U.S. patent application number 17/479530 was filed with the patent office on 2022-05-26 for novel spiropyrrolidine derived antiviral agents.
The applicant listed for this patent is Enanta Pharmaceuticals, Inc.. Invention is credited to Hui Cao, Xuri Gao, Yong He, Yat Sun Or, Joseph D. Panarese, Ruichao Shen, Guoqiang Wang, Xuechao Xing, Jiajun Zhang.
Application Number | 20220162217 17/479530 |
Document ID | / |
Family ID | |
Filed Date | 2022-05-26 |
United States Patent
Application |
20220162217 |
Kind Code |
A1 |
Wang; Guoqiang ; et
al. |
May 26, 2022 |
NOVEL SPIROPYRROLIDINE DERIVED ANTIVIRAL AGENTS
Abstract
The present invention discloses compounds of Formula (Ia), and
pharmaceutically acceptable salts, thereof: ##STR00001## which
inhibit coronavirus replication activity. The invention further
relates to pharmaceutical compositions comprising a compound of
Formula (Ia) or a pharmaceutically acceptable slat thereof, and
methods of treating or preventing a coronavirus infection in a
subject in need thereof, comprising administering to the subject a
therapeutically effective amount of a compound of Formula (Ia) or a
pharmaceutically acceptable salt thereof.
Inventors: |
Wang; Guoqiang; (Belmont,
MA) ; Gao; Xuri; (Newtonville, MA) ; Shen;
Ruichao; (Belmont, MA) ; He; Yong; (Lexington,
MA) ; Zhang; Jiajun; (Cambridge, MA) ;
Panarese; Joseph D.; (Newton, MA) ; Cao; Hui;
(Belmont, MA) ; Xing; Xuechao; (Wilmington,
MA) ; Or; Yat Sun; (Waltham, MA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Enanta Pharmaceuticals, Inc. |
Watertown |
MA |
US |
|
|
Appl. No.: |
17/479530 |
Filed: |
September 20, 2021 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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63117170 |
Nov 23, 2020 |
|
|
|
63142663 |
Jan 28, 2021 |
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International
Class: |
C07D 487/10 20060101
C07D487/10; A61P 31/14 20060101 A61P031/14 |
Claims
1. A compound represented by the formula ##STR00205## wherein X is
CN; R.sub.3 is hydrogen, methyl or CD.sub.3; R.sub.1 is
C.sub.1-C.sub.8-alkyl, arylalkyl or
C.sub.3-C.sub.6-cycloalkyl-C.sub.1-C.sub.4-alkyl; R.sub.4 is
hydrogen; and R.sub.5 is C.sub.1-C.sub.6-alkyl or phenyl optionally
substituted with 1 to 3 substituents independently selected from
halogen, C.sub.1-C.sub.6-alkyl and C.sub.1-C.sub.6-haloalkyl.
2. The compound of claim 1, wherein the compound is
##STR00206##
3. The compound of claim 1, wherein the compound is
##STR00207##
4. A pharmaceutical composition comprising the compound of claim 1
and a pharmaceutically acceptable carrier or excipient.
5. A pharmaceutical composition comprising the compound of claim 2
and a pharmaceutically acceptable carrier or excipient.
6. A pharmaceutical composition comprising the compound of claim 3
and a pharmaceutically acceptable carrier or excipient.
7. A method of treating or preventing a coronavirus infection in a
subject in need thereof, comprising administering to the subject a
therapeutically effective amount of the compound of claim 1.
8. A method of treating or preventing a coronavirus infection in a
subject in need thereof, comprising administering to the subject a
therapeutically effective amount of the compound of claim 2.
9. A method of treating or preventing a coronavirus infection in a
subject in need thereof, comprising administering to the subject a
therapeutically effective amount of the compound of claim 3.
Description
RELATED APPLICATIONS
[0001] This application claims the benefit of U.S. Provisional
Application No. 63/117,170, filed on Nov. 23, 2020 and U.S.
Provisional Application No. 63/142,663, filed on Jan. 28, 2021. The
entire teachings of the above applications are incorporated herein
by reference.
TECHNICAL FIELD
[0002] The invention relates to compounds and methods of inhibiting
coronavirus replication activity by targeting the 3C-Like protease
(sometimes referred to as "3CLpro", "Main protease", or "Mpro")
with a therapeutically effective amount of a 3C-Like protease
inhibitor. The invention further relates to pharmaceutical
compositions containing the coronavirus 3C-Like protease inhibitor
in a mammal by administering effective amounts of such coronavirus
3C-Like protease inhibitor.
BACKGROUND OF THE INVENTION
[0003] Coronaviruses are enveloped, positive-sense, single-stranded
RNA viruses. The genomic RNA of CoVs has a 5'-cap structure and
3'-poly-A tail and contains at least 6 open reading frames (ORFs).
The first ORF (ORF 1a/b) directly translates two polyproteins: pp1a
and pp1ab. These polyproteins are processed by a 3C-Like protease
(3CLpro), also known as the main protease (Mpro), into 16
non-structural proteins. These non-structural proteins engage in
the production of subgenomic RNAs that encode four structural
proteins, namely envelope, membrane, spike, and nucleocapsid
proteins, among other accessory proteins. As a result, it is
understood that 3C-Like protease has a critical role in the
coronavirus life cycle.
[0004] 3CLpro is a cysteine protease involved in most cleavage
events within the precursor polyprotein. Active 3CLpro is a
homodimer containing two protomers and features a Cys-His dyad
located in between domains I and II. 3CLpro is conserved among
coronaviruses and several common features are shared among the
substrates of 3CLpro in different coronaviruses. As there is no
human homolog of 3CLpro, it is an ideal antiviral target. Although
compounds have been reported to inhibit 3CLpro activity, they have
not been approved as coronavirus therapies. (Refer to WO 2004101742
A2, US 2005/0143320 A1, US 2006/0014821 A1, US 2009/0137818 A1, WO
2013/049382 A2, WO 2013/166319 A1, WO2018042343, WO2018023054,
WO2005113580, and WO2006061714).
[0005] More effective therapies for coronavirus infections are
needed due to this high unmet clinical need. This invention
provides compounds which inhibit the coronavirus lifecycle and
methods for preparation and use of these compounds. These compounds
are useful for treating or preventing coronavirus infections and
decreasing occurrence of disease complications such as organ
failure or death.
SUMMARY OF THE INVENTION
[0006] The present invention relates to novel antiviral compounds,
pharmaceutical compositions comprising such compounds, as well as
methods to treat or prevent viral (particularly coronavirus)
infection in a subject in need of such therapy with said compounds.
Compounds of the present invention inhibit the protein(s) encoded
by a coronavirus or interfere with the life cycle of a coronavirus
and are also useful as antiviral agents. In addition, the present
invention provides processes for the preparation of said
compounds.
