PLATELET ACTIVATING FACTOR ANTAGONISTS

Technical Field This invention relates to compounds having pharmacological activity, to compositions containing these compounds, and to a medical method of treatment employing the compounds and compositions. More particularly, this invention concerns certain indolecarbonyl pyridylpyrrolothiazole compounds and their salts which have platelet activating factor (PAF) antagonist activity, to pharmaceutical compositions containing these compounds, and to a method of treating PAF-mediated disorders.

Background of the Invention Platelet activating factor (PAF) is a phospholipid released from human and other animal cells and is an acetylglyceryl ether of phosphorylcholine as represented by the following formula:

where n is 15 or 17. . PAF is physiologically active and causes contraction of the airway smooth muscle, increased vascular permeability, platelet aggregation, hypotension, and the like. It is now recognized as a powerful mediator of inflammation and may play a physiological or pathobiological role in a variety of clinical conditions, such as asthma and pulmonary dysfunction, acute inflammation, transplanted organ rejection, shock, thrombosis, anaphylaxis, gastrointestinal ulceration, allergic skin diseases, retinal and corneal diseases, chemically induced liver cirrhosis, and ovimplantation in pregnancy.

Several PAF antagonists have been reported (e.g., United States Patent 4,948,795, European Patent Application EP 279681, and U.S. 4,786,645) but none have received wide acceptance. Therefore, there is a continuing need for the development of potent, orally active antagonists of PAF.

Summary ofthe Invention The present invention provides, in its principal aspect, compounds having PAF antagonist activity ofthe formula:

I or a pharmaceutically acceptable Salt thereof.

In the formula given above, R ¹ is one or more groups independently selected from the group consisting of (A) hydrogen; (B) halogen; (C) alkyl of from one to six l o carbon atoms; (D) alkoxy of from one to six carbon atoms; (E) alkoyl of from one to seven carbon atoms; (F) phenyl, optionally substituted by (1) alkyl of from one to six carbon atoms, (2) alkoxy of from one to six carbon atoms, or (3) halogen; (G) NR ⁷ R ⁸ where R ⁷ and R ⁸ are independently selected from (1) hydrogen, and (2) alkyl of from one to six carbon atoms, or (3) taken together with the nitrogen atom to which they are 5 attached form a saturated 5- or 6-membered nitrogen-containing ring; (H) -COOR ⁹ where R ⁹ is independently selected from (1) hydrogen, and (2) alkyl of from one to six carbon atoms, 0) -CONR ⁷ R ⁸ where R ⁷ and R ⁸ are as defined above; (J) -Sθ2NR ⁷ R ⁸ where R ⁷ and R ⁸ are as defined above; (K) 2- or 3-furyl, (L) 2- or 3-thienyl, (M) 2-, 4-, or 5-thiazolyl, (N) 2-, 3-, or 4-pyridyl, (0) 2-, or 4-pyrimidyl, (P) benzoyl, 0 wherein the phenyl moiety is optionally substituted by (1) halogen, (2) alkyl of from one to six carbon atoms, or (3) alkoxy of from one to six carbon atoms; (Q) phenoxy optionally substituted by (1) halogen, (2) alkyl of from one to six carbon atoms, or (3) alkoxy of from one to six carbon atoms; (R) phenylalkyloxy in which the alkyl portion contains from one to six carbon atoms and the phenyl is optionally substituted 5 with (1) halogen, (2) alkyl of from one to six carbon atoms, or (3) alkoxy of from one to six carbon atoms, and (S) phenylalkoyl in which the alkoyl portion contains from one to seven carbon atoms and the phenyl moiety is optionally substituted by; (1) halogen, (2) alkyl of from one to six carbon atoms, or (3) alkoxy of from one to six carbon atoms.

The substituent group R ² is selected from the group consisting of (A) hydrogen, (B) alkyl of from one to six carbon atoms; (C) -(CE_2)pCOOR ⁹ , where p is 0 or an integer of from 1 to 4 and R ⁹ is as defined above, (D) -(CH2)qNR ⁷ R ⁸ , where q is an integer of from 2 and 4 and R ⁷ and R ⁸ are as defined above, (E) -(CH2)pCOR ⁹ 5 where R ⁹ is as defined above; (F) -(CRtøqOH where q is as defined above; (G)

-(CH2)pS02R ⁹ where p and R ⁹ are as defined above, (H) -(CH2)pSC>2NR ⁷ R ⁸ where p, R ⁷ and R ⁸ are as defined above, (I) -(CH2) _P CONR ¹⁰ R ¹¹ , where p is as defined above and R ¹⁰ and R ¹¹ are independently selected from (1) hydrogen, (2) alkyl of from one to six carbon atoms, (3) -(CH2) _r COOR ⁹ , where r is an integer of from 1 to 4 and R ⁹ is l o as defined above, (4) -(CH2)rNR ⁷ R ⁸ where r, R ⁷ and R ⁸ are as defined above, (5) -(CH2) _r OH, (6) -(CH2)rS02R ⁹ where r and R ⁹ are as defined above, (7) -(CH2)rS02NR ⁷ R ⁸ where r, R ⁷ and R ⁸ are as defined above, (8) -(CH2) _P CN where p is as defined above; (9) -(CH2)p-lH-tetrazol-5-yl where p is as defined above; (10) -CONΗNΗ2, and (11) -(CH2)rphenyl, where r is as defined above and the 5 phenyl moiety is optionally substituted by halogen, alkyl of from one to six carbon atoms, or alkoxy of from one to six carbon atoms.

The groups R ³ , R ⁴ , and R ⁵ are independently selected from hydrogen or alkyl of from one to six carbon atoms.

X represents an atom or group of atoms selected from the group consisting of 0 S, SO, SO2, O, and CH2.

Y represents an atom or group selected from the group consisting of (A) N, (B) N+-R ¹² where R ¹² is an alkyl group of from one to six carbon atoms, (C) N ⁺ -*~ O- , (D) N+-OR ¹² where R ¹² is as defined above, (E) N+-NR ⁷ R ⁸ where R ⁷ and R ⁸ are as defined above, (F) N ⁺ -NHCONR ⁷ R ⁸ R ⁷ and R ⁸ are as defined above, 5 (G) N+-NHCOR ⁹ where R ⁹ is as defined above, (H) N ⁺ -CR ⁷ R ⁸ OCOR ¹² where R ⁷ , R ⁸ and R ¹² are as defined above, (D N ⁺ -OCR ⁷ R ⁸ OCOR ¹² where R ⁷ , R ⁸ and R ¹² are as defined above, (J) N ⁺ -CR ⁷ R ⁸ OCONR ⁷ R ⁸ where R ⁷ and R ⁸ are as defined above, and (K) N ⁺ -0-CR ⁷ R ⁸ OCONR ⁷ R ⁸ where R ⁷ and R ⁸ are as defined above.

A represents O, N+OR ¹⁰ , N ⁺ OCOR ¹⁰ , or N ⁺ NR ⁷ R ⁸ , where where R ⁷ , R ⁸ and 0 R ¹⁰ are as defined above.

The pharmaceutically acceptable salts and individual stereoisomers of compounds of structural formula I above, as well as mixtures thereof, are also contemplated as falling within the scope ofthe present invention.

In another aspect, the present invention provides pharmaceutical compositions 5 useful for the treatment of PAF-mediated disorders comprising a therapeutically

effective amount of a compound of formula I above in combination with a pharmaceutically acceptable carrier.

In another aspect, the present invention provides a method of inhibiting PAF activity by administering to a host mammal in need of such treatment an effective 5 amount of a PAF-inhibiting compound having structure I above.

In yet another aspect of the present invention, there is provided a method of treating PAF-mediated disorders including asthma, shock, respiratory distress syndrome, acute inflammation, delayed cellular immunity, parturition, fetal lung maturation, and cellular differentiation by administering to a host mammal in need of l o such treatment a therapeutically effective amount of a compound of structure I above.

Detailed Description and Preferred Embodiments In a preferred embodiment, compounds of the present invention are represented by formula I wherein: 5 R ¹ is phenyl, optionally substituted by (a) alkyl of from one to six carbon atoms, (b) alkoxy of from one to six carbon atoms, or (c) halogen; R ² is as defined above; R ³ , R ⁴ , and R ⁵ are hydrogen; X is -S-; Y is selected from the groups consisting of (a) -N-, (b) >N-O, (c) >N-CR ⁷ R ⁸ OCOR ¹² or (d) >N-OCR ⁷ R ⁸ OCORl ² ; A is selected from the groups consisting of (a) =0, or (b) =NOH. Preferred 0 compounds of Formula I are those in which X is -S-, -SO-, or -SO2-; R ² is hydrogen, carbamoyl, alkyl of from one to six carbon atoms, -COOR ⁸ , or -SO2R ⁸ ; R3 is hydrogen or alkyl of from one to six carbon atoms; and Rl is hydrogen, phenyl, or phenylalkoxy or a pharmaceutically acceptable salt thereof.

In a particularly preferred embodiment, compounds of the present invention are 5 represented by Formula I wherein R ¹ is phenyl or 4-fluorophenyl; R ² is CONH2, CONHCH3, or CON(CH3)2; and R ³ , R ⁴ , X, Y, and A are as defined immediately above.

Examples of compounds contemplated as falling within the scope ofthe present invention include, but are not necessarily limited to: 3-(pyridin-3-yl)-7-(indol-3-yl)carbonyl-lH,3H-pyrrolo[l^-c]t hiazole;

3-(pyridin-3-yl)-7-(l-N^V-dimethylcarbamoylindol-3-yl)car bonyl-lH,3H- pyrrolo[1.2-c]thiazole; 3-(pyridin-3-yl)-7-(5-phenylmethoxyindol-3-yl)carbonyl-lH,3H - pyrrolo[l,2-c]thiazole; 3-(pyridin-3-yl)-7-(6-phenylmethoxyindol-3-yl)carbonyl- lH,3H-pyrrolo[l,2- c]thiazole;

3-(pyridin-3-yl)-7-(7-phenylmethoxyindol-3-yl)carbonyl-lH,3H -pyιτolo[l,2- cjthiazole; 3-(pyridin-3-yl)-7-(l-N^v ^" -dimethylcarbamoyl-5-phenylmethoxyindol-3- yl)carbonyl- lH,3H-pyrrolo[ 1 ,2-c] thiazole; 3-(pyridin-3-yl)-7-(l-N^V-dimethylcarbamoyl-6-phenylmethoxyi ndol-3- yl)carbonyl- lH,3H-pyrrolo[ 1 ,2-c] thiazole; 3-(pyridin-3-yl)-7-(l-N^V-dimethylcarbamoyl-7-phenylmethoxyi ndol-3- yl)carbonyl- lH,3H-pyrrolo[ 1 ,2-c]thiazole; 3-(pyridin-3-yl)-7-(l-rerf-butyloxycarbonylindol-3-yl)carbon yl-lH,3H- pyrrolo[l,2-c]thiazole;

3-(pyridin-3-yl)-7-(6-phenylindol-3-yl)carbonyl-lH,3H-pyr rolo[l,2-c]thiazole; 3-(pyridin-3-yl)-7-[l-(morpholin-4-ylcarbonyl)indol-3-yl]car bonyl-lH,3H- pyrrolo[l,2-c]thiazole; 3-(pyridin-3-yl)-7-(l-N^V-dimethylcarbamoyl-6-phenylindol-3- yl)carbonyl- lH,3H-pyrrolo[l,2-c]thiazole;

2-oxide-3-(pyridin-3-yl)-7-(l-rerf-butyoxycarbonylindol-3 -ylcarbonyl)- lH,3H-pyrrolo[ 1 ,2-c]thiazole; 2-oxide-3-(pyridin-3-yl)-7-(indol-3-ylcarbonyl)-lH,3H-pyrrol o[l,2-c]thiazole; 3-(pyridin-3-yl)-7-(indol-3-ylcarbonyl)-lH,3H-pyrrolo[l,2-c] oxazole; 3-(pyridin-3-yl)-7-(l-N^\ ^' -diisopropylcarbamoyl-6-phenylmethoxyindol-3- ylcarbonyl)- lH,3H-pyrrolo[ 1 ,2-c] thiazole; l,l-dimethyl-3-(pyridin-3-yl)-7-(indol-3-ylcarbonyl)-lH,3H-p yrrolo[l,2- c]thiazole; 3-(pyridin-3-yl)-7-(l-carbomethoxycarbamoyl-6-phenylmethoxyi ndol-3- ylcarbonyl)-lH,3H-pyπolo[l,2-c]thiazole; l,l-dimethyl-3-(pyιidin-3-yl)-7-(l-N^V-dimethylcarbamoyl-in dol-

3-ylcarbonyl)-lH,3H-pyrrolo[l,2-cl ' ^* .iazole; 3-(pyridin-3-yl)-7-(l-N-methyl-N-phenylcaroamoyl-6-phenylmet hoxyindol- 3-ylcarbonyl)-lH,3H-pyrrolo[l,2-c]thiazole; 3-(p ridin-3-yl)-7-(l-methyl-6-phenylmethoxyindol-3-ylca^bony ^, ' - lH,3H-pyrrolo[l,2-c]thiazole; 3-(pyridin-3-yl)-7-(l-N-methylcarbamoyl-6-phenylmethoxyindol -

3-ylcarbonyl)-lH,3H-pyrrolo[l,2-c]thiazole; 2-oxide-3-(pyrid__n-3-yl)-7-(l-N V-dimethylcarbamoyl-6-phenylindol-3- ylcarbonyl)- lH,3H-pyrrolo[ 1 ,2-c]thiazole; l,l-dimethyl-3-(pyridin-3-yl)-7-(l-iV^-dimethylcarbamoyl-6-p henylindol- 3-ylcarbonyl)- lH,3H-pyrrolo[ 1 ,2-c]thiazole;

l,l-dimethyl-3-(pyridin-3-yl)-7-[6-(4-methoxyphenyl)indol-3- ylcarbonyl]- lH,3H-pyrrolo[l,2-c]thiazole; l,l-diιnethyl-3-(pyridin-3-yl)-7-[l-N^V-dimethylcarbamoyl-

6-(4-methoxyphenyl)indol-3-ylcarbonyl]-lH,3H-pyrrolo[l^-c ]thiazole; 5 3-(pyridin-3-yl)-7-(l-carbophenoxy-6-phenylmethoxyindol-3-yl carbonyl)- lH,3H-pyπolo[l,2-c]thiazole; 3-(pyridin-3-yl)-7-[6-(4-fluorophenyl)indol-3-ylcarbonyl]- lH,3H-pyrrolo[l,2-c]thiazole; 3-(pyridin-3-yl)-7-[l-N^V-dimethylcarbamoyl-6-(4-fluoropheny l)indol- l o 3-ylcarbonyl]-lH,3H-pyrrolo[l,2-c]thiazole;

3-(pyridin-3-yl)-7-(l-N-methylcarbamoyl-6-phenylindol-3-y lcarbonyl)- lH,3H-pyrrolo[l,2-c]thiazole; 3-φyridin-3-yl)-7-[l-N-methylcarbamoyl-6-(4-fluorophenyl)in dol- 3-ylcarbonyl]-lH,3H-pyrrolo[l,2-c]thiazole; 15 l,l-dimethyl-3-(pyridin-3-yl)-7-[l-N-methylcarbamoyl-

6-(4-methoxyphenyl)indol-3-ylcarbonyl]- lH,3H-pyrrolo[ 1 ,2-c] thiazole; 3-(l-methylpyridin-3-yl)-7-(l-iV V-dimethylcarbamoyl-6-phenylindol-3- ylcarbonyl)-lH,3H-pyrrolo[ 1 ,2-c] thiazole; 3-(l-oxide-pyridin-3-yl)-7-(l-N^V-dimethylcarbamoyl-6-phenyl indol-3- 0 ylcarbonyl)-lH,3H-pyπσlo[l,2-c]thiazole;

3-(l-oxide-pyridin-3-yl)-7-(l-N-methylcarbamoyl-6-phenyli ndol-3- ylcarbonyl)-lH,3H-pyrrolo[l,2-c]thiazole; l,l-dimethyl-3-(pyridin-3-yl)-7-[6-(4-fIuorophenyl)indol-3-y lcarbonyl]- lH,3H-pyrrolo[l,2-c]thiazoIe; 5 3-φyridin-3-yl)-7-(l-N-methylcarbamoyl-6-phenylmethoxyindol -3- ylcarbonyl)-lH,3H-pyrrolo[l,2-c]thiazole; 3-φyridin-3-yl)-7-[6-(4-methoxyphenyl)indol-3-yl]carbonyl- lH,3H-pyrrolo[l,2-c]thiazole; 3-(l-oxide-pyridin-3-yl)-7-[l-N _. N-dimethylcarbamoyl- o 6-(4-fluorophenyl)indol-3-ylcarbonyl]- lH,3H-pyrrolo[l,2-c]thiazole;

3-(pyridin-3-yl)-7-[l-N^-dimethylcarbamoyl-6-(4-methoxyph enyl)indol-

3-ylcarbonyl]-lH,3H-pyrrolo[l,2-c]thiazole; 3-(pyridin-3-yl)-7-(6-pyrid-3-yIindol-3-ylcarbonyl)-lH,3H-py rrolo- [1,2-cjthiazole; 3-(pyridin-3-yl)-7-(l-N^-dimethylcarbamoyl-6-pyrid-4-ylindol -3-ylcarbonyl)- lH,3H-pyrrolo[l,2-c]thiazole;

3-(pyridin-3-yl)-7-[l-N-methylcarbamoyl-6-(4-methoxyphenyl)i ndol-

3-ylcarbonyl]- lH,3H-pyrrolo[ l,2-c]thiazole; 3-(l-oxide-pyridin-3-yl)-7-(l-N^V-dimethylcarbamoylindol-3-y lcarbonyl)- lH,3H-pyrrolo[ 1 ,2-c]thiazole; 5 3-(l-oxide-pyridin-3-yl)-7-[l-N^v ^" -dimethylcarbamoyl-6-(4-methoxyphenyl)- indol-3-ylcarbonyl]-lH,3H-pyrrolo[l,2-c]thiazole; 3-(pyridin-3-yl)-7-[l-(2-carbomethoxyethyl)-6-(4-fluoropheny l)indol-

3-ylcarbonyl]-lH,3H-pyrrolo[l,2-c]thiazole; 3-(pyridin-3-yl)-7-(6-chloroindol-3-ylcarbonyl)-lH,3H-pyrrol o[l,2-c]thiazole; l o 3-(pyridin-3-yl)-7-[l-N^V-dimethylcarbamoyl-6-(3,4,5-ttimeth oxyphenyl)- indol-3-ylcarbonyl]-lH,3H-pyrrolo[l,2-c]thiazole; 3-(pyridin-3-yl)-7-[l-(2-carboxyethyl)-6-(4-fluorophenyl)ind ol-3-ylcarbonyl]- lH,3H-pyrrolo[ 1 ,2-c] thiazole; 3-(pyridin-3-yl)-7-[l-(2-sulfamylethyl)-6-(4-fluorophenyl)in dol-3-ylcarbonyl]- 5 lH,3H-pyrτolo[l,2-c]thiazole;

3-(pyrid n-3-yl)-7-[l-methanesulfonyl-6-(4-fluorophenyl)indol-3-ylcar bonyl]- lH,3H-pyrrolo[ 1 ,2-c]thiazole; 3-(pyridin-3-yl)-7-(l-N^V-dimethylcarbamoyl-6-phenylindol-3- ylcarbonyl)- lH,3H-pyrrolo[l,2-c]thiazole Ηydrochloride; 0 3-(pyridin-3-yl)-7-[l-(2-N^V-dimethylcarbamoylmethyl)-6-(4-f luorophenyl)- indol-3-ylcarbonyl]-lH,3H-pyπOlo[l,2-c]thiazole; 3-( 1 -oxide-pyridin-3-yl)-7-( 1 -N^V-dimethylcarbamoyl-6-phenylindol-3- ylcarbonyl)-lH,3H-pyrrolo[l,2-c]thiazole hydrochloride; 3-(pyridin-3-yl)-7-[l-iV^V-dimethylsulfamyl-6-(4-fluoropheny l)indol- 5 3-ylcarbonyl]-lH,3H-pyrrolo[l,2-c]thiazole;

3-(pyridin-3-yl)-7-[l-N^v ^* -dimethylcarbamoyl-6-(3-aminophenyl)indol-3- ylcarbonyl]-lH,3H-pyrrolo[l,2-c]thiazole; 3-φyridin-3-yl)-7-[l-(2-fβ/ -butoxycarbonylaminoethyl)-6-(4-fluorophenyl)- indol-3-ylcarbonyl]-lH,3H-pyrrolo[l,2-c]thiazole; o 3-(l -oxide-pyridin-3-yl)-7-( 1 -methyl-6-phenylmethoxyindol-3-ylcarbonyl)- lH,3H-pyrrolo[ 1 ,2-c] thiazole; 3- yridin-3-yl)-7-[l-(2-aminoethyl)-6-(4-fluorophenyl)indol-3-y lcarbonyl]- lH,3H-ρyrrolo[ 1 ,2-c]thiazole; 3-( 1 -oxide-pyridin-3-yl)-7-[ l-N^-dimethylsulfamyl-6-(4-fluorophenyl)indol- 5 3-ylcarbonyl]- lH,3H-pyrrolo[l,2-c]thiazole;

3-(pyridin-3-yl)-7-[l-phenylsulfonyl-6-(4-fluorophenyl)in dol-3-ylcarbonyl]- lH,3H-pyrrolo[ 1 ,2-c]thiazole;

3-(pyridin-3-yl)-7-[l-N-(2-hydroxyethyl)carbamoyl-6-(4-fluor ophenyl)indol-

3-ylcarbonyl]-lH,3H-pyrrolo[l,2-c]thiazole; 3-(pyridin-3-yl)-7-(6^bromomdol-3-ylcarbonyl)-lH,3H-pyrrolo[ l^-c]thiazole; 3-(pyridin-3-yl)-7-(l-N V-dimethylcarbamoyl-6^bromoindol-3-ylcarbonyl)- lH,3H-pyrrolo[l,2-c]thiazole;

3-(pyriα^-3-yl)-7-(l-N^-dimethylcarbamoyl-6-chloroindol- 3-ylcarbonyl)- lH,3H-pyrrolo[l,2-c]thiazole; 3-(l-oxide-Pyridin-3-yl)-7-(l-N V-dimethylcarbamoyl-6-chloroindol- 3-ylcarbonyl)-lH,3H-pyrrolo[l,2-c]thiazole; 3-(l-aπ_ino-pyridin-3-yl)-7-[l-N^v ^" -dimethylcarbamoyl-6-(4-fluorophenyl)- indol-3-ylcarbonyl]- lH,3H-pyrrolo[l ,2-c]thiazole; 3-φyridin-3-yl)-7-[l-(2-memanesulfonylaminoethyl)-6-(4-fluo rophenyl)indol-

3-ylcarbonyl]-lH,3H-pyrrolo[l,2-c]thiazole; 3-φyriά^-3-yl)-7-[l-hydrazinocarbonyl-6-(4-fluorophenyl)in dol-3-yl- carbonyl]-lH,3H-pyrτolo[l,2-c]thiazole;

3-(pyridin-3-yl)-7-[l-(2-aminoethyl)-6-(4-fluorophenyl)in dol-3-ylcarbonyl]- lH,3H-pyrrolo[l,2-c]thiazole Ηydrochloride; 3-φyridin-3-yl)-7-[l-ethanesulfonyl-6-(4-fluorophenyl)indol -3-ylcarbonyl]- lH,3H-pyrrolo[l,2-c]thiazole; 3-φyridin-3-yl)-7-[l-(2-hydroxyethyl)-6-(4-fluorophenyl)ind ol-3-ylcarbonyl]- lH,3H-pyrrolo[l,2-cl thiazole; 3-(l-oxide-pyridin-3-yl)-7-[l-phenylsulfonyl-6-(4-fluorophen yl)indol-

3-ylcarbonyl]-lH,3H-pyrrolo[l,2-c]thiazole; -(pyridin-3-yl)-7-(l-N-V-dimethylcarbamoyl-6-pyrimid-2-ylind ol- 3-ylcarbonyl)- lH,3H-pyrrolo[l,2-c]thiazole; -(l-oxide-pyridin-3-yl)-7-[l-(2-N^V-dimethylcarbamoylmethyl) -

6-(4-fluorophenyl)indol-3-ylcarbonyl]-lH,3H-pyrrolo[l,2-c ]thiazole; -φyridin-3-yl)-7-[l-carbamoyl-6-(4-fluorophenyl)indol-3-ylc arbonyl]- lH,3H-ρyrrolo[l,2-c]thiazole; -(l-carbamoylarr_incΗpyridin-3-yl)-7-[l-iv ^' ^v ^' -dimethylcarbamoyl-

6-(4-fluorophenyl)indol-3-ylcarbonyl]-lH,3H-pyrrolo[l,2-c ]thiazole; -(l-pyrid-3-oylam o-pyridin-3-yl)-7-[l-N^V ^' -dimethylcarbamoyl-

6-(4-fluorophenyl)indol-3-ylcarbonyl]-lH,3H-pyrrolo[l,2-c ]thiazole; -(l-oxide-pyridin-3-yl)-7-[l-(2-aminosulfonylethyl)-6-(4-flu orophenyl)indol- 3-ylcarbonyl]-lH,3H-pyrrolo[l,2-c]thiazole; -(pyridin-3-yl)-7-[l-NJV ^' -dimethylcarbamoyl-6^(3-aminosulfonyIphenyl)- indol-3-ylcarbonyl]-lH,3H-pyrrolo[l,2-c]thiazoIe;

3-(pyridin-3-yl)-7-[l-(2-N-methylcarbamoylmethyl)-6-(4-fluor ophenyl)indol-

3-ylcarbonyl]-lH,3H-pyrrolo[l,2-c]thiazole; 3-(pyridin-3-yl)-7- [ 1 -N^V-dimethylcarbamoyl-6-(4-fluorophenyl)indol- 3-ylcarbonyloxime]-lH,3H-pyrrolo[l^-c]thiazole; 5 3-(pyridin-3-yl)-7-[6-(4-fluorophenyl)indol-3-ylcarbonyloxim e]- lH,3H-pyrrolo[ l,2-c]thiazole; 3-(pyridin-3-yl)-7-[l-(N-memyl-N-(dimethylaminoethyl))carbam oyl-

6-(4-fluorophenyl)indol-3-ylcarbonyl]- lH,3H-pyrrolo[ 1 ,2-c]thiazole; 3-(pyridin-3-yl)-7-[l-N-carboxymethylcarbamoyl-6-(4-fluoroph enyl)indol- l o 3-ylcarbonyl]- lH,3H-pyrrolo[ 1 ,2-c]thiazole;

3-(l-methyl-pyridin-3-yl)-7-[l-N V-dimethylcarbamoyl-6-(4-fluorophenyl)- indol-3-ylcarbonyl]-lH,3H-pyrrolo[l,2-c]thiazole; 3-(pyridin-3-yl)-7-(l-N^v ^" -dimethylcarbamoyl-6-thiazol-2-ylindol-3-yl- carbonyl)- lH,3H-pyrrolo[l ,2-c]thiazole; 15 3-(pyridin-3-yl)-7-[ l-N-sulfoethylcarbamoyl-6-(4-fluorophenyl)indol-

3-ylcarbonyl]- lH,3H-pynrolo[ 1 ,2-c]thiazole; 3-(pyridin-3-yl)-7-[l-N^-dimethylcarbamoyl-6-(2-ammopyrimid- 5-yl)indol-3- yl)carbonyl]-lH,3H-pyrrolo[l,2-c]thiazole; 3-(l-oxide-pyridin-3-yl)-7-[l-(2-aminoethyl)-6-(4-fiuorophen yl)indol- 0 3-ylcarbonyl]- lH,3H-pyrrolo[l,2-c]thiazole;

3-(l-oxide-pyridin-3-yl)-7-[l-N -dinιethylcarbamoyl-

6-(4-hydrazinylcarbonylphenyl)indol-3-ylcarbonyl]- lH,3H-pyrrolo[ 1 ,2-c] thiazole; 3-(l-acetoxymethylpyridin-3-yl)-7-[l-N^V-dimethylcarbamoyl- 5 6-(4-fluorophenyl)indol-3-ylcarbonyl]- lH,3H-pyrrolo[ l,2-c]thiazole;

3-(pyridin-3-yl)-7-[l-N-methyl-N-hydroxymethylcari)amoyl-

6-(4-fluorophenyl)indol-3-ylcarbonyl]-lH,3H-pyrrolo[l,2-c ]thiazole; 3-(pyridin-3-yl)-7-[l-cyanomethyl-6-(4-fluorophenyl)indol-3- ylcarbonyl]- lH,3H-ρyrrolo[ 1 ,2-c] thiazole; 0 3-(pyridin-3-yl)-7-[l-carbamoylmethyl-6-(4-fluorophenyl)indo l-3-ylcarbonyl]- lH,3H-ρyrrolo[ 1 ,2-c] thiazole; 3-(pyridin-3-yl)-7-[l-carboxymethyl-6-(4-fluorophenyl)indol- 3-ylcarbonyl]- lH,3H-pyrrolo[ 1 ,2-c]thiazole; 3-(pyridin-3-yl)-7-[l-(lH-tetrazol-5-ylmethyl)-6-(4-fluoroph enyl)indol- 5 3-ylcarbonyl]-lH,3H-pyrrolo[l,2-c]thiazole;

3-(pyrid -3-yl)-7-[l-N^-dimethylcarbamoyl-6-(2,4(lH,3H)-pyrimidinedio n- 5-yl)indol-3-yl)carbonyl]-lH,3H-pyrrolo[l,2-c]thiazole;

3-(pyridin-3-yl)-7-[l-N-sulfoethylcarbamoyl-6-(4-fluoropheny l)indol-

3-ylcarbonyl]-lH,3H-pyrrolo[l,2-c]thiazole; 3-(pyridin-3-yl)-7-[l-N-sulfoethylcarbamoyl-6-(4-fluoropheny I)indol- 3-ylcarbonyl]-lH,3H-pyrrolo[l,2-c]thiazole; 5 3-(pyridin-3-yl)-7-(l-N-N-dimethylcarbamoyl-6-thiophen-2-yli ndol-3-yl- carbonyl)-lH,3H-pyrrolo[l,2-c]thiazole; 3-(pyridin-3-yl)-7-(l-N V-dimethylcarbamoyl-6-(4-hydroxymethyl)- phenyIindol-3-ylcarbonyl)-lH,3H-pyτrolo[l,2-c]thiazole; 2-oxide-3-(l-oxide-pyridin-3-yl)-7-[l-iV V-dimethylcarbamoyl-6-(4- l o fluorophenyl)indole-3-ylcarbonyl]-lH,3H-pynolo[l,2-c]thiazol e;

3-(pyridin-3-yl)-7-[l-ΛyV-dimethylcarbamoyl-6-(4-fluorop henyl)indol-

3-ylcarbonylhydrazone]-lH,3H-pyrrolo[l,2-c]thiazole; 3-φyridin-3-yl)-7-[l-N-(2-(4-imidazolyl)ethyl)carbamoyl-6-( 4-fluorophenyl)- dol-3-ylcarbonyl]-lH,3H-pyrrolo[l,2-c]thiazole; and 15 3-(pyridin-3-yl)-7-[l-i ^γ VV-dimethylcarbamoyl-6-(4-fluorophenyl)indol-

3-ylcarbonylsemicaτbazide]-lH,3H-pyrrolo[l,2-c]thiazole; or a pharmaceutically acceptable salt of each thereof.

