CA2355374A1 - 1-heterocycle substituted diarylamines - Google Patents
1-heterocycle substituted diarylamines Download PDFInfo
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- CA2355374A1 CA2355374A1 CA002355374A CA2355374A CA2355374A1 CA 2355374 A1 CA2355374 A1 CA 2355374A1 CA 002355374 A CA002355374 A CA 002355374A CA 2355374 A CA2355374 A CA 2355374A CA 2355374 A1 CA2355374 A1 CA 2355374A1
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- iodo
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- C07D291/04—Five-membered rings
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- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members 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
- C07D231/18—One oxygen or sulfur atom
- C07D231/20—One oxygen atom attached in position 3 or 5
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- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members 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
- C07D231/44—Oxygen and nitrogen or sulfur and nitrogen atoms
- C07D231/46—Oxygen atom in position 3 or 5 and nitrogen atom in position 4
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- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/04—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles
- C07D249/06—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles with aryl radicals directly attached to ring atoms
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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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- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- 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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- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D263/10—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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- C07D271/06—1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles
- C07D271/07—1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles with oxygen, sulfur or nitrogen atoms, directly attached to ring carbon atoms, the nitrogen atoms not forming part of a nitro radical
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- C07D285/01—Five-membered rings
- C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
- C07D285/04—Thiadiazoles; Hydrogenated thiadiazoles not condensed with other rings
- C07D285/08—1,2,4-Thiadiazoles; Hydrogenated 1,2,4-thiadiazoles
Abstract
1-Heterocycle substituted diarylamines, methods of making and using them, and compositions containing them.
Description
This invention relates to diaryl amines such as 1-heterocycle substituted diarylamines.
BACKGROUND
MEK enzymes are dual specificity kinases involved in, for example, immunomodulation, inflammation, and proliferative diseases such as cancer and restenosis.
Proliferative diseases are caused by a defect in the intracellular signaling system, or the signal transduction mechanism of certain proteins. Defects include a change either in the intrinsic activity or in the cellular concentration of one or more signaling proteins in the signaling cascade . The cell may produce a growth factor that binds to its own receptors, resulting in an autocrine loop, which continually stimulates proliferation. Mutations or overexpression of intracellular signaling proteins can lead to spurious mitogenic signals within the cell.
Some of the most common mutations occur in genes encoding the protein known as Ras, a G-protein that is activated when bound to GTP, and inactivated when bound to GDP. The above-mentioned growth factor receptors, and many other mitogenic receptors, when activated, lead to Ras being converted from the GDP-bound state to the GTP-bound state. This signal is an absolute prerequisite for proliferation in most cell types. Defects in this signaling system, especially in the deactivation of the Ras-GTP complex, are common in cancers, and lead to the signaling cascade below Ras being chronically activated.
Activated Ras leads in turn to the activation of a cascade of serine/threonine kinases. One of the groups of kinases known to require an active Ras-GTP for its own activation is the Raf family. These in turn activate MEK (e.g., MEK1 and MEKZ) which then activates MAP kinase, ERK (ERK~ and ERK2). Activation of MAP kinase by mitogens appears to be essential for proliferation; constitutive activation of this kinase is sufficient to induce cellular transformation. Blockade of downstream Ras signaling, for example by use of a dominant negative Raf-1 protein, can completely inhibit mitogenesis, whether induced from cell surface receptors or from oncogenic Ras mutants. Although Ras is not itself a protein kinase, it participates in the activation of Raf and other kinases, most likely through a phosphorylation mechanism. Once activated, Raf and other kinases phosphorylate MEK on two closely adjacent serine residues, S21 s and S222 in the case of MEK-1, which are the prerequisite for activation of MEK as a kinase. MEK in turn phosphorylates MAP kinase on both a tyrosine, Y185, and a threonine residue, T1$3, separated by a single amino acid. This double phosphorylation activates MAP kinase at least 100-fold. Activated MAP
kinase can then catalyze the ohosphorylation of a large number of proteins, including several transcription factors and other kinases. Many of these MAP
kinase phosphorylations are mitogenically activating for the target protein, such as a kinase, a transcription factor, or another cellular protein. In addition to Raf-1 and MEKK, other kinases activate MEK, and MEK itself appears to be a signal integrating kinase. Current understanding is that MEK is highly specific for the phosphorylation of MAP kinase. In fact, no substrate for MEK other than the MAP kinase , ERK, has been demonstrated to date and MEK does not phosphorylate peptides based on the MAP kinase phosphoryiation sequence, or even phosphorylate denatured MAP kinase. MEK also appears to associate strongly with MAP kinase prior to phosphorylating it, suggesting that phosphorylation of MAP kinase by MEK may require a prior strong interaction between the two proteins. Both this requirement and the unusual specificity of MEK are suggestive that it may have enough difference in its mechanism of action to other protein kinases that selective inhibitors of MEK, possibly operating through allosteric mechanisms rather than through the usual blockade of the ATP
binding site, may be found.
BACKGROUND
MEK enzymes are dual specificity kinases involved in, for example, immunomodulation, inflammation, and proliferative diseases such as cancer and restenosis.
Proliferative diseases are caused by a defect in the intracellular signaling system, or the signal transduction mechanism of certain proteins. Defects include a change either in the intrinsic activity or in the cellular concentration of one or more signaling proteins in the signaling cascade . The cell may produce a growth factor that binds to its own receptors, resulting in an autocrine loop, which continually stimulates proliferation. Mutations or overexpression of intracellular signaling proteins can lead to spurious mitogenic signals within the cell.
Some of the most common mutations occur in genes encoding the protein known as Ras, a G-protein that is activated when bound to GTP, and inactivated when bound to GDP. The above-mentioned growth factor receptors, and many other mitogenic receptors, when activated, lead to Ras being converted from the GDP-bound state to the GTP-bound state. This signal is an absolute prerequisite for proliferation in most cell types. Defects in this signaling system, especially in the deactivation of the Ras-GTP complex, are common in cancers, and lead to the signaling cascade below Ras being chronically activated.
Activated Ras leads in turn to the activation of a cascade of serine/threonine kinases. One of the groups of kinases known to require an active Ras-GTP for its own activation is the Raf family. These in turn activate MEK (e.g., MEK1 and MEKZ) which then activates MAP kinase, ERK (ERK~ and ERK2). Activation of MAP kinase by mitogens appears to be essential for proliferation; constitutive activation of this kinase is sufficient to induce cellular transformation. Blockade of downstream Ras signaling, for example by use of a dominant negative Raf-1 protein, can completely inhibit mitogenesis, whether induced from cell surface receptors or from oncogenic Ras mutants. Although Ras is not itself a protein kinase, it participates in the activation of Raf and other kinases, most likely through a phosphorylation mechanism. Once activated, Raf and other kinases phosphorylate MEK on two closely adjacent serine residues, S21 s and S222 in the case of MEK-1, which are the prerequisite for activation of MEK as a kinase. MEK in turn phosphorylates MAP kinase on both a tyrosine, Y185, and a threonine residue, T1$3, separated by a single amino acid. This double phosphorylation activates MAP kinase at least 100-fold. Activated MAP
kinase can then catalyze the ohosphorylation of a large number of proteins, including several transcription factors and other kinases. Many of these MAP
kinase phosphorylations are mitogenically activating for the target protein, such as a kinase, a transcription factor, or another cellular protein. In addition to Raf-1 and MEKK, other kinases activate MEK, and MEK itself appears to be a signal integrating kinase. Current understanding is that MEK is highly specific for the phosphorylation of MAP kinase. In fact, no substrate for MEK other than the MAP kinase , ERK, has been demonstrated to date and MEK does not phosphorylate peptides based on the MAP kinase phosphoryiation sequence, or even phosphorylate denatured MAP kinase. MEK also appears to associate strongly with MAP kinase prior to phosphorylating it, suggesting that phosphorylation of MAP kinase by MEK may require a prior strong interaction between the two proteins. Both this requirement and the unusual specificity of MEK are suggestive that it may have enough difference in its mechanism of action to other protein kinases that selective inhibitors of MEK, possibly operating through allosteric mechanisms rather than through the usual blockade of the ATP
binding site, may be found.
SUMMARY
The invention features a compound having the formula (I) below:
\ X I \
/ /
Ri R3 I
I
W is one of the following formulae (i) - (xiii):
Xz , H O ,0 ~.~x2 R5N 1 N NRS ~-~~ O N O O-S
N~ X~ N~ . /~X2 N~.~X~ O / ~ N,H N~ NRs (i) (ii) (iii) (i~ (v) (vi) (vii) ,N NRS N~ N=N ,T1 NRS Xi N N
IV,N~O N.N~ RSN / X2 N , X2 ~ ~ X ~ X~
I
(viii) (ix) (x) (xi) (xii) (xiii ) HO O O
-N ~-O O ~N-N
X1y N X, , N N~N
(xiv) (xv) (xvi) (xvii) WO 00/42029 PCT/US99/30~16 X~ is O, S, or NRF. X2 is OH, SH, or NHRE. Each of RE and RF is H or C ,~ alkyl; each of R, and R~ is independently selected from H, F, N02, Br and CI; R~ can also be S02NR~F;H, or R, and R2 together with the benzene ring to which they are attached constitute an indole, isoindole, benzofuran, benzothiophene, indazole, benzimidazole, or benzthioazole. R3 is selected from H and F; each of R~, RH, and R4 is independently selected from H, CI and CH3.
R5 is H or C » alkyl. Each hydrocarbon radical above is optionally substituted with between 1 and 3 substituents independently selected from halo, hydroxyl, amino, (amino)sulfonyl, and N02. Each heterocyclic radical above is optionally substituted with between 1 and 3 substituents independently selected from halo, C ~~ alkyl, C 3_6 cycloalkyl, G 3.~ aikenyl, C 3~ alkynyl, phenyl, hydroxyl, amino, (amino)sulfonyl, and NOz, wherein each substituent alkyl, cycloalkyl, alkenyl, alkynyl or phenyl is in turn optionally substituted with between 1 and 2 substituents independently selected from halo, C ~_2 alkyl, hydroxyl, amino, and N02. The invention also features a pharmaceutically acceptable salt or C ,$
ester of a disclosed compound. For example, the disclosed alcohol compounds may form esters having the structure obtained by replacing the H of a hydroxyl group with a -C(=O)C ~_~ acyf group.
The invention also relates to a pharmaceutical composition including (a) a compound of formula (I;~ and (b) a pharmaceutically-acceptable carrier.
The invention further relates to a method for treating proliferative diseases, such as cancer, restenosis, psoriasis, autoimmune disease, and atherosclerosis.
Other aspects of the invention include methods for treating MEK-related (including ras-related) cancers, whether solid or hematopoietic. Examples of cancers include colorectal, cervical, breast, ovarian, brain, acute leukemia, gastric, non-small cell lung, pancreatic, and renal cancer. Further aspects of the invention include methods for- treating or reducing the symptoms of xenograft (cell(s), skin, limb, organ or bone marrow transplant) rejection, osteoarthritis, rheumatoid arthritis, cystic fibrosis, complications of diabetes (including diabetic retinopathy and diabetic nephropathy), hepatomegaly, cardiomegaly, stroke (such as acute focal ischemic stroke and global cerebral ischemia), heart failure, septic shock, asthma, and Alzheimer's disease. Compounds of the invention are also useful as antiviral agents for treating viral infections such as HIV, hepatitis (B) virus (HBV), human papilloma virus (HPV), cytomegalovirus (CMV), and Epstein-Barr virus (EBV). These methods include the step of administering to a patient in need of such treatment, ar suffering from such a disease or condition, a pharmaceutically-effective amount of a disclosed compound or pharmaceutical composition thereof.
The invention also features methods of combination therapy, such as a method for treating cancer, wherein the method further includes providing radiation therapy or chemotherapy, for example, with mitotic inhibitors such as a taxane or a vinca alkaloid. Examples of mitotic inhibitors include paclitaxel, docetaxel, vincristine, vinblastine, vinorelbine, and vinflunine. Other therapeutic combinations include a MEK inhibitor of the invention and an anticancer agent such-as cisplatin, 5-fluorouracil or 5-fluoro-2-4(1H,3H)-pyrimidinedione (5FU), flutamide, and gemcitabine.
The chemotherapy or radiation therapy may be administered before, concurrently, or after the administration of a disclosed compound according to the needs of the patient.
The invention also features synthetic intermediates and methods disclosed herein.
Other aspects of the invention are provided in the description, examples, and claims below.
DETAILED DESCRIPTION
The invention features diaryl amine compounds, pharmaceutical compositions thereof, and methods of using such compounds and compositions.
According to one aspect of the invention, the compounds are MEK
inhibitors. MEK inhibition assays include the in vitro cascade assay for inhibitors of MAP kinase pathway described at column 6, line 36 to column 7, line 4 of U.S.
Patent Number 5,525,625 and the in vitro MEK assay at column 7, lines 4-27 of the same patent, the entire disclosure of which is incorporated by reference (see also Examples 9-12 below).
The invention features a compound having the formula (I) below:
\ X I \
/ /
Ri R3 I
I
W is one of the following formulae (i) - (xiii):
Xz , H O ,0 ~.~x2 R5N 1 N NRS ~-~~ O N O O-S
N~ X~ N~ . /~X2 N~.~X~ O / ~ N,H N~ NRs (i) (ii) (iii) (i~ (v) (vi) (vii) ,N NRS N~ N=N ,T1 NRS Xi N N
IV,N~O N.N~ RSN / X2 N , X2 ~ ~ X ~ X~
I
(viii) (ix) (x) (xi) (xii) (xiii ) HO O O
-N ~-O O ~N-N
X1y N X, , N N~N
(xiv) (xv) (xvi) (xvii) WO 00/42029 PCT/US99/30~16 X~ is O, S, or NRF. X2 is OH, SH, or NHRE. Each of RE and RF is H or C ,~ alkyl; each of R, and R~ is independently selected from H, F, N02, Br and CI; R~ can also be S02NR~F;H, or R, and R2 together with the benzene ring to which they are attached constitute an indole, isoindole, benzofuran, benzothiophene, indazole, benzimidazole, or benzthioazole. R3 is selected from H and F; each of R~, RH, and R4 is independently selected from H, CI and CH3.
R5 is H or C » alkyl. Each hydrocarbon radical above is optionally substituted with between 1 and 3 substituents independently selected from halo, hydroxyl, amino, (amino)sulfonyl, and N02. Each heterocyclic radical above is optionally substituted with between 1 and 3 substituents independently selected from halo, C ~~ alkyl, C 3_6 cycloalkyl, G 3.~ aikenyl, C 3~ alkynyl, phenyl, hydroxyl, amino, (amino)sulfonyl, and NOz, wherein each substituent alkyl, cycloalkyl, alkenyl, alkynyl or phenyl is in turn optionally substituted with between 1 and 2 substituents independently selected from halo, C ~_2 alkyl, hydroxyl, amino, and N02. The invention also features a pharmaceutically acceptable salt or C ,$
ester of a disclosed compound. For example, the disclosed alcohol compounds may form esters having the structure obtained by replacing the H of a hydroxyl group with a -C(=O)C ~_~ acyf group.
The invention also relates to a pharmaceutical composition including (a) a compound of formula (I;~ and (b) a pharmaceutically-acceptable carrier.
The invention further relates to a method for treating proliferative diseases, such as cancer, restenosis, psoriasis, autoimmune disease, and atherosclerosis.
Other aspects of the invention include methods for treating MEK-related (including ras-related) cancers, whether solid or hematopoietic. Examples of cancers include colorectal, cervical, breast, ovarian, brain, acute leukemia, gastric, non-small cell lung, pancreatic, and renal cancer. Further aspects of the invention include methods for- treating or reducing the symptoms of xenograft (cell(s), skin, limb, organ or bone marrow transplant) rejection, osteoarthritis, rheumatoid arthritis, cystic fibrosis, complications of diabetes (including diabetic retinopathy and diabetic nephropathy), hepatomegaly, cardiomegaly, stroke (such as acute focal ischemic stroke and global cerebral ischemia), heart failure, septic shock, asthma, and Alzheimer's disease. Compounds of the invention are also useful as antiviral agents for treating viral infections such as HIV, hepatitis (B) virus (HBV), human papilloma virus (HPV), cytomegalovirus (CMV), and Epstein-Barr virus (EBV). These methods include the step of administering to a patient in need of such treatment, ar suffering from such a disease or condition, a pharmaceutically-effective amount of a disclosed compound or pharmaceutical composition thereof.
The invention also features methods of combination therapy, such as a method for treating cancer, wherein the method further includes providing radiation therapy or chemotherapy, for example, with mitotic inhibitors such as a taxane or a vinca alkaloid. Examples of mitotic inhibitors include paclitaxel, docetaxel, vincristine, vinblastine, vinorelbine, and vinflunine. Other therapeutic combinations include a MEK inhibitor of the invention and an anticancer agent such-as cisplatin, 5-fluorouracil or 5-fluoro-2-4(1H,3H)-pyrimidinedione (5FU), flutamide, and gemcitabine.
The chemotherapy or radiation therapy may be administered before, concurrently, or after the administration of a disclosed compound according to the needs of the patient.
The invention also features synthetic intermediates and methods disclosed herein.
Other aspects of the invention are provided in the description, examples, and claims below.
DETAILED DESCRIPTION
The invention features diaryl amine compounds, pharmaceutical compositions thereof, and methods of using such compounds and compositions.
According to one aspect of the invention, the compounds are MEK
inhibitors. MEK inhibition assays include the in vitro cascade assay for inhibitors of MAP kinase pathway described at column 6, line 36 to column 7, line 4 of U.S.
Patent Number 5,525,625 and the in vitro MEK assay at column 7, lines 4-27 of the same patent, the entire disclosure of which is incorporated by reference (see also Examples 9-12 below).
A. Terms Certain terms are defined below and by their usage throughout this disclosure.
Alkyl groups include aliphatic (i.e., hydrocarbyl or hydrocarbon radical structures containing hydrogen and carbon atoms) with a free valence. Alkyl groups are understood to include straight chain and branched structures.
Examples include methyl, ethyl, propyl, isopropyl, butyl, n-butyl, isobutyl, t-butyl, pentyl, isopentyl, 2,3-dimethylpropyl, hexyl, 2,3-dimethylhexyl, 1,1-dimethylpentyl, heptyl, and octyl. Cycloaikyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
Alkyl groups can be substituted with 1, 2, 3 or more substituents which are independently selected from halo (fluoro, chloro, bromo, or iodo), hydroxy, amino, alkoxy, alkylamino, dialkylamino, cycloalkyl, aryl, aryloxy, arylalkyloxy, heterocyclic radical, and (heterocyclic radical)oxy. Specific examples include fluoromethyl, hy~droxyethyl, 2,3-dihydroxyethyl, (2- or 3-furanyl)methyl, cyclopropylmethyl, benzyloxyethyl, (3-pyridinyl)methyl, (2- or 3-furanyl)methyl, (2-thienyl)ethyl, hydroxypropy!, aminocyciohexyl, 2-dimethylaminobutyl, methoxymethyl, N-pyridinylethyl, diethylaminoethyl, and cyclobutylmethyl.
Alkenyl groups are analogous to alkyl groups, but have at least one double bond (two adjacent sp2 carbon atoms). Depending on the placement of a double bond and substituents, if any, the geometry of the double bond may be entgegen (E), or zusammen (Z), cis, or traps. Similarly, alkynyl groups have at least one triple bond (two adjacent sp carbon atoms). Unsaturated alkenyl or alkynyl groups may have one or rnor~~ double or triple bonds, respectively, or a mixture thereof; like alkyl groups, unsaturated groups may be straight chain or branched, and they may be substituted as described both above for alkyl groups and throughout the disclosure by example. Examples of alkenyls, alkynyls, and substituted forms include cis-2-butenyl, traps-2-butenyl, 3-butynyl, 3-phenyl-propynyl, 3-(2'~;luorophenyl)-2-propynyl, 3-methyl(5-phenyl}-4-pentynyl, 2-hydroxy-2-propynyl, 2-methyl-2-propynyl, 2-propenyl, 4-hydroxy-3-butynyl, 3-(3-fluorophenyl)-2-propynyl, and 2-methyl-2-propenyl. In formula (I), alkenyls and alkynyls can be C 2~ or C. 2_e, for example, and are preferably C 3.~ or C
3_a.
More general forms of substituted hydrocarbon radicals include hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, hydroxycycloalkyl, hydroxyaryl, and corresponding forms for the prefixes amino-, halo- (e.g., fluoro-, chloro-, or bromo-), vitro-, alkyl-, phenyl-, cycloalkyl- and so on, or combinations of substituents. According to formula (I), therefore, substituted alkyls include hydroxyalkyl, aminoalkyl, nitroalkyl, haloalkyl, alkylalkyl (branched alkyls, such as methyipentyl), (cycloalkyl;)alkyl, phenylalkyl, alkoxy, alkylaminoalkyl, dialkylaminoalkyl, arylalkyl, aryloxyaikyl, arylalkyloxyalkyl, {heterocyclic radical)alkyl, and (heterocyciic radical)oxyalkyl. R~ thus includes hydroxyalkyl, hydroxyalkeny', hydroxyalkynyl, hydroxycycloalkyl, hydroxyaryl, aminoalkyl, aminoalkenyl, aminoalkynyl, aminocycloalkyl, aminoaryl, alkylalkenyl, (alkylaryl)alkyl; (haloaryl)alkyl, (hydroxyaryl)alkynyl, and so forth.
Similarly, RA
includes hydroxyalkyl and aminoaryl, and RB includes hydroxyalkyl, aminoalkyl, and hydroxyalkyl(heterocyclic radical)alkyl.
Heterocyclic radicals, which include but are not limited to heteroaryls, include: furyl, oxazolyl, isc.xazolyl, thiophenyi, thiazolyl, pyrrolyl, imidazolyl, 1,3,4-triazalyl, tetrazolyl, pyridinyl, pyrimidinyl, pyridazinyl, indolyl, and their nonaromatic counterparts. Further examples of heterocyclic radicals include piperidyl, quinolyl, isothiazolyl, piperidinyl, morpholinyl, piperazinyl, tetrahydrofuryl, tetrahydropyrrolyl, pyrrolidinyl, octahydroindolyl, octahydroben?othiofuranyl, and octahydrobenzofuranyl.
Selecti~~e MEK 1 or MEK 2 inhibitors are those compounds which inhibit the MEK 1 or PAEK 2 enzyme, respectively, without substantially inhibiting other enzymes such as MKK3, PKC, Cdk2A, phosphorylase kinase, EGF, and PDGF
receptor kinases, and C-src. In general, a selective MEK 1 or MEK 2 inhibitor has an IC5o for ME',K 1 or MEK 2 that is at feast one-fiftieth {1/50) that of its IC5o for one of the above--gamed other enz~~mes. Preferably, a selective inhibitor has an IC5o th~~t is at least 11100, more preferably 1/500, and even more preferably 1/1000, 1/5000 or less thin that of its IC5oor one or more of the above-named enzymes.
Alkyl groups include aliphatic (i.e., hydrocarbyl or hydrocarbon radical structures containing hydrogen and carbon atoms) with a free valence. Alkyl groups are understood to include straight chain and branched structures.
Examples include methyl, ethyl, propyl, isopropyl, butyl, n-butyl, isobutyl, t-butyl, pentyl, isopentyl, 2,3-dimethylpropyl, hexyl, 2,3-dimethylhexyl, 1,1-dimethylpentyl, heptyl, and octyl. Cycloaikyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
Alkyl groups can be substituted with 1, 2, 3 or more substituents which are independently selected from halo (fluoro, chloro, bromo, or iodo), hydroxy, amino, alkoxy, alkylamino, dialkylamino, cycloalkyl, aryl, aryloxy, arylalkyloxy, heterocyclic radical, and (heterocyclic radical)oxy. Specific examples include fluoromethyl, hy~droxyethyl, 2,3-dihydroxyethyl, (2- or 3-furanyl)methyl, cyclopropylmethyl, benzyloxyethyl, (3-pyridinyl)methyl, (2- or 3-furanyl)methyl, (2-thienyl)ethyl, hydroxypropy!, aminocyciohexyl, 2-dimethylaminobutyl, methoxymethyl, N-pyridinylethyl, diethylaminoethyl, and cyclobutylmethyl.
Alkenyl groups are analogous to alkyl groups, but have at least one double bond (two adjacent sp2 carbon atoms). Depending on the placement of a double bond and substituents, if any, the geometry of the double bond may be entgegen (E), or zusammen (Z), cis, or traps. Similarly, alkynyl groups have at least one triple bond (two adjacent sp carbon atoms). Unsaturated alkenyl or alkynyl groups may have one or rnor~~ double or triple bonds, respectively, or a mixture thereof; like alkyl groups, unsaturated groups may be straight chain or branched, and they may be substituted as described both above for alkyl groups and throughout the disclosure by example. Examples of alkenyls, alkynyls, and substituted forms include cis-2-butenyl, traps-2-butenyl, 3-butynyl, 3-phenyl-propynyl, 3-(2'~;luorophenyl)-2-propynyl, 3-methyl(5-phenyl}-4-pentynyl, 2-hydroxy-2-propynyl, 2-methyl-2-propynyl, 2-propenyl, 4-hydroxy-3-butynyl, 3-(3-fluorophenyl)-2-propynyl, and 2-methyl-2-propenyl. In formula (I), alkenyls and alkynyls can be C 2~ or C. 2_e, for example, and are preferably C 3.~ or C
3_a.
More general forms of substituted hydrocarbon radicals include hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, hydroxycycloalkyl, hydroxyaryl, and corresponding forms for the prefixes amino-, halo- (e.g., fluoro-, chloro-, or bromo-), vitro-, alkyl-, phenyl-, cycloalkyl- and so on, or combinations of substituents. According to formula (I), therefore, substituted alkyls include hydroxyalkyl, aminoalkyl, nitroalkyl, haloalkyl, alkylalkyl (branched alkyls, such as methyipentyl), (cycloalkyl;)alkyl, phenylalkyl, alkoxy, alkylaminoalkyl, dialkylaminoalkyl, arylalkyl, aryloxyaikyl, arylalkyloxyalkyl, {heterocyclic radical)alkyl, and (heterocyciic radical)oxyalkyl. R~ thus includes hydroxyalkyl, hydroxyalkeny', hydroxyalkynyl, hydroxycycloalkyl, hydroxyaryl, aminoalkyl, aminoalkenyl, aminoalkynyl, aminocycloalkyl, aminoaryl, alkylalkenyl, (alkylaryl)alkyl; (haloaryl)alkyl, (hydroxyaryl)alkynyl, and so forth.
Similarly, RA
includes hydroxyalkyl and aminoaryl, and RB includes hydroxyalkyl, aminoalkyl, and hydroxyalkyl(heterocyclic radical)alkyl.
Heterocyclic radicals, which include but are not limited to heteroaryls, include: furyl, oxazolyl, isc.xazolyl, thiophenyi, thiazolyl, pyrrolyl, imidazolyl, 1,3,4-triazalyl, tetrazolyl, pyridinyl, pyrimidinyl, pyridazinyl, indolyl, and their nonaromatic counterparts. Further examples of heterocyclic radicals include piperidyl, quinolyl, isothiazolyl, piperidinyl, morpholinyl, piperazinyl, tetrahydrofuryl, tetrahydropyrrolyl, pyrrolidinyl, octahydroindolyl, octahydroben?othiofuranyl, and octahydrobenzofuranyl.
Selecti~~e MEK 1 or MEK 2 inhibitors are those compounds which inhibit the MEK 1 or PAEK 2 enzyme, respectively, without substantially inhibiting other enzymes such as MKK3, PKC, Cdk2A, phosphorylase kinase, EGF, and PDGF
receptor kinases, and C-src. In general, a selective MEK 1 or MEK 2 inhibitor has an IC5o for ME',K 1 or MEK 2 that is at feast one-fiftieth {1/50) that of its IC5o for one of the above--gamed other enz~~mes. Preferably, a selective inhibitor has an IC5o th~~t is at least 11100, more preferably 1/500, and even more preferably 1/1000, 1/5000 or less thin that of its IC5oor one or more of the above-named enzymes.
B. Compounds One aspect of the invention features the disclosed compounds shown in formula (l) in the Summary section.
Embodiments of the invention include compounds wherein: (a) R~ is bromo or chloro; (b) R2 is fluoro; (c) R3 is H; (d) each of R2 and R3 is H;
(e) each of R2 and R3 is fluoro; (f) R~ is bromo; (g) each of R~, R2 and R3 is fluoro;
(h) R2 is vitro; {i) R3 is H; (j) R4 is chioro; (k) R4 is methyl; (I) R5 is H;
(m) R5 is CH3; (n} X~ is O or S; (o) X~ is NH or NCH3; {p) X2 is OH, SH, or NH2; (q) X2 is OH; (r) X2 is NHRE; (s) R4 is H; (t) R4 is chloro or methyl; or combinations thereof.
Preferably, where one of the substituents on a heterocyclic radical is an alkenyl or alkynyl group, the double or triple bond, respectively, is not adjacent the point of attachment when it is a heteroatom. For example, in such a situation, the substituent is preferably prop-2-ynyl, or but-2 or 3-enyl, and less preferably prop-1-ynyl or but-1-enyl.
Examples of compounds include:: [5-fluoro-2-(1 H-tetrazol-5-yl)-phenyl]-(4-iodo-2-methyl-phenyl)-amine; [?,3-difluoro-6-{1 H-tetrazol-5-yl)-phenyl]-(4-iodo-2-methyl-phenyl)- amine; (4-iodo-2-methyl-phenyl)-[2,3,4-trifluoro-6-(1 H-tetrazol-5-yl)-phenyl]-amine; [4-bro~mo-2,3-difiuoro-6-(1 H-tetrazol-5-yl)-phenyl]-(4-iodo-2-methyl-phenyl)-amine; [5-fluoro-4-vitro-2-(1 H-tetrazol-5-yl)-phenyl]-(4-iodo-methyl-phenyl)-amine; [2.-(4,4-dimethyl-4,5-dihydro-oxazol-2-yl)-5-fluoro-phenyl]-(4-iodo-2-methyl-phenyl)-amine; [6-(4,4-dimethyl-4,5-dihydro-oxazol-2-yl)-2,3-difluoro-phenyl]-(4-iodo-2-methy'-phenyl)-amine; [6-(4,4-dimethyl-4,5-dihydro-oxazol-2-yl)-2,3,4-trifluoro-phenyl]-(4-iodo-2-methyl-phenyl)-amine; [4-bromo-(4,4-dimethyl-~'~ 5-dihydrc>-oxazol-2-yl)-2,3-difiuoro-phenyl]-(4-iodo-2-methyl-phenyl)-amine' [2-(4,4-dimethyl-4,5-dihydro-oxazol-2-yl)-5-fluoro-4-vitro-phenyl]-(4-iodo-2-methyl-phenyl)-ami-~~; 5-[4-fluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-[1,3,4]thiadiazol-,~-ol; 5-[3,4-difluoro-2-{4-iodo-2-methyl-phenyiamino)-phenyl]-[1,3,4~thiaaiazol-2-0.; 5-[3,4,5-~~ifluoro-2-{4-iodo-2-methyl-phenylamino)-phenyl]-[1,3,4]tr,iadiazol-2-0l; 5-[5-bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-[1,3,4]thiadiazol-2-0l; 5-[4-fluoro-2-(4-iodo-2-methyl-phenylamino)-5-vitro-phenyl]-[1,3,4]thiadiazol-2-0l; 5-(4-fluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-[1,3,4]oxadiazol-2-0l; 5-[3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-[1,3,4]oxadiazol-2-0l; 5-[3,4,5-trifluoro-2-(4-iodo-2-methyl-phenyfamino)-phenyl]-(1,3,4]oxadiazol-2-0l; 5-[5-bromo-3,4-difluoro-2-(4-iodo-methyl-phenyiamino)-phony']-[1,3,4]oxadiazol-2-0l; 5-[4-fluoro-2-(4-iodo-2-methyl-phenylamino)-5-vitro-phenyl]-[1.3,4]oxadiazol-2-0l; 5-[4-fluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-4H-[1,2,4]triazol-3-0l; 5-[3,4-difiuoro-2-{4-iodo-2-methyl-phenylamino)-phenyl]-4H-[1,2,4]triazol-3-0l; 5-[3,4,5-trifluoro-2-(4-iodo-2-methyl-phenylamino)-phenylj-4t-!-[1,2,4]triazol-3-0l; 5-[5-bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-4H-[1,2,4]ti~iazol-3-0l; and 5-[4-fluoro-2-(4-iodo-methyl-phenylamino)-5-vitro-phenyl]-4H-[1,2,4]triazol-3-0l.
Further examples include: 5-(4-fluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-[1,3,4]thiadiazol-2-ylamine; 5-[3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-[1,3,4]thiadiazol-2-ylamine; 5-[3,4,5-Trifluoro-2-(4-iodo-methyl-phony!amino)-phe~~ylJ-[1;3,4]thiadiazol-2-ylamine; 5-[5-bromo-3,4-difluoro-2-(4-iodo-2-methyl-p!~enylamino)-phenyl]-[1,3,4]thiadiazol-2-ylamine;
[4-fluoro-2-(4-iodo-2-meth,yl-phenylamino)-5-vitro-phenyl]-[1,3,4]thiadiazol-2-ylamine; 5-(4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-[1,3,4]oxadiazol-ylamine; 5-~3;4-difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-[1,3,4]oxadiazol-2-ylamine; 5-[,:,4,5-trifluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-[1,3,4]cxadiazol-2-ylamine; 5-[5-bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino;~-:~henyf]-[1.,3,4j~~xadiazol-2-ylamine; 5-[4-fluoro-2-(4-iodo-2-methyl-phenylamino)-~-vitro-phenylj-;1,3.4]oxadiazol-2-ylamine; 5-[4-fluoro-2-(4-iodo-methyl-phony!a.mine)-phenyl]-4H-[1,2,4]triazol-3-ylarnine; 5-(3,4-difluoro-2-(4-iodo-2-me':hyl-phenylamino)-phenylj-4H-[1,2,4]triazol-3-ylamine; 5-[3,4,5-trifluoro-2-(4-iodo-2-methyl-phen~ylamino)-phenyl]-4H-[1,2,4]triazol-3-ylamine; 5-[5-bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-4H-[1,2,4]triazol-3-ylamine;
5-[4-fluore~-2-(4--iodo-2-me ihy!-phenylamino)-5-vitro-phenyl]-4H-[1,2,4]triazol-3-ylamine; 5-[4-fvoro-2-(4-ic~dc-2-methyl-phenylamino)-phenyl]-[1,3,4]thiadiazole-2-thiol; 5-(3,4-dif'uora-2-(4-iodr>-2-methyl-phenylamino)-phenyl]-[1,3,4]thiadiazole-2-thiol; 5-[3,4,5-~.riftuoro-2-{4-io~o-2-methyl-phenylamino)-phenyl]-[1,3,4]thiadiazole-2-thiol; 5-[5-bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-MISSING AT THE TIME OF PUBLICATION
l0 phenylamino)-5-nitro-phenyl]-isothiazol-3-0l; 4-[4-fluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-isoxazol-3-0l; 4-[3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-isoxazol-3-0l; 4-[3,4,5-trifluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-isoxazol-3-0l; 4-[5-bromo-3,4-difluoro-2-{4-iodo-2-methyl-phenylamino)-phenyl]-isoxazol-3-0l; 4-[4-fluoro-2-(4-iodo-2-methyl-phenylamino)-5-nitro-phenyl]-isoxazol-3-0l; 4-[4-fluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-1-methyl-1 H-pyrazol-3-oi; 4-[3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-1-methyl-1 H-pyrazol-3-0l; 1-methyl-4-[3,4,5-trifluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-1 H-pyrazol-3-0l; 4-[5-bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-1-methyl-1 H-pyrazol-3-0l; and 4-[4-fluoro 2-(4-iodo-2-methyl-phenylamino)-5-nitro-phenyl]-1-methyl-1 H-pyrazol-3-0l.
