# US 7,244,721 B2 · Peptides as NS3-serine protease inhibitors of hepatitis C virus

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- Number: US 7,244,721 B2
- Document ID: US7244721B2
- Status: Granted
- Kind: B2
- Application number: 10/052,386
- Filed: 2002-01-18
- Published: 2007-02-08
- Granted: 2007-07-17
- Earliest claimed: 2000-07-21
- Assignees: Schering Corporation; Dendreon Corporation
- Inventors: Anil K. Saksena; Viyyoor Moopil Girijavallabhan; Raymond G. Lovey; Edwin Jao; Frank Bennett; Jinping L. Mc Cormick; Haiyan Wang; Russell E. Pike; Stephane L. Bogen; Tin-Yau Chan; Yi-Tsung Liu; Zhaoning Zhu; F. George Njoroge; Ashok Arasappan; Tejal Parekh; Ashit K. Ganguly; Kevin X. Chen; Srikanth Venkatraman; Henry A. Vaccaro; Patrick A. Pinto; Bama Santhanam; Scott Jeffrey Kemp; Odile Esther Levy; Marguerita Lim-Wilby; Susan Y. Tamura; Wanli Wu; Siska Hendrata; Yuhua Huang; Jesse K. Wong; Latha G. Nair
- Web page: https://patentgrep.com/patent/US7244721B2

## CPC

- C07K 5/0804: {and aliphatic}
- A61P 1/16: for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
- A61P 31/12: Antivirals
- A61P 31/14: for RNA viruses
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07K 5/0202: {containing the structure -NH-X-X-C(=0)-, X being an optionally substituted carbon atom or a heteroatom, e.g. beta-amino acids}
- C07K 5/0812: {and aromatic or cycloaliphatic}
- C07K 5/0827: {containing heteroatoms different from O, S, or N}
- C07K 7/02: Linear peptides containing at least one abnormal peptide link
- A61K 38/00: Medicinal preparations containing peptides (peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00)
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)

## Abstract

The present invention discloses novel compounds which have HCV protease inhibitory activity as well as methods for preparing such compounds. In another embodiment, the invention discloses pharmaceutical compositions comprising such compounds as well as methods of using them to treat disorders associated with the HCV protease.

