# US 7,608,599 B2 · Antiviral phosphoramidates

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- Number: US 7,608,599 B2
- Document ID: US7608599B2
- Status: Granted
- Kind: B2
- Application number: 11/503,558
- Filed: 2006-08-11
- Published: 2007-02-22
- Granted: 2009-10-27
- Earliest claimed: 2005-08-15
- Assignees: Roche Palo Alto LLC
- Inventors: Klaus Klumpp; Joseph Armstrong Martin; Christopher McGuigan; David Bernard Smith
- Web page: https://patentgrep.com/patent/US7608599B2

## CPC

- C07H 19/10: with the saccharide radical esterified by phosphoric or polyphosphoric acids
- A61P 31/12: Antivirals
- C07H 19/04: Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H: SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS (derivatives of aldonic or saccharic acids C07C, C07D; aldonic acids, saccharic acids C07C59/105, C07C59/285; cyanohydrins C07C255/16; glycals C07D; compounds of unknown constitution C07G; polysaccharides, derivatives thereof C08B; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification C12N15/00; sugar industry C13)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The invention provides novel nucleoside compounds of formula I wherein R1, R2a, R2b, R3, R4, R5 R6, R8a, R9 and R10 are as defined herein which are useful for the treatment of Hepatitis C Virus (HCV) mediated diseases. The invention further provides methods for treatment or prophylaxis of HCV mediated diseases with compounds of formula I and pharmaceutical compositions comprising these compounds,

## Claims

### Claim 1

A compound according to formula I
wherein:
R1 is hydrogen or aryl wherein said aryl is phenyl or naphthyl optionally substituted with one to three substituents independently selected from the group consisting of C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, halogen, C1-6 haloalkyl, —N(R1a)2, C1-6 acylamino, —NHSO2C1-6 alkyl, —SO2N(R1a)2, —SO2C1-6 alkyl, COR1b, nitro and cyano;
R1a is independently hydrogen or C1-6 alkyl;
R1b is —OR1a or —N(R1a)2;
R2a and R2b are (i) independently selected from the group consisting of hydrogen, C1-10 alkyl, —(CH2)rNR1a2, C1-6 hydroxyalkyl, —CH2SH, —(CH2)2S(O)pMe, —(CH2)3NHC(═NH)NH2, (1H-indol-3-yl)methyl, (1H-imidazol-4-yl)methyl, —(CH2)mCOR1b, aryl and aryl C1-3 alkyl, said aryl groups optionally substituted with a group selected from the group consisting of hydroxyl, C1-10 alkyl, C1-6 alkoxy, halogen, nitro and cyano,; (ii) R2a is hydrogen and R2b and R4 together are (CH2)3; (iii) R2a and R2b together are (CH2)n; or, (iv) R2a and R2b both are C1-6 alkyl;
R3 is hydrogen, C1-10 alkyl, C1-10 haloalkyl, aryl or aryl-C1-3 alkyl wherein said aryl is phenyl;
R4 is hydrogen, C1-3 alkyl, or R2b and R4 together are (CH2)3;
R5 is azide, C≡CH or -(Z)-CH═CHCl;
R6 is A, B, C or D wherein R11 is hydrogen or C1-3 alkyl;
R7 is hydrogen, methyl, halomethyl or halogen;
either
(a) R9 is OR8b and R10 is hydrogen wherein R8a and R8b are (i) independently hydrogen, benzoyl or C1-6 acyl or (i) together R8a and R8b are C(Me)2, C(CH2)4, CHPh, or
(b) R9 is hydrogen and R10 is OR8b wherein R8a and R8b are independently hydrogen or C1-6 acyl;
m is 0 to 3;
n is 4 or 5;
p is 0 to 2;
r is 1 to 6; and,
pharmacologically acceptable salts thereof.

### Claim 2 (depends on 1)

A compound according to claim 1 wherein R3 is hydrogen, C1-10 alkyl, aryl or aryl-C1-3 alkyl wherein said aryl is phenyl and R11 is hydrogen.

