# US 2009/0270367 A1 · Substituted hydroxyethylamine aspartyl protease inhibitors

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- Number: US 2009/0270367 A1
- Document ID: US20090270367A1
- Status: Published application
- Kind: A1
- Application number: 12/396,989
- Filed: 2009-03-03
- Published: 2009-10-29
- Earliest claimed: 2004-03-09
- Assignees: Elan Pharmaceuticals, Inc.
- Inventors: Varghese JOHN; Michel MAILLARD; John TUCKER; Jose AQUINO; Barbara JAGODZINSKA; Louis BROGLEY; Jay TUNG; Simeon BOWERS; Darren DRESSEN; Gary PROBST; Neerav SHAH
- Web page: https://patentgrep.com/patent/US20090270367A1

## CPC

- C07D 419/12: linked by a chain containing hetero atoms as chain links
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/16: Anti-Parkinson drugs
- A61P 25/28: for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07C 215/28: and containing six-membered aromatic rings
- C07C 215/50: with amino groups and the six-membered aromatic ring, or the condensed ring system containing that ring, bound to the same carbon atom of the carbon chain
- C07C 217/30: having the oxygen atom of at least one of the etherified hydroxy groups further bound to a carbon atom of a six-membered aromatic ring
- C07C 217/34: by halogen atoms, by trihalomethyl, nitro or nitroso groups, or by singly-bound oxygen atoms
- C07C 217/48: the carbon skeleton being unsaturated and containing rings
- C07C 217/52: having etherified hydroxy groups or amino groups bound to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
- C07C 217/58: with amino groups and the six-membered aromatic ring, or the condensed ring system containing that ring, bound to the same carbon atom of the carbon chain
- C07C 225/06: and acyclic
- C07C 225/20: having amino groups bound to carbon atoms of rings other than six-membered aromatic rings of the carbon skeleton
- C07C 229/16: to carbon atoms of hydrocarbon radicals substituted by amino or carboxyl groups, e.g. ethylenediamine-tetra-acetic acid, iminodiacetic acids
- C07C 229/42: with carboxyl groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by saturated carbon chains
- C07C 229/60: with amino and carboxyl groups bound in meta- or para- positions
- C07C 233/43: having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of a saturated carbon skeleton
- C07C 237/20: the carbon skeleton containing six-membered aromatic rings
- C07C 237/30: having the nitrogen atom of the carboxamide group bound to hydrogen atoms or to acyclic carbon atoms
- C07C 271/12: to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
- C07C 311/24: of an acyclic saturated carbon skeleton
- C07C 317/28: with sulfone or sulfoxide groups bound to acyclic carbon atoms of the carbon skeleton
- C07C 323/25: the carbon skeleton being acyclic and saturated
- C07C 323/30: having the sulfur atom of at least one of the thio groups bound to a carbon atom of a ring other than a six-membered aromatic ring of the carbon skeleton
- C07C 323/32: having at least one of the nitrogen atoms bound to an acyclic carbon atom of the carbon skeleton
- C07D 207/323: with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to the ring nitrogen atoms
- C07D 207/325: with substituted hydrocarbon radicals directly attached to the ring nitrogen atom
- C07D 213/38: having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom
- C07D 215/42: attached in position 4
- C07D 231/12: with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D 231/38: Nitrogen atoms (nitro radicals C07D231/16)
- C07D 233/54: having two double bonds between ring members or between ring members and non-ring members
- C07D 233/64: with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
- C07D 233/88: Nitrogen atoms, e.g. allantoin
- C07D 239/42: One nitrogen atom (nitro radicals C07D239/30)
- C07D 239/48: Two nitrogen atoms
- C07D 249/04: 1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles
- C07D 249/06: with aryl radicals directly attached to ring atoms
- C07D 249/14: Nitrogen atoms
- C07D 257/04: Five-membered rings
- C07D 263/34: with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D 271/113: with oxygen, sulfur or nitrogen atoms, directly attached to ring carbon atoms, the nitrogen atoms not forming part of a nitro radical
- C07D 275/02: not condensed with other rings
- C07D 277/42: Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
- C07D 285/08: 1,2,4-Thiadiazoles; Hydrogenated 1,2,4-thiadiazoles
- C07D 285/10: 1,2,5-Thiadiazoles; Hydrogenated 1,2,5-thiadiazoles
- C07D 285/135: Nitrogen atoms
- C07D 307/52: Radicals substituted by nitrogen atoms not forming part of a nitro radical
- C07D 309/14: Nitrogen atoms not forming part of a nitro radical
- C07D 311/74: Benzo[b]pyrans, hydrogenated in the carbocyclic ring
- C07D 333/36: Nitrogen atoms
- C07D 335/06: Benzothiopyrans; Hydrogenated benzothiopyrans
- C07D 401/12: linked by a chain containing hetero atoms as chain links
- C07D 403/12: linked by a chain containing hetero atoms as chain links
- C07D 405/12: linked by a chain containing hetero atoms as chain links
- C07D 409/12: linked by a chain containing hetero atoms as chain links
- C07D 413/04: directly linked by a ring-member-to-ring-member bond
- C07D 413/12: linked by a chain containing hetero atoms as chain links
- C07D 417/12: linked by a chain containing hetero atoms as chain links
- C07D 495/04: Ortho-condensed systems
- C07C 2601/02: with a three-membered ring
- C07C 2601/14: The ring being saturated
- C07C 2602/04: One of the condensed rings being a six-membered aromatic ring
- C07C 2602/10: the other ring being six-membered, e.g. tetraline
- C07C 2602/42: the bicyclo ring system containing seven carbon atoms
- C07C 2603/18: Fluorenes; Hydrogenated fluorenes
- C07C 2603/74: Adamantanes
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS

## Abstract

The invention relates to novel compounds and also to methods of treating at least one disease, disorder, or condition associated with amyloidosis using such compounds. Amyloidosis refers to a collection of diseases, disorders, and conditions associated with abnormal deposition of A-beta protein.