As used throughout this specification and the appended claims, the following terms have the meanings ascribed to them: 0 The term "alkenyl" as used herein refers to straight or branched chain groups of

2 to 6 carbon atoms containing a carbon-carbon double bond Representative examples of alkenyl groups include ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, and the like. The term "alkoxy" as used herein refers to an alkyl group, as defined herein, which is bonded to the parent molecular moiety through an oxygen atom. 5 Representative examples of alkoxy groups include methoxy, ethoxy, rerr-butoxy, and the like.

The term "alkoyl" as used herein refers to formyl and radicals of the structure -C(0)-alkyl in which the alkyl portion is a straight or branched alkyl group of from one to six carbon atoms. Representative examples of alkoyl groups include formyl, acetyl, o propionyl, butyryl, isobutyryl, pivaloyl, and the like.

The term "alkyl" as used herein refers to straight or branched chain radicals derived from saturated hydrocarbons by the removal of one hydrogen atom. Representative examples of alkyl groups include methyl, ethyl, n-propyl, iro-propyl, n- butyl, sec-butyl, wø-butyl, rerr-butyl, and the like. The term "alkylsulfonyl" is used herein to mean -Sθ2(alkyl) where the alkyl group is as defined above. Representative examples of alkylsulfonyl groups include methylsulfonyl, ethylsulfonyl, isopropylsulfonyl, and the like.

The term "benzyl" as used herein refers specifically to a phenyl substituted methyl in which the phenyl group may be substituted with 1, 2, or 3 substituents independently selected from halo, nitro, cyano, alkyl of from one to six carbon atoms, alkoxy, and halo-substituted alkyl and the like. 5 The term "carboalkoxy" as used herein refers to a structure of formula

-C(0)OR wherein R is a straight or branched alkyl radical of from one to six carbon atoms, benzyl, or substituted benzyl. Representative examples of carboalkoxy groups include carbomethoxy, carboethoxy, carbo(wo-propoxy), carbobutoxy, caϊbo(sec- butoxy), carbo(wo-butoxy), carbo(r -butoxy), benzyloxycarbonyl, and the like. l o The term "nitrogen heterocycle" as used herein refers to any 5- or 6-membered saturated ring containing from one to three heteroatoms independently selected from the group consisting of one, two, or three nitrogens, one oxygen and one nitrogen, and one sulfur and one nitrogen; wherein the nitrogen and sulfur heteroatoms may be optionally oxidized, wherein the nitrogen heteroatom may be optionally quatemized, 5 and wherein one or more carbon or nitrogen atoms may be substituted with alkyl of from one to six carbon atoms. Representative nitrogen heterocycles include, but are not limited to, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, thiomorpholinyl, and the like.

The term "carbamoyl" refers to a structure of formula -CONR'R" wherein R' 0 and R" are independently selected from hydrogen, a straight or branched alkyl radical of from one to six carbon atoms, or taken together may form a nitrogen heterocycle, as previously defined. Representative examples of carbamoyl groups, include -C(0)NH ₂ , N,N-dimethylcarbamoyl, N-rerr-butylcarbamoyl, N-methyl-N-ethylcarbamoyl, (morpholin-4-yl)carbonyl, (piperidin-l-yl)carbonyl, (4-methylpiperazin-l-yl)carbonyl 5 and the like.

The term "phenylalkoxy" is used herein to mean a phenyl group appended to an alkoxy radical as previously defined Representative examples of phenylalkoxy groups include phenylmethoxy (i.e. benzyloxy), 1-phenylethoxy, 2-phenylethoxy, 2- phenylpropoxy, and the like. o The term "phenylalkoyl" is used herein to mean a phenyl group appended through an alkyl or alkenyl group of from one to six carbon atoms or a valence bond to a formyl radical of the structure -C(O)- in which the phenyl group may optionally be substutited with alkyl of from one to six carbon atoms, halogen, or alkoxy as previously defined. Representative examples of phenylalkoyl groups include benzoyl, 5 phenylacetyl, cinnamoyl, phenylpropionyl, and the like.

The terms "PAF-related disorders" and "PAF-mediated disorders" are used herein to mean disorders related to PAF or mediated by PAF, including asthma, shock,

respiratory distress syndromes, acute inflammation, gastric ulceration, transplant organ rejection, psoriasis, allergic skin disease, ischemia and reperfusion injury, delayed cellular immunity, parturtition, fetal lung maturation, and cellular differentiation.

The term "pharmaceutically acceptable salts" 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, lactiobionate, laurylsulphonate salts, 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.) Individual enantiomeric forms of compounds of the present invention can be separated from mixtures thereof by techniques well known in the art For example, a mixture of diastereomeric salts may be formed by reacting the compounds of the present invention with a optically pure form of an acid, followed by purification of the mixture of diastereomers by recrystallization or chromatography and subsequent recovery of the resolved compound from the salt by basification. Alternatively, the enantiomers of the compounds of the present invention can be separated from one another by chromatographic techniques employing separation on a chiral chromatographic medium.

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 administration.

The pharmaceutical compositions of this invention can be administered to humans and other animals orally, rectally, parenterally, intracistemally, inttavaginally, 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 forreconstitution into sterile

injectable solutions or dispersions just prior to use. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents, or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters such as 5 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 ofthe action of l o 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 15 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 0 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 ofthe drug in biodegradable polymers such as polylactide-polyglycolide. Depending upon 5 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. 0 The injectable formulations can be sterilized, for example, by filtration through a bacterial-r taining filter or by incorporating sterilizing agents in the form of sterile solid comp; : itions 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, 5 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, 5 (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 l o 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 5 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 ingredients) 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 0 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 5 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

I S 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- 5 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. Compounds of the present invention can also be administered in the form of liposomes. As is known in the art, liposomes are generally derived from phospholipids l o or other lipid substances. Liposomes are formed by mono- or multi-lamellar hydrated liquid crystals that are dispersed in an aqueous medium. Any non-toxic, physiologically acceptable and metabolizable lipid capable of forming liposomes can be used. The present compositions in liposome form can contain, in addition to a compound of the present invention, stabilizers, preservatives, excipients, and the like. 15 The preferred lipids are the phospholipids and the phosphatidyl cholines (lecithins), both natural and synthetic.

Methods to form liposomes are known in the art. See, for example, Prescott, Ed., Methods in Cell Biology. Volume XIV, Academic Press, New York, N.Y. (1976), p. 33 et seq. 0 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 propellents which may be required. Opthalmic formulations, eye ointments, powders and solutions are also contemplated as being within the scope 5 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 0 the activity of the particular compound, the route of administration, the severity of the condition being treated, and the condition and prior medical history of the patient being treated. However, it is within the skill of the art to start doses of the compound at levels lower than required to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved. 5 Generally dosage levels of about 0.001 to about 100 mg, more preferably of about 0.01 to about 20 mg, and most preferably about 0.1 to about 10 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.

Li general, the compounds of the present invention are synthesized by reaction

Schemes 1 through 15 as illustrated below. It should be understood that X, A, Rl, R ² ,

5 R3, R5, R6, R7, R8_ R9, RIO, Rll, and Rl ² as used herein correspond to the groups identified by Formula I.

The compounds of Formula I may be prepared using the reactions and techniques described in this section. The reactions are performed in a solvent appropriate to the reagents and materials employed and suitable for the transformation l o being effected. It is understood by those skilled in the art of organic synthesis that the functionality present on the heterocycle and other portions of the molecule must be consistent with the chemical transformation proposed. This will frequently necessitate judgement as to the order of synthetic steps, protecting groups required, and deprotection conditions.

Scheme 1

5 1 2 3

Scheme I

According to die foregoing reaction Scheme 1, L-Cysteine, L-Serine, L- Penicillamine, or a related amino acid (1) is condensed with nicotinaldehyde to produce the thiazolidine or oxazolidine acids 2. The secondary nitrogen atom is then 0 foπnylated by the action of formic acid/acetic anhydride to yield the N-formyl heterocycles 3.

Scheme 2

8

Scheme 2

According to the foregoing reaction Scheme 2, the nitrogen atom of L- 5 pyroglutamic acid may be protected with an appropriate group, preferably tert- butyloxycarbonyl (BOC) with di-ferf-butyl dicarbonate followed by methyl ester formation which gives lactam 5. Addition of 3-pyridylmagnesium bromide cleaves the heterocyclic ring and gives ketone 6. The nittogen atom is deprotected under acidic conditions and reductive cyclization is achieved upon treatment with sodium l o cyanoborohydride. Hydrolysis of the methyl ester followed by formylation with formic acid/acetic anhydride gives the N-formyl pyrrolidine 8.

Scheme 3

1 2 1 1 1 0

Scheme 3

According to the foregoing reaction Scheme 3, iV-formyl heterocycles 3 and 8 may be heated independendy widi 2-chloroacrylonitrile in the presence of triethylamine and/7-toluenesulfonyl chloride to afford die corresponding fused bicyclic heterocycle 9. Base catalyzed hydrolysis ofthe nitrile group followed by acidification affords acid 10. The indole group is introduced by treatment of the anhydrous acid chlorides (prepared from 10 by treatment with sodium hydride followed by oxalyl chloride) widi indole Grignard 11 derived from the reaction of the appropriate substituted indole and ediylmagnesium bromide.

Scheme 4

MgBr 1 1

Scheme 4

According to the foregoing reaction Scheme 4, die appropriately substituted indole group is also introduced by treatment of magnesium indole salt with zinc chloride in ether followed by reaction with the anhydrous acid chloride of 10.

Scheme 5

Scheme 5

According to die foregoing reaction Scheme 5, the r. le nitrogen atom of die l o bicyclic heterocycle 12 may be functionalized widi an amide group by reaction widi the

corresponding acid chloride, preferably using potassium hydroxide in 1,2- di ethoxyethane, giving N-acyl indoles 13. Alternatively, compound 12 may be tteated independendy with the appropriate carbamoyl chloride under similar conditions to give urea 14. Treatment of a potassium hydroxide solution of 12 in 1,2- dimethoxyethane widi the appropriate sulfonyl chloride gives the corresponding sulfonamide 15. Finally, 12 in a potassium hydroxide solution with the appropriate sulfamoyl chloride gives the sulfonylurea 16.

Scheme 6

Scheme 6

According to die foregoing reaction Scheme 6, 3-acyl indole heterocycle 12 are treated widi the appropriate isocyanate to give the urea substituted indole 17.

Scheme 7

Scheme 7

According to the foregoing reaction Scheme 7, 3-acyl indole heterocycle 12 is treated widi the appropriate alkyl dicarbonate in the presence of 4-dimethylaminopyridine to give the corresponding N-carboalkoxy indole 18.

Scheme 8

Scheme 8

According to the foregoing reaction Scheme 8, 3-acyl indole heterocycle 12 is treated widi sodium hydride followed by die addition of the appropriate alkyl halide to give the corresponding N-alkyl indole 19.

Scheme 9

Scheme 9

According to the foregoing reaction Scheme 9, 3-acyl indole heterocycle 12 is treated widi 4-nitrophenylchloroformate to give the activated acylindole derivative 20 that is subsequently reacted widi an appropriately substituted amine to afford urea 14.

Scheme 10

According to the foregoing reaction Scheme 10, 3-acyl indole heterocycle 12 is treated widi sodium hydride and then reacted wid an α,β unsaturated carbonyl compound to give 21, with an α,β unsaturated sulfonyl compound to give 22, with an α,β unsaturated nitrile to give 23, or with an acyl aziridine to afford 24. R ¹³ in 21 and 22 is used herein to indicate R ⁹ , OR ⁹ , or NR ¹⁰ R ⁿ .

Scheme 11

25 26 : X = 1 27 : X = 2

Scheme 11

According to die foregoing reaction Scheme 11, die 3-acyl indole heterocycle 25 is treated with ferf-butyl hydroperoxide, titanium tettaisopropoxide, and (R,R)- diethyl tartrate, or with -chloroperoxybenzoic acid to give die corresponding sulfoxide 26 or sulfone 27.

Scheme 12

According to the foregoing reaction Scheme 12, die 3-acyl indole heterocycle 25 is treated widi 2,4-dinitrophenyl 4-toluenesulfonate to the pyridinium salt 28. The salt is treated widi hydroxylamine to give N-oxide 30 or alternatively widi hydrazine to give 29.

Scheme 13

Scheme 13

According to d e foregoing reaction Scheme 13, die 3-acyl indole heterocycle 25 is treated widi an alkyl halide to give pyridinium salt 30. R ¹⁴ is used herein to indicate R ¹² or CR^SOCOR ⁸ .

Scheme 14

Scheme 14

According to die foregoing reaction Scheme 14, die 3-acyl indole N-oxide heterocycle 30 is treated with an alkyl halide to give pyridinium salt 32.

Scheme 15

Scheme 15

According to die foregoing reaction Scheme 15, the bromo indole heterocycle 33 (prepare as described in reaction Scheme 4) is treated widi hexametiiyltin in the presence of tetrakis(triphenylphoshine)palladium to give 34. This tin reagent is then treated wid an aryl halide also in the presence of tetrakis(triphenylphoshine)palladium to afford the aryl indole 35. Alternatively 33 may be converted to 35 directly using the appropriate arylboronic acid in d e presence of tetrakis(ttiphenylphoshine)palladium. AT is used herein to indicate substituted or unsubstituted phenyl, diiazolyl, pyridyl, pyrimidyl, and die like.

Scheme 16

Scheme 16

According to die foregoing reaction Scheme 16, the indole heterocycle 25 is treated widi hydroxylamine to give oxime 36. This oxime can be alkylated with an appropriate alkyl halide to give 37, or acylated with an activated acyl compound to give 38.

PAF Inhibitory Activity ofthe Compounds of die Present Invention l o The ability of representative compounds of die present invention to inhibit PAF activity was determined in an in vitro test using the following method.

Qtrated whole rabbit blood was obtained from Pel-Freez (Rogers, AR). Rabbit platelets were prepared by centrifugation and washing. The platelets were lysed by freeze-thawing and sonication; platelet membranes were prepared by centrifugation and 5 washing. Final membrane preparations were stored frozen in 10 mM Tris 5 mM

MgCl2/2 mM 1DTA (TME buffer, pH 7.0) with 0.25 M sucrose added for membrane stabilization.

The standard PAF receptor binding assay contained 10 μg platelet membrane protein, 0.6 nM [3H]Ci8-PAF (from Amersham or New England Nuclear; specific 0 activity 120-180 Ci/mmol), with and witiiout test compound, in "binding buffer" consisting of TME with 0.25% bovine serum albumin added (Sigma, RIA grade). The final volume of the assay was 100 μl. The assay was conducted in Millititre-GV™

(Millipore Corp.) filtration plates; incubation time was for 60 minutes at room temperature (22-23°C). "Specific binding" was operationally defined as the arithmetic difference between "total binding" of 0.6 nM [3H]Ci8-PAF (in the absence of added PAF) and "nonspecific binding" (in die presence of 1 μM PAF). After the prescribed 5 incubation, platelet membranes were filtered under vacuum and washed widi 1 millilitre of "binding buffer". The filters were dried and removed. The bound radioactivity was quantitated with a Berthold TLC-Linear Analyzer model LB2842.

Dose-response curves of inhibition of specific pH]C_.8-PAF binding by test compounds were conducted in triplicate, with at least four doses covering die active l o range. Experiments were repeated at least once. IC50 values (concenttation producing 50% inhibition) were determined by point-to-point evaluation. Kj values of inhibitory binding constants were calculated according to die metiiod of Cheng and Prusoff [Biochem. Pharmacol. 22 (1973) 3099-3108] whereby

5 Ki = ICso

1 + ([[3H]PAF]/K _d [ ³ H]PAF)

IC50

1 + (0.6 nM/0.6 nM)

IC50

^" 2 0 The values of Kj for representative compounds of the present invention appear in Table 1.

Table 1 PAF Receptor Binding Activity

The foregoing may be better understood from the following Examples, which are presented for the purpose of illustration and not intended to limit the scope of the inventive concept.

Example 1

Preparation of 3-(Pyridin-3-yl)-7-(indol-3-yl)carbonyl- lH.3H-pyrrolor 1.2-cltiιiazole.

To a solution of 3-(pyridin-3-yl)-lH,3H-pyrrolo[l,2-c]thiazole-7-carboxylic acid, prepared as described in United States Patent 4,529,728, (1.00 g) in anhydrous 5 tetrahydrofuran (TΗF) (50 mL) under dry nittogen was added sodium hydride, 60% oil dispersion (0.18 g, 1.1 equivalents) and stirred 1.0 hour at ambient temperature. To die resulting suspension was added a catalytic amount of dimediylformamide (DMF) followed by die dropwise addition of oxalyl chloride (0.43 mL, 1.2 equivalents). After the reaction mixture had stirred 2.0 hours at ambient temperature, the solvent was l o evaporated in vacuo at 45°C. The residue was suspended in a mixture of methylene chloride and benzene (3:1 v/v, 30 mL).

In a separate flask, a 3.0 M solution of methyl magnesium bromide in edier (2.0 mL, 1.5 equivalents) was added dropwise to a solution of indole (0.72 g, 1.5 equivalents) in benzene (30 mL) at room temperature and stirred 0.75 hour. The

15 resulting green indolylmagnesium bromide solution was cannulated into the suspension of acid chloride described above. The reaction mixture was stirred at room temperature for 18 hours and tiien quenched with water (equal volume) and extracted with etiier (2 x equal volume). The combined organic phases were dried over magnesium sulfate and concentrated in vacuo at 45°C to afford crude product which was purified by flash 0 chromatography (15 p.s.i.) on 250 g silica gel eluting with 1:1 TΗF/hexane. The resulting yellow solid was triturated widi metiiylene chloride, filtered, and dried at 50° in vacuo to afford die tide compound as a white powder (112 mg, 8 %). m.p. 237- 238°C. -H NMR (DMSO-d6, 300 MHz) δ 4.45 (d, J = 15Hz, 1H), 4.63 (dd, J = 15, 2Hz, 1H), 6.69 (d, J = 3Hz, 1H), 6.77 (d, J = 1.5Hz, 1H), 6.88 (d, J = 3Hz, 1H), 5 7.20 (dquintet, J = 7.5Hz, 1H), 7.43 (dd, J = 7.5, 5.3Hz, 1H), 7.48 (d, J = 8Hz, 1H), 7.65 (dt, J = 2, 8.4Hz, 1H), 8.21 (d, J = 3Hz, 1H), 8.24-8.28 (m, 1H), 8.53- 8.58 (m, 2H), 11.86 (s, 1H). MS (DCI NH3) m/e 346 (M+H) ⁺ .

Example 2 0 Preparation of 3-(Pyridin-3-yl)-7-(l-NJV-dimethylcarbamoylindol-3-yl)carbon yl- lH.3H-ρyrrolori .2-cl thiazole.

3-(Pyridin-3-yl)-7-(indol-3-yl)carbonyl- lH,3H-pyrrolo[l ,2-c]dιiazole prepared as described in Example 1, (0.11 g) was dissolved in dimetiioxyetiiane (DME) (20 mL) and powdered potassium hydroxide (0.09 g, 5 equivalents) was added in one portion. 5 After stirring at ambient temperature for 0.5 hour, NN-dimediylcarbamoyl chloride

(0.038 g, 1.1 equivalents) was added dropwise and the reaction was stirred for 1 hour.

The reaction mixture was poured into water (50 mL) and extracted with edier (2 x 50

mL). The combined extracts were dried over magnesium sulfate and concentrated in vacuo at 50°C to afford crude product as an amber oil. The crude product was dissolved in the minimal amount of toluene (2 mL) and edier was added until cloudy (20 mL). After standing for 18 hours at -20°C, die supernatant was decanted from a yellow precipitate. The desired product was dien precipitated from the supernatant with die addition of excess pentane (50 mL). The white floculent precipitate was dried in vacuo at 50°C to afford die tide compound as a white powder (28 mg, 21%). m.p. 241-243°C. *H NMR (DMSO-dβ, 300 MHz) δ 3.05 (s, 6H), 4.48 (d, J = 15Hz, IH), 4.66 (dd, J = 15, 2Hz, IH), 6.73 (d, J = 3Hz, IH), 6.79 (d, J = 1Hz, IH), 6.89 (d, J = 3Hz, IH), 7.28-7.47 (m, 3H), 7.60-7.70 (m, 2H), 8.23-8.28 (m, IH), 8.32 (s, IH), 8.55-8.59 (m, 2H). MS (DCI/NH3) m/e 417 (M+H) ⁺ . IR (KBr) 1600, 1687, 2930, 3440 cm-l.

Example 3 Preparation of 3-(Pyridin-3-yl ^' )-7-(5-phenylmethoxyindol-3-yl ^' )carbonyl-lH.3H- pyrroloπ .2-clthiazole.

The tide compound was prepared by die procedure described in Example 1 except 5-phenylmethoxyindole was used instead of indole. The crude product was purified by flash chromatography (15 p.s.i.) on 250 g silica gel eluting widi 3:2 TΗF/hexane to afford the tide compound. m.p. 178-179°C. ^X Η NMR (DMSO-dβ, 300 MHz) δ 4.45 (d, IH, J = 15Hz), 4.62 (dd, IH, J = 15, 2Hz), 5.13 (s, 2H), 6.68 (d, IH, J = 3Hz), 6.76 (d, IH, J = 1Hz), 6.87 (d, IH, J = 3Hz), 6.94 (dd, IH, J = 9, 3Hz), 7.29-7.53 (m, 7H), 7.65 (dt, IH, J = 2.4, 8.4Hz), 7.91 (d, IH, J = 2.5Hz), 8.18 (d, IH, J = 3Hz), 8.53-8.58 (m, 2H), 11.77 (d, IH, J = 2.5Hz). Anal calcd for C27H21N3O2S: C, 71.82; H, 4.69; N, 9.31. Found: C, 71.41; H, 4.78; N, 9.19. MS (DCI NH3) m/e 452 (M+H) ⁺ . IR (KBr) 1422, 1585, 3400 cm-l.

Example 4

Preparation of S-d^ridin-S-vD^-rό-Dhenylmedioxyindol-S-vDcarbonyl-lH.SH- pyrroloπ .2-clthiazole. The tide compound was prepared by die procedure described in Example 1 using 6-phenylmethoxyindole instead of indole. The crude product was purified by flash chromatography (15 p.s.i.) on 250 g silica gel eluting widi 3:2 TΗF/hexane and tiien recrystallized from TΗF, a minimum of methanol, and excess edier to afford the tide compound. m.p. 229-231°C. ^X Η NMR (DMSO-dδ, 300 MHz) δ 4.45 (d, J = 15Hz, IH), 4.62 (dd, J = 15, 2Hz, IH), 5.15 (s, 2H), 6.67 (d, J = 3Hz, IH), 6.75 (d, J = 2Hz, IH), 6.85 (d, J = 3Hz, IH), 6.91 (dd, J = 9, 2.5Hz, IH), 7.04 (d, J = 2.5Hz, IH), 7.30-7.52 (m, 6H), 7.65 (dt, J = 8, 2Hz, IH), 8.09 (s, IH), 8.13 (d, J =

9Hz, IH), 8.53-8.58 (m, 2H), 11.68 (m, IH). Anal calcd for C27H21N3O2S: C, 71.82; H, 4.69; N, 9.31. Found: C, 71.72; H, 4.78; N, 9.16. MS (DCI/NH3) m/e 452 (M+H) ⁺ . IR (KBr) 1520, 1570, 1620, 3200, 3420 cm-l.

Example 5

Preparation of 3-(Pyridin-3-yl)-7-(7-phenylmethoxyindol-3-yl)carbonyl- 1H.3H- pyrrolor 1.2-clthiazole.

The tide compound was prepared by die procedure described in Example 1 using 7-phenylmethoxyindole instead of indole. The crude product was purified by flash chromatography (15 p.s.i.) on 250 g silica gel eluting with 1 : 1 TΗF/hexane and tiien recrystallized from ethyl acetate/ether to afford die tide compound. m.p. 184- 188°C. *Η NMR (DMSO-d6, 300 MHz) δ 4.45 (d, J = 15Hz, IH), 4.62 (dd, J = 15, 2Hz, IH), 5.30 (s, 2H), 6.68 (d, J = 3Hz, IH), 6.76 (d, J = 1Hz, IH), 6.85 (d, J = 3Hz, IH), 6.89 (d, J = 8Hz, IH), 7.08 (t, J = 8Hz, IH), 7.31-7.46 (m, 4H), 7.56- 7.67 (m, 3H), 7.83 (d, J = 8Hz, IH), 8.03 (d, J = 3Hz, IH), 8.53-8.58 (m, 2H), 12.06 (d, J = 3Hz). Anal calcd for C27H21N3O2S: C, 71.82; H, 4.69; N, 9.31. Found: C, 71.33; H, 4.70; N, 9.16. MS (DCI/NH3) m/e 452 (M+H) ⁺ .

Example 6 Preparation of 3-(Pyridin-3- yl)-7-( 1 -NJV-dimethylcarbamoyl-5-phen ylmethox vindol- 3-v carbonyl- lH.3H-pyrroloπ .2-clthiazole.

The tide compound was prepared by the procedure described in Example 2 using the compound resulting from Example 3, 3-(pyridin-3-yl)-7-(5- phenylmethoxyindol-3-yl)carbonyl-lH,3H-pyrrolo[l,2-c]thiazol e, instead of 3- (pyridin-3-yl)-7-(indol-3-yl)carbonyl-lH,3H-pyrrolo[l^-c]thi azole. The product was recrystallized from ethyl acetate/pentane to give the tide compound. m.p. 87-91°C. Η ΝMR (DMSO-d ₆ , 300 MHz) δ 3.04 (s, 6H), 4.48 (d, J = 15Hz, IH), 4.65 (dd, J = 2, 15Hz, IH), 5.16 (s, 2H), 6.72 (d, J = 3Hz, IH), 6.79 (d, J = 1Hz, IH), 6.89 (d, J = 3Hz, IH), 7.06 (dd, J = 15, 3Hz, IH), 7.30-7.56 (m, 7H), 7.66 (dt, H = 8, 2Hz, IH), 7.88 (d, J = 3Hz, IH), 8.28 (s, IH), 8.55-8.59 (m, 2H). Anal calcd for

C30H26Ν4O3S: C, 68.95; H, 5.01; N, 10.72. Found: C, 68.44; H, 5.17; N, 10.43. MS (DCI/NH3) m/e 523 (M+H) ⁺ .

