INDOLE DERIVATIVES WHICH INHIBIT LEUKOTRIENE BIOSYNTHESIS

Cross-Reference to Related Applications This application is a continuation-in-part of copending application Serial No.

570,248 filed 20 August 1990.

Technical Field This invention relates to compounds having pharmacological activity, to pharmaceutical compositions containing such compounds and to medical methods of treatment. More particularly, the present invention concerns certain substituted indole urea, oxime, acetamide and hydroxamic acid compounds, pharmaceutical compositions containing the compounds, and to a method of treating disease states which involve leukotrienes and other metabolic products resulting from the action of 5-lipoxygenase on arachidonic acid.

Background of the Invention 5-Lipoxygenase is the first dedicated enzyme in the pathway leading to the biosynthesis of leukotrienes. This important enzyme has a rather restricted distribution, being found predominantly in leukocytes and mast cells of most mammals. Normally 5-lipoxygenase is present in the cell in an inactive form; however, when leukocytes respond to external stimuli, intracellular 5-lipoxygenase can be rapidly activated. This enzyme catalyzes the addition of molecular oxygen to fatty acids with cw,cw-l,4-pentadiene structures, converting them to 1-hydroperoxy- trαn_y,c«-2,4-pentadienes. Arachidonic acid, the 5-lipoxygenase substrate which leads to leukotriene products, is found in very low concentrations in mammalian cells and must first be hydrolyzed from membrane phospholipids through the actions of phospholipases in response to extracellular stimuli. The initial product of 5- lipoxygenase action on arachidonate is 5-hydroperoxyeicosatetraenoic acid (5- HPETE) which can be reduced to 5-hydroxyeicosatetraenoic acid (5-HETE) or converted to leukotriene A4 (LTA ₄ ). This reactive leukotriene intermediate is enzymatically hydrated to leukotriene B4 (LTB4) or conjugated to the tripeptide, glutathione, to produce leukotriene C4 (LTC4). LTA4 can also be hydrolyzed nonenzymatically to form two isomers of LTB4. Successive proteolytic cleavage steps convert LTC4 to leukotrienes D4 and E4 (LTD4 and LTE4). Other products resulting from further oxygenation steps have also been described in the literature. Products of the 5-lipoxygenase cascade are extremely potent substances which

produce a wide variety of biological effects, often in the nanomolar to picomolar concentration range.

The remarkable potencies and diversity of actions of products of the 5- lipoxygenase pathway have led to the suggestion that they play important roles in a variety of diseases. Alterations in leukotriene metabolism have been demonstrated in a number of disease states including asthma, allergic rhinitis, rheumatoid arthritis, gout, psoriasis, adult respiratory distress syndrome, inflammatory bowel disease, endotoxin shock syndrome, atherosclerosis, ischemia induced myocardial injury, and central nervous system pathology resulting from the formation of leukotrienes following stroke or subarachnoid hemorrhage.

The enzyme 5-lipoxygenase catalyzes the first step leading to the biosynthesis of all the leukotrienes and therefore inhibition of this enzyme provides an approach to limit the effects of all the products of this pathway. Compounds which inhibit 5- lipoxygenase are thus useful in the treatment of disease states such as those listed above in which the leukotrienes play an important role.

United States Patent 3,859,305 to Posselt, et al. discloses certain indole aminoketones which are useful as cardiovascular agents.

United States Patent 3,931,229 to Zinnes, et al. discloses and claims certain 3- thiomethyl-(2-[2-(dialkyla___ino)ethyl]indoles having utility as central nervous system depressants and anti-aggression agents.

United States Patent 4,021,448 to Bell discloses and claims certain 2- substituted-indole-1 -(lower alkane)carboxamides having utility for decreasing gastric secretions and as anti-ulcer agents.

United States Patent 4,119,638 to Ray discloses and claims certain thioesters of l-(4-chlorobenzoyl)-5-methoxy-2-methylindole-3-acetic acid useful as antiinflammatory agents.

United States Patent 4,464,379 to Betzing, et al. discloses and claims certain l-(4-chlorobenzoyl)-2-methyl-5-methoxyindole-3-acetic acid derivatives having antithrombic, antiarteriosclerotic, and antiphlogistic activity. European Patent Application 87 311031.6 (Publication No. 0 275 667) to

Gillard, et al. discloses and claims certain 3-(hetero-substituted)-N-benzylindoles as leukotriene biosynthesis inhibitors.

S. Raucher, et al., in "Indole Alkaloid Synthesis via Claissen Rearrangement," J. Am. Chem. Soc.. 103(9):2419-2412 (1981), disclose certain lH-indole-2-acetic acid derivatives.

Kobayashi, et al., in "Indole Derivatives XII. Reaction of Indole-2-carboxylic Acid Derivatives with Carbon Disulfide," Yakugaku Zasshi. 91(11 .: 1164-1173 (1971) (in Japanese; Chemical Abstracts English-language abstract: CA76: 46033k (1972)), disclose the synthesis of certain l-methyl-2-carboxamido-3-(dithioester)- indoles.

Summary of the Invention It has been found, in accordance with the present invention that certain substituted indolyl compounds are effective inhibitors of leukotriene biosynthesis and are thus useful for the treatment or amelioration of inflammatory disease states in which the leukotrienes play a role. In one embodiment of the present invention, there are provided compounds of Formula I :

I or a pharmaceutically acceptable salt, ester, or amide thereof.

In the compounds of this invention, A is selected from the group consisting of straight or branched divalent alkylene of from one to twelve carbon atoms, straight or branched divalent alkenylene of from two to twelve carbon atoms, and divalent cycloalkylene of from three to eight carbon atoms.

The substituent group R is selected from the group consisting of hydrogen; alkylthio of from one to six carbon atoms; phenylthio; phenylalkylthio in which the alkyl portion contains from one to six carbon atoms; 2-, 3-, and 4-pyridylthio; 2- and 3-thienylthio; 2-thiazolylthio; and a group having the

structure with the proviso that when R ¹ is

-C(O)(CH ₂ ) _n NHC(O)N(O_vI)R5, then R is selected from -COOH, -COO" B+ where

B is a pharmaceutically acceptable cation, and -COO(alkyl) where the alkyl group is of from one to six carbon atoms. In the foregoing definition of R ¹ , the phenyl ring of the phenylthio or phenylalkylthio groups are optionally substituted with one or two

groups selected from alkyl of from one to six carbon atoms, haloalkyl of from one to six carbon atoms, alkoxy of from one to twelve carbon atoms, hydroxy and halogen.

The substituent group R^ is selected from the group consisting of

OM R ⁶ R ⁶ OM R ⁶

^N _W R ⁵ ^N _W N ^ _W

II II II

(a) O , (b) O , (c) O

R6 O R6 NH

Y II , II

/ ^C * _N _ _N NH ₂ / ^C * _N ._ _N NH ₂

(1) H and (m) ^% H

In the foregoing definitions of R ² , n is an integer of from one to four, and R ⁵ cted from the group consisting of

(1) alkyl of from one to six carbon atoms,

(2) hydroxyalkyl of from one to six carbon atoms, (3) phenylalkyl in which the alkyl portion contains from one to six carbon atoms,

(4) alkoxyalkyl in which the alkoxy and alkyl portions each, independently, contain from one to six carbon atoms,

(5) phenoxyalkyl in which the alkyl portion contains from one to six carbon atoms,

(6) (alkoxyalkoxyl)alkyl in which each alkoxy portion, independently, contains from one to six carbon atoms, and the alkyl portion contains from one to six carbon atoms,

(7) (alkoxycarbonyl)alkyl in which the alkoxycarbonyl portion contains from two to six carbon atoms and the alkyl portion contains from one to six carbon atoms,

(8) (aminocarbonyl)alkyl in which the alkyl portion contains from one to six carbon atoms,

(9) ((alkylamino)carbonyl)alkyl in which each alkyl portion independently contains from one to six carbon atoms,

(10) ((dialkylamino)carbonyl)alkyl in which each alkyl portion independently contains from one to six carbon atoms,

(11) 2-, 3-, and 4-pyridylalkyl in which the alkyl portion contains from one to six carbon atoms, (12) (2-furyl)alkyl in which the alkyl portion contains from one to six carbon atoms,

(13) (3-thienyl)alkyl in which the alkyl portion contains from one to six carbon atoms,

(14) (2-benzo[b]thienyl)alkyl in which the alkyl portion contains from one to six carbon atoms, ^•

(15) (2-benzo[b]furyl)alkyl in which the alkyl portion contains from one to six carbon atoms,

(16) (5-(l,2,4-triazolyl))alkyl in which the alkyl portion contains from one to six carbon atoms,

(17) (2-_midazolyl)alkyl in which the alkyl portion contains from one to six carbon atoms,

(18) (2-thiazolyl)alkyl in which the alkyl portion contains from one to six carbon atoms, (19) (2-pyrimidyl)alkyl in which the alkyl portion contains from one to six carbon atoms, and (20) (5-tetrazolyl)alkyl in which the alkyl portion contains from one to six carbon atoms. In the foregoing definition of R ² , the substituent group R° is, at each occurrence, selected from hydrogen, and alkyl of from one to six carbon atoms and the substituent group R ⁷ is selected from the group consisting of

( 1 ) alkyl of from one to six carbon atoms,

(2) hydroxyalkyl of from one to six carbon atoms,

(3) phenylalkyl in which the alkyl portion contains from one to six carbon atoms,

(4) ((carboxy)phenyl)alkyl in which the alkyl portion contains from one to six carbon atoms,

(5) alkoxyalkyl in which the alkoxy and alkyl portions each, independently, contain from one to six carbon atoms, (6) phenoxyalkyl in which the alkyl portion contains from one to six carbon atoms,

(7) (carboxyl)alkyl in which the alkyl portion contains from one to six carbon atoms,

(8) (C-malanato)alkyl in which the alkyl portion contains from one to six carbon atoms,

(9) (C-(dialkylmalanato))alkyl in which each alkyl portion, independently, contains from one to six carbon atoms,

(10) (alkoxyalkoxyl)alkyl in which each alkoxy portion, independently, contains from one to six carbon atoms, and the alkyl portion contains from one to six carbon atoms,

(11) (alkoxy carbonyl)alkyl in which the alkoxycarbonyl portion contains from two to six carbon atoms and the alkyl portion contains from one to six carbon atoms,

(12) ((N-alkyl-N-hydroxyamino)carbonyl)alkyl in which each alkyl portion, independently, contains from one to six carbon atoms,

(13) (aminocarbonyl)alkyl in which the alkyl portion contains from one to six carbon atoms,

(14) ((alkylamino)carbonyl)alkyl in which each alkyl portion independently contains from one to six carbon atoms, (15) ((dialkylamino)carbonyl)alkyl in which each alkyl portion independently contains from one to six carbon atoms,

(16) (N-morpholinyl)alkyl in which the alkyl portion contains from one to six carbon atoms,

(17) (N-thiomorpholinyl)alkyl in which the alkyl portion contains from one to six carbon atoms,

(18) (N-piperidinyl)alkyl in which the alkyl portion contains from one to six carbon atoms,

(19) (N-piperazinyl)alkyl in which the alkyl portion contains from one to six carbon atoms, (20) 2-, 3-, and 4-pyridylalkyl in which the alkyl portion contains from one to six carbon atoms,

(21) (2-furyl)alkyl in which the alkyl portion contains from one to six carbon atoms,

(22) (3-thienyl)alkyl in which the alkyl portion contains from one to six carbon atoms,

(23) (2-benzo[b]thienyl)alkyl in which the alkyl portion contains from one to six carbon atoms,

(24) (2-benzo[b]furyl)alkyl in which the alkyl portion contains from one to six carbon atoms, (25) (5-(l,2,4-triazolyl))alkyl in which the alkyl portion contains from one to six carbon atoms,

(26) (2-imidazolyl)alkyl in which the alkyl portion contains from one to six carbon atoms,

(27) (2-thiazolyl)alkyl in which the alkyl portion contains from one to six carbon atoms,

(28) (2-pyrimidyl)alkyl in which the alkyl portion contains from one to six carbon atoms, and

(29) (5-tetrazolyl)alkyl in which the alkyl portion contains from one to six carbon atoms.

The group M is selected from the group consisting of hydrogen, a pharmaceutically acceptable cation, and a pharmaceutically acceptable metabolically cleavable group.

R3 is selected from the group consisting of phenylalkyl in which the alkyl portion contains from one to six carbon atoms; and heteroarylalkyl in which the alkyl portion contains from one to six carbon atoms and the heteroaryl group is selected from the group consisting of 2-, 3- and 4-pyridyl, 2- and 3-thienyl, 2- and 3-furyl, indolyl, pyrazinyl, isoquinolyl, quinolyl; imidazolyl, pyrrolyl, pyrimidyl, benzofuryl, benzothienyl, thiazolyl; and carbazolyl. In the foregoing definition of R ³ , the rings of the phenylalkyl or heteroarylalkyl groups are optionally substituted with one or two groups selected from alkyl of from one to six carbon atoms; alkoxy of from one to twelve carbon atoms; phenyl, optionally substituted with alkyl of from one to six carbon atoms, haloalkyl of from one to six carbon atoms, alkoxy of from one to six carbon atoms, hydroxy, or halogen; phenoxy, optionally substituted with alkyl of from one to six carbon atoms, haloalkyl of from one to six carbon atoms, alkoxy of from one to six carbon atoms, hydroxy, or halogen; 2-, 3-, or 4-pyridyl, optionally substituted with alkyl of from one to six carbon atoms, haloalkyl of from one to six carbon atoms, alkoxy of from one to six carbon atoms, hydroxy, or halogen; and 2-, 3-, or 4- pyridyloxy, optionally substituted with alkyl of from one to six carbon atoms, haloalkyl of from one to six carbon atoms, alkoxy of from one to six carbon atoms, hydroxy, or halogen; and -(CH2) _n N(OH)C(O)NR5R6 _; and

-(CH2) _n N(R5)C(O)N(OM)R6; with the proviso that when R3 is -(CH ₂ ) _n N(OH)C(O)NR5R6 or -(CH ₂ ) _n N(R ⁶ )C(O)N(OM)R6, then R ² is selected from -COOH, -COO ^" B ⁺ where B is a pharmaceutically acceptable cation, and

-COO(alkyl) where the alkyl group is of from one to six carbon atoms.

In the compounds of this invention, R^ is selected from the group consisting R is selected from the group consisting of (1) alkyl of from one to six carbon atoms; (2) alkoxy of from one to twelve carbon atoms; (3) phenyl; (4) phenoxy; (5) phenylalkyloxy in which the alkyloxy portion contains from one to six carbon atoms; and (6) 1- and 2-naphthylalkyloxy in which the alkyloxy portion contains from one to six carbon atoms ; in which the ring portion of each of the foregoing is optionally substituted with (a) alkyl of from one to six carbon atoms, (b) haloalkyl of from one to six carbon atoms, (c) alkoxy of from one to six carbon atoms, (d) hydroxy or (e) halogen. Additionally, R ⁴ is selected from heteroarylalkyloxy in which the alkyloxy portion contains from one to six carbon atoms and the heteroaryl portion is selected

from the group consisting of (7) 2-, 3-, and 6-quinolyl; (8) 2-, 3-, and 4-pyridyl; (9) 2-benzothiazolyl; (10) 2-quinoxalyl; (11) 2- and 3-indolyl; (12) 2- and 3- benzimidazolyl; (13) 2- and 3-benzo[b]thienyl; (14) 2- and 3-benzo[b]furyl; (15) 2-benzimidazolyl; (16) 2-thiazolyl, and (17) 1-, 3-, and 4-isoquinolyl, wherein the ring portion of each of the foregoing groups (7) through (17) is optionally substituted with alkyl of from one to six carbon atoms, haloalkyl of from one to six carbon atoms, alkoxy of from one to twelve carbon atoms, halogen, or hydroxy.

Detailed Description and Preferred Embodiments As used throughout this specification and the appended claims, the term

"alkyl" refers to a monovalent group derived from a straight or branched chain saturated hydrocarbon by the removal of a single hydrogen atom. Alkyl groups are exemplified by methyl, ethyl, n- and isø-propyl, n-, sec-, iso- and r -butyl, and the like. The term "alkylene" denotes a divalent group derived from a straight or branched chain saturated hydrocarbon by the removal of two hydrogen atoms, for example methylene, 1,2-ethylene, 1,1-ethylene, 1,3-propylene, and the like.

