; N, 11.76.
Example. 254
N-(2-f1-cyclohexenyl1ethvl)-Ν' -Γ2- (4-Γ4brgmg 1 pheny Dthiazolyll thiourea
A solution of 2 - (1-cyclohexenyl) ethyl isothiocyanate (1.67 g, 10 mmol) and 2-amino-[4-(4bromophenyl)]thiazole (2.55 g, 10 mmol) in N,N10 dimethylformamide (20 mL) was heated at 100 *C for 72 h. The reaction was cooled to room temperature, solvent removed under reduced, recrystallized from ethyl acetatehexanes to provide 455 mg (11%) of the titled product: mp 219-220’C;
IR (KBr, cm’1) 3171, 2927, 1566, 1516, 1301, 1211, 1071, 1110;
!h NMR (300 MHz, DMSO-cfg) δ 11.70 (s, 1H) , 9.30 (br s, 1H) 7.80 (d, 2H), 7.60 (m, 3H), 5.43 (s, 1¾), 3.67 (q, 2H),
2.25 (t, 2H), 1.95 (s, 4H>, 1.62-1.42 (m, 4H) ;
MS (FD) m/e 421 <M+);
UV (EtOH) 285nm (£=27781), 245 nm (£=17426), 202nm (£=31192) Anal. Calcd for Ci8H20BrN3S2: C,' 51.18; H, 4.77; N, 9.95
Found: C, 51.08; H, 4.47; N, 9.91.
X-8571A
-348Example 255
Ν-(2-fl-cvclohexenvllethyl)-Ν' -Γ2-(4-f2-Lhexadecvloxvlphenvl]) thiazolvll thiourea
A solution of 2-(1-cyclohexenyl) ethyl isothiocyanate (840 mg, 5 mmol) and 2-amino-4-(2[hexadecyloxy]phenyl)thiazole (2.10 g, 5 mmol) in N,Ndimethylformamide (20 mL) was heated at 100 °C for 72 h.
The reaction was cooled to room temperature, solvent removed under reduced, recrystallized from ethyl acetatehexanes to provide 900 mg (31%) of the titled product: mp 98-99'C;
IR (KBr, cm-1) 2919, 1567, 1473, 1222,1062, 681;
ςΗ NMR (300 MHz, DMSO-dg) δ 11.62 (s, IH), 9.62 (br s, IH) ,
7.95 (d, IH), 7.56 (s, IH), 7.30 (t, IH), 7.12 (d, IH) ,
7.0 (t, IH), 5.43 (s, IH), 4.10 (t, 2H), 3.65 (q, 2H), 2.25 t, 2H), 1.95 (br s, 2H) , 1.83 (t, 3H), 1.94-1.73 (m, 4H), 1.40-1.38 (m, 2H), 1.23 (s, 28H);
MS (FD) m/e 583 (M+);
UV (EtOH, 299nm (£=21244), 263 nm (£=21549), 202nm (£=30773). Anal. Calcd for C34H53N3OS2: C, 69.93; H, 9.15; N, 7.19. Found: C, 69.70; H, 8.99; N, 7.28.
Example 256
K-f(2-thiazolvl)amino1thioxomethyl-DL-2-fluorophenvlalanine methyl ester
A solution of 1-( (2-thiazolyl) thiocarbamoyl] imidazole (3.15 g, 15 mmol) and DL-2-fluorophenylalanine methyl ester hydrochloride (3.51 g, 15 mmol) in N,Ndimethylformamide (100 mL) was heated at 80'C for 8 h. The reaction was cooled to room temperature, the solvent removed under reduced pressure, and the residue
AP Ο Ο Ο 3 8 4
-349X-8571A recrystallized from ethyl ether-hexanes to provide 1.89 g (37%) of the titled product:
IR (KBr, cm’1) 3187, 3122, 3090, 3037, 2950, 1739, 1566,
1495, 1209, 1182;
^H NMR ’(300 MHz, DMSO-dg) δ 11.81 (br s, IH) , 7.39 (d, IH) ,
7.26 (m, 2H), 7.18 (m, 3H), 5.16 (q, IH) , 3.64 (s, 3H),
3.28 (m, 2H);
MS (FD) m/e 339 (M+);
UV (EtOH) 290nm (£=18548), 256 nm (£=10899), 203nm (£=19927). 10 Anal. Calcd for C14H14FN3O2S2: C, 49.67; H, 3.87; N,
12.42. Found: C, 49.45; H, 4.07; N, 12.40.
Example 257
DL-3- (2-thiazolvJJ -5-f(2-fluoro)phenvlmethvll-2-thioxo-415 jjiidaz.QlidinQne
A solution of N-((2-thiazolyl)amino]thioxomethylDL-2-fluorophenylalanine methyl ester (l.Og, 2.95 mmol) and p-toluenesulfonic acid hydrate (0.20 g 1.05 mmol) in toluene (100 mL) was refluxed with a Dean-Stark trap for 48
h. The reaction was cooled to room temperature, solvent removed under reduced pressure, residue taken up in ethyl acetate, washed with saturated sodium bicarbonate and saturated sodium chloride, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting product was recrystallized from ethyl acetate-hexanes to provide 305 mg (23%) of the titled product:
IR (KBr, cm-1) 3104, 2870, 1781, 1531 , 1438, 1330, 1255,
1204;
XH NMR (300 MHz, DMSO-dg) 5 10.95 (br s, IH), 7.85 (d, IH),
30 7.78 (d, IH), 7.30 (m, 2H), 7.18 (m, 2H), 4.83 (t, IH) ,
3.18 (d, 2H);
X-8571A
-350MS (FD) m/e 307(M+);
UV (EtOH)397 (£=586), 263nm (£=16615), 201nm (£=15980)
Anal. Calcd for C13H10N2 FOS2: C, 50.80; H,3.28; N,13.67. Found: C, 50.84; H, 3.33; N, 13.38.
Example 258
N- f (2-thiazolvl)amino)thioxomethvl-DL-3.5bis(trifluoromethyl)phenylalanine methvl ester
A solution of 1-[(2-thiazolyl) thiocarbamoyl] imidazole (0.46 g, 2.19 mmol) and DL-3,5ditrifluoromethylphenylalanine methyl ester hydrochloride (0.77 g, 2.19 mmol) in NzN-dimethylformamide (75 mL) was heated at 80'C for 7 h. The reaction was cooled to room temperature, the solvent removed under reduced pressure, and the residue recrystallized from ethyl ether-hexanes to provide 203 mg (20%) of the titled product:
IR (KBr, cm*1) 3179, 3022, 1745, 1568, 1379, 1291, 1212;
!h NMR (300 MHZ, DMSO-dg) δ 11.82 (br s, IH) , 7.98 (s, 3H) ,
7.10 (m, IH), 5.12 (m, IH), 3.31 (s, 3H) , 3.08 (m, 2H);
MS (FD) m/e 457(M+);
UV (EtOH) 291 (£=18895), 255nm (£=10490), 202nm (£=19571) Anal. Calcd for CigHi3FgN3O2S2: C, 42.01; H, 2.86; N,
9.19. Found: C, 41.90; H, 2.74; N, 9.36.
Example 259
DL-3- (2-thiazolyl)-5-f(3.5bisftrifluoromethyl])phenvlmethvl)-2-thicxo-4imidazolidinone
A solution of N-[(2-thiazolyl)amino]thioxomethyl30 DL-3,5-bistrifluoromethylphenylalanine methyl ester (0.15
AP Ο Ο Ο 3 8 4
Χ-8571Α
-351g, 0.32 mmol) and p-toluene sulfonic acid hydrate (0.10 g 0.53 mmol) in toluene (65 mL) was refluxed with a DeanStark trap for 48 h. The reaction was cooled tc room temperature, the solvent removed under reduced pressure, and the residue taken up in ethyl acetate, washed with saturated sodium bicarbonate and saturated sodium chloride, dried over magnesium sulfate, concentrated under reduced pressure to provide 39 mg (29%) of the titled product.
IR (KBr, cm-1) 3105, 1771, 1535, 1500, 1444, 1380, 1278,
1217;
Ih NMR (300 MHz, DMSO-dg) δ 10.93 (br s, IH), 8.03 (s, IH) ,
7.96 (s, 2H), 7.89 (d, IH), 7.80 (d, IH), 5.01 (t, IH),
3.37 (d, 2H);
MS (FD) m/e 425 (M+);
UV (EtOH) 440nm (£=1169), 264nm (£=14109).
Anal. Calcd for Ci5HgFgN3OS2: C, 42.35; H,2.13; N,9.88. Found: C, 42.60; H, 2.33; N, 9.63.
Example 260
M.-f (2-thia.zgly_l)aminolthioxomethvl-DL-2-chlorophenvlalanine methvi ester
A solution of 1-[ (2-thiazolyl) thiocarbamoyl] imidazole (1.5 g, 7.1 mmol) and DL-2-chlorophenylalanine methyl ester hydrochloride (1.78 g, 7.1 mmol) in N,N25 dimethylformamide (65 mL) was heated at 80°C for 7 h. The reaction was cooled to room temperature, the solvent removed under reduced pressure, and the residue recrystallized from ethyl ether-hexanes to provide 280 mg (12%) of the titled product:
IH NMR (300 MHz, DMSO-dg) 67.38 (m, 3H), 7.23 (m, 2H), 7.08
X-8571A
-352(br s, IH), 5.17 (q, IH), 3.62 (s, 3H) , 3.21 (m, 2H); MS (FD) m/e 355 (M+).
Example 261
N-f(2-thiazolvl)aminolthioxomethvl-DL-4-chlorophenvlalanine methyl ester
A solution of 1-[(2-thiazolyl) thiocarbamoyl] imidazole (1.5 g, 7.1 mmol) and DL-4-chlorophenylalanine methyl ester hydrochloride (1.78 g, 7.1 mmol) in Ν,Νdimethylformamide (65 mL) was heated at 80'C for 6 h. The reaction was cooled to room temperature, the solvent removed under reduced pressure, and the residue recrystallized from ethyl ether-hexanes to provide 840 mg (20%) of the titled product:
IR (KBr, cm-1 ) 3176, 3025, 1735, 1562, 1510, 1493, 1467, 1452, 1387, 1353, 1306, 1202, 1191;
!h NMR (300 MHz, DMSO-dg) δ 11.81 (br s, IH, , 7.39 (m, 3H) ,
7.26 (d, 2H), 7.18 (br s, IH), 5.09 (q, IH), 3.64 (s, 3H) ,
3.18 (m, 2H);
MS (FD) m/e 355(M+);
UV (EtOH) 291nm (£=18545), 255 nm (£=11222), 220nm (£=16171), 201 (£=18545) .
Anal. Calcd for C12H14CIN3O2S2: C, 47.25; H, 3.96; N,
11.81. Found: C, 47.28; H, 3.94; N, 11.88.
Example. 262
PE.- 3^12 r-th i a z q 1 y 11-5^1.14^.chlpr.Q ? pheny lme thy 11-2-1 h i qxp - 4 imidazolidinone
A solution of N-[(2-thiazolyl)amino]thioxomethylDL-4-chlorophenylalanine methyl ester (0.84 g, 2.36 mmol) and p-toluene sulfonic acid hydrate (0.20 g, 1.05 mmol) in
AP Ο Ο Ο 3 8 4
Χ-8571Α'
-353toluene (100 mL) was refluxed with a Dean-Stark trap for 48h. The reaction was cooled to room temperature, the solvent removed under reduced pressure, residue taken up in ethyl acetate, washed with saturated sodium bicarbonate and saturated sodium chloride, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting product was recrystallized from ethyl acetate-hexanes to provide 176 mg (23%) of the titled product:
!h NMR (300 MHz, DMSO-dg) δ 7.83 (d, IH), 7.78 (d, IH), 7.38 10 (d, 2H), 7.22 (d, 2H), 4.85 (t, IH), 3.11 (d, 2H);
MS (FD) m/e 323 (M+).
Example 263
R-f. {2 -1 h i.a z q ly 1) ami np 11 h i oxamei by1-PL- 41 15 trifluoromethvlphenvlalanine methvl ester
A solution of 1-[(2-thiazolyl) thiocarbamoyl] imidazole (1.03 g, 4.1 mmol) and DL-4trifluoromethylphenylalanine methyl ester hydrochloride (1.15 g, 4.1 mmol) in Ν,Ν-dimethylformamide (75 mL) was heated at 80‘C for 6 h. The reaction was cooled to room temperature, the solvent removed under reduced pressure, and the residue recrystallized from ethyl ether-hexanes to provide 389 mg (24%) of the titled product:
IR (KBr, cm1 ) 3178, 3020, 1747, 1577, 1509, 1325, 1278,
1185;
IH NMR (300 MHz, DMSO-dg) δ 11.82 (br s, IH), 9.82 (br s,
IH), 7.63 (d, 2H), 7.39 (d, 2H), 7.35 (d, IH), 7.13 (s,
IH), 5.18 (g, IH), 3.62 (s, 3H), 3.31 (m, 2H) ;
MS (FD) m/e 389 (M+) ;
UV (EtOH) 291nm (£=18127) , 255 nm (£=10867), 201nm (£=20712) .
X-8571A
-354Anal. Calcd for C15H14N3F3O2S2: C, 46.26; H, 3.62; N, 10.79. Found: C, 46.21; H, 3.69; N, 11.00.
Example 264
DL-3-(2-thiazolvl)-5-Γ(4-trifluoromethvl)phenvlmethvll-2thioxo-4-imidazolidinone
A solution of N-[(2-thiazolyl)amino]thioxomethyl DL-4-trifluoromethylphenylalanine methyl ester (0.34 g,
0.87 mmol) and p-toluene sulfonic acid hydrate (0.20 g 0.106 mmol) in toluene (100 mL, was refluxed with a DeanStark trap for 48 h. The reaction was cooled to room temperature, the solvent removed under reduced pressure, and the residue taken up in ethyl acetate, washed with saturated sodium bicarbonate and saturated sodium chloride, dried over magnesium sulfate, concentrated under reduced pressure to provide 145 mg (46%) of the titled product.
IR (KBr, cm-1) 3176, 1779, 1619, 1532, 1508, 1432, 1327, 1270, 1194, 1129;
1H NMR (300 MHz, DMSO-dg) δ 10.90 (br s, IH), 7.83 (d, IH),
7.79 (d, IH), 7.65 (d, 2H), 7.41 (d, 2H), 4.88 (t, IH),
3.22 (d, 2H) ;
MS (FD) m/e 357(M+);
UV (EtOH) 264nm (8=15626), 201nm (8=16341).
Anal. Calcd for C14H10F3N3OS2: C, 47.05; H, 2.82; N,11.76. Found: C, 47.17; H, 2.82; N, 11.53.
Example 265,
N-Γ (2-thiazolvl)aminolthioxomethvl-DL-2,6difluorophenvlalanine methvl ester
A solution of 1-[(2-thiazolyl) thiocarbamoyl] imidazole (0.65 g, 3.08 mmol) and DL-2,6AP Ο Ο Ο 3 8 4
Χ-8571Α
-355difluorophenylalanine methyl ester hydrochloride (0.78 g, 3.08 mmol) in N,N-dimethylformamide (75 mL) was heated at 80‘C for 7 h. The reaction was ccoied to room temperature, the solvent removed under reduced pressure, and the residue recrystallized from ethyl ether-hexanes to provide 413 mg (38%) of the titled product:
IR (KBr, cm’1) 3205, 3036, 1737, 1625, 1554, 1511, 1468, 1442, 1388, 1265;
!η NMR (300 MHz, DMSO-dg) 6 11.83 (br s, IH), 7.37 (q, 2H),
7.08 (m, 2H), 5.21 (q, IH), 3.62 (s, 3H), 3.31 (m, 2H);
MS (FD) m/e 357(M+);
UV (EtOH) 291nm (£=18495), 256 nm (£=10699), 202nm (£=20082). Anal. Calcd for C14H13F2N3O2S2: C, 47.05; H, 3.67; N,
11.76. Found: C, 47.08; H, 3.76; N, 11.93.
Example 26$
N-f 2 - (1-cvclohexenv-l) ethvl] -N‘ - f4,5.6,7tetrahvdrobenzothiazolvl1 thiourea
A solution of 2-(1-cyclohexenyl) ethyl isothiocyanate (1.67 g, 10 mmol) and 2-amino-4,5,6,7tetrahydrobenzothiazole (1.54 g, 10 mmol) in N,Ndimethylformamide (100 mL) was heated at 100‘C for 120 h.
The reaction was cooled to room temperature, the solvent removed under reduced pressure, the residue taken up in ethyl acetate and washed with IN HCl. The organic layer was concentrated and the residue recrystallized from ethyl acetate-hexanes to provide 426 mg (13 %) of the titled product:
X-8571A
-356IR (KBr, cm1) 3169, 3031, 2931, 1580, 1258, 1198 ;
XH NMR (300 MHz, DMSO-dg) 8 11.41 (br s, IH), 10.05 (br s,
IH) , 5.43 (s, IH), 3.58 (m, 2H), 2.6-1.9 (m, 10H), 1.7 (m, 4H), 1.5 (m, 4H) ;
MS (FD) m/e 321 (M+);
UV (EtOH) 298nm (£=12157) , 257nm (£=6569 ) , 201nm (£=12172 ) . Anal, calcd for ClgH23N3S2: C, 59.97 H, 7.21; N, 13.07. Found: C, 60.06; H, 6.95; N, 12.82.
Example 267
M-_i2.-_(l-.cvclPhexenvl)ethvn-N' - f2- (5-chloro)pyrazinyl] thiourea
A solution of 2-(1-cyclohexenyl) ethyl isothiocyanate (2.30 g, 13.7 mmol) and 2-amino-515 chloropyrazine (1.75 g, 13.7 mmol) in Ν,Ν-dimethylformamide (40 mL) was heated at 100’C for 192 h. The reaction was cooled to room temperature, the solvent removed under reduced pressure, and the residue taken up in ethyl acetate and washed with IN aqueous HCl. The organic layer was concentrated and the resulting product was recrystallized from ethyl acetate-hexanes'; to provide 64 mg (1.6%) of the titled product:
IR (KBr, cm’1) 3192, 2931, 1588, 1515, 1457, 1320, 1251,
1153;
25 1H NMR (300 MHz, DMSO-dg) δ 11.01 (br s. , IH) , 10.45 (t, IH),
8.38 (d. IH), 8.29 (d, IH), 5.50 (br s. IH) , 3.63 ( q, 2H),
2.21 (t', 2H), 1.95 (m, 4H), 1.52 (m, 4H ) ;
MS (FD) m/e 296 (M+);
_UV (EtOH) 330nm (£=9176), 273nm (£=21432), 201nm (£=10972).
AP Ο Ο Ο 3 8 4
-357X-8571A
Anal. Calcd for C13H17N4SCI: C, 67.28; H, 8.30; N, 13.85. Found: C, 67.55; H, 8.48; N, 13.94.
Ex amp
N-J2- (l-cvclohexenvl) ethvl) -N'_--(2-i 4- (3,4diphlgrophenyl LlPhiazolyl·)... thio-urea
A solution of 2 - (1-cyclohexenyl) ethyl isothiocyanate (1.67 g, 10 mmol) and 4-(3,4dichlorophenyl)-2-thiazolamine (2.45 g, 10 mmol) in N,N10 dimethylformamide (50 mL) was heated at 100'C for 120 h.
The reaction was cooled to room temperature, the solvent removed under reduced pressure, and the residue taken up in ethyl acetate and washed with IN HCl. The organic layer was concentrated and the residue recrystallized from ethyl acetate-hexanes to provide 933 mg (2.3%) of the titled product :
IR (KBr', cm1) 3169, 2927, 1295, 1214 ; 1573, 1558, 1523, 1460, 1393,
TH NMR (300 MHz, DMSO-<?6) δ 11.72 (br s, IH), 9.11 (br s,
20 IH), 8.07 (d, IH), 7.83 (m, IH) , 7.62 (m, 2H) , 5.45 (m,
IH), 3.60 tin, 2H), 2.21 tin, 2H) , 1.85 (m, 4H) , 1.43 (m,
4H) ;
MS (FD) m/e 411 (M+);
UV (MeOH) 287nm (£=25040), 241nm (£=16142), 205nm (£=29362). 25 Anal. Calcd for C18H19N3S2CI2: C, 52.42; H, 4.64; N, 10.19.
Found: C, 52.63; H, 4.48; N, 10.21.
Example 269
1=12-IZ-methoxyphenvllethvl)thiocarbamoyl imidazole 30 A solution of 1,1·-thiocarbonyldiimidazole (1.78 g, 10 mmol) and 2-methoxyphenethylamine (1.51 g, 10 mmol)
X-8571A
-358in acetonitrile (25 mL) was stirred at room temperature for 20 h. The resulting precipitate was collected by filtration to provide 1.40 g (53%) of the titled product:
IR (KBr, cnT1) 2944, 1563, 1493, 1409, 1282, 1246, 1031,
755;
!h NMR (300 MHz, DMSO-dg) 5 12.0 (br s, lH) , 7.65 (s, IH) , 7.25 (m, 2H), 7.05-6.9 (m, 4H), 3.8 (m, 2H), 3.8 (s, 3H),
2.95 (t, J=7 Hz, 2H);
MS (FD) m/e 261 (M+);
UV (EtOH) 278nm (£=7083), 216 nm (£=12683), 203 nm (£=22221).
Example 270
N-(2-(2-methoxyphenyl)ethvll-N'-(2-pvridvl) thiourea
A solution of 1-(2-(215 methoxyphenyl]ethyl)thiocarbamoyl imidazole (0.52 g, 2 mmol) and 2-aminopyridine (0.19 g, 2 mmol) in N,Ndimethylformamide (5 mL) was stirred at 90'C for 4 h, the reaction was cooled to room temperature and the solvent removed in vacuo. The residue was crystallized from ethyl acetate to provide 0.25 g (44%) of the titled product: IR (KBr, cm’1) 3219, 3048, 1607, 1557, 1236, 1036, 756; χΗ NMR (300 MHz, DMSO-dg) δ 11.65 (m, IH) , 10.55 (br s, IH) , 8.1 (m, IH), 7.75 (m, IH), 7.3-6.9 (m, 6H), 3.8 (m, 2H),
3.78 (s, 3H), 2.9 (t, J=7 Hz, 2H);
MS (FD) m/e 287 (M+); UV (EtOH) 290nm (£=10141), 267nm (£=13121), 247 nm (£=10959), 202 nm (£=24078).
AP Ο Ο Ο 3 8 4
X-8 57 ΙΑ'
-359Εχample 211
Ν- f2- (1-cvclohexenvl)ethvll-Ν'- f2-<6-methvl)pvridvl1 xkipurea.
A solution of 2-(1-cyclohexenyl)ethyl 5 isothiocyanate (1.67 g, 10.0 mmol) and 2-amino-6methylpyridine (1.08 g, 10.0 mmol) in N,N-dimethyIformamide (25 mL) was heated at 90’C for 20 h. The reaction was cooled to room temperature and the solvent removed under reduced pressure. The resulting product was recrystallized from ethyl acetate-hexanes to provide 1.04 g (38%) of the titled product:
IR (KBr, cnT1) 3230, 2920, 1608, 1572, 1540, 1457, 1378, 1317, 1235, 1164;
TH NMR (300 MHz, DMSO-c?6) δ 11.7 (br t, IH) , 10.45 (s, IH) , 15 7.62 (t, IH), 6.95 (d, IH) , 6.90 (d, IH), 5.50 (br s, IH),
3.7 (q, 2H), 2.4 (s, 3H) , 2.25 (t, 2H), 1.95 (m, 4H), 1.55 (m, 4H);
MS (FD) m/e 275 (M+);
UV (EtOH) 296nm (£=17669), 265nm (£=16667), 247nm (£=15266). 20 Anal. Calcd for C15H21N3S: C, 65.42; H, 7.69; N, 15.26.
Found: C, 65.42; H, 7.75; N, 15.20.
Example 272
Mt f 2.- ί 1-cyclohexenyl) ethylLrN 1-,11-1 S.-mexhyllpyridyl I 25 thiourea
A solution of 2-(1-cyclohexenyl)ethyl isothiocyanate (1.67 g, 10.0 mmol) and 2-amino-5methylpyridine (1.08 g, 10.0 mmol) in Ν,Ν-dimethylformamide (25 mL) was heated at 90’C for 20 h. The reaction was cooled to room temperature and the solvent removed under reduced pressure. The resulting product was recrystallized
X-8571A
-3 60from ethyl acetate-hexanes to provide 1.06 g (39%) of the titled product:
IR (KBr, cm'1) 3225, 2933, 1596, 1569, 1532, 1494, 1344, 1311, 1232, 827;
1H NMR (300 MHz, DMSO-dg) δ 11.55 (br t, IH) , 10.45 (s, IH) ,
7.95 (br s, IH), 7.6 (dd, IH), 7.05 (d, IH) , 5.5 (br s,
IH), 3.7 (q, 2H), 2.3 (m, 5H), 1.95 (m, 4H) , 1.55 (m, 4H); MS (FD) m/e 275 (M+);
UV (EtOH) 298nm (£=13 663) , 268nm (£=21631) , 249nm (£=14893 ) .
Anal. Calcd for C15H21N3S: C, 65.42; H, 7.69; N, 15.26.
Found: C, 65.15; H, 7.75; N, 15.33.
Example 273
N--(-2-.(l--cv.clohexenvl)ethvll-NΓ2- (4-methvl) pyridvll £bi<2ur,ea
A solution of 2-(1-cyclohexenyl)ethyl isothiocyanate (1.67 g, 10.0 mmol) and 2-amino-4methylpyridine (1.08 g, 10.0 mmol) in Ν,Ν-dimethylformamide (25 mL) was heated at 90’C for 16 h. The reaction was cooled to room temperature and the solvent removed under reduced pressure. The resulting product was purified by HPLC to provide 1.67 g (61%) of the titled product;
IR (KBr, cm-1) 3220, 2935, 1617, 1535, 1487, 1322, 1188,
866;
ΣΗ NMR (300 MHZ, DMSO-dg) δ 11.65 (br t, IH), 10.45 (S, IH),
8.0 (d, IH), 6. 95 (s, IH) , 6.85 (d, IH), 5.5 (br s, IH),
3.65 (q, 2H), 2 . 3 (m, 5H) , 1.95 (m, 4H) , 1.55 (m , 4H) ;
MS (FD) m/e 275 (M+) ;
UV (EtOH) 289nm (£=16865) , 266nm (£=17870), 247nm (£=14179
202nm (£=20105) .
AP 0 0 0 3 8 4
X-8571A
-361Anal. Calcd for C15H21N3S: C, 65.42; H, 7.69; N, 15.26. Found: C, 65.16; H, 7.55; N, 15.30.
Exampl£_221
Ης12-·.·(1 7cyclp.hexe.nyl.)..e.hhyl ] -N ’.-.12-. (3 rmethyl) gyxii&ll.
thiourea
A solution of 2-(1-cyclohexenyl)ethyl isothiocyanate (1.67 g, 10.0 mmol) and 2-amino-3methylpyridine (1.08 g, 10.0 mmol) in Ν,Ν-dimethylformamide (25 mL) was heated at 90’C for 16 h. The reaction was cooled to room temperature and the solvent removed under reduced pressure. The resulting product was purified by HPLC to provide 1.8 g (65%) of the titled product;
IR (KBr, cm1) 3220, 2931, 1589, 1513, 1462, 1325, 1164;
1H NMR (300 MHz, DMSO-άζ) θ 11.6 (br t, 1H) , 8.65 (s, 1H) , 8.05 (d, 1H), 7.65 (d, 1H) , 7.05 (dd, 1H), 5.5 (br s, 1H) ,
3.65 (q, 2H), 2.3 (s, 3H), 2.25 (t, 2H), 1.95 (m, 4H) , 1.55 (m, 4H) ;
MS (FD) m/e 275 (M+);
UV (EtOH) 293nm (£=16 693) , 264nm (£=14464) , 244nm (£=14762) , 201nm (£=16723) .
Example 275,
M- L2.~ (1-cyclQhexepyJJ ethyl! -Nl.z, 12- (6-ethyl.)pvridy.ll thiourea
A solution of 2-(1-cyclohexenyl)ethyl isothiocyanate (1.67 g, 10.0 mmol) and 2-amino-6ethylpyridine (1.22 g, 10.0 mmol) in N,N-dimethylformamide (25 mL) was heated at 90'C for 20 h. The reaction was cooled to room temperature and the solvent removed under
X-8571A
-362reduced pressure. The resulting product was purified by HPLC to provide 1.55 g (54%) of the titled product;
IR (KBr, cm1) 3230, 2930, 1604, 1533, 1450, 1211, 1157;
!h NMR (300 MHz, DMSO-dg) δ 11.8 (br t, IH) , 10.45 (s, IH) , 7.62 (t, IH), 6.95 (d, IH), 6.90 (d, IH), 5.45 (br s, IH), 3.7 (q, 2H), 2.7 (q, 2H), 2.25 (t, 2H), 1.95 (m, 4H), 1.55 (m, 4H), 1.2 (t, 3H);
MS (FD) m/e 289 (M+);
UV (EtOH) 296nm (8=17903), 265nm (8=16556), 247nm (8=14932), 201nm (8=14174) .
Anal. Calcd for CigH23N3S: C, 66.40; H, 8.01; N, 14.52. Found: C, 66.40; H, 8.00; N, 14.75.
Example 276
Ν-ί2- (l-cvclohexenvl) ethyl)-N1 -f2- (4-ethyl)pyridyl1 .thjour.ea
A solution of 2-(1-cyclohexenyl) ethyl isothiocyanate (1.67 g, 10.0 mmol) and 2-amino-4ethylpyridine (1.22 g, 10.0 mmol) in N,N-dimethylformamide (25 mL) was heated at 90*C for 16 h. The reaction was cooled to room temperature and the solvent removed under reduced pressure. The resulting product was purified by HPLC to provide 1.2 g (42%) of the titled product;
IR (KBr, cm-1) 3215, 2931, 1615, 1535, 1407, 1334, 1198,
843;
!h NMR (300 MHz, DMSO-dg) δ 11.68 (br t, IH) , 10.45 (s, IH) , 8.0 (d, IH), 7.0 (s, IH), 6.9 (d, IH), 5.5 (br s, IH), 3.65 (q, 2H) , 2.6 (q, 2H) , 2.25 (t, 2H) , 1.95 (m, 4H) , 1.55 (m, 4H), 1.15 (t, 3H);
MS (FAB) m/e 290 (M+H);
AP Ο Ο Ο 3 8 4
Χ-8571Α -363UV (EtOH) 289nm (ε=17 3 7 8 ) , 266nm (£=18654), 247nm (£=14847), 202nm (£=23101) .
Anal. Calcd for C16H23N3S: C, 66.40; H, 8.01; N, 14.52. Found: C, 66.45; H, 7.99; N, 14.26.
Example .2.77
N- f2-(1-cvclohexenvl) ethvl) -N*.-f 2-.(.5trifluoromethyl)pvridvl1 thiourea A solution of 2-(1-cyclohexenyl)ethyl isothiocyanate (1.67 g, 10.0 mmol) and 2-amino-5trifluoromethyIpyridine (1.62 g, 10.0 mmol) in N,Ndimethylformamide (25 mL) was heated at 90'C for 72 h. The reaction was cooled to room temperature and the solvent removed under reduced pressure. The resulting product was purified by HPLC to provide 0.33 g (10%) of the titled product;
IR (KBr, cm1) 3220, 2929, 1618, 1551, 1500, 1324, 1238, 1132, 1078, 828;
XH NMR (300 MHz, DMSO-c?6) δ 11.4 (br t, IH) , 10.95 (s, IH) ,
8.5 (br s, IH), 8.15 (dd, IH), 7.3 (d, IH), 5.55 (br s,
IH), 3.7 (q, 2H) , 2.3 (t, 2H), 1.95 (m, 4H), 1.55 (m, 4H); MS (FD) m/e 329 (M+);
UV (EtOH) 296nm (£=17058), 255nm (£=14250).
Anal. Calcd for C15K18N3F3S: C, 54.70; H, 5.51; N, 12.76.
Found: C, 54.98; H, 5.67; N, 12.59.
X-8571A
-364ExampL£-2-78
Η- (2- fcvclohex.anyLl-ethvl) -Ν' - ί 2 - (4-methvl) thiazolvll thiourea
A solution of 1-[(2-[4-methyl]thiazolyl) thiocarbamoyl) imidazole (1.0 g, 4.46 mmol) and 2cyclohexanylethylamine (0.567 g, 4.46 mmol) in Ν,Νdimethylformamide (25 mL) was stirred at 90 C for 16 h, the reaction was cooled to room temperature and the solvent removed' in vacuo. The residue was crystallized from ethyl acetate to provide 0.72 g (57%) of the titled product:
IR (KBr, cm1) 3220, 2922, 1565, 1505, 1227, 1168;
2H NMR (300 MHz, DMSO-dg) δ 11.5 (br s, IH) , 9.9 (br s, IH) ,
6.65 (s, IH), 3.55 (m, 2H), 2.25 (s, 3H), 1.8-0.8 (m, 13H); MS (FD) m/e 283 (M+);
UV (EtOH) 291nm (6=5315), 257nm (6=2711).