Example 7

Preparation of 3-(Pyridin-3-yl -7-(l-N V ^" -dimedivIcarbamoyl-6-phenylmethoxyindol- 3-yl carbonvI-lH.3H-pyττoloπ.2-c1thiazole.

The tide compound was prepared by die procedure described in Example 2 using the compound resulting from Example 4, 3-(pyridin-3-yl)-7-(6- phenylmethoxyindol-3-yl)carbonyl-lH,3H-pyrrolo[l^-c]thiazole , instead of 3- (pyridin-3-yl)-7-(indol-3-yl)carbonyl-lH,3H-pyrrolo[l,2-c]th iazole. The product was recystallized from toluene/ether/excess pentane to give the tide compound m.p. 85- 91°C. *Η ΝMR (DMSO-d6, 300 MHz) δ 3.01 (s, 6H), 4.47 (d, J = 15Hz, IH), 4.55 (dd, J = 15, 2Hz, IH), 5.17 (s, 2H), 6.71 (d, J = 3Hz, IH), 6.78 (d, J = IHz, IH), 6.88 (d, J = 3Hz, IH), 7.30-7.52 (m, 6H), 7.66 (dt, J = 8, 2Hz, IH), 8.12 (d, J = 15Hz, IH), 8.19 (s, IH), 8.54-8.58 (m, 2H). Anal calcd for C30H26Ν ₄ O3S: C, 68.95; H, 5.01; N, 10.72. Found: C, 68.66; H, 5.04; N, 10.55. MS (DCI/NH3) m/e 523 (M+H) ⁺ . Example 8

Preparation of 3-(Pyridin-3-ylV7-f l-N V-dimedιylcarbamoyl-7-phenylmethoxyindol- 3-yl)carbonyl-lH.3H-pyrrolon.2-c1thiazole.

The tide compound was prepared by die procedure described in Example 2 using the compound resulting from Example 5, 3-(pyridin-3-yl)-7-(7- phenylmethoxyindol-3-yl)carbonyl-lH,3H-pyrrolo[l^-c]thiazole , instead of 3-

(pyridin-3-yl)-7-(indol-3-yl)carbonyl-lH,3H-pyrrolo[l,2-c ]thiazole. The product was recrystallized from methylene chloride TΗF/hexane to give the tide compound m.p. 210-211°C. ^X Η ΝMR (DMSO-d6, 300 MHz) δ 2.70 (d, J = 21Hz, 6H), 4.45 (d, J = 15Hz, IH), 4.54 (dd, J = 15, 2Hz, IH), 5.21 (s, 2H), 6.70 (d, J = 3Hz, IH), 6.78 (d, J = IHz, IH), 6.88 (s, IH), 7.05 (d, J = 8Hz, IH), 7.23 (t, J = 8Hz, IH), 7.33- 7.53 (m, 6H), 7.66 (dt, J = 8, 2Hz, IH), 7.89 (d, J = 8Hz, IH), 8.28 (s, IH), 8.52- 8.58 (m, 2H). MS (DCI/ΝH3) m/e 523 (M+H) ⁺ .

Example 9 Preparation of 3-fPyridin-3-ylV7-f l-fgrr-butyloxycarbonylindol-3-yl)carbonyl-lH.3H- pyrrolόπ ,2-clthiazole.

The compound resulting from Example 1 was reacted widi di-f-butyl- dicarbonate in acetonitrile in the presence of 4-dimedιylaminopyridine to give, after recrystallization from etiier/pentane at -20 °C, the tide compound. m.p. 150-151°C. ^! Η NMR (DMSO-d6, 300 MHz) δ 1.66 (s, 9H), 4.48 (d, J = 15Hz, IH), 4.65 (dd, J = 15, 2Hz, IH), 6.75 (d, J = 3Hz, IH), 6.83 (d, J = 3Hz, IH), 7.34-7.48 (m, 3H), 7.69 (dt, J = 9, 2Hz, IH), 8.12 (d, J = 9Hz, IH), 8.26 (s, IH), 8.56-8.60 (m, 2H).

Anal calcd for C25H23N3O3S: C, 67.40; H, 5.20; N, 9.43. Found: C, 67.26; H, 5.53; N, 9.10. MS (DCI/NH3) m/e 446 (M+H) ⁺ . IR(KBr) 1540, 1605, 1735, 2980 cm-l.

Example 10 Pre ^p aration of 3- ⁽ Pyridin-3-vD-7-f6-phenylindol-3-yl)carbonyl-lH.3H-Dyrr oloπ.2- clthiazole.

The title compound was prepared by die procedure described in Example 1 using 6-phenylindole instead of indole. The product was recrystallized from THF/methanol/ether and dien triturated in methylene chloride to afford the tide compound. m.p. 258°C. *H NMR (DMSO-d6, 300 MHz) δ 4.48 (d, J = 15Hz, IH), 4.65 (dd, J = 15, 2Hz, IH), 6.71 (d, J = 3Hz, IH), 6.78 (s, IH), 6.90 (d, J = 3Hz, IH), 7.32-7.53 (m, 5H), 7.64-7.73 (m, 4H), 8.27 (d, J = 3Hz, IH), 8.33 (d, J = 9Hz, IH), 8.54-8.59 (m, 2H), 11.96 (d, J = 3Hz, IH). Anal calcd for C26H19N3OS: C, 74.09; H, 4.54; N, 9.97. Found: C, 73.93; H, 4.57; N, 9.92. MS (DCI NH3) m/e 422 (M+H) ⁺ . IR(KBr) 1505, 1522, 1550, 1580, 3180, 3420 cm-l.

Example 11

Preparation of 3-(Pyridin-3-yl)-7-ri-(morpholin-4-ylcarbonyl)indol-3-vncarb onyl- lH.3H-pyrrolor 1.2-clthiazole. The tide compound was prepared by die procedure described in Example 2 using the compound resulting from Example 1, 3-(pyridin-3-yl)-7-(indol-3- yl)carbonyl-lH,3H-pyrrolo[l,2-c]thiazole, and (morpholin-4-yl)chloroformate to give, after recrystallization from ethyl acetate/ether, die tide compound. m.p. 161-163°C. *Η NMR (DMSO-d6, 300 MHz) δ 3.53-3.58 (m, 4H), 3.66-3.72 (m, 4H), 4.48 (d, J = 15Hz, IH), 4.65 (d, J = 15Hz, IH), 6.75 (d, J = 2Hz, IH), 6.80 (s, IH), 6.90 (d, J = 3Hz, IH), 7.28-7.47 (m, 3H), 7.68 (d, J = 8Hz, 2H), 8.22-8.30 (m, 2H), 8.55- 8.59 (m, 2H). MS (DCI/NH3) m/e 459 (M+H) ⁺ . (CDCl ₃ 1540, 1605, 1690, 2850, 2920, 2970 cm-l.

Example 12 Preparation of 3-(Pyridin-3-ylV7-(l-N_N-dimethylcarbamoyl-6-phenylindol-3- vDcarbonyl- lH.3H-pyrrolor 1 ,2-clthiazole.

The tide compound was prepared by die procedure described in Example 2 using die compound resulting from Example 10, 3-(pyridin-3-yl)-7-(6-phenylindol-3- yl)carbonyl-lH,3H-pyrrolo[l,2-c]thiazole, instead of 3-(pyridin-3-yl)-7-(indoI-3- yl)carbonyl-lH,3H-pyrrolo[l,2-c]dιiazole. The crude product was purified by flash chromatography (15 p.s.i.) on 250 g silica gel eluting widi etiiyl acetate to give die tide compound as an amorphous solid. m.p. 115-125°C. *Η ΝMR (DMSO-d6, 300 MHz)

δ 3.09 (s, 6H), 4.50 (d, J = 15Hz, IH), 4.68 (dd, J = 15, 2Hz, IH), 6.74 (d, J = 3Hz, IH), 6.80 (d, J = IHz, IH), 6.92 (d, J = 3Hz, IH), 7.34-7.53 (m, 4H), 7.84 (d, J = IHz, IH), 8.33 (d, J = 9Hz, IH), 8.38 (s, IH), 8.57-8.60 (m, 2H). MS (DCI/NH3) m/e 493 (M+H) ⁺ . IR(CDC1 ₃ ) 1540, 1610, 1690, 2930 cm-l.

Example 13 Preparation of 2-Oxide-3-(pyridin-3-v -7-(l-rerr-butyloxycarbonylindol-3-ylcarbonyl'.- lH.3H-pyrroloπ .2-cl thiazole.

To a solution of 3-(pyridin-3-yl)-7-(l-re/ϊ-butyloxycarbonylindol-3- yl)carbonyl-lH,3H-pyrrolo[l,2-c]thiazole (270mg, 0.61 mmol) prepared as described in example 9, in CΗC13 (50 mL) at -20°C was added a solution of 3-chloroperbenzoic acid in CHC13 (50 mL). The reaction mixture was stirred for three hours at -20°C and tiien was partitioned between CHCI3 and saturated aqueous NaHCθ3. The organic phase was washed widi brine, dried over MgS04, filtered, and concentrated. Purification by flash chromatography on silica gel (ethyl acetate) afforded die desired sulfoxide (150 mg). m.p. 155-157°C. ^l H NMR (DMSO-d6, 300 MHz) δ 1.67 (s, 9H), 4.27 (d, IH, J=17 Hz), 4.68 (d, IH, J=17 Hz), 6.72 (s, IH), 6.97 (d, IH, J=3 Hz), 7.12 (d, IH, J=3 Hz), 7.36-7.50 (m, 4H), 8.11-8.16 (m, IH), 8.20-8.24 (m, IH), 8.31 (s, IH), 8.45 (m, IH), 8.61 (dd, IH, J=2, 4 Hz). MS (DCI/NH3) m/e 462 (M+H)+ 479 (M+NH4)+, 414. IR (CDC13) 2980, 1740, 1620, 1545. Anal calcd for C25H23N3O4S: C, 65.06; H, 5.02; N, 9.10. Found: C, 63.92; H, 5.16; N, 8.72.

Example 14

Preparation of 2-Oxide-3-rpyridin-3-yl)-7-(indol-3-ylcarbonyl)-lH.3H-pyrrol ori.2- c]thiazole.

The tide compound was prepared by die procedure described in Example 13 using the compound resulting from Example 1, 3-(Pyridin-3-yl)-7-(indol-3- yl)carbonyl-lH,3H-pyrrolo[l,2-c]dιiazole, instead of 3-(pyridin-3-yl)-7-(l-ferr- butyloxycarbonylindol-3-yl)carbonyl-lH,3H-pyrrolo[l^-c]thiaz ole. m.p. 158°C (decomp). lΗ NMR (DMSO-d6, 300 MHz) δ 4.25 (d, IH, J=18 Hz), 4.67 (d, IH, J=18 Hz), 6.68 (s, IH), 7.00 (d, IH, J=3 Hz), 7.06 (d, IH, J=3 Hz), 7.16-7.27 (m, 2H), 7.39-7.52 (m, 3H), 8.25-8.29 (m, 2H), 8.42 (d, IH, J=2 Hz), 8.59-8.62 (m, IH), 11.92 (s, IH). MS (DCI NH3) m/e 362 (M+H) ⁺ 379 (M+NH4) ⁺ , 346, 315. IR (KBr) 3420, 2920, 1592, 1422. Anal calcd for C20H15N3O2S: C, 66.47; H, 4.18; N, 11.63. Found: C, 63.69; H, 4.64; N, 10.39.

Example 15

Preparation of 3- ⁽ Pyridin-3-vD-7-(indol-3-ylcarbonyl ⁾ -lH.3H-pyπOloπ.2-c1oxazole.

The desired compound was prepared according to the method of Example 1, except substituting 3-(3-pyridin-3-yl)-lH,3H-pyrrolo[l,2-c]oxazole-7-carboxylic acid, prepared from 3-pyridinecarboxaldehyde and L-serine as described in United States Patent 4,529,728, for 3-(3-pyridin-3-yl)-lH,3H-pyιτolo[l,2-c]thiazole-7-carboxyl ic acid. Η NMR (DMSO-d6) δ 5.28 (dd, 1Η, J = 1.5, 13.0Ηz), 5.44 (dd, IH, J = 2.0, 13.0Hz), 6.80 (d, IH, J = 3.0Hz), 6.84 (s, IH), 6.90 (d, IH, J = 3.0Hz), 7.19 (pd, 2H, J = 1.5, 7.0Hz), 7.47 (d, IH, J = 7.0Hz), 7.49 (m, IH), 7.825 (m, 2H), 8.68 (dd, IH, J = 2.0, 5.0Hz), 8.71 (d, IH, J = 2.0Hz). MS (DCI/NH3) m/e 330 (M+l)+.

Example 16

Preparation of 3-(Pyridin-3-ylV7-(l-N_N-diisopropylcarbamoyl-6- phenylmethoxyindol-3-ylcarbonyl)-lH.3H-pyrrolori.2-clthiazol e. The tide compound was prepared by die procedure described in Example 2 using the compound resulting from Example 4, 3-(pyridin-3-yl)-7-(6- phenylmethoxyindol-3-yl)carbonyl-lH,3H-pyrrolo[l,2-c]thiazol e, instead of 3- (pyridin-3-yl)-7-(indol-3-yl)carbonyl-lH,3H-pyrrolo[l,2-c]di iazole and using diisopropylcarbamoylchloride instead of dimethylcarbamoylchloride. ^! Η ΝMR (CDCI ₃ , 300 MHz) δ 1.30 (d, 12H, 1=1 Hz), 3.63 (m, 2H), 4.47 (d, IH, J=15 Hz),

4.65 (d, IH, J=15 Hz), 5.18 (s, 2H), 6.72 (d, IH, J=3 Hz), 6.78 (s, IH), 6.88 (d, IH, J=3 Hz), 6.97 (s, IH), 7.04 (d, IH, J=10 Hz), 7.29-7.50 (m, 6H), 7.62-7.69 (m, IH), 8.15 (d, IH, J=9 Hz), 8.19 (s, IH), 8.53-8.58 (m, 2H). MS (DCVΝH3) m/e 579 (M+H)+, 457. IR (CDCI3) 2970, 1685, 1616. Anal calcd for C3 ₄ H ₃₄ N ₄ O ₃ S: C, 70.56; H, 5.92; N, 9.68. Found: C, 69.08; H, 5.84; N, 9.39.

Example 17

Preparation of l.l-Dimethyl-3-fρyridin-3-vn-7-(indol-3-ylcarbonvn-lH.3H- pyrrolor 1.2-clthiazole. Step 1. 2-(3-pyridinyl'.-5.5-dimedιyl-4-dιiazolidinecarboxylic acid.

To a suspension of DL-penicillamine (50g, 335 mmol) in 1:1 aqueous ethanol (500 mL) was added 3-pyridinecarboxaldehyde (36g, 335 mmol). The resulting clear- yellow solution was stirred for 17 hours at ambient temperature during which time a white precipitate formed. The white solid was filtered off and rinsed widi 3:1 H2O, edianol and ether to give 2-(3-pyridinyl)-5,5-dimedιyl-4-dιiazolidinecarboxylic acid (51g, 64%).

Step 2. 2-f3-pyridinylV3-formyl-5.5-dimethyl-4-thiazolidinecarboxyli c acid.

Formic acid (17g, 378 mmol) and acetic anhydride (13g, 126 mmol) were combined at 0°C. A slurry of 2-(3-pyriclinyl)-5,5-dime&yl-4-thiazolidinecarboxylic acid (lOg, 42 mmol), prepared as in step 1, in THF (250 mL) was added over five minutes. The resulting clear-yellow solution was warmed slowly to ambient temperature and stirred for 17 hours, during which time it became a white suspension. The THF was removed in vacuo, and the resulting slurry was filtered to yield a white solid. The solid was rinsed with edier to give 2-(3-pyridinyl)-3-formyl-5,5-dimethyl- 4-thiazolidinecarboxylic acid (lOg) which was used widiout further purification.

Step 3. methyl l.l-dimethyl-3-(pyrid-3-viyiH.3H-pyrtθlori.2-clthiazole-7- carboxylate.

To a solution of p-toluenesulfonyl chloride (18g, 95 mmol) and mediyl 2,3- dichloropropionate (15g, 95 mmol) in refluxing CΗ2CI2 (125 mL) was added a mixture of2-(3-pyridinyl)-3-formyl-5,5-dimethyl-4-tWazoUdinecarboxyl ic acid (5.1g, 19 mmol) and triethylamine (2.3g, 22 mmol) in CH2CI2 (125 mL). After one hour at reflux triethylamine (4.6g, 44 mmol) was added and die reaction mixture was refϊuxed for a further 17 hours. The reaction mixture was cooled to ambient temperature and partitioned between cold IN aqueous NaOH and ethyl acetate. The organic phase was washed with cold IN aqueous NaOH and brine, dried over MgSθ ₄ , filtered, and concentrated in vacuo. The crude product was dissolved in 5% aqueous HC1 and die solution was extracted twice with edier. The aqueous phase was neutralized widi solid Na2C03 and extracted twice with ediyl acetate. The combined ediyl acetate extracts were washed with brine, dried over MgSO ₄ , and concentrated in vacuo. Chromatography on silica gel (150g, 1:1 ediyl acetate, hexanes), afforded mediyl 1,1- dimemyl-3-(pyrid-3-yl)-lH,3H-pyrrolo[l,2-c]thiazole-7-carbox ylate (l.lg, 20%) as an off-white powder.

Step 4. l.l-dimethyl-3-(pyrid-3-yl)-lH.3H-pyrrolori.2-c1thiazole-7-c arboxylic acid. A mixture of mediyl l,l-dimedιyl-3-φyrid-3-yl)-lH,3H-pyrrolo[l,2- c]dιiazole-7-carboxylate (l.lg, 3.8 mmol), IN aqueous NaOΗ (19 mmol), and medianol (40 mL) was refluxed for 17 hours. The reaction mixture was cooled to ambient temperature and taken to pΗ 4 with concentrated ΗC1. The thick solution was extracted twice with 9:1 CΗCI3, isopropanol. The combined organic layers were washed widi brine, dried over MgS04, filtered, and concentrated in vacuo to give a yellow powder. The powder was triturated with ether to afford l,l-dimethyl-3-(pyrid- 3-yl)-lH,3H-ρyrrolo[l,2-c]thiazole-7-carboxylic acid as a pale-yellow powder.

Step 5. l.l-Dimethyl-3-(pyridin-3-vn-7-(indol-3-ylcarbonyl)-lH.3H-ρ yrroloπ .2- clthiazole.

The desired compound was prepared according to die mediod of Example 1, except substituting l,l-dimedιyl-3-(pyrid-3-yl)-lH,3H-pyrrolo[l,2-c]dιiazole-7 - carboxylic acid (l.Og, 3.6 mmol) for 3-(pyridin-3-yl)-lH,3H-pyrrolo[l,2-c]thiazole-7- carboxylic acid to give l,l-Dimedιyl-3-(pyridin-3-yl)-7-(indol-3-ylcarbonyl)-lH,3H- pyrrolo[l ,2-c]thiazole (183mg, 14%). m.p. 254-257°C. Η NMR (CDC1 ₃ , 300 MHz) δ 2.05 (s, 3H), 2.07 (s, 3H), 6.19 (d, J=3Hz, IH), 6.50 (s, IH), 6.70 (d, J=3 Hz, IH), 7.29 (m, 2H), 7.35 (m, IH), 7.43 (m, IH), 7.70 (dt, J=9.0, 1.5 Hz, IH), 7.82 (d, J=3 Hz, IH), 8.53 (bs, IH), 8.64 (dd, J=6.0, 1.5 Hz, 2H). MS (DCI/NH3) m/e 374 (M+l)+, 253, 141, 124.

Example 18 Preparation of 3-(Pyridin-3-yl)-7-(l-carbomethoxycarbamoyl-6-phenylmethoxyi ndol- 3-ylcarbonyl)-lH.3H-pyrrolon.2-c1thiazole.

The desired compound was prepared according to the mediod of Example 2, except substituting 3-(pyridin-3-yl)-7-(6-phenylmethoxyindol-3-yl)carbonyl- 1H,3H- pyrrolo[l,2-c]dιiazole, prepared as in Example 4 for 3-(pyridin-3-yl)-7-(indol-3- yl)carbonyl- lH,3H-pyrrolo[l ,2-c]thiazole and substituting methyl chloroformate for N^-dimethylcarbamoyl chloride. m.p. 152-153°C. Η ΝMR (DMSO-d6, 300 MHz) δ 4.03 (s, 3H), 4.47 (d, IH, J=15 Hz), 4.63 (dd, IH, J=2, 15 Hz), 5.20 (s, 2H), 6.73 (d, IH, J=3 Hz), 6.80 (d, IH, J=2 Hz), 6.81 (d, IH, J=3 Hz), 7.12 (dd, IH, J=3, 9 Hz), 7.30-7.52 (m, 6H), 7.67 (dt, IH, J=8, 2 Hz), 7.79 (d, IH, J=3 Hz), 8.08 (d, IH, J=9 Hz), 8.16 (s, IH), 8.55-8.59 (m, 2H). MS (DCI/ΝH3) m/e 510 (M+H)+ Anal calcd for C29H23N3O4S: C, 68.35; H, 4.55; N, 8.25. Found: C, 67.84; H, 4.63; N, 8.04.

Example 19 Preparation of l.l-DimethvI-3-(pyridin-3-yl)-7-(l-NJV-dimethylcarbamoyl-ind ol- 3-ylcarbonylVlH.3H-pyπOlori.2-clthiazole.

The tide compound was prepared by the procedure described in Example 2 using the compound resulting from Example 17, l,l-dimethyl-3-(pyridin-3-yl)-7- (indol-3-ylcarbonyl)-lH,3H-pyrrolo[l,2-c]dιiazole, instead of 3-(Pyridin-3-yl)-7- (indol-3-yl)carbonyl-lH,3H-pyrrolo[l,2-c]dιiazole. ^l Η ΝMR (CDCI3, 300 MHz) δ 2.05 (s, 3H), 2.06 (s, 3H), 3.13 (s, 6H), 6.20 (d, IH, J=3Hz), 6.51 (s, IH), 6.72 (d, IH, J=3Hz), 7.36 (m, 3H), 7.58 (m, IH), 7.69 (dt, IH, J=7.5, 1.5Hz), 7.91 (s, IH), 8.34 (m, IH), 8.64 (b, 2H). MS (DCI/ΝH3) 445(M+H)+, 322, 124.

Example 20

Preparation of 3-(Pyridin-3-yl)-7-f 1-N-methyl-N-phenylcarbamoyl- 6-phenylmethoxyindol-3-vIcarbonyl ^' .-lH.3H-pyrτolori.2-c1thiazole. The tide compound was prepared by the procedure described in Example 2 using the compound resulting from Example 4, 3-φyridin-3-yl)-7-(6- phenylmethoxyindol-3-yl)carbonyl-lH,3H-pyrrolo[l,2-c]dιiazo le, instead of 3- (pyridin-3-yl)-7-(indol-3-yl)carbonyl-lH,3H-pyrrolo[l,2-c]di iazole and usingN- methyl-N-phenylcarbamoylchloride instead of NN-dimediylcarbamoylchloride. lΗ ΝMR (DMSO-d6, 300 MHz) δ 3.49 (s, 3H), 4.34 (d, IH, J=15Hz), 4.52 (dd, IH, J=15, 2Hz), 5.18 (s, 2H), 5.72 (d, IH J=3Hz), 6.55 (d, IH, J=3Hz), 6.72 (d, IH, J=2Hz), 7.00 (dd, IH, J=9, 3Hz), 7.18-7.55 (m, 12H), 7.60-7.66 (m, 2H), 7.98 (d, IH, J=8Hz), 8.52 (d, IH, J=2Hz), 8.58 (dd, IH, J=2, 8Hz). MS (DCI ΝH3) m e 585 (M+H)+, 463, 452, 372. IR (KBr) 1690, 1610, 1592, 1540, 1485. Anal calcd for C35H28N4O3S: C, 71.90; H, 4.83; N, 9.58. Found: C, 71.43; H, 4.95; N, 9.45.

Example 21

Preparation of 3-(Pyridin-3-vD-7-(l-methyl-6-phenylmethoxyindol-3-ylcarbony l ^' .- lH.3H-pyrroloπ.2-clthiazole. The tide compound was prepared by the procedure described in Example 2 using the compound resulting from Example 4, 3-(pyridin-3-yl)-7-(6- phenylmethoxyindol-3-yl)carbonyl-lH,3H-pyrrolo[l,2-c]thiazol e, instead of 3- (pyridin-3-yl)-7-(indol-3-yl)carbonyl-lH,3H-pyrrolo[l,2-c]th iazole and using methyl iodide instead of NN-dimethylcarbamoylchloride. m.p. 172-173°C. Η ΝMR (DMSO-d6, 300 MHz) δ 3.84 (s, 3H), 4.45 (d, lH,J=5Hz),4.62 (dd, IH, J=15, 2Hz),5.18 (s, 2H),6.69 (d, IH, J=3Hz),6.76 (d, IH, J=lHz),6.90 (d, IH, J=3Hz),6.95 (dd, IH, J=9, 2Hz),7.20 (d, IH, J=2Hz), 7.32-7.53 (m, 6H),7.65 (dt, IH, J=8, 2Hz),8.15 (d, IH, 9Hz),8.17 (s, lH),8.53-8.58 (m, 2H). MS (DCI/ΝH3) m/e 466 (M+H)+, 436, 374, 345. IR (CDC13) 1595, 1570, 1525, 1245, 1080. Anal calcd for C28H23N3O2S: C, 72.24; H, 4.98; N, 9.03. Found: C, 72.34; H, 5.06; N, 8.88.

Example 22 Preparation of 3-(Pyridin-3-yl)-7-ri-N-medιylcarbamoyl-6-phenylmedιoxyind oI- 3-ylcarbonvn- lH.3H-pyrroloπ .2-clthiazole. The tide compound was prepared by die procedure described in Example 2 using the compound resulting from Example 4, 3-(pyridin-3-yl)-7-(6- phenyIme oxyindol-3-yl)carbonyl-lH,3H-pyrrolo[l,2-c]thiazole, instead of 3-

(pyridin-3-yl)-7-(indol-3-yl)carbonyl-lH,3H-pyrrolo[l,2-c]th iazole and using metiiylisocyanate instead of N^V-dimediylcarbamoylchloride. m.p.212-214°C. Η ΝMR (DMSO-d6) δ 3.84 (s, 3Η), 4.45 (d, IH, J=5Hz), 4.62 (dd, IH, J=15, 2Hz), 5.18 (s, 2H), 6.69 (d, IH, J=3Hz), 6.76 (d, IH, J=lHz), 6.90 (d, IH, J=3Hz), 6.95 (dd, IH, J=9, 2Hz), 7.20 (d, IH, J=2Hz), 7.327.53 (m, 6H), 7.65 (dt, IH, J=8, 2Hz), 8.15 (d, IH, 9Hz), 8.17 (s, IH), 8.53-8.58 (m, 2H). MS (DCI/ΝH3) m/e 509 (M+H)+, 452. Anal calcd for C29H24N4O3S: C, 68.49; H, 4.76; N, 11.02. Found: C, 68.43; H, 4.31; N, 11.47.

Example 23 Preparation of 2-Oxide-3-(pyridin-3-yl)-7-(l-N V-dimethylcarbamoyl-6-phenylindol- 3-ylcarbonyl)-lH.3H-pyrrolori.2-c1thiazole.