The invention also features compounds such as: 5-[2-(2-amino-4-iodo-phenylamino)-4-fluoro-phenyl]-1-methyl-1H-[1,2,3]triazol-4-0l; 5-[2-{2-amino-4-iodo-phenylamino)-3,4-difluoro-phenylJ-1-methyl-1H-[1,2,3Jtriazol-4-0l; 5-[2-(2-amino-4-iodo-phenylamino)-3,4,5-trifluoro-phenyl]-1-methyl-1H-[1,2,3]triazol-4-0l;
5-[2-(2-amino-4-iodo-phenylamino)-5-bromo-3,4-difluoro-phenyl]-1-methyl-1 H-[1,2,3]triazol-4-0l; 5-[2-(2-amino-4-iodo-phenylamino)-4-fluoro-5-nitro-phenyl]-1-methyl-1H-[1,2,3)triazol-4-0l; 5-[4-fluoro-2-(4-iodo-2-methyl-phenylamino)-phenylJ-3-methyl-3H-[1,2,3]triazol-4-0l; 5-[3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-3-methyl-3H-[1,2,3]triazol-4-0l; 3-methyl-5-[3,4,5-trifluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-3H-[1,2,3]triazol-4-0l; 5-[5-bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-3-methyl-3H-[1,2,3Jtriazol-4-0l;
5-[4-fluoro-2-(4-iodo-2-methyl-phenylamino)-5-nitro-phenyl]-3-methyl-3H-[1,2,3)triazol-4-0l; 4-[4-fluoro-2-(4-iodo-2-methyl-phenyfamino)-phenyl]-2-methyl-2H-pyrazol-3-0l; 4-[3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-2-methyl-2H-pyrazol-3-0l; 2-methyl-4-[3,4,5-trifluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-2H-pyrazol-3-0l; 4-[5-bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-2-methyl-2H-pyrazol-3-0l; 4-[4-fluoro-2-(4-iodo-2-methyl-phenylamino)-5-vitro-phenyl]-2-methyl-2H-pyrazol-3-0l; 1-[4-fluoro-2-(4-iodo-2-methyl-phenylamina)-phenyl)-4-methyl-1,4-dihydro-tetrazol-5-one; 1-[3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-phenylJ-4-methyl-1,4-dihydro-tetrazol-one; 1-methyl-4-[3,4,5-trifluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-1,4-dihydro-tetrazol-5-one; 1-[5-bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-4-methyl-1,4-dihydro-tetrazol-5-one; 1-[4-fluoro-2-(4-iodo-2-methyl-phenylamino)-5-nitro-phenyl]-4-methyl-1,4-dihydro-tetrazol-5-one; 1-[4-fluoro-(4-iodo-2-methyl-phenylamino)-phenyl]-1H-[1,2,3jtriazol-4-0l; 1-[3,4-difluoro-2-(4-iodo-2-methyl-phenyiamino)-phenyl]-1H-[1,2,3]triazol-4-0l; 1-[3,4,5-trifluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-1H-[1,2,3]triazol-4-0l; 1-[5-bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-1 H-[1,2,3]triazol-4-0l; and 1-[4-fluoro-2-(4-iodo-2-methyl-phenylamino)-5-nitro-phenyl]-1 H-[1,2,3]triazol-4-0l.
Further examples of the invention include 3-[4-fluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-2H-isoxazol-5-one; 3[3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-2H--isoxazol-5-one; 3-[3,4,5-trifluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-2H-isoxazol-5-one; 3-[5-bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-2H-isoxazol-5-one; 3-[4-fluoro-2-(4-iodo-2-methyl-phenylamino)-5-nitro-phenyl]-2H-isoxazol-5-one; [5-fluoro-2-(2-oxo-2,3-dihydro-21>4 -[1,2,3,5]oxathiadiazol-4-yl)-phenyl]-(4-iodo-2-methyl-phenyl)-amine;
[2,3-difluoro-6-(2-oxo-2, 3-dihydro-21>4_-[1,2, 3, 5]oxathiadiazol-4-yl)-phenyl]-(4-iodo-2-methyl-phenyl)-amine; (4-lodo-2-methyl-phenyl)-[2,3,4-trifluoro-6-(2-oxo-2,3-dihydro-21>4- [1,2,3,5]oxathiadiazol-4-yl)-phenyl]-amine; [4-bromo-2,3-difluoro-6-(2-oxo-2,3-dihydro-21>4_-[1,2,3,5]oxathiadiazol-4-yl)-phenyl]-(4-iodo-2-methyl-phenyl)-amine; [5-fluoro-4-nitro-2-(2-oxo-2,3-dihydro-21>4=
[1,2,3,5]oxathiadiazol-4-yl)-phenyl]-(4-iodo-2-methyl-phenyl)-amine; 4-[4-fluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-4H-isoxazol-5-one; 4-[3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-4H-isoxazol-5-one; 4-[3,4,5-trifluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-4H-isoxazol-5-one; 4-[5-bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-4H-isoxazol-5-one; and 4-[4-fluoro-2-(4-iodo-2-methyl-phenylamino)-5-nitro-phenyl]-4H-isoxazol-5-one.
Further compounds, where R, can also be SOzNR~RH, or R~ and R2 together with the benzene ring to which they are attached constitute an indole, isoindole, benzofuran, benzothiophene, indazole, benzimidazoie, or benzthioazole, include the following groups:
Group 1 (1) 2-Fluoro-5-(5-hydroxy-1,3,4-oxadiazol-2-yl)-4-(4-iodo-2-methyl-phenyiamino)-benzenesulfonamide (2) 4-(2-Chloro-4-iodo-phenylamino)-2-fluoro-5-(5-hydroxy-1,3,4-oxadiazol-2-yl)-N-methyl-benzenesulfonamide (3) 2,3-Difluoro-5-(5-hydroxy-1,3,4-oxadiazoi-2-yl)-4-(4-iodo-2-methyl-phenylamino)-N,N-dimethyl-benzenesulfonamide (4) 4-(2-Chloro-4-iodo-phenylamino)-2,3-difluoro-5-(5-hydroxy-1,3,4-oxadiazol-yl)-N-methyl-N-(3-rnorpholin-4-yi-propyl)-benzenesulfonamide {5) 2-Fluoro-5-(5-hydroxy-1,3,4-oxadiazol-2-yl)-4-(4-iodo-phenylamino)-N-(2-(2-methoxy-ethoxy)-ethyl]-benzenesulfonamide (6) N-(2-Dimethylamino-ethyl)-2-fluoro-5-(5-hydroxy-1,3,4-oxadiazo!-2-yl)-4-(4-iodo-phenylamino)-N-methyl-benzenesulfonamide Group 2 (1) 5-(5-Amino-1,3,4-oxadiazol-2-yl)-2-fluoro-4-(4-iodo-2-methyl-phenylamino}-benzenesulfonamide (2) 5-(5-Amino-1,3,4-oxadiazol-2-yl)-4-(2-chloro-4-iodo-phenylamino)-2-fluoro-benzenesulfonamide (3) 5-(5-Amino-1,3,4-oxadiazol-2-yl)-2,3-difluoro-4-(4-iodo-2-methyl-phenylamino)-benzenesuifonamide (4) 5-(5-Amino-1,3,4-oxadiazol-2-yl)-4-(2-chloro-4-iodo-phenylamino)-2,3-difluoro-benzenesulfonamide (5) 5-(5-Amino-1,3,4-oxadiazol-2-yl)-2-fluoro-4-(4-iodo-phenylamino)-benzenesulfonamide {6) 4-(5-Amino-'1,3,4-oxadiazol-2-yl)-2-fluoro-5-(4-iodo-phenylamino)-benzenesulfonamide Group 2b (1 ) 5-(5-Amino-1,3,4-oxadiazol-2-yl)-2-fluoro-4-(4-iodo-2-methyl-phenylamino)-benzenesulfonamide {2) 5-(5-Amino-1,3,4-oxadiazol-2-yl)-2-fluoro-4-{4-iodo-phenylamino)-N-methyl-N-(3-morpholin-4-yl-propyl)-benzenesulfonamide (3) 5-(5-Amino-1,3,4-oxadiazol-2-yl)-2,3-difluoro-4-(4-iodo-2-methyl-phenylamino)-benzenesulfonamide (4) 5-(5-Amino-1,3,4-oxadiazol-2-yl)-2-fluoro-4-(4-iodo-phenylamino)-benzenesulfonamide (5) 5-(5-Amino-1,3,4-oxadiazol-2-yl)-4-(2-chloro-4-iodo-phenylamino)-2,3-difluoro-N-[3-(4-methyl-piperazin-1-yl)-propyl]-benzenesulfonamide (6) 5-(5-Amino-1,3,4-oxadiazol-2-yl)-4-(2-chforo-4-iodo-phenylamino)-2-fluoro-N-(3-piperidin-1-yl-propyl)-benzenesulfonamide Group 3 (1) 2-Fluoro-4-(4-iodo-2-methyl-phenylamino)-5-(5-mercapto-1,3,4-oxadiazol-2-yl)-benzenesulfonamide (2) 2-Fluoro-5-(4-iodo-phenylamino)-4-(5-mercapto-1,3,4-oxadiazol-2-yl)-benzenesulfonamide (3) 2,3-Difluoro-4-(4-iodo-2-methyl-phenylamino)-5-(5-mercapto-1,3,4-oxadiazol-2-yl)-benzenesulfonamide (4) 2-Fluoro-4-(4-iodo-phenylamino)-5-(5-mercapto-1,3,4-oxadiazol-2-yl)-benzenesulfonamide (5) 4-(2-Chloro-4-iodo-phenylamino)-2,3-difluoro-5-(5-mercapto-1,3,4-oxadiazol-2-yl)-benzenesulfonamide (6) 4-(2-Chloro-4-iodo-phenylamino)-2-fluoro-5-(5-mercapto-1,3,4-oxadiazol-2-yl)-benzenesulfonamide Group 4 (1) 2-Fluoro-5-(5-hydroxy-1,3,4-thiadiazol-2-yl)-4-(4-iodo-2-methyl-phenylamino)-benzenesulfonamide (2) 2-Fluoro-4-{5-hydroxy-1,3,4-thiadiazol-2-yl)-5-(4-iodo-phenyiamino)-benzenesulfonamide (3) 2,3-Difluoro-5-(5-hydroxy-1,3,4-thiadiazol-2-yl)-4-(4-iodo-2-methyl-phenylamino)-benzenesulfonamide {4) 2-Fluoro-5-(5-hydroxy-1,3,4-thiadiazol-2-yl)-4-(4-iodo-phenylamino)-benzenesulfonamide (5) 4-{2-Chloro-4-iodo-phenylamino)-2,3-difluoro-5-(5-hydroxy-1,3,4-thiadiazol-yl)-benzenesulfonamide (6) 4-(2-Chloro-4-iodo-phenylamino)-2-fluoro-5-(5-hydroxy-1,3,4-thiadiazol-2-yl)-benzenesulfonamide Group 5 (1) 5-(5-Amino-1,3,4-thiadiazol-2-yl)-2-fluoro-4-(4-iodo-2-methyl-phenylamino)-benzenesulfonamide (2) 4-(5-Amino-1,3,4-thiadiazol-2-yl)-5-(4-iodo-phenylamino)-2-mercapto-benzenesulfonamide (3) 5-(5-Amino-1,3,4-thiadiazol-2-yl)-2,3-diffuoro-4-(4-iodo-2-methyl-phenylamino)-benzenesulfonamide (4) 5-(5-Amino-1,3,4-thiadiazol-2-yl)-2-fluoro-4-(4-iodo-phenylamino)-benzenesulfonamide (5) 5-(5-Amino-7 ,3,4-thiadiazol-2-yl)-4-(2-chloro-4-iodo-phenylamino}-2,3-difluoro-benzenesulfonamide (6) 5-(5-Amino-1,3,4-thiadiazol-2-yl)-4-(2-chloro-4-iodo-phenylamino}-2-fluoro-benzenesulfonamide Group 6 (1) 2-Fluoro-5-(5-hydroxy-4H-1,2,4-triazol-3-yl)-4-(4-iodo-2-methyl-phenylamino)-benzenesulfonamide (2) 2-Fluoro-4-(5-hydroxy-4H-1,2,4-triazol-3-yl)-5-(4-iodo-phenylamino)-benzenesulfonamide (3) 2,3-Difluoro-5-(5-hydroxy-4H-1,2,4-triazol-3-yl}-4-(4-iodo-2-methyl-phenylamino)-benzenesulfonamide WO 00!42029 PCT/US99/30416 (4) 5-[4-(2-Dimethylamino-ethyl)-5-hydroxy-4H-1,2,4-triazol-3-yl]-2-fluoro-4-(4-iodo-phenylamino;l-benzenesulfonamide (5) 4-(2-Chloro-4-iodo-phenylamino)-2,3-difluoro-5-(5-hydroxy- 4H-1,2,4-triazol-yl)-benzenesuifonamide {6) 4-(2-Chloro-4-iodo-phenylamino)-2-fluoro-5-(5-hydroxy-4-methyl-4H-1,2,4-triazol-3-yl)-benzenesulfonamide Group 7 (1 ) 5-(5-Amino-4H-1,2,4-triazol-3-yl)-2-fluoro-4-(4-iodo-2-methyl-phenylamino)-benzenesulfonamide (2) 4-(5-Amino-4H-1,2,4-triazol-3-yl)-2-fluoro-5-(4-iodo-phenylamino)-benzenesulfonamide (3) 5-(5-Amino-4-methyl-4H-1,2,4-triazol-3-yl)-2,3-difluoro-4-{4-iodo-2-methyl-phenylamino)-benzenesulfonamide (4) 5-[5-Amino-4-(3-dimethylamino-propyl)-4H-1,2,4-triazol-3-yl]-2-fluoro-4-(4-iodo- phenylamino)-benzenesulfonamide (5) 5-(5-Amino-4H-1,2,4-triazol-3-yl)-4-(2-chloro-4-iodo-phenylamino}-2,3-difluoro-benzenesulfonarnide (6) 5-(5-Amino-4-methyl-4H-1,2,4-triazol-3-yl)-4-(2-chloro-4-iodo-phenylamino)-2-fluoro-benzenesulfonamide Group 8 (1) 2-Fluoro-5-(3-hydroxy-isoxazol-5-yl)-4-(4-iodo-2-methyl-phenylamino)-benzenesulfonamide (2) 2-Fluoro-4-(3-hydroxy-isoxazol-5-yl)-5-(4-iodo-phenylamino)-benzenesulfonamide (3) 2,3-Difluoro-5-(3-hydroxy-isoxazol-5-yl)-4-(4-iodo-2-methyl-phenylamino)-benzenesulfonamide (4} 2-Fluoro-5-(3-hydroxy-isoxazol-5-yl)-4-(4-iodo-phenylamino)-benzenesulfonamide (5) 4-(2-Chloro-4-iodo-phenylamino)-2,3-difiuoro-5-{3-hydroxy-isoxazol-5-yl)-benzenesulfonamide (6) 4-(2-Chloro-4-iodo-phenylamino)-2-fluoro-5-(3-hydroxy-isoxazol-5-yl)-benzenesulfonamide Group 9 (1) 5-(3-Amino-isoxazol-5-yl)-2-fluoro-4-(4-iodo-2-methyl-phenylamino)-benzenesulfonamide (2) 4-(3-Amino-isoxazol-5-yl)-2-bromo-5-(4-iodo-phenylamino)-benzenesulfonamide (3) 5-(3-Amino-isoxazol-5-yl)-2,3-difluoro-4-(4-iodo-2-methyl-phenylamino)-benzenesulfonamide (4) 5-(3-Amino-isoxazol-5-yl)-2-fluoro-4-(4-iodo-phenylamino)-benzenesulfonamide (5) 5-(3-Amino-isoxazol-;i-yl)-4-(2-chioro-4-iodo-phenylamino)-2,3-difluoro-benzenesulfonamide (6) 5-(3-Amino-isoxazol-5-yl)-4-(2-chloro-4-iodo-phenylamino)-2-fluoro-benzenesulfonamide Group 10 (1 ) 2-Fluoro-4-(4-iodo-2-methyl-phenylamino}-5-(3-mercapto-isoxazol-5-yl)-benzenesulfonamide (2) 4-(2-Chloro-4-iodo-phenylamino)-2-fluoro-5-(3-mercapto-isoxazol-5-yl)-benzenesulfonamide (3) 2,3-Difluoro-4-(4-iodo-2-methyl-phenylamino)-5-(3-mercapto-isoxazol-5-yl)-benzenesulfonamide (4) 4-(2-Chloro-4-iodo-phenylamino)-2,3-difluoro-5-(3-mercapto-isoxazol-5-yl)-benzenesulfonamide (5) 2-Fluoro-4-(4-iodo-phenylamino)-5-(3-mercapto-isoxazol-5-yl)-benzenesulfonamide (6) 2-Bromo-5-{4-iodo-phenylamino)-4-(3-mercapto-isoxazol-5-yl)-benzenesulfonamide Group 11 (1) 2-Fluoro-5-(3-hydroxy-isoxazol-4-yl)-4-(4-iodo-2-methyl-phenylamino)-benzenesulfonamide (2) 4-(2-Chloro-4-iodo-phenylamino)-2-fluoro-5-{3-hydroxy-isoxazol-4-yl)-benzenesulfonamide (3) 2,3-Difluoro-5-(3-hydroxy-isoxazol-4-yl)-4-(4-iodo-2-methyl-phenylamino)-benzenesulfonamide (4) 4-(2-Chloro-4-iodo-phenylamino)-2,3-difluoro-5-(3-hydroxy-isoxazol-4-yl)-benzenesuifonamide (5) 2-Fluoro-5-(3-hydroxy-isoxazol-4-yl)-4-(4-iodo-phenylamino)-benzenesulfonamide (6) 2-Bromo-4-(3-hydroxy-isoxazol-4-yl)-5-(4-iodo-phenylamino)-benzenesulfonamide Group 12 (1) 5-(3-Amino-isoxazol-4-yl)-2-fluoro-4-(4-iodo-2-methyl-phenylamino)-benzenesulfonamide (2) 5-(3-Amino-isoxazol-~t-yl)-4-(2-chloro-4-iodo-phenylamino)-2-fluoro-benzenesulfonamide (3) 5-(3-Amino-isoxazol-4-yl)-2,3-difluoro-4-(4-iodo-2-methyl-phenylamino}-benzenesulfonamide (4) 5-(3-Amino-isoxazol-4-yl)-4-(2-chloro-4-iodo-phenylamino)-2,3-difluoro-benzenesulfonamide (5} 5-(3-Amino-isoxazol-~4-yl)-2-fluoro-4-(4-iodo-phenylamino)-benzenesulfonamide (6) 4-(3-Amino-isoxazol-4~-yl)-2-chloro-5-(4-iodo-phenylamino)-benzenesulfonamide Group 13 (1 ) 5-(3-Amino-isoxazol-4-yl)-2-fluoro-4-(4-iodo-2-methyl-phenylamino)-benzenesulfonamide (2) 5-(3-Amino-isoxazol-4-yl)-4-(2-chloro-4-iodo-phenylamino)-2-fluoro-benzenesulfonamide (3) 5-(3-Amino-isoxazol-4-yl)-2,3-difluoro-4-(4-iodo-2-methyl-phenyiamino)-benzenesulfonamide (4) 5-(3-Amino-isoxazol-4-yl)-4-(2-chloro-4-iodo-phenylamino)-2,3-difluoro-benzenesulfonamide"
(5) 5-(3-Amino-isoxazol-4-yl)-2-fluoro-4-(4-iodo-phenylamino)-benzenesulfonamide (6) 4-(3-Amino-isoxazol-4-yl)-2-chioro-5-(4-iodo-phenylamino)-benzenesulfonamide Group 14 (1 ) 5-(2-Amino-5H-pyrrol-3-yl)-2-fluoro-4-(4-iodo-2-methyl-phenylamino)-benzenesulfonamide (2) 5-(2-Amino-5H-pyrrol-~3-yl)-4-(2-chloro-4-iodo-phenylamino)-2-fluoro-benzenesulfonamide (3) 5-(2-Amino-5H-pyrrol-~3-yl)-2,3-difluoro-4-(4-iodo-2-methyl-phenylamino)-benzenesulfonamide (4) 5-(2-Amino-5H-pyrrol-~3-yl)-4-(2-chloro-4-iodo-phenylamino)-2,3-difluoro-benzenesulfonamide (5) 5-(2-Amino-5H-pyrrol--3-yl)-2-fluoro-4-(4-iodo-phenylamino)-benzenesulfonamide {6) 4-(2-Amino-5H-pyrrol-3-yl)-2-chloro-5-(4-iodo-phenylamino)-benzenesulfonamide Group 15 (1 ) 2-Fluoro-5-(5-hydroxy-1-methyl-1 H-pyrazol-4-yl)-4-(4-iodo-2-methyl-phenylamino)-benzenesulfonamide {2) 4-(2-Chloro-4-iodo-phenylamino)-2-fluoro-5-(5-hydroxy-1 H-pyrazol-4-yl)-benzenesulfonamide (3) 2,3-Difluoro-5-(5-hydroxy-1 H-pyrazol-4-yl)-4-(4-iodo-2-methyl-phenylamino)-benzenesulfonamide (4) 4-{2-Chloro-4-iodo-phenylamino)-2,3-difluoro-5-(5-hydroxy-1H-pyrazol-4-yl)-benzenesulfonamide (5) 2-Fluoro-5-{5-hydroxy-1-[3-(4-methyl-piperazin-1-yl)-propylJ-1 H-pyrazol-4-yl}-4-(4-iodo-phenylarnino)-benzenesulfonamide (6) 2-Fluoro-4-(5-hydroxy-1 H-pyrazol-4-yl)-5-(4-iodo-phenylamino)-benzenesulfonamide Group 16 (1) 2-Fluoro-5-(5-hydroxy-3-methyl-3H-1,2,3-triazol-4-yl)-4-(4-iodo-2-methyl-phenylamino)-benzenesulfonamide (2) 4-(2-Chloro-4-iodo-phenylamino)-2-fluoro-5-(5-hydroxy-3H-1,2,3-triazol-4-yl)-benzenesulfonamide (3) 2,3-Difluoro-5-(5-hydroxy-3H-1,2,3-triazol-4-yl)-4-(4-iodo-2-methyl-phenylamino)-benzenesulfonamide (4) 4-(2-Chloro-4-iodo-phenyiamino)-2,3-difluoro-5-(5-hydroxy-3H-1,2,3-triazol-yl)-benzenesulfonamide (5) 2-Fluoro-5-(5-hydroxy-3H-1,2,3-triazol-4-yl)-4-(4-iodo-phenylamino)-benzenesulfonamide (6) 2-Fluoro-5-{5-hydroxy-3-[2-(2-methoxy-ethoxy)-ethyl]-3H-1,2,3-triazol-4-yl}-4-(4-iodo-phenylamino)-benzenesulfonamide Group 17 (1) 2-Fluoro-5-(5-hydroxy-3-methyl-3H-1,2,3-triazol-4-yl}-4-(4-iodo-2-methyl-phenylamino)-benzenesulfonamide (2) 4-(2-Chloro-4-iodo-phenylamino)-2-fluoro-5-(5-hydroxy-3H-1,2,3-triazol-4-yl)-benzenesulfonamide (3) 2,3-Difluoro-5-(5-hydroxy-3H-1,2,3-triazol-4-yl)-4-(4-iodo-2-methyl-phenylamino)-benzenesulfonamide (4) 4-(2-Chloro-4-iodo-phenylamino)-2,3-difiuoro-5-(5-hydroxy-3H-1,2,3-triazol-yl)-benzenesulfonamide (5) 2-Fluoro-5-(5-hydroxy-3H-1,2,3-triazol-4-yl)-4-(4-iodo-phenylamino)-benzenesulfonamide (6) 2-Fluoro-5-{5-hydroxy-3-[2-(2-methoxy-ethoxy)-ethyl]-3H-1,2,3-triazol-4-yl}-4-(4-iodo-phenylamino)-benzenesulfonamide Group 18 (1) 2-Fluoro-4-(4-iodo-2-methyl-phenylamino)-5-(5-oxo-4,5-dihydro-tetrazol-1-yl)-benzenesulfonamide (2) 4-(2-Chloro-4-iodo-phenylamino)-2-fluoro-5-(5-oxo-4,5-dihydro-tetrazol-1-yl)-benzenesulfonarnide (3) 2,3-Difluoro-4-(4-iodo-2-methyl-phenylamino)-5-(5-oxo-4,5-dihydro-tetrazol-yl)-benzenesulfonamide (4) 4-(2-Chloro-4-iodo-phenylamino)-2,3-difluoro-5-(5-oxo-4,5-dihydro-tetrazol-yl)-benzenesulfonamide (5) 2-Fluoro-4-(4-iodo-phenylamino)-5-(5-oxo-4,5-dihydro-tetrazol-1-yl)-benzenesulfonamide (6) 2,6-Difluoro-3-(4-iodo-phenylamino)-4-(5-oxo-4,5-dihydro-tetrazol-1-yl)-benzenesulfonamide Group 19 (1) 2-Fluoro-4-(4-iodo-2-methyl-phenylamino)-5-(4-methyl-5-oxo-4,5-dihydro-tetrazol-1-yi)-benzenesulfonamide {2) 4-(2-Chloro-4-iodo-phenylamino)-2-fluoro-5-(4-methyl-5-oxo-4,5-dihydro-tetrazol-1-yl)- benzenesulfonamide (3) 2,3-Difluoro-4-(4-iodo-2-methyl-phenylamino)-5-(5-oxo-4,5-dihydro-tetrazol-yl)-benzenesulfonamide (4) 4-(2-Chloro-4-iodo-phenylarnino)-2,3-difluoro-5-(5-oxo-4,5-dihydro-tetrazol-1-yl)-benzenesulfonamide (5) 5-[4-(2-Dimethylamino-ethyl)-5-oxo-4,5-dihydro-tetrazol-1-ylJ-2-fluoro-4-(4-iodo-phenylamino)-benzenesulfonamide (6) 2-Fluoro-5-(4-iodo-phenylamino)-4-(4-methyl-5-oxo-4,5-dihydro-tetrazol-1-yl)-benzenesulfonamide Group 20 (1) 2-Fluoro-4-(4-iodo-2-methyl-phenylamino)-5-(2-oxo-2,3-dihydro-1,2,3,5-oxathiadiazol-4-yl)~-benzenesulfonamide (2) 4-(2-Chloro-4-iodo-phenylamino)-2-fluoro-5-(2-oxo-2,3-dihydro-1,2,3,5-oxathiadiazol-4-yl)-benzenesulfonamide (3) 2,3-Difluoro-4-(4-iodo-2-methyl-phenylamino)-5-(2-oxo-2,3-dihydro-1,2,3,5-oxathiadiazol-4-yl)--benzenesulfonamide (4) 4-(2-Chloro-4-iodo-phenylamino)-2,3-difluoro-5-(2-oxo-2,3-dihydro-1,2,3,5-oxathiadiazol-4-yi)-~benzenesulfonamide (5) 2-Fluoro-4-(4-iodo-phenylamino)-5-(2-oxo-2,3-dihydro-1,2,3,5-oxathiadiazol-4-yl)-benzenesulfonamide (6) 2-Fluoro-5-(4-iodo-phenylamino)-4-(2-oxo-2,3-dihydro-1,2,3,5-oxathiadiazol-4-yl)-benzenesulfonamide Group 21 (1) 2-Fluoro-4-(4-iodo-2-methyl-phenylamino)-5-(3-methyl-2-oxo-2,3-dihydro-1,2,3,5-oxathiadiazol-4-yl)-benzenesulfonamide (2) 2,6-Difluoro-3-(4-iodo-phenylamino)-4-{3-methyl-2-oxo-2,3-dihydro-1,2,3,5-oxathiadiazol-4.-yl)-benzenesulfonamide (3) 2,3-Difluoro-4-(4-iodo-2-methyl-phenylamino)-5-(3-methyl-2-oxo-2,3-dihydro-1,2,3,5-oxathiadiazoi-4-yl)-benzenesulfonamide (4) 2-Fluoro-4-(4-iodo-phenylamino)-5-(3-methyl-2-oxo-2,3-dihydro-1,2,3,5-oxathiadiazol-4-yl)-benzenesulfonamide (5} 4-(2-Chloro-4-iodo-phenylamino)-2,3-difluoro-5-(3-methyl-2-oxo-2,3-dihydro-1,2,3,5-oxathiadiazol-4-yl)-benzenesuifonamide (6) 4-(2-Chloro-4-iodo-phenylamino)-2-fluoro-N-methyl-5-(3-methyl-2-oxo-2,3-dihydro-1,2,3,5-oxathiadiazol-4-yl)-benzenesulfonamide Group 22 (1) 2-Fluoro-4-(4-iodo-2-methyl-phenylamino)-5-(5-oxo-2,5-dihydro-isoxazol-3-yl)-benzenesulfonarnide (2) 2,6-Difluoro-3-(4-iodo-phenylamino)-4-(5-oxo-2,5-dihydro-isoxazol-3-yl)-benzenesulfonamide (3) 2,3-Difluoro-4-(4-iodo-2-methyl-phenylamino)-5-(5-oxo-2,5-dihydro-isoxazol-3-yl)-benzenesulfonamide (4} 2-Fluoro-4-(4-iodo-phenylamino)-5-(5-oxo-2,5-dihydro-isoxazol-3-yl)-benzenesulfonamide (5) 4-(2-Chloro-4-iodo-phenylamino)-2,3-difluoro-5-(5-oxo-2,5-dihydro-isoxazol-3-yl)-benzenesulfonamide (6) 4-(2-Chloro-4-iodo-phenylamino)-2-fluoro-5-(5-oxo-2,5-dihydro-isoxazol-3-yl)-benzenesuifonamide Group 23 (1) 5-[6-(4-lodo-2-methyl-phenylamino)-1H-benzimidazol-5-yl]-1,3,4-oxadiazol-2-of (2) 5-[6-(4-lodo-phenylamino)-benzofuran-5-yl]-1,3,4-oxadiazol-2-0l (3) 5-[7-Fluoro-6-(4-iodo-2-methyl-phenylamino)-benzoxazol-5-yl]-1,3,4-oxadiazol-2-0l (4) 5-[5-(4-lodo-phenyiamino)-benzofuran-6-yl]-1,3,4-oxadiazol-2-0l (5) 5-[6-(2-Chloro-4-iodo-phenylamino)-7-fluoro-1,3-dihydro-isobenzofuran-5-yl]-1,3,4- oxadiazol-2-0l (6) 5-[6-(2-Chloro-4-iodo-phenylamino)-1-methyl-1 H-benzimidazol-5-yl]-1,3,4-oxadiazol-2-0l Group 24 (1 ) 5-[2-Amino-6-(4-iodo-2-methyl-phenylamino)-1 H-benzimidazol-5-yl]-1,3,4-oxadiazol-2-0l (2) 5-[6-(4-lodo-phenylamino)-benzo[b]thiophen-5-yl]-1,3,4-oxadiazol-2-0l (3) 5-[7-Fluoro-6-(4-iodo-2-methyl-phenylamino)-benzothiazol-5-yl]-1,3,4-oxadiazol-2-0l (4) 5-[5-(4-lodo-phenylamino)-benzo[b]thiophen-6-yl]-1,3,4-oxadiazol-2-0l (5) 5-(6-(2-Chloro-4-iodo-phenylamino)-7-fluoro-1,3-dihydro-benzo[c]thiaphen-5-yl]-1,3,4-oxadiazol-2-0l (6) 5-[6-{2-Chloro-4-iodo-phenylamino)-2-oxo-2,3-dihydro-1H-2$I>4=2,1,3-benzothiadiazol-5-yl]-1, 3,4-oxadiazol-2-0l Group 25 (1) 5-[2-Amino-6-(4-iodo-2-methyl-phenyiamino)-benzothiazol-5-yl]-1,3,4-oxadiazol-2-0l (2) 5-[6-(4-lodo-phenylamino)-1H-indol-5-yl]-1,3,4-oxadiazol-2-0l (3) 5-[7-Fluoro-6-(4-iodo-2-methyl-phenylamino)-benzothiazol-5-yl]-1,3,4-oxadiazol-2-0l (4) 5-[5-(4-lodo-phenylamino)-1H-indol-6-yl]-1,3,4-oxadiazol-2-0l (5) 5-[6-(2-Chloro-4-iodo-phenylamino)-7-fluoro-2,3-dihydro-1 H-isoindol-5-yl]-1,3,4- oxadiazol-2-0l (6) 5-[5-(2-Chloro-4-iodo-phenylamino)-1 H-indazol-6-yl]-1,3,4-oxadiazol-2-0l Group 26 (1) 5-[2-Amino-6-(4-iodo-2-methyl-phenylamino)-benzothiazol-5-yl]-1,3,4-oxadiazol-2-0l (2) 5-[6-(4-lodo-phenylamino)-1H-indol-5-yl]-1,3,4-oxadiazoi-2-of (3) 5-[7-Fluoro-6-(4-iodo-2-methyl-phenylamino)-benzoxazol-5-yl]-1,3,4-oxadiazol-2-0l (4) 5-[5-(4-lodo-phenylamino)-benzoxazol-6-ylj-1,3,4-oxadiazol-2-0l (5) 5-[6-(2-Chloro-4-iodo-phenylamino)-7-fluoro-2,3-dihydro-1 H-isoindol-5-yl]-1,3,4- oxadiazol-2-0l {6) 5-[5-(2-Chloro-4-iodo-phenylamino)-1 H-indazol-6-yl]-1,3,4-oxadiazol-2-0l C. Synthesis The disclosed compounds can be synthesized according to Schemes 1-25 or analogous variants thereof. These synthetic strategies are further exemplified in Examples 1-8 below. The solvent between compounds 4 and 5 in Scheme 1 is toluene (PhMe).