Anal. Calcd for C13H21N3S2: C, 55.09 H, 7.47; N, 14.82. Found: C, 55.29; H, 7.60; N, 14.64.
Example 279
Ν- Γ2- (2-methoxyphenyl)ethvl1-N' - f 2- (5-methyl)pvridvl) thiourea
A solution of 1-(2-[2methoxyphenyl]ethyl)thiocarbamoyl imidazole (0.7 g, 2.68 mmol) and 2-amino-5-methylpyridine (0.29 g, 2.68 mmol) in N,N-dimethylformamide (5 mL) was stirred at 90'C for 16 h, the reaction was cooled to room temperature and the solvent removed in vacuo. The residue was crystallized from ethyl acetate to provide 0.62 g (77%) of the titled product:
IR (KBr, cm’1) 3227, 2932, 1612, 1534, 1493, 1273, 1037;
*H NMR (300 MHz, DMSO-d6) δ 11.55 (br t, IH), 10.45 (s, IH) ,
AP 0 0 0 3 8 4
X-8571A
-3657.9 (br s, IH), 7.6 (m, IH) , 7.2-6.9 (m, 5H), 3.8 (m, 5H),
2.9 (t, J=7 Hz, 2H), 2.2 (s, 3H);
MS (FAB) m/e 302 (M+H);
UV (EtOH) 298nm (£=13316), 268nm (£=23132), 249 nm (£=15574), 202 nm (£=25460) .
Anal. Calcd for C16H19N3OS: C, 63.76; H, 6.35; N, 13.94. Found: C, 63.71; H, 6.34; N, 13.79.
Example 280 l-J2zl2zPhlprQEbenv.il ethyl·.] -thiocarbamovl imidazole
A solution of 1,11-thiocarbonyldiimidazole (1.8 g, 10 mmol) and 2-(2-chlorophenyl) ethyl amine (1.56 g, 10 mmol) in acetonitrile (100 mL) was stirred at room temperature for 3 h. The solution was concentrated to about 50 ml and was placed in the freezer for 4 days. The resulting crystals were collected by filtration to provide 2.37 g (89%) of crude title product.
mp 74-78’C.
IR (KBr, cm-1) 3134, 2924, 1564, 1529, 1474, 1448, 1411, 1353, 1287, 1215;
MS (FD) m/e 266 (M+);
UV (EtOH) 278nm (£=5421), 247 nm (£=5655), 202 nm (£=22240).
Example 281
N.-J2- (2-chlprpphenyllethvn -N1-Γ2- (5-methyl) pyridyl] thiourea
A solution of 1-(2-(2chlorophenyl]ethyl) thiocarbamoyl imidazole (1.0 g, 3.76 mmol) and 2-amino-5-methylpyridine (0.41 g, 3.76 mmol) in Ν,Ν-dimethylformamide (10 mL) was stirred at 90'C for 16 h,
X-8571A
-366the reaction was cooled to room temperature and the solvent removed in vacuo. The residue was crystallized from ethyl acetate to provide 0.92 g (80%) of the titled product:
IR (KBr, cm-1) 3226, 1597, 1532, 1491, 1273, 1050;
NMR (300 MHz, DMSO-dg) δ 11.6 (br t, IH) , 10.5 (s, IH) ,
7.9 (br s, IH), 7.6-7.0 (m, 6H), 3.9 (q, 2H), 3.1 (t, J=7 Hz, 2H), 2.2 (s, 3H);
MS (FD) m/e 305 (M+);
UV (EtOH) 298nm (£=14145), 268nm (£=21034), 249 nm (£=15757), 202 nm (£=23053) .
Anal. Calcd for C15H16N3CIS: C, 58.91; H, 5.27; N, 13.74. Found: C, 58.65; H, 5.39; N, 13.77.
Example. 28,2
1-L12-J.4-ethvl) thiazolyl) thiocarbamoyl 1 imidazole
A solution of 1,1'-thiocarbonyldiimidazole (11.9 g, 60 mmol) and 2-amino(4-ethyl) thiazole (8.0 g, 60 mmol) in acetonitrile (250 mL) was stirred at room temperature for about 5 h. The resulting precipitate was collected by filtration to provide 12.0 g (85%) of the titled product, mp. 198-200’C; IR (KBr, cm-1) 2970, 2637, 1609, 1529,
1461, 1398, 1357, 1226, 1262;
IH NMR (300 MHz, DMSO-dg) δ 8.6 (s, IH), 7.9 (s, IH), 7.0 (s, IH) , 6.9 (s, IH) , 2.6 (q, J=7 Hz, 2H) , 1.2 (t, J=7 Hz, 3H) ;
MS (FD) m/e 238 (M+);
UV (EtOH) 361 nm (£=11223), 290 nm (£=8828), 203 nm (£=20303) .
Anal. Calcd for C9H10N4S2: C, 45.36 H, 4.23; N, 23.51. Found: C, 45.51; H, 4.20; N, 23.53.
AP Ο Ο Ο 3 8 4
Χ-8571Α
-367Εχ ample. 2.82
Ν- (2zi„2..-pyridyllethyl).-N' -J2- (4-e.thyli thiazslyl] thiourea
A solution of 1-((2-(4ethyl] thiazolyl) thiocarbamoyl] imidazole (1.00 g, 4.2 mmol) 5 and 2-(2-aminoethylJpyridine (0.51 g, 4.2 mmol) in Ν,Νdimethyl formamide (25 mL) was stirred at 90’C for 3 h, the reaction was cooled to room temperature and the solvent removed in vacuo. The residue was crystallized from ethyl acetate to provide 0.75 g (61%) of the titled product:
IR (KBr·, cm-1) 3163, 1557, 1524, 1222, 757;
NMR (300 MHz, DMSO-dg) δ 11.3 (br s, IH), 10.0 (br s,
IH), 8.5 (m, IH) , 7.7 (m, IH), 7.25 (m, 2H), 6.6 (s, IH) ,
3.9 (m, 2H), 3.05 (m, 2H,, 2.45 (q, J=7 Hz, 2H), 1.05 (t, J=7 Hz, 3H) ; MS (FD) m/e 292 (M+);
UV (EtOH) 292nm (ε=17803), 261nm (£=12919), 201 nm (£=17809). Anal. Calcd for C13H16N4S2: C, 53.40 H, 5.51; N, 19.16. Found: C, 53.64; H, 5.51; N, 19.02.
Example.. 284
M-_(2--fl-cyclohexenvnethvl) -Ν' - ί2- (4-ethyl) thiazolvll ,thiourea
A solution of 1-[ (2-[4-ethyl]thiazolyl) thiocarbamoyl] imidazole (0.75 g, 3.15 mmol) and 2-(1cyclohexenyl)ethylamine (0.39 g, 3.15 mmol) in N,N25 dimethylformamide (15 mL) was stirred at 90’C for 4 h, the reaction was cooled to room temperature and the solvent removed in vacuo. The residue was crystallized from ethyl acetate to provide 0.77g (83%) of the titled product:
MP 155-156’C; IR (KBr, cm'1) 3172, 2914, 1560, 1507, 1202,
710;
X-8571A
-3681H NMR (300 MHz, DMSO-dg) δ 11.5 (br s, IH), 9.8 (br s, IH)
6.6 (s, IH), 5.42 (s, IH), 3.56 (q, J=7 Hz, 2H), 2.45 (m, 2H), 2.16 (m, 2H), 1.9 (m, 4H), 1.5 (m, 4H), 1.12 (t, J=7 Hz, 3H);
MS (FD) m/e 295 (M+);
UV (EtOH) 291nm (8=19227), 257nm (8=9628), 201 nm (8=15736). Anal. Calcd for C3.4H21N3S2: C, 56.91 H, 7.16; N, 14.22. Found: C, 57.20; H, 7.22; N, 14.16.
Examp l£_28.S
N-F2- (2-chlorophenvl)ethvll-Ν'-f2-(4-ethvl)thiazolvll phipuraa
A solution of 1-[ (2-[4-ethyl]thiazolyl) thiocarbamoyl] imidazole (0.75 g, 3.15 mmol) and 2-(2chlorophenyl)ethylamine (0.49 g, 3.15 mmol) in N,Ndimethylformamide (15 mL) was stirred at 90'C for 2 h, the reaction was cooled to room temperature and the solvent removed in vacuo. The residue was crystallized from ethyl acetate to provide 0.85 g (83%) of the titled product:
MP 153-155’C; IR (KBr, cm-1) 3167, 3018, 1570, 1505, 1215, 749, 699;
iH NMR (300 MHz, DMSO-dg) 6 11.65 (br s, IH), 9.85 (br s, IH), 7.5-7.2 (m, 4H), 6.65 (s, IH), 3.85 (m, 2H), 3.05 (t, J=7 Hz, 2H), 2.55 (q, J=7 Hz, 2H), 1.1 (t, J=7 Hz, 3H) ;
MS (FD) m/e 325 (M+);
UV (EtOH) 292nm (8=19154), 257nm (8=10451), 202 nm (8=24308). Anal. Calcd for Ci4HigN3S2Cl: C, 51.60; H, 4.95; N, 12.87. Found: C, 51.75; H, 4.98; N, 12.79.
AP Ο Ο Ο 3 8 4
Χ-8571Α
-369Example .2.86.
Ν-f2-(2-methoxvphenvl)ethyl1-N*-f2-(4-ethyl)thiazolvll thiourea
A solution of 1-[ (2-(4-ethyl]thiazolyl) thiocarbamoyl] imidazole (0.70 g, 2.94 mmol) and 2-(2methoxyphenyl)ethylamine (0.44 g, 2.94 mmol) in N,Ndimethylformamide (15 mL) was stirred at 95’C for 2 h, the reaction was cooled to room temperature and the solvent removed in vacuo. The residue was crystallized from ethyl acetate to provide 0.67 g (71%) of the titled product:
MP 166-167.5’C; IR (KBr, cm1) 3173, 3025, 1528, 1248,
1209, 755, 677;
1H NMR (300 MHz, DMSO-dg) δ 11.5 (br s, IH) , 9.85 (br s, IH), 7.2-6.8 (m, 4H) , 6.57 (s, IH), 3.7 (m, 5H), 2.82 (t,
J=7 Hz, 2H) , 2.4 (q, J=7 Hz, 2H) , 1.06 (t, J=7 Hz, 3H) ;
MS (FD) m/e 321 (M+);
UV (EtOH) 291nm (€=12114), 259nm (€=6792), 201 nm (€=18914). Anal. Calcd for C15H19N3OS2: C, 56.04; H, 5.96; N, 13.07. Found: C, 55.83; H, 6.00; N, 13.08.
Example .,,287
N- f2 - (3.-methoxy33heayi.) sthY.11 -N* - (2.7.(4-shhy II thiazgly 11 thiourea
A solution of 1-[(2-(4-ethyl]thiazolyl) thiocarbamoyl] imidazole (0.70 g, 2.94 mmol) and 2-(3methoxyphenyl)ethylamine (0.44 g, 2.94 mmol) in N,Ν'dimethylformamide (15 mL) was stirred at 90’C for 2 h, the reaction was cooled to room temperature and the solvent removed in vacuo. The residue was crystallized from ethyl acetate to provide 0.76 g (80%) of the titled product:
MP 123-125*C;
X-8571A
-370IR (KBr, cm'1) 3167, 3027, 1587, 1207, 699;
1H NMR (300 MHz, DMSO-c?6) δ 11.5 (br s, IH) , 9.9 (br s, IK) ,
7.2-6.8 (m, 4H), 6.58 (s, IH), 3.75 (m, 2H), 3.67 (s, 3H),
2.84 (t, J=7 Hz, 2H) , 2.45 (q, J=7 Hz, 2H), 1.05 (t, J=7 Hz, 3H);
MS (FD) m/e 321 (M+);
UV (EtOH) 292nm (£=19113), 258nm (£=10607), 202 nm (£=29289). Anal. Calcd for C15H19N3OS2: C, 56.04; H, 5.96; N, 13.07. Found: C, 56.08; H, 5.96; N, 13.16.
Example 288
1-f(2-f4-cvano1 thiazolyl)thiocarbamovl1 imidazole
A solution of 1,1'-thiocarbonyldiimidazole (3.2 g, 16 mmol) and 2-amino-4-cyanothiazole (2.0 g, 16 mmol) in acetonitrile (40 mL) was stirred at room temperature for 72 h and heated at 60’C for 24 h. The resulting precipitate was collected by filtration to provide 2.74 g (73%) of the titled product:
IR (KBr, cm’1) 3097, 2230;
^•Η NMR (300 MHz, DMSO-c?6) δ 11.99 (br s, IH) , 8.76 (s, IH) ,
8.67 (s, IH), 8.07 (s, IH) , 7.92 (s, IH) ;
MS (FAB) m/e 236 (M+H).
Example 289
Ν-Γ2-. (2-chlorophenvl) ethvll -Ν' -f2- (4-cvano)thiazolvll Phipurea
A solution of 1-((2-(4cyano]thiazolyl) thiocarbamoyl] imidazole (0.66 g, 2.8 mmol) and 2-(2-chlorophenyl)ethylamine (0.45 g, 2.8 mmol) in N,Ndimethylformamide (15 mL) was stirred at 100’C for 2 h.
AP 0 0 0 3 8 4
Χ-8571Α
-371The reaction was cooled to room temperature, poured into ethyl acetate, washed with water, IN aqueous HCI, water, saturated sodium bicarbonate, and brine. The organic layer was concentrated and the residue purified by chromatography on silica gel to provide 0.24 g (26%) of the titled product :
mp 165-168’C; IR (KBr, cm-1) 3119, 2955, 2232, 1577, 1505, 1461, 1328, 1299, 1221, 1053, 826;
!h NMR (300 MHz, DMSO-dg) δ 11.8 (br S, IH) , 8.5 (br s, IH) ,
8.1 (s, IH), 7.2-7.4 (m, 4H) , 3.74 (m, 2H) , 2.98 (t, J=7 Hz, 2H);
MS (FD) m/e 322 (M+);
UV (EtOH) 287nm (£=10082), 258 nm (£=15462), 205 nm (£=31601) .
Example.-29.Q.
N-. 3-.chlQrQPhenyl) ethyl 1 -N.‘ - [.2-.. (4-cyano,.)thia,s,ply 11.
thiaurea A solution of 1-((2-(4cyano]thiazolyl) thiocarbamoyl] imidazole (0.66 g, 2.8 mmol) and 2-(3-chlorophenyl) ethylamine (0.44 g, 2.8 mmol) in Ν,Νdimethylformamide (15 mL) was stirred at 90’C for 2 h. The reaction was cooled to room temperature, poured into ethyl acetate, washed with water, IN aqueous HCi, water, saturated sodium bicarbonate, and brine. The organic layer was concentrated and the resultant solid was crystallized from methylene chloride to provide 0.21 g (23%) of the titled product as a tan solid:
mp 180-185’C; IR (KBr, cm1) 2955, 2239, 1559, 1522, 1331,
1251, 1206, 1168, 823;
X-8571A
-372ΧΗ NMR (300 MHz, DMSO-c?6) δ 11.8 (br s, IH) , 8.4 (br s, IH)
8.1 (s, IH), 7.1-7.3 (m, 4H), 3.71 (m, 2H), 2.86 (t, J=7 Hz, 2H);
MS (FD) m/e 322 (M+), 324;
UV (EtOH) 287nm (6=10684), 258 nm (6=16406), 207 nm (6=33113) .
Example.251
N- (2- (2-methoxv~Dhenvl) ethvll -N1 - f2- (4-cvano) thiazolyl ]
EiliQUESa A solution of 1-((2-(4cyano]thiazolyl) thiocarbamoyl] imidazole (0.66 g, 2.8 mmol) and 2-(2-methoxyphenyl)ethylamine (0.46 g, 2.8 mmol) in N,N-dimethylformamide (15 mL) was stirred at 90'C for 2 h. The reaction was cooled to room temperature, poured into ethyl acetate, washed with water, IN aqueous HCl, water, saturated sodium bicarbonate, and brine. The organic layer was concentrated and the residue purified by chromatography on silica gel to provide 0.21 g (23%) of the titled product as a yellow solid:
mp 159-161’C;
IR (KBr, cm1) 2937, 2235, 1566, 1454, 1301, 1243, 1208,
1173, 754;
3H NMR (300 MHz, DMSO-dg) δ 11.8 (br s, IH), 8.4 (br s, IH),
8.1 (s, IH), 6.8-7.2 (m, 4H), 3.73 (s, 3H), 3.66 (m, 2H), 2.81 (t, J=7 Hz, 2H);
MS (FD) m/e 318 (M+);
UV (EtOH) 279nm (6=12102), 259 nm (6=16281), 203 nm (6=33347) .
AP Ο Ο Ο 3 8 4
-373X-8571A
Εχample 29.2.
Ν- (2- /3-methoxyphenyl)ethvl 1 -Ν' - f2 - (4-cvano)thiazolyl 1 thiourea A solution of 1-((2-(45 cyano] thiazolyl) thiocarbamoyl] imidazole (0.66 g, 2.8 mmol) and 2-(3-methoxyphenyl)ethylamine (0.44 g, 2.8 mmol) in N,N-dimethylformamide (15 mL) was stirred at 90’C for 2 h. The reaction was cooled to room temperature, poured into ethyl acetate, washed with water, IN aqueous HCl, water, saturated sodium bicarbonate, and brine. The organic layer was concentrated and the residue purified by chromatography on silica gel to provide 0.21 g (23%) of the titled product- as a yellow solid:
mp 151-153’C;
IR (KBr, cm'1) 3065, 2235, 1564, 1515, 1295, 1250, 1209,
1155, 1058, 874, 768, 748, 684;
1H nmr (300 MHz, DMSO-dg) δ 11.8 (br s, IH) , 8.4 (br s, IH) ,
8.1 (s, IH), 7.18 (m, IH) , 6.77 (m, 3Η), 3.68 (m, 5H),
2.80 (t, J=7 Hz, 2H);
MS (FD) m/e 318 (M+);
UV (EtOH) 280nm (£=11770), 258 nm (£=16613), 204 nm (£=34785) .
Example 293
N-(.2-(1-cvclohexenvl)ethyl]-N'-(2 - (4cvano)thiazolyl1 thiourea
A solution of 1-((2-(4cyano]thiazolyl)thiocarbamoyl] imidazole (0.82 g, 3.5 mmol) and 2-(1-cyclohexenyl)ethylamine (0.45 g, 3.5 mmol) in N,N30 dimethylformamide (15 mL) was stirred at 90‘C for 1.5 h.
The reaction was cooled to room temperature, poured into
X-8571A
-374ethyl acetate, washed with water, IN aqueous HCl, water, saturated sodium bicarbonate, and brine. The organic layer was concentrated and the resultant solid was purified by chromatography on silica gel to provide 0.27 g (26%) of the titled product as a pale yellow solid:
mp 176-178'C;
IR (KBr, cm1) 3169, 3075, 2924, 2233, 1556, 1513, 1330, 1298, 1260, 1217, 1200, 1167, 1145, 983, 922;
1H nmr (300 MHz, DMSO-c?6) δ 11.87 (br s, IH) , 8.40 (br s,
IH), 8.11 (s, IH), 5.42(br s, IH), 3.52 (m, 2H), 2.14 (t,
J=7 Hz, 2H), 1.90 (m, 4H), 1.49 (m, 4H);
MS (FD) m/e 292 (M+);
UV (EtOH) 288nm (£=11250), 258 nm (£=16113), 206 nm (£=25473)
Anal. Calcd for C13H16N4S2: C, 53.40; H, 5.52; N, 19.16.
Found: C, 53.10; H, 5.55; N, 18.96.
Example 294 l-f (2-Γ4-(3-chlorophenvll thiazolyl )thiocarbamovn imidazole
A solution of 1,1'-thiocarbonyldiimidazole (2.52g, 12 mmol) and 4-(3-chlorophenyl)-2-thiazoleamine (2.14 g, 12 mmol) in acetonitrile (35 mL) was stirred at room temperature for 30 hours. The resulting precipitate was collected by filtration to provide 2.77 g (72%) of the titled product:
_ MS (FAB) m/e__321 (M+H).
AP Ο Ο Ο 3 8 4
Χ-8571Α
-375Example.295
Η-.ί 2-,( 2-chlQrophenyl· ? ethyl1 -.Ν L-J 2.-14--.13-.
chlorophenylί11thiazolyl thiourea
A solution of 1-( (2-(4-(35 chlorophenyl]thiazolyl)thiocarbamoyl] imidazole (0.92 g,
2.86 mmol) and 2-(2-chlorophenyl)ethylamine (0.46 g, 2.86 mmol) in N,N-dimethylformamide (15 mL) was stirred at 90 *C for 2 h. The reaction was cooled to room temperature, poured into ethyl acetate, washed with water, IN aqueous
HCl, water, saturated sodium bicarbonate, and brine. The organic layer was concentrated and the resultant solid was
crystallized from EtOAc to provide 1.0 g (86%, of the titled product as yellow needles:
mp 193-195‘C;
15 IR (KBr, cm-1) 3018, 1560, 1515, 1470, 1291, 1210, 1065, 935, 785, 757, 716; Ih NMR (300 MHz, DMSO-dg) δ 11.66 (br s, IH) , 9.29 (br s,
IH), 7.79 (s, IH), 7.63 (m, 2H), 7.35 (m, 4H), 7.23 (m,
2H), 3.83 (m, 2H), 3.02 (t, J=7 Hz, 2H) ;
MS (FD) m/e 407 (M+), 409 (M+2);
UV (EtOH) 285nm (£=22709), 266 nm (£=20608), 202 nm (£=37861) .
Anal. Calcd for C18H15N3S2CI2: C, 52.94; H, 3.70; N, 10.29. Found: C, 52.96; H, 3.74; N, 10.49.
Example 296
N- f 2 - (3-methoxyphenyl)ethvl1-Ν'-(2-(4-(3chlorophenvl)11thiazolyl thiourea
A solution of 1-((2-(4-(330 chlorophenyl]thiazolyl)thiocarbamoyl] imidazole (0.92 g,
2.86 mmol) and 2-(3-methoxyphenylIethylamine (0.45 g, 2.86
X-8571A
-376mmol) in Λ', N-dimethyl formamide (15 mL) was stirred at 90*C for 2 h. The reaction was cooled to room temperature, poured into ethyl acetate, washed with water, IN aqueous HCl, water, saturated sodium bicarbonate, and brine. The organic layer was concentrated and the resultant solid was crystallized from EtOAc to provide 0.85 g (74%) of the titled product as a white solid:
mp 183-185’C;
IR (KBr, cm-1)3172, 3024, 1569, 1515, 1466, 1319, 1287, 1260, 1220, 1067, 996, 775, 728, 604;
1H NMR (30C MHz, DMSO-dg) δ 11.66 (br s, IH) , 9.20 (br s, IH), 7.81 's, IH), 7.63 (m, 2H), 7.35 (m, 2H), 7.16 (m,
IH), 6.73 m, 3H), 3.77 (m, 2H), 3.64 (s, 3H), 2.86 (t, J=7 Hz, 2H);
MS (FD) m/e 403 (M+), 405 (M+2);
UV (EtOH) 250nm (£=23880), 202 nm (£=42912).
Anal. Calcc for C19H18N3OS2CI: C, 56.49; H, 4.49; N,
10.40. Found: C, 56.62; H, 4.50; N, 10.58.
Example ,297
Ν-!2-(1-cvclohexenvl)ethvl)-N‘-(2-f4 - (3chlorophenvl)))thiazolyl thiourea
A solution of 1-((2-(4-(3chlorophenyl)thiazolyl)thiocarbamoyl] imidazole (0.92 g,
2.86 mmol) and 2-(1-cyclohexenyl)ethylamine (0.37 g, 2.86 mmol) in N, .’.'-dimethylformamide (15 mL) was stirred at 90'C for 0.5 h. The reaction was cooled to room temperature, poured into ethyl acetate, washed with water, IN aqueous HCl, water, saturated sodium bicarbonate, and brine. The organic layer was concentrated and the resultant solid was
AP Ο Ο Ο 3 8 4
Χ-8571Α
-377crystallized from EtOAc to provide 0.7 g (65%) of the titled product as a white solid: mp 196-197’C;
IR (KBr, cm-1) 2939, 1557, 1514, 1469, 1287, 1202, 1062,
881, 784, 719, 661;
!h NMR (300 MHz, DMSO-dg) δ 11.66 (br s, IH), 9.17 (br s, IH), 7.85 (s, IH), 7.76 (m, IH), 7.61 (s, IH) , 7.37 (m,
2H), 5.41(br s, IH), 3.60 (m, 2H), 2.20 (t, J=7 Hz, 2H),
1.87 (m, 4H), 1.46 (m, 4H) ;
MS (FD) m/e 377 (M+), 379 (M+2);
UV (EtOH) 285nm (8=23385) , 232 nm (8=18756), 202 nm (8=31779)
Anal. Calcd for C18H20N3S2CI: C, 57.20; H, 5.33; N, 11.12. Found: C, 57.04; H, 5.32; N, 11.09.
Example 298 lmf 12--.14-13.-nitrQPhenY3JxhiaaQlYl)thiQcarbamoy 11 ..imidazole
A solution of 1,1 ’-thiocarbonyldiimidazole (0.41g, 2.3mmol) and 4-(3-nitrophenyl)-2-thiazoleamine (0.5g, 2.3 mmol) in acetonitrile (25 mL) was stirred at room temperature for 72 h and heated at 60'C for 72 h. The resulting precipitate was collected by filtration to provide 0.51 g (68%) of the titled product:
MS (FAB) m/e 332 (M+H).
Anal. Calcd for C13H9N5O2S2: C, 47.12; H, 2.73; N, 21.13. ______Found: C, 47.35; H, 2.69; N, 21.03.
X-8571A.
-378Example 299.
N-f2-(1-cvclohexenvl)ethvl!-Ν' - Γ2- f4- (3nitxppheiiyl )..l.l.thi.azQlyl thiourea A solution of 1-((2-(4-(3nitrophenyl]thiazolyl) thiocarbamoyl] imidazole (0.5g, 1.5 mmol) and 2-(1-cyclohexenyl)ethylamine (0.19 g, 1.5 mmol) in Ν,Ν-dimethylformamide (15 mL) was stirred at 90‘C for
0.75 h. The reaction was cooled to room temperature, poured into ethyl acetate, washed with water, IN aqueous HCl, water, saturated sodium bicarbonate, and brine. The organic layer was concentrated and the resultant solid was crystallized from EtOAc to provide 0.37 g (63%) of the titled product as a yellow solid:
mp 218-221’C;
IR (KBr, cm'1) 3165, 3017, 2922, 1569, 1513, 1465, 1352,
1265, 1216, 1167, 1065, 877, 788, 713, 676;
l-H NMR (300 MHz, DMSO-dg) δ 11.76 (s, IH) , 8.85 (br s, IH) ,
8.61 (s, IH), 8.25 (d, J=8 Hz, IH), 8.11 (d. J=8 Hz, IH) ,
7.77 (s, IH), 7.67 (m, IH), 5. . 42 (br s, IH) , 3.58 (m, 2H) ,
2.2G (t, J=7 Hz, 2H), 1.89 (m, 4H), 1.46 (m, 4H); MS (FD)
m/e 388 (M+) ;
UV (EtOH) 286nm (£=22903), 265nm (£=23582), 237 nm (£=17806), 202 nm (£=24107)
Anal. Calcd for CI8H20N4O2S2: C, 55.65; H, 5.19; N, 14.42. Found: C, 55.45; H, 5.14; N, 14.51.
Example 3QQ
N-f2-(4-chloroohenyl) ethyl!-Ν' -f2-(4-cvano)thiazolyl!
thiourea A solution of 1-((2-(4cyano]thiazolyl) thiocarbamoyl] imidazole (0.71 g, 3.0 mmol)
AP Ο Ο Ο 3 8 4
Χ-8571Α
-379and 2-(4-chlorophenyl)ethylamine (0.48 g, 3.0 mmol) in Ν, Ndimethylformamide (20 mL) was stirred at 90'C for 2 h. The reaction was cooled to room temperature, poured into ethyl acetate, washed with water, IN aqueous HCl, water, saturated sodium bicarbonate, and brine. The organic layer was concentrated and the resultant solid was crystallized from EtOAc to provide 0.4 g (41%) of the titled product as a tan solid:
mp 188-190*C;
IR (KBr, cm-1) 3396, 3110, 2226, 1586, 1518, 1490, 1353,
1248, 1087, 808, 766, 649, 517;
iH NMR (300 MHz, DMSO-dg) 8 11.8 (s, IH) , 8.43 (br s, IH) ,
8.12 (s, IH), 7.33 (d. J= 8Hz, 2H), 7.24 (d, J= 8Hz, 2H), 3.69 (m, 2H), 2.84 (t, J=7 Hz, 2H);
MS (FD) m/e 322 (M+);
UV (EtOH) 287nm (£=10775), 257 nm (£=17025), 206 nm (£=31350) .
Ex ample,...3 01
N-(2-i4-methoxvphenvl)ethvl)-Ν'-(2-(4-cvano)thiazolyl)
Lhiputea
A solution of 1-((2-(4cyano]thiazolyl)thiocarbamoyl) imidazole (0.9 g, 3.8 mmol) and 2-(4-methoxyphenyl)ethylamine (0.59 g, 3.8 mmol) in
N,N-dimethylformamide (25 mL) was stirred at 90'C for 2 h.
The reaction was cooled to room temperature, poured into ethyl acetate, washed with water, IN aqueous HCl, water, saturated sodium bicarbonate, and brine. The organic layer was concentrated and the resultant solid was crystallized from EtOAc to provide 0.66 g (55%) of the titled product as a yellow solid:
X-8571A
-380mp 185-190'C;
IR (KBr, cm*1) 3208, 3064, 2236, 1547, 1514, 1259, 1201,
1164, 1033, 886, 775, 748, 680;
!h NMR (300 MHz, DMSO-dg) δ 11.8 (br s, IH), 8.4 (br s, IH) 8.1 (s, IH), 7.13 (d, J= 9Hz, 2H), 6.83 (d, J= 9Hz, 2H),
3.68 (s, 3H) , 3.64 (m, 2H) , 2.77 (t, J=7 Hz, 2H);
MS (FD) m/e 318 (M+);
UV (EtOH) 284nm (e=12158) , 258 nm (£=17248), 204 nm (£=30994) .
Example. .3.Q.2
1-f(2-benzimidazolvl)thiocarbamoyl1 imidazole
A solution of 1,1'-thiocarbonyldiimidazole (8.91g, 50 mmol) and 2-aminobenzimidazole (6.66g, 50 mmol) in acetonitrile (50 mL) was stirred at room temperature for 19 hours. The resulting precipitate was collected by filtration to provide 8.92 g (73%) of the titled product:
IR (KBr, cm-1) 3058, 2621, 1623, 1580, 1509, 1469, 1445,
1355, 1290, 1252, 1212, 1153, 1099, 1081, 1048, 925, 898, 746, 659;
XH NMR (300 MHz, DMSO-dg) δ 13.24 (br ε, 2H) , 8.52 (s, IH) ,
7.87 (s, IH), 7.57 (m, 2H), 7.33 (m, 2H), 6.96 (s, IH) ;
MS (FAB·) m/e 244 (M+1);
UV (EtOH) 351nm (£=18204), 283nm (£=13099), 227 nm (£=17339), 204 nm (£=31915) .
Example 3Q3
N- (2-(2-chlorophenvl)ethvll -N1 -(2-benzimidazolvl) thiourea
A solution of 1-((2benzimidazoly1)thiocarbamoyl) imidazole (1.22 g, 5.0 mmol) and 2-(2-chlorophenyl)ethylamine (0.81 g, 5.0 mmol) in N,NAP 0 0 0 3 8 4
-381X-8571A dimethylformamide (20 mL) was stirred at 90'C for 2 h. The reaction was cooled to room temperature, poured into ethyl acetate, washed with water, IN aqueous HCl, water, saturated sodium bicarbonate, and brine. The organic layer was concentrated and the resultant solid was crystallized from EtOAc to provide 0.67 g (40%) of the titled product as a white solid:
mp 166-169‘C;
IR (KBr, cm-1) 3235, 1656, 1554, 1459, 1248, 1224, 1192,
754, 737, 629;
!h NMR (300 MHz, DMSO-dg) 8 11.95 (br s, IH) , 10.82 (br s, IH), 7.42 (m, 5H) , 7.25 (m, 2H), 7.12 (m, 2H) , 3.83 (m,
2H) , 3.05 (t, J=7 Hz, 2H);
MS (FD)· m/e 330 (M+);
UV (EtOH) 301nm (£=18044), 293 nm (£=18559), 266 nm (£=11113), 260nm (£=10441), 239 nm (£=8428), 206 nm (£=27620).