[0007] In certain embodiments, the present invention provides
compounds represented by Formula (Ia), and pharmaceutically
acceptable salts, esters and prodrugs thereof,
##STR00002##
wherein: A is selected from: [0008] 1) --R.sub.11; [0009] 2)
--OR.sub.12; and [0010] 3) --NR.sub.13R.sub.14; B is an optionally
substituted aryl or optionally substituted heteroaryl; X is
selected from: [0011] 1) --CN; [0012] 2) --C(O)R.sub.15; [0013] 3)
--CH(OH)SO.sub.3R.sub.16; [0014] 4) --C(O)NR.sub.13R.sub.14; and
[0015] 5) --C(O)C(O)NR.sub.13R.sub.14; R.sub.1, R.sub.2, and
R.sub.3 are each independently selected from: [0016] 1) Hydrogen;
[0017] 2) Optionally substituted --C.sub.1-C.sub.8 alkyl; [0018] 3)
Optionally substituted --C.sub.2-C.sub.8 alkenyl; [0019] 4)
Optionally substituted --C.sub.2-C.sub.8 alkynyl; [0020] 5)
Optionally substituted --C.sub.3-C.sub.8 cycloalkyl; [0021] 6)
Optionally substituted 3- to 8-membered heterocycloalkyl; [0022] 7)
Optionally substituted aryl; [0023] 8) Optionally substituted
arylalkyl; [0024] 9) Optionally substituted heteroaryl; and [0025]
10) Optionally substituted heteroarylalkyl; alternatively, R.sub.1
and R.sub.2 are taken together with the carbon atom to which they
are attached to form an optionally substituted 3- to 8-membered
carbocyclic ring or an optionally substituted 3 to 8-membered
heterocyclic ring. R.sub.4 is hydrogen, optionally substituted
--C.sub.1-C.sub.4 alkyl, optionally substituted
C.sub.2-C.sub.4-alkenyl, or optionally substituted
--C.sub.3-C.sub.6 cycloalkyl. R.sub.11 and R.sub.12 are each
independently selected from: [0026] 1) Optionally substituted
--C.sub.1-C.sub.8 alkyl; [0027] 2) Optionally substituted
--C.sub.2-C.sub.8 alkenyl; [0028] 3) Optionally substituted
--C.sub.2-C.sub.8 alkynyl; [0029] 4) Optionally substituted
--C.sub.3-C.sub.8 cycloalkyl; [0030] 5) Optionally substituted 3-
to 8-membered heterocycloalkyl; [0031] 6) Optionally substituted
aryl; [0032] 7) Optionally substituted arylalkyl; [0033] 8)
Optionally substituted heteroaryl; and [0034] 9) Optionally
substituted heteroarylalkyl; R.sub.13 and R.sub.14 each
independently selected from: [0035] 1) Hydrogen; [0036] 2)
Optionally substituted --C.sub.1-C.sub.8 alkyl; [0037] 3)
Optionally substituted --C.sub.2-C.sub.8 alkenyl; [0038] 4)
Optionally substituted --C.sub.2-C.sub.8 alkynyl; [0039] 5)
Optionally substituted --C.sub.3-C.sub.8 cycloalkyl; [0040] 6)
Optionally substituted 3- to 8-membered heterocycloalkyl; [0041] 7)
Optionally substituted aryl; [0042] 8) Optionally substituted
arylalkyl; [0043] 9) Optionally substituted heteroaryl; and [0044]
10) Optionally substituted heteroarylalkyl; [0045] alternatively,
R.sub.13 and R.sub.14 are taken together with the nitrogen atom to
which they are attached to form an optionally substituted 3- to
8-membered heterocyclic ring; R.sub.15 is hydrogen, hydroxy, or
optionally substituted --C.sub.1-C.sub.8 alkyl; and R.sub.16 is
hydrogen or Na.sup.+.
[0046] In certain embodiments, the present invention provides
compounds represented by Formula (I), and pharmaceutically
acceptable salts, esters and prodrugs thereof,
##STR00003##
wherein: A is selected from: [0047] 1) --R.sub.11; [0048] 2)
--OR.sub.12; and [0049] 3) --NR.sub.13R.sub.14; B is an optionally
substituted aryl or optionally substituted heteroaryl; X is
selected from: [0050] 1) --CN; [0051] 2) --C(O)R.sub.15; [0052] 3)
--CH(OH)SO.sub.3R.sub.16; [0053] 4) --C(O)NR.sub.13R.sub.14; and
[0054] 5) --C(O)C(O)NR.sub.13R.sub.14; R.sub.1, R.sub.2, and
R.sub.3 are each independently selected from: [0055] 1) Hydrogen;
[0056] 2) Optionally substituted --C.sub.1-C.sub.8 alkyl; [0057] 3)
Optionally substituted --C.sub.2-C.sub.8 alkenyl; [0058] 4)
Optionally substituted --C.sub.2-C.sub.8 alkynyl; [0059] 5)
Optionally substituted --C.sub.3-C.sub.8 cycloalkyl; [0060] 6)
Optionally substituted 3- to 8-membered heterocycloalkyl; [0061] 7)
Optionally substituted aryl; [0062] 8) Optionally substituted
arylalkyl; [0063] 9) Optionally substituted heteroaryl; and [0064]
10) Optionally substituted heteroarylalkyl; alternatively, R.sub.1
and R.sub.2 are taken together with the carbon atom to which they
are attached to form an optionally substituted 3- to 8-membered
carbocyclic ring or an optionally substituted 3 to 8-membered
heterocyclic ring. R.sub.11 and R.sub.12 are each independently
selected from: [0065] 1) Optionally substituted --C.sub.1-C.sub.8
alkyl; [0066] 2) Optionally substituted --C.sub.2-C.sub.8 alkenyl;
[0067] 3) Optionally substituted --C.sub.2-C.sub.8 alkynyl; [0068]
4) Optionally substituted --C.sub.3-C.sub.8 cycloalkyl; [0069] 5)
Optionally substituted 3- to 8-membered heterocycloalkyl; [0070] 6)
Optionally substituted aryl; [0071] 7) Optionally substituted
arylalkyl; [0072] 8) Optionally substituted heteroaryl; and [0073]
9) Optionally substituted heteroarylalkyl; R.sub.13 and R.sub.14
each independently selected from: [0074] 1) Hydrogen; [0075] 2)
Optionally substituted --C.sub.1-C.sub.8 alkyl; [0076] 3)
Optionally substituted --C.sub.2-C.sub.8 alkenyl; [0077] 4)
Optionally substituted --C.sub.2-C.sub.8 alkynyl; [0078] 5)
Optionally substituted --C.sub.3-C.sub.8 cycloalkyl; [0079] 6)
Optionally substituted 3- to 8-membered heterocycloalkyl; [0080] 7)
Optionally substituted aryl; [0081] 8) Optionally substituted
arylalkyl; [0082] 9) Optionally substituted heteroaryl; and [0083]
10) Optionally substituted heteroarylalkyl; [0084] alternatively,
R.sub.13 and R.sub.14 are taken together with the nitrogen atom to
which they are attached to form an optionally substituted 3- to
8-membered heterocyclic ring; R.sub.15 is hydrogen, hydroxy, or
optionally substituted --C.sub.1-C.sub.8 alkyl; and R.sub.16 is
hydrogen or Na.sup.+.
DETAILED DESCRIPTION OF THE INVENTION
[0085] In one embodiment of the present invention is a compound of
Formula (I) or Formula (Ia) as described above, or a
pharmaceutically acceptable salt thereof.
[0086] In one embodiment of the present invention, the compound of
Formula (Ia) is represented by Formula (Ia-A) or Formula (Ia-B), or
a pharmaceutically acceptable salt, ester or prodrug thereof:
##STR00004##
wherein A, B, X, R.sub.1, R.sub.2, R.sub.3, and R.sub.4 are as
previously defined.
[0087] In a preferred embodiment, the compound of Formula (Ia) has
the stereochemistry shown in Formula (Ia-A).
[0088] In one embodiment of the present invention, the compound of
Formula (I) is represented by Formula (I-A) or Formula (I-B), or a
pharmaceutically acceptable salt, ester or prodrug thereof:
##STR00005##
wherein A, B, X, R.sub.1, R.sub.2, and R.sub.3 are as previously
defined.
[0089] In a preferred embodiment, the compound of Formula (I) has
the stereochemistry shown in Formula (I-A).
[0090] In certain embodiments of the compounds of Formula (I) or
Formula (Ia), R.sub.1 is hydrogen or optionally substituted
--C.sub.1-C.sub.4 alkyl; optionally substituted --C.sub.3-C.sub.6
cycloalkyl; optionally substituted aryl; optionally substituted
arylalkyl; optionally substituted heteroarylalkyl.
[0091] In certain embodiments of the compounds of Formula (I) or
Formula (Ia), R.sub.2 is hydrogen or optionally substituted
--C.sub.1-C.sub.4 alkyl; optionally substituted --C.sub.3-C.sub.6
cycloalkyl; optionally substituted aryl; optionally substituted
arylalkyl; optionally substituted heteroarylalkyl.
[0092] In certain embodiments of the compounds of Formula (I) or
Formula (Ia), R.sub.3 is hydrogen or optionally substituted
--C.sub.1-C.sub.4 alkyl; R.sub.4 is hydrogen or optionally
substituted --C.sub.1-C.sub.4 alkyl.
[0093] In certain embodiments of the compounds of Formula (I) or
Formula (Ia), R.sub.3 is hydrogen, -Me, -Et, --Pr, -i-Pr, -allyl,
--CF.sub.3, -CD.sub.3 or cyclopropyl.
[0094] In certain embodiments of the compounds of Formula (Ia),
R.sub.4 is hydrogen, -Me, -Et, --Pr, -i-Pr, -allyl, --CF.sub.3 or
cyclopropyl.
[0095] In certain embodiments of the compounds of Formula (I) or
Formula (Ia), X is --CN.