W O' 00/42029 PCTNS99/304 Z 6 Scheme 1 N~OH \ O
''~H ~( H'N.N O H R4 O N~ O R % ~H~N O
H a H R
I \ N I \ CI~~I \ N \ DMF \ N \
R~ / R3 / I PhCI ~ Ri I / R3 I / I R I / R I / I
t 3 Rz R_, R
I ~ 2 3 os.cH3 ~a0~
HO
N~ 00 ,= N
N~ O N~ O
H Ra H R4 I \ N I \ I \ N I \
/ /
R~ R3 I Ri / R3 / 1 R2 6 R: 5 HO~ NHZ
a Pn/e N~O~NHZ
R N3~N O
H H a I \ ( \ O I \ N I \
/ /
R~ R3 1 R~ / R3 / 1 Rz R2 Ph ~ N-'OH
N . N S N ~~S
H H R4 H Rq \ N \ c;onc.HCl \ N \
R I / R I / 1 EtOH R' I / R I / I
R~ RZ
Scheme 2 N~OH
Ph~O NH Ra O N ~~'~(NH R
\ N \ HzN_ _N~NHz \
Fl R, ~ / R3 ~ / I Pyridine R~ ~ / R3 ~ / I
Rz Rz 1~ I1 OH N~OH
CI N H Ra N ~~NH Ra N ~ \ K_N=S=O H
\ N ~ \
/ Et3N/Ph R~ R3 I Ri / R / 1 Rz Rz Ph o Ho N -N
O~S \ Ra ~ NH
R
N \ H2NNH2 \ N \
/ I / EtOH
Ri R3 I Ri ~ / Rs ~ / 1 Rz R2 HO O
~ O ~ O
H Ra SOCK / I OCH3 LDA ~ ( N I \
R3 HzN' vOlj R~ \ R3 Ra R~ \ R3 Rz ~ Rz 16 17 ~ I 18 Scheme 3 O N'/OEt z ~ . N N ~ ~~ 1.SOCI C OH
H N H \ F 1. ACONa/BI'Z 2 I \ ~ ' \ r/AcOH~ I \ F 2. KSCN_ t R, / R, R, / R, 2. KOH. EtOH R~ / Rl 3. EtOH R, / R3 Rz Rz Rz 4. NHZNHZ Rz HCI
. NHz HzN ~ N
H
H N~OH R' N/OH
HO o ,N a N., NH ~ Nv~NH
HzN N HzN
H I \ H Ra \ F NaOH \ F ~ t \ N \
R, R3 R, / Rl HzO Ri / R3 LDA R~ / R3 /
Rz Rz Rz Rz 1. HC1/ HZO
NHzNHz 2. NaOH/Hz0 PyBOP H
H N~N O
z \ F HOCN
/ + NHs R, R3 Rz Scheme 4 OH ~OH
;'I N
HzN , h O O N ~ O H,N I R~ ~ O H R
~ a \ F CI"CI \ F I \ N
/
R, R3 R~ R~ LDA R~ I / R3 I / 1 Rz Rz Rz S
CI ~CI PCIS/POC13 1. PCIS/POC13 ~SH ~. CI
O N 2, HO~NHz O
a \ F \ F
R~ R3 R ~~R3 Rz Itz HO~ NHz 1. CH3I
a 2. KMn04 O' ~
N~ S O N~O~ NHz HO~NHZ N
O
F a H R
\ \ N \
I/
R~ R3 Ri / R3 / 1 Rz Rz Scheme 5 N~OH R N~OH
'''~ 4 CH3 H O ~ S HzN w N ~ S R
\ F Ph'N~N~OEt \ F I i I N
H I \ \
R, ~ R3 Lawesson's reagent R~ ~ R3 LDA R~ I ~ R3 I ~ i Rz Rz Rz 0 o HS S O HO' vS S O'' Ph~N~N.N S
\ F HO' v Br F Ph.N~N.NHz H H F
H H ~ \
R, I ~ R3 piperidine/acetone I ~
Ri R3 R~ R3 Rz R2 Rz N~oH N~oH
RQ
N ~ S FizN~ N \ S R
H °
conc. HC1 \ F ~ ( \ N \
-->i EtOH R~ I ~ R3 . LDA R~ ' ~ R3 I
Rz Rz Scheme 6 F
~a ..
LHMDS
R1 ~ ~R3 R1 ~ R3 I
N~ O
(~)(COCi)2 R4 ----~ , a (2) HZN~~~OH R1 ~R3 (3) SOCIZ
Scheme 7 F
\ ~~ , \ a \
R1 I / R3 LHMDS R1 I / R3 I / i O
,a O
H N ~ a ~ O R4 CZH ~ R4 a CICOZC2H6 ~ a NHZNHZ,PY-BOP
\ --~ ~ \ ~ \
r~ / / /
R1 R3 I R1 ~ 'R3 I
R~ R2 OH
N-(~
Poci, N O
--~ \ R4 \ -a \
R1 ~ R3 I
Scheme 8 F I, ~ ~ a O
~ ,a O
H N~a O R4 CZH5 \ R4 a ~I~OZ~2Hs a a NHZNHZ,PY-BOP
R1 I ~ ~R3 I ~ 1 R1 ~ R3 r 'I
Lawesson's Reagent Lawesson's Reagent Xylene Toluene SH OH
N~ N-N~ S N~ S
~,.a ~ ~ a R1 I ~ ~~R3 I ~ 1 R1 , ~ R3 I ~ I
Scheme 9 COOH HzN COOH R4 F
~~ -~.. ~ ~ y R1 ~ R3 ~HMDS R1 ~ R3 ~i NHZ
S N
O N~ S
(~)ICOCI)~ HZN ~ R4 ~H'I ~ R4 (2) NHZNHC(S) H
R1 ~ I ~ R3 I v \I R1 ~ R3 / 1 NaOCH~ICH~OH
Reflux SH
N
N ~ NH
R1 ~ R3 ~ I
Scheme 10 COOH HzN \ COOHH R4 F ~I ~ \ N I \
R1 ~r R3 LHMDS ~R1 / R3 / I
NHZ
N-HZN~~ O R4 c , N ~ O R4 NH2NHZ t3rCNINaH O~(aq ) py.gp~ \ ~ \ Dioxane, r.t. \ ~ \
R1 ~ ~ R3 / I 1 I / R3 R
1 )CSi, KOH
2)HCI
SH
N
N .~ O
\ .a \
R1 I / ~R3 I / I
Scheme 11 HiN
\ ~F ~ , \ ~ \
R1 ( ~ \~R3 LHMDS R1 I ~ R3 I ~ I
NHZ
N
COOCH 3 R4 N ~ N H
CH30H/HZS04 N aminoguanidine nitrate R4 -~- I \ I \ NaOCH~ICHzOH \ ~ \
R1 ~ R3 / I
R1 I ~ R3 I / I
S
MeNH--~ NHZ
MeNCS
\a \
R1 ~ ~R3 ~ I
Scheme 12 C~2C2H5 F (1)PPh3,CBr4 ~ F
R1 I / R3 (2)n-BuLi, then CICOZCZHsR1 R3 ~ ~..COZCZHS HO
_.N
/ R4 ~ NHCH3 LHMDS ~ ~-~ .~ _ H2N ~ R1 / °R3 / I
R1 / R / 'I
Scheme 13 COOH HsN COOH R4 \ .F I ~ \ b \
I
--~. / /
R1 / 'R3 LHMDS R1 R3 I
CH OH R4 CHZBr R4 CHZCN R4 ~H~ \ ~ Bromination \ ~ \ ~ \ ~ \
--/ I ~~ R1 / R3 / I R1 I / R3 I / I
R1 ~ 'R3 I
N-S
NC CSZNa R4 HO / SO3N R4 NaH,CS2 \ ~ \ excess H202 \ ~ \
HCONMe2 ~ / ~ / ~ /
R1 ~ 'R3 1 R1 ~ ~R3 I
N-S
~H'~ HO / /
\ \
R1 I / ~R3 I / I
Scheme 14 COOH O COOH
/
\ F i j.- \ KI \ f0~ ~ / ~ /
R1 / R3 t_HMDS
O COSCZHS O~H -O
R4 BFI H \ SC H R4 eth erate H z 5.
\ I ~~ ~ \ N \
R1' / R3 "I R1 I / R3 I / I
R
~N-N
O ~ OH R4 NH2NHz R4 Alkalation ~"' \ ~ \ --~ \ ~ \
Scheme 15 II 2 \
\ F I, \ a \
__ I
R1 , ~ R3 LHMDS~R1 I ~ R3 I ~ I
OH
N-' a R4 NH2NHZ,EtOH N \ R4 _ ~.. \
\a \
i R1 ~ R3 I R1 / R3 / i NHZNHCH"EtOH
OH
N
i N;~
,a \
R1 ~R3 I
Scheme 16 \ F z I \ N
\ \
R1 ~ / R3 LHMDS R1 I / R3 I / I
Et00C Br CHLCOOEt R4 R4 1 ~LDA \ ~ \
\ ~ \
I /~ ~ / 2~Br~1 / R3 / 1 R1 ~ R3 I
NHz EtOOC N~ EtOOC N=N~ R4 NaNzJDMF Hz > , \ _..~. \ a \
R
_N .N_N
O ~N alkylation HO ~ \N
R4 -~ R4 --->
\ ~ \ \ ~ \
R1 ~ ~R3 I R1 ~ ~R3 I
alkylation N=N
HO \ N--R
\ .~ \
R1 I /~.R3 I ~I
Scheme 17 \ F
\a \
R1 ( ~ R3 ~HMns R1 ~ ~R3 I
O
OH ~S-O
I /
NHzOH.HCI HZN ~ N R4 HN i N R4 NaOCH~/CH~OH \ a \ SOCIZ/Et~N
--\ \
R1 I ~ R3 l r I
R1 ~ ~R3 I
O
w S-O
alkylation R~'~N ~.~N R4 e~ a \
R1 ~~ R3 ~ I
Scheme 18 \ F
i i \ ~ \
R1 ~R3 ~HMDS R1 ~R3 ~I
OH
N
H N~~ O R4 N ~ NH R4 UreaIKOHIEtOH a NH2NHZ~PY-BOP ~ \ -' \
\ a \_ R1 I ~ R3 I ~ 1 R1 'R3 I
R6NCO/NaOHJH20 OH
N-N ~rN''R5 R4 ~, a a \
R1 ~~ R3 / I
Scheme 19 J.
I ~. a R1 ~ R3 ~HMDS R1 ~ R3 ~ I
O
OH
HZN ~ i N NJ N
NHzOH.HCI R4 CICOOC2H6 ~ R4 NaOCH~lCH30H pyridine w I w -----~ w a w R1 ~~R3 / I R1 I ~ R3 I / I
Scheme 20 p / '~CO2C2H5 COZCsHs \ F (1)PPh~,CBr, F LHMDS
\ ~\ a~\
(2)n-BuLi, R1 R3 then CICOzCZH5R1 ~ ~R3 H=N \ R1 ~ R3 / 1 i R2 HO
_N
O
NHi~I ~ a R4 CHZN~/~
R1 ~ ~ R3 ~ I
Me0 Me0 1)n-BuLiITHF -N 1)DPPAIEt~N
2)COs 1 2)TMS(CHz)ZOH '-N
3)H~O~ HOOC ~ ~O R4 3)n-Bu4NFITHF HZN ~ O
a a R1 ~ R3 ~ I R1 ~ R3 ~ I
HO
~N
HzN.,- \ O
HBrIHOAc R4 ,a R1 I ~ R3 I ~~I
Scheme 21 . /~ ~ /
R1 ~ R3 LHMDS R1 ~ R3 / I
N~~ N
EtO2C ~ O R4 HzNHNOC ~ O R4 NHiNHZ,EtOH
(1)(COCI)2 __ (2)CNCHZCOiC2H
Et~NITHF R1 ~ ~R3 / I R1 R3 / I
HO
_: N
~ NH
HCllreflux HEN ~ R4 /
R1 ~ R3 ~I
Scheme 22 NOz HZN \ NOZ R4 NHZ R4 F
( \ ~ / I \ a \ IH1 \ a \
LHMDS R1 ~ / R3 ( / I R1 / R3 / I
O
'H
N5 a R4 _ N~N~N R4 CHZ=CHI
w \a \
R1 ~ R3 I R1 R3 / I
N
N ~ N
'N 'OH R4 ~N OH R4 .\a \ \a \
R1 ~ / R3 I / 1 R1 ~ / R3 / t Alternate synthesis: OH(TMS) ii ii N R4 OH TMS N ~OH(TMS) N
HC -~ ~ ~ N R4 N R4 a \ I \ ~~ +
\a \ \a~ \
/ /
Scheme 23 N02 HzN \ N02 ~ R4 NHi R4 \ F ~ \ ~ \
y \ \ ~H~
R1 I / R3 LHMDS R1 I ~ R3 I ~ I R1 ~ R3 / ~I
N-N
N ~~ \
N~ s R4 N~N~ R4 HC/OEt)3, NaN3 \
R1 ~ ~ ~ R3 ~ 1 R1 ~ R3 / t N-N
~t~ _ N N \
12, KMnO"H2SOd N'N~I R4 ArOH,KZCO, ~N~OAr R4 R1 ~~ ~ R3 I ~ I R1 ~ R3 / t RS
~ N ~O
NaHsPO~IPd-C ~N~O R4 Alkylation ~N R4 w \ ~ ~ \
!''~R3 I ~ I R1 ~ R3 / I
Scheme 24 \ .F ~ , \ a \
i i R1 ~ R3 LHMDS R1 / R3 / I
O
HO ~ N
KCN/(NH4)ZCO~INH4Ci EtOHIH20 \ a \
Alternate Sythesis: NH
O
CHO HO ~ N
KCNI(NH4)ZC031NH4C1 EtOH/Hz0 R1 ~ R3 R~, R1 ~ R3 NHZ
HZN
HO ~ N R4 I
\a LHMDS
R1 ~ ~R3 I
Scheme 25 COOH H2N \ COOHH R4 ~ ~ \ N \
I ~ LHMDS
R1 ~ ~ R3 R1 ~ ~ R3 1 COOH O
C N~ O
O ~NH R4 H N~COOH R4 DMF/SOCl2 \a a 1 .\ t \ y R1 ~~ R3 ~ ~ R1 ~ ~R3 D. Uses The disclosed compositions are useful as both prophylactic and therapeutic treatments for diseases or conditions as provided in the Summary section, as well as diseases or conditions modulated by the MEK cascade.
Examples include stroke, heart failure, osteoarthritis, rheumatoid arthritis, organ transplant rejection, and a variety of tumors such as ovarian, lung, pancreatic, brain, prostatic, and colorectal.
1. Dosages Those skilled in the art will be able to determine, according to known methods, the appropriate dosage for a patient, taking into account factors such as age, weight, general health, the type of pain requiring treatment, and the presence of other medications. In general, an effective amount will be between 0.1 and 1000 mglkg per day, preferably between 1 and 300 mg/kg body weight, and daily dosages will be between 10 and 5000 mg for an adult subject of normal weight. Commercially available capsules or other formulations (such as liquids and film-coated tablets) of 100 mg, 200 mg, 300 mg, or 400 mg can be administered according to the disclosed methods.
2. Formulations Dosage unit forms include tablets, capsules, pills, powders, granules, aqueous and nonaqueous oral solutions and suspensions, and parenteral solutions packaged in containers adapted for subdivision into individual doses.
Dosage unit forms can also be adapted for various methods of administration, including controlled release formulations, such as subcutaneous implants.
Administration methods include oral, rectal, parenteral (intravenous, intramuscular, subcutaneous), intracisternal, intravaginal, intraperitoneal, intravesical, local (drops, powders, ointments, gels, or cream), and by inhalation (a buccal or nasal spray).
Parenteral formulations include pharmaceutically acceptable aqueous or nonaqueous solutions, dispersion, suspensions, emulsions, and sterile powders for the preparation thereof. Examples of carriers include water, ethanol, polyols (propylene glycol, polyethylene glycol), vegetable oils, and injectable organic esters such as ethyl oleate~. Fluidity can be maintained by the use of a coating such as lecithin, a surfactant, or maintaining appropriate particle size.
Carriers for solid dosage forms include (a) fillers or extenders, (b) binders, (c) humectants, (d) disintegrating agents, (e) solution retarders, (f) absorption acccelerators, (g) adsorbants, (h) lubricants, (i) buffering agents, and (j) propellants.
Compositions may also contain adjuvants such as preserving, wetting, emulsifying, and dispensing agents; antimicrobial agents such as parabens, chlorobutanol, phenol, and sorbic acid; isotonic agents such as a sugar or sodium chloride; absorption-prolonging agents such as aluminum monostearate and gelatin; and absorption-enhancing agents.
3. Related compounds The invention provides the disclosed compounds and closely related, pharmaceutically acceptable forms of the disclosed compounds, such as salts, esters, amides, hydrates or solvated forms thereof; masked or protected forms;
and racemic mixtures, or enantiomerically or optically pure forms.
Pharmaceutically acceptable salts, esters, and amides include carboxylate salts (e.g., C ~_8 alkyl, cycloalkyl, aryl, heteroaryl, or non-aromatic heterocyclic), amino acid addition salts, esters, and amides which are within a reasonable benefit/risk ratio, pharmacologically effective, and suitable for contact with the tissues of patients without undue toxicity, irritation, or allergic response.
Representative salts include hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactiobionate, and laurylsulfonate. These may include alkali metal and alkali earth cations such as sodium, potassium, calcium, and magnesium, as well as non-toxic ammonium, quaternary ammonium, and amine cations such as tetramethyl ammonium, methylamine, trimethylamine, and ethyiamine. See, for example, S.M. Berge, et al., "Pharmaceutical Salts," J. Pharm. Sci., 1977, 66:1-19 which is incorporated herein by reference. Representative pharmaceutically acceptable amides of the invention include those derived from ammonia, primary C ~_6 alkyl amines and secondary di (C ,_6 alkyl) amines. Secondary amines include 5- or 6-membered heterocyclic or heteroaromatic ring moieties containing at least one nitrogen atom and optionally between 1 and 2 additional heteroatoms. Preferred amides are derived from ammonia, C ,_3 alkyl primary amines, and di (C ~_2 alkyl)amines.
Representative pharmaceutically acceptable esters of the invention include C ~_~ alkyl, C 5_7 cycloalkyl, phenyl, and phenyl(C ,_s)alkyl esters.
Preferred esters include methyl esters.
The invention also includes disclosed compounds having one or more functional groups (e.g., hydroxyl, amino, or carboxyl) masked by a protecting group. Some of these masked or protected compounds are pharmaceutically acceptable; others will be useful as intermediates. Synthetic intermediates and processes disclosed herein, and minor modifications thereof, are also within the scope of the invention.
HYDROXYL PROTECTING GROUPS
Hydroxyl protecting groups include: ethers, esters, and protection for 1,2-and 1,3-diols. The ether protecting groups include: methyl, substituted methyl ethers, substituted ethyl ethers, substituted benzyl ethers, silyl ethers and conversion of silyl ethers to other functional groups.
Substituted Methyl Ethers Substituted methyl ethers include: methoxymethyl, methylthiomethyl, t-utylthiomethyl, (phenyldimethylsilyl) methoxymethyl, benzyloxymethyl, p-ethoxybenzyloxymethyl, (4-methoxyphenoxy) methyl, guaiacolmethyl, t-butoxymethyl, 4-pentenyloxymethyl, siloxymethyl, 2-methoxyethoxymethyl, 2,2,2-trichloroethoxymethyl, bis(2-chloro- ethoxy)methyl, 2-(trimethylsilyl)ethoxymethyl, tetrahydropyranyl, 3-bromotetrahydro-pyranyl, tetrahydrothiopyranyl, 1-methoxycyclohexyl, 4-methoxytetrahydropyranyl, 4-methoxytetrahydrothio-pyranyl, 4-methoxytetrahydrothiopyranyl S,S-dioxido, 1-[(2-chioro-4-methyl)phenyl]-4-methoxypiperidin-4-yl, 1,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl, and 2,3,3a,4,5,6,7,7a-octahydro-7,8,8-trimethyl-4,7-ethanobenzofuran-2-yl.
Substituted Ethyl Ethers Substituted ethyl ethers include: 1-ethoxyethyl, 1-(2,chloroethoxy)ethyl, 1-methyl-1-methoxyethyl, 1-methyl-1-benzyloxyethyl, 1-methyl-1-benzyloxy-2-fluoroethyl, 2,2,2-trichloroethyl, 2-trimethylsilyethyl, 2-(phenylselenyl)ethyl, t-butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2,4-dinitrophenyl, and benzyl.
Substituted Benzyl Ethers Substituted benzyl ethers include: p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl, p-phenylbenzyl, 2- and 4-picolyl, 3-methyl-2-picolyl N-oxido, diphenylmethyl, p, p'-dinitrobenzhydryl, 5-dibenzosuberyl, triphenylmethyl, a-naphthyldiphenyl-methyl, p-methoxyphenyldiphenylmethyl, di(p-methoxyphenyl)phenylmethyl, tri-(p-methoxyphenyl)methyl, 4-(4'-bromophenacyloxy)phenyldiphenylmethyl, 4,4',4"-tris(4,5-dichlorophthalimidophenyl)methyl, 4,4',4"-tris(levulinoyloxyphenyl) methyl, 4,4',4"tris(benzoyloxyphenyl)methyi, 3-(imidazol-1-ylmethyl)bis(4',4"-dimethoxyphenyl)-methyl, 1,1-bis(4-methoxyphenyl)-1'-pyrenylmethyl, 9-anthryl, 9-(9-phenyl) xanthenyl, 9-(9-phenyl-10-oxo) anthryl, 1,3-benzodithiolan-2-yl, and benzisothiazolyl S,S-dioxido.
Silyl Ethers Silyl ethers include: trimethylsilyl, triethylsilyl, triisopropylsilyl, dimethylisopropylsilyl, diethylisopropylsilyl, dimethylthexylsilyl, t-butyldimethylsilyl, t-butyldiphenyisilyl, tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl, diphenylmethylsilyl, and t-butylmethoxyphenylsilyl.
ESTERS
Esters protecting groups include: esters, carbonates, assisted cleavage, miscellaneous esters, and sulfonates.
Esters Examples of protective esters include: formate, benzoylformate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, phenoxyacetate, p-chlorophenoxyacetate, p-P-phenylacetate, 3-phenylpropionate, 4-oxopentanoate (levulinate), 4,4-(ethylenedithio) pentanoate, pivaloate, adamantoate,crotonate,4-methoxycrotonate, benzoate, p-phenylbenzoate, and 2,4,6-trimethylbenzoate (mesitoate).
Carbonates Carbonates include: methyl, 9-fluorenylmethyl, ethyl, 2,2,2-trichloroethyl, 2-(trimethylsilyl) ethyl, 2-(phenyisulfonyl) ethyl, 2-(triphenylphosphonio) ethyl, isobutyl, vinyl, allyl, p-nitrophenyl, benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, S-benzyl thiocarbonate, 4-ethoxy-1-naphthyl, and methyl dithiocarbonate.
Assisted Cleavage Examples of assisted cleavage protecting groups include: 2-iodobenzoate, 4-azido-butyrate, 4-nitro-4-methylpentanoate, o-(dibromomethyl) benzoate, 2-formylbenzene-sulfonate, 2-(methylthiornethoxy) ethyl carbonate, 4-(methylthiomethoxymethyl) benzoate, and 2-(methylthiomethoxymethyl) benzoate.
Miscellaneous Esters In addition to the above classes, miscellaneous esters include: 2,6-dichloro-4-methylphenoxyacetate, 2,6-dichloro-4-(1,1,3,3-tetramethylbutyl) phenoxyacetate, 2,4-bis(1,1-dimethylpropyl) phenoxyacetate, chlorodiphenylacetate, isobutyrate, monosuccinoate, (~-2-methyl-2-butenoate (tigloate), o-(methoxycarbonyl) benzoate, p-P-benzoate, a-naphthoate, nitrate, alkyl N,N,N' N'-tetramethylphosphorodiamidate, N-phenylcarbamate, borate, dimethylphosphinothioyl, and 2,4-dinitrophenylsulfenate.
Sulfonates Protective sulfates includes: sulfate, methanesulfonate(mesylate), benzylsulfonate, and tosylate.
PROTECTION FOR 1.2- AND 1,3-DIOLS
The protection for 1,2 and 1,3-diols group includes: cyclic acetals and ketals, cyclic ortho esters, and silyl derivatives.
Cyclic Acetals and ICetals Cyclic acetals and ketals include: methylene, ethylidene, 1-t-butylethylidene, 1-phenylethylidene, (4-methoxyphenyl) ethylidene, 2,2,2-trichloroethylidene, acetonide (isopropylidene), cyclopentylidene, cyclohexylidene, cycloheptylidene, benzylidene, p-methoxybenzylidene, 2,4-dimethoxybenzylidene, 3,4-dimethoxybenzylidene, and 2-nitrobenzylidene.
C rLclic Ortho Esters Cyclic ortho esters include: rnethoxymethylene, ethoxymethylene, dimethoxy-methylene, 1-methoxyethylidene, 1-ethoxyethylidine, 1,2-dimethoxyethylidene, a-methoxybenzylidene, 1-(N,N-dimethylamino)ethylidene derivative, a-(N,N-dimethylamino) benzylidene derivative, and 2-oxacyclopentylidene.
PROTECTION FOR THE CARBOXYL GROUP
ESTERS
Ester protecting groups include: esters, substituted methyl esters, 2-substituted ethyl esters, substituted benzy) esters, silyl esters, activated esters, miscellaneous derivatives, and stannyl esters.
Substituted Methyl Esters Substituted methyl esters include: 9-fluorenylmethyl, methoxymethyl, methylthiomethyl, tetrahydropyranyl, tetrahydrofuranyl, methoxyethoxymethyl, 2-(trimethylsilyl)ethoxy-methyl, benzyloxymethyl, phenacyl, p-bromophenacyl, a-methylphenacyl, p-methoxyphenacyl, carboxamidomethyl, and N-phthalimidomethyl.
2-Substituted Ethyl Esters 2-Substituted ethyl esters include: 2,2,2-trichloroethyl, 2-haloethyl, ~-chloroalkyl, 2-{trimethylsily)ethyl, 2-methylthioethyl, 1,3-dithianyl-2-methyl, 2(p-nitrophenylsulfenyl)-ethyl, 2-(p-toluenesulfonyl)ethyl, 2-{2'-pyridyl)ethyl, 2-(diphenylphosphino)ethyi, 1-methyl-1-phenylethyl, f-butyl, cyclopentyl, cyclohexyl, allyl, 3-buten-1-yl, 4-(trimethylsily)-2-buten-1-yl, cinnamyl, a-methylcinnamyl phenyl, p-(methylmercapto)-phenyl, and benzyl.
Substituted Benzyl Esters Substituted benzyl esters include: triphenylmethyl, diphenylmethyl, bis(o-nitrophenyl)methyl, 9-anthrylmethyl, 2-(9,10-dioxo)anthrylmethyl, 5-dibenzo-suberyl, 1-pyrenylmethyf,2-{trifiuoromethyl)-6-chromylmethyl, 2,4,fi-trimethylbenzyl, p-bromobenzyl, o-nitrobenzyl, p-nitrobenzyl, p-methoxybenzyl, 2,6-dimethoxybenzyl, 4-(methylsulfinyl)benzyl, 4-sulfobenzyl, piperonyl, and 4-P-benzyl.
Silyl Esters Silyl esters include: trimethylsilyl, triethylsilyl, t butyldimethylsilyl, i-propyldimethyfsilyl, phenyldimethylsilyl, and di- t-butylmethylsilyl.
Miscellaneous Derivatives Miscellaneous derivatives includes: oxazofes, 2-alkyl-1,3-oxazolines, 4-alkyl-oxo-1,3-oxazolidines, 5-alkyl-4-oxo-1,3-dioxolanes, ortho esters, phenyl group, and pentaaminocobalt(III) complex.
Stannyl Esters Examples of stannyl esters include: triethylstannyl and tri-n-butylstannyl.
AMIDES AND HYDRAZIDES
Amides include: N,N -dimethyl, pyrrolidinyl, piperidinyl, 5,6-dihydrophenanthridinyl, o-nitroanilides, N-7-nitroindolyl, N-8-nitro-1,2,3,4-tetrahydroquinolyl, and p-P-benzenesulfonamides. Hydrazides include: N-phenyl, N,N'-diisopropyl and other dialkyl hydrazides.
PROTECTION FOR THE AMINO GROUP
CARBAMATES
Carbamates include: carbamates, substituted ethyl, assisted cleavage, photolytic cleavage, urea-type derivatives, and miscellaneous carbamates.
Carbamates Carbamates include: methyl and ethyl, 9-fluorenylmethyl, 9-(2-sulfo)fluorenylmethyl, 9-(2,7-dibromo)fluorenylmethyl, 2,7-di-t-butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydro- thioxanthyl)]methyl, and 4-methoxyphenacyl.
Substituted Ethyl Substituted ethyl protective groups include: 2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2-phenylethyl, 1-(1-adamantyl)-1-methylethyl, 1,1-dimethyl-2-haloethyl, 1,1dimethyl-2,2-dibromoethyl, 1,1-dimethyl-2,2,2-trichloroethyl, 1-methyl-1-(4-biphenylyl)ethyl, 1-(3,5-di-t-butylphenyl)-1-methylethyl, 2-(2'-and 4'-pyridyl)ethyl, 2-(N,N-icyclohexylcarboxamido)- ethyl, t-butyl, 1-adamantyl, vinyl, allyl, 1-isopropylallyl, connamyl, 4-nitrocinnamyl, quinolyl, N-hydroxypiperidinyl, alkyldithio, benzyl, p-methaxybenzyl, p-nitrobenzyl, p-bromobenzyl, p-chlorobenzyl, 2,4dichlorobenzyl, 4-methylsulfinylbenzyl, 9-anthrylmethyl, and diphenylmethyl.
Assisted Cleavage Protection via assisted cleavage includes: 2-methylthioethyl, 2-methylsulfonylethyl, 2-(p-toluenesulfonyl)ethyl, [2-(1,3-dithianyl)]methyl, 4-methylthiophenyl, 2,4-dimethyl-thiophenyl, 2-phosphonioethyl, 2-triphenylphosphonioisopropyl, 1,1-dimethyl-2cyanoethyl, m-chloro-p-acyloxybenzyl, p-(dihydroxyboryl)benzyl, 5-benzisoxazolyl-methyl, and 2-(trifluoromethyi)-6-chromonylmethyl.
Photola~tic Cleavage Photolytic cleavage methods use groups such as: m-nitrophenyl, 3,5-dimethoxybenzyl, o-nitrobenzyl, 3,4-dimethoxy-6-nitrobenzyl, and phenyl(o-nitrophenyl)methyl.
Urea-Type Derivatives Examples of of urea-type derivatives include: phenothiazinyl-(10)-carbonyl derivative, N'-p-toluenesulfonylaminocarbonyl, and N'-phenylaminothiocarbonyl.
Miscellaneous Carbamates In addition to the above, miscellaneous carbamates include: t-amyl, S-benzyl thiocarbamate, p-cyanobenzyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclopropylmethyl, p-decyioxy-benzyl, diisopropylmethyl, 2,2-dimethoxycarbonylvinyl, o-(N,N-dimethyl-carboxamido)-benzyl, 1,1-dimethyl-3(N,N-dimethylcarboxamido)propyl, 1,1-dimethyl-propynyl, di(2-pyridyl)methyl, 2-furanylmethyl, 2-iodoethyl, isobornyl, isobutyl, isonicotinyl, p{p'-methoxyphenyl-azo)benzyl, 1-methylcyclobutyl, 1-methylcyclohexyl, 1-methyl-1-cycfopropyl-methyl, 1-methyl-(3,5-dimethoxyphenyl)ethyl, 1-methyl-1 (p-henylazophenyl)-ethyl, 1-methyl-1-phenylethyl, 1-methyl-1-(4-pyridyl)ethyl, phenyl, p-(phenylazo)benzyl, 2,4,6-tri-t-butylphenyl, 4-(trimethylammonium) benzyl, and 2,4,6-trimethylbenzyl.
AMIDES
Amides Amides includes: N-formyl, N-acetyl, N-chloroacetyl, N-trichloroacetyl, N-trifluoroacetyl, N-phenylacetyl, N-3-phenylpropionyl, N-picolinoyl, N-3-pyridyl-carboxamide, N-benzoylphenylalanyl derivative, N-benzoyl, and N-p-phenylbenzoyl.
Assisted Cleavage Assisted cleavage groups include: N-o-nitrophenylacetyl, N-o-nitrophenoxyacetyl, N-acetoacetyl, (N~dithiobenzylaxycarbonyfamino)acetyl, N-3-(p-hydroxphenyl) propionyl" N-3-(o-nitrophenyl)propionyl, N-2-methyl-2-(0-nitrophenoxy)propionyl, N 2-methyl-2-(o-phenylazophenoxy)propionyl, N-4-chlorobutyryl, N-3-methyl-3-nitrobutyryl, N-o-nitrocinnamoyl, N-acetylmethionine derivative, N o-nitrobenzoyl, N-o-(benzoyloxymethyl)benzoyl, and 4,5-Biphenyl-oxazolin-2-one.
Cyclic Imide Derivatives Cyclic imide derivatives include: N-phthalimide, N-dithiasuccinoyl, N-2,3-Biphenyl-maleoyl, N-2,5-dimethylpyrrolyl, N-1,1,4,4-tetramethyldisilylazacyclopentane adduct, 5-substituted 1,3-dimethyl-1,3,5-triazacyclohexan-2-one, 5-substituted 1,3-dibenzyl-1,3,5-triazacyclohexan-2-one, and 1-substituted 3,5-dinitro-4-pyridonyl.
SPECIAL -NH PROTECTIVE GROUPS
Protective groups for - NI-I include: N-alkyl and N-aryl amines, imine derivatives, enamine derivatives, and N-hetero atom derivatives {such as N-metal, N-N, N-P, N-Si, and N-S), N-sulfenyl, and N-sulfonyl.
N-Alkvl and N-Aryl Amines N-alkyl and N-aryl amines include: N-methyl, N-allyl, N-[2-(trimethylsilyl)ethoxyl]-methyl, N-3-acetoxypropyl, N-(1-isopropyl-4-nitro-2-oxo-3-pyrrolin-3-yl), quaternary ammonium salts, N-benzyl, N-di(4-methoxyphenyl)methyl, N-5-dibenzosuberyl, N-triphenylmethyl, N-(4-methoxyphenyl)diphenylmethyl, N-9-phenylfluorenyl, N-2,7-dichloro-9-fluorenylmethylene, N-ferrocenylmethyl, and N-2-picolylamine N '-oxide.
Imine Derivatives (mine derivatives include: N 1,1-dimethylthiomethylene, N benzylidene, N-p-methoxybenzylidene, X11 diphenylmethylene, N-[(2-pyridyl)mesityljmethylene, N-(N',N'-dimethylaminomethylene), N,N'-isopropylidene, N-p-nitrobenzylidene, N-salicylidene, N-5-chlorosalicylidene, N-(5-chloro-2-hydroxyphenyl)phenyl-methylene, and N-cyclohexylidene.
Enamine Derivative An example of an enamine derivative is N-(5,5-dimethyl-3-oxo-1-cyclohexenyl).
N-Hetero Atom Derivatives N-metal derivatives include: N-borane derivatives, N diphenyiborinic acid derivative, N-[phenyl(pentacarbonylchromium- or -tungsten)jcarbenyl, and N-copper or N-zinc chelate. Examples of N-N derivatives include: N-nitro, N-nitroso, and N-oxide. Examples of N-P derivatives include:
N-diphenylphosphinyl, N-dimethylthiophosphinyl, N-diphenylthiophosphinyl, N dialkyl phosphoryl, N dibenzyl phosphoryl, and N-diphenyl phosphoryl.
