United States Patent (19) 11 Patent Number: 6,066,653 Gregg Et Al

US006066653A United States Patent (19) 11 Patent Number: 6,066,653 Gregg et al. (45) Date of Patent: May 23, 2000

54 METHOD OF TREATING ACID LIPASE FOREIGN PATENT DOCUMENTS DEFICIENCY DISEASES WITH AN MTP 643057A1 3/1995 European Pat. Off.. INHIBITOR AND CHOLESTEROL WO96/26205 8/1996 WIPO. LOWERING DRUGS OTHER PUBLICATIONS 75 Inventors: Richard E. Gregg, Pennington, N.J.; John R. Wetterau, II, Langhorne, Pa. Scriver et all “The Metabolic and Molecular Bases of Inher ited Disease”, Seventh Edition, vol. II, Chapter 82, "Acid 73 Assignee: Bristol-Myers Squibb Co., Princeton, Lipase Deficiency: Wolman Disease and Cholesteryl Ester N.J. Storage Disease”, pp. 2563–2587, (1995). Scriver et all “The Metabolic and Molecular Bases of Inher 21 Appl. No.: 09/005,437 ited Disease”, Seventh Edition, vol. II, Chapter 85, 22 Filed: Jan. 10, 1998 “Niemann-Pick Disease Type C: A Cellular Cholesterol Lipidosis”, pp. 2625–2639, (1995). Related U.S. Application Data 60 Provisional application No. 60/036,183, Jan. 17, 1997. Primary Examiner Kimberly Jordan 51) Int. Cl." ...... A61K 3.144s. A61k 3/21 Attorney, Agent, or Firm Burton Rodney; Ronald S. 52 U.S. Cl...... s14/325.514,510,514824. "a" 58 Field of Search ...... 514/325, 510, 57 ABSTRACT 514/824 A method is provided for inhibiting------or treating diseases 56) References Cited asSociated with acid lipase deficiency by administering to a patient an MTP inhibitor, alone or optionally, in combination U.S. PATENT DOCUMENTS with another cholesterol lowering drug, Such as pravastatin. 4,346,227 8/1982 Terahara et al...... 560/119 5,712,279 1/1998 Biller et al...... 514/252 27 Claims, No Drawings 6,066,653 1 2 METHOD OF TREATING ACID LIPASE Several species, including humans (2). MTP is composed of DEFICIENCY DISEASES WITH AN MTP two subunits. The small subunit is the previously character INHIBITOR AND CHOLESTEROL ized multifunctional protein, protein disulfide isomerase. LOWERING DRUGS This is supported by biochemical analysis of the protein (3) as well as co-expression Studies performed in insect Sf9 cells using the baculovirus expression System. Expression of This application claims the benefit of U.S. Provisional soluble active MTP requires the co-expression of PDI and Application Ser. No. 60/036,183, filed Jan. 17, 1997. the unique large subunit of MTP (4). FIELD OF THE INVENTION 1: Wetterau, J. R. and Zilversmit, D. B. (1985) Chem. Phys. Lipids 38, 205-222. The present invention related to a method for inhibiting or Wetterau, J. R., et al., (1990) J. Biol. Chem. 265, treating diseases associated with acid lipase deficiency, 98OO-98.07. including Wolman disease and/or cholesteryl ester Storage Wetterau, J. R., et al., (1991) Biochemistry 30, 4406-4412. disease, by administering an MTP inhibitor alone or in Atzel, A., and Wetterau, J. R. (1993) Biochemistry 32, combination with another cholesterol lowering drug, Such as 10444-10450. pravastatin. 15 Atzel, A., and Wetterau, J. R. (1994) Biochemistry 33, 15382-15388. BACKGROUND OF THE INVENTION Jamil, H., et al., (1995) J. Biol. Chem. 270, 6549–6554. 2. Sharp, D. et al., (1993) Nature 365, 65–69. Wolman disease and cholesteryl ester Storage disease are Lin, M. C. M., et al., J. Biol. Chem. 269, 29138-29145. characterized by a deficiency in activity of lysomal acid Nakamuta, M., et al., (1996) Genomics 33, 313–316. lipase which results in massive accumulation of cholesteryl 3. Wetterau, J. R., et al., (1990) J. Biol. Chem. 265, esters and triglycerides in most tissueS of the body. Choles 98OO-98.07. teryl esters and triglycerides are derived from plasma lipo Wetterau, J. R., et al., (1991) Biochemistry 30,9728–9735. proteins taken up by the cells and are Substrates for acid 4. Ricci, B., et al., (1995) J. Biol. Chem. 270, 14281–14285. lipase. Acid lipase is responsible for the hydrolysis of 25 In vitro, MTP catalyzes the transport of lipid molecules cholesteryl esters and triglycerides in the lySOSomes. between phospholipid membranes. Presumably, it plays a If plasma cholesterol levels are lowered sufficiently, then Similar role in Vivo, and thus playS. Some role in lipid cholesteryl ester and triglyceride accumulation in the lyso metabolism. The Subcellular (lumen of the microsomal Somes and the consequences of the accumulation could be fraction) and tissue distribution (liver and intestine) of MTP minimized. have led to speculation that it plays a role in the assembly of Wolman disease is the more severe of the two diseases plasma lipoproteins, as these are the Sites of plasma lipo and is almost always fatal before the age of 1 year. In protein assembly. Wetterau & Zilversmit, Biochem. BiophyS. contrast, cholesteryl ester storage disease may go undetected Acta 875, 610-7 (1986). The ability of MTP to catalyze the until adulthood by which time lipid deposition is wide transport of TG between membranes is consistent with this Spread. Hyperbetalipoproteinemia is common in cholesteryl 35 hypothesis, and Suggests that MTP may catalyze the trans ester Storage disease, and premature atherosclerosis may be port of TG from its site of synthesis in the endoplasmic SCWCC. reticulum (ER) membrane to nascent lipoprotein particles To date, there has been no specific therapy for acid lipase within the lumen of the ER. deficiency other than attempts at Suppression of cholesterol Abetalipoproteinemia is an autosomal recessive disease Synthesis and apolipoprotein B production by 3-hydroxy-3- 40 characterized by a virtual absence of plasma lipoproteins methylglutaryl coenzyme A reductase inhibitors in combi which contain apolipoprotein B (apoB). Kane & Havel in nation with cholestyramine treatment and a diet eXcluding The Metabolic Basis of Inherited Disease, Sixth edition, foods rich in cholesterol and triglycerides. The above appar 1139-64 (1989). Plasma TG levels may be as low as a few ently provided improvement in only one or two cases of mg/dL, and they fail to rise after fat ingestion. Plasma 45 cholesterol levels are often only 20–45 mg/dL. These abnor cholesteryl ester Storage disease. Thus, for the most part, malities are the result of a genetic defect in the assembly Wolman disease and cholesteryl ester Storage disease have and/or secretion of very low density lipoproteins (VLDL) in been untreatable. the liver and chylomicrons in the intestine. The molecular See Scriver, C. R. et all “The Metabolic and Molecular basis for this defect had not been previously determined. In Bases of Inherited Disease”, Vol. II (1995), Chap. 82, “Acid 50 Subjects examined, triglyceride, phospholipid, and choles Lipase Deficiency: Wolman Disease and Cholesteryl Ester terol Synthesis appear normal. At autopsy, Subjects are free Storage Disease”, pp. 2563-2587. of atherosclerosis. Schaefer et al., Clin. Chem. 34, B9-12 Until now, there have not been any therapeutic agents (1988). A link between the apoB gene and abetalipopro available which could lower plasma cholesterol levels suf teinemia has been excluded in Several families. Talmud et ficiently to minimize cholesteryl ester and triglyceride accu 55 al., J. Clin. Invest. 82, 1803-6 (1988) and Huang et al., Am. mulation in the lySOSomes. J. Hum. Genet. 46, 1141-8 (1990). The microsomal triglyceride transfer protein (MTP) cata Recent reports (5) demonstrate that the defect causing lyzes the transport of triglyceride (TG), cholesteryl ester abetalipoproteinemia is in the MTP gene, and as a result, the (CE), and phosphatidylcholine (PC) between small unila MTP protein. When examined, individuals with abetalipo mellar vesicles (SUV). Wetterau & Zilversmit, Chem. Phys. 60 proteinemia have no MTP activity, as a result of mutations Lipids 38,205-22 (1985). When transfer rates are expressed in the MTP gene, some of which have been characterized. as the percent of the donor lipid transferred per time, MTP These results indicate that MTP is required for the synthesis expresses a distinct preference for neutral lipid transport of apoB containing lipoproteins, Such as VLDL, the precur (TG and CE), relative to phospholipid transport. The Sor to LDL. It therefore follows that inhibitors of MTP microSomal triglyceride transfer protein from bovine liver 65 would inhibit the synthesis of VLDL and LDL, thereby has been isolated and extensively characterized (1). This has lowering VLDL levels, LDL levels, cholesterol levels, and led to the cloning of cDNA expressing the protein from triglyceride levels in animals and man. 6,066,653 3 4 5. Wetterau, J. R., et al., (1992) Science 258,999-1001. Patent Application Ser. No. 2,091,102 described hereinbe Sharp, D., et al., (1993) Nature 365, 65–69. fore (corresponding to U.S. application Ser. No. 117,362), Ricci, B., et al., (1995) J. Biol. Chem. 270, 14281–14285. WO 92/26205 published Aug. 29, 1996, U.S. application Shoulders, C. C., et al., (1993) Hum. Mol. Genetics 2, Ser. No. 472,067, filed Jun. 6, 1995 (file DC21e), U.S. 2109-2116. application Ser. No. 548,811, filed Jan. 11, 1996 (file Narcisi, T. M. E., et al., (1995) Am. J. Hum. Genet. 57, DC21h), U.S. provisional application Ser. No. 60/017,224, 1298-1310. filed May 9, 1996 (file HX79a), U.S. provisional applica Rehberg, E. F., et al., J. Biol. Chem (in press). tion Ser. No. 60/017.253, filed May 10, 1996 (file HX82), Canadian Patent Application No. 2,091,102 published U.S. provisional application Ser. No. 60/017,254, filed May Mar. 2, 1994 (corresponding to U.S. application Ser. No. 10, 1996 (file HX84*), and U.S. provisional application Ser. 117,362, filed Sep. 3, 1993 (file DC21b)) which is incorpo No. 60/028.216, filed Oct. 1, 1996 (file HX86*). Preferred rated herein by reference), reports MTP inhibitors which are each of the preferred MTP inhibitors disclosed in each of also block apoB containing lipoprotein Secretion in a human the above applications. hepatic cell line (HepG2 cells). This provides further support All of the above U.S. applications are incorporated herein for the proposal that an MTP inhibitor would lower apoB 15 by reference. containing lipoprotein and lipid levels in Vivo. This Cana The MTP inhibitors disclosed in U.S. Application Ser. No. dian patent application discloses a method for identifying 472,067, filed June 6, 1995 (file DC21e) are piperidine the MTP inhibitors. compounds of the Structure The use of microSomal triglyceride transfer protein (MTP) inhibitors for decreasing serum lipids including R2 O cholesterol and triglycerides and their use in treating atherosclerosis, obesity, hyperglycemia, and pancreatitis is X^n disclosed in WO 96/26205, published Aug. 29, 1996, U.S. R- N N-R, or application Ser. No. 472,067, filed Jun. 6, 1995 (file DC21e), y-six21 U.S. application Ser. No. 548,811, filed Jan. 11, 1996 (file 25 DC21h), U.S. provisional application Ser. No. 60/017,224, 1. filed May 9, 1996 (file HX79a), U.S. provisional applica R2 O tion Ser. No. 60/017.253, filed May 10, 1996 (file HX82), N U.S. provisional application Ser. No. 60/017,254, May 10, R An N Or 1996 (file HX84*) and U.S. provisional application Ser. No. A-4NX 60/028.216, filed Oct. 1, 1996 (file HX86*). R4 All of the above U.S. applications are incorporated herein by reference. N N-R, or A 35 r)-OR6 DESCRIPTION OF THE INVENTION R1 In accordance with the present invention, a method is provided for inhibiting or treating a disease associated with N Or acid lipase deficiency, including Wolman disease and/or 40 A cholesteryl ester storage disease (CESD), in mammalian R6 Species, wherein a therapeutically effective amount of a O microsomal triglyceride transfer protein (MTP) inhibitor is R2 R administered to a patient in need of treatment. 3 \ N r 7 The MTP inhibitor may optionally be administered in 45 R N combination with another cholesterol lowering drug or ya y1 delipidating agent. R4 O O The MTP inhibitor alone or optionally in combination || | with another cholesterol lowering drug is administered where Q is C O S-; Systemically, Such as orally or parenterally or transdermally, 50 to patients in need of treatment. | In accordance with the present invention, the MTP inhibi X is: CHR, -C-, -CH-CH O C=C-: tor lowers plasma cholesterol (LDL-cholesterol) to at least y k k k k about 50% of normal LDL blood level, preferably down to 55 less than about 25% of normal, and most preferably down to less than about 15% of normal, and lowers triglycerides to R, R and R' are independently hydrogen, alkyl, at least about 50% of normal triglyceride blood level, and alkenyl, alkynyl, aryl, arylalkyl, hete roaryl, preferably down to about 25% or less of normal, and thereby heteroarylalkyl, cycloalkyl, or cycloalkylalkyl, minimizes cholesteryl ester and triglyceride accumulation in 60 the lySOSomes. Y is (CH2) O C The terms "another cholesterol lowering drug or agent' or O "another delipidating drug' will be employed interchange ably herein. 65 wherein m is 2 or 3; MTP inhibitors to be employed in the methods of the R" is alkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl invention include MTP inhibitors disclosed in Canadian wherein alkyl has at least 2 carbons, diarylalkyl, 6,066,653 S 6 arylalkenyl, diarylalkenyl, arylalkynyl, diarylalkynyl, -continued diarylalkylaryl, heteroarylalkyl wherein alkyl has at F least 2 carbons, cycloalkyl, or cycloalkylalkyl wherein R13NC X1 R14 alkyl has at least 2 carbons, all optionally Substituted through available carbon atoms with 1, 2, 3 or 4 groups Selected from halo, haloalkyl, alkyl, alkenyl, alkoxy, -R11-Zl O aryloxy, aryl, arylalkyl, alkylmercapto, arylmercapto, R12-Z2 R16a cycloalkyl, cycloalkylalkyl, heteroaryl, fluorenyl, heteroarylalkyl, hydroxy or oxo; 1O R15a G or R' is a fluorenyl-type group of the structure