Example 304
N- f 2-13 nghlorophenYllPthYU .-N ’ r (IrbenzimidazalYlL ...thiaurea
A solution of 1-((2benzimidazolyl) thiocarbamoyl]imidazole (1.22 g, 5.0 mmol) and 2-(3-chiorophenyl)ethylamine (0.79 g, 5.0 mmol) in N,Ndimethylformamide (20 mL) was stirred at 90’C for 2 h. The reaction was cooled to room temperature, poured into ethyl acetate, washed with water, IN aqueous HCl, water, saturated sodium bicarbonate, and brine. The organic layer was concentrated and the resultant solid was crystallized from EtOAc to provide 0.24 g (14%) of the titled product as a white solid:
mp 171-177‘C;
X-8571A
-382IR (KBr, cm’1) 3387, 1574, 1539, 1461, 1426, 1237, 1175, 734, 699, 477;
1H NMR (300 MHz, DMSO-c?6) δ 11.18 (m, 2H) , 7.28 (m, 8H) , 7.06 (m, IH), 3.83 (m, 2H), 2.94 (t, J=7 Hz, 2H) ;
MS (FD) m/e 330 (M+);
UV (EtOH) 293 nm (£=17219), 266 nm (£=9969), 260nm (£=9196), 240 nm (£=8196), 203 nm (£=27483).
Example.,.3 05.
N-f2-(4-chlorophenvl)ethyll-Ν'-(2-benzimidazolyl) thiourea
A solution of 1-((2benzimidazolyl)thiocarbamoyl]imidazole (1.22 g, 5.0 mmol) and 2-(4-chlorophenyl)ethylamine (0.79 g, 5.0 mmol) in Ν,Νdimethylformamide (20 mL) was stirred at 90 °C for 2 h.
The reaction was cooled to room temperature, poured into ethyl acetate, washed with water, IN aqueous HCl, water, saturated sodium bicarbonate, and brine. The organic layer was concentrated and the resultant solid was crystallized from EtOAc to provide 1.31 g (79%) of the titled product as a white solid:
mp 173-182'C;
IR (KBr, cm1) 3168, 3031, 1668, 1562, 1494, 1470, 1327, 1221, 1174, 1090, 817, 777, 742, 657, 526, 457;
XH NMR (300 MHz, DMSO-c?6) 5 12.18 (br s, IH) , 10.36 (br s, IH), 7.52 (m, 2H), 7.22-7.38 (m, 7H), 3.76 (m, 2H), 2.89 (t, J=7 Hz, 2H);
MS (FD) m/e 330 (M+), 332 (M+2);
UV (EtOH) 301nm (£=21672), 293 nm (£=22296), 266 nm (£=13408), 260nm (£=12591) , 206 nm (£=29310) .
X-8571A
APO00384
-383Ex ample ...3.06.
Ν- Γ2-(2-methoxvphenvl)ethvl]-Ν' - (2-benzimidazolyl.) -thiourea
A solution of 1-((2benzimidazolyl)thiocarbamoyl]imidazole (1.22 g, 5.0 mmol) and 2-(2-methoxyphenyl)ethylamine (0.82 g, 5.0 mmol) in
N, N-dimethylformamide (20 mL) was stirred at 90’C for 2 h. The reaction was cooled to room temperature, poured into ethyl acetate, washed with water, IN aqueous HCl, water, saturated sodium bicarbonate, and brine. The organic layer was concentrated and the resultant solid was crystallized from EtOAc to provide 0.62 g (38%) of the titled product as a white solid:
mp 176-184’C;
IR (KBr, cm’1) 3035, 1644, 1539, 1495, 1463, 1331, 1246,
1203, 1025, 750, 454;
TH NMR (300 MHz, DMSO-άζ) δ 11.95 (br s, IH), 10.32 (br s,
IH) , 7.52 (m, 2H), 7.20 (m, 5H), 6.88 (m, 2H), 3.75 (s, 3H) 3.70 (m, 2H), 2.88 (t, J=7 Hz, 2H) ;
MS (FD) m/e 326 (M+) ;
UV (EtOH) 301nm (£=20950), 293 nm (£=21508), 265 nm (£=14212), 239 nm (£=9552), 204 nm (£=30277).
Example.. 3.QZ
IL· (2- (3-methQ.xyphenvl) ethvl] -Ν' - (2-benzimidazolyl) thiourea
A solution of 1-((2benzimidazolyl) thiocarbamoyl] imidazole (1.22 g, 5.0 mmol) and 2-(3-methoxyphenyl) ethylamine (0.78 g, 5.0 mmol) in N, N-dimethylformamide (20 mL) was stirred at 90 *C for 2 h. The reaction was cooled to room temperature, poured into ethyl acetate, washed with water, IN aqueous HCl,.water, saturated sodium bicarbonate, and brine. The organic layer
X-8571A
-384was concentrated and the resultant solid was purified by chromatography on silica gel to provide 1.2 g (73%) of the titled product as a white solid:
mp 161-167’C;
IR (KBr, cm-1) 2932, 1574, 1541, 1460, 1230, 1152, 1016, 737, 694, 577, 461;
XH NMR (300 MHz, DMSO-dg) δ 11.14 (br s, 1H) , 10.95 (br s, 1H), 7.30 (m, 2H), 7.16 (m, 1H), 7.06(m, 2H), 6.87 (m, 2H),
6.75 (m, 2H), 3.83 (m, 2H) 3.80 (s, 3H), 2.89 (t, J=7 Hz, 2H) ;
MS (FD) m/e 326 (M+) ;
UV (EtOH) 301nm (£=23757), 293 nm (£=24495), 265 nm (£=16068), 260 nm (£=14682), 239 nm (£=11477), 204 nm (£=3 6963).
Example, .IQS
Ν-.Γ2- (4-methoxvphenvl)ethvll-N‘ - (2-benzimidazolvl) thiourea
A solution of 1-((2benzimidazolyl)thiocarbamoyl]imidazole (1.22 g, 5.0 mmol) and 2-(4-methoxyphenyl)ethylamine (0.77 g, 5.0 mmol) in Ν,Ν-dimethylformamide (20 mL) was stirred at 90’C for 1 h. The reaction was cooled to room temperature, poured into ethyl acetate, washed with water, IN aqueous HCl, water, saturated sodium bicarbonate, and brine. The organic layer was concentrated and the resultant solid was purified by chromatography on silica gel to provide 1.1 g (67%) of the titled product as a white solid:
mp 166-172’C;
IR (KBr, cm4) 3416, 3195, 3065, 1575, 1543, 1511, 1464, 1243, 1176, 1037, 747, 442;______
AP 0 0 0 3 8 4
X-8571A
-385!h NMR (300 MHz, DMSO-de) δ 11.11 (br s, IH) , 10.95 (br s, IH), 7.36 (m, 2H), 7.20 (d, J=8 Hz, 2H), 7.08(m, 3H), 6.82 (d, J=8 Hz, 2H), 3.78 (m, 2H) 3.67 (s, 3H), 2.85 (t, J=7 Hz, 2H);
MS (FD) m/e 326 (M+) ;
UV (EtOH) 301nm (£=24618), 293 nm (£=25247), 265 nm (£=16716), 260 nm (£=15557), 203 nm (£=3 5060).
Example 2.02
N-f2-(l-cvclohexenvl)ethvl1-N' -(2-benzimidazolvl) thiourea
A solution of 1-((2benzimidazolyl)thiocarbamoyl]imidazole (1.22 g, 5.0 mmol) and 2-(1-cyclohexenyl)ethylamine (0.64 g, 5.0 mmol) in Ν,Νdimethylformamide (20 mL) was stirred at 90*C for 2 h. The reaction was cooled to room temperature, poured into ethyl acetate, washed with water, IN aqueous HCl, water, saturated sodium bicarbonate, and brine. The organic layer was concentrated and the resultant solid was crystallized from EtOAc to provide 0.82 g (55%) of the titled product as yellow needles:
mp 178-180’C;
IR (KBr, cm1) 3182, 2922, 1576, 1540, 1421, 1271, 1232, 1033, 740, 450;
!h NMR (300 MHz, DMSO-c?6) δ 11.08 (br s, IH) , 11.07 (br s, IH), 11.02 (br s, IH), 7.36 (m, 2H), 7.06(m, 2H), 5.51 (s, IH), 3.66 (m, 2H), 2.21 (t, J=7 Hz, 2H), 1.93 (m, 4H), 1.51 (m, 4H) ;
MS (FD) m/e 300 (M+);
- j ~
Χ-8571Α
-386ID
UV (EtOH) 301nm (£=25279), 292 nm (£=26214), 265 nm (£=15965), 259 nm (£=14734), 239 nm (£=11012), 206 nm (£=30007) .
Anal. Calcd for C16H20N4S: C, 63.97; H, 6.71; N, 18.65. Found: C, 64.25; H, 6.99; N, 18.63.
Example .11Q.
l-f(2-pvridvl)thiocarbamoyl1 imidazole A solution of 1,1'-thiocarbonyldiimidazole (9.9 g, 50 mmol) and 2-aminopyridine (4.75 g, 50 mmol) in acetonitrile (50 mL) was stirred at room temperature for 72
h. The resulting solution was evaporated to a black oil and triturated with hexane. The remaining oily residue was placed under vacuum to provide 13.6 g of crude titled product as a black solid:
Th NMR (300 MHz, DMSO-dg) δ 8.89 (br s, IH) , 8.58 (m, IH) ,
8.35 (m, IH) , 7.80 (m. 2H), 7.40 (m, IH), 7.15 (m, IH) ,
6.95 (m, IH) ;
MS (FAB) m/e 204 (M+, weak)
Example 211
N-f2-(2-chlorophenvl)ethvll-N1-(2-pvridvl)thiourea
A solution of 1-[(2-pyridyl)thiocarbamoyl] imidazole (1.02 g, 5.0 mmol) and 2-(225 chlorophenyl)ethylamine (0.81 g, 5.0 mmol) in N,Ndimethylformamide (20 mL) was stirred at 90’C for 24 h.
The reaction was cooled to room temperature, poured into ethyl acetate, washed with water, IN aqueous HCl, water, saturated sodium bicarbonate, and brine. The organic layer
3C was concentrated and the resultant oil was purified by
AP 0 0 0 3 8 4
X-8571A -387chromatography on silica gel to provide 0.21 g (14%) of the titled product as a yellow solid: mp 116-122'C;
IR (KBr, cm1) 3235, 1606, 1592, 1558, 1537, 1477, 1439, 1332, 1259, 1234, 1212, 1185, 1150, 1088, 1057, 861;
1H NMR (300 MHz, DMSO-c?6) δ 11.63 (m, IH) , 10.53 (s, IH) , 8.03 (m, IH) , 7.68 (m, IH) , 7.41 (m, 2H) , 7.30 (m, 2H) ,
7.07 (m, IH) , 6.96 (m, IH) , 3.84 (m, 2H) , 3.04 (t, J=7 Hz, 2H) ;
MS (FD) m/e 291 (M+);
UV (EtOH) 293 nm (£=14959), 266 nm (£=15723), 246nm (£=15174), 201 nm (£=23340).
ExaiBB.lg„ 312
2-(2.6-Difluorophenyl)ethylamine
2,6-Difluorophenylacetonitrile (15.8g, 100 mmoDwas dissolved in tetrahydrofuran (75 mLj at room temperature. The solution was cooled in an ice bath and borane-THF complex (lOOmL, 100 mmol) was added dropwise over 15 minutes under nitrogen atmosphere. The ice bath was removed after borane addition was complete and the mixture was stirred at room temperature for 23 hours under nitrogen atmosphere. Saturated aqueous ammonium chloride solution (20 mL) was added dropwise with stirring over 30 minutes. The reaction mixture was filtered through diatomaceous earth, concentrated to an oil, redissolved in ethyl acetate/water, and adjusted to pH 1.0 with concentrated hydrochloric acid. The mixture was filtered through diatomaceous earch and the ethyl acetate layer extracted with IN hydrochloric acid (4 x 10 mL). The combined acidic aqueous extracts were washed with ethyl
X-8571A — 388 — acetate (2 x 50 ml). Solid sodium chloride was added to the acidic aqueous extracts, adjusted to pH 9.0 with solid sodium bicarbonate and 5N sodium hydroxide solution, and the mixture extracted with methylene chloride (7 x 50 mL).
The combined methylene chloride extracts were washed with brine solution, dried over anhydrous sodium sulfate, filtered, and concentrated to yield 10.6g (68%) of the titled product as a nearly colorless oil:
IR (KBrT cm'1) 2967, 2876, 1626, 1590, 1469, 1265, 1236,
1213, 1157, 1128, 1085, 1051, 1016, 956, 843;
XH NMR (300 MHz, CDCI3) δ 7.13 (m, IH), 6.83 (m, 2H), 2.89 (m, 2H), 2.80 (t, J=7 Hz, 2H), 1.19 (s, 2H) ;
MS (FD) m/e 157 (M+, weak);
UV (EtOH) 265nm (6=650), 260nm (6=674) , 204nm (6=7922) ;
TITRATION (66% DMF/H2O) pKa 9.06
Anal. Calcd for C8HgF2N: C, 61.14; H, 5.77; N, 8.91. Found: C, 60.88; H, 5.88; N, 8.63.
Example 313
N- L2- (2,$.ndiflvQrgphenY,l)ethY.l·,] -N1 -,.(2-(4ethvl)thiazolvllthiourea
A solution of 2-(2,6difluorophenyl)ethylamine(0.16 g, 1 mmol) and 1-((2-(4ethyl]thiazolyl) thiocarbamoyl] imidazole (0.24g, 1 mmol) in Ν,Ν-dimethylformamide (15 mL) was stirred at 90‘C for 2
h. The reaction was cooled to room temperature, poured into ethyl acetate, washed with water, IN aqueous HCl, water, saturated sodium bicarbonate, and brine. The organic layer was concentrated and the resultant solid was crystallized from EtOAc to provide 0.29 g (89%) of the titled product as a pale yellow solid:
AP 0 0 0 3 β 4
-389X-8571A mp 157-158’C;
IR (KBr, cm1) 3178, 2972, 1584, 1502, 1469, 1340, 1351, 1293, 1267, 1212, 1075, 1014, 953, 787, 726, 672;
!h NMR (300 MHz, DMSO-dg) δ 11.54 (br s, IH), 9.75 (br s, IH) , 7.29 (tn, IH) , 7.01 (m, 2H) , 6.58 (s, IH) , 3.77 (m,
2H), 2.92 (t, J=7 Hz, 2H), 2.45 (q, J=8 Hz, 2H), 1.05 (t, J=8 Hz, 3H);
MS (FD) m/e 327 (M+);
UV (EtOH) 292nm (£=18786), 257nm (£=10109), 202nm (£=19042) Anal. Calcd for C14H15F2N3S2: C, 51.36; H, 4.62; N, 12.83. Found: C, 51.60; H, 4.78; N, 13.08.
Example.. 11.4
N-I2-(2,6-dif luorophenyllethvl) -N' - (2-pvridvl) thiourea
A solution of 2-(2,6-difluorophenyl)ethylamine (0.43 g, 2.7 mmol) and 1-[(2-pyridyl)thiocarbamoyl] imidazole (0.55 g, 2.7 mmol) in N,N-dimethylformamide (20 mL) was stirred at 90'C for 27 h. The reaction was cooled to room temperature, poured into ethyl acetate, washed with water, IN aqueous HCl, water, saturated sodium bicarbonate, and brine. The organic layer was concentrated and the resultant oil was purified by chromatography on silica gel to provide 0.08 g (10%) of the titled product as a pale yellow solid:
mp 157-160'C;
IR (KBr, cm-1) 3226, 1605, 1539, 1466, 1332, 1260, 1236, 1188, 1100, 974, 899, 861, 774, 725, 635, 516; iH NMR (300 MHz, DMSO-dg) δ 11.68 (br S, IH) , 10.53 (br s, IH), 7.99 (m, IH), 7.70 (m, IH), 7.28 (m, IH), 7.04 (m,
4H), 3.82 (m, 2H), 2.97 (t, J=7 Hz, 2H);
X-8571A
-390MS (FD) m/e 293 (M+);
UV(EtOH) 292nm (£=15506) , 266nm (£=16020 ) , 245nm (£=14709)
Example 315
1-J (2-(2.6-difluorophenyl)ethvl)thiocarbamoylI imidazole
A solution of 1,11-thiocarbonyldiimidazole (9.5 g, 48 mmol) and 2-(2,6-difluorophenyl)ethylamine (7.54 g, mmol) in acetonitrile (100 mL) was stirred at room temperature for 20 h. The solution was concentrated under reduced pressure and the resulting precipitate was collected by filtration and triturated with hexane to provide 16 g of crude titled product as a brown solid:
IR (KBr, cm-1) 3129, 1565, 1468, 1355, 1259, 1203, 1120, 1065, 1031, 937, 900, 827, 787, 751, 664, 621, 499;
1H NMR (300 MHz, DMSO-d6) δ 10.50 (br s, IH), 8.29 (s, IH), 7.71 (s, IH), 7.35 (m, IH), 7.04 (m, 3H), 3.85 (m, 2H), 3.0 (m, 2H);
MS (FAB) m/e 268 (M+H);
UV(EtOH) 280nm (£=4068), 250nm (£=4341), 201nm (£=15062)
Example 316
Ν-Γ2- (1-cvclohexenvl)ethvll-Ν' -(2-(6chloro)PYrazinyllPhiQuraa
A solution of 2-amino-6-chloropyrazine (2.59 g, mmol) and 2-(1-cyclohexenyl)ethylisothiocyanate (3.34 g, 20 mmol) in N,N-dimethylformamide (25 mL) was stirred at 95 °C for 27 h. The reaction was cooled to room temperature, poured into ethyl acetate, washed with water, IN aqueous HCl, water, saturated sodium bicarbonate, and brine. The organic layer was concentrated and the resultant solid was
AP 0 0 0 3 8 4
X-8571A -391purified by chromatography on silica gel and crystallized from EtOAc to provide 0.44 g (7%) of the titled product as white needles:
mp 170-171‘C;
IR (KBr, cm4) 3207, 2926, 1584, 1514, 1414, 1295, 1161, 1005, 866, 714, 459;
!η NMR (300 MHz, DMSO-dg) δ 11.08 (br s, IH) , 10.02 (br s, IH), 8.49 (s, IH), 8.29 (s, IH), 5.48 (br s, IH) , 3.64 (m, 2H), 2.21 (t, J=7 Hz, 2H) , 1.90 (m, 4H), 1.49 (m, 4H) ;
MS (FD) m/e 296 (M+), 298 (M+2);
UV (EtOH) 327nm (£=12429), 266 nm (£=17577)
Anal. Calcd for C13H17N4SCI: C, 52.60; H, 5.77; N, 18.87. Found: C, 52.89; H, 5.89; N, 19.11.
Example, 31,7.
N--_f2- (2,.6-d-ifluorophenyl)ethvl) -Ν' -f2-(6methvl)pvridvl1 thiourea A solution of 1-((2-(2,6difluorophenyl)ethyl)thiocarbamoyl]imidazole (0.53 g, 2 mmol) and 2-amino-6-methylpyridine (0.22g, 2 mmol) in Ν,Νdimethylformamide (20 mL) was stirred at 90‘C for 3 h. The reaction was cooled to room temperature, poured into ethyl acetate, washed with water, IN aqueous HCI, water, saturated sodium bicarbonate, and brine. The organic layer was concentrated and the resultant solid was crystallized from EtOAc to provide 0.14 g (23%) of the titled product as nearly colorless prisms:
mp 187-189‘C;
IR (KBr, cm1) 3195, 1612, 1544, 1468, 1451, 1380, 1293, 1269, 1230, 1192, 1160, 1072, 950, 788, 722, 635, 501;
X-8571A
-392-
!η NMR (300 MHz, DMSO· -<?6) 1 δ 11. 83 (br s, IH ), 10.44 (br s
IH), 7.56 (t, J= 8 Hz, IH) , 7.26 (m, IH), 6. 98 (m, 2H) ,
6.87 (d, J=8 Hz, IH) , 6.79 (a, J=8 Hz, IH), 3.87 (m, 2H) ,
2.94 (t, J=7 Hz, 2H) , 2.11 (s, 3H) ;
MS (FD) m/e 307 (M+ ) ;
UV(EtOH) 296nm (£=12052) , 265nm (£=10578 ) , 24 6nm (£=10257) Anal. Calcd for C15H15F2N3S: C, 58.62; H, 4.92; N, 13.67. Found: C, 58.35; H, 4.98; N, 13.39.
Example 318
Ν- Γ2-(1-cvclohexenvl)ethvl)-N’-f2-(3,5dimethvl)ovrazinvllthiourea A solution of 2-amino-3,5-dimethylpyrazine (0.62 g, 5 mmol) and 2-(1-cyclohexenyl)ethylisothiocyanate (0.84 g, 5 mmol) in N, N-dimethylformamide (20 mL) was stirred at 90'C for 24 h. The reaction was cooled to room temperature, poured into ethyl acetate, washed with water, IN aqueous HCl, water, saturated sodium bicarbonate, and brine. The organic layer was concentrated and the resultant oil was purified by chromatography on silica gel to provide 0.27 g (19%) of the titled product as an off-white solid: mp 100-103’C;
IR (KBr, cr1) 3387, 2929, 1515, 1329, 1214, 1164, 1014, 966, 907;
!h NMR (300 MHz, DMSO-dg ) δ 10.57 (br s, IH) , 9.12 (br s,
IH) , 7.91 (S, IH) , 5.44 (br s, IH), 3.61 (m, 2H) , 2.47 (S,
3H) , 2.35 (s, 3H) , 2.18 (t, J=7 Hz, 2H), 1.90 (m, 4H) , 1.48
(m, 4H);
MS (FD) m/e 290 (M+);
AP Ο Ο Ο 3 8 4
Χ-8571Α -393UV (EtOH) 320nm (£=11659), 265 nm (£=16153), 201 nm (£=11795)
Anal. Calcd for C15H22N4S: C, 62.03; H, 7.63; N, 18.29. Found; C, 62.06; H, 7.65; N, 18.58.
Example. 319, lir..I2,-J2x.6-d,iflv,QrQBh.enYl) ethYl.I.-Ν·' tL2.-.(5trifluoromethvl) pvridvl 1 thiourea A solution of 1-((2-(2,δ10 difluorophenyl) ethyl) thiocarbamoyl] imidazole (1.07 g, 4 mmol) and 2-amino-5-trif luoromethylpyridine (0.65 g, 4 mmol) in N, N-dimethylformamide (20 mL) was stirred at 95* C for 25 h. The reaction was cooled to room temperature, poured into ethyl acetate, washed with water, IN aqueous
HCl, water, saturated sodium bicarbonate, and brine. The organic layer was concentrated and the resultant solid was purified by chromatography on silica gel to provide 0.26 g (18%) of the titled product as a white solid:
mp 148-152’C;
IR (KBr, cm-1) 3165, 3033, 1619, 1600, 1548, 1470, 1332, 1248, 1189, 1160, 1138, 1106, 1079, 964, 886, 776, 669,
603, 435;
Ih NMR (300 MHz, DMSO-d6) δ 11.42 (br s, IH), 10.94 (br s, IH), 8.36 (s, IH), 8.08 (m, IH), 7.28 (m, 2H), 7.02 im,
2H), 3.82 (m, 2H), 2.98 (t, J=7 Hz, 2H);
MS (FD) m/e 361 (M+);
UV(EtOH) 297nm (£=18455), 253nm (£=14782) , 201nm (£=15765) Anal. Calcd for C15H12F5N3S: C, 49.86; H, 3.35; N, 11.63. Found: C, 4 9.59; H, 3.28; Ν, 11^35
X-8571A
-394Examole 320
N-f 2 -12.x.£-difluor-OPhenvl) ethvl)-N1 -f 2 - (5 chloro)pvridvllthiourea
A solution of 1-((2-(2,6cifluorophenyl) ethyl)thiocarbamoyl] imidazole (1.07 g, 4 mmol) and 2-amino-5-chloropyridine (0.53 g, 4 mmol) in N,Kdimethylformamide (20 mL) was stirred at 90'C for 22 h.
The reaction was cooled to room temperature, poured into ethyl acetate, washed with water, IN aqueous HCl, water, saturated sodium bicarbonate, and brine. The organic layer was concentrated and the resultant solid was crystallized from EtOAc to provide 0.65 g (50%) of the titled product as a tan solid:
mp 172-175*C;
IR (KBr, cm*1) 3233, 1597, 1557, 1529, 1468, 1340, 1308, 1265, 1231, 1190, 1112, 1072, 950, 857, 834;
-H NMR (300 MHz, DMSO-dg) δ 11.19 (m, IH) , 10.67 (s, IH),
8.03 (s, IH), 7.82 (m, IH) , 7.30 (m. IH) , 7.13 (m, IH) ,
7.03 (m, 2H), 3.79 (m, 2H) , 2.96 (t, J=7 Hz, 2H);
MS (FD) m/e 327 (M+), 329 (M+2);
UV (EtOH) 304nm (£=13180) , 274nm (£=23154) , 253 nm
(£=15998), 201 nm (£=19019)
Example 321
N- (2-(2,6-difluorophenyl)ethvl1-N'-Γ2 - (5methvl)pvridvl1 thiourea A solution of 1-((2-(2,6cifluorophenyl) ethyl)thiocarbamoyl]imidazole (1.33 g, 5 mmol; and 2-amino-5-methylpyridine (0.54 g, 5 mmol) in N,Kdimethylformamide (20 mL) was stirred at 90‘C for 7 h. The reaction was cooled to room temperature, poured into ethyl
AP Ο Ο Ο 3 8 4
Χ-8571Α
-395acetate, washed with water, IN aqueous HCl, water, saturated sodium bicarbonate, and brine. The organic layer was concentrated and the resultant solid was crystallized from EtOAc to provide 0.83 g (86%) of the titled product as yellow crystals: mp 195-196’C;
IR (KBr, cm-1) 3230, 1611, 1535, 1492, 1468, 1334, 1274, 1236, 1190, 1111, 1065, 957, 821, 777, 716, 657, 608, 513; !h NMR (300 MHz, DMSO-d6) δ 11.59 (br s, IH), 10.44 (br s,
IH), 7.83 (br s, IH), 7.53 (d, J=8 Hz, IH), 7.30 (m, IH), 7.02 (m, 3H), 3.80 (m, 2H), 2.96 (t, J=7 Hz, 2H), 2.16 (s, 3H) ;
MS (FD) m/e 307 (M+);
UV(EtOH) 297nm (£=5129) , 2 68nm (£=7508) , 247nm (£=53 83)
Anal. Calcd for C15H15F2N3S: C, 58.62; H, 4.92; N, 13.67.
Found: C, 58.36; H, 4.98; N, 13.73.
Example.322
N- (2- (2,6-difluorophenyl)ethvll-Ν' -12-(520 bromo)pyrazinyl 1 thiguraa
A solution of 1-((2-(2,6difluorophenyl) ethyl)thiocarbamoyl] imidazole (1.33 g, 5 mmol) and 2-amino-5-bromopyrazine (0.87 g, 5 mmol) in N,Ndimethylformamide (20 mL) was stirred at 95’C for 26 h.
The reaction was cooled to room temperature, poured into ethyl acetate, washed with water, IN aqueous HCl, water, saturated sodium bicarbonate, and brine. The organic layer was concentrated and the resultant solid was purified by chromatography on silica gel to provide 0.31 g (17%) of the titled product as a white solid:
________mp 175-178’C;_____
X-8571A
-396IR (KBr, cm'1) 3200, 1596, 1560, 1526, 1469, 1441, 1324, 1259, 1179, 1161, 1114, 1012, 962, 899, 874, 788, 780, 667 601;
1H NMR (300 MHz, DMSO-d6) δ 10.98 (br s, IH) , 10.51 (br s, IK), 8.33 (s, IH), 8.24 (s, IH), 7.31 (m, IH), 7.04 (m,
2H), 3.81 (m, 2H), 2.97 (t, J=7 Hz, 2H);
MS (FD) m/e 372 (M+) , 374 (M+2);
UV (EtOH) 333nm (£=10125) , 275nm (£=22570) , 201 nm (£=16801)
Anal. Calcd for Cl3HllBrF2N4S: C, 41.84; H, 2.97; N,
15.01. Found: C, 42.10; H, 3.12; N, 14.73.
Example 323
N-f2 - (2.6-difluorophenyl)ethvl)-N’-f2-(6ethyl)pyridyl1 thiourea A solution of 1-((2-(2,6difluorophenyl)ethyl)thiocarbamoyl]imidazole (1.33 g, 5 mmol) and 2-amino-6-ethyIpyridine (0.61 g, 5 mmol) in N,Ndimet'nyl formamide (20 mL) was stirred at 95‘C for 21 h.
The reaction was cooled to room temperature, poured into ethyl acetate, washed with water, IN aqueous HCl, water, saturated sodium bicarbonate, and brine. The organic layer was concentrated and the resultant solid was crystallized from EtOAc to provide 0.63 g (39%) of the titled product as dense yellow crystals:
mp 147-148’C;
IR (KBr, cm’1) 2972, 1609, 1541, 1468, 1344, 1292, 1265, 1225, 1155, 1073, 951, 804, 786, 727, 692, 635, 501;
^H NMR (300 MHz, DMSO-d6) δ 11.97 (m, IH) , 10.48 (br s, IH) , 7.59 (t, J=8 Hz, IH), 7.27 (m, IH), 6.98 (m, 2H), 6.89 (a,
AP Ο Ο Ο 3 8 4
Χ-8571Α
-398Example 325
Ν.-Ι2-(2-pyridylJ.ethyl] -12-(.4-cyano! thia spiv! 1.. thic:;r.sa
A solution of 1-((2-(4cyano]thiazolyl)thiocarbamoyl] imidazole (2.35 g, 10 mmol) and 2-(2-pyridyl)ethylamine (1.29 g, 10 mmol) in Ν,Νdimethylformamide (25 mL) was stirred at 95*C for 2 h. The reaction was cooled to room temperature, poured into ethyl acetate, washed with water, saturated sodium bicarbonate, and brine. The organic layer was concentrated and the residue purified by chromatography on silica gel to provide 0.4 g (14%) of the titled product as a yellow solid: mp 160C;
IR (KBr, cm-1) 3165, 3100, 2996, 2234, 1540, 1489, 1433, 1305, 1266, 1219, 1159, 1132, 999, 904, 817, 758, 574, 435;
Ih NMR (300 MHz, DMSO-dg) δ 11.88 (br s, IH) , 8.67 (br s,
IH) , 8.49 (d, J=4 Hz, IH), 8.11 (s, IH), 7.69 (m, IH) , 7.23 (m, 2H), 3.87 (ra, 2H) , 3.01 (t, J=7 Hz, 2H) ;
MS (FD) m/e 289 (M+);
UV (EtOH) 288nm (£=10826), 257 nm (£=19925), 205 nm (£=28658) .
Example 326
K- (.2- (2, 6.rhif luorophenylLgthyll.-K’.z (3-.(.4-.
methvl)pvridvl1 thiourea
A solution of 1-((2-(2,6difluorophenyl) ethyl)thiocarbamoyl]imidazole (1.33 g, 5 mmol) and 2-amino-4-methylpyridine (0.54 g, 5 mmol) in Ν,Νdimethylf ormamide (20 mL) was stirred at 90‘C for 3 h. The reaction was cooled to room temperature, poured into ethyl acetate, washed with water, IN aqueous HCl, water, ___saturated sodium bicarbonate, and brine. The organic layer
X-8571A
-399was concentrated and the resultant solid was crystallized from EtOAc to provide 0.49g (32%) of the titled product as yellow needles:
mp 168-170'C;
IR (KBr, cm-1) 3233, 1616, 1536, 1465, 1335, 1262, 1191, 1104, 959, 815, 783, 719, 653, 442;
1H NMR (300 MHz, DMSO-dg) δ 11.74 (br s, 1H) , 10.44 (br s,
1H) , 7.85 (d, J=5 Hz, 1H), 7.27 (m, 1H) , 7.02 (m, 2H), 6.88
(s, 1H), 6.80 (d, J=5 Hz, 1H), 3.80 (m, 2H), 2.96 (t, J=7
Hz, 2H), 2.20 (s, 3H) , t
MS (FD) · m/e 307 (M+);
UV(EtOH) 290nm (£=16210), 266nm (£=15920), 246nm (£=13211), 202nm (£=13211)
Example 327
N-.f 2- (2,6-di.fluorophenyl) ethvll -N' -12-(4fithvl1pvridvl1 thiourea A solution of 1-((2-(2,6difluorophenyl) ethyl) thiocarbamoyl]imidazole (1.33 g, 5 mmol) and 2-amino-4-ethylpyridine (0.61 g, 5 mmol) in Ν,Νdimethylformamide (20 mL) was stirred at 95'C for 3 h. The reaction was cooled to room temperature, poured into ethyl acetate, washed with water, IN aqueous HCl, water, saturated sodium bicarbonate, and brine. The organic layer was concentrated and the resultant solid was crystallized from EtOAc to provide 0.32 g (20%) of the titled product as a light brown solid:
mp 140-142*C;
IR (KBr, cm-1) 2939, 1616, 1590, 1536, 1469, 1341, 1267,
1189, 1104, 1064, 960, 868, 826, 781, 759, 721, 668, 652;
AP 0 0 0 3 8 4
X-8571A !h NMR (300 MHz, DMSO-dg) 8 11.74 (br s, IH), 10.42 (br s,
-400-
IH), 7.87 (d, J=5 HZ, IH) , 7. 29 (m, IH) , 6.99 tin, 2H), 6.85
(s, IH), 6.84 (d, J=5 Hz, IH) , 3.81 (m, 2H), 2.95 (t, J=7
Hz, 2H), 2.49 <Q r J=8 Hz, 2H) , 1.09 (t, J=8 Hz, 3H);
MS (FD) m/e 321 (M+);
UV(EtOH) 290nm (ε=18247), 266nm (£=18045), 246nm (£=15212), 202nm (£=27817)
Anal. Calcd for C16H17F2N3S: C, 59.79; H, 5.33; N, 13.07. Found; C, 59.50; H, 5.31; N, 12.87.