Examples of N-sulfenyl derivatives include: N-benzenesulfenyl, N-o-nitrobenzenesulfenyl, N-2,4-dinitrobenzenesulfenyl, N-pentachlorobenzenesulfenyl, N-2-vitro-4-methoxy-benzenesulfenyl, N-triphenylmethylsulfenyl, and N-3-nitropyridinesulfenyl. N-sulfonyl derivatives include: N-p-toluenesuLFonyl, N-benzenesuifonyl, N-2,3,6-trimethyl-4-methoxybenzenesulfonyl, N-2,4,6-trimethoxybenzenesulfonyl, N-2,6-dimethyl-4-methoxy-benzenesulfonyl, N-pentamethylbenzenesulfonyl, N-2,3,5,6-tetramethyl-4-methoxybenzene- sulfonyl, N-4-methoxybenzenesulfonyl.
N-2,4,6-trimethylbenzenesulfonyl, N-2,6-dimethoxy- 4-methylbenzenesulfonyl, N-2,2,5,7,8-pentamethylchroman-6-sulfonyl, N-methanesulfonyl, N-~trimethylsilylethanesulfonyl, N-9-anthracenesulfonyl, N-4-(4',8'-dimethoxynaphthylmethyl)-benzenesulfonyl, N-benzylsulfonyl, N-trifluoromethylsulfonyl, and N-phenacylsulfonyl.
Disclosed compounds which are masked or protected may be prodrugs.
compounds metabolized or otherwise transformed in vivo to yield a disclosed compound e.g., transiently during metabolism. This transformation may be a hydrolysis or oxidation which results from contact with a bodily fluid such as blood, or the action of acids, or liver, gastrointestinal, or other enzymes.
Features of the invention are further described in the examples below.
E. EXAMPLES
~Chloro-2-(4 4-Dimethyl-4 5-dihydro oxazol 2 yl) ahenyll l4 iodo 2 methyl phenyl)-amore (18) (Scheme 2, R~=CI, R2=R3=H, R4=CH3) a). A mixture of 5-chloro-2-methoxybenzoic acid 16 (14.8 g, 0.0793 mole) and SOC12 (28.31 g, 14.97 ml, 0.1584 mole) was refluxed for 2 hours and excess SOC12 removed leaving a white residue. The solid was dissolved in CH2C12 and added to a solution of 2-amino-2-methyl-1-propanol (13.98 g, 14.97 ml, 0.1584 mole) in CH2C12 cooled with ice-bath. The ice-bath was removed, and after stirring at room temperature for 3 hours a white solid precipitated. The precipitate was separated by filtration and discarded. The filtrate was concentrated leaving a thick colorless oil. SOC12 1;17.4 ml} was added to the oil dropwise. An exothermic reaction took place resulting in to a freely flowing solution. After stirring for 30 minutes, the reaction mixture was poured in to Et20 (200 ml). An oil separated out. The Et20 layer was removed by decanting and discarded. The oily residue was dissolved in a minimum amount of water, basified with aqueous 20% NaOH, and extracted with Et20. The Et20 layer was dried (K2C03) and concentrated to give 17 as tan oil. Yield 14.63 g (77%).
b). LDA (5 ml of 2.0 M solution in THF) was added to a solution of 4-iodo-2-methylaniline (2.33 g, 0.010 mole) in THF (15 ml) at -78 °C. The mixture was stirred at-78 °C for 30 minutes. To this, a solution of 17 (1.199 g, 0.005 mole) in THF (15 ml) was added. The mixture stirred for 16 hours as it warmed up to room temperature. The reaction mixture was quenched with aqueous NH4C1 and extracted with Et20. The Et20 layer was dried (MgS04) and concentrated to give crude 18 as brown oil. The oil was purified on silica column chromatography.
Eluting with CH2C12 gave pure 1.7 g (77%) of 18 as brown oil. Four hundred and nine milligrams of the oil were dissolved in Et20 and treated with Et20-HCI
giving the HCI salt as a light yellaw solid precipitate. Yield 356.4 mg (81 %); mp °C; Anal. Calcd/found for C~8H~8N20CILHC1Ø5H20: C, 44.47/44.32; H, 4.15/3.94; N, 5.76/5.66.
[2.3-Difluoro-6-(1H-tetrazol-5-yl)-phenyll ~4-iodo-2-meth-phenyl)-amine N=N
/
CN N ~ NH
N ~ NaN3, (C2H5}3N.HCl ~~ toluene/reflux F I ~ ~ F ~ ~ I
F F
[2,3-Difluoro-6-cyano-phenyl]-(4-iodo-2-methyl-phenyl)-amine (1.118, 3mmol) and Sodium azide(0.255g, 3.9mmol) and triethylamine hydrochloride (0.537g, 3.9mmol) were all suspended in 10m1 toluene and stirred at 100°C for 12 hours. The mixture was concentrated and the residue purified by column chromatography with ethyl acetate/methanol (10/1) to give the product as a foam-like solid. The yield: ~50%
m. p: 83.4-88.7°C
'H NMR(CDC13, 400Hz): 8/ppm 7.69(1 H, m, Phenyl-H); 7.42(1 H, s, Phenyl-H);
7.27(1 H, m, Phenyl-H); 6.91 (1 H, dd, J=16.2Hz, 8.3Hz, Phenyl-H); 6.40(1 H, dd, Phenyl-H); 2.28(3H, s, CH3) L6-(4,4-Dimethyl-4 5-dihydro-oxazol-2-yl) 2 3 difiuoro phenyll (4 iodo 2 meth ~henyl)-amine COOH
H N~ O
N ~ (~) (cocl)2 H
/ ~ / (2)2-amino-2-methyl-1-propanol ~ N
,F ,I
F
~F I
F
A solution of 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-benzoic acid (1.17g, 3mmol), oxalyl chloride (0.457g, 3.6mmol) in 30m1 dichloromethane was treated with 2 drops of dimethylformamide, stirred at room temperature for 3 hours then concentrated. The residue was dissolved in 25 ml dichloromethane then the solution was added dropwi.se to a solution of 2 amino-2-methyl-1-propanol (0.623g, 7mmol) in 25 ml dichloromethane at 0°C, then stirred at room temperature for 12 hours, filtered off the precipitate, the filtration was washed with water, 5% aqueous sodium bicarbonate, 1 N HCL, brine, dried with sodium sulfate. Concentration gave the dude product, then resuspended in 25 ml chloroform, then thionyl chloride was added at 0°C and stirred at room temperature for 15 hours, then concentrated and the residue was dissolved in ml dichloromethane , 1 N HCI was added to adjusted the pH value to 11, the separated and extracted with chloroform, dried with sodium sulfate.
Concentrated and then run column with hexanes/dichloromethane (20/1) to give the compound as a white crystal. The yield: 65%
m.p.: 103.7-104.4°C
'H NMR(CDC13, 400Hz): /ppm 10.2(1 H, s, NH), 7.48-7.58(1 H, m, Phenyl-H);
7.48(1 H, s, Phenyl-H); 7.38(1 H, d, J=8.5Hz, Phenyl-H), 6.66-6.72(1 H, m, Phenyl-H); 6.58(1 H, t, J=B.OHz, Phenyl-H); 4.01(2H, s, -CH2-); 2.31(3H, s, Phenyl-CH3);
1.32(6H, s, -C(CH3)2-) 3.4-Difluoro-2-(4-iodo-2-methyl-ahenvlamino) benzoic acid methyl ester COOH O O
H
y HzS04/CH30H
.'~" ~ \ ~ \
reflux / F ~/ I / F / I
F
F
3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-benzoic acid (5g) was dissolved in 100m1 methanol and 5 drops of concentrated sulfuric acid was added, reflux for days. Run column with hexanesldichloromethane to give the product as a white solid, yield: 50%.
m.p.:90.1-90.4°C
'H NMR(CDC13, 400Hz): / ppm 8.92(1 H, s, NH), 7.75-7.78(1 H, m, Phenyl-H);
7.49(1 H, s, Phenyl-H); 7.38(1 H, dd, J=8.5Hz, 2.OHz, Phenyl-H), 6.66-6.73(1 H, m, Phenyl-H); 6.56-6.60(1 H, m, Phenyl-H); 3.88(3H, s, -OCH3); 2.30(3H, s. Phenyl-CH3) 5-f3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino~-phenyll-4H-f 1.2 4]triazol-3-lamine O O
N ~ NH
H H
N ~ ~~ aminohuanidine nitrate N
NaOCH3/CH30H
F ~ I '~ F ~ I
F F
Aminoguanidine nitrate (1.65g, 12mmol) was added to a solution of sodium methoxide (0.648g, 12mmol) in methanol (12m1) at 0°C, then 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-benzoic acid methyl ester was added as a solution of methanol and refulx for 20 hours, concentration and run column with hexanes/ethyl acetate to give the product as a white crystal. The yield: 60%
m.p.:191.7-192.0°C
'H NMR(DMSO, 400Hz): / ppm 9.45(1 H, s, -NH-); 7.79(1 H, t, J=7.3Hz, Phenyl-H); 7.51 (1 H, s, Phenyl-H); 7.35(1 H, d, J=10.1 Hz, Phenyl-H); 7.05-7.11 (1 H, m, Phenyl-H); 6.44-6.48(1 H, rn, Phenyl-H); 6.32(2H, s, -NH2), 2.32(3H, s, CH3) 5-f3,4-Difluoro-2-(4-iodo-2-methyl-phe~lamino~phenyll-f1 3 4loxadiazol-2-lamine H2N, /~. N
O NHNHZ
O ,N
H H
N ~~ BrCN/NaHC03(aq) N
dioxane, r.t.
~F . I / F / I
F F
To a solution of 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-benzoic acid hydrazide (0.806g, 2mmol) in 5ml of dioxane was added cyanogen bromide (0.212g, 2mmol) followed by a solution of sodium bicarbonate (0.17g, 2mmol) in 5ml of water. The resulting mixture was stirred 18 ours at room temperature .
the solution was concentrated and the residure was run column with hexanes/ethyl acetate (3/1 ) to give the product which was recrystallized from ethyl acetate /
hexanes to provide a pale-yellow crystal. The yield: 58%
m.p.: 183.7-184.0°C
'H NMR(CDC13, 400Hz): / ppm 8.87(1 H, s, -NH-); 7.52(1 H, s, Phenyl-H); 7.45-7.49(1 H, m, Phenyl-H); 7.4.0(1 H, d, J=8.3Hz, Phenyl-H); 6.77-6.83(1 H, m, Phenyl-H); 6.60-6.63(1 H, m, Phenyl-H); 5.02(2H, s, -NH2), 2.36(3H, s, CH3) 2-f3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-benzoyllhydrazinecarbothioamide S
COOHH H N~N~N O
N ~ _ ( 1 ) (COCI)z _ 2 H H
(2) thiosemicarbaz d ~ ~ N
/ F I / I /
F I
F
F
A solution of 3,4-Difluoro-2-{4-iodo-2-methyl-phenylamino)-benzoic acid (3.9g, 0.01mo1), oxalyl chloride (1.90g, 0.015mo1) in 40m1 dichloromethane was treated with 2 drops of dimethylformamide, stirred at room temperature for 3 hours before concentration. The residue was dissolved in 10 ml tetrahydrofuran and added to a solution of thiosemicarbazide (2.Og, 0.022mo1) in 50m1 tetrahydrofuran at 0°C, stirred at room temperature for 14 hours. Concentrated and run column chromatography with hexanes/ethyl acetate (1/1 ) to give the product as a yellow solid. 2.91g. The yield: 63%
m.p.:159.5-160.0°C
'H NMR(DMSO, 400Hz): /ppm 10.58(1H, s, -NH-); 9.28{1H, s, -NH-); 8.83(1H, s, -NH-); 7.95(1 H, s, Phenyl-H); 7.12-7.75(2H, m, NH2); 7.51 (1 H, s, Phenyl-H);
7.37(1 H, dd, J=8.6Hz, 1.7Hz, Phenyl-H); 7.16(1 H,dd, J=17Hz, 9.OHz, Phenyl-H);
6.40-6.50(1 H, m, Phenyl-H); 5.02(2H, s, -NH2), 2.00(3H, s, CH3) 5-j,3 4-Difuoro-2-(4-iodo-2-methyl-phenylamino)-phenyll-4H-(1.2,41triazole-3-thiol S
H N-H N~N~N O N ~ NH
z H ~ N \ NaOCH3/CH30H
reflux °F ~ I ~ F ~ I
F F
2-[3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-benzoyl]hydrazinecarbothioamide (1.386g, 3mmol) was dissolved in 15 ml anhydrous methanol, sodium methoxide (25% wt% in methanol) 2.5m1 was added at 0°C in one portion. The resulting mixture was heated at reflux for 17 hours before concentration. Run column with hexaneslethyl acetate to give the product as a needle white crystal. The yield: 40%
m.p.: 196.5(dec.) ' H NMR(DMSO, 400Hz): / ppm 13.87(1 H, s, -NH-); 13.80(1 H, s, -NH-); 8.16(1 H, s, -NH-); 7.61-7.65(1 H, m, Phenyl-H); 7.48(1 H, s, Phenyl-H); 7.32(1 H, dd, J=8.6Hz, 2.2Hz, Phenyl-H); 7.24(1 H,dd, J=16.4Hz, 9.5Hz, Phenyl-H); 6.42-6.46(1H, m, Phenyl-H); 5.02(2H, s, -NH2), 2.20(3H, s, CH3).
(2 3-Difluoro-6-f 1 3 4loxadiazol-2-yl-phenyl)-(4-iodo-2-methyl-phenyl)-amine N N
N O Nv O
N \ HC(C>Et)3 ~ N
pTsOH, EtOH I
F I ~ F / I
F F
3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-benzoic acid hydrazide (146 mg, 0.36 mmol) was suspended in 7 mL of absolute EtOH and 2 mL of HC(OEt)3 was added along with approximately 3 mg of pTsOH> The reaction was heated to reflux for 3h, cooled and concentration on a rotary evaporator. The reaction was purified (Si02, 4:1 Hexane,lEtOAc) to afford 117 mg (79%) of (2,3-difluoro-6-[1,3,4]oxadiazol-2-yl-phenyl)-(4-iodo-2-methyl-phenyl)-amine as a yellow powder.
M.p. = 144.4 -145.5 °C. ' H NMR (400MHz, CDC13) 8 8.89 (s, 1 H), 8.44 (s, 1 H), 7.66 (m, 1 H), 7.52 (d, J = 1.7 Hz, 1 H), 7.38 (dd, J = 8.5, 1.9 Hz, 1 H), 6.83 (m, 1 H), 6.14 (dd, J
= 8.5, 5.9 Hz, 1 H), 2.37 (s, 3 H).
5-[3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl f 1 3 4]oxadiazole-2-thiol S
N N
N O N ~ tO
N CS2, KOH N
\ I \ EtOH
F ~ I ~ F / I
F F
3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-benzoic acid hydrazide (170 mg, 0.42 mmol) was suspended in 7 mL of absolute EtOH and cooled to 0 °C.
Carbon disulfide (74 mg, 0.97 mmol) was added followed by 24 mg (0.42 mmol) of powdered KOH. The reaction was stirred for 1 h at 0 °C, 1 h at rt, and refluxed for 3 h to afford a homogeneous reaction. The reaction was cooled to rt, at which point a ppt formed. Water was added and the reaction diluted with 5 mL of EtOAc. 1 N HCI was added to acidify the aqueous layer (pH = 2). The aqueous layer was extracted with EtOAc (3x). The combined organic layers were dried over Na2S04 and concentrated to obtain 96 mg (51 %) of 5-[3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-[1,3,4]oxadiazole-2-thiol as a yellow powder.
M.p. = 231.8 - 232.8 °C. ° H NMR (400MHz, CDC13) 8 7.62 (m, 2H), 7.47 (s, 1 H), 7.30 (complex m, 2H), 6.44 (dd, J = 8.0, 4.5 Hz, 1 H), 2.19 (s, 3H).
Cascade assay for inhibitors of the MAP kinase pathway Incorporation of 32P into myelin basic protein (MBP) is assayed in the presence of a glutathione S-transferase fusion protein containing p44MAP
kinase (GST-MAPK) and a glutathione S-transferase fusion protein containing p45MEK
(GST-MEK). The assay solution contains 20 mM HEPES, pH 7.4, 10 mM MgCl2, 1 mM MnCl2, 1 mM EGTA, 50,~M [y-32P]ATP, 10 ~g GST-MEK, 0.5 ~g GST-MAPK and 40 ~.g MBP in a final volume of 100 ~L. Reactions are stopped after 20 minutes by addition of trichloroacetic acid and filtered through a GF/C
filter mat. 32P retained on the filter mat is determined using a 120S
Betaplate.
Compounds are assessed at 10 ~M for ability to inhibit incorporation of 32P.
To ascertain whether compounds are inhibiting GST-MEK or GST MAPK, two additional protocols are employed. In the first protocol, compounds are added to tubes containing GST-MEK, followed by addition of GST-MAPK, MBP
and [y-32P]ATP. In the second protocol, compounds are added to tubes containing both GST-MEK and GST-MAPK, followed by MBP and [y-32P]ATP.
Compounds that show activity in both protocols are scored as MAPK
inhibitors, while compounds showing activity in only the first protocol are scored as MEK inhibitors.
In vitro MAP kinase assay Inhibitory activity can be confirmed in direct assays. For MAP kinase, 1 ~g GST-MAPK is incubated with 40 ~g MBP for 15 minutes at 30°C in a final volume of 50 pL containing 50 mM Tris (pH 7.5), 10 ~M MgC12, 2 ~M EGTA, and pM [y-32P]ATP. The reaction is stopped by addition of Laemmli SDS sample buffer and phosphorylated MBP resolved by electrophoresis on a 10%
polyacrylamide gel. Radioactivity incorporated into MBP is determined by both 10 autoradiography, and scintillation counting of excised bands.
In vitro MEK assay For evaluation of direct MEK activity, 10 ~,g GST-MEK~ is incubated with 5 pg of a glutathione S-transferase fusion protein containing p44MAP kinase with a lysine to alanine mutation at position 71 (GST-MAPK-KA). This mutation eliminates kinase activity of MAPK, so only kinase activity attributed to the added MEK remains. Incubations are 15 minutes at 30°C in a final volume of 50 ~,L
containing 50 mM Tris (pH 7.5), 10 ~M MgC12, 2 , ~M EGTA, and 10 pM
[y-32P]ATP. The reaction is stopped by addition of Laemrnli SDS sample buffer.
Phosphorylated GST-MAPK-KA is resolved by electrophoresis on a 10%
polyacrylamide gel. Radioactivity incorporated into GST-MAPK-KA is determined by autoradiography, and subsequent scintillation counting of excised bands.
Additionally, an artificially activated MEK containing serine to glutamate mutations at positions 218 and 222 (GST-MEK-2E) is used. When these two sites are phosphorylated, MEK activity is increased. Phosphorylation of these sites can be mimicked by mutation of the serine residues to glutamate. For this assay, 5 ~g GST-MEK-2E is incubated with 5 ~g GST-MAPK-KA for 15 minutes at 30°C in the same reactian buffer as described above. Reactions are terminated and analyzed as above.
Whole cell MAP kinase assay To determine if compounds block activation of MAP kinase in whole cells, the following protocol is used. Cells are plated in multi-well plates and grown to confluence. Cells are serum-deprived overnight. Cells are exposed to the desired concentrations of compound or vehicle (DMSO) for 30 minutes, followed by addition of a growth factor, for example, PDGF (100 ng/mL). After a 5-minute treatment with the growth factor, cells are washed with PBS, and lysed in a buffer consisting of 70 mM NaCI, 10 mM HEPES (pH 7.4), 50 mM glycerol phosphate, and 1 % Triton X-100. Lysates are clarified by centrifugation at 13,000 x g for 10 minutes. Five micrograms of the resulting supernatants are incubated with 10 wg microtubule associated protein-2 {Map2) for 15 minutes at 30°C in a final volume of 25 ~L containing 50 mM Tris (pH 7.4), 10 mM MgCl2, 2 mM EGTA and 30 wM
[y s2P]ATP. Reactions are terminated by addition of Laermmli sample buffer.
Phosphorylated Map2 is resolved on 7.5% acrylamide gels and incorporated radioactivity is determined by scintillation counting of excised bands.
Monola~rer growth Cells are plated into multi-well plates at 10 to 20,000 ceIIs/mL. Forty-eight hours after seeding, test compounds are added to the cell growth medium and incubation is continued for 2 additional days. Cells are then removed from the wells by incubation with trypsin and enumerated with a Coulter counter.
Growth in soft-a~iar Cells are seeded into 35-mm dishes at 5 to 10,000 cells/dish using growth medium containing 0.3% agar. After chilling to solidify the agar, cells are transferred to a 37°C incubator. After 7 to 10 days' growth. visible colonies are manually enumerated with the aid of a dissecting microscope.
Collagen-Induced Arthritis in Mice Type II collagen-induced arthritis (CIA) in mice is an experimental model of arthritis that has a number of pathologic, immunologic, and genetic features in common with rheumatoid arthritis. The disease is induced by immunization of DBA/1 mice with 100 pg type II collagen, which is a major component of joint cartilage, delivered intradermally in Freund's complete adjuvant. The disease susceptibility is regulated by the class II MHC gene locus, which is analogous to the association of rheumatoid arthritis with HLA-DR4.
A progressive and inflammatory arthritis develops in the majority of mice immunized, characterized by paw width increases of up to 100%. A test compound is administered to mice in a range of amounts, such as 20, 60, 100, and 200 mg/kg body weight/day. The duration of the test can be several weeks to a few months, such as 40, 60, or 80 days. A clinical scoring index is used to assess disease progression from erythema and edema (stage 1), joint distortion (stage 2), to joint ankylosis (stage 3). The disease is variable in that it can affect one or all paws in an animal, resulting in a total possible score of 12 for each mouse. Histopathology of an arthritic joint reveals synovitis, pannus formation, and cartilage and bone erosions. All mouse strains that are susceptible to CIA
are high antibody responders to type II collagen, and there is a marked cellular response to CII.
SCW-induced monoarticular arthritis Arthritis is induced as described by Schwab, et al., Infection and Immunity, 59:4436-4442 (1991 ) with minor modifications. Rats receive 6 ~g sonicated SCW
[in 10 ~I Dulbecco's PBS (UPBS)] by an intraarticular injection into the right tibiotalar joint on day 0. On day 21, the DTH is initiated with 100 pg of SCW
(250 p.l) administered i.v. For oral compound studies, compounds are suspended in vehicle (0.5% hydroxypropyl-methylcellulose/0.2% Tween 80), sonicated, and administered twice daily (10 ml/kg volume) beginning 1 hr prior to reactivation with SCW. Compounds are administered in amounts between 10 and 500 mg/kg body weight/day, such as 20, 30, 60, 100, 200, and 300 mg/kglday. Edema measurements are obtained by determining the baseline volumes of the sensitized hindpaw before reactivation on day 21, and comparing them with volumes at subsequent time points such as day 22, 23, 24, and 25. Paw volume is determined by mercury plethysmography.
Mouse ear-heart transalant model Fey, T.A. et al. describe methods for transplanting split-heart neonatal cardiac grafts into the ear pinna of mice and rats (J. Pharm. and Toxic. Meth.
39:9-17 (1998)). Compounds are dissolved in solutions containing combinations of absolute ethanol, 0.2% hydroxypropyl methylcellulose in water, propylene glycol, cremophor, and dextrose, or other solvent or suspending vehicle. Mice are dosed orally or intraperitoneally once, twice or three times daily from the day of transplant (day 0) through day 13 or until grafts have been rejected. Rats are dosed once, twice, or three times daily from day 0 through day 13. Each animal is anesthetized and an incision is made at the base of the recipient ear, cutting only the dorsal epidermis and derrnis. The incision is spread open and down to the cartilage parallel to the head, and sufficiently wide to accommodate the appropriate tunneling for a rat or insertion tool for a mouse. A neonatal mouse or rat pup less than 60 hours old is anesthetized and cervically dislocated. The heart is removed from the chest, rinsed with saline, bisected longitudinally with a scalpel, and rinsed with sterile saline. The donor heart fragment is placed into the preformed tunnel with the insertion tool and air or residual fluid is gently expressed from the tunnel with light pressure. No suturing, adhesive bonding, bandaging, or treatment with antibiotics is required.
Implants are examined at 10-20-fold magnification with a stereoscopic dissecting microscope without anesthesia. Recipients whose grafts are not visibly beating may be anesthetized and evaluated for the presence of electrical activity using Grass E-2 platinum subdermal pin microelectodes placed either in the pinna or directly into the graft and a tachograph. Implants can be examined 1-4 times a day for 10, 20, 30 or more days. The ability of a test compound to ameliorate symptoms of transplant rejection can be compared with a control compound such as cyclosporine, tacrolimus, or orally-administered lefluonomide.
Murine ovalbumin-induced eosinoahilia Female C57BL/6 imice are obtained from the Jackson Laboratory (Bar Harbor, ME). All animals are given food and water ad libitum. Mice are sensitized with a single i.p. injection of OVA (grade V, Sigma Chemical Company, St.
Louis, MO) adsorbed to alum, ( 10 pg OVA + 9 mg alum in 200 ~I saline) or vehicle control, (9 mg alum in 200 ~I saline) on day 0. On day 14, the mice are challenged with a 12-minute inhalation of an aerosol consisting of 1.5% OVA
(weight/volume) in saline produced by a nebulizer (small particle generator, model SPAG-2; ICN Pharmaceuticals, Costa Mesa, CA). Groups of eight mice are dosed with oral vehicle (0.5% hydroxypropylmethylcellulose / 0.25% TWEEN-80), or a test compound at 10, 30, or 100 mg/kg in oral vehicle, 200 ~.! per mouse p.o. Dosing is performed once per day starting on day 7 or day 13, and extending through day 16.
For determination of pulmonary eosinophilia, three days after the first OVA aerosol challenge (day 17), the mice are anesthetized with an i.p.
injection of anesthetic (Ketamine/Acepromazine/Xylazine), and the tracheae is exposed and cannulated. The lungs and upper airways are lavaged twice with 0.5 ml of cold PBS. A portion (200 pl) of the bronchoalveolar lavage (BAL) fluid is enumerated using a Coulter counter Model ZB1 (Coulter Electronics, Hialeah, FL). The remaining BAL fluid is then centrifuged at 300 x g for five minutes, and the cells are resuspended in 1 ml of HBSS (Gibco BRL) containing 0.5% fetal calf serum (HyClone) and 10 mM HEPES (Gibco BRL). The cell suspension is centrifuged in a cytospin (Shandon Southern Instruments, Sewickley, PA) and stained by Diff Quick (American Scientific Products, McGraw Park, IL) to differentiate BAL leukocytes into neutrophil, eosinophil, monocyte or lymphocyte subsets. The number of eosinophils in the BAL fluid is determined by multiplying the percentage of eosinophils by the total cell count.
F. OTHER EMBODIMENTS
From the above disclosure and examples, and from the claims below, the essential features of the invention are readily apparent. The scope of the invention also encompasses various modifications and adaptations within the knowledge of a person of ordinary skill. Examples include a disclosed compound modified by addition or removal of a protecting group, or an ester, pharmaceutical salt, hydrate, acid, or amide of a disclosed compound. Publications cited herein are hereby incorporated by reference in their entirety.
What is claimed is:
Embodiments of the invention include compounds wherein: (a) R~ is bromo or chloro; (b) R2 is fluoro; (c) R3 is H; (d) each of R2 and R3 is H;
(e) each of R2 and R3 is fluoro; (f) R~ is bromo; (g) each of R~, R2 and R3 is fluoro;
(h) R2 is vitro; {i) R3 is H; (j) R4 is chioro; (k) R4 is methyl; (I) R5 is H;
(m) R5 is CH3; (n} X~ is O or S; (o) X~ is NH or NCH3; {p) X2 is OH, SH, or NH2; (q) X2 is OH; (r) X2 is NHRE; (s) R4 is H; (t) R4 is chloro or methyl; or combinations thereof.
Preferably, where one of the substituents on a heterocyclic radical is an alkenyl or alkynyl group, the double or triple bond, respectively, is not adjacent the point of attachment when it is a heteroatom. For example, in such a situation, the substituent is preferably prop-2-ynyl, or but-2 or 3-enyl, and less preferably prop-1-ynyl or but-1-enyl.
Examples of compounds include:: [5-fluoro-2-(1 H-tetrazol-5-yl)-phenyl]-(4-iodo-2-methyl-phenyl)-amine; [?,3-difluoro-6-{1 H-tetrazol-5-yl)-phenyl]-(4-iodo-2-methyl-phenyl)- amine; (4-iodo-2-methyl-phenyl)-[2,3,4-trifluoro-6-(1 H-tetrazol-5-yl)-phenyl]-amine; [4-bro~mo-2,3-difiuoro-6-(1 H-tetrazol-5-yl)-phenyl]-(4-iodo-2-methyl-phenyl)-amine; [5-fluoro-4-vitro-2-(1 H-tetrazol-5-yl)-phenyl]-(4-iodo-methyl-phenyl)-amine; [2.-(4,4-dimethyl-4,5-dihydro-oxazol-2-yl)-5-fluoro-phenyl]-(4-iodo-2-methyl-phenyl)-amine; [6-(4,4-dimethyl-4,5-dihydro-oxazol-2-yl)-2,3-difluoro-phenyl]-(4-iodo-2-methy'-phenyl)-amine; [6-(4,4-dimethyl-4,5-dihydro-oxazol-2-yl)-2,3,4-trifluoro-phenyl]-(4-iodo-2-methyl-phenyl)-amine; [4-bromo-(4,4-dimethyl-~'~ 5-dihydrc>-oxazol-2-yl)-2,3-difiuoro-phenyl]-(4-iodo-2-methyl-phenyl)-amine' [2-(4,4-dimethyl-4,5-dihydro-oxazol-2-yl)-5-fluoro-4-vitro-phenyl]-(4-iodo-2-methyl-phenyl)-ami-~~; 5-[4-fluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-[1,3,4]thiadiazol-,~-ol; 5-[3,4-difluoro-2-{4-iodo-2-methyl-phenyiamino)-phenyl]-[1,3,4~thiaaiazol-2-0.; 5-[3,4,5-~~ifluoro-2-{4-iodo-2-methyl-phenylamino)-phenyl]-[1,3,4]tr,iadiazol-2-0l; 5-[5-bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-[1,3,4]thiadiazol-2-0l; 5-[4-fluoro-2-(4-iodo-2-methyl-phenylamino)-5-vitro-phenyl]-[1,3,4]thiadiazol-2-0l; 5-(4-fluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-[1,3,4]oxadiazol-2-0l; 5-[3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-[1,3,4]oxadiazol-2-0l; 5-[3,4,5-trifluoro-2-(4-iodo-2-methyl-phenyfamino)-phenyl]-(1,3,4]oxadiazol-2-0l; 5-[5-bromo-3,4-difluoro-2-(4-iodo-methyl-phenyiamino)-phony']-[1,3,4]oxadiazol-2-0l; 5-[4-fluoro-2-(4-iodo-2-methyl-phenylamino)-5-vitro-phenyl]-[1.3,4]oxadiazol-2-0l; 5-[4-fluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-4H-[1,2,4]triazol-3-0l; 5-[3,4-difiuoro-2-{4-iodo-2-methyl-phenylamino)-phenyl]-4H-[1,2,4]triazol-3-0l; 5-[3,4,5-trifluoro-2-(4-iodo-2-methyl-phenylamino)-phenylj-4t-!-[1,2,4]triazol-3-0l; 5-[5-bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-4H-[1,2,4]ti~iazol-3-0l; and 5-[4-fluoro-2-(4-iodo-methyl-phenylamino)-5-vitro-phenyl]-4H-[1,2,4]triazol-3-0l.
Further examples include: 5-(4-fluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-[1,3,4]thiadiazol-2-ylamine; 5-[3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-[1,3,4]thiadiazol-2-ylamine; 5-[3,4,5-Trifluoro-2-(4-iodo-methyl-phony!amino)-phe~~ylJ-[1;3,4]thiadiazol-2-ylamine; 5-[5-bromo-3,4-difluoro-2-(4-iodo-2-methyl-p!~enylamino)-phenyl]-[1,3,4]thiadiazol-2-ylamine;
[4-fluoro-2-(4-iodo-2-meth,yl-phenylamino)-5-vitro-phenyl]-[1,3,4]thiadiazol-2-ylamine; 5-(4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-[1,3,4]oxadiazol-ylamine; 5-~3;4-difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-[1,3,4]oxadiazol-2-ylamine; 5-[,:,4,5-trifluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-[1,3,4]cxadiazol-2-ylamine; 5-[5-bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino;~-:~henyf]-[1.,3,4j~~xadiazol-2-ylamine; 5-[4-fluoro-2-(4-iodo-2-methyl-phenylamino)-~-vitro-phenylj-;1,3.4]oxadiazol-2-ylamine; 5-[4-fluoro-2-(4-iodo-methyl-phony!a.mine)-phenyl]-4H-[1,2,4]triazol-3-ylarnine; 5-(3,4-difluoro-2-(4-iodo-2-me':hyl-phenylamino)-phenylj-4H-[1,2,4]triazol-3-ylamine; 5-[3,4,5-trifluoro-2-(4-iodo-2-methyl-phen~ylamino)-phenyl]-4H-[1,2,4]triazol-3-ylamine; 5-[5-bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-4H-[1,2,4]triazol-3-ylamine;
5-[4-fluore~-2-(4--iodo-2-me ihy!-phenylamino)-5-vitro-phenyl]-4H-[1,2,4]triazol-3-ylamine; 5-[4-fvoro-2-(4-ic~dc-2-methyl-phenylamino)-phenyl]-[1,3,4]thiadiazole-2-thiol; 5-(3,4-dif'uora-2-(4-iodr>-2-methyl-phenylamino)-phenyl]-[1,3,4]thiadiazole-2-thiol; 5-[3,4,5-~.riftuoro-2-{4-io~o-2-methyl-phenylamino)-phenyl]-[1,3,4]thiadiazole-2-thiol; 5-[5-bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-MISSING AT THE TIME OF PUBLICATION
l0 phenylamino)-5-nitro-phenyl]-isothiazol-3-0l; 4-[4-fluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-isoxazol-3-0l; 4-[3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-isoxazol-3-0l; 4-[3,4,5-trifluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-isoxazol-3-0l; 4-[5-bromo-3,4-difluoro-2-{4-iodo-2-methyl-phenylamino)-phenyl]-isoxazol-3-0l; 4-[4-fluoro-2-(4-iodo-2-methyl-phenylamino)-5-nitro-phenyl]-isoxazol-3-0l; 4-[4-fluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-1-methyl-1 H-pyrazol-3-oi; 4-[3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-1-methyl-1 H-pyrazol-3-0l; 1-methyl-4-[3,4,5-trifluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-1 H-pyrazol-3-0l; 4-[5-bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-1-methyl-1 H-pyrazol-3-0l; and 4-[4-fluoro 2-(4-iodo-2-methyl-phenylamino)-5-nitro-phenyl]-1-methyl-1 H-pyrazol-3-0l.