A. R"S4 y-R 15 7 W

-R11 H Z. O R13 R12 R14 R31, SR 4 B R"S4 y-R 25 // W

-R11-Zl Z" and Z are the same or different and are independently Z. O R12-Z2 a bond, O, S,

S., f S \ , -NH-C-, -N-C-,-C- or || || | | R1313.(-7 R14 O \O/ O alkyl O O C 35 H R"S4 y-R W W --OH -R1-Z with the proviso that with respect to B, at least one of Z' and Z. O 40 Z will be other than a bond; R' is a bond, alkylene, R12-Z2 alkenylene or alkynylene of up to 10 carbon atoms, arylene or mixed arylene-alkylene; R' is hydrogen, alkyl, alkenyl, R13 e R14 aryl, haloalkyl, trihaloalkyl, trihaloalkylalkyl, heteroaryl, heteroarylalkyl, arylalkyl, arylalkenyl, cycloalkyl, aryloxy, D 45 alkoxy, arylalkoxy or cycloalkylalkyl, with the provisoS that R16 R15 preferably (1) when R' is H, aryloxy, alkoxy or arylalkoxy, then Z S -R11-Zl Z. ; or R12-Z2 50 R13 e R14 or a bond and 55 (2) when Z is a bond, R' cannot be heteroaryl or heteroarylalkyl, Z is a bond, O, S, N-alkyl, N-aryl, or alkylene or alk E enylene from 1 to 5 carbon atoms; R', R', R', and R" are independently hydrogen, alkyl, halo, haloalkyl, 60 aryl, cycloalkyl, cycloheteroalkyl, alkenyl, alkynyl, hydroxy, alkoxy, nitro, amino, thio, alkylsulfonyl, arylsulfonyl, alkylthio, arylthio, aminocarbonyl, alkyl carbonyl oxy, a ryl carbonyl a mino, alkylcarbonylamino, arylalkyl, heteroaryl, heteroaryla 65 lkyl or aryloxy; R'' and R'' are independently hydrogen, alkyl, halo, haloalkyl, aryl, cycloalkyl, cycloheteroalkyl, alkenyl, 6,066,653 7 8 alkynyl, alkoxy, alkylsulfonyl, arylsulfonyl, alkylthio, arylthio,arylcarbonylamino, amino carbonyl, alkylcarbonylamino, alkylcarbonyloxy, arylalkyl, ( O ) heteroaryl, heteroarylalkyl, or aryloxy, s or R' is a group of the structure -(CH-( R17 R18 10 (us) , (e) and (e) wherein p is 1 to 8 and R'' and Rare each independently H, alkyl, alkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or cycloalkylalkyl at least one of R'' and R' are the same or different and are independently Selected from being other than H; is heteroaryl containing 5- or 6-ring members; and or R' is a group of the structure N-oxides

R20 -n N1O -R'-( 2O flu R1 wherein R"19 is aryl or heteroaryl; R thereof, and R" is aryl or heteroaryl; 25 21 pharmaceutically acceptable Salts thereof, with the pro R" is H, alkyl, aryl, alkylaryl, arylalkyl, aryloxy, visos that preferably where in the first formula X is arylalko Xy, he tero aryl, he tero arylalkyl, 2 3 4 1 - . heteroarylalkoxy, cycloalkyl, cycloalkylalkyl or CH, and R, R and R" are each H, then R will be cycloalkylalkoxy, other than 3,3-diphenylpropyl, and preferably in the R. R. R" are independently hydrogen, halo, alkyl, 3O fifth formula, where one of R, R and R' is 6-fluoro, alkenyl, alkoxy, aryloxy, aryl, arylalkyl, alkylmercapto, and the others are H, R' will be other than 4-(2- arylmercapto, cycloalkyl, cycloalkylalkyl, heteroaryl, methoxyphenyl). heteroarylalkyl, hydroxy or haloalkyl; The MTP inhibitors disclosed in U.S. application Ser. No. R is independently alkyl, alkenyl, alkynyl, aryl, alkoxy, 548,811 filed Jan. 11, 1996 (file DC21h), have the structure aryloxy, arylalkoxy, he tero aryl, arylalkyl, 35 hete roarylalkyl, cycloalkyl, cycloalkylalkyl, X1 polycycloalkyl, polycycloalkylalkyl, cycloalkenyl, cycloheteroalkyl, heteroaryloxy, cycloalkenylalkyl, polycycloalkenyl, polycycloalkenylalkyl, 40 O heteroarylcarbonyl, amino, alkylamino, arylamino, !--ch -CF heteroarylamino, cycloalkyloxy, cycloalkylamino, all 2 3 O optionally Substituted through available carbon atoms Z. | with 1, 2, 3 or 4 groups Selected from hydrogen, halo, (CH2), N. N-C-Rs alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, H cycloalkyl, cycloalkylalkyl, cycloheteroalkyl, 45 ( ) cycloheteroalkylalkyl, aryl, heteroaryl, arylalkyl, arylcycloalkyl, arylalkenyl, arylalkynyl, aryloxy, X2 aryloxyalkyl, arylalkoxy, arylaZo, heteroaryloxo, heteroarylalkyl, heteroarylalkenyl, heteroaryloxy, hydroxy, nitro, cyano, amino, Substituted amino, thiol, 50 including the piperidine N-oxide thereof or a pharmaceuti alkylthio, arylthio, heteroarylthio, arylthioalkyl, cally acceptable salt thereof, wherein Z is a bond, O or S; alkylcarbonyl, arylcarbonyl, arylaminocarbonyl, X' and X’ are independently selected from H or halo; alko Xy carbonyl, a mino carbonyl, alkyny lamino carbonyl, alkylamino carbonyl, 55 s an integer from 2 to 6; alkenylamino carbonyl, alkyl carbonyloxy, R is heteroaryl, aryl, heterocycloalkyl or cycloalkyl, each aryl carbonyl oxy, alkyl carbony la mino, R group being optionally substituted with 1, 2, 3 or 4 arylcarbonylamino, arylsulfinyl, arylsulfinylalkyl, Substituents which may be the same or different. arylsulfonyl, alkylsulfonyl, arylsulfonylamino, The MTP inhibitors disclosed in U.S. provisional appli hetero arylcarbonylamino, heteroarylsulfinyl, cation Ser. No. 60/017,224, filed May 9, 1996 (file HX79a) heteroarylthio, heteroarylsulfonyl, alkylsulfinyl; have the Structure R is hydrogen or C-C alkyl or C-C alkenyl; all optionally Substituted with 1, 2, 3 or 4 groups which I may independently be any of the Substituents listed in O the definition of R set out above; 65 L2 us L R7 is alkyl, aryl or arylalkyl wherein alkyl by itself or as R21" NA B1 NR1 or part of arylalkyl is optionally substituted with oxo 6,066,653 9 10 -continued R" is alkyl, alkenyl, alkynyl, alkoxyl, (alkyl or aryl)-Si IA (where each alkyl or aryl group is independent), cycloalkyl, cycloalkenyl, Substituted alkylamino, Sub Stituted arylalkylamino, aryl, arylalkyl, arylamino, aryloxy, heteroaryl, heteroarylamino, heteroaryloxy, 5 arylsulfonylamino, heteroarylsulfonylamino, arylthio, IB arylsulfinyl, arylsulfonyl, alkylthio, alkylsulfinyl, alkylsulfonyl, heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl, -PO (R') (R'), (where R' and R" are independently alkyl, aryl, alkoxy, aryloxy, 1O he tero aryl, he tero arylalkyl, he tero aryloxy, he tero arylalko Xy, cyclohe tero alkyl, cyclohetero alkylalkyl, cyclohete roalkoxy, or including pharmaceutically acceptable Salts thereof, wherein cycloheteroalkylalkoxy); R' can also be aminocarbonyl q is 0, 1 or 2, (where the amino may optionally be substituted with A is (1) a bond; 15 one or two aryl, alkyl or heteroaryl groups); cyano, (2) -O-, or 1,1-(alkoxyl or aryloxy)-alkyl (where the two aryl or alkyl Substituents can be independently defined, or (3) linked to one another to form a ring, Such as 1,3- -N-; dioxane or 1,3-dioxolane, connected to L' (or L in the 2O case of R) at the 2-position); 1,3-dioxane or 1,3- dioxolane connected to L' (or L in the case of R) at the 4-position. where R is H or lower alkyl or R together with R forms The R' group may have from one to four substituents, a carbocyclic or heterocyclic ring System containing 4 to 8 which can be any of the R groups or R' groups, and any of 25 the preferred R' substituents set out below. members in the ring. R" may be substituted with the following preferred sub B is a fluorenyl-type group of the Structure: Stituents: alkylcarbonylamino, cycloalkylcarbonylamino, arylcarbonylamino, he tero arylcarbonylamino, alkoxy carbonylamino, aryloxycarbonylamino, R3 R" R3 R4' heteroaryloxylcarbonylamino, uriedo (where the uriedo S4 nitrogens may be Substituted with alkyl, aryl or heteroaryl), O heterocyclylcarbonylamino (where the heterocycle is con O C nected to the carbonyl group via a nitrogen or carbon atom), R4 R3 X K. alkylsulfonyla mino, aryl Sulfonyl a mino, 35 heteroarylsulfonylamino,