## Claims

### Claim 1

A compound, including enantiomers, stereoisomers, rotamers, tautomers, racemates and prodrug of said compound, and pharmaceutically acceptable salts or solvates of said compound, or of said prodrug, said compound having the general structure shown in Formula I:
wherein:
Y is selected from the group consisting of the following moieties: alkyl, alkyl-aryl, heteroalkyl, heteroaryl, arylheteroaryl, alkyl-heteroaryl, cycloalkyl, alkyloxy, alkylaryloxy, aryloxy, heteroaryloxy, heterocycloalkyloxy, cycloalkyloxy, alkylamino, arylamino, alkyl-arylamino, arylamino, heteroarylamino, cycloalkylamino and heterocycloalkylamino, with the proviso that Y may be optionally substituted with X11 or X12;
X11 is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, alkylaryl, arylalkyl, heteroaryl, alkylheteroaryl, or heteroarylalkyl, with the proviso that X11 may be additionally optionally substituted with X12;
X12 is hydroxy, alkoxy, aryloxy, thio, alkylthio, arylthio, amino, alkylamino, arylamino, alkylsulfonyl, arylsulfonyl, alkylsulfonamido, arylsulfonamido, carboxy, carbalkoxy, carboxamido, alkoxycarbonylamino, alkoxycarbonyloxy, alkylureido, arylureido, halogen, cyano, or nitro, with the proviso that said alkyl, alkoxy, and aryl may be additionally optionally substituted with moieties independently selected from X12;
R1 is COR5 wherein R5 is COOR8, CONR9R10, CF3, C2F5, C3F7, CF2R6, or R6, wherein R6, R8, R9 and R10 are independently selected from the group consisting of H, alkyl, aryl, heteroalkyl, heteroaryl, cycloalkyl, arylalkyl, heteroarylalkyl, [CH(R1′)]pCOOR11, [CH(R1′)] pCONR12R13, [CH(R1′)]pSO2R11, [CH(R1′)]pCOR11, [CH(R1′)]pCH(OH)R11, CH(R1′)CONHCH(R2′) COO R11, CH(R1′)CONHCH(R2′)CONR12R13, CH(R1′)CONHCH(R2′)R′, CH(R1′)CONHCH(R2′)CONHCH(R3′) COO R11, CH(R1′)CONHCH(R2′)CONHCH(R3′) CONR12R13, CH(R1′)CONHCH(R2′)CONHCH(R3′) CONHCH(R4′) COO R11, CH(R1′)CONHCH(R2′)CONHCH(R3′)CONHCH(R4′)CONR12R13, CH(R1′)CONHCH(R2′)CONHCH(R3′) CONHCH(R4′) CONHCH(R5′)COO R11 and CH(R1′)CONHCH(R2′)CONHCH(R3′)CONHCH(R4′)CONHCH(R5′)CONR12R13, wherein R1′, R2′, R3′, R4′, R5′, R11, R12, and R13 are independently selected from the group consisting of H, alkyl, aryl, heteroalkyl, heteroaryl, cycloalkyl, alkyl-aryl, alkylheteroaryl, aryl-alkyl and heteroaralkyl;
Z is selected from O, N, CH or CR;
W may be present or absent, and if W is present, W is selected from C═O, C═S, C(═N—CN), or SO2;
Q may be present or absent, and when Q is present, Q is CH, N, P, (CH2)p, (CHR)p, (CRR′)p, O, NR, S, or SO2; and when Q is absent, M may be present or absent; when Q and M are absent, A is directly linked to L;
A is O, CH2, (CHR)p, (CHR—CHR′)p, (CRR′)p, NR, S, or SO2;
E is CH, N, CR, or a double bond towards or L;
G is absent, and E is directly connected to the carbon atom in Formula I as G is linked to;
J is present, J is (CH2)p, (CHR) p, or (CRR′)p, SO2, NH, NR or O;
L is present, L is CH, CR, O, S or NR;
M may be present or absent, and when M is present, M is O, NR, S, SO2, (CH2)p, (CHR)p (CHR—CHR′)p, or (CRR′)p;
p is a number from 0 to 6; and
R, R′, R2, R3 and R4 are independently selected from the group consisting of H; C1–C10 alkyl; C2–C10 alkenyl; C3–C8 cycloalkyl; C3–C8 heterocycloalkyl, alkoxy, aryloxy, alkylthio, arylthio, amino, amido, ester, carboxylic acid, carbamate, urea, ketone, aldehyde, cyano, nitro, halogen; (cycloalkyl)alkyl and (heterocycloalkyl)alkyl, wherein said cycloalkyl is made of three to eight carbon atoms, and zero to six oxygen, nitrogen, sulfur, or phosphorus atoms, and said alkyl is of one to six carbon atoms; aryl; heteroaryl; alkyl-aryl; alkylheteroaryl; and further with respect to R2, the group
wherein said alkyl, heteroalkyl, alkenyl, heteroalkenyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl moieties may be optionally and chemically-suitably substituted, with said term “substituted” referring to optional and chemically-suitable substitution with one or more moieties selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, aralkyl, cycloalkyl, heterocyclic, halogen, hydroxy, thio, alkoxy, aryloxy, alkylthio, arylthio, amino other than for R2, amido, ester, carboxylic acid, carbamate, urea, ketone, aldehyde, cyano, nitro, sulfonamido, sulfoxide, sulfone, sulfonyl urea, hydrazide, and hydroxamate;
further wherein said unit N-C-E-L-J-N represents a five-membered or six-membered cyclic ring structure with the proviso that when said unit N-C-E-L-J-N represents a five-membered cyclic ring structure, or when the bicyclic ring structure in Formula I comprising N, C, E, L, J, N, A, Q, and M represents a five-membered cyclic ring structure, then said five-membered cyclic ring structure lacks a carbonyl group as part of the cyclic ring.