Example. 3.2 £
1-f(2-(2-pvridvl)ethvl)thiocarbamovl1 imidazole
A solution of 1,1'-thiocarbonyldiimidazole (9.9 g, 50 mmol) and 2-(2-pyridyl)ethylamine (6.43 g, 50mmol) in acetonitrile (120 mL) was stirred at room temperature for 24 h. The solution was concentrated under reduced pressure and the resulting brown oil was triturated with ethyl ether. The remaining oil was placed under vacuum to provide 10.7 g of crude titled product as a black solid;
IR (KBr, cirr1) 3125, 2930, 2098, 1548, 1477, 1437, 1363, 1329, 1284, 1221, 1098, 1063, 1030, 925, 828, 750, 661,
620;
!h NMR (300 MHz, DMSO-dg) 8 10.35 (br s, IH) , 8.48 (m, IH) ,
8.33 (s, IH), 7.76 (s, IH), 7.72 (m, 2H) , 7.25 (m, 2H),
3.95 (m, 2H), 3.1 (m, 2H);
MS (FAB) m/e 233 (M+H);
UV(EtOH) 267nm (£=5516) , 261nm (£=6306) , 256nm (£=6220) ,
203nm (£=14929)
AP 0 0 0 3 8 4
X-8571A
-401Example...
N-f2-(2-pvridvl)ethvl1-N'-f2-(Ξ-bromo)pyrazinyl!thiourea
A solution of 1-((2-(2pyridyl)ethyl)thiocarbamoyl] imidazole (1.16 g, 5 mmol) and
2-amino-5-bromopyrazine (0.87 g, 5 mmol) in Ν,Νdimethylformamide (20 mL) was stirred at 95’C for 27 h.
The reaction was cooled to rocm temperature, poured into ethyl acetate, washed with water, saturated sodium bicarbonate, and brine. The organic layer was concentrated and the residue purified by chromatography on silica gel and crystallized from EtOAc to provide 0.13 g (7%) of the titled product as a tan solid:
mp 185-190'C;
IR (KBr, cm1) 3186, 1588, 1558, 1517, 1479, 1439, 1356, 1325, 1289, 1268, 1220, 1185, 1155, 1100, 1083, 1013, 996, 900, 876, 800, 760, 716, 569, 511, 431;
XH NMR (300 MHz, DMSO-dg) δ 10.93 (br s, IH), 10.74 (br s, IH) , 8.54 (d, J=5 Hz, IH), 8.31 (s, IH), 8.28 (s, IH), 7.69 (m, IH), 7.28 (m, IH), 7.21 (m, IH) , 3.96 (m, 2H), 3.05 (t, J=7 Hz, 2H);
MS (FD) m/e 337 (M+), 339 (M+2);
UV (EtOH) 333nm (€=10984) , 270 nm (€=25064) .
Anal. Calcd for Ci2Hi2BrN5S: C, 42.61; H, 3.58; N, 20.71. Found: C, 42.41; H, 3.83; N, 20.54 .
Example 330
N-_f2- (2.6-dif luoropher.vl’ ethvl! -Ν' -f2-(5£hlorp?.pyrazinYl,'..thigur,ea A solution of 1-((2-(2,6difluorophenyl) ethyl) thiocarbamoylj imidazole (1.33 g, 5 mmol) and 2-amino-5-chloropyrazine (0.65 g, 5 mmol) in N,N-
bad original
X-8571A
-402dimethylformamide (20 mL) was stirred at 95'C for 24 h.
The reaction was cooled to room temperature, poured into ethyl acetate, washed with water, IN aqueous HCl, water, saturated sodium bicarbonate, and brine. The organic layer was concentrated and the resultant solid was purified by chromatography on silica gel and crystallized from EtOAc to provide 0.1 g (6%) of the titled product as a white solid: mp 170-171*C;
IR (KBr, cm4) 3199, 3070, 1593, 1563, 1529, 1468, 1443, 1418, 1327, 1263, 1184, 1166, 1128, 1016, 779;
!h NMR (300 MHz, DMSO-dg) δ 11.00 (br s, IH) , 10.53 (br s, IH), 8.33 (s, IH), 8.19 (s, IH), 7.30 (m, IH) , 7.04 (m,
2H), 3.81 (m, 2H), 2.96 (t, J=7 Hz, 2H) ;
MS (FD) m/e 328 (M+), 330 (M+2);
UV (EtOH) 332nm (£=10097) , 274nm (£=22879)
Anal. Calcd for C13H11CIF2N4S: C, 47.49; H, 3.37; N,
17.04. Found: C, 47.54; H, 3.45; N, 17.19.
Example 331
1-ί(2-(5-ethoxv carbonvl)thiazolyl)thiocarbamovl) imidazole
A solution of 1,1‘-thiocarbonyldiimidazole (8.9 g, 50 mmol) and 2-amino(5-ethoxy carbonyl)thiazole (8.9 g, mmol) in acetonitrile (600 mL) was stirred at 50'C for 20 h. The resulting precipitate was collected by filtration to provide 6.5 g (40%) of the titled product, mp 208-210’C (d).
IR (KBr, cm1) 3205, 3176, 3146, 3115, 1708, 1557, 1470, 1352, 1298, 1244, 1225;
iH NMR (300 MHz, DMSO-dg) δ 13.2 (br s, IH) , 8.1 (s, IH) ,
7.9 (s, IH), 7.6 (s, IH), 7.1 (s, IH), 4.2 (q, 2H), 1.3 (t, 3H) ;
AP 0 0 0 3 8 4
X-8571A
-403MS (FD) m/e (no correct pk) (M+);
UV (EtOH) 349 nm (£=4746), 269 nm (£=8713), 209 nm (£=21033). Anal. Calcd for C10H10N4O2S2: C, 42.54 H, 3.57; N, 19.84. Found: C, 42.37; H, 3.55; N, 19.59.
Example. 33.2
N- f 2-(l-cvclohexenvl)ethyl]-N,_-J2- (5-ethoxv .carfeppy 1 ).t h i a s o ly 11 t h i our e.a A solution of 1-[(2-[5-ethoxy carbonyl)thiazolyl)thiocarbamoyl] imidazole ¢1.12 g, 4.0 mmol) and 2-(1-cyclohexenyl)ethylamine (0.5 g, 4.0 mmol) in Ν,Ν-dimethylformamide (40 mL) was stirred at 90 °C for 1 h. The reaction was cooled to room temperature, poured into ethyl acetate, washed with water, IN aqueous HCI, water, saturated sodium bicarbonate, and brine. The organic layer was concentrated and the residue recrystallized from ethyl acetate to provide 0.790 g (56%) of the titled product: mp. 197-198’C;
IR (KBr, cm-1) 3243, 3121, 3044, 2991, 2925, 1707, 1582, 1543, 1458, 1190;
1H NMR (300 MHz, DMSO-d6) δ 12.0 (br s, IH) , 8.5 (br s, IH) ,
7.9 (s, IH), 5.5 (s, IH), 4.3 (q, 2H) , 3.6 (m, 2H) , 2.2 (t, J=7 Hz, 2H), 1.9 (m, 4H), 1.5 (m, 4H) , 1.3 (t, J=7 Hz, 3H); MS (FD) m/e 339 (M+);
UV (EtOH) 262nm (£=17510) , 205 nm (£=19237).
Anal. Calcd for C15H21N3O2S2: C, 53.07; H, 6.23; N, 12.38. Found: C, 53.31; H, 6.44; N, 12.42.
X-8571A
-404Example 333
N-(2-phenethyl)-Ν' -f2-(5-ethoxy carbonyl)thiazolyll thiourea
A solution of 1-[ (2-[5-ethoxy carbonyl]thiazolyl)thiocarbamoyl] imidazole (1.1 g, 4.0 mmol) and 2-(1-phenyl)ethylamine (0.6 g, 4.0 mmol) in N,Ndimethylformamide (40 mL) was stirred at 90‘C for 1 h. The reaction was cooled to room temperature, poured into ethyl acetate, washed with water, IN aqueous HCl, water, saturated sodium bicarbonate, and brine. The organic layer was concentrated and the residue crystallized from ethyl acetate to provide 1.07 g (80%) of the titled product: mp. 174-175’C;
IR (KBr, cm-1) 3340, 3253, 3124, 3056, 1707, 1682, 1579, 1537, 1454, 1252, 1222;
Th NMR (300 MHz, DMSO-dg) δ 12.0 (br s, IH) , 8.7 (br s, IH) ,
7.9 (s, IH), 7.3 (m, 5H), 4.3 (q, 2H), 3.8 (m, 2H), 2.9 (t, J=7 Hz, 2H), 1.3 (t, J=7 Hz, 3H);
MS (FD) m/e 335 (M+);
UV (EtOH) 262nm (£=19184), 206 nm (£=26117).
Anal. Calcd for C15H17N3O2S2: C, 53.71; H, 5.11; N, 12.53. Found: C, 53.48; H, 5.10; N, 12.68.
Example.,, 331
N-J2-(lrcvclohexenvl)ethvll-Ν' -Γ2-(5-chIoro)pvridvll
LhiciiEjea
A solution of 2-amino-5-chloropyridine (1.28 g, 10.0 mmol) and 2-(l-cyclohexenyl)ethylisothiocyanate (1.67 g, 10.0 mmol) in N,N-dimethylformamide (30 mL) was stirred at 90'C for 1 h. The reaction was cooled to room temperature, concentrated under vacuum to remove solvent.
AP 0 0 0 3 8 4
-405X-8571A
The residue was purified by HPLC to provide 0.560 g (19%) of the titled product: mp. 166-167’C;
IR (KBr, cm'1) 3455, 3159,1599, 1555, 1534, 1476;
!h NMR (300 MHz, DMSO-dg) δ 11.1 (br s, IH) , 10.7 (s, IH) ,
8.2 (d, IH), 7.9 (m, IH), 7.2 (d, IH), 5.5 (s, IH), 3.6 (m, 2H), 2.2 (t, J=7 Hz, 2H), 1.9 (m, 4H), 1.5 (m, 4H);
MS (FD) m/e 295 (M+);
UV (EtOH) 305nm (e=12139), 273nm (6=15505), 244 nm (6=25052). Anal. Calcd for C14H18N3SCI C, 56.84; H, 6.13; N, 14.20. Found: C, 56.59; H, 6.00; N, 14.09.
Example, 22?
N.-12--(2--chlorophenvI) ethvl1 -Ν' - f2-(5-chloro)pvridvl1 thiourea
A solution of N-[2-(2-chlorophenyl)ethyl]-Ν'thiocarbamoyl imidazole (1.3 g, 5.0 mmol) and 2-amino-5chloro pyridine (0.65 g, 5.0 mmol) in Ν,Ν-dimethylformamide (25 mL) was stirred at 100’C for 1 h. The reaction was cooled to room temperature, poured into ethyl acetate, washed with water and brine. The organic layer was concentrated and the residue triturated with hexane to provide 0.83 g (55%) of the titled product:
mp 178-179’C;
1H NMR ¢300 MHz, DMSO-dg) δ 11.2 (m, IH) , 10.7 (s, IH), 8.1 (m, IH), 7.5 (m, IH), 7.4 (m, 2H), 7.2 (m, 2H), 7.1 (d,
IH) , 3.8 (rr., 2H) , 3.1 (t, J=7 Hz, 2H) ;
MS (FD) m/e 325 (M+);
UV (EtOH) 305nm (6=12931), 273 nm (6=22583), 253 nm (6=16558) 201 nm (6=25277) .
X-8571A
-406Anal. Calcd for C3.4H13N3SCI: C, 51.54; H, 4.02; N, 12.88. Found: C, 51.26; H, 3.99; N, 12.79.
Examgls.....
N- f2 - (1-cvclchexenvl) ethvl) -Ν' - f 3- (6-chloro)pyridazinyl) thiourea
A solution of 3-amino-6-chloropyridazine (1.3 g, 10.0 mmol) and 2 - (1-cyclohexenyl) ethylisothiocyanate (1.67 g, 10.0 mmol) in Ν,Ν-dimethylformamide (20 mL) was stirred at 90 °C for 1.5 h. The reaction was cooled to room temperature and concentrated under vacuum to remove solvent. The residue was purified by HPLC to provide 0.220 g (7.5%) of the titled product:
mp. 149-153’C;
pKa in (66% DMF) 12.8;
IR (KBr, cm-1) 3203, 3072, 2935, 1599, 1565, 1520, 1424, 1351, 1308, 1280, 1184, 1147, 1073;
!h NMR (300 MHz, DMSO-dg) δ 11.1 (m, IH), 10.9 (s, IH), 7.8 (d, 1Η) , 7.6 (d, 1Η) , 5.5 (s, IH) , 3.7 (m, 2H) , 2.2 (t, J=7
Hz, 2H) , 1.9 (m, 4H) , 1.5 (m, 4H) ;
MS (FD) m/e 296 (M+) ;
UV (EtOH) 275nm (6=23066) .
Anal. Calcd for C13H17N4SCI C, 52.60; H, 5.77; N, 18.87. Found: C, 52.85; H, 5.84; N, 19.15.
Example 337
Ν- ί2- (2, 6-difluorophenyl)ethvl)-N*-F3-(6chloro)pyridazinyl) thiourea A solution of N-[2-(2, 6-difluorophenyl)ethyl]30 Ν'-thiocarbamoyl imidazole (1.33 g, 5.0 mmol) and 3-amino__________6nchloropyridazine (0.65 g, 5.0 mmol) in Ν, NAP 0 0 0 3 8 4
X-8571A
-407dimethylformamide (20 mL) was stirred at 80'C for 19 h.
The reaction was cooled to room temperature, poured into ethyl acetate, washed with water and brine. The organic layer was concentrated and the residue was purified by HPLC to provide 0.12 g (7.5%) of the titled product: mp 187-189*C;
IR (KBr, cm1) 3199, 3055, 1626, 1593, 1555, 1522, 1469,
1425, 1348,1313, 1263;
1H NMR (300 MHz, DMSO-d6) δ 11.2 (m, IH) , 10.9 (s, IH) , 7.9 (d, IH), 7.6 (d, IH), 7.3 (m, IH) , 7.1 (m, 2H), 3.9 (m,
2H), 3.0 (t, J=7 Hz, 2HJ;
MS (FD) m/e 328 (M+);
pKa in (66% DMF) 12.73;
UV (EtOH) 277nm (£=20141), 252 nm (£=12935), 201 nm (£=17891) .
Example .33$
N-(2-(2. 6-difluorophenyl) ethyl)-Ν'-f3-(6methoxv)pyridazinyl) thiourea A solution of N-(2-(2, 6-difluorophenyl)ethyl]N'-thiocarbamoyl imidazole (0.8 g, 3.0 mmol) and 3-amino-6methoxy pyridazine (0.4 g, 3.0 mmol) in Ν,Νdimethyl formamide (20 mL) was stirred at 70’C for 19 h.
The reaction was cooled to room temperature, poured into ethyl acetate, washed with water and brine. The organic layer was concentrated and the residue was precipitated with diethyl ether to provide 0.235 g (24%) of the titled product:
mp 193-196*C;
IR (KBr, οη’1) 3222, 3084, 1628, 1586, 1560, 1531, 1468,
1423, 1356, 1310, 1266;
X-8571A
-408ΪΗ NMR (300MHz, DMSO-dg) δ 11.45 (m, IH), 10.7 (s, IH), 7.42 (d, J=10 Hz, IH), 7.28 (m, IH), 7.21 (d, J=10 Hz, IH), 7.0 (t,J=8 Hz, 2H), 3.9 (s, 3H), 3.85 (m, 2H), 3.0 (t, J=7 Hz, 2H);
MS (FD) m/e 324 (M+) ;
UV (EtOH) 269nm (£=18845), 235 nm (£=10636), 201 nm (£=16622) .
Example 339
N- f2 - (2-pyridvl)ethvll-Ν’-Γ3- L6-chloro)pyridazinyl1
PhiQvrea
A solution of 1,1'-thiocarbonyldiimidazole (1.83 g, 10.0 mmol) and 3-amino-6-chloro pyridazine (1.3 g, 10.0 mmol) in acetonitrile (100 mL) was stirred at room temperature for 288 h. To this solution was added 2-(2aminoethyl) pyridine (1.22 g, 10 mmol) and the resultant mixture stirred at room temperature for 48 h. The solvent was removed in vacuo and the residue purified by HPLC to provide 0.300 g (10.0%) of the titled product:
mp 197-199*C;
R (KBr, cm1) 3172, 3045, 1583, 1562, 1511, 1478, 1428,
1345,1313, 1280;
!h NMR (300MHz, DMSO-dg) δ 11.3 (m, IH), 10.9 (s, IH), 8.6 (d, J=5 Hz, IH), 7.8 (d, J=10 Hz, IH), 7.7 (m, 1Η), 7.55 (d, J=10 Hz, 1Η), 7.3 (d, J=8 Hz, IH), 7.2 (m, 1Η), 4.0 (m, 2Η), 3.1 (t, J=7 Hz, 2H);
MS (FD) m/e 293 (M+);
pka (66% DMF) is 4.17, 12.32;
UV (EtOH) 275nm (£=21715), 270 nm (£=21836), 221 nm (£=9867).
AP 0 0 0 3 8 4
X-8571A
-409Anal. Calcd for C12H12N5SCI2: C, 49.06; H, 4.12; N, 23.84. Found: C, 48.91; H, 4.14; N, 23.76.
Example 340
N-.f.2- (2-, 6-Dif luorophenyl lethy Π -N‘ -.12- (5-bromo) pyridyl 1 thiaurea
A stirred solution of N-(thioimidazoyl)-2(2,6-difluorophenyl)ethyl amine (2.67 g, 10 mmol) and 2amino-5'-bromopyridine (1.73 g, 10 mmol) in l-methyl-2pyrrolidinone (20 mL) was heated to 90 C. After 16.5 h, the reaction was cooled to room temperature and poured into ethyl acetate. The organic phase was washed with H2O (2x), IN HCI, H2O and brine. The organic layer was dried over Na2SO4, filtered and concentrated. The solid obtained was purified by recrystallization from 1:1 EtOAc/hexanes to provide 1.6 g (43%) of the titled product. This material was recrystallized again from 70% EtOAc/hexanes to provide 1.16 g of the titled product as a light brown crystalline solid:
mp 174-175°C;
IR (KBr, cm-1) 3229, 1593, 1558, 1529, 1468, 1265, 1188, 1071, 832;
^H NMR (300 MHZ, DMSO-dg) δ 11.20 (s, IH) , 10.68 (s, IH) ,
8.11 (s', IH) , 7.95-7.91 (m, IH) , 7.33-7.28 (m, IH) , 7.097.01 (m, 3H), 3.83-3.77 (m, 2H) , 2.98-2.94 (m, 2H);
MS (FD) m/e 371 (M+), 373 (M+2);
UV (EtOH) 306nm (£=12790) , 275nm (£=22096), 257nm (£=14120), 201nm (£=17270) .
Anal. Calcd for Cl4H].2BrF2N3S: C, 45.17; H,
3.25; N, 11.29. Found: C, 44.96; H, 3.29; N, 11.21.
X-8571A
-410Example 341
2-cvanomethyl-3-ethoxvpvridine A solution of thionyl chloride (3.26 g, 27.4 mmol, 2.0 mL) in CH2CI2 (10 mL) was added dropwise with stirring to a solution of 2-ethoxy-3hydroxymethylpyridine (3.0 g, 19.6 mmol) in CH2CI2 (20 mL) at 0°C. The ice bath was removed and the reaction stirred 2 h at RT. The reaction was concentrated in vacuo and redissolved in MeOH (30 mL). Potassium cyanide (3.82 g, 58.7 mmol) was dissolved in H2O (10 mL) and added to the reaction in one amount. The reaction was heated to reflux and stirred for 66 h, then quenched with saturated Na2CO3 solution. The reaction was diluted with H2O and extracted with Et2O (3x). The combined organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated to yield 2.84 g (89%) of the titled product as a brownish oil. A small sample was further purified by flash chromatography (40% EtOAc/hexanes) to provide a clear, colorless oil:
IR (KBr, cm4) 3020, 2988, 2936, 1579, 1450, 1397, 1282, 1122, 1041;
iH NMR (300 MHZ, CDCI3) δ 8.17-8.15 (m, IH) , 7.25-7.15 (m, 2H), 4.09 (q, J=7 Hz, 2H), 3.90 (s, 2H), 1.47 (t, J=7 Hz, 3H) ;
MS (FD) m/e 162 (M+);
UV (EtOH) 278nm (£= 5241), 220nm (ε= 7490).
AP 0 0 0 3 β 4
X-8571A
-411Exampl.g-.242
Ν- Γ2- (3-ethoxypvridvl)ethvll -Ν' -(2- (5-bromo)pyridyl!
thiourea
A solution of 2-cyanomethyl-3-ethoxypyridine (22.03 g, 136 mmol) in EtOH (475 mL) and 5N HCl (3 mL) was treated with PtO2 catalyst (4.5 g) under 60 psi of H2. The reaction was stirred overnight at RT, then filtered. The crude reaction was concentrated and redissolved in H2O and EtOAc. The aqueous layer was made basic with 5N NaOH and extracted with EtOAc. The organic layer was washed with brine, dried on Na2SO4, filtered and concentrated to give 16.89 g of a yellow oil. This crude product was dissolved in l-methyl-2-pyrrolidinone (175 mL) and N-(thioimidazoyl)-2-amino-5-bromopyridine (36 g, 127 mmol) was added. The reaction was heated to 100°C and stirred for 68 h. The crude reaction was cooled and poured into EtOAc. The organic layer was washed with H2O (4x), brine, dried on Na2SO4, filtered and concentrated. The resulting solid was again dissolved in EtOAc and extracted with IN HCl (3x). The acid extracts were stirred with CH2CI2, made basic with 5N NaOH and extracted with CH2CI2 (2x). The CH2CI2 extracts were combined, washed with brine, dried on
MgSO4, filtered and concentrated. The crude product was purified by flash chromatography (10% EtOAc/CH2Cl2), followed by trituration with 1:1 EtOAc/hexanes to provide
3.76 g of the titled product (7%) as a white crystalline solid :
mp 170-172°C;
1H NMR (300 MHZ, DMSO-c?g) δ 11.39 (s, 1H) , 10.59 (s, 1H) , 8.13-8.11 (m, 2H), 7.92-7.87 (m, 1H), 7.30 (d, J=8.1 Hz,
X-8571A
-4121H), 7.22-7.18 (m, IH), 7.05 (d, J = 8.9 Hz, IH) , 4.05-3.95 (m, 4H), 3.00 (t, J = 6.3 Hz, 2H) , 1.29 (t, J = 6.9 Hz, 3H); MS (FD) m/e 380 (M+), 382 (M+2);
UV (EtOH) 305nm (ε= 16251), 27 6nm (ε= 36829).
Example,J, 4 3
N-f2-(3-ethoxvpvridvl)ethvl)-Ν' -f2-(5-bromo)pvridvl1 thiour.ee hydrochloride N-[2-(3-ethoxypyridyl) ethyl]-N'-[2-{5bromo)pyridyl] thiourea (5.17 g, 13.5 mmol) was dissolved in a saturated solution of methanolic HCl (100 mL) with stirring. After complete dissolution, a precipitate started to form. The solution was poured into Et2O (400 mL) with stirring, and the resulting white solid was filtered. The crude product was triturated with 10% MeOH/EtOAc to provide 5.47 g of the titled product (97%) as a white solid:
mp 203-205°C (d);
IR (KBr, cm1) 3226, 3007, 2306, 1593, 1565, 1530, 1472, 1290, 1197, 1172;
1H NMR (300 MHZ, DMSO-dg) δ 11.24-11.20 (m, IH) , 10.65 (s, IH) , 8.29 (d, J=5.3 Hz, IH) , 8.17 (d, J = 2.3 Hz, IH) , 7.96-7.88 (m, 2H) , 7.73-7.68 (m, 2H) , 7.08 (d, J=8.9 Hz, IH), 4.10-4.03 (m, 4H), 3.24 (t, J=6.0 Hz, 2H), 1.27 (t, J=6.9 Hz, 3H);
MS (FD) m/e 380 (M+), 382 (M+2);
UV (EtOH) 304nm (£=13635), 276nm (£=28876).
Anal. Calcd for Ci5Hi8BrClN4OS: C, 43.13; H,
4.34; N, 13.41. Found: C, 42.90; H, 4.36; N, 13.11.
AP 0 0 0 3 8 4
-413X-8571A £x ample. 344
1-f(2-amino-5-bromopyridvl)thiocarbamoyl1 imidazole
A solution of 1,1’-thiocarbonyldiimidazole (17.8G, 0.1m) and 2-amino-5“bromopyridine (17.3g, 0.1m) in acetonitrile (150 mL) was stirred at room temperature for 2 hours. To this suspension was added the material described below.
Hml 2 - C2 -.pyr idyll ethvl)1-Ν' -(2-amino-5-bromopyridvl) thiourea
To the above solution of l-[(2-amino-5bromopyridyl)thiocarbamoyl]imidazole was added 2-(2aminoethyl)pyridine (14.7g, 0.12m) stirred at r.t. for 2 hours and at 50 C 12 hours. The reaction was cooled to room temperature, filtered, washed with acetonitrile.
The resultant solid was dissolved in methanol, filtered, hydrogen chloride gas was bubbled into this solution with cooling. Solvents removed under reduced pressure and the resulting residue was recrystallized from methanol ethyl ether to provide 24.8g (76%) of the titled product as a white solid:
mp 215-216 C;
IR (KBr, cm-1·) 3015, 2576, 1634, multiple peaks between (1633-400) ;
2H NMR (300 MHz, DMSO-dg) δ 11.30 (s, IH) , 10.75 (s, IH), 10.78 (S,1H), 8.80 (d, IH), 8.40 (t, IH), 8.22 (s, IH), 7.97-8.00 (q, IH), 7.82-7.90(d, IH), 7.80(t, IH), 7.10 (d, IH), 4.10(q,2H), 3.35(t, 2H);
MS (FD) m/e 338(M+);
X-8571A-414UV (EtOH) 305nm (£=13565), 274nm (£=24201), 201 nm (£=17 628) .
Anal. Calcd for Ci3Hi4N4BrClS: C, 41.78; H, 3.78; N, 14.99. Found: C, 42.02; H, 3.86; N, 15.16.
Example 346
N-f 2 - ((3-Methoxy)pvridvl) ethyl1-N'-f2-(5bromo)pvridvl]thiourea hydrochloride
A) Preparation of 2-Hydroxymethyl-3-methoxy pyridine.
Potassium hydroxide (41.66g ,0.744 mol) was ground under nitrogen and stirred in DMSO (130 ml, anhydrous) for 20 min. 3-Hydroxy-2-hydroxymethyl pyridine hydrochloride [Aldrich] (47 g, 0.248 mol) was added and stirred for 30 min in an ice bath. Methyl iodide (35.2 g, 0.248 mol, 15.43 ml) in DMSO (20 ml) was added dropwise to the solution and then allowed to stir overnight at room temperature. 5N HCl was added to pH 1 and the solution was extracted with dichioromethane (5Χ 500ml). The aqueous was then basified with 5N NaOH to pH 14 and extracted with dichioromethane (3Χ 500 ml). The organics (base wash) were dried over sodium sulfate, and concentrated leaving tan colored crystals. The solid was recrystallized (50% ethyl acetate/hexanes) providing 10.8 g (32%) of the titled product as light tan crystals: mp 72°C;
IR (KBr', cm1) 3080, 1575, 1459, 1424, 1278, 1218, 1066, 809;
AP 0 0 0 3 8 4
X-8571A
-4151H NMR (300 MHZ, DMSO-dg) δ 8.5 (d,J = 4.5Hz, 1H) , 7.3 (d,J=8.3Hz,lH), 7.25 (dd,J=8.2,4.6 Hz,IK), 4.77 (t,J=5.74Hz,lH), 4.48 (d,J=5.6Hz,2H) , 3.77 (s,3H);
MS (FD) m/e 139(M+);
UV (EtOH) 278nm (£=4909) , 220nm (£=6984) .
Anal. Calcd for C7H9NO2: C,60.42; H,6.52; N,10.07.
Found: C, 60.32; H,6.54; N,10.23.
B) Preparation of 2-f(3-methoxv)pvridvl1acetonitrile,
Thionylchloride (100 ml) was added dropwise to
2-Hydroxymethyl-3-methoxy pyridine (13.9 g, 0.1 mol) while stirring in an ice bath. After initial fuming subsided, the thionyl chloride was added more rapidly.
The solution was then heated to reflux for 2 h. After cooling, the thionyl chloride was removed under reduced pressure leaving brown crystals. The solid was taken up in 190 ml methanol and potassium cyanide (19.4 g, 0.298 mol) dissolved in 80 ml of water was added to the methanolic solution. This solution was heated to reflux and allowed to reflux overnight. The solution was cooled down and 150 ml of saturated sodium carbonate was added and then poured into diethyl ether (500 ml). The solution was extracted 3 more times with 500 ml diethyl ether. The collected organics were washed with brine and saturated sodium bicarbonate. The organics were dried over sodium sulfate and concentrated giving 12.1 g (81.7%) of brown crystalline solid. This solid was used in the reduction without further purification: mp 71°C;
X-8571A
-416IR (KBr, cm'1) 3074, 2949, 2253, 1578, 1459, 1286, 1017, 821;
1H NMR (300 MHZ, DMSO-dg-) 8 8.07 (m, IH) , 7.43 (m,lH),
7.35 (m,lH), 4.0 (s,2H), 3.8 (s,3H);
MS (FD) m/e 148(M+);
UV (EtOH) 278rw (£=5407), 219nm (£=7435).
Anal. Calcd for C8H8N2O: C,64.85; H,5.44; N,18.91 .
Found: C, 64.62; H,5.50; N,19.0.
C) Preparation of 2-Ethvlamine-3-methoxvpvridine.
2-[(3-methoxy)pyridyl]acetonitrile (2.0 g, 13 mmol) in 25 ml ethanol was reduced at room temperature under 60 p.s.i. for 24 h using platinum oxide (0.5 g) and 5N HCl (0.2 ml) as catalyst. The organics were concentrated and then taken up in ethyl acetate and water. IN NaOH was added to pH 12 and the amine was extracted out (2x300 ml ethyl acetate). The organics were then washed with brine and saturated sodium bicarbonate and then dried over sodium sulfate. The solution is filtered and concentrated giving 1.5 g of oily material. This is used without further purification.
D) Preparation of _N-i2-( (3-Methoxy)pyridyl)ethyl1-Ν'-(ΣΙ 5 -bromo ). pyridyl I thiourea
Thiocarbonyldiimidazole (5 g, 28 mmol) was taken up in acetonitrile (50 ml, anhydrous) and stirred. 2-Amino-5-bromopyridine [Aldrich] (4.85 g, 28 mmol) and 30 ml acetonitrile was added to the solution. The solution was allowed to stir overnight forming a
AP 0 0 0 3 8 4
X-8571A
-417precipitate. The cream colored solid was filtered off and used in the next reaction without further purification. (6.89 g, 87%)
The cream colored solid (2.88 g, 10.3 mmol) was taken up in l-methyl-2-pyrrolidinone [Aldrich]. 2Ethylamine-3-methoxypyridine was added and the solution was heated to 100°C overnight. The solution was poured into ethyl acetate and washed with water and saturated sodium bicarbonate (3x 200 ml) . The organics were then dried over sodium sulfate and concentrated. The crude material was purified by flash chromatography on silica gel using 40% ethyl acetate /hexanes, giving lOOmg (3%) of needle-like crystals:
mp 178°C;
IR (KBr, cr1) 3157, 3037, 1595, 1562, 1534, 1314, 1275, 1178, 1023, 825;
!h NMR (300 MHZ, DMSO-dg) δΐΐ.53 (s,lH), 8.5 (S,1H), 8.17-8.12 (m,2H), 7.68-7.65 (dd, J=8.75, 8.73Hz, IH) , 4.24-4.18 (m,2H), 3.8 (s,3H), 3.2-3.17 (t, J=6.63Kz, 2H) ; MS (FD) m/e 366(M+), 368(M+l),369(M+2};
UV (EtOH) 305nm (£=13005), 275nm (£=28998) .
Anal. Calcd for Ci4Hi5N4OSBr: C,45.78; H,4.12; N,15.25 . Found: C,45.85; H,4.12; N, 15.12.