[0096] In certain embodiments of the compounds of Formula (I) or
Formula (Ia), X is --C(O)H.
[0097] In certain embodiments of the compounds of Formula (I) or
Formula (Ia), X is --C(O)CH.sub.2OH, --C(O)CH.sub.2C.sub.1 or
--C(O)CH.sub.2F.
[0098] In certain embodiments of the compounds of Formula (I) or
Formula (Ia), X is --C(O)C(O)NR.sub.13R.sub.14, wherein R.sub.13
and R.sub.14 are previously defined.
[0099] In certain embodiments of the compounds of Formula (I) or
Formula (Ia), A is derived from one of the following by removal of
a hydrogen atom and is optionally substituted:
##STR00006## ##STR00007## ##STR00008##
[0100] In certain embodiments of the compounds of Formula (I) or
Formula (Ia), A is selected from the following groups, and A is
optionally substituted:
##STR00009##
preferably the substituents are independently selected from
halogen, CN, NH.sub.2, optionally substituted --C.sub.1-C.sub.3
alkoxy, optionally substituted --C.sub.1-C.sub.3 alkyl, optionally
substituted --C.sub.3-C.sub.6 cycloalkyl, optionally substituted
aryl, and optionally substituted heteroaryl. Preferably the number
of substituents is 0 to 3.
[0101] In certain embodiments of the compounds of Formula (I) or
Formula (Ia), A is selected from the following groups, and A is
optionally substituted:
##STR00010##
preferably the substituents are independently selected from
halogen, CN, NH.sub.2, optionally substituted --C.sub.1-C.sub.3
alkoxy, optionally substituted --C.sub.1-C.sub.3 alkyl, optionally
substituted --C.sub.3-C.sub.6 cycloalkyl, optionally substituted
aryl, and optionally substituted heteroaryl. Preferably the number
of substituents is 0 to 3.
[0102] In certain embodiments of the compounds of Formula (I) or
Formula (Ia), B is selected from the following groups, and B is
optionally substituted:
##STR00011##
[0103] In certain embodiments, the compound of Formula (Ia), is
represented by Formula (Ia-1):
##STR00012##
wherein A, B, R.sub.1, R.sub.2, R.sub.4, and X are as previously
defined.
[0104] In certain embodiments, the compound of Formula (Ia) is
represented by Formula (Ia-2):
##STR00013##
wherein A, B, R.sub.1, R.sub.3, R.sub.4, and X are as previously
defined.
[0105] In certain embodiments, the compound of Formula (Ia) is
represented by Formula (Ia-3):
##STR00014##
wherein A, B, R.sub.1, R.sub.4, and X are as previously
defined.
[0106] In certain embodiments, the compound of Formula (I), is
represented by Formula (I-1):
##STR00015##
wherein A, B, R.sub.1, R.sub.2, and X are as previously
defined.
[0107] In certain embodiments, the compound of Formula (I) is
represented by Formula (I-2):
##STR00016##
wherein A, B, R.sub.1, R.sub.3, and X are as previously
defined.
[0108] In certain embodiments, the compound of Formula (I) is
represented by Formula (I-3):
##STR00017##
wherein A, B, R.sub.1, and X are as previously defined.
[0109] In certain embodiments, the compound of Formula (Ia) is
represented by Formula (IIa):
##STR00018##
wherein A, R.sub.1, R.sub.2, R.sub.3, R.sub.4, and X are as
previously defined and each R.sub.9 is independently selected from:
[0110] 1) Halogen; [0111] 2) --CN; [0112] 3) --OR.sub.13; [0113] 4)
--SR.sub.13; [0114] 5) --NR.sub.13R.sub.14; [0115] 6)
--OC(O)NR.sub.13R.sub.14; [0116] 7) Optionally substituted
--C.sub.1-C.sub.6 alkyl; [0117] 8) Optionally substituted
--C.sub.3-C.sub.8 cycloalkyl; [0118] 9) Optionally substituted 3-
to 8-membered heterocycloalkyl; [0119] 10) Optionally substituted
aryl; and [0120] 11) Optionally substituted heteroaryl; and n is 0,
1, 2, 3, or 4.
[0121] In certain embodiments, the compound of Formula (I) is
represented by Formula (II):
##STR00019##
wherein A, R.sub.1, R.sub.2, R.sub.3, and X are as previously
defined and each R.sub.9 is independently selected from: [0122] 1)
Halogen; [0123] 2) --CN; [0124] 3) --OR.sub.13; [0125] 4)
--SR.sub.13; [0126] 5) --NR.sub.13R.sub.14; [0127] 6)
--OC(O)NR.sub.13R.sub.14; [0128] 7) Optionally substituted
--C.sub.1-C.sub.6 alkyl; [0129] 8) Optionally substituted
--C.sub.3-C.sub.8 cycloalkyl; [0130] 9) Optionally substituted 3-
to 8-membered heterocycloalkyl; [0131] 10) Optionally substituted
aryl; and [0132] 11) Optionally substituted heteroaryl; and n is 0,
1, 2, 3, or 4.
[0133] In certain embodiments, the compound of Formula (Ia) is
represented by Formula (IIIa-1):
##STR00020##
wherein A, R.sub.1, R.sub.3, R.sub.4, R.sub.9, n and X are as
previously defined.
[0134] In certain embodiments, the compound of Formula (Ia) is
represented by Formula (IIIa-2):
##STR00021##
wherein A, R.sub.1, R.sub.2, R.sub.4, R.sub.9, n and X are as
previously defined.
[0135] In certain embodiments, the compound of Formula (I) is
represented by Formula (III):
##STR00022##
wherein A, R.sub.1, R.sub.2, R.sub.9, n and X are as previously
defined.
[0136] In certain embodiments, the compound of Formula (Ia) is
represented by one of Formulae (IVa-1) to (IVa-6):
##STR00023##
wherein A, B, R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.13 and
R.sub.14 are as previously defined.
[0137] In certain embodiments, the compound of Formula (I) is
represented by one of Formulae (IV-1) to (IV-6):
##STR00024##
wherein A, B, R.sub.1, R.sub.2, R.sub.3, R.sub.13 and R.sub.14 are
as previously defined.
[0138] In certain embodiments, the compound of Formula (Ia), is
represented by one of Formulae (Va-1) to (Va-6):
##STR00025##
wherein [0139] A, R.sub.1, R.sub.2, R.sub.3, R.sub.9, R.sub.13,
R.sub.14 and n are as previously defined.
[0140] In certain embodiments, the compound of Formula (I) is
represented by one of Formulae (V-1) to (V-6):
##STR00026##
wherein A, R.sub.1, R.sub.2, R.sub.3, R.sub.9, R.sub.13, R.sub.14
and n are as previously defined.
[0141] In certain embodiments, the compound of Formula (Ia) is
represented by one of Formulae (VIa-1) to (VIa-6):
##STR00027##
wherein A, R.sub.1, R.sub.3, R.sub.4, R.sub.9, R.sub.13, R.sub.14
and n are as previously defined.
[0142] In certain embodiments, the compound of Formula (I) is
represented by one of Formulae (VI-1) to (VI-6):
##STR00028##
wherein A, R.sub.1, R.sub.3, R.sub.9, R.sub.13, R.sub.14 and n are
as previously defined.
[0143] In certain embodiments, the compound of Formula (I) is
represented by one of Formulae (VII-1) to (VII-5):
##STR00029##
wherein A, R.sub.1, R.sub.3, and X are as previously defined.
Preferably, A is selected from the following:
##STR00030## ##STR00031##
R.sub.1 is selected from the following:
##STR00032##
and X is selected from the following:
##STR00033##
[0144] In certain embodiments, the compound of Formula (I) is
represented by one of Formulae (VII-1a).about.(VII-5a):
##STR00034##
wherein A, R.sub.1, R.sub.3, and X are as previously defined.
Preferably, A is selected from the following:
##STR00035## ##STR00036##
R.sub.1 is selected from the following:
##STR00037##
and X is selected from the following:
##STR00038##
[0145] In certain embodiments, the compound of Formula (I) is
represented by one of Formulae (VII-1) to (VII-5) and Formulae
(VII-la) to (VII-5a), wherein A is selected from, the
following:
##STR00039## ##STR00040## ##STR00041## ##STR00042##
##STR00043##
X is selected from the following:
##STR00044##
and R.sub.1 is selected from the following:
##STR00045##
[0146] In certain embodiments, the compound of Formula (Ia) is
represented by one of Formulae (VIII-1) to (VIII-5):
##STR00046##
wherein A, X, R.sub.1, R.sub.3, R.sub.4, and R.sub.9 are as
previously defined.