The term "alkenyl" denotes a monovalent group derived from a hydrocarbon containing at least one carbon-carbon double bond by the removal of a single hydrogen atom. Alkenyl groups include, for example, ethenyl, propenyl, butenyl, 1- methyl-2-buten-l-yl and the like.

The term "alkenylene" denotes a divalent group derived from a straight or branched chain hydrocaron containing at least one carbon-carbon double bond.

Examples of alkenylene include -CH=CH-, -CH2CH=CH-, -C(CH3)=CH-, - CH2CH=CHCH ₂ -, and the like.

The term "cycloalkylene" refers to a divalent group derived from a saturated carbocyclic hydrocarbon by the removal of two hydrogen atoms, for example cyclopropylene, cyclopentylene, cyclohexylene, and the like.

The term "alkylthio" denotes an alkyl group, as defined above, attached to the parent molecular moiety through a sulfur atom.

The terms "heterocyclic aryl" and "heteroaryl" as used herein refers to substituted or unsubstituted 5-or 6-membered ring aromatic groups containing one, two or three nitrogen atoms, one nitrogen and one sulfur atom, or one nitrogen and one oxygen atom. The term heteroaryl also includes bi- or tricyclic groups in which the aromatic heterocyclic ring is fused to one or two benzene rings. Representative heteroaryl groups are pyridyl, thienyl, furyl, indolyl, pyrazinyl, isoquinolyl, quinolyl,

imidazolyl, pyrrolyl, pyrimidyl, benzofuryl, benzothienyl, carbazolyl, and the like.

The term "metabolically cleavable group" denotes a group which is cleaved in vivo to yield the parent molecule in which M is hydrogen. Examples of metabolically cleavable groups include -COR, -COOR, -CONRR and -CH2OR radicals where R is selected independently at each occurrence from alkyl, trialkylsilyl, carbocyclic aryl or carbocyclic aryl substituted with one or more of -C4 alkyl, halogen, hydroxy or

C1-C4 alkoxy. Representative metabolically cleavable groups include acetyl, methoxycarbonyl, benzoyl, methoxymethyl and trimethylsilyl groups.

The term "hydroxyalkyl" means an alkyl group as defined above, having one, two or three hydrogen atoms replaced by hydroxyl groups, with the proviso that no more than one hydroxy group may be attached to a single carbon atom of the alkyl group.

The term "phenylalkyl" denotes a phenyl group attached to the parent molecular moiety through an alkylene group. "Alkoxy" means an alkyl group, as defined above, attached to the parent molecular moeity through an oxygen atom. Representative alkoxy groups include methoxy, ethoxy, propoxy, rerr-butoxy and the like.

"Alkoxyalkyl" means an alkoxy group, as defined above, attached to the parent molecular moiety through an alkylene group. The term "phenoxy" represents a phenyl group attached to the parent molecular moiety through an oxygen atom.

The term "phenoxyalkyl" denotes a phenoxy group attached to the parent molecular moiety through an alkylene group. Typical phenoxyalkyl groups include phenoxymethyl, phenoxyethyl, and the like. "(Alkoxyalkoxy)alkyl stands for a group in which an alkoxy group, as defined above is attached through its oxygen atom to a second alkoxy group which, in turn, is attached through an alkylene group to the parent molecular moiety. Representative

(alkoxyalkoxy)al yl groups include methoxymethoxymethyl, methylethoxymethyl, ethoxyethoxymethyl, and the like. The term "(alkoxycarbonyl)alkyl denotes an ester group (-COOalkyl)) attached through an alkylene group to the parent molecular moiety, for example, ethoxycarbonylmethyl, ethoxycarbonylethyl, and the like.

The terms "(aminocarbonyl)alkyl," "(a_Jcylaminocarbonyl)alkyl," and

"(dialkylaminocarbonyl) Alkyl" mean, respectively, an amino group, or an amino group substituted by one or two alkyl groups, as defined above, attached through a carbonyl group and thence through an alkylene group to the parent molecular moiety.

Representative groups of this type include -(CH ₂ )C(O)NH ₂ , -(CH ₂ )C(O)NHCH ₃ , -(CH ₂ )C(O)N(CH ₃ ) ₂ and the like.

The term "(C-malanato)alkyl" represents a malonic acid group, attached

"(C-(dialkylmalanato))alkyl represents a malonic acid group in which the two acid functional groups have been esterified with alkyl groups, attached to the parent molecular moiety at its methylene carbon through an alkylene group.

The term "((N-alkyl-N-hydroxyamino)carbonyl)alkyl" stands for a group of

OH ^(alkylene)^ .N. _(a|ky|) the formula O in which "alkylene" and "alkyl" are as defined above.

The compounds of the present invention comprise a class of substituted indoles in which the 3-position is substituted by an alkylthio group or an

(N-hydroxyamido)alkylcarbonyl group of the formula OM in which n is an integer of from one to four, M is as previously defined, and R ⁵ is hydrogen or lower alkyl. Preferred compounds of the present invention are those in which the 3-position substituent is alkylthio.

The 2-position of the indole nucleus of the compounds of the present invention is substituted with a urea, N-hydroxyurea, hydroxamate, guanidyl, or hydroximino group, any of which may be further substituted. These groups are attached to the indole nucleus through an alkylene, alkenylene, or cycloalkylene spacing group. Preferred compounds of the present invention are those in which the substituent at the 2-position of the indole nucleus is selected from N-hydroxyurea groups of the structures

R ⁵ OM R ⁵

O O ; N'-hydroxyurea groups of the structures

ur groups of the structure and O-substituted oxime groups of the

PR ⁷ N

II structure ^ ^S R ⁶ where R ⁵ , R ⁶ and R ⁷ are as defined above. The 1 -position of the indole nucleus of compounds of this invention is substituted by an alkyl-substituted carbocyclic aromatic group, an alkyl-substituted heteroaryl group, an N-hydroxyurea of the structure -(CH2) _Π N(OH)C(O)NR5R6 _OΓ

-CH2) _n N(R ⁵ )C(O)N(OH)R ⁶ , where R ⁵ at each occurrence selected from hydrogen and lower alkyl and R ⁶ has the values defined above. The integer, n, is 1 to 4, inclusive. Preferred compounds of the present invention are those where the substituent at position 1 of the indole nucleus is benzyl or benzyl substituted by C -

C(j alkyl, Cj-Cg alkoxy, phenoxy, halogen, or hydroxy.

Specific examples of compounds contemplated as falling within the scope of this invention include, but are not limited to the following examples, including the pharmaceutically acceptable salts and esters thereof:

N'-hydroxy-N ^, -methyl-N-2-[2-methyl-3-(l-(4-chlorophenylmethyl)-3-(l ,l- dimethylethylthio)-5-(l-methylethyl)indol-2-yl)]propyl urea;

2,2-dimethyl-3-[ 1 -(4-chlorophenylmethyl)-3-( 1 , 1 -dime thylethylthio)-5-( 1 - methylethyl)indol-2-yl]propionaldehyde oxime;

N-hydroxy-N-2,2-dimethyl-3- [( 1 -(4-chlorophenylmethyl)-3-( 1 , 1 -dimethylethylthio)-

5-( 1 -methylethyl))indol-2-yl]propyl urea;

N'-hydroxy-N'methyl-N-2-[(l-(4-chlorophenylmethyl)-3-(l,l -dimethylethylthio)-5- ( 1 -me thylethyl))indol-2-yl] ethyl urea;

N-2,2-dimethyl-3- [( 1 -(4-chlorophenylmethyl)-3-( 1 , 1 -dimethylethyl-thio)-5-( 1 - methylethyl))indol-2-yl]propyl urea;

N'-hydroxy-N'-methyl-N-2-[3-(l-(4-chlorophenylmethyl)-3-( l,l-dimethylethylthio)- 5-(l-methylethyl)indol-2-yl)-2,2-dimethylpropionylamino]ethy l urea;

l-(4-chlorophenylmethyl)-2-[2,2-dimethyl-3-((3-hydroxypro pyl)-amino)propyl]-3- (1.1 -dimethylethylthio)-5-( 1 -methylethyl)indole;

N-2-[2-methyl-3-(l-(4-chlorophenylmethyl)-3-(l,l-dimethyl ethylthio)-5-(l- methylethyl)indol-2-yl)] propyl urea;

3-[3-(l-(4-chlorophenylmethyl)-3-(l,l-dimethylethylthio)- 5-(l-methylethyl)indol-2- yl)-2-aminocarbonylamino-2-methylpropyl]propanoic acid, ethyl ester;

3-[3-( l-(4-chlorophenylmethyl)-3-( 1 , 1 -dimethylethylthio)-5-(l -methylethyl)indol-2- yl)-2-aminocarbonylamino-2-methylpropyl]propanoic acid;

N'-hydroxy-N'-methyl-N-[l-(4-chlorophenylmethyl)-5-(l-met hylethyl)-2-((2-methyl- 2-ethoxycarbonyl)propyl)indol-2-yl]-3-oxopropylurea;

l-(4-chlorophenylmethyl)-3-(l,l-dimethylethylthio)-2-[3-( 2,2-dimethyl-l- guanidinylimino)propyl]-5-(l-methylethyl)indole;

N-hydroxy-N-[rr_./w-2-(l-(4-chlorophenylmethyl)-3-(l,l-di methylethylthio)-5-(l- methylethyl)indol-2-yl)cyclopropyl]methylurea;

3-[3-(l,l-d_methylethylthio)-5-(l-methylethyl)-l-(4-pyridiny lmethyl)indol-2-yl]-2,2- dimethylpropanoic acid;

3-[3-(l,l-dimethylethylthio)-5-(l-methylethyl)-l-(2-thien ylmethyl)indol-2-yl]-2,2- dimethylpropanoic acid;

N-hydroxy-N-rrfln_?-[3-(l-(4-chlorophenylmethyl)-3-(l,l-d imethylethylthio)-5-(l- methylethyl)indol-2-yl)]prop-2-enylurea;

N-[3-(l-(4-chlorophenylmethyl)-3-(l,l-dimethylethylthio)- 5-(l-methylethyl)indol-2- yl)-2,2dimethylpropyl] acetohydroxamic acid;

N-hydroxy-N-3-[3-(l-(4-chlorophenylmethyl)-3-(l,l-dimethy lethylthio)-5-(l- methylethyl)indol-2-yl)-2,2-dimethylpropionylamino]propyl urea;

3-[l-(4-chlorophenylmethyl)-3-(l,l-dimethylethylthio)-5-( l-methylethyl)indol-2-yl]- 2,2-dimethylpropionaldehyde oxime-O-2-acetic acid;

2-(3-__mino-2,2-dimethylpropyl )-l-(4-chlorophenylmethyl)-3-(l,l- dimethylethylthio)-5-(l-methylethyl)indole;

N-[3-(l-(4-chlorophenylmethyl)-3-(l,l-dimethylethylthio)- 5-(l-methylethyl)indol-2- yl)-2,2-dimethylpropyl]acetamide;

N-[rrai«-2-(l-(4-chlorophenylmethyl)-3-(l,l-dimethylethy lthio)-5-(l- methylethyl)indol-2-yl)cyclopropyl]methyl urea;

N'-hydroxy-N-3-[3-(l,l-dimethylethylthio)-5-(l-methylethy l)-2-((2-methyl-2- ethoxycarbonyl)propyl)indol-l-yl]propyl urea; '

2,2-dimethyl-3-[l-(2-thiophenylmethyl)-3-(l,l-dimethyleth ylthio)-5- ( 1 -me thylethyl)indol-2-yl]propionaldehyde oxime;

N-2,2-dimethyl-3-[(l-(2-thiophenylmethyl)-3-(l,l-dimethyl ethyl-thio)-5-

(l-methylethyl)indol-2-yl]propyl urea;

3- [1 -(4-chlorophenylmethyl)-3-( 1 , 1 -dimethylethylthio)-5-(methoxy)indol-2- yl]-2,2-dimethylpropionaldehyde oxime-O-2-acetic acid;

3-[ 1 -(4-chlorophenylmethyl)-3-( 1 , 1 -dimethylethylthio)-5-( 1 -methylethyl)- indol-2-yl]-2,2-dimethylpropionaldehyde oxime-O-3-propionic acid;

N- { 3-[l-(4-chlorophenylmethyl)-3-(l, l-dimethylethylthio)-5-

( 1 -methylethyl)indol-2-yl]-2,2-dimethylpropionaldehyde oxime-O } - methyl urea;

N-2-[l-(4-chlorophenylmethyl)-3-(l,l-dimethylethylthio)-5 -

( 1 -methyle thyl)indol-2-yl)-2,2-dimethylpropionylaιnino]ethyl urea;

3-[ l-(4-fluorophenylmethyl)-3-( 1 , 1 -dimethylethylthio)-5-( 1-methylethyl)- indol-2-yl]-2,2-dimethylpropionaldehyde oxime-O-2-acetic acid;

3-[ 1 -(4-chlorophenylmethyl)-3-( 1 , 1 -dimethylethylthio)-5-( 1 -methylethyl)- indol-2-yl] -2,2-dimethylpropionaldehyde oxime-O-2-propionic acid;

3- [3-( 1 , 1 -dimethylethylthio)-5-(quinolin-2-ylmethoxy)- 1 -(4-chlorophenylmethyl)- indol-2-yl]-2,2-dimethylpropionaldehyde oxime-O-2-acetic acid;

3- [3- ( 1 , 1 -dimethylethylthio)-5-(quinolin-2-ylmethoxy)- 1 -(4-chlorophenylmethyl) indol-2-yl]-2,2-dimethylpropionaldehyde oxime-O-2-(3-methyl)butyric acid

3-[3-(l,l-dimethylethylthio)-5-(6,7-dichloroquinolin-2-yl methoxy)-l-(4- chlorophenylmethyl) indol-2-yl]-2,2-dimethylpropionaldehyde oxime-O-2- acetic acid

3-[3-(l,l-dimethylethylthio)-5-(6-fluoroquinolin-2-ylmeth oxy)-l-(4- chlorophenylmethyl) indol-2-yl] -2,2-dimethylpropionaldehyde oxime-O- 2- propionic acid;

3- [3- ( 1 , 1 -dimethylethylthio)-5-(6-methoxycarbonyloxy quinolin-2-ylmethoxy)- 1 - (4- chlorophenylmethyl) indol-2-yl]-2,2-dimethylpropionaldehyde oxime-O-2- propionic acid;

3-[3-(l,l-dimethylethylthio)-5-(quinoxalin-2-ylmethoxy)-l-(4 -chlorophenylmethyl) indol-2-yl] -2,2-dimethylpropionaldehyde oxime-O-2-acetic acid;

3-[3-(l,l-dimethylethylthio)-5-(6-methoxynaphth-2-ylmetho xy)-l-(4- chlorophenylmethyl) indol-2-yl]-2,2-dimethylpropionaldehyde oxime-O-2- acetic acid;

3-[3-(l,l-dimethylethylthio)-5-(2-oxyquinolin-6-ylmethoxy )-l-(4- chlorophenylmethyl) indol-2-yl]-2,2-dimethylpropionaldehyde oxime-O-2- acetic acid;

3-[3-(l,l-dimethylethylthio)-5-(pyrid-2-ylmethoxy)-l-(4-c hlorophenylmethyl) indol- 2-yl]-2,2-dimethylpropionaldehyde oxime-O-2-acetic acid;

3-[3-(l,l-dimethylethylthio)-5-(N-methylindol-2-ylmethoxy )-l-(4- chlorophenylmethyl) indol-2-yl] -2,2-dimethylpropionaldehyde oxime-O-2- acetic acid;

3-[3-(l,l-dimethylethylthio)-5-(4-fluorophen-2-ylmethoxy) -l-(4- chlorophenylmethyl) indol-2-yl]-2,2-dimethylpropionaldehyde oxime-O-2- acetic acid; and

3-[3-(l,l-dimethylethylthio)-5-((3-(4-fluorophenoxy)-4-fl uorophen-2-ylmethoxy)-l- (4-chlorophenylmethyl)) indol-2-yl]-2,2-dimethylpropionaldehyde oxime-O- 2-acetic acid.