The invention also features compounds such as: 5-[2-(2-amino-4-iodo-phenylamino)-4-fluoro-phenyl]-1-methyl-1H-[1,2,3]triazol-4-0l; 5-[2-{2-amino-4-iodo-phenylamino)-3,4-difluoro-phenylJ-1-methyl-1H-[1,2,3Jtriazol-4-0l; 5-[2-(2-amino-4-iodo-phenylamino)-3,4,5-trifluoro-phenyl]-1-methyl-1H-[1,2,3]triazol-4-0l;
5-[2-(2-amino-4-iodo-phenylamino)-5-bromo-3,4-difluoro-phenyl]-1-methyl-1 H-[1,2,3]triazol-4-0l; 5-[2-(2-amino-4-iodo-phenylamino)-4-fluoro-5-nitro-phenyl]-1-methyl-1H-[1,2,3)triazol-4-0l; 5-[4-fluoro-2-(4-iodo-2-methyl-phenylamino)-phenylJ-3-methyl-3H-[1,2,3]triazol-4-0l; 5-[3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-3-methyl-3H-[1,2,3]triazol-4-0l; 3-methyl-5-[3,4,5-trifluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-3H-[1,2,3]triazol-4-0l; 5-[5-bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-3-methyl-3H-[1,2,3Jtriazol-4-0l;
5-[4-fluoro-2-(4-iodo-2-methyl-phenylamino)-5-nitro-phenyl]-3-methyl-3H-[1,2,3)triazol-4-0l; 4-[4-fluoro-2-(4-iodo-2-methyl-phenyfamino)-phenyl]-2-methyl-2H-pyrazol-3-0l; 4-[3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-2-methyl-2H-pyrazol-3-0l; 2-methyl-4-[3,4,5-trifluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-2H-pyrazol-3-0l; 4-[5-bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-2-methyl-2H-pyrazol-3-0l; 4-[4-fluoro-2-(4-iodo-2-methyl-phenylamino)-5-vitro-phenyl]-2-methyl-2H-pyrazol-3-0l; 1-[4-fluoro-2-(4-iodo-2-methyl-phenylamina)-phenyl)-4-methyl-1,4-dihydro-tetrazol-5-one; 1-[3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-phenylJ-4-methyl-1,4-dihydro-tetrazol-one; 1-methyl-4-[3,4,5-trifluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-1,4-dihydro-tetrazol-5-one; 1-[5-bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-4-methyl-1,4-dihydro-tetrazol-5-one; 1-[4-fluoro-2-(4-iodo-2-methyl-phenylamino)-5-nitro-phenyl]-4-methyl-1,4-dihydro-tetrazol-5-one; 1-[4-fluoro-(4-iodo-2-methyl-phenylamino)-phenyl]-1H-[1,2,3jtriazol-4-0l; 1-[3,4-difluoro-2-(4-iodo-2-methyl-phenyiamino)-phenyl]-1H-[1,2,3]triazol-4-0l; 1-[3,4,5-trifluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-1H-[1,2,3]triazol-4-0l; 1-[5-bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-1 H-[1,2,3]triazol-4-0l; and 1-[4-fluoro-2-(4-iodo-2-methyl-phenylamino)-5-nitro-phenyl]-1 H-[1,2,3]triazol-4-0l.
Further examples of the invention include 3-[4-fluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-2H-isoxazol-5-one; 3[3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-2H--isoxazol-5-one; 3-[3,4,5-trifluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-2H-isoxazol-5-one; 3-[5-bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-2H-isoxazol-5-one; 3-[4-fluoro-2-(4-iodo-2-methyl-phenylamino)-5-nitro-phenyl]-2H-isoxazol-5-one; [5-fluoro-2-(2-oxo-2,3-dihydro-21>4 -[1,2,3,5]oxathiadiazol-4-yl)-phenyl]-(4-iodo-2-methyl-phenyl)-amine;
[2,3-difluoro-6-(2-oxo-2, 3-dihydro-21>4_-[1,2, 3, 5]oxathiadiazol-4-yl)-phenyl]-(4-iodo-2-methyl-phenyl)-amine; (4-lodo-2-methyl-phenyl)-[2,3,4-trifluoro-6-(2-oxo-2,3-dihydro-21>4- [1,2,3,5]oxathiadiazol-4-yl)-phenyl]-amine; [4-bromo-2,3-difluoro-6-(2-oxo-2,3-dihydro-21>4_-[1,2,3,5]oxathiadiazol-4-yl)-phenyl]-(4-iodo-2-methyl-phenyl)-amine; [5-fluoro-4-nitro-2-(2-oxo-2,3-dihydro-21>4=
[1,2,3,5]oxathiadiazol-4-yl)-phenyl]-(4-iodo-2-methyl-phenyl)-amine; 4-[4-fluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-4H-isoxazol-5-one; 4-[3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-4H-isoxazol-5-one; 4-[3,4,5-trifluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-4H-isoxazol-5-one; 4-[5-bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-4H-isoxazol-5-one; and 4-[4-fluoro-2-(4-iodo-2-methyl-phenylamino)-5-nitro-phenyl]-4H-isoxazol-5-one.
Further compounds, where R, can also be SOzNR~RH, or R~ and R2 together with the benzene ring to which they are attached constitute an indole, isoindole, benzofuran, benzothiophene, indazole, benzimidazoie, or benzthioazole, include the following groups:
Group 1 (1) 2-Fluoro-5-(5-hydroxy-1,3,4-oxadiazol-2-yl)-4-(4-iodo-2-methyl-phenyiamino)-benzenesulfonamide (2) 4-(2-Chloro-4-iodo-phenylamino)-2-fluoro-5-(5-hydroxy-1,3,4-oxadiazol-2-yl)-N-methyl-benzenesulfonamide (3) 2,3-Difluoro-5-(5-hydroxy-1,3,4-oxadiazoi-2-yl)-4-(4-iodo-2-methyl-phenylamino)-N,N-dimethyl-benzenesulfonamide (4) 4-(2-Chloro-4-iodo-phenylamino)-2,3-difluoro-5-(5-hydroxy-1,3,4-oxadiazol-yl)-N-methyl-N-(3-rnorpholin-4-yi-propyl)-benzenesulfonamide {5) 2-Fluoro-5-(5-hydroxy-1,3,4-oxadiazol-2-yl)-4-(4-iodo-phenylamino)-N-(2-(2-methoxy-ethoxy)-ethyl]-benzenesulfonamide (6) N-(2-Dimethylamino-ethyl)-2-fluoro-5-(5-hydroxy-1,3,4-oxadiazo!-2-yl)-4-(4-iodo-phenylamino)-N-methyl-benzenesulfonamide Group 2 (1) 5-(5-Amino-1,3,4-oxadiazol-2-yl)-2-fluoro-4-(4-iodo-2-methyl-phenylamino}-benzenesulfonamide (2) 5-(5-Amino-1,3,4-oxadiazol-2-yl)-4-(2-chloro-4-iodo-phenylamino)-2-fluoro-benzenesulfonamide (3) 5-(5-Amino-1,3,4-oxadiazol-2-yl)-2,3-difluoro-4-(4-iodo-2-methyl-phenylamino)-benzenesuifonamide (4) 5-(5-Amino-1,3,4-oxadiazol-2-yl)-4-(2-chloro-4-iodo-phenylamino)-2,3-difluoro-benzenesulfonamide (5) 5-(5-Amino-1,3,4-oxadiazol-2-yl)-2-fluoro-4-(4-iodo-phenylamino)-benzenesulfonamide {6) 4-(5-Amino-'1,3,4-oxadiazol-2-yl)-2-fluoro-5-(4-iodo-phenylamino)-benzenesulfonamide Group 2b (1 ) 5-(5-Amino-1,3,4-oxadiazol-2-yl)-2-fluoro-4-(4-iodo-2-methyl-phenylamino)-benzenesulfonamide {2) 5-(5-Amino-1,3,4-oxadiazol-2-yl)-2-fluoro-4-{4-iodo-phenylamino)-N-methyl-N-(3-morpholin-4-yl-propyl)-benzenesulfonamide (3) 5-(5-Amino-1,3,4-oxadiazol-2-yl)-2,3-difluoro-4-(4-iodo-2-methyl-phenylamino)-benzenesulfonamide (4) 5-(5-Amino-1,3,4-oxadiazol-2-yl)-2-fluoro-4-(4-iodo-phenylamino)-benzenesulfonamide (5) 5-(5-Amino-1,3,4-oxadiazol-2-yl)-4-(2-chloro-4-iodo-phenylamino)-2,3-difluoro-N-[3-(4-methyl-piperazin-1-yl)-propyl]-benzenesulfonamide (6) 5-(5-Amino-1,3,4-oxadiazol-2-yl)-4-(2-chforo-4-iodo-phenylamino)-2-fluoro-N-(3-piperidin-1-yl-propyl)-benzenesulfonamide Group 3 (1) 2-Fluoro-4-(4-iodo-2-methyl-phenylamino)-5-(5-mercapto-1,3,4-oxadiazol-2-yl)-benzenesulfonamide (2) 2-Fluoro-5-(4-iodo-phenylamino)-4-(5-mercapto-1,3,4-oxadiazol-2-yl)-benzenesulfonamide (3) 2,3-Difluoro-4-(4-iodo-2-methyl-phenylamino)-5-(5-mercapto-1,3,4-oxadiazol-2-yl)-benzenesulfonamide (4) 2-Fluoro-4-(4-iodo-phenylamino)-5-(5-mercapto-1,3,4-oxadiazol-2-yl)-benzenesulfonamide (5) 4-(2-Chloro-4-iodo-phenylamino)-2,3-difluoro-5-(5-mercapto-1,3,4-oxadiazol-2-yl)-benzenesulfonamide (6) 4-(2-Chloro-4-iodo-phenylamino)-2-fluoro-5-(5-mercapto-1,3,4-oxadiazol-2-yl)-benzenesulfonamide Group 4 (1) 2-Fluoro-5-(5-hydroxy-1,3,4-thiadiazol-2-yl)-4-(4-iodo-2-methyl-phenylamino)-benzenesulfonamide (2) 2-Fluoro-4-{5-hydroxy-1,3,4-thiadiazol-2-yl)-5-(4-iodo-phenyiamino)-benzenesulfonamide (3) 2,3-Difluoro-5-(5-hydroxy-1,3,4-thiadiazol-2-yl)-4-(4-iodo-2-methyl-phenylamino)-benzenesulfonamide {4) 2-Fluoro-5-(5-hydroxy-1,3,4-thiadiazol-2-yl)-4-(4-iodo-phenylamino)-benzenesulfonamide (5) 4-{2-Chloro-4-iodo-phenylamino)-2,3-difluoro-5-(5-hydroxy-1,3,4-thiadiazol-yl)-benzenesulfonamide (6) 4-(2-Chloro-4-iodo-phenylamino)-2-fluoro-5-(5-hydroxy-1,3,4-thiadiazol-2-yl)-benzenesulfonamide Group 5 (1) 5-(5-Amino-1,3,4-thiadiazol-2-yl)-2-fluoro-4-(4-iodo-2-methyl-phenylamino)-benzenesulfonamide (2) 4-(5-Amino-1,3,4-thiadiazol-2-yl)-5-(4-iodo-phenylamino)-2-mercapto-benzenesulfonamide (3) 5-(5-Amino-1,3,4-thiadiazol-2-yl)-2,3-diffuoro-4-(4-iodo-2-methyl-phenylamino)-benzenesulfonamide (4) 5-(5-Amino-1,3,4-thiadiazol-2-yl)-2-fluoro-4-(4-iodo-phenylamino)-benzenesulfonamide (5) 5-(5-Amino-7 ,3,4-thiadiazol-2-yl)-4-(2-chloro-4-iodo-phenylamino}-2,3-difluoro-benzenesulfonamide (6) 5-(5-Amino-1,3,4-thiadiazol-2-yl)-4-(2-chloro-4-iodo-phenylamino}-2-fluoro-benzenesulfonamide Group 6 (1) 2-Fluoro-5-(5-hydroxy-4H-1,2,4-triazol-3-yl)-4-(4-iodo-2-methyl-phenylamino)-benzenesulfonamide (2) 2-Fluoro-4-(5-hydroxy-4H-1,2,4-triazol-3-yl)-5-(4-iodo-phenylamino)-benzenesulfonamide (3) 2,3-Difluoro-5-(5-hydroxy-4H-1,2,4-triazol-3-yl}-4-(4-iodo-2-methyl-phenylamino)-benzenesulfonamide WO 00!42029 PCT/US99/30416 (4) 5-[4-(2-Dimethylamino-ethyl)-5-hydroxy-4H-1,2,4-triazol-3-yl]-2-fluoro-4-(4-iodo-phenylamino;l-benzenesulfonamide (5) 4-(2-Chloro-4-iodo-phenylamino)-2,3-difluoro-5-(5-hydroxy- 4H-1,2,4-triazol-yl)-benzenesuifonamide {6) 4-(2-Chloro-4-iodo-phenylamino)-2-fluoro-5-(5-hydroxy-4-methyl-4H-1,2,4-triazol-3-yl)-benzenesulfonamide Group 7 (1 ) 5-(5-Amino-4H-1,2,4-triazol-3-yl)-2-fluoro-4-(4-iodo-2-methyl-phenylamino)-benzenesulfonamide (2) 4-(5-Amino-4H-1,2,4-triazol-3-yl)-2-fluoro-5-(4-iodo-phenylamino)-benzenesulfonamide (3) 5-(5-Amino-4-methyl-4H-1,2,4-triazol-3-yl)-2,3-difluoro-4-{4-iodo-2-methyl-phenylamino)-benzenesulfonamide (4) 5-[5-Amino-4-(3-dimethylamino-propyl)-4H-1,2,4-triazol-3-yl]-2-fluoro-4-(4-iodo- phenylamino)-benzenesulfonamide (5) 5-(5-Amino-4H-1,2,4-triazol-3-yl)-4-(2-chloro-4-iodo-phenylamino}-2,3-difluoro-benzenesulfonarnide (6) 5-(5-Amino-4-methyl-4H-1,2,4-triazol-3-yl)-4-(2-chloro-4-iodo-phenylamino)-2-fluoro-benzenesulfonamide Group 8 (1) 2-Fluoro-5-(3-hydroxy-isoxazol-5-yl)-4-(4-iodo-2-methyl-phenylamino)-benzenesulfonamide (2) 2-Fluoro-4-(3-hydroxy-isoxazol-5-yl)-5-(4-iodo-phenylamino)-benzenesulfonamide (3) 2,3-Difluoro-5-(3-hydroxy-isoxazol-5-yl)-4-(4-iodo-2-methyl-phenylamino)-benzenesulfonamide (4} 2-Fluoro-5-(3-hydroxy-isoxazol-5-yl)-4-(4-iodo-phenylamino)-benzenesulfonamide (5) 4-(2-Chloro-4-iodo-phenylamino)-2,3-difiuoro-5-{3-hydroxy-isoxazol-5-yl)-benzenesulfonamide (6) 4-(2-Chloro-4-iodo-phenylamino)-2-fluoro-5-(3-hydroxy-isoxazol-5-yl)-benzenesulfonamide Group 9 (1) 5-(3-Amino-isoxazol-5-yl)-2-fluoro-4-(4-iodo-2-methyl-phenylamino)-benzenesulfonamide (2) 4-(3-Amino-isoxazol-5-yl)-2-bromo-5-(4-iodo-phenylamino)-benzenesulfonamide (3) 5-(3-Amino-isoxazol-5-yl)-2,3-difluoro-4-(4-iodo-2-methyl-phenylamino)-benzenesulfonamide (4) 5-(3-Amino-isoxazol-5-yl)-2-fluoro-4-(4-iodo-phenylamino)-benzenesulfonamide (5) 5-(3-Amino-isoxazol-;i-yl)-4-(2-chioro-4-iodo-phenylamino)-2,3-difluoro-benzenesulfonamide (6) 5-(3-Amino-isoxazol-5-yl)-4-(2-chloro-4-iodo-phenylamino)-2-fluoro-benzenesulfonamide Group 10 (1 ) 2-Fluoro-4-(4-iodo-2-methyl-phenylamino}-5-(3-mercapto-isoxazol-5-yl)-benzenesulfonamide (2) 4-(2-Chloro-4-iodo-phenylamino)-2-fluoro-5-(3-mercapto-isoxazol-5-yl)-benzenesulfonamide (3) 2,3-Difluoro-4-(4-iodo-2-methyl-phenylamino)-5-(3-mercapto-isoxazol-5-yl)-benzenesulfonamide (4) 4-(2-Chloro-4-iodo-phenylamino)-2,3-difluoro-5-(3-mercapto-isoxazol-5-yl)-benzenesulfonamide (5) 2-Fluoro-4-(4-iodo-phenylamino)-5-(3-mercapto-isoxazol-5-yl)-benzenesulfonamide (6) 2-Bromo-5-{4-iodo-phenylamino)-4-(3-mercapto-isoxazol-5-yl)-benzenesulfonamide Group 11 (1) 2-Fluoro-5-(3-hydroxy-isoxazol-4-yl)-4-(4-iodo-2-methyl-phenylamino)-benzenesulfonamide (2) 4-(2-Chloro-4-iodo-phenylamino)-2-fluoro-5-{3-hydroxy-isoxazol-4-yl)-benzenesulfonamide (3) 2,3-Difluoro-5-(3-hydroxy-isoxazol-4-yl)-4-(4-iodo-2-methyl-phenylamino)-benzenesulfonamide (4) 4-(2-Chloro-4-iodo-phenylamino)-2,3-difluoro-5-(3-hydroxy-isoxazol-4-yl)-benzenesuifonamide (5) 2-Fluoro-5-(3-hydroxy-isoxazol-4-yl)-4-(4-iodo-phenylamino)-benzenesulfonamide (6) 2-Bromo-4-(3-hydroxy-isoxazol-4-yl)-5-(4-iodo-phenylamino)-benzenesulfonamide Group 12 (1) 5-(3-Amino-isoxazol-4-yl)-2-fluoro-4-(4-iodo-2-methyl-phenylamino)-benzenesulfonamide (2) 5-(3-Amino-isoxazol-~t-yl)-4-(2-chloro-4-iodo-phenylamino)-2-fluoro-benzenesulfonamide (3) 5-(3-Amino-isoxazol-4-yl)-2,3-difluoro-4-(4-iodo-2-methyl-phenylamino}-benzenesulfonamide (4) 5-(3-Amino-isoxazol-4-yl)-4-(2-chloro-4-iodo-phenylamino)-2,3-difluoro-benzenesulfonamide (5} 5-(3-Amino-isoxazol-~4-yl)-2-fluoro-4-(4-iodo-phenylamino)-benzenesulfonamide (6) 4-(3-Amino-isoxazol-4~-yl)-2-chloro-5-(4-iodo-phenylamino)-benzenesulfonamide Group 13 (1 ) 5-(3-Amino-isoxazol-4-yl)-2-fluoro-4-(4-iodo-2-methyl-phenylamino)-benzenesulfonamide (2) 5-(3-Amino-isoxazol-4-yl)-4-(2-chloro-4-iodo-phenylamino)-2-fluoro-benzenesulfonamide (3) 5-(3-Amino-isoxazol-4-yl)-2,3-difluoro-4-(4-iodo-2-methyl-phenyiamino)-benzenesulfonamide (4) 5-(3-Amino-isoxazol-4-yl)-4-(2-chloro-4-iodo-phenylamino)-2,3-difluoro-benzenesulfonamide"
(5) 5-(3-Amino-isoxazol-4-yl)-2-fluoro-4-(4-iodo-phenylamino)-benzenesulfonamide (6) 4-(3-Amino-isoxazol-4-yl)-2-chioro-5-(4-iodo-phenylamino)-benzenesulfonamide Group 14 (1 ) 5-(2-Amino-5H-pyrrol-3-yl)-2-fluoro-4-(4-iodo-2-methyl-phenylamino)-benzenesulfonamide (2) 5-(2-Amino-5H-pyrrol-~3-yl)-4-(2-chloro-4-iodo-phenylamino)-2-fluoro-benzenesulfonamide (3) 5-(2-Amino-5H-pyrrol-~3-yl)-2,3-difluoro-4-(4-iodo-2-methyl-phenylamino)-benzenesulfonamide (4) 5-(2-Amino-5H-pyrrol-~3-yl)-4-(2-chloro-4-iodo-phenylamino)-2,3-difluoro-benzenesulfonamide (5) 5-(2-Amino-5H-pyrrol--3-yl)-2-fluoro-4-(4-iodo-phenylamino)-benzenesulfonamide {6) 4-(2-Amino-5H-pyrrol-3-yl)-2-chloro-5-(4-iodo-phenylamino)-benzenesulfonamide Group 15 (1 ) 2-Fluoro-5-(5-hydroxy-1-methyl-1 H-pyrazol-4-yl)-4-(4-iodo-2-methyl-phenylamino)-benzenesulfonamide {2) 4-(2-Chloro-4-iodo-phenylamino)-2-fluoro-5-(5-hydroxy-1 H-pyrazol-4-yl)-benzenesulfonamide (3) 2,3-Difluoro-5-(5-hydroxy-1 H-pyrazol-4-yl)-4-(4-iodo-2-methyl-phenylamino)-benzenesulfonamide (4) 4-{2-Chloro-4-iodo-phenylamino)-2,3-difluoro-5-(5-hydroxy-1H-pyrazol-4-yl)-benzenesulfonamide (5) 2-Fluoro-5-{5-hydroxy-1-[3-(4-methyl-piperazin-1-yl)-propylJ-1 H-pyrazol-4-yl}-4-(4-iodo-phenylarnino)-benzenesulfonamide (6) 2-Fluoro-4-(5-hydroxy-1 H-pyrazol-4-yl)-5-(4-iodo-phenylamino)-benzenesulfonamide Group 16 (1) 2-Fluoro-5-(5-hydroxy-3-methyl-3H-1,2,3-triazol-4-yl)-4-(4-iodo-2-methyl-phenylamino)-benzenesulfonamide (2) 4-(2-Chloro-4-iodo-phenylamino)-2-fluoro-5-(5-hydroxy-3H-1,2,3-triazol-4-yl)-benzenesulfonamide (3) 2,3-Difluoro-5-(5-hydroxy-3H-1,2,3-triazol-4-yl)-4-(4-iodo-2-methyl-phenylamino)-benzenesulfonamide (4) 4-(2-Chloro-4-iodo-phenyiamino)-2,3-difluoro-5-(5-hydroxy-3H-1,2,3-triazol-yl)-benzenesulfonamide (5) 2-Fluoro-5-(5-hydroxy-3H-1,2,3-triazol-4-yl)-4-(4-iodo-phenylamino)-benzenesulfonamide (6) 2-Fluoro-5-{5-hydroxy-3-[2-(2-methoxy-ethoxy)-ethyl]-3H-1,2,3-triazol-4-yl}-4-(4-iodo-phenylamino)-benzenesulfonamide Group 17 (1) 2-Fluoro-5-(5-hydroxy-3-methyl-3H-1,2,3-triazol-4-yl}-4-(4-iodo-2-methyl-phenylamino)-benzenesulfonamide (2) 4-(2-Chloro-4-iodo-phenylamino)-2-fluoro-5-(5-hydroxy-3H-1,2,3-triazol-4-yl)-benzenesulfonamide (3) 2,3-Difluoro-5-(5-hydroxy-3H-1,2,3-triazol-4-yl)-4-(4-iodo-2-methyl-phenylamino)-benzenesulfonamide (4) 4-(2-Chloro-4-iodo-phenylamino)-2,3-difiuoro-5-(5-hydroxy-3H-1,2,3-triazol-yl)-benzenesulfonamide (5) 2-Fluoro-5-(5-hydroxy-3H-1,2,3-triazol-4-yl)-4-(4-iodo-phenylamino)-benzenesulfonamide (6) 2-Fluoro-5-{5-hydroxy-3-[2-(2-methoxy-ethoxy)-ethyl]-3H-1,2,3-triazol-4-yl}-4-(4-iodo-phenylamino)-benzenesulfonamide Group 18 (1) 2-Fluoro-4-(4-iodo-2-methyl-phenylamino)-5-(5-oxo-4,5-dihydro-tetrazol-1-yl)-benzenesulfonamide (2) 4-(2-Chloro-4-iodo-phenylamino)-2-fluoro-5-(5-oxo-4,5-dihydro-tetrazol-1-yl)-benzenesulfonarnide (3) 2,3-Difluoro-4-(4-iodo-2-methyl-phenylamino)-5-(5-oxo-4,5-dihydro-tetrazol-yl)-benzenesulfonamide (4) 4-(2-Chloro-4-iodo-phenylamino)-2,3-difluoro-5-(5-oxo-4,5-dihydro-tetrazol-yl)-benzenesulfonamide (5) 2-Fluoro-4-(4-iodo-phenylamino)-5-(5-oxo-4,5-dihydro-tetrazol-1-yl)-benzenesulfonamide (6) 2,6-Difluoro-3-(4-iodo-phenylamino)-4-(5-oxo-4,5-dihydro-tetrazol-1-yl)-benzenesulfonamide Group 19 (1) 2-Fluoro-4-(4-iodo-2-methyl-phenylamino)-5-(4-methyl-5-oxo-4,5-dihydro-tetrazol-1-yi)-benzenesulfonamide {2) 4-(2-Chloro-4-iodo-phenylamino)-2-fluoro-5-(4-methyl-5-oxo-4,5-dihydro-tetrazol-1-yl)- benzenesulfonamide (3) 2,3-Difluoro-4-(4-iodo-2-methyl-phenylamino)-5-(5-oxo-4,5-dihydro-tetrazol-yl)-benzenesulfonamide (4) 4-(2-Chloro-4-iodo-phenylarnino)-2,3-difluoro-5-(5-oxo-4,5-dihydro-tetrazol-1-yl)-benzenesulfonamide (5) 5-[4-(2-Dimethylamino-ethyl)-5-oxo-4,5-dihydro-tetrazol-1-ylJ-2-fluoro-4-(4-iodo-phenylamino)-benzenesulfonamide (6) 2-Fluoro-5-(4-iodo-phenylamino)-4-(4-methyl-5-oxo-4,5-dihydro-tetrazol-1-yl)-benzenesulfonamide Group 20 (1) 2-Fluoro-4-(4-iodo-2-methyl-phenylamino)-5-(2-oxo-2,3-dihydro-1,2,3,5-oxathiadiazol-4-yl)~-benzenesulfonamide (2) 4-(2-Chloro-4-iodo-phenylamino)-2-fluoro-5-(2-oxo-2,3-dihydro-1,2,3,5-oxathiadiazol-4-yl)-benzenesulfonamide (3) 2,3-Difluoro-4-(4-iodo-2-methyl-phenylamino)-5-(2-oxo-2,3-dihydro-1,2,3,5-oxathiadiazol-4-yl)--benzenesulfonamide (4) 4-(2-Chloro-4-iodo-phenylamino)-2,3-difluoro-5-(2-oxo-2,3-dihydro-1,2,3,5-oxathiadiazol-4-yi)-~benzenesulfonamide (5) 2-Fluoro-4-(4-iodo-phenylamino)-5-(2-oxo-2,3-dihydro-1,2,3,5-oxathiadiazol-4-yl)-benzenesulfonamide (6) 2-Fluoro-5-(4-iodo-phenylamino)-4-(2-oxo-2,3-dihydro-1,2,3,5-oxathiadiazol-4-yl)-benzenesulfonamide Group 21 (1) 2-Fluoro-4-(4-iodo-2-methyl-phenylamino)-5-(3-methyl-2-oxo-2,3-dihydro-1,2,3,5-oxathiadiazol-4-yl)-benzenesulfonamide (2) 2,6-Difluoro-3-(4-iodo-phenylamino)-4-{3-methyl-2-oxo-2,3-dihydro-1,2,3,5-oxathiadiazol-4.-yl)-benzenesulfonamide (3) 2,3-Difluoro-4-(4-iodo-2-methyl-phenylamino)-5-(3-methyl-2-oxo-2,3-dihydro-1,2,3,5-oxathiadiazoi-4-yl)-benzenesulfonamide (4) 2-Fluoro-4-(4-iodo-phenylamino)-5-(3-methyl-2-oxo-2,3-dihydro-1,2,3,5-oxathiadiazol-4-yl)-benzenesulfonamide (5} 4-(2-Chloro-4-iodo-phenylamino)-2,3-difluoro-5-(3-methyl-2-oxo-2,3-dihydro-1,2,3,5-oxathiadiazol-4-yl)-benzenesuifonamide (6) 4-(2-Chloro-4-iodo-phenylamino)-2-fluoro-N-methyl-5-(3-methyl-2-oxo-2,3-dihydro-1,2,3,5-oxathiadiazol-4-yl)-benzenesulfonamide Group 22 (1) 2-Fluoro-4-(4-iodo-2-methyl-phenylamino)-5-(5-oxo-2,5-dihydro-isoxazol-3-yl)-benzenesulfonarnide (2) 2,6-Difluoro-3-(4-iodo-phenylamino)-4-(5-oxo-2,5-dihydro-isoxazol-3-yl)-benzenesulfonamide (3) 2,3-Difluoro-4-(4-iodo-2-methyl-phenylamino)-5-(5-oxo-2,5-dihydro-isoxazol-3-yl)-benzenesulfonamide (4} 2-Fluoro-4-(4-iodo-phenylamino)-5-(5-oxo-2,5-dihydro-isoxazol-3-yl)-benzenesulfonamide (5) 4-(2-Chloro-4-iodo-phenylamino)-2,3-difluoro-5-(5-oxo-2,5-dihydro-isoxazol-3-yl)-benzenesulfonamide (6) 4-(2-Chloro-4-iodo-phenylamino)-2-fluoro-5-(5-oxo-2,5-dihydro-isoxazol-3-yl)-benzenesuifonamide Group 23 (1) 5-[6-(4-lodo-2-methyl-phenylamino)-1H-benzimidazol-5-yl]-1,3,4-oxadiazol-2-of (2) 5-[6-(4-lodo-phenylamino)-benzofuran-5-yl]-1,3,4-oxadiazol-2-0l (3) 5-[7-Fluoro-6-(4-iodo-2-methyl-phenylamino)-benzoxazol-5-yl]-1,3,4-oxadiazol-2-0l (4) 5-[5-(4-lodo-phenyiamino)-benzofuran-6-yl]-1,3,4-oxadiazol-2-0l (5) 5-[6-(2-Chloro-4-iodo-phenylamino)-7-fluoro-1,3-dihydro-isobenzofuran-5-yl]-1,3,4- oxadiazol-2-0l (6) 5-[6-(2-Chloro-4-iodo-phenylamino)-1-methyl-1 H-benzimidazol-5-yl]-1,3,4-oxadiazol-2-0l Group 24 (1 ) 5-[2-Amino-6-(4-iodo-2-methyl-phenylamino)-1 H-benzimidazol-5-yl]-1,3,4-oxadiazol-2-0l (2) 5-[6-(4-lodo-phenylamino)-benzo[b]thiophen-5-yl]-1,3,4-oxadiazol-2-0l (3) 5-[7-Fluoro-6-(4-iodo-2-methyl-phenylamino)-benzothiazol-5-yl]-1,3,4-oxadiazol-2-0l (4) 5-[5-(4-lodo-phenylamino)-benzo[b]thiophen-6-yl]-1,3,4-oxadiazol-2-0l (5) 5-(6-(2-Chloro-4-iodo-phenylamino)-7-fluoro-1,3-dihydro-benzo[c]thiaphen-5-yl]-1,3,4-oxadiazol-2-0l (6) 5-[6-{2-Chloro-4-iodo-phenylamino)-2-oxo-2,3-dihydro-1H-2$I>4=2,1,3-benzothiadiazol-5-yl]-1, 3,4-oxadiazol-2-0l Group 25 (1) 5-[2-Amino-6-(4-iodo-2-methyl-phenyiamino)-benzothiazol-5-yl]-1,3,4-oxadiazol-2-0l (2) 5-[6-(4-lodo-phenylamino)-1H-indol-5-yl]-1,3,4-oxadiazol-2-0l (3) 5-[7-Fluoro-6-(4-iodo-2-methyl-phenylamino)-benzothiazol-5-yl]-1,3,4-oxadiazol-2-0l (4) 5-[5-(4-lodo-phenylamino)-1H-indol-6-yl]-1,3,4-oxadiazol-2-0l (5) 5-[6-(2-Chloro-4-iodo-phenylamino)-7-fluoro-2,3-dihydro-1 H-isoindol-5-yl]-1,3,4- oxadiazol-2-0l (6) 5-[5-(2-Chloro-4-iodo-phenylamino)-1 H-indazol-6-yl]-1,3,4-oxadiazol-2-0l Group 26 (1) 5-[2-Amino-6-(4-iodo-2-methyl-phenylamino)-benzothiazol-5-yl]-1,3,4-oxadiazol-2-0l (2) 5-[6-(4-lodo-phenylamino)-1H-indol-5-yl]-1,3,4-oxadiazoi-2-of (3) 5-[7-Fluoro-6-(4-iodo-2-methyl-phenylamino)-benzoxazol-5-yl]-1,3,4-oxadiazol-2-0l (4) 5-[5-(4-lodo-phenylamino)-benzoxazol-6-ylj-1,3,4-oxadiazol-2-0l (5) 5-[6-(2-Chloro-4-iodo-phenylamino)-7-fluoro-2,3-dihydro-1 H-isoindol-5-yl]-1,3,4- oxadiazol-2-0l {6) 5-[5-(2-Chloro-4-iodo-phenylamino)-1 H-indazol-6-yl]-1,3,4-oxadiazol-2-0l C. Synthesis The disclosed compounds can be synthesized according to Schemes 1-25 or analogous variants thereof. These synthetic strategies are further exemplified in Examples 1-8 below. The solvent between compounds 4 and 5 in Scheme 1 is toluene (PhMe).