[0147] In certain embodiments, the compound of Formula (Ia) is
represented by one of Formulae (IX-1) to (IX-5):
##STR00047##
wherein A, X, R.sub.1, R.sub.3, R.sub.4, and R.sub.9 are as
previously defined.
[0148] In certain embodiments, the compound of Formula (Ia) is
represented by one of Formulae (VIII-1) to (VIII-5) and Formulae
(IX-1) to (IX-5), wherein R.sub.3 is hydrogen, -Me, -Et, --Pr,
-i-Pr, -allyl, --CF.sub.3, -CD.sub.3, or cyclopropyl; R.sub.4 is
hydrogen, -Me, -Et, --Pr, -i-Pr, -allyl, --CF.sub.3 or cyclopropyl;
R.sub.9 is halogen, --OCH.sub.3, --NH.sub.2, --CH.sub.3, or
--CF.sub.3; A is selected from the following
##STR00048## ##STR00049## ##STR00050## ##STR00051##
##STR00052##
X is selected from the following:
##STR00053##
and R.sub.1 is selected from the following:
##STR00054##
[0149] In certain embodiments, the compound of Formula (Ia) is
represented by one of Formulae (X-1) to (X-4):
##STR00055##
wherein m is 0, 1, 2, 3, 4 or 5; v is 0, 1 or 2; R.sub.10 is
optionally substituted --C.sub.1-C.sub.4 alkyl or optionally
substituted --C.sub.3-C.sub.6 cycloalkyl; X, R.sub.1, R.sub.3,
R.sub.4, R.sub.9, and n are as previously defined and R.sub.5 is
hydrogen, optionally substituted --C.sub.1-C.sub.6 alkyl;
optionally substituted --C.sub.3-C.sub.8 cycloalkyl; Optionally
substituted 3- to 8-membered heterocycloalkyl; optionally
substituted aryl; or optionally substituted heteroaryl.
[0150] In certain embodiments, the compound of Formula (Ia) is
represented by one of Formulae (XI-1) to (XI-3):
##STR00056##
wherein R.sub.1, R.sub.3, R.sub.4, R.sub.9, R.sub.10, m, n, and v
are as previously defined.
[0151] In certain embodiments, the compound of Formula (Ia) is
represented by one of Formulae (XII-1) to (XII-6):
##STR00057##
wherein R.sub.1, R.sub.4, R.sub.9, R.sub.10, m, n, and v are as
previously defined.
[0152] In certain embodiments, the compound of Formula (Ia) is
represented by one of Formulae (XIII-1) to (XIII-6):
##STR00058## ##STR00059##
wherein R.sub.4, R.sub.9, R.sub.10, m, n, and v are as previously
defined.
[0153] In certain embodiments, the compound of Formula (Ia) is
represented by one of Formulae (XIV-1) to (XIV-6):
##STR00060## ##STR00061##
wherein R.sub.4, R.sub.9, R.sub.10, m, n, and v are as previously
defined.
Definitions
[0154] Listed below are definitions of various terms used to
describe this invention. These definitions apply to the terms as
they are used throughout this specification and claims, unless
otherwise limited in specific instances, either individually or as
part of a larger group.
[0155] The term "aryl," as used herein, refers to a mono- or
polycyclic carbocyclic ring system comprising at least one aromatic
ring, including, but not limited to, phenyl, naphthyl,
tetrahydronaphthyl, indanyl, and indenyl. A polycyclic aryl is a
polycyclic ring system that comprises at least one aromatic ring.
Polycyclic aryls can comprise fused rings, covalently attached
rings or a combination thereof.
[0156] The term "heteroaryl," as used herein, refers to a mono- or
polycyclic aromatic radical having one or more ring atom selected
from S, O and N; and the remaining ring atoms are carbon, wherein
any N or S contained within the ring may be optionally oxidized.
Heteroaryl includes, but is not limited to, pyridinyl, pyrazinyl,
pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl,
isooxazolyl, thiadiazolyl, oxadiazolyl, thiophenyl, furanyl,
quinolinyl, isoquinolinyl, benzimidazolyl, benzoxazolyl,
quinoxalinyl. A polycyclic heteroaryl can comprise fused rings,
covalently attached rings or a combination thereof.
[0157] In accordance with the invention, aromatic groups can be
substituted or unsubstituted.
[0158] The term "bicyclic aryl" or "bicyclic heteroaryl" refers to
a ring system consisting of two rings wherein at least one ring is
aromatic; and the two rings can be fused or covalently
attached.
[0159] The term "alkyl" as used herein, refers to saturated,
straight- or branched-chain hydrocarbon radicals. "C.sub.1-C.sub.4
alkyl," "C.sub.1-C.sub.6 alkyl," "C.sub.1-C.sub.8 alkyl,"
"C.sub.1-C.sub.12 alkyl," "C.sub.2-C.sub.4 alkyl," or
"C.sub.3-C.sub.6 alkyl," refer to alkyl groups containing from one
to four, one to six, one to eight, one to twelve, 2 to 4 and 3 to 6
carbon atoms respectively. Examples of C.sub.1-C.sub.8 alkyl
radicals include, but are not limited to, methyl, ethyl, propyl,
isopropyl, n-butyl, tert-butyl, neopentyl, n-hexyl, heptyl and
octyl radicals.
[0160] The term "alkenyl" as used herein, refers to straight- or
branched-chain hydrocarbon radicals having at least one
carbon-carbon double bond by the removal of a single hydrogen atom.
"C.sub.2-C.sub.8 alkenyl," "C.sub.2-C.sub.12 alkenyl,"
"C.sub.2-C.sub.4 alkenyl," "C.sub.3-C.sub.4 alkenyl," or
"C.sub.3-C.sub.6 alkenyl," refer to alkenyl groups containing from
two to eight, two to twelve, two to four, three to four or three to
six carbon atoms respectively. Alkenyl groups include, but are not
limited to, for example, ethenyl, propenyl, butenyl,
2-methyl-2-buten-2-yl, heptenyl, octenyl, and the like.
[0161] The term "alkynyl" as used herein, refers to straight- or
branched-chain hydrocarbon radicals having at least one
carbon-carbon double bond by the removal of a single hydrogen atom.
"C.sub.2-C.sub.8 alkynyl," "C.sub.2-C.sub.12 alkynyl,"
"C.sub.2-C.sub.4 alkynyl," "C.sub.3-C.sub.4 alkynyl," or
"C.sub.3-C.sub.6 alkynyl," refer to alkynyl groups containing from
two to eight, two to twelve, two to four, three to four or three to
six carbon atoms respectively. Representative alkynyl groups
include, but are not limited to, for example, ethynyl, 2-propynyl,
2-butynyl, heptynyl, octynyl, and the like.
[0162] The term "cycloalkyl", as used herein, refers to a
monocyclic or polycyclic saturated carbocyclic ring or a bi- or
tri-cyclic group fused, bridged or spiro system, and the carbon
atoms may be optionally oxo-substituted or optionally substituted
with exocyclic olefinic double bond.
[0163] Preferred cycloalkyl groups include C.sub.3-C.sub.12
cycloalkyl, C.sub.3-C.sub.6 cycloalkyl, C.sub.3-C.sub.8 cycloalkyl
and C.sub.4-C.sub.7 cycloalkyl. Examples of C.sub.3-C.sub.12
cycloalkyl include, but not limited to, cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, cyclopentyl, cyclooctyl,
4-methylene-cyclohexyl, bicyclo[2.2.1]heptyl, bicyclo[3.1.0]hexyl,
spiro[2.5]octyl, 3-methylenebicyclo[3.2.1]octyl, spiro[4.4]nonanyl,
and the like.
[0164] The term "cycloalkenyl", as used herein, refers to
monocyclic or polycyclic carbocyclic ring or a bi- or tri-cyclic
group fused, bridged or spiro system having at least one
carbon-carbon double bond and the carbon atoms may be optionally
oxo-substituted or optionally substituted with exocyclic olefinic
double bond. Preferred cycloalkenyl groups include C.sub.3-C.sub.12
cycloalkenyl, C.sub.3-C.sub.8 cycloalkenyl or C.sub.5-C.sub.7
cycloalkenyl groups. Examples of C.sub.3-C.sub.12 cycloalkenyl
include, but not limited to, cyclopropenyl, cyclobutenyl,
cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl,
bicyclo[2.2.1]hept-2-enyl, bicyclo[3.1.0]hex-2-enyl,
spiro[2.5]oct-4-enyl, spiro[4.4]non-2-enyl,
bicyclo[4.2.1]non-3-en-12-yl, and the like.