## Claims

### Claim 1

A compound of formula (I),
or a pharmaceutically acceptable salt thereof, wherein
R1 is selected from
wherein
X, Y, and Z are independently, selected from
—C(H)0-2—,
—O—,
—C(O)—,
—NH—, and
—N—,
wherein at least one bond of the (IIf) ring may optionally be a double bond;
L is selected from
—O—,
—SO2—,
—C(O)—,
—C(R55)(R60)—, and
—CH(NR55R60)—;
R55 and R60 are each independently selected from hydrogen and alkyl;
R50, R50a, and R50b are independently selected from
—H,
-halogen,
—OH,
—C(O)H,
—C(O)CH3,
—CH2OH,
—SH,
—S(O)0-2CH3,
—CN,
—NO2,
—NH2,
—NHCH3,
—N(CH3)2
—C1—C2 alkyl,
—OCH2,
—OCF3, and
—CF3;
R2 is selected from
—H,
wherein when R1 is benzyl, and RC is 6-Isopropyl-2,2-dioxo-2λ6-isothiochroman-4-yl, R2 is not —H;
wherein, when R1 is 3,5-difluorobenzyl, and RC is 6-Ethyl-2,2-dioxo-2λ6-isothiochroman-4-yl, R2 is not —H;
wherein when R1 is 3,5-difluorobenzyl, and RC is 7-ethyl-1,2,3,4-tetrahydro-naphthalen-1-yl, R2is not —H;
—OH,
—O-alkyl, optionally substituted with at least one group independently selected from R200;
—O-aryl, optionally substituted with at least one group independently selected from R200;
-alkyl, optionally substituted with at least one group independently selected from R200;
—NH-alkyl, optionally substituted with at least one group independently selected from R200;
-heterocycloalkyl, (wherein at least one carbon is optionally replaced with a group independently selected from —(CR245R250—, —O—, —C(O)—, —C(O)C(O)—, —N(R200)0-1—, and —S(O)0-2—, and wherein the heterocycloalkyl is optionally substituted with at least one group independently selected from R200);
—NH-heterocycloalkyl, wherein at least one carbon is optionally replaced with a group independently selected from —(CR245R250)—, —O—, —C(O)—, —C(O)C(O)—, —N(R200)0-2—, and —S(O)0-2—, and wherein the heterocycloalkyl is optionally substituted with at least one group independently selected from R200;
—C(O)—N(R315)(R320),
wherein R315 and R320 are each independently selected from —H, -alkyl, and phenyl,
wherein when R1 is 3,5-difluorobenzyl, and RC is 7-ethyl-1,2,3,4-tetrahydro-naphthalen-1-yl, R2 is not methylcarbamoyl;
—O—C(O)—N(R315)(R320),
—NH—R400,
—R400,
—NH—R500,
—R500
—NH—R600,
—R600, and
—NH—R700;
R400 is
wherein R405 is selected from —H, —N(R515)2, and O-alkyl;
R500 is a heteroaryl selected from III(a) and III(b),
wherein
M1 and M4 are independently selected from
—C(R505)—,
—N—,
—N(R515)—,
—S—, and
—O—;
M2 and M3 are independently selected from
—C(R510)—,
—N—,
—N(R520)—,
—S—, and
—O—;
M5 is selected from —C— and —N—;
R505 is independently selected from
—H,
-alkyl,
-halogen,
—NO2,
—CN,
—R200, and
phenyl;
R510 is independently selected from
—H,
-alkyl,
-halogen,
-amino,
—CF3,
—R200, and
-phenyl;
R515 is independently selected from
—H,
-alkyl, and
-phenyl;
R520 is independently selected from
—H,
-alkyl,
—(CH2)0-2-phenyl, and
—C(Ph)3;
R600 is a monocyclic, bicyclic, or tricyclic heteroaryl ring system of 6, 7, 8, 9, 10, 11, 12, 13, or 14 atoms, optionally substituted with at least one group independently selected from R605;
R605 is selected from -hydrogen, -halogen, -alkyl, -phenyl, alkyl-O—C(O)—, -nitro, —CN, -amino, —NR220R225, -thioalkyl, —CF3, —OH, —O-alkyl, and -heterocycloalkyl;
wherein when R1 is 3,5-difluoro-benzyl, and RC is 6-ethyl-2,2-dioxo-2λ6-isothiochroman-4-yl, R2 is not Benzothiazol-2-ylamino, or Benzooxazol-2-ylamino;
wherein when R1 is 3,5-difluoro-benzyl, and RC is 3-methoxy-benzyl, R2 is not 3-methyl-5-nitro-3H-imidazol-4-ylamino, Benzooxazol-2-ylamino, 1-phenyl-1H-tetrazol-5-ylamino, Benzothiazol-2-ylamino; or 2,5-dimethyl-4-nitro-2H-pyrazol-3-ylamino;
R700 is aryl optionally substituted with at least one R205;
RC is selected from
—(CH2)0-3-cycloalkyl wherein the cycloalkyl is optionally substituted with at least one group independently selected from —R205 and —CO2-(alkyl),
-alkyl optionally substituted with at least one group independently selected from R205,
—(CR245R250)0-4—RX, wherein at least one —(CR245R250)13 is optionally replaced with a group independently selected from —O—, —N(R215)—, —C(O)1-2—, —C(O)N(R215)—, and —S(O)0-2—, and
-formulae (IVa), (IVb), (IVc), (IVd), (IVe), (IVf), and (IVg);
RX is selected from
-hydrogen,
-aryl,
-heteroaryl,
-cycloalkyl,
-heterocycloalkyl, and
RXa—RXb, wherein RXa and RXb are independently selected from aryl, heteroaryl, cycloalkyl, and heterocycloalkyl;
wherein each aryl or heteroaryl group attached directly or indirectly to —(CR245R250)0-4— is optionally substituted with at least one group independently selected from R200;
wherein each cycloalkyl or heterocycloalkyl group attached directly or indirectly to —(CR245R250)0-4— is optionally substituted with at least one group independently selected from R210 and —(CR245R250)0-4—R200;
wherein at least one atom of the heteroaryl or heterocycloalkyl group attached directly or indirectly to —(CR245R250)0-4— is independently optionally replaced with a group selected from —O—, —C(O)—, —N(R215)0-1—, and —S(O)0-2—;
wherein at least one heteroatom of the heteroaryl or heterocycloalkyl group attached directly or indirectly to —(CR245R250)0-4— is independently optionally substituted with a group selected from
—(CO)0-1R215,
—(CO)0-1R220,
—S(O)0-2R200, and
—N(R200)—S(O)0-2R200;
R245 and R250 at each occurrence are independently selected from
—H,
—(CH2)0-4C(O)—OH,
—(CH2)0-4C(O)—O—alkyl,
—(CH2)0-4C(O)-alkyl,
-alkyl,
-hydroxyalkyl,
—O-alkyl,
-haloalkoxy,
—(CH2)0-4-cycloalkyl,
—(CH2)0-4-aryl,
—(CH2)0-4-heteroaryl, and
—(CH2)0-4-heterocycloalkyl; or
R245 and R250 are taken together with the carbon to which they are attached to form a monocyclic or bicyclic ring system of 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms,
wherein at least one bond in the monocyclic or bicyclic ring system is optionally a double bond,
wherein the bicyclic ring system is optionally a fused or spiro ring system,
wherein at least one carbon atom in the monocyclic or bicyclic ring system is optionally replaced by a group independently selected from
—O—,
—C(O)—,
—S(O)0-2—,
—C(═N—R255)—,
—N—,
—NR220—,
—N((CO)0-1R200)—, and
—N(SO2R200)—,
wherein the aryl, heteroaryl, and heterocycloalkyl groups included in R245 and R250 are optionally substituted with at least one group independently selected from -halogen, -alkyl, —N(R220)(R225), —CN, and —OH;
wherein the monocyclic and bicyclic groups included in R245 and R250 are optionally substituted with at least one group independently selected from halogen, —(CH2)0-2—OH, —O-alkyl, alkyl, —(CH2)0-2—S-alkyl, —CF3, aryl, —N(R220)(R225), —CN, —(CH2)0-2—NH2, —(CH2)0-2—NH(alkyl), —NHOH, —NH—O-alkyl, —N(alkyl)(alkyl), —NH-heteroaryl, —NH-C(O)-alkyl, and —NHS(O2)-alkyl;
formula (IVa) is
wherein Q1 is selected from (—CH2—)0-1, —CH(R200)—, —C(R200)2—, and —C(O)—; Q2 and Q3 each are independently selected from (—CH2—)0-1, —CH(R200)—, —C(R200)2—, —O—, —C(O)—, —S—, —S(O)2—, —NH—, and —N(R7)—;
Q4 is selected from a bond, (—CH2—)0-1, —CH(R200)—, —C(R200)2—, —O—, —C(O)—, —S—, —S(O)2—, —NH—, and —N(R7); and
P1, P2, P3, and P4 each are independently selected from —CH—, —C(R200)—, and —N—; formula (IVb) is
wherein R4 is selected from —H and -alkyl, and
P1, P2, P3, and P4 at each occurrence are independently selected from —CH—, —C(R200)—, and —N—;
formula (IVc) is
wherein R4 is selected from —H and -alkyl; and
P1, P2, P3, and P4 at each occurrence are independently selected from —CH—, —CR200—, and —N—;
formula (IVd) is
wherein m is 0, 1, 2, 3, 4, 5, or 8;
Y′ is selected from —H, —CN, —OH, —O-alkyl, —CO2H, —C(O)OR215, -amino, -aryl, and -heteroaryl; and
P1 and P2 at each occurrence are independently selected from —CH—, —C(R200)—, and —N—,
or P1 and P2 are optionally taken together to form a monocyclic or bicyclic ring system of 3, 4, 5, 8, 7, 8, 9, or 10 carbon atoms,
P3 and P4 at each occurrence are independently selected from —CH—, —C(R200)—, and —N—,
or P3 and P4 are optionally taken together to form a monocyclic or bicyclic ring system of 3, 4, 5, 8, 7, 8, 9, or 10 carbon atoms,
P5 at each occurrence is independently selected from —CH—, —C(R200)—, and —N—,
wherein at least one bond in the monocyclic or bicyclic ring system included in P1 and P2 or P3 and P4 is optionally a double bond,
wherein the bicyclic ring system included in P1 and P2 or P3 and P4 is optionally a fused or spiro ring system,
wherein at least one carbon atom in the monocyclic or bicyclic ring system included in P1 and P2 or P3 and P4 is optionally replaced by a group independently selected from
—O—,
—C(O)—,
—S(O)0-2—,
—C(═N—R255)—,
—N—,
—NR220—,
—N((CO)0-1R200—, and
—N(SO2R200)—; and
P5 at each occurrence is independently selected from —CH—, —C(R200)—, and —N—, formula (IVe) is
wherein
U is selected from —CH2—CR100R101—, —CH2—S—, —CH2S(O)—, —CH2—S(O)2—, —CH2—N(R100)—, —CH2—C(O)—, —CH2—O—, —C(O)—C(R100)(R101)—, —SO2—N(R100)—, —C(O)—N(R55)—, —N(R55)—C(O)—N(R55)—, —O—C(O)—O—, —N(R55)—C(O)—O—-, and —C(O)—O—;
wherein R100 and R101 at each occurrence are independently selected from —H, -alkyl, -aryl, —C(O)-alkyl, —(CO)0-1R215, —(CO)0-1R220, and —S(O)2-alkyl;
formula (IVf) is
wherein the B ring is optionally substituted with at least one group independently selected from -alkyl, -halogen, —OH, —SH, —CN, —CF3, —O-alkyl, —N(R5)C(O)H, —C(O)H, —C(O)N(R5)(R6), —NR5R6, R280, R285, -aryl, and -heteroaryl;
wherein R280 and R285, and the carbon to which they are attached form a C3—C7 spirocycle which is optionally substituted with at least one group independently selected from -alkyl, —O-alkyl, -halogen, —CF3, and —CN;
wherein the A ring is aryl or heteroaryl, each optionally substituted with at least one group independently selected from R290 and R295;
wherein R290 and R295 at each occurrence are independently selected from -alkyl optionally substituted with at least one group selected from -alkyl, -halogen, —OH, —SH, —CN, —CF3, —O-alkyl, and —NR5R6,
—OH,
—NO2,
-halogen,
—CO2H,
—CN,
—(CH2)0-4—C(O)—NR21R22,
—(CH2)0-4—CO2R20,
—(CH2)0-4—SO2—NR21R22,
—(CH2)0-4S(O)-alkyl),
—(CH2)0-4—S(O)2-(alkyl),
—(CH2)0-4-S(O)2-(cycloalkyl),
—(CH2)0-4—N(H or R20)—C(O)—O—R20,
—(CH2)0-4—N(H or R20)—C(O)—N(R20)2,
—(CH2)0-4—N—C(S)—N(R20)2,
—(CH2)0-4—N(H or R20)—CO—R21,
—(CH2)0-4—NR21R22,
—(CH2)0-4—R11,
—(CH2)0-4—O—C(O)—(alkyl),
—(CH2)0-4—O—P(O)—(OR5)2,
—(CH2)0-4≧O—C(O)—N(R20)2,
—(CH2)0-4—O—C(S)—N(R20)2,
—(CH2)0-4—O—(R20)2,
—(CH2)0-4—(R20)—CO2H,
—(CH2)0-4—S—(R20),
—(CH2)0-4—O-(alkyl optionally substituted with at least one halogen),
-cycloalkyl,
—(CH2)0-4—N(H or R20)—S(O)2—R21, and
—(CH2)0-4-cycloalkyl;
formula (IVg) is
wherein
a is 0 or 1;
b is 0 or 1;
S′ is selected from —C(O)— and —CO2—;
T′ is —(CH2)0-4—;
U′ is —(CR245R250)—;
V′ is selected from -aryl- and -heteroaryl-;
W′ is selected from
-a bond,
-alkyl-substituted with at least one group independently selected from R205,
—(CH2)0-4—(CO)0-1—N(R220)—,
—(CH2)0-4—(CO)0-1—,
—(CH2)0-4—CO2—,
—(CH2)0-4—SO2—N(R220)—,
—(CH2)0-4—N(H or R215)—CO2—,
—(CH2)0-4—N(H or R215)—SO2—,
—(CH2)0-4—N(H or R215)—C(O)—N(R215)—,
—(CH2)0-4—N(H or R215)—C(O)—,
—(CH2)0-4—N(R220)—,
—(CH2)0-4—O—, and
—(CH2)0-4—S—;
X′ is selected from aryl and heteroaryl;
wherein each cycloalkyl included in formula (IVg) is optionally substituted with at least one group independently selected from R205;
wherein each aryl or heteroaryl group included in formula (IVg) is optionally substituted with at least one group independently selected from R200;
wherein at least one heteroatom of the heteroaryl group included within formula (IVg) is optionally substituted with a group selected from
—(CO)0-1R215,
—(CO)0-1R220, and
—S(O)0-2R200;
R21 and R22 each independently are selected from
—H,
-alkyl optionally substituted with at least one group independently selected from —OH, amino, -halogen, -alkyl, -cycloalkyl, -(alkyl-cycloalkyl), -alkyl-O-alkyl, —R17, and —R18,
—(CH2)0-4—C(O)-(alkyl),
—(CH2)0-4—C(O)-(cycloalkyl),
—(CH2)0-4—C(O)—R17,
—(CH2)0-4—C(O)—R18,
—(CH2)0-4—C(O)—R19, and
—(CH2)0-4—C(O)—R11;
R17 at each occurrence is aryl optionally substituted with at least one group independently selected from
-alkyl optionally substituted with at least one group independently selected from -alkyl, -halogen, —OH, —SH, —NR5R6, —CN, —CF3, and —O-alkyl,
-halogen,
—O-alkyl optionally substituted with at least one group independently selected from halogen, —NR21R22, —OH, —CN, and -cycloalkyl optionally substituted with at least one group independently selected from -halogen, —OH, —SH, —CN, —CF3, —O-alkyl, and —NR5R6,
—C(O)-(alkyl),
—S(O)—O—NR5R6,
—C(O)—NR5R6, and
—S(O)2-(alkyl);
R18 at each occurrence is heteroaryl optionally substituted with at least one group independently selected from
-alkyl optionally substituted with at least one group independently selected from -alkyl, -halogen, —OH, —SH, —CN, —CF3, —O-alkyl, and —NR5R6,
-halogen,
—O-alkyl optionally substituted with at least one group independently selected from -halogen, —NR21R22, —OH, and —CN,
-cycloalkyl optionally substituted with at least one group independently selected from -halogen, —OH, —SH, —CN, CF3, —O-alkyl, and —NR5R6,
—C(O)-(alkyl),
—S(O)2—NR5R6,
—C(O)—NR5R6, and
—S(O)2-(alkyl);
R19 at each occurrence is heterocycloalkyl wherein at least one carbon is optionally replaced with —C(O)—, —S(O)—, and —S(O)2—, wherein the heterocycloalkyl is optionally substituted with at least one group independently selected from
-alkyl optionally substituted with at least one group independently selected from -alkyl, -halogen, —OH, —SH, —CN, —CF3, —O-alkyl, and —NR5R6,
-halogen,
—O-alkyl optionally substituted with at least one group independently selected from -halogen, —OH, —CN, —NR21R22, and -cycloalkyl optionally substituted with at least one group independently selected from -halogen, —OH, —SH, —CN, —CF3, —O-alkyl, and —NR5R6,
—C(O)-(alkyl),
—S(O)2—NR5R6,
—C(O)—NR5R6, and
—S(O)2-(alkyl);
R11 at each occurrence is heterocycloalkyl
wherein at least one carbon of the heterocycloalkyl is optionally replaced with —C(O)—, —S(O)—, and —S(O)2—,
wherein the heterocycloalkyl is optionally substituted with at least one group independently selected from -alkyl, —O-alkyl, and -halogen;
R20 is selected from -alkyl, -cycloalkyl, —(CH2)0-2—(R17), and —(CH2)0-2—(R18);
R200 at each occurrence is Independently selected from
-alkyl optionally substituted with at least one group independently selected from R205,
—OH,
—NO2,
—NH2,
-halogen,
—CN,
—CF3,
—OCF3,
—(CH2)0-4—C(O)H,
—(CO)0-1R215,
—(CO)0-1R220,
—(CH2)0-4—C(O)—NR220R225,
—(CH2)0-4—(C(O))0-1R215,
—(CH2)0-4—(C(O))0-1—R220,
—(CH2)0-4—C(O)-alkyl,
—(CH2)0-4—(C(O))0-1-cycloalkyl,
—(CH2)0-4—(C(O))0-1-heterocycloalkyl,
—(CH2)0-4—(C(O))0-1-aryl,
—(CH2)0-4—(C(O))0-1-heteroaryl,
—(CH2)0-4—C(O)—O—R215,
—(CH2)0-4—S(O)0-2—NR220R225,
—(CH2)0-4—S(O)0-2-alkyl,
—(CH2)0-4—S(O)0-2-cycloalkyl,
—(CH2)0-4—N(H or R215)—C(O)—O—R215,
—(CH2)0-4—N(H or R215)—S(O)1-2—R220,
—(CH2)0-4—N(H or R215)—C(O)—N(R215)2,
—(CH2)0-4—N(H or R215)—C(O)—R220,
—(CH2)0-4—NR220R225,
—(CH2)0-4—O—C(O)-alkyl,
—(CH2)0-4—O—(R215),
—(CH2)0-4—S—(R215),
—(CH2)0-4—C(O)H,
—(CH2)0-4—O-(alkyl optionally substituted with at least one halogen), and
-adamantane,
wherein each aryl and heteroaryl group included within R200 is optionally substituted with at least one group independently selected from
—R205,
R210, and
-alkyl optionally substituted with at least one group independently selected from R205 and R210;
wherein each cycloalkyl or heterocycloalkyl group included within R200 is optionally substituted with at least one group independently selected from
—R205,
—R210 , and
-alkyl optionally substituted with at least one group independently selected from R205 and R210;
R205 at each occurrence is independently selected from
-alkyl,
-heteroaryl,
-heterocycloalkyl,
-aryl,
-haloalkoxy,
—(CH2)0-3-cycloalkyl,
-halogen,
—(CH2)0-6—OH,
—O-phenyl,
—SH,
—(CH2)0-4—C(O)CH3
—(CH2)0-4—C(O)H
—(CH2)0-4—CO2H,
—(CH2)0-6—CN,
—(CH2)0-6—C(O)—NR235R240,
—(CH2)0-6—C(O)—R235,
—(CH2)0-4—N(H or R215)—SO2—R235,
—CF3,
—CN,
—OCF3,
—C(O)2-benzyl,
—O-alkyl,
—C(O)2-alkyl, and
—NR235R240;
R210 at each occurrence is independently selected from
—OH,
—CN,
—(CH2)0-4—C(O)H,
-alkyl wherein a carbon atom is optionally replaced with —C(O)—, and a carbon atom is optionally substituted with at least one group independently selected from R205,
—S-alkyl,
-halogen,
—O-alkyl,
-haloalkoxy,
—NR220R225,
-cycloalkyl optionally substituted with at least one group independently selected from R205,
—C(O)-alkyl,
—S(O)2—NR235R240,
—C(O)—NR235R240, and
—S(O)2-alkyl;
R215 at each occurrence is independently selected from
-alkyl,
—(CH2)0-2-aryl,
—(CH2)0-2-cycloalkyl,
—(CH2)0-2-heteroaryl, and
—(CH2)0-2-heterocycloalkyl;
wherein the aryl groups included within R215 are optionally substituted with at least one group independently selected from R205 or R210;
wherein the heterocycloalkyl and heteroaryl groups included within R215 are optionally substituted with at least one group independently selected from R210;
R220 and R225 at each occurrence are independently selected from
—H,
—OH,
-alkyl,
—(CH2)0-4—C(O)H,
-alkyl-OH,
—(CH2)0-4—CO2-alkyl, wherein alkyl is optionally substituted with at least one group independently selected from R205,
-aminoalkyl,
—S(O)2-alkyl,
—(CH2)0-4—C(O)-alkyl, wherein alkyl is optionally substituted with at least one group independently selected from R205,
—(CH2)0-4—C(O)—NH2,
—(CH2)0-4—C(O)—NH(alkyl), wherein alkyl is optionally substituted with at least one group independently selected from R205,
—(CH2)0-4—C(O)—N(alkyl)(alkyl),
-haloalkyl,
—(CH2)0-2-cycloalkyl,
-alkyl-O-alkyl,
O-alkyl,
-aryl,
-heteroaryl, and
-heterocycloalkyl;
wherein the aryl, heteroaryl and heterocycloalkyl groups included within R220 and R225 are each optionally substituted with at least one group independently selected from R270;
R270 at each occurrence is independently selected from
R205,
-alkyl optionally substituted with at least one group independently selected from R205,
-phenyl,
-halogen,
—O-alkyl,
-haloalkoxy,
—NR235R240,
—OH,
—CN,
-cycloalkyl optionally substituted with at least one group independently selected from R205,
—C(O)-alkyl,
—S(O)2—NR235R240,
—CO—NR235R240,
—S(O)2-alkyl, and
—(CH2)0-4—C(O)H;
R235 and R240 at each occurrence are independently selected from
—H,
-alkyl,
—C(O)-alkyl,
—OH,
—CF3,
—OCH3,
—NH—CH3,
—N(CH3)2,
—(CH2)0-4—C(O)—(H or alkyl),
—SO2-alkyl, and
-phenyl;
R255 is selected from -hydrogen, —OH, —N(R220)(R225), and —O-alkyl;
R5 and R6 are independently selected from —H and -alkyl, or
R5 and R6, and the nitrogen to which they are attached, form a 5 or 6 membered heterocycloalkyl ring; and
R7 is independently selected from
—H,
-alkyl optionally substituted with at least one group independently selected from —OH, amino, and halogen,
-cycloalkyl, and
-alkyl-O-alkyl.

