US 8,188,137 B2Granted

HCV protease inhibitors and uses thereof

AssigneeAvila Therapeutics, Inc.

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

Life of this patent

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Abstract

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

Claims29

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 (a), (b), (c), (h), (i), (k), (l), (m), (n), (o), and (p) combinations of -L- and —Y:
(a) L is a bivalent C2-8 straight or branched, hydrocarbon chain wherein L has at least one double bond and one or two additional methylene units of L are optionally and independently replaced by —NRC(O)—, —C(O)NR—, —N(R)SO2—, —SO2N(R)—, —S—, —S(O)—, —SO2—, —OC(O)—, —C(O)O—, cyclopropylene, —O—, —N(R)—, or —C(O)—;
and Y is hydrogen or C1-6 aliphatic optionally substituted with oxo, halogen, NO2, or CN;
or
(b) L is a bivalent C2-8 straight or branched, hydrocarbon chain wherein L has at least one double bond and at least one methylene unit of L is replaced by —C(O)—, —NRC(O)—, —C(O)NR—, —N(R)SO2—, —SO2N(R)—, —S—, —S(O)—, —SO2—, —OC(O)—, or —C(O)O—, and one or two additional methylene units of L are optionally and independently replaced by cyclopropylene, —O—, —N(R)—, or —C(O)—;
and Y is hydrogen or C1-6 aliphatic optionally substituted with oxo, halogen, NO2, or CN;
or
(c) L is a bivalent C2-8 straight or branched, hydrocarbon chain wherein L has at least one double bond and at least one methylene unit of L is replaced by —C(O)—, and one or two additional methylene units of L are optionally and independently replaced by cyclopropylene, —O—, —N(R)—, or —C(O)—;
and Y is hydrogen or C1-6 aliphatic optionally substituted with oxo, halogen, NO2, or CN;
or
(h) L is a bivalent C2-8 straight or branched, hydrocarbon chain wherein L has at least one alkylidenyl double bond and at least one methylene unit of L is replaced by —C(O)—, —NRC(O)—, —C(O)NR—, —N(R)SO2—, —SO2N(R)—, —S—, —S(O)—, —SO2—, —OC(O)—, or —C(O)O—, and one or two additional methylene units of L are optionally and independently replaced by cyclopropylene, —O—, —N(R)—, or —C(O)—;
and Y is hydrogen or C1-6 aliphatic optionally substituted with oxo, halogen, NO2, or CN;
or
(i) L is a bivalent C2-8 straight or branched, hydrocarbon chain wherein L has at least one triple bond and one or two additional methylene units of L are optionally and independently replaced by —NRC(O)—, —C(O)NR—, —N(R)SO2—, —SO2N(R)—, —S—, —S(O)—, —SO2—, —OC(O)—, or —C(O)O—, and Y is hydrogen or C1-6 aliphatic optionally substituted with oxo, halogen, NO2, or CN;
or
(k) L is a bivalent C2-8 straight or branched, hydrocarbon chain wherein one methylene unit of L is replaced by cyclopropylene and one or two additional methylene units of L are independently replaced by —NRC(O)—, —C(O)NR—, —N(R)SO2—, —SO2N(R)—, —S—, —S(O)—, —SO2—, —OC(O)—, or —C(O)O—;
and Y is C1-6 aliphatic substituted with oxo, halogen, NO2, or CN;
or
(l) L is a covalent bond and Y is selected from:
(i) C1-6 alkyl substituted with oxo, halogen, NO2, or CN;
(ii) C2-6 alkenyl optionally substituted with oxo, halogen, NO2, or CN;
or
(iii) C2-6 alkynyl optionally substituted with oxo, halogen, NO2, or CN;
or
(vii) a saturated 3-6 membered carbocyclic ring, wherein said ring is substituted with 1-4 Re groups;
or
(ix) a partially unsaturated 3-6 membered carbocyclic ring, wherein said ring is substituted with 1-4 Re groups;
or
(xvii) an 8-10 membered bicyclic, saturated or partially unsaturated ring, wherein said ring is substituted with 1-4 Re groups;
(m) L is —C(O)—and Y is selected from:
(i) C1-6 alkyl substituted with oxo, halogen, NO2, or CN;
or
(ii) C2-6 alkenyl optionally substituted with oxo, halogen, NO2, or CN;
or
(iii) C2-6 alkynyl optionally substituted with oxo, halogen, NO2, or CN;
or
(vii) a saturated 3-6 membered carbocyclic ring, wherein said ring is substituted with 1-4 Re groups;
or
(ix) a partially unsaturated 3-6 membered carbocyclic ring, wherein said ring is substituted with 1-4 Re groups;
or
(xvii) an 8-10 membered bicyclic, saturated or partially unsaturated ring, wherein said ring is substituted with 1-4 Re groups;
(n) L is —N(R)C(O)—and Y is selected from:
(i) C1-6 alkyl substituted with oxo, halogen, NO2, or CN;
or
(ii) C2-6 alkenyl optionally substituted with oxo, halogen, NO2, or CN;
or
(iii) C2-6 alkynyl optionally substituted with oxo, halogen, NO2, or CN;
or
(vii) a saturated 3-6 membered carbocyclic ring, wherein said ring is substituted with 1-4 Re groups;
or
(ix) a partially unsaturated 3-6 membered carbocyclic ring, wherein said ring is substituted with 1-4 Re groups;
or
(xvii) an 8-10 membered bicyclic, saturated or partially unsaturated ring, 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:
(i) C1-6 alkyl substituted with oxo, halogen, NO2, or CN;
(ii) C2-6 alkenyl optionally substituted with oxo, halogen, NO2, or CN;
or
(iii) C2-6 alkynyl optionally substituted with oxo, halogen, NO2, or CN;
or
(vii) a saturated 3-6 membered carbocyclic ring, wherein said ring is substituted with 1-4 Re groups;
or
(ix) a partially unsaturated 3-6 membered carbocyclic ring, wherein said ring is substituted with 1-4 Re groups;
or
(xvii) an 8-10 membered bicyclic, saturated or partially unsaturated ring, 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:
(i) C1-6 alkyl substituted with oxo, halogen, NO2, or CN;
or
(ii) C2-6 alkenyl optionally substituted with oxo, halogen, NO2, or CN;
or
(iii) C2-6 alkynyl optionally substituted with oxo, halogen, NO2, or CN;
or
(vii) a saturated 3-6 membered carbocyclic ring, wherein said ring is substituted with 1-4 Re groups;
or
(ix) a partially unsaturated 3-6 membered carbocyclic ring, wherein said ring is substituted with 1-4 Re groups;
or
(xvii) an 8-10 membered bicyclic, saturated or partially unsaturated ring, 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 1-2heteroatoms 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.