### Claim 3 (depends on 2)

A compound according to claim 2 wherein:
R2a and R2b are (i) independently hydrogen, methyl, iso-propyl, iso-butyl, sec-butyl, —CH2OH, —CH(OH)CH3, —CH2SH, —CH2CH2S(O)pMe, —(CH2)mCOR1b wherein m is 1 or 2, —(CH2)r—NH2 wherein r is 3 or 4, —(CH2)3—NHC(═NH)NH2, —CH2C6H5, —CH2-p-C6H4—OH, (3-indolinyl)methylene, (4-imidazolyl)methylene; (ii) R2a and R2b together are (CH2)n; or, (iii) R2a and R2b both are C1-3 alkyl;
R3 is hydrogen, C1-10 alkyl or benzyl;
R9 is OR8b; and,
R4, R7, R8a, R8b and R10 are hydrogen.

### Claim 4 (depends on 3)

A compound according to claim 3 wherein:
R2a is hydrogen and R2b is selected from the group consisting of hydrogen, methyl, iso-propyl, iso-butyl, sec-butyl, —CH2OH, —CH(OH)CH3, —CH2SH, —CH2CH2SMe, —(CH2)mCOR1b wherein m is 1 or 2, —(CH2)r—NH2 where r is 3 or 4, —(CH2)3—NHC(═NH)NH2, —CH2C6H5, —CH2-p-C6H4—OH, (3-indolinyl)methylene, and (4-imidazolyl)methylene; and,
R5 is azide or C≡CH.

### Claim 5 (depends on 4)

A compound according to claim 4 wherein R2b is hydrogen, -Me, —CH2CH(Me)2, —CH(Et)Me or —CHMe2.

### Claim 6 (depends on 3)

A compound according to claim 3 wherein both R2a and R2b are Me or R2a and R2b together are (CH2)4 and R5 is azide or C≡CH.

### Claim 7 (depends on 2)

A compound according to claim 2 wherein:
R2a and R2b are (i) independently hydrogen, methyl, iso-propyl, iso-butyl, sec-butyl, —CH2OH, —CH(OH)CH3, —CH2SH, —CH2CH2S(O)pMe, —(CH2)mCOR1b wherein m is 1 or 2, —(CH2)r—NH2 wherein r is 3 or 4, —(CH2)3—NHC(═NH)NH2, —CH2C6H5, —CH2-p-C6H4—OH, (3-indolinyl)methylene, (4-imidazolyl)methylene; (ii) R2a and R2b together are (CH2)n; or, (iii) R2a and R2b both are C1-3 alkyl;
R3 is C1-10 alkyl or benzyl;
R10 is OR8b; and,
R4, R7, R8a, R8b and R9 are hydrogen.

### Claim 8 (depends on 7)

A compound according to claim 7 wherein:
R2a is hydrogen and R2b is selected from the group consisting of hydrogen, methyl, iso-propyl, iso-butyl, sec-butyl, —CH2OH, —CH(OH)CH3, —CH2SH, —CH2CH2SMe, —(CH2)mCOR1b wherein m is 1 or 2, —(CH2)r—NH2 wherein r is 3 or 4, —(CH2)3—NHC(═NH)NH2, —CH2C6H5, —CH2-p-C6H4—OH, (3-indolinyl)methylene, and (4-imidazolyl)methylene; and,
R5 is azide or C≡CH.

### Claim 9 (depends on 8)

A compound according to claim 8 wherein R2b is hydrogen, -Me, —CH2CH(Me)2, —CH(Et)Me or —CHMe2.

### Claim 10 (depends on 7)

A compound according to claim 7 wherein both R2a and R2b are Me or R2a and R2b together are (CH2)4 and R5 is azide or C≡CH.

### Claim 11 (depends on 1)

A method for inhibiting HCV replication in a cell comprising administering an effective amount of a compound according to claim 1.

### Claim 12 (depends on 4)

A method for inhibiting HCV replication in a cell comprising administering an effective amount of a compound according to claim 4.

### Claim 13 (depends on 1)

A pharmaceutical composition comprising an effective quantity of a compound according to claim 1 admixed with at least one pharmaceutically acceptable carrier, diluent, or excipient.