### Claim 2 (depends on 1)

The compound according to claim 1, wherein R1 is selected from —CH2-phenyl, wherein the phenyl ring is optionally substituted with at least one group independently selected from -halogen, —C1—C2 alkyl, —O-methyl, and —OH.

### Claim 3 (depends on 1)

The compound according to claim 1, wherein R1 is selected from 4-hydroxy-benzyl, 3-hydroxy-benzyl, 5-chloro-thiophen-2-yl-methyl, 5-chloro-3-ethyl-thiophen-2-yl-methyl, 3,5-difluoro-2-hydroxy-benzyl, piperidin-4-yl-methyl, 2-oxo-piperidin-4-yl-methyl, 2-oxo-1,2-dihydro-pyridin-4-yl-methyl, 5-hydroxy-6-oxo-6H-pyran-2-yl-methyl, 3,5-difluoro-4-hydroxy-benzyl, 3,5-difluoro-benzyl, 3-fluoro-4-hydroxy-benzyl, 3-fluoro-5-hydroxy-benzyl, and 3-fluoro-benzyl.

### Claim 4 (depends on 1)

The compound according to claim 1, wherein RC is —C(R245)(R250)—RX, wherein R245 and R250 are taken together with the carbon to which they are attached to form a monocyclic or bicyclic ring system of 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms,
wherein at least one bond in the monocyclic or bicyclic ring system is optionally a double bond, wherein the bicyclic ring system is optionally a fused or spiro ring system, wherein at least one atom within the monocyclic or bicyclic ring system is optionally replaced by a group independently selected from
—O—,
—C(O)—,
—S(O)0-2—,
—C(═N—R255)—,
—N—,
—NR220—,
N((CO)0-1R200)—, and
—N(SO2R200)—; and
wherein the monocyclic or bicyclic groups included within R245 and R250 are optionally substituted with at least one group independently selected from halogen, —(CH2)0-2—OH, —(CH2)0-2—S-alkyl, —CF3, —O-alkyl, alkyl, aryl, —N(R220)(R225), —CN, —(CH2)0-2—NH2, —(CH2)0-2—NH(alkyl), —NHOH, —NH—O-alkyl, —N(alkyl)(alkyl), —NH-heteroaryl, —NH—C(O)-alkyl, and —NHS(O2)-alkyl; and wherein RX, R220, R225, R255, and R200 are as defined in claim 1.

### Claim 5 (depends on 1)

The compound according to claim 1, wherein RC is selected from formulae (Va), (Vb), (Vc), and (Vd),
wherein,
A, B, and C are independently selected from
—CH2—,
—O—,
—C(O)—,
—S(O)0-2—,
—N((CO)0-1R200)—,
—N(SO2R200)—,
—C(═N—R255)—, and
—N(R220)—;
A′ at each occurence is independently selected from —CH2— and —O—;
wherein (Va), (Vb), (Vc), and (Vd) are each optionally substituted with at least one group independently selected from -alkyl, —O-alkyl, —(CH2)0-2—OH, —(CH2)0-2—S-alkyl, —CF3, —CN, -halogen, —(CH2)0-2—NH2, —(CH2)0-2—NH(alkyl), —NHOH, —NH—O-alkyl, —N(alkyl)(alkyl), —NH-heteroaryl, —NH—C(O)-alkyl, and —NHS(O2)-alkyl; and
RX, R220, R255, and R200 are as defined in claim 1.

### Claim 6 (depends on 1)

The compound according to claim 1, wherein RC is selected from formulae (Vla) and (Vlb)
wherein at least one carbon of the heterocycloalkyl of formula (Vla) and the cycloalkyl of formula (Vlb) is optionally replaced with a group independently selected from —O—, —SO2—, and —C(O)—, wherein at least one carbon of the heterocycloalkyl or cycloalkyl is optionally substituted with at least one group Independently selected from R205, R245, and R250, wherein R100, R200, R205, R245, and R250 are as defined in claim 1.