E) Preparation of N-f2-((3-Methoxv)pvridvl)ethvl]-N‘-f2.(5-bromo)pvridvl]thiourea hydrochloride
N-[2 - ( (3-Methoxy)pyridyl)ethyl] -N’-{2-(5bromo)pyridyl] thiourea (70 mg, 0.02 mmol) was taker, up in a solution of methanol saturated with HCl. The solid immediately went into solution and then came back out as a white solid. More of the solid was crashed out with
X-8571A
-418diethyl ether. This solid was filtered providing 65 mg (84%) of the hydrochloride salt.
Example.^ 4.7
N- (2-_(2-Fluoro-6-methoxv) -phenethyl) -Ν' -(2-thiazclvl) thiourea
3-Fluoro-anisole (10 ml, 88 mmol) was dissolved in dry THF (200 ml). The solution was cooled to -75° C and n-BuLi (52 ml, 105 mmol) was added slowly. The pale yellow solution was stirred at -70°C for 10 minutes. DMF (20 ml) was added and the solution was warmed to ambient temperature. Toluene (200 ml) was added and the solution was washed with water and evaporated to dryness. The product formed crystals. The aldehyde was transformed into the corresponding titled thiazolyl-thiourea product according to the procedure in Example 151.
XH NMR,CDCl3 δ 2.9-3.0 (2H, t) 3.7-3.9 (2H, t) 6.7-6.9 (2H, q, m) 7-7.1 (IH, d, ) 7.15-7.3 (IH, q) 7.4 (IH, d) .
Example .348
Cis- (D, Ll.-2-phenvlcvclopropylamine
Styrene (100 ml, 873 mmol), Cul (10 mg, 0.05 mmol) and Pd(OAc>2 (10 mg, 0.045 mmol) in 1,2dichloroethane (100 ml) was heated to reflux. Ethyl diazoacetate (50 ml, 475 mmol) in styrene (100 ml, 873 mmol) was added over 30 minutes. The solution was refluxed for an additional 5 minutes. The solution was cooled and filtered through a short column of alumina which was eluted with ethyl acetate/hexane
AP 0 0 0 3 8 4
X-8571A
-419(1:9). The solvents including styrene were evaporated. The residual oil contained a cis-trans mixture (3:7). The oil was dissolved in methanol (200 ml), and potassium hydroxide (30 g, 535 mmol) in water (50 ml) was added. The solution was refluxed for 2 hours. The solution was cooled and diluted with toluene (100 ml) and water (100 ml).
The water-phase was separated and acidified with hydrochloric acid. The solution was extracted with toluene. The organic phase was dried with sodium sulphate, filtered and evaporated, yielding a pale brown solid. The solid (70 g, 430 mmol) was dissolved in acetone (400 ml) with mechanical stirring under an atmosphere of N2-gas. Triethylamine (70 ml, 502 mmol) was added. The solution was cooled to 5° C and ethyl chloroformate (41 ml, 430 mmol) was added during 20 minutes. The solution was stirred for an additional 5 minutes. Sodium azide (30 g, 460 mmol) in water (100 ml) was added and the solution was stirred for 30 minutes. Toluene (400 ml) was added and a thick, white precipitate formed. The solution was decanted to remove the precipitate and dried with sodium sulphate (50 g). The solution was evaporated to 1/4 of the original volume. The solution was diluted with
1,2-dichloro-ethane (400 ml) and was refluxed for 3 hours with evolution of nitrogen gas.
To the solution was added a mixture of hydrochloric acid (cone, aq.) (100 ml), water (100 ml) and dioxane (200 ml). The solution was refluxed for 3 hours with evolution of CO2 gas. The solution was diluted with water (200 ml), the water-phase was
X-8571A
-42 0separated and washed with 1,2-dichloroethane, basified with ammonia (cone, aq.) and extracted with dichloromethane (3 x 100 ml). The organic-phase was washed with water (100 ml), dried with sodiumsulphate, filtered and evaporated.
g of the residual cil was separated on 1000 ml silica-gel, by elution with ethyl acetate, the product (cis) is the faster-eluting component. The pure cis-fractions were evaporated to yield an oil (14g).
Τη-NMR CDCI3 δ ppm 0.8-0.9 (IH, CH2 , m) 1.1-1.2 (IH, CH2, m) 2.-2.1 (IH, PhCH, q) 2.6-2.7 (IH, CHNH2m.)
7.1-7.4 (5H, Ph.).
Example 349
N- (cis-(D.L)-2-phenvlcvclopropvl)-Nz- (2-thiazolyl) thiourea
The product cis-(D,L)-2phenylcyclopropylamine from Example 348 was transformed into the titled product according to the procedure in Example 151.
Τη-NMR CDCI3 δρρπι 1.2-1.3 (IH, CH2, m) 1.5-1.6 (IH, m) 2.4-2.5 (IH, q, PhCH) 3.6-3.7 (IK, m) 6.6-6.7 (IH, d)
6.8-6.9 (IH, d) 7.2-7.4 (5H, m)
Example 3.5..Q
N- (cis-(D.L)-2=phenylcvclobutvl)-N'-(2-thiazolyl)thiaurea.
A cis/trans mixture of 2phenylcyclobutylamine (C. Beard, A. Burger, JOC, 2Ί,
AP 0 0 0 3 8 4
-421X-8571A
1647 (1962)) (0.150 g, 1 mmol) was condensed with 165 mg of the product of Example 103 according to the procedure of Example 105. The solution was put into a refrigerator (-10°C) over night and the crystals were collected on a filter and washed with CH3CN. The stereochemistry was determined with NOE-difference NMR. The crystals were pure cis.
^-H-NMR CDCI3 δρρπι 2.2-2.4 (3H, m) 2.6-2.7 (IH, m)
3.9-4.0 (1H, q) 5.1-5.2 (IH, q) 6.6-6.7 (1H, d, thiazole) 6.8-6.9 (IH, d, thiazole) 7.3-7.5 (5H, m,
Ph) .
Example 351
N-JciSn i.D^L).-2Tmethvl--2-phenvl-cvclopropyl) -N‘ - (4gfalprophenyl )xhi.Quc£A a-Methylstyrene (Aldrich) was transformed into the corresponding amine as a cis-trans mixture according to the procedure of Example 348. The amine (300 mg‘, 2.04 mmol) and 4-chloro-phenylisothiocyanate were refluxed in CH3CN (5 ml) for 60 minutes. The solution was evaporated and final purification was made by flash-chromatography on silica-gel by elution with ethyl acetate/n-hexane (1:4). The collected fractions were pure cis as determined by NOEdifference NMR.
Ιη-NMR CDCI3 δΐ.1-1.2 (2H, m, 0¾) 1.4-1.5 (3H, S, CH3), 3.2-3.4 (IH, m, CHN), 6.4-6.5 (IH, b.s., NH),
7.0-7.1 (2H, Ph), 7.3-7.5 <7H, s,+m. Ph), 7.9-8.1 (IH, b.s., NH) . ........_
X-8571A
-422Example 352
Μ-12 - (2.6-d if luprophenyl lethy 1)-Ν'-(2-pvrazinvl)thiourea
2.6- Difluorophenethylamine (1.0 g, 6.4 mmol), 2-aminopyrazine (0.61 g, 6.4 mmol) and N,Nthiocarbonyl-diimidazole (1.13 g, 6.4 mmol) were condensed according to the procedure of Example 93 to give the titled compound as crystals.
l-H-NMR CDCI3 5ppm 3.1-3.2 (2H, t, PhCfl2) , 3.9-4.0 (2H, t, CH2N),
6.8-6.9 (2H, t, Ph), 7.1-7.3 (IH, m, Ph), 7.9-8.0 (IH, s, pyr), 8.1-8.2 (IH, d, pyr), 8.3-8.4 (IH, s, pyr), 9.3-9.4 (IH, b.s., NH) , 11.0-11.2 (IH, b.s.,
NH)
Example 353
N- (2 - (2.6-difluoro-3-carboxamidomethyl phenyl)ethyl)N‘ -12- (5-brom.opyridyll-.thio.urea
2.6- Difluorobenzaldehyde (10 g, 70.4 mmol), ethylene glycol (20 ml), triethyl-orthoformate (10 ml) and para-toluene sulphonic acid in 1,2-dichloroethane were heated to 80° C for 2 hours. The solution was neutralized with sodium hydrogen carbonate, washed with water, dried with sodium sulfate, filtered and evaporated. The residual oil was dissolved in tetrahydrofurane (700 ml) under nitrogen-atmosphere. The solution was stirred and cooled to -70°C and nBuLi (48ml, 1.6 M) was added slowly. The solution was stirred for 20 minutes. Dry-ice (20 g, 455 mmol) was added as quickly as possible (foaming).
AP Ο Ο Ο 3 8 4
Χ-8571Α
-423The solution was slowly brought up to ambient temperature. Water was added and the solution was washed with ethyl acetate, acidified with acetic acid and extracted with ethyl acetate.
The organic phase was dried with sodium sulfate, filtered and evaporated. 1 g of the residual solid (4.35 mmol) and N,N-diisopropylamine (2.0 ml) were dissolved in dichloromethane (50 ml) and the solution was cooled to 0°C.
Thionylchloride (0.50 ml, 6.9 mmol) was added and the solution was slowly heated to ambient temperature. Methylamine (3 ml) was added. The solution was stirred for 30 minutes and was washed with water, dried with sodium sulfate, filtered and evaporated.
The residue was dissolved in a mixture of water and dioxane (1:2, 20 ml) and para-toluene sulphonic acid (0.5 g, 2.63 mmol) was added. The solution was stirred and heated to 60° C for 2 hours.
The solution was neutralized with sodium hydrogen carbonate, extracted with ethyl acetate, dried with sodium sulfate, filtered and evaporated.
The residue was dissolved in toluene and benzyloxycarbonylmethyl triphenyl-phosphorane (1.5 g,
3.7 g) was added. The solution was stirred for 30 minutes at 50°C. The solution was put onto a silicagel column. The column was eluted with ethyl acetatehexane (1:2) and the collected fractions were evaporated. 0.15 g of the residue was hydrogenated in methanol (50 ml) and acetic acid (5 ml) with Pd/C (10
X-8571A
-424%, 100 mg) and hydrogen gas, using a Parr apparatus at
1.5 bar for 1 hour.
The solution was filtered through Celite and evaporated. A part of the residue (50 mg, 0.26 mmol) was dissolved in acetone at 0°C.
Triethylamine (50 ml, 0.36 mmol) was added followed by ethyl chloroformate (30 ml, 0.32 mmol). The solution was stirred for 15 minutes and sodium azide (30 mg, 0.46 mmol) in water (2 ml) was added. The solution was stirred for 15 minutes, diluted with ethyl acetate, washed with water, dried with sodium sulfate, filtered and evaporated.
The residue was dissolved in toluene (20 ml) and was stirred and heated at 90° C for 1 hour. The solution was evaporated and dissolved in a dioxanewater-hydrochloric acid (cone. aq.) mixture (1:3:1). The solution was stirred at ambient temperature for 20 minutes. The solution was evaporated and the residual 2- (2,6-difluoro-3-carboxamidomethyl phenyl)ethylamine hydrochloride was condensed with l-(2-amino-5bromcpyridyl)-1'-(imidazolyl) thiocarbonyl using the procedure of Example 94.
The reaction mixture was evaporated and the residue was purified by flash chromatography on silica-gel by elution with ethyl acetate-hexane (1:1). Evaporation of the collected fractions yielded the titled product.
1H-NMR CDCI3 8ppm 2.9-3.0 (3H, s, CH3), 3.1-3.2 (2H, t, PhCH2), 4.0-4.1 (2H, t, CH2N), 6.8-6.9 (IH, d),
6.9-7.0 (2H, t), 7.7-7.8 (2H, m), 8.0-8.1 (IH, s).
AP Ο Ο Ο 3 8 4
Χ-8571Α
-425Examole 354
Ν- (2 - (3-acetamidomethyl-2.6-dif luorophenyl) -ethvl)-K.zi2.nlSrbrgmppyr.idyl.) J.-thiQunga 5 Under an atmosphere of nitrogen-gas, 2,4difluorobenzonitrile (Aldrich) (4.6 g, 33 mmol) was dissolved in tetrahydrofurane (200 ml) with stirring under an atmosphere of nitrogen gas. The solution was cooled to -75° C and lithium-diisopropylamide (25 ml,
1.5 M solution) was added. The solution was stirred for 15 minutes and dimethylformamide (10 ml) was added. The cooling was withdrawn and the solution was diluted with toluene (200 ml), washed with water, dried with sodium sulfate, filtered and evaporated.
The residue (4.76 g, 28.5 mmol) was dissolved in 250 ml toluene and benzyloxycarbonylmethyl triphenylphosphorane (14 g, 34 mmol) was added.
The solution was stirred for 40 minutes at 35°C (slightly exothermic reaction) , and then put onto a column of silica gel. The column was eluted with ethyl acetate-hexane 1:4, and the collected fractions were evaporated. A small part of the residue (0.5 g) was dissolved in methanol (50 ml) and acetic acid (6 ml) and 5 % - Pd/C (300 mg) was added. The mixture was hydrogenated in a Parr apparatus at 1.5 bar for 1 hour.
The solution was filtered through celite and evaporated. The residue was dissolved in acetic anhydride and the solution was stirred and heated to ___50°C for 20 minutes. Excess reagent was evaporated
X-8571A
-426and the residue was dissolved in water. The solution was heated to 60°C for 20 minutes under stirring. The residue (0.29 g, 1.14 mmol) was dissolved in acetone at 0°C.
Triethylamine (0.315 ml, 2.3 mmol) was added, followed by ethyl chloroformate (0.16 ml, 1.7 mmol). The solution was stirred for 15 minutes and sodium azide (220 mg, 3.3 mmol) in water (2 ml) was added. The solution was stirred for 15 minutes, diluted with ethyl acetate, washed with water, dried with sodium sulfate, filtered and evaporated.
The residue was dissolved in toluene (20 ml) and was stirred and heated at 90°C for 1 hour. The solution was evaporated and dissolved in a dioxane15 water-hydrochloric acid (cone, aq.) mixture (50:10:1, ml). The solution was stirred at ambient temperature for 20 minutes. The solution was evaporated and the residual amine-hydrochloride was condensed with 1-(2-amino-5-bromopyridyl)-1’20 (imidazolyl) thiocarbonyl using the procedure of
Example 94.
The reaction-mixture was evaporated and the residue was purified by flash chromatography on silica-gel by elution with ethyl acetate-hexane (1:1).
The collected fractions were evaporated to yield the titled product as crystals.
1H-NMR CDCI3 δ ppm 1.9-2.0 (3H, s, CH3CON), 3.0-3.1 (2H, b.s., PhCH2CH2N) - 3.9-4.1 (2H, b.s., PhCi^Ci^N) ,
4.3-4.4 (2H, s, PhCH2N), 6.8-6.9 (2H, m) , 7.2-7.4 (IH,
m), 7.7,-7.8 (IH, d), 8.1-8.2 (IH, s) .
AP 0 0 0 3 8 4
X-8571A
-427Ex ample .155.
N- (4-methvl-3-pentenvl·)-Ν' - (4-methvl-2thiazolvl) thiourea
4-Methyl-3-pentenylamine and an activated derivative of 2-amino-4-methylthiazole, i.e. 1-(2amino-4-methylthiazole)-1'-imidazole thiocarbonyl, were condensed according to the procedures of Example
105 to give the titled product.
Mp.: 164.5 - 165.5°C.
Analyses: Calculated C 51.73, H 6.71, N 16.45; Found C
52.0, H 6.9, N 16.7.
!k-NMR (CDCI3 d): 1.65 (s, 3H), 1.73 (d, 3H), 2 .29 (d,
3K), 2.40 (q, 2H), 3.70 -3.78 (m, 2H) , 5.16-5.22 (m,
IK), 6.36 (q, 1H), 10.14 (broad ε, 1H), 10.90 (broad s, 1H) .
13c NMR (CDCl3d) : 17.16, 17.93, 25.83, 27.28, 45.69, 105.04, 120.53, 134.84, 147.99, 160.79, 177.28.
Example- 3 5.6
No. (2.- 12^.&.-liil.u.Q.rp)_-phenet2iy·!·) .rN.'.- (2.-, benzimidazolvl) thiourea
2,6-Difluorphenetylamine and 2aminobenzimidazole were reacted according to the procedures of Examples 93 and 94, using 2aminobenzimidazole instead of 2-aminothiazole, to give the titled product.
Mp: 195-7°C (dec) !h-NMR (DMSO-dg d): 3.16 it, 2H), 4.02 (q, 2H) , 7.147.24 (m, 4H), 7.43-7.49 (m, 3H) , 11.13 (broad s, 1H), 11.40 (broad s, 1H).
X-8571A
-428 Example 35.7.
Ν- (2- (3-hvdroxv)-phenethyl)-Ν' -(5-bromo-2pyridinvl)thiourea
3-Hydroxyphenethylamine and 5-bromo-2aminopyridine were reacted according to the procedures of Examples 93 and 94, using 4-bromo-2-aminopyridine instead of 2-aminothiazole, to give the titled product..
Yield: 35 %.
Mp: 176.5 - 178.0°C. !h-NMR (DMSO-dg d): 2.95 (t, 2H), 3.90 (q- 2H), 6.73
6.85 (m, 3H), 7.20-7.27 (m, 2H) , 8.08 ( dd, IH), 8.32
(d, IH), 9.49 (s, IH), 10.84 (s. Η) , 11 .33 (t, IH).
13C-NMR (DMSO-dg d): 34.01, 46.30, 111. 70, 113.26,
114.41, 115.70, 119.32, 129.35, 140.41, 141 .29,
145.79, 152.29, 157.34, 179.07.
Example. 3.S3
N- (2.- (l-me.thvl) -2-Pvrrolvlethvl) -Ν' - (5-chlorc-2pyridiny.l) thiourea
2-(Aminoethyl)-1-methylpyrrole and an isothiocyanate of 5-chloro-2-aminopyridine were condensed analogous to the procedures described in Example 105, to give the titled product.
Yield: 78 %.
Mp: 169.5-170.0°C.
1h-NMR (DMSO-dg d): 3.01 (t, 2H), 3.67 (s, 3H), 3.93 (q, 2H), 6.00 - 6.02 (m, 2H), 6.74 (s, IH), 7.32 (d,
AP 0 0 0 3 8 4
X-8571A -4291H), 7.97 (dd, IH), 8.27 (d, IH) , 10.76 (s, IH), 11.36 (broad s, IH).
13C-NMR (DMSO-dg d): 24.97, 33.19, 44.37, 106.22, 106.39, 114.02, 121.58, 123.70, 129.32, 138.70,
143.61, 152.05, 179.31.
Example. .,3.52
N-.(2- (3-Methvl)Phenethyl) -Ν’ - (2-thiazolvl)thiourea (3-Methyl-phenyl)acetic acid was reduced with lithium aluminum hydride in tetrahydrofurane under reflux to 2-(3-methyl-phenyl)ethanol, which was further transformed to 2-(3-methyl-phenyl)ethylamine by the procedure described in Example 106.
Condensation of this amine with the product of Example 103 and using the procedure described in Example 105, gave the titled product.
13C-NMR (250MHz, CDCl3): δΐ78, 162, 138, 137, 137,
130, 128, 127, 126, 102, 47, 35, 22.
Mp: 145 - 146°C.
Example ..3 6.Q
N.-.I2 - ί 2.tES hQXY) phene thy U--K1 .-.12 r. I 4c
E£.thyJL.) Phi ezolyDthiourea In a manner analogous to Example 105, 2-(2ethoxyphenyl)ethylamine was condensed with l-(2-amino4-methylthiazolyl)-1’-imidazole thiocarbonyl, which was made in a similar way as described in Example 103, to give the titled product.
3H-NMR (250 MHz, DMSO): δ 7.32 - 6.73 (m, 5H, phenyl, thiazole), 4.09 (q, 2H, OCH2CH3), 3.86 (q, 2H, CH2NH),
X-8571A
-4302.97 (t, 2H, Ph-Ch2), 2.25 (s, 3H, thiazole-Ci^), 1.43 (t, 3H, OCH2CH3).
13C-NMR (250MHz, DMSO): δΐ76, 162, 157, 130, 128,
127, 120, 112, 107, 106, 63, 44, 29, 17, 15.
Mp: 188 - 189°C.
Example 361
N-(2-(3-Ethoxv)phenethyl)-N‘-(2-thiazolyl)thiourea
3-Hydroxybenzaldehyde (3.0 g, 24.6 mmol), ethyl iodide (5.9 ml, 73.8 mmol) and K2CO3 (3.4 g,
24.6 mmol) in 50 ml of acetone was stirred at +40°C for 6 h and at RT overnight. The mixture was filtered and evaporated. The product was purified by silica gel column chromatography (EtOAc/petroleum ether 15:100) to give 3-ethoxybenzaldehyde.
Yield 2.91 g (79%).
1H-NMR (250 MHz, CDCI3): 9.97 (s, IH, CHO), 7.45 7.14 (m, 4H, phenyl), 4.10 (q, 2H, CH2CH3), 1.44 (t,
3H, CH2CH3).
By using the procedure of Example 151, 3ethoxybenzaldehyde was transformed to 2-(3ethoxyphenyl)ethylamine, which was reacted with the product of Example 103, following the procedure of Example 105 to give the titled product.
^-H-NMR (250 MHz, DMSO): δ7.60 (d, IH, thiazole), 7.30 - 6.93 (m, 4H, phenyl), 4.08 (q, 2H, OCH2CH3), 3.87 (q, 2H, CH2-NH), 2.96 (t, 2H, phenyl-CH2), 1.42 (t,
3H, OCH2CB3).
Mp: 169 - 170°C.
AP 0 0 0 3 8 4
X-8571A
-431Exampl,£,.J 6.2
M.-.12.-..12 zEthQW? 6.-f luorQ) ph€.Qe.th.YlltKlthiaozolvl) thiourea
1) 3-Fluorophenol (20.0 g, 178.4 mmol), ethyl iodide (83.5 g, 535.2 mmol) and K2CO3 (49.3 g,
356.8 mmol) in 250 ml of acetone were stirred at 50°C overnight. The mixture was filtered and evaporated to give l-ethoxy-3-fluorobenzene.
Yield 19.84 g (79%) .
iH-NMR (250 MHz, CDCI3): δ7.20 (q, IH, phenyl), 6.69 6.57 (m, 3H, phenyl), 4.00 (q, 2H, CH2CH3), 1.40 (t, 3H, CH2CH3).
2) 1.6 M Butyl lithium in hexane (24 ml, 38.4 mmol) was added slowly (0.5 h) to a solution of l-ethoxy-3-fluorobenzene (5.0 g, 35.7 mmol) in 100 ml of dry THF at -65°C under nitrogen. The solution was stirred at -65°C for 25 min. DMF (5.22 g, 71.4 mmol) was added dropwise to the solution. The mixture was allowed to warm to room temperature. 300 ml of ice was poured to this mixture and it was extracted with diethyl ether. Diethyl ether was washed with brine, dried over Na2SC>4 and evaporated. The product was purified by silica gel column chromatography (EtOAc/petroleum ether 10:100) to give 2-ethoxy-6fluorobenzaldehyde.
Yield: 3.69 g (61 %).
Χ-8571Α
-432iH-NMR (250 MHz, CDCI3): δ7.52 - 7.40, 6.80 - 6.64 (m, 3H, phenyl), 4.18(q, 2H, CH2CH3), 1.50 (t, 3H,
CH2CH3).
13C-NMR (250 MHz, CDCI3): 8188, 165, 161, 136, 109, 108, 65, 14.
3) Following the procedure of Example 151, this aldehyde was transformed to 2-(2-ethoxy-6fluorophenyl)ethylamine, which was condensed with the product of Example 103, using the procedure of Example 105 to give the titled product.
3H-NMR (250 MHz, DMSO): 87.32 - 6.72 (m, 5H, phenyl, thiazole), 4.00 (q, 2H, CH2CH3), 3.78 (q, 2H, CH2-NH), 2.92 (t, phenyl-CH2), 1.33 (t, 3H, CH2CH3).
Example 363
N- (2- (3-~sopropoxv)phenethyl)-N'- (2-thiazolvl)thiourea
3-Isopropoxybenzaldehyde was prepared from
3-hydroxybenzaldehyde and isopropyl iodide analogous to the procedure described in Example 361. By using the procedure of Example 151 this aldehyde was transformed to 2- (3-isopropoxyphenyl)ethylamine, which was reached with the product of. Example 103, following the procedure of Example 105 to give the titled product.
iH-NMR (250 MHz, DMSO): 87.44 - 6.84 (m, 6H, phenyl, thiazole), 4.69 - 4.64 (m, IH, isopropoxy-CH), 3.87 (q, 2H, CH2NH), 2.96 (t, 2H, phenyl-CH2), 1.36 - 1.32 (m, 6H, 2CH3).
AP 0 0 0 3 8 4
X-8571A
-433Examp.ls..36A
N- (2-(5-Bromo-2-ethoxy)phenethyl-Ν' -(2thiazolyl)thiourea
1) 5-Bromo-2-hydroxybenzylalcohol (5.0 g,
24.6 mmol), ethyl iodide (11.5 g, 73.8 mmol) and K2CO3 (3.4 g, 24.6 mmol) in 50 ml of acetone was stirred at + 50°C overnight. The mixture was filtered and evaporated. The product was purified by silica gel column chromatography (EtOAc/petroleum ether 30:100) to give 5-bromo-2-ethoxybenzyl alcohol.
Yield: 5.24 g (92 %).
1H-NMR (250 MHz, CDCI3): 57.42 - 7.31 (m, 2H, phenyl), 6.73 (d, IH, phenyl), 4.67 (d, 2H, £Η2θΗ), 4.07 (q, 2H, £h2CH3)' 1-60 (s, IH, OH), 1.43 (t, 3H, CH2<3h3) ·
2) 5-Bromo-2-ethoxybenzyl alcohol (2.78 g, 12.0 mmol) and pyridinium dichromate (4.51 g, 12.0 mmol) in 120 ml of CH2CI2 was stirred at RT for 6 h. The mixture was filtered, washed with H2O, 0.5 N HCI and brine and dried over Na2SO4. The product was purified by silica gel column chromatography (EtOAc/petroleum ether 10:100) to give 5-bromo-2ethoxybenzaldehyde.
Yield: 2.33 g (85 %).
1H-NMR (250 MHz, CDCI3): δΐ0.4 (s, IH, CHO), 7.91 (d,
IH, phenyl), 7.60 (dd, IH, phenyl), 6.88 (d, IH, phenyl), 4.14 (q, 2H, CH2CH3), 1.51 (t, 3H, CH2CH3).
3) Following the procedure of Example 151, the aldehyde was transformed to 2-(5-bromo-2X-8571A
-434ethoxyphenyl)ethylamine, which was condensed with the product of Example 103, using the procedure of Example
105, to give the titled product.
^-H-NMR (250 MHz, DMSO): δ 7.10 - 6.62 (m, 5H, phenyl, thiazole), 3.73 (q, 2H, CH2CH3), 3.52 (q, 2H, CH2NH),
2.62 (t, 2K, phenyl-CH2), 1.07 (t, 3H, CH2CH3).
Example—365
K.712-. 12.x5..-DimethoxvJphenexhvl) -N.’ - i2-pvridvl)thiourea
2,5-Dimethoxy phenethylamine (0.36 g, 2.0 mmol) in 7 ml of DMF was added to a solution of 1,1thiocarbonyldiimidazole (0.36 g, 2.0 mmol) in 7 ml of DMF at 0°C. After 5 minutes 2-aminopyridine (0.19 g, 2.0 mmol) in 7 ml of DMF was added at 0°C.
This mixture was refluxed at 150°C for 4 hours. After cooling to room temperature it was poured into ice-water and extracted with diethyl ether, dried over Na2SO4 and the solvent was evaporated. The product was purified by silica gel column chromatography (EtOAc/petroleum ether 15:100).
Yield: 0.24 g (39 %) .
iH-NMR (250 MHz, CDCI3): δ8.41 (broad s, IH, NH) , 8.04 (d, IH, pyridine), 7.61 (t, IH, pyridine), 6.94 - 6.67 (m, 5H, phenyl, pyridine), 4.03 (q, 2H, CH2NH), 3.78 (s, 3H, CH3C;, 3.73 (s, 3H, CH3O), 3.00 (t, 2H, phenyl-CH2).
AP Ο Ο Ο 3 8 4
Χ-8571Α
-435Example 366
Ν- (2 - (2-Ethoxv)phenethyl)-Ν'-(2-(5bromo)pyridyl)thiourea In a manner analogous to Example 151, 25 ethoxy phenethylamine was obtained from 2ethoxybenzaldehyde.
2-Ethoxy phenethylamine (1.1 g, 6.7 mmol) in 20 ml of acetonitrile was added slowly to a mixture of
1,1-thiocarbonyldiimidazole (1.32 g, 7.4 mmol) in 20 ml of acetonitrile at 0°C. The mixture was warmed to
RT and evaporated. 2-Amino-5-bromo-pyridine (1.63 g, 9.4 mmol) and this crude reaction mixture in 30 ml of DMF were refluxed for 6 h at 140°C. After cooling to room temperature the reaction mixture was poured into ice-water and extracted with diethyl ether, dried over
Na2SC>4 and the solvent was evaporated. The product was purified by silica gel column chromatography (EtOAc/petroleum ether 15/100).
1H-NMR (250MHz, CDCl3)58.73 (broad s, IK, NH), 8.00 (d, IH,. pyridine), 7.68 (dd, IH, pyridine), 7.26 7.16 (m, 2H, phenyl), 6.96 - 6.82 (m, 2H, phenyl),
6.68 (d, IH, pyridine), 4.03 (q, 2H, CH2CH3)· 4.03 (q, 2H, CH2NH), 3.02, (t, 2H, phenyl-CH2), 1.42 (t, 3H, CH2CH3).
13C-NMR (250MHz, CDCl3)6l79, 157, 152, 146, 141,
131, 128, 127, 120, 113, 112, 111, 63, 46, 30, 15.
X-8571A
-436Example 367
Ν- (2-(2-Ethoxy-6-fluoro)phenethvl)-Ν' -(2pvridvl) thiourea
The starting material 2-(2-ethoxy-6fluorophenyl)ethylamine was prepared as described in Example 362. Following the condensation procedure described in Example 366, and using 2-aminopyridine instead of 2-amino-5-bromopyridine, the titled product resulted.
!h-NMR (250MHz, CDCl3)68.00 (d, IH, pyridine), 7.58 (t, IH,. pyridine), 7.14 (q, IH, pyridine), 6.91 - 6.59 (m, 4H, phenyl, pyridine), 3.95 (q, 2H, CH2CH3), 3.95 (q, 2H, CH2-NH), 3.09 (t, 2H, phenyl-CH2), 1.39 (t,
3H, CH2CH3).
13C-NMR (250MHz, CDCl3)6l79, 164, 153, 145, 138,
128, 128, 117, 112, 108, 107, 107, 64, 45, 22, 15.
Example 368
N-2-(2-Methoxy)phenethyl)-Ν' -(2thiazolyl)methylthioether Methyl iodide (0.425 g, 3.0 mmol) was added to a solution of N-(2-(2-methoxy)phenethyl)-Ν' -(2thiazolyl)thiourea, (Example 94), (0.3 g 1.0 mmol) in 15 ml of DMF. The mixture was stirred at RT for 8 h. Methyl iodide was evaporated and the mixture was poured to ice, extracted with methylene chloride, dried over Na2SC>4 and evaporated. The product was purified by silica gel column chromatography (EtOAc/petroleum ether 10:100).
X-8571A -437AP000384 !k-NMR (250 MHz, CDCl3): δ7.25 (d, IH, thiazole), 7.24
- 7.16 (m, 2H, phenyl), 6.92 - 6.81 (m, 2H, phenyl), 6.70 (d, IH, thiazole), 3.79 (s, 3H, CH3O), 3.57 (q, 2H, CH2NH), 2.95 (t, 2H, phenyl-CH2), 2,46, (s, 3H,
SCH3).
13C-NMR (250MHz, CDCI3): 5173, 162, 157, 137, 130,
127, 126, 120, 111, 110, 55, 43, 30, 13.
Example, .269
N- (2- (2-Ethoxv-6-fluoro)Phenethyl)-N* -(2- (5methvl)pvridvl) thiourea
The starting material 2-(2-ethoxy-6fluorophenyl)ethylamine was prepared as described in Example 362. Following the condensation procedure described in Example 366 and using 2-amino-5methylpyridine instead of 2-amino-5-bromopyridine, the titled product resulted.
iH-NMR (250 MHz, CDCI3): δ8.65 (broad s, IH, NH), 7.83 (s, IH, pyridine), 7.41 (d, IH, pyridine), 7.22 - 7.05 (q, IH, phenyl), 6.73 - 6.58 (m, 3H, phenyl, pyridine), 3.98 (q, 2H, £fl2CH3}' 3·98 (<5, 2H' ·
3.07 (t, 2H, phenyl-£H2>' 2·25 (s- 3H» CH3), 1.40 (t, 3H, CH2£H3).