Certain compounds of this invention may exist in geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis- and trans- geometric isomers, R- and S-enantiomers, diastereomers, and mixtures thereof as falling within the scope of the invention. If a particular enantiomer is desired, it may be prepared by chiral synthesis or by derivatization with a chiral auxiliary where the resulting diastereomeric mixture is separated and the auxiliary group cleaved to provide the pure desired enantiomers. Alternatively, where the molecule contains a basic functional group such as amino or an acidic functional group such as carboxyl, diastereomeric salts are formed with an appropriate optically active acid or base, followed by resolution of the diastereomers thus formed by fractional crystallization

or chromatographic means well known in the art and subsequent recovery of the pure enantiomers.

Certain compounds of the present invention may contain a basic functional group such as amino, alkylamino, or dialkylamino and are thus capable of forming salts with pharmaceutically acceptable acids. The term "pharmaceutically acceptable salts" in this respect, refers to the relatively non-toxic, inorganic and organic acid addition salts of compounds of the present invention. These salts can be prepared in situ during the final isolation and purification of the compounds or by separately reacting the purified compound in its free base form with a suitable organic or inorganic acid and isolating the salt thus formed. Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactobionate, laurylsulphonate salts and the like. (See, for example S. M. Berge, et al., "Pharmaceutical Salts," ∑. Pharm. Sci.. 66: 1-19 (1977) which is incorporated herein by reference.)

In other cases, the compounds may contain one or more acidic functional groups such as carboxyl and the like and are capable of forming salts with pharmaceutically acceptable bases. The term "pharmaceutically acceptable salts" in these instances refers to the relatively non-toxic, inorganic and organic base addition salts of compounds of the present invention. These salts can be likewise prepared in situ during the final isolation and purification of the compounds or by separately reacting the purified compound in its free acid form with a suitable base such as the hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation or with ammonia, or an organic primary, secondary, or tertiary amine. Representative alkali or alkaline earth salts include the lithium, sodium, potassium, calcium, magnesium and aluminum salts and the like. Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like. (See, for example S. M. Berge, et al., "Pharmaceutical Salts," J. Pharm. Sci.. 66: 1-19 (1977) which is incorporated herein by reference.)

Synthesis of the Compounds The compounds of the present invention are synthesized by the following general synthetic routes. One general method for the synthesis of intermediate indoles used to prepare compounds of this invention, shown in Reaction Scheme 1,

employs the Fischer indole synthesis (cf. Advanced Organic Chemistry, Reactions, Mechanisms, and Structure, 3rd Ed. by J. March, John Wiley and Sons, 1985, p. 1032). In this method a hydrazine I is reacted with ketone II in a sutiable solvent at a temperature between 20°C and the refluxing temperature of the chosen solvent to provide the indole product HI. The intermediate indole HI is subsequently transformed by the procedures described for individual examples to provide the final products of this invention.

Reaction Scheme 1

π

Another general method illustrated in Reaction Scheme 2, involves the reaction of hydrazine intermediate IV with the ketone intermediate V to provide the indole intermediate VI. The intermediate VI is then treated under basic conditions with a halogenated alkylaryl compound Vπ, where aryl is a heteroaryl group such as furanyl, thienyl, pyridyl, pyrimidyl, thiazoyl, benzothiazolyl, benzothiophenyl, benzofuranyl, or substituted phenyl.

Reaction Scheme 2

IV V VI

NaH/DMSO

Aryl CH ₂ Aryl

vπ

Inhibition of Leukotriene Biosynthesis In Vitro Inhibition of leukotriene biosynthesis by representative compounds of the present invention was evaluated in assays involving calcium ionophore-induced LTB4 biosynthesis expressed by human polymorphonuclear leukocytes (PMNL) or human whole blood. Human PMNL were isolated from heparinized (20 USP units/mL) venous blood using Ficoll-Hypaque Mono-Poly Resolving Medium. Human PMNL suspensions (5 x 10^ cells/250 μL) were preincubated with test compounds or vehicle for 15 min at 37 °C followed by calcium ionophore A23187 challenge (final concentration of 8.3 μM) and the reaction terminated after 10 min by adding two volumes of methanol containing prostaglandin B as an internal recovery standard.

The methanol extracts were analyzed for LTB4 content by HPLC or radioimmunoassay.

The assay using human heparinized whole blood was incubated for 30 minutes at 37 °C after adding 50 μM of ionophore A23187. The plasma layer was obtained by centrifugation and deproteinized by the addition of four volumes of methanol. The methanol extract was analyzed for LTB4 by HPLC or radioimmunoassay.

The inhibitory activity of representative examples is shown in Table 1.

Table 1

Inhibition of LTB4 Biosynthesis in Human PMNL and Human Whole Blood

11 12 13 14 15 16 20 21 22

23 24 1.1

Inhibition of Leukotriene Biosynthesis In Vivo

Inhibition of the biosynthesis of leukotrienes in vivo after oral administration of compound was determined using a rat peritoneal anaphylaxis model in a similar manner as that described by Young and coworkers (Young, P. R.; Dyer, R.D.; Carter, G. W. Fed. Proc, Fed. Am. Soc. Exp. Biol. 1985, 44, 1185). In this model rats were injected intraperitoneally (ip) with rabbit antibody to bovine serum albumin (BSA) and three hours later injected ip with BSA to induce an antigen-antibody response. Rats were sacrificed 15 minutes after this challenge and the peritoneal fluids were collected and analyzed for leukotriene levels. Test compounds were administered by gavage one hour prior to the antigen challenge. Percent inhibition values were determined by comparing the treatment group to the mean of the control group.

Compounds of this invention are orally effective in preventing the in vivo bio¬ synthesis of leukotrienes as illustrated for representative examples shown in Table 2.

Table 2

Inhibition of Leukotriene (LT) Biosynthesis In Vivo

The present invention also provides pharmaceutical compositions which comprise one or more of the compounds of formula I above formulated together with one or more non-toxic pharmaceutically acceptable carriers. The pharmaceutical compositions may be specially formulated for oral administration in solid or liquid form, for parenteral injection, or for rectal or vaginal administration. The pharmaceutical compositions of this invention can be administered to humans and other animals orally, rectally, parenterally , intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), bucally, or as an oral or nasal spray. The term "parenteral" administration as used herein refers to modes of administration which include intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous and intraarticular injection and infusion.

Pharmaceutical compositions of this invention for parenteral injection comprise pharmaceutically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions as well as sterile powders for reconstitution into sterile injectable solutions or dispersions just prior to use. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, pol ols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

These compositions may also contain adjuvants such as preservative, wetting agents, emulsifying agents, and dispersing agents. Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents such as sugars, sodium chloride, and the like, Prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents which delay absorption such as aluminum monostearate and gelatin.

In some cases, in order to prolong the effect of the drug, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.

Injectable depot forms are made by forming microencapsule matrices of the drug in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides) Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissues.

The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium just prior to use.

Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example,

cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.

The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes. The active compounds can also be in micro-encapsulated form, if appropriate, with one or more of the above-mentioned excipients.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethyl formamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.

Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar- agar, and tragacanth, and mixtures thereof.

Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non- irritating excipients or carriers such as cocoa butter, polyethylene glycol or a

suppository wax which are solid at room temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.

Dosage forms for topical administration of a compound of this invention include powders, sprays, ointments and inhalants. The active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives, buffers, or propellants which may be required. Opthalmic formulations, eye ointments, powders and solutions are also contemplated as being within the scope of this invention.

Actual dosage levels of active ingredients in the pharmaceutical compositions of this invention may be varied so as to obtain an amount of the active compound(s) that is effective to achieve the desired therapeutic response for a particular patient, compositions, and mode of administration. The selected dosage level will depend upon the activity of the particular compound, the route of administration, the severity of the condition being treated, and the condition and prior medical history of the patient being treated. However, it is within the skill of the art to start doses of the compound at levels lower than required for to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved.

Generally dosage levels of about 1 to about 50, more preferably of about 5 to about 20 mg of active compound per kilogram of body weight per day are administered orally to a mammalian patient. If desired, the effective daily dose may be divided into multiple doses for purposes of administration, e.g. two to four separate doses per day.

The following examples are presented to enable one skilled in the art to practice the present invention. These examples are merely illustrative and should not be read as limiting the invention as it is defined by the appended claims.

Example 1 α.l-dimethvlethvlthioV5-fl-methvlethvl)indol-2-vl_1propvl urea

Compound 1.1 was prepared by adaptation of the procedure reported in EPA 87311031.6. To a stirring benzene (7.4 mL) solution of Compound 1.1 (525 mg, 1.11 mmol), triethylamine (0.16 mL, 1.17 mmol) and diphenylphosphorylazide (0.25 mL,l.l 1 mmol) were added. The reaction was refluxed for one hour; N-methyl- hydroxylamine hydrochloride (96 mg, 1.12 mmol) in triethylamine (0.16 mL, 1.13 mmol) and H2O (0.25 ιr ^τ _ ) was added, and the reaction stirred two hours at reflux.

The cooled reaction mixture was poured into aq. sat'd NH4CI and extracted with EtOAc (2x). The combined organic extracts were washed (sat'd, aq NaHCO3 H2O, and brine), dried (MgSO4), and concentrated in vacuo to yield 362 mg of desired product 1 as a cream-colored amorphous solid, after purification by chromatography (silica gel, 35% EtOAc/hexanes). m.p. 95-100°C; ^l NMR (300 MHz, DMSO-de); 1.20 (9H, s), 1.23 (6H, d, 7.5 Hz), 1.3 (6H, s), 2.95 (4H, m), 3.38 (2H, s), 5.57 (2H, s), 6.35 (IH, s), 6.87 (2H, d, J = 8.4 Hz), 6.97 (IH, dd, J = 8.4, 1.5 Hz), 7.27 (IH, d, J = 9Hz), 7.34 (2H, d, J = 9Hz), 7.48 (IH, d, J = 1.5 Hz), 9.42 (IH, s); MS (M+H)+ =

516. Analysis calc'd for C28H38CIN3O2S: C, 65.16; H, 7.42; N, 8.14; Found: C, 64.87; H, 7.45; N, 7.94.

Example 2

Preparation of 2.2-dimethyl-3-f 1 -f4-chlorophenylmethyl . -3-( 1.1 -dimethylethylthio _ - 5- .1 -methyleth yl _ indol-2- vflpropionaldehvde oxime

2.2

Compound 2.1 was prepared by reduction of compound 1.1 as follows. To a 0°C solution of Compound 1.1 (2.61 g, 5.53 mmol) in 50 mL of dry THF, a 2.0 M (THF) borane dimethylsulfide solution was added dropwise (5.80 mL, 11.6 mmol). The reaction was stirred 17 hours at room temperature; methanol (10 mL) was added, and it was then concentrated in vacuo, filtered through a silica gel pad, and purified by chromatography (silica gel, 20% EtOAc hexanes) to obtain 1.69 g of compound 2.1 as a white, amorphous solid. m.p. 67-70°C; - NMR (300 MHz, DMSO-d6); 0.82 (6H, s), 1.18 (9H, s), 1.22 (6H, d, J = 7.75 Hz), 2.93 (3H, m), 3.15 (2H, d, J = 6 Hz), 4.82 (IH, t, J = 6 Hz), 5.58 (2H, s), 6.87 (2H, d, J = 8.25 Hz), 6.97 (IH, dd, J = 8.25 and 1.5 Hz), 7.25 (IH, d, J = 8.25), 7.33 (2H, d, J = 8.25 Hz), 7.47 (IH, d, J = 1.5 Hz); MS (M+H)+ = 458.

To a -63°C solution of oxalylchloride (0.41 mL, 4.66 mmol) in dry methylene chloride (4.7 mL), the following reagents were added: DMSO (0.41 mL, 5.32 mmol) in dry methylene chloride (5.32 mL) (dropwise over a five minute period) and Compound 2 (1.22 g, 2.66 mmol) in dry methylene chloride (18 mL) (also dropwise over a five minute period). The reaction was stirred ten minutes after the addition of

Compound 2 was completed, and then triethylamine (1.67 mL, 12.0 mmol) in dry methylene chloride (4.0 mL) was added dropwise over a five minute period and stirred one hour before quenching the cold reaction mixture with 10% KHSO4 (aq). This solution was poured into a separatory funnel containing hexanes. The layers were separated, and the aqueous back extracted with ether. The organic layers were combined, washed (1 x sat'd, aq NaHCO3; 1 x H ₂ O; and 3 x brine), dried (MgSO4), and concentrated in vacuo to yield 1.16 g of a yellow, amorphous solid aldehyde intermediate 2.2.

To a stirring solution of Compound 2.2 (1.16 g, 2.54 mmol) in ethanol (8.5 mL), under N ₂ (g), pyridine (0.26 mL, 3.18 mmol) and hydroxylamine hydrochloride

(210 mg, 3.05 mmol) were added neat and sequentially. The reaction was stirred 16 hours before concentrating in vacuo to yield 1.20 g of Compound 2 as a pale, yellow amorphous solid. A portion of oxime was purified by flash chromatography (silica gel, 10% EtOAc/hexanes) to yield 179 mg of the title compound as an amorphous white solid, m.p. 80 - 85°C; - . NMR (300 MHz, DMSO-ctø); 1.08 (6H, s), 1.20

(9H, s), 1.23 (6H, d, J = 6.75 Hz), 2.95 (IH, septet, J = 6.75 Hz), 3.08 (2H, br s), 5.45 (2H, s), 6.88 (2H, d, J = 8.25 Hz), 6.97 (IH, dd, J = 1.5 and 8.25 Hz), 7.26 (IH, d, J = 8.25 Hz), 7.32 (2H, d, J = 8.25 Hz), 7.39 (IH, s), 7.46 (IH, d, J = 1.5 Hz), 10.43 (IH, s); MS (M+H)+ = 471. Analysis calc'd for C27H35CIN2OS: C, 68.84; H, 7.49; N, 5.95; Found: C, 68.56; H, 7.58; N, 5.70.

Example 3

Preparation of N-hvdroxv-N-2.2-dimethvl-3-rfl-r4-chlorophenvlmethvn-3-ri.l- dimethylethylthio -5-r 1 -methylethyl indol-2-ynpropyl urea

To a stirring solution of Compound 2 (1.16 g, 2.46 mmol) in ethanol (5.0 mL), under N (g) atmosphere, borane pyridine complex (0.84 mL, 8.33 mmol) was added neat. The reaction was stirred for two hours, cooled to 0°C, and 12M HC1 (1.4 mL, 16.7 mmol) in ethanol (1.0 mL) added dropwise over a 30 minute period. After stirring 16 hours at room temperature, 50 mL of H ₂ O was added to the reaction, and 4N NaOH(aq) added to raise the pH to 14. The basic solution was extracted with ether. The organic layer was washed (brine), dried (MgS0 ), and concentrated in vacuo. The crude material was purified by chromatography (silica gel, 50% EtOAc/hexanes), yielding 898 mg of hydroxylamine intermediate 3.1 as an amorphous, white solid.

To a stirring solution of 3.1 (642 mg, 1.36 mmol) in THF (5 mL) was added trimethylsilyl isocyanate (0.24 mL, 1.5 mmol). After stirring 90 minutes, additional trimethylsilyl isocyanate(TMSNCO) (0.10 mL, 0.73 mmol) was added. The reaction was stirred for one hour then poured into a separatory funnel containing NH4CI (sat'd, aq) and extracted with ethyl acetate. The organic layer was washed (brine), dried (MgSO4), concentrated in vacuo, and purified by chromatography (silica gel, 50-75% EtOAc/hexane) to yield 427 mg of desired product 3 as a white amorphous solid. m.p. 95 - 100°C; *H NMR (300 MHz, DMSO-d ); 0.90 (6H, s), 1.18 (9H, s), 1.22 (6H, d, J = 6.75 Hz), 2.95 (3H, m), 3.35 (2H, s), 5.52 (2H, s), 6.25 (2H, s), 6.90 (2H, d, J = 9 Hz), 6.95 ( IH, dd, J = 1.5, 9 Hz), 7.23 (IH, d, J = 9 Hz), 7.33 (2H, d, J = 9 Hz), 7.47 (IH, d, 1.5 Hz), 9.28 (IH, s); MS (M+H)+ = 516. Analysis calc'd for C28H38CIN3O2S (0.25 H ₂ O): C, 64.59; H, 7.45; N, 8.07; Found: C, 64.58; H, 7.45; N, 7.95.