[0165] As used herein, the term "arylalkyl" means a functional
group wherein an alkylene chain is attached to an aryl group, e.g.,
--CH.sub.2CH.sub.2-phenyl. The term "substituted arylalkyl" means
an arylalkyl functional group in which the aryl group is
substituted. Similarly, the term "heteroarylalkyl" means a
functional group wherein an alkylene chain is attached to a
heteroaryl group. The term "substituted heteroarylalkyl" means a
heteroarylalkyl functional group in which the heteroaryl group is
substituted. Preferably, as used herein, arylalkyl is
aryl-C.sub.1-C.sub.6 alkyl, and heteroarylalkyl is
heteroaryl-C.sub.1-C.sub.6 alkyl.
[0166] As used herein, the term "alkoxy" employed alone or in
combination with other terms means, unless otherwise stated, an
alkyl group having the designated number of carbon atoms connected
to the rest of the molecule via an oxygen atom, such as, for
example, methoxy, ethoxy, 2-propoxy, 2-propoxy (isopropoxy) and the
higher homologs and isomers. Preferred alkoxy are (C.sub.2-C.sub.3)
alkoxy.
[0167] It is understood that any alkyl, alkenyl, alkynyl,
cycloalkyl, heterocyclic and cycloalkenyl moiety described herein
can also be an aliphatic group or an alicyclic group.
[0168] An "aliphatic" group is a non-aromatic moiety comprised of
any combination of carbon atoms, hydrogen atoms, halogen atoms,
oxygen, nitrogen or other atoms, and optionally contains one or
more units of unsaturation, e.g., double and/or triple bonds.
Examples of aliphatic groups are functional groups, such as alkyl,
alkenyl, alkynyl, O, OH, NH, NH.sub.2, C(O), S(O).sub.2, C(O)O,
C(O)NH, OC(O)O, OC(O)NH, OC(O)NH.sub.2, S(O).sub.2NH,
S(O).sub.2NH.sub.2, NHC(O)NH.sub.2, NHC(O)C(O)NH, NHS(O).sub.2NH,
NHS(O).sub.2NH.sub.2, C(O)NHS(O).sub.2, C(O)NHS(O).sub.2NH or
C(O)NHS(O).sub.2NH.sub.2, and the like, groups comprising one or
more functional groups, non-aromatic hydrocarbons (optionally
substituted), and groups wherein one or more carbons of a
non-aromatic hydrocarbon (optionally substituted) is replaced by a
functional group. Carbon atoms of an aliphatic group can be
optionally oxo-substituted. An aliphatic group may be straight
chained, branched, cyclic, or a combination thereof and preferably
contains between about 1 and about 24 carbon atoms, more typically
between about 1 and about 12 carbon atoms. In addition to aliphatic
hydrocarbon groups, as used herein, aliphatic groups expressly
include, for example, alkoxyalkyls, polyalkoxyalkyls, such as
polyalkylene glycols, polyamines, and polyimines, for example.
Aliphatic groups may be optionally substituted.
[0169] The terms "heterocyclic" or "heterocycloalkyl" can be used
interchangeably and referred to a non-aromatic ring or a bi- or
tri-cyclic group fused, bridged or spiro system, where (i) each
ring system contains at least one heteroatom independently selected
from oxygen, sulfur and nitrogen, (ii) each ring system can be
saturated or unsaturated (iii) the nitrogen and sulfur heteroatoms
may optionally be oxidized, (iv) the nitrogen heteroatom may
optionally be quaternized, (v) any of the above rings may be fused
to an aromatic ring, and (vi) the remaining ring atoms are carbon
atoms which may be optionally oxo-substituted or optionally
substituted with exocyclic olefinic double bond. Representative
heterocycloalkyl groups include, but are not limited to,
1,3-dioxolane, pyrrolidinyl, pyrazolinyl, pyrazolidinyl,
imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl,
oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl,
isothiazolidinyl, quinoxalinyl, pyridazinonyl,
2-azabicyclo[2.2.1]-heptyl, 8-azabicyclo[3.2.1]octyl,
5-azaspiro[2.5]octyl, 2-oxa-7-azaspiro[4.4]nonanyl,
7-oxooxepan-4-yl, and tetrahydrofuryl. Such heterocyclic groups may
be further substituted. Heteroaryl or heterocyclic groups can be
C-attached or N-attached (where possible).
[0170] It is understood that any alkyl, alkenyl, alkynyl,
alicyclic, cycloalkyl, cycloalkenyl, aryl, heteroaryl,
heterocyclic, aliphatic moiety or the like, described herein can
also be a divalent or multivalent group when used as a linkage to
connect two or more groups or substituents, which can be at the
same or different atom(s). One of skill in the art can readily
determine the valence of any such group from the context in which
it occurs.
[0171] The term "substituted" refers to substitution by independent
replacement of one, two, or three or more of the hydrogen atoms
with substituents including, but not limited to, --F, --Cl, --Br,
--I, --OH, C.sub.1-C.sub.12-alkyl; C.sub.2-C.sub.12-alkenyl,
C.sub.2-C.sub.12-alkynyl, --C.sub.3-C.sub.12-cycloalkyl, protected
hydroxy, --NO.sub.2, --N.sub.3, --CN, --NH.sub.2, protected amino,
oxo, thioxo, --NH--C.sub.1-C.sub.12-alkyl,
--NH--C.sub.2-C.sub.8-alkenyl, --NH--C.sub.2-C.sub.8-alkynyl,
--NH--C.sub.3-C.sub.12-cycloalkyl, --NH-aryl, --NH-heteroaryl,
--NH-heterocycloalkyl, -dialkylamino, -diarylamino,
-diheteroarylamino, --O--C.sub.1-C.sub.12-alkyl,
--O--C.sub.2-C.sub.8-alkenyl, --O--C.sub.2-C.sub.8-alkynyl,
--O--C.sub.3-C.sub.12-cycloalkyl, --O-aryl, --O-heteroaryl,
--O-heterocycloalkyl, --C(O)--C.sub.1-C.sub.12-alkyl,
--C(O)--C.sub.2-C.sub.8-alkenyl, --C(O)--C.sub.2-C.sub.8-alkynyl,
--C(O)--C.sub.3-C.sub.12-cycloalkyl, --C(O)-aryl, --C(O)--
heteroaryl, --C(O)-heterocycloalkyl, --CONH.sub.2,
--CONH--C.sub.1-C.sub.12-alkyl, --CONH--C.sub.2-C.sub.8-alkenyl,
--CONH--C.sub.2-C.sub.8-alkynyl,
--CONH--C.sub.3-C.sub.12-cycloalkyl, --CONH-aryl,
--CONH-heteroaryl, --CONH-- heterocycloalkyl,
--OCO.sub.2--C.sub.1-C.sub.12-alkyl,
--OCO.sub.2--C.sub.2-C.sub.8-alkenyl,
--OCO.sub.2--C.sub.2-C.sub.8-alkynyl,
--OCO.sub.2--C.sub.3-C.sub.12-cycloalkyl, --OCO.sub.2-aryl,
--OCO.sub.2-heteroaryl, --OCO.sub.2-heterocycloalkyl,
--CO.sub.2-C.sub.1-C.sub.12 alkyl, --CO.sub.2-C.sub.2-C.sub.8
alkenyl, --CO.sub.2-C.sub.2-C.sub.8 alkynyl,