W O' 00/42029 PCTNS99/304 Z 6 Scheme 1 N~OH \ O
''~H ~( H'N.N O H R4 O N~ O R % ~H~N O
H a H R
I \ N I \ CI~~I \ N \ DMF \ N \
R~ / R3 / I PhCI ~ Ri I / R3 I / I R I / R I / I
t 3 Rz R_, R
I ~ 2 3 os.cH3 ~a0~
HO
N~ 00 ,= N
N~ O N~ O
H Ra H R4 I \ N I \ I \ N I \
/ /
R~ R3 I Ri / R3 / 1 R2 6 R: 5 HO~ NHZ
a Pn/e N~O~NHZ
R N3~N O
H H a I \ ( \ O I \ N I \
/ /
R~ R3 1 R~ / R3 / 1 Rz R2 Ph ~ N-'OH
N . N S N ~~S
H H R4 H Rq \ N \ c;onc.HCl \ N \
R I / R I / 1 EtOH R' I / R I / I
R~ RZ
Scheme 2 N~OH
Ph~O NH Ra O N ~~'~(NH R
\ N \ HzN_ _N~NHz \
Fl R, ~ / R3 ~ / I Pyridine R~ ~ / R3 ~ / I
Rz Rz 1~ I1 OH N~OH
CI N H Ra N ~~NH Ra N ~ \ K_N=S=O H
\ N ~ \
/ Et3N/Ph R~ R3 I Ri / R / 1 Rz Rz Ph o Ho N -N
O~S \ Ra ~ NH
R
N \ H2NNH2 \ N \
/ I / EtOH
Ri R3 I Ri ~ / Rs ~ / 1 Rz R2 HO O
~ O ~ O
H Ra SOCK / I OCH3 LDA ~ ( N I \
R3 HzN' vOlj R~ \ R3 Ra R~ \ R3 Rz ~ Rz 16 17 ~ I 18 Scheme 3 O N'/OEt z ~ . N N ~ ~~ 1.SOCI C OH
H N H \ F 1. ACONa/BI'Z 2 I \ ~ ' \ r/AcOH~ I \ F 2. KSCN_ t R, / R, R, / R, 2. KOH. EtOH R~ / Rl 3. EtOH R, / R3 Rz Rz Rz 4. NHZNHZ Rz HCI
. NHz HzN ~ N
H
H N~OH R' N/OH
HO o ,N a N., NH ~ Nv~NH
HzN N HzN
H I \ H Ra \ F NaOH \ F ~ t \ N \
R, R3 R, / Rl HzO Ri / R3 LDA R~ / R3 /
Rz Rz Rz Rz 1. HC1/ HZO
NHzNHz 2. NaOH/Hz0 PyBOP H
H N~N O
z \ F HOCN
/ + NHs R, R3 Rz Scheme 4 OH ~OH
;'I N
HzN , h O O N ~ O H,N I R~ ~ O H R
~ a \ F CI"CI \ F I \ N
/
R, R3 R~ R~ LDA R~ I / R3 I / 1 Rz Rz Rz S
CI ~CI PCIS/POC13 1. PCIS/POC13 ~SH ~. CI
O N 2, HO~NHz O
a \ F \ F
R~ R3 R ~~R3 Rz Itz HO~ NHz 1. CH3I
a 2. KMn04 O' ~
N~ S O N~O~ NHz HO~NHZ N
O
F a H R
\ \ N \
I/
R~ R3 Ri / R3 / 1 Rz Rz Scheme 5 N~OH R N~OH
'''~ 4 CH3 H O ~ S HzN w N ~ S R
\ F Ph'N~N~OEt \ F I i I N
H I \ \
R, ~ R3 Lawesson's reagent R~ ~ R3 LDA R~ I ~ R3 I ~ i Rz Rz Rz 0 o HS S O HO' vS S O'' Ph~N~N.N S
\ F HO' v Br F Ph.N~N.NHz H H F
H H ~ \
R, I ~ R3 piperidine/acetone I ~
Ri R3 R~ R3 Rz R2 Rz N~oH N~oH
RQ
N ~ S FizN~ N \ S R
H °
conc. HC1 \ F ~ ( \ N \
-->i EtOH R~ I ~ R3 . LDA R~ ' ~ R3 I
Rz Rz Scheme 6 F
~a ..
LHMDS
R1 ~ ~R3 R1 ~ R3 I
N~ O
(~)(COCi)2 R4 ----~ , a (2) HZN~~~OH R1 ~R3 (3) SOCIZ
Scheme 7 F
\ ~~ , \ a \
R1 I / R3 LHMDS R1 I / R3 I / i O
,a O
H N ~ a ~ O R4 CZH ~ R4 a CICOZC2H6 ~ a NHZNHZ,PY-BOP
\ --~ ~ \ ~ \
r~ / / /
R1 R3 I R1 ~ 'R3 I
R~ R2 OH
N-(~
Poci, N O
--~ \ R4 \ -a \
R1 ~ R3 I
Scheme 8 F I, ~ ~ a O
~ ,a O
H N~a O R4 CZH5 \ R4 a ~I~OZ~2Hs a a NHZNHZ,PY-BOP
R1 I ~ ~R3 I ~ 1 R1 ~ R3 r 'I
Lawesson's Reagent Lawesson's Reagent Xylene Toluene SH OH
N~ N-N~ S N~ S
~,.a ~ ~ a R1 I ~ ~~R3 I ~ 1 R1 , ~ R3 I ~ I
Scheme 9 COOH HzN COOH R4 F
~~ -~.. ~ ~ y R1 ~ R3 ~HMDS R1 ~ R3 ~i NHZ
S N
O N~ S
(~)ICOCI)~ HZN ~ R4 ~H'I ~ R4 (2) NHZNHC(S) H
R1 ~ I ~ R3 I v \I R1 ~ R3 / 1 NaOCH~ICH~OH
Reflux SH
N
N ~ NH
R1 ~ R3 ~ I
Scheme 10 COOH HzN \ COOHH R4 F ~I ~ \ N I \
R1 ~r R3 LHMDS ~R1 / R3 / I
NHZ
N-HZN~~ O R4 c , N ~ O R4 NH2NHZ t3rCNINaH O~(aq ) py.gp~ \ ~ \ Dioxane, r.t. \ ~ \
R1 ~ ~ R3 / I 1 I / R3 R
1 )CSi, KOH
2)HCI
SH
N
N .~ O
\ .a \
R1 I / ~R3 I / I
Scheme 11 HiN
\ ~F ~ , \ ~ \
R1 ( ~ \~R3 LHMDS R1 I ~ R3 I ~ I
NHZ
N
COOCH 3 R4 N ~ N H
CH30H/HZS04 N aminoguanidine nitrate R4 -~- I \ I \ NaOCH~ICHzOH \ ~ \
R1 ~ R3 / I
R1 I ~ R3 I / I
S
MeNH--~ NHZ
MeNCS
\a \
R1 ~ ~R3 ~ I
Scheme 12 C~2C2H5 F (1)PPh3,CBr4 ~ F
R1 I / R3 (2)n-BuLi, then CICOZCZHsR1 R3 ~ ~..COZCZHS HO
_.N
/ R4 ~ NHCH3 LHMDS ~ ~-~ .~ _ H2N ~ R1 / °R3 / I
R1 / R / 'I
Scheme 13 COOH HsN COOH R4 \ .F I ~ \ b \
I
--~. / /
R1 / 'R3 LHMDS R1 R3 I
CH OH R4 CHZBr R4 CHZCN R4 ~H~ \ ~ Bromination \ ~ \ ~ \ ~ \
--/ I ~~ R1 / R3 / I R1 I / R3 I / I
R1 ~ 'R3 I
N-S
NC CSZNa R4 HO / SO3N R4 NaH,CS2 \ ~ \ excess H202 \ ~ \
HCONMe2 ~ / ~ / ~ /
R1 ~ 'R3 1 R1 ~ ~R3 I
N-S
~H'~ HO / /
\ \
R1 I / ~R3 I / I
Scheme 14 COOH O COOH
/
\ F i j.- \ KI \ f0~ ~ / ~ /
R1 / R3 t_HMDS
O COSCZHS O~H -O
R4 BFI H \ SC H R4 eth erate H z 5.
\ I ~~ ~ \ N \
R1' / R3 "I R1 I / R3 I / I
R
~N-N
O ~ OH R4 NH2NHz R4 Alkalation ~"' \ ~ \ --~ \ ~ \
Scheme 15 II 2 \
\ F I, \ a \
__ I
R1 , ~ R3 LHMDS~R1 I ~ R3 I ~ I
OH
N-' a R4 NH2NHZ,EtOH N \ R4 _ ~.. \
\a \
i R1 ~ R3 I R1 / R3 / i NHZNHCH"EtOH
OH
N
i N;~
,a \
R1 ~R3 I
Scheme 16 \ F z I \ N
\ \
R1 ~ / R3 LHMDS R1 I / R3 I / I
Et00C Br CHLCOOEt R4 R4 1 ~LDA \ ~ \
\ ~ \
I /~ ~ / 2~Br~1 / R3 / 1 R1 ~ R3 I
NHz EtOOC N~ EtOOC N=N~ R4 NaNzJDMF Hz > , \ _..~. \ a \
R
_N .N_N
O ~N alkylation HO ~ \N
R4 -~ R4 --->
\ ~ \ \ ~ \
R1 ~ ~R3 I R1 ~ ~R3 I
alkylation N=N
HO \ N--R
\ .~ \
R1 I /~.R3 I ~I
Scheme 17 \ F
\a \
R1 ( ~ R3 ~HMns R1 ~ ~R3 I
O
OH ~S-O
I /
NHzOH.HCI HZN ~ N R4 HN i N R4 NaOCH~/CH~OH \ a \ SOCIZ/Et~N
--\ \
R1 I ~ R3 l r I
R1 ~ ~R3 I
O
w S-O
alkylation R~'~N ~.~N R4 e~ a \
R1 ~~ R3 ~ I
Scheme 18 \ F
i i \ ~ \
R1 ~R3 ~HMDS R1 ~R3 ~I
OH
N
H N~~ O R4 N ~ NH R4 UreaIKOHIEtOH a NH2NHZ~PY-BOP ~ \ -' \
\ a \_ R1 I ~ R3 I ~ 1 R1 'R3 I
R6NCO/NaOHJH20 OH
N-N ~rN''R5 R4 ~, a a \
R1 ~~ R3 / I
Scheme 19 J.
I ~. a R1 ~ R3 ~HMDS R1 ~ R3 ~ I
O
OH
HZN ~ i N NJ N
NHzOH.HCI R4 CICOOC2H6 ~ R4 NaOCH~lCH30H pyridine w I w -----~ w a w R1 ~~R3 / I R1 I ~ R3 I / I
Scheme 20 p / '~CO2C2H5 COZCsHs \ F (1)PPh~,CBr, F LHMDS
\ ~\ a~\
(2)n-BuLi, R1 R3 then CICOzCZH5R1 ~ ~R3 H=N \ R1 ~ R3 / 1 i R2 HO
_N
O
NHi~I ~ a R4 CHZN~/~
R1 ~ ~ R3 ~ I
Me0 Me0 1)n-BuLiITHF -N 1)DPPAIEt~N
2)COs 1 2)TMS(CHz)ZOH '-N
3)H~O~ HOOC ~ ~O R4 3)n-Bu4NFITHF HZN ~ O
a a R1 ~ R3 ~ I R1 ~ R3 ~ I
HO
~N
HzN.,- \ O
HBrIHOAc R4 ,a R1 I ~ R3 I ~~I
Scheme 21 . /~ ~ /
R1 ~ R3 LHMDS R1 ~ R3 / I
N~~ N
EtO2C ~ O R4 HzNHNOC ~ O R4 NHiNHZ,EtOH
(1)(COCI)2 __ (2)CNCHZCOiC2H
Et~NITHF R1 ~ ~R3 / I R1 R3 / I
HO
_: N
~ NH
HCllreflux HEN ~ R4 /
R1 ~ R3 ~I
Scheme 22 NOz HZN \ NOZ R4 NHZ R4 F
( \ ~ / I \ a \ IH1 \ a \
LHMDS R1 ~ / R3 ( / I R1 / R3 / I
O
'H
N5 a R4 _ N~N~N R4 CHZ=CHI
w \a \
R1 ~ R3 I R1 R3 / I
N
N ~ N
'N 'OH R4 ~N OH R4 .\a \ \a \
R1 ~ / R3 I / 1 R1 ~ / R3 / t Alternate synthesis: OH(TMS) ii ii N R4 OH TMS N ~OH(TMS) N
HC -~ ~ ~ N R4 N R4 a \ I \ ~~ +
\a \ \a~ \
/ /
Scheme 23 N02 HzN \ N02 ~ R4 NHi R4 \ F ~ \ ~ \
y \ \ ~H~
R1 I / R3 LHMDS R1 I ~ R3 I ~ I R1 ~ R3 / ~I
N-N
N ~~ \
N~ s R4 N~N~ R4 HC/OEt)3, NaN3 \
R1 ~ ~ ~ R3 ~ 1 R1 ~ R3 / t N-N
~t~ _ N N \
12, KMnO"H2SOd N'N~I R4 ArOH,KZCO, ~N~OAr R4 R1 ~~ ~ R3 I ~ I R1 ~ R3 / t RS
~ N ~O
NaHsPO~IPd-C ~N~O R4 Alkylation ~N R4 w \ ~ ~ \
!''~R3 I ~ I R1 ~ R3 / I
Scheme 24 \ .F ~ , \ a \
i i R1 ~ R3 LHMDS R1 / R3 / I
O
HO ~ N
KCN/(NH4)ZCO~INH4Ci EtOHIH20 \ a \
Alternate Sythesis: NH
O
CHO HO ~ N
KCNI(NH4)ZC031NH4C1 EtOH/Hz0 R1 ~ R3 R~, R1 ~ R3 NHZ
HZN
HO ~ N R4 I
\a LHMDS
R1 ~ ~R3 I
Scheme 25 COOH H2N \ COOHH R4 ~ ~ \ N \
I ~ LHMDS
R1 ~ ~ R3 R1 ~ ~ R3 1 COOH O
C N~ O
O ~NH R4 H N~COOH R4 DMF/SOCl2 \a a 1 .\ t \ y R1 ~~ R3 ~ ~ R1 ~ ~R3 D. Uses The disclosed compositions are useful as both prophylactic and therapeutic treatments for diseases or conditions as provided in the Summary section, as well as diseases or conditions modulated by the MEK cascade.
Examples include stroke, heart failure, osteoarthritis, rheumatoid arthritis, organ transplant rejection, and a variety of tumors such as ovarian, lung, pancreatic, brain, prostatic, and colorectal.
1. Dosages Those skilled in the art will be able to determine, according to known methods, the appropriate dosage for a patient, taking into account factors such as age, weight, general health, the type of pain requiring treatment, and the presence of other medications. In general, an effective amount will be between 0.1 and 1000 mglkg per day, preferably between 1 and 300 mg/kg body weight, and daily dosages will be between 10 and 5000 mg for an adult subject of normal weight. Commercially available capsules or other formulations (such as liquids and film-coated tablets) of 100 mg, 200 mg, 300 mg, or 400 mg can be administered according to the disclosed methods.
2. Formulations Dosage unit forms include tablets, capsules, pills, powders, granules, aqueous and nonaqueous oral solutions and suspensions, and parenteral solutions packaged in containers adapted for subdivision into individual doses.
Dosage unit forms can also be adapted for various methods of administration, including controlled release formulations, such as subcutaneous implants.
Administration methods include oral, rectal, parenteral (intravenous, intramuscular, subcutaneous), intracisternal, intravaginal, intraperitoneal, intravesical, local (drops, powders, ointments, gels, or cream), and by inhalation (a buccal or nasal spray).
Parenteral formulations include pharmaceutically acceptable aqueous or nonaqueous solutions, dispersion, suspensions, emulsions, and sterile powders for the preparation thereof. Examples of carriers include water, ethanol, polyols (propylene glycol, polyethylene glycol), vegetable oils, and injectable organic esters such as ethyl oleate~. Fluidity can be maintained by the use of a coating such as lecithin, a surfactant, or maintaining appropriate particle size.
Carriers for solid dosage forms include (a) fillers or extenders, (b) binders, (c) humectants, (d) disintegrating agents, (e) solution retarders, (f) absorption acccelerators, (g) adsorbants, (h) lubricants, (i) buffering agents, and (j) propellants.
Compositions may also contain adjuvants such as preserving, wetting, emulsifying, and dispensing agents; antimicrobial agents such as parabens, chlorobutanol, phenol, and sorbic acid; isotonic agents such as a sugar or sodium chloride; absorption-prolonging agents such as aluminum monostearate and gelatin; and absorption-enhancing agents.
3. Related compounds The invention provides the disclosed compounds and closely related, pharmaceutically acceptable forms of the disclosed compounds, such as salts, esters, amides, hydrates or solvated forms thereof; masked or protected forms;
and racemic mixtures, or enantiomerically or optically pure forms.
Pharmaceutically acceptable salts, esters, and amides include carboxylate salts (e.g., C ~_8 alkyl, cycloalkyl, aryl, heteroaryl, or non-aromatic heterocyclic), amino acid addition salts, esters, and amides which are within a reasonable benefit/risk ratio, pharmacologically effective, and suitable for contact with the tissues of patients without undue toxicity, irritation, or allergic response.
Representative salts include hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactiobionate, and laurylsulfonate. These may include alkali metal and alkali earth cations such as sodium, potassium, calcium, and magnesium, as well as non-toxic ammonium, quaternary ammonium, and amine cations such as tetramethyl ammonium, methylamine, trimethylamine, and ethyiamine. See, for example, S.M. Berge, et al., "Pharmaceutical Salts," J. Pharm. Sci., 1977, 66:1-19 which is incorporated herein by reference. Representative pharmaceutically acceptable amides of the invention include those derived from ammonia, primary C ~_6 alkyl amines and secondary di (C ,_6 alkyl) amines. Secondary amines include 5- or 6-membered heterocyclic or heteroaromatic ring moieties containing at least one nitrogen atom and optionally between 1 and 2 additional heteroatoms. Preferred amides are derived from ammonia, C ,_3 alkyl primary amines, and di (C ~_2 alkyl)amines.
Representative pharmaceutically acceptable esters of the invention include C ~_~ alkyl, C 5_7 cycloalkyl, phenyl, and phenyl(C ,_s)alkyl esters.
Preferred esters include methyl esters.
The invention also includes disclosed compounds having one or more functional groups (e.g., hydroxyl, amino, or carboxyl) masked by a protecting group. Some of these masked or protected compounds are pharmaceutically acceptable; others will be useful as intermediates. Synthetic intermediates and processes disclosed herein, and minor modifications thereof, are also within the scope of the invention.
HYDROXYL PROTECTING GROUPS
Hydroxyl protecting groups include: ethers, esters, and protection for 1,2-and 1,3-diols. The ether protecting groups include: methyl, substituted methyl ethers, substituted ethyl ethers, substituted benzyl ethers, silyl ethers and conversion of silyl ethers to other functional groups.
Substituted Methyl Ethers Substituted methyl ethers include: methoxymethyl, methylthiomethyl, t-utylthiomethyl, (phenyldimethylsilyl) methoxymethyl, benzyloxymethyl, p-ethoxybenzyloxymethyl, (4-methoxyphenoxy) methyl, guaiacolmethyl, t-butoxymethyl, 4-pentenyloxymethyl, siloxymethyl, 2-methoxyethoxymethyl, 2,2,2-trichloroethoxymethyl, bis(2-chloro- ethoxy)methyl, 2-(trimethylsilyl)ethoxymethyl, tetrahydropyranyl, 3-bromotetrahydro-pyranyl, tetrahydrothiopyranyl, 1-methoxycyclohexyl, 4-methoxytetrahydropyranyl, 4-methoxytetrahydrothio-pyranyl, 4-methoxytetrahydrothiopyranyl S,S-dioxido, 1-[(2-chioro-4-methyl)phenyl]-4-methoxypiperidin-4-yl, 1,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl, and 2,3,3a,4,5,6,7,7a-octahydro-7,8,8-trimethyl-4,7-ethanobenzofuran-2-yl.
Substituted Ethyl Ethers Substituted ethyl ethers include: 1-ethoxyethyl, 1-(2,chloroethoxy)ethyl, 1-methyl-1-methoxyethyl, 1-methyl-1-benzyloxyethyl, 1-methyl-1-benzyloxy-2-fluoroethyl, 2,2,2-trichloroethyl, 2-trimethylsilyethyl, 2-(phenylselenyl)ethyl, t-butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2,4-dinitrophenyl, and benzyl.
Substituted Benzyl Ethers Substituted benzyl ethers include: p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl, p-phenylbenzyl, 2- and 4-picolyl, 3-methyl-2-picolyl N-oxido, diphenylmethyl, p, p'-dinitrobenzhydryl, 5-dibenzosuberyl, triphenylmethyl, a-naphthyldiphenyl-methyl, p-methoxyphenyldiphenylmethyl, di(p-methoxyphenyl)phenylmethyl, tri-(p-methoxyphenyl)methyl, 4-(4'-bromophenacyloxy)phenyldiphenylmethyl, 4,4',4"-tris(4,5-dichlorophthalimidophenyl)methyl, 4,4',4"-tris(levulinoyloxyphenyl) methyl, 4,4',4"tris(benzoyloxyphenyl)methyi, 3-(imidazol-1-ylmethyl)bis(4',4"-dimethoxyphenyl)-methyl, 1,1-bis(4-methoxyphenyl)-1'-pyrenylmethyl, 9-anthryl, 9-(9-phenyl) xanthenyl, 9-(9-phenyl-10-oxo) anthryl, 1,3-benzodithiolan-2-yl, and benzisothiazolyl S,S-dioxido.
Silyl Ethers Silyl ethers include: trimethylsilyl, triethylsilyl, triisopropylsilyl, dimethylisopropylsilyl, diethylisopropylsilyl, dimethylthexylsilyl, t-butyldimethylsilyl, t-butyldiphenyisilyl, tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl, diphenylmethylsilyl, and t-butylmethoxyphenylsilyl.
ESTERS
Esters protecting groups include: esters, carbonates, assisted cleavage, miscellaneous esters, and sulfonates.
Esters Examples of protective esters include: formate, benzoylformate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, phenoxyacetate, p-chlorophenoxyacetate, p-P-phenylacetate, 3-phenylpropionate, 4-oxopentanoate (levulinate), 4,4-(ethylenedithio) pentanoate, pivaloate, adamantoate,crotonate,4-methoxycrotonate, benzoate, p-phenylbenzoate, and 2,4,6-trimethylbenzoate (mesitoate).
Carbonates Carbonates include: methyl, 9-fluorenylmethyl, ethyl, 2,2,2-trichloroethyl, 2-(trimethylsilyl) ethyl, 2-(phenyisulfonyl) ethyl, 2-(triphenylphosphonio) ethyl, isobutyl, vinyl, allyl, p-nitrophenyl, benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, S-benzyl thiocarbonate, 4-ethoxy-1-naphthyl, and methyl dithiocarbonate.
Assisted Cleavage Examples of assisted cleavage protecting groups include: 2-iodobenzoate, 4-azido-butyrate, 4-nitro-4-methylpentanoate, o-(dibromomethyl) benzoate, 2-formylbenzene-sulfonate, 2-(methylthiornethoxy) ethyl carbonate, 4-(methylthiomethoxymethyl) benzoate, and 2-(methylthiomethoxymethyl) benzoate.
Miscellaneous Esters In addition to the above classes, miscellaneous esters include: 2,6-dichloro-4-methylphenoxyacetate, 2,6-dichloro-4-(1,1,3,3-tetramethylbutyl) phenoxyacetate, 2,4-bis(1,1-dimethylpropyl) phenoxyacetate, chlorodiphenylacetate, isobutyrate, monosuccinoate, (~-2-methyl-2-butenoate (tigloate), o-(methoxycarbonyl) benzoate, p-P-benzoate, a-naphthoate, nitrate, alkyl N,N,N' N'-tetramethylphosphorodiamidate, N-phenylcarbamate, borate, dimethylphosphinothioyl, and 2,4-dinitrophenylsulfenate.
Sulfonates Protective sulfates includes: sulfate, methanesulfonate(mesylate), benzylsulfonate, and tosylate.
PROTECTION FOR 1.2- AND 1,3-DIOLS
The protection for 1,2 and 1,3-diols group includes: cyclic acetals and ketals, cyclic ortho esters, and silyl derivatives.
Cyclic Acetals and ICetals Cyclic acetals and ketals include: methylene, ethylidene, 1-t-butylethylidene, 1-phenylethylidene, (4-methoxyphenyl) ethylidene, 2,2,2-trichloroethylidene, acetonide (isopropylidene), cyclopentylidene, cyclohexylidene, cycloheptylidene, benzylidene, p-methoxybenzylidene, 2,4-dimethoxybenzylidene, 3,4-dimethoxybenzylidene, and 2-nitrobenzylidene.
C rLclic Ortho Esters Cyclic ortho esters include: rnethoxymethylene, ethoxymethylene, dimethoxy-methylene, 1-methoxyethylidene, 1-ethoxyethylidine, 1,2-dimethoxyethylidene, a-methoxybenzylidene, 1-(N,N-dimethylamino)ethylidene derivative, a-(N,N-dimethylamino) benzylidene derivative, and 2-oxacyclopentylidene.
PROTECTION FOR THE CARBOXYL GROUP
ESTERS
Ester protecting groups include: esters, substituted methyl esters, 2-substituted ethyl esters, substituted benzy) esters, silyl esters, activated esters, miscellaneous derivatives, and stannyl esters.
Substituted Methyl Esters Substituted methyl esters include: 9-fluorenylmethyl, methoxymethyl, methylthiomethyl, tetrahydropyranyl, tetrahydrofuranyl, methoxyethoxymethyl, 2-(trimethylsilyl)ethoxy-methyl, benzyloxymethyl, phenacyl, p-bromophenacyl, a-methylphenacyl, p-methoxyphenacyl, carboxamidomethyl, and N-phthalimidomethyl.
2-Substituted Ethyl Esters 2-Substituted ethyl esters include: 2,2,2-trichloroethyl, 2-haloethyl, ~-chloroalkyl, 2-{trimethylsily)ethyl, 2-methylthioethyl, 1,3-dithianyl-2-methyl, 2(p-nitrophenylsulfenyl)-ethyl, 2-(p-toluenesulfonyl)ethyl, 2-{2'-pyridyl)ethyl, 2-(diphenylphosphino)ethyi, 1-methyl-1-phenylethyl, f-butyl, cyclopentyl, cyclohexyl, allyl, 3-buten-1-yl, 4-(trimethylsily)-2-buten-1-yl, cinnamyl, a-methylcinnamyl phenyl, p-(methylmercapto)-phenyl, and benzyl.
Substituted Benzyl Esters Substituted benzyl esters include: triphenylmethyl, diphenylmethyl, bis(o-nitrophenyl)methyl, 9-anthrylmethyl, 2-(9,10-dioxo)anthrylmethyl, 5-dibenzo-suberyl, 1-pyrenylmethyf,2-{trifiuoromethyl)-6-chromylmethyl, 2,4,fi-trimethylbenzyl, p-bromobenzyl, o-nitrobenzyl, p-nitrobenzyl, p-methoxybenzyl, 2,6-dimethoxybenzyl, 4-(methylsulfinyl)benzyl, 4-sulfobenzyl, piperonyl, and 4-P-benzyl.
Silyl Esters Silyl esters include: trimethylsilyl, triethylsilyl, t butyldimethylsilyl, i-propyldimethyfsilyl, phenyldimethylsilyl, and di- t-butylmethylsilyl.
Miscellaneous Derivatives Miscellaneous derivatives includes: oxazofes, 2-alkyl-1,3-oxazolines, 4-alkyl-oxo-1,3-oxazolidines, 5-alkyl-4-oxo-1,3-dioxolanes, ortho esters, phenyl group, and pentaaminocobalt(III) complex.
Stannyl Esters Examples of stannyl esters include: triethylstannyl and tri-n-butylstannyl.
AMIDES AND HYDRAZIDES
Amides include: N,N -dimethyl, pyrrolidinyl, piperidinyl, 5,6-dihydrophenanthridinyl, o-nitroanilides, N-7-nitroindolyl, N-8-nitro-1,2,3,4-tetrahydroquinolyl, and p-P-benzenesulfonamides. Hydrazides include: N-phenyl, N,N'-diisopropyl and other dialkyl hydrazides.
PROTECTION FOR THE AMINO GROUP
CARBAMATES
Carbamates include: carbamates, substituted ethyl, assisted cleavage, photolytic cleavage, urea-type derivatives, and miscellaneous carbamates.
Carbamates Carbamates include: methyl and ethyl, 9-fluorenylmethyl, 9-(2-sulfo)fluorenylmethyl, 9-(2,7-dibromo)fluorenylmethyl, 2,7-di-t-butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydro- thioxanthyl)]methyl, and 4-methoxyphenacyl.
Substituted Ethyl Substituted ethyl protective groups include: 2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2-phenylethyl, 1-(1-adamantyl)-1-methylethyl, 1,1-dimethyl-2-haloethyl, 1,1dimethyl-2,2-dibromoethyl, 1,1-dimethyl-2,2,2-trichloroethyl, 1-methyl-1-(4-biphenylyl)ethyl, 1-(3,5-di-t-butylphenyl)-1-methylethyl, 2-(2'-and 4'-pyridyl)ethyl, 2-(N,N-icyclohexylcarboxamido)- ethyl, t-butyl, 1-adamantyl, vinyl, allyl, 1-isopropylallyl, connamyl, 4-nitrocinnamyl, quinolyl, N-hydroxypiperidinyl, alkyldithio, benzyl, p-methaxybenzyl, p-nitrobenzyl, p-bromobenzyl, p-chlorobenzyl, 2,4dichlorobenzyl, 4-methylsulfinylbenzyl, 9-anthrylmethyl, and diphenylmethyl.
Assisted Cleavage Protection via assisted cleavage includes: 2-methylthioethyl, 2-methylsulfonylethyl, 2-(p-toluenesulfonyl)ethyl, [2-(1,3-dithianyl)]methyl, 4-methylthiophenyl, 2,4-dimethyl-thiophenyl, 2-phosphonioethyl, 2-triphenylphosphonioisopropyl, 1,1-dimethyl-2cyanoethyl, m-chloro-p-acyloxybenzyl, p-(dihydroxyboryl)benzyl, 5-benzisoxazolyl-methyl, and 2-(trifluoromethyi)-6-chromonylmethyl.
Photola~tic Cleavage Photolytic cleavage methods use groups such as: m-nitrophenyl, 3,5-dimethoxybenzyl, o-nitrobenzyl, 3,4-dimethoxy-6-nitrobenzyl, and phenyl(o-nitrophenyl)methyl.
Urea-Type Derivatives Examples of of urea-type derivatives include: phenothiazinyl-(10)-carbonyl derivative, N'-p-toluenesulfonylaminocarbonyl, and N'-phenylaminothiocarbonyl.
Miscellaneous Carbamates In addition to the above, miscellaneous carbamates include: t-amyl, S-benzyl thiocarbamate, p-cyanobenzyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclopropylmethyl, p-decyioxy-benzyl, diisopropylmethyl, 2,2-dimethoxycarbonylvinyl, o-(N,N-dimethyl-carboxamido)-benzyl, 1,1-dimethyl-3(N,N-dimethylcarboxamido)propyl, 1,1-dimethyl-propynyl, di(2-pyridyl)methyl, 2-furanylmethyl, 2-iodoethyl, isobornyl, isobutyl, isonicotinyl, p{p'-methoxyphenyl-azo)benzyl, 1-methylcyclobutyl, 1-methylcyclohexyl, 1-methyl-1-cycfopropyl-methyl, 1-methyl-(3,5-dimethoxyphenyl)ethyl, 1-methyl-1 (p-henylazophenyl)-ethyl, 1-methyl-1-phenylethyl, 1-methyl-1-(4-pyridyl)ethyl, phenyl, p-(phenylazo)benzyl, 2,4,6-tri-t-butylphenyl, 4-(trimethylammonium) benzyl, and 2,4,6-trimethylbenzyl.
AMIDES
Amides Amides includes: N-formyl, N-acetyl, N-chloroacetyl, N-trichloroacetyl, N-trifluoroacetyl, N-phenylacetyl, N-3-phenylpropionyl, N-picolinoyl, N-3-pyridyl-carboxamide, N-benzoylphenylalanyl derivative, N-benzoyl, and N-p-phenylbenzoyl.
Assisted Cleavage Assisted cleavage groups include: N-o-nitrophenylacetyl, N-o-nitrophenoxyacetyl, N-acetoacetyl, (N~dithiobenzylaxycarbonyfamino)acetyl, N-3-(p-hydroxphenyl) propionyl" N-3-(o-nitrophenyl)propionyl, N-2-methyl-2-(0-nitrophenoxy)propionyl, N 2-methyl-2-(o-phenylazophenoxy)propionyl, N-4-chlorobutyryl, N-3-methyl-3-nitrobutyryl, N-o-nitrocinnamoyl, N-acetylmethionine derivative, N o-nitrobenzoyl, N-o-(benzoyloxymethyl)benzoyl, and 4,5-Biphenyl-oxazolin-2-one.
Cyclic Imide Derivatives Cyclic imide derivatives include: N-phthalimide, N-dithiasuccinoyl, N-2,3-Biphenyl-maleoyl, N-2,5-dimethylpyrrolyl, N-1,1,4,4-tetramethyldisilylazacyclopentane adduct, 5-substituted 1,3-dimethyl-1,3,5-triazacyclohexan-2-one, 5-substituted 1,3-dibenzyl-1,3,5-triazacyclohexan-2-one, and 1-substituted 3,5-dinitro-4-pyridonyl.
SPECIAL -NH PROTECTIVE GROUPS
Protective groups for - NI-I include: N-alkyl and N-aryl amines, imine derivatives, enamine derivatives, and N-hetero atom derivatives {such as N-metal, N-N, N-P, N-Si, and N-S), N-sulfenyl, and N-sulfonyl.
N-Alkvl and N-Aryl Amines N-alkyl and N-aryl amines include: N-methyl, N-allyl, N-[2-(trimethylsilyl)ethoxyl]-methyl, N-3-acetoxypropyl, N-(1-isopropyl-4-nitro-2-oxo-3-pyrrolin-3-yl), quaternary ammonium salts, N-benzyl, N-di(4-methoxyphenyl)methyl, N-5-dibenzosuberyl, N-triphenylmethyl, N-(4-methoxyphenyl)diphenylmethyl, N-9-phenylfluorenyl, N-2,7-dichloro-9-fluorenylmethylene, N-ferrocenylmethyl, and N-2-picolylamine N '-oxide.
Imine Derivatives (mine derivatives include: N 1,1-dimethylthiomethylene, N benzylidene, N-p-methoxybenzylidene, X11 diphenylmethylene, N-[(2-pyridyl)mesityljmethylene, N-(N',N'-dimethylaminomethylene), N,N'-isopropylidene, N-p-nitrobenzylidene, N-salicylidene, N-5-chlorosalicylidene, N-(5-chloro-2-hydroxyphenyl)phenyl-methylene, and N-cyclohexylidene.
Enamine Derivative An example of an enamine derivative is N-(5,5-dimethyl-3-oxo-1-cyclohexenyl).
N-Hetero Atom Derivatives N-metal derivatives include: N-borane derivatives, N diphenyiborinic acid derivative, N-[phenyl(pentacarbonylchromium- or -tungsten)jcarbenyl, and N-copper or N-zinc chelate. Examples of N-N derivatives include: N-nitro, N-nitroso, and N-oxide. Examples of N-P derivatives include:
N-diphenylphosphinyl, N-dimethylthiophosphinyl, N-diphenylthiophosphinyl, N dialkyl phosphoryl, N dibenzyl phosphoryl, and N-diphenyl phosphoryl.
Examples of N-sulfenyl derivatives include: N-benzenesulfenyl, N-o-nitrobenzenesulfenyl, N-2,4-dinitrobenzenesulfenyl, N-pentachlorobenzenesulfenyl, N-2-vitro-4-methoxy-benzenesulfenyl, N-triphenylmethylsulfenyl, and N-3-nitropyridinesulfenyl. N-sulfonyl derivatives include: N-p-toluenesuLFonyl, N-benzenesuifonyl, N-2,3,6-trimethyl-4-methoxybenzenesulfonyl, N-2,4,6-trimethoxybenzenesulfonyl, N-2,6-dimethyl-4-methoxy-benzenesulfonyl, N-pentamethylbenzenesulfonyl, N-2,3,5,6-tetramethyl-4-methoxybenzene- sulfonyl, N-4-methoxybenzenesulfonyl.