### Claim 7 (depends on 1)

The compound according to claim 1, wherein RC is selected from 6-isobutyl-1,1-dioxo-1λ6-thiochroman-4-yl, 6-isopropyl-2,2-dioxo-2λ6-isothiochroman-4-yl, 6-ethyl-2,2-dioxo-2λ6-isothiochroman-4-yl, 7-ethyl-1,2,3,4-tetrahydro-naphthalen-1-yl, 1-(3-tert-Butyl-phenyl)-cyclohexyl, and 3-methoxy-benzyl.

### Claim 8 (depends on 1)

The compound according to claim 1, wherein R2 is selected from hydrogen, 3-Bromo-[1,2,4]thiadiazol-5-ylamino, [1,2,4]thiadiazol-5-ylamino, 4-Chloro-[1,2,5]thiadiazol-3-ylamino, [1,2,5]thiadiazol-3-ylamino, thiazol-2-ylamino, 5-Bromo-[1,3,4]thiadiazol-2-ylamino, [1,3,4]thiadiazol-2-ylamino, 5-Amino-[1,3,4]thiadiazol-2-ylamino, 2-Bromo-thiazol-5-ylamino, thiazol-5-ylamino, 5-trifluoromethyl-[1,3,4]thiadiazol-2-ylamino, 5-trifluoromethyl-[1,3,4]oxadiazol-2-ylamino, 5-Amino-[1,3,4]oxadiazol-2-ylamino, 1-trityl-1H-[1,2,4]triazol-3-ylamino, 1H-[1,2,4]triazol-3-ylamino, oxazol-2-ylamino, 5-Bromo-2-trityl-2H-[1,2,3]triazol-4-ylamino, 2-trityl-2H-[1,2,3]triazol-4-ylamino, 5-Bromo-2H-[1,2,3]triazol-4-ylamino, 2H-[1,2,3]triazol-4-ylamino, thiophen-2-ylamino, 3-methyl-5-nitro-3H-imidazol-4-ylamino, 4-Cyano-5-phenyl-isothiazol-3-ylamino, 4-phenyl-[1,2,5]thiadiazol-3-ylamino, 3,4-dioxo-cyclobut-1-enylamino, 2-methoxy-3,4-dioxo-cyclobut-1-enylamino, and 2-methylamino-3,4-dioxo-cyclobut-1-enylamino.

### Claim 9 (depends on 2)

The compound according to claim 2, wherein RX is selected from 3-(1,1-dimethyl-propyl)-phenyl, 3-(1-ethyl-propyl)-phenyl, 3-(1H-pyrrol-2-yl)-phenyl, 3-(1-hydroxy-1-methyl-ethyl)-phenyl, 3-(1-methyl-1H-imidazol-2-yl)-phenyl, 3-(1-methyl-cyclopropyl)-phenyl, 3-(2,2-dimethyl-propyl)-phenyl, 3-(2,5-dihydro-1H-pyrrol-2-yl)-phenyl, 3-(2-Chloro-thiophen-3-yl)-phenyl, 3-(2-Cyano-thiophen-3-yl)-phenyl, 3-(2-fluoro-benzyl)-phenyl, 3-(3,5-dimethyl-3H-pyrazol-4-yl)-phenyl, 3-(3,6-dimethyl-pyrazin-2-yl)-phenyl, 3-(3-Cyano-pyrazin-2-yl)-phenyl, 3-(3-formyl-furan-2-yl)-phenyl, 3-(3H-[1,2,3]triazol-4-yl)-phenyl, 3-(3H-imidazol-4-yl)-phenyl, 3-(3-methyl-butyl)-phenyl, 3-(3-methyl-pyridin-2-yl)-phenyl, 3-(3-methyl-thiophen-2-yl)-phenyl, 3-(4-Cyano-pyridin-2-yl)-phenyl, 3-(4-fluoro-benzyl)-phenyl, 3-(4H-[1,2,4]triazol-3-yl)-phenyl, 3-(4-methyl-thiophen-2-yl)-phenyl, 3-(5-Acetyl-thiophen-2-yl)-phenyl, 3-(5-Acetyl-thiophen-3-yl)-phenyl, 3-(5-formyl-thiophen-2-yl)-phenyl, 3-(5-oxo-pyrrolidin-2-yl)-phenyl, 3-(6-methyl-pyridazin-3-yl)-phenyl, 3-(6-methyl-pyridin-2-yl)-phenyl, 3-(Cyano-dimethyl-methyl)-phenyl, 3-[1-(2-tert-Butyl-pyrimidin-4-yl)-cyclohexylamino, 3-[1,2,3]triazol-1-yl-phenyl, 3-[1,2,4]oxadiazol-3-yl-phenyl, 3-[1,2,4]oxadiazol-5-yl-phenyl, 3-[1,2,4]thiadiazol-3-yl-phenyl, 3-[1,2,4]thiadiazol-5-yl-phenyl, 3-[1,2,4]triazol-4-yl-phenyl, 3-Acetyl-5-tert-butyl-phenyl, 3′-Acetylamino-biphenyl-3-yl, 3-Adamantan-2-yl-phenyl, 3-Bromo-[1,2,4]thiadiazol-5-yl)-phenyl, 3-Bromo-5-tert-butyl-phenyl, 3-Cyano-phenyl, 3-Cyclobutyl-phenyl, 3-Cyclopentyl-phenyl, 3-Cyclopropyl-phenyl, 3-ethyl-phenyl, 3-ethynyl-phenyl, 3-fluoro-5-(2-hydroxy-1,1-dimethyl-ethyl)-phenyl, 3-furan-3-yl-phenyl, 3-imidazol-1-yl-phenyl, 3-isobutyl-phenyl, 3-isopropyl-phenyl, 3-isoxazol-3-yl-phenyl, 3-isoxazol-4-yl-phenyl, 3-isoxazol-5-yl-phenyl, 3-pent-4-enyl-phenyl, 3-pentyl-phenyl, 3-Phenyl-propionic acid ethyl ester, 3-pyrazin-2-yl-phenyl, 3-pyridin-2-yl-phenyl, 3-pyrrolidin-2-yl-phenyl, 3-sec-Butyl-phenyl, 3-tert-Butyl-4-chloro-phenyl, 3-tert-Butyl-4-cyano-phenyl, 3-tert-Butyl-4-ethyl-phenyl, 3-tert-Butyl-4-methyl-phenyl, 3-tert-Butyl-4-trifluoromethyl-phenyl, 3-tert-Butyl-5-chloro-phenyl, 3-tert-Butyl-5-cyano-phenyl, 3-tert-Butyl-5-ethyl-phenyl, 3-tert-Butyl-5-fluoro-phenyl, 3-tert-Butyl-5-methyl-phenyl, 3-tert-Butyl-5-trifluoromethyl-phenyl, 3-tert-Butyl-phenyl, 3-thiazol-2-yl-phenyl, 3-thiazol-4-yl-phenyl, 3-thiophen-3-yl-phenyl, 3-trifluoromethyl-phenyl, 4-Acetyl-3-tert-butyl-phenyl, 4-tert-Butyl-pyridin-2-yl, 4-tert-Butyl-pyrimidin-2-yl, 5-tert-Butyl-pyridazin-3-yl, 6-tert-Butyl-pyridazin-4-yl, and 6-tert-Butyl-pyrimidin-4-yl.