13C-NMR (250 MHz, CDCI3): δ 179, 168, 152, 145, 139,
127, 127, 126, 111, 108, 108, 107, 63, 44, 22, 17, 14.
Example .3.7Q
N-Phenethvl-N·-(2-(5-chloro)pvridvl) thiourea
The product from example 374 (0.3 g, 1.76 mmol) and phenethylamine (0.22 ml, 1.76 mmol) in 8 ml
X-8571A
-438of acetonitrile was stirred at RT for 0.5 h. The mixture was filtered. The precipitate was dried and recrystallized from acetonitrile.
Mp: 152 - 153°C.
1H-NMR (250 MHz, DMSO): δ8.20 (d, IH, pyridine), 7.98
(dd, IH, pyridine), 7.45 - 7.40 (m, 5H, phenyl), 7.27
(d, IH, pyridine), 3.94 (q, 2H, ch2nh), 3.04 (t, 2H,
phenyl-CH2) . 13C-NMF. (250 MHz, DMSO) : δ 179, 152, 143 , 139, 139,
129, 128, 126, 124, 114, 46, 34 .
Example 371
N-(cis-(D.L)-2-Phenylcyclopropvl)-Ν' -(2pyrldyl)thiourea c cis-(D,L)-2-Phenylcyclopropylamine (Example 348) and 2-aminopyridine were reacted according to the procedures of Examples 93 and 94, using 2aminopyridine instead of 2-aminothiazole, to give the titled product.
!h-NMR: 1.19 - 1.27 (m, IH), 1.45 - 1.55 (m, IH) , 2.50 (q, IH), 3.67 - 3.78 (m, IH), 6.73 - 6.78 (m, 2H),
7.27 - 7.34 (m, 5H) , 7.41 - 7.53 (m, 2H), 1.08 (broad s, IH).' 13C-NMR: 12.4, 21.9, 34.6, 111.8, 117.3, 126.5, 128.2,
129.1, 136.5, 138.2, 145.1, 153.0, 180.3.
Mp: 184.5 - 156.0°C.
AP 0 0 0 3 8 4
X-8571A
-439Example 372
N_-_( 5-ChIoro-2-pyridyl.)--N1 - (cis- (P,L).-.2.-.
phenylcvclopropvl) thiourea cis-(D,L)-2-Phenylcyclopropylamine (Example
348) and an activated derivative of 2-amino-5chloropyridine, i.e. 1-(2-amino-5-chloropyridine)-11 imidazole-thiocarbonyl, were condensed using the procedures of Example 105 to give the titled product. ^-H-NMR (CDCI3): 1.19 - 1.26 (m, IH) , 1.46 - 1.55 (m, IH), 2.51 (q, IH), 3.64 - 3.74 (m, IH), 6.74 (dd, IH), 7.30 - 7.40 (m, 6H) , 7.47 (dd, IH), 9.2 (broad s, IH),
10.9 (broad s, IH), 13C-NMR (CDCI3): 12.4, 22.0, 34.7, 112.7, 124.7,
126.8, 128.4, 129.2, 136.5, 138.3, 143.9, 151.1,
180.2.
Mp: 194 - 195.5°C.
Example .373.
N.-L5.- Er QIRQ.-.2 -pyridy 1 LzlL··-1 c is-(P<L?-2phenvlcvclopropyl) thiourea cis- (D,L)-2-Phenylcyclopropylamine (Example
348) and 2-amino-5-bromopyridine were reacted according to the procedures of Examples 93 and 94, using 2-amino-5-bromopyridine instead of 2aminothiazole, to give the titled product.
!h-NMR (CDCI3 ) : 1.19-1.26 (m, IH), 1.47 - 1.55 (m,
IH), 2.52 (q, IH), 3.66 - 3.75 (m, IH), 6.66 (dd, IH),
7.27 - 7.41 (m, 5H), 7.47 (d, IH), 7.60 (dd, IH), 8.98 (broad s, IH) , 10.88 (broad s, IH).
X-8571A
-44013C-NMR (CDC13): 12.4, 22.0, 34.7, 112.3, 113.1,
126.8, 128.4, 129.2, 136.5, 140.9, 146.2, 151.3,
180.2.
Mp: 20.4 - 205° C
Anal, calcd. for C^Hj^Br^S: C, 51.7; H, 4.05; N, 12.07. Found C, 51.5; H, 4.0; N, 12.0.
Examp le..,3 7.4
5-Chloropvrid-2-vlisothiocyanate 2-Amino-5-chloropyridine (10.28 g) was added in portions, with stirring, over a period of 25 minutes to a solution of thiocarbonyl diimidazole (14.26 g) in acetonitrile (100 ml) at ambient temperature. The stirring was continued and the solution/suspension was left at ambient temperature for a few hours. The precipitate was filtered and washed with acetonitrile (3 x 25 ml). The solid residue was dissolved in hot acetone and filtered.
The acetone solution was evaporated in vacuo, the residue was dissolved in hot ethyl acetate and filtered through a pad of silica (diam. 7 c m x 3 cm). The silica was washed with another portion of hot ethyl acetate. The combined solutions were evaporated in vacuo to yield a crude product (5 g) of the titled product.
1h-NMR (DMSO): 7.54 (d, J = 8.7 Hz, 1Η), 8.17 (dd, J = 2.7, 8.7 Hz, IH), 8.63 (d, J = 2.7 Hz, IH).
13C-NMR (DMSO): 121.4, 130.1, 139.4, 140.7, 143.9,
148.6.
AP 0 0 0 3 8 4
X-8571A
-441Example, 375
N-cis- (D.L) - (2- (3-Methoxv)-phenvlcyclppropyl). (2thiazolv1) thiourea
The starting material, 3-methoxystyrene, was prepared in following manner:
To a mixture of 26.2 g (73.4 mmol) of methyl triphenylphosphonium bromide in 200 ml of THF cooled to 0°C, was added 42 ml (2M in THF, 82 mmol) of a lithium diisopropyl amide solution over 30 min. The mixture was stirred for an additional 2 hours then 10 g (73.4 mmol) 3-methoxybenzaldehyde was added dropwise over 25 min. The reaction mixture was stirred for one hour at room temperature and then heated under reflux for 14 hours. After cooling the solvent was evaporated in vacuo, the residue was diluted with 200 ml diethyl ether and the precipitate was removed by filtration. The ether solution was washed with water, dried with Na2SO4 and evaporated in vacuo. The product was purified by silica gel column chromatography (diethyl ether/cyclohexane).
Yield: 2.83 g (29 %).
iH-NMR (CDCl3)d: 7.24 (t, J = 8.1 Hz, IH, Ph), 7.216.98 (m, IH, Ph), 6.95 (t, J = 2.3 Hz, IH, Ph), 6.81 (ddd, J. = 8.1 Hz, 2.3Hz, 0.9 Hz, IH, Ph), 6.69 (dd, J = 17.6 Hz, 10.8 Hz, IH, CH) , 5.74 (dd, J = 17.6 Hz,
0.9 Hz, IH, CH2), 5.25 (dd, J = 10.8 Hz, 0.9 Hz, IH, CH2), 3.81 (s, 3H, CH3) .
13C-NMR (CDCl3)d: 159.81 (C-3), 139.04 (C-l), 136.79 (C-a), 129.51 (C-5), 118.92 (C-6), 114.15 (C-4),
113.46 (C-2), 111.53 (C-b), 55.22 (O-£H3).
X-8571A
-442The titled compound was prepared in a manner analogous to the procedures described in Examples 348 and 349, using 3-methoxystyrene instead of styrene. 1H-NMR (CDCl3)d: 7.26-7.19 (t and d, 2H, o and thiazole), 6.90-6.69 (m, 4H, o, m, p, thiazole), 3.76 (s, 3H, OMe), 3.65 (broad s, IH, NH-CH-), 2.50 (q, IH, Ph-Cft-), 1.22 (m, 2H, Cyclopropyl).
13C-NMR (CDCl3)d: 178.6 (C=S), 161.3 (thiazole), 159.8 (£-0Me), 137.8 (Ph), 137.7 (thiazole), 129.5 (Ph),
121.6 (Ph), 114.5 (Ph), 112.8 (Ph), 111.0 (thiazole),
55.2 (O-£H3), 44.0 (£H-NH), 22.0 (£H-Ph) , 12.1 (£H2).
Example. 37$
N-cis-(D.L)- (2 - (2-Fluoroohenvl)cvclooroovl)-Ν'-(2thiazovl thiourea
In a manner analogous to the procedures described in Examples 348 and 349 and using 2fluorostyrene instead of styrene, the titled product was prepared.
1H-NMR (CDCl3)d: 7.32-7.05 (m, 4H), 6.91-6.64 (m, 2H),
3.68 (broad s, IH, CH-NH), 2.57 (q, IH, CH-Ph), 1.701.40 (m, 3H), 1.31-1.18 (m, IH) .
13C-NMR (CDCl3)d: 178.8 (C=S), 162.5 and 160.5 (£-F, Ph), 161.2 (thiazole), 137.4 (thiazole), 129.9 (Ph),
128.5 and 128.4 (m to F,Ph), 124.0 (p to F, Ph) 115.4 and 115.1 ( o to F, Ph), 111.8 (thiazole), 33.8 (CHNH), 16.4 (£H-Ph), 12.2 (£H2).
AP 0 0 0 3 8 4
X-8571A
-44 3Exampie.. 3.7.7
N- (2 - [3- (6-Chloro-2-methoxv.)j>VEi.dvi1 ethvl) -Ν' - (2-(5bromo)pyridyl)thiourea
The starting material, 3-(2-aminoethyl)-6-chloro2-methoxypyridine, was prepared in following manner:
To a solution of 1.0 g (7.0 mmol) of 2chloro-6-methoxypyridine in 20 ml of dry THF cooled to -78°C was added 10.9 ml (1.6 M in hexanes, 17.4 mmol) n-BuLi under an atmosphere of nitrogen. The temperature of the mixture was allowed to raise to -40°C before an addition of 4 ml ethylene oxide in 6 ml ether. The mixture was warmed to room temperature, 50 ml water was added and the aqueous layer was separated and extracted with 2 x 100 ml EtOAc. The organic extracts were combined, washed once with water, dried with Na2SO4, and concentrated in vacuo. The crude material was purified by dry column flash chromatography (hexane/EtOAc ) to afford 0.22 g of 3(2-hydroxyethyl)-6-chloro-2-methoxypyridine as a yellowish oil.
To a solution of 0.20 g (0.8 mmol) of 3-(2hydroxyethyl)-6-chlcro-2-methoxypyridine in 10 ml of dry CH2C12 cooled to -50°C was added 0.18 ml (0.8 mmol) trifluoromethanesulfonic anhydride under an atmosphere of nitrogen. The mixture was stirred for 30 min at this temperature and an additional 10 min at -78°C before a rapid addition of 30 ml of cold (~78°C) NH3 (1). The mixture was stirred for 15 min at room temperature, and then concentrated in vacuo to afford 1.0 g of crude 3-(2-aminoethyl)-6-chloro-2X-8571A
-444methoxypyridine as a trifluoromethanesulfonic acid salt.
^-H-NMR (CD3OD)d: 7.66 (d, IH, Py) , 7.03 !d, IH, Py) , 4.04 (s, 3H, CH3-O), 3.24 (t, 2H, CH2-N), 3.03 (t, 2H, CH2-Py).
The crude 3-(2-aminoethyl)-6-chloro-2methoxypyridine was condensed with N-(2-(5bromo)pyridyl-N'- (1-imidazolyl) thiourea in a manner analogous to Example 103, to give the titled product.
^-H-NMR (CD3OD )d: 11.25 (broad s, IH, N-Hi , 10 .82
(broad s, IH, N-H ), 8.31 (s, IH, Br- py) - 8.08 (d, IH,
Br-Py), 7.89 (d, IH, Cl-Py), 7.21 (m , 2H, Cl- and Br-
Py), 3.96 (m, 5H, CH2-N, and CH3-O), 3.03 (t, 2H, ch2-
Py) .
13C-NMR (CD3OD)d: 179.45 (C=S), 161.43 (Cl-C in Py), 152.41 (Br-C in Py), 145.92 (Cl-Py), 145.14 (MeO-CPy), 141.89 (Br-Py), 141.51 (Br-Py), 120.32 (Cl-Py), 116.48 (Cl-Py), 114.60 (Br-Py), 111.95 (Br-Py), 55.10 (CH3-O), 43.76 (CH2-NH), 27.89 (CH2-Ph).
Example 378
N-(2-Γ3 - (2-Fluoro)pvridvl1ethvl)-N'-f2-(5bromo'pvridvl thiourea The starting material, 3-(2-aminoethyl)-2fluoropyridine, was prepared in following manner:
A solution of 2.0 g (20.6 mmol) of 2fluoropyridine in 25 ml cf dry THF was cooled to -78°C was added 25 ml (1.6 M in hexanes, 41.6 mmol) n-BuLi under an atmosphere of nitrogen. The mixture was stirred at this temperature for 2 hours before an /
addition of 4 ml ethylene oxide in 7 ml ether. The
AP 0 0 0 3 8 4
-445X-8571A mixture was warmed to room temperature, 150 ml ether and 25 ml acetone was added. The precipitate was removed by filtration, and the filtrate was concentrated to 1/3 of volume in vacuo. The remainder was washed once with brine, dried with Na2SC>4, and concentrated in vacuo. The crude material was purified by dry column flash chromatography (hexane/EtOAc) to afford 0.42 g of 3-(2-hydroxyethyl)2-fluoropyridine as a brown oil.
To a solution of 0.20 g (1.42 mmol) of 3-(2hydroxyethyl)-2-fluoropyridine in 8 ml of dry CH2C12 cooled to -40°C was added 0.18 ml (0.8 mmol) trifluoromethanesulfonic anhydride under an atmosphere of nitrogen. After stirring for 30 min at -40°C, 30 ml of cold (-78°C) ΝΉ3 (1) was added. The mixture was stirred, for 30 min at -40°C, and then concentrated in vacuo to afford 1.03 g of crude salt which was washed twice with 20 ml diethyl ether to yield 0.82 g of 3(2-aminoethyl)-2-fluoropyridine as a trifluoromethanesulfonic acid salt.
1h-NMR (CD3OD)d: 8.23 (d, IH, Py), 7.98 (t, IH, Py) , 7.40 (m, IH, Py), 3.30 (t, 2H, CH2-N), 3.12 (t, 2H, CH2-Py).
The crude 3-(2-aminoethyl)-2-fluoropyridine was condensed with N- (2-(5-bromo) pyr idyl-Ν'-(1imidazolyl) thiourea in a manner analogous to example 103, to give the titled product.
l-H-NMR (CD3OD)d: 8.31 (d, IH, Br-Py) , 8.23 (m, IH, FPy), 8^06 (m, 2H, Br-and F-Py), 7.45 (m, IH, F-Py),
X-8571A
-44 67.23 (d, IH, Br-Py), 4.00 (q, 2H, CH2-N)» 3.14 (m, 2H, CH2-Py)· 13c-NMR (CD3OD)d: 179.59 (C=S), 163.53 and 159.78 (F-£ in Py), 152.39 (Br-Py), 145.87 (F-Py),145.63 and
142.38 (F-Py), 142.28 (Br-Py),141.54 (Br-Py), 122.31 and 122.26 (F-Py), 120.94 and 120.45 (F-Py), 114.59 (Br-Py), 111.97 (Br-Py), 44.29 (£H2-NH), 27.32 (£H2Ph) .
Example 379
N-(2-(2.6-difluoro)phenethyl)-Ν'-(2-benzothiazolyl) thiourea
In a manner analogous to Example 105, 2,6difluorophenethylamine was condensed with 1-(2aminobenzothiazole)-1'-imidazole thiocarbonyl which was made in similar way as described in Example 103. The titled compound crystallized from methylene chloride .
1H-NMR (CDCI3 + CD3OD) d: 7.64 (m, 2H, benzo), 7.38 (m, 3H, DFPh, benzo), 7.24 (t, 2H, DFPh), 4.04 (t, 2H, CH2), 3.15 ( t, 2H, CH2).
Example... j
N-(2- (2,6-difluoro)phenethyl)-N‘-(2-(4.5d imethy 1.) thiazoly.llthiQurea
In a manner analogous to Example 105, 2,6difluorophenethylamine was condensed with l-(2-amino4,5-dimethylthiazole)-1'-imidazole thiocarbonyl which was made in a similar way as described in Example 103.
AP Ο Ο Ο 3 8 4
Χ-8571Α -447The titled compound crystallized from methylene chloride .
1H-NMR (CDCI3) d: 7.21 (m, IH, DFPh), 7.15 <t, 2H, DFPh), 4.00 (q, 2H, CH2), 3.09 (t, 2H, CH2), 2.22 id,
J=0.5Hz, 3H, Me), 2.08 (d, J=0.6Hz, 3H, Me).
Example, 381,
N- (2- (2-fluoro)phenethvl)-Ν' -¢2- (6f lvprQbenzQ,th,iaz,glY.,l) ttiigvxea
In a manner analogous to Example 105, 2fluorophenethylamine was condensed with l-(2-amino-6fluorobenzothiazole)-1'-imidazole thiocarbonyl which was made in a similar way as described in Example 103 . The titled compound crystallized from methylene chloride.
1H-NMR(CDC13 + CD3OD) d: 7.53-7.06 (m, 7H, benzo,
FPh), 4.04 (t, 2H, CH2), 3.10 (t, 2H, CH2).
Example 382
Mr_(2 n ¢.2., 6 -di f luoro) phenethy 1)-Nz(2- (6 fluorobenzothiazolvl) thiourea
In a manner analogous to Example 105, 2,6difluorophenethylamine was condensed with l-(2-amino6-fluorobenzothiazole)-1'-imidazole thiocarbonyl which was made in a similar way as described in Example 1C3 . The titled compound crystallized from methylene chloride.
3H-NMR (CDCI3 + CD3OD) d: 7.52 (m, IH, benzo), 7.40 (m, IH, benzo), 7.14 (m, 2H, DFPh, benzo), 6.88 (m,
3C 2H, DFPh), 4.02 (t, 2H, CH2), 3.14 (t, 2H, CH2).
X-8571A
-448Example 383
Ν-(2 - (2 - fluoro) phenethyl)-N * - (2 benzothiazolyl)thiourea
In a manner analogous to Example 105, 2fluorophenethylamine was condensed with 1-(2aminobenzothiazole)-1'-imidazole thiocarbonyl which was made in a similar way as described in Example 103 The titled compound crystallized from methylene chloride.
1H-NMR (CDCI3 + CD3OD) d: 7.63 (q, 2H, benzo), 7.32 (m, 4H, benzo, FPh), 7.10 (q, 2H, FPh), 4.06 (t, 2H, CH2), 3.11 (t, 2H, CH2).
Example 38.4
N-(2-(2-fluoro)phenethyl)-N‘-(2-(4inethylthias.olYl.),thiourea In a manner analogous to Example 105, 2fluorophenethylamine was condensed with 1-(2-amino-4methylthiazole)-1'-imidazole thiocarbonyl which was made in a similar way as described in Example 103.
The titled compound crystallized from methylene chloride.
1H-NMR (CDCI3 + CD3OD) d: 7.23 (m, 2H, FPh), 7.06 (m,
2H, FPh), 6.34 (d, J=lHz, IH, thiazole), 3.99 ( t, 2H, CH2), 3.05 (m, 2H, CH2), 2.20 (d, J=0.9Hz, 3H, Me).
Example 385
N-(2 - (2,6-dif luoro) phenethyl) -N* -(2-(4Eethyl-thiazoly 1) thiourea In a manner analogous to Example 105, 2,6difluorophenethylamine was condensed with l-(2-aminoAP 0 0 0 3 8 4
X-8571A
-4494-methylthiazole)-1'-imidazole thiocarbonyl which was made in a similar way as described in Example 103.
The titled compound crystallized from methylene chloride.
^H-NMR (CDCI3 + CD3OD) d: 7.19 (m, 1H, DFPh), 6.87 (t, 2H, DFPh), 6.35 (s, IH, thiazole), 3.98 (t, 2H, CH2), 3.09 (t, 2H, CH2), 2.22 (s, 3H, Me).
Example.. J.S 5
N-(2,2-dimethvl-2-(2-chloro-6-fluoro)phenethvl) -Nzri2thiazolvl)thiourea
A solution of 2-chloro-6-fluorophenyl acetonitrile (1.69 g, 10 mmole) in dry THF (70 ml) was cooled to -60°C, and lithium diisopropylamide (5.25 ml, 10.5 mmole) was added. After 30 min, methyl iodide (0.68 ml, 11 ml ) was added into the reaction mixture, and the reaction was slowly warmed to 0°C, and kept at 0° C for 1 hr. Then it was cooled to -60°C again, and more lithium diisopropylamide (6 ml, 12 mmole) was added. After 30 min, methyl iodide (1.87 ml, 30 mmole) was added. The reaction mixture was allowed to warm to room temperature and kept there for 2 hr after which it was poured into a sodium hydrogen carbonate solution, and extracted with chloroform.
The organic phase was washed with water, dried, and the solvent was evaporated in vacuo. The product 2,2dimethyl-2(2-chloro-6-fluorophenyl) acetonitrile (1.07 g) was isolated by silica gel column chromatography. 1H-NMR (CDCI3) d: 7.25 ( m, 2H, Ph), 7.03 ( m, IH,
Ph), 1.98 (s, 3H, Me ), 1.96 (s, 3H, Me).
X-8571A
-450The 2,2-dimethyl-2-(2-chloro-6fluorophenyl)ethylamine was obtained by reduction of
2,2-dimethyl-2(2-chloro-6-fluorophenyl) acetonitrile with cobalt chloride and sodium borohydride according to the method described by L.S. Heizman in J. Am.
Chem. Soc., 104, p.6801, (1980). It was then condensed with 1-(2-aminothiazole)-11-imidazole thiocarbonyl in the analogous manner to Example 105. The titled compound was isolated by silica gel column chromatography.
1h-NMR (CDCI3) d: 7.35-7.09 (m, 3H, Ph), 6.95 ( d, IH, thiazole), 6.73 ( d, IH, thiazole), 4.09 (d, 2H, CH2),
1.50 ( s, 6H, Me ).
Example 3§7
N-(2-(5-bromo-2-methoxv)phenethvl) -Nx-(2-(4methvlthiazolvl) thiourea
In a manner analogous to Example 105, 5bromo-2-methoxyphenethylamine was condensed with 1-(2amino-4-methylthiazole)-1’-imidazole thiocarbonyl which was made in a similar way as described in Example 103. The titled compound crystallized from methylene chloride.
^•H-NMR (CDCI3 + CD3OD) d: 7.31 (d, IH, Ph), 7.29 (s,
IH, Ph), 6.72 (d, IH, Ph), 6.34 (s, IH, thiazole),
3.95 (t, 2H, CH2), 3.79 (s, 3H, MeO), 2.96 (t, 2H,
CH2), 2.23 (s, 3H, Me).
AP Ο Ο Ο 3 8 4
Χ-8571Α
-451Examp±£_J£&
N-.(2- (5-bromo-2-methoxy)phenethyl) -Ν’- (2- (4cYaaQXhiazglyll thiourea In a manner analogous to Example 105, 55 bromo-2-methoxyphenethyl-amine was condensed with 1(2-amino-4-cyanothiazole)-1'-imidazole thiocarbonyl which was made in a similar way as described in Example 103. The titled compound was purified by silica gel column chromatography.
!h-NMR (CDCI3 + CD3OD) d: 7.51 (thiazole), 7.32 (d,
IH, Ph), 7.27 (s, IH, Ph), 6.76 (d, IH, Ph), 3.90 (t, 2H, CH2), 3.83 (s, 3H, MeO), 2.97 (t, 2H, CH2 ) ·
Example. .3.SJ.
(2, luoro) phenethyl) (2.-.(.4.,pyangtfaiasolyl) .thiourea
In a manner analogous to Example 105, 2,6difluorophenethylamine was condensed with l-(2-amino4-cyanothiazole)-1’-imidazole thiocarbonyl which was made in a similar way as described in Example 103.
The titled compound crystallized from methylene chloride.
(CDCI3 + CD3OD) d: 7.51 (s, IH, thiazole), 7.22 (m, IH, DFPh), 6.90 (t, 2H, DFPh), 3.93 (t, 2H, CH2), 3.08 (s, 2H, CH2).
X-8571A
-452Exaraple 33.Q.
N-(2-(2.6-difluoro)phenethvl)-Ν'-(2ircidaz-plyl),thiourea
In a manner analogous to Example 93, using
2,6-difluorophenethylamine and 2-aminoimidazole, the titled compound was obtained.
3H-NMR (DMSO + D2O) d: 7.28 (m, IH, DFPh), 7.02 (t,
2H, DFPh), 6.78 (broad, IH, imidazole), 6.62 (broad, IH, imidazole), 3.79 (t, 2H, CH2), 2.97 (t, 2H, CK2).
Example. 321
N-.(l-amino-2- (5-imidazolvl) -ethvl) -Ν' - (2- (5-methvl) thiazolyl) thiourea
1-(2-(5-methyl)-aminothiazole-1'imidazolethiocarbonyl (prepared as described in Example 103, using 2-amino-5-methylthiazole instead of 2-aminothiazole) (4.06 mmol, 910 mg) and histamine (4.05 mmol, 450 mg) in dimethylformamide (10 ml) was heated to 50° C for 3 hrs. The mixture was concentrated and partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The organic layer was dried over MgSC>4 and concentrated to give the titled compound in 43 % yield (463 mg).
ςΗ NMR (250 MHz, DMSO-dg) δ 2.18 (s, 3 Η), 2.80 (m, 2 H), 6.57 (s, 1 H), 6.90 (s, 1 Η), 7.60 (s, 1 H).
Example 392
1- (2-Aroino-5-bromopvridyl.) -1 ’ - (imidazolyl) thiocarbonyl
A mixture of 2-amino-5-bromopyridine, 97% (25.0 g, 140 mmol) and 1,1’-thiocarbonyldiimidazole,
AP 0 0 0 3 8 4
X-8571A
-45390% (27.72 g, 140 mmol) in 300 mol of acetonitrile was stirred at ambient temperature overnight and then filtered. The precipitate was dried in vacuo to give the titled compound as a crude product which was stored and used for further condensations with various phenethylamines.
Yield: 37.5 g (95 %).
Ex amp3_e .33.3.
1- (5.-.chXgrQpy.ri<3.-2..Tyl.-£hip£^rt>amg>v3·) imidazols
In a 500 ml reaction-flask, N,Nthiocarbonyl-diimidazole (60.0 g, 337 mmol) was dissolved in acetonitrile (400 ml) at 50°C with stirring. The solution was then cooled to 20°C. 2Amino-5-chloropyridine (43 g, 337 mmol) was then added.
The solution was stirred for 35 minutes and kept at ambient temperature over night. The solution was filtered and the crystalline mass consisted of a mixture of needles and pellets. The pellets were separated mechanically and purified by fluidization with a hair-dryer to give the titled product.
1H-NMR DMSO-dg δ ppm 7.1-7.2 (2H, s, imid) 7.5-7.6 (IH, d, orto-coupling, pyr.) 7.9-8.0 (IH, s, imid.) 8.1-8.2 (IH, d,d, pyr.) 8.6-8.7 (IH, d, meta-coupling, pyr.)
X-8571A
-454Example 394
N-2 - (2,5-dimethoxvphenvlethvl)-Ν' -(2-(6fluorobenzothiazolyl)) thiourea
450 mg 2,5-dimethoxyphenethylamine (2.5 mmol) and 740 mg 1-((2-(6fluoro)benzothiazolyl)thiocarbamoyl) imidazole (2.5 mmol) (Example 80) in 5 ml acetonitrile were refluxed for one half hour. The mixture was cooled, and crystals were filtered off. Recrystallization from a mixture of ethanol and dimethylformamide gave 640 mg of the pure product as very fine needles.
Mp: 196°C 1H-NMR: 3.00 2H (t), 3.77 3H (s), 3.84 3H (s), 3.91 2H (m) , 6.91-7.03 3H (m), 7.38 IH (m), 7.70 IH (m), 7.94 IH (m), 9.9 IH broad singlet, 12.0 IH broad singlet Analysis C]_gH]_gFN3O2S2: calculated C 55.22 H 4.63 N 10.73; found: C 55.3 H 4.70 N 10.75
Example 395
N-2-(-2.5-dimethoxvphenylethvl)-Ν' -(2-(4methvlthiazolvl)) thiourea 1000 mg (4.46 mmol) 1-(2-(4methylthiazolyl)thiocarbamoyl)imidazole (prepared analogously to 1-(2-thiazolyl)thiocarbamoyl) imidazole described in Example 103) and 800 mg 2,5dimethoxyphenethylamine (4.42 mmol) in 7 ml acetonitrile were refluxed for one half hour. The mixture was cooled to 0°C, crystals were filtered off, rinsed with acetonitrile and dried. Recrystallization
AP 0 0 0 3 8 4
X-8571A
-455from ethanol-dimethylformamide gave 1.42 g of the pure product.
Mp: 210°C
1h-NMR (DMSO-dg): 2.27 3H (s), 2.96 2H (t), 3.78 3H (s), 3.83 3H (s), 3.84 2H (m), 6.73 1H (s), 6.85-7.04 3H (m)
Analysis C15H19N3O2S2: calculated C 53.39 H 5.67 N 12.45; found: C 53.1 H 5.65 N 12.35
Example .3.9.6
N-2-(-2.5-dimethoxvphenethvl)-N‘- (2-(2benzothiazolvl)) thiourea
556 mg 1-(2-benzothiazolyl) thiocarbamoyl) imidazole (2 mmol) (Example 66) and 362 mg 2,5dimethoxyphenethylamine (2 mmol) in 5 ml acetonitrile were refluxed for one half hour. Recrystallization from ethanol-dimethylformamide gave 565 mg pure product.
!h-NMR (DMSO-dg): 3.02 2H (t), 3.77 3H (s), 3.85 3H (s), 3.93 2H (m), 6.92-7.04 3H (m) , 7.38 1H (m), 7.53 1H (m), 7.70 1H (m), 8.01 1H (m)
Analysis Ci8H19N3°2s2: calculated C 57.88 H 5.13 N 11.25; found: C 57.95 H 5.15 N 11.25
Example,.. 227.
Mr2--..(2,6.---dichl.prophenyle.thyl) -N‘ -(2-thiazolvl)thiourea
9.3 g 2,6-Dichlorophenylacetonitrile (50 mmol) in 50 ml diethylether was added dropwise to a mixture of 5 g lithium aluminum hydride.in 200 ml ether. The mixture was heated to reflux, and reaction was allowed to take place for 2 hours. The mixture
X-8571A
-456was cooled to room temperature, and 5 ml water was added dropwise, followed by 5 ml 25 % sodium hydroxide in water. 10 ml water was then added, and the mixture was filtered. 10 ml acetic acid was added rapidly to the stirred filtrate. The 2,6dichlorophenethylammonium acetate that precipitated was filtered off and dried.
500 mg 2,6-dichlorophenethylammonium acetate (2 mmol), 0.42 g 1-(2-aminothiazole)-1'-imidazole thiocarbonyl (Example 103) and 0.5 g diisopropylethylamine were mixed in 5 ml acetonitrile and refluxed for 30 minutes. The mixture was then kept at 0°C for 17 hours and the crystals were filtered off.
Recrystallization from acetonitrile gave 265 mg of the titled product.
!h-NMR (DMSO-dg): 3.3 2H (t), 3.9 2H (m), 7.2 IH (d),
7.35-7.6 4H (m).
Ex.gtffig.Ie 3S8.
N-2-(2.6-dichlorophenvlethvl)-Ν' -(2-(4methvlthiazolvl)) thiourea 500 mg 2,6-dichlorophenylethylammonium acetate (2 mmol) (Example 397), 0.48 g 1-(2-(4methylthiazolyl)thiocarbamoyl)imidazole (prepared analogously to 1-(2-thiazolyl)thiocarbamoyl)imidazole described in Example 103) (2 mmol) and 0.5 g diisopropylethylamine were mixed in 5 ml acetonitrile and refluxed for 30 minutes. The mixture was cooled and crystals were filtered off. Recrystallization from acetonitrile gave 598 mg of the titled product.
AP 0 0 0 3 8 4
X-8571A
-457^-H-NMR (DMSO-dg): 2.2 3H (s), 3.3 2H (t) , 4.0 2H (m) , 6.7 IH (s), 7.4 IH (m), 7.5 2H (m), 9.8 IH broad singlet, 11.7 IH broad singlet
Analysis C13H23CI2N3S2: calculated C 45.09 H 3.78 N 12.13; found: C 45.45 H 3.9 N 12.55
N- (-2-(2.6-dichlorophenvl)ethvl)-Ν' -(2bengQtbiazo.3.Yl) thiourea 500 mg 2,6-dichlorophenylethylammonium acetate (2 mmol) (Example 397), 0.55 g 1-(2benzothiazolyl)thiocarbamoyl) imidazole (2 mmol) (Example 66) and 0.5 g diisopropyl-ethylamine were mixed in 5 ml acetonitrile and refluxed for 30 minutes. The mixture was cooled and crystals were filtered off. Recrystallization from acetonitrile gave 497 mg of the titled product.