### Claim 2 (depends on 1)

The compound of claim 1, wherein R1 is COCONR9R10, and R9 is H, R10 is H, R14, CH(R1′)COOR11, CH(R1′)CH(R1′)COOR11, CH(R1′)CONR12R13, CH(R1′)CH(R1′)CONR12R13, CH(R1′)SO2R11, CH(R1′)SO2NR12R13, CH(R1′)CH(R1′)COR11, CH(R1′)CONHCH(R2′)COOR11, CH(R1′)CONHCH(R2′) CONR12R3, or CH(R1′)CONHCH(R2′)(R′), wherein R14 is H, alkyl, aryl, heteroalkyl, heteroaryl, cycloalkyl, alkyl-aryl, alkylheteroaryl, aryl-alkyl, alkenyl, alkynyl or heteroaralkyl; wherein R1′ is H or alkyl, and R2′ is phenyl, substituted phenyl, hetero atom-substituted phenyl, thiophenyl, cycloalkyl, piperidyl or pyridyl; and wherein R11 is H, methyl, ethyl, allyl, tert-butyl, benzyl, α-methylbenzyl, α,α-dimethylbenzyl, 1-methylcyclopropyl or 1-methylcyclopentyl; R′ is hydroxymethyl or CH2CONR12R13; R2′ is independently selected from the group consisting of:
wherein:
U1 and U2 maybe same or different and are selected from H, F, CH2COOH, CH2COOMe, CH2CONH2, CH2CONHMe, CH2CONMe2, azido, amino, hydroxyl, substituted amino, substituted hydroxyl;
U3 and U4 maybe same or different and are selected from O and S;
U5 is selected from the moieties consisting of alkyl sulfonyl, aryl, sulfonyl, heteroalkyl sulfonyl, heteroaryl sulfonyl, alkyl carbonyl, aryl carbonyl, heteroalkyl carbonyl, heteroaryl carbonyl, alkoxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, alkylaminocarbonyl, arylaminocarbonyl, heteroarylaminocarbonyl or a combination thereof; and NR12R13 is selected from the group consisting of:
wherein U6 is H, OH, or CH2OH, and
R14 is selected from the group consisting of: H, Me, Et, n-propyl, methoxy, cyclopropy, n-butyl, 1-but-3-ynyl, benzyl, α-methylbenzyl, phenethyl, allyl, 1-but-3-enyl, OMe, cyclopropylmethyl.

### Claim 3 (depends on 2)

The compound of claim 2, wherein R2 is selected from the group consisting of the following moieties:

### Claim 4 (depends on 3)

The compound of claim 3, wherein R3 is selected from the group consisting of:
wherein R51=H, COCH3, COOtBu or CONHtBu
wherein R31 OH or O-alkyl;
Y19 is selected from the following moieties:
and Y20 is selected from the following moieties:

### Claim 5 (depends on 4)

The compound of claim 4, wherein R3 is selected from the group consisting of the following moieties:

### Claim 6 (depends on 5)

The compound of claim 5, wherein Z is N and R4 is H.

### Claim 7 (depends on 6)

The compound of claim 6, wherein W is C═O.

### Claim 8 (depends on 7)

The compound of claim 7, wherein Y is selected from the following moieties:
wherein:
Y11 is selected from H, COOH, COOEt, OMe, Ph, OPh, NHMe, NHAc, NHPh, CH(Me)2, 1-triazolyl, 1-imidazolyl, and NHCH2COOH;
is selected from H, COOH, COOMe, OMe, F, Cl, or Br;
Y13 is selected from the following moieties:
Y14 is selected from MeSO2, Ac, Boc, iBoc, Cbz, or Alloc;
Y15 and Y16 are independently selected from alkyl, aryl, heteroalkyl, and heteroaryl;
Y17 is CF3, NO2, CONH2, OH, COOCH3, OCH3, OC6H5, C6H5, COC6H5, NH2, or COOH; and
Y18 is COOCH3, NO2, N(CH3)2, F, OCH3, CH2COOH, COOH, SO2NH2, or NHCOCH3.