Example 4

Preparation of N'-hvdroxv-N'methvl-N-2-rri-r4-chlorophenvImethvn-3-ri.l- riιmethvlethvlthio.-5-ri-methvlethvl_ _indol-2-vl1ethvl urea

To a solution of diisopropylamine (11.5 mL, 81.1 mmol) in dry THF (175 mL) at 0°C, under N ₂ (g) atmosphere, n-BuLi (2.5M in hexanes) (31.0 mL, 77 mmol) was added over a fifteen minute interval. The reaction was stirred for 15 additional minutes at both 0°C and -78°C; t-butyl acetate (10.0 mL, 69.9 mmol) in dry THF (15 mL) was added dropwise over a 15 minute period. After stirring 45 minutes at -78°C, 2-chloro, 3-iodo-l-propene (15.8 g, 78 mmol) was added, and the reaction stirred for 15 minutes at -78°C and 15 minutes at 0°C before quenching with excess NH4CI (sat'd, aq). The quenched reaction mixture was poured into a separatory funnel and extracted with EtOAc (2x). The combined organic layers were washed (10% aq HC1, H ₂ O, and brine), dried (MgSO4), and concentrated in vacuo to yield 18.87 g of a dark red oil. 10.18 g of intermediate 4.1, as a pale red oil, was obtained after distillation ( b.p. 79.5-83°C). Starting with Compound 4.1 (2.5 g, 13.11 mmol) and adapting the procedure reported in EPA 87311031.6 used in Example 1, 1.09 g of the Fischer-Indole product 4.2, was obtained as a yellow waxy solid after purification by chromatography (silica gel, 5% EtOAc/hexane). Compound 4.2 ( 293 mg, 0.586 mmol) was stirred in CH2CI2 (2.5 mL), TFA 0.45 mL (5.86 mmol), and anisole (0.13 mL, 1.17 mmol)

overnight. After purification by chromatography (silica gel, EtOAc and 5-10% MeOH/CHC- ₃ ), 187 mg of the acid intermediate 4.3 was obtained.

Starting with intermediate 4.3 (161 mg, 0.363 mmol) and following the procedure outlined in Example 1, 100 mg of desired product 4 was obtained as a white solid after purification by chromatography (silica gel, 50% EtOAc/hexane). m.p. 87 - 93°C; ^l H NMR (300 MHz, DMSO-de); 1.23 (6H, d, J = 7.5 Hz), 1.28 (9H, s), 2.95 (4H, m), 3.08 (2H, m), 3.15 (2H, m), 5.62 (2H, s), 6.98 (3H, m), 7.20 (IH, d, J = 8.25 Hz), 7.25 (IH, m), 7.37 (2H, m), 7.46 (IH, d, J = 1.5 Hz), 9.33 (IH, m); MS (M+H) ⁺ = 488, (M+NH ₄ . + = 505. Analysis calc'd for C2 ₆ H3 ₄ CIN ₃ O2S: C, 63.98; H, 7.02; N, 8.61; Found: C, 63.69; H, 7.13; N, 8.37.

Example 5 Preparation of N-2.2-dimethyl-3-[Yl -r4-chlorophenylmethyI _ -3-r 1.1 -dimethylethyl- thioV5-ri-methylethyl))indol-2-ynpropyl urea

3 5

A stirring solution of 3 (632 mg, 1.22 mmol) in methanol (10 mL), under N (g) atmosphere, was warmed to 45°C ( H2O bath). To this solution was added NaOAc x 3H ₂ O (2.0 g, 14.64 mmol) in H ₂ O (3 mL). After stirring a few minutes the reaction became homogeneous, and 3.1 mL of a 1.2 M TiCl3 aqueous was added dropwise over a few minutes. After stirring 24 hours, the reaction was partially concentrated in vacuo. The resultant concentrate was poured into 50% aq NaCl (100 mL) and extracted carefully with a 2/1 THF/ethyl acetate (2 x 100 mL) solution. The organic extracts were combined, washed (sat'd, aq NaHCO3 and brine), dried (MgSO ₄ ), concentrated in vacuo, and purified by chromatography (silica gel, 5% MeOH/CH ₂ Cl2) to yield 350 mg of desired product 5 as a white amorphous solid. m.p. 109 - 112°C; ¹ H NMR (300 MHz, DMSO-dβ); 0.82 (6H, s), 1.20 (9H, s), 1.23 (6H, d, 6.75 Hz), 2.83 - 2.98 (5H, m), 5.43 (2H, s), 5.52 (2H, s), 6.06 (IH, br t, J = 6

Hz), 6.88 (2H, d, J = 8.25 Hz), 6.97 (IH, dd, J = 8.25, 1.5 Hz), 7.24 (IH, d, J = 8.25 Hz), 7.32 (2H, d, J = 8.25 Hz), 7.47 (IH, d, J = 1.5 Hz); MS (M+H)+ = 500. Analysis calc'd for C28H38CIN3OS: C, 67.24; H, 7.66; N, 8.40; Found: C, 67.11; H, 7.74; N, 8.25.

Example 6

Preparation of N'-hvdroxv-N'-methvl-N-2-r3-ri-r4-chlorophenvlmethvl .-3-π.l- dimethylethylthioV5-ri-methylethyl ^' )indol-2-yl)-2.2-dimethylpropionylaminolethyl urea

The following reactants were combined in a round-bottom flask: Compound 1.1 (8.0 g, 16.9 mmol), β-alanine ethyl ester hydrochloride (2.65 g, 16.9 mmol), and

1-hydroxybenztriazole hydrate (6.85 g, 50.7 mmol). The vessel was placed under N (g) atmosphere; DMF (43 mL) and N-methyl morpholine (3.70 mL, 33.8 mmol) were then added. The reaction was cooled to -23°C (CCI4 CO2 bath) and stirred ten minutes before adding l-ethyl-3-(3-aminomethyl) carbodiimide hydrochloride (3.24 g, 16.9 mmol). The reaction was allowed to slowly warm to room temperature and stir overnight. The reaction mixture was poured into NaHCO3 (200 mL) (aq, sat'd) and extracted with EtOAc (2 x 500 mL). The combined organic extracts were washed

(4 x H ₂ O, 3 x brine), dried (MgSO4), concentrated in vacuo, and purified by chromatography (silica gel, 20-35% EtOAc hexane) to yield 8.83 g of intermediate ester 6.1. m.p. 45 - 50°C; -H NMR (300 MHz, DMSO-djs); 1.08 (6H, s), 1.14 (3H, t, J = 6.75 Hz), 1.19 (9H, s), 1.23 (6H, d, J = 6.75 Hz), 2.42 (2H, t, J = 7.50 Hz), 2.95 (IH, septet, J = 6.75 Hz), 3.15 (2H, s), 3.22 - 3.32 (2H, m), 4.0 (2H, quartet, J = 6.75

Hz), 5.45 (2H, s), 6.86 (2H, d, J = 8.25 Hz), 6.97 (IH, dd, J = 8.25, 1.5 Hz), 7.24 (IH, d, 8.25 Hz), 7.32 (2H, d, J = 8.25 Hz), 7.47 (IH, d, 1.5 Hz), 7.58 (IH, br t, J = 5.25 Hz); MS (M+H)+ = 571.

To a stirring solution of ester 6.1 (7.31 g, 12.8 mmol) in THF (40 mL), LiOH (880 mg, 21.0 mmol) in H ₂ O (23 mL) was added. The reaction was stirred for four hours then acidified with HC1 (12M). The aqueous solution was extracted with EtOAc (2 x 300 mL). The combined aqueous extracts were dried (MgSO ₄ ), concentrated in vacuo and purified by chromatography (silica gel, 20-50% EtOAc hexane/2%HOAc) to yield 6.80 g of acid 6.2 as a white, amorphous solid. m.p. 80.3 - 83.0°C; ^l H NMR (300 MHz, DMSO-dό); 1-08 (6H, s), 1.20 (9H, s),

1.23 (6H, d, J = 6.75 Hz), 2.36 (2H, t, J = 7.50 Hz), 2.95 (IH, septet, J = 6.75 Hz), 3.17 (2H, s), 3.20-3.30 (2H, m), 5.45 (2H, s), 6.87 (2H, d, J = 8.25 Hz), 6.97 (IH, dd, J = 1.5 Hz, 8.25 Hz), 7.24 (IH, d, J = 8.25 Hz), 7.32 (2H, d, J = 8.25 Hz), 7.47 (IH, d, J = 1.5 Hz), 7.57 (IH, br t, J = 5.25 Hz); MS (M+H)+ = 543. Starting with acid intermediate 6.2 (746 mg, 1.37 mmol) and following the procedure of Example 1 listed above, 315 mg of desired product 6 was obtained as a white, amorphous solid. m.p. 99.3 - 105°C; *H NMR (300 MHz, DMSO-dg); 1.08 (6H, s), 1.20 (9H, s), 1.23 (6H, d, J = 7.5 Hz), 2.88 - 3.00 (4H, m), 3.05 - 3.15 (4H, m), 3.17 (2H, s), 5.43 (2H, s), 6.87 (2H, d, J = 8.25 Hz), 6.98 (IH, dd, J = 1.5, 8.25 Hz), 7.05 (IH, m), 7.25 (IH, d, J = 8.25 Hz), 7.32 (2H, d, J = 8.25 Hz), 7.47 (IH, d, J

= 1.5 Hz), 7.59 (IH, m), 9.32 (IH, s); MS (M+H)+ = 587. Analysis calc'd for C3iH43ClN ₄ O ₃ S(0.5 H2O): C, 62.45; H, 7.44; N, 9.40; Found: C, 62.71; H, 7.33; N, 9.38.

Example 7

Preparation of 1 -f 4-chlorophenvlmethvl _-2-r2.2-dimethvl-3-fr3-hvdroxvpropvl V amino)propyl_-3-ri.l-dimethylethylthio)-5-ri-methylethyl_ind ole

6.1 7

To a stirring solution, under N2 (g) atmosphere, of ester 6.1 (964 mg, 1.69 mmol) in E.2O (4 mL) and THF (10 mL), 1.0 M LAH (ether) solution (3.38 mL, 3.38 mmol with respect to aluminum) was added dropwise over a 90 second period. After stirring 3 hours, the reaction mixture was quenched with H2O (0.2 mL), 15% aqueous NaOH (0.2 mL), and H ₂ O (0.6 mL). The resulting aluminum salts were filtered off through a celite pad with EtOAc (200 mL). The filtrate was concentrated in vacuo and purified by chromatography (silica gel, 10-35%

EtOAc hexane/2%isopropylamine) to yield 680 mg of desired product 7 as a clear, colorless oil. -H NMR (300 MHz, DMSO-dό); 0.87 (6H, s), 1.20 (9H, s), 1.23 (6H, d, J = 7.5 Hz), 1.55 -1.64 (3H, m), 2.27 (2H, br s), 2.58 (2H, br t, J = 6.0 Hz), 2.90 -

3.00 (3H, m), 3.48 (2H, t, J = 6.0 Hz), 4.50 (IH, br s), 5.65 (2H, br s), 6.87 ( 2H, d, J = 8.25 Hz), 6.95 ( IH, dd, J = 1.5, 8.25 Hz), 7.23 ( IH, d, J = 8.25 Hz), 7.32 (2H, d, J = 8.25 Hz), 7.47 (IH, d, J = 1.5 Hz); MS (M+H)+ = 515. Analysis calc'd for C30H43CIN2OS: C, 69.94; H, 8.41 ; N, 5.44; Found: C, 70.56; H, 8.57; N, 5.49.

Example 8

Preparation of N-2-r2-methvl-3-ri-r4-chlorophenvlmethvn-3-π.1-dimethvlethv lthioV 5-ri-methvlethvl.indol-2-vl_1propvl urea -

1.1 8

Starting with Compound 1.1 (1.00 g, 2.12 mmol) and 14.8 N ammonium hydroxide (0.90 g, 2.23 mmol) and following the procedure outlined in Example 1, 344 mg of desired product 8 was obtained as white, powdery solid after recrystallization (Et2O/CH ₂ Cl2/hexane). m.p. 206.1-206.5°C; -H NMR (300 MHz, DMSO-d6); 1.18 (15H, s), 1.23 (6H, d, J = 6.75 Hz), 2.95 (IH, septet, J = 6.75 Hz), 3.4 (2H, s), 5.41 (2H, s), 5.58 (2H, s), 5.92 (IH, s), 6.90 (2H, d, J = 8.25 Hz), 6.97 (IH, dd, J = 1.5 and 8.25 Hz), 7.28-7.35 (3H, m), 7.46 (IH, d, J = 1.5 Hz); MS (M-) ⁺ = 485. Analysis calc'd for C27H36CIN3OS: C, 66.71; H, 7.46 ; N, 8.64; Found: C, 66.89; H, 7.51; N, 8.59.

Example 9

Preparation of 3-r3-(l-r4-chlorophenylmethyl)-3-ri. l-dimethylethylthio)-5-ri- methylethyl)indol-2-ylV2-aminocarbonylamino-2-methylpropyllp ropanoic acid, ethyl ester

Starting with Compound 1.1 (1.34 g, 2.84 mmol) and β-alanine ethyl ester hydrochloride (445 mg, 2.84 mmol) and following the procedure outlined in Example 1, 1.28 g of Compound 9 was obtained as a white, amorphous solid after purification by chromatography (silica gel, 30% EtOAc/hexane). m.p. 131°C; -H NMR (300 MHz, DMSO-d6); 1.18-1.21 (18 H, m), 1.23 (6H, d, J = 6.9 Hz), 2.42 (2H, t, J = 6.7

Hz), 2.95 (IH, septet, J = 7.5 Hz), 3.23 (2H, quartet, J = 6.0 Hz), 3.38 (2H, br s), 4.08 (2H, quartet, J = 7.2 Hz), 5.52 (2H, s), 5.83 (IH, t, J = 6.25 Hz), 5.87 ( IH, s), 6.89 (2H, d, J = 8.6 Hz), 6.97 (IH, dd, J = 1.5 and 8.4 Hz), 7.22 (IH, d, J = 8.2 Hz), 7.32 (2H, d, J = 8.4 Hz), 7.46 (IH, d, J = 1.7 Hz); MS (M+H)+ = 586. Analysis calc'd for C3 H44ClN ₃ O3S: C, 65.56; H, 7.56 ; N, 7.17; Found: C, 65.76; H, 7.65; N, 7.12.

Example 10

Preparation of 3-r3-π -r4-chlorophenvlmethvn-3-π.l-dimethvlethvlthioV5-ri-

Starting with Compound 9 (1.00 g, 1.71 mmol) and following the procedure outlined in Example 6, 930 mg of desired product 10 was obtained as white, amorphous solid after purification by chromatography (silica gel, 15-50%EtOAc 2%HOAc/hexane). m.p. 139-141°C;

- NMR (300 MHz, DMSO-ctø; 1.18 (15H, s), 1.23 (6H, d, J = 6.9 Hz), 2.36 (2H, t, J = 6.5 Hz), 2.95 (IH, septet, J = 6.9 Hz), 3.20 (2H, quartet, J = 6.0 Hz), 3.37 (2H, br s), 5.52 (2H, s), 5.83 (IH, t, J = 6.25 Hz), 5.89 (IH, s), 6.88 (2H, d, J = 8.6 Hz), 6.97 (IH, dd, J = 1.7 and 8.6 Hz), 7.22 (IH, d, J = 8.2 Hz), 7.32 (2H, d, J = 8.2 Hz), 7.46 (lH, J = 1.7 Hz); MS (M+H) ⁺ = 558/560. Analysis calc'd for C30H40CIN3O3S: C,

62.54; H, 7.35 ; N, 7.29; Found: C, 62.56; H, 7.12; N, 6.97.