N-2,4,6-trimethylbenzenesulfonyl, N-2,6-dimethoxy- 4-methylbenzenesulfonyl, N-2,2,5,7,8-pentamethylchroman-6-sulfonyl, N-methanesulfonyl, N-~trimethylsilylethanesulfonyl, N-9-anthracenesulfonyl, N-4-(4',8'-dimethoxynaphthylmethyl)-benzenesulfonyl, N-benzylsulfonyl, N-trifluoromethylsulfonyl, and N-phenacylsulfonyl.
Disclosed compounds which are masked or protected may be prodrugs.
compounds metabolized or otherwise transformed in vivo to yield a disclosed compound e.g., transiently during metabolism. This transformation may be a hydrolysis or oxidation which results from contact with a bodily fluid such as blood, or the action of acids, or liver, gastrointestinal, or other enzymes.
Features of the invention are further described in the examples below.
E. EXAMPLES
~Chloro-2-(4 4-Dimethyl-4 5-dihydro oxazol 2 yl) ahenyll l4 iodo 2 methyl phenyl)-amore (18) (Scheme 2, R~=CI, R2=R3=H, R4=CH3) a). A mixture of 5-chloro-2-methoxybenzoic acid 16 (14.8 g, 0.0793 mole) and SOC12 (28.31 g, 14.97 ml, 0.1584 mole) was refluxed for 2 hours and excess SOC12 removed leaving a white residue. The solid was dissolved in CH2C12 and added to a solution of 2-amino-2-methyl-1-propanol (13.98 g, 14.97 ml, 0.1584 mole) in CH2C12 cooled with ice-bath. The ice-bath was removed, and after stirring at room temperature for 3 hours a white solid precipitated. The precipitate was separated by filtration and discarded. The filtrate was concentrated leaving a thick colorless oil. SOC12 1;17.4 ml} was added to the oil dropwise. An exothermic reaction took place resulting in to a freely flowing solution. After stirring for 30 minutes, the reaction mixture was poured in to Et20 (200 ml). An oil separated out. The Et20 layer was removed by decanting and discarded. The oily residue was dissolved in a minimum amount of water, basified with aqueous 20% NaOH, and extracted with Et20. The Et20 layer was dried (K2C03) and concentrated to give 17 as tan oil. Yield 14.63 g (77%).
b). LDA (5 ml of 2.0 M solution in THF) was added to a solution of 4-iodo-2-methylaniline (2.33 g, 0.010 mole) in THF (15 ml) at -78 °C. The mixture was stirred at-78 °C for 30 minutes. To this, a solution of 17 (1.199 g, 0.005 mole) in THF (15 ml) was added. The mixture stirred for 16 hours as it warmed up to room temperature. The reaction mixture was quenched with aqueous NH4C1 and extracted with Et20. The Et20 layer was dried (MgS04) and concentrated to give crude 18 as brown oil. The oil was purified on silica column chromatography.
Eluting with CH2C12 gave pure 1.7 g (77%) of 18 as brown oil. Four hundred and nine milligrams of the oil were dissolved in Et20 and treated with Et20-HCI
giving the HCI salt as a light yellaw solid precipitate. Yield 356.4 mg (81 %); mp °C; Anal. Calcd/found for C~8H~8N20CILHC1Ø5H20: C, 44.47/44.32; H, 4.15/3.94; N, 5.76/5.66.
[2.3-Difluoro-6-(1H-tetrazol-5-yl)-phenyll ~4-iodo-2-meth-phenyl)-amine N=N
/
CN N ~ NH
N ~ NaN3, (C2H5}3N.HCl ~~ toluene/reflux F I ~ ~ F ~ ~ I
F F
[2,3-Difluoro-6-cyano-phenyl]-(4-iodo-2-methyl-phenyl)-amine (1.118, 3mmol) and Sodium azide(0.255g, 3.9mmol) and triethylamine hydrochloride (0.537g, 3.9mmol) were all suspended in 10m1 toluene and stirred at 100°C for 12 hours. The mixture was concentrated and the residue purified by column chromatography with ethyl acetate/methanol (10/1) to give the product as a foam-like solid. The yield: ~50%
m. p: 83.4-88.7°C
'H NMR(CDC13, 400Hz): 8/ppm 7.69(1 H, m, Phenyl-H); 7.42(1 H, s, Phenyl-H);
7.27(1 H, m, Phenyl-H); 6.91 (1 H, dd, J=16.2Hz, 8.3Hz, Phenyl-H); 6.40(1 H, dd, Phenyl-H); 2.28(3H, s, CH3) L6-(4,4-Dimethyl-4 5-dihydro-oxazol-2-yl) 2 3 difiuoro phenyll (4 iodo 2 meth ~henyl)-amine COOH
H N~ O
N ~ (~) (cocl)2 H
/ ~ / (2)2-amino-2-methyl-1-propanol ~ N
,F ,I
F
~F I
F
A solution of 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-benzoic acid (1.17g, 3mmol), oxalyl chloride (0.457g, 3.6mmol) in 30m1 dichloromethane was treated with 2 drops of dimethylformamide, stirred at room temperature for 3 hours then concentrated. The residue was dissolved in 25 ml dichloromethane then the solution was added dropwi.se to a solution of 2 amino-2-methyl-1-propanol (0.623g, 7mmol) in 25 ml dichloromethane at 0°C, then stirred at room temperature for 12 hours, filtered off the precipitate, the filtration was washed with water, 5% aqueous sodium bicarbonate, 1 N HCL, brine, dried with sodium sulfate. Concentration gave the dude product, then resuspended in 25 ml chloroform, then thionyl chloride was added at 0°C and stirred at room temperature for 15 hours, then concentrated and the residue was dissolved in ml dichloromethane , 1 N HCI was added to adjusted the pH value to 11, the separated and extracted with chloroform, dried with sodium sulfate.
Concentrated and then run column with hexanes/dichloromethane (20/1) to give the compound as a white crystal. The yield: 65%
m.p.: 103.7-104.4°C
'H NMR(CDC13, 400Hz): /ppm 10.2(1 H, s, NH), 7.48-7.58(1 H, m, Phenyl-H);
7.48(1 H, s, Phenyl-H); 7.38(1 H, d, J=8.5Hz, Phenyl-H), 6.66-6.72(1 H, m, Phenyl-H); 6.58(1 H, t, J=B.OHz, Phenyl-H); 4.01(2H, s, -CH2-); 2.31(3H, s, Phenyl-CH3);
1.32(6H, s, -C(CH3)2-) 3.4-Difluoro-2-(4-iodo-2-methyl-ahenvlamino) benzoic acid methyl ester COOH O O
H
y HzS04/CH30H
.'~" ~ \ ~ \
reflux / F ~/ I / F / I
F
F
3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-benzoic acid (5g) was dissolved in 100m1 methanol and 5 drops of concentrated sulfuric acid was added, reflux for days. Run column with hexanesldichloromethane to give the product as a white solid, yield: 50%.
m.p.:90.1-90.4°C
'H NMR(CDC13, 400Hz): / ppm 8.92(1 H, s, NH), 7.75-7.78(1 H, m, Phenyl-H);
7.49(1 H, s, Phenyl-H); 7.38(1 H, dd, J=8.5Hz, 2.OHz, Phenyl-H), 6.66-6.73(1 H, m, Phenyl-H); 6.56-6.60(1 H, m, Phenyl-H); 3.88(3H, s, -OCH3); 2.30(3H, s. Phenyl-CH3) 5-f3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino~-phenyll-4H-f 1.2 4]triazol-3-lamine O O
N ~ NH
H H
N ~ ~~ aminohuanidine nitrate N
NaOCH3/CH30H
F ~ I '~ F ~ I
F F
Aminoguanidine nitrate (1.65g, 12mmol) was added to a solution of sodium methoxide (0.648g, 12mmol) in methanol (12m1) at 0°C, then 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-benzoic acid methyl ester was added as a solution of methanol and refulx for 20 hours, concentration and run column with hexanes/ethyl acetate to give the product as a white crystal. The yield: 60%
m.p.:191.7-192.0°C
'H NMR(DMSO, 400Hz): / ppm 9.45(1 H, s, -NH-); 7.79(1 H, t, J=7.3Hz, Phenyl-H); 7.51 (1 H, s, Phenyl-H); 7.35(1 H, d, J=10.1 Hz, Phenyl-H); 7.05-7.11 (1 H, m, Phenyl-H); 6.44-6.48(1 H, rn, Phenyl-H); 6.32(2H, s, -NH2), 2.32(3H, s, CH3) 5-f3,4-Difluoro-2-(4-iodo-2-methyl-phe~lamino~phenyll-f1 3 4loxadiazol-2-lamine H2N, /~. N
O NHNHZ
O ,N
H H
N ~~ BrCN/NaHC03(aq) N
dioxane, r.t.
~F . I / F / I
F F
To a solution of 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-benzoic acid hydrazide (0.806g, 2mmol) in 5ml of dioxane was added cyanogen bromide (0.212g, 2mmol) followed by a solution of sodium bicarbonate (0.17g, 2mmol) in 5ml of water. The resulting mixture was stirred 18 ours at room temperature .
the solution was concentrated and the residure was run column with hexanes/ethyl acetate (3/1 ) to give the product which was recrystallized from ethyl acetate /
hexanes to provide a pale-yellow crystal. The yield: 58%
m.p.: 183.7-184.0°C
'H NMR(CDC13, 400Hz): / ppm 8.87(1 H, s, -NH-); 7.52(1 H, s, Phenyl-H); 7.45-7.49(1 H, m, Phenyl-H); 7.4.0(1 H, d, J=8.3Hz, Phenyl-H); 6.77-6.83(1 H, m, Phenyl-H); 6.60-6.63(1 H, m, Phenyl-H); 5.02(2H, s, -NH2), 2.36(3H, s, CH3) 2-f3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-benzoyllhydrazinecarbothioamide S
COOHH H N~N~N O
N ~ _ ( 1 ) (COCI)z _ 2 H H
(2) thiosemicarbaz d ~ ~ N
/ F I / I /
F I
F
F
A solution of 3,4-Difluoro-2-{4-iodo-2-methyl-phenylamino)-benzoic acid (3.9g, 0.01mo1), oxalyl chloride (1.90g, 0.015mo1) in 40m1 dichloromethane was treated with 2 drops of dimethylformamide, stirred at room temperature for 3 hours before concentration. The residue was dissolved in 10 ml tetrahydrofuran and added to a solution of thiosemicarbazide (2.Og, 0.022mo1) in 50m1 tetrahydrofuran at 0°C, stirred at room temperature for 14 hours. Concentrated and run column chromatography with hexanes/ethyl acetate (1/1 ) to give the product as a yellow solid. 2.91g. The yield: 63%
m.p.:159.5-160.0°C
'H NMR(DMSO, 400Hz): /ppm 10.58(1H, s, -NH-); 9.28{1H, s, -NH-); 8.83(1H, s, -NH-); 7.95(1 H, s, Phenyl-H); 7.12-7.75(2H, m, NH2); 7.51 (1 H, s, Phenyl-H);
7.37(1 H, dd, J=8.6Hz, 1.7Hz, Phenyl-H); 7.16(1 H,dd, J=17Hz, 9.OHz, Phenyl-H);
6.40-6.50(1 H, m, Phenyl-H); 5.02(2H, s, -NH2), 2.00(3H, s, CH3) 5-j,3 4-Difuoro-2-(4-iodo-2-methyl-phenylamino)-phenyll-4H-(1.2,41triazole-3-thiol S
H N-H N~N~N O N ~ NH
z H ~ N \ NaOCH3/CH30H
reflux °F ~ I ~ F ~ I
F F
2-[3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-benzoyl]hydrazinecarbothioamide (1.386g, 3mmol) was dissolved in 15 ml anhydrous methanol, sodium methoxide (25% wt% in methanol) 2.5m1 was added at 0°C in one portion. The resulting mixture was heated at reflux for 17 hours before concentration. Run column with hexaneslethyl acetate to give the product as a needle white crystal. The yield: 40%
m.p.: 196.5(dec.) ' H NMR(DMSO, 400Hz): / ppm 13.87(1 H, s, -NH-); 13.80(1 H, s, -NH-); 8.16(1 H, s, -NH-); 7.61-7.65(1 H, m, Phenyl-H); 7.48(1 H, s, Phenyl-H); 7.32(1 H, dd, J=8.6Hz, 2.2Hz, Phenyl-H); 7.24(1 H,dd, J=16.4Hz, 9.5Hz, Phenyl-H); 6.42-6.46(1H, m, Phenyl-H); 5.02(2H, s, -NH2), 2.20(3H, s, CH3).
(2 3-Difluoro-6-f 1 3 4loxadiazol-2-yl-phenyl)-(4-iodo-2-methyl-phenyl)-amine N N
N O Nv O
N \ HC(C>Et)3 ~ N
pTsOH, EtOH I
F I ~ F / I
F F
3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-benzoic acid hydrazide (146 mg, 0.36 mmol) was suspended in 7 mL of absolute EtOH and 2 mL of HC(OEt)3 was added along with approximately 3 mg of pTsOH> The reaction was heated to reflux for 3h, cooled and concentration on a rotary evaporator. The reaction was purified (Si02, 4:1 Hexane,lEtOAc) to afford 117 mg (79%) of (2,3-difluoro-6-[1,3,4]oxadiazol-2-yl-phenyl)-(4-iodo-2-methyl-phenyl)-amine as a yellow powder.
M.p. = 144.4 -145.5 °C. ' H NMR (400MHz, CDC13) 8 8.89 (s, 1 H), 8.44 (s, 1 H), 7.66 (m, 1 H), 7.52 (d, J = 1.7 Hz, 1 H), 7.38 (dd, J = 8.5, 1.9 Hz, 1 H), 6.83 (m, 1 H), 6.14 (dd, J
= 8.5, 5.9 Hz, 1 H), 2.37 (s, 3 H).
5-[3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl f 1 3 4]oxadiazole-2-thiol S
N N
N O N ~ tO
N CS2, KOH N
\ I \ EtOH
F ~ I ~ F / I
F F
3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-benzoic acid hydrazide (170 mg, 0.42 mmol) was suspended in 7 mL of absolute EtOH and cooled to 0 °C.
Carbon disulfide (74 mg, 0.97 mmol) was added followed by 24 mg (0.42 mmol) of powdered KOH. The reaction was stirred for 1 h at 0 °C, 1 h at rt, and refluxed for 3 h to afford a homogeneous reaction. The reaction was cooled to rt, at which point a ppt formed. Water was added and the reaction diluted with 5 mL of EtOAc. 1 N HCI was added to acidify the aqueous layer (pH = 2). The aqueous layer was extracted with EtOAc (3x). The combined organic layers were dried over Na2S04 and concentrated to obtain 96 mg (51 %) of 5-[3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-[1,3,4]oxadiazole-2-thiol as a yellow powder.
M.p. = 231.8 - 232.8 °C. ° H NMR (400MHz, CDC13) 8 7.62 (m, 2H), 7.47 (s, 1 H), 7.30 (complex m, 2H), 6.44 (dd, J = 8.0, 4.5 Hz, 1 H), 2.19 (s, 3H).
Cascade assay for inhibitors of the MAP kinase pathway Incorporation of 32P into myelin basic protein (MBP) is assayed in the presence of a glutathione S-transferase fusion protein containing p44MAP
kinase (GST-MAPK) and a glutathione S-transferase fusion protein containing p45MEK
(GST-MEK). The assay solution contains 20 mM HEPES, pH 7.4, 10 mM MgCl2, 1 mM MnCl2, 1 mM EGTA, 50,~M [y-32P]ATP, 10 ~g GST-MEK, 0.5 ~g GST-MAPK and 40 ~.g MBP in a final volume of 100 ~L. Reactions are stopped after 20 minutes by addition of trichloroacetic acid and filtered through a GF/C
filter mat. 32P retained on the filter mat is determined using a 120S
Betaplate.
Compounds are assessed at 10 ~M for ability to inhibit incorporation of 32P.
To ascertain whether compounds are inhibiting GST-MEK or GST MAPK, two additional protocols are employed. In the first protocol, compounds are added to tubes containing GST-MEK, followed by addition of GST-MAPK, MBP
and [y-32P]ATP. In the second protocol, compounds are added to tubes containing both GST-MEK and GST-MAPK, followed by MBP and [y-32P]ATP.
Compounds that show activity in both protocols are scored as MAPK
inhibitors, while compounds showing activity in only the first protocol are scored as MEK inhibitors.
In vitro MAP kinase assay Inhibitory activity can be confirmed in direct assays. For MAP kinase, 1 ~g GST-MAPK is incubated with 40 ~g MBP for 15 minutes at 30°C in a final volume of 50 pL containing 50 mM Tris (pH 7.5), 10 ~M MgC12, 2 ~M EGTA, and pM [y-32P]ATP. The reaction is stopped by addition of Laemmli SDS sample buffer and phosphorylated MBP resolved by electrophoresis on a 10%
polyacrylamide gel. Radioactivity incorporated into MBP is determined by both 10 autoradiography, and scintillation counting of excised bands.
In vitro MEK assay For evaluation of direct MEK activity, 10 ~,g GST-MEK~ is incubated with 5 pg of a glutathione S-transferase fusion protein containing p44MAP kinase with a lysine to alanine mutation at position 71 (GST-MAPK-KA). This mutation eliminates kinase activity of MAPK, so only kinase activity attributed to the added MEK remains. Incubations are 15 minutes at 30°C in a final volume of 50 ~,L
containing 50 mM Tris (pH 7.5), 10 ~M MgC12, 2 , ~M EGTA, and 10 pM
[y-32P]ATP. The reaction is stopped by addition of Laemrnli SDS sample buffer.
Phosphorylated GST-MAPK-KA is resolved by electrophoresis on a 10%
polyacrylamide gel. Radioactivity incorporated into GST-MAPK-KA is determined by autoradiography, and subsequent scintillation counting of excised bands.
Additionally, an artificially activated MEK containing serine to glutamate mutations at positions 218 and 222 (GST-MEK-2E) is used. When these two sites are phosphorylated, MEK activity is increased. Phosphorylation of these sites can be mimicked by mutation of the serine residues to glutamate. For this assay, 5 ~g GST-MEK-2E is incubated with 5 ~g GST-MAPK-KA for 15 minutes at 30°C in the same reactian buffer as described above. Reactions are terminated and analyzed as above.
Whole cell MAP kinase assay To determine if compounds block activation of MAP kinase in whole cells, the following protocol is used. Cells are plated in multi-well plates and grown to confluence. Cells are serum-deprived overnight. Cells are exposed to the desired concentrations of compound or vehicle (DMSO) for 30 minutes, followed by addition of a growth factor, for example, PDGF (100 ng/mL). After a 5-minute treatment with the growth factor, cells are washed with PBS, and lysed in a buffer consisting of 70 mM NaCI, 10 mM HEPES (pH 7.4), 50 mM glycerol phosphate, and 1 % Triton X-100. Lysates are clarified by centrifugation at 13,000 x g for 10 minutes. Five micrograms of the resulting supernatants are incubated with 10 wg microtubule associated protein-2 {Map2) for 15 minutes at 30°C in a final volume of 25 ~L containing 50 mM Tris (pH 7.4), 10 mM MgCl2, 2 mM EGTA and 30 wM
[y s2P]ATP. Reactions are terminated by addition of Laermmli sample buffer.
Phosphorylated Map2 is resolved on 7.5% acrylamide gels and incorporated radioactivity is determined by scintillation counting of excised bands.
Monola~rer growth Cells are plated into multi-well plates at 10 to 20,000 ceIIs/mL. Forty-eight hours after seeding, test compounds are added to the cell growth medium and incubation is continued for 2 additional days. Cells are then removed from the wells by incubation with trypsin and enumerated with a Coulter counter.
Growth in soft-a~iar Cells are seeded into 35-mm dishes at 5 to 10,000 cells/dish using growth medium containing 0.3% agar. After chilling to solidify the agar, cells are transferred to a 37°C incubator. After 7 to 10 days' growth. visible colonies are manually enumerated with the aid of a dissecting microscope.
Collagen-Induced Arthritis in Mice Type II collagen-induced arthritis (CIA) in mice is an experimental model of arthritis that has a number of pathologic, immunologic, and genetic features in common with rheumatoid arthritis. The disease is induced by immunization of DBA/1 mice with 100 pg type II collagen, which is a major component of joint cartilage, delivered intradermally in Freund's complete adjuvant. The disease susceptibility is regulated by the class II MHC gene locus, which is analogous to the association of rheumatoid arthritis with HLA-DR4.
A progressive and inflammatory arthritis develops in the majority of mice immunized, characterized by paw width increases of up to 100%. A test compound is administered to mice in a range of amounts, such as 20, 60, 100, and 200 mg/kg body weight/day. The duration of the test can be several weeks to a few months, such as 40, 60, or 80 days. A clinical scoring index is used to assess disease progression from erythema and edema (stage 1), joint distortion (stage 2), to joint ankylosis (stage 3). The disease is variable in that it can affect one or all paws in an animal, resulting in a total possible score of 12 for each mouse. Histopathology of an arthritic joint reveals synovitis, pannus formation, and cartilage and bone erosions. All mouse strains that are susceptible to CIA
are high antibody responders to type II collagen, and there is a marked cellular response to CII.
SCW-induced monoarticular arthritis Arthritis is induced as described by Schwab, et al., Infection and Immunity, 59:4436-4442 (1991 ) with minor modifications. Rats receive 6 ~g sonicated SCW
[in 10 ~I Dulbecco's PBS (UPBS)] by an intraarticular injection into the right tibiotalar joint on day 0. On day 21, the DTH is initiated with 100 pg of SCW
(250 p.l) administered i.v. For oral compound studies, compounds are suspended in vehicle (0.5% hydroxypropyl-methylcellulose/0.2% Tween 80), sonicated, and administered twice daily (10 ml/kg volume) beginning 1 hr prior to reactivation with SCW. Compounds are administered in amounts between 10 and 500 mg/kg body weight/day, such as 20, 30, 60, 100, 200, and 300 mg/kglday. Edema measurements are obtained by determining the baseline volumes of the sensitized hindpaw before reactivation on day 21, and comparing them with volumes at subsequent time points such as day 22, 23, 24, and 25. Paw volume is determined by mercury plethysmography.
Mouse ear-heart transalant model Fey, T.A. et al. describe methods for transplanting split-heart neonatal cardiac grafts into the ear pinna of mice and rats (J. Pharm. and Toxic. Meth.
39:9-17 (1998)). Compounds are dissolved in solutions containing combinations of absolute ethanol, 0.2% hydroxypropyl methylcellulose in water, propylene glycol, cremophor, and dextrose, or other solvent or suspending vehicle. Mice are dosed orally or intraperitoneally once, twice or three times daily from the day of transplant (day 0) through day 13 or until grafts have been rejected. Rats are dosed once, twice, or three times daily from day 0 through day 13. Each animal is anesthetized and an incision is made at the base of the recipient ear, cutting only the dorsal epidermis and derrnis. The incision is spread open and down to the cartilage parallel to the head, and sufficiently wide to accommodate the appropriate tunneling for a rat or insertion tool for a mouse. A neonatal mouse or rat pup less than 60 hours old is anesthetized and cervically dislocated. The heart is removed from the chest, rinsed with saline, bisected longitudinally with a scalpel, and rinsed with sterile saline. The donor heart fragment is placed into the preformed tunnel with the insertion tool and air or residual fluid is gently expressed from the tunnel with light pressure. No suturing, adhesive bonding, bandaging, or treatment with antibiotics is required.
Implants are examined at 10-20-fold magnification with a stereoscopic dissecting microscope without anesthesia. Recipients whose grafts are not visibly beating may be anesthetized and evaluated for the presence of electrical activity using Grass E-2 platinum subdermal pin microelectodes placed either in the pinna or directly into the graft and a tachograph. Implants can be examined 1-4 times a day for 10, 20, 30 or more days. The ability of a test compound to ameliorate symptoms of transplant rejection can be compared with a control compound such as cyclosporine, tacrolimus, or orally-administered lefluonomide.
Murine ovalbumin-induced eosinoahilia Female C57BL/6 imice are obtained from the Jackson Laboratory (Bar Harbor, ME). All animals are given food and water ad libitum. Mice are sensitized with a single i.p. injection of OVA (grade V, Sigma Chemical Company, St.
Louis, MO) adsorbed to alum, ( 10 pg OVA + 9 mg alum in 200 ~I saline) or vehicle control, (9 mg alum in 200 ~I saline) on day 0. On day 14, the mice are challenged with a 12-minute inhalation of an aerosol consisting of 1.5% OVA
(weight/volume) in saline produced by a nebulizer (small particle generator, model SPAG-2; ICN Pharmaceuticals, Costa Mesa, CA). Groups of eight mice are dosed with oral vehicle (0.5% hydroxypropylmethylcellulose / 0.25% TWEEN-80), or a test compound at 10, 30, or 100 mg/kg in oral vehicle, 200 ~.! per mouse p.o. Dosing is performed once per day starting on day 7 or day 13, and extending through day 16.
For determination of pulmonary eosinophilia, three days after the first OVA aerosol challenge (day 17), the mice are anesthetized with an i.p.
injection of anesthetic (Ketamine/Acepromazine/Xylazine), and the tracheae is exposed and cannulated. The lungs and upper airways are lavaged twice with 0.5 ml of cold PBS. A portion (200 pl) of the bronchoalveolar lavage (BAL) fluid is enumerated using a Coulter counter Model ZB1 (Coulter Electronics, Hialeah, FL). The remaining BAL fluid is then centrifuged at 300 x g for five minutes, and the cells are resuspended in 1 ml of HBSS (Gibco BRL) containing 0.5% fetal calf serum (HyClone) and 10 mM HEPES (Gibco BRL). The cell suspension is centrifuged in a cytospin (Shandon Southern Instruments, Sewickley, PA) and stained by Diff Quick (American Scientific Products, McGraw Park, IL) to differentiate BAL leukocytes into neutrophil, eosinophil, monocyte or lymphocyte subsets. The number of eosinophils in the BAL fluid is determined by multiplying the percentage of eosinophils by the total cell count.
F. OTHER EMBODIMENTS
From the above disclosure and examples, and from the claims below, the essential features of the invention are readily apparent. The scope of the invention also encompasses various modifications and adaptations within the knowledge of a person of ordinary skill. Examples include a disclosed compound modified by addition or removal of a protecting group, or an ester, pharmaceutical salt, hydrate, acid, or amide of a disclosed compound. Publications cited herein are hereby incorporated by reference in their entirety.
What is claimed is:
Claims (45)
1. A compound of formula (I):
W is one of the following formulae (i) - (xiii):
X1 is O, S, or NRF;
X2 is OH, SH, or NHRE;
each of R E and R F is H or C 1-4 alkyl;
each of R1 and R2 is independently selected from H, F, NO2, Br and Cl;
R1 can also be SO2NR G R H, or R1 and R2 together with the benzene ring to which they are attached constitute an indole, isoindole, benzofuran, benzothiophene, indazole, benzimidazole, or benzthioazole;
R3 is H or F;
each of R G, R H, and R4 is independently selected from H, Cl and CH3;
R5 is H or C3-4 alkyl; and wherein each hydrocarbon radical above is optionally substituted with between and 3 substituents independently selected from halo, hydroxyl, amino, (amino)sulfonyl, and NO2; and wherein each heterocyclic radical above is optionally substituted with between and 3 substituents independently selected from halo, C 3-4 alkyl, C 3-6 cycloalkyl, C 3-4 alkenyl, C 3-4 alkynyl, phenyl, hydroxyl, amino, (amino)sulfonyl, and NO2, wherein each substituent alkyl, cycloalkyl, alkenyl, alkynyl or phenyl is in turn optionally substituted with between 1 and 2 substituents independently selected from halo, C 1-2 alkyl, hydroxyl, amino, and NO2;
or a pharmaceutically acceptable salt or C 1-8 ester thereof.
W is one of the following formulae (i) - (xiii):
X1 is O, S, or NRF;
X2 is OH, SH, or NHRE;
each of R E and R F is H or C 1-4 alkyl;
each of R1 and R2 is independently selected from H, F, NO2, Br and Cl;
R1 can also be SO2NR G R H, or R1 and R2 together with the benzene ring to which they are attached constitute an indole, isoindole, benzofuran, benzothiophene, indazole, benzimidazole, or benzthioazole;
R3 is H or F;
each of R G, R H, and R4 is independently selected from H, Cl and CH3;
R5 is H or C3-4 alkyl; and wherein each hydrocarbon radical above is optionally substituted with between and 3 substituents independently selected from halo, hydroxyl, amino, (amino)sulfonyl, and NO2; and wherein each heterocyclic radical above is optionally substituted with between and 3 substituents independently selected from halo, C 3-4 alkyl, C 3-6 cycloalkyl, C 3-4 alkenyl, C 3-4 alkynyl, phenyl, hydroxyl, amino, (amino)sulfonyl, and NO2, wherein each substituent alkyl, cycloalkyl, alkenyl, alkynyl or phenyl is in turn optionally substituted with between 1 and 2 substituents independently selected from halo, C 1-2 alkyl, hydroxyl, amino, and NO2;
or a pharmaceutically acceptable salt or C 1-8 ester thereof.
2. A compound of claim 1, wherein R1 is bromo or chloro.
3. A compound of claim 1, wherein R2 is fluoro.
4. A compound of claim 1, wherein R3 is H.
5. A compound of claim 4, wherein each of R2 and R3 is H.
6. A compound of claim 1, wherein each of R2 and R3 is fluoro.
7. A compound of claim 6, wherein R1 is bromo.
8. A compound of claim 6, wherein R1 is fluoro.
9. A compound of claim 1, wherein R2 is nitro.
10. A compound of claim 8, wherein R3 is H.
11. A compound of claim 1, wherein R4 is chloro.
12. A compound of claim 1, wherein R4 is methyl.
13. A compound of claim 1, wherein R5 is H.
14. A compound of claim 1, wherein R5 is CH3.
15. A compound of claim 1, wherein X1 is O or S.
16. A compound of claim 1, wherein X1 is NH or NCH3.
17. A compound of claim 1, wherein X2 is OH, SH, or NH2.
18. A compound of claim 1, wherein X2 is NHCH3 or OH.
19. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically-acceptable carrier.
20. A compound of claim 1, having a structure: [5-fluoro-2-(1H-tetrazol-5-yl)-phenyl]-(4-iodo-2-methyl-phenyl)-amine; [2,3-difluoro-6-(1 H-tetrazol-5-yl)-phenyl]-(4-iodo-2-methyl-phenyl)- amine; (4-iodo-2-methyl-phenyl)-[2,3,4-trifluoro-6-(1 H-tetrazol-5-yl)-phenyl)-amine; [4-bromo-2,3-difluoro-6-(1H-tetrazol-5-yl)-phenyl)-(4-iodo-2-methyl-phenyl)-amine; [5-fluoro-4-nitro-2-(1H-tetrazol-yl)-phenyl]-(4-iodo-2-methyl-phenyl)-amine; [2-(4,4-dimethyl-4,5-dihydro-oxazol-2-yl)-5-fluoro-phenyl]-(4-iodo-2-methyl-phenyl)-amine; [6-(4,4-dimethyl-4,5-dihydro-oxazol-2-yl)-2,3-difluoro-phenyl]-(4-iodo-2-methyl-phenyl)-amine; [6-(4,4-dimethyl-4,5-dihydro-oxazol-2-yl)-2,3,4-trifluoro-phenyl]-(4-iodo-2-methyl-phenyl)-amine; [4-bromo-6-(4,4-dimethyl-4,5-dihydro-oxazol-2-yl)-2,3-difluoro-phenyl]-(4-iodo-2-methyl-phenyl)-amine; [2-(4,4-dimethyl-4,5-dihydro-oxazol-2-yl)-5-fluoro-4-nitro-phenyl]-(4-iodo-2-methyl-phenyl)-amine; 5-[4-fluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-[1,3,4]thiadiazol-2-ol; 5-[3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-[1,3,4]thiadiazol-2-ol; 5-[3,4,5-trifluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-[1,3,4]thiadiazol-2-ol; 5-[5-bromo-3,4-difluoro-2-(4-iodo-methyl-phenylamino)-phenyl]-[1,3,4]thiadiazol-2-ol; 5-[4-fluoro-2-(4-iodo-2-methyl-phenylamino)-5-nitro-phenyl]-[1,3,4]thiadiazol-2-ol; 5-[4-fluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-[1,3,4)oxadiazol-2-ol; 5-(3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-[1,3,4]oxadiazol-2-ol; 5-[3,4,5-trifluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-[1,3,4]oxadiazol-2-ol; 5-[5-bromo-3,4-difluoro-2-(4-iodo-methyl-phenylamino)-phenyl]-[1,3,4]oxadiazol-2-ol; 5-[4-fluoro-2-(4-iodo-2-methyl-phenylamino)-5-nitro-phenyl]-[1,3,4]oxadiazol-2-ol; 5-[4-fluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-4H-[1,2,4]triazol-3-ol; 5-[3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-4H-[1,2,4]triazol-3-ol; 5-[3,4,5-trifluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl)-4H-[1,2,4]triazol-3-ol; 5-[5-bromo-3,4-difluoro-2-(4-iodo-methyl-phenylamino)-phenyl]-4H-[1,2,4]triazol-3-ol; or 5-[4-fluoro-2-(4-iodo-2-methyl-phenylamino)-5-nitro-phenyl)-4H-[1,2,4]triazol-3-ol.