### Claim 10

A method of preventing or treating at least one condition which benefits from inhibition of at least one aspartyl-protease, comprising:
administering to a host a composition comprising a therapeutically effective amount of at least one compound of formula (I),
or pharmaceutically acceptable salts thereof, wherein
R1 is selected from
wherein
X, Y, and Z are independently, selected from
—C(H)0-2—,
—O—,
—C(O)—,
—NH—, and
—N—,
wherein at least one bond of the (IIf) ring may optionally be a double bond;
L is selected from
—O—,
—C(O)—,
—C(R55)(R60)—, and
—CH(NR55R60)—;
R55 and R60 are each independently selected from hydrogen and alkyl;
R50, R50a, and R50b are independently selected from
—H
-halogen,
—OH,
—C(O)H,
—C(O)CH3,
—CH2OH,
—SH,
—S(O)0-2CH3,
—CN,
—NO2,
—NH2,
—NHCH3,
—N(CH3)2
—C1—C2 alkyl,
—OCH3,
—OCF3, and
—CF3;
R2 is selected from
—H,
wherein when R1 is benzyl, and RC is 6-Isopropyl-2,2-dioxo-2λ6-isothiochroman-4-yl, R2 is not —H;
wherein, when R1 is 3,5-difluorobenzyl, and RC is 6-Ethyl-2,2-dioxo-2λ6-isothiochroman-4-yl, R2 is not —H;
wherein when R1 is 3,5-difluorobenzyl, and RC is 7-ethyl-1,2,3,4-tetrahydro-naphthalen-1-yl, R2 is not —H;
—OH,
—O-alkyl, optionally substituted with at least one group independently selected from R200;
—O-aryl, optionally substituted with at least one group, independently selected from R200;
-alkyl, optionally substituted with at least one group independently selected from R200;
—NH-alkyl, optionally substituted with at least one group independently selected from R200;
-heterocycloalkyl, (wherein at least one carbon is optionally replaced with a group independently selected from —(CR245R250)—, —O—, —C(O)—, —C(O)C(O)—, —N(R200)0-1, and —S(O)0-2—, and wherein the heterocycloalkyl is optionally substituted with at least one group independently selected from R200);
—NH-heterocycloalkyl, wherein at least one carbon is optionally replaced with a group independently selected from —(CR245R250)—, —O—, —C(O)—, —C(O)C(O)—, —N(R200)0-2—, and —S(O)0-2—, and wherein the heterocycloalkyl is optionally substituted with at least one group Independently selected from R200;
—C(O)—N(R315)(R320),
wherein R315 and R320 are each independently selected from —H, -alkyl, and phenyl,
wherein when R1 is 3,5-difluorobenzyl, and RC is 7-ethyl-1,2,3,4-tetrahydro-naphthalen-1-yl, R2 is not methylcarbamoyl;
—O—C(O)—N(R315)(R320),
—NH—R400,
—R400,
—NH—R500,
—R500
—NH—R600,
—R600, and
—NH—R700,
R400 is
wherein R405 is selected from —H, —N(R515)2, and O-alkyl;
R500 is a heteroaryl selected from III(a) and III(b),
wherein
M1 and M4 are independently selected from
—C(R505)—,
—N—,
—N(R515)—,
—S—, and
—O—;
M2 and M3 are independently selected from
—C(R510)—,
—N—,
—N(R520)—,
—S—, and
—O—;
M5 is selected from —C— and —N—;
R505 is independently selected from
—H,
-alkyl,
-halogen,
—NO2,
—CN,
—R200, and
phenyl;
R510 is independently selected from
—H,
-alkyl,
-halogen,
-amino,
—CF3,
—R200, and
-phenyl;
R515 is independently selected from
—H,
-alkyl, and
-phenyl;
R520 is independently selected from
—H,
-alkyl,
—(CH2)0-2-phenyl, and
—C(Ph)3;
R600 is a monocyclic, bicyclic, or tricyclic heteroaryl ring system of 6, 7, 8, 9, 10, 11, 12, 13, or 14 atoms, optionally substituted with at least one group independently selected from R605;
R605 is selected from -hydrogen, -halogen, -alkyl, -phenyl, alkyl-O—C(O)—, -nitro, —CN, -amino, —NR220R225, -thioalkyl, —CF3, —OH, —O-alkyl, and -heterocycloalkyl;
wherein when R1 is 3,5-difluoro-benzyl, and RC is 6-ethyl-2,2-dioxo-2λ6-isothiochroman-4-yl, R2 is not Benzothiazol-2-ylamino, or Benzooxazol-2-ylamino;
wherein when R1 is 3,5-difluoro-benzyl, and RC is 3-methoxy-benzyl, R2 is not 3-methyl-5-nitro-3H-imidazol-4-ylamino, Benzooxazol-2-ylamino, 1-phenyl-1H-tetrazol-5-ylamino, Benzothiazol-2-ylamino; or 2,5-dimethyl-4-nitro-2H-pyrazol-3-ylamino;
R700 is aryl optionally substituted with at least one R205;
RC is selected from
—(CH2)0-3-cycloalkyl wherein the cycloalkyl is optionally substituted with at least one group independently selected from —R205 and —CO2-(alkyl),
-alkyl optionally substituted with at least one group independently selected from R205,
—(CR245R250)0-4—RX, wherein at least one —(CR245R250)— is optionally replaced with a group independently selected from —O—, —N(R215)—, —C(O)1-2—, —C(O)N(R215)—, and —S(O)0-2—, and
-formulae (IVa), (IVb), (IVc), (IVd), (IVe), (IVf), and (IVg);
RX is selected from
-hydrogen,
-aryl,
-heteroaryl,
-cycloalkyl,
-heterocycloalkyl, and
—RXa—RXb, wherein RXa and RXb are independently selected from aryl, heteroaryl, cycloalkyl, and heterocycloalkyl;
wherein each aryl or heteroaryl group attached directly or indirectly to —(CR245R250)0-4— is optionally substituted with at least one group independently selected from R200;
wherein each cycloalkyl or heterocycloalkyl group attached directly or indirectly to —(CR245R250)0-4— is optionally substituted with at least one group independently selected from R210 and —(CR245R250)0-4—R200;
wherein at least one atom of the heteroaryl or heterocycloalkyl group attached directly or indirectly to —(CR245R250)0-4— is independently optionally replaced with a group selected from —O—, —C(O)—, —N(R215)0-1—, and —S(O)0-2—;
wherein at least one heteroatom of the heteroaryl or heterocycloalkyl group attached directly or indirectly to —(CR245R250)0-4— is independently optionally substituted with a group selected from
—(CO)0-1R215,
—(CO)0-1R220,
—S(O)0-2R200, and
—N(R200)—S(O)0-2R200;
R245 and R250 at each occurrence are independently selected from
—H,
—(CH2)0-4C(O)—OH,
—(CH2)0-4C(O)—O-alkyl,
—(CH2)0-4C(O)-alkyl,
-alkyl,
-hydroxyalkyl,
—O-alkyl,
-haloalkoxy,
—(CH2)0-4-cycloalkyl,
—(CH2)0-4-aryl,
—(CH2)0-4-heteroaryl, and
—(CH2)0-4-heterocycloalkyl; or
R245 and R250 are taken together with the. carbon to which they are attached to form a monocyclic or bicyclic ring system of 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms,
wherein at least one bond in the monocyclic or bicyclic ring system is optionally a double bond,
wherein the bicyclic ring system is optionally a fused or spiro ring system,
wherein at least one carbon atom in the monocyclic or bicyclic ring system is optionally replaced by a group independently selected from
—O—,
—C(O)—,
—S(O)0-2—,
—(═N—R255)—,
—N—,
—NR220—,
—NR((CO)0-1R200)—, and
—N(SO2R200)—;
wherein the aryl, heteroaryl, and heterocycloalkyl groups included in R245 and R250 are optionally substituted with at least one group independently selected from -halogen, -alkyl, —N(R220)(R225), —CN, and —OH;
wherein the monocyclic and bicyclic groups included in R245 and R250 are optionally substituted with at least one group independently selected from halogen, —(CH2)0-2—OH, —O-alkyl, alkyl, —(CH2)0-2—S-alkyl, —CF3, aryl, —N(R220)(R225), —CN, —(CH2)0-2—NH2, —(CH2)0-2—NH(alkyl), —NHOH, —NH—O-alkyl, —N(alkyl)(alkyl), —NH—C(O)-alkyl, and —NHS(O2)-alkyl;
formula (IVa) is
wherein Q1 is selected from (—CH2—)0-1, —CH(R200)—, —C(R200)2—, and —C(O)—;
Q2 and Q3 each are independently selected from (—CH2—)0-1, —CH(R200)—, —C(R200)2—, —O—, —C(O)—, —S—, —S(O)2—, —NH—, and —N(R7)—;
Q4 is selected from a bond, (—CH2—)0-1, —CH(R200)—, 13 C(R200)2—, —O—, —C(O)—, —S—, —S(O)2—, —NH—, and —N(R7); and
P1, P2, P3, and P4 each are independently selected from —CH—, —C(R200)—, and —N—; formula (IVb) is
wherein R4 is selected from —H and -alkyl, and
P1, P2, P3, and P4 at each occurrence are independently selected from —CH—, —C(R200)—, and —N—;
formula (IVc) is
wherein R4 is selected from —H and -alkyl; and
P1, P2, P3, and P4 at each occurrence are independently selected from —CH—, —CR200—, and —N—;
formula (IVd) is
wherein m is 0, 1, 2, 3, 4, 5, or 6;
Y′ is selected from —H, —CN, —OH, —O-alkyl, —CO2H, —C(O)OR215, -amino, -aryl, and -heteroaryl; and
P1 and P2 at each occurrence are independently selected from —CH—, —C(R200)—, and —N—,
or P1 and P2 are optionally taken together to form a monocyclic or bicyclic ring system of 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms,
P3 and P4 at each occurrence are independently selected from —CH—, —C(R200)—, and —N—,
or P3 and P4 are optionally taken together to form a monocyclic or bicyclic ring system of 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms,
P5 at each occurrence is independently selected from —CH—, —C(R200)—, and —N—,
wherein at least one bond in the monocyclic or bicyclic ring system included in P1 and P2 or P3 and P4 is optionally a double bond,
wherein the bicyclic ring system included in P1 and P2 or P3 and P4 is optionally a fused or spiro ring system,
wherein at least one carbon atom in the monocyclic or bicyclic ring system included in P1 and P2 or P3 and P4 is optionally replaced by a group independently selected from
—O—,
—C(O)—,
—S(O)0-2—,
—C(═N—R255)—,
—N—,
—NR220—,
—N((CO)0-1R200)—, and
—N(SO2R200)—;
formula (IVe) is
wherein
U is selected from —CH2—CR100R101—, —CH2—S—, —CH2—S(O)—, —CH2—S(O)2—, —CH2—N(R100)—, —CH2—C(O)—, —CH2—O—, —C(O)—C(R100)(R101)—, —SO2—N(R100)—, —C(O)—N(R55)—, —N(R55)—C(O)—N(R55)—, —O—C(O)—O—, —N(R55)—C(O)—O—, and —C(O)—O—;
wherein R100 and R101 at each occurrence are independently selected from —H, -alkyl, -aryl, —C(O)-alkyl, —(CO)0-1R215, —(CO)0-1R220, and —S(O)2-alkyl;
formula (IVf) is
wherein the B ring is optionally substituted with at least one group independently selected from -alkyl, -halogen, —OH, —SH, —CN, —CF3, —O-alkyl, —N(R5)C(O)H, —C(O)H, —C(O)N(R5)(R6), —NR5R6, R280, R285, -aryl, and -heteroaryl;
wherein R280 and R285, and the carbon to which they are attached form a C3—C7 spirocycle which is optionally substituted with at least one group independently selected from -alkyl, —O-alkyl, -halogen, —CF3, and —CN;
wherein the A ring is aryl or heteroaryl, each optionally substituted with at least one group independently selected from R290 and R295;
wherein R290 and R295 at each occurrence are independently selected from -alkyl optionally substituted with at least one group selected from -alkyl, -halogen, —OH, —SH, —CN, —CF3, —O-alkyl, and —NR5R6,
—OH,
—NO2,
-halogen,
—CO2H,
—CN,
—(CH2)0-4—C(O)—NR21R22,
—(CH2)0-4—CO2R20,
—(CH2)0-4—SO2NR21R22,
—(CH2)0-4S(O)-alkyl),
—(CH2)0-4—S(O)2-(alkyl),
—(CH2)0-4—S(O)2-(cycloalkyl),
—(CH2)0-4—N(H or R20)—C(O)—O—R20,
—(CH2)0-4—N(H or R20)—C(O)—N(R20)2,
—(CH2)0-4—N—C(S)—N(R20)2,
—(CH2)0-4—N(H or R20)—CO—R21,
—(CH2)0-4—NR21R22,
—(CH2)0-4—R11,
—(CH2)0-4—O—C(O)-(alkyl),
—(CH2)0-4—O—P(O)—(OR5)2,
—(CH2)0-4—O—C(O)—N(R20)2,
—(CH2)0-4—O—C(S)—N(R20)2,
—(CH2)0-4—O—(R20)2,
—(CH2)0-4—O—(R20)—CO2H,
—(CH2)0-4—S—(R20),
—(CH2)0-4—O-(alkyl optionally substituted with at least one halogen),
-cycloalkyl,
—(CH2)0-4—N(H or R20)—S(O)2—R21, and
—(CH2)0-4-cycloalkyl;
formula (IVg) is
wherein
a is 0 or 1;
b is 0 or 1;
S′ is selected from —C(O)— and —CO2—;
T′ is —(CH2)0-4—;
U′ is —(CR245R250)—;
V′ is selected from -aryl- and -heteroaryl-;
W′ is selected from
-a bond,
-alkyl-substituted with at least one group independently selected from R205,
—(CH2)0-4—(CO)0-1—N(R220)—,
—(CH2)0-4—(CO)0-1—,
—(CH2)0-4—CO2—,
—(CH2)0-4—SO2—N(R220)—,
—(CH2)0-4—N(H or R215)—CO2—,
—(CH2)0-4—N(H or R215)—SO2—,
—(CH2)0-4—N(H or R215)—C(O)—N(R215)—,
—(CH2)0-4—N(H or R215)—C(O)—,
—(CH2)0-4—N(R220)—,
—(CH2)0-4—O—, and
—(CH2)0-4—S—;
X′ is selected from aryl and heteroaryl;
wherein each cycloalkyl included in formula (IVg) is optionally substituted with at least one group independently selected from R205;
wherein each aryl or heteroaryl group included in formula (IVg) is optionally substituted with at least one group independently selected from R200;
wherein at least one heteroatom of the heteroaryl group included within formula (IVg) is optionally substituted with a group selected from
—(CO)0-1R215,
—(CO)0-1R220, and
—S(O)0-2R200;
R21 and R22 each independently are selected from
—H,
-alkyl optionally substituted with at least one group independently selected from —OH, amino, -halogen, -alkyl, -cycloalkyl, -(alkyl-cycloalkyl), -alkyl-O-alkyl, —R17, and —R18,
—(CH2)0-4—C(O)-(alkyl),
—(CH2)0-4—C(O)-(cycloalkyl),
—(CH2)0-4—C(O)—R17,
—(CH2)0-4—C(O)—R18,
—(CH2)0-4—C(O)—R19, and
—(CH2)0-4—C(O)—R11;
R17 at each occurrence is aryl optionally substituted with at least one group independently selected from
-alkyl optionally substituted with at least one group independently selected from -alkyl, -halogen, —OH, —SH, —NR5R6, —CN, —CF3, and —O-alkyl,
-halogen,
—O-alkyl optionally substituted with at least one group independently selected from halogen, —NR21R22, —OH, —CN, and -cycloalkyl optionally substituted with at least one group independently selected from -halogen, —OH, —SH, —CN, —CF3, —O-alkyl, and —NR5R6,
—C(O)-(alkyl),
—S(O)—O—NR5R6,
—C(O)—NR5R6, and
—S(O)2-(alkyl);
R18 at each occurrence is heteroaryl optionally substituted with at least one group independently selected from
-alkyl optionally substituted with at least one group independently selected from -alkyl, -halogen, —OH, —SH, —CN, —CF3, —O-alkyl, and —NR5R6,
-halogen,
—O-alkyl optionally substituted with at least one group independently selected from -halogen, —NR21R22, —OH, and —CN,
-cycloalkyl optionally substituted with at least one group independently selected from -halogen, —OH, —SH, —CN, CF3, —O-alkyl, and —NR5R6,
—C(O)-alkyl),
—S(O)2—NR5R6,
—C(O)—NR5R6, and
—S(O)2-(alkyl);
R19 at each occurrence is heterocycloalkyl wherein at least one carbon is optionally replaced with —C(O)—, —S(O)—, and —S(O)2—, wherein the heterocycloalkyl is optionally substituted with at least one group independently selected from
-alkyl optionally substituted with at least one group independently selected from -alkyl, -halogen, —OH, —SH, —CN, —CF3, —O-alkyl, and —NR5R6,
-halogen,
—O-alkyl optionally substituted with at least one group independently selected from -halogen, —OH, —CN, —NR21R22, and -cycloalkyl optionally substituted with at least one group independently selected from -halogen, —OH, —SH, —CN, —CF3, —O-alkyl, and —NR5R6,
—C(O)-(alkyl),
—S(O)2—NR5R6,
—C(O)—NR5R6, and
—S(O)2-(alkyl);
R11 at each occurrence is heterocycloalkyl
wherein at least one carbon of the heterocycloalkyl is optionally replaced with —C(O)—, —S—(O)—, and —S(O)2—,
wherein the heterocycloalkyl is optionally substituted with at least one group independently selected from -alkyl, —O-alkyl, and -halogen;
R20 is selected from -alkyl, -cycloalkyl, —(CH2)0-2—(R17), and —(CH2)0-2—(R18);
R200 at each occurrence is independently selected from
-alkyl optionally substituted with at least one group independently selected from R205,
—OH,
—NO2,
—NH2,
-halogen,
—CN,
—CF3,
—OCF3,
—(CH2)0-4—C(O)H,
—(CO)0-1R215,
—(CO)0-1R220,
—(CH2)0-4—C(O)—NR220R225,
—(CH2)0-4—(C(O))0-1—R215,
—(CH2)0-4—(C(O))0-1—R220,
—(CH2)0-4—C(O)-alkyl,
—(CH2)0-4—(C(O))0-1-cycloalkyl,
—(CH2)0-4—(C(O))0-1-heterocycloalkyl,
—(CH2)0-4—C(O)0-1-aryl,
—(CH2)0-4—(C(O)0-1-heteroaryl,
—(CH2)0-4—C(O)—O—R215,
—(CH2)0-4—S(O)0-2—NR220R225,
—(CH2)0-4—S(O)0-2-alkyl,
—(CH2)0-4S(O)0-2-cycloalkyl,
—(CH2)0-4—N(H or R215)—C(O)—O—R215,
—(CH2)0-4—N(H or R215)—S(O)1-2—R220,
—(CH2)0-4—N(H or R215)—C(O)—N(R215)2,
—(CH2)0-4—N(H or R215)—C(O)—R220,
—(CH2)0-4—NR220R225,
—(CH2)0-4—O—C(O)-alkyl,
—(CH2)0-4—O—(R215),
—(CH2)0-4—S—(R215),
—(CH2)0-4—C(O)H,
—(CH2)0-4—O-(alkyl optionally substituted with at least one halogen), and
-adamantane,
wherein each aryl and heteroaryl group included within R200 is optionally substituted with at least one group independently selected from
—R205,
—R210, and
-alkyl optionally substituted with at least one group independently selected from R205 and R210;
wherein each cycloalkyl or heterocycloalkyl group included within R200 is optionally substituted with at least one group independently selected from
—R205,
—R210, and
-alkyl optionally substituted with at least one group independently selected from R205 and R210;
R205 at each occurrence is independently selected from
-alkyl,
-heteroaryl,
-heterocycloalkyl,
-aryl,
-haloalkoxy,
—(CH2)0-3-cycloalkyl,
-halogen,
—(CH2)0-6—OH,
—O-phenyl,
—SH,
—(CH2)0-4—C(O)CH3
—(CH2)0-4—C(O)H
—(CH2)0-4—CO2H,
—(CH2)0-6—CN,
—(CH2)0-6—C(O)—NR235R240,
—(CH2)0-6—C(O)—R235,
—(CH2)0-4—N(H or R215)—SO2—R235,
—CF3,
—CN,
—OCF3,
—C(O)2-benzyl,
—O-alkyl,
—C(O)2-alkyl, and
—NR235R240;
R210 at each occurrence is independently selected from
—OH,
—CN,
—(CH2)0-4—C(O)H,
-alkyl wherein a carbon atom is optionally replaced with —C(O)—, and a carbon atom is optionally substituted with at least one group independently selected from R205,
—S-alkyl,
-halogen,
—O-alkyl,
-haloalkoxy,
—NR220R225,
-cycloalkyl optionally substituted with at least one group independently selected from R205,
—C(O)-alkyl,
—S(O)2—NR235R240,
—C(O)—NR235R240, and
—S(O)2-alkyl;
R215 at each occurrence is independently selected from
-alkyl,
—(CH2)0-2-aryl,
—(CH2)0-2-cycloalkyl,
—(CH2)0-2-heteroaryl, and
—(CH2)0-2-heterocycloalkyl;
wherein the aryl groups included within R215 are optionally substituted with at least one group independently selected from R205 or R210;
wherein the heterocycloalkyl and heteroaryl groups included within R215 are optionally substituted with at least one group independently selected from R210;
R220 and R225 at each occurrence are independently selected from
—H,
—OH,
-alkyl,
—(CH2)0-4—C(O)H,
-alkyl-OH,
—(CH2)0-4CO2-alkyl, wherein alkyl is optionally substituted with at least one group independently selected from R205,
-aminoalkyl,
—S(O)2-alkyl,
—(CH2)0-4—C(O)-alkyl, wherein alkyl is optionally substituted with at least one group independently selected from R205,
—(CH2)0-4—C(O)—NH2,
—(CH2)0-4—C(O)—NH(alkyl), wherein alkyl is optionally substituted with at least one group independently selected from R205,
—(CH2)0-4—C(O)—N(alkyl)(alkyl),
-haloalkyl,
—(CH2)0-2-cycloalkyl,
-alkyl-O-alkyl,
—O-alkyl,
-aryl,
-heteroaryl, and
-heterocycloalkyl;
wherein the aryl, heteroaryl and heterocycloalkyl groups included within R220 and R225 are each optionally substituted with at least one group independently selected from R270;
R270 at each occurrence is independently selected from
—R205,
-alkyl optionally substituted with at least one group independently selected from R205,
-phenyl,
-halogen,
—O-alkyl,
-haloalkoxy,
—NR235R240,
—OH,
—CN,
-cycloalkyl optionally substituted with at least one group independently selected from R205,
—C(O)-alkyl,
—S(O)2—NR235R240,
—CO—NR235R240,
—S(O)2-alkyl, and
—(CH2)0-4—C(O)H;
R235 and R240 at each occurrence are independently selected from
—H,
-alkyl,
—C(O)-alkyl,
—OH,
—CF3,
—OCH3,
—NH—CH3,
—N(CH3)2,
—(CH2)0-4—C(O)—(H or alkyl),
—SO2-alkyl, and
-phenyl;
R255 is selected from -hydrogen, —OH, —N(R220)(R225), and —O-alkyl;
R5 and R6 are independently selected from —H and -alkyl, or
R5 and R6, and the nitrogen to which they are attached, form a 5 or 6 membered heterocycloalkyl ring; and
R7 is independently selected from
—H,
-alkyl optionally substituted with at least one group independently selected from —OH, amino, and halogen,
-cycloalkyl, and
-alkyl-O-alkyl.