The tide compound was prepared by die procedure described in Example 13 using the compound resulting from Example 12, 3-(pyridin-3-yl)-7-(l-N^- dimediylcarbamoyl-6-phenylindol-3-yl)carbonyl-lH,3H-pyrrolo[ l,2-c]thiazole, instead of 3-(pyridin-3-yl)-7-(l-ferr-butyloxycarbonylindol-3-yl)carbon yl-lH,3H- pyrrolo[l,2-c]thiazole. ^l Η ΝMR (DMSO-d6, 300 MHz) δ 3.09 (s, 0.12H), 3.11 (s, 0.88H), 4.29 (d, 0.12H, J=17Hz), 4.30 (d, 0.88H, J=17Hz), 4.72 (d, 0.88H, J=17Hz), 4.82 (d, 0.12H, J=17Hz), 6.72 (s, O.88H), 6.77 (d, 0.12H, J=3Hz), 6.81 (s, 0.12), 6.96 (d, 0.12, J=3Hz), 7.05 (d, 0.88H, J=3Hz), 7.35-7.44 (m, IH), 7.45- 7.53 (m, 4H), 7.65 (dd, IH, 1=9, 2Hz), 7.72 (dd, 2H, 1=9, IHz), 7.86 (m, IH), 8.34 (d, IH, J=9Hz), 8.43 (m, 2H), 8.62 (dd, 0.88H, 4, 2Hz), 8.69 (dd, 0.12H, 4Hz, 2Hz). MS (DCI/ΝH3) m/e 526 (M+NH4)+, 509 (M+H)+, 461, 403, 388. Anal calcd for C29H24N ₄ O3S: C, 68.49; H, 4.76; N, 11.02. Found: C, 70.44; H, 5.33; N, 12.05. Example 24

Preparation of l.l-Dimethyl-3-(pyridin-3-yl)-7-(l-NJV-dimethylcarbamoyl- 6-phenylindol-3-ylcarbonv - lH.3H-pyrrolon .2-clthiazole.

The tide compound was prepared by die procedure described in Example 19 using, 6-phenylindole instead of indole. ^! Η ΝMR (CDCI3, 300 MHz) δ 2.04 (s, 3H), 2.07 (s, 3H), 6.22 (d, IH, J=3Hz), 6.53 (s, IH), 6.75 (d, IH, J=3Hz), 7.36 (m, IH), 7.4 ^* : , 2H), 7.60 (dd, IH, J=r7.5, 1.5Hz), 7.67 (m, 2H), 7.81 (m, 2H), 7.92 (s, IH), 8.37 (d, IH, J=9Hz), 8.67 (b, 2H). MS (DCI/ΝH3) m/e 521(M+H) ⁺ , 398.

Example 25

Preparation of l.l-Dimethyl-3-(pyridin-3-yl)-7-r6-(4-methoxyphenyl indol- 3-ylcarbonvn-lH.3H-pyrrolori.2-clthiazole.

Step 1. Preparation of 6W4-methoxyphenyl -rert-butoxycarbonylindole. 5 To a solution of l-rerf-butoxycarbonyl-6-bromoindole (5.0g, 17 mmol) in toluene (200 mL) was added tetrakis(triphenylphosphine)palladium(0) (0.94g, 0.84 mmol), 2N aqueous Na2Cθ3 (100 mL), and a solution of 4-methoxyboronic acid in edianol (50 mL). The 2-phase mixture was heated at 110- 125°C for two hours. The reaction mixture was cooled to ambient temperature and the layers were separated. The l o aqueous phase was extracted twice with edier. The combined organic layers were washed twice with brine, dried over MgSO filtered, and concentrated in vacuo to give a brown oil. Chromatography on silica gel (250g, 5% ether, hexanes) afforded 6-(4- methoxyphenyl)-l-rerr-butoxycarbonylindole (3.2g, 58%).

5 Step 2. Preparation of 6-(4-methoxyphenyl ndole.

To a suspension of 6-(4-methoxyphenyl)-l-ferr-butoxycarbonylindole (3.9g, 12 mmol) in metiianol (50 mL) was added IN metiianolic NaOΗ (60 mL) and CΗ2CI2 (20 mL). The reaction was stirred for one hour at ambient temperature and 1.5 hours at reflux. The reaction mixture was cooled to ambient temperature and H2O (50 mL) was 0 added to dissolve all solids. The two-phase mixture was poured into CHCI3 and die layers were separated. The organic phase was washed with brine, dired over MgS04, filtered, and concentrated in vacuo. Flash chromatography on silica gel (lOOg, 25% ethyl acetate, hexanes) afforded 6-(4-medιoxyphenyl)indole as white flakes (2.2g, 81%). 5

Step 3. Preparation of l.l-Dinnethyl-3-(pyridin-3-vD-7-r6-(4-methoxyphenvπindol- 3-ylcarbonvn-lH.3H-pyrrolori.2-c1thiazole.

The tide compound was prepared by the procedure described in Example 17 using 6-(4-methoxyphenyl)indole instead of indole. m.p. 236-239°C. ΗNMR (CDCI3, 300 MHz) δ 2.06 (s, 3H), 2.08 (s, 3H), 4.06 (s, 3H), 6.19 (d, 1=3 Hz, IH), 6.49 (s, IH), 6.70 (d, 1=3 Hz, IH), 6.99 (d, 1=9 Hz, 2H), 7.36 (dd, J=7.5, 6.0 Hz, IH), 7.51 (dd, J=7.5, 1.5 Hz, IH), 7.58 (m, 3H), 7.71 (dt, J=9.0, 1.5 Hz, IH), 7.81 (d, J=3 Hz, IH), 8.40 (d, 1=9 Hz, IH), 8.62 (b, 3H). MS (DCI/NH3) m/e 480 (M+l)+.

Example 26

Preparation of l.l-Dimethyl-3-(pyridin-3-yl)-7-ri-NJV-dimethylcarbamoyl- 6-(4-methoxyphenyl)indol-3-ylcarbonvn- lH.3H-pyrroloπ .2-clthiazole.

The tide compound was prepared by the procedure described in Example 2 using the compound resulting from Example 25, l,l-dimethyl-3-(pyridin-3-yl)-

7-[6-(4-methoxyphenyl)indol-3-ylcarbonyl]- lH,3H-pyrrolo[ 1 ,2-c]thiazole, instead of 3-(pyridin-3-yl)-7-(indol-3-yl)carbonyl- lH,3H-ρyrrolo[ 1 ,2-c]thiazole. m.p.271-273°C. ^l Η ΝMR (CDCI3, 300 MHz) δ 2.06 (s, 3H), 2.07 (s, 3H), 3.15 (s, 3H), 3.86 (s, 3H), 6.20 (d, 1=3 Hz, IH), 6.51 (s, IH), 6.73 (d, 1=3 Hz, IH), 6.99 (dd, J=9.0, 6.0 Hz, 2H), 7.37 (m, IH), 7.55 (dd, J=9.0, 1.5 Hz, IH), 7.59 (d, 1=9 Hz, 2H), 7.70 (dt, J=9.0, 1.5 Hz, IH), 7.73 (d, J=1.5 Hz, IH), 7.89 (s, IH), 8.34 (d, J=9 Hz, IH), 8.64 (b, 2H). MS (DCI/ΝH3) m/e 551 (M+l)+, 428. Anal cacld for C32H30N4O3S: C, 69.80; H, 5.49; N, 10.17. Found: C, 69.57; H, 5.59; N, 9.89.

Example 27

Preparation of 3-(Pyridin-3-yl)-7-(l-carbophenoxy-6-phenylmethoxyindol- 3- ylcarbonyl ^' .- lH.3H-pyrroloπ .2-clthiazole.

The desired compound was prepared according to die mediod of Example 2, except substituting 3-(pyridin-3-yl)-7-(6-phenylmedιoxyindol-3-yl)carbonyl- 1H,3H- pyrrolo[l,2-c]thiazole, prepared as in Example 4 for 3-(pyridin-3-yl)-7-(indol-3- yl)carbonyl-lH,3H-pyrrolo[l,2-c]dιiazole and substituting phenyl chloroformate for N^V-dimethylcarbamoyl chloride. Η ΝMR (DMSO-d6, 300 MHz) δ 4.45 (d, IH, J=15Hz), 4.62 (dd, IH, J=15Hz, 2Hz), 5.16 (s, 2H), 6.69 (d, IH, J=3Hz), 6.76 (s, IH), 6.85 (d, IH, J=3Hz), 7.12 (dd, IH, J=9Hz, 3Hz), 7.26-7.52 (m, 11H), 7.60- 7.68 (m, IH), 7.77 (d, IH, J=3Hz), 8.08 (d, IH, J=9Hz), 8.30 (s, IH), 8.51-8.54 (m, 2H). MS (DCVΝH3) m/e 572 (M+H) ⁺ .

Example 28

Preparation of 3-(Pyridin-3-yl)-7-r6-(4-fluorophenyl indol-3-ylcaτbonvn- lH.3H-pyrrolon .2-clthiazole.

Step 1. Preparation of 6-(4-fluorophenyl)indole.

The desired compound was prepared according to d e mediod of Exaι_. ie 25, step 1, except substituting 4-fluorophenylboronic acid for 4-methoxyphenylboronic acid, and 6-bromoindole for l-rerf-butoxy-6-bromoindole.

Step 2. Preparation of 3-(Pyridin-3-vD-7-r6-r4-fluorophenyl)indol-3-ylcarbonvn- lH.3H-pyrroloπ .2-cl thiazole.

3-(Pyridin-3-yl)-7-[6-(4-fluorophenyl)indol-3-ylcarbonyl] - lH,3H-pyrrolo[l,2-c]thiazole was prepared according to d e mediod of Example 1, except substituting 6-(4-fluorophenyl)indole for indole. nxp.248-252°C. ^! ΗNMR (DMSO-d6, 300 MHz) δ 4.47 (d, IH, J=15Hz), 4.64 (dd, IH, J=15Hz, 2Hz), 6.71 (d, IH, J=3Hz), 6.78 (s, IH), 6.90 (d, IH, J=3Hz), 7.30 (t, 2H, J=9Hz), 7.41-7.50 (m, 2H), 7.63-7.78 (m, 4H), 8.27 (d, IH, J=3Hz), 8.31 (d, IH, J=8Hz), 8.55-8.60 (m, 2H), 11.96 (d, IH, J=3Hz). MS (DCI/NH3) m/e 440 (M+H)+, 406, 315, 212. IR (KBr) 3420, 1590, 1510, 1425, 1230, 860. Anal calcd for C ₂ 6Hι ₈ N ₃ OSF: C, 71.05; H, 4.13; N, 9.56. Found: C, 70.06; H, 4.19; N, 9.31.

Example 29

Preparation of 3-(Pyridin-3-yl -7-ri-N v ^" -dimethylcarbamoyl-6-(4-fluorophenvI ^' )indol- 3-ylcarbonvπ-lH.3H-pyrroloQ.2-c1thiazole.

The tide compound was prepared by die procedure described in Example 2 using the compound resulting from Example 28, 3-(pyridin-3-yl)- 7-[6-(4-fluorophenyl)indol-3-ylcarbonyl]-lH,3H-pyrrolo[l,2-c ]thiazole, instead of 3- (pyridin-3-yI)-7-(indol-3-yl)carbonyl-lH,3H-pyrrolo[l,2-c]th ϊazole. m.p.212-214°C. Η ΝMR (DMSO-d6, 300 MHz) δ 3.08 (s, 6H), 4.50 (d, IH, J=15Hz), 4.67 (dd, IH, J=15, 2Hz), 6.73 (d, IH, J=3Hz), 6.80 (d, IH, J=lHz), 6.92 (d, IH, J=3Hz), 7.32 (t, 2H, J=9Hz), 7.44 (dd, IH, J=5, 8Hz), 7.61 (dd, IH, 1=9, IHz), 7.68 (dt, IH, J=8, IHz), 7.72-7.84 (m, 3H), 8.32 (d, IH, J=9Hz), 8.37 (s, IH), 8.55-8.60 (m, 2H). MS (DCI ΝH3) m/e 511 (M+H)+, 465, 387. IR (KBr) 1690, 1605, 1540, 1515, 1480. Anal calcd for C29H23FN4O2S: C, 68.22; H, 4.54; N, 10.97. Found: C, 67.46; H, 4.58; N, 10.67.

Example 30 Preparation of 3-(Pyridin-3-yl)-7-(l-N-methylcarbamoyl-6-phenylindol-3-ylca rbonv - lH.3H-pyrrolori .2-cldιiazole. The tide compound was prepared by die procedure described in Example 2 using die compound resulting from Example 10, 3-(pyridin-3-yl)-7-(6-phenylindol-3- yl)carbonyl-lH,3H-pyrrolo[l,2-c]dιiazole, instead of 3-(pyridin-3-yl)-7-(indol-3- yl)carbonyl-lH,3H-pyrrolo[l,2-c]thiazole and using mediylisocyanate instead of N,N- dimethylcarbamoyl chloride. m.p. 238-240°C. ^J Η ΝMR (DMSO-d6, 300 MHz) δ 2.89 (d, 3H, J=4Hz), 4.51 (d, IH, J=Hz), 4.68 (dd, IH, J=15, 2Hz), 6.77 (d, IH, J=3Hz), 6.81 (d, IH, J=lHz), 7.06 (d, IH, 3Hz), 7.35-7.53 (m, 4H), 7.63 (dd, IH, 1=9, IHz), 7.66 (m, 3H), 8.32 (d, IH, J=9Hz), 8.53-8.63 (m, 5H). MS (DCI/ΝH3)

m/e 479 (M+H)+, 422, 298. IR (KBr) 1710, 1600, 1530, 1470. Anal calcd for C28H22N4O2S: C, 70.27; H, 4.63; N, 11.71. Found: C, 69.63; H, 4.87; N, 11.20.

Example 31 Preparation of 3-fPvridin-3-vlV7-r l-N-methvlcarbamovl-6-(4-fluorophenvnindol- 3-vlcarbonvl1-l H.3H-pvrroloπ ,2-clthiazole.

The tide compound was prepared by the procedure described in Example 2 using the compound resulting from Example 28, 3-(pyridin-3-yl)- 7-[6-(4-fluorophenyl)indol-3-ylcarbonyli-lH,3H-pyrrolo[l,2-c ]thiazole, instead of 3- (pyridin-3-yl)-7-(indol-3-yl)carbonyl- lH,3H-pyrrolo[l ,2-c]thiazole and using mediylisocyanate instead of N,N-dimethylcarbamoyl chloride. m.p. 227-228°C. Η ΝMR (DMSO-d6, 300 MHz) δ 2.89 (d, 3H, J=4Hz), 4.51 (d, IH, J=15Hz), 4.67 (dd, IH, J=15, 2Hz), 6.78 (d, IH, J=3Hz), 6.81 (d, IH, J=lHz), 7.05 (d, IH, J=3Hz), 7.32 (t, 2H, J=9Hz), 7.45 (dd, IH, J=8, 5Hz), 7.61 (dd, IH, J=9, IHz), 7.65-7.77 (m, J=3H), 8.31 (d, IH, J=8Hz),

8.50-8.63 (m, 5H). MS (DCI ΝH3) m/e 497 (M+H)+, 440. IR (KBr) 1712, 1600, 1535, 1510, 1430. Anal calcd for C28H2 ₁ N4O2SF: C, 67.73; H, 4.26; N, 11.28. Found: C, 67.05; H, 4.31; N, 10.94.

Example 32

Preparation of l-DimethvI-3-(pvridin-3-vlV7-ri-N-methvlcarbamovl- 6-(4-methoxvphenvnindol-3-vlcarhonvn-lH.3H-pvrroloπ.2-c1thi azole.

The tide compound was prepared by die procedure described in Example 2 using the compound resulting from Example 25, l,l-dimedιyl-3-(pyridin-3-yl)- 7-[6-(4-medιoxyphenyl)indol-3-ylcarbonyl]- lH,3H-pyrrolo[ 1 ,2-c]thiazole, instead of 3-(pyridin-3-yl)-7-(indol-3-yl)carbonyl-lH,3H-pyrrolo[l,2-c] dιiazole and using mediylisocyanate instead of N,N-dimethylcarbamoyl chloride. Η ΝMR (CDCI3, 300 MHz) δ 2.03 (s, 6H), 3.12 (s, 3H), 3.14 (s, 3H), 3.86 (s, 3H), 6.16 (b, IH), 6.19 (d, IH, J=3Hz), 6.51 (s, IH), 6.70 (d, IH, J=3Hz), 6.96 (d, 2H, J=9Hz), 7.49 (m, IH), 7.50-7.60 (c, 3H), 7.73 (d, IH, J=9Hz), 7.96 (s, IH), 8.06 (s, IH), 8.24 (d, IH, J=9Hz), 8.58-8.70 k 2H). MS (DCI/HΝ3) 537(M+H) ⁺ , 480.

Example 33

Preparation of 3- ⁽ l-medιylpyridin-3-vD-7-fl-N V-dimethylcarbamoyl-6-phenylindoI- 3-ylcaτbonv -lH.3H-pyrτoloπ.2-c1thiazole.

To a solution of 3-(pyridin-3-yl)-7-(l-NN-dimedιylcarbamoyl-6-phenylindol- 5 3-ylcarbonyl)-lH,3H-pyπolo[l^-c]dιiazole (lOOmg, 0.20 mmol), prepared as in Example 11, in acetone (15 mL) was added iodometiiane (19μL, 0.30 mmol) via syringe. The reaction mixture was stirred at reflux for 18 hours. The reaction mixture was cooled to ambient temperature and iodometiiane (7μL) ^" was added and die reaction mixture was warmed back to reflux and stirred for 18 hours. The reaction mixture was l o concentrated in vacuo and the residue taken up in metiianol. Crude material was precipitated by addition of edier. Pure 3-(l-Methylpyridin-3-yI)-7-(l-NN- dimethylcarbamoyl-6-phenylindol-3-yIcarbonyl)- lH,3H-pyrrolo[l ,2-c]thiazole (38 mg),.was obtained by recrystallization from medianol, ether. m.p. 171-174C. lΗ ΝMR (D3COD, 300 MHz) δ 3.17 (s, 6H), 4.44 (s, 3H), 4.57 (d, IH, J=15Hz), 4.76 5 (dd, IH, J=15, 2Hz), 6.76 (d, IH, J=3Hz), 6.87 (d, IH, J=2Hz), 6.98 (d, IH, J=3Hz), 7.35 (t, IH, J=8Hz), 7.47 (t, 2H, J=8Hz), 7.62 (dd, IH, 1=9, 2Hz), 7.65- 7.72 (m, 2H), 7.81-7.82 (m, IH), 8.10 (dd, IH, 1=6, 8Hz), 8.25 ( s, IH), 8.32 (d, IH, J=9Hz), 8.45 (d, IH, J=9Hz), 8.91 (d, IH, J=6Hz), 8.97 (s, IH). MS (FAB) m/e 507 (M+l)+. IR (KBr) 1690, 1610, 1535, 1475. Anal calcd for C30H27IΝ4O2S: 0 C, 56.79; H, 4.29; N, 8.83. Found: C, 54.50; H, 4.12; N, 8.45.

Example 34

Preparation of 3-(l-Qxide-pyridin-3-yl)-7-(l-N v ^" -dimethylcarbamoyl-6-phenylindol- 3-ylcarbonyl -lH.3H-pyrroloπ.2-c1thiazole. 5 Step 1. Preparation of 3-ri-(2.4-dinitrophenyl)pyridin-3-yl1-7-(l-N.N- dimediylcarbamoyl-6-phenylindol-3-yl)carbonyl-lH.3H-pyrrolor i.2-clthiazole.

A mixture of 3-φyridin-3-yl)-7-(l-N^-dimethylcarbamoyl-6-phenylindol-3- yl)carbonyl-lH,3H-pyrrolo[l,2-c]thiazole (500 mg, 1.01 mmol), prepared as described in Example 12, and 2,4-dimtrophenyl-/?-toluenesulfbnate (515 mg, 1.5 mmol), prepared according to die mediod described in J. Amer. Chem. Soc., 24, 5859 (1952), in acetonitrile (10 mL) was heated at 100-110°C for 23 hours. The heterogeneous reaction mixture was cooled to ambient temperature, ether (30 mL) was added, and die slurry was stirred for 10 min. The solid was filtered off and recrystallized from medianol to afford 3-[l-(2,4-dinitrophenyl)pyridin-3-yl]-7-(l-NN- dimediylcarbamoyl-6-phenylindol-3-yl)carbonyl-lH,3H-pyrrolo[ l,2-c]thiazole (608 mg) as a tan solid.

Step 2. Preparation of 3-(l-Oxide-pyridin-3-yl)-7-(l-NJV-dimethylcarbamoyl-6- phenylindol-3-ylcarbonyl)-lH.3H-pyrrolori.2-clthiazole.

To a suspension of 3-[l-(2,4-dinitrophenyl)pyridin-3-yl]-7-(l-N^V- dimemylcarbamoyl-6-phenylindol-3-yl)carbonyl-lH,3H-pynolo[l, 2-c]diiazole (250 5 mg, 0.30 mmol), prepared as in step 1, in methanol (6 ml) was added aqueous hydroxylamine (IN, 0.60 mmol) and die reaction mixture was heated at 90°C for three hours. The reaction mixture was concentrated in vacuo and triturated widi ether to give a reddish powder. Pure 3-(l-Oxide-pyridin-3-yl)-7-(l-N,N-dimeΛylcarbamoyl-6- phenylindol-3-ylcarbonyl)-lH,3H-pyrrolo[l,2-c]dιiazole was obtained by flash l o chromatography on silica gel (24: 1 CΗ2CI2, 5% aqueous medianol). IH ΝMR

(CD3OD, 300 MHz) δ 3.18 (s, 6H), 4.52 (d, IH, J = 15.0Hz), 4.68 (dd, IH, J = 1.5, 15.0Hz), 6.69 (d, IH, J = l.OHz), 6.72 (d, IH, J = 3.0Hz), 6.95 (d, IH, J = 3.0Hz), 7.34 (m, IH), 7.43-7.50(c, 3H), 7.55 (dd, IH, J = 7.0, 8.5Hz), 7.61 (dd, IH, J = 1.5, 9.0Hz), 7.69 (d, 2H, J = 8.0Hz), 7.82 (d, IH, J = l.OHz), 8.25 (s, IH), 8.28

15 (br s, IH), 8.30 (d, IH, J = 8.0Hz), 8.31 (m, IH). MS (DCI/ΝH3) 509 (M+l), 493.

Example 35

Preparation of 3-(l-Oxide-pyridin-3-yl)-7-(l-N-methylcarbamoyl-6-phenylindo l-3- ylcarbonviy lH.3H-p yrrolor 1.2-cl thiazole. 0 The tide compound is prepared by the procedure described in Example 34 using die compound resulting from Example 30, 3-(pyridin-3-yl)-7-(l-N-medιylcarbamoyl-

6-phenylindol-3-ylcarbonyl)-lH,3H-pyrrolo[l,2-c]thiazole instead of 3-(pyridin-3-yl)-

7-(l-N^V-dimethylcarbamoyl-6-phenylindol-3-yl)carbonyl- lH,3H-pyrrolo[l,2-c]thiazole. ^l Η ΝMR (CD3OD, 300 MHz) δ 3.00 (s, 3H), 4.52 (d, 5 IH, J = 15.0Hz), 4.66 (dd, IH, J = 1.5, 15.0Hz), 6.69 (d, IH, J = l.OHz), 6.73 (d,

IH, J = 3.0Hz), 7.03 (d, IH, J = 3.0Hz), 7.34 (m, IH), 7.45-7.48 (c, 3H), 7.55 (dd,

IH, J = 7.0, 9.0Hz), 7.61 (dd, IH, J = 1.5, 9.0Hz), 7.70 (d, 2H, J = 8.0Hz), 8.23

(d, IH, J = 1.5Hz), 8.29 (d, IH, J = 8.0Hz), 8.30 (dd, IH, J = 1.5, 7.0Hz), 8.49 (s,

IH), 8.50 (s, IH). MS (FA ) 495 (M+l)+ 479. 0

Example 36

Preparation of l.l-Dimethyl-3-(pyridin-3-yl)-7-r6-(4-fluorophenyl ^' )indol- 3-ylcarbonvn-lH.3H-ρyrrolon.2-c1thiazole.

The tide compound was prepared by die procedure described in Example 17 5 using 6-(4-fluorophenyl)indole, prepared as in Example 28, instead of indole. Η

ΝMR (CDCI3, 300 MHz) δ 2.05 (s, 6H), 6.18 (d, IH, J=3Hz), 6.51 (s, IH), 6.69 (d, IH, J=3Hz), 7.13 (t, 2H, J=14.9Hz), ^* 3 (m, IH), 1A ^V ;dd, IH, 1=9, 1.5Hz), 7.58

(m, 3H), 7.78 (m, IH), 7.80 (d, IH, J=3Hz), 8.42 (d, IH, J=9Hz), 8.61 (d, IH, J=1.5Hz), 8.65 (m, IH), 8.98 (bs, IH). MS (DCI/NH3) 468 (M+H)+.

Example 37 Preparation of 3-(Pyridin-3-yl)-7-(l-carbamoyl-6-phenylmethoxyindol-3-ylcar bonvD- 1 H.3H-pyrroloπ .2-clthiazole.

Step 1. Preparation of 3-(Pyridin-3-yl -7-ri-(4-nitrophenoxycarbonyl)-6- phenylmethoxyindol-3-ylcarbonvn-lH.3H-pyrrolori.2-c1thiazole .

To a solution of 3-(pyridin-3-yl)-7-(6-phenylmethoxyindol-3-yl)carbonyl- lH,3H-pyrrolo[l ,2-c] thiazole (200 mg, 0.443 mmol), prepared as in Example 4, in DMF (12 mL) was added NaΗ (60% oil dispersion, 19 mg, 0.465 mmol) and die reaction mixture was stirred for 7 min at ambient temperature. 4-nittophenyl chloroformate (94 mg, 0.45 mmol) was added and d e amber solution was stirred for two hours at ambient temperature. The reaction mixture was partitioned between Η2O and ediyl acetate. The organic phase was dried over MgSθ4, filtered, and concentrated. The tide compound (98 mg).was purified by flash chromagraphy on silica gel (60 g, 1:1 ethyl acetate, hexanes).

Step 2. Preparation of Preparation of 3-(Pyridin-3-yl ^' )-7-(l-carbamoyl-6- phenylmethoxyindol-3-ylcarbonyl)-lH.3H-pyrrolori.2-c1thiazol e.

Several drops of anhydrous ammonia were condensed into a solution of 3- (Pyridin-3-yl)-7-[l-(4-mtrophenoxycarrx)nyl)-6-phenylmedιox yindol-3-ylcarbonyl]- lH,3H-pyrrolo[l,2-c]thiazole (50 mg) in 1:1 TΗF medianol (4 mL) at -78°C. The reaction mixture was stirred for 1 hour at -78°C. The reaction mixture was warmed to ambient temperature and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel (50 g, ethyl acetate) to yield 32 mg of 3-(Pyridin-3- ylH-(l-carbamoyl-6-phenyhnethoxyindol-3-ylcarrx>nyl)-lH,3 H-pyrrolo[l^- c]thiazole. *Η NMR (DMSO-d6, 300 MHz) δ 4.48 (d, IH, J=15Hz), 4.55 (dd IH, J=15, 2Hz), 5.15 (s, 2H), 6.74 (d, IH, J=3Hz), 6.79 (d, IH, J=lHz), 7.01 (d, IH, J=3Hz), 7.04 (dd, IH, J=3, 9Hz) 7.30-7.52 (m, 6H), 7.68 (dt, IH, J=8, 2Hz), 7.89 (s, 2H), 7.98 (d, IH, J=3Hz), 8.11 (d, IH, J=9Hz), 8.41 (s, IH), 8.55-8.59 (m, 2H). MS (DCI/NH3) m/e 495 (M+H)+, 452. IR (KBr) 1710, 1600, 1540, 1480. Anal calcd for C28H22N ₄ O3S: C, 68.00; H, 4.48; N, 11.33. Found: C, 67.14; H, 4.68; N, 10.87.

Example 38

Preparation of 3-(Pyridin-3-yl)-7-r6-(4-medιoxyphenyl)indol-3-yllcarbonyl- lH.3H-pvrroloπ .2-clthiazole.

The desired compound was prepared using die procedure of example 28, except using 4-methoxybromobenzene instead of 4-fluorobromobenzene. m.ρ.246-248°C. H NMR (DMSO-d6, 300 MHz) δ 3.81 (s, 3H), 4.47 (d, IH, J=15Hz), 4.64 (dd, IH, J=15Hz, 2Hz), 6.70 (d, IH, J=3Hz), 6.77 (s, IH), 6.90 (d, IH, J=3Hz), 7.04 (d, 2H, J=2Hz), 7.41-7.48 (m, 2H), 7.61-769 (m, 4H), 8.23 (d, IH, J=2Hz), 8.29 (d, IH, J=9Hz), 8.53-8.59 (m, 2H), 11.90 (s, IH). MS (DCI NH3) m/e 452 (M+H)+. IR (KBr) 1605, 1575, 1510. Anal calcd for C27H21N3O2S: C, 71.82; H, 4.69; N, 9.31. Found: C, 70.97; H, 4.74; N, 9.06.

Example 39

Preparation of 3-(l-Oxide-pyridin-3-yl>7-ri-N_N-dimethylc.arbamoyl- 6-(4-fluorophenyl)indol-3-ylcarbonvn-lH.3H-pyrrolori.2-clthi azole.

