HCV protease inhibitors and uses thereof

Patent metadata

Field	Value
Publication number	US-9694086-B2
Application number	US-201514855299-A
Country	US
Kind code	B2
Filing date	Sep 15, 2015
Priority date	Dec 21, 2007
Publication date	Jul 4, 2017
Grant date	Jul 4, 2017

Abstract

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

First claim

We claim:

1. A covalent adduct of the formula: Cys159-linker-inhibitor moiety,
wherein:
the Cys159 is Cys159 of HCV protease;
the inhibitor moiety is a moiety that selectively binds HCV protease;
the linker is a bivalent group resulting from the reaction of Cys159 of HCV protease with a -L-Y warhead group, wherein -L-Y is selected from the following:
(a) L is a bivalent C 2-8 straight or branched, hydrocarbon chain wherein L has at least one double bond and one or two methylene units of L are independently replaced by a functional group selected from —NRC(O)—, —C(O)NR—, —N(R)SO 2 —, —SO 2 N(R)—, —S(O)—, —SO 2 —, —OC(O)—, —C(O)O—, or —C(O)—, wherein at least one double bond is located in an alpha-beta position relative to the carbonyl, sulfoxide, or —SO 2 — functional group; and Y is hydrogen or C 1-6 aliphatic optionally substituted with oxo, halogen, NO 2 , or CN; or
(b) L is a bivalent C 2-8 straight or branched, hydrocarbon chain wherein L has at least one double bond and at least one methylene unit of L is replaced by a functional group selected from —C(O)—, —NRC(O)—, —C(O)NR—, —N(R)SO 2 —, —SO 2 N(R)—, —S(O)—, —SO 2 —, —OC(O)—, or —C(O)O—, wherein at least one double bond is located in an alpha-beta position relative to the carbonyl, sulfoxide, or —SO 2 — functional group, 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 C 1-6 aliphatic optionally substituted with oxo, halogen, NO 2 , or CN; or
(c) L is a bivalent C 2-8 straight or branched, hydrocarbon chain wherein L has at least one double bond and at least one methylene unit of L is replaced by a functional group selected from —C(O)—, wherein at least one double bond is located in an alpha-beta position relative to the functional group, 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 C 1-6 aliphatic optionally substituted with oxo, halogen, NO 2 , or CN; or
(h) L is a bivalent C 2-8 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 a functional group selected from —C(O)—, —NRC(O)—, —C(O)NR—, —N(R)SO 2 —, —SO 2 N(R)—, —S(O)—, —SO 2 —, —OC(O)—, or —C(O)O—, wherein at least one double bond is located in an alpha-beta position relative to the carbonyl, sulfoxide, or —SO 2 — functional group, 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 C 1-6 aliphatic optionally substituted with oxo, halogen, NO 2 , or CN; or
(i) L is a bivalent C 2-8 straight or branched, hydrocarbon chain wherein L has at least one triple bond and one or two methylene units of L are optionally and independently replaced by —NRC(O)—, —C(O)NR—, —N(R)SO 2 —, —SO 2 N(R)—, —S—, —S(O)—, —SO 2 —, —OC(O)—, or —C(O)O—, and Y is hydrogen or C 1-6 aliphatic optionally substituted with oxo, halogen, NO 2 , or CN; or
(k) L is a bivalent C 2-8 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)SO 2 —, —SO 2 N(R)—, —S—, —S(O)—, —SO 2 —, —OC(O)—, or —C(O)O—; and Y is C 1-6 aliphatic substituted with oxo, halogen, NO 2 , or CN; or
(l) L is a covalent bond and Y is selected from:
(i) —CH 2 F, —CH 2 Cl, —CH 2 CN, or —CH 2 NO 2 ; or
(ii) C 2-6 alkenyl substituted with oxo, NO 2 , or CN, and optionally substituted with halogen; or
(iii) C 2-6 alkynyl optionally substituted with oxo, halogen, NO 2 , or CN; or
(iv) a saturated 3-4 membered heterocyclic ring having 1 heteroatom selected from oxygen or nitrogen wherein said ring is substituted with 1-2 R e groups; or
(v) a saturated 5-6 membered heterocyclic ring having 1-2 heteroatoms selected from oxygen or nitrogen wherein said ring is substituted with 1-4 R e groups; or
(vii) a saturated 3-6 membered carbocyclic ring, wherein said ring is substituted with 1-4 R e groups; or
(viii) a partially unsaturated 3-6 membered monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-4 R e groups; or
(ix) a partially unsaturated 3-6 membered carbocyclic ring, wherein said ring is substituted with 1-4 R e 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 R e groups; or
(xiii) a 6-membered aromatic ring having 0-2 nitrogens wherein said ring is substituted with 1-4 R e 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 R e groups; or
(xvii) an 8-10 membered bicyclic, saturated, partially unsaturated, or aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-4 R e groups;

(m) L is —C(O)— and Y is selected from:
(i) C 1-6 alkyl substituted with oxo, halogen, NO 2 , or CN; or
(ii) C 2-6 alkenyl optionally substituted with oxo, halogen, NO 2 , or CN; or
(iii) C 2-6 alkynyl optionally substituted with oxo, halogen, NO 2 , or CN; or
(iv) a saturated 3-4 membered heterocyclic ring having 1 heteroatom selected from oxygen or nitrogen wherein said ring is substituted with 1-2 R e groups; or
(v) a saturated 5-6 membered heterocyclic ring having 1-2 heteroatoms selected from oxygen or nitrogen wherein said ring is substituted with 1-4 R e groups; or
(vii) a saturated 3-6 membered carbocyclic ring, wherein said ring is substituted with 1-4 R e groups; or
(viii) a partially unsaturated 3-6 membered monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-4 R e groups; or
(ix) a partially unsaturated 3-6 membered carbocyclic ring, wherein said ring is substituted with 1-4 R e 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 R e groups; or
(xiii) a 6-membered aromatic ring having 0-2 nitrogens wherein said ring is substituted with 1-4 R e 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 R e groups; or
(xvii) an 8-10 membered bicyclic, saturated, partially unsaturated, or aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-4 R e groups;

(n) L is —N(R)C(O)— and Y is selected from:
(i) C 1-6 alkyl substituted with oxo, halogen, NO 2 , or CN; or
(ii) C 2-6 alkenyl optionally substituted with oxo, halogen, NO 2 , or CN; or
(iii) C 2-6 alkynyl optionally substituted with oxo, halogen, NO 2 , or CN; or
(iv) a saturated 3-4 membered heterocyclic ring having 1 heteroatom selected from oxygen or nitrogen wherein said ring is substituted with 1-2 R e groups; or
(v) a saturated 5-6 membered heterocyclic ring having 1-2 heteroatoms selected from oxygen or nitrogen wherein said ring is substituted with 1-4 R e groups; or
(vii) a saturated 3-6 membered carbocyclic ring, wherein said ring is substituted with 1-4 R e groups; or
(viii) a partially unsaturated 3-6 membered monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-4 R e groups; or
(ix) a partially unsaturated 3-6 membered carbocyclic ring, wherein said ring is substituted with 1-4 R

Assignees

• Celgene Car Llc

Inventors

• Petter Russell C
• Singh Juswinder
• Kluge Arthur F
• Niu Deqiang
• Qiao Lixin
• Ghosh Shomir

Classifications

• C07K5/0815

  with the first amino acid being basic · CPC title

• C07K5/0202

  containing the structure -NH-X-X-C(=0)-, X being an optionally substituted carbon atom or a heteroatom, e.g. beta-amino acids · CPC title

• A61K38/12

  Cyclic peptides {, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C (A61K38/043 - A61K38/046 take precedence)} · CPC title

• C12N9/96

  Stabilising an enzyme by forming an adduct or a composition; Forming enzyme conjugates · CPC title

• C07K5/0804

  and aliphatic · CPC title