### Claim 11 (depends on 10)

The method according to claim 10, wherein R1 is selected from —CH2-phenyl, wherein the phenyl ring is optionally substituted with at least one group independently selected from -halogen, —C1—C2 alkyl, —O-methyl, and —OH.

### Claim 12 (depends on 10)

The method according to claim 10, wherein R1 is selected from 4-hydroxy-benzyl, 3-hydroxy-benzyl, 5-chloro-thiophen-2-yl-methyl, 5-chloro-3-ethyl-thiophen-2-yl-methyl, 3,5-difluoro-2-hydroxy-benzyl, piperidin-4-yl-methyl, 2-oxo-piperidin-4-yl-methyl, 2-oxo-1,2-dihydro-pyridin-4-yl-methyl, 5-hydroxy-6-oxo-6H-pyran-2-yl-methyl, 3,5-difluoro-4-hydroxy-benzyl, 3,5-difluoro-benzyl, 3-fluoro-4-hydroxy-benzyl, 3-fluoro-5-hydroxy-benzyl, and 3-fluoro-benzyl.

### Claim 13 (depends on 10)

The method according to claim 10, wherein RC is —C(R245)(R250)—RX, wherein R245 and R250 are taken together with the carbon to which they are attached to form a monocyclic or bicyclic ring system of 3, 4, 5, 8, 7, 8, 9, or 10 carbon atoms, wherein at least one bond in the monocyclic or bicyclic ring system is optionally a double bond, wherein the bicyclic ring system is optionally a fused or spiro ring system, wherein at least one atom within the monocyclic or bicyclic ring system is optionally replaced by a group independently selected from
—O—,
—C(O)—,
—S(O)0-2—,
—C(═N—R255)—,
—N—,
—NR220—,
—N((CO)0-1R200—, and
—N(SO2R200)—; and
wherein the monocyclic or bicyclic groups included within R245 and R250 are optionally substituted with at least one group independently selected from halogen, —OH, —O-alkyl, alkyl, aryl, —N(R200(R225), —CN, —NH2, —NH(alkyl), —NHOH, —NH—O-alkyl, —N(alkyl)(alkyl), —NH-C(O)-alkyl, and —NHS(O2)-alkyl; and wherein RX, R220 , R225, R255, and R200 are as defined in claim 10.