Example 11

Preparation of N'-hvdroxv-N'-methvl-N-ri-r4-chlorophenvlmethylV5-ri- methvlethvl -2-rr2-methvl-2-ethoxvcarbonvnpropvDindol-2-vll-3-oxopropylu rea

11.3 11

Starting with Compound 11.1 (3.60 g, 7.20 mmol), the ethyl ester of Compound 1.1, in benzene (70 mL), AICI3 (2.88 g, 21.6 mmol) was added neat. The reaction was stirred for one hour, under N ₂ (g) atmosphere. The brown reaction mixture was poured into a separatory funnel containing 10% aqueous HC1 and extracted with EtOAc. The combined organic extracts were washed (2 x H ₂ O and 1 x brine), dried (MgSO4), and concentrated in vacuo to yield 3.63 g of a dark orange syrup. After purification by chromatography (silica gel, 10-20% Et ₂ O hexane), 1.68 g of Compound 11.2 was obtained as a viscous oil.

To a stirring solution, under N2 (g) atmosphere, of Compound 11.2 (1.68 g, 4.08 mmol) in distilled CH2CI2 (35 mL), succinic anhydride (410 mg, 4.10 mmol) was added neat The reaction was cooled to 0°C, and AICI3 (1.25 g, 9.40 mmol) added via a powder addition funnel (over a three minute interval). After stirring overnight at room temperature, the reaction mixture was poured into dilute aqueous

HC1 and extracted with EtOAc. The combined organic extracts were washed (lx brine), dried (MgSO4), and concentrated in vacuo . The crude concentrate was purified by chromatography (silica gel, 20% EtOAc/2%HOAc hexane), followed by recrystallization (CH2θ2/hexane) to yield 535 mg of Compound 11.3 as a fine white solid. m.p. 172.5-174°C.

Starting with Compound 11.3 (385 mg, 0.752 mmol) and following the procedure outlined in Example 1, 30 mg of Compound 11 as a salmon-colored solid was obtained after purification by chromatography (silica gel, 20 - 50% EtOAc/hexane/2%HOAc) and recrystallization (EtOAc hexane). m.p. 150.5- 152°C; -H NMR (300 MHz, DMSO-dό); 1.10 (3H, t, J = 6.75 Hz), 1.16 (9H, s), 1.25 (6H, d,

J = 6.75 Hz), 2.95 (3H, s), 3.02 (IH, septet, J = 6.75 Hz), 3.23 (2H, t, J = 6.75 Hz), 3.45 (2H, quartet, J = 6.0 Hz), 3.58 (2H, s), 4.0 (2H, quartet, J = 6.75 Hz), 5.50 (2H, br s), 6.92 (3H, m), 7.08 (IH, dd, J = 1.5 and 8.25 Hz), 7.32 (IH, d, J = 8.25 Hz), 7.35 (2H, d, J = 8.25 Hz), 7.76 (IH, br s), 9.39 (IH, s); MS (M+H)+ = 556. Analysis calc'd for C ₃ oH38ClN3θ ₅ (0.25 H ₂ 0): C, 64.28; H, 6.92 ; N, 7.50; Found:

C, 64.33; H, 6.86; N, 7.35.

Example 12

Preparation of l-r4-chlorophenylmethyl)-3-ri. l-dimethylethylthio ^' )-2-r3-r2.2- dimethvl-l-guanidinvlimino propvn-5-ri-methvlethvl)indole

Compound 2.2 (676 mg, 1.48 mmol) was suspended in EtOH (3 mL) and stirred under N2(g) atmosphere. Aminoguanadinium hydrogen carbonate (205 mg,

1.50 mmol) was suspended in MeOH (3 mL) and 6N HC1 aqueous added until all of the solid dissolved. The aminoguanidinium solution was added to the solution of Compound 2.2, and the reaction allowed to stir 16 hours. The reaction was concentrated in vacuo and purified by chromatography (silica gel, 5.5% MeOH/2% isopropylamine/CHCl3) to yield 374 mg of Compound 12 as a cream-colored

amorphous solid. m.p. 105-107°C; -U NMR (300 MHz, DMSO-d6); 1.07 (6H, s), 1.20 (9H, s), 1.22 (6H, d, J = 6.75 Hz), 2.95 (IH, septet, J = 6.75 Hz), 3.05 (2H, br s), 5.22 (2H, br s), 5.40 (2H, s), 5.51 (2H, br s), 6.85 (2H, d, J = 8.25 Hz), 6.97 ( IH, dd, J = 8.25 and 1.5 Hz), 7.27 (IH, d, J = 8.25 Hz), 7.32 (3H, m), 7.46 (IH, d, J = 1.5 Hz); MS (M+H)+ = 512/514.

Analysis calc'd for C ₂ 8H3 ₈ C1N ₅ S(0.25 H ₂ O): C, 65.09; H, 7.51 ; N, 13.67; Found: C, 64.97; H, 7.51; N, 13.47.

Example 13 Preparation of 3-r3-ri-r4-chlorophenvlmethvl.-3-ri.l-dimethvlethvlthio.-5-n - methylethyl)indol-2-yπ-2-aminocarbonylamino-2-methylpropynp ropanoic acid. sodium salt

To a stirring THF (2 mL) solution of Compound 10 (314 mg, 0.563 mmol),

NaOMe (30.4 mg, 0.563 mmol) was added and the reaction stirred at room temperature. The reaction was carried out under N (g) atmosphere. After one hour the reaction was taken up in 50% EtOAc/THF, washed (2 x brine), dried (MgSO4), and purified by chromatography (silica gel, 5% MeOH/CH C_2) to yield 236 mg of Compound 13 as an off-white amorphous solid. m.p. 176 - 185°C; H NMR (300

MHz, DMSO-de); 1.18 (15H, s), 1.22 (6H, d, J = 6.75 Hz), 2.26 (2H, t, J = 6.0 Hz), 2.95 (IH, septet, J = 6.75 Hz), 3.17 (2H, m), 3.38 (2H, br s), 5.53 (2H, br s), 5.88 (IH, br s), 6.0 (IH, br s), 6.89 (2H, d, J = 8.25 Hz), 6.96 (IH, dd, J = 8.25 and 1.5 Hz), 7.23 (IH, d, J = 8.25 Hz), 7.32 (2H, d, J = 8.25 Hz), 7.46 (IH, d, J = 1.5 Hz); MS (M+H)+ = 580 and (M+Na) = 602. Analysis calc'd for C30H39CIN3O3: C, 62.12; H,

6.78 ; N, 7.24; Found: C, 62.21; H, 6.78; N, 7.34.

Example 14

Preparation of N-hydroxy-N-rtrfl/t -2-(l-r4-chlorophenylmethyl)-3-π.l- dimethvlethvlthio -5-ri-methvlethvl indol-2-vncvclopropvnmethvlurea

To a solution of ethyl bromopyruvate (10.00 g, 51.3 mmol) in THF (250 mL) at

0°C, was added 2-methyl-2-propanethiol (4.86 g, 53.87 mmol) followed by the dropwise addition of triethylamine (6.22 g, 61.56 mmol). The cooling bath was removed and the reaction allowed to come to rt and stir for 15 h. The reaction was then diluted with brine (250 mL) and extracted with ethyl acetate (3x 250 mL). The organics were combined, dried with MgSO4 and concentrated. Vacuum distillation of the resulting residue (0.7 mm Hg) afforded 6.47 g (62%) of ethyl t-butylthiopyruvate as a colorless oil (b.p.89-92°C) which was used immediately.

To a solution of ethyl t-butylpyruvate (6.46 g, 31.7 mmol) in toluene (120 mL) was added N-(4-isopropylphenyl)-N-(4-chlorobenzyl)-hydrazine (11.43 g, 36.7 mmol), sodium acetate (3.30 g, 40.26 mmol) and acetic acid (60 mL). The reaction was stirred for 24 h in the dark. It was then diluted with brine (200 mL) and extracted with ethyl acetate (3x 200 mL). The organics were combined, dried with MgSO4 and concentrated. The resulting residue was chromatographed (silica gel, etheπhexanes, 2:98) to afford 7.53 g (46%) of intermediate 14.1.

To a solution of intermediate 14.1 (7.51 g, 16.91 mmol) in toluene (25 mL) at - 78°C, was added diisobutylaluminum hydride (50.73 mL of a 1.0 M solution in hexanes, 50.73 mmol) dropwise. Upon completion of addition, the reaction was stirred for 30 min at -78°C. It was then quenched with aqueous 10% HC1 (75 mL) and warmed to rt and extracted with ethyl acetate (3x 75 mL). The organics were combined, dried with MgSO4 and concentrated. The unpurified residue was taken up in CH2CI2 (80 mL) and pyridinium dichromate (9.54 g, 25.37 mmol) was added. The reaction was stirred for 15 h, then filtered through Celite. The filtrate was concentrated. The resulting residue was chromatographed (silica gel, etheπhexanes, 3:97) to afford 4.16 g (61% over the two steps) of intermediate 14.2 as an off-white solid.

A solution of intermediate 14.2 (4.15 g, 10.4 mmol) and malonic acid (1.40 g, 13.5 mmol) in pyridine (5 mL) containing piperidine (177 mg, 2.08 mmol) was refluxed for 18 h. It was then cooled to rt and poured into ice/cone. HC1 (50 mL). This aqueous solution was then extracted with ethyl acetate (3x 50 mL). The organics were combined, dried with MgSO4 and concentrated. The resulting residue was chromatographed (silica gel, etheπhexanes:acetic acid, 30:69:1) to afford 1.06 g (23%) of intermediate 14.3 as a gold foam.

To a solution of intermediate 14.3 (1.05 g, 2.4 mmol) in CH2CI2 (10 mL) was added oxalyl chloride (362 mg, 2.9 mmol) followed by a drop of N,N- dimethylformamide. The reaction was stirred for 1 hr, then concentrated. The resulting residue was taken up in CH2CI2 (10 mL) and cooled to 0°C. N,O- Dimethylhydroxylamine hydrochloride (283 mg, 2.9 mmol) was added followed by pyridine (456 mg, 5.76 mmol). The cooling bath was withdrawn and the reaction allowed to warm to rt, diluted with brine (10 mL), and the layers were separated.

The aqueous layer was extracted with CH2CI2 (2x 10 mL). The organics were combined, dried with MgSO4 and concentrated. The resulting residue was chromatographed (silica gel, etheπhexanes, 1:1) to afford 1.04 g (89%) of intermediate 14.4 as a brown oil. To a suspension of trimethylsulfoxonium iodide (514 mg, 2.3 mmol) in DMSO (5 mL) was added sodium hydride (57 mg of 97% dry, 2.3 mmol) and the resulting mixture was stirred for 20 min. Intermediate 14.4 (1.03 g, 2.1 mmol) was then added dropwise as a solution in DMSO (5 mL) and the reaction was stirred for 2 h at rt then brought to 50°C for 18 h. It was then cooled to rt and diluted with brine (15 mL). This aqueous solution was extracted with ethyl acetate (3x 20 mL). The organics were combined, dried with MgSO4 and concentrated. The resulting residue was

chromatographed (silica gel, etheπhexanes, 25:75) to afford intermediate 972 mg (93%) of intermediate 14.7 as a colorless oil.

To a solution of intermediate 14.7 (962 mg, 1.93 mmol) in THF (9 mL) at 0°C, was added diisobutylaluminum hydride (2.02 mL of a 1.0 M solution in hexanes, 2.02 mmol) dropwise. Upon complete addition, the reaction was stirred for 30 min. It was then diluted with 10% aqueous HC1 (10 mL) and extracted with ethyl acetate (3x 10 mL). The organics were combined, dried with MgSO4 and concentrated. The resulting residue was chromatographed (silica gel, etheπhexanes, 15:85) to afford 349 mg (41%) of intermediate 14.8 along with 372 mg (44%) of intermediate 14.9. Intermediate 14.9 (362 mg, 0.819 mmol) was recycled to intermediate 14.8 (218 mg,

61%) following the oxidation procedure described for the conversion of 2.1 to 2.2. A solution of intermediate 14.8 (567 mg, 1.29 mmol) in 1:1 ethanohpyridine (6 mL) was stirred for 18 h and concentrated. The resulting residue was taken up in brine (5 mL) and extracted with ethyl acetate (3x 5 mL). The organics were combined, dried with MgSO4 and concentrated to afford intermediate 14.10.

To a solution of intermediate 14.10 from above in ethanol (6 mL) was added borane-pyridine (264 mg, 2.84 mmol) and the mixture was stirred for 30 min. Aqueous 6N HC1 (0.516 mL, 3.10 mmol) was added dropwise and the reaction was stirred for 1 hr. It was then neutralized by the addition of aqueous 2N NaOH, diluted with brine (5 mL) and extracted with ethyl acetate(3x 10 mL). The organics were combined, dried with MgSO4 and concentrated to afford intermediate 14.11.

To a solution of intermediate 14.11 in THF (6 mL) was added trimethylsilyl isocyanate (163 mg, 1.42 mmol) and the reaction was stiπred for 10 min and concentrated. The resulting residue was chromatographed (silica gel, etheπhexanes to etheπmethanol, 70:30 to 90: 10) to afford the desired material as a foam. 1H NMR

(300 MHz, DMSO-d6): 0.98 (m, IH), 1.22 (d, 6H), 1.24 (s, 9H), 1.31 (m, IH), 1.62 (m, IH), 1.72 (m, IH), 2.95 (septet, IH), 3.21 (m, IH), 3.66 (dd, IH, J = 5 Hz, J = 14 Hz), 5.58 (br s, 2H), 6.30 (br s, 2H), 6.98 (m, 3H), 7.24 (d, IH, J = 8.5 Hz), 7.35 (m, 2H), 7.46 (m, IH), 9.30 (s, IH); MS (M+H)+=500; Analysis calc'd for C27H34CIN3O2S.1/4H2O: C, 64.27, H, 6.89, N, 8.33; Found: C, 64.26, H, 6.82, N,

7.92.

Example 15

Preparation of 3-R-π .l-dimethvletfavlthioV5-ri-methvlefhy1Vl -.4- pyridinylmethyl . indol-2- yll -2.2-dimethylpropanoic acid

15.1 15.2 15

Compound 15.1 was prepared by adaptation of the procedure reported in EPA 87311031.6 using 4-isopropylphenyl hydrazine hydrochloride hydrate. To a -23°C (CO2(s)/CCl4 bath) stirred THF (80 mL) solution of 4-pyridinemethanol (2.18 g, 20 mmol) under N2(g) atmosphere, methanesulfonyl chloride (1.60 mL, 20 mmol) and triethylamine (2.88 mL, 20 6 mmol) were added neat and sequentially. The reaction was stirred at -23°C one hour to give the corresponding mesylate. To a stirred DMSO (25 mL) solution of 15.1 (5.0 g, 13.3 mmol) under N2(g) atmosphere, neat NaH (1.08 g, 35.9 mmol) was added. The above-formed mesylate was cannulated into the reaction mixture within 2 minutes of adding the NaH. The reaction was stirred for 120 minutes before it was quenched with sat'd aqueous NH4CI and extracted with EtOAc (2 x 200 mL) and 1/1 THF/EtOAc (1 x 100 mL). The combined organic extracts were washed (brine), dried (Na ₂ SO4), and concentrated in vacuo to yield 1.24 g of compound 15.2 as a pale yellow solid. 15.2 (1.24 g, 2.66 mmol) was converted to 15 by adapting the procedure outlined in Example 1, to provide 0.60 g of 15 as a white, fibrous solid after recrystallization from CH2Cl2/EtOAc/hexane. m.p. 258 °C; *H NMR (300 MHz, DMSO-dό); 1-01 (6H, s), 1.18-1.27 (15H, m), 2.96 (IH, septet, J = 6.75 Hz), 3.18 (2H, br s), 5.55 (2H, s), 6.77 (2H, d, J = 6.75 Hz), 7.0 (IH, dd, J = 8.25 and 1.5 Hz), 7.27 (IH, d, J = 8.25 Hz), 7.50 (IH, d, J = 1.5 Hz), 8.45 (2H, d, J = 6.75 Hz), 12.45 (IH, br s). MS

(M+H)+ = 439. Analysis calc'd for C 6H34N ₂ O2S(0.5 H ₂ O): C, 70.47; H, 7.85 ; N, 6.32; Found: C, 70.57; H, 7.82; N, 6.30.