^-NMR (DMSO-dg) 3.3 2H (t) , 4.0 2H (m) , 7.3- 7.7 6H (m), 8.0 IH (d), 10.0 IH broad peak, 12.1 IH broad peak.
Analysis C16H13CI2N3S2: calculated C 50.26 H 3.43 N 10.99; found: C 50.3 H 3.45 N 11.1
Example 400 .S.-Jighlaragheny-lLethvl) -N '..z±2.-L5. z
JilugrpbgngQthi^.s.plvJ-). Lthiourea 500 mg 2,6-dichlorophenylethylammonium acetate (2 mmol) (Example 397), 0.59 g 1-((2-(6fluoro)benzothiazolyl)thiocarbamoyl) imidazole (2 mmol) (Example 80) and 0.5 g diisopropylethylamine
X-8571A
-458were mixed in 5 ml acetonitrile and refluxed for 30 minutes. The mixture was cooled and crystals were filtered off. Recrystallization from acetonitrile gave 548 mg of the titled product.
^H-NMR (DMSO-dg): 3.4 2H (t), 4.0 2H (m) , 7.3-7.4 2H (m), 7.5-7.7 2H (m), 8.0 IH (m) , 9.8 IH broad peak, 12.0 IH broads peak.
Analysis C]_gH32Cl2FN3S2 : calculated C 48.00 H 3.02 N 10.50; found: C 48.25 H 3.1 N 10.6
Example 401
N- (2-(2.6-difluoro-3-methoxvphenvl)ethvl)-Ν' - (-2thiazolvl)thiourea
6.25 ml 1.6M n-butyl lithium in hexane was added dropwise to a solution of 10 mmol 2,4difluoroanisole in 30 ml diethyl ether. The mixture was kept at -65°C during the addition. 3 ml Dimethylformamide was then added, and the mixture was slowly (lh) allowed to wartn to room temperature. The mixture was poured into a separation funnel containing 50 ml ice-water. The ether layer was separated, washed with 50 ml water and dried (Na2SO4>. The solvent was evaporated, and the residue was redissolved in 50 ml ethanol. 2 g Ammonium acetate and 3 ml nitromethane were added and the mixture was refluxed for 3 hours. The solvent was evaporated, and the residue was partitioned between 50 ml dichloromethane and 50 ml water. The organic layer was dried, and the solvent was evaporated. Crystallization from cold ethanol gave 480 mg brown
AP Ο Ο Ο 3 8 4
Χ-8571Α
-459crystals of l-nitro-2(2, 6-difluoro-3methoxyphenyl)ethene.
^H-NKF. (CDCI3): 3.9 3H (s), 6.9-7.1 2H (m) , 7.8 IH (d) , 8.1 IH (d).
420 mg l-nitro-2-(2,6-difluoro-3methoxyphenyl)ethene was dissolved in 50 ml tetrahydrofurane and added dropwise under stirring to a solution of 2 g lithium aluminum hydride in 50 ml tetrahydrofurane. The mixture was refluxed for 3 hours. The product amine was worked-up by the dropwise addition of 2 ml water followed by 2 ml 25% sodium hydroxide in water followed by 4 ml water.
The mixture was then filtered. The filtrate was extracted with 2 x 20 ml 1 M HCl. The aqueous layer was made basic by the addition of 50 ml 45 % sodium hydroxide solution, and then extracted with 3 x 50 ml dichloro-methane. The 2-(2,6-cifluoro-3methoxyphenyl) ethyl-amine obtained by the evaporation of solvent was pure enough for use in the next step.
^-H-NMR: 1.2 2H broad singlet, 2.6 2K (m) , 2.7 2H (m) ,
3.65 3H (s), 6.4-6.6 2H (m)
172 mg 2-(2,6-difluoro-3methoxyphenyl)ethylamine (1.0 mmol) and 210 mg 1-(2aminothiazole)-1'-imidazole thiocarbonyl (1.0 mmol) in
5 ml acetonitrile were refluxed for one hour. The solution was cooled, and crystallization was allowed for overnight. Solid material was filtered off, and recrystallized from acetonitrile to give 138 mg of the titled product.
APO00384
X-8571A
-460^H-NMR (DMSO-dg): 3.1 2H (t), 3.8-4.0 5H (m) , 6.9-7.2 3H (m), 7.4 IH (d), 9.8 IH broad peak, 11.7 IH broad peak
Analysis Ci3Hj_3F2N3OS2 ·· calculated C 47.40% H 3.98% N 12.76%; found: C47.6% H 4.1% N 12.75%
-.1-2jL>.eazQ.txiazQl,y.llatbYil..7.N it ί2 t thiazol.yjJ XhiauEea
59.5 g benzotriazole (0.50 mol) was dissolved in 700 ml dimethylformamide. 160 g Sodium carbonate {1.5 mol) was added and then dropwise 73.5 g ethyl chloroacetate (0.60 mol). The stirred mixture was slowly heated to 40°C, and kept at that temperature for 17 h. The solvent was evaporated and the residue was extracted with ethyl acetate. GC showed one major and one minor product. The minor product ethyl-2-(2-benzotriazolyl)acetate was isolated by fractional crystallization from cold mixtures of ethanol and ethyl acetate.
7.1 g Of this minor product (40 mmol) was dissolved in 50 ml diethyl ether-tetrahydrofurane 1:1 and 1.5 g of lithium borohydride was added. The reaction mixture was stirred for 17 h at room temperature. The solvent was removed and replaced with 50 ml butanol. 5 ml Water was added and the temperature was slowly raised to about 50°C. After 4 h at this temperature the solvent was removed and the residue was partitioned between dichloromethane and water. The organic layer was dried, and the product
X-8571A
-4612-(2-benzotriazolyl)ethanol was isolated by crystallization from cold ethanol.
4.70 g Of the 2-(2-benzotriazolyl) ethanol (28.8 mmol) was dissolved in 200 ml diethyl ether and
2.28 g pyridine (28.8 mmol) was added. The mixture was cooled to -50°C, and 8.18 g triflic anhydride (29 mmol) was added. The mixture was removed from the cooling bath, and was allowed to reach room temperature. The mixture was filtered under dry conditions and added to a cold -40°C solution of ca 150 ml ammonia in 50 ml diethyl ether. This mixture was allowed to reach room temperature, and ether was removed. 50 ml 2M HCl was added, and this mixture was washed with methylene chloride. The aqueous phase was made basic by addition of 50 ml 25 % sodium hydroxide and extracted with 3 x 25 ml methylene chloride. Evaporation of the solvent gave 2.10 g 2-(2benzotriazolyl)ethylamine (12.9 mol). This amine was used in the next step without further purification.
324 mg 2- (2-benzotriazolyl)ethylamine (2 mmol) and 420 mg 1-(2-aminothiazole)-1'-imidazole thiocarbonyl (2 mmol) were mixed in 3 ml acetonitrile. The mixture was slowly heated to reflux, and was then cooled to allow the product to crystallize. Repeated crystallization from acetonitrile gave 234 mg pure N(2-(-2-benzotriazolyl)ethyl)Ν' -(2-thiazolyl)thiourea. 1H-I'JMR (DMSO-dg): 4.5 2H (m) , 5.1 2H (m), 6.75 IH (d), 7.05 IH (d) , 7.4 2H (m) , 7.9 2H (m).
13c-NMR 47, 56, 112, 119, 127, 145, 180.
Analysis C].2H12N6S2: calculated C 47.35% H 3.97% N 27,61%; found: C 47.3% H 3.95% N 27.2%'
AP 0 0 0 3 8 4
X-8571A
-462Example .40.3 cis/trans N- (2- (2-ethoxvphe.nvlcy-Clopropanvl)-).TNl.-T..(2jT pvridvl) thiourea
28.56 g methyl triphenylphosphonium bromide (80 mmol) in 500 ml tetrahydrofurane was cooled to -50°C. 50 ml n-Butyllithium in hexane (about 1.6 M, mmol) was added dropwise under stirring. The mixture was slowly warmed to room temperature, and kept there for two hours. The mixture was then cooled to -30°, and 12 g 2-ethoxybenzaldehyde (80 mmol) was added. The mixture was warmed to room temperature, and most of the solvent was removed and the residue was mixed with 400 ml ether and filtered. The solvent was evaporated and ethyl acetate was added to residue. The solution was passed through a pad of silica gel. This crude 2-ethoxystyrene was dissolved in 50 ml dichloroethane and used as such in the next reaction step:
0.1 g Cul was added, and the mixture was heated to reflux temperature. 8.80 g Ethyl diazoacetate in 30 ml dichloroethane was then added dropwise over a period of 1 hour. GC-analysis showed the formation of two products in a about 1:2 ratio. The two isomeric products were separated from other material by column chromatography (silica-gel, mixtures of hexane - ethyl acetate). This gave 3.1g of a cis/trans mixture of 2(2-ethoxyphenyl)-1-carboxyethyl cyclopropanes. The product mixture was hydrolysed in a refluxing mixture of 50 ml ethanol + 10 ml water + 4 g sodium hydroxide
X-8571A
-4 63(2 hours). The solvent was evaporated and the residue was made acidic with 100 ml 2M hydrochloric acid and extracted with 2 x 50 ml dichloromethane. The organic layers were dried and solvent was evaporated. 50 ml Toluene was added followed by 6 g thionyl chloride.
The mixture was heated to 80°C for one hour and the solvent was then removed. 100 ml Acetone was added, the solution was cooled in an ice-bath and 4 g sodium azide in 20 ml water and 100 ml toluene was added after which the mixture was washed with 3 x 50 ml water. The organic layer was dried (Na2SO4), the solvent was evaporated and the residue was dissolved in 100 ml dioxane. The dioxane solution was heated slowly to reflux, and kept at reflux 30 min. 25 ml Concentrated hydrochloric acid was added and the mixture was refluxed for 2 hours. The solvent was removed and the residue was partitioned between 50 ml dichloromethane and 50 ml 2m hydrochloric acid. The aqueous layer was made basic by the addition of 50 ml 25% sodium hydroxide solution, and extracted with 3 x 50 ml dichloromethane. The dichloromethane solvent was evaporated and the residue was purified by column chromatography (silica-gel, mixtures of ethanol and ethyl acetate to give about 1:1 mixture of cis/trans 2-(2-ethoxyphenyl) cyclopropyl-amines .
0.24 g 2-Aminopyridine ( 2.6 mmol) and 0.46 g thiocarbonyldiimidazole (2.6 mmol, were stirred in 5 ml acetonitrile for 2 hours. 0.41 g (2.6 mmol) of the mixture of cyclopropylamines was added, and the reaction mixture was heated slowly to 70°C and stirred
AP 0 0 0 3 8 4
-464Χ-8571Α at that temperature for 17 hours. The solvent was evaporated, and the titled product was isolated by column chromatography (silica-gel, mixtures of hexaneethyl acetate.
XH-NMR: 1.15-1.25 5H (m), 2.50 IH (m) , 3.42 0.55H (m) , 3.73 0.45% (m), 4.0-4.1 2H (q) , 6.7-8.15 8H (m)
E.X3ffiD.l €...401
N-(2-(2-pvridvlethvl))-N’-(2-(5ChlQrppyridyl)1LhiQUTSa
1.73 g 2-Amino-5-chloropyridine (10 mmol) and 1.78 g thiocarbonyl diimidazole (10 mmol) were stirred for 2 hours in 15 ml acetonitrile. 1.47 g 2(2-Aminoethyl)pyridine (12 mmol) was added, and the mixture, was stirred at room temperature for 2 hours. The reaction mixture was then heated to 50°C and was stirred for 17 hours. Crystals were collected by filtration after cooling of the mixture.
Recrystallization from acetonitrile gave pure titled product.
!h-NMR (DMSO-dg): 3.2 2H (t), 4.1 2H (m), 7.2-7.5 3H (m) , 7.8-8.0 2H (m), 8.2 IH (d) , 8.7 IH (m), 18.0 IH (s), 11.5 IH (s)
Example 405
N-- (2- (2-pyridylethvl) I-Ν' - (2- (5-bromopyridvl) ) thiourea
1.28 g 2-Amino-5-bromopyridine (10 mmol) and 1.78 g thiocarbonyl diimidazole (10 mmol) were stirred for 2 hours in 15 ml acetonitrile. 1.47g 2-(2Aminoethyl) pyridine (12 mmol) was added, and the mixture was stirred at room temperature for 2 hours.
X-8571A
-46 5The reaction mixture was then heated to 50°C and was stirred for 17 hours. Crystals were collected by filtration after cooling of the mixture. Recrystaliization from acetonitrile gave pure titled product.
1H-NMR .(DMSO-dg): 3.5 2H (t), 4.2 2H (m) , 7.2 2H (d) ,
7.9-8.1 3H (m), 8.3 IH (d), 8.6 IH (m) , 8.9 IH (d)
10.9 IH (s), 11.4 IH (t)
Example 406
N-(2-(2-pvridvlethvl))-Ν' -(2-(5-nitropvridvl)) thiourea
1.39 g 2-Amino-5-nitropyridine (10 mmol) was dissolved in 20 ml tetrahydrofurane. 0.68g (10 mmol)
Sodium ethoxide (10 mmol) was added. The mixture was heated to 50°C and stirred for 30 minutes. The mixture was cooled, and most of the liquid was decanted from the formed red precipitate. The precipitate was taken up in 20 ml acetonitrile, and added to 1.78 g thiocarbonyl diimidazole in 10 ml acetonitrile. This mixture was stirred for 10 minutes at room· temperature . 1.22 g 2-(2-Amino-ethyl)pyridine was added and the mixture was stirred for one hour. 1 ml Acetic acid was added, and the solvent was evaporated. The residue was washed with water.
Repeated crystallizations from acetonitrile gave 1.28 g yellow crystals of the titled product.
!h-NMR (DMSO-dg): 3.1 2H (t), 3.2 2H (t), 7.2 IH (m),
7.3 3H (m), 7.7 IH (m), 8.4 IH (m), 8.5 IH (m), 8.9 IH (d)
AP 0 0 0 3 8 4
-46 6X-8571A' gxample.. iQJ.
N- (2 - (2-pyridylethvl) ) -N.·. - (2.-(6-.
methvlpvridvl) ) thiourea 1.78 g thiocarbonyl diimidazole (10 nunol) and 1.58 g 2-amino-5-methylpyridine (10 mmol) in 15 ml acetonitrile were stirred for 1 h at room temperature.
1.22 g 2-(2-Aminoethyl)-pyridine was added. The mixture was stirred 1 h at room temperature, and then 17 h at 50°C. The mixture was cooled and crystals were collected by filtration. Recrystallization from acetonitrile gave 1.30 g pure titled product.
1H-NMR (DMSO-dg): 2.2 3H (s), 3.1 2H (t), 4.0 2H (m) , 7.0 IH (d), 7.2 IK (m), 7.3 IH (d) . 7.6 IH (m), 7.7 IH (m), 7.8 IH (m), 8.6 IH tin) 13C-NMR: 17.3, 36.3, 44.0, 112.1, 121.7, 123.5, 126.7,
136.6, 139.7, 144.6, 149.2, 151.8, 159.0, 179.2
Example. jQ.g
IN- (2 - (.2-pvridvlethvl) )-N'-(2-(5bromopvrldvl))thiourea HCl salt)
100 mg N- ;2-(2-pyridylethyl))-N’-(2-(5bromopyridyl)) thiourea (Example 405) was added to about 10 ml water. The suspension was heated to about 90°C and pH was adjusted to about 3 by addition of hydrochloric acid. The titled product was isolated by freeze-drying.
^-H-NMR (DMSO-dg): 3.6 2H (t), 4.2 2H (m) , 7.2 2H (d) ,
7.9-8.1 3H (m), 8.3 IH (d), 8.6 IH <m), 8.9 IH (d)
10.9 IH (s), 11.4 IE (t)
Χ-8571Α
-467Example 409 (Ν- (2-IZzpyr idyls,thyl)) -Ν' - (2-(5chloropvridvl)) thiourea HCl salt)
100 mg N-(2-(2-pyridylethyl))-Ν' -(2-(5chloropyridyl)) thiourea (Example 404) was added to about 10 ml water. The suspension was heated to about 90°C and pH was adjusted to about 3 by addition of hydrochloric acid. The titled product was isolated by freeze-drying.
!h-NMR (DMSO-dg): 3.6 2H (t), 4.2 2H (m), 7.3 IH (d), 8.0-8.2 3H (m) , 8.3 IH (m), 8.6 IH (m), 9.0 IH (m),
10.9 IH (s), 11.4 IH (t).
Example 410
N-(2-(-2-Benzotriazolvl)ethvl)Ν' -(2-(5bromopvridyl)) thiourea
356 mg Thiocarbonyl diimidazole (2 mmol) and 346 mg 2-amino-5-bromopyridine (2 mmol) in 2 ml acetonitrile were stirred for 1 h at room temperature. 324 mg 2- (2-Benzotriazolyl)ethylamine (Example 402) (2 mmol) was then added. This mixture was stirred for 10 min, and was then heated to reflux. After 20 min 5 ml more acetonitrile and 3 ml dimethylformamide were added to give a clear solution. The solution was cooled and the resulting precipitate was collected after centrifugation. Recrystallization from acetonitrile-dimethylformamide gave 310 mg of the pure titled product.
1H-NMR (DMSO-dg): 4.44 2H (m), 5.15 2H (m), 7.18 IH (d) , 7.56 2H (m) , 7.90 IH (d), 8.04 3H (m), 10.93 IH (s), 11.41 IH (s)
AP Ο Ο Ο 3 8 4
Χ-8571Α
-46813C-NMR: 44, 55, 114, 118, 118, 127, 142, 144, 146,
152, 180 PPM
ExamB.l£-411
Ν-(2-(2,6-difluoro-3-methoxyphenvl)ethvl)-Ν'-(2-(5bromopvridvl)) thiourea
334 mg 2-(-2,6-difluoro-3methoxyphenyl)ethylamine (Example 401) (mw 167, 2 mmo1) and 566 mg 1-(2-(510 bromopyridyl)thiocarbamoyl) imidazole (Example 392) (mw 283.15) (2 mmol) were mixed in 3 ml acetonitrile. The mixture was slowly heated to reflux, and was then cooled to crystallize. Repeated crystallization from acetonitrile gave 238 mg of the pure titled product.
Th-HNMR: (DMSO) 3.12 2H (t), 3.86 3H (s), 4.00 2H (m),
6.82 3H (m), 7.68-7.72 IH (m) , 8.12 IH (d), 9.16 IH is), 11.35 IH (s)
Example 412
N.-J2-(3,4,5-trimethoxy)-benzvl)-Ν'-(2thiazolvl)thiourea
The starting material 3,4,5trimethoxybenzylamine was prepared by reduction of
3,4,5-trimethoxybenzonitrile with cobalt chloride and sodium borohydride, according to the general method described by L.S.Heinzman in J. Am. Chem. Soc., 104, p. 6801 (1980).
3,4,5-trimethylbenzonitrile (965 mg, 5 mmole) and cobolt chloride (2.37 g, 10 mmole) were dissolved in methanol (70 ml). To the solution was
X-8571A
-469 added sodium borohydride (1.89 g, 50 mmole). After 3 hrs, the reaction mixture was filtered through Celite, and concentrated to small volume. It was then taken up in chloroform and extracted with IN HCl (100 ml).
The organic phase was discarded. The aqueous phase was basified with aqueous ammonia, and extracted with chloroform. The organic phase was dried over magnesium sulfate, and evaporated in vacuo to yield 3,4,5trimethoxybenzylamine (427 mg).
Ιη-NMR(CDC13)d: 6.58 (s, 2H, TMPh), 3.85 (m, 6H, 2 x MeO), 3.82 (s, 3H, MeO), 3.80 (m, 2H, CH2).
The titled compound was prepared analogous to Example 105 .
^H-NMR (CDCl3)d: 7.26 (d, IH, thiazole), 6.85 (d, IH, thiazole), 6.64 (s, 2H, TMPh), 4.84 (d, J= 5.7Hz, 2H,
CH2), 3.86 (m,6H, MeO), 3.85 (s, 3H, MeO).
13C-NMR(CDCI3)d: 177 (C=S), 161 (thiazole), 153 (TMPh), 138 (TMPh), 137 (thiazole), 132 (TMPh), 111 (thiazole), 104 (TMPh), 61 (MeO), 56 (MeO), 50 (CH2).
Example 413
2-Formyl- 3 -fluoropyridine Dry ethyl ether (500 mL) , n-BuLi (1.6 fcj in hexane, 62.5 mL, 0.1 mol), and dry 1,4diazabicyclo[2.2.2]octane (DABCO) (11.56 g, 0.1 mol) were introduced into a 1 L flask under a dry N2 stream at -60°C and the resulting cloudy solution was stirred for 1 hour at -20°C. 'The mixture was then cooled to -75°C and an ethyl ether (50 mL) solution of 3 - fluoropyridine (9.81 g, 0.1 mol) was added dropwise and stirring continued for 1 1/2
AP 0 0 0 3 8 4
Χ-8571Α
-470hours at -60°C. The mixture was recooled to -75°C, dry N,N-dimethylformamide (8.52 mL, 0.11 mol) dissolved in ethyl ether (50 mL) was added dropwise and the mixture stirred for 2 hours at -75°C. Water (175 mL) was introduced slowly at -10°C, the aqueous layer extracted with ethyl acetate (5 x 200 mL), and the combined extracts were dried over anhydrous sodium sulfate. Solvent removal produced a dark brown oil which after vacuum distillation and purification by chromatography on silica gel provided
4.4 g (35%) of the titled product as an off-white crystalline solid:
mp 48-49°C;
IR (CHCI3, cm1) 3071, 3020, 2873, 2842, 1720, 1588, 1461, 1441;
^•H NMR (300 MHz, CDCI3) δ 10.21 (s, IH) , 8.62 (m, IH) ,
7.57 (m, 2Η);
MS (FD) m/e 125 (M+);
UV (EtOH) 263nm (£=1551), 201nm (£=2188)
Example 414
2-Hydroxymethyl-3-fluoropyridine A solution of 2 - formyl-3 - fluoropyridine (4.0 g, mmol) and sodium borohydride (309 mg, 8 mmol) in absolute ethanol (40 mL) was stirred at O°C for 15 minutes and at room temperature for 1 hour. The reaction was quenched with saturated aqueous ammonium chloride (5 mL) and filtered through diatomaceous earth to remove solids. The filtrate was evaporated and the resultant white solid was dissolved in ethyl acetate and water. The aqueous layer was extracted with ethyl acetate (5 x 30 mL) and the combined extracts were dried over anhydrous sodium sulfate.
X-8571A
-471Solvent removal provided 3.78 g (93%) of the titled product as a pale yellow oil:
IR (CHCI3, cm'1) 3607, 3439, 3019, 1607, 1576, 1451, 1416,
1312, 1257, 1218, 1209, 1167, 1105, 1053, 857, 803;
!h NMR (300 MHz, CDCI3) δ 8.38 (m, IH), 7.39 (m, IH) , 7.26 (m, IH), 4.83 (s, 2H), 3.73 (br s, IH) ;
MS (FD) m/e 127 (M+);
UV (EtOH) 263nm (ε=2796), 201nm (£=3651)
Anal. Calcd for CgHgFNO: C, 56.69; H, 4.76; N, 11.02. Found: C, 56.45; H, 4.97; N, 10.89
Example 415
2-chloromethvl-3-fluoropyridine hydrochloride
To a solution of 2-hydroxymethyl-3fluoropyridine(3 . 43 g, 27 mmol) in dichloromethane (30 mL) cooled to -10°C was added neat thionyl chloride (4.4 mL, 60 mmol) dropwise over 5 minutes. The resultant pale green solution Was stirred at -10°C for 3 hours followed by evaporation to dryness to provide 4.66 g (95%) of the titled product as an off-white crystalline solid:
IR (CHCI3, cm-l) 2984, 1732, 1551, 1470, 1452, , 1333, 1286,
1273, 1237, 1219 , 1208, 1193, 1094, 905, 863, 806;
NMR (300 MHz, CDCI3) δ 8.69 (m, IH) , 8.06 (m, IH) , 7.89
(m, IH), 5.09 (s , 2H) ;
MS (FD) m/e 145 (M+ free base), 147 (M+2 free base)
Examplg. ,416.
2-cvanomethvl-3-fluoropyridine A solution of 2-chloromethyl-3-fluoropyridine hydrochloride (4.85 g, 26.7 mmol) and potassium cyanide (3.47 g, 53.4 mmol) in methanol (50 mL) and water (20 mL)
AP 0 0 0 3 8 4
X-8571A
-472was stirred at approximately 55°C for 17 hours. The resultant black solution was concentrated to an oil under reduced pressure, redissolved in ethyl acetate and water, and adjusted to pH 11.5 with solid sodium carbonate. The aqueous layer was salted with sodium chloride, extracted with ethyl acetate (7 x 40 mL), and the combined extracts were dried over anhydrous sodium sulfate. Solvent removal provided 3.6 g (99%) of (4) as a black solid:
I? (CHCI3, cm-1) 3019, 3011, 2977, 1708, 1603, 1578, 1454, 1412, 1259, 1222, 1219, 1215, 1161, 1097, 1047, 804; ί-Η NMR (300 MHz, CDCI3) δ 8.43 (m, IH), 7.42 (m, IH) , 7.33 (m,
IE), 3.97 (s, IH), 3.96 (s, IH); MS (FD) m/e 136 (M+); UV (EtOH) 263nm (£=3719), 203nm (£=3707)
Example .417
2-aminoethvl-3-fluoropyridine To a solution of 2-cyanomethyl-3-fluoropyridinein absolute ethanol (75 mL) and 5N hydrochloric acid (0.3 mL) was added platinum oxide catalyst (0.64 g) and the mixture was hydrogenated at 60 psig for 1 hour in a Paar hydrogenation apparatus. Filtered off the catalyst, concentrated the filtrate under reduced pressure to a brown oil, dissolved the oil in water (40 mL) and ethyl acetate (1C mL) and adjusted to pH 0.9 with concentrated hydrochloric acid. Separated the layers, extracted the ethyl acetate layer with IN HCi (1 x 10 mL), combined the acidic aqueous extracts and washed them with ethyl acetate (4 x 30 mL) . Adjusted the aqueous layer to pH 10.8, extracted with dichloromethane (6 x 30 mL) , and the corbined extracts were dried over anhydrous sodium sulfate.
X-8571A
-473Solvent removal provided 1.58g (70%) of the titled product as a brown oil:
IR (CHCI3, cm4! 2969, 2873, 1632, 1602, 1575, 1550, 1450,
1414, 1359, 1246, 1219, 1212, 1203, 1169, 1093;
!h NMR (300 MHz, CDCI3) δ 8.31 (m, IH) , 7.29 (m, IH), 7.13 (m, IH), 3.03 (m, 4H), 1.80 (br s, 2H) ;
MS(FD) m/e 140(M+);
Titration (66% DMF/H2O) pKa 9.56
Example 418 l-f (2-f 5-chloro]pvridv3.) thiocarbamovll imidazole
A solution of 1,1’-thiocarbonyldiimidazole (4.95g, 25 mmol) and 2-amino-5-chloropyridine (3.28g, 25 mmol) in acetonitrile (75 mL) was stirred at room temperature for 23 hours. The resulting precipitate was collected by filtration to provide 3.42 g (57%) of the titled product:
IR (KBr, cm*1) 3218, 3090, 1599, 1572, 1551, 1529, 1471,
1455, 1390, 1375, 1340, 1310, 1228, 1183, 1109, 1053, 939, 831;
1H NMR (300 MHz, DMSO-dg) δ 8.58 (m, IH) , 8.25 (m, IH) ,
8.05 (br s, IH), 8.03 (m, IH) , 7.65 (m, IH), 7.15 (d, J=8 Hz, IH) , 6.80 (s, IH) ;
MS (FAB) m/e 239 (M+l);
UV (EtOH) 305nm (6=15141), 273nm (6=14730), 226 nm (6=11407), 203 nm (6=16456).
Example 419 l-f(2-f5-bromolpyridvl)thiocarbamovll imidazole
A solution of 1,1'-thiocarbonyldiimidazole (4.95g, 25 mmol) and 2-amino-5-bromopyridine (4.46g, 25
AP 0 0 0 3 8 4
-474X-8571A· mmol) in acetonitrile (75 mL) was stirred at room temperature for 23 hours. The resulting precipitate was collected by filtration to provide 5.42 g (76%) of the titled product:
IR (KBr, cm*1) 3218, 3088, 1594, 1565, 1550, 1465, 1387,
1370, 1340, 1309, 1251, 1196, 1182, 1096, 1053, 938, 828;
1H NMR (300 MHz, DMSO-dg) δ 8.57 (m, IH) , 8.30 (m, IH) , 8.15 (m, IH), 8.03 (br s, IH), 7.75 (m, IH) , 7.15 (d, J=8 Hz, IH), 6.80 (s, IH); MS (FAB) m/e 284 (M+l); UV (EtOH) 304nm (€=13932), 274nm (€=13051), 230 nm (€=11098), 204 nm (€=17821) .
Examole 420
Nr (2 - (.2 - f 3-fluoro) pvridvl) ethvl 1 -N1 -(2-(5bromo)pvridvl)thiourea A solution of 1-((2-(5bromo]pyridyl)thiocarbamoyl] imidazole (7) (1.42 g, 5 mmol) and 2-aminoethyl-3-fluoropyridine (5) (0.7g, 5 mmol) in N, N-dimethylformamide (20 mL) was stirred at 95°C for 3 hours. The reaction was cooled to room temperature, poured into ethyl acetate, and washed with water, saturated aqueous sodium bicarbonate, and brine. The organic layer was dried over anhydrous sodium sulfate, concentrated and the resultant solid was purified by chromatography on silica gel to provide 0.33 g (19%) of the titled product as a white solid:
mp 184-187 °C;
IR (KBr, cm-1) 3161( 3023, 1597, 1579, 2555, 1524, 1488, 1473, 1447, 1364, 1342, 1315, 1236, 1221, 1172, 1142, 1087, 83 3 ;
X-8571A
-4751H NMR (300 MHz, DMSO-dg) δ 11.38 (m, 1H) , 10.64 (s, 1H) , 8.41 (m, 1H) , 8.14 (d, J=2 Hz, 1H) , 7.91 (m, 1H) , 7.63 (rr., 1H) , 7.33 (m, 1H), 7.06 (d, J=9 Hz, 1H), 4.01 (m, 2H) ,
3.10 (t, J=6 Hz, 2H) ;
MS (FD) m/e 355 (M+), 357 (M+2);
UV (EtOH) 305nm (£=13169), 273nm (£=25811), 201 nm (£=17 4 93) .
Example 421
N-f2-(2-f3-fluoro1pvridvl)ethvll-Ν' -(2-(5chloro) pvridvl] thiourea A solution of 1-((2-(5chloro]pyridyl)thiocarbamoyl] imidazole (2.39 g, 10 mmol) and 2-aminoethyl-3-fluoropyridine (1.4g, 10 mmol) in Ν,Νdimethylformamide (25 mL) was stirred at 95 °C for 3 hours The reaction was cooled to room temperature, poured into ethyl acetate, and washed with water, saturated aqueous sodium bicarbonate, and brine. The organic layer was dried over anhydrous sodium sulfate, concentrated and the resultant solid was purified by chromatography on silica gel to provide 0.96 g (31%) of the titled product as an off-white solid:
mp 170-173 °C;
IR (KBr, cm1) 3167, 3022, 1603, 1583, 1554, 1524, 1492, 1474, 1449, 1367, 1342, 1317, 1238, 1222, 1173, 1142, 1087, 835, 803;
!h NMR (300 MHz, DMSO-dg) δ 11.39 (m, 1H) , 10.65 (s, 1H) ,
8.42 (m, 1H), 8.07 (d, J=2 Hz, 1H), 7.81 (m, 1H), 7.63 (m, 1H), 7.33 (m, 1H), 7.11 (d, J=9 Hz, 1H), 4.01 (m, 2H) ,
3.10 (t, J=6 Hz, 2H);
AP 0 0 0 3 8 4
X-8571A
-476MS (FD) m/e 310 (M+), 312 (M+2);
UV (EtOH) 305nm (£=11338), 272nm (£=23394).
Example 422
-( + ) and (-) N-(cis-2-phenvlcvcloprooyl)-S-a-methoxv phenyl ace tasiidg
S-a-methoxyphenylacetic acid (2.0 g, 12 mmol) was dissolved in dichloro-methane (100 ml) and oxalylchloride (1.36 ml, 16 mmol) was added together with 2 drops of N,Ndimethylformamide. The solution was stirred under an atmosphere of nitrogen gas at ambient temperature for 120 minutes. The solvent and excess reagent were removed on a rotavapor. The oily residue was dissolved in 100 ml dichloromethane and D,L-cis-phenylcyclopropylamine (Example 202) (2.0 g, 15 mmol) in pyridine (5.0 ml) was added. The solution was stirred for 15 minutes and diethyl ether (200 ml) was added. The precipitate was filtered off and the solution was evaporated. The residual crystalline diastereoisomerical mixture was purified by flashchroma thography by elution with ethyl acetate-toluenedichloroethane (1:2:2). The fractions containing the faster eluting product were evaporated to yield product A. The slower eluting fractions were evaporated to yield product B.