21. A compound of claim 1, having a structure:
5-[4-fluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-[1,3,4]thiadiazol-2-ylamine;
5-[3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-[1,3,4]thiadiazol-2-ylamine; 5-[3,4,5-Trifluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-[1,3,4]thiadiazol-2-ylamine; 5-[5-bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-[1,3,4]thiadiazol-2-ylamine; 5-[4-fluoro-2-(4-iodo-2-methyl-phenylamino)-5-nitro-phenyl]-[1,3,4]thiadiazol-2-ylamine; 5-[4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-[1,3,4]oxadiazol-2-ylamine; 5-[3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-[1,3,4]oxadiazol-2-ylamine; 5-[3,4,5-trifluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-[1,3,4]oxadiazol-2-ylamine; 5-[5-bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-[1,3,4]oxadiazol-2-ylamine;
5-[4-fluoro-2-(4-iodo-2-methyl-phenylamino)-5-nitro-phenyl]-[1, 3,4]oxadiazol-ylamine; 5-[4-fluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-4H-[1,2,4]triazol-ylamine; 5-[3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-4H-[1,2,4]triazol-3-ylamine; 5-[3,4,5-trifluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-4H-[1,2,4]triazol-3-ylamine; 5-[5-bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-4H-[1,2,4]triazol-3-ylamine; 5-[4-fluoro-2-(4-iodo-2-methyl-phenylamino)-5-nitro-phenyl]-4H-[1,2,4]triazol-3-ylamine; 5-[4-fluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-[1,3,4]thiadiazote-2-thiol; 5-[3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-[1,3,4]thiadiazole-2-thiol; 5-[3,4,5-trifluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-[1,3,4]thiadiazole-2-thiol; 5-[5-bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-[1,3,4]thiadiazole-2-thiol; 5-[4-fluoro-2-(4-iodo-2-methyl-phenylamino)-n-vitro-phenyl]-[1,3,4]thiadiazole-2-thiol; 5-[4-fluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-[1,3,4]oxadiazole-2-thiol; 5-[3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-[1,3,4]oxadiazole-2-thiol; 5-[3,4,5-trifluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-[1,3,4]oxadiazole-2-thiol;
5-[5-bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-[1,3,4]oxadiazole-2-thiol; 5-[4-fluoro-2-(4-iodo-2-methyl-phenylamino)-5-nitro-phenyl]-[1,3,4]oxadiazole-2-thiol; 5-[4-fluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-4H-[1,2,4]triazole-3-thiol; 5-[3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-4H-[1,2,4]triazole-3-thiol; 5-[3,4,5-trifluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-4H-[1,2,4]triazole-3-thiol; 5-[5-bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-4H-[1,2,4]triazole-3-thiol; or 5-[4-fluoro-2-(4-iodo-2-methyl-phenylamino)-5-vitro-phenyl]-4H-[1,2,4]triazole-3-thiol.
5-[4-fluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-[1,3,4]thiadiazol-2-ylamine;
5-[3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-[1,3,4]thiadiazol-2-ylamine; 5-[3,4,5-Trifluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-[1,3,4]thiadiazol-2-ylamine; 5-[5-bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-[1,3,4]thiadiazol-2-ylamine; 5-[4-fluoro-2-(4-iodo-2-methyl-phenylamino)-5-nitro-phenyl]-[1,3,4]thiadiazol-2-ylamine; 5-[4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-[1,3,4]oxadiazol-2-ylamine; 5-[3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-[1,3,4]oxadiazol-2-ylamine; 5-[3,4,5-trifluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-[1,3,4]oxadiazol-2-ylamine; 5-[5-bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-[1,3,4]oxadiazol-2-ylamine;
5-[4-fluoro-2-(4-iodo-2-methyl-phenylamino)-5-nitro-phenyl]-[1, 3,4]oxadiazol-ylamine; 5-[4-fluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-4H-[1,2,4]triazol-ylamine; 5-[3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-4H-[1,2,4]triazol-3-ylamine; 5-[3,4,5-trifluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-4H-[1,2,4]triazol-3-ylamine; 5-[5-bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-4H-[1,2,4]triazol-3-ylamine; 5-[4-fluoro-2-(4-iodo-2-methyl-phenylamino)-5-nitro-phenyl]-4H-[1,2,4]triazol-3-ylamine; 5-[4-fluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-[1,3,4]thiadiazote-2-thiol; 5-[3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-[1,3,4]thiadiazole-2-thiol; 5-[3,4,5-trifluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-[1,3,4]thiadiazole-2-thiol; 5-[5-bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-[1,3,4]thiadiazole-2-thiol; 5-[4-fluoro-2-(4-iodo-2-methyl-phenylamino)-n-vitro-phenyl]-[1,3,4]thiadiazole-2-thiol; 5-[4-fluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-[1,3,4]oxadiazole-2-thiol; 5-[3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-[1,3,4]oxadiazole-2-thiol; 5-[3,4,5-trifluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-[1,3,4]oxadiazole-2-thiol;
5-[5-bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-[1,3,4]oxadiazole-2-thiol; 5-[4-fluoro-2-(4-iodo-2-methyl-phenylamino)-5-nitro-phenyl]-[1,3,4]oxadiazole-2-thiol; 5-[4-fluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-4H-[1,2,4]triazole-3-thiol; 5-[3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-4H-[1,2,4]triazole-3-thiol; 5-[3,4,5-trifluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-4H-[1,2,4]triazole-3-thiol; 5-[5-bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-4H-[1,2,4]triazole-3-thiol; or 5-[4-fluoro-2-(4-iodo-2-methyl-phenylamino)-5-vitro-phenyl]-4H-[1,2,4]triazole-3-thiol.
22. A compound of claim 1, having a structure: 5-[4-fluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl)-isothiazol-3-ol; 5-[3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-isothiazol-3-ol; 5-[3,4,5-trifluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl)-isothiazol-3-ol; 5-[5-bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl)-isothiazol-3-ol; 5-[4-fluoro-2-(4-iodo-2-methyl-phenylamino)-5-nitro-phenyl]-isothiazol-3-ol; 5-[4-fluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-isoxazol-3-ol; 5-[3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-isoxazol-3-ol; 5-[3,4,5-trifluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-isoxazol-3-ol; 5-[5-bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-isoxazol-3-ol; 5-[4-fluoro-2-(4-iodo-2-methyl-phenylamino)-5-nitro-phenyl]-isoxazol-3-ol; 5-[4-fluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-1H-pyrazol-3-ol; 5-[3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-1H-pyrazol-3-ol; 5-[3,4,5-trifluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-1H-pyrazol-3-ol; 5-[5-bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-1H-pyrazol-3-ol; 5-[4-fluoro-2-(4-iodo-2-methyl-phenylamino)-5-nitro-phenyl)-pyrazol-3-ol; 4-[4-fluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-isothiazol-3-ol;
4-[3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-isothiazol-3-ol; 4-[3,4,5-trifluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-isothiazol-3-ol; 4-[5-bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-isothiazol-3-ol; 4-[4-fluoro-2-(4-iodo-2-methyl-phenylamino)-5-nitro-phenyl]-isothiazol-3-ol; 4-[4-fluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-isoxazol-3-ol; 4-[3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-isoxazol-3-ol; 4-[3,4,5-trifluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-isoxazol-3-ol; 4-[5-bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-isoxazol-3-ol; 4-[4-fluoro-2-(4-iodo-2-methyl-phenylamino)-5-nitro-phenyl]-isoxazol-3-ol; 4-[4-fluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-1-methyl-1H-pyrazol-3-ol; 4-[3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl)-1-methyl-1H-pyrazol-3-ol; 1-methyl-4-[3,4,5-trifluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-1H-pyrazol-3-ol; 4-[5-bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-1-methyl-1H-pyrazol-3-ol; or 4-[4-fluoro-(4-iodo-2-methyl-phenylamino)-5-nitro-phenyl)-1-methyl-1H-pyrazol-3-ol.
4-[3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-isothiazol-3-ol; 4-[3,4,5-trifluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-isothiazol-3-ol; 4-[5-bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-isothiazol-3-ol; 4-[4-fluoro-2-(4-iodo-2-methyl-phenylamino)-5-nitro-phenyl]-isothiazol-3-ol; 4-[4-fluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-isoxazol-3-ol; 4-[3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-isoxazol-3-ol; 4-[3,4,5-trifluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-isoxazol-3-ol; 4-[5-bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-isoxazol-3-ol; 4-[4-fluoro-2-(4-iodo-2-methyl-phenylamino)-5-nitro-phenyl]-isoxazol-3-ol; 4-[4-fluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-1-methyl-1H-pyrazol-3-ol; 4-[3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl)-1-methyl-1H-pyrazol-3-ol; 1-methyl-4-[3,4,5-trifluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-1H-pyrazol-3-ol; 4-[5-bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-1-methyl-1H-pyrazol-3-ol; or 4-[4-fluoro-(4-iodo-2-methyl-phenylamino)-5-nitro-phenyl)-1-methyl-1H-pyrazol-3-ol.
23. A compound of claim 1, having a structure: 5-[2-(2-amino-4-iodo-phenylamino)-4-fluoro-phenyl]-1-methyl-1H-[1,2,3]triazol-4-ol; 5-[2-(2-amino-4-iodo-phenylamino)-3,4-difluoro-phenyl]-1-methyl-1H-[1,2,3]triazol-4-ol; 5-[2-(2-amino-4-iodo-phenylamino)-3,4,5-trifluoro-phenyl]-1-methyl-1H-[1,2,3]triazol-4-ol;
5-[2-(2-amino-4-iodo-phenylamino)-5-bromo-3,4-difluoro-phenyl]-1-methyl-1H-[1,2,3]triazol-4-ol; 5-[2-(2-amino-4-iodo-phenylamino)-4-fluoro-5-nitro-phenyl]-1-methyl-1H-[1,2,3]triazol-4-ol; 5-[4-fluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-3-methyl-3H-[1,2,3]triazol-4-ol; 5-[3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-3-methyl-3H-[1,2,3]triazol-4-ol; 3-methyl-5-[3,4,5-trifluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-3H-[1,2,3]triazol-4-ol; 5-[5-bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-3-methyl-3H-[1,2,3]triazol-4-ol;
5-[4-fluoro-2-(4-iodo-2-methyl-phenylamino)-5-nitro-phenyl]-3-methyl-3H-[1,2,3]triazol-4-ol; 4-[4-fluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-2-methyl-2H-pyrazol-3-ol; 4-[3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-2-methyl-2H-pyrazol-3-ol; 2-methyl-4-[3,4,5-trifluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-2H-pyrazol-3-ol; 4-[5-bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-2-methyl-2H-pyrazol-3-ol; 4-[4-fluoro-2-(4-iodo-2-methyl-phenylamino)-5-nitro-phenyl]-2-methyl-2H-pyrazol-3-ol; 1-[4-fluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-4-methyl-1,4-dihydro-tetrazol-5-one; 1-[3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-4-methyl-1,4-dihydro-tetrazol-one; 1-methyl-4-[3,4,5-trifluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-1,4-dihydro-tetrazol-5-one; 1-[5-bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-4-methyl-1,4-dihydro-tetrazol-5-one; 1-[4-fluoro-2-(4-iodo-2-methyl-phenylamino)-5-nitro-phenyl]-4-methyl-1,4-dihydro-tetrazol-5-one; 1-[4-fluoro-(4-iodo-2-methyl-phenylamino)-phenyl]-1H-[1,2,3]triazol-4-ol; 1-[3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-1H-[1,2,3]triazol-4-ol; 1-[3,4,5-trifluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-1H-[1,2,3]triazol-4-ol; 1-[5-bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-1H-[1,2,3]triazol-4-ol; or 1-[4-fluoro-2-(4-iodo-2-methyl-phenylamino)-5-nitro-phenyl]-1H-[1,2,3]triazol-4-ol.
5-[2-(2-amino-4-iodo-phenylamino)-5-bromo-3,4-difluoro-phenyl]-1-methyl-1H-[1,2,3]triazol-4-ol; 5-[2-(2-amino-4-iodo-phenylamino)-4-fluoro-5-nitro-phenyl]-1-methyl-1H-[1,2,3]triazol-4-ol; 5-[4-fluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-3-methyl-3H-[1,2,3]triazol-4-ol; 5-[3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-3-methyl-3H-[1,2,3]triazol-4-ol; 3-methyl-5-[3,4,5-trifluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-3H-[1,2,3]triazol-4-ol; 5-[5-bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-3-methyl-3H-[1,2,3]triazol-4-ol;
5-[4-fluoro-2-(4-iodo-2-methyl-phenylamino)-5-nitro-phenyl]-3-methyl-3H-[1,2,3]triazol-4-ol; 4-[4-fluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-2-methyl-2H-pyrazol-3-ol; 4-[3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-2-methyl-2H-pyrazol-3-ol; 2-methyl-4-[3,4,5-trifluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-2H-pyrazol-3-ol; 4-[5-bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-2-methyl-2H-pyrazol-3-ol; 4-[4-fluoro-2-(4-iodo-2-methyl-phenylamino)-5-nitro-phenyl]-2-methyl-2H-pyrazol-3-ol; 1-[4-fluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-4-methyl-1,4-dihydro-tetrazol-5-one; 1-[3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-4-methyl-1,4-dihydro-tetrazol-one; 1-methyl-4-[3,4,5-trifluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-1,4-dihydro-tetrazol-5-one; 1-[5-bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-4-methyl-1,4-dihydro-tetrazol-5-one; 1-[4-fluoro-2-(4-iodo-2-methyl-phenylamino)-5-nitro-phenyl]-4-methyl-1,4-dihydro-tetrazol-5-one; 1-[4-fluoro-(4-iodo-2-methyl-phenylamino)-phenyl]-1H-[1,2,3]triazol-4-ol; 1-[3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-1H-[1,2,3]triazol-4-ol; 1-[3,4,5-trifluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-1H-[1,2,3]triazol-4-ol; 1-[5-bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-1H-[1,2,3]triazol-4-ol; or 1-[4-fluoro-2-(4-iodo-2-methyl-phenylamino)-5-nitro-phenyl]-1H-[1,2,3]triazol-4-ol.
24. A compound of claim 1, having a structure: 3-[4-fluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-2H-isoxazol-5-one; 3[3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-2H-isoxazol-5-one; 3-[3,4,5-trifluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-2H-isoxazol-5-one; 3-[5-bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-2H-isoxazol-5-one; 3-[4-fluoro-2-(4-iodo-2-methyl-phenylamino)-5-nitro-phenyl]-2H-isoxazol-5-one; [5-fluoro-2-(2-oxo-2,3-dihydro-2~ > 4_[1,2,3,5]oxathiadiazol-4-yl)-phenyl]-(4-iodo-2-methyl-phenyl)-amine; [2,3-difluoro-6-(2-oxo-2,3-dihydro-2~ > 4_-[1,2,3,5]oxathiadiazol-4-yl)-phenyl]-(4-iodo-2-methyl-phenyl)-amine; (4-lodo-2-methyl-phenyl)-[2,3,4-trifluoro-6-(2-oxo-2,3-dihydro-2~ > 4_-[1,2,3,5]oxathiadiazol-4-yl)-phenyl)-amine; [4-bromo-2,3-difluoro-6-(2-oxo-2,3-dihydro-2~ > 4_-[1,2,3,5]oxathiadiazol-4-yl)-phenyl]-(4-iodo-2-methyl-phenyl)-amine; [5-fluoro-4-nitro-2-(2-oxo-2,3-dihydro-2~ > 4_-[1,2,3,5]oxathiadiazol-4-yl)-phenyl)-(4-iodo-2-methyl-phenyl)-amine; 4-[4-fluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-4H-isoxazol-5-one; 4-(3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-4H-isoxazol-5-one; 4-[3,4,5-trifluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-4H-isoxazol-5-one; 4-[5-bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-4H-isoxazol-5-one; or 4-[4-fluoro-2-(4-iodo-2-methyl-phenylamino)-5-nitro-phenyl]-4H-isoxazol-5-one.
25. A method for treating a proliferative disease, said method comprising administering to a patient in need of such treatment a pharmaceutically-effective amount of a composition comprising a compound of claim 1.
26. A method of claim 25, wherein said proliferative disease is selected from psoriasis, restenosis, autoimmune disease, and atherosclerosis.
27. A method for treating cancer, said method comprising administering to a patient in need of such treatment a pharmaceutically-effective amount of a composition comprising a compound of claim 1.
28. A method of claim 27, wherein said cancer is MEK-related.
29. A method of claim 27, wherein said cancer is brain, breast, lung, ovarian, pancreatic, prostate, renal, or colorectal cancer.
30. A method for treating, or ameliorating the sequelae of, a stroke, said method comprising administering to a patient in need of such treatment a pharmaceutically-effective amount of a composition comprising a compound of claim 1.
31. A method for treating, or ameliorating the sequelae of, heart failure, said method comprising administering to a patient in need of such treatment a pharmaceutically-effective amount of a composition comprising a compound of claim 1.
32. A method for treating or reducing the symptoms of xenograft rejection, said method comprising administering to an organ transplant, limb transplant, skin transplant, cell(s) transplant, or bone marrow transplant patient a pharmaceutically-effective amount of a composition comprising a compound of claim 1.
33. A method for treating osteoarthritis, said method comprising administering to a patient in need of such treatment a pharmaceutically-effective amount of a composition comprising a compound of claim 1.
34. A method for treating rheumatoid arthritis, said method comprising administering to a patient in need of such treatment a pharmaceutically-effective amount of a composition comprising a compound of claim 1.
35. A method for treating cystic fibrosis, said method comprising administering to a patient in need of such treatment a pharmaceutically-effective amount of a composition comprising a compound of claim 1.
36. A method for treating hepatomegaly, said method comprising administering to a patient in need of such treatment a pharmaceutically-effective amount of a composition comprising a compound of claim 1.
37. A method for treating cardiomegaly, said method comprising administering to a patient in need of such treatment a pharmaceutically-effective amount of a composition comprising a compound of claim 1.
38. A method for treating Alzheimer's disease, said method comprising administering to a patient in need of such treatment a pharmaceutically-effective amount of a composition comprising a compound of claim 1.
39. A method for treating a complication of diabetes, said method comprising administering to a patient in need of such treatment a pharmaceutically-effective amount of a composition comprising a compound of claim 1.
40. A method for treating septic shock, said method comprising administering to a patient in need of such treatment a pharmaceutically-effective amount of a composition comprising a compound of claim 1.
41. A method for treating a viral infection, said method comprising administering to a patient in need of such treatment a pharmaceutically-effective amount of a composition comprising a compound of claim 1.
42. A method of claim 41, wherein said infection is an infection of HIV.
43. A method for treating cancer, said method comprising (a) administering to a patient in need of such treatment, a pharmaceutically-effective amount of a composition comprising a compound of claim 1; and (b) administering a therapy selected from radiation therapy and chemotherapy.
44. A method of claim 43, wherein said chemotherapy comprises a mitotic inhibitor.
45. A method of claim 44, wherein said mitotic inhibitor is selected from paclitaxel, docetaxel, vincristine, vinblastine, vinorelbine, and vinflunine.
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| US60/122,420 | 1999-03-02 | ||
| PCT/US1999/030416 WO2000042029A1 (en) | 1999-01-13 | 1999-12-21 | 1-heterocycle substituted diarylamines |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010068738A1 (en) | 2008-12-10 | 2010-06-17 | Dana-Farber Cancer Institute, Inc. | Mek mutations conferring resistance to mek inhibitors |
| WO2011106298A1 (en) | 2010-02-25 | 2011-09-01 | Dana-Farber Cancer Institute, Inc. | Braf mutations conferring resistance to braf inhibitors |
| WO2013169858A1 (en) | 2012-05-08 | 2013-11-14 | The Broad Institute, Inc. | Diagnostic and treatment methods in patients having or at risk of developing resistance to cancer therapy |
| US11078540B2 (en) | 2010-03-09 | 2021-08-03 | Dana-Farber Cancer Institute, Inc. | Methods of diagnosing and treating cancer in patients having or developing resistance to a first cancer therapy |
Families Citing this family (89)
| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2001005391A2 (en) * | 1999-07-16 | 2001-01-25 | Warner-Lambert Company | Method for treating chronic pain using mek inhibitors |
| US7345051B2 (en) | 2000-01-31 | 2008-03-18 | Genaera Corporation | Mucin synthesis inhibitors |
| WO2001054685A1 (en) | 2000-01-31 | 2001-08-02 | Genaera Corporation | Mucin synthesis inhibitors |
| WO2001068619A1 (en) * | 2000-03-15 | 2001-09-20 | Warner-Lambert Company | 5-amide substituted diarylamines as mex inhibitors |
| EP1339702A1 (en) | 2000-03-15 | 2003-09-03 | Warner-Lambert Company | 5-amide substituted diarylamines as mek inhibitors |
| DE10017480A1 (en) * | 2000-04-07 | 2001-10-11 | Transmit Technologietransfer | Use of substances that act as MEK inhibitors for the manufacture of a medicament against DNA and RNA viruses |
| WO2002017952A2 (en) | 2000-09-01 | 2002-03-07 | Van Andel Institute | Inhibition of mitogen-activated protein kinase (mapk) pathway: a selective therapeutic strategy against melanoma |
| ES2242771T5 (en) | 2000-09-15 | 2011-10-14 | Vertex Pharmaceuticals Incorporated | PIRAZOL COMPOUNDS USEFUL AS PROTEIN QUINASE INHIBITORS. |
| US6613776B2 (en) | 2000-09-15 | 2003-09-02 | Vertex Pharmaceuticals Incorporated | Pyrazole compounds useful as protein kinase inhibitors |
| US6660731B2 (en) | 2000-09-15 | 2003-12-09 | Vertex Pharmaceuticals Incorporated | Pyrazole compounds useful as protein kinase inhibitors |
| ATE327989T1 (en) | 2000-12-21 | 2006-06-15 | Vertex Pharma | PYRAZOLE COMPOUNDS AS PROTEIN KINASE INHIBITORS |
| WO2002076496A1 (en) * | 2001-03-22 | 2002-10-03 | Van Andel Institute | Anthrax lethal factor inhibits tumor growth and angiogenesis |
| WO2003035626A2 (en) * | 2001-10-23 | 2003-05-01 | Applied Research Systems Ars Holding N.V. | Azole derivatives and pharmaceutical compositions containing them |
| DK1847534T3 (en) | 2001-12-11 | 2011-08-29 | Kyowa Hakko Kirin Co Ltd | Thiadiazoline derivatives for the treatment of cancer |
| AU2003218157C1 (en) | 2002-03-13 | 2011-11-24 | Array Biopharma, Inc | N3 alkylated benzimidazole derivatives as mek inhibitors |
| US7235537B2 (en) * | 2002-03-13 | 2007-06-26 | Array Biopharma, Inc. | N3 alkylated benzimidazole derivatives as MEK inhibitors |
| US20050004186A1 (en) * | 2002-12-20 | 2005-01-06 | Pfizer Inc | MEK inhibiting compounds |
| ES2394850T3 (en) | 2003-04-18 | 2013-02-06 | Kyowa Hakko Kirin Co., Ltd. | Mitotic kinesin inhibitor |
| DE10321297B4 (en) * | 2003-05-13 | 2005-11-10 | Clariant Gmbh | Flame retardant thermosetting compounds, a process for their preparation and their use |
| EP1632484A4 (en) * | 2003-06-10 | 2008-09-03 | Kyowa Hakko Kogyo Kk | Thiadiazoline derivative |
| US7144907B2 (en) | 2003-09-03 | 2006-12-05 | Array Biopharma Inc. | Heterocyclic inhibitors of MEK and methods of use thereof |
| US7538120B2 (en) | 2003-09-03 | 2009-05-26 | Array Biopharma Inc. | Method of treating inflammatory diseases |
| EP1671957A4 (en) * | 2003-10-10 | 2007-03-14 | Thiadiazoline derivatives | |
| CA2542210A1 (en) | 2003-10-21 | 2005-05-06 | Warner-Lambert Company Llc | Polymorphic form of n-[(r)-2,3-dihydroxy-propoxy]-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide |
| US7517994B2 (en) | 2003-11-19 | 2009-04-14 | Array Biopharma Inc. | Heterocyclic inhibitors of MEK and methods of use thereof |
| CA2545659C (en) | 2003-11-19 | 2013-06-04 | Array Biopharma Inc. | Bicyclic inhibitors of mek |
| US7732616B2 (en) * | 2003-11-19 | 2010-06-08 | Array Biopharma Inc. | Dihydropyridine and dihydropyridazine derivatives as inhibitors of MEK and methods of use thereof |
| KR101223914B1 (en) * | 2003-11-21 | 2013-01-18 | 어레이 바이오파마 인크. | Akt protein kinase inhibitors |
| EP1799656A4 (en) * | 2004-08-25 | 2009-09-02 | Targegen Inc | Heterocyclic compounds and methods of use |
| US7449486B2 (en) * | 2004-10-19 | 2008-11-11 | Array Biopharma Inc. | Mitotic kinesin inhibitors and methods of use thereof |
| EP1802579B1 (en) | 2004-10-20 | 2013-11-20 | Merck Serono SA | Derivatives of 3-arylaminopyridine |
| WO2006101103A1 (en) * | 2005-03-22 | 2006-09-28 | Kyowa Hakko Kogyo Co., Ltd. | Agent for treatment of hematopoietic tumor |
| TW200714593A (en) * | 2005-03-22 | 2007-04-16 | Kyowa Hakko Kogyo Kk | Agent for treatment of solid tumor |
| CN102898364A (en) | 2005-05-18 | 2013-01-30 | 阵列生物制药公司 | Heterocyclic inhibitors of MEK and methods of use thereof |
| US7910611B2 (en) * | 2005-06-24 | 2011-03-22 | Kyowa Hakko Kirin Co., Ltd. | Therapeutic agent for restenosis |
| US8101799B2 (en) | 2005-07-21 | 2012-01-24 | Ardea Biosciences | Derivatives of N-(arylamino) sulfonamides as inhibitors of MEK |
| EP1940792B1 (en) * | 2005-10-06 | 2014-06-04 | Exelixis, Inc. | Aminopyrimidine, aminopyridine and aniline derivatives as inhibitors of pim-1 and/or pim-3 |
| EA025871B9 (en) | 2005-10-07 | 2017-08-31 | Экселиксис, Инк. | Mek inhibitors and methods of using the same |
| WO2007123939A2 (en) | 2006-04-19 | 2007-11-01 | Laboratoires Serono S.A. | Novel arylamino n-heteraryls as mek inhibitors |
| AU2007240860A1 (en) * | 2006-04-19 | 2007-11-01 | Merck Serono Sa | Novel heteroaryl-substituted arylaminopyridine derivatives as MEK inhibitors |
| WO2007132867A1 (en) | 2006-05-15 | 2007-11-22 | Takeda Pharmaceutical Company Limited | Prophylactic and therapeutic agent for cancer |
| CN101511842B (en) | 2006-07-06 | 2012-10-31 | 阵列生物制药公司 | Dihydrofuro pyrimidines as AKT protein kinase inhibitors |
| US8003651B2 (en) | 2006-07-06 | 2011-08-23 | Array Biopharma Inc. | Pyrimidyl cyclopentanes as AKT protein kinase inhibitors |
| US9303040B2 (en) | 2006-07-06 | 2016-04-05 | Array Biopharma Inc. | Substituted piperazines as AKT inhibitors |
| US8063050B2 (en) | 2006-07-06 | 2011-11-22 | Array Biopharma Inc. | Hydroxylated and methoxylated pyrimidyl cyclopentanes as AKT protein kinase inhibitors |
| CN105106199A (en) | 2006-12-14 | 2015-12-02 | 埃克塞利希斯股份有限公司 | Methods of using MEK inhibitors |
| US9409886B2 (en) | 2007-07-05 | 2016-08-09 | Array Biopharma Inc. | Pyrimidyl cyclopentanes as AKT protein kinase inhibitors |
| JP5542282B2 (en) | 2007-07-05 | 2014-07-09 | アレイ バイオファーマ、インコーポレイテッド | Pyrimidylcyclopentane as an AKT protein kinase inhibitor |
| US8846683B2 (en) | 2007-07-05 | 2014-09-30 | Array Biopharma, Inc. | Pyrimidyl cyclopentanes as Akt protein kinase inhibitors |
| ES2551352T3 (en) | 2007-07-05 | 2015-11-18 | Array Biopharma, Inc. | Pyrimido cyclopentanes useful for the treatment of inflammatory or hyperproliferative diseases |
| JP5479337B2 (en) * | 2007-07-30 | 2014-04-23 | アルディア バイオサイエンス，インク． | Combination of MEK inhibitor and RAF kinase inhibitor and use thereof |
| CN103479604B (en) * | 2007-07-30 | 2016-08-10 | 阿迪生物科学公司 | N-(virtue amino) sulfamide derivative including polymorph and compositions, its using method and preparation method as mek inhibitor |
| CA2694499A1 (en) | 2007-07-31 | 2009-02-05 | Vertex Pharmaceuticals Incorporated | Process for preparing 5-fluoro-1h-pyrazolo [3, 4-b] pyridin-3-amine and derivatives thereof |
| AU2009204019B2 (en) | 2008-01-09 | 2014-02-20 | Array Biopharma Inc. | Hydroxylated pyrimidyl cyclopentane as AKT protein kinase inhibitor |
| KR101624753B1 (en) | 2008-01-09 | 2016-05-26 | 어레이 바이오파마 인크. | Hydroxylated pyrimidyl cyclopentanes as akt protein kinase inhibitors |
| US8044240B2 (en) | 2008-03-06 | 2011-10-25 | Ardea Biosciences Inc. | Polymorphic form of N-(S)-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl)cyclopropane-1-sulfonamide and uses thereof |
| JP2011518786A (en) * | 2008-04-14 | 2011-06-30 | アルデア バイオサイエンシズ，インコーポレイティド | Compositions and methods for preparation and use |
| KR101651700B1 (en) | 2008-08-04 | 2016-08-26 | 메르크 파텐트 게엠베하 | Novel phenylamino isonicotinamide compounds |
| WO2010051933A2 (en) | 2008-11-10 | 2010-05-14 | Bayer Schering Pharma Aktiengesellschaft | Substituted sulphonamido phenoxybenzamides |
| JP2013508320A (en) | 2009-10-21 | 2013-03-07 | バイエル・ファルマ・アクチェンゲゼルシャフト | Substituted halophenoxybenzamide derivatives |
| US8962606B2 (en) | 2009-10-21 | 2015-02-24 | Bayer Intellectual Property Gmbh | Substituted benzosulphonamides |
| CA2777430A1 (en) | 2009-10-21 | 2011-04-28 | Bayer Pharma Aktiengesellschaft | Substituted benzosulphonamides |
| EP2495238A4 (en) | 2009-10-30 | 2013-04-24 | Mochida Pharm Co Ltd | Novel 3-hydroxy-5-arylisoxazole derivative |
| CA2780759A1 (en) | 2009-12-01 | 2011-06-09 | Rigel Pharmaceuticals, Inc. | Protein kinase c inhibitors and uses thereof |
| MA33952B1 (en) | 2009-12-25 | 2013-01-02 | Mochida Pharmacal Co Ltd | NEW 3-HYDROXY-5-ARYLISOTHIAZOLE DERIVATIVE |
| AU2011313191A1 (en) | 2010-10-08 | 2013-05-02 | Mochida Pharmaceutical Co., Ltd. | Cyclic amide derivative |
| CA2816188A1 (en) | 2010-10-29 | 2012-05-03 | Marion Hitchcock | Substituted phenoxypyridines |
| CN102020651B (en) | 2010-11-02 | 2012-07-18 | 北京赛林泰医药技术有限公司 | 6-aryl amino pyridone formamide MEK (methyl ethyl ketone) inhibitor |
| AU2012236138A1 (en) | 2011-04-01 | 2013-11-14 | Genentech, Inc. | Combinations of AKT inhibitor compounds and erlotinib, and methods of use |
| EP2694073B1 (en) | 2011-04-01 | 2018-08-08 | Genentech, Inc. | Combinations of akt and mek inhibitors for treating cancer |
| WO2012147518A1 (en) | 2011-04-27 | 2012-11-01 | 持田製薬株式会社 | Novel 3-hydroxyisothiazole 1-oxide derivative |
| EP2716636A4 (en) | 2011-04-28 | 2014-11-26 | Mochida Pharm Co Ltd | Cyclic amide derivative |
| ES2597052T3 (en) | 2011-05-25 | 2017-01-13 | Université Paris Descartes | ERK inhibitors for use in the treatment of spinal muscular atrophy |
| CN103204827B (en) | 2012-01-17 | 2014-12-03 | 上海科州药物研发有限公司 | Benzothiadiazole compounds as protein kinase inhibitors, and preparation method and application thereof |
| PL2855434T3 (en) * | 2012-05-30 | 2016-12-30 | Solid state forms of n-((s)-2,3-dihydroxy-propyl)-3-(2-fluoro-4-iodo-phenylamino)-isonicotinamide | |
| CN104394855A (en) | 2012-05-31 | 2015-03-04 | 拜耳医药股份有限公司 | Biomarkers for determining effective response of treatments of hepatocellular carcinoma (HCC) patients |
| IN2015DN03928A (en) | 2012-10-12 | 2015-10-02 | Exelixis Inc | |
| WO2014081689A1 (en) | 2012-11-20 | 2014-05-30 | Vertex Pharmaceuticals Incorporated | Compounds useful as inhibitors of indoleamine 2,3-dioxygenase |
| WO2015038704A1 (en) | 2013-09-11 | 2015-03-19 | The J. David Gladstone Institutes, A Testamentary Trust Established Under The Will Of J. David Gladstone | Compositions for preparing cardiomyocytes |
| AU2015328411C1 (en) | 2014-10-06 | 2022-03-03 | Dana-Farber Cancer Institute, Inc. | Angiopoietin-2 biomarkers predictive of anti-immune checkpoint response |
| MA41866A (en) | 2015-03-31 | 2018-02-06 | Massachusetts Gen Hospital | SELF-ASSEMBLING MOLECULES FOR TARGETED DRUG DELIVERY |
| EP3618818A4 (en) | 2017-05-03 | 2020-12-09 | Vivace Therapeutics, Inc. | Non-fused tricyclic compounds |
| EP3691623B1 (en) | 2017-08-21 | 2022-10-05 | Vivace Therapeutics, Inc. | Benzosulfonyl compounds |
| CA3084648A1 (en) | 2017-12-06 | 2019-06-13 | Vivace Therapeutics, Inc. | Benzocarbonyl compounds |
| EP3793551A4 (en) | 2018-05-16 | 2022-01-26 | Vivace Therapeutics, Inc. | Oxadiazole compounds |
| JP7406264B2 (en) | 2018-11-20 | 2023-12-27 | エヌフレクション セラピューティクス インコーポレイテッド | Cyanoaryl-aniline compounds for the treatment of skin disorders |
| AU2019383310A1 (en) * | 2018-11-20 | 2021-06-10 | H. Lee Moffitt Cancer Center & Research Institute | Aryl-aniline and heteroaryl-aniline compounds for treatment of skin cancers |
| BR112022001346A2 (en) * | 2019-07-29 | 2022-06-07 | Basilea Pharm Int Ag | 1,2,4-oxadiazol-5-one derivatives for the treatment of cancer |
| TW202342018A (en) | 2022-03-04 | 2023-11-01 | 美商奇奈特生物製藥公司 | Inhibitors of mek kinase |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CH479599A (en) | 1965-04-12 | 1969-10-15 | Bristol Myers Co | Process for the preparation of compounds of nitriles with hydrazoic acid or azides |
| US5525625A (en) * | 1995-01-24 | 1996-06-11 | Warner-Lambert Company | 2-(2-Amino-3-methoxyphenyl)-4-oxo-4H-[1]benzopyran for treating proliferative disorders |
| WO1998037881A1 (en) | 1997-02-28 | 1998-09-03 | Warner Lambert Company | Method of treating or preventing septic shock by administering a mek inhibitor |
| NZ501276A (en) * | 1997-07-01 | 2000-10-27 | Warner Lambert Co | 4-bromo or 4-iodo phenylamino benzhydroxamic acid derivatives and their use as MEK inhibitors in treating proliferative disorders |
| BR9810385A (en) * | 1997-07-01 | 2000-09-05 | Warner Lambert Co | Derivatives of benzoic acid 2- (4-bromine or 4-iodine phenylamino) and their use as mek inhibitors |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US9084781B2 (en) | 2008-12-10 | 2015-07-21 | Novartis Ag | MEK mutations conferring resistance to MEK inhibitors |
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