R20 O (the above B is also referred to as a fluorenyl- type ring or moiety);or X^n R21 A. N-, 40 y 21 / R22

where J is: CHR, -C-, -CH-CH Or

45 l l ls

R°, R' and R are independently hydrogen, alkyl, 50 alkenyl, alkynyl, aryl, arylalkyl, hete roaryl, heteroarylalkyl, cycloalkyl, or cycloalkylalkyl, R', R, Rf are independently hydrogen, halo, alkyl, alkenyl, alkoxy, aryloxy, aryl, arylalkyl, alkylmercapto, R3 55 arylmercapto, cycloalkyl, cycloalkylalkyl, heteroaryl, R3 R3 R3 heteroarylalkyl, hydroxy or haloalkyl, and these pre ferred substituents may either be directly attached to R", or attached via an alkylene chain at an open position. O Q 60 R is the same or different from R and is independently 3a 52.(CH2) R3b R3b any of the groups set out for R, H, polyhaloalkyl (such R R3a as CFCH, CFCFCH or CF) or cycloheteroalkyl, (The above B is also referred to as and may be substituted with one to four of any of the an indenyl-type ring or moiety); groups defined for R, or any of the Substituents pre 65 ferred for R. L' is a linking group containing from 1 to 10 carbons in R is H, alkyl or aryl; a linear chain (including alkylene, alkenylene or 6,066,653 11 12 alkynylene), which may contain, within the linking R is H, lower alkyl, aryl, -C(O)-R' or -C (O) chain any of the following: one or two alkenes, one or -O-R': two alkynes, an oxygen, an amino group optionally Substituted with alkyl or aryl, an OXO group; and may be R" and Rare the same or different and are independently Substituted with one to five alkyl or halo groups H, alkyl, aryl, halogen, -O-R'', or (preferably F). R" and R together can be oxygen to form a ketone; L may be the same or different from L and may R, R', R'' and R'' are the same or different and are independently be any of the L' groups set out above or independently H, lower alkyl, aryl or -O-R'; a singe bond. R" and R'" are the same or different and are indepen R, R, R" and R" may be the same or different and are 1O independently Selected from H, halogen, CF, dently H, lower alkyl, aryl, halogen or -O-R'; haloalkyl, hydroxy, alkoxy, alkyl, aryl, alkenyl, R' is alky or aryl; alkenyloxy, alkynyl, alkynyloxy, alkanoyl, nitro, R’ is H, alkyl or aryl. amino, thiol, alkylthio, alkylsulfinyl, alkylsulfonyl, The following provisos apply to formula I preferred carboxy, alkoxy carbonyl, a mino carbonyl, 15 compounds: alkyl carbonyl oxy, alkyl carbony la mino, cycloheteroalkyl, cycloheteroalkylalkyl, cyano, Ar, (a) when R is unsubstituted alkyl or unsubstituted Ar-alkyl, Ar-O, Ar-amino, Ar-thio, Ar-Sulfinyl, arylalkyl, L' cannot contain amino; Ar-Sulfonyl, Ar-carbonyl, Ar-carbonyloxy or (b) when R is alkyl, L' cannot contain amino and OXO in Ar-carbonylamino, wherein Aris aryl or heteroaryland adjacent positions (to form an amido group); Ar may optionally include 1, 2 or 3 additional rings (c) when RL A- is HN-, R'L' cannot contain amino; fused to Ar; (d) when R is cyano, L' must have more than 2 carbons; R" and R are the same or different and are indepen (e) R'L' must contain at least 3 carbons. dently any of the R groups except hydroxy, nitro, amino or With respect to compounds IA and IB, RL cannot have thio; 25 an O or N atom directly attached to S=(O), or CR'(OH), and for IA, RL cannot be H. With respect to preferred compounds of formula IA and IB, where R' is cycloheteroalkyl, R' is exclusive of (e) s (e) and (9 1-piperidinyl, 1-pyrrolidinyl, 1-aZetidinyl or 1-(2-oxo pyrrolidinyl). The MTP inhibitors disclosed in U.S. provisional appli are the same or different and independently represent a 5 or cation Ser. No. 60/017,253, filed May 10, 1996, (file 6 membered heteroaryl ring which may contain 1, 2, 3 or 4 HX82*) are pyrrolidine compounds and have the structure heteroatoms in the ring which are independently N, S or O; 35 and including N-oxides. I X (in the fluorenyl type ring) is a bond, or is one of the following groups: R2 O

(1) 40 R-tY 2Nx N N-R1 Or R W (2) II 45 (3) R51n k N-R1 W (4) 50 O O where Q is -- O – s

(5) O

55 W is H.H or O; (6) X is: CHR, -- s --- O O R9 R10 (7) 60 - kCEC- k ; wherein 65 R, R and R' are independently hydrogen, alkyl, Y is O, N-R or S; alkenyl, alkynyl, aryl, arylalkyl, hete roaryl, n' is 0, 1 or 2; heteroarylalkyl, cycloalkyl, or cycloalkylalkyl, 6,066,653 13 14 R" is alkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl R" is an indenyl-type group of the structure (wherein alkyl preferably has at least 2 carbons, more preferably at least 3 carbons), diarylalkyl, arylalkenyl, E diarylalkenyl, arylalky nyl, diarylalky nyl, diarylalkylaryl, heteroarylalkyl (wherein alkyl prefer- 5 ably has at least 2 carbons, more preferably at least 3 carbons), cycloalkyl, or cycloalkylalkyl (wherein alkyl preferably has at least 2 carbons, more preferably at O least 3 carbons); all of the aforementioned R' groups being optionally Substituted through available carbon 10 atoms with 1, 2, 3 or 4 groupS. Selected from halo, haloalkyl, alkyl, alkenyl, alkoxy, aryloxy, aryl, (a = 2.3 or 4) arylalkyl, alkylmercapto, arylmercapto, cycloalkyl, cycloalkylalkyl, heteroaryl, fluorenyl, heteroarylalkyl, F hydroxy or Oxo, or 15 Ring y- R14 R" is a fluorenyl-type group of the structure \ / O A. -R11-Zl RS4 it 2O R12-Z2 R16a R15a -R G O R12 Z. R13 R14 / \ 25 (i. -D 11-71 O R13 1, 7SR4 R Z. R12-Z1/ R16a R (CH2). 3O B H RQM,NQ y1V R' R13 R14

-D 11-71 R Z. Z. O -R1-Z Q R12-Z2 R12-Z2 R16a

R31, SR4 40 Z" and Z are the same or different and are independently a bond, O, S, C

R13 R14 55 with the proviso that with respect to B, at least one of Z' and D Z will be other than a bond; R16 R15 G. R'' is a bond, alkylene, alkenylene or alkynylene of up to 60 10 carbon atoms, arylene (for example -R11-Zl R12-Z2 ( ) ; or 76. R13 R14 65 -O- 6,066,653 15 16 or mixed arylene-alkylene (for example cycloalkylalkyl, polycycloalkyl, polycycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, polycycloalkenyl, polycycloalkenylalkyl, heteroarylcarbonyl, amino, alkylamino, arylamino, he tero arylamino, cycloalkyloxy, cycloalkylamino, all of the R substitu ents and R substituents (set out hereinafter) being optionally Substituted through available carbon atoms where n is 1 to 6; with 1, 2, 3 or 4 groups Selected from hydrogen, halo, Rf is hydrogen, alkyl, alkenyl, aryl, haloalkyl, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, trihalo alkyl, trihalo alkylalkyl, he tero aryl, cycloalkyl, cycloalkylalkyl, cycloheteroalkyl, heteroarylalkyl, arylalkyl, arylalkenyl, cycloalkyl, cycloheteroalkylalkyl, aryl, heteroaryl, arylalkyl, aryloxy, alkoxy, arylalkoxy or cycloalkylalkyl, with the arylcycloalkyl, arylalkenyl, arylalkynyl, aryloxy, provisos that (1) when R' is H, aryloxy, alkoxy or aryloxyalkyl, arylalkoxy, arylaZo, heteroaryloxo, arylalkoxy, then Z is heteroarylalkyl, heteroarylalkenyl, heteroaryloxy, 15 hydroxy, nitro, cyano, amino, Substituted amino -NH-C- , -N-C-, -C- (wherein the amino includes 1 or 2 substituents which | || | are alkyl, aryl or heteroaryl, or any of the other aryl O alkyl O O compounds mentioned in the definitions), thiol, alkylthio, arylthio, heteroarylthio, arylthioalkyl, alkylcarbonyl, arylcarbonyl, arylaminocarbonyl, or a bond; alko Xy carbonyl, a mino carbonyl, and (2) when Z is a bond, R' cannot be heteroaryl or alkyny lamino carbonyl, alkylamino carbonyl, heteroarylalkyl, alkenylamino carbonyl, alkyl carbonyloxy, Z is a bond, O, S, N-alkyl, N-aryl, or alkylene or alk aryl carbonyl oxy, alkyl carbonyl a mino, enylene of from 1 to 5 carbon atoms; 25 arylcarbonylamino, arylsulfinyl, arylsulfinylalkyl, R", R', R', and Rare independently hydrogen, alkyl, arylsulfonyl, alkylsulfonyl, arylsulfonylamino, halo, haloalkyl, aryl, cycloalkyl, cycloheteroalkyl, hetero arylcarbonylamino, he tero arylsulfinyl, alkenyl, alkynyl, hydroxy, alkoxy, nitro, amino, thio, heteroarylthio, heteroarylsulfonyl, or alkylsulfinyl. alkylsulfonyl, arylsulfonyl, alkylthio, arylthio, Where R is phenyl, aryl, heteroaryl or cycloalkyl; this aminocarbonyl, alkylcarbonyloxy, arylcarbonylamino, group preferably includes an Ortho hydrophobic Sub alkylcarbonylamino, arylalkyl, he te roary 1, Stituent Such as alkyl, haloalkyl (with up to 5 halo heteroarylalkyl, or aryloxy, groups), alkoxy, haloalkoxy (with up to 5 halo groups), R'' and R'' are independently any of the R' or R' aryl, aryloxy or arylalkyl, groups except hydroxy, nitro, amino or thio; 35 R is hydrogen or C-C alkyl or C-C alkenyl; or R' is