Example 16

Preparation of 3-r3-ri.l-dimethvlethvlthio)-5-ri-methvlethvl_-l-r2- thienylmethyDindol-2-yn-2.2-dimethylpropanoic acid

Compound 16 was prepared following the procedure described in Example 15 where 2-thiophenemethanol was substituted for 4-pyridinemethanol. Purification by flash chromatography (sg, 5 -10% EtOAc/CCW 2% HOAc) afforded 1.95 g of

Compound 16 as a pale yellow solid. m.p. 130.5 - 132 °C; *H NMR (300 MHz, DMSO-d6); 1.12 (6H, s), 1.18 (9H, s), 1.23 (6H, d, J = 7 Hz), 2.95 (IH, septet, J = 7 Hz), 3.31 (2H, s), 5.65 (2H, s), 6.91 (IH, dd, J = 4 and 5 Hz), 6.97 (IH, dd, J = 1.5 and 4 Hz), 7.02 (IH, dd, J = 1.5 and 8.25 Hz), 7.33 (IH, dd, J = 1.5 and 5 Hz), 7.42 - 7.48 (2H, m), 12.47 (IH, br s). MS (M+H)+ = 444 and (M+Nft ÷ = 461. Analysis calc'd for C25H33NO2S2: C, 67.68; H, 7.50 ; N, 3.16; Found: C, 67.45; H, 7.50; N, 3.10.

Example 17 Preparation of N-hydroxy-N-rra -r3-ri -r4-chlorophenylmethyl)-3-r 1.1 - diπ _. gthylgthylthiQ)-5-α -me_hyiethyl)indPl-2-yDlprς>p-2-enylyrea

Compound 14.3 is converted to the corresponding oxime, 17.1, following the procedures described for the conversion of 1.1 to 2. Subsequently, 17.1 is converted into 17 following the procedures for the conversion of 2 into 3.

Example 18

Preparation of N-r3-(l-r4-chlorophenylmethyl -3-π. l-dimethylethylthio -5-ri- methylethyl indol-2-yl -2.2dimethylpropynacetohydroxamic acid

3.1 18

Hydroxylamine 3.1 is converted to 18 by treatment with acetyl chloride (2 equiv) and triethylamine to give the N,O-diacetate 18.1, which is O-deprotected by treatment with aqueous NaOH to provide 18.

Example 19

Preparation of N-hydroxy-N-3-r3-ri-r4-chlorophenylmethyl)-3- i.l- dimethylethylthio)-5-ri-methylethyl)indol-2-yl)-2.2-dimethyl propionylaminolpropyl urea

7 19

Compound 7 is reduced to the corresponding alcohol, 19.1, following the procedure employed for the conversion of 1.1 to 2.1, and is subsequently converted to 19 following the procedure employed to transform 15.3 into 15.

Example 20

Preparation of 3-ri-r4-chlorophenvlmethvn-3-n.l-dimethvlethvlthio.-5-n - methylethyl)indol-2-yn-2.2-dimethylpropionaldehvde oxime-O-2-acetic acid

2.2 20

Compound 20 was prepared by following the procedure employed for the conversion of 2.2 to 2 where Carboxymethoxylamine hemihydrochloride was used in place of hydroxylamine hydrochloride. After purification by flash chromatography (silica gel, 20 75/5 EtOAc/Hexane/HOAc), 500 mg of a white amorphous solid was obtained. m.p. 65 - 75°C; -U NMR (300 MHz, DMSO-dβ); 1-08 (6H, s), 1.20 (9H, s), 1.23 (6H, d, J = 7 Hz), 2.95 (IH, septet, J = 7 Hz), 3.09 (2H, bs), 4.43 (2H, s), 5.47 (2H, s), 6.88 (2H, d, J = 8.25 Hz), 6.98 (IH, dd, J = 1.5 and 8.25 Hz), 7.25 (IH, d, J = 8.25 Hz), 7.34 (2H, d, J = 8.25 Hz), 7.47 (IH, d, J = 1.5 Hz), 7.55 (IH, s), 12.67 (IH, bs); MS (M+H)+ = 529. Analysis calc'd for C29H37CIN2O3S: C,

65.83; H, 7.05; N, 5.29; Found: C, 66.07; H, 7.09; N, 5.15.

Example 21

Preparation of 2-r3-amino-2.2-dimethylpropyl -r4-chlorophenylmethyl -3- i.l- dimethylethylthio)-5-ri-methylethyl)indole

3.1 21

To a stirring solution of Compound 3.1 (10.9 g, 23.1 mmol) in 2/1/1 EtOH/EtOAc THF, 20 g of an aqueous preparation of RaNi (50% in H ₂ O) was added. After stirring for thirty minutes, the reaction was carefully filtered. The

catalyst was washed with THF — making sure it was not allowed to go completely dry. The resulting filtrate was concentrated and purified by flash chromatography (silica gel, 3.5/96.5 MeOH/CH Cl ₂ ) to yield 7.84 g of Compound 21 as an amorphous white solid. M.p. 58 - 68°C; *H NMR (300 MHz, DMSO-dό); 0.82 (6H, s), 1.20 (9H, s), 1.23 (6H, d, J = 7 Hz), 1.85 (2H, bs), 2.38 (2H, s), 2.87 - 3.00 (3H, m), 5.58 (2H, s), 6.88 (2H, d, J = 8.25 Hz), 6.96 (IH, dd, J = 1.5 and 8.25 Hz), 7.23 (IH, d, J = 8.25 Hz), 7.33 (2H, d, J = 8.25 Hz), 7.46 (IH, d, J = 1.5 Hz); MS (M+H) ⁺ = 457. Analysis calc'd for C27H37CIN2S: C, 70.94; H, 8.16; N, 6.13; Found: C, 70.64; H, 8.13; N, 6.11.

Example 22

Preparation of N-l ^" 3-ri-r4-chlorophenylmethyl_-3-π .1-dimethylethylthio .-5-ri- methvlethvl_indol-2-vl.-2.2-dimethvlpropvl1acetamide

21 22

To a 0°C stirring solution of Compound 21 (525 mg, 1.15 mmol) in CH3CN (4 mL), diisopropylethylamine (0.40 mL, 2.3 mmol) and acetic anhydride (0.11 mL, 1.15 mol) were added neat and sequentially. The cooling bath was removed immediately. After five minutes, the reaction was poured into 10% HC1 (aq) and extracted with EtOAc (2 x 50 mL). The organic layers were combined, washed (3 x brine), dried (MgSO4), and concentrated in vacuo to yield 591 mg of an off-white solid. Recrystallization from Et2θ/CH2CL2/EtOAc/Hexane afforded 130 mg of a white solid.

M.p. 137.8 - 139°C; ^X H NMR (300 MHz, DMSO-dβ); 0.82 (6H, s), 1.20 (9H, s), 1.22 (6H, d, J = 7 Hz), 1.85 (3H, s), 2.82 - 3.08 (5H, m), 5.52 (2H, s), 6.87 (2H, d, J = 8.25 Hz), 6.97 (IH, dd, J = 1.5 and 8.25 Hz), 7.23 (IH, d, J = 8.25 Hz), 7.33 (2H, d, J = 8.25 Hz), 7.47 (IH, d, J = 1.5 Hz), 7.83 (IH, t, J = 6Hz); MS

(M+H)+ = 499. Analysis calc'd for C29H39CIN2OS: C, 69.78; H, 7.88; N, 5.16; Found: C, 69.87; H, 7.91; N, 5.60.

Example 23 Preparation of N-r<rfl«.y-2-ri-r4-chlorophenvlmethvl.-3-π.l-dimethvlet hvlιhioV5-n- methvlethvl.indol-2-vl.cvclopropvnmethvl urea

14 23

Compound 23 was prepared starting with Compound 14 and following the procedure employed for the conversion of 3 to 5. Purification by flash chromatography (silica gel, 95/5 Et ₂ O MeOH) afforded 20 mg of 23 as an amorphous white solid. -B. NMR (300 MHz, DMSO-dό); 0.89 (lH,m), 1.18 (IH, m), 1.21 (6H, d, J = 7Hz), 1.24 (9H, s), 1.45 (IH, m), 1.68 (IH, m), 2.94 (2H, m), 3.30 (IH, m),

5.44 (2H, bs), 5.58 (2H, bs), 6.06 (IH, J = 6 Hz); MS (M+H) ⁺ = 484 and (M+NH4) = 501.

Example 24 Preparation of N'-hvdroxy-N-3- \3-( 1.1 -dimethylethylthio _ -5-r 1 -me thylethyl . -2-rr2- methyl-2-ethoxycarbonyl)propyl)indol- 1-ynpropyl urea

15.1 24.2

24.3 24

To a stirring DMSO solution (15 mL) of 15.1 (2.91 g, 8.22 mmol), NaH (271 mg, 9.05 mmol) and allyl bromide (0.78 mL, 9.05 mmol) were added neat and sequentially. The reaction was stirred under N ₂ (g) for 18 hours then poured into 50% aqueous NH4CI and extracted with EtOAc (2 x 50 mL). The combined organic extracts were washed (2 x H2O and 3 x brine), dried (MgSO4), and concentrated in vacuo to yield 273 mg of a viscous, yellow oil. This was purified by chromatography (silica gel, 2% EtOAc/CCL to yield 214 mg of allyl intermediate

24.1 as a viscous oil.

To a stirring THF (17 mL) solution of 24.1 (1.80 g, 4.33 mmol) under N2(g) , a 0.5 M solution of 9-BBN in THF (43.3 mL, 21.7 mmol) was added rapidly, and the reaction allowed to stir 18 hours at room temperature. NaOH (868 mg, 21.7 mmol) in H2O (7 mL) was added all at once. The reaction was cooled to 0°C (ice/H2θ bath) and a 30% aqueous H2O2 solution (7.4 g, 65 mmol) added in three portions over a 5 minute period. The reaction was stirred for 10 minutes at 0°C before diluting with brine (75 mL) and extracting with Et ₂ O (2 x 100 mL). The Et2θ extracts were combined, washed (2 x 50 mL, brine), dried (Na2SO4), and concentrated in vacuo to yield 1.12 g of hydroxy intermediate 24.2 as an orange, viscous oil after purification by chromatography (silica gel, 35% EtOAc hexane).

To a stirring THF (10 mL) solution of 24.2 under N2(g) atmosphere, triphenylphosphine (810 mg, 3.09 mmol) and bis-N,O-tert-butyloxycarbonyl- hydroxylamine (665 mg, 2.85 mmol) were added neat and sequentially. The homogeneous solution was cooled to -10°C (ice EtOH bath) and diethylazodicarboxylate (0.49 mL, 3.09 mmol) in THF (2 mL) was added dropwise over a 5 minute interval. The reaction was allowed to warm to room temperature and stir 18 hours. The reaction was concentrated in vacuo and purified by

chromatography (silica gel, 3% EtOAc/CC ) to obtain 702 mg of 24.3 as an amorphous solid.

To a stirring CH2CI2 (5 mL) solution of 24.3, was added TFA (5 mL) . The reaction was stirred 8 minutes and then immediately poured into a sat'd aqueous Na ₂ CO3 solution and extracted with EtOAc (2 x 100 mL). The organic extracts were combined, washed (50% aqueous NaHCO3. and brine), dried (Na2SO4), and concentrated in vacuo to yield 384 mg of the resulting hydroxylamine, 24.4. This was used without further purification.

To a stirring THF (3 mL) solution of 24.4 (355 mg, 0.791 mmol) under N ₂ (g) atmosphere, trimethylsilyl isocyanate (0.63 mL, 3.96 mmol) was added. The reaction was stirred for 90 minutes, concentrated in vacuo , and purified by chromatography (silica gel, 3% MeOH/CH ₂ Cl2) to yield 184 mg of 24 as an amorphous solid, m.p. 64°C; -U NMR (300 MHz, DMSO-d*,); 1.10 (6H, s), 1.13-1.20 (12 H, m), 1.25 (6H, d, J = 6.9 Hz), 1.81 (2H, quintet, J = 6.9 Hz), 2.97 (IH, septet, J = 6.9 Hz), 3.22- 3.32 (4H, m), 4.06 (2H, quartet, J = 6.9 Hz), 4.21 (2H, t, J = 6.9 Hz), 6.33 (2H, s),

7.05 (IH, dd, J = 1.5 and 8.25 Hz), 7.41 (IH, d, J = 8.25 Hz), 7.43 (IH, d, J = 1.5 Hz), 9.28 (lH, s); MS (M+H) ⁺ = 492 and (M+NH ₄ .+ = 509. Analysis calc'd for C26H4iN ₃ O ₄ S(0.5 H ₂ O): C, 62.94; H, 8.43 ; N, 8.47; Found: C, 62.99; H, 8.49; N, 8.39.

Substituted indole N-hydroxyureas presented in Table 3 are prepared by the method used for Example 1 substituting N-methylhydroxylamine for the requisite N- substituted hydroxylamine, R ² NHOH.

Table 3

Example R2

25 -CH2CH3 26 -CH2CH2C6H5

27 -CH ₂ CH ₂ COOCH ₃ 28 -CH2CH2CONH2 29 -CH ₂ CH ₂ CH ₂ OH 30 -CH ₂ CH ₂ OH 31 -CH2CH2OCH3 32 -CH2CH2OQ5H5 33 -CH2CH2OCOCH3 34 -CH ₂ CH2-2-pyridyl 35 -CH2CH2-3-pyridyl 36 -CH2CH ₂ -4-pyridyl

Substituted indole N-hydroxyurea compounds of the present invention presented in Table 4 are prepared by the method used for Example 3 substituting trimethylsilylisocyanate with the requisite N-substituted isocyanate, R ³ -N=C=O.

Table 4

Example R ³

37 -CH ₂ CH ₃

38 -CH2CH ₂ C6H5

39 -CH ₂ CH ₂ COOCH ₃

40 -CH ₂ CH ₂ CONH ₂

41 -CH2CH2CH2COOCH3 42 -(CH ₂ )4 COOCH3

43 -CH ₂ C6H ₅

44 -CH2CH2OCH3

45 -CH2CH2OC6H5

46 -CH ₂ CH ₂ OC(O)CH3 47 -CH ₂ CH2-2-pyridyl

48 -CH ₂ CH2-3-pyridyl

49 -CH ₂ CH ₂ -4-pyridyl

50 -C6H5

51 -3-pyridyl 52 -2-furyl

53 -3-thienyl

54 -2-benzo[b] thienyl

55 -2-benzo[b]furyl

56 -2-thiazoyl ===_^=_=_ ₌ ====_==:_ =__:__=_=^^

Substituted indole urea compounds in accordance with the present invention presented in Table 5 are prepared by the method used for Example 5 by deoxygenation of the N-hydroxyurea examples shown in Table 4.

Table 5

Example R ³

57 -CH ₂ CH ₃

58 -CH ₂ CH ₂ C6H ₅

59 -CH ₂ CH ₂ COOCH ₃

60 -CH2CH2CONH2

61 -CH2CH2CH2COOCH3 62 -(CH ₂ )4 COOCH3

63 -CH2C6H5

64 -CH2CH2OCH3

65 -CH2CH2OC6H5

66 -CH2CH2OCOCH3 67 -CH ₂ CH2-2-pyridyl

68 -CH2CH2-3-pyridyl

69 -CH2CH2-4-pyridyl

70 -C6H5

71 -3-pyridyl 72 -2-furyl

73 -3-thienyl

74 -2-benzo[b]thienyl

75 -2-benzo[b]furyl

76 -2-thiazoyl === - = = ===== _== ^■ _ _=__===_________

Substituted indole oxime derivatives presented in Table 6 are prepared by the method used for Example 2 substituting hydroxylamine with the requisite O- substituted hydroxylamine R ² ONH2.