CO.sub.2-C.sub.3-C.sub.12-cycloalkyl, --CO.sub.2-- aryl,
CO.sub.2-heteroaryl, CO.sub.2-heterocyloalkyl, --OCONH.sub.2,
--OCONH-C.sub.1C.sub.12-alkyl, --OCONH-C.sub.2-C.sub.8-alkenyl,
--OCONH-C.sub.2-C.sub.8-alkynyl,
--OCONH-C.sub.3-C.sub.12-cycloalkyl, --OCONH-aryl,
--OCONH-heteroaryl, --OCONH-heterocycloalkyl, --NHC(O)H,
--NHC(O)--C.sub.1-C.sub.12-alkyl,
--NHC(O)--C.sub.2-C.sub.8-alkenyl,
--NHC(O)--C.sub.2-C.sub.8-alkynyl,
--NHC(O)--C.sub.3-C.sub.12-cycloalkyl, --NHC(O)-aryl,
--NHC(O)-heteroaryl, --NHC(O)-heterocycloalkyl,
--NHCO.sub.2--C.sub.1-C.sub.12-alkyl,
--NHCO.sub.2--C.sub.2-C.sub.8-alkenyl, --NHCO.sub.2--
C.sub.2-C.sub.8-alkynyl, --NHCO.sub.2--C.sub.3-C.sub.12-cycloalkyl,
--NHCO.sub.2-aryl, --NHCO.sub.2-heteroaryl, --NHCO.sub.2--
heterocycloalkyl, --NHC(O)NH.sub.2,
--NHC(O)NH--C.sub.1-C.sub.12-alkyl,
--NHC(O)NH--C.sub.2-C.sub.8-alkenyl,
--NHC(O)NH--C.sub.2-C.sub.8-alkynyl,
--NHC(O)NH--C.sub.3-C.sub.12-cycloalkyl, --NHC(O)NH-aryl,
--NHC(O)NH-heteroaryl, --NHC(O)NH-heterocycloalkyl, NHC(S)NH.sub.2,
--NHC(S)NH--C.sub.1-C.sub.12-alkyl,
--NHC(S)NH--C.sub.2-C.sub.8-alkenyl,
--NHC(S)NH--C.sub.2-C.sub.8-alkynyl,
--NHC(S)NH--C.sub.3-C.sub.12-cycloalkyl, --NHC(S)NH-aryl,
--NHC(S)NH-heteroaryl, --NHC(S)NH-heterocycloalkyl,
--NHC(NH)NH.sub.2, --NHC(NH)NH--C.sub.1-C.sub.12-alkyl,
--NHC(NH)NH--C.sub.2-C.sub.8-alkenyl,
--NHC(NH)NH--C.sub.2-C.sub.8-alkynyl,
--NHC(NH)NH--C.sub.3-C.sub.12-cycloalkyl, --NHC(NH)NH-aryl,
--NHC(NH)NH-heteroaryl, --NHC(NH)NH-heterocycloalkyl,
--NHC(NH)--C.sub.1-C.sub.12-alkyl,
--NHC(NH)--C.sub.2-C.sub.8-alkenyl,
--NHC(NH)--C.sub.2-C.sub.8-alkynyl,
--NHC(NH)--C.sub.3-C.sub.12-cycloalkyl, --NHC(NH)-aryl,
--NHC(NH)-heteroaryl, --NHC(NH)-heterocycloalkyl,
--C(NH)NH--C.sub.1-C.sub.12-alkyl,
--C(NH)NH--C.sub.2-C.sub.8-alkenyl,
--C(NH)NH--C.sub.2-C.sub.8-alkynyl,
--C(NH)NH--C.sub.3-C.sub.12-cycloalkyl, --C(NH)NH-aryl,
--C(NH)NH-heteroaryl, --C(NH)NH-heterocycloalkyl,
--S(O)--C.sub.1-C.sub.12-alkyl, --S(O)--C.sub.2-C.sub.8-alkenyl,
--S(O)--C.sub.2-C.sub.8-alkynyl,
--S(O)--C.sub.3-C.sub.12-cycloalkyl, --S(O)-aryl,
--S(O)-heteroaryl, --S(O)-heterocycloalkyl, --SO.sub.2NH.sub.2,
--SO.sub.2NH--C.sub.1-C.sub.12-alkyl,
--SO.sub.2NH--C.sub.2-C.sub.8-alkenyl,
--SO.sub.2NH--C.sub.2-C.sub.8-alkynyl,
--SO.sub.2NH--C.sub.3-C.sub.12-cycloalkyl, --SO.sub.2NH-aryl,
--SO.sub.2NH-heteroaryl, --SO.sub.2NH-- heterocycloalkyl,
--NHSO.sub.2--C.sub.1-C.sub.12-alkyl,
--NHSO.sub.2--C.sub.2-C.sub.8-alkenyl,
--NHSO.sub.2--C.sub.2-C.sub.8-alkynyl,
--NHSO.sub.2--C.sub.3-C.sub.12-cycloalkyl, --NHSO.sub.2-aryl,
--NHSO.sub.2-heteroaryl, --NHSO.sub.2-heterocycloalkyl,
--CH.sub.2NH.sub.2, --CH.sub.2SO.sub.2CH.sub.3, -aryl, -arylalkyl,
-heteroaryl, -heteroarylalkyl, -heterocycloalkyl,
--C.sub.3-C.sub.12-cycloalkyl, polyalkoxyalkyl, polyalkoxy,
-methoxymethoxy, -methoxyethoxy, --SH, --S--C.sub.1-C.sub.12-alkyl,
--S--C.sub.2-C.sub.8-alkenyl, --S--C.sub.2-C.sub.8-alkynyl,
--S--C.sub.3-C.sub.12-cycloalkyl, --S-aryl, --S-heteroaryl,
--S-heterocycloalkyl, or methylthio-methyl. In certain embodiments,
the substituents are independently selected from halo, preferably
Cl and F; C.sub.1-C.sub.4-alkyl, preferably methyl and ethyl;
halo-C.sub.1-C.sub.4-alkyl, such as fluoromethyl, difluoromethyl,
and trifluoromethyl; C.sub.2-C.sub.4-alkenyl;
halo-C.sub.2-C.sub.4-alkenyl; C.sub.3-C.sub.6-cycloalkyl, such as
cyclopropyl; C.sub.1-C.sub.4-alkoxy, such as methoxy and ethoxy;
halo-C.sub.1-C.sub.4-alkoxy, such as fluoromethoxy,
difluoromethoxy, and trifluoromethoxy; acetyl; --CN; --OH;
NH.sub.2; C.sub.1-C.sub.4-alkylamino;
di(C.sub.1-C.sub.4-alkyl)amino; and NO.sub.2. It is understood that
the aryls, heteroaryls, alkyls, and the like can be further
substituted. In some cases, each substituent in a substituted
moiety is additionally optionally substituted with one or more
groups, each group being independently selected from
C.sub.1-C.sub.4-alkyl; --CF.sub.3, --OCH.sub.3, --OCF.sub.3, --F,
--Cl, --Br, --I, --OH, --NO.sub.2, --CN, and --NH.sub.2.
Preferably, a substituted alkyl group is substituted with one or
more halogen atoms, more preferably one or more fluorine or
chlorine atoms.
[0172] The term "halo" or halogen" alone or as part of another
substituent, as used herein, refers to a fluorine, chlorine,
bromine, or iodine atom.
[0173] The term "optionally substituted", as used herein, means
that the referenced group may be substituted or unsubstituted. In
one embodiment, the referenced group is optionally substituted with
zero substituents, i.e., the referenced group is unsubstituted. In
another embodiment, the referenced group is optionally substituted
with one or more additional group(s) individually and independently
selected from groups described herein.
[0174] The term "hydrogen" includes hydrogen and deuterium. In
addition, the recitation of an atom includes other isotopes of that
atom so long as the resulting compound is pharmaceutically
acceptable.
[0175] The term "hydroxy activating group," as used herein, refers
to a labile chemical moiety which is known in the art to activate a
hydroxyl group so that it will depart during synthetic procedures
such as in a substitution or an elimination reaction. Examples of
hydroxyl activating group include, but not limited to, mesylate,
tosylate, triflate, p-nitrobenzoate, phosphonate and the like.
[0176] The term "activated hydroxyl," as used herein, refers to a
hydroxy group activated with a hydroxyl activating group, as
defined above, including mesylate, tosylate, triflate,
p-nitrobenzoate, phosphonate groups, for example.
[0177] The term "hydroxy protecting group," as used herein, refers
to a labile chemical moiety which is known in the art to protect a
hydroxyl group against undesired reactions during synthetic
procedures. After said synthetic procedure(s) the hydroxy
protecting group as described herein may be selectively removed.