R17 o (CH, K R18 40 wherein p is 1 to 8 and R7 and R' are each independently are the same or different and are independently Selected from H, alkyl, alkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heteroaryl containing 5- or 6-ring members, and cycloalkyl or cycloalkylalkyl, at least one of R'' and R' 45 including N-oxides of the formulae I and II compounds, being other than H; that is or R' is

R20 50 ^x) O ; and V R21 R1 wherein R' is aryl or heteroaryl; 55 including pharmaceutically acceptable Salts thereof. R’ is aryl or heteroaryl; The MTP inhibitors disclosed in U.S. provisional appli R is H, alkyl, aryl, alkylaryl, arylalkyl, aryloxy, cation Ser. No. 60/017,254, filed May 10, 1996, (file arylalko Xy, he tero aryl, he tero arylalkyl, heteroarylalkoxy, cycloalkyl, cycloalkylalkyl or HX84*) are azetidine compounds which have the structure cycloalkylalkoxy, 60 I R. R. R" are independently hydrogen, halo, alkyl, O alkenyl, alkoxy, aryloxy, aryl, arylalkyl, alkylmercapto, arylmercapto, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, hydroxy or haloalkyl, N-(CH2) N-R1; or M R is alkyl, alkenyl, alkynyl, aryl, alkoxy, aryloxy, 65 X arylalkoxy, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkyl, cyclohetero alkyl, he tero aryloxy, 6,066,653 17 -continued -continued II D R16 R15 R51 O -cha-(ON-R l -R11-Z O O Z ; or R12-Z2 where Q is -- O – | O R13 R14 X is: CHR - C- -CH-CH- -C=C-: s | s 9 10 O 9 10 O R R R. R. R" is an indenyl-type group of the structure R, R and R'' are independently hydrogen, alkyl, 15 E alkenyl, alkynyl, aryl, arylalkyl, he teroaryl, R13 heteroarylalkyl, cycloalkyl, or cycloalkylalkyl, R14 R" is alkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl / aW (wherein alkyl preferably has at least 2 carbons, more preferably at least 3 carbons), diarylalkyl, arylalkenyl, -R11-Z O diarylalkenyl, arylalkynyl, diarylalkynyl, diarylalkylaryl, R2-Z1/ R16a heteroarylalkyl (wherein alkyl preferably has at least 2 R (CH2) carbons, more preferably at least 3 carbons), cycloalkyl, or (a = 2, 3 or 4) cycloalkylalkyl (wherein alkyl preferably has at least 2 25 F carbons, more preferably at least 3 carbons); all of the Rise y R' aforementioned R' groups being optionally Substituted through available carbon atoms with 1, 2, 3 or 4 groups Selected from halo, haloalkyl, alkyl, alkenyl, alkoxy, -R11-Zl O aryloxy, aryl, arylalkyl, alkylmercapto, arylmercapto, R12-Z2 R16a cycloalkyl, cycloalkylalkyl, heteroaryl, fluorenyl, R15a heteroarylalkyl, hydroxy or oxo; or G

R" is a fluorenyl-type group of the structure 35 RS4 x R15 40 -R11 H Z. O R12

Z. O Z" and Z are the same or different and are independently a bond, O, S,

55 S., f S \ , -NH-C-, -N-C-,-C- or || || | || | O \O/ O alkyl O O H

60 --OH

Z. O with the proviso that with respect to B, at least one of Z' and Z will be other than a bond; 65 R' is a bond, alkylene, alkenylene or alkynylene of up to 10 carbon atoms, arylene (for example 6,066,653 19 20 arylmercapto, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, hydroxy or haloalkyl, R is alkyl, alkenyl, alkynyl, aryl, alkoxy, aryloxy, -O- arylalkoxy, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkyl, cyclohetero alkyl, he tero aryloxy, cycloalkylalkyl, polycycloalkyl, polycycloalkylalkyl, or mixed arylene-alkylene (for example cycloalkenyl, cycloalkenylalkyl, polycycloalkenyl, polycycloalkenylalkyl, heteroarylcarbonyl, amino, alkylamino, arylamino, he tero arylamino, cycloalkyloxy, cycloalkylamino, all of the R substitu ents and R substituents (set out hereinafter) being optionally Substituted through available carbon atoms with 1, 2, 3 or 4 groups Selected from hydrogen, halo, where q is 1 to 6; 15 Rf is hydrogen, alkyl, alkenyl, aryl, haloalkyl, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, trihalo alkyl, trihalo alkylalkyl, he tero aryl, cycloalkyl, cycloalkylalkyl, cycloheteroalkyl, heteroarylalkyl, arylalkyl, arylalkenyl, cycloalkyl, cycloheteroalkylalkyl, aryl, heteroaryl, arylalkyl, aryloxy, alkoxy, arylalkoxy or cycloalkylalkyl, with the arylcycloalkyl, arylalkenyl, arylalkynyl, aryloxy, provisos that (1) when R' is H, aryloxy, alkoxy or aryloxyalkyl, arylalkoxy, arylaZo, heteroaryloxo, arylalkoxy, then Z is heteroarylalkyl, heteroarylalkenyl, heteroaryloxy, hydroxy, nitro, cyano, amino, Substituted amino (wherein the amino includes 1 or 2 substituents which ------O ls O O are alkyl, aryl or heteroaryl, or any of the other aryl 25 compounds mentioned in the definitions), thiol, alkylthio, arylthio, heteroarylthio, arylthioalkyl, or a bond; and (2) when Z is a bond, R' cannot be heteroaryl or alkylcarbonyl, arylcarbonyl, arylaminocarbonyl, heteroarylalkyl, alko Xy carbonyl, a mino carbonyl, Z is a bond, O, S, N-alkyl, N-aryl, or alkylene or alk alkyny lamino carbonyl, alkylamino carbonyl, enylene of from 1 to 5 carbon atoms; alkenylamino carbonyl, alkyl carbonyloxy, R", R', R', and R'' are independently hydrogen, alkyl, aryl carbonyl oxy, alkyl carbonyl a mino, halo, haloalkyl, aryl, cycloalkyl, cycloheteroalkyl, arylcarbonylamino, arylsulfinyl, arylsulfinylalkyl, alkenyl, alkynyl, hydroxy, alkoxy, nitro, amino, thio, arylsulfonyl, alkylsulfonyl, arylsulfonylamino, alkylsulfonyl, arylsulfonyl, alkylthio, arylthio, 35 hetero arylcarbonylamino, he tero arylsulfinyl, aminocarbonyl, alkylcarbonyloxy, arylcarbonylamino, heteroarylthio, heteroarylsulfonyl, or alkylsulfinyl. alkylcarbonylamino, arylalkyl, he te roary 1, Where R is phenyl, aryl, heteroaryl or cycloalkyl; this heteroarylalkyl, or aryloxy, group preferably includes an Ortho hydrophobic Sub R'' and R'' are independently any of the R' or R' Stituent Such as alkyl, haloalkyl (with up to 5 halo groups except hydroxy, nitro, amino or thio; 40 groups), alkoxy, haloalkoxy (with up to 5 halo groups), or R' is aryl, aryloxy or arylalkyl, R is hydrogen or C-C alkyl or C-C alkenyl; R17 45 R18 wherein p is 1 to 8 and R7 and R' are each independently H, alkyl, alkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or cycloalkylalkyl, at least one of R'' and R' 50 being other than H; are the same or different and are independently Selected from or R' is heteroaryl containing 5- or 6-ring members, and