### Claim 14 (depends on 10)

The method according to claim 10, wherein RC is selected from formulae (Va), (Vb), (Vc), and (Vd),
wherein,
A, B, and C are independently selected from
—CH2—,
—O—,
—C(O)—,
—S(O)0-2—,
—N((CO)0-1R200)—,
—N(SO2R200)—,
—C(═N—R255)—, and
—N(R220)—;
A′ at each occurence is independently selected from —CH2— and —O—;
wherein (Va), (Vb), (Vc), and (Vd) are each optionally substituted with at least one group independently selected from -alkyl, —O-alkyl, —(CH2)0-2—OH, —(CH2)0-2—S-alkyl, —CF3, —CN, -halogen, —(CH2)0-2—NH2, —(CH2)0-2—NH(alkyl), —NHOH, —NH—O-alkyl, —N(alkyl)(alkyl), —NH-heteroaryl, —NH—C(O)-alkyl, and —NHS(O2)-alkyl; and
RX, R220, R255, and R200 are as defined in claim 10.

### Claim 15 (depends on 10)

The method according to claim 10, wherein RC is selected from formulae (Vla) and (Vlb),
wherein at least one carbon of the heterocycloalkyl of formula (Vla) and the cycloalkyl of formula (Vlb) is optionally replaced with a group independently selected from —O—, —SO2—, and —C(O)—, wherein at least one carbon of the heterocycloalkyl or cycloalkyl is optionally substituted with at least one group independently selected from R205, R245, and R250, wherein R100, R200, R205, R245, and R250 are as defined in claim 10.

### Claim 16 (depends on 10)

The method according to claim 10, wherein RC is selected from 6-isobutyl-1,1-dioxo-1λ6-thiochroman-4-yl, 6-isopropyl-2,2-dioxo-2λ6-isothiochroman-4-yl, 6-ethyl-2,2-dioxo-2λ6-isothiochroman-4-yl, 7-ethyl-1,2,3,4-tetrahydro-naphthalen-1-yl, 1-(3-tert-Butyl-phenyl)-cyclohexyl, and 3-methoxy-benzyl.

### Claim 17 (depends on 10)

The method according to claim 10, wherein R2 is selected from hydrogen, 3-Bromo-[1,2,4]thiadiazol-5-ylamino, [1,2,4]thiadiazol-5-ylamino, 4-Chloro-[1,2,5]thiadiazol-3-ylamino, [1,2,5]thiadiazol-3-ylamino, thiazol-2-ylamino, 5-Bromo-[1,3,4]thiadiazol-2-ylamino, [1,3,4]thiadiazol-2-ylamino, 5-Amino-[1,3,4]thiadiazol-2-ylamino, 2-Bromo-thiazol-5-ylamino, thiazol-5-ylamino, 5-trifluoromethyl-[1,3,4]thiadiazol-2-ylamino, 5-trifluoromethyl-[1,3,4]oxadiazol-2-ylamino, 5-Amino-[1,3,4]oxadiazol-2-ylamino, 1-trityl-1H-[1,2,4]triazol-3-ylamino, 1H-[1,2,4]triazol-3-ylamino, oxazol-2-ylamino, 5-Bromo-2-trityl-2H-[1,2,3]triazol-4-ylamino, 2-trityl-2H-[1,2,3]triazol-4-ylamino, 5-Bromo-2H-[1,2,3]triazol-4-ylamino, 2H-[1,2,3]triazol-4-ylamino, thiophen-2-ylamino, 3-methyl-5-nitro-3H-imidazol-4-ylamino, 4-Cyano-5-phenyl-isothiazol-3-ylamino, 4-phenyl-[1,2,5]thiadiazol-3-ylamino, 3,4-dioxo-cyclobut-1-enylamino, 2-methoxy-3,4-dioxo-cyclobut-1-enylamino, and 2-methylamino-3,4-dioxo-cyclobut-1-enylamino.

### Claim 18 (depends on 11)

The method according to claim 11, wherein RX is selected from 3-(1,1-dimethyl-propyl)-phenyl, 3-(1-ethyl-propyl)-phenyl, 3-(1H-pyrrol-2-yl)-phenyl, 3-(1-hydroxy-1-methyl-ethyl)-phenyl, 3-(1-methyl-1H-imidazol-2-yl)-phenyl, 3-(1-methyl-cyclopropyl)-phenyl, 3-(2,2-dimethyl-propyl)-phenyl), 3-(2,5-dihydro-1H-pyrrol-2-yl)-phenyl, 3-(2-Chloro-thiophen-3-yl)-phenyl, 3-(2-Cyano-thiophen-3-yl)-phenyl, 3-(2-fluoro-benzyl)-phenyl, 3-(3,5-dimethyl-3H-pyrazol-4-yl-phenyl, 3-(3,6-dimethyl-pyrazin-2-yl)-phenyl, 3-(3-Cyano-pyrazin-2-yl)-phenyl, 3-(3-formyl-furan-2-yl)-phenyl, 3-(3H-[1,2,3]triazol-4-yl)-phenyl, 3-(3H-imidazol-4-yl)-phenyl, 3-(3-methyl-butyl)-phenyl, 3-(3-methyl-pyridin-2-yl)-phenyl, 3-(3-methyl-thiophen-2-yl)-phenyl, 3-(4-Cyano-pyridin-2-yl)-phenyl, 3-(4-fluoro-benzyl)-phenyl, 3-(4H-[1,2,4]triazol-3-yl)-phenyl, 3-(4-methyl-thiophen-2-yl)-phenyl, 3-(5-Acetyl-thiophen-2-yl)-phenyl, 3-(5-Acetyl-thiophen-3-yl)-phenyl, 3-(5-formyl-thiophen-2-yl)-phenyl, 3-(5-oxo-pyrrolidin-2-yl)-phenyl, 3-(6-methyl-pyridazin-3-yl)-phenyl, 3-(6-methyl-pyridin-2-yl)-phenyl, 3-(Cyano-dimethyl-methyl)-phenyl, 3-[1-(2-tert-Butyl-pyrimidin-4-yl)-cyclohexylamino, 3-[1,2,3]triazol-1-yl-phenyl, 3-[1,2,4]oxadiazol-3-yl-phenyl, 3-[1,2,4]oxadiazol-5-yl-phenyl, 3-[1,2,4]thiadiazol-3-yl-phenyl, 3-[1,2,4]thiadiazol-5-yl-phenyl, 3-[1,2,4]triazol-4-yl-phenyl, 3-Acetyl-5-tert-butyl-phenyl, 3′-Acetylamino-biphenyl-3-yl, 3-Adamantan-2-yl-phenyl, 3-Bromo-[1,2,4]thiadiazol-5-yl)-phenyl, 3-Bromo-5-tert-butyl-phenyl, 3-Cyano-phenyl, 3-Cyclobutyl-phenyl, 3-Cyclopentyl-phenyl, 3-Cyclopropyl-phenyl, 3-ethyl-phenyl, 3-ethynyl-phenyl, 3-fluoro-5-(2-hydroxy-1,1-dimethyl-ethyl)-phenyl, 3-furan-3-yl-phenyl, 3-imidazol-1-yl-phenyl, 3-isobutyl-phenyl, 3-isopropyl-phenyl, 3-isoxazol-3-yl-phenyl, 3-isoxazol-4-yl-phenyl, 3-isoxazol-5-yl-phenyl, 3-pent-4-enyl-phenyl, 3-pentyl-phenyl, 3-Phenyl-propionic acid ethyl ester, 3-pyrazin-2-yl-phenyl, 3-pyridin-2-yl-phenyl, 3-pyrrolidin-2-yl-phenyl, 3-sec-Butyl-phenyl, 3-tert-Butyl-4-chloro-phenyl, 3-tert-Butyl-4-cyano-phenyl, 3-tert-Butyl-4-ethyl-phenyl, 3-tert-Butyl-4-methyl-phenyl, 3-tert-Butyl-4-trifluoromethyl-phenyl, 3-tert-Butyl-5-chloro-phenyl, 3-tert-Butyl-5-cyano-phenyl, 3-tert-Butyl-5-ethyl-phenyl, 3-tert-Butyl-5-fluoro-phenyl, 3-tert-Butyl-5-methyl-phenyl, 3-tert-Butyl-trifluoromethyl-phenyl, 3-tert-Butyl-phenyl, 3-thiazol-2-yl-phenyl, 3-thiazol-4-yl-phenyl, 3-thiophen-3-yl-phenyl, 3-trifluoromethyl-phenyl, 4-Acetyl-3-tert-butyl-phenyl, 4-tert-Butyl-pyridin-2-yl, 4-tert-Butyl-pyrimidin-2-yl, 5-tert-Butyl-pyridazin-3-yl, 6-tert-Butyl-pyridazin-4-yl, and 6-tert-Butyl-pyrimidin-4-yl.

### Claim 19 (depends on 10)

The method according to claim 10, wherein at least one compound of formula (I) is administered in combination with a pharmaceutically acceptable carrier or diluent.

### Claim 20 (depends on 10)

The method according to claim 10, wherein the condition is selected from Alzheimer's disease, Down's syndrome or Trisomy 21, hereditary cerebral hemorrhage with amyloidosis of the Dutch type, chronic inflammation due to amyloidosis, prion diseases, Familial Amyloidotic Polyneuropathy, cerebral amyloid angiopathy, other degenerative dementias, dementia associated with Parkinson's disease, dementia associated with progressive supranuclear palsy and dementia associated with cortical basal degeneration, diffuse Lewy body type of Alzheimer's disease, and frontotemporal dementias with parkinsonism.

### Claim 21 (depends on 10)

The method according to claim 10, wherein the condition is Alzheimer's disease.

### Claim 22 (depends on 10)

The method according to claim 10, wherein the condition is dementia.

### Claim 23 (depends on 10)

A method of preventing or treating at least one condition associated with amyloidosis, comprising:
administering to a host a composition comprising a therapeutically effective amount of at least one beta-secretase inhibitor of formula (I),
or pharmaceutically acceptable salt thereof, wherein R1, R2, and RC are defined in claim 10.

### Claim 24 (depends on 10)

A method of preventing or treating at least one condition associated with amyloidosis, comprising:
administering to a host a composition comprising a therapeutically effective amount of at least one beta-secretase inhibitor of formula (I),
further comprising a composition including beta-secretase complexed with at least one compound of formula (I), or pharmaceutically acceptable salt thereof, wherein R1, R2, and RC are defined in claim 10.

### Claim 25 (depends on 1)

A method of preventing or treating the onset of dementia comprising: administering to a patient a therapeutically effective amount of at least one compound of formula (I),
or a pharmaceutically acceptable salt thereof to the patient, wherein R1, R2, and RC are defined as in claim 1.

### Claim 26 (depends on 1)

A method of preventing or treating at least one condition associated with amyloidosis by administering to a host an effective amount of at least one compound of formula (I):
or pharmaceutically acceptable salt thereof, wherein R1, R2, and RC are defined as in claim 1.

### Claim 27 (depends on 1)

A method of preventing or treating Alzheimer's disease by administering to a host an effective amount of at least one compound having the following structure:
or pharmaceutically acceptable salt thereof, wherein R1, R2, and RC are defined as in claim 1.

### Claim 28 (depends on 1)

A method of preventing or treating dementia by administering to a host an effective amount of at least one compound having the following structure:
or pharmaceutically acceptable salt thereof, wherein R1, R2, and RC are defined as in claim 1.