The tide compound is prepared by die procedure described in Example 34 using the compound resulting from Example 29, 3-(pyridin-3-yl)-7-[l- N^V-dimethylcarbamoyl-6-(4-fluorophenyl)indol-3-ylcarbonyl]- lH,3H-pyrrolo[l,2-c]thiazole instead of 3-(pyridin-3-yl)-7-(l-N,N- dimemylcarbamoyl-6-phenylindol-3-yl)carbonyl-lH,3H-pyrrolo[l ,2-c]thiazole. ^l Η ΝMR (CD3OD, 300 MHz) δ 3.15 (s, 6H), 4.48 (d, IH, J=15 Hz), 4.65 (IH, J=15, 2Hz), 6.68 (d, IH, J=lHz), 6.73 (d, IH, J=3Hz), 6.95 (IH, J=4Hz), 7.2 (t, 2H, J=9Hz), 7.45 (m, IH), 7.5-7.6 (cm, 2H), 7.65-7.75 (m, 2H), 7.8 (d, IH, J=lHz), 8.23-8.33 (m, 4H). MS (FAB) m/e 527. IR (CDCI3) 1690, 1600, 1540, 1510, 1480, 1440, 1390, 1225, 1180.

Example 40 Preparation of 3-(Pyridin-3-yl>7-ri-N.N-dimethylcarbamoyl- 6-(4-methoxyphenyl)indol-3- ylcarbonyll- lH.3H-pyrroloπ .2-clthiazole.

The tide compound was prepared by die procedure described in Example 2 using the compound resulting from Example 38, 3-(pyridin-3-yl)-

7-[6-(4-methoxyphenyl)indol-3-yl]carbonyl-lH,3H-pyιτolo [l,2-c]thiazole, instead of 3-(pyridin-3-yl)-7-(indol-3-yl)carbonyl-lH,3H-pyrrolo[l,2-c] thiazole. m.p.204- 205°C. Η ΝMR (DMSO-d6, 300 MHz) δ 3.08 (s, 6H), 3.81 (s, 3H), 4.49 (d, IH, J=15Hz), 4.68 (dd, IH, J=15, 2Hz), 6.73 (d, IH, J=3Hz), 6.80 (s, IH), 6.91 (d, IH, J=3Hz), 7.05 (d, 2H, J=9Hz), 7.45 (dd, IH, J=5, 8Hz), 7.58 (dd, IH, J=l, 8Hz), 7.63-7.70 (m, 3H), 7.78 (s, IH), 8.29 (d, IH, J=9Hz), 8.33 (s, IH), 8.55- 8.59 (m, 2H). MS (DCI/ΝH3) m/e 523 (M+H) ⁺ . IR (KBr) 1690, 1605, 1540, 1520,

1480. Anal calcd for C ₂ 0H20N ₄ O ₃ S: C, 68.95; H, 5.01; N, 10.72. Found: C, 67.22; H, 5.05; N, 9.93.

Example 41 Preparation of 3-(Pyridin-3-vIV7-(6-pyrid-4-ylindol-3-ylcarbonvD- lH.3H-pyrrok>π .2-cl thiazole.

Step 1. Preparation of 6-indolylboronic acid.

To a suspension of potassium hydride (35% oil dispersion, 0.84 g, 7.33 mmol) in TΗF (10 mL) at 0°C was added a solution of 6-bromoindole (1.43 g, 7.29 mmol) in TΗF (6 mL). The reaction mixture was stirred for 15 min at 0°C, tiien cooled to -78°C and r-butyllithium solution (1.7M in pentane, 14.6 mmol) was added quickly dropwise. After stirring for 20 min. at -78°C, a solution of tri-n-butyl borate (3.94 mL, 14.6 mmol) in TΗF (4 mL) was added quickly. The reaction mixture was stirred for 1 hour at -78°C and 2 hours at 0°C. The reaction was quenched by addition of IN aqueous ΗC1 (15 mL) and stirring for 30 min at 0°C. The reaction mixture was partitioned between Η2O and edier. The aqueous phase was extracted 3 times with edier. The combined etiiereal extracts were washed 3 times widi cold IN aqueous NaOH, and then discarded. The basic aqueous extracts were acidified widi IN aqueous HC1 and extracted 3 times widi edier. The combined organic layers were dried over Na2SC»4, filtered, and concentrated in vacuo to give 6-indolylboronic acid (0.86 g) which was used witiiout further purification.

Step 2. Preparation of 6-(3-pyridinv indole.

The desired compound was prepared according to die method of Example 25, step 1, except substituting 6-indoIylboronic acid, prepared as in step 1 for 4- methoxyphenylboronic acid, and 3-bromopyridine for l-rerr-butoxycarbonyl-6- bromoindole.

Step 3. Preparation of 3-(Pyridin-3-yl)-7-(6-pyrid-3-ylindol-3-ylcarbonyl)- lH.3H-pyτroloπ .2-cl thiazole. To a suspension of 3-(pyridin-3-yl)-lH,3H-pyrrolo[l,2-c]dιiazole-7-carboxyIic acid (0.84 g, 3.43 mmol), prepared as described in United States Patent 4,529,728, in dry CΗCI3 under N2 was added NaH (60% oil dispersion, 151 mg, 3.77 mmol) in a single portion. The suspension was stirred for 30 min at ambient temperature, then 2 drops of DMF were added, followed by oxalyl chloride (0.34 mL, 3.77 mmol). The suspension was stirred for 30 min at ambient temperature.

In a separate flask, methylmagnesium bromide solution (3.0M in ether, 2.3 mL, 6.9 mmol) was added to a suspension of 6-(3-pyridinyl)indole, prepared in step 2, in

edier (35 mL). The yellow suspension was stirred for 30 min at ambient temperature, after which zinc chloride solution (1.0M in edier, 6.9 mmol) was added quickly and die suspension was stirred for a further 20 min.

The solution of acid chloride in CHCI3 was cannulated into the indolylzinc chloride suspension and the reaction mixture was stirred for 18 hours at ambient temperature. The reaction was quenched with saturated aqueous NH4CI and extracted widi THF, ethyl acetate, and again widi THF. The combined organic layers were dried over MgS04, filtered, and concentrated in vacuo. Flash chromatography on silica gel (200 g, 7% methanol, CHCI3) afforded 3-(Pyridin-3-yl)-7-(6-pyrid-3-ylindol- 3-ylcarbonyl)-lH,3H-pvrrolo[l,2-c]thiazole (116 mg). m.p.270-271°C. *Η NMR (DMSO-d6, 300 MHz) δ 4.48 (d, IH, J=15Hz), 4.65 (dd, IH, 1=2, 15Hz), 6.71 (d, IH, J=3Hz), 6.78 (d, IH, J=lHz), 6.91 (d, IH, J=3Hz), 7.45 (dd, IH, J=8, 5Hz), 7.50 (dd, IH, 1=5, 8Hz), 7.55 (dd, IH, 1=9, 2Hz), 7.66 (dt, IH, 1=9, 2Hz), 7.79 (d, IH, J=2Hz), 8.30 (s, IH), 8.37 (d, IH, J=9Hz), 8.53-8.59 (d, IH, J=9Hz), 8.53- 8.59 (m, 3H), 8.94 (d, IH, J=2Hz). MS (DCI/NH3) m/e 423 (M+H)+, 223, 195. IR (KBr) 3180, 1585, 1575, 1540. Anal calcd for C25H18N ₄ OS: C, 71.07; H, 4.29; N, 13.26. Found: C, 70.14; H, 4.28; N, 12.93.

Example 42 Preparation of 3-(Pyridin-3-ylV7-(l-NJv ^" -dimethylcarbamoyl-6-pyrid-4-ylindol- 3-ylcarbonyl)-lH.3H-pyrrolori.2-c1thiazole.

The tide compound was prepared by the procedure described in Example 2 using the compound resulting from Example 41, 3-(pyridin-3-yl)-7-(6-pyrid-4-ylindol- 3-ylcarbonyl)-lH,3H-pyrrolo[l,2-c]dιiazole, instead of 3-(pyridin-3-yl)-7-(indol-3- yl)carbonyl-lH,3H-pyrrolo[ -c]thiazole. Η ΝMR (DMSO-d6, 300 MHz) δ 3.09 (s, 6H), 4.50 (d, IH, J=15Hz), 4.68 (dd, IH, J=2, 15Hz), 6.74 (d, IH, J=3Hz), 6.80 (d, IH, J=lHz), 6.92 (d, IH, J=3Hz), 7.45 (dd, IH, J=5, 8Hz), 7.51 (dd, IH, J=5, 8Hz), 7.65-7.71 (m, 2H), 7.90 (d, IH, J=lHz), 8.14 (dt, IH, 1=2, 8Hz), 8.36 (d, IH, J=8Hz), 8.40 (s, IH), 8.56-8.61 (m, 3H), 8.95 (d, IH, J=2Hz). MS (DCI/ΝH3) m/e 494 (M+H)+, 387, 337. IR (KBr) 2920, 1690, 1602, 1530, 1480. Anal calcd for C28H23N5O2S: C, 68.14; H, 4.70; N, 14.19. Found: C, 67.27; H, 4.75; N, 14.06.

Example 43

Preparation of 3- ⁽ Pyridin-3-v -7-ri-N-methylcarbamoyl-6-(4-methoxyphenyl)indol- 3-ylcarbonvn-lH.3H-pyrroloπ.2-cTthiazole.

The tide compound was prepared by die procedure described in Example 2 using the compound resulting from Example 38, 3-(pyridin-3-yl

7-[6-(4-methoxyphenyl)indol-3-yl]carbonyl-lH,3H-pyrτolo[ l,2-c]thiazole, instead of 3-(pyridin-3-yl)-7-(indol-3-yl)carbonyl-lH,3H-pyrrolo[l,2-c] thiazole and using mediylisocyanate instead of N,N-dimethylcarbamoyl chloride. m.p.251°C. lΗ ΝMR (DMSO-d6, 300 MHz) δ 2.89 (d, 3H, J=5Hz), 3.81 (s, 3H), 4.51 (d, IH, J=15Hz), 4.68 (dd, IH, 1=2, 15Hz), 6.78 (d, IH, J=3Hz), 6.81 (d, IH, J=lHz), 7.03-7.08 (m, 3H), 7.45 (dd, IH, J=5, 8Hz), 7.59 (dd, IH, J=l, 9Hz), 7.61-7.71 (m, 3H), 8.28 (d, IH, J=9Hz), 8.48-8.52 (m, 2H),

8.56-8.62 (m, 3H). MS (DCI/ΝH3) m/e 509 (M+H)+, 452. IR (KBr) 1705, 1605, 1530, 1515, 1475. Anal calcd for C29H2 ₄ N4O3S: C, 68.49; H, 4.76; N, 11.02. Found: C, 67.56; H, 4.96; N, 10.58.

Example 44

Preparation of 3-(l-Oxide-pyridin-3-v -7-(l-N V-dimethylcarbamoylindol- 3-ylcarbonyl)-lH.3H-pyπOlon.2-clthiazoIe. The tide compound was prepared by the procedure described in Example 34 using the compound resulting from Example 2, 3-(pyridin-3-yl)-7-(l-NN- dimethylcarbamoylindol-3-yl)carbonyl-lH,3H-pyπ'olo[l,2-c]th iazole instead of 3-(pyridin-3-yl)-7-(l-N^-dimethylcarbamoyl-6-phenylindol-3-y l)carbonyl- lH,3H-pyrrolo[l,2-c]thiazole. ^l Η ΝMR (DMSO-d6, 300 MHz) δ 3.05 (s, 6H), 4.46 ( d, IH, J=15Hz), 4.65 (dd, IH, 1=2, 15Hz), 6.70 (d, IH, J=2Hz), 6.86 (d, IH, J=3Hz), 6.91 (d, IH, J=3Hz), 7.13 (d, IH, J=8Hz), 7.28-7.47 (m, 3H) 7.62 (d, IH, J=8Hz), 8.18-8.28 (m, 3H), 8.33 (s, IH). IR (KBr) 2920, 1690, 1600, 1535, 1480.

Example 45 Preparation of 3-(l-Oxide-pyridin-3-yl)-7-ri-NN-dimethylcarbamoyl- 6- 4-methoxyphenyl indoI-3-ylcarbonvn-lH.3H-pyrroloπ.2-c1thiazole.

The tide compound was prepared by die procedure described in Example 34 using the compound resulting from Example 40, 3-(pyridin-3-yl)-7-[l-NN- dimethylcarbamoyl-6-(4-methoxyphenyl)indol-3-ylcarbonyl]- lH,3H-pyrrolo[l,2-c]dιiazole instead of 3-(pyridin-3-yl)-7-(l-N,N- dimethylcarbamoyl-6-phenylindol-3-yl)carbonyl-lH,3H-pyrrolo[ l,2-c]thiazole. lΗ ΝMR (DMSO-d6, 300 MHz) δ 3.09 (s, 6H), 3.81 (s, 3H), 4.47 (d, IH, J=15Hz),

4.67 (dd, IH, 1=2, 15Hz), 6.71 (d, IH, J=lHz), 6.87 (d, IH, J=3Hz), 6.94 (d, IH, J=3Hz), 7.05 (d, 2H, J=9Hz), 7.15 (d, IH, J=8Hz), 7.40-7.46 (m, IH), 7.59 (dd, IH, 1=2, 9Hz), 7.63-7.70 (m, 2H), 7.78 (d, IH, J=lHz), 8.19-8.22 (m, 2H), 8.29 (d, IH, J=9Hz), 8.34 (s, IH). MS (DCI/NH3) m/e 523 (M+H)+, 539.

Example 46 Preparation of 3-(Pyridin-3-yl)-7-ri-( ^' 2-carbomethoxyethyl)-6-(4-fluorophenyl indol- 3-ylcarbonvn- lH.3H-pyrroloπ ,2-clthiazole.

Sodium hydride (95%, 37.4 mg, 1.48 mmol) was added to a solution of 3- (pyridin-3-yl)-7-[6-(4-fluorophenyl)indol-3-ylcarbonyl]-lH,3 H-pyrrolo[l,2-c]dιiazole (0.50 g, 1.14 mmol), prepared according to die mediod of Example 28, in DMF (30 mL). The reaction mixture was stirred for 30 min. at ambient temperature, and then mediyl acrylate (0.40 mL, 4.56 mmol) was added. The reaction mixure was poured into brine and extracted tiiree times with ethyl acetate. The combined organic layers were dried over MgS04, filtered, and concentrated in vacuo. 3-(Pyridin-3-yl)-7-[ l-(2- carbomethoxyedιyl)-6-(4-fluorophenyl)indol-3-ylcarbonyl]- lH,3H-pyrrolo[l,2-c]thiazole (190 mg, 32%) was obtained by flash chromatography on silica gel (5g, 40%, then 60%, tiien 80% ethyl acetate, hexanes). !Η NMR (CDCI3, 300 MHz) δ 2.93 (t, 2H, J=6, 8Hz), 3.68 (s, 3H), 4.53 (dd, 3H, 1=6, 11Hz), 4.7 (dd, IH, 1=2, 15Hz), 6.38 (d, IH, J=3Hz), 6.43 (s, IH), 6.78 (d, IH, J=3Hz), 7.15 (t, 2H, J=9, 10Hz), 7.35 (dd, IH, J=5, 8Hz), 7.5 (dd, 2H, J=3, 10Hz), 7.6-7.1 (m, 3H), 7.95 (s, IH), 8.45 (dd, IH, J=l, 9Hz), 8.6-8.68 (m, 2H). MS (DCI/NH3) m/e 526 (M+H)+.

Example 47 Preparation of 3-(Pyridin-3-yl)-7-(6-chloroindol-3-ylcarbonyl)- lH.3H-pyrrolori.2-c1thiazole.

The desired compound was prepared by the procedure of Example 28, using 6- chloroindole instead 6-phenylindole. m.p. 263-265°C. -H NMR (DMSO-d6, 300 MHz) δ 4.45 (d, IH, J=15Hz), 4.62 (dd, IH, 1=2, 15Hz), 6.70 (d, IH, J=3Hz), 6.77 (s, IH), 6.89 (d, IH, J=3Hz), 7.20 (dd, IH, 1=2, 9Hz), 7.43 (dd, IH, J=5, 7Hz), 7.52 (d, IH, J=2Hz), 7.65 (dt, IH, 1=1, 8Hz), 8.25 (d, IH, J=9Hz), 8.28 (d, IH, J=2Hz), 8.53-8.58 ( m, 2H), 11.98 (s, IH). MS (DCI/NH3) m/e 380 (M+H)+, 350. Anal calcd for C20H14CIN3OS: C, 63.24; H, 3.71; N, 11.06. Found: C, 61.98; H, 2.89; N, 10.73.

Example 48

Preparation of 3-(Pyridin-3-yl -7-ri-N V-dimethylcarbamoyl-6-(3.4.5- trimethoxyphenyl)indol-3-ylcarbonvn-lH.3H-pyrrolon.2-c1thiaz ole.

The tide compound was prepared by the method of Example 2, using 3- (pyridin-3-yl)-7-[6-(3,4,5-trimethoxyphenyl)indol-3-ylcarbon yl]-lH,3H-pyτrolo- [l,2-c]thiazole, prepared according to the metiiods of Example 28, except using 3,4,5- trimethoxybromobenzene instead of 4-fluorobromobenzene, instead of 3-(pyridin-3- yl)-7-(indol-3-yl)carbonyl-lH,3H-pyrrolo[l,2-c]thiazole. m.p. 194-196°C. ^X Η ΝMR (DMSO-d6, 300 MHz) δ 3.09 (s, 6H), 3.71 (s, 3H), 3.89 (s, 6H), 4.50 (d, IH, J=15Hz), 4.68 (dd, IH, 1=2, 15Hz), 6.74 (d, IH, J=3Hz), 6.80 (s, IH), 6.91-6.95 (m, 3H), 7.45 (dd, IH, J=5, 8Hz), 7.62 (dd, IH, J=l, 9Hz), 7.68 (dt, IH, J=l, 9Hz), 7.82 (s, IH), 8.30 (d, IH, J=8Hz), 8.36 (s, IH), 8.55-8.60 (m, 2H). MS (DCI/ΝH3) m/e 583 (M+H)+, 461, 387. IR (KBr) 2940, 1690, 1605, 1580, 1535. Anal calcd for C32H3 ₀ N ₄ O5S: C, 65.96; H, 5.19; N, 6.92. Found: C, 64.28; H, 4.06; N, 9.26.

Example 49 Preparation of 3-(Pyridin-3-yl)-7-ri-(2-carboxyethyl)-6-(4-fluorophenyl)ind ol- 3-ylcarbonvn- lH.3H-pyrroloπ .2-clthiazole.

Step 1. Preparation of 3-(pyridin-3-v -7-ri-f2-carboethoxyethyl)- 6-(4-fluorophenyl indol-3-ylcarbonvn- lH.3H-pyrrolof ^" l .2-clthiazole.

The desired compound was prepared according to die mediod of Example 46, except substituting ediyl acrylate for methyl acrylate.

Step 2. Preparation of 3-(Pyridin-3-yl)-7-ri-(2-carboxyethyl ^' )-6-r4-fluorophenyl ndol- 3-ylcarbonyll-lH.3H-pyrroloπ.2-c1thiazole.

A mixture of 3-(pyridin-3-yl)-7-[l-(2-carboethoxyedιyl)- 6-(4-fluorophenyl)indol-3-ylcarbonyl]-lH,3H-pyrrolo[l,2-c]th iazole (90 mg, 0.17 mmol), and lithium hydroxide (11 mg), were stirred in 33% aqueous TΗF (15 mL) for 45 min. The reaction mixture was diluted widi Η2O and taken to pH 4 widi 1M aqueous HC1. The reaction mixture was extracted tiiree times with ediyl acetate. The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. 3-(Pyridin-3-yl)-7-[l-(2-carboxyethyl)-6-(4-fluorophenyl)ind ol-3-ylcarbonyl]- lH,3H-pyrrolo[l,2-c]thiazole (63 mg), was crystallized from ethyl acetate, hexanes. Η NMR (CDCI3, 300MHz) δ 2.95 (t, 2H, 1=6, 7Hz), 4.5-4.65 (m, 4H), 6.14 (d, IH, J=3Hz), 6.45 (s, IH), 6.73 (d, IH, J=3Hz), 7.15 (t, 2H, 1=9, 11Hz), 7.38-7.43 (m, IH), 7.52 (d, 2H, J=8Hz), 7.6-7.7 (m, 3H), 8.05 (s, IH), 8.46 (d, IH, J=9Hz),

8.57 (bs, 2H). MS (DCI/NH3) m/e 512 (M+H) ⁺ . Anal calcd for C29H22N3O3SF: C, 68.09; H, 4.33; N, 8.21. Found: C, 67.78; H, 3.90; N, 8.06.

Example 50 Preparation of 3-(Pvridin-3-vn-7-π -( 2-sulf.Mivlethvtt-6-f4-fluorophenvninrio1-

3-vlcarbonvll-lH.3H-pvπOloπ.2-c1thiazole.

The tide compound was prepared by die procedure described in Example 46 using vinylsulfonamide instead of methyl acrylate. ^! Η NMR (DMSO-d6, 300 MHz) δ

3.6 (t, 2H, 1=7, 9Hz), 4.48 (d, IH, J=15Hz), 4.65 (d, IH, J=15Hz), 4.77 (t, 2H, J=6, 8Hz), 6.73 (d, IH, J=3Hz), 6.78 (s, IH), 6.95 (d, IH, J=3Hz), 7.13 (s, 2H),

7.33 (t, 2H, 1=9, 10Hz), 7.45 (dd, IH, J=5, 9Hz), 7.54 (d, IH, J=9Hz), 7.67 (d,

IH, J=8Hz),

7.8-7.88 (m, 3H), 8.32 (d, IH, J=9Hz), 8.39 (s, IH), 8.55-8.6 (m, 2H). MS

(DCI/NH3) m/e 547 (M+H) ⁺ . Anal calcd for C28H23N4O3S2F: C, 61.52; H, 4.24; N, 10.25. Found: C, 60.82; H, 3.95; N, 9.95.

Example 51

Preparation of 3-rPvridin-3-vlV7-π -methanesulfonvl-6-(-4-fluorophenvl)indol- 3-vlcarbonvn-lH3H-ρvrτolori.2-c1thiazole.

The desired compound was prepared according to the mediod of Example 29, except substituting medianesulfonyl chloride for N^V-dimethylcarbamoyl chloride. H ΝMR (DMSO -d6) δ 3.76 (s,3H), 4.48 (d, IH, J =15Hz), 4.66 (dd, IH, J =15, 1.5Hz), 6.78 (d, IH, J =3Hz), 6.82 (bs, IH), 6.9 (d, IH, J =3Hz), 7.35 (t, 2H, J =9Hz), 7.45 (dd, IH, J =4.5, 6Hz), 7.65-7.74 (cm, 2H), 7.82 (dd, 2H, J =6, 3Hz), 8.08 (bs, IH), 8.2 (s, IH), 8.3 (d, IH, J =9Hz), 8.55-9.0 (cm, 2H). MS (DCI/ΝH3) m/e 517 (M+H)+ 440. Anal calcd for C27H20FN3O3S2 O.75H2O: C, 51.06; H, 4.08; N, 7.91. Found: C, 51.14; H, 3.69; N, 7.62.

Example 52 Preparation of 3-fPvridin-3-vlV7-f l-N_N-dimethvlcarbamovl-6-phenvlindol- - vlcarbonvlV lH.3H-ρvrroloπ .2-cl thiazole Hvdrochloride.

A solution of 3-(pyridin-3-yl)-7-(l-N,N-dimemylcarbamoyl-6-phenylindol-3- yl)carbonyl-lH,3H-pyrrolo[l,2-c]thiazole, prepared as in Example 12, was tteated at ambient temperature with excess 4Ν ΗC1 in dioxane. After stirring for two hours, 3-(Pyridin-3-yl)-7-(l-N^V-dimedιylcarbamoyl-6-phenylindol-3 -ylcarbonyl)- lH,3H-pyπolo[l,2-c]thiazole Ηydrochloride was isolated by filtration. Η ΝMR

(CD3OD, 300 MHz) δ 3.17 (s, 6H), 4.55 (d, IH, J = 15.0Hz), 4.72 (dd, IH, J = 15.0, l.OHz), 6.72 (d, IH, J = 3.0Hz), 6.89 (d, IH, J = l.OHz), 6.98 (d, IH, J = 3.0Hz), 7.36 (t, IH, J = 7.5Hz), 7.46 (t, 2H, J = 7.5Hz), 7.61 (dd, IH, J = 9.0, l.OHz), 7.69 (d, 2H, J = 8.0Hz), 7.81 (bs, IH), 8.09 (dd, IH, J = 9.0, 6.0Hz), 8.24 (s, IH), 8.31 (d, IH, J = 9.0Hz), 8.49 (dt, IH, J = 8.5, l.OHz), 8.84 (bs, IH), 8.85 (m, IH). IR (KBr) 3450, 1695, 1540, 1390. Anal calcd for C29H25CIN4O2S: C, 65.84; H, 4.76; N, 10.59. Found: C, 65.96; H, 4.91; N, 10.48.

Example 53 Preparation of 3-(Pyridin-3-yl)-7-ri-(2-N v ^* -dimethylcarbamoyImethyl)- 6-(4-fluorophenyl)indol-3-ylcarbonyl1-lH.3H-pyrrolori.2-c1th iazole.

The desired compound was prepared according to d e mediod of Example 46, except substituting N dimethylchloroacetamide for methyl acrylate. Η ΝMR (DMSO-d6, 300 MHz) δ 2.88 (s, 3H), 3.15 (s, 3H), 4.48 (d, IH, J=15 Hz), 4.65 (dd, IH, J=15, 2 Hz), 5,37 (s, 2H), 6.72 (d, IH, 1=3 Hz), 6.78 (bs, IH), 6.85 (d, IH, 1=3 Hz), 7.31 (t, 2H, J=12 Hz), 7.44 (cm, 2H), 7.52 (dd, 2H, J=12, 2Hz), 7.66 (cm, IH), 7.78 (cm, 3H), 8.25 (s, IH), 8.32 (d, IH, J=12 Hz), 8.57 (cm, 2H). MS (DCI/ΝH3) m/e 525 (M+H)+, 542 (M+ NH4) ⁴ -. IR (KBr) 1600(s), 1660(s). Anal calcd for C30H25N ₄ O2SF: C, 68.69; H, 4.80; N, 10.68. Found: C, 68.20; H, 4.63; N, 10.68.

Example 54 Preparation of 3-ri-Oxide-pyridin-3-ylV7-(l-N V-dimedιylcarbamoyl-6-phenylindol- 3-ylcarbonvD- lH.3H-pyrroloπ .2-clthiazole hvdrochloride.

The tide compound was prepared by die procedure described in Example 52 using the compound resulting from Example 34, 3-(l-oxide-pyridin-3-yl)-7-(l-NN- dimedιylcarbamoyl-6-phenylindol-3-ylcarrx)nyl)-lH,3H-pyrrol o[l^-c]dιiazole instead of 3-φyridin-3-yl)-7-(l-N V-dimethylcarbamoyl-6-phenylindol-3-yIcarbonyl)- lH,3H-pyrrolo[l,2-c]thiazole. m.p. 122-130°C. 1Η ΝMR (CD3OD, 300 MHz) δ 3.16 (s, 6H), 4.53 (d, IH, J = 15.0Hz), 4.69 (d, IH, J = 15.0Hz), 6.73 (s, IH, J = 3.0Hz), 6.74 (bs, IH), 6.97 (d, IH, J = 3.0Hz), 7.33 (t, IH, J = 7.5Hz), 7.45 (t, 2H, J = 7.5Hz), 7.62 (dd, IH, J = 9.0, l.OHz), 7.68 (d, 2H, J = 7.5Hz), 7.81 (m, 2H), 8.23 (s, IH), 8.31 (d, IH, J = 9.0Hz), 8.58 (bs, IH), 8.60 (m, IH). IR (KBr) 3410, 1695, 1535, 1395.

Example 55

Preparation of 3-(Pyridin-3-yl ⁾ -7-ri-NJV-dimedιylsulfamyl-6-(4-fluorophenyl)indol- 3-ylcarbonvn-lH.3H-pyrrolori.2-c1thiazole.

