WO2005035525B1 - 2-amido-4-aryloxy-1-carbonylpyrrolidine derivatives as inhibitors of serine proteases, particularly hcv ns3-ns4a protease - Google Patents

2-amido-4-aryloxy-1-carbonylpyrrolidine derivatives as inhibitors of serine proteases, particularly hcv ns3-ns4a protease

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Publication number
WO2005035525B1
WO2005035525B1 PCT/US2004/029093 US2004029093W WO2005035525B1 WO 2005035525 B1 WO2005035525 B1 WO 2005035525B1 US 2004029093 W US2004029093 W US 2004029093W WO 2005035525 B1 WO2005035525 B1 WO 2005035525B1
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WIPO (PCT)
Prior art keywords
aliphatic
independently
compound according
aryl
heteroaryl
Prior art date
Application number
PCT/US2004/029093
Other languages
French (fr)
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WO2005035525A3 (en
WO2005035525A2 (en
Filing date
Publication date
Priority to JP2006525519A priority Critical patent/JP4767852B2/en
Priority to CN2004800254182A priority patent/CN1845920B/en
Priority to AU2004279800A priority patent/AU2004279800B9/en
Priority to EP04809688A priority patent/EP1667998A2/en
Priority to NZ545158A priority patent/NZ545158A/en
Priority to MXPA06002476A priority patent/MXPA06002476A/en
Priority to CA2536436A priority patent/CA2536436C/en
Priority to BRPI0414176-8A priority patent/BRPI0414176A/en
Application filed filed Critical
Publication of WO2005035525A2 publication Critical patent/WO2005035525A2/en
Publication of WO2005035525A3 publication Critical patent/WO2005035525A3/en
Priority to IL173627A priority patent/IL173627A0/en
Priority to NO20061426A priority patent/NO20061426L/en
Publication of WO2005035525B1 publication Critical patent/WO2005035525B1/en
Priority to HK07102734.0A priority patent/HK1095594A1/en

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Abstract

The present invention relates to compounds of formula I-A and I-B that inhibit serine protease activity, particularly the activity of hepatitis C virus NS3-NS4A protease. As such, they act by interfering with the life cycle of the hepatitis C virus and are also useful as antiviral agents. The invention further relates to compositions comprising these compounds either for ex vivo use or for administration to a patient suffering from HCV infection. The invention also relates to methods of treating an HCV infection in a patient by administering a composition comprising a compound of this invention. The invention further relates to processes for preparing these compounds.

Claims

AMENDED CLAIMS[received by the International Bureau on 26 October 2005 (26.10.2005); original claims 1-40 replaced by amended claims 1-40 (46 pages)]We claim :
1 . A compound of formula I :
Figure imgf000002_0001
wherein:
Ar is a 5- to 10-membered aromatic ring having up to 4 heteroatoms selected from O, S, N(H), SO, and SO2, wherein 1 to 3 ring atoms are optionally and independently substituted with J; R1 and R2 are independently: (C1-C12) -aliphatic-,
(C3-C10) -cycloalkyl- or -cycloalkenyl-, [ (C3-C10) -cycloalkyl- or -cycloalkenyl] - (C1-C12) - aliphatic-,
(C6-C10) -aryl- (C1-C12) aliphatic-, (C6-C10) -heteroaryl- (C1-C12)aliphatic-, wherein up to 3 aliphatic carbon atoms in R1 and R2 may be replaced by a heteroatom selected from 0, N, S, SO, or SO2 in a chemically stable arrangement; wherein each of R1 and R2 is independently and optionally substituted with up to 3 substituents independently selected from J;
