US2016130275A1PendingUtilityA1
Pyrazolo[1,5-a]pyrimidines for antiviral treatment
Est. expiryJun 24, 2030(~3.9 yrs left)· nominal 20-yr term from priority
Inventors:Kerim BabaogluConstantine G. BoojamraEugene J. EisenbergHon Chung HuiRichard L. MackmanJay P. ParrishMichael SangiOliver L. SaundersDustin SiegelDavid SperandioHai Yang
A61P 31/16A61P 31/14A61P 31/12A61P 11/00C07D 519/00C07D 495/04C07D 513/04A61K 31/519C07D 487/04A61K 31/5377A61K 31/551A61K 45/06A61K 31/675A61K 31/55C07F 9/65616
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Claims
Abstract
The invention provides compounds of Formula I or Formula II: or a pharmaceutically acceptable salt or ester, thereof, as described herein. The compounds and compositions thereof are useful for treating Pneumovirinae virus infections. The compounds, compositions, and methods provided are particularly useful for the treatment of Human respiratory syncytial virus infections.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A compound of Formula I or Formula II:
or a pharmaceutically acceptable salt or ester, thereof;
wherein:
A is —(C(R 4 ) 2 ) n — wherein any one C(R 4 ) 2 of said —(C(R 4 ) 2 ) n — may be optionally replaced with —O—, —S—, —S(O) p —, NH or NR a ;
n is 3, 4, 5 or 6;
each p is 1 or 2;
Ar is a C 2 -C 20 heterocyclyl group or a C 6 -C 20 aryl group, wherein the C 2 -C 20 heterocyclyl group or the C 6 -C 20 aryl group is optionally substituted with 1 to 5 R 6 ;
X is —C(R 13 )(R 14 )—, —N(CH 2 R 14 )— or X is absent;
Y is N or CR 7 ;
each R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 or R 8 is independently H, oxo, OR 11 , NR 11 R 12 , NR 11 C(O)R 11 , NR 11 C(O)OR 11 , NR 11 C(O)NR 11 R 12 , N 3 , CN, NO 2 , SR 11 , S(O) p R a , NR 11 S(O) p R a , —C(═O)R 11 , —C(═O)OR 11 , —C(═O)NR 11 R 12 , —C(═O)SR 11 , —S(O) p (OR 11 ), —SO 2 NR 11 R 12 , —NR 11 S(O) p (OR 11 ), —NR 11 SO p NR 11 R 12 , NR 11 C(═NR 11 )NR 11 R 12 , halogen, (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, aryl(C 1 -C 8 )alkyl, C 6 -C 20 aryl, C 2 -C 20 heterocyclyl, (C 3 -C 7 )cycloalkyl or (C 4 -C 8 )carbocyclylalkyl;
two R 4 on adjacent carbon atoms, when taken together, may form a double bond between the two carbons to which they are attached or may form a (C 3 -C 7 )cycloalkyl ring wherein one carbon atom of said (C 3 -C 7 )cycloalkyl ring may be optionally replaced by —O—, —S—, —S(O) p —, —NH— or —NR a —;
four R 4 on adjacent carbon atoms, when taken together, may form an optionally substituted C 6 aryl ring;
two R 4 on the same carbon atom, when taken together, may form a (C 3 -C 7 )cycloalkyl ring wherein one carbon atom of said (C 3 -C 7 )cycloalkyl ring may be optionally replaced by —O—, —S—, —S(O) p —, —NH— or —NR a —;
two R 6 on adjacent carbon atoms, when taken together, may form a (C 3 -C 7 )cycloalkyl ring wherein one carbon atom of said (C 3 -C 7 )cycloalkyl ring may be optionally replaced by —O—, —S—, —S(O) p —, —NH— or —NR a —;
any R 6 adjacent to the obligate carbonyl group of said Ar, when taken together with R 3 , may form a bond or a —(C(R 5 ) 2 ) m — group wherein m is 1 or 2;
any R 6 adjacent to the obligate carbonyl group of said Ar, when taken together with R 2 , may form a bond;
each R a is independently (C 1 -C 8 )alkyl, (C 1 -C 8 )haloalkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, aryl(C 1 -C 8 )alkyl, C 6 -C 20 aryl, C 2 -C 20 heterocyclyl, (C 3 -C 7 )cycloalkyl or (C 4 -C 8 )carbocyclylalkyl wherein any (C 1 -C 8 )alkyl, (C 1 -C 8 )haloalkyl, (C 2 -C 8 )alkenyl or (C 2 -C 8 )alkynyl of R a is optionally substituted with one or more OH, NH 2 , CO 2 H, C 2 -C 20 heterocyclyl, and wherein any aryl(C 1 -C 8 )alkyl, C 6 -C 20 aryl, C 2 -C 20 heterocyclyl, (C 3 -C 7 )cycloalkyl or (C 4 -C 8 )carbocyclylalkyl of R a is optionally substituted with one or more OH, NH 2 , CO 2 H, C 2 -C 20 heterocyclyl or (C 1 -C 8 )alkyl;
each R 11 or R 12 is independently H, (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, aryl(C 1 -C 8 )alkyl, C 6 -C 20 aryl, C 2 -C 20 heterocyclyl, (C 3 -C 7 )cycloalkyl, (C 4 -C 8 )carbocyclylalkyl, —C(═O)R a , —S(O) p R a , or aryl(C 1 -C 8 )alkyl; or R 11 and R 12 taken together with a nitrogen to which they are both attached form a 3 to 7 membered heterocyclic ring wherein any one carbon atom of said heterocyclic ring can optionally be replaced with —O—, —S—, —S(O) p —, —NH—, —NR a — or —C(O)—;
R 13 is H or (C 1 -C 8 )alkyl;
R 14 is (C 1 -C 8 )alkyl, NR 11 R 12 , NR 11 C(O)R 11 , NR 11 C(O)OR 11 , NR 11 C(O)NR 11 R 12 , NR 11 S(O) p R a , —NR 11 S(O) p (OR 11 ) or NR 11 SO p NR 11 R 12 ; and
wherein each (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, aryl(C 1 -C 8 )alkyl, C 6 -C 20 aryl, C 2 -C 20 heterocyclyl, (C 3 -C 7 )cycloalkyl or (C 4 -C 8 )carbocyclylalkyl of each R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 11 or R 12 is, independently, optionally substituted with one or more oxo, halogen, hydroxy, NH 2 , CN, N 3 , N(R a ) 2 , NHR a , SH, SR a , S(O) p R a , OR a , (C 1 -C 8 )alkyl, (C 1 -C 8 )haloalkyl, —C(O)R a , —C(O)H, —C(═O)OR a , —C(═O)OH, —C(═O)N(R a ) 2 , —C(═O)NHR a , —C(═O)NH 2 , NHS(O) p R a , NR a S(O) p R a , NHC(O)R a , NR a C(O)R a , NHC(O)OR a , NR a C(O)OR a , NR a C(O)NHR a , NR a C(O)N(R a ) 2 , NR a C(O)NH 2 , NHC(O)NHR a , NHC(O)N(R a ) 2 , NHC(O)NH 2 , ═NH, ═NOH, ═NOR a , NR a S(O) p NHR a , NR a S(O) p N(R a ) 2 , NR a S(O) p NH 2 , NHS(O) p NHR a , NHS(O) p N(R a ) 2 , NHS(O) p NH 2 , —OC(═O)R a , —OP(O)(OH) 2 or R a .
2 . The compound of claim 1 which is a compound of Formula I.
3 . The compound of claim 1 wherein each R 3 is H.
4 . The compound of claim 1 which is a compound of Formula VII or a compound of Formula VIII:
or a pharmaceutically acceptable salt or ester, thereof.
5 . The compound of claim 4 which is a compound of Formula VII.
6 . The compound of claim 1 wherein R 2 is H.
7 . The compound of claim 1 wherein R 7 is H, halogen or (C 1 -C 8 )alkyl.
8 . The compound of claim 1 wherein n is 3 or 4.
9 . The compound of claim 1 wherein each R 4 is independently H or optionally substituted (C 1 -C 8 )alkyl, or four R 4 on adjacent carbon atoms, when taken together, may form an optionally substituted C 6 aryl ring.
10 . The compound of claim 1 wherein A is —(CH 2 ) 3 —, —(CH 2 ) 4 —, —CH 2 —O—CH 2 —, —CH 2 —CH(CH 3 )—CH 2 —, —CH 2 —CH(CF 3 )—CH 2 —, —CH 2 —CH 2 —CH(CH 3 )— or the structure:
11 . The compound of claim 1 wherein A is —(CH 2 ) 3 —.
12 . The compound of claim 1 wherein X is —CR 13 (NR 11 C(O)OR 11 )—, —CR 13 (NR 11 R 12 )—, —CR 13 (NR 11 S(O) p R a )— or X is absent.
13 . The compound of claim 1 wherein X is absent.
14 . The compound of claim 1 wherein R 1 is H, OR 11 , NR 11 R 12 , CN, (C 1 -C 8 )alkyl, C 6 -C 20 aryl, C 2 -C 20 heterocyclyl or (C 3 -C 7 )cycloalkyl, wherein any (C 1 -C 8 )alkyl, C 6 -C 20 aryl, C 2 -C 20 heterocyclyl or (C 3 -C 7 )cycloalkyl of R 1 is optionally substituted with one or more oxo, halogen, hydroxy, NH 2 , CN, N 3 , N(R a ) 2 , NHR a , SH, SR a , S(O) p R a , OR a , (C 1 -C 8 )alkyl, (C 1 -C 8 )haloalkyl, —C(O)R a , —C(O)H, —C(═O)OR a , —C(═O)OH, —C(═O)N(R a ) 2 , —C(═O)NHR a , —C(═O)NH 2 , NHS(O) p R a , NR a S(O) p R a , NHC(O)R a , NR a C(O)R a , NHC(O)OR a , NR a C(O)OR a , NR a C(O)NHR a , NR a C(O)N(R a ) 2 , NR a C(O)NH 2 , NHC(O)NHR a , NHC(O)N(R a ) 2 , NHC(O)NH 2 , ═NH, ═NOH, ═NOR a , NR a S(O) p NHR a , NR a S(O) p N(R a ) 2 , NR a S(O) p NH 2 , NHS(O) p NHR a , NHS(O) p N(R a ) 2 , NHS(O) p NH 2 , —OC(═O)R a , —OP(O)(OH) 2 or R a .
15 . The compound of claim 1 wherein R 1 is H or C 2 -C 20 heterocyclyl, wherein any C 2 -C 20 heterocyclyl of R 1 is optionally substituted with or more oxo, halogen, hydroxy, NH 2 , CN, N 3 , N(R a ) 2 , NHR a , SH, SR a , S(O) p R a , OR a , (C 1 -C 8 )alkyl, (C 1 -C 8 )haloalkyl, —C(O)R a , —C(O)H, —C(═O)OR a , —C(═O)OH, —C(═O)N(R a ) 2 , —C(═O)NHR a , —C(═O)NH 2 , NHS(O) p R a , NR a S(O) p R a , NHC(O)R a , NR a C(O)R a , NHC(O)OR a , NR a C(O)OR a , NR a C(O)NHR a , NR a C(O)N(R a ) 2 , NR a C(O)NH 2 , NHC(O)NHR a , NHC(O)N(R a ) 2 , NHC(O)NH 2 , ═NH, ═NOH, ═NOR a , NR a S(O) p NHR a , NR a S(O) p N(R a ) 2 , NR a S(O) p NH 2 , NHS(O) p NHR a , NHS(O) p N(R a ) 2 , NHS(O) p NH 2 , —OC(═O)R a , —OP(O)(OH) 2 or R a .
16 . The compound of claim 1 wherein R 1 is selected from:
17 . The compound of claim 1 wherein R 1 is H or:
18 . The compound of claim 1 wherein Ar is a C 6 -C 20 aryl group, wherein the C 6 -C 20 aryl group is optionally substituted with 1 to 5 R 6 .
19 . The compound of claim 1 wherein Ar is phenyl optionally substituted with 1 to 5 R 6 .
20 . The compound of claim 1 wherein each R 6 is independently selected from OR 11 , NR 11 R 12 , NR 11 C(O)R 11 , NR 11 C(O)OR 11 , CN, NR 11 S(O) p R a , —C(═O)NR 11 R 12 , —NR 11 SO p NR 11 R 12 , halogen, (C 1 -C 8 )alkyl, (C 2 -C 8 )alkynyl, C 6 -C 20 aryl, C 2 -C 20 heterocyclyl and (C 3 -C 7 )cycloalkyl, wherein any C 1 -C 8 )alkyl, (C 2 -C 8 )alkynyl, C 6 -C 20 aryl, C 2 -C 20 heterocyclyl and (C 3 -C 7 )cycloalkyl of R 6 is optionally substituted with one or more oxo, halogen, hydroxy, NH 2 , CN, N 3 , N(R a ) 2 , NHR a , SH, SR a , S(O) p R a , OR a , (C 1 -C 8 )alkyl, (C 1 -C 8 )haloalkyl, —C(O)R a , —C(O)H, —C(═O)OR a , —C(═O)OH, —C(═O)N(R a ) 2 , —C(═O)NHR a , —C(═O)NH 2 , NHS(O) p R a , NR a S(O) p R a , NHC(O)R a , NR a C(O)R a , NHC(O)OR a , NR a C(O)OR a , NR a C(O)NHR a , NR a C(O)N(R a ) 2 , NR a C(O)NH 2 , NHC(O)NHR a , NHC(O)N(R a ) 2 , NHC(O)NH 2 , ═NH, ═NOH, ═NOR a , NR a S(O) p NHR a , NR a S(O) p N(R a ) 2 , NR a S(O) p NH 2 , NHS(O) p NHR a , NHS(O) p N(R a ) 2 , NHS(O) p NH 2 , —OC(═O)R a , —OP(O)(OH) 2 or R a .
21 . The compound of claim 1 wherein each R 6 is independently selected from NR 11 S(O) p R a , NR 11 C(O)OR 11 , NR 11 C(O)R 11 , (C 1 -C 8 )alkyl and halogen.
22 . The compound of claim 1 wherein Ar is:
23 . The compound of claim 1 wherein Ar is:
24 . The compound of claim 1 wherein R 8 is H, NR 11 R 12 , NR 11 C(═NR 11 )NR 11 R 12 , halogen, (C 1 -C 8 )alkyl, (C 2 -C 8 )alkynyl, C 6 -C 20 aryl, C 2 -C 20 heterocyclyl or (C 3 -C 7 )cycloalkyl, wherein any (C 1 -C 8 )alkyl, (C 2 -C 8 )alkynyl, C 6 -C 20 aryl, C 2 -C 20 heterocyclyl, or (C 3 -C 7 )cycloalkyl of R 8 is optionally substituted with one or more oxo, halogen, hydroxy, NH 2 , CN, N 3 , N(R a ) 2 , NHR a , SH, SR a , S(O) p R a , OR a , (C 1 -C 8 )alkyl, (C 1 -C 8 )haloalkyl, —C(O)R a , —C(O)H, —C(═O)OR a , —C(═O)OH, —C(═O)N(R a ) 2 , —C(═O)NHR a , —C(═O)NH 2 , NHS(O) p R a , NR a S(O) p R a , NHC(O)R a , NR a C(O)R a , NHC(O)OR a , NR a C(O)OR a , NR a C(O)NHR a , NR a C(O)N(R a ) 2 , NR a C(O)NH 2 , NHC(O)NHR a , NHC(O)N(R a ) 2 , NHC(O)NH 2 , ═NH, ═NOH, ═NOR a , NR a S(O) p NHR a , NR a S(O) p N(R a ) 2 , NR a S(O) p NH 2 , NHS(O) p NHR a , NHS(O) p N(R a ) 2 , NHS(O) p NH 2 , —OC(═O)R a , —OP(O)(OH) 2 or R a .
25 . The compound of claim 1 wherein R 8 is C 2 -C 20 heterocyclyl, wherein C 2 -C 20 heterocyclyl is optionally substituted with one or more oxo, halogen, hydroxy, NH 2 , CN, N 3 , N(R a ) 2 , NHR a , SH, SR a , S(O) p R a , OR a , (C 1 -C 8 )alkyl, (C 1 -C 8 )haloalkyl, —C(O)R a , —C(O)H, —C(═O)OR a , —C(═O)OH, —C(═O)N(R a ) 2 , —C(═O)NHR a , —C(═O)NH 2 , NHS(O) p R a , NR a S(O) p R a , NHC(O)R a , NR a C(O)R a , NHC(O)OR a , NR a C(O)OR a , NR a C(O)NHR a , NR a C(O)N(R a ) 2 , NR a C(O)NH 2 , NHC(O)NHR a , NHC(O)N(R a ) 2 , NHC(O)NH 2 , ═NH, ═NOH, ═NOR a , NR a S(O) p NHR a , NR a S(O) p N(R a ) 2 , NR a S(O) p NH 2 , NHS(O) p NHR a , NHS(O) p N(R a ) 2 , NHS(O) p NH 2 , —OC(═O)R a , —OP(O)(OH) 2 or R a .
26 . The compound of claim 1 wherein R 8 is pyrrolidinyl or azetidinyl, wherein pyrrolidinyl or azetidinyl is optionally substituted with one or more hydroxy, NH 2 , CN or —OP(O)(OH) 2 .
27 . The compound of claim 1 wherein R 8 is:
28 . The compound of claim 1 wherein R 8 is:
29 . The compound according to claim 1 selected from the group consisting of:
and pharmaceutically acceptable salts and esters thereof.
30 . The compound according to claim 1 selected from the group consisting of:
and pharmaceutically acceptable salts and esters thereof.
31 . The compound of claim 1 which is a compound as described in any one of Examples 258-412, or a pharmaceutically acceptable salt or ester thereof.
32 . A pharmaceutical composition comprising a compound of Formula IX:
or a pharmaceutically acceptable salt or ester thereof and a pharmaceutically acceptable carrier;
wherein:
A is —(C(R 4 ) 2 ) n — wherein any one C(R 4 ) 2 of said —(C(R 4 ) 2 ) n — may be optionally replaced with —O—, —S—, S(O) p —, NH or NR a ;
n is 3, 4, 5 or 6;
each p is 1 or 2;
Ar is a C 2 -C 20 heterocyclyl group or a C 6 -C 20 aryl group, wherein the C 2 -C 20 heterocyclyl group or the C 6 -C 20 aryl group is optionally substituted with 1 to 5 R 6 ;
X is —(CR 13 R 14 )—, —N(CH 2 R 14 )— or X is absent;
Y is N or CR 7 ;
each R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 or R 8 is independently H, oxo, OR 11 , NR 11 R 12 , NR 11 C(O)OR 11 , NR 11 C(O)OR 11 , NR 11 C(O)NR 11 R 12 , N 3 , CN, NO 2 , SR 11 , S(O) p R a , NR 11 S(O) p R a , —C(═O)R 11 , —C(═O)OR 11 , —C(═O)NR 11 R 12 , —C(═O)SR 11 , —S(O) p (OR 11 ), —SO 2 NR 11 R 12 , —NR 11 S(O) p (OR 11 ), —NR 11 SO p NR 11 R 12 , NR 11 C(═NR 11 )NR 11 R 12 , halogen, (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, aryl(C 1 -C 8 )alkyl, C 6 -C 20 aryl, C 2 -C 20 heterocyclyl, (C 3 -C 7 )cycloalkyl or (C 4 -C 8 )carbocyclylalkyl;
two R 4 on adjacent carbon atoms, when taken together, may form a double bond between the two carbons to which they are attached or may form a (C 3 -C 7 )cycloalkyl ring wherein one carbon atom of said (C 3 -C 7 )cycloalkyl ring may be optionally replaced by —O—, —S—, —S(O) p —, —NH— or —NR a —;
four R 4 on adjacent carbon atoms, when taken together, may form an optionally substituted C 6 aryl ring;
two R 4 on the same carbon atom, when taken together, may form a (C 3 -C 7 )cycloalkyl ring wherein one carbon atom of said (C 3 -C 7 )cycloalkyl ring may be optionally replaced by —O—, —S—, —S(O) p —, —NH— or —NR a —;
two R 6 on adjacent carbon atoms, when taken together, may form a (C 3 -C 7 )cycloalkyl ring wherein one carbon atom of said (C 3 -C 7 )cycloalkyl ring may be optionally replaced by —O—, —S—, —S(O) p —, —NH— or —NR a —;
any R 6 adjacent to the obligate carbonyl group of said Ar, when taken together with R 3 , may form a bond or a —(C(R 5 ) 2 ) m — group wherein m is 1 or 2;
any R 6 adjacent to the obligate carbonyl group of said Ar, when taken together with R 2 , may form a bond;
each R a is independently (C 1 -C 8 )alkyl, (C 1 -C 8 )haloalkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, aryl(C 1 -C 8 )alkyl, C 6 -C 20 aryl, C 2 -C 20 heterocyclyl, (C 3 -C 7 )cycloalkyl or (C 4 -C 8 )carbocyclylalkyl wherein any (C 1 -C 8 )alkyl, (C 1 -C 8 )haloalkyl, (C 2 -C 8 )alkenyl or (C 2 -C 8 )alkynyl of R a is optionally substituted with one or more OH, NH 2 , CO 2 H, C 2 -C 20 heterocyclyl, and wherein any aryl(C 1 -C 8 )alkyl, C 6 -C 20 aryl, C 2 -C 20 heterocyclyl, (C 3 -C 7 )cycloalkyl or (C 4 -C 8 )carbocyclylalkyl of R a is optionally substituted with one or more OH, NH 2 , CO 2 H, C 2 -C 20 heterocyclyl or (C 1 -C 8 )alkyl;
each R 11 or R 12 is independently H, (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, aryl(C 1 -C 8 )alkyl, C 6 -C 20 aryl, C 2 -C 20 heterocyclyl, (C 3 -C 7 )cycloalkyl, (C 4 -C 8 )carbocyclylalkyl, —C(═O)R a , —S(O) p R a , or aryl(C 1 -C 8 )alkyl; or R 11 and R 12 taken together with a nitrogen to which they are both attached form a 3 to 7 membered heterocyclic ring wherein any one carbon atom of said heterocyclic ring can optionally be replaced with —O—, —S—, —S(O) p —, —NH—, —NR a — or —C(O)—;
R 13 is H or (C 1 -C 8 )alkyl;
R 14 is H, (C 1 -C 8 )alkyl, NR 11 R 12 , NR 11 C(O)R 11 , NR 11 C(O)OR 11 , NR 11 C(O)NR 11 R 12 , NR 11 S(O) p R a , —NR 11 S(O) p (OR 11 ) or NR 11 SO p NR 11 R 12 ; and
wherein each (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, aryl(C 1 -C 8 )alkyl, C 6 -C 20 aryl, C 2 -C 20 heterocyclyl, (C 3 -C 7 )cycloalkyl or (C 4 -C 8 )carbocyclylalkyl of each R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 11 or R 12 is, independently, optionally substituted with one or more oxo, halogen, hydroxy, NH 2 , CN, N 3 , N(R a ) 2 , NHR a , SH, SR a , S(O) p R a , OR a , (C 1 -C 8 )alkyl, (C 1 -C 8 )haloalkyl, —C(O)R a , —C(O)H, —C(═O)OR a , —C(═O)OH, —C(═O)N(R a ) 2 , —C(═O)NHR a , —C(═O)NH 2 , NHS(O) p R a , NR a S(O) p R a , NHC(O)R a , NR a C(O)R a , NHC(O)OR a , NR a C(O)OR a , NR a C(O)NHR a , NR a C(O)N(R a ) 2 , NR a C(O)NH 2 , NHC(O)NHR a , NHC(O)N(R a ) 2 , NHC(O)NH 2 , ═NH, ═NOH, ═NOR a , NR a S(O) p NHR a , NR a S(O) p N(R a ) 2 , NR a S(O) p NH 2 , NHS(O) p NHR a , NHS(O) p N(R a ) 2 , NHS(O) p NH 2 , —OC(═O)R a , —OP(O)(OH) 2 or R a .
33 . A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt or ester thereof and a pharmaceutically acceptable carrier.
34 . The pharmaceutical composition of claim 32 or claim 33 further comprising at least one other therapeutic agent selected from ribavirin, palivizumab, motavizumab, RSV-IGIV MEDI-557, A-60444, MDT-637, BMS-433771, ALN-RSV0 or ALX-0171 mixtures thereof.
35 . A method of treating a Pneumovirinae virus infection in a mammal in need thereof comprising administering to the mammal a therapeutically effective amount of a compound of Formula IX:
or a pharmaceutically acceptable salt or ester thereof,
wherein:
A is —(C(R 4 ) 2 ) n — wherein any one C(R 4 ) 2 of said —(C(R 4 ) 2 ) n — may be optionally replaced with —O—, —S—, S(O) p —, NH or NR a ;
n is 3, 4, 5 or 6;
each p is 1 or 2;
Ar is a C 2 -C 20 heterocyclyl group or a C 6 -C 20 aryl group, wherein the C 2 -C 20 heterocyclyl group or the C 6 -C 20 aryl group is optionally substituted with 1 to 5 R 6 ;
X is —(CR 13 R 14 )—, —N(CH 2 R 14 )— or X is absent;
Y is N or CR 7 ;
each R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 or R 8 is independently H, oxo, OR 11 , NR 11 R 12 , NR 11 C(O)R 11 , NR 11 C(O)OR 11 , NR 11 C(O)NR 11 R 12 , N 3 , CN, NO 2 , SR 11 , S(O) p R a , NR 11 S(O) p R a , —C(═O)R 11 , —C(═O)OR 11 , —C(═O)NR 11 R 12 , —C(═O)SR 11 , —S(O) p (OR 11 ), —SO 2 NR 11 R 12 , —NR 11 S(O) p (OR 11 ), —NR 11 SO p NR 11 R 12 , NR 11 C(═NR 11 )NR 11 R 12 , halogen, (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, aryl(C 1 -C 8 )alkyl, C 6 -C 20 aryl, C 2 -C 20 heterocyclyl, (C 3 -C 7 )cycloalkyl or (C 4 -C 8 )carbocyclylalkyl;
two R 4 on adjacent carbon atoms, when taken together, may form a double bond between the two carbons to which they are attached or may form a (C 3 -C 7 )cycloalkyl ring wherein one carbon atom of said (C 3 -C 7 )cycloalkyl ring may be optionally replaced by —O—, —S—, —S(O) p —, —NH— or —NR a —;
four R 4 on adjacent carbon atoms, when taken together, may form an optionally substituted C 6 aryl ring;
two R 4 on the same carbon atom, when taken together, may form a (C 3 -C 7 )cycloalkyl ring wherein one carbon atom of said (C 3 -C 7 )cycloalkyl ring may be optionally replaced by —O—, —S—, —S(O) p —, —NH— or —NR a —;
two R 6 on adjacent carbon atoms, when taken together, may form a (C 3 -C 7 )cycloalkyl ring wherein one carbon atom of said (C 3 -C 7 )cycloalkyl ring may be optionally replaced by —O—, —S—, —S(O) p —, —NH— or —NR a —;
any R 6 adjacent to the obligate carbonyl group of said Ar, when taken together with R 3 , may form a bond or a —(C(R 5 ) 2 ) m — group wherein m is 1 or 2;
any R 6 adjacent to the obligate carbonyl group of said Ar, when taken together with R 2 , may form a bond;
each R a is independently (C 1 -C 8 )alkyl, (C 1 -C 8 )haloalkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, aryl(C 1 -C 8 )alkyl, C 6 -C 20 aryl, C 2 -C 20 heterocyclyl, (C 3 -C 7 )cycloalkyl or (C 4 -C 8 )carbocyclylalkyl wherein any (C 1 -C 8 )alkyl, (C 1 -C 8 )haloalkyl, (C 2 -C 8 )alkenyl or (C 2 -C 8 )alkynyl of R a is optionally substituted with one or more OH, NH 2 , CO 2 H, C 2 -C 20 heterocyclyl, and wherein any aryl(C 1 -C 8 )alkyl, C 6 -C 20 aryl, C 2 -C 20 heterocyclyl, (C 3 -C 7 )cycloalkyl or (C 4 -C 8 )carbocyclylalkyl of R a is optionally substituted with one or more OH, NH 2 , CO 2 H, C 2 -C 20 heterocyclyl or (C 1 -C 8 )alkyl;
each R 11 or R 12 is independently H, (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, aryl(C 1 -C 8 )alkyl, C 6 -C 20 aryl, C 2 -C 20 heterocyclyl, (C 3 -C 7 )cycloalkyl, (C 4 -C 8 )carbocyclylalkyl, —C(═O)R a , —S(O) p R a , or aryl(C 1 -C 8 )alkyl; or R 11 and R 12 taken together with a nitrogen to which they are both attached form a 3 to 7 membered heterocyclic ring wherein any one carbon atom of said heterocyclic ring can optionally be replaced with —O—, —S—, —S(O) p —, —NH—, —NR a — or —C(O)—;
R 13 is H or (C 1 -C 8 )alkyl;
R 14 is H, (C 1 -C 8 )alkyl, NR 11 R 12 , NR 11 C(O)R 11 , NR 11 C(O)OR 11 , NR 11 C(O)NR 11 R 12 , NR 11 S(O) p R a , —NR 11 S(O) p (OR 11 ) or NR 11 SO p NR 11 R 12 ; and
wherein each (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, aryl(C 1 -C 8 )alkyl, C 6 -C 20 aryl, C 2 -C 20 heterocyclyl, (C 3 -C 7 )cycloalkyl or (C 4 -C 8 )carbocyclylalkyl of each R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 11 or R 12 is, independently, optionally substituted with one or more oxo, halogen, hydroxy, NH 2 , CN, N 3 , N(R a ) 2 , NHR a , SH, SR a , S(O) p R a , OR a , (C 1 -C 8 )alkyl, (C 1 -C 8 )haloalkyl, —C(O)R a , —C(O)H, —C(═O)OR a , —C(═O)OH, —C(═O)N(R a ) 2 , —C(═O)NHR a , —C(═O)NH 2 , NHS(O) p R a , NR a S(O) p R a , NHC(O)R a , NR a C(O)R a , NHC(O)OR a , NR a C(O)OR a , NR a C(O)NHR a , NR a C(O)N(R a ) 2 , NR a C(O)NH 2 , NHC(O)NHR a , NHC(O)N(R a ) 2 , NHC(O)NH 2 , ═NH, ═NOH, ═NOR a , NR a S(O) p NHR a , NR a S(O) p N(R a ) 2 , NR a S(O) p NH 2 , NHS(O) p NHR a , NHS(O) p N(R a ) 2 , NHS(O) p NH 2 , —OC(═O)R a , —OP(O)(OH) 2 or R a .
36 . A method of treating a Pneumovirinae virus infection in a mammal in need thereof comprising administering to the mammal a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt or ester thereof.
37 . The method of claim 35 or 36 wherein the Pneumovirinae virus infection is caused by a respiratory syncytial virus.
38 . The method of claim 35 or 36 further comprising administering a therapeutically effective amount of at least one other therapeutic agent or composition thereof selected from the group consisting of ribavirin, palivizumab, motavizumab, RSV-IGIV MEDI-557, A-60444, MDT-637, BMS-433771, ALN-RSV0 and ALX-0171 or mixtures thereof.Join the waitlist — get patent alerts
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