The tide compound was prepared by the procedure described in Example 51, using N^V-dimediylaminosulfonylchloride instead of methanesulfonylchloride. m.p. 100°C. ^l Η ΝMR (DMSO-d6, 300 MHz) δ 3.35 (s, 6H), 4.48 (d, IH, J=15Hz), 4.67 (d, IH, J=15Hz), 6.75-6.77 (m, IH), 6.82 (d, 2H, J=3Hz), 7.35 (t, 2H, J=9Hz), 7.42-7.46 (dd, IH, J=4.5,J =3Hz), 7.65-7.73 (cm, 2H), 7.75 (dd, 2H, 1=6, 3Hz), 8.08 (m, IH), 8.22 (s, IH), 8.3 (d, IH, J=9Hz), 8.58 (m, 2H). MS (FAB) m/e 546 (M+l), 563. Anal calcd for C28H23FΝ4O3S2O.75H2O: C, 60.04; H, 4.41; N, 10.00. Found: C, 60.84; H, 4.75; N, 9.66.

Example 56

Preparation of 3-flPyridin-3-vD-7-r 1 -NN-dimethylcarbamoyl-6-(3-aminophenyl)indol- 3-ylcarbonvn-lH.3H-pyrrolori.2-clthiazole.

To a solution of 3-(pyridin-3-yl)-7-(6-bromoindol-3-ylcarbonyl)- lH,3H-pyrrolo[l,2-c]thiazole (370 mg, 0.75 mmol), prepared as in Example 64, in DME (15 mL), was added a solution of 3-aminophenylboronic acid (182 mg, 1.2 mmol). The reaction mixture was warmed to reflux, diluted with DME (15 mL), and stirred at reflux for 17 hours. The reaction mixture was cooled to ambient termperature and partitioned between saturated aqueous ΝaΗC03 and ediyl acetate. The aqueous phase was extracted twice widi ethyl acetate, then once widi 3% methanol, methylene chloride. The combined organic layers were dried over MgSθ ₄ , filtered, and concentrated in vacuo. Purification by chromatography on silica gel (3% methanol, methylene chloride) gave 3-(pyridin-3-yl)-7-( l-N^V-dimethylcarbamoyl-6-(3- arm^ophenyl)indol-3-ylcarbonyl)-lH,3H-pyrrolo[l,2-c]thiazole as a pale-yellow foam. m.p. 86-88°C. Η ΝMR (DMSO-d6, 300 MHz) δ 8.57 (m, 2H), 8.28 (d, IH, 1= 8.1Hz), 7.77 (m, IH), 7.68 (m, IH), 7.60 (m, 6H), 7.56 (m, IH), 6.91 (d, IH, J= 3.0Hz), 6.79 (bds, IH), 6.73 (d, IH, J= 3.3Hz), 5.19 (bds, 2H), 4.67 (dd, IH, J= 2.2, 14.7Hz), 4.49 (d, IH, J= 14.7Hz), 3.08 (s, 6H). MS (DCI/ΝH3) m/e 508

(M+H)+ (75), 182 (100). Anal calcd for C29H25N5O2S: C, 68.62; H, 4.96; N, 13.80. Found: C, 67.20; H, 4.88; N, 11.08.

Example 57

Preparation of 3-(T^din-3-vD-7-ri-(2-fgrt-butoxycaτtx)nylaminoethyl'.- 6-(4-fluorophenyl ^' )indol-3-ylcarbonyll-lH.3H-pyrroIori.2-c1thiazole. Step 1. N-fgrr-butoxycarbonylazide. The desired compound was prepared according to die mediod of Example 9, except substituting aziridine for 3-(Pyridin-3-yl)-7-(indol-3-yl)carbonyl-lH,3H- pyrrolo[l ,2-c]thiazole

Step 2. 3-(Pyridin-3-yl)-7-ri-(2-rβrr-butoxycarbonylaιninoedιyl)- 6-(4-fluorophenvDindol-3-ylcarbonyll-lH.3H-pyrroloπ.2-c1thi azole.

The desired compound was prepared according to die mediod of Example 46, except substituting N-r -butoxycarbonylaziridine, prepared in step 1 for methyl acrylate. ^l Η ΝMR (CDC1 ₃ , 300 MHz) δ 1.5-1.7 (bs, 2H), 3.25 (t, 2H, 1=6, 8Hz), 4.3 (t, 2H, 1=6, 7Hz), 4.56 (d, IH, J=15Hz), 4.70 (dd, IH, J=15, 3Hz), 6.35 (d, IH, J=3Hz), 6.42 (s, IH), 6.78 (d, IH, J=3Hz), 7.15 (t, 2H, 1=9, 12Hz), 7.35 (dd, lh, 1=5, 9Hz), 7.5 (m, 2H), 7.62 (dd, 3H, 1=7, 9Hz), 7.93 (s, IH), 8.45 (d, IH, J=9Hz), 8.6 (d, IH, J=3Hz) 8.65 ( dd, IH, 1=3, 5Hz). MS (DCI/ΝH3) m/e 483 (M+H)+. Anal calcd for C ₂ 8H23N ₄ OSF: C, 69.69; H, 4.80; N, 11.61. Found: C, 69.41; H, 4.55; N, 11.46. Example 58

Preparation of 3-(l -Oxide-pyridin-3-yl)-7-f l-methvI-6-phenylmethoxyindol-3- ylc.ffbonylVlH.3H-pyrrolori.2-clthiazole.

The tide compound was prepared by die procedure described in Example 34 using the compound resulting from Example 21, 3-(pyridin-3-yl)-7-(l-methyl- 6-phenylmedιoxyindol-3-ylcarbonyl)- lH,3H-pyrrolo[l,2-c]thiazole instead of 3-(pyridin-3-yl)-7-(l-N V-dimemylcarbamoyl-6-phenylindol-3-yl)carbonyl- lH,3H-pyπrolo[l,2-c]thiazole. m.p.98-100°C. lΗ ΝMR (DMSO-d6, 300 MHz) δ 8.22 (m, IH), 8.18 (bds, IH), 8.16 (m, IH), 8.13 (s, IH), 7.51 (m, 2H), 7.41 (m, 3H), 7.36 (m, IH), 7.20 (d, IH, 1= 2Hz), 7.12 (bdd, IH, J= 7.2Hz), 6.94 (dd, IH, J= 2.8, 6.9Hz), 6.92 (d, IH, J= 3.0Hz), 6.92 (d, IH, J= 3.0Hz), 6.67 (bds, IH), 5.18 (s, 2H), 4.62 (bdd, IH, 1= 15.1Hz), 4.43 (d, IH, J= 15.1Hz), 3.85 (s, 3H). MS (DCI/ΝH3) m/e 499(M+NH4)+ (30), 482 (M+H)+ (50), 466 (100).

Example 59

Preparation of 3-fPyridin-3-yl ^' .-7-ri-(2-aminoethyl)-6-(4-fluorophenyl)indol- 3-ylcarbonvn-lH.3H-pyrrolori.2-c1thiazole.

A solution of 3-(pyridin-3-yl)-7-[l-(2-rerf-butoxycarbonylaminoethyl)- 6-(4-fluorophenyl)indol-3-ylcarbonyl]-lH,3H-pyrrolo[l,2-c]th iazole (104 mg), prepared as in Example 57, in CΗ2CI2 at 0°C was treated with 4N HCl/dioxane (1 mL). The reaction mixture was stirred for 15 min at 0°C and men concentrated in vacuo. The resulting solid was azeotroped diree times widi CH2CI2 to give 3-(Pyridin-3-yl)-7-[l- (2-aminoethyl)-6-(4-fluorophenyl)indol-3-ylcarbonyl]-lH,3H-p yrτolo[l,2-c]thiazole hydrochloride (115 mg). ^l Η NMR (D3COD, 300 MHz) δ 3.48-3.60 (m, 3H), 3.64-

3.75 (m, 4H), 4.53 (d, IH, J=15Hz) 4.68-4.77 (m, 3H), 6.76 (d, IH, J=3Hz), 6.9 (d, IH, J=1.5Hz), 7.55 (dd, IH, J=1.5, 9Hz), 7.75 (dd, 2H, 1=6, 8Hz), 7.83 (s, IH), 8.13 (dd, IH, 1=6, 8Hz), 8.30 (s, IH), 8.35 (d, IH, J=9Hz), 8.49 (d, IH, J=9Hz), 8.87 (d, 2H, J=7Hz). MS (DCI/NH3) m/e 483 (M+H)+.

Example 60

Preparation of 3-d-Oxide-pyridin-3-yl)-7-ri-N v ^" -dimethylsulfamyl- 6-(4-fluorophenyl indol-3-ylcarbonvn-lH.3H-pyπOlori.2-c1thiazole.

The tide compound was prepared by die procedure described in Example 34 using the compound resulting from Example 55, d_methylsulfamyl-6-(4-fluorophenyl)indol-3-ylcarbonyl]-lH,3H -pyrrolo[l,2-c]thiazole instead of 3-(pyridin-3-yl)-7-(l-N^V-dimedιylcarbamoyl-6-phenylindol-3 -yl)carbonyl- lH,3H-pyrrolo[l,2-c]thiazole. m.p. 118°C. Η ΝMR (CDCI3, 300 MHz) δ 2.95 (s,6H), 4.57 (d, IH, J =15Hz), 4.67 (dd, IH, J=12, 3Hz), 6.34 (s, IH), 6.48 (d, IH, J=3Hz), 6.82 (d, IH, J=3Hz), 7.13-7.2 (m, 3H), 7.26 (s, IH), 7.32 (t, IH, J=6Hz), 7.58-7.64 (cm, 3H), 8.11 (d, 2H, J=4.5Hz), 8.19 (d, IH, J=6Hz), 8.37 (d, IH, J=9Hz). MS (DCI/ΝH3) m/e 562 (M+H)+, 547.

Example 61 Preparation of 3-(Pyridin-3-yl)-7-r 1 -phenylsulfonyl-6-(4-fluorophenyl)indol-

3-ylcarbonyll-lH.3H-pyπOloπ.2-c1thiazole.

The tide compound was prepared by die procedure described in Example 51, using phenylsulfonylchloride instead of metiiane sulfonyl chloride. m.p. 115-116°C. H NMR (CDCI3, 300 MHz) δ 4.55 (d, IH, J=12Hz), 4.67 (dd, IH, J=12, 1.5Hz), 6.42 (d, IH, J=3Hz), 6.46 (s, IH), 6.8 (m, IH), 7.13-7.2 (cm, IH), 7.25 (s, IH),

7.38 (dd, IH, J=4.5, 0.75Hz), 8.14 (s, IH), 8.2 (m, IH), 8.28 (d, IH, J=9Hz), 8.62

(s, IH), 8.66 (d, IH, J=3Hz). MS (FAB) m/e 508 (M+H) ⁺ , 307. Anal calcd for

C32H22FN3O3S2O.25H2O: C, 65.79; H, 3.88; N, 7.19. Found: C, 65.68; H, 3.93; N, 6.81.

Example 62 Preparation of 3-fPvridin-3-vlV7-ri-N-f2-hvdroxvethvncarbamovl- 6-f4-fluoro henvDindol-3-vlcarbonvn- lH.3H-pvrroloπ .2-cl thiazole.

The desired compound was prepared according to die mediod of Example 37 except substituting 3-φyridin-3-yl)-7-[6-(4-fluorophenyl)indol-3-ylcarbonyl]- lH,3H-pyrrolo[l,2-c]thiazole, prepared as in Example 28, for 3-(Pyridin-3-yl)-7-(6- phenylmethoxyindol-3-yl)carbonyl-lH,3H-pyrrolo[l^-c]thiazole , and substituting edianolamine for ammonia. ^l Η ΝMR (DMSO-d6, 300 MHz) δ 3.32-3.42 (m, 2H), 3.60 (q, 2H, J=6Hz), 4.51 (d, IH, J=15Hz), 4.68 (dd, IH, 1=2, 15Hz), 4.88 (t, IH, J=6Hz), 6.79 (d, IH, J=3Hz), 6.81 (d, IH, J=lHz), 7.09 (d, IH, J=3Hz), 7.32 (t, 2H, J=9Hz), 7.45 (dd, IH, J=5, 8Hz), 7.61 (dd, IH, J=l, 8Hz), 7.69 (dt, IH, J=l, 8Hz), 7.71-7.76 (m, 2H), 8.32 (d, IH, J=8Hz), 8.51 (d, IH, J=lHz), 8.56-8.61 (m, 3H), 8.47 (t, IH, J=6Hz). MS (FAB) m/e 527 (M+H)+ 440. IR (KBr) 1701, 1601, 1530, 1510, 1475. Anal calcd for C29H23FΝ4O3S: C, 66.15; H, 4.40; N, 10.64. Found: C, 64.93; H, 4.14; N, 10.00.

Example 63 lH,3H-pyττQiQri ,2-clthiazQle.

The tide compound was prepared by the procedure described in Example 1, using 6-bromoindole instead of indole. m.p. 265°C. ^J H NMR (DMSO-d6, 300 MHz) δ 4.45 (d, IH, J=15Hz), 4.52 (dd, IH, J=l, 15Hz), 6.70 (d, IH, J=3Hz), 6.77 (s, IH), 6.89 (d, IH, J=3Hz), 7.31 (dd, IH, J=l, 9Hz), 7.43 (dd, IH, J=5, 8Hz), 7.61- 7.69 (m, 2H), 8.20 (d, IH, J=9Hz), 8.27 (d, IH, J=3Hz), 8.53-8.59 (m, 2H), 11.98 (s, IH). MS (DCI/NH3) m/e 443 (M+NH4) ⁺ , 441 (M+NH4) ⁺ , 426 (M+H)+, 424 (M+H) ⁺ , 394. ffi. (KBr) 1582, 1560, 1530, 1510, 1480. Anal calcd for C2θHi4BrN ₃ OS: C, 56.61; H, 3.33; N, 9.90. Found: C, 55.82; H, 3.25; N, 9.54.

Example 64

Preparation of 3-rPyridin-3-ylV7-π-N_N-dimethylcarbamoyl-6-bromoindol- 3-vlc__rbonvn-lH.3H-pvrrolorL2-clthiazole.

The tide compound was prepared by the procedure described in Example 2 using the compound resulting from Example 63, 3-(pyridin-3-yl)-7-(6-bromoindol- 3-ylcarbonyl)-lH,3H-pyrrolo[l,2-c]thiazole, instead of 3-(pyridin-3-yl)-7-(indol-3-

yl)carbonyl-lH,3H-pyrrolo[l,2-c]thiazole and using mediylisocyanate instead of N,N- dimethylcarbamoyl chloride. m.p. 199-201°C. ^X Η ΝMR (DMSO-d6, 300 MHz) δ 3.05 (s, 6H), 4.48 (d, IH, J=15Hz), 4.55 (dd, IH, J=2, 15Hz), 6.73 (d, IH, J=3Hz), 6.79 (d, IH, J=lHz), 6.90 (d, IH, J=3Hz), 7.40-7.50 (m, 2H), 7.68 (dt, IH, 1=2, 8Hz), 7.82 (d, IH, J=lHz), 8.19 (d, IH, J=9Hz), 8.37 (s, IH), 8.55-8.59 (m, 2H). MS (DCVΝH3) m/e 497 (M+H)+, 495 (M+H) ⁺ . IR (KBr) 3100, 2920, 1680, 1590, 1530. Anal calcd for C23Hι ₉ BrN ₄ θ2S: C, 55.76; H, 3.87; N, 11.31. Found: C, 55.63; H, 3.59; N, 11.06.

Example 65

Preparation of 3-(Pyridin-3-yl)-7-(l-NJV-dimethylcarbamoyl-6-chloroindol- 3-ylcarbonyl)-lH.3H-pyrrolori.2-clthiazole.

The tide compound was prepared by die procedure described in Example 2 using the compound resulting from Example 47, 3-(pyridin-3-yl)-7-(6-chloroindol- 3-ylcarbonyl)- lH,3H-pyrrolo[ 1 ,2-c]tiιiazole, instead of 3-(pyridin-3-yl)-7-(indol-3- yl)carbonyl-lH,3H-pyrrolo[l,2-c]thiazole and using mediylisocyanate instead of N,N- dimethylcarbamoyl chloride. m.p. 214-215°C. ^J Η ΝMR (DMSO-d6, 300 MHz) δ

3.05 (s, 6H), 4.48 (d, IH, J=15Hz), 4.56 (dd, IH, 1=2, 15Hz), 6.73 (d, IH, J=3Hz), 6.79 (d, IH, J=lHz), 6.90 (d, IH, J=3Hz), 7.36 (dd, IH, 1=2, 8Hz), 7.43 (dd, IH, J=5, 8Hz), 7.65-7.70 (m, 2H), 8.24 (d, IH, J=9Hz), 8.38 (s, IH), 8.55- 8.59 (m, 2H). MS (DCI/ΝH3) m/e 451 (M+H)+, 329, 141, 124. Anal calcd for C23H19CIN4O2S: C, 61.26; H, 4.25; N, 12.42. Found: C, 60.99; H, 4.16; N, 12.13.

Example 66 Preparation of 3-(l-Oxide-Pyridin-3-yl)-7-(l-N V-dimethylcarbamoyl-6-chloroindol- 3-ylcarbonylV lH.3H-pyrroloπ ,2-clthiazole.

The tide compound was prepared by the procedure described in Example 34 using the compound resulting from Example 65, 3-(pyridin-3-yl)-7-(l-N^V- dimethylcarbamoyl-6-chloroindol-3-ylcarbonyl)-iH,3H-pyrrolo[ l,2-c]thiazole instead of 3-(pyridin-3-yl)-7-(l-N^V-dimediylcarbamoyl-6-phenylindol-3- yl)carbonyl- lH,3H-pyrrolo[l ,2-c]thiazole. m.p. 192-193°C. *Η ΝMR (DMSO-d6, 300 MHz) δ 3.06 (s, 6H), 4.45 (d, IH, J=2, L,d.z), 4.55 (dd, IH, 1=2, 15Hz), 6.70 (d, IH, J=lHz), 6.87 (d, IH, J=3Hz), 6.92 (d, IH, J=3Hz), 7.14 (d, IH, J=8Hz), 7.36 (dd, IH, 1=2, 9Hz), 7.39-7.45 (m, IH), 7.69 (d, IH, J=2Hz), 8.18-8.27 (m, 3H), 8.40 (s, IH). MS (DCVΝH3) m/e 484 ( -NH4)+, 467 (M+H)+, 451. Anal calcd for C23H19CIN4O3S: C, 59.16; H, 4.10; I ..00. Found: C, 57.61; H, 3.96; N, 11.53.

Example 67

Preparation of 3-ri-Amino-pyridin-3-v -7-ri-N v ^" -dimethylcarbamoyl- 6-(4-fluorophenyl)indol-3-vIcarbonvn-lH.3H-pyrroIori.2-c1thi azole.

The desired compound was prepared according to die mediod of Example 34, except substituting 3-(Pyridin-3-yl)-7-[l-N^V-dimedιylcarbamoyl- 6-(4-fluorophenyl)indol-3-ylcarbonyl]-lH,3H-pyrrolo[l,2-c]th iazole, prepared as in Example 29, for 3-φyridijι-3-yl)-7-(l-N^-dimemylcarbamoyl-6-phenylindol-3- yl)carbonyl-lH,3H-pyrτolo[l,2-c]thiazole, and aqueous hydrazine for aqueous hydroxylamine. m.p.253-258°C. ^l Η ΝMR (CD3OD, 300 MHz) δ 2.36(s, 3Η),

3_17(s, 6H), 4.55(d, IH, J= 15.0Hz), 4.71 (d, IH, J= 15.0, l.OHz), 6.78 (d, IH, J= 3.0Hz), 6.82 (d, IH, J= l.OHz), 6.98 (d, IH, J= 3.0Hz), 7.20 (t, 2H, J= 7.5Hz), 7.22 (d, 2H, J= 8.5Hz), 7.58 (dd, IH, J= 9.0, l.OHz), 7.69 (d, 2H, J= 8.5Hz), 7.71 (m, 2H), 7.79 (bs, IH), 7.99 (dd, IH, J= 7.5, 6.0Hz), 8.17 (d, IH, 1= 8.5Hz), 8.25 (s, IH), 8.31 (d, IH, J= 9.0Hz), 8.66 (bs, IH), 8.71 (bd, IH, J= 6.0Hz). MS (FAB) m/e 526 (M+l)+. IR (KBr) 3410, 1695, 1610, 1210. Anal calcd for C29H25FΝ5O2S: C, 61.18; H, 4.71; N, 9.91. Found: C, 61.19; H, 4.72; N, 9.95.

Example 68 Preparation of 3-(Pyridin-3-yl)-7-ri-(2-methanesulfonylaminoethv - 6-f4-fluorophenyl'.indoI-3-ylcarbonyl1- lH.3H-pyrrolor 1.2-cl thiazole.

To a solution of 3-φyridin-3-yl)-7-[l-(2-aminoethyl)-6-(4-fluorophenyl)indol - 3-ylcarbonyl]-lH,3H-pyrτolo[l,2-c]dιiazole (0.20 g, 0.062 mmol), prepared according to die method of Example 59, and trietiiylamine (13 μL, 0.093 mmol) in TΗF (15 mL) was added medianesulfonyl chloride (6 μL, 0.074 mmol). The reaction mixture was stirred for two hours at ambient temperature. The reaction mixture was quenched with saturated aqueous NΗ4CI and extracted with ediyl acetate. The organic phase was washed widi brine, dried over MgSθ ₄ , filtered, and concentrated in vacuo. 3-(Pyridin- 3-yl)-7-[l-(2-ιr_edιanesulfonylaιm^oedιyl)-6-(4-fluoroph enyl)indol-3-ylcarbonyl]- lH,3H-pyrrolo[l,2-c]thiazole (66 mg) was obtained by flash chromatography on silica gel (98:2 CΗC13, methanol). ^l H NMR (CDCI3, 300 MHz) δ 2.83 (s, 3H), 3.6 (d, 2H, J=6Hz), 4.42-4.52 (m, 3H), 4.65 (d, IH, J=15Hz), 5.57 (bs, IH), 6.38 (bs, IH), 6.46 (bs, IH), 6.8 (d, IH, J=3Hz), 7.15 (t, 2H, J=9Hz, 11Hz), 7.47 (d, 2H, J=7Hz), 7.52 7.65 (m, 3H), 7.8 (d, IH, J=9Hz), 7.95 (s, IH), 8.38 (d, IH, 9Hz), 8.55 (bs, 2H). MS (DCI/NH3) m/e 561 (M+H) ⁺ . Anal calcd for C29H25FN4O3S2: C, 62.13; H, 4.49; N, 9.99. Found: C, 61.37; H, 4.57; N, 9.58.

Example 69

Preparation of 3-(Pyridin-3-yl)-7-ri-hvdrazinocarbonyl-6-(4-fluorophenyl)in dol- 3-ylcarbonvn- lH.3H-pyrrolor 1 ,2-clthiazole. The tide compound was prepared by die procedure described in Example 62 using hydrazine instead of edianolamine. ^l H NMR (DMSO-d6, 300 MHz) δ 4.50 (d, IH, J=15Hz), 4.60 (bs, 2H), 4.68 (dd, IH, 1=2, 15Hz), 6.78 (d, IH, J=3Hz), 6.81 (d, IH, J=lHz), 7.09 (s, IH), 7.33 (t, 2H, J=9Hz), 7.45 (dd, IH, J=5, 8Hz), 7.61 (dd, IH, J=l, 9Hz), 7.65-7.76 (m, 3H), 8.31 (d, IH, J=9Hz), 8.47-8.51- (m, 2H), 8.56 8.60 (m, 2H), 9.90 (bs, IH). MS (DCI/NH3) m/e 498 (M+H)+, 440. Anal calcd for C27H20FN5O2S: C, 65.18; H, 4.05; N, 14.08. Found: C, 64.18; H, 4.03; N, 13.79.

Example 70 Preparation of 3-(Pyridin-3-yl -7-ri-(2-aminoedιyl)-6-(4-fluorophenyl indol- 3- ylcarbonyll- lH.3H-pyrrolor 1.2-clthiazole Hydrochloride.

The tide compound was prepared by die procedure described in Example 52 using die compound resulting from Example 59, 3-(pyridin-3-yl)-7-[l-(2-aminoetiιyl)- 6-(4-fluorophenyl)indol-3-ylcarbonyl]- lH,3H-pyrrolo[l ,2-c]thiazole instead of 3-(pyridin-3-yl)-7-(l-N _^ V-dimediylcarbamoyl-6-phenylindol-3-ylcarbonyl)- lH,3H-pyrrolo[l,2-c]thiazole. ^l Η ΝMR (CDC13, 300 MHz) δ 1.35 (s, 9H), 3.57 (q, 2H, J=15Hz), 4.35-4.45 (m, 2H), 4.57 (d, IH, J=15Hz), 4.63 (m, IH), 4.7 (dd, IH, J=3Hz), 7.15 (t, 2H, J=9Hz, 11Hz), 7.35 (dd, IH, 1=6, 11Hz), 7.5 (m, 2H), 7.6- 7.7 (m, 3H), 7.83 (s, IH), 8.45 (d, IH, J=9Hz), 8.60 (d, IH, J=2Hz), 8.65 (d, IH, J=5Hz). MS (DCI/ΝH3) m/e 583 (M+H)+.

Example 71

Preparation of 3-(Pyridin-3-yl)-7-ri-ethanesulfonyl-6-(4-fluorophenyl indol- 3-ylcarbonvn- lH.3H-pyrroloπ .2-clthiazole.

The tide compound was prepared by the procedure described in Example 51, using ethanesulfonylchloride instead of methanesulfonylchloride. m.p. 132°C. ^! Η NMR (CDCI3, 300 MHz) δ 1.25 (cm, 2H), 3.4-3.52 (m, 3H), 4.57 (d, IH, J=13.5Hz), 4.7 (dd, IH, J=1.5, 13.5Hz), 6.42 (d, IH, J=3Hz), 6.52 (bs, IH), 6.8 (m, IH), 7.16 (t, 2H, J=6Hz), 7.55-7.68 (cm, 5H), 7.8 (d, IH, J=4.5Hz), 8.05-8.12 (m, 2H), 8.4 (d, IH, J=7.5), 8.68 (bs, IH). MS (DCI/NH3) m/e 532 (M+H)+, 440, 534. Anal calcd for C28H22N3F0 ₃ S2-1H ₂ 0: C, 61.19; H, 4.40; N, 7.65. Found: C, 61.37; H, 4.40; N, 6.47.

Example 72

Preparation of 3-(Pyridin-3-yl)-7-ri-(2-hvdroxyethyl)-6-(4-fluorophenyl)ind ol- 3-ylcarbonvn-lH.3H-pyrrolorL2-c1thiazole.

Step 1. Preparation of 3-(Pyridin-3-yl -7-ri-(2-dimedιyl-ferr-butylsilyloxyethylV 6-(4-fluorophenyl)indol-3-ylcarbonvn-lH.3H-pyπOlon.2-c1thia zole.

The desired compound was prepared according to die method of Example 46, except subsuming 2-bromoethoxydimethyl-rerr-butylsilane for methyl acrylate.

Step 2. Preparation of 3-(Pyridin-3-v -7-ri-(2-hvdroxyethvD- 6-(4-fluorophenv indol-3-ylcarbonvn-lH.3H-pyrrolon.2-clthiazole

To a solution of 3-(Pyridin-3-yl)-7-[l-(2-dimethyl-tert-butylsiIyloxyethyl)- 6-(4-fluorophenyl)indol-3-ylcarbonyl]-lH,3H-pyrrolo[l,2-c]th iazole (365 mg, 0.61 mmol) and 18-crown-6 (168 mg, 0.64 mmol) in acetonitrile (8 mL) was added cerium fluoride (695 mg, 4.6 mmol). The reaction mixture was stirred 17 hours at ambient temperature. The reaction mixture was quenched widi Η2O and concenttated in vacuo. The residue was taken up in CH2CI2 and filtered. The filtrate was concenttated in vacuo. 3-(Pyridin-3-yl)-7-[l-(2-hydroxyed yl)-6-(4-fluorophenyl)indol-3-ylcarbonyl]- lH,3H-pyrrolo[l,2-c]thiazole was obtained by flash chromatography on silica gel. m.p. 170-171°C. ^l Η NMR (DMSO-d6, 300 MHz) δ 3.73 (dd, 2H, 1=6, 6Hz), 4.37 (t, 2H, J=1.5, 13.5Hz), 4.41 (d, !H, J=13.5Hz), 4.57 (dd, IH, J=1.5, 13.5Hz), 4.89 (t, IH, J=6Hz), 6.65 (d, IH, J=3Hz), 6.70 (bs, IH), 6.82 (d, IH, J=3Hz), 7.20 (t, 2H, J=9Hz), 7.29-7.35 (c, IH), 7.63-7.70 (c, 2H), 7.85 (bs, IH), 8.15 (s, IH), 8.19 (d, IH, J=6Hz), 8.31-8.35 (c, 2H). MS (DCI/NH3) m/e 484 (M+H)+. IR (KBr) 3440, 1590, 1510, 1480, 1380, 1230, 1230, 1180, 1160, 1080, 1070, 870, 820, 710. Anal calcd for C28H23FN3O2S: C, 68.27; H, 4.91; N, 8.53. Found: C, 68.57; H, 4.71; N, 8.42.