R3 and R3' are independently hydrogen or (C1-C12) - aliphatic, wherein any hydrogen is optionally replaced with halogen; wherein any terminal carbon atom of R3 is optionally substituted with sulfhydryl or hydroxy; or R3 is phenyl or -CH2phenyl, wherein said phenyl group 151 is optionally substituted with up to 3 substituents independently selected from J; or
R3 and R3' together with the atom to which they are bound is a 3- to β-membered ring having up to 2 heteroatoms selected from N, NH, 0, SO, and SO2; wherein the ring has up to 2 substituents selected independently from J;
R4 and R4' are independently: hydrogen-, (C1-C12) -aliphatic-,
(C3-C10) -cycloalkyl- or -cycloalkenyl- , (C3-C10) -cycloalkyl- (C1-C12) -aliphatic-, (C6-C10) -aryl-, (C3-C10) -heterocyclyl-; or (C5-C10) -heteroaryl-; wherein up to two aliphatic carbon atoms in R4 and R4' may be replaced by a heteroatom selected from 0, N, S, SO, and SO2; wherein each of R4 and R4' is independently and optionally substituted with up to 3 substituents independently selected from J;
Figure imgf000003_0001
wherein each R6 is independently : hydrogen- , 152
(C1-C12) -aliphatic-,
(C6-C10) -aryl-,
(C6-C10) -aryl- (C1-C12) aliphatic- ,
(C3-C10) -cycloalkyl- or cycloalkenyl-,
[ (C3-C10) -cycloalkyl- or cycloalkenyl] - (C1-C12) - aliphatic-,
(C3-C10) -heterocyclyl-,
(C3-C10) -heterocyclyl- (C1-C12) -aliphatic-,
(C5-C10) heteroaryl-, or
(C5-C10)heteroaryl- (C1-C12) -aliphatic-, or two R6 groups, which are bound to the same nitrogen atom, form together with that nitrogen atom, a (C3-C10) -heterocyclic ring; wherein R6 is optionally substituted with up to 3 J substituents; wherein each R8 is independently -OR' ; or the R8 groups together with the boron atom, is a (C3-C10) - membered heterocyclic ring having in addition to the boron up to 3 additional heteroatoms selected from N, NH, 0, SO, and SO2;
T is:
(C1-C12) -aliphatic-;
(C6-C10) -aryl-,
(C6-C10) -aryl- (C1-C12) aliphatic-,
(C5-C10)heteroaryl-, or
(C5-ClO) heteroaryl- (C1-C12) -aliphatic-; wherein each T is optionally substituted with up to 3 J substituents;
J is halogen, -OR1, -NO2, -CN, -CF3, -OCF3, -R1, oxo, thioxo, 1, 2-methylenedioxy, 1 , 2-ethylenedioxy, =N(R') , =N(0R') , -N(R')2, -SR1 , -SOR' , -SO2R' , -SO2N(R1J2, -SO3R- , -C(O)R' , -C(O)C(O)R' , -C(O)CH2C(O)R' , -C(S)R' , 153
-C(S)OR', -C(O)OR1, -C(O)C(O)OR1, -C (0) C (0) N (R • ) 2,
-OC(O)R1, -C(O)N(RM2, -0C(0)N(R1)2, -C(S)N(R1J2,
- (CH2) 0-2NHC(O) R1 , -N(R' ) N (R1) COR' , -N (R ' ) N (R ' ) C (0) OR' ,
-N(R1 ) N(R1 JCON(R1 ) 2, -N (R1) SO2R1, -N (R ' ) SO2N (R ' ) 2 ,
-N(R1JC(O)OR1, -N(R1 )C(O)R' , -N(R1JC(S)R1,
-N(R1 )C(O)N(R' )2, -N(R1JC(S)N(RM2, -N(CORMCOR1,
-N(OR')R', -C(=NH)N(R' )2, -C(O)N(ORMR1, -C(=NOR')R',
-OP(O) (ORM2, -P(O) (RM2, -P(O) (ORM2, Or -P(O) (H) (OR') ;
R1 is: hydrogen- ,
(C1-C12) -aliphatic-,
(C3-C10) -cycloalkyl- or -cycloalkenyl- ,
[ (C3-C10) -cycloalkyl or -cycloalkenyl] - (C1-C12) - aliphatic-,
(C6-C10) -aryl-,
(C6-C10) -aryl- (C1-C12) aliphatic- ,
(C3-C10) -heterocyclyl-,
(C6-C10) -heterocyclyl- (C1-C12) aliphatic-,
(C5-C10) -heteroaryl-, or
(C5-C10) -heteroaryl- (C1-C12) -aliphatic- ; wherein R1 is optionally substituted with up to 3 J groups; wherein two R1 groups bound to the same atom form a 3- to 10-membered aromatic or non-aromatic ring having up to 3 heteroatoms independently selected from N, 0, S, SO, or SO2, wherein said ring is optionally fused to a (C6-C10) aryl, (C5- ClOJheteroaryl, (C3-C10) cycloalkyl, or a (C3- ClO)heterocyclyl, wherein any ring has up to 3 substituents selected independently from J.
2. A compound of formula I :
Figure imgf000006_0001
wherein: n is 0 or 1;
Ar is a 5- to 10-membered aromatic ring having up to 4 heteroatoms selected from 0, S, N(H) , SO, and SO2, wherein 1 to 3 ring atoms are optionally and independently substituted with J; R1, R2, R12, and R13 are independently: (C1-C12) -aliphatic-,
(C3-C10) -cycloalkyl- or -cycloalkenyl-, [ (C3-C10) -cycloalkyl- or -cycloalkenyl] - (C1-C12) - aliphatic-,
(C6-C10) -aryl- (C1-C12) aliphatic-, (C6-C10) -heteroaryl- (C1-C12) aliphatic-, wherein up to 3 aliphatic carbon atoms in R1 and R2 may be replaced by a heteroatom selected from 0, N, NH, S, SO, or SO2 in a chemically stable arrangement; wherein each of R1 and R2 is independently and optionally substituted at each substitutable position with up to 3 substituents independently selected from
J;
R3 and R3' are independently hydrogen or (C1-C12) - aliphatic, wherein any hydrogen is optionally replaced with halogen; wherein any terminal carbon atom of R3 is optionally substituted with sulfhydryl or hydroxy; or R3 is phenyl or -CH2phenyl, wherein said phenyl group is optionally substituted with up to 3 substituents independently selected from J; or
R3 and R3' together with the atom to which they are bound is a 3- to 6-membered ring having up to 2 heteroatoms 155 selected from N, NH, 0, SO, and SO2; wherein the ring has up to 2 substituents selected independently from J;
R4 and R4' are independently: rrydrogen- , (C1-C12) -aliphatic-,
(C3-C10) -cycloalkyl- or -cycloalkenyl- , (C3-C10) -cycloalkyl- (C1-C12) -aliphatic-, (C6-C10) -aryl-, (C3-C10) -heterocyclyl-; or (C5-C10) -heteroaryl-; wherein up to two aliphatic carbon atoms in R4 and R4' may be replaced by a heteroatom selected from 0, N, S, SO, and SO2; wherein each of R4 and R4' is independently and optionally substituted with up to 3 substituents independently selected from J;
Figure imgf000007_0001
wherein
Y is -CO2H, a derivative of -CO2H, or a bioisostere of -CO2H; each R6 is independently : hydrogen- , 156
(C1-C12) -aliphatic-, (C6-C1O) -aryl-,
(Cβ-CIO) -aryl- (C1-C12) aliphatic- , (C3-C1O) -cycloalkyl- or cycloalkenyl-, [ (03-C-LO) -cycloalkyl- or cycloalkenyl] - (C1-C12) - aliphatic- ,
(C3-C1O) -heterocyclyl-,
(C3-C1O) -heterocyclyl- (C1-C12) -aliphatic-, (C5-C10)heteroaryl-, or
(C5-C10)heteroaryl- (C1-C12) -aliphatic-, or two R6 groups, which are bound to the same nitrogen atom, form together with that nitrogen atom, a (C3-ClO) -heterocyclic ring; wherein R6 is optionally substituted with up to 3 J substituents; wherein each R8 is independently -OR1; or the R8 groups together with the boron atom, is a (C3-C10)- membered heterocyclic ring having in addition to the boron up to 3 additional heteroatoms selected from N, NH, 0, SO, and SO2;
T is:
(C1-C12) -aliphatic-;
(C6-C10) -ar-yl-,
(C6-C10) -ar-yl- (C1-C12) aliphatic-,
(C5-C10)heteroaryl-, or
(C5-C10)heteroaryl- (C1-C12) -aliphatic-; wherein each T is optionally substituted with up to 3 J substituents; and wherein up to 3 aliphatic carbon atoms in T may be replaced by a heteroatom selected from 0, N, NH, S, SO, or SO2 in a chemically stable arrangement; provided that if T is pyrrole, the pyrrole is not substituted at the 3-position with J, with J being 157
-C(O)R' , -C(O)C(O)R' , -C(O)CH2C(O)R' , -C(S)R1 , -C(S)OR' , -C(O)OR' , -C(O)C(O)OR', -C(O)C(O)N(R' J2, -C(O)N(R1J2, -C(S)N(R')2, -C(=NH)N(R') 2, -C (0) N (OR ' ) R ' , -C (=NOR ' ) R ' ;
J is halogen, -OR' , -NO2, -CN, -CF3, -OCF3, -R1 , oxo, thioxo, 1, 2-methylened±oxy, 1 , 2-ethylenedioxy, =N(R') , =N(0R') , -N(R')2, -SR' , -SOR' , -SO2R' , -SO2N(R')2, -SO3R' , -C(O)R' , -C(O)C(O)R' , -C(O)CH2C(O)R' , -C(S)R' , -C(S)OR1 , -C(O)OR' , -C (O)C(O)OR1 , -C (0) C (0) N (R ■ ) 2, -OC(O)R' , -C(O)N(R1J2, -OC(O)N(R1J2, -C(S)N(R')2, - (CH2) 0-2NHC (O)R' , -N(R1 )N(R')C0R' , -N (R ' ) N (R' ) C (0) OR ' , -N(R' ) N(R' ) CON(R' ) 2, -IST (R ' ) SO2R ' , -N (R ' ) SO2N (R- ) 2 , -N(R' JC(OJOR' , -N(R1JC (O)R' , -N(R1JC(S)R1 , -N(R')C(O)N(R')2, -N(R' JC(S)N(R1 )2, -N(COR1JCOR' , -N(OR1JR' , -C(=NH)N(R' >2, -C (0) N (OR ' ) R ' , -C(=NOR')R' , -OP(O) (OR1J2, -P(O) (R') 2, -P(O) (OR')2, Or -P(O) (H) (OR') ;
R1 is: hydrogen- ,
(C1-C12) -aliphatic-,
(CS-ClO -cycloalkiyl- or -cycloalkenyl- ,
[ (C3-C10) -cycloalkyl or -cycloalkenyl] - (C1-C12) - aliphatic- ,
(C6-C10) -aryl-,
(C6-C10) -aryl- (C1-C12) aliphatic-,
(C3-C10) -heterocyclyl-,
(C6-C10) -heterocyclyl- (C1-C12) aliphatic-,
(C5-C10) -heteroar-yl-, or
(C5-C10J -heteroar-yl- (C1-C12) -aliphatic-; wherein R' is optionally substituted with up to 3 J groups; wherein two R' groups bound to the same atom form a 3- to 10-membered aromatic or non-aromatic ring having up to 3 heteroatoms independently selected from N, 0, S, SO, or 158
SO2, wherein said ring is optionally fused to a (C6- ClO) aryl, (C5-C10)heteroaryl, (C3-C10) cycloalkyl, or a (C3-C10)heterocyclyl, wherein any ring has up to 3 substituents selected independently from J.
3. The compound according to claim 1 or claim 2, wherein Ar is phenyl, pyridyl, quinolinyl, pyrimidinyl, or naphthyl, wherein each group is optionally substituted with I7 2, or 3 J groups.
4. The compound according to claim 1 or claim 2, wherein Ar is
Figure imgf000010_0001
Figure imgf000010_0002
or
5. The compound according to claim 1 or claim 2, wherein Ar is :
Figure imgf000010_0003
159
6. The compound according to claim 1 or claim 2, wherein Ar is a 6 or a 10-membered aromatic ring having 0, 1, or 2 nitrogen heteroatoms, wherein 1, 2, or 3 ring atoms are optionally and independently substituted with J.
7. The compound according to any one of claims 1-6, wherein each J group on Ar is independently OR', MO2, CN, CF3, OCP3, R', COR', C(O)OR1, C (O)N(R' )2, SO2R1, SO2-N(R') 2, 1,2-methylenedioxy, 1,2-ethylene dioxy, or NR1C(O)OR', NR'SO2R' .
8. The compound according to any one of claims 1-6, wherein each J group on Ar is independently OR', halogen, CN, CF3, R1 , or COR' .
9. The compound according to any one of claims 1-6, wherein each J group on Ar is independently halo, trifluoromethyl, methyl, or NO2.
10. The compound according to any one of claims 1- 9, wherein W is :
Figure imgf000011_0001
wherein the NR6R6 is -NH- (C1-C6 aliphatic) , -NH-(C3-C6 cycloalkyl) , -NH-CH(CH3) -aryl, or -NH-CH(CH3) -heteroaryl, wherein said aryl or said heteroaryl is optionally substituted with up to 3 halogens.
11. The compound according to any one of claims 1- 10, wherein in the W, the NR6R6 is:
Figure imgf000012_0001
12. The compound according to any one of claims 1- 10, wherein in the W, the NR6R6 is:
Figure imgf000012_0002
13. The compound according to any one of claims 1- 10, wherein in the W, the NR6R5 is:
Figure imgf000012_0003
14. The compound according to any one of claims 1- 10, wherein in the W, the NR6R6 is:
Figure imgf000012_0004
161
15. Title compound according to any one of claims 1- 4, wherein R3' is hydrogen and R3 is:
Figure imgf000013_0001
16. The compound according to any one of claims 1- 4, wherein. R3' is hydrogen and R3 is:
Figure imgf000013_0002
17 . The compound according to any one of claims 1 - 6 , wherein. R2 is :
Figure imgf000013_0003
18 . The compound according to claim 17 , wherein R2 s :
Figure imgf000013_0004
19. The compound according to claim 18, wherein R2 is :
Figure imgf000014_0001
20. The compound according to any one of claims 1- 19, wherein R1 is:
Figure imgf000014_0002
21. The compound according to claim 20, wherein R1 i s :
Figure imgf000014_0003
22. The compound according to claim 21, wherein R1 is cyclohexyl .
23. The compoxmd according to any one of claims 1- 22, wherein T is (C6-C10) -aryl- or (C5-C10)heteroaryl-, wherein each T is optionally substituted with 1, 2, or 3 J substituents.
24. The compound according to any one of claims 1- 22, wherein T is:
Figure imgf000015_0001
wherein each T group is optionally fused to a 5-membered or a 6-membered aryl or heteπroaryl group.
25. The compound according to claim 24, wherein T is :
Figure imgf000015_0002
26. The compound according to claim 1 wherein, the compound is :
164
Figure imgf000016_0001
Figure imgf000017_0001
166
Figure imgf000018_0001
Figure imgf000019_0001
168
Figure imgf000020_0001
Figure imgf000021_0001
Figure imgf000022_0001
Figure imgf000023_0001
Figure imgf000024_0001
Figure imgf000025_0001
174
Figure imgf000026_0001
175
Figure imgf000027_0001
176
Figure imgf000028_0001
177
Figure imgf000029_0001
178
Figure imgf000030_0001
179
Figure imgf000031_0001
180
Figure imgf000032_0001
181
Figure imgf000033_0001
182
Figure imgf000034_0001
183
Figure imgf000035_0001
184
Figure imgf000036_0001
185
Figure imgf000037_0001
186
Figure imgf000038_0001
187
Figure imgf000039_0001
188
Figure imgf000040_0001
189
Figure imgf000041_0001
190
Figure imgf000042_0001
191
Figure imgf000043_0001
192
Figure imgf000044_0001
27. A composition comprising a compound according to any one of claims 1-26 or a pharmaceutically acceptable salt thereof, in an amount effective to inhibit a serine protease; and a acceptable carrier, adjuvant or vehicle.
28. The composition according to claim 27, wherein said composition is formulated for administration to a patient.
29. The composition according to claim 28, wherein said composition comprises an additional agent selected 193 from an immunomodulatory agent; an antiviral agent; a second inhibitor of HCV protease; an inhibitor of another target in the HCV life cycle; a cytochrome P-450 inhibitor; or combinations thereof.
30. The composition according to claim 29, wherein said immunomodulatory agent is α-, β-, or γ-interferon or thymosin; the antiviral agent is ribavirin, amantadine, or telbivudine; or the inhibitor of another target in the HCV life cycle is an inhibitor of HCV helicase, polymerase, or metalloprotease.
31. The composition according to claim 30, wherein said cytochrome P-450 inhibitor is ritonavir.
32. A method of inhibiting the activity of a serine protease comprising the step of contacting said serine protease with a compound according to any one of claims 1-26.
33. The method according to claim 32, wherein said protease is an HCV NS3 protease.
34. A method of treating an HCV infection in a patient comprising the step of administering to said patient a composition according to claim 27.
35. The method according to claim 34, comprising the additional step of administering to said patient an additional agent selected from an immunomodulatory agent; an antiviral agent; a second inhibitor of HCV protease; an inhibitor of another target in the HCV life cycle; or combinations thereof; wherein said additional agent is 194 administered to said patient as part of said composition according to claim 30 or as a separate dosage for-τn.
36. The method according to claim 35, wherein said immunomodulatory agent is α—, β-, or γ-interferon or thymosin; said antiviral agent is ribavarin or amantadine; or said inhibitor of another target i_n the HCV life cycle is an inhibitor of HCV helicase, polymerase, or metalloprotease.
37. A method of eliminating or reducing HCV contamination of a biological sample or medical or laboratory equipment, comprising the step of contacting said biological sample or medical or laboratory equipment with a compound according to any one of claims 1—26.
38. The method according to claim 37, wherein said sample or equipment is selected from a body fluid, biological tissue, a surgical instrument, a surgrLcal garment, a laboratory instrument, a laboratory garment, a blood or other body fluid collection apparatus; s blood or other bodily fluid storage material.
39. The method according to claim 38, wherein said body fluid is blood.
40. A process for preparing a compound of formula I, as defined in any one of claims 1-26, comprising the step of: reacting a compound of formula II in the presence of a compound of formula III to provide a compound of formula IV:
Figure imgf000047_0001
II III IV wherein:
R10 is an amine protecting group, a P3- residue of an HCV protease inhibitor described herein, or a P4-P3- residue of an HCV protease inhibitor as described herein, and wherein the P3 and the P4-P3 residues are optionally protected the an amino-terminal capping group; R11 is a carboxy protecting group or a Pl residue of an HCV protease inhibitor described herein, wherein the Pl residue is optionally substituted at the terminal carboxy position with a carboxy protecting group or with W.
PCT/US2004/029093 2003-09-05 2004-09-07 2-amido-4-aryloxy-1-carbonylpyrrolidine derivatives as inhibitors of serine proteases, particularly hcv ns3-ns4a protease WO2005035525A2 (en)

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Application Number Priority Date Filing Date Title
CA2536436A CA2536436C (en) 2003-09-05 2004-09-07 2-amido-4-aryloxy-1-carbonyl pyrrolidine derivatives as inhibitors of serine proteases, particularly hcv ns3-ns4a protease
AU2004279800A AU2004279800B9 (en) 2003-09-05 2004-09-07 2-amido-4-aryloxy-1-carbonylpyrrolidine derivatives as inhibitors of serine proteases, particularly HCV NS3-NS4A protease
EP04809688A EP1667998A2 (en) 2003-09-05 2004-09-07 2-amido-4-aryloxy-1-carbonylpyrrolidine derivatives as inhibitors of serine proteases, particularly hcv ns3-ns4a protease
NZ545158A NZ545158A (en) 2003-09-05 2004-09-07 2-Amido-4-aryloxy-1-carbonylpyrrolidine derivatives as inhibitors of serine proteases, particularly HCV NS3-NS4A protease
MXPA06002476A MXPA06002476A (en) 2003-09-05 2004-09-07 2-amido-4-aryloxy-1-carbonylpyrrolidine derivatives as inhibitors of serine proteases, particularly hcv ns3-ns4a protease.
JP2006525519A JP4767852B2 (en) 2003-09-05 2004-09-07 Inhibitors of serine proteases, especially HCV NS3-NS4A
BRPI0414176-8A BRPI0414176A (en) 2003-09-05 2004-09-07 serine protease inhibitors, in particular hcv ns3-ns4a protease
CN2004800254182A CN1845920B (en) 2003-09-05 2004-09-07 2-amido-4-aryloxy-1-carbonylpyrrolidine derivatives as inhibitors of serine proteases, particularly HCV NS3-NS4A protease
IL173627A IL173627A0 (en) 2003-09-05 2006-02-09 2-amido-4-aryloxy-1-carbonylpyrrolidine derivatives and pharmaceutical compositions containing the same
NO20061426A NO20061426L (en) 2003-09-05 2006-03-29 Inhibitors of serine proteases, especially HCV NS3-NS4A protease
HK07102734.0A HK1095594A1 (en) 2003-09-05 2007-03-13 2-amido-4-aryloxy-1-carbonylpyrrolidine derivatives as inhibitors of serine proteases, particularly hcv ns3-ns4a protease

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