Hydroxy protecting groups as known in the art are described
generally in T. H. Greene and P. G. M. Wuts, Protective Groups in
Organic Synthesis, 3rd edition, John Wiley & Sons, New York
(1999). Examples of hydroxyl protecting groups include
benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl,
tert-butoxy-carbonyl, isopropoxycarbonyl, diphenylmethoxycarbonyl,
2,2,2-trichloroethoxycarbonyl, allyloxycarbonyl, acetyl, formyl,
chloroacetyl, trifluoroacetyl, methoxyacetyl, phenoxyacetyl,
benzoyl, methyl, t-butyl, 2,2,2-trichloroethyl, 2-trimethylsilyl
ethyl, allyl, benzyl, triphenyl-methyl (trityl), methoxymethyl,
methylthiomethyl, benzyloxymethyl, 2-(trimethylsilyl)-ethoxymethyl,
methanesulfonyl, trimethylsilyl, triisopropylsilyl, and the
like.
[0178] The term "protected hydroxy," as used herein, refers to a
hydroxy group protected with a hydroxy protecting group, as defined
above, including benzoyl, acetyl, trimethylsilyl, triethylsilyl,
methoxymethyl groups, for example.
[0179] The term "hydroxy prodrug group," as used herein, refers to
a promoiety group which is known in the art to change the
physicochemical, and hence the biological properties of a parent
drug in a transient manner by covering or masking the hydroxy
group. After said synthetic procedure(s), the hydroxy prodrug group
as described herein must be capable of reverting back to hydroxy
group in vivo. Hydroxy prodrug groups as known in the art are
described generally in Kenneth B. Sloan, Prodrugs, Topical and
Ocular Drug Delivery, (Drugs and the Pharmaceutical Sciences;
Volume 53), Marcel Dekker, Inc., New York (1992).
[0180] The term "amino protecting group," as used herein, refers to
a labile chemical moiety which is known in the art to protect an
amino group against undesired reactions during synthetic
procedures. After said synthetic procedure(s) the amino protecting
group as described herein may be selectively removed. Amino
protecting groups as known in the art are described generally in T.
H. Greene and P. G. M. Wuts, Protective Groups in Organic
Synthesis, 3rd edition, John Wiley & Sons, New York (1999).
Examples of amino protecting groups include, but are not limited
to, methoxycarbonyl, t-butoxycarbonyl,
12-fluorenyl-methoxycarbonyl, benzyloxycarbonyl, and the like.
[0181] The term "protected amino," as used herein, refers to an
amino group protected with an amino protecting group as defined
above.
[0182] The term "leaving group" means a functional group or atom
which can be displaced by another functional group or atom in a
substitution reaction, such as a nucleophilic substitution
reaction. By way of example, representative leaving groups include
chloro, bromo and iodo groups; sulfonic ester groups, such as
mesylate, tosylate, brosylate, nosylate and the like; and acyloxy
groups, such as acetoxy, trifluoroacetoxy and the like.
[0183] The term "aprotic solvent," as used herein, refers to a
solvent that is relatively inert to proton activity, i.e., not
acting as a proton-donor. Examples include, but are not limited to,
hydrocarbons, such as hexane and toluene, for example, halogenated
hydrocarbons, such as, for example, methylene chloride, ethylene
chloride, chloroform, and the like, heterocyclic compounds, such
as, for example, tetrahydrofuran and N-methylpyrrolidinone, and
ethers such as diethyl ether, bis-methoxymethyl ether. Such
compounds are well known to those skilled in the art, and it will
be obvious to those skilled in the art that individual solvents or
mixtures thereof may be preferred for specific compounds and
reaction conditions, depending upon such factors as the solubility
of reagents, reactivity of reagents and preferred temperature
ranges, for example. Further discussions of aprotic solvents may be
found in organic chemistry textbooks or in specialized monographs,
for example: Organic Solvents Physical Properties and Methods of
Purification, 4th ed., edited by John A. Riddick et al., Vol. II,
in the Techniques of Chemistry Series, John Wiley & Sons, N Y,
1986.
[0184] The term "protic solvent," as used herein, refers to a
solvent that tends to provide protons, such as an alcohol, for
example, methanol, ethanol, propanol, isopropanol, butanol,
t-butanol, and the like. Such solvents are well known to those
skilled in the art, and it will be obvious to those skilled in the
art that individual solvents or mixtures thereof may be preferred
for specific compounds and reaction conditions, depending upon such
factors as the solubility of reagents, reactivity of reagents and
preferred temperature ranges, for example. Further discussions of
protogenic solvents may be found in organic chemistry textbooks or
in specialized monographs, for example: Organic Solvents Physical
Properties and Methods of Purification, 4th ed., edited by John A.
Riddick et al., Vol. II, in the Techniques of Chemistry Series,
John Wiley & Sons, N Y, 1986.
[0185] Combinations of substituents and variables envisioned by
this invention are only those that result in the formation of
stable compounds. The term "stable," as used herein, refers to
compounds which possess stability sufficient to allow manufacture
and which maintains the integrity of the compound for a sufficient
period of time to be useful for the purposes detailed herein (e.g.,
therapeutic or prophylactic administration to a subject).
[0186] The synthesized compounds can be separated from a reaction
mixture and further purified by a method such as column
chromatography, high pressure liquid chromatography, or
recrystallization. As can be appreciated by the skilled artisan,
further methods of synthesizing the compounds of the Formula herein
will be evident to those of ordinary skill in the art.
Additionally, the various synthetic steps may be performed in an
alternate sequence or order to give the desired compounds.
Synthetic chemistry transformations and protecting group
methodologies (protection and deprotection) useful in synthesizing
the compounds described herein are known in the art and include,
for example, those such as described in R. Larock, Comprehensive
Organic Transformations, 2.sup.nd Ed. Wiley-VCH (1999); T. W.
Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis,
3rd Ed., John Wiley and Sons (1999); L. Fieser and M. Fieser,
Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and
Sons (1994); and L. Paquette, ed., Encyclopedia of Reagents for
Organic Synthesis, John Wiley and Sons (1995), and subsequent
editions thereof.
[0187] The term "subject," as used herein, refers to an animal.
Preferably, the animal is a mammal. More preferably, the mammal is
a human. A subject also refers to, for example, dogs, cats, horses,
cows, pigs, guinea pigs, fish, birds and the like.
[0188] The compounds of this invention may be modified by appending
appropriate functionalities to enhance selective biological
properties. Such modifications are known in the art and may include
those which increase biological penetration into a given biological
system (e.g., blood, lymphatic system, central nervous system),
increase oral availability, increase solubility to allow
administration by injection, alter metabolism and alter rate of
excretion.
[0189] The compounds described herein contain one or more
asymmetric centers and thus give rise to enantiomers,
diastereomers, and other stereoisomeric forms that may be defined,
in terms of absolute stereochemistry, as (R)- or (S)-, or as (D)-
or (L)- for amino acids. The present invention is meant to include
all such possible isomers, as well as their racemic and optically
pure forms. Optical isomers may be prepared from their respective
optically active precursors by the procedures described above, or
by resolving the racemic mixtures. The resolution can be carried
out in the presence of a resolving agent, by chromatography or by
repeated crystallization or by some combination of these techniques
which are known to those skilled in the art. Further details
regarding resolutions can be found in Jacques, et al., Enantiomers,
Racemates, and Resolutions (John Wiley & Sons, 1981). When the
compounds described herein contain olefinic double bonds, other
unsaturation, or other centers of geometric asymmetry, and unless
specified otherwise, it is intended that the compounds include both
E and Z geometric isomers or cis- and trans-isomers. Likewise, all
tautomeric forms are also intended to be included. Tautomers may be
in cyclic or acyclic. The configuration of any carbon-carbon double
bond appearing herein is selected for convenience only and is not
intended to designate a particular configuration unless the text so
states; thus a carbon-carbon double bond or carbon-heteroatom
double bond depicted arbitrarily herein as trans may be cis, trans,
or a mixture of the two in any proportion.
[0190] Certain compounds of the present invention may also exist in
different stable conformational forms which may be separable.
Torsional asymmetry due to restricted rotation about an asymmetric
single bond, for example because of steric hindrance or ring
strain, may permit separation of different conformers. The present
invention includes each conformational isomer of these compounds
and mixtures thereof.