Example 73 Preparation of 3-(l -Oxide-pyridin-3-yl)-7-ri -phenylsulfonyl-6-(4-fluorophenv indol- 3-ylcarbonvn-lH.3H-pyrroloπ.2-clthiazole. The tide compound was prepared by die procedure described in Example 34 using the compound resulting from Example 61, 3-(pyridin-3-yl)-7-[l-phenylsulfonyl- 6-(4-fluorophenyl)indol-3-ylcarbonyl]-lH,3H-pyrrolo[l^-c]thi azole instead of 3-(pyriα n-3-yl)-7-(l-N V ^' -dimethylcarbamoyl-6-phenylindol-3-yl)carbonyl- lH,3H-pyrrolo[l,2-c]thiazole. m.p. 135-137°C. ^l Η ΝMR (CDCI3, 300 MHz) δ 4.55 (d, IH, J=13.5Hz), 4.62-4.69 (dd, IH, J=13.5, 3Hz), 6.38 (s, IH), 6.53 (d, IH, J=3Hz), 6.85 (d, IH, J=3Hz), 7.18 (t, 2H, J=7.5Hz), 7.25-7.32 (m, IH), 7.43 (t,

IH, J=3Hz), 7.47-7.64 (cm, 6H), 7.95 (m, IH), 7.97 (s, IH), 8.15 (d, IH, J=1.5Hz), 8.22 (s, IH), 8.26 (s, IH), 8.28-8.34 (m, 2H). MS (FAB) m/e 596 (M+l)+.

Example 74 Preparation of 3-(Pyridin-3-yl)-7-(6-pyrimid-2-ylindol-3-ylcarbonv - lH.3H-pyrroloπ .2-clthiazole.

Step 1. Preparation of 3-(pyridin-3- vD-7-(l -N.N-dimethylcarbamoyl- 6-trimethylstannvIindol-3-ylcarbonyl)-lH.3H-pyrrolori.2-clth iazole.

3-(pyridin-3-yl)-7-( 1 -NN-dimethylcarbamoyl-6-bromoindol-3-ylcarbonyl)- lH,3H-pyrrolo[l,2-c]thiazole (2.00 g, 4.04 mmol), prepared according to the mediod of Example 64, and hexametiiylditin (1.65 g, 5.04 mmol) were combined under Ν2 in a dry flask. Toluene (81 mL) was added via syringe and tetrakis(triphenylphosphine)palladium(0) (0.34 g, 0.29 mmol) was added under a stream of N2. The reaction mixture was warmed to reflux and stirred for 2.5 hours. The reaction mixture was cooled to ambient temperature and partitioned between ethyl acetate and pΗ 7 K2ΗPθ ₄ "/NaOΗ buffer. The organic phase was washed widi buffer and brine, dried over Na2Sθ4, filtered, and concentrated in vacuo to a small volume. The suspension was filtered, and die filtrate concentrated in vacuo and azeotroped widi edianol and CH2CL2 to give an orange solid. Pure 3-(pyridin-3-yl)-7-(l-N,N- dimedιylcarbamoyl-6-trimethylstannylindol-3-ylcarbonyl)- lH,3H-pyrrolo[l,2-c]thiazole (1.88 g, 80%), was obtained as a pale-yellow foam by flash chromatography on silica gel (3:1 then 5:1 ediyl acetate, hexanes).

Step 2. Preparation of 3-fPyridin-3-yl)-7-(6-pyrimid-2-ylindol-3-ylcarbonviy lH.3H-pyrroloπ .2-cl thiazole.

3-(pyridin-3-yl)-7-(l-N^-dimethylcarbamoyl-6-trimethylsta nnylindol- 3-ylcarbonyl)-lH,3H-pyrτolo[l,2-c]thiazole (0.23 g, 0.40 mmol), prepared in step 1, and 5-bromopyrimidine (76 mg, 0.48 mmol) were combined under Ν2 in a dry flask. Toluene (4 mL) was added via syringe and tetrakis(triphenylphosphine)palladium(0) (30 mg, 0.026 mmol) was added under a stream of N2. The reaction mixture was warmed to reflux and heated for 23 hours. The reaction mixture was cooled to ambient temperature and partitioned between ediyl acetate and pΗ 7 K2ΗPθ4"/NaOΗ buffer. The organic phase was washed once widi buffer, and the combined aqueous layers were extracted once widi ediyl acetate. The combined organic layers were washed with brine, dried over Na2S04, filtered, and concentrated in vacuo. Flash chromatography on silica gel (100:1, then 65:1, then 40:1 then 20:1 CHCI3, methanol) afforded pure 3- (Pyridin-3-yl)-7-(6-pyrimid-2-ylindol-3-ylcarbonyl)- lH,3H-pyrrolo[ 1 ,2-c]thiazole

(0.14 g,.70%). m.p. 125-128°C. ^l H NMR (CDCI3, 300 MHz) δ 3.18 (s, 6H), 4.60 (d, IH, J=15.1 Hz), 4.72 (dd, IH, J=1.8, 15.1 Hz), 6.40 (d, IH, J=2.9 Hz), 6.49 (s, IH), 6.79 (d, IH, J=2.9 Hz), 7.44 (dd, IH, J=5.0, 7.9 Hz), 7.57 (dd, IH, J=1.5, 8.5 Hz), 7.74 (d, IH, J=8.1 Hz), 7.87 (s, IH), 8.04 (s, IH), 8.48 (d, IH, J=8.1 Hz), 8.62-8.70 (c, 2H), 9.03 (s, 2H), 9.22 (s, IH). MS (DCI/NH3) m/e 495 (M+l)+. IR (KBr) 866 (s), 1181 (s), 1226 (m), 1386 (s), 1416 (s), 1484 (m), 1539 (s), 1612 (m), 1695 (s), 3437 (br). Anal calcd for C27H22N6O2S O.75H2O: C, 63.82; H, 4.67; N, 16.54. Found: C, 53.45; H, 4.31; N, 16.19.

Example 75

Preparation of 3-(l-Oxide-pyridin-3-yl -7-ri-(2-N V-dimethylcarbamoylmethyD- 6-(4-fluorophenyl)indol-3-ylcarbonyl1-lH.3H-pyπOloπ.2-c1th iazole.

The tide compound was prepared by die procedure described in Example 34 using the compound resulting from Example 53, 3-φyridin-3-yl)-7-[l-(2-NN- dimethylcarbamoylmethyl)-6-(4-fluorophenyl)indol-3-ylcarbony l]- lH,3H-pyτrolo[l,2-c]thiazole instead of c^imemylcaitjamoyl-6-phenyl__ndol-3-yl)carbonyl-lH,3H-pyrrol o[l,2-c]thiazole. m.p. 180.7°C. lΗ ΝMR (DMSO-d6, 300 MHz) δ 4.55 (d, IH, J=13.5Hz), 4.62-4.69 (dd, IH, J=13.5, 3Hz), 6.38 (s, IH), 6.53 (d, IH, J=3Hz), 6.85 (d, IH, J=3Hz), 7.18 (t, 2H, J=7.5Hz), 7.25-7.32 (m, IH), 7.43 (t, IH, J=3Hz), 7.47-7.64 (cm, 6H), 7.95 (m, IH), 7.97 (s, IH), 8.15 (d, IH, J=1.5Hz), 8.22 (s, IH), 8.26 (s, IH), 8.28-8.34 (m, 2H). MS (FAB) m e 541 (M+l)+. IR (KBr) 1600(s), 1660(s). Anal calcd for C30H25FΝ ₄ O3S: C, 62.98; H, 5.02; N, 9.79. Found: C, 62.65; H, 3.97; N, 9.47.

Example 76

Preparation of 3-(Pyridin-3-v -7-ri-carbamoyl-6-f4-fluorophenv indol-3-ylcarbonyl1- lH.3H-pyrrolori .2-cl thiazole.

The tide compound was prepared by die procedure described in Example 37 using 3-(pyridin-3-yl)-7-[6-(4-fluorophenyl)indol-3-ylcarbonyl]- lH,3H-pyιrolo[l,2-c]dιiazole, prepared as in Example 28, instead of 3-(Pyridin-3-yl)- 7-(6-phenylmemoxyindol-3-yl)carbonyl-lH,3H-pyrrolo[l,2-c]thi azole. ^l Η NMR (DMSO-d6, 300 MHz) δ 4.50 (d, IH, J=15Hz), 4.68 (dd, IH, 1=2, 15Hz), 6.78 (d, IH, J=3Hz), 6.81 (s, IH), 7.05 (d, IH, J=3Hz), 7.32 (t, 2H, J=9Hz), 7.45 (dd, IH, J=5, 8Hz), 7.61 (dd, IH, J=l, 9Hz), 7.66-7.77 (m, 3H), 8.00 (bs, 2H), 8.30 (d, IH, J=9Hz), 8.53-8.60 (m, 4H). MS (DCI/NH3) m/e 483 (M+H) ⁺ , 440. Anal calcd for C27H ₁ 9FN4O2S: C, 67.21; H, 3.97; N, 11.61. Found: C, 66.92; H, 3.88; N, 11.44.

Example 77

Preparation of 3-(l-Carbamoylamino-pyridin-3-yl)-7-ri-N V-dimethylcarbamoyl- 6-f4-fluorophenyl'-indol-3-ylcarbonvn-lH.3H-pyrrolori.2-c1th iazole. The tide compound was prepared by d e procedure described in Example 67 using semicarbazide instead of hydrazine. m.p. 156-163. *Η ΝMR (CD3OD, 300 MΗz) δ 3.14 (s, 6Η), 4.52 (d, IH, J= 15.0Hz), 4.69 (dd, IH, J= 15.0, l.OHz), 6.76 (d, IH, J= 3.0Hz), 6.79 (d, IH, J= l.OHz), 6.93 (d, IH, 1= 3.0Hz), 7.19 (t, 2H, J= 9.0Hz), 7.58 (dd, IH, J= l.OHz), 7.70 (dd, 2H, 1 =9.0, 6.0Hz), 7.80 (d, IH, J= l.OHz), 7.81 (m, IH), 7.98 (d, IH, J= 8.5Hz), 8.26 (s, IH), 8.30 (d, IH, J=

9.0Hz), 8.57 (d, IH, J= l.OHz), 8.58 (m, IH). IR (KBr) 3410, 1695, 1610, 1480, 1380. MS (FAB) m/e 569 (M+l)+ 552. Anal calcd for C3oH25FΝ ₆ 0 S: C, 63.37; H, 4.43; N, 14.78. Found: C, 60.91; H, 4.99; N, 13.65.

Example 78

Preparation of 3-(l-Pyrid-3-oylamino-pyridin-3-yl)-7-ri-N v ^" -dimethylcarbamoyl- 6-(4-fluorophenyl)indol-3-ylcarbonvn- lH.3H-pyrrolor 1.2-clthiazole.

The tide compound was prepared by d e procedure described in Example 62 using 3-pyridinehydrazide instead of hydrazine. m.p. 140-149°C. ^l H ΝMR (C 30D, 300 MHz) δ 3.15 (s, 6H), 4.56 (d, IH, J= 15.0Hz), 4.73 (dd, IH, J= 15.0, 3.0Hz), 6.78 (d, IH, J= 3.0Hz), 6.82 (d, IH, J= l.OHz), 6.96 (d, IH, J= 3.0Hz), 7.19 (t, 2H, J= 9.0Hz), 7.50 (dd, IH, 1= 8.5, 4.5Hz), 7.57 (dd, IH, J= 9.0, l.OHz), 7.70 (dd, IH, J= 8.5, 4.5Hz), 7.79 (d, IH, J= l.OHz), 7.96 (dd, IH, 1= 8.5, 4.5Hz), 8.12 (d, IH, J= 8.5Hz), 8.25 (s, IH), 8.30 (d, IH, J= 9.0Hz), 8.93 (dt, IH, J= 8.5, l.OHz), 8.62 (dd, IH, J= 4.5, l.OHz), 8.78 (bd, IH, J= 6.5Hz), 8.80 (bs, IH), 9.20 (bs, IH). MS (FAB) m/e 631 (M+l)+ IR (KBr) 3410, 1695, 1600, 1540, 1480, 1390.

Example 79 Preparation of 3-(l-Oxide-pyridin-3-yl)-7-ri-(2-aminosulfonylethyl)- 6-(4-fluorophenyl)indol-3-ylcarbonvn-lH.3H-pyrrolori.2-c1thi azole.

The tide compound was prepared by the procedure described in Example 34 using the compound resulting from Example 50, 3-(pyridin-3-yl)-7-[l-(2- sulfamyledιyl)-6-(4-fluorophenyl)indol-3-ylcarbonyl]-lH,3H- pyrrolo[l,2-c]dιiazole instead of 3-(pyridin-3-yl)-7-(l-N^-dimethylcarbamoyl-6-phenylindol-3-y l)carbonyl- lH,3H-pyrrolo[l,2-c]thiazole. m.p. 171-176°C. lΗ (ΝMR D3COD, 300 MΗz) δ 3.65 (t, 2Η, 1=7, 81Hz), 4.5 (d, IH, J=15Hz), 4.65 (dd, IH, 1=2, 15Hz), 4.8 (m, 2H), 6.67 (d, IH, J=2Hz), 6.73 (d, IH, J=3Hz), 6.97 (d, IH, J=3Hz), 7.2 (t, 2H,

1=9, 12Hz), 7.45 (d, IH, J=9Hz), 7.52-7.6 (m, 2H), 7.7-7.78 (m, 3H), 8.24 (s, IH), 8.25-8.34 (m, 3H). MS (FAB) m/e 563 (M+H)+ Anal calcd for C2 ₈ H23N ₄ O ₄ S2F: C, 59.77; H, 4.12; N, 9.96. Found: C, 58.83; H, 4.37; N, 9.57.

Example 80

Preparation of 3-(Pyridin-3-yl -7-ri-NN-dimedιylcarbamoyl-6-f 3- aminosulfonylphenyl)indol-3-ylcarbonyl1-lH.3H-pyrrolori.2-cl thiazole.

The tide compound was prepared by die procedure described in Example 74, using 4-bromophenylsulfbnamide instead of 2-bromopyrimidine. nxp. 155-160°C. ^l Η ΝMR (DMSO-d6, 300 MΗz) δ 3.09 (s, 6Η), 4.50 (d, IH, J=15.1 Hz), 4.68 (d, IH, J=15.1 Hz), 6.74 (d, IH, J=3.3 Hz), 6.81 (s, IH), 6.94 (d, IH, J=2.9 Hz), 7.42 (s, 2H), 7.44 (dd, IH, J=5.0, 7.9 Hz), 7.66-7.73 (c, 2H), 7.93 (s, 5H), 8.36 (d, IH, J=8.1 Hz), 8.41 (s, IH), 8.57 (br s, 2H). MS (DCI/ΝH3) m/e 572(M+H)+. IR 865 (s), 1163 (s), 1182 (s), 1226 (m), 1341 (m), 1388 (s), 1433 (m), 1483 (m), 1537 (s), 1595 (m), 1609 (m), 1693 (s), 3427 (br). Anal calcd for C29H25N5O ₄ S2O.6H2O: C, 67.09; H, 4.25; N, 11.25. Found C, 67.17; H, 4.15; N, 11.06.

Example 81

Preparation of 3-(Pyridin-3-yl)-7-ri-f2-N-methylcarbamoylmethv - 6-f4-fluorophenyl')indol-3-ylcarbonvn-lH.3H-pyrrolori.2-c1th iazole.

The tide compound was prepared by d e procedure described in Example 53, using N-methyl bromoacetamide instead of NN-dimethyl bromoacetamide. m.p. 166-

168°C. ^l Η ΝMR (DMSO-d6, 300 MΗz) δ 2.62 (d, 3Η, J=5 Hz), 4.48 (d, IH, J=15

Hz), 4.65 (dd, IH, J=15, 2Hz), 5.02 (s, 2H), 6.72 (d, IH, J=3 Hz), 6.78 (bs, IH), 6.89 (d, IH, J=3 Hz), 7.31 (t, 2H, J=12 Hz), 7.44 (dd, 2H, J=12, 8 Hz), 7.66 (cm,

IH), 7.77 (cm, 3H), 8.15 (bd, IH, J=5 Hz), 8.33 (d, 2H, J=12 Hz), 8.57 (cm, 2H).

MS (DCI ΝH3) m/e 511 (M+H)+, 528 (M+NH4) ⁺ . IR (KBr) 1600(s), 1660(s). Anal calcd for C29H23FN4O2S: C, 66.46; H, 4.71; N, 10.69. Found: C, 66.74; H, 4.38;

N, 10.22. Example 82

Preparation of 3-(Pyridin-3-vD-7-ri-N v ^" -dimethvIcarbamoyl-6-(4-fluorophenyl)indol-

3-vIcarbonyloximel- lH.3H-pyrrolor 1 ,2-cldιiazole.

To a solution of 3-(pyridin-3-yl)-7-[l-NN-dimedιylcarbamoyl-

6-(4-fluorophenyl)indol-3-ylcarbonyl]-lH,3H-pyrrolo[l,2-c ]thiazole (0.33 g, 0.64 mmol), prepared as in Example 29, in 1: 1 pyridine, edianol (8 mL) was added hydroxylamine hydrochloride (0.36 g, 5.2 mmol). The reaction mixture was heated for

30 πώi at 110°C. The reaction mixture was cooled to ambient temperature and

partitioned between ether and H2O. The organic phase was washed widi pH 7 buffer and brine, dried over Na2Sθ4, filtered, and concentrated in vacuo. Flash chromatography on silica gel (3:1 hexanes, ethyl acetate, then ediyl acetate) afforded 3- (Pyridin-3-yl)-7-[ 1 -N^V-dimethylcarbamoyl-6-(4-fluorophenyl)indol- 3-ylcarbonyloxime]-lH,3H-pyrrolo[l,2-c]thiazole. m.p. 132°C. ^l H ΝMR (D3COD, 300 MΗz) δ 3.1 (s, 3Η), 3.13 (s, 3H), 3.93-4.0 (c, 2H),6.35 (d, 0.5H, J=3Hz), 6.45 (d, 0.5H, J=3Hz), 6.51 (d, 0.5H, J=1.5Hz), 6.52 (s, 0.5H), 6.54 (s, 0.5H), 6.55 (d, 0.5H, J=4.5Hz), 7.11-7.19 (m, 2H), 7.38-7.45 (m, 2H), 7.53 (s, IH), 7.61-7.7 (m, 2H), 7.8-7.84 (c, 2H), 7.95 (s, 0.5H),7.97 (s, 0.5H), 8.43-8.53 (m, 2H). MS (FAB) m/e 526 (M+l)+.

Example 83 Preparation of 3- (Pyridin-3-yl)-7-r6-(4-fluorophenyl)indol-3-ylcarbonyloxime1 - lH.3H-pyrrolon .2-clthiazole.

The tide compound was prepared by the procedure described in Example 82, using 3-(pyridin-3-yl)-7-[6-(4-fluorophenyl)indol-3-ylcarbonyl]- lH,3H-pyrrolo[l,2-c]thiazole instead of 3-(pyridin-3-yl)-7-[l- N^v ^* -dimethylcarbamoyl-6-(4-fluorophenyl)indol-3-ylcarbony l]-lH,3H-pyrrolo- [l,2-c]thiazole. m.p. 106-108°C. ^l Η ΝMR (CDCI3, 300 MΗz) δ 3.94-4.21 (c, 2Η), 6.36 (d,.5H, J=3Hz), 6.46 (d, 0.5H,J=3Hz), 6.54 (s, 0.5H), 6.55 (s, 0.5H), 6.56- 6.6 (c, IH), 7.12-7.2 (m, 2H), 7.4-7.46 (m, 2H), 7.54 (s, IH), 7.62-7.7 (m, 4H), 7.8-7.82 (br s, IH), 7.95 (s, 0.5H),7.98 (s, 0.5H), 8.42-8.54 (m, 2H). MS (DCI/ΝH3) m/e 454 (M+H)+.

Example 84 Preparation of 3-(Pyridin-3-yl)-7-ri-(N-methyl-N-(dimethylaminoethyl))carba moyl- 6-(4-fluorophenyl)indol-3-ylcarbonvπ-lH.3H-pyrrolori.2-c1th iazole.

The tide compound was prepared by die procedure described in Example 62 using N,N,N ^' -trimemyleΛylenediamine instead of edianolamine. m.p. 149-152°C. ^! Η ΝMR (DMSO-d6, 300 MHz) δ 2.08 (s, 6H), 2.50 (m, 2H), 3.02 (s, 3H), 3.58 (t, 2H, J=6Hz), 4.49 (d, IH, J=15Hz), 4.68 (dd, IH, J=l, 15Hz), 6.73 (d, IH, J=3Hz), 6.80 (s, IH), 6.91 (d, IH, J=3Hz), 7.32 (t, 2H, J=9Hz), 7.44 (dd, IH, 1=5, 8Hz), 7.49-7.79 (m, 4H), 7.88 (s, IH), 8.32 (d, IH, J=8Hz), 8.37 (s, IH), 8.56-8.60 (m, 2H). MS (DCI/ΝH3) m e 568 (M-*-H)+, 440. IR (CDCI3) 1685, 1600, 1540, 1510. Anal calcd for C32H30FN5O2S: C 67.71; H, 5.33; N, 12.34. Found: C, 66.96; H, 5.10; N, 12.06.

Example 85

Preparation of 3-(Pyridin-3-yl)-7-ri-N-carboxymethylcarbamoyl- 6-(4-fluorophenvDindol-3-ylcarbonyll-lH.3H-pyrrolori.2-c1thi azole.

The title compound was prepared by the procedure described in Example 62 using glycine instead of edianolamine. m.p.255°C. ^l ΕL ΝMR (DMSO-d6, 300 MΗz) δ 4.01 (d, 2Η, J=6Hz), 4.52 (d, IH, J=15Hz), 4.69 (dd, IH, J=15, 2Hz), 6.79 (d, IH, J=3Hz), 6.81 (d, IH, J=lHz), 7.06 (d, IH, J=3Hz), 7.32 (t, 2H, J=9Hz), 7.45 (dd, IH, J=5Hz, 8Hz), 7.63 (dd, IH, J=l, 8Hz), 7.69 (dt, IH, 1=2, 9Hz), 7.72-7.78 (m, 2H), 8.32 (d, IH, J=8Hz), 8.51 (d, IH, J=lHz), 8.5-8.61 (m, 3H), 9.12 (t, IH, J=6Hz). MS (DCI ΝH3) m/e 541 (M+H)+, 440. IR (KBr) 1708, 1600, 1532, 1510, 1475. Anal calcd for C29H21FN4O4S: C, 64.44; H, 3.92; N, 10.36. Found: C, 63.53; H, 3.82; N, 10.08.

Example 86 Preparation of 3-π-Methyl-pyridin-3-yl)-7-ri-N V-dimethylcarbamoyl- 6-(4-fluorophenv indol-3-vIcarbonvn-lH3H-pyrrolori.2-c1thiazole.

The tide compound was prepared by the procedure described in Example 33 using the compound resulting from Example 29, 3-(pyridin-3-yl)-7-[l- N^-dimethylcarbamoyl-6-(4-fluorophenyl)indol-3-ylcarbonyl]- lH,3H-pyrrolo[l,2-c]thiazole instead of 3-(pyridin-3-yl)-7-(l-N,N- dimethylcarbamoyl-6-phenylindol-3-ylcarbonyl)-lH,3H-pyrrolo[ l,2-c]thiazole. m.p. 168°C. Η ΝMR (DMSO-d6, 300 MΗz) δ 3.08 (s, 6Η), 4.37 (s, 3H), 4.54 (d, IH, J=15Hz), 4.78 (dd, IH, 1=2, 15Hz), 6.83 (d, IH, J=3Hz), 6.95 (d, IH, J=lHz), 6.99 (d, IH, J=3Hz), 7.32 (t, 2H, J=6Hz), 7.61 (dd, IH, 1=2, 9Hz), 7.73-7.82 (m, 3H), 8.16 (dd, IH, 1=7, 9Hz), 8.32 (d, IH, J=9Hz), 8.38 (s, IH), 8.49 (d, IH, J=8Hz), 8.98 (d, IH, J=6Hz), 9.03 (s, IH). MS (FAB) m/e 525 (M+H) ⁺ , 307, 289. Anal calcd for C30H26FIΝ4O2S: C, 55.22; H, 4.02; N, 8.59. Found: C, 53.97; H, 3.88; N, 8.39.

Example 87 Preparation of 3-(Pyridin-3-yl -7-fl-N v ^" -dimethylcarbamoyl-6-thiazol-2-vIindol-3- vIcarbonvI -lH.3H-pyrrolon.2-c1dιiazole.

The tide compound was prepared by die procedure described in Example 74, using 2-bromothiazole instead of 2-bromopyrimidine. m.p. 123-126°C. ^l Η ΝMR (CDCI3, 300 MΗz) δ 3.17 (s, 6Η), 4.58 (d, IH, J=15.4 Hz), 4.71 (dd, IH, J=2.2, 15.1 Hz), 6.38 (d, IH, J=3.0 Hz), 6.47 (s, IH), 6.80 (d, IH, J=2.9 Hz), 7.36 (d, IH, J=2.9 Hz), 7.42 (dd, IH, J=5.0, 7.9 Hz), 7.72 (d, IH, J=7.7 Hz), 7.88 (d, IH, J=3.3 Hz), 7.92 (dd, IH, J=1.6, 8.3 Hz), 8.07 (s, IH), 8.25 (s, IH), 8.42 (d, IH,

J=8.1 Hz), 8.63 (br s, IH), 8.65 (br s, IH). MS (DCI/NH3) m/e 500 (M+H)+. IR (KBr) 857 (s), 1181 (s), 1223 (m), 1388 (s), 1435 (s), 1482 (s), 1538 (s), 1612 (s), 1696 (s), 3439 (br). Anal calcd for C26H21N5O2S2O.4H2O: C, 61.61; H, 4.34; N, 13.82. Found: C, 61.59; H, 3.95; N, 13.41.

Example 88 Preparation of 3-(Pvridin-3-vn-7-ri-N-sulfoethvlcarbamovl-6-(4-fluorophenvn indol- 3-ylcarbonyl1-lH.3H-pyrrolori.2-clthiazole

The tide compound was prepared by die procedure described in Example 62 using taurine instead of edianolamine. m.ρ.238°C (dec). *Η ΝMR (DMSO-dό, 300 MHz) δ 2.79(t,2H,J=6Hz), 4.51(d,lH,J=15Hz), 4.70 (d,lH,J=15Hz), 6.80 (d,lH,J=3Hz), 6.85 (s,lH),7.05(d,lH,J=3Hz), 7.32(t,2H,J=2Hz), 7.57-7.65(c,2H), 7.73-7.81 (c,2H),7.84-7.90 (c,2H), 8.31 (d,lH,J=9Hz), 8.49 (s,lH), 8.53 (s,lH), 8.67 (bs,2H), 8.75 (bs,lH). IR (KBr cm- ¹ ) 3440, 1710, 1610, 1540, 1510, 1475, 1425,1220, 1040, 875, 820. MS (FAB) m/e 613(M+Νa) ⁺ , 591(M+H)+, 207, 185, 115.

Example 89 Preparation of 3-fPvridin-3-vl V7-H -N_N-dimethvlcarbamovl-6-r2-aminopvrimid-5- vl)indol-3-vl)carbonvn-lH.3H-pvrroloπ.2-c1thiazole. The tide compound was prepared by the procedure described in Example 74, using 2-amino-5-bromopyrimidine instead of 2-bromopyrimidine. m.p. 145-148°C. ^! H ΝMR (DMSO-d6, 300 MHz) δ 3.07 (s, 6H), 4.49 (d, IH, J=15.2 Hz), 4.66 (dd,

IH, J=1.6, 15.2 Hz), 6.73 (d, IH, J=2.9 Hz), 6.77 (s, 2H), 6.80 (s, IH), 6.91 (d, IH, J=3.3 Hz), 7.44 (dd, IH, J=4.9, 7.8 Hz), 7.56 (dd, IH, J=1.6, 8.6 Hz), 7.68 (d, IH, J=8.2 Hz), 7.76 (s, IH), 8.29 (d, IH, J=8.2 Hz), 8.33 (s, IH), 8.58 (s, 2H), 8.62 (s, 2H). MS (DCVΝH3) m/e 510 (M+H) ⁺ . IR (KBr) 863 (m), 1183 (m), 1225 (m), 1384 (m), 1437 (m), 1464 (s), 1539 (s), 1612 (s), 1693 (s), 3409 (br), 3438 (br). Anal calcd for C27H23N7O2S H2O: C, 51.47; H, 4.78; N, 18.58. Found: C, 51.87; H, 4.74; N, 18.12.