Table 6

Example R ²

77 -CH2CH3

78 -CH2CH2C6H5

79 -CH2CH2COOCH3 80 -CH2CH2CONH2

81 -CH ₂ CONH ₂

82 -(CH ₂ ) ₂ CON(Et) ₂

83 -CH2-(N-morpholine)

84 -CH ₂ -(N-piperidine) 85 -CH2-(N-piperazine)

86 -CH2-COO-CH2CH2NH2

87 -CH ₂ -COO-CH ₂ CH(OH)CH ₂ OH

88 -CH ₂ -COOCH(CH ₃ )O(O)CC(CH3)3

89 -CH2-COO-CH2-N-succinimide 90 -(CH ₂ )3COOCH ₃

91 -(CH ₂ )4 COOCH

92 -(CH ₂ )2COOH

93 -(CH ₂ ) ₃ COOH

94 -(CH ₂ ) ₄ COOH 95 -(CH2 _. 2CH2OH

10

15

20

25

Substituted indole acid derivatives presented in Table 7 are prepared by the method used for Example 15 substituting 4-pyridylmethanol with the requisite heteroarylmethanol intermediate B-OH.

Table 7

Example B

120 -CH -2-pyridyl

121 -CH2-3-pyridyl

122 -CH ₂ -4-pyridyl

123 -CH ₂ -2-furyl

124 -CH2-3-furyl

125 -CH2-2-thienyl

126 -CH -3-thienyl

127 -CH2-2-benzo[b]thienyl

128 -CH ₂ -2-benzo[b]furyl

129 -CH ₂ -2-thiazoyl

130 -CH2-2-imidazoyl

131 -CH2-2-pyrimidyl

Substituted indole oxime derivatives as shown in Table 8 are prepared by the method used for Example 2 substituting compound 1.1 with the indole acid compounds described in Table 7 and reaction of the requisite aldehyde with the appropriate hydroxylamine, R ² ONH ₂ .

Table 8

Substituted indole oxime derivatives as shown in Table 9 are prepared by the method used for Example 11 where 11.1 is desulfurized to provide the indole intermediate 11.2 and then 11.2 is converted to various oxime derivatives by the method of Example 2 substituting hydroxylamine with the requisite O-substituted hydroxylamine, R ² ONH ₂ .

Table 9

Example R ²

144 -CH ₂ COOH

145 -CH ₂ CH ₂ OH 146 -CH2CH3

147 -CH2CH2C6H5

148 -CH2CH2COOCH3

149 -CH2CH2CONH2

150 -CH2CONH2 151 -(CH ₂ )2CON(Et)2

152 -CH2-morpholinylamide

153 -CH2-piperidinylamide

154 -CH2-l,5-piperizinylamide

155 -CH2-COO-CH2CH2NH2 156 -CH2-COO-CH ₂ CH(OH)CH ₂ OH

157 -CH ₂ -COO-CH(CH ₃ )OOC(CH ₃ )3

158 -CH2-COO-CH2-N-succinimide

159 -(CH ₂ )3COOCH ₃

160 -(CH ₂ )4 COOCH3 161 -(CH ₂ ) ₂ COOH

162 -(CH ₂ )3COOH

163 -(CH2.4COOH

Substituted indole amine derivatives presented in Table 10 are prepared by reductive amination (with for example sodium cyanoborohydride) of the aldehyde 2.2 using the requisite amine.

Table 10

10

15

20

25

Substituted indole hydroxamic acid derivatives as shown in Table 11 are prepared by the method of Example 3 substituting trimethylsilylisocyanate with the requisite carboxylic acid chloride or anhydride and suitable base such as pyridine or triethylamine.

Table 11

Example R2

233 -CH ₂ COOCH ₃

234 -CH(CH ₃ )OCH ₃

235 -CH2CH3

236 -CH2CH2C6H5

238 -CH(CH ₃ )COOCH ₃

238 -CH2CH2CONH2

239 -CH ₂ CONH ₂

240 -(CH ₂ )2CON(Et) ₂

241 -CH ₂ COOCH(CH ₃ )O(O)CC(CH3)3

242 -CH(CH ₃ )COOCH ₃

243 -(CH2 _. 4 COOCH3 244 -(CH ₂ )2COOCH ₃ 245 -(CH ₂ )2CH ₂ OCH ₃ 246 -(CH ₂ )3CH ₂ OCH ₃ 247 -(CH ₂ )4CH ₂ OCH3 248 -CH(COOCH ₃ ) ₂ 249 -CH2C6H5 250 -CH2CH2OCH3

Substituted indole hydroxamic acid derivatives X presented in Table 12 are prepared by the method of Example 4 substituting the intermediate 4.1 with the requisite alpha-substituted ketone intermediate VIII to provide the indole intermediate IX which is then converted to the corresponding oxime derivatives X.

Table 12

Example 279

Preparation of 2.2-dimethvl-3-ri-r2-thiophenylmethylV3-π .1 - dimethvIethylthio_-5-n-methyIethyl)indoI-2-yl1propionaldehyd e oxime

16 279

Starting with the product of Example 16 (2.36 g, 5.49 mmol) and adapting the procedure described in Example 2, 3.12 g of crude oxime (containing pyridinium hydrochloride) was obtained. A portion (165 mg) of this product was purified by chromatography (silica gel, 595 EtOAc hexanes) to yield 25 mg of 279 as a solid, m.p. 115.5 - 117°C; -Η. NMR (300 MHz, DMSO-dβ); 1.10 (6H, s), 1.18 (9H, s), 1.23 (6H, d), 2.95 (IH, septet, J = 7 Hz), 3.17 (2H, bs), 5.62 (2H, bs), 6.92 (IH, dd, J = 4 and 5 Hz), 6.95 - 7.05 (2H, m), 7.33 (IH, dd, J = 1.5 and 5 Hz), 7.38 - 7.45 (3H, m), 10.44 (IH, s); MS (M+H)+ = 443 and (M+NH ₄ ) = 460. Analysis calc'd for C25H3 ₄ N2OS ₂ : C, 67.83; H,

7.74; N, 6.33; Found: C, 67.50; H, 7.81; N, 6.18.

Example 280

Preparation of N-2.2-dimethvl-3-rri-r2-thiθDhenvlmethvl .-3-ri.l- dimethvlethvl-thio . -5-r 1 -methvlethvl . indol-2-vl Ipropvl urea

279 280.1

280

Starting with the product of Example 279 (1.31 g, 2.95 mmol) and adapting the procedure described in Example 21, 0.63 g of Compound 280.1 was obtained after purification by chromatography (silica gel, 20/78/2 EtOAc/hexanes/isopropylamine and 10/90 MeOH/CH2Cl2). Compound 280 was prepared from 280.1 (0.24 g, 0.57 mmol) by adapting the procedure of Example 3. After purification by chromatography (silica gel, 75/25 THF/hexanes) and recrystallization from EtOAc/hexanes/MeOH, 19 mg of Compound 280 was obtained as a white solid. m.p. 163.5 - 164.5°C; *H NMR (300 MHz, DMSO-dβ); 0.83 (6H, s), 1.18 (9H, s), 1.22 (6H, d, J = 7

Hz), 2.88 - 3.00 (5H, m), 5.45 (2H, bs), 5.67 (2H, bs), 6.07 (IH, bt, J = 6 Hz), 6.91 (IH, dd, J = 4 and 5.3 Hz), 6.96 - 7.02 (2H, m), 7.32 (IH, dd, J = 1,5 and 5.3 Hz), 7.37 - 7.46 (2H, m); MS (M+H)+ = 472. Analysis calc'd for C26H37N3OS2: C, 66.20; H, 7.91; N, 8.91; Found: C, 66.53; H, 8.00; N, 8.93.

Example 281

Preparation of 3-H -r4-chlorophenvlmethvn-3-r 1.1 -d_methv1ethvlthioV5- rmethoxy.indol-2-yπ-2.2-dimethylpropionaldehvde oxirne-O-2-acetic acid

281.1 281.2

281.3 281

Compound 281.1 was prepared by adapting the procedure reported in EPA 87311031.6 using 4-methoxyphenylhydrazine hydrochloride hydrate.

Starting with 281.1 (8.0 g, 23 mmol) and adapting the procedure described in Example 15, in which 4-chlorobenzyl bromide was substituted for 4-pyridinemethanol, 6.17 g of crude 281.2 was obtained. A portion (1.05 g) of this crude material was purified by recrystallization from EtOAc hexanes to yield 0.87 g of Compound 281.2 as a white solid. m.p. 193.5 - 194.5°C;

*H NMR (300 MHz, DMSO-dό); 1.06 (6H, s), 1.17 (9H, s), 3.15 (2H, bs), 3.72 (3H, s), 5.43 (2H, s), 6.68 (IH, dd, J = 2.25 and 9 Hz), 6.78 (2H, d, J = 9 Hz), 7.06 (IH, d, J = 2.25 Hz), 7.25 (IH, d, J = 9 Hz), 7.28 (2H, d, J = 9 Hz), 12.42 (IH, bs); MS (M+H)+ = 460 and (M+Na)+ = 482. Analysis calc'd for C ₂ 5H ₃₀ C1NO3S(0.25 H ₂ O): C, 64.64; H, 6.62; N, 3.02; Found: C, 64.57; H,

6.39; N, 3.02.

Starting with 281.2 (5.1 g, 11 mmol) and adapting the procedure described in Example 2, 4.1 g of 281.3 was obtained after purification by chromatography (silica gel, 10/90 and 20/80 EtOAc/hexanes). Compound 281 was prepared by following the procedure detailed in

Example 20. After purification by chromatography (silica gel, 20/78/2

EtOAc/hexanes/HOAc) and recrystallization from benzene/hexanes, 0.57 g of 281 was obtained as a white powder, m.p. 138 - 139°C; -H NMR (300 MHz, DMSO-d6); 1.08 (6H, s), 1.22 (9H, s), 3.07 (2H, bs), 3.75 (3H, s), 4.42 (2H, s), 5.47 (2H, s), 6.72 (IH, dd, J = 1.5 and 9 Hz), 6.85 (2H, d, J = 9 Hz), 7.08 (IH, d, J = 1.5 Hz), 7.23 (IH, d, J = 9 Hz), 7.32 (2H, d, J = 9 Hz), 7.55

(lH _. s); MS (M+H)+ = 516. Analysis calc'd for C27H33CIN2O4S: C, 62.72; H, 6.43; N, 5.42; Found: C, 62.68; H, 6.43; N, 5.34.

Example 282 Preparation of 3- 1 ^" 1 -r4-chlorophenylmethyl . -3-r 1.1 -dimethylethylthio. -5-r 1 - methylethyl) indol-2-yn-2.2-dimethylpropionaldehyde oxime-O-3-propionic acid

To a stirring EtOH (6.5 mL) solution of the product of Example 2, ethyl acrylate (0.27 mL, 2.5 mmol) and 0.25 mL of 2N KOH (EtOH) were added.

The reaction was heated to 60°C under N2(g) for 18 hours. The reaction was cooled to room temperature, concentrated in vacuo and diluted with Et ₂ θ. The Et2θ solution was washed with 50% (aq) NaHCO3. The layers were separated and the aqueous layer back-extracted with Et2θ. The combined organic extracts were washed (lxbrine), dried (MgSO4), concentrated in vacuo, and purified by chromatography (silica gel, 10/90 E_2θ/hexanes and 20/80 EtOAc hexanes) to yield 0.64 g of recovered 2 and 0.58 g of 282.1 as a pale yellow oil.

Compound 282 was prepared by the methodology in Example 6 used to convert 6.1 to 6.2. After purification by chromatography (silica gel, 20/80

EtOAc/hexanes and 20 78/2 EtOAc/hexanes/HOAc) and recrystallization

from benzene/petroleum ether, 0.20 g of 282 as a white solid was obtained. m.p. 50 - 70°C; *H NMR (300 MHz, DMSO-c ); 1.04 (6H, s), 1.16 (9H, s), 1.18 (6H, d, J = 7 Hz), 2.43 (2H, t, J = 6 Hz), 2.91 (IH, septet, J = 7 Hz), 3.06 (2H, bs), 4.02 (2H, t, J = 6 Hz), 5.39 (2H, s), 6.85 (2H, d, J = 9 Hz), 6.93 (IH, dd, J = 1.5 and 9 Hz), 7.18 (IH, d, J = 9 Hz), 7.29 (2H, d, J = 9 Hz), 7.43 (2H, s), 12.26 (IH, bs); MS (M+H) ⁺ = 542. Analysis calc'd for C ₃₀ H ₃₉ CIN2O3S: C, 66.34; H, 7.24; N, 5.16; Found: C, 66.37; H, 7.28; N, 5.08.

Example 283 Preparation of N-r3-ri-r4-chlorophenvlmethvl.-3-ri.l-dimethvlethvlthioV5- ri-methylethyl_indol-2-yl1-2.2-dimethylpropionaldehvde oxime-O)-methyl urea

283 Starting with 282 (0.49 g, 0.92 mmol) and adapting the procedure described in Example 1, substituting ammonium chloride for ammonium hydroxide, 59 mg of 283 was obtained as a white amorphous solid after purification by chromatography (silica gel, 50/50 EtOAc/hexanes and EtOAc). m.p. 90 - 110°C; -H. NMR (300 MHz, DMSO-dβ); 1.05 (6H, s), 1.16 (9H, s),1.18 (6H, d, J = 7 Hz), 2.91 (IH, septet, J = 7 Hz), 3.07 (2H, bs), 4.79 (2H, d, J = 7 Hz), 5.37 (2H, s), 5.72 (2H, s), 6.84 (2H, d, J = 9 Hz), 6.88 - 6.96 (2H, m), 7.18 (IH, d, J = 9 Hz), 7.30 (2H, d, J = 9 Hz), 7.43 (IH, d, J = 1.5 Hz), 7.45 (IH, s); MS (M+H)+ = 542 and (M+Na)+ = 565. Analysis calc'd for C29H39CIN4O2S: C, 64.13; H, 7.24; N, 10.31; Found: C, 63.86; H, 7.34; N, 10.01.

Example 284

Preparation of N-2-ri-r4-chlorophenvlmethvlV3-π. l-dimethv1ethvlthioV5-n- methvlethvnindol-2-vn-2.2-dimethvlpropionvlamino1ethvl urea

6.2 284

Starting with Compound 6.2 (0.99 g, 1.82 mmol) and adapting the procedure described in Example 1, substituting ammonium chloride for ammonium hydroxide, 0.43 g of Compound 284 was obtained as a white amorphous solid after purification by chromatography (silica gel, 5/95

MeOH/CH ₂ C_2). m.p. 100 - 111°C; -H NMR (300 MHz, DMSO-dβ); 1.08(6H, s), 1.19 (9H, s), 1.24 (6H, d, J = 7 Hz), 2.88 - 3.12 (5H, m), 3.16 (2H, s), 5.44 (2H, s), 5.52 (2H, s), 6.03 (IH, t, J = 4.5 Hz), 6.85 (2H, d, J = 8 Hz), 7.25 (IH, d, J = 8 Hz), 7.33 (2H, d, J = 8 Hz), 7.47 (IH, d, J = 1.5 Hz), 7.67 (IH, t, J = 4.5 Hz); MS (M+H)+ = 557/559. Analysis calc'd for

C3oH4iClN O2S(0.25 H ₂ O): C, 64.15; H, 7.45; N, 9.97; Found: C, 64.13; H, 7.33; N, 9.94.

Example 285

Preparation of 3-ri-r4-fluorophenvlmethvlV3-ri . l-dimethvlethvlthio.-5-ri- methvlethvl . indol-2-vn-2.2-dimethvlpropionaldehvde oxime-O-2-acetic acid

285.2 285

Compound 285.1 was obtained from Compound 15.1 by adapting the hydrolysis procedure reported in EPA 87311031.6.