55 including N-oxides of the formulae I and II compounds, that is wherein R' is aryl or heteroaryl; R" is aryl or heteroaryl; 60 R is H, alkyl, aryl, alkylaryl, arylalkyl, aryloxy, arylalko Xy, he tero aryl, he tero arylalkyl, heteroarylalkoxy, cycloalkyl, cycloalkylalkyl or including pharmaceutically acceptable Salts thereof. cycloalkylalkoxy, 65 The MTP inhibitors disclosed in U.S. provisional appli R. R. R" are independently hydrogen, halo, alkyl, cation Ser. No. 60/028,216, filed Oct. 1, 1996, have the alkenyl, alkoxy, aryloxy, aryl, arylalkyl, alkylmercapto, Structure 6,066,653 21 22 polycycloalkyl, polycycloalkylalkyl, cycloalkenyl, I cycloheteroalkyl, heteroaryloxy, cycloalkenylalkyl, O O polycycloalkenyl, polycycloalkenylalkyl, L2 us L heteroarylcarbonyl, amino, alkylamino, arylamino, R21" NA B1 SK 5 heteroarylamino, cycloalkyloxy, cycloalkylamino, all \Yo O optionally Substituted through available carbon atoms | with 1, 2, 3 or 4 groups Selected from hydrogen, halo, NHCR alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, 1O cycloalkyl, cycloalkylalkyl, cycloheteroalkyl, including pharmaceutically acceptable Salts thereof, wherein cycloheteroalkylalkyl, aryl, heteroaryl, arylalkyl, A is (1) a bond; arylcycloalkyl, arylalkenyl, arylalkynyl, aryloxy, (2) -O-, or aryloxyalkyl, arylalkoxy, arylaZo, heteroaryloxo, heteroarylalkyl, heteroarylalkenyl, heteroaryloxy, (3) 15 hydroxy, nitro, cyano, amino, Substituted amino, thiol, -- alkylthio, arylthio, heteroarylthio, arylthioalkyl, R5 alkylcarbonyl, arylcarbonyl, arylaminocarbonyl, alko Xy carbonyl, a mino carbonyl, where R is H or lower alkyl or R together with R forms 20 alkyny lamino carbonyl, alkylamino carbonyl, a carbocyclic or heterocyclic ring System containing 4 to 8 alkenylamino carbonyl, alkylcarbonyloxy, members in the ring. aryl carbonyl oxy, alkyl carbonyl a mino, B is a fluorenyl-type group of the Structure: arylcarbonylamino, arylsulfinyl, arylsulfinylalkyl, arylsulfonyl, alkylsulfonyl, arylsulfonylamino, 25 hetero arylcarbonylamino, he tero arylsulfinyl, heteroarylthio, heteroarylsulfonyl, alkylsulfinyl, 4. 4. R is alkyl, alkenyl, alkynyl, alkoxyl, (alkyl or aryl)-Si R R3 Y (where each alkyl or aryl group is independent), O (C or 30 cycloalkyl, cycloalkenyl, Substituted alkylamino, Sub eX Stituted arylalkylamino, aryl, arylalkyl, arylamino, R4 R3 X R4 aryloxy, heteroaryl, heteroarylamino, heteroaryloxy, arylsulfonylamino, heteroarylsulfonylamino, arylthio, arylsulfinyl, arylsulfonyl, alkylthio, alkylsulfinyl, 35 alkylsulfonyl, heteroarylthio, heteroarylsulfinyl, so . R setts heteroarylsulfonyl, -PO(R') (R'), (where R' and R" are independently alkyl, aryl, alkoxy, aryloxy, he tero aryl, he tero arylalkyl, he tero aryloxy, 40 he tero arylalko Xy, cyclohe tero alkyl, cyclohetero alkylalkyl, cyclohete roalkoxy, or cycloheteroalkylalkoxy); R' can also be aminocarbonyl (where the amino may optionally be substituted with one or two aryl, alkyl or heteroaryl groups); cyano, 45 1,1-(alkoxyl or aryloxy)-alkyl (where the two aryl or alkyl Substituents can be independently defined, or linked to one another to form a ring, Such as 1,3- dioxane or 1,3-dioxolane, connected to L' (or L in the case of R) at the 2-position); 1,3-dioxane or 1,3- 50 dioxolane connected to L' (or L in the case of R) at the 4-position. R3 The R group may have from one to four substituents, R3 R3 R3 which can be any of the R groups or R groups, and any of (i. G. 55 the preferred R substituents set out below. R may be substituted with the following preferred sub O C Stituent S : alkyl carbonyl a mino, 52. R3b R3b cycloalkylcarbonylamino, arylcarbonylamino, R3a (CH2) R3a 60 heteroarylcarbonylamino, alkoxycarbonylamino, aryloxycarbonylamino, heteroaryloxylcarbonylamino, (the above B is also referred to as uriedo (where the uriedo nitrogens may be substituted an indenyl-type ring or moiety); with alkyl, aryl or heteroaryl), heterocyclylcarbony lamino (where the heterocycle is connected to the R" is independently alkyl, alkenyl, alkynyl, aryl, alkoxy, 65 carbonyl group via a nitrogen or carbon atom), aryloxy, arylalkoxy, he tero aryl, arylalkyl, alkylsulfonyla mino, aryl Sulfonylamino, hete roarylalkyl, cycloalkyl, cycloalkylalkyl, heteroarylsulfonylamino, 6,066,653 23

R20 O (1) X^n R21 N-, y 2 / (2) R22 where J is: CHR, -C-, -CH-CH O (3)

l k is 1O -C=C-: k ls (4)

(5) R, R and R are independently hydrogen, alkyl, 15 alkenyl, alkynyl, aryl, arylalkyl, he teroaryl, heteroarylalkyl, cycloalkyl, or cycloalkylalkyl, R', R, Rf are independently hydrogen, halo, alkyl, (6) alkenyl, alkoxy, aryloxy, aryl, arylalkyl, alkylmercapto, arylmercapto, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, hydroxy or haloalkyl, and these pre (7) ferred substituents may either be directly attached to R", or attached via an alkylene chain at an open position. 25 L' is a linking group containing from 1 to 10 carbons in wherein a linear chain (including alkylene, alkenylene or alkynylene), which may contain, within the linking Y is O, N-R or S; chain any of the following: one or two alkenes, one or n' is 0, 1 or 2; two alkynes, an oxygen, an amino group optionally R is H, lower alkyl, aryl, -C(O)-R' or -C(O)-O- Substituted with alkyl or aryl, an OXO group; and may be R11; Substituted with one to five alkyl or halo groups R7 and Rare the same or different and are independently (preferably F). H, alkyl, aryl, halogen, -O-R' or L may be the same or different from L and may 35 R" and R together can be oxygen to form a ketone; independently be any of the L' groups set out above or R. R', R'' and R'' are the same or different and are a singe bond. independently H, lower alkyl, aryl or -O-R'; R, R, R" and R" may be the same or different and are R" and R'" are the same or different and are indepen independently selected from H, halogen, CF, dently H, lower alkyl, aryl, halogen or -O-R'; haloalkyl, hydroxy, alkoxy, alkyl, aryl, alkenyl, 40 alkenyloxy, alkynyl, alkynyloxy, alkanoyl, nitro, R' is alky or aryl; amino, thiol, alkylthio, alkylsulfinyl, alkylsulfonyl, R’ is H, alkyl or aryl. carboxy, alkoxy carbonyl, a mino carbonyl, Compounds disclosed as preferred in each of the above alkyl carbonyl oxy, alkyl carbony la mino, applications are preferred for use in the present invention. cycloheteroalkyl, cycloheteroalkylalkyl, cyano, Ar, 45 Most preferred MTP inhibitors to be employed in accor Ar-alkyl, Ar0, Ar-amino, Ar-thio, Ar-Sulfinyl, dance with the present invention include preferred MTP Ar-Sulfonyl, Ar-carbonyl, Ar-carbonyloxy or inhibitors as set out in U.S. patent application Ser. No. Ar-carbonylamino, wherein Aris aryl or heteroaryland 548,811, filed Jan. 11, 1996 (file DC21h) and in U.S. Ar may optionally include 1, 2 or 3 additional rings provisional application Ser. No. 60/017,224, filed May 9, fused to Ar; 50 1996 (file HX79a). R" and R are the same or different and are indepen Thus, preferred compounds in U.S. patent application Ser. dently any of the R groups except hydroxy, nitro, No. 548,811 (file DC21h) for use herein are compounds amino or thio; where Z is a bond; 55 X' and X’ are H; R is aryl such as phenyl substituted with (e) s (e) and (e) (1) aryl Such as phenyl, 60 CH are the same or different and independently represent a 5 or 6 membered heteroaryl ring which may contain 1, 2, 3 or 4 heteroatoms in the ring which are independently N, S or O; -O- s s and including N-oxides. 65 C X (in the fluorenyl type ring) is a bond, or is one of the following groups: 6,066,653 25 26 (2) heteroaryl Such as

(3) halo such as Cl 15 R is heteroaryl such as Preferred compounds in U.S. provisional application Ser. No. 60/017,224 (file HX79a) for use herein are MTP inhibitor compounds of formula I that is