### Claim 9 (depends on 8)

The compound of claim 8, wherein Y is selected m the group consisting of:
wherein:
Y17=CF3, NO2, CONH2, OH, NH2, or COOH;
Y18=F, COOH.

### Claim 10 (depends on 9)

The compound of claim 9, wherein Y is selected from the group consisting of:

### Claim 11 (depends on 3)

The compound of claim 3, wherein R2 is the moiety:

### Claim 12 (depends on 10)

The compound of claim 10, wherein G and M are absent.

### Claim 13 (depends on 10)

The compound of claim 10, wherein:
wherein G is absent and J is selected from the group consisting of (CH2)p, (CHR)p, (CHR—CHR′)p, and (CRR′)p; A and M are independently selected from the group consisting of O, S, SO2, NR, (CH2)p, (CHR)p, (CHR—CHR′)p, and (CRR′)p; and Q is CH2, CHR, CRR′, NH, NR, O, S, SO2, NR, (CH2) p, (CHR)p, and (CRR′)p.

### Claim 14 (depends on 13)

The compound of claim 13, wherein structure c is selected from the following structures:

### Claim 15 (depends on 10)

The compound of claim 10, wherein:
is selected from the following structures:

### Claim 16 (depends on 15)

The compound of claim 15, wherein:
is selected from the following structures:

### Claim 17 (depends on 15)

The compound of claim 15, wherein:
is selected from the following structures:

### Claim 18 (depends on 1)

A pharmaceutical composition comprising as an active ingredient a compound of claim 1.

### Claim 19 (depends on 18)

The pharmaceutical composition of claim 18 suitable for use in treating disorders associated with hepatitis C virus.

### Claim 20 (depends on 18)

The pharmaceutical composition of claim 18 additionally comprising a pharmaceutically acceptable carrier.

### Claim 21 (depends on 20)

The pharmaceutical composition of claim 20, additionally containing an antiviral agent.

### Claim 22 (depends on 21)

The pharmaceutical composition of claim 21, further containing an interferon.

### Claim 23 (depends on 22)

The pharmaceutical composition of claim 22, wherein said antiviral agent is ribavirin and said interferon is α-interferon or pegylated interferon.

### Claim 24 (depends on 4)

The compound of claim 4, wherein R3 is:

### Claim 25 (depends on 1)

A method of treating disorders associated with the hepatitis C virus, said method comprising administering to a patient in need of such treatment a pharmaceutical composition which comprises therapeutically effective amounts of a compound of claim 1.

### Claim 26 (depends on 25)

The method of claim 25, wherein said administration is oral or subcutaneous.

### Claim 27 (depends on 1)

The use of a compound of claim 1 for the manufacture of a medicament to treat disorders associated with the hepatitis C virus.

### Claim 28 (depends on 1)

A compound of claim 1 suitable for use in the manufacture of a medicament to treat disorders associated with the hepatitis C virus.

### Claim 29 (depends on 1)

A method of treating disorders associated with the hepatitis C virus (HCV), said method comprising administering to a patient in need of such treatment, a compound of claim 1 and an interferon.

### Claim 30 (depends on 29)

The method of claim 29, wherein said interferon is alpha-interferon or pegylated interferon.

### Claim 31 (depends on 30)

The method of claim 30, wherein said administration is oral or subcutaneous.

### Claim 32 (depends on 29)

The method of claim 29, wherein said treatment further comprises administering an antiviral agent.