Example 90

Preparation of 3-C1 -Oxide-pvridin-3-viy7-ri-f2-aminoethvl'.-6-( ^' 4-fluorophenvl'.indol- 3-ylcarbonvπ-lH.3H-pvrrolori.2-c1thiazole.

The tide compound was prepared by die procedure described in Example 34 using the compound resulting from Example 59, 3-(Pyridin-3-yl)-7-[l-(2-aminoethyl)- 6-(4-fluorophenyl)indol-3-ylcarbonyl]-lH,3H-pyrrolo[l,2-c]d� �iazole instead of

3-(pyridin-3-yl)-7-(l-N^-dimethylcarbamoyl-6-pheny_indol-3-y I)carbonyl- lH,3H-pyrrolo[l_2-c]thiazole. m.p. 178-190°C. Η ΝMR (CDCI3, 300 MΗz) δ 3.87 (t, 2Η, J=9Hz), 4.44 (t, 2H, J=9Hz), 4.59 (d, IH, J=15Hz), 4.69 (dd, IH, J=15, IHz) 6.37 (bs, IH), 6.48 (d, IH, J=3Hz), 6.87 (d, IH, J=3Hz), 7.15 (t, 2H, J=12Hz), 7.37 (cm, 2H), 7.47 (bs, IH) 7.53 (bd, IH, J=12Hz), 7.62 (cm, 2H), 7.92 (s, IH), 8.32 (cm, 2H), 8.48 (d, IH, J=12Hz). MS (FAB) m/e 499 (M+l)+. IR (KBr) 1515 (s), 1600 (s), 3430 (br). Anal calcd for C28H23FΝ4O2S: C, 67.45; H, 4.65; N, 11.24. Found: C, 55.69; H, 4.63; N, 8.40.

Example 91

Preparation of 3-(l-Oxide-pyridin-3-yl -7-ri-N V-dimethylcarbamoyl- 6- ^(' 4-hvdτazinylcarbonylphenvDindol-3-ylcarbonvn-lH.3H-py πOlori.2-c1thiazole. The tide compound was prepared by die procedure described in Example 74, using 4-bromobenzoyl hydrazide instead of 2-bromopyrimidine. m.p. 151-154°C. lΗ ΝMR (DMSO-d6, 300 MΗz) δ 3.09 (s, 6Η), 4.50 (d, IH, J=14.7 Hz), 4.52 (s, 2H), 4.68 (d, IH, J=14.3 Hz), 6.74 (d, IH, J=2.9 Hz), 6.80 (s, IH), 6.92 (d, IH, J=2.9 Hz), 7.44 (dd, IH, J=4.8, 7.7 Hz), 7.68 (d, 2H, J=8.1 Hz), 7.82 (d, IH, J=8.5 Hz), 7.83 (s, IH), 7.92 (d, 2H, J=9.6 Hz), 7.95 (d, IH, J=8.5 Hz), 8.34 (d, IH, J=8.5 Hz), 8.39 (s, IH), 8.57 (br s, 2H), 9.85 (br s, IH). MS (DCI/ΝH3) m/e 551 (M+H)+. IR (KBr) 864 (s), 1182 (m), 1226 (m), 1387 (s), 1433 (m), 1480 (s), 1538 (s), 1609 (s), 1692 (s), 3431 (br). Anal calcd for C30H26N6O3S O.85H2O: C, 63.66; H, 4.94; N, 14.85. Found: C, 63.99; H, 4.86; N, 14.47.

Example 92 Preparation of 3-(l-Acetoxymethylpyridin-3-yl)-7-ri-N V-dimedιylcarbamoyl- 6-(4-flnorophenyl)indol-3-ylcarbonvn-lH.3H-pyrroIon.2-c1thia zole.

To a solution of 3-(Pyridin-3-yl)-7-[l-NN-dimedιylcarbamoyl- 6-(4-fluorophenyl)indol-3-ylcarbonyl]-lH,3H-pyrτolo[l,2-c]t hiazole (206 mg, 0.41 mmol), prepared as in Example 29, in acetone (8 mL) was added bromomethyl acetate (60 μL, 0.62 mmol). The reaction mixture was warmed to reflux and stirred for four hours. The reaction mixture was cooled to ambient temperature and concentrated to a foam. The foam was dissolved in methanol, and 3-(l-Acetoxymethylpyridin-3-yl)- 7-[l-N^-dimethylcarbamoyl-6-(4-fluorophenyl)indol-3-ylcarbon yl]- lH,3H-pyπolo[l,2-c]thiazole was precipitated by addition of ether. m.p.218-223°C. Η ΝMR (DMSO-d6, 300 MΗz) δ 2.18 (s, 3Η), 3.09 (s, 6H), 4.55 (d, IH, J=

15.0Hz), 4.75 (dd, IH, J= 15.0, l.OHz), 6.41 (s, 2H), 6.86 (d, IH, J= 3.0Hz), 7.00 (d, IH, J= 3.0Hz), 7.01 (s, IH), 7.32 (t, 2H, J= 8.5Hz), 7.62 (dd, IH, J= 8.5,

l.OHz), 7.77 (m, 2H), 7.81 (bs, IH), 8.26 (dd, IH, J= 8.5, l.OHz), 8.31 (d, IH, J= 8.5Hz), 8.39 (s, IH), 8.61 (bd, IH, J= 8.5Hz), 9.20 (d, IH, J= 6.0Hz), 9.22 (bs, IH). MS (FAB) m/e 583, 511. IR (KBr) 3450(br), 1685, 1480, 1220.

Example 93

Preparation of 3-(Pyridin-3-vD-7-ri-N-mediyl-N-hvdroxymethylcarbamoyl- 6-(4-fluorophenyl)indol-3-ylcarbonyn-lH.3H-pyπOlori.2-c1thi azole.

To a solution of 3-(pyridin-3-yl)-7-[l-(2-N-medιylcarbamoylmethyl)- 6-(4-fluorophenyl)indol-3-ylcarbonyl]-lH,3H-ρyrrolo[l,2-c]t hiazole (100 mg, 0.20 mmol), prepared as in Example 81, in TΗF (5 mL) was added a solution of K2CO3 (13 mg, 0.098 mmol) in Η2O (5 mL). Formaldehyde (37% aqueous solution, 10 mL, 123 mmol) was added and die reaction mixture was stirred overnight at ambient temperature. The THF was removed in vacuo and the residue was extracted three times with ethyl acetate. The combined organic layers were washed with saturated aqueous ΝaHC03 and concentrated in vacuo. Purification by flash chromatography on silica gel (2% methanol, ethyl acetate) afforded 3-(Pyridin-3-yl)-7-[l-N-methyl-N- hydroxymethylcarbamoyl-6-(4-fluorophenyl)indol-3-ylcarbonyl] - lH,3H-pyrrolo[l,2-c]thiazole (32 mg). m.p. 172-182°C (decomp). ^l Η ΝMR (DMSO-d6, 300 MΗz) δ 2.89 (s, 2.25Η), 3.15 (s, 0.75H), 4.48 (d, IH, J=15Hz), 4.62 (dd, IH, J=15, IHz), 4.71 (d, 0.5H, J=10Hz), 4.92 (d, 1.5H, J=10Hz), 5.39 (s, 0.5H), 5.47 (s, 1.5H), 5.9 (t, 0.25, J=10Hz), 6.21 (t, 0.75H, J=10Hz), 6.71 (d, IH, J=3Hz), 6.78 (s, IH), 6.87 (d, 0.25H, J=3Hz), 6.88 (d, 0.75, J=3Hz), 7.312 (t, 2H, J=12Hz), 7.44 (cm, IH), 7.51 (d, IH, J=12Hz), 7.65 (d, IH, J=12Hz), 7.75 (cm, 3H), 8.27 (s, IH), 8.32 (d, IH, J=12Hz), 8.57 (d, 2H, J=9Hz). MS (FAB) m/e 541 (M+l)+. Anal calcd for C30H25Ν4O3SF: C, 63.48; H, 4.97; N, 9.87. Found: C, 63.77; H, 5.87; N, 7.45.

Example 94

Preparation of 3-(Pyridin-3-yl)-7-ri-cvanomethyl-6-(4-fluorophenyl)indol- 3-ylcarbonvn-lH.3H-pyπOlori.2-c1thiazole.

The desired compound was prepared according to die method of Example 46, except substituting iodoacetonitrile for methyl acrylate. m.p.219-223. ^l Η NMR (DMSO-d6, 300 MΗz) δ 4.5 (d, 1Η, J=1.5Ηz), 4.65 (dd, IH, J=1.5, 0.3Hz), 5.7 (s, 2H), 6.75 (d, IH, J=0.3Hz), 6.8 (d, IH, J=0.2Hz), 6.93 (d, IH, J=0.3Hz), 7.35 (t, 2H, J=0.9, 1.2Hz), 7.4 (dd, IH, 0.6, 0.9Hz), 7.63 (dd, IH, J=0.9, 0.3Hz), 7.68 (dd, IH, J=0.9, 0.3Hz), 7.83 (dd, 2H, J=0.3, 0.9Hz), 8.2 (s, IH), 8.35 (d, IH,

J=0.9Hz), 8.48 (s, IH), 8.55-8.60 (m, 2H). MS (DCI/NH3) m/e 479 (M+H)+. IR (KBr) 2200.

Example 95

5 Preparation of 3-(Pvridin-3-vlV7-π -carbamovlmethvl-6-f4-fluorophenvr.indol- 3-vlcarbonvll-lH.3H-pvrτoloπ.2-clthiazole.

To a solution of 3-(pyridin-3-yl)-7-[l-cyanomethyl-6-(4-fluorophenyl)indol- 3-ylcarbonyl]-lH,3H-pyrrolo[l^-c]dιiazole (290 mg, 0.607 mmol), prepared as in Example 94, in 2:1 isopropanol, methanol (60 mL), was added a solution of borax 10 (sodium tetraborate decahydrate, 0.693 g, 1.82 mmol) in Η2O (20 mL). The reaction mixture was heated for four hours at 80°C. The reaction mixture was cooled to ambient temperature and concentrated in vacuo. The residue was taken up in CHCI3 and filtered through a pad of celite. The organic phase was washed widi brine, dried over MgSθ4, filtered, and concentrated in vauco. The crude product was purified by flash 15 chromatography on silica gel to give 3-(Pyridin-3-yl)-7-[l-carbamoylmethyl-

6-(4-fluorophenyl)indol-3-ylcarbonyl]-lH,3H-pyrrolo[l^-c] thiazole (20 mg). m.p. 215-225°C. lΗ NMR (DMSO-d6, 300 MΗz) δ 4.49 (d, 1Η, J=15Ηz), 4.65 (d, IH, r J=15Hz), 5.03 (s, 2H), 6.73 (d, IH, J=3Hz), 6.79 (s, IH), 6.9 (d, IH, J=3Hz),

7.28-7.39 (m, 3H), 7.40-7.48 (m, IH), 7.53 (d, IH, J=9Hz), 7.6-7.8 (m, 5H), 8.33 20 (m, IH), 8.58 (m, IH). MS (DCI/NH3) m/e 497 (M+H) ⁺ . Anal calcd for

C28H2 ₁ FN4O2S: C, 67.73; H, 4.26; N, 11.28. Found: C, 65.63: H, 4.37; N, 10.31.

Example 96

Preparation of 3-π ³ vridin-3-vn-7-ri-carboxvmethvl-6-r4-fluorophenvl ndol- 25 3-ylcarbonyn-lH.3H-pyrrolori.2-c1thiazole.

Step 1. Preparation of 3-(pyridin-3-yD-7-ri-carboethoxymethyl- 6-f4-fluorophenvnindol-3-vlcarbonvπ-lH.3H-pvrroloπ.2-clthi azole.

The desired compound was prepared according to die mediod of Example 46, except subsitiuting ethyl chloroacetate for methyl acrylate.

30

Step 2. Preparation of 3-fPvridin-3-vn-7-ri-carboxvmethvl-6-r4-fluorophenvnindol- 3-ylcarbonvn-lH.3H-pvrrolori.2-c1thiazole.

The desired compound was prepared according to die mediod of Example 49, step 2 except subsitiuting 3-φyridin-3-yl)-7-[l-carboethoxymedιyl- 35 6-(4-fluorophenyl)indol-3-ylcarbonyl]-lH,3H-pyrrolo[l,2-c]th iazole, prepared in step 1, for 3-(Pyridin-3-yl)-7-[l-(2-carbomedιoxyedιyl)-6-(4-fluorophe nyl)indol- 3-ylcarbonyl]-lH,3H-pyrrolo[l,2-c]thiazole. m.p. 240-249°C. ^l Η NMR (DMSO-d6,

300 MHz) δ 4.45 (d, IH, J=1.5Hz), 4.65 (dd, IH, J=1.5, 0.3Hz), 4.84 (s, 2H), 6.7

(d, IH, J=0.3Hz), 6.78 (s, IH), 6.87 (d, IH, J=0.3Hz), 7.3 (t, 2H, J=0.9, 1.5Hz),

7.4-7.5 (m, 2H), 7.6-7.8 (m, 4H), 8.25-8.33 (m, 2H), 8.5-8.6 (m, 2H). MS

(DCI/NH3) m/e 498 (M+H)+.

Example 97

Preparation of 3-(Pyridin-3-yl)-7-ri-(lH-tetrazol-5-ylmethyl)-6-(4-fluoroph envnindol-

3-ylcarbonyn-lH.3H-pyrrolori.2-c1thiazole.

A mixture of 3-(pyridin-3-yl)-7-[l-cyanomethyl-6-(4-fluorophenyl)indol- 3-ylcarbonyl]-lH,3H-pyrrolo[l,2-c]dιiazole (77 mg, 0.161 mmol), prepared as in Example 94, dibutyltin oxide (40 mg, 0.161 mmol), and trimethylsilylazide (47.3 μL, 0.322 mmol) in toluene (15 mL) was heated at reflux for tiiree hours. The reaction mixture was cooled to ambient temperature and concenttated in vacuo. The crude product was azeotroped with CΗ2CI2 and purified by flash chromatography on silica gel (9: 1 CHCI3, methanol) to give 3-(Pyridin-3-yl)-7-[l-(lH-tetrazol-5-ylmethyl)- 6-(4-fluorophenyl)indol-3-ylcarbonyl]-lH,3H-pyrrolo[l,2-c]th iazole (53 mg). m.p. 110-118°C. lΗ NMR (D3COD, 300 MΗz) δ 4.5 (d, 1Η, J=15Ηz), 4.63 (dd, IH, 15,

3Hz), 5.75 (s, 2H), 6.57 (d, IH, J=3Hz), 6.67 (bs, IH), 6.98 (d, IH, J=3Hz), 7.15 (t, 2H, J=9Hz), 7.45-7.51 (m, 2H), 7.67-7.77 (m, 3H), 7.79 (s, IH), 8.25 (s, IH), 8.31 (d, IH, 9Hz), 8.55 (bs, 2H). MS (FAB) m/e 522 (M+H)+.

Example 98

Preparation of 3-(Pyrim^-3-ylV7-ri-N.N-dimethylcarbamoyl-6-f2.4αH.3//y pyrimidinedion-5-yl)indol-3-yl)carbonyn- lH.3H-pyrrolor 1.2-clthiazole. The tide compound was prepared by die procedure described in Example 74, using 5-bromouracil instead of 2-bromopyrimidine. !Η ΝMR (DMSO-d6, 300 MΗz) δ 3.06 (s, 6Η), 4.48 (d, IH, J=15.1 Hz), 4.66 (d, IH, J=15.4 Hz), 6.72 (d, IH, J=3.3 Hz), 6.79 (s, IH), 6.90 (d, IH, J=2.9 Hz), 7.40-7.47 (c, 2H), 7.65-7.70 (c, 2H), 7.83 (s, IH), 8.20 (d, IH, J=8.1 Hz), 8.32 (s, IH), 8.55-8.59 (c, 2H), 11.17 (br s, 0.67H), 11.24 (br s, 0.33H), 11.27 (s, 0.67H), 11.52 (br s, 0.33H). MS (DCI/ΝH3) m/e 527 (M+H)+.

Example 99 Preparation of 3-(Pyridin-3-yl)-7-ri-N-sulfoethylcarbamoyl-6-(4-fluorophenv indol- 3-ylcarbonvn-lH.3H-pyrrolon.2-clthiazole. The title compound was prepared by d e procedure described in Example 62 using ethylamine instead of edianolamine. m.p. 210-213°C. lH ΝMR (DMSO-d6, 300 MHz) δ 1.21 (t, 3H, J=7Hz), 3.35-3.42 (m, 2H), 4.51 (d, IH, J=15Hz), 4.68

(dd, IH, 1=2, 15Hz), 6.78 (d, IH, J=3Hz), 6.81 (s, IH), 7.05 (d, IH, J=3Hz), 7.32 (t, 2H, J=9Hz), 7.45 (dd, IH, J=5, 8Hz), 7.61 (dd, IH, J=l, 9Hz), 7.65 (m, 3H), 8.31 (d, IH, J=8Hz), 8.50-861 (m, 4H), 8.68 (t, IH, J=6Hz). MS (DCI NH3) m/e 511 (M+H) ⁺ , 441, 417. IR (KBr) 1710, 1600, 1532, 1512, 1475. Anal calcd for C29H23FN4O2S: C, 68.22; H, 4.54; N, 10.97. Found: C, 67.96; H, 4.42; N, 10.73.

Example 100

Preparation of 3- ⁽ Pyridin-3-yl ^' .-7-ri-N-sulfoethylcarbamoyl-6-(4-fluorophenyl)indol- 3-ylcarbonyll-lH.3H-pyπOlon.2-c1thiazole. The tide compound was prepared by die procedure described in Example 62 using leucine instead of edianolamine. m.p.214-215°C. 1Η ΝMR (DMSO-d6, 300 MΗz) δ 0.91 (bs, 6Η), 1.24 (bs, 3H), 1.72 (bs, 3H), 4.25 (bs, IH), 4.51 (bd, IH, J=15Hz), 4.67 (bd, IH, J=15Hz), 6.80 (bs, 2H), 7.09 (bs, IH), 7.33 (t, 2H, J=9Hz), 7.40-7.48 (c, IH), 7.61 (bd, IH, J=9Hz), 7.67-7.81 (c, 3H), 8.32 (d, IH, J=7.5Hz), 8.51-8.62(c, 4H). MS (DCI ΝH3) m/e 597 (M+H)+, 440, 228, 200. IR (KBr) 3420, 2950, 2940, 1710, 1600, 1535, 1515, 1480, 1430, 1380, 1220, 1160, 1140, 820, 710.

Example 101 Preparation of 3-(Pyridin-3-v -7-(l-N V-dimethylcarbamoyl-6-thiophen-2-vIindol- 3-ylcarbonv -lH.3H-pyrrolon.2-c1thiazole.

The desired compound was prepared according to die mediod of Example 74, except substituting 2-bromodιiophene for 5-bromopyrimidine. m.p. 115-118°C. ^l Η ΝMR (DMSO-d6, 300 MΗz) δ 3.08 (s, 6Η), 4.50 (d, IH, J=15.1 Hz), 4.66 (dd, IH, J=1.8, 15.1 Hz), 6.72 (d, IH, J=2.9 Hz), 6.80 (d, IH, J=1.5 Hz), 6.91 (d, IH, J=3.3 Hz), 7.16 (dd, IH, J=3.8, 5.0 Hz), 7.44 (dd, IH, J=5.0, 7.9 Hz), 7.55 (d, IH, J=5.5 Hz), 7.56 (d, IH, J=3.7 Hz), 7.64 (dd, IH, J=1.5, 8.4 Hz), 7.68 (dt, IH, J=1.9, 8.1 Hz), 7.85 (dd, IH, J=0.7, 1.5 Hz), 8.26 (d, IH, J=8.4 Hz), 8.35 (s, IH), 8.54-8.60 (c, 2H). MS (DCI/ΝH3) m/e 499 (M+H)+. IR (KBr) 707 (m), 862 (m), 1180 (s), 1224 (m), 1387 (s), 1435 (m), 1483 (s), 1539 (s), 1611 (m), 1694 (s), 3439 (br). Anal calcd for C27H22N4O2S2O.IC5H ₁₂ : C, 65.30; H, 4.62; N, 11.08. Found: C, 65.23; H, 4.73; N, 10.72.

Example 102

Preparation of 3-(Pyridin-3-yl)-7-(l-N V-dimethylcarbamoyl-6-(4- hvdroxymethyl)phenylindol-3-ylcarbonyl)-lH.3H-pyrrolon.2-c1t hiazole.

The desired compound was prepared according to die mediod of Example 74, except substituting 4-bromobenzyl alcohol for 5-bromopyriιnidine. m.p. 134-137°C.

IH NMR (DMSO-d6, 300 MHz) δ 3.08 (s, 6H), 4.50 (d, IH, J=15.1 Hz), 4.56 (d, 2H, J=5.5 Hz), 4.67 (dd, IH, J=2.0, 15.2 Hz), 5.20 (t, IH, J=5.7 Hz), 6.74 (d, IH, J=3.3 Hz), 6.80 (d, IH, J=1.8 Hz), 6.92 (d, IH, J=3.3 Hz), 7.41-7.47 (m, IH),

7.42 (d, 2H, J=8.5 Hz), 7.62 (dd, IH, J=1.8, 8.4 Hz), 7.66-7.71 (m, IH), 7.68 (d, 2H, J=8.1 Hz), 7.83 (s, IH), 8.30 (d, IH, J=8.5 Hz), 8.35 (s, IH), 8.56-8.59 (c,

2H). MS (FAB) m/e 523 (M+l)+. IR (KBr) 866 (s), 1182 (s), 1225 (m), 1388 (s), 1433 (m), 1482 (s), 1538 (s), 1610 (m), 1694 (s), 3436 (br). Anal calcd for C30H26N4O3SO.75H2O: C, 67.21; H, 5.17; N, 10.45. Found: C, 67.44; H, 4.83; N, 10.46. Example 103

Preparation of 2-Oxide-3-(l-oxide-pyridin-3-yl)-7-ri-N V ^" -dimethylcarbamoyl-6-(4- fluorophenyl)indole-3-ylcarbonyn- lH.3H-pyrroloπ .2-clthiazole.

The desired compound was prepared according to die method of Example 13, except substituting 3-(l-oxide-pyridin-3-yl)-7-[l-N^v ^* -dimethylcarbamoyl-6-(4- fluorophenyl)indole-3-ylcarbonyl]-lH,3H-pyrrolo[l,2-c]thiazo le, prepared as in Example 39, for 3-(pyridin-3-yl)-7-(l-rerr-butyloxycarbonylindol-3-yl)carbon yl- lH,3H-pyrrolo[l,2-c]thiazole. m.p. 187-206°C. ^! Η ΝMR (DMSO-d6, 300 MHz) δ 3.10 (s, 6H), 4.29 (d, IH, J=17.0Hz), 4.75 (d, IH, J=17.0Hz), 6.61 (s, IH), 6.92 (bd, IH, J=8.0Hz), 7.04 (d, IH, J=3.0Hz), 7.18 (d, IH, J=3.0Hz), 7.31 (t, 2H, J=8.5Hz), 7.45 (dd, IH, J=7.0, 8.0Hz), 7.52 (dd, IH, J=1.5, 8.5Hz), 7.78 (m, 2H), 7.82(d, IH, J=1.5Hz), 8.09 (s, IH), 8.24 (d, IH, J=6.0Hz), 8.31 (d, IH, J=8.0Hz),

8.43 (s, IH). MS (FAB) m/e 543 (M+l)+. IR (KBr) 1695, 1480.

Example 104 Preparation of 3-(Pyridin-3-yl)-7-ri-N V ^* -dimethylcarbamoyl-6-(4-fluorophenyl)indol- 3-ylcarbonylhydrazone]- lH.3H-pyrrolon .2-c|tiιiazole.

To a solution of 3-(pyridin-3-yl)-7-[l-N -dimedιylcarbamoyl- 6-(4-fluorophenyl)indol-3-ylcarbonyl]-lH,3H-pyιτolo[l,2-c] thiazole (0.30 g, 0.59 mmol), prepared as in Example 29, in n-butanol was added hydrazine hydrate (55% solution LΛ Η20, 0.20 mL, 2.9 mmol) and acetic acid (0.20 mL). The reaction mixture was heated at 80-90°C for 72 hours. The reaction mixture was cooled to ambient temperature and concenttated in vauco. 3-(Pyri&n-3-yl)-7-[l-N,N-dimemylcarbamoyl- 6-(4-fluorophenyl)indol-3-ylcarbonylhydrazone]-lH,3H-pyrrolo [l,2-c]thiazole was obtained by flash chromatography on silica gel. m.p. 150-151°C. ^l H ΝMR (D3COD, 300 MΗz) δ 3.1 (s, 6Η), 3.95-4.1 (dd, 2H, J=1.5, 12Hz),6.5 (d, IH, J=3Hz), 6.63 (br s, IH), 6.66 (d, IH, J=3Hz), 7.13-7.2 (c, 2H), 7.35 (s, IH), 7.42 (dd, IH,

J=1.5, 6Hz), 7.45-7.5 (c, IH), 7.64-7.59 (c, 2H), 7.75-7.78 (c, IH), 7.79-7.8 (c, IH), 8.08 (d, IH, J=7.5Hz), 8.5 (br s, IH), 8.54 (d, IH, J=3Hz). MS (FAB) m/e 525 (M+l)+.

Example 105 Preparation of 3-(Pyridin-3-yl -7-ri-N-(2-(4-imidazolv ethyl)carbamoyl- 6-(4-fluorophenyl)indol-3-ylcarbonyll- lH.3H-pyrroloπ .2-clthiazole.

The desired compound was prepared according to die mediod of Example 62, except substituting histamine for edianolamine. m.p. 156-158°C. ^l H ΝMR (D3COD, 300 MΗz) δ 2.97 (t, 2Η, J=7.5Hz), 3.68 (t, 2H, J=7.5Hz), 4.50 (d, IH, J=15Hz), 4.65 (dd, IH, J=3, 15Hz), 6.60 (d, IH, J=3Hz), 6.79 (d, IH, J=1.5Hz), 6.92 (bs, IH), 6.96 (d, IH, J=3Hz), 7.19 (t, 2H, J=9Hz), 7.45-7.51 (c, IH), 7.55 (dd, IH, J=1.5, 9Hz), 7.59 (d, IH, J=lHz), 7.63-7.70 (c, 2H), 7.75 (dt, IH, J=1.5, 7.5Hz), 8.26 (d, IH, J=7.5Hz), 8.34 (s, IH), 8.37 (d, IH, J=lHz), 8.52 (d, IH, J=1.5Hz), 8.55 (dd, IH, J=1.5, 4.5Hz). MS (FAB) m/e 577 (M+H)+, 460, 440, 154, 136. IR (KBr) 3410, 1710, 1600, 1530, 1510, 1475, 1430, 1220, 875, 820. Anal calcd for C32H27FΝ6O3S: C, 64.63; H, 4.58; N, 14.13. Found: C, 64.88; H, 4.28; N, 14.16.

Example 106

Preparation of 3-(pyridin-3-yl -7-ri-N v ^" -dimethvIcarbamoyl-6-(4-fluorophenyl)indol- 3-ylcarbonylsemicarbazide1-lH.3H-pyrrolori.2-c1thiazole.

To a suspension of 3-(pyridin-3-yl)-7-[l-N,N-dimethylcarbamoyl- 6-(4-fluorophenyl)indol-3-ylcarbonyl]-lH,3H-pyrrolo[l,2-c3th iazole (0.62 g, 1.21 mmol), prepared as in Example 29, in 1:1 ethanol, pyridine (12 mL) was added semicarbazide hydrochloride (1.08 g, 9.72 mmol) and die reaction mixtue was heated for 24 hours at 105°C. The reaction mixture was cooled to ambient temperature and concentrated in vacuo. The residue was taken up in CΗ2CI2 and die solution was washed with saturated aqueous ΝaHCθ3, dried over Na2S04, filtered, and concentrated. Flash chromatography on silica gel (20% methanol/acetone) provided 3- φyridin-3-yl)-7-[l-N^-dimedιylcarbamoyl-6-(4-fluorophenyl) indol- 3-ylcarbonylsemicarbazide]-lH,3H-pyrrolo[l,2-c]thiazole (30 mg). m.p. 160-161°C. lΗ ΝMR (D3COD, 300 MΗz) δ 3.3 (s, 6Η), 4.03-4.35 (2H), 6.45-6.67 (3H), 7.07- 7.2 (3H), 7.35-7.5 (4H), 7.6-7.75 (4H), 8.4-8.53 (2H). MS (FAB) m/e 567 (M+l)+.