Using compound 285.1 (0.11 g, 0.33 mmol) and adapting the procedure used to convert 15.1 to 15.2, substituting 4-fluorobenzyl bromide for 4-pyridinemethanol, 43 mg of Compound 285.2 was obtained as a white solid after purification by chromatography (silica gel, 5/93/2 EtOAc/CCLj/HOAc) followed by recrystallization from benzene/hexanes. m.p. 180 -181°C; Η NMR (300 MHz, DMSO-ds); 1.10 (6H, s), 1.19 (9H, s), 1.22 (6H, d, J = 7 Hz), 2.96 (IH, septet, J = 7 Hz), 3.22 (2H, bs), 5.47 (2H, s), 6.88 (2H, dd, J = 6 and 9 Hz), 6.99 (IH, dd, J = 1.5 and 9 Hz), 7.11 (2H, t, J = 9 Hz), 7.29 (IH, d, J = 9 Hz), 7.47 (IH, d, J = 1.5 Hz), 12.45 (IH, bs); MS (M+H)+ = 456 and (M+Na)+ = 478. Analysis calc'd for C ₂ 7H34FNO2S(0.25

H ₂ O): C, 70.48; H, 7.56; N, 3.04; Found: C, 70.67; H, 7.37 N, 3.05.

Starting with Compound 285.2 and adapting the procedure described in Example 281, 0.82 g of 285 was obtained as a white powder after purification by chromatography (silica gel, 20/78/2 EtOAc/hexanes HOAc) followed by recrystallization from hexanes. m.p. 124 -125°C; ^X H NMR (300

MHz, DMSO-d6); 1.06 (6H, s), 1.13 - 1.30 (15H, m), 2.95 (IH, m), 3.10 (2H, bs), 4.43 (2H, s), 5.47 (2H, bs), 6.87 - 7.02 (3H, m), 7.10 (2H, bt, J = 9 Hz), 7.25 (IH, d, J = 9 Hz), 7.47 (IH, s), 7.56 (IH, s), 12.67 (IH, bs); MS

(M+H) ⁺ = 512 and (M+Na) ⁺ = 535. Analysis calc'd for C29H37FN2O3S: C, 67.94; H, 7.27; N, 5.46; Found: C, 68.45; H, 7.29 N, 5.48.

Example 286 Preparation of 3- f 1 -.4-chlorophenylmethyl 3-r 1.1 -dimethylethylthio. -5-r 1 - methvlethvl. indol-2-vll-2.2-dimethvlρropionaldehvde oxime-O-2-acetic acid, sodium salt

20 286

Starting with 20 (1.16 g, 2.19 mmol) and adapting the procedure described in Example 13, 0.51 g of 286 was obtained as a pale pink solid. m.p. 218 - 220°C; -H NMR (300 MHz, DMSO-de); 1.06 (6H, s), 1.19 (9H, s),1.23 (6H, d, J = 6 Hz), 2.95 (IH, septet, J = 6 Hz), 3.05 (2H, bs), 4.12 (2H, s), 5.50 (2H, s), 6.90 (2H, d, J = 9 Hz), 6.97 (IH, dd, J = 1.5 and 9 Hz), 7.25

(IH, d, J = 9 Hz), 7.32 (2H, d, J = 9 Hz), 7.41 (IH, s), 7.47 (IH, d, J = 1.5 Hz); MS (M+H)+ = 551. Analysis calc'd for C29H ₃₆ ClN ₂ O3SNa: C, 63.20; H, 6.58; N, 5.08; Found: C, 63.09; H, 6.59; N, 5.04.

Example 287

Preparation of 3-f 1 -r4-chlorophenylmethyl)-3-r 1.1 -dimethylethylthio _ -5-r 1 - methylethyl) indol-2-vn-2.2-dimethylpropionaldehvde oxime-O-2-propionic acid

2.2 287

Starting with 2.2 and adapting the procedure described in Example 20, substituting carboxy-1-ethyoxylamine hydrochloride for carboxymethoxylamine hemihydrochloride, 0.20 g of Compound 287 was obtained as a white amorphous solid after purification by chromatography (silica gel, 20 78/2 EtOAc/hexanes/HOAc). m.p. 70 -90°C; ^l H NMR (300

MHz, DMSO-dό); 1.07 (6H, d, J = 7 Hz), 1.20 (9H, s), 1.22 (6H, d , J = 7 Hz), 1.28 (3H, d , J = 7 Hz), 2.95 (septet, J = 7 Hz), 3.08 (IH, bs), 4.45 (IH, quartet, J = 7 Hz), 5.45 (2H, bs), 6.87 (2H, d, J = 9 Hz), 6.97 (IH, dd, J = 1.5 and 9 Hz), 7.24 (IH, J = 9 Hz), 7.33 (2H, J = 9 Hz), 7.47 (IH, J = 1.5 Hz), 7.50 (IH, s), 12.61 (IH, bs); MS (M+H) ⁺ = 543 and (M+NH ₄ ) ⁺ = 560.

Analysis calc'd for C30H39CIN2O3S: C, 66.34; H, 7.24; N, 5.16; Found: C, 66.46; H, 7.39; N, 5.08.

Example 288 Preparation of 3-r3-π. l-dimethylethylthio.-5-rquinolin-2-ylmethoxy.-l-r4- chlorophenylmethyl . indol-2-yl ^" l-2.2-dimethylpropionaldehyde oxime-O-2-acetic acid

288 A solution of 4-acetamidophenol (14.28g, 94.4 mmol), 2-

(chloromethyl)quinoline monohydrochloride (20.22 g, 94.4 mmol) and freshly powdered K2CO3 (39.14 g, 283.2 mmol) in DMF (250 mis) for 4 days. It was then poured into 1:1 ice:H2θ (600 mis). The resulting precipitate was collected and washed with water. It was then crystallized in 95% ethanol to afford 25.31 g (91%) of 4-(quinolin-2-ylmethoxy)acetanilide.

A suspension of 4-(quinolin-2-ylmethoxy)acetanilide (25.29 g, 86.6 mmol) in 95% ethanol (200 mis) containing 10 M KOH (25 mis) was heated at reflux for 3 days. It was then cooled to r.t. and the ethanol was stripped off in vacuo. The resulting residue was diluted with water (40 mis) and the precipitate collected and washed well with water. It was then taken up in hot ethylacetate (500 mis) and decolorized with charcoal. The solution was boiled to leave a volume of 200 mis, and

hexane was added (200 mis). The solution was allowed to cool to r.t. and the crystals collected to afford 16.63 g (77%) of 4-(quinolin-2-ylmethoxy)aniline.

To a suspension of 4-(quinolin-2-ylmethoxy)aniline (10.62 g, 42.5 mmol) in H2O (40 mis) was added concentrated HC1 (10.63 mis, 127.5 mmol) and the suspension was vigorously stirred to obtain a fine white suspension, then cooled to

0°C. A solution of sodium nitrite (3.02 g, 43.78 mmol) in H2O (9 mis) was then added dropwise. Upon completion of addition, the reaction was stirred for 1 hr at 0°C to afford the diazonium salt as a clear orange/yellow solution.

To a solution of Na2S2θ4 (56.20 g of an 85% purity sample, 274.35 mmol) in water (250 mis ), and ether (250 mis) containing NaOH (1.90 mis of a 2N solution,

3.79 mmol) at 0°C, was added the solution of the diazonium salt from above, dropwise and with vigorous stirring. Upon completion of addition, NaOH (75.89 mis of a 2N solution, 151.8 mmol) was added dropwise. The cooling bath was removed and the reaction allowed to warm to r.t. and stirred for 1 hr. The orange solid was then collected, washed well with ether and finally with water. The resulting solid was freeze dried for 18 hrs to afford 9.84 g (87%) of 4-(quinolin-2- ylmethoxy)phenylhydrazine as a pale orange solid.

To a solution of diisopropylethylamine (7.67 g, 59.36 mmol) in CH2CI2 (150 mis) was added 4-(quinolin-2-ylmethoxy)phenylhydrazine (9.83 g, 37.1 mmol). This wa? followed by the addition of 4-chlorobenzyl chloride (8.96 g, 55.65 mmol), tetrabutylammonium bromide (3.59 g, 11.13 mmol) and an additional 50 mis of CH2CI2 and the reaction was stirred for 24 hrs. It was then diluted with H2O (200 mis) and the layers were separated. The aqueous was extracted with CH2CI2 (2x 200 mis), the organics were combined, dried with MgSO4 and concentrated. The resulting solid was washed with 9: 1 etheπmethanol (250 mis) to afford 8.89 g (64%) of 1 -(4-chlorophenylmethyl)- l-(4-(quinolin-2-ylmethoxy)phenyl)hydrazine as a pale yellow solid.

To a solution of methyl 2,2-dimethyl-4-keto-5-(l,l- dimethylethylthio)pentenoate (5.29 g, 21.5 mmol) in toluene (50 mis) and acetic acid (25 mis) was added sodium acetate (2.03 g, 24.73 mmol) followed by l-(4- chlorophenylmethyl)-l-(4-(quinolin-2-ylmethoxy)phenyl)hydraz ine (8.88 g, 22.8 mmol) and the reaction was stirred for 5 days in the dark. It was then poured into water (500 mis) and extracted with ethylacetate (3x 100 mis). The combined organics were then washed with water (3 x 100 mis). Solid NaHCO3 (10 g) was added to the organics and the mixture was filtered and finally washed with water (2x 100 mis). It was then dried with MgSO4 and concentrated. The resulting residue was

chromatographed (silica gel, etheπhexanes, 2:8 to 3:7) to afford methyl 3-[3-(l,l- dimethylethylthio)-5-(quinolin-2-ylmethoxy)-l-(4-chloropheny lmethyl)indol-2-yl]-

2,2-dimethylpropionate.

A solution of methyl 3-[3-(l,l-dimethylethylthio)-5-(quinolin-2-ylmethoxy)- l-(4-chlorophenylmethyl)indol-2-yl]-2,2-dimethylpropionate (3.48 g, 5.8 mmol) in

1:2:1 THF:methanol:lN LiOH (80 is) was heated at 80°C for 3 hrs. It was then cooled to r.t., diluted with water (50 mis) and washed with ether (lx 60 mis). The aqueous layer was then acidified to pH5 by the addition of solid citric acid and extracted with ethylacetate (3x 60 mis). The organics were combined, dried with MgSO4, decolorized with charcoal and concentrated. Crystallization in ethylacetate/hexanes afforded 3-[3-(l,l-dimethylethylthio)-5-(quinolin-2-ylmethoxy)- 1 -(4-chlorophenylmed yl)indol-2-yl]-2,2-dimethylpropionic acid.

To a solution of 3-[3-(l,l-dimethylethylthio)-5-(quinolin-2-ylmethoxy)-l-(4- chlorophenylmethyl)indol-2-yl]-2,2-dimethylpropionic acid (2.57 g, 4.4 mmol) in THF (20 mis) was added borane dimethyl sulfide complex (1.06 g, 14.0 mmol) dropwise. Upon completion of addition, the reaction was stirred for 18 hrs. It was then quenched slowly and dropwise with aqueous sat'd NaHCO3 (30 mis). The THF was stripped off in vacuo and the aqueous residue was extracted with ethylacetate (3x 50 mis). The organics were combined, dried with MgSO4 and concentrated. The resulting residu e was chromatographed (silica gel, etheπhexanes, 1:1) to afford 1.82 g (72%) of 3-[3-(l,l-dimethylethylthio)-5-(quinolin-2-ylmethoxy)-l-(4- chlorophenylmethyl)indol-2-yl]-2,2-dimethylpropanol as a white foam.

To a solution of oxalyl chloride (461 mg, 3.6 mmol) in CH2CI2 (10 mis) at - 78°C was added dimethylsulfoxide (600 mg, 7.68 mmol) dropwise and the resulting mixture was stirred for 5 mins. A solution of 3-[3-(l,l-dimethylethylthio)-5-

(quinolin-2-ylmethoxy)- 1 -(4-chlorophenylmethyl)indol-2-yl] -2,2-dimethylpropanol (1.81 g, 3.2 mmol) in CH2CI2 (5 mis) was then added dropwise and the reaction was stirred for 20 mins at -78°C. Triethylamine (1,62 g, 16.0 mmol) was then added dropwise, the cooling bath was withdrawn and the reaction allowed to warm to r.L It was then diluted with aqueous sat'd NaHCO3 (20 mis) and the layers were separated.

The aqueous was extracted with CH2CI2 (2x 20 mis). The organics were combined, dried with MgSO4 and concentrated. The resulting residue was chromatographed (silica gel, etheπhexanes, 1:1) to afford 1.58 g (86%) of 3-[3-(l,l-dimethylethylthio)- 5-(quinolin-2-ylmethoxy)-l-(4-chlorophenylmethyl)indol-2-yl] -2,2- dimethylpropionaldehyde as a lemon yellow solid.

A solution of 3-[3-(l,l-dimethylethylthio)-5-(quinolin-2-ylmethoxy)-l-(4- chlorophenylmethyl)indol-2-yl]-2,2-dimethylpropionaldehyde (1.57 g, 2.7 mmol) and carboxymethoxylamine hemihydrochloride (361 gm, 1.6 mmol) in 1:1 ethanol :pyridine (15 mis) was stirred for 18 hrs. The reaction was then concentrated in vacuo. The resulting residue was taken up in water (20 mis) and extracted with ethylacetate (3x 20 mis). The organics were combined, dried with MgSO4 and concentrated. The sample was chromatographed (silica gel, etheπhexanes containing 2% HOAc, 1:1) to afford 3-[3-(l,l-dimethylethylthio)-5-(quinolin-2-ylmethoxy)-l- (4-chlorophenylmethyl)indol-2-yl]-2,2-dimethylpropionaldehyd e oxime-O-2-acetic acid as a foam. -H NMR (300 MHz,. DMSO-dό): 0.98m (s, 9H), 1.05 (s, 6H), 3.04

(bs, 2H), 4.42 (s, 2H), 5.39 (s, 2H), 5.45 (s, 2H), 6.85 (m, 3H), 7.13 (d, IH, J = 2.5 Hz), 7.30 (m, 3H), 7.53 (s, IH), 7.58-7.68 (m, 2H), 7.79 (m, IH), 7.97 (m, IH), 8.05 (d, IH, J = 8.5 Hz), 8.37 (d, IH, J = 8.5 Hz); MS (M+H) ⁺ =644; Analysis calc'd for C36H38CIN3O4SI/2H2O: C, 66.19, H, 6.02, N, 6.43; Found: C, 66.30, H, 6.12, N, 6.22.

Example 289

Preparation of Sodium 3-ri-r4-chlorophenylmethyl)-3-π.l-imethylethylthio)-

5-ri-methylethyl indol-2-yl_-2.2-dimethylpropionaldehvde oxime-O-

2-propionate

The desired product 289 is prepared from 287 according to the procedure of

Example 12.

Example 290

Preparation of Sodium 3-r3-ri.l-dimethylethylthio)-5-rquinolin-2-ylmethoxy)-l-r4- chlorophenyl methyl . indol-2-yl 1-2.2-dimethylpropionaldehvde oxime-O-2-acetate

The desired product 290 is prepared from 288 according to the procedure of Example 12.

Example 291

Preparation of 3-ri-r4-chlorophenvlmethvl .-3-π.l-dimethvlethvlthioV5-

281.3 291

The desired product 291 is prepared from 281.3 by the procedure of Example 287.

Example 292 Preparation of 3-ri-r4-fluorophenylmethyl_-3-ri.l-dimethylethylthio.-5-ri- methylethyl. indol-2-yl1-2.2-dimethylpropionaldehyde oxime-O-2-propionic

285.2 292

The desired product 292 is prepared from 285.2 by the procedure of Example 285 substituting carboxy-1-ethoxylamine hydrochloride for carboxymethoxylamine hemihydrochloride.

Example 293

Preparation of 3- .3-r 1.1 -dimethylethylthio .-5-_quinolin-2-ylmethoxy.- 1-(4- chlorophenylmethyπ indol-2-yn-2.2-dimethylpropionaldehyde oxime-O-2-propionic acid

The desired product 293 is prepared by the procedure of Example 288 substituting carboxy-1-ethoxylamine hydrochloride for carboxymethoxylamine hemihydrochloride.

Additional examples of the present invention are prepared by the procedure of Example 288 utilizing the requisite hydrazine and carboxyalkoxyamine as indicated in Table 13.

Table 13

Example Hydrazine Carboxyalkoxyamine Product

The foregoing examples are provided to enable one skilled in the art to practice the present invention. These examples are merely illustrative, however, and should not be read as limiting the scope of the invention as it is claimed in the appended claims.