### Claim 33

A compound exhibiting hepatitis C virus protease inhibitory activity, including enantiomers, stereoisomers, rotamers, tautomers, racemates and prodrug of said compound, and pharmaceutically acceptable salts or solvates of said compound, or of said prodrug, said compound being selected from the compounds of structures listed below:

### Claim 34 (depends on 33)

A pharmaceutical composition for treating disorders associated with the hepatitis C virus, said composition comprising therapeutically effective amount of one or more compounds in claim 33 and a pharmaceutically acceptable carrier.

### Claim 35 (depends on 34)

The pharmaceutical composition of claim 34, additionally containing an antiviral agent.

### Claim 36 (depends on 35)

The pharmaceutical composition of claim 35, additionally containing an interferon or pegylated-interferon alpha conjugate.

### Claim 37 (depends on 36)

The pharmaceutical composition of claim 36, wherein said antiviral agent is ribavirin and said interferon is α-interferon.

### Claim 38 (depends on 33)

A method of treatment of a hepatitis C virus (HCV) associated disorder, comprising administering an effective amount of one or more compounds of claim 33.

### Claim 39 (depends on 33)

A method of modulating the activity of hepatitis C virus (HCV) protease, comprising contacting HCV protease with one or more compounds of claim 33.

### Claim 40 (depends on 33)

A method of treating, or ameliorating one or more symptoms of hepatitis C, comprising administering an effective amount of one or more compounds of claim 33.

### Claim 41 (depends on 39)

The method of claim 39, wherein the HCV protease is the NS3/NS4a protease.

### Claim 42 (depends on 41)

The method of claim 41, wherein the compound or compounds inhibit HCV NS3/NS4a protease.

### Claim 43 (depends on 33)

A method of modulating the activity of hepatitis C virus (HCV) polypeptide, comprising contacting a composition containing the HCV polypeptide under conditions in which the polypeptide is processed with one or more compounds of claim 33.

### Claim 44 (depends on 33)

A method of treating disorders associated with the hepatitis C virus (HCV), comprising administering to a patient in need of such treatment, a compound of claim 33 and an interferon.

### Claim 45 (depends on 44)

The method of claim 44, wherein said interferon is alpha-interferon or pegylated interferon.

### Claim 46 (depends on 45)

The method of claim 45, wherein said administration is oral or subcutaneous.

### Claim 47

A compound exhibiting hepatitis C virus protease inhibitory activity, including enantiomers, stereoisomers, rotamers, tautomers, racemates and prodrug of said compound, and pharmaceutically acceptable salts or solvates of said compound, or of said prodrug, said compound being the compound of structure shown below:

### Claim 48 (depends on 47)

A compound of claim 47 having the formula shown below:

### Claim 49 (depends on 47)

A compound of claim 47 having the formula shown below:

### Claim 50

A pharmaceutical composition comprising as an active ingredient a compound, including enantiomers, stereoisomers, rotamers, tautomers, racemates and prodrug of said compound, and pharmaceutically acceptable salts or solvates of said compound, or of said prodrug, said compound being selected from the following:

### Claim 51 (depends on 47)

The pharmaceutical composition of claim 47, additionally containing an antiviral agent.

### Claim 52 (depends on 50)

The pharmaceutical composition of claim 50, further containing an interferon or pegylated-interferon alpha conjugate.

### Claim 53 (depends on 51)

The pharmaceutical composition of claim 51, wherein said antiviral agent is ribavirin and said interferon is α-interferon.

### Claim 54 (depends on 50)

The pharmaceutical composition of claim 50, wherein said compound is selected from the following:

### Claim 55 (depends on 54)

The pharmaceutical composition of claim 54, additionally containing an antiviral agent.

### Claim 56 (depends on 55)

The pharmaceutical composition of claim 55, additionally containing an interferon or pegylated-interferon alpha conjugate.

### Claim 57 (depends on 56)

The pharmaceutical composition of claim 56, wherein said antiviral agent is ribavirin and said interferon is alpha-interferon.