92 more elements

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 —(CH2)n-L-Y, wherein:
n is an integer from 0 to 5, inclusive;
L is a bivalent C2-8 straight or branched, hydrocarbon chain wherein L has at least one double bond and one or two additional methylene units of L are optionally and independently replaced by —NRC(O)—, —C(O)NR—, —N(R)SO2—, —SO2N(R)—, —S—, —S(O)—, —SO2—, —OC(O)—, —C(O)O—, cyclopropylene, —O—, —N(R)—, or —C(O)—;
Y is hydrogen, C1-6 aliphatic optionally substituted with oxo, halogen, NO2, or CN, or a 3-10 membered monocyclic or bicyclic, saturated, partially unsaturated, or aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and wherein said ring is substituted with 1-4 Re groups;
and
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
Z is 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.

18 more elements

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 —(CH2)n-L-Y, wherein:
n is an integer from 0 to 5, inclusive;
L is a covalent bond, —C(O)—, —N(R)C(O)—, —NH—, —CH2NH—, —NHCH2—NHC(O)CH2OC(O)—, —CH2NHC(O)—, —NHSO2—, —NHSO2CH2—, —NHC(O)CH2OC(O)—, or —SO2NH—, or a bivalent C1-8 saturated or unsaturated, straight or branched, hydrocarbon chain;
and
Y is selected from the following (i), (ii), (iii), (iv), (v), (vi), (vii), (viii), (ix), (x), (xi), (xii), (xiii), (xiv), (xv), (xvi), or (xvii):
(i) C1-6 alkyl substituted with oxo, halogen, NO2, or CN;
(ii) C2-6 alkenyl optionally substituted with oxo, halogen, NO2, or CN;
or
(iii) C2-6 alkynyl optionally substituted with oxo, halogen, NO2, or CN;
or
(vii) a saturated 3-6 membered carbocyclic ring, wherein said ring is substituted with 1-4 Re groups;
or
(ix) a partially unsaturated 3-6 membered carbocyclic ring, wherein said ring is substituted with 1-4 Re groups;
or
(x)
(xvii) an 8-10 membered bicyclic, saturated or partially unsaturated ring, wherein said ring is substituted with 1-4 Re groups;
wherein:
each 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;
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
Z is 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.

31 more elements

Dependencies are inferred from the claim text.