A] 1H-NMR (35 mg in 0.6 ml CDCI3, 294 K) 0.99-1.06 (IH, m) , 1.29-1.38 (IH, m), 2.29-2.38 (IH, q) , 3.00 (3H, s) , 3.07-3.17 (m), 4.41 (IH, s), 6.3 (IH), 7.16-7.32 (10H, m).
X-8571A
-47713C-NMR: 11.18, 21.83, 27.82, 57.11, 83.68, 126.34, 126.43, 128.08, 128.18, 128.26, 128.78, 136.15, 136.85, 171.75, 171.75.
calc for CqgHigN: C 76.84 %, H 6.80 %, N 4.99%
Mp. 136.7-137.1°C
B] 3H-NMR (same conditions as for A): 1.09-1.16 (IH, q) ,
1.32-1.41 (IH, q), 2.24-2.38 (IH, q), 3.10-3.20 (4H, m), 4.45, (IH, s), 6.4 (IH), 6.95-6.99 (2H, m) , 7.15-7.27 (7H, m) .
13C-NMR: 10.69, 21.82, 27.85, 56.87, 83.63, 126.35, 126.87, 128.00, 128.13, 128.19, 128.83, 135.88, 136.54, 171.55.
Calc for CigHigN: C 76.84 %, H 6.80 %, N 4.99 %
Mp. 143.6-144.7°C.
Example 423
1-) cis-2-phenvlcvclopropvlamine Compound A (1.2 g) was refluxed in a mixture of water-dioxane-hydrochloric acid conc.aq. (1:1:1) for 4 hours. The solution was diluted with water, washed with dichloromethane, basified with ammonium hydroxide (cone, aq.), extracted with dichloromethane, dried with sodium sulfate, filtered and evaporated to yield the titled product as an oil.
3H-NMR CDCI3 δ ppm 0.8-0.9 (IH, CK2 · m) , 1.1-1.2 (IH, CH2,
m), 2.-2.1 (IH, PhCH, q), 2.6-2.7 (IH, CHNH2, m), 7.1-7.4 (5H, Ph).
AP 0 00 3 8 4
X-8571A
-478Exawlfi -42.4 (+) cis-2-phenylcvcloprooylamine Compound B (1.2 g) was refluxed in a mixture of water-dioxane-hydrochloric acid cone. aq. (1:1:1) for 4 hours. The solution was diluted with water, washed with dichloromethane, basified with ammonium hydroxide (cone, aq.), extracted with dichloromethane, dried with sodiumsulfate, filtered and evaporated to yield the titled product as an oil.
1H-NMR CDCI3 δ ppm 0.8-0.9 (IH, CH2 , m) , 1.1-1.2 (IH, CH2, m) , 2.0-2.1 (IH, PhCH, q), 2.6-2.7 (IH, CHNH2, m), 7.1-7.4 (5H, Ph).
D (a] = + 62.70 (C 1, CHCI3)
Example-. 42 5 (-)-N- (cis-2-phenvlcvclooroovl)-Ν'-(5-chloropvrid-2-yl).thiourea (+)-N-cis-2-phenylcyclopropylamine (0.23 g, 1.7 mmol) from Example 424 was condensed with 1-(5-chloropyrid2-yl-thiocarbamoyl)-imidazole (0.4 g, 1.7 mmol) according to the procedure of Example 372 to yield the titled product as crystals.
^-H-NMR CDCI3 δ ppm 1.2-1.3 (IH, m, CH2) > 1.5-1.6 (IH, m, CH2)» 2.5-2.6 (IH, q, PhCH), 3.7-3.8 (CHN), 6.6-6.7 <1H, d, pyr), 7.2-7.5 (7H, Ph, pyr), 8.9-9.0 (IH, NH) , 10.8-10.9 (IH, NH).
X-8571A
-479Mp. 189.6-191.3°C.
D [a] = - 62.7° (C 1, CHC13)
Example 426 ( + ) -N- (cis-2-phenvlcvclopropvl) -N,--15-chlQropvrid-2-vl) thiQur.sa (-)-N-cis-2-phenylcyclopropylamine (0.23 g, 1.7 10 mmol) from Example 423 was condensed with 1-(5-chloropyrid2-yl-thiocarbamoyl)-imidazole (0.4 g, 1.7 mmol) according to the procedure of Example 372 to yield the titled product as crystals.
^-H-NMR CDCI3 δ ppm 1.2-1.3 (1H, m, CH2) , 1.5-1.6 (IH, m,
Cfl2), 2.5-2.6 (IH, q, PhCH). 3.7-3.8 (CfiN) , 6.6-6.7 (IH, d, pyr), 7.2-7.5 (7H, Ph, pyr), 8.9-9.0 (IH, NH)< 10.8-10.9 (IH, NH).
Mp. 189.2-191.8°C.
D [a] = + 59.3° (C 1, CHCI3)
Example 427 (-) -N- (cis-2-phenvlcvclopropvl) -Ν' - (5-bromopvridz2.-yl) 25 rhipurpa (+)-N-cis-2-phenylcyclopropylamine from Example 424 and 2-amino-5-bromopyridine were reacted according to the procedures of Examples 93 and 94 using 2-amino-5bromopyridine instead of 2-aminothiazole, to give the titled product as crystals.
AP Ο Ο Ο 3 8 4
Χ-8571Α
-4801H-NMR {CDCI3): 1.19 - 1.26 (m, 1Η), 1.47 - 1.55 (m, IH),
2.52 (q, IH), 3.66 - 3.75 (m, IH), 6.66 (dd, IH), 7.27 7.41 (m, 5H), 7.47 (d, IH), 7.60 (dd, IH), 8.98 (broad s.
IH), 10.88 (broad s., IH).
Mp = 192.0 - 193.0°C
D [a] = - 52.8° (C 1, CHCI3)
Example .42.8 ( + ) -N- (cis-2-phenylcvclopropvl) -Ν'- (5-bromopvrid.-2-vl) thiourea (-)-N-cis-2-phenylcyclopropylamine from Example 15 423 and 2-amino-5-bromopyridine were reacted according to the procedures of Examples 93 and 94 using 2-amino-5bromopyridine instead of 2-aminothiazcle, to give the titled product as crystals.
1h-NMR (CDCI3): 1.19 - 1.26 (m, IH), 1.47 - 1.55 (m, IH), 20 2.52 (q, IH), 3.66 - 3.75 (m, 1Η), 6.66 (dd, 1Η), 7.27 7.41 (m, 5H), 7.47 (d, IH), 7.60 (dd, IH), 8.98 (broad s. IH), 10.88 (broad s., IH).
Mp = 195.5 - 196.5°C
D [a] = + 50° (C 1, CHCI3)

Claims (32)

  1. We Claim·.
    1. A method for inhibiting the replication of HIV which comprises contacting a compound of the formula (IB)
    R-,
    S
    II
    R,/ (CH2)n wherein n is 0 to 4; Z is
    IB) \ = Y or ^CH2 / /
    Y is 0 or S;
    Rll is of the formula i
    c—R14
    1 s
    Rj.4 is a stable saturated or unsaturated, substitut or unsubstituted, 3 to 8 membered organic monocyclic rir having 0 to 4 hetero atoms selected from S, O, and N; or
    X-8571A
    -482R14 is a stable, saturated or unsaturated, substituted or unsubstituted, 7 to 10 membered organic bicyclic ring having 0 to 5 hetero atoms selected from S, 0, and N; or
    Rl4 is a group of the formula 5 (RlO)y-Xwherein y is 1 or 2; X is N, S, 0 and Rio is a stable saturated or unsaturated, substituted or unsubstituted, 3 to 8 membered organic monocyclic ring having 0 to 4 hetero atoms selected from S, O, and N; or Rio is a stable,
    1 0 saturated or unsaturated, substituted or unsubstituted, 7 to 10 membered organic bicyclic ring having 0 to 5 hetero atoms selected from S, 0, and N; or Rio is hydrogen, Ci-Cg alkyl, C2~Cg alkenyl, or C2-Cg alkynyl; or
    Rl4 is hydrogen, halo, cyano, carboxy, amino, thio,
    15 hydroxy, C1-C4 alkoxy, Ci-Cg alkyl, C2-C8 alkenyl, C2-C8 alkynyl, or C2-C8 alkenoxy;
    R15 and Rig are independently C3-C8 cycloalkyl, hydrogen, Ci~Cg alkyl, C2~Cg alkenyl, halo, amino, nitro, cyano, C1-C5 alkoxy, hydroxy, carboxy, hydroxymethyl,
    20 aminomethyl, carboxymethyl, C1-C4 alkylthio, C1-C4 aikanoyloxy, carbamoyl, or a halo substituted Ci~Cg alkyl;
    Rl2 is hydrogen, hydroxy, Ci-Cg alkyl, C2-Cg alkenyl, amino, cyano, nitro, C1-C5 alkoxy, carboxy, hydroxymethyl, aminomethyl, carboxymethyl, C1-C4 alkylthio, C1-C4
    25 aikanoyloxy, halo-substituted (Cq-Cg) alkyl, or carbamoyl;
    Rl3 is a stable saturated or unsaturated, substituted or unsubstituted, 3 to 8 membered organic monocyclic ring having 0 to 4 hetero atoms selected from S, 0, and N; or Rl3 is a stable, saturated or unsaturated, substituted or
    30 unsubstituted, 7 to 10 membered organic bicyclic ring having 0 to 5 hetero atoms selected from S, O, and N; or
    AP Ο Ο Ο 3 8 4
    Χ-8571Α -483Rl3 is Rn as defined; or salts thereof, with HIV.
  2. 2. The method as recited in claim 1 wherein Rl2> Rl5< and Rig are hydrogen, R13 is C1-C6 alkyl, thiazolyl, substituted thiazolyl, pyrazinyl, substituted
    5 pyrazinyl, pyridyl, substituted pyridyl, pyridazinyl, substituted pyridazinyl, phenyl, or substituted phenyl, and R14 is phenyl, substituted phenyl, pyridyl, substituted pyridyl, or cyclohexenyl.
  3. 3. The method as recited in claim 2 wherein
    10 R14 is phenyl, difluorphenyl, fluorophenyl, cyclohexenyl, pyridyl, or p-hydroxypheny1.
  4. 4. The method as recited in Claim 1 further comprising also contacting at least one other anti-HIV agent with said HIV.
    15 5. The method as recited in Claim 4 wherein said agent is selected from ddl, ddC, or AZT.
    6. A method for treating or inhibiting HIV in a human which comprises administering a compound of the formula (IB) wherein n is 0 to 4;
    Z is ^C = Y Or ^CH2
    X-8571A
    -484 Y is C or S;
    Rll is of the formula
    C
    Rl4 is a stable saturated or unsaturated, substituted or unsubstituted, 3 to 8 membered organic monocyclic ring having 0 to 4 hetero atoms selected from S, O, and N; or
    Rl4 is a stable, saturated or unsaturated, substituted or unsubstituted, 7 to 10 membered organic bicyclic ring having 0 to 5 hetero atoms selected from S, 0, and N; or
    Rl4 is 3 group of the formula (RlO)y-Xwherein y is 1 or 2; X is N, S, 0 and Rio is a stable saturated or unsaturated, substituted or unsubstituted, 3 to 8 membered organic monocyclic ring having 0 to 4 hetero atoms selected from S, 0, and N; or Rio is a stable, saturated or unsaturated, substituted or unsubstituted, 7 to 10 membered organic bicyclic ring having 0 to 5 hetero atoms selected from S, 0, and N; or Rio is hydrogen, Ci-Cg alkyl, C2-T5 alkenyl, or C2~Cg alkynyl; or
    Rl4 is hydrogen, halo, cyano, carboxy, amino, thio, hydroxy, C-.-C4 alkoxy, C1-C6 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, cr C2-C8 alkenoxy;
    Rl5 and Rig are independently C3-C8 cycloalkyl, hydrogen, Ci-Og alkyl, C2-C5 alkenyl, halo, amino, nitro, cyano, C1-C5 alkoxy, hydroxy, carboxy, hydroxymethyl,
    AP Ο Ο Ο 3 8 4
    Χ-8571Α.
    -485am.inomethyl, carboxymethyl, C3.-C4 alkylthio, C1-C4 alkanoyloxy, carbamoyl, or a halo substituted Ci~Cg alkyl;
    Rl2 is hydrogen, hydroxy, Ci~Cg alkyl, C2-Cg alkenyl, amino, cyano, nitro, C1-C5 alkoxy, carboxy, hydroxymethyl,
  5. 5 aminomethyl, carboxymethyl, C1-C4 alkylthio, C1-C4 alkanoyloxy, halo-substituted (Ci-Cg) alky1, or carbamoyl;
    Rl3 is a stable saturated or unsaturated, substituted or unsubstituted, 3 to 8 membered organic monocyclic ring having 0 to 4 hetero atoms selected from S, 0, and N; or
    10 R13 is a stable, saturated or unsaturated, substituted or unsubstituted, 7 to 10 membered organic bicyolic ring having 0 to 5 hetero atoms selected from S, 0, and N; or
    Rl3 is Rh as defined; or pharmaceutically acceptable salts thereof, to said human.
    15 7. The method as recited in claim 6 wherein R12. R15, and Ri6 are hydrogen, R13 is Ci-Cg alkyl, thiazolyl, substituted thiazolyl, pyrazinyl, substituted pyrazinyl, pyridyl, substituted pyridyl, pyridazinyl, substituted pyridazinyl, phenyl, or substituted phenyl, and
    2 0 R3.4 is phenyl, substituted phenyl, pyridyl, substituted pyridyl, or cyclohexenyl.
  6. 8. The method as recited in claim 7 wherein Rl4 is phenyl,difluorophenyl, fluorophenyl, pyridyl, cyclohexenyl, or p-hydroxyphenyl.
    25
  7. 9. The method as recited in Claim 6 further comprising also administering at least one other therapeutic agent to said human.
  8. 10. The method as recited in Claim 9 wherein said agent is selected from ddl, ddc, or AZT.
    Χ-8571Α
    -48611. A method for treating or inhibiting acquired immonodeficiency syndrome in a human which comprises administering a compound of the formula (IB)
    S wherein n is 0 Z is or
    CH,
    Y is 0 or S;
    Rll is of the formula
    C-Rh
    Ris
    1 5 R14 is a stable saturated or unsaturated, substituted or unsubstituted, 3 to 8 membered organic monocyclic ring having 0 to 4 hetero atoms selected from S, 0, and N; or
    Rl4 is a stable, saturated or unsaturated, substituted or unsubstituted, 7 to 10 membered organic bicyclic ring having 0 to 5 hetero atoms selected from S, 0, and N; or Rl4 is a group of the formula (RlQ)y-XAP Ο Ο Ο 3 8 4
    Χ-8571Α
    -487wherein y is 1 or 2; X is N, S, 0 and Rio is a stable saturated or unsaturated, substituted or unsubstituted, 3 to 8 membered organic monocyclic ring having 0 to 4 hetero atoms selected from S, 0, and N; or Rio is a stable,
    5 saturated or unsaturated, substituted or unsubstituted, 7 to 10 membered organic bicyclic ring having 0 to 5 hetero atoms selected from S, O, and N; or Rio is hydrogen, Ci~Cg alkyl, C2~Cg alkenyl, or C2-C6 alkynyl; or
    R14 is hydrogen, halo, cyano, carboxy, amino, thio,
    10 hydroxy, C1-C4 alkoxy, Ci-Cg alkyl, C2-C8 alkenyl, C2~Cg alkynyl, or C2-C8 alkenoxy;
    R15 and Rig are independently C3-C8 cycloalkyl, hydrogen, Ci~Cg alkyl, C2-Cg alkenyl, halo, amino, nitro, cyano, C1-C5 alkoxy, hydroxy, carboxy, hydroxymethyl,
    1 5 aminomethyl, carboxymethyl, C1-C4 alkylthio, C1-C4 alkanoyloxy, carbamoyl, or a halo substituted Cj-Cg alkyl;
    Rl2 is hydrogen, hydroxy, Ci-Cg alkyl, C2-C6 alkenyl, amino, cyano, nitro, C1-C5 alkoxy, carboxy, hydroxymethyl, aminomethyl, carboxymethyl, C1-C4 alkylthio, C3.-C4
    20 alkanoyloxy, halo-substituted (C1-C5) alkyl, or carbamoyl;
    Rl3 is a stable saturated or unsaturated, substituted or unsubstituted, 3 to 8 membered organic monocyclic ring having 0 to 4 hetero atoms selected from S, O, and N; or Rl3 is a stable, saturated or unsaturated, substituted or
    25 unsubstituted, 7 to 10 membered organic bicyclic ring having 0 to 5 hetero atoms selected from S, O, and N; or
    Rl3 is R
  9. 11 as defined, or pharmaceutically acceptable salts thereof, to said human.
  10. 12. The method as recited in claim 11 wherein 30 Rl2- R15, a^d Rig are hydrogen, R13 is Ci-Cg alkyl, thiazolyl, substituted thiazolyl, pyrazinyl, substituted
    X-8571A
    -488pyrazinyl, pyridyl, substituted pyridyl, pyridazinyl, substituted pyridazinyl, phenyl, or substituted phenyl, and Rl4 is phenyl, substituted phenyl, pyridyl, substituted pyridyl, or cyclohexenyl.
  11. 13. The method as recited in claim 12 wherein Rl4 is phenyl, difluorophenyl, fluorophenyl, pyridyl, cyclohexenyl, or p-hydroxyphenyl.
  12. 14. The method as recited in Claim 11 further comprising also administering at least one other therapeutic agent to said human.
  13. 15. The method as recited in Claim 14 wherein said agent is selected from ddl, ddC, or AZT.
  14. 16. A pharmaceutical formulation comprising a compound of the formula (IB) ib;
    wherein n is 0 to 4; Z is
    C=Y or /CH2
    Y is 0 or S;
    Rll is of the formula
    AP 0 0 0 3 8 4
    -489X-8571A •R·
    Rl4 is a stable saturated or unsaturated, substituted or unsubstituted, 3 to 8 membered organic monocyclic ring having 0 to 4 hetero atoms selected from S, 0, and N; or
    Rl4 is a stable, saturated or unsaturated, substituted or unsubstituted, 7 to 10 membered organic bicyclic ring having 0 to 5 hetero atoms selected from S, 0, and N; or
    Rl4 is is a group of the formula (RlO)y-Xwherein y is 1 or 2; X is N, S, 0 and Rio is a stable saturated or unsaturated, substituted or unsubstituted, 3 to 8 membered organic monocyclic ring having 0 to 4 hetero atoms selected from S, 0, and N; or Rio is a stable, saturated or unsaturated, substituted or unsubstituted, 7 to 10 membered organic bicyclic ring having 0 to 5 hetero atoms selected from S, O, and N; or Rio is hydrogen, Ci-Cg alkyl, C2-C5 alkenyl, or C2-C6 alkynyl; or
    Rl4 is hydrogen, C]_-C6 alkyl, halo, cyano, carboxy, amino, thio, hydroxy, C1-C4 alkoxy, C2-C8 alkenyl, C2-C8 alkynyl, or C2-C8 alkenoxy;
    Rl5 and R15 are independently C3-C8 cycloalkyl, hydrogen, C1-C6 alkyl, C2-C6 alkenyl, halo, amino, nitro, cyano, C1-C5 alkoxy, hydroxy, carboxy, hydroxymethyl, aminomethyl, carboxymethyl, C1-C4 alkylthio, C1-C4 alkanoyloxy, carbamoyl, or a halo substituted Ci-C$ alkyl;
    X-8571A
    -490R12 is hydrogen, hydroxy, Ci~Cg alkyl, C2-Cg alkenyl, amino, cyano, nitro, C1-C5 alkoxy, carboxy, hydroxymethyl, aminomethyl, carboxymethyl, C1-C4 alkylthio, C1-C4 alkanoyloxy, trihalo(Ci-Cg) alkyl, or carbamoyl; or a halo5 substituted Ci-Cg alkyl;
    R13 is a stable saturated or unsaturated, substituted or unsubstituted, 3 to 8 membered organic monocyclic ring having 0 to 4 hetero atoms selected from S, 0, and N; or Rl3 is a stable, saturated or unsaturated, substituted or
    1 0 unsubstituted, 7 to 10 membered organic bicyclic ring having 0 to 5 hetero atoms selected from S, O, and N; or
    Rl3 is Rn as defined; or pharmaceutically acceptable salts thereof, and a suitable carrier; with the proviso that R12 is not hydrogen when
    15 i) Rn is Ci-Cg alkyl; R13 is C2-C8 alkenyl; Z is ,C = O ; and n=0; or /
    ii) Rn is Ci-Cg alkyl or
    Rl3 is Ci-Cg alkyl or phenyl; Z is \
    C=0 ; and n=O .
  15. 17. The formualtion as recited in claim 16 wherein R12. P-15- and Rig are hydrogen, R13 is Ci-Cg alkyl, thiazolyl, substituted thiazolyl, pyrazinyl, substituted pyrazinyl, pyridyl, substituted pyridyl, pyridazinyl,
    AP Ο Ο Ο 3 8 4
    Χ-8571Α
    -491substituted pyridazinyl, phenyl, or substituted phenyl, and P.14 is phenyl, substituted phenyl, pyridyl, substituted pyridyl, or cyclohexenyl.
  16. 18. The forr.ulation as recited in claim 17
    5 wherein R14 is phenyl, pyridyl, or p-hydroxyphenyl.
  17. 19. The formulation as recited in Claim 16 further comprising at least one other therapeutic agent.
  18. 20. The forr.ulation as recited in Claim 19 wherein said agent is selected from ddl, ddC, or AZT.
    10
  19. 21. A compound of the formula
    S wherein n is 0 to 4;
    15 Z is \=Y or ^CHn / Z wherein Y is S or C;
    Rll is of the formula
    Ri s
    BAD ORIGINAL ft
    X-8571A
    -492 wherein R14 is cyclo(C3-C8) alkyl, cyclo (C3-C8) alkenyl; isothiazolyl, substituted isothiazolyl, tetrazolyl, substituted tetrazolyl, triazolyl, substituted triazolyl, pyridyl, substituted pyridyl, imidazolyl, substituted
    5 imidazolyl, phenyl, substituted phenyl, naphthyl, substituted naphthyl, benzoxazolyl, substituted benzoxazolyl, benzimidazolyl, substituted benzimidazolyl,thiazolyl, substituted thiazolyl, oxazolyl, substituted oxazolyl, benzothiazolyl, substituted
    10 benzothiazolyl, pyrazinyl, substituted pyrazinyl, pyridazinyl, substituted pyridazinyl, thiadiazolyl, substituted thiadiazolyl, benzotriazolyl, substituted benzotriazolyl, pyrrolyl, substituted pyrrolyl, indolyl, substituted indolyl, benzothienyl, substituted
    15 benzothienyl, thienyl, substituted thienyl, benzcfuryl, substituted benzofuryl, furyl, substituted furyl, quinolinyl, substituted quinolinyl, isoquinolinyl, substituted isoquinolinyl, pyrazolyl, and substituted pyrazolyl; or
    2 0 R14 is a group of the formula (RlO)y-Xwherein y is 1 or 2; X is N, S, or 0, and
    RlO is cyclo(C3-C8) alkyl, cyclo {C3-C8; alkenyl;
    isothiazolyl, substituted isothiazolyl, tetrazolyl,
    25 substituted tetrazolyl, triazolyl, substituted triazolyl, pyridyl, substituted pyridyl, imidazolyl, substituted imidazolyl, phenyl, substituted phenyl, naphthyl, substituted naphthyl, benzoxazolyl, substituted benzoxazolyl, benzimidazolyl, substituted
    30 benzimidazolyl,thiazolyl, substituted thiazolyl, cxazolyl, substituted oxazolyl, benzothiazolyl, substituted
    BAD OFUG'NAL
    AP Ο Ο Ο 3 8 4
    Χ-8571Α
    -493benzothiazolyl, pyrazinyl, substituted pyrazinyl, pyridazinyl, substituted pyridazinyl, thiadiazolyl, substituted thiadiazolyl, benzotriazolyl, substituted benzotriazolyl, pyrrolyl, substituted pyrrolyl, indolyl,
    5 substituted indolyl, benzothienyl, substituted benzothienyl, thienyl, substituted thienyl, benzofuryl, substituted benzofuryl, furyl, substituted furyl, quinolinyl, substituted quinolinyl, isoquinolinyl, substituted isoquinolinyl, pyrazolyl, and substituted
    10 pyrazolyl; or
    Rl4 is halo, cyano, carboxy, amino, thio, hydroxy, C1-C4 alkoxy, C2-Cg alkonyl, C2-Cg alkynyl, or C2~ Cg alkenoxy;
    Rl2 is hydrogen, hydroxy, C1-C6 alkyl, C2~Cg 15 alkenyl, amino, cyano, nitro, C1-C5 alkoxy, carboxy, hydroxymethyl, aminomethyl, carboxymethyl, C1-C4 alkylthio, C1-C4 alkanoyloxy, halo substituted Cq-Cg alkyl, or carbamoyl; and
    Rl3 is cyclo(C3-Cg)alkyl, cyclo (C3~Cg) alkenyl; 20 isothiazolyl, substituted isothiazolyl, tetrazolyl, substituted tetrazolyl, triazolyl, substituted triazolyl, pyridyl, substituted pyridyl, imidazolyl, substituted imidazolyl, phenyl, substituted phenyl, naphthyl, substituted naphthyl, benzoxazolyl, substituted
    25 benzoxazolyl, benzimidazolyl, substituted benzimidazolyl,thiazolyl, substituted thiazolyl, oxazolyl, substituted oxazolyl, benzothiazolyl, substituted benzothiazolyl, pyrazinyl, substituted pyrazinyl, pyridazinyl, substituted pyridazinyl, thiadiazolyl,
    30 substituted thiadiazolyl, benzotriazolyl, substituted benzotriazolyl, pyrrolyl, substituted pyrrolyl, indolyl, r
    BAD ORIGINAL
    X-8571A
    -494substituted indolyl, benzothienyl, substituted benzothienyl, thienyl, substituted thienyl, benzofuryl, substituted benzofuryl, furyl, substituted furyl, quinolinyl, substituted quinolinyl, isoquinolinyl, substituted isoquinolinyl, pyrazolyl, and substituted pyrazolyl;
    or R13 is Rii as defined;
    Rl5 and Rig are independently C3-C8 cycloalkyl, hydrogen, Ci-Cg alkyl, C2~Cg alkenyl, halo, amino, nitro, cyano, C1-C5 alkoxy, hydroxy, carboxy, hydroxymethyl, aminomethyl, carboxymethyl, C1-C4 alkylthio, C1-C4 alkanoyloxy; carbamoyl, or halo substituted (Ci-Cg) alkyl; and salts thereof, with the proviso that R12 is not hydrogen when R15 and Rig are both hydrogen, R14 is phenyl, Rl3 is phenyl, Z is \
    zC=o .
    and n is 0.
  20. 22. The compound as recited in Claim 21 in 2 0 combination with at least one other therapeutic agent.
  21. 23. The compound as recited in Claim 22 wherein said agent is selected from ddl, ddC, or AZT.
  22. 24. A compound of the formula bad ORIGINAL
    AP Ο Ο Ο 3 8 4
    Χ-8571Α
    -495wherein Rn is a group of the formula
    -CH2-R14 wherein R14 is phenyl, p-hydroxyphenyl, difluorophenyl, fluorophenyl, pyridyl, or cyclohexenyl; and
    Rl3 is methyl, ethyl, n-butyl, phenylmethyl, thiazolyl, benzothiazolyl, pyridyl, or thiadiazole, and R3.3
    10 may be phenyl when R14 is p-hydroxyphenyl, and salts thereof .
  23. 25. The compound as recited in Claim 24 in combination with at least one other therapeutic agent.
  24. 26. The method as recited in Claim 25 wherein
    15 said agent is selected from ddl, ddC, or AZT.
  25. 27. A method for inhibiting the replication of HIV which comprises contacting a compound of the formula below
    S
    II
    R?-N-C-N R, (IA)
    I I '
    2 0 R, R, .
    in which Ri is a stable saturated or unsaturated, substituted or unsubstituted, 3 to 8 membered organic monocyclic ring having 0 to 4 hetero atoms selected from S,
    25 0, and N; or Ri is a stable, saturated or unsaturated, substituted or unsubstituted, 7 to 10 membered organic bicyclic ring having 0 to 5 hetero atoms selected from S,
    0, and N;
    X-8571A -496R2 is a group of the formula Ro |7
    R;-C-CI I
    Rs R,
    5 wherein R5 is Rq as defined above; or R5 is a group of the formula (RlO)y-Xwherein y is 1 or 2; X is N, S, 0 and Rio is Rl as defined; or Rio is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6
    10 alkynyl; or R5 is hydrogen, halo, cyano, carboxy, amino, thio, hydroxy, C1-C4 alkoxy, C1-C6 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, or C2-C8 alkenoxy;
    R6, R7, Κθ, and Rg are independently C3-C8 cycloalkyl, hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6
    1 5 alkynyl, halo, amino, nitro, cyano, C1-C5 alkoxy, hydroxy, carboxy, hydroxymethyl, aminomethyl, carboxymethyl, C1-C4 alkylthio, C1-C4 alkanoyloxy, carbamoyl, or a halo substituted Ci-Cg alkyl; or two of which, along with the carbons to which they are attached, combine to form a
    20 stable, saturated or unsaturated, substituted or unsubstituted, 3 to 7 membered organic monocylic ring having 0 to 4 hetero atoms selected from S, 0, or N; or P.g and Rs, or R7 and Rg, along with the carbon to which they are attached, form a stable, saturated cr unsaturated,
    25 substituted or unsubstituted, 3 to 7 membered organic monocylic ring having 0 to 4 hetero atoms selected from. S, 0, or N;
    AP Ο Ο Ο 3 8 4
    C
    Χ-8571Α -497R3 and R4 are independently hydrogen, hydroxy, Cy-Cg alkyl, C2~Cg alkenyl, C2-Cg alkynyl, amino, cyano, nitro, C1-C5 alkoxy, carboxy, hydroxymethyl, aminomethyl, carboxymethyl, C1-C4 alkylthio, C3.-C4 alkanoyloxy, halo5 substituted (Ci-Cg) alkyl, or carbamoyl; or salts thereof, with HIV.
  26. 28. The method of claim 27 wherein R3 , R4 , Rg, P-7, P.3, and Rg are all hydrogen.
  27. 29. The method as recited in claim 28 wherein 10 R5 is phenyl, substituted phenyl, naphthyl, substituted naphthyl, pyridyl, substituted pyridyl, or cyclohexeny1.
  28. 30. The method as recited in claim 23 wherein Rl is thiazolyl, substituted thiazolyl, benzothiazolyl, substituted benzothiazolyl, pyrazinyl, substituted
    15 pyrazinyl, pyridyl, substituted pyridyl, pyridazinyl, substituted pyridazinyl, thiadiazolyl, or substituted thiadiazolyl.
  29. 31. The method as recited in claim 27 wherein said compound is N-[2-(2-pyridyl)ethyl]-N’-(2- (520 bromo)pyridyl]thiourea and its hydrochloride salt.
  30. 32. The method as recited in Claim 27 further comprising also contacting at least one other anti-HIV agent with said HIV.
  31. 33. The method as recited in Claim 32 wherein 25 said agent is selected from ddl, ddC, or AZT.
  32. 34. A method for treating or inhibiting HIV in a human which comprises administering a compound of the formula below
    34. A method for treating cr inhibiting HIV in formula below bad ORIG'naL
    ABSTRACT
    AP/P/92/00412
    Method for inhibiting the replication of HIV by contacting HIV with a compound of the formula
    M2 /W1
    Ri (CH,).
    is 0 to 4 is )C=S or )C=0 or )CH2
    Ml
    IS
    R16
    I c—r14
    R»
    Ru is (a) a stable 3 to 8 monocyclic ring having 0 to 4 hetero atoms selected from S, 0 and N (b) a stable 7 to 10 bicyclic ring having 0 to 5 hetero atoms selected from S, O and N (c) (Rio)y~X wherein : y is 1 or 2
    X is S, O or N
    R,„ is either R14(a) or (b) (d) H, -CN, -COOH, -N<, -COSH, -OH or C,-C4 alkyl (e) halo, C,-C4 alkoxy, C2-C, alkenyl, alkynyl or alkenoxy
    Ri2, R(j and R14 are independently (a) the same as R,4(d) (b) -CHjOH,-CHjNH2, -CH2C00H, Cj-C4 alkenyl, -NOj, C,-C4 alkanoyloxy, C,-C4 alkylthio, carbamoyl or halo substituted (C,-C4)alkyl
    Ru is R14(a) or (b) , or Ru
APAP/P/1992/000412A 1991-08-02 1992-07-30 Inhibition of the replication of HIV and related viruses using thiourea derivative compounds or salts thereof. AP384A (en)

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