### Claim 58 (depends on 50)

A method of treating disorders associated with the hepatitis C virus (HCV), comprising administering to a patient in need of such treatment the pharmaceutical composition of claim 50 and an interferon.

### Claim 59 (depends on 58)

The method of claim 58, wherein said interferon is alpha-interferon or pegylated interferon.

### Claim 60 (depends on 59)

The method of claim 59, wherein said administration is oral or subcutaneous.

### Claim 61 (depends on 48, 49)

A method of treating disorders associated with the hepatitis C virus (HCV), comprising administering to a patient in need of such treatment a compound of any of claims 48 or 49 and an interferon.

### Claim 62 (depends on 54)

A method of treating disorders associated with the hepatitis C virus (HCV), comprising administering to a patient in need of such treatment the pharmaceutical composition of claim 54 and an interferon.

### Claim 63

A method of treating disorders associated with the hepatitis C virus, said method comprising administering to a patient in need of such treatment, a pharmaceutical composition which comprises therapeutically effective amounts of a compound, including enantiomers, stereoisomers, rotamers, tautomers, racemates and prodrug of said compound, and pharmaceutically acceptable salts or solvates of said compound, or of said prodrug, said compound being selected from the following:

### Claim 64 (depends on 63)

The method of claim 63, wherein said compound is selected from the following:

### Claim 65 (depends on 64)

The method of claim 64, further comprising administering an interferon.