Facts

Application: 12/541,347Filed 14 Aug 2009 · us provisional application
Priority: 15 Aug 2008
Published: US 2010/0041674 A118 Feb 2010
Granted: 29 May 2012
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
US 2010/0041674 A1Pre-grant publication · published 18 Feb 2010
US 8,188,137 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 (a), (b), (c), (h), (i), (k), (l), (m), (n), (o), and (p) combinations of -L- and —Y:
(a) L is a bivalent C2-8 straight or branched, hydrocarbon chain wherein L has at least one double bond and one or two additional methylene units of L are optionally and independently replaced by —NRC(O)—, —C(O)NR—, —N(R)SO2—, —SO2N(R)—, —S—, —S(O)—, —SO2—, —OC(O)—, —C(O)O—, cyclopropylene, —O—, —N(R)—, or —C(O)—;
and Y is hydrogen or C1-6 aliphatic optionally substituted with oxo, halogen, NO2, or CN;
or
(b) L is a bivalent C2-8 straight or branched, hydrocarbon chain wherein L has at least one double bond and at least one methylene unit of L is replaced by —C(O)—, —NRC(O)—, —C(O)NR—, —N(R)SO2—, —SO2N(R)—, —S—, —S(O)—, —SO2—, —OC(O)—, or —C(O)O—, and one or two additional methylene units of L are optionally and independently replaced by cyclopropylene, —O—, —N(R)—, or —C(O)—;
and Y is hydrogen or C1-6 aliphatic optionally substituted with oxo, halogen, NO2, or CN;
or
(c) L is a bivalent C2-8 straight or branched, hydrocarbon chain wherein L has at least one double bond and at least one methylene unit of L is replaced by —C(O)—, and one or two additional methylene units of L are optionally and independently replaced by cyclopropylene, —O—, —N(R)—, or —C(O)—;
and Y is hydrogen or C1-6 aliphatic optionally substituted with oxo, halogen, NO2, or CN;
or
(h) L is a bivalent C2-8 straight or branched, hydrocarbon chain wherein L has at least one alkylidenyl double bond and at least one methylene unit of L is replaced by —C(O)—, —NRC(O)—, —C(O)NR—, —N(R)SO2—, —SO2N(R)—, —S—, —S(O)—, —SO2—, —OC(O)—, or —C(O)O—, and one or two additional methylene units of L are optionally and independently replaced by cyclopropylene, —O—, —N(R)—, or —C(O)—;
and Y is hydrogen or C1-6 aliphatic optionally substituted with oxo, halogen, NO2, or CN;
or
(i) L is a bivalent C2-8 straight or branched, hydrocarbon chain wherein L has at least one triple bond and one or two additional methylene units of L are optionally and independently replaced by —NRC(O)—, —C(O)NR—, —N(R)SO2—, —SO2N(R)—, —S—, —S(O)—, —SO2—, —OC(O)—, or —C(O)O—, and Y is hydrogen or C1-6 aliphatic optionally substituted with oxo, halogen, NO2, or CN;
or
(k) L is a bivalent C2-8 straight or branched, hydrocarbon chain wherein one methylene unit of L is replaced by cyclopropylene and one or two additional methylene units of L are independently replaced by —NRC(O)—, —C(O)NR—, —N(R)SO2—, —SO2N(R)—, —S—, —S(O)—, —SO2—, —OC(O)—, or —C(O)O—;
and Y is C1-6 aliphatic substituted with oxo, halogen, NO2, or CN;
or
(l) L is a covalent bond and Y is selected from:
(i) C1-6 alkyl substituted with oxo, halogen, NO2, or CN;
(ii) C2-6 alkenyl optionally substituted with oxo, halogen, NO2, or CN;
or
(iii) C2-6 alkynyl optionally substituted with oxo, halogen, NO2, or CN;
or
(vii) a saturated 3-6 membered carbocyclic ring, wherein said ring is substituted with 1-4 Re groups;
or
(ix) a partially unsaturated 3-6 membered carbocyclic ring, wherein said ring is substituted with 1-4 Re groups;
or
(xvii) an 8-10 membered bicyclic, saturated or partially unsaturated ring, wherein said ring is substituted with 1-4 Re groups;
(m) L is —C(O)—and Y is selected from:
(i) C1-6 alkyl substituted with oxo, halogen, NO2, or CN;
or
(ii) C2-6 alkenyl optionally substituted with oxo, halogen, NO2, or CN;
or
(iii) C2-6 alkynyl optionally substituted with oxo, halogen, NO2, or CN;
or
(vii) a saturated 3-6 membered carbocyclic ring, wherein said ring is substituted with 1-4 Re groups;
or
(ix) a partially unsaturated 3-6 membered carbocyclic ring, wherein said ring is substituted with 1-4 Re groups;
or
(xvii) an 8-10 membered bicyclic, saturated or partially unsaturated ring, wherein said ring is substituted with 1-4 Re groups;
(n) L is —N(R)C(O)—and Y is selected from:
(i) C1-6 alkyl substituted with oxo, halogen, NO2, or CN;
or
(ii) C2-6 alkenyl optionally substituted with oxo, halogen, NO2, or CN;
or
(iii) C2-6 alkynyl optionally substituted with oxo, halogen, NO2, or CN;
or
(vii) a saturated 3-6 membered carbocyclic ring, wherein said ring is substituted with 1-4 Re groups;
or
(ix) a partially unsaturated 3-6 membered carbocyclic ring, wherein said ring is substituted with 1-4 Re groups;
or
(xvii) an 8-10 membered bicyclic, saturated or partially unsaturated ring, 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:
(i) C1-6 alkyl substituted with oxo, halogen, NO2, or CN;
(ii) C2-6 alkenyl optionally substituted with oxo, halogen, NO2, or CN;
or
(iii) C2-6 alkynyl optionally substituted with oxo, halogen, NO2, or CN;
or
(vii) a saturated 3-6 membered carbocyclic ring, wherein said ring is substituted with 1-4 Re groups;
or
(ix) a partially unsaturated 3-6 membered carbocyclic ring, wherein said ring is substituted with 1-4 Re groups;
or
(xvii) an 8-10 membered bicyclic, saturated or partially unsaturated ring, 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:
(i) C1-6 alkyl substituted with oxo, halogen, NO2, or CN;
or
(ii) C2-6 alkenyl optionally substituted with oxo, halogen, NO2, or CN;
or
(iii) C2-6 alkynyl optionally substituted with oxo, halogen, NO2, or CN;
or
(vii) a saturated 3-6 membered carbocyclic ring, wherein said ring is substituted with 1-4 Re groups;
or
(ix) a partially unsaturated 3-6 membered carbocyclic ring, wherein said ring is substituted with 1-4 Re groups;
or
(xvii) an 8-10 membered bicyclic, saturated or partially unsaturated ring, 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 1-2heteroatoms 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.

92 more elements

Facts

Application

12/541,347Filed 14 Aug 2009 · us provisional application

Priority

15 Aug 2008

Published

US 2010/0041674 A118 Feb 2010

Granted

29 May 2012

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