### Claim 29 (depends on 1)

A method of inhibiting beta-secretase activity in a cell, the method comprising the step of administering to the cell an effective amount of at least one compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R1, R2, and RC are defined as in claim 1.

### Claim 30 (depends on 1)

A method of inhibiting beta-secretase activity in a host, the method comprising the step of administering to the host an effective amount of at least one compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R1, R2, and RC are defined as in claim 1.

### Claim 31 (depends on 30)

The method according to claim 30, wherein the host is a human.

### Claim 32 (depends on 1)

A method of affecting beta-secretase-mediated cleavage of amyloid precursor protein in a patient, comprising administering a therapeutically effective amount of at least one compound of formula (I),
or a pharmaceutically acceptable salt thereof, wherein R1, R2, and RC are defined as in claim 1.

### Claim 33 (depends on 1)

A method of inhibiting cleavage of amyloid precursor protein at a site between Met596 and Asp597 (numbered for the APP-695 amino acid isotype), or at a corresponding site of an isotype or mutant thereof, comprising: administering a therapeutically effective amount of at least one compound of formula (I),
or a pharmaceutically acceptable salt thereof, wherein R1, R2, and RC are defined as in claim 1.

### Claim 34 (depends on 1)

A method of inhibiting cleavage of amyloid precursor protein or mutant thereof at a site between amino acids, comprising: administering a therapeutically effective amount of at least one compound of formula (I),
or a pharmaceutically acceptable salt thereof, wherein R1, R2 and RC are defined as in claim 1, wherein the site between amino acids corresponds to
between Met652 and Asp653 (numbered for the APP-751 isotype);
between Met671 and Asp672 (numbered for the APP-770 isotype);
between Leu596 and Asp597 of the APP-695 Swedish Mutation;
between Leu652 and Asp653 of the APP-751 Swedish Mutation; or
between Leu671 and Asp672 of the APP-770 Swedish Mutation.

### Claim 35 (depends on 1)

A method of inhibiting production of A-beta, comprising: administering to a patient a therapeutically effective amount of at least one compound of formula (I),
or a pharmaceutically acceptable salt thereof, wherein R1, R2, and RC are defined as in claim 1.

### Claim 36 (depends on 1)

A method of preventing or treating deposition of A-beta, comprising: administering a therapeutically effective amount of at least one compound of formula (I),
or a pharmaceutically acceptable salt thereof, wherein R1, R2, and RC are defined as in claim 1.

### Claim 37 (depends on 1)

A method of preventing, delaying, halting, or reversing a disease characterized by A-beta deposits or plaques, comprising: administering a therapeutically effective amount of at least one compound of formula (I),
or a pharmaceutically acceptable salt thereof, wherein R1, R2, and RC are defined as in claim 1.

### Claim 38 (depends on 37)

The method in claim 37, wherein the A-beta deposits or plaques are in a human brain.

### Claim 39 (depends on 1)

A method of preventing, delaying, halting, or reversing a condition associated with a pathological form of A-beta in a host comprising: administering to a patient in need thereof an effective amount of at least one compound of formula (I),
or a pharmaceutically acceptable sail thereof, wherein R1, R2, and RC are defined as in claim 1.

### Claim 40 (depends on 1)

A method of inhibiting the activity of at least one aspartyl protease in a patient in need thereof, comprising: administering a therapeutically effective amount of at least one compound of formula (I),
or a pharmaceutically acceptable salt thereof, wherein R1, R2, and RC are defined as in. claim 1, to the patient.

### Claim 41 (depends on 40)

The method according to claim 40 wherein the at least one aspartyl protease is beta-secretase.

### Claim 42 (depends on 1)

A method of interacting an inhibitor with beta-secretase, comprising: administering to a patient In need thereof a therapeutically effective amount of at least one compound of formula (I),
or a pharmaceutically acceptable salt thereof, wherein R1, R2, and RC are defined as in claim 1, wherein the at least one compound interacts with at least one of the following beta-secretase subsites S1, S1′, and S2′.

### Claim 43 (depends on 1)

A method of treating at least one condition in a patient, comprising: administering a therapeutically effective amount of at least one compound of formula (I),
or a pharmaceutically acceptable salt, derivative or biologically active metabolite thereof, to the patient, wherein R1, R2, and RC are defined as in claim 1.

### Claim 44 (depends on 43)

The method according to claim 43, wherein the condition is selected from Alzheimer's disease, Down's syndrome or Trisomy 21 (including mild cognitive impairment (MCI) Down's syndrome), hereditary cerebral hemorrhage with amyloidosis of the Dutch type, chronic inflammation due to amyloidosis, prion diseases (including Creutzfeldt-Jakob disease, Gerstmann-Straussler syndrome, kuru scrapie, and animal scrapie), Familial Amyloidotic Polyneuropathy, cerebral amyloid angiopathy, other degenerative dementias, dementia associated with Parkinson's disease, dementia associated with progressive supranuclear palsy and dementia associated with cortical basal degeneration, diffuse Lewy body type of Alzheimer's disease, and frontotemporal dementias with parkinsonism (FTDP).

### Claim 45 (depends on 44)

The method according to claim 44, wherein the condition is Alzheimer's disease.

### Claim 46 (depends on 44)

The method according to claim 44, wherein the condition is dementia.

### Claim 47 (depends on 1)

A method of prescribing a medication for preventing, delaying, halting, or reversing at least one disorder, condition or disease associated with amyloidosis comprising: identifying in a patient symptoms associated with at least one disorder, condition or disease associated with amyloidosis; and prescribing at least one dosage form of at least one compound of formula (I),
or a pharmaceutically acceptable salt, derivative or biologically active metabolite thereof, to the patient, wherein R1, R2, and RC are defined as in claim 1.

### Claim 48 (depends on 1)

An article of manufacture, comprising:
(a) at least one dosage form of at least one compound of formula (I),
or a stereoisomer, or pharmaceutically acceptable salt thereof, wherein R1, R2, and RC are defined as in claim 1;
(b) a package insert providing that a dosage form comprising a compound of formula (I) should be administered to a patient in need of therapy for at least one disorder, condition or disease associated with amyloidosis; and
(c) at least one container in which at least one dosage form of at least one compound of formula (I) is stored,

### Claim 49 (depends on 1)

A packaged pharmaceutical composition for treating at least one condition related to amyloidosis, comprising:
(a) a container which holds an effective amount of at least one compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined in claim 1; and
(b) instructions for using the pharmaceutical composition.

### Claim 50 (depends on 1)

An article of manufacture, comprising:
(a) a therapeutically effective amount of at least one compound of formula (I)
or a stereoisomer, or pharmaceutically acceptable salt thereof, wherein R1, R2, and RC are defined as in claim 1;
(b) a package insert providing an oral dosage form should be administered to a patient in need of therapy for at least one disorder, condition or disease associated with amyloidosis; and
(c) at least one container comprising: at least one oral dosage form of at least one compound of formula (I).

### Claim 51 (depends on 1)

An article of manufacture, comprising:
(a) at least one oral dosage form of at least one compound of formula (I)
or a stereoisomer, or pharmaceutically acceptable salt thereof, wherein R1, R2, and RC are defined as in claim 1;
in a dosage amount ranging from about 2 mg to about 1000 mg; associated with
(b) a package insert providing that an oral dosage form comprising: a compound of formula (I) in a dosage amount ranging from about 2 mg to about 1000 mg should be administered to a patient in need of therapy for at least one disorder, condition or disease associated with amyloidosis; and
(c) at least one container In which at least one oral dosage form of at least one compound of formula (I) in a dosage amount ranging from about 2 mg to about 1000 mg is stored.

### Claim 52 (depends on 1)

An article of manufacture, comprising:
(a) at least one oral dosage form of at least one compound of formula (I)
wherein R1, R2, and RC are defined as in claim 1, in a dosage amount ranging from about 2 mg to about 1000 mg in combination with
(b) at least one therapeutically active agent; associated with
(c) a package insert providing that an oral dosage form comprising: a compound of formula (I) in a dosage amount ranging from about 2 mg to about 1000 mg in combination with at least one therapeutically active agent should be administered to a patient in need of therapy for at least one disorder, condition or diseases associated with amyloidosis; and
(d) at least one container in which at least one dosage form of at least one compound of formula (I) in a dosage amount ranging from about 2 mg to about 1000 mg in combination with a therapeutically active agent is stored.

### Claim 53 (depends on 52)

The article of manufacture according to claim 52 wherein the therapeutically active agent, is selected from an antioxidant, an anti-inflammatory, a gamma-secretase inhibitor, a neurotrophic agent, an acetyl cholinesterase inhibitor, a statin, an A-beta, and an anti-A-beta antibody.

### Claim 54 (depends on 1)

An article of manufacture, comprising:
(a) at least one parenteral dosage form of at least one compound of formula (I)
wherein R1, R2, and RC are defined as in claim 1, in a dosage amount ranging from about 0.2 mg/mL to about 50 mg/mL; associated with
(b) a package insert providing that a parenteral dosage form comprising: a compound of formula (I) in a dosage amount ranging from about 0.2 mg/mL to about 50 mg/mL should be administered to a patient in need of therapy for at least one disorder, condition or disease associated with amyloidosis; and
(c) at least one container in which at least one parenteral dosage form of at least one compound of formula (I) in a dosage amount ranging from about 0.2 mg/mL to about 50 mg/mL is stored.

### Claim 55 (depends on 1)

An article of manufacture comprising:
(a) a medicament comprising: an effective amount of at least one compound of formula (I)
wherein R1, R2, and RC are defined as in claim 1, in combination with active and/or inactive pharmaceutical agents;
(b) a package insert providing that an effective amount of at least one compound of formula (I) should be administered to a patient in need of therapy for at least one disorder, condition or disease associated with amyloidosis; and
(c) a container in which a medicament comprising: an effective amount of at least one compound of formula (I) in combination with active and/or inactive pharmaceutical agents is stored.

### Claim 56 (depends on 1)

A kit comprising:
(a) at least one dosage form of at least one compound according to claim 1; and
(b) at least one container in which at least one dosage form of at least one compound according to claim 1 is stored,

### Claim 57 (depends on 1, 58)

A kit according to claim 58, further comprising a package insert:
a) containing information of the dosage amount and duration of exposure of a dosage form containing at least one compound of formula (I) as defined in claim 1, and
b) providing that the dosage form should be administered to a patient in need of therapy for at least one disorder, condition or disease associated with amyloidosis.

### Claim 58 (depends on 57)

The kit according to claim 57 further comprising: at least one therapeutically active agent.

### Claim 59 (depends on 58)

The kit according to claim 58 wherein the therapeutically active agent is selected from an antioxidant, an anti-inflammatory, a gamma-secretase inhibitor, a neurotrophic agent, an acetyl cholinesterase inhibitor, a statin, an A-beta, and an anti-A-beta antibody.

### Claim 60 (depends on 1)

A method of producing A-beta-secretase complex comprising: exposing beta-secretase to a compound of formula (I) as defined in claim 1, or a pharmaceutically acceptable salt thereof, in a reaction mixture under conditions suitable for the production of the complex.

### Claim 61 (depends on 1)

A manufacture of a medicament for preventing, delaying, halting, or reversing Alzheimer's disease, comprising: adding an effective amount of at least one compound of formula (I) as defined in claim 1, to a pharmaceutically acceptable carrier.