25 Substituted with wherein A is NH, B is (1) aroyl Such as 3O O

-C s

35 X is a bond, oxygen or sulfur; R and R' are indepen (2) arylthio Such as dently H or F. Preferred R' groups are aryl, preferably phenyl, 40 heteroaryl, preferably imidazoyl or pyridyl (preferably sub stituted with one of the preferred R' substituents: arylcarbonylamino, he tero arylcarbonylamino, cycloalkylcarbonylamino, alkoxycarbonylamino, alkylsulfonyla mino, aryl Sulfonyl a mino, 45 heteroarylsulfonylamino), PO(OAlkyl), heteroarylthio, benzthiazole-2-thio, imidazole-2-thio, alkyl, or alkenyl, wherein the R substituent is preferably in the position cycloalkyl Such as cyclohexyl, or 1,3-dioxan-2-yl. adjacent to the carbon linked to Preferred R groups are alkyl, polyfluoroalkyl (such as 1,1,1-trifluoroethyl), alkenyl, aryl or heteroaryl (preferably O 50 substituted with one of the preferred R' substituents above), | or PO(OAlkyl). C. If R is alkyl, 1,1,1-trifluoroethyl, or alkenyl, it is pre ferred that R is other than alkyl or alkenyl. It is preferred that L' contains 1 to 5 atoms in the linear 55 chain and L is a bond or lower alkylene. (CH) is -(CH2)- or Preferred embodiments of formula IA and formula IB compounds of the invention include those where B, L, L, f R" and R are as set out with respect to the preferred -CH-CH-C-CH-. embodiments of the formula I compounds, q is 0 or 2 and R' 60 is H. The other cholesterol lowering drugs or delipidating drugs which may be used in the method of the invention include HMG CoA reductase inhibitors, squalene synthetase Most preferred is inhibitors, fibric acid derivatives, bile acid Sequestrants, 9-4-4-2-(2,2,2-trifluoromethyl)-benzoylamino]-1- 65 probucol, niacin, niacin derivatives and the like. piperidinylbutyl-N-(2,2,2-trifluoroethyl)-9H The HMG CoA reductase inhibitors Suitable for use fluorene-9-carboxamide herein include, but are not limited to, mevastatin and related 6,066,653 27 28 compounds as disclosed in U.S. Pat. No. 3,983,140, lovas -continued tatin (mevinolin) and related compounds as disclosed in U.S. Pat. No. 4,231,938, pravastatin and related compounds such as disclosed in U.S. Pat. No. 4,346,227, simvastatin and 2^4 related compounds as disclosed in U.S. Pat. Nos. 4,448,784 and 4,450,171, with pravastatin, lovastatin or Simvastatin being preferred. Other HMG CoA reductase inhibitors which may be employed herein include, but are not limited including the triacids thereof, triesters thereof and tripotas to, fluvastatin, cerivastatin, atorvastatin, pyrazole analogs of sium and trisodium Salts thereof as well as other Squalene synthetase inhibitors disclosed in U.S. Pat. Nos. 4,871,721 mevalonolactone derivatives as disclosed in U.S. Pat. No. and 4,924,024 and in Biller et al., J. Med. Chem., 1988, Vol. 4,613,610, indene analogs of mevalonolactone derivatives 31, No. 10, pp 1869 to 1871. as disclosed in PCT application WO 86/03488, 6-2- In addition, other Squalene Synthetase inhibitors Suitable (Substituted-pyrrol-1-yl)alkylpyran-2-ones and derivatives for use herein include the terpenoid pyrophosphates dis thereof as disclosed in U.S. Pat. No. 4,647,576, Searle's 15 closed by P. Ortiz de Montellano et al., J. Med. Chem.; 1977, SC-45355 (a 3-substituted pentanedioic acid derivative) 20, 243-249, the farnesyl diphosphate analog A and dichloroacetate, imidazole analogs of mevalonolactone as preSqualene pyrophosphate (PSQ-PP) analogs as disclosed disclosed in PCT application WO 86/07054, 3-carboxy-2- by Corey and Volante, J. Am. Chem. Soc. 1976, 98, hydroxy-propane-phosphonic acid derivatives as disclosed 1291-1293, phosphinylphosphonates reported by McClard, in French Patent No. 2,596,393, 2,3-di-substituted pyrrole, R. W. et al., J.A.C.S., 1987, 109, 5544 and cyclopropanes furan and thiophene derivatives as disclosed in European reported by Capson, T. L., PhD dissertation, June, 1987, Patent Application No. 0221025, naphthyl analogs of meva Dept. Med. Chem. U. of Utah, Abstract, Table of Contents, lonolactone as disclosed in U.S. Pat. No. 4,686,237, octahy pp. 16, 17, 40-43, 48-51, Summary. Preferred are pravastatin, lovastatin or Simvastatin. dronaphthalenes such as disclosed in U.S. Pat. No. 4,499, All of the above U.S. applications are incorporated herein 289, keto analogs of mevinolin (lovastatin) as disclosed in 25 by reference. European Patent Application No. 0,142,146 A2, as well as Other cholesterol lowering drugs Suitable for use herein other known HMG CoA reductase inhibitors. include, but are not limited to, antihyperlipoproteinemic In addition, phosphinic acid compounds useful in inhib agents Such as fibric acid derivatives, Such as fenofibrate, iting HMG CoA reductase suitable for use herein are dis gemfibrozil, clofibrate, bezafibrate, ciprofibrate, clinofibrate closed in GB 2205837. and the like, probucol, and related compounds as disclosed The Squalene Synthetase inhibitorS Suitable for use herein in U.S. Pat. No. 3,674,836, probucol and gemfibrozil being include, but are not limited to, C.-phosphonoSulfonates dis preferred, bile acid Sequestrants Such as cholestyramine, closed in U.S. application Ser. No. 08/266,888, filed Jul. 5, colestipol and DEAE-Sephadex (Secholex(R, Polidexide(R), 1994 (HX59b), those disclosed by Biller et al., J. Med. as well as clofibrate, lipostabil (Rhone-Poulenc), Eisai Chem. 1988, Vol. 31, No. 10, pp 1869–1871, including 35 E-5050 (an N-substituted ethanolamine derivative), imanixil isoprenoid (phosphinylmethyl)phosphonates Such as those (HOE-402), tetrahydrolipstatin (THL), istigmastanylphos of the formula phorylcholine (SPC, Roche), aminocyclodextrin (Tanabe Seiyoku), Ajinomoto AJ-814 (azulene derivative), melina mide (Sumitomo), Sandoz 58-035, American Cyanamid CL-277,082 and CL-283,546 (disubstituted urea 40 derivatives), nicotinic acid, acipimox, acifran, neomycin, R-B-CH-E-O" p-aminosalicylic acid, aspirin, poly(diallylmethylamine) derivatives such as disclosed in U.S. Pat. No. 4,759,923, quaternary amine poly(diallyldimethylammonium chloride) II and ionenes Such as disclosed in U.S. Pat. No. 4,027,009, 45 and other known Serum cholesterol lowering agents. The above-mentioned U.S. patents are incorporated herein by reference. O O The MTP inhibitor will be employed in a weight ratio to R1 the other cholesterol lowering or delipidating agent (where 50 present), in accordance with the present invention, within the range from about 500:1 to about 1:500, preferably from about 100:1 to about 1:100. 21 21 21 In carrying out the method of the present invention, the MTP inhibitor alone or optionally in combination with the other cholesterol lowering drug may be administered to b 55 mammalian Species, Such as monkeys, dogs, cats, rats, humans, etc., and as Such may be incorporated in a conven tional Systemic dosage form, Such as a tablet, capsule, elixir 21 21 2n-4 or injectable. The above dosage forms will also include the necessary carrier material, excipient, lubricant, buffer, 60 antibacterial, bulking agent (Such as mannitol), anti-oxidants (ascorbic acid of sodium bisulfite) or the like. Oral dosage forms are preferred, although parenteral forms are quite Satisfactory as well. 21 21 21 The dose administered must be carefully adjusted accord 65 ing to age, weight and condition of the patient, as well as the route of administration, dosage form and regimen and the desired result. 6,066,653 29 30 The dosages and formulations for the MTP inhibitor will materials according to accepted pharmaceutical practice. be as disclosed in the various patents and applications These tablets can, of course, be Scored to provide for discussed above. fractional doses. Gelatin capsules can be similarly formu The dosages and formulations for the other delipidating lated. agent to be employed, where applicable, will be as Set out in Liquid formulations can also be prepared by dissolving or the latest edition of the Physicians Desk Reference. Suspending one or the combination of active Substances in a For oral administration, a Satisfactory result may be conventional liquid vehicle acceptable for pharmaceutical obtained employing the MTP inhibitor in an amount within administration So as to provide the desired dosage in one to the range of from about 0.01 mg/kg to about 100 mg/kg and four teaspoonsful. preferably from about 0.1 mg/kg to about 75 mg/kg, one to Such dosage forms can be administered to the patient on four times daily. a regimen of one to four doses per day. A preferred oral dosage form, Such as tablets or capsules, According to another modification, in order to more finely will contain the MTP inhibitor in an amount of from about regulate the dosage Schedule, the active Substances may be 1 to about 500 mg, preferably from about 2 to about 400 mg, administered Separately in individual dosage units at the and more preferably from about 5 to about 250 mg, one to 15 Same time or carefully coordinated times. Since blood levels four times daily. are built up and maintained by a regulated Schedule of For parenteral administration, the MTP inhibitor will be administration, the same result is achieved by the Simulta employed in an amount within the range of from about 0.005 neous presence of the two Substances. The respective Sub mg/kg to about 10 mg/kg and preferably from about 0.005 stances can be individually formulated in Separate unit mg/kg to about 8 mg/kg, one to four times daily. dosage forms in a manner Similar to that described above. The other cholesterol lowering or delipidating agent will Fixed combinations of MTP inhibitor and other choles be employed in amounts Set out in the latest edition of the terol lowering drug are more convenient and are preferred, Physician's Desk Reference (PDR). especially in tablet or capsule form for oral administration. For oral administration, a Satisfactory result may be In formulating the compositions, the active Substances, in obtained employing an HMG CoA reductase inhibitor in 25 the amounts described above, are compounded according to dosages employed, for example, pravastatin, lovastatin, accepted pharmaceutical practice with a physiologically Simvastatin, atorvastatin, fluvastatin or cerivastatin as indi acceptable vehicle, carrier, excipient, binder, preservative, cated in the Physician's Desk Reference, Such as in an Stabilizer, flavor, etc., in the particular type of unit dosage amount within the range of from about 1 to 2000 mg, and form. preferably from about 4 to about 200 mg. Illustrative of the adjuvants which may be incorporated in The Squalene Synthetase inhibitor may be employed in tablets are the following: a binder Such as gum tragacanth, dosages in an amount within the range of from about 10 mg acacia, corn Starch or gelatin; an excipient Such as dicalcium to about 2000 mg and preferably from about 25 mg to about phosphate or cellulose; a disintegrating agent Such as corn 200 mg. Starch, potato Starch, alginic acid or the like; a lubricant Such A preferred oral dosage form, Such as tablets or capsules, 35 as Stearic acid or magnesium Stearate; a Sweetening agent will contain the HMG CoA reductase inhibitor in an amount Such as Sucrose, aspartame, lactose or Saccharin; a flavoring of from about 0.1 to about 100 mg, preferably from about 5 agent Such as orange, peppermint, oil of Wintergreen or to about 80 mg, and more preferably from about 10 to about cherry. When the dosage unit form is a capsule, it may 40 mg. contain in addition to materials of the above type a liquid A preferred oral dosage form, Such as tablets or capsules 40 carrier Such as a fatty oil. Various other materials may be will contain the Squalene Synthetase inhibitor in an amount present as coatings or to otherwise modify the physical form of from about 10 to about 500 mg, preferably from about 25 of the dosage unit. For instance, tablets or capsules may be to about 200 mg. coated with shellac, Sugar or both. A Syrup of elixir may The Serum cholesterol lowering drugs when present will contain the carrier, glycerol as Solubilizer, Sucrose as Sweet be employed in dosages normally employed as indicated in 45 ening agent, methyl and propyl parabens as preservatives, a the Physician's Desk Reference, for each of such agents dye and a flavoring Such as cherry or orange. Such as in an amount within the range of from about 2 mg Some of the active Substances described above form to about 7500 mg and preferably from about 2 mg to about commonly known, pharmaceutically acceptable Salts. Such as 4000 mg. alkali metal and other common basic Salts or acid addition A preferred oral dosage form, Such as tablets or capsules, 50 Salts, etc. References to the base Substances are therefore will contain MTP inhibitor in an amount of from about 10 intended to include those common Salts known to be Sub to about 400 mg, and the HMG CoA reductase inhibitor Stantially equivalent to the parent compound. (where present) in an amount of from about 0.1 to about 100 The formulations as described above will be administered mg, preferably from about 5 to about 80 mg, and more for a prolonged period, that is, for as long as the acid lipase preferably from about 10 to about 50 mg. 55 deficiency exists. Sustained release forms of Such formula The MTP inhibitor and other cholesterol lowering drug tions which may provide Such amounts biweekly, weekly, may be employed together in the same oral dosage form or monthly and the like may also be employed. in Separate oral dosage forms taken at the Same time. The following Examples represent preferred embodi The compositions described above may be administered ments of the present invention. in the dosage forms as described above in Single or divided 60 doses of one to four times daily. It may be advisable to start EXAMPLES 1 AND 2 a patient on a low dose combination and work up gradually to a high dose combination. Formulations Suitable for oral administration are prepared Tablets of various sizes can be prepared, e.g., of about 2 as described below. to 2000 mg in total weight, containing one or both of the 65 Capsules containing 1 mg MTP inhibitor BMS 201,038 active Substances in the ranges described above, with the (Example 1) and capsules containing 50 mg BMS 201,038 remainder being a physiologically acceptable carrier of other (Example 2) are produced from the following ingredients. 6,066,653 31 32 4. The method as defined in claim 3 wherein the HMG CoA reductase inhibitor is pravastatin, lovastatin, Simvastatin, atorvastatin, fluvastatin or cerivastatin. Example 1 Example 2 5. The method as defined in claim 2 wherein the choles Amount (mg/ Amount (mg/ Ingredient Capsule) Capsule) terol lowering drug is a fibric acid derivative which is gemfibrozil, fenofibrate, clofibrate, beZafibrate, ciprofibrate, BMS-201038 (1) 1.1 56.9 clinofibrate, probucol, gemfibrozil, dextrothyroxine or its Lactose, Hydrous, NF Ca. Ca. 30.2 99.9 Sodium Salt, colestipol or its hydrochloride, cholestyramine, Lactose, Anhydrous, NF 47.3 O.O nicotinic acid, neomycin, p-aminoSalicylic acid or aspirin. Microcrystalline Cellulose, 1.O.O SO.O 1O 6. The method as defined in claim 2 wherein the MTP NF Pregelatinized Starch, NF 5.0 25.0 inhibitor is present in a weight ratio to other cholesterol Sodium Starch Glycolate, NF 5.0 12.5 lowering drug within the range from about 500:1 to about Colloidal Silicon Dioxide, 1.O 5.0 1:500. NF 7. The method as defined in claim 1 or 2 wherein the MTP Magnesium Stearate, NF O.3 O6 15 inhibitor has the structure Purified Water, USP or C.S. C.S. Water for Injection, USP C.S. C.S. Gray, Opaque, Size #0 One Capsule One Capsule Capsule Shell about about Total Fill Weight 1OO.O ( ) | H (1) In Example 1 this amount is expressed in terms of the amount of C-N-CH-CF, methane sulfonic acid salt per capsule at 100% potency. In Example 2, Z. O| this amount is expressed in terms of the free base This is equivalent to 1 mg and 50 mg (Examples 1 and 2, respectively) of the free base. 25 ( ) (CH2), N. N- C-Rs The MTP inhibitor BMS 201,038, and colloidal silicon dioxide are blended in a Suitable blender with lactose hydrous, microcrystalline cellulose, pregelatinized Starch and a portion of Sodium Starch glycolate. The resulting blend X2 is wet granulated with water. The wet granulation is dried in a Suitable dryer. The remaining portion of Sodium Starch wherein Z is a bond, O or S; glycolate is added to the granulation and mixed therein. x' and x are independently selected from H or halo; Magnesium Stearate is added to the granulation and mixed X is an integer from 2 to 6; therein. The resulting blend is filled into capsules. R is heteroaryl, aryl, heterocycloalkly or cycloalkyl, each EXAMPLE 3 35 R group being optionally substituted with 1, 2, 3 or 4 Pravastatin tablets (10, 20 or 40 mg as described in the substituents which may be the same or different; 1996 PDR) and MTP inhibitor (BMS 201,238) tablets may the piperidine N-oxide thereof, and pharmaceutically be administered as a combination in accordance with the acceptable Salts thereof. teachings of the present invention. In addition, the pravas 8. The method as defined in claim 7 where in the MTP tatin and MTP inhibitor tablets may be ground up into 40 inhibitor Z is a bond. powders and used together in a Single capsule. 9. The method as defined in claim 7 where the MTP EXAMPLE 4 inhibitor is a piperidine N-oxide. 10. The method as defined in claim 7 where in the MTP Tablets containing 500 mg clofibrate by itself or in inhibitor (CH) is optionally substituted with 1, 2 or 3 combination with 10 mg BMS 201,038 may be employed in 45 Substituents which are the Same or different and are alkyl or Separate dosage forms or combined in a Single capsule form. halo. EXAMPLES 5, 6 AND 7 11. The method as defined in claim 7 where in the MTP inhibitor R is substituted with 1,2,3 or 4 substituents which Ciprofibrate, bezafibrate, gemfibrozil alone or in combi may be the same or different and are halogen, monocyclic nation with an MTP inhibitor may also be prepared in a 50 hete roaryl, bicyclic hete roaryl, hete roarylalkyl, manner described hereinbefore in Examples 1 to 3. cycloheteroalkyl, alkyl, alkoxy, cycloalkyl, aryl, aryloxy, What is claimed is: Substituted aryl, arylalkyloxy, heteroaryloxy, amino, 1. A method for inhibiting or treating a disease associated alkylamino, alkyl(aryl)amino, heteroarylamino, arylamino, with acid lipase deficiency in a mammalian Species, which alkylthio, arylthio, arylthioalkyl, heteroarylthio, arylsulfinyl comprises administering to a patient in need thereof a 55 therapeutically effective amount of at least one MTP inhibi or acyl. tor to lower plasma cholesterol and triglycerides and thereby 12. The method as defined in claim 7 wherein at least one minimize cholesteryl ester and triglyceride accumulation in of the substituents of the MTP inhibitor R is attached to a lySOSomes. carbon in the position adjacent to the carbon linked to 2. The method as defined in claim 1 wherein the MTP 60 inhibitor is employed in combination with another type of C. cholesterol lowering drug. O 3. The method as defined in claim 2 wherein the other cholesterol lowering drug is an HMG CoA reductase inhibitor, a Squalene Synthetase inhibitor, a fibric acid 65 13. The method as defined in claim 11 where in the MTP derivative, probucol, a bile acid Sequestrant, nicotinic acid inhibitor R is substituted with 1, 2, 3 or 4 of one or more or neomycin. of the following 6,066,653 33 I, Cl, F, CF -continued

H -N -S Cl; , , , CF CHO

-S , -S OCH3,

OCH3

15 NC 21 CH 2 S sy- s s / \ N-N -S s NRN N-N alkanoyl, alkoxycarbonyl, aroyl, heteroarylaminocarbonyl, arylalkyloxycarbonyl, 21 als, CH N Sa | 21 \, Nf : N OH 25 =o CF CH N - N(CH)-CH / \

S where x is 1 to 5 35 V o o-cu-O- --()– CF3,

O COC), 40 CH - s --O-g alkyl, phenyl, phenyl substituted with halo, alkyl, CF3O, alkoxy, Cl 45 CF 14. The method as defined in claim 13 where in the MTP inhibitor R is phenyl substituted with haloalkylphenyl or CF, CF, or phenyl: heteroaryl. where p is 1 to 5, -N(CH3)CHs: S (CH2)CF, 50 15. The method as defined in claim 14 where in the MTP CF inhibitor R is

where p is 1 to 5, CF3, S-alkyl, CF O 55 —s-cis--cal -O-(CH2) -CF, O

CF 60 CF3, OCH3; cyclohexyl, O G

Cl; 65 amino, 16. The method as defined in claim 13 where in the MTP inhibitor is 6,066,653 35 36 (2) -o-; or (3) -N- CF

where R is H or lower alkyl, or R together with R forms a carbocyclic or heterocyclic ring System containing 4 to 8 10 members in the ring; B is a fluorenyl-type group of the Structure

B is an indenyl-type group of the Structure

17. The method as defined in claim 1 wherein the disease to be treated is Wolman disease. 18. The method as defined in claim 1 wherein the disease to be treated is cholesteryl ester Storage disease. 19. The method as defined in claim 1 wherein the MTP 35 inhibitor lowers plasma LDL-cholesterol to at least 50% of normal LDL blood levels, and lowers triglycerides to at least 50% of normal triglyceride blood levels. (a = 2, 3 or 4) 20. The method as defined in claim 2 wherein the MTP 40 R3 inhibitor has the structure R R3 R3

O 45 O Q R21 sus-lYA B1 NR1 3a 52.(CH2) 3. R3b R3b O R R3a

(SR)4 50 R is H, alkyl or aryl; I R" is alkyl, alkenyl, alkynyl, alkoxyl, (alkyl or aryl)-Si R N.1N1'N, (there each alkyl or aryl group is independent), O cycloalkyl, cycloalkenyl, Substituted alkylamino, Sub IB Stituted arylalkylamino, aryl, arylalkyl, arylamino, OH 55 aryloxy, heteroaryl, heteroarylamino, heteroaryloxy, arylsulfonylamino, heteroarylsulfonylamino, arylthio, arylsulfinyl, arylsulfonyl, alkylthio, alkylsulfinyl, alkylsulfonyl, heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl, -PO(R') (R'), (where R' and 60 R" are independently alkyl, aryl, alkoxy, aryloxy, he tero aryl, he tero arylalkyl, he tero aryloxy, including pharmaceutically acceptable Salts thereof, he tero arylalko Xy, cyclohe tero alkyl, N-oxides thereof, cyclohetero alkylalkyl, cyclohete roalkoxy, or cycloheteroalkylalkoxy); aminocarbonyl (where the 65 amino may optionally be Substituted with one or two wherein q is 0, 1 or 2, aryl, alkyl or heteroaryl groups); cyano, 1,1-(alkoxyl or A is (1) a bond; aryloxy)-alkyl (where the two aryl or alkyl Substituents 6,066,653 37 38 can be independently defined, or linked to one another R" and R are the same or different and are indepen to form a ring connected to L' (or L in the case of R) dently any of the R groups except hydroxy, nitro, at the 2-position); 1,3-dioxane or 1,3-dioxolane con amino or thio; nected to L' (or L in the case of R) at the 4-position; the R' group may optionally be substituted with 1, 2, 3 or 4 substituents, which can be any of the R or R' group S O alkyl carbony la mino, cycloalkylcarbonylamino, arylcarbonylamino, (e) s (e) and (9 heteroarylcarbonylamino, alkoxycarbonylamino, aryloxycarbonylamino, heteroaryloxylcarbonylamino, 1O uriedo (where the uriedo nitrogens may optionally be are the same or different and independently represent a 5 or Substituted with alkyl, aryl or heteroaryl), heterocyclyl 6 membered heteroaryl ring which contains 1, 2, 3 or 4 carbonylamino (where the heterocycle is connected to heteroatoms in the ring which are independently N, S or O; the carbonyl group via a nitrogen or carbon atom), and including N-oxides, alkylsulfonyl amino, aryl Sulfonylamino, 15 X is a bond, or is one of the following groups: heteroarylsulfonylamino, (1) R20 O -S-; (O) R21 \ N N-, (2) yeS/ -O-; R22 (3) where J is: CHR2, -C-, -CH-CH-, or -N-; 25 4 - is R -C=C-: (4) k ls -R? CYrs -; (5) R, R and R are independently hydrogen, alkyl, C C - ; alkenyl, alkynyl, aryl, arylalkyl, he teroaryl, R? YRio R/ YRio heteroarylalkyl, cycloalkyl, or cycloalkylalkyl, (6) R', R, Rf are independently hydrogen, halo, alkyl, - CEC ; or alkenyl, alkoxy, aryloxy, aryl, arylalkyl, alkylmercapto, 35 le arylmercapto, cycloalkyl, cycloalkylalkyl, heteroaryl, (7) heteroarylalkyl, hydroxy or haloalkyl, and these Sub -C-Y- stituents may either be directly attached to R', or R? YRio attached via an alkylene at an open position; R’ is independently any of the groups set out for R, H, 40 polyhaloalkyl, or cycloheteroalkyl, and may be option wherein ally Substituted with one to four of any of the groups Y is O, N-R or S; defined for R or substituents defined for R'; n' is 0, 1 or 2; L' is a linking group containing from 1 to 10 carbons in R is H., lower alkyl, aryl, -C(O)-R' or -C(O) a linear chain including alkylene, alkenylene or 45 -O-R', alkynylene, which may contain, within the linking R" and RS are the same or different and are independently chain any of the following: one or two alkenes, one or H, alkyl, aryl, halogen, -O-R'', or two alkynes, an oxygen, an amino group, an OXO group, R" and R together can be oxygen to form a ketone; and may be substituted with one to five alkyl or halo 50 R. R', R'' and R'' are the same or different and are groups, independently H, lower alkyl, aryl or -O-R'; L may be the same or different from L and may R" and R'" are the same or different and are indepen independently be any of the L' groups set out above or dently H, lower alkyl, aryl, halogen or -O-R'; a singe bond; R'' is alky or aryl; R, R, R and R" may be the same or different and are 55 R" is H, alkyl or aryl. independently Selected from H, halogen, CF, 21. The method as defined in claim 20 wherein the MTP haloalkyl, hydroxy, alkoxy, alkyl, aryl, alkenyl, inhibitor has the structure alkenyloxy, alkynyl, alkynyloxy, alkanoyl, nitro, amino, thiol, alkylthio, alkylsulfinyl, alkylsulfonyl, O carboxy, alkoxy carbonyl, a mino carbonyl, 60 alkyl carbonyl oxy, alkyl carbony la mino, L3 us L cycloheteroalkyl, cycloheteroalkylalkyl, cyano, Ar-, R21" NA B1 NR 1. Ar-alkyl, Ar0, Ar-amino, Ar-thio, Ar-Sulfinyl, Ar-Sulfonyl, Ar-carbonyl, Ar-carbonyloxy or 22. The method as defined in claim 21 wherein A is a Ar-carbonylamino, wherein Aris aryl or heteroaryland 65 bond. Ar may optionally include 1, 2 or 3 additional rings 23. The method as defined in claim 21 wherein A is fused to Ar; 6,066,653 39 40 24. The method as defined in claim 21 wherein A is B is a fluorenyl-type group of the Structure

-N- R3 5 Xs

25. The method as defined in claim 21 wherein B is a fluorenyl-type group. CC 26. The method as defined in claim 21 having the formula 1O

O R21NAis-s-l B1 NR1 15 wherein B is B is an indenyl-type group of the Structure

R3 / | Ax' Rayy-R o O \ / O

25 1 A is NH; 3 s/ (CH2) R3b R3b X is a bond, oxygen or Sulfur, R3a R3a (a = 2, 3 or 4) R and R" are the same or different and are H or F; R3 R" is aryl, phenyl, heteroaryl, imidazolyl, pyridyl, R3 R3 R3 cyclohexyl, PO(R') (R'), hetero arylthio, benzthiazole-2-thio, imidazole-2-thio, alkyl, alkenyl, or 1,3dioxan-2-yl, wherein each of the above is option ally substituted; 35 52. R3b O C R3b R is alkyl, polyfluoroalkyl, alkenyl, aryl, phenyl, R33. (CH2) 3. heteroaryl, imidazolyl or pyridyl, wherein each of the R3a above is optionally Substituted; L' is a chain containing 1 to 5 atoms in a linear chain; 40 R is H, alkyl or aryl; L is a bond or lower alkylene. R" is independently alkyl, alkenyl, alkynyl, aryl, alkoxy, 27. The method as defined in claim 1 wherein the MTP aryloxy, arylalkoxy, hete roaryl, arylalkyl, hetero arylalkyl, cycloalkyl-, cycloalkylalkyl, inhibitor has the-structure polycycloalkyl, polycycloalkylalkyl, cycloalkenyl, 45 cycloheteroalkyl, heteroaryloxy, cycloalkenylalkyl, O polycycloalkenyl, polycycloalkenylalkyl, heteroarylcarbonyl, amino, alkylamino, arylamino, R21NAL3 us B1 LNa O WNo heteroarylamino, cycloalkyloxy, cycloalkylamino, all O O optionally Substituted through available carbon atoms | with 1, 2, 3 or 4 groups Selected from hydrogen, halo, NHCR alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloheteroalkyl, cycloheteroalkylalkyl, aryl, heteroaryl, arylalkyl, including pharmaceutically acceptable Salts thereof, aryloycloalkyl, arylalkenyl, arylalkynyl, aryloxy, N-oxides thereof, wherein 55 aryloxyalkyl, arylalkoxy, arylaZo, heteroaryloxo, heteroarylalkyl, heteroarylalkenyl, heteroaryloxy, A is (1) a bond; hydroxy, nitro, cyano, amino, Substituted amino, thiol, (2) -O-, or alkylthio, arylthio, heteroarylthio, arylthioalkyl, alkylcarbonyl, arylcarbonyl, arylaminocarbonyl, (3) 60 alko Xy carbonyl, a mino carbonyl, -N- alkyny lamino carbonyl, alkylamino carbonyl, alkenylamino carbonyl, alkyl carbonyloxy, aryl carbonyl oxy, alkyl carbonyl- a mino, arylcarbonylamino, arylsulfinyl, arylsulfinylalkyl, where R is H or lower alkyl, or R together with R forms 65 arylsulfonyl, alkylsulfonyl, arylsulfonylamino, a carbocyclic or heterocyclic ring System containing 4 to 8 hetero arylcarbonylamino, he tero arylsulfinyl, members in the ring, heteroarylthio, heteroarylsulfonyl, alkylsulfinyl, 6,066,653 41 42 R is alkyl, alkynyl, alkynyl, alkoxyl, (alkyl or aryl)-Si haloalkyl, hydroxy, alkoxy, alkyl, aryl, alkenyl, (where each alkyl or aryl group is independent), alkenyloxy, alkynyl, alkynyloxy, alkanoyl, nitro, cycloalkyl, cycloalkenyl, Substituted alkylamino, Sub amino, thiol, alkylthio, alkylsulfinyl, alkylsulfonyl, Stituted arylalkylamino, aryl, arylalkyl, arylamino, carboxy, alkoxy carbonyl, a mino carbonyl, aryloxy, heteroaryl, heteroarylamino, heteroaryloxy, alkyl carbonyl oxy, alkyl carbonyl a mino, arylsulfonylamino, heteroarylsulfonylamino, arylthio, cycloheteroalkyl, cycloheteroalkylalkyl, cyano, Ar-, arylsulfinyl, arylsulfonyl, alkylthio, alkylsulfinyl, Ar-alkyl, Ar0, Ar-amino, Ar-thio, Ar-Sulfinyl, alkylsulfonyl, heteroarylthio, heteroarylsulfinyl, Ar-Sulfonyl, Ar-carbonyl, Ar-carbonyloxy or heteroarylsulfonyl, -PO(R') (R'), (where R' and Ar-carbonylamino, wherein Aris aryl or heteroaryland R" are independently alkyl, aryl, alkoxy, aryloxy, Ar may optionally include 1, 2 or 3 additional rings hetero aryl, he tero arylalkyl, he tero aryloxy, fused to Ar; he tero arylalko Xy, cyclohe tero alkyl, R" and R are the same or different and are indepen cyclohetero alkylalkyl, cyclohete roalkoxy, or dently any of the R groups except hydroxy, nitro, cycloheteroalkylalkoxy); aminocarbonyl (where the amino or thio; amino may optionally be Substituted with one or two aryl, alkyl or heteroaryl groups); cyano, 1,1-(alkoxyl or 15 aryloxy)-alkyl (where the two aryl or alkyl Substituents can be independently defined, or linked to one another to form a ring connected to L' (or L in the case of R) at the 2-position); 1,3-dioxane or 1,3-dioxolane con (e) s (e) and (e.9 nected to L' (or L in the case of R) at the 4-position; the R group may optionally be substituted with 1, 2, 3 are the same or different and independently represent a 5 or or 4 substituents, which can be any of the R or R' 6 membered heteroaryl ring which contains 1, 2, 3 or 4 group S O alkyl carbony la mino, cycloalkylcarbonylamino, arylcarbonylamino, heteroatoms in the ring which are independently N, S or O; heteroarylcarbonylamino, alkoxycarbonylamino, and including N-oxides, aryloxycarbonylamino, heteroaryloxylcarbonylamino, 25 X is a bond, or is one of the following groups: uriedo (where the uriedo nitrogens may optionally be Substituted with alkyl, aryl or heteroaryl), heterocyclyl (1) carbonylamino (where the heterocycle is connected to -S-; the carbonyl group via a nitrogen or carbon atom), (O) alkylsulfonyl amino, aryl Sulfonylamino, (2) heteroarylsulfonylamino, -O-; (3) R20 O -N-; 35 X^n R R21 A. N-, (4) y 21 / - C-: R22 R? Yrs where J is: CHR, -C-, -CH-CH Or 40 (5) l k ls R?C YRio R/ CYRio - ; (6) -CEC ; or 45 k le R’, R' and R are independently hydrogen, alkyl, (7) alkenyl, alkynyl, aryl, arylalkyl, he teroaryl, heteroarylalkyl, cycloalkyl, or cycloalkylalkyl, R? YRio R', R, R’ are independently hydrogen, halo, alkyl, alkenyl, alkoxy, aryloxy, aryl, arylalkyl, alkylmercapto, 50 arylmercapto, cycloalkyl, cycloalkylalkyl, heteroaryl, wherein heteroarylalkyl, hydroxy or haloalkyl, and these Sub Y is O, N-R or S; stituents may either be directly attached to R', or n' is 0, 1 or 2; attached via an alkylene at an open position; R is H., lower alkyl, aryl, -C(O)-R', or -C(O) L' is a linking group containing from 1 to 10 carbons in 55 -O-R'; a linear chain including alkylene, alkenylene or R" and Rare the same or different and are independently alkynylene, which may contain, within the linking H, alkyl, aryl, halogen, -O-R'', or chain any of the following: one or two alkenes, one or R" and R together can be oxygen to form a ketone; two alkynes, an oxygen, an amino group, an OXO group, 60 R. R', R'' and R'' are the same or different and are and may be substituted with one to five alkyl or halo independently H, lower alkyl, aryl or -o-R'; groups, R" and R" are the same or different and are indepen L may be the same or different from L' and may dently H, lower alkyl, aryl, halogen or -O-R'; independently be any of the L' groups set out above or R'' is alky or aryl; a singe bond; 65 R’ is H, alkyl or aryl. R, R, R" and R" may be the same or different and are independently selected from H. halogen, CF, k k k k k