### Claim 66

A compound, including enantiomers, stereoisomers, rotamers, tautomers, racemates and prodrug of said compound, and pharmaceutically acceptable salts or solvates of said compound, or of said prodrug, said compound having the general structure shown in Formula II:
wherein Y is selected from the group consisting of:
R1 is COR5 and R5 is H, OH, COOR8, CONR9R10, wherein R8, R9 and R10 are independently selected from the group consisting of H, alkyl, aryl, heteroalkyl, heteroaryl, cycloalkyl, arylalkyl, heteroarylalkyl, [CH(R1′)]pCOOR11, [CH(R1′)]pCONR12R13, [CH(R1′)]pCOR11, [CH(R1′)]pCH(OH)R11, CH(R1′)CONHCH(R2′)COO R11, CH(R1′)CONHCH(R2′)CONR12R13, CH(R1′)CONHCH(R2′)R′, CH(R1′)CONHCH(R2′)CONHCH(R3′)COO R11, CH(R1′)CONHCH(R2′)CONHCH(R3′)CONR12R13, CH(R1′)CONHCH(R2′)CONHCH(R3′)CONHCH(R4′)COO R11, CH(R1′)CONHCH(R2′)CONHCH(R3′)CONHCH(R4′)CONR12R13, CH(R1′)CONHCH(R2′)CONHCH(R3′)CONHCH(R4′)CONHCH(R5′)COO R11 and CH(R1′)CONHCH(R2′)CONHCH(R3′)CONHCH(R4′)CONHCH(R5′) CONR12R13, wherein R1′, R2′, R3′, R4′, R5′, R11, R12, and R13 are independently selected from the group consisting of H, alkyl, aryl, heteroalkyl, heteroaryl, cycloalkyl, alkyl-aryl, alkyl-heteroaryl, aryl-alkyl and heteroaralkyl;
Z is N and R4 is H;
W is C=O;
Q may be present or absent, and when Q is present, Q is CH, N, P, (CH2)p, (CHR)p, (CRR′)p, O, NR, S, or SO2; and when Q is absent, M is directly linked to A;
A is O, CH2, (CHR)p, (CHR-CHR′)p, (CRR′)p, NR, S, or SO2;
M may be present or absent, and when M is present, M is O, NR, S, SO2, (CH2)p, (CHR)p (CHR-CHR′)p, or (CRR′)p;
p is a number from 0 to 6; and
R, and R′ are independently selected from the group consisting of H; C1-C10 alkyl; C2-C10 alkenyl; C3-C8 cycloalkyl; C3-C8 heterocycloalkyl, alkoxy, aryloxy, alkylthio, arylthio, amino, amido, ester, carboxylic acid, carbamate, urea, ketone, aldehyde, cyano, nitro, halogen; (cycloalkyl)alkyl and (heterocycloalkyl)alkyl, wherein said cycloalkyl is made of three to eight carbon atoms, and zero to six oxygen, nitrogen, sulfur, or phosphorus atoms, and said alkyl is of one to six carbon atoms; aryl; heteroaryl; alkyl-aryl; and alkyl-heteroaryl; wherein said alkyl, heteroalkyl, alkenyl, heteroalkenyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl moieties may be optionally and chemically-suitably substituted, with said term “substituted” referring to optional and chemically-suitable substitution with one or more moieties selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, aralkyl, cycloalkyl, heterocyclic, halogen, hydroxy, thio, alkoxy, aryloxy, alkylthio, arylthio, amino, amido, ester, carboxylic acid, carbamate, urea, ketone, aldehyde, cyano, nitro, sulfonamido, sulfoxide, sulfone, sulfonyl urea, hydrazide, and hydroxamate; and
wherein R2 is selected from the group consisting of the following moieties:
and
R3 is selected from the group consisting of the following moieties:
wherein R51=H, COCH3, COOtBu or CONHtBu;
wherein R31=OH or O-alkyl; and
Y19 is selected from the following moieties:
and Y20 is selected from the following moieties:
wherein R1 is -C(O)C(O)NR9R10; R9 is H;
R10 is H, -R14, CH(R1′)COOR11, CH(R1′)CH(R1′)COOR11, CH(R1′)CONR12R13, CH(R1′)CH(R1′)CONR12R13, CH(R1′)CH(R1′)SO2R11, CH(R1′)CH(R1′)SO2N R12R13, CH(R1′)CH(R1′)COR11, CH(R1′)CONHCH(R2′)COOR11, CH(R1′)CONHCH(R2′) CONR12R13, or CH(R1′)CONHCH(R2′)(R′), wherein R14 is H, alkyl, aryl, heteroalkyl, heteroaryl, cycloalkyl, alkyl-aryl, alkyl-heteroaryl, aryl-alkyl, alkenyl, alkynyl or heteroaralkyl;
wherein R1′ is H or alkyl, and R2′ is phenyl, substituted phenyl, hetero atom-substituted phenyl, thiophenyl, cycloalkyl, piperidyl or pyridyl; and wherein R11 is H, methyl, ethyl, allyl, tert-butyl, benzyl, α-methylbenzyl, α, α-dimethylbenzyl, 1-methylcyclopropyl or 1-methylcyclopentyl;
R′ is hydroxymethyl or CH2CONR12R13;
R2′ is independently selected from the group consisting of:
wherein:
U1 and U2 may be same or different and are selected from H, F, CH2COOH, CH2COOMe, CH2CONH2, CH2CONHMe, CH2CONMe2, azido, amino, hydroxyl, substituted amino, substituted hydroxyl;
U3 and U4 may be same or different and are selected from O and S;
U5 is selected from the moieties consisting of alkyl sulfonyl, aryl sulfonyl, heteroalkyl sulfonyl, heteroaryl sulfonyl, alkyl carbonyl, aryl carbonyl, heteroalkyl carbonyl, heteroaryl carbonyl, alkoxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, alkylaminocarbonyl, arylaminocarbonyl, heteroarylaminocarbonyl or a combination thereof; and NR12R13 is selected from the group consisting of:
wherein U6 is H, OH, or CH2OH, and
R14 is selected from the group consisting of: H, Me, Et, n-propyl, methoxy, cyclopropyl, n-butyl, 1-but-3-ynyl, benzyl, α-methylbenzyl, phenethyl, allyl, 1-but-3-enyl, OMe, cyclopropylmethyl.

### Claim 67 (depends on 66)

The compound of claim 66, wherein the portion of Formula II between and including C=O is selected from the following structures: