US 8,524,760 B2Granted

HCV protease inhibitors and uses thereof

AssigneeCelgene Avilomics Research, Inc.

InventorsDeqiang Niu, Russell C. Petter, Lixin Qiao, Juswinder Singh

Life of this patent

Estimating the term…

Abstract

The present invention provides compounds, pharmaceutically acceptable compositions thereof, and methods of using the same.

Claims13

Dependent claims

A compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein:
one of Ra and Rb is hydrogen and the other is —OH or —OC(O)R′, or Ra and Rb are taken together to form an oxo group;
R′ is an optionally substituted group selected from C1-6 aliphatic, C3-7 cycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 4-7 membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
Rx and Ry are taken together to form an optionally substituted C3-7 membered ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
R1 is an optionally substituted group selected from C1-6 aliphatic or C3-7 cycloalkyl(C1-3 alkyl);
R2 is hydrogen or an optionally substituted group selected from C1-6 aliphatic or C3-7 cycloalkyl;
R3 is a warhead group —(CH2)n-L-Y, wherein n is an integer from 0 to 5, inclusive, and -L-Y is selected from the following:
(l) L is a covalent bond and Y is selected from:
(iv) a saturated 3-4 membered heterocyclic ring having 1 heteroatom selected from oxygen or nitrogen wherein said ring is substituted with 1-2 Re groups;
or
(v) a saturated 5-6 membered heterocyclic ring having 1-2 heteroatom selected from oxygen or nitrogen wherein said ring is substituted with 1-4 Re groups;
or
(xi) a partially unsaturated 4-6 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-4 Re groups;
or
(xiii) a 6-membered aromatic ring having 0-2 nitrogens wherein said ring is substituted with 1-4 Re groups;
or
(xv) a 5-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-3 Re groups;
or
(xvii) an 8-10 membered bicyclic aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-4 Re groups;
(m) L is —C(O)— and Y is selected from:
(iv) a saturated 3-4 membered heterocyclic ring having 1 heteroatom selected from oxygen or nitrogen wherein said ring is substituted with 1-2 Re groups;
or
(v) a saturated 5-6 membered heterocyclic ring having 1-2 heteroatom selected from oxygen or nitrogen wherein said ring is substituted with 1-4 Re groups;
or
(xi) a partially unsaturated 4-6 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-4 Re groups;
or
(xiii) a 6-membered aromatic ring having 0-2 nitrogens wherein said ring is substituted with 1-4 Re groups;
or
(xv) a 5-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-3 Re groups;
or
(xvii) an 8-10 membered bicyclic aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-4 Re groups;
(n) L is —N(R)C(O)— and Y is selected from:
(iv) a saturated 3-4 membered heterocyclic ring having 1 heteroatom selected from oxygen or nitrogen wherein said ring is substituted with 1-2 Re groups;
or
(v) a saturated 5-6 membered heterocyclic ring having 1-2 heteroatom selected from oxygen or nitrogen wherein said ring is substituted with 1-4 Re groups;
or
(xi) a partially unsaturated 4-6 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-4 Re groups;
or
(xiii) a 6-membered aromatic ring having 0-2 nitrogens wherein said ring is substituted with 1-4 Re groups;
or
(xv) a 5-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-3 Re groups;
or
(xvii) an 8-10 membered bicyclic aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-4 Re groups;
(o) L is a bivalent C1-8 saturated or unsaturated, straight or branched, hydrocarbon chain;
and Y is selected from:
(iv) a saturated 3-4 membered heterocyclic ring having 1 heteroatom selected from oxygen or nitrogen wherein said ring is substituted with 1-2 Re groups;
or
(v) a saturated 5-6 membered heterocyclic ring having 1-2 heteroatom selected from oxygen or nitrogen wherein said ring is substituted with 1-4 Re groups;
or
(xi) a partially unsaturated 4-6 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-4 Re groups;
or
(xiii) a 6-membered aromatic ring having 0-2 nitrogens wherein said ring is substituted with 1-4 Re groups;
or
(xv) a 5-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-3 Re groups;
or
(xvii) an 8-10 membered bicyclic aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-4 Re groups;
(p) L is a covalent bond, —CH2—, —NH—, —C(O)—, —CH2NH—, —NHCH2—, —NHC(O)—, —NHC(O)CH2OC(O)—, —CH2NHC(O)—, —NHSO2—, —NHSO2CH2—, —NHC(O)CH2OC(O)—, or —SO2NH—;
and Y is selected from:
(iv) a saturated 3-4 membered heterocyclic ring having 1 heteroatom selected from oxygen or nitrogen wherein said ring is substituted with 1-2 Re groups;
or
(v) a saturated 5-6 membered heterocyclic ring having 1-2 heteroatom selected from oxygen or nitrogen wherein said ring is substituted with 1-4 Re groups;
or
(xi) a partially unsaturated 4-6 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-4 Re groups;
or
(xiii) a 6-membered aromatic ring having 0-2 nitrogens wherein said ring is substituted with 1-4 Re groups;
or
(xv) a 5-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-3 Re groups;
or
(xvii) an 8-10 membered bicyclic aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-4 Re groups;
each Re is independently selected from -Q-Z, oxo, NO2, halogen, CN, a suitable leaving group selected from alkoxy, sulphonyloxy, optionally substituted alkylsulphonyloxy, optionally substituted alkenylsulfonyloxy, optionally substituted arylsulfonyloxy, acyl, diazonium, or C1-6 aliphatic optionally substituted with oxo, halogen, NO2 or CN, wherein:
Q is a covalent bond or a bivalent C1-6 saturated or unsaturated, straight or branched, hydrocarbon chain, wherein one or two methylene units of Q are independently replaced by —N(R)—, —S—, —O—, —C(O)—, —OC(O)—, —C(O)O—, —SO—, or —SO2—, —N(R)C(O)—, —C(O)N(R)—, —N(R)SO2— or —SO2N(R)—;
and
each Z is independently hydrogen or C1-6 aliphatic optionally substituted with oxo, halogen, NO2 or CN;
R4 is —NHC(O)NHR5, —NHC(O)OR6, or
R5 is an optionally substituted group selected from C1-6 aliphatic, bridged bicyclic, 6-10 membered aryl, 5-10 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 4-7 membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
R6 is an optionally substituted group selected from C1-6 aliphatic, bridged bicyclic, 6-10 membered aryl, 5-10 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 4-7 membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
R7 is an optionally substituted group selected from C1-6 aliphatic, bridged bicyclic, 6-10 membered aryl, 5-10 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 4-7 membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
and
R is hydrogen or an optionally substituted group selected from C1-6 aliphatic, C3-7 cycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 4-7 membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

76 more elements

Dependencies are inferred from the claim text.

Facts

Application: 13/443,847Filed 10 Apr 2012 · division
Priority: 15 Aug 2008
Published: US 2012/0190614 A126 Jul 2012
Granted: 3 Sep 2013
Term ends: Not estimatedThe source records don’t support an estimate.

Classification37 codes

C07K 7/06
Linear peptides containing only normal peptide links: having 5 to 11 amino acids
A61K 31/40
Having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins: having five-membered rings with one nitrogen as the only ring hetero atom,…
A61K 31/403
Having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil: condensed with…
A61K 31/4439
Containing further heterocyclic ring systems: containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole

Family

Application61/089,269Us provisional application · filed 15 Aug 2008
Application61/098,662Us provisional application · filed 19 Sep 2008
Application12/541,347Parent of this division · filed 14 Aug 2009
US 2012/0190614 A1Pre-grant publication · published 26 Jul 2012
US 8,188,137 B2Parent of this division
US 2010/0041674 A1Published application
US 8,524,760 B2This patent

From the US filing history. Foreign family members aren’t listed.

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A compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein:
one of Ra and Rb is hydrogen and the other is —OH or —OC(O)R′, or Ra and Rb are taken together to form an oxo group;
R′ is an optionally substituted group selected from C1-6 aliphatic, C3-7 cycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 4-7 membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
Rx and Ry are taken together to form an optionally substituted C3-7 membered ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
R1 is an optionally substituted group selected from C1-6 aliphatic or C3-7 cycloalkyl(C1-3 alkyl);
R2 is hydrogen or an optionally substituted group selected from C1-6 aliphatic or C3-7 cycloalkyl;
R3 is a warhead group —(CH2)n-L-Y, wherein n is an integer from 0 to 5, inclusive, and -L-Y is selected from the following:
(l) L is a covalent bond and Y is selected from:
(iv) a saturated 3-4 membered heterocyclic ring having 1 heteroatom selected from oxygen or nitrogen wherein said ring is substituted with 1-2 Re groups;
or
(v) a saturated 5-6 membered heterocyclic ring having 1-2 heteroatom selected from oxygen or nitrogen wherein said ring is substituted with 1-4 Re groups;
or
(xi) a partially unsaturated 4-6 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-4 Re groups;
or
(xiii) a 6-membered aromatic ring having 0-2 nitrogens wherein said ring is substituted with 1-4 Re groups;
or
(xv) a 5-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-3 Re groups;
or
(xvii) an 8-10 membered bicyclic aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-4 Re groups;
(m) L is —C(O)— and Y is selected from:
(iv) a saturated 3-4 membered heterocyclic ring having 1 heteroatom selected from oxygen or nitrogen wherein said ring is substituted with 1-2 Re groups;
or
(v) a saturated 5-6 membered heterocyclic ring having 1-2 heteroatom selected from oxygen or nitrogen wherein said ring is substituted with 1-4 Re groups;
or
(xi) a partially unsaturated 4-6 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-4 Re groups;
or
(xiii) a 6-membered aromatic ring having 0-2 nitrogens wherein said ring is substituted with 1-4 Re groups;
or
(xv) a 5-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-3 Re groups;
or
(xvii) an 8-10 membered bicyclic aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-4 Re groups;
(n) L is —N(R)C(O)— and Y is selected from:
(iv) a saturated 3-4 membered heterocyclic ring having 1 heteroatom selected from oxygen or nitrogen wherein said ring is substituted with 1-2 Re groups;
or
(v) a saturated 5-6 membered heterocyclic ring having 1-2 heteroatom selected from oxygen or nitrogen wherein said ring is substituted with 1-4 Re groups;
or
(xi) a partially unsaturated 4-6 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-4 Re groups;
or
(xiii) a 6-membered aromatic ring having 0-2 nitrogens wherein said ring is substituted with 1-4 Re groups;
or
(xv) a 5-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-3 Re groups;
or
(xvii) an 8-10 membered bicyclic aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-4 Re groups;
(o) L is a bivalent C1-8 saturated or unsaturated, straight or branched, hydrocarbon chain;
and Y is selected from:
(iv) a saturated 3-4 membered heterocyclic ring having 1 heteroatom selected from oxygen or nitrogen wherein said ring is substituted with 1-2 Re groups;
or
(v) a saturated 5-6 membered heterocyclic ring having 1-2 heteroatom selected from oxygen or nitrogen wherein said ring is substituted with 1-4 Re groups;
or
(xi) a partially unsaturated 4-6 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-4 Re groups;
or
(xiii) a 6-membered aromatic ring having 0-2 nitrogens wherein said ring is substituted with 1-4 Re groups;
or
(xv) a 5-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-3 Re groups;
or
(xvii) an 8-10 membered bicyclic aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-4 Re groups;
(p) L is a covalent bond, —CH2—, —NH—, —C(O)—, —CH2NH—, —NHCH2—, —NHC(O)—, —NHC(O)CH2OC(O)—, —CH2NHC(O)—, —NHSO2—, —NHSO2CH2—, —NHC(O)CH2OC(O)—, or —SO2NH—;
and Y is selected from:
(iv) a saturated 3-4 membered heterocyclic ring having 1 heteroatom selected from oxygen or nitrogen wherein said ring is substituted with 1-2 Re groups;
or
(v) a saturated 5-6 membered heterocyclic ring having 1-2 heteroatom selected from oxygen or nitrogen wherein said ring is substituted with 1-4 Re groups;
or
(xi) a partially unsaturated 4-6 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-4 Re groups;
or
(xiii) a 6-membered aromatic ring having 0-2 nitrogens wherein said ring is substituted with 1-4 Re groups;
or
(xv) a 5-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-3 Re groups;
or
(xvii) an 8-10 membered bicyclic aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-4 Re groups;
each Re is independently selected from -Q-Z, oxo, NO2, halogen, CN, a suitable leaving group selected from alkoxy, sulphonyloxy, optionally substituted alkylsulphonyloxy, optionally substituted alkenylsulfonyloxy, optionally substituted arylsulfonyloxy, acyl, diazonium, or C1-6 aliphatic optionally substituted with oxo, halogen, NO2 or CN, wherein:
Q is a covalent bond or a bivalent C1-6 saturated or unsaturated, straight or branched, hydrocarbon chain, wherein one or two methylene units of Q are independently replaced by —N(R)—, —S—, —O—, —C(O)—, —OC(O)—, —C(O)O—, —SO—, or —SO2—, —N(R)C(O)—, —C(O)N(R)—, —N(R)SO2— or —SO2N(R)—;
and
each Z is independently hydrogen or C1-6 aliphatic optionally substituted with oxo, halogen, NO2 or CN;
R4 is —NHC(O)NHR5, —NHC(O)OR6, or
R5 is an optionally substituted group selected from C1-6 aliphatic, bridged bicyclic, 6-10 membered aryl, 5-10 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 4-7 membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
R6 is an optionally substituted group selected from C1-6 aliphatic, bridged bicyclic, 6-10 membered aryl, 5-10 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 4-7 membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
R7 is an optionally substituted group selected from C1-6 aliphatic, bridged bicyclic, 6-10 membered aryl, 5-10 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 4-7 membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
and
R is hydrogen or an optionally substituted group selected from C1-6 aliphatic, C3-7 cycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 4-7 membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

76 more elements

Facts

Application

13/443,847Filed 10 Apr 2012 · division

Priority

15 Aug 2008

Published

US 2012/0190614 A126 Jul 2012

Granted

3 Sep 2013

Term ends

Not estimatedThe source records don’t support an estimate.

Classification37 codes

C07K 7/06
Linear peptides containing only normal peptide links: having 5 to 11 amino acids
A61K 31/40
Having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins: having five-membered rings with one nitrogen as the only ring hetero atom,…
A61K 31/403
Having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil: condensed with…
A61K 31/4439
Containing further heterocyclic ring systems: containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole

Family

Application61/089,269Us provisional application · filed 15 Aug 2008

Application61/098,662Us provisional application · filed 19 Sep 2008

Application12/541,347Parent of this division · filed 14 Aug 2009

US 2012/0190614 A1Pre-grant publication · published 26 Jul 2012

US 8,188,137 B2Parent of this division

US 2010/0041674 A1Published application

US 8,524,760 B2This patent

From the US filing history. Foreign family members aren’t listed.