[0191] As used herein, the term "pharmaceutically acceptable salt,"
refers to those salts which are, within the scope of sound medical
judgment, suitable for use in contact with the tissues of humans
and lower animals without undue toxicity, irritation, allergic
response and the like, and are commensurate with a reasonable
benefit/risk ratio. Pharmaceutically acceptable salts are well
known in the art. For example, S. M. Berge, et al. describes
pharmaceutically acceptable salts in detail in J. Pharmaceutical
Sciences, 66: 2-19 (1977). The salts can be prepared in situ during
the final isolation and purification of the compounds of the
invention, or separately by reacting the free base function with a
suitable organic acid. Examples of pharmaceutically acceptable
salts include, but are not limited to, nontoxic acid addition salts
are salts of an amino group formed with inorganic acids such as
hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid
and perchloric acid or with organic acids such as acetic acid,
maleic acid, tartaric acid, citric acid, succinic acid or malonic
acid or by using other methods used in the art such as ion
exchange. Other pharmaceutically acceptable salts include, but are
not limited to, adipate, alginate, ascorbate, aspartate,
benzenesulfonate, benzoate, bisulfate, borate, butyrate,
camphorate, camphorsulfonate, citrate, cyclopentane-propionate,
digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate,
glucoheptonate, glycerophosphate, gluconate, hemisulfate,
heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate,
lactobionate, lactate, laurate, lauryl sulfate, malate, maleate,
malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate,
nitrate, oleate, oxalate, palmitate, pamoate, pectinate,
persulfate, 3-phenylpropionate, phosphate, picrate, pivalate,
propionate, stearate, succinate, sulfate, tartrate, thiocyanate,
p-toluenesulfonate, undecanoate, valerate salts, and the like.
Representative alkali or alkaline earth metal salts include sodium,
lithium, potassium, calcium, magnesium, and the like. Further
pharmaceutically acceptable salts include, when appropriate,
nontoxic ammonium, quaternary ammonium, and amine cations formed
using counterions such as halide, hydroxide, carboxylate, sulfate,
phosphate, nitrate, alkyl having from 1 to 6 carbon atoms,
sulfonate and aryl sulfonate.
[0192] As used herein, the term "pharmaceutically acceptable ester"
refers to esters which hydrolyze in vivo and include those that
break down readily in the human body to leave the parent compound
or a salt thereof. Suitable ester groups include, for example,
those derived from pharmaceutically acceptable aliphatic carboxylic
acids, particularly alkanoic, alkenoic, cycloalkanoic and
alkanedioic acids, in which each alkyl or alkenyl moiety
advantageously has not more than 6 carbon atoms. Examples of
particular esters include, but are not limited to, formates,
acetates, propionates, butyrates, acrylates and
ethylsuccinates.
Pharmaceutical Compositions
[0193] The pharmaceutical compositions of the present invention
comprise a therapeutically effective amount of a compound of the
present invention formulated together with one or more
pharmaceutically acceptable carriers or excipients.
[0194] As used herein, the term "pharmaceutically acceptable
carrier or excipient" means a non-toxic, inert solid, semi-solid or
liquid filler, diluent, encapsulating material or formulation
auxiliary of any type. Some examples of materials which can serve
as pharmaceutically acceptable carriers are sugars such as lactose,
glucose and sucrose; starches such as corn starch and potato
starch; cellulose and its derivatives such as sodium carboxymethyl
cellulose, ethyl cellulose and cellulose acetate; powdered
tragacanth; malt; gelatin; talc; excipients such as cocoa butter
and suppository waxes; oils such as peanut oil, cottonseed oil,
safflower oil, sesame oil, olive oil, corn oil and soybean oil;
glycols such as propylene glycol; esters such as ethyl oleate and
ethyl laurate; agar; buffering agents such as magnesium hydroxide
and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic
saline; Ringer's solution; ethyl alcohol, and phosphate buffer
solutions, as well as other non-toxic compatible lubricants such as
sodium lauryl sulfate and magnesium stearate, as well as coloring
agents, releasing agents, coating agents, sweetening, flavoring and
perfuming agents, preservatives and antioxidants can also be
present in the composition, according to the judgment of the
formulator.
[0195] The pharmaceutical compositions of this invention may be
administered orally, parenterally, by inhalation spray, topically,
rectally, nasally, buccally, vaginally or via an implanted
reservoir, preferably by oral administration or administration by
injection. The pharmaceutical compositions of this invention may
contain any conventional non-toxic pharmaceutically-acceptable
carriers, adjuvants or vehicles. In some cases, the pH of the
formulation may be adjusted with pharmaceutically acceptable acids,
bases or buffers to enhance the stability of the formulated
compound or its delivery form. The term parenteral as used herein
includes subcutaneous, intracutaneous, intravenous, intramuscular,
intraarticular, intra-arterial, intrasynovial, intrasternal,
intrathecal, intralesional and intracranial injection or infusion
techniques.
[0196] Liquid dosage forms for oral administration include
pharmaceutically acceptable emulsions, microemulsions, solutions,
suspensions, syrups and elixirs. In addition to the active
compounds, the liquid dosage forms may contain inert diluents
commonly used in the art such as, for example, water or other
solvents, solubilizing agents and emulsifiers such as ethyl
alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl
alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol,
dimethylformamide, oils (in particular, cottonseed, groundnut,
corn, germ, olive, castor, and sesame oils), glycerol,
tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid
esters of sorbitan, and mixtures thereof. Besides inert diluents,
the oral compositions can also include adjuvants such as wetting
agents, emulsifying and suspending agents, sweetening, flavoring,
and perfuming agents.
[0197] Injectable preparations, for example, sterile injectable
aqueous or oleaginous suspensions, may be formulated according to
the known art using suitable dispersing or wetting agents and
suspending agents. The sterile injectable preparation may also be a
sterile injectable solution, suspension or emulsion in a nontoxic
parenterally acceptable diluent or solvent, for example, as a
solution in 1,3-butanediol. Among the acceptable vehicles and
solvents that may be employed are water, Ringer's solution, U.S.P.
and isotonic sodium chloride solution. In addition, sterile, fixed
oils are conventionally employed as a solvent or suspending medium.
For this purpose, any bland fixed oil can be employed including
synthetic mono- or diglycerides. In addition, fatty acids such as
oleic acid are used in the preparation of injectable.
[0198] The injectable formulations can be sterilized, for example,
by filtration through a bacterial-retaining filter, or by
incorporating sterilizing agents in the form of sterile solid
compositions which can be dissolved or dispersed in sterile water
or other sterile injectable medium prior to use.
[0199] In order to prolong the effect of a drug, it is often
desirable to slow the absorption of the drug from subcutaneous or
intramuscular injection. This may be accomplished by the use of a
liquid suspension of crystalline or amorphous material with poor
water solubility. The rate of absorption of the drug then depends
upon its rate of dissolution, which, in turn, may depend upon
crystal size and crystalline form. Alternatively, delayed
absorption of a parenterally administered drug form is accomplished
by dissolving or suspending the drug in an oil vehicle.
[0200] Injectable depot forms are made by forming microencapsule
matrices of the drug in biodegradable polymers such as
polylactide-polyglycolide. Depending upon the ratio of drug to
polymer and the nature of the particular polymer employed, the rate
of drug release can be controlled. Examples of other biodegradable
polymers include poly(orthoesters) and poly(anhydrides). Depot
injectable formulations are also prepared by entrapping the drug in
liposomes or microemulsions that are compatible with body
tissues.
[0201] Compositions for rectal or vaginal administration are
preferably suppositories which can be prepared by mixing the
compounds of this invention with suitable non-irritating excipients
or carriers such as cocoa butter, polyethylene glycol or a
suppository wax which are solid at ambient temperature but liquid
at body temperature and therefore melt in the rectum or vaginal
cavity and release the active compound.
[0202] Solid dosage forms for oral administration include capsules,
tablets, pills, powders, and granules. In such solid dosage forms,
the active compound is mixed with at least one inert,
pharmaceutically acceptable excipient or carrier such as sodium
citrate or dicalcium phosphate and/or: a) fillers or extenders such
as starches, lactose, sucrose, glucose, mannitol, and silicic acid,
b) binders such as, for example, carboxymethylcellulose, alginates,
gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants
such as glycerol, d) disintegrating agents such as agar-agar,
calcium carbonate, potato or tapioca starch, alginic acid, certain
silicates, and sodium carbonate, e) solution retarding agents such
as paraffin, f) absorption accelerators such as quaternary ammonium
compounds, g) wetting agents such as, for example, cetyl alcohol
and glycerol monostearate, h) absorbents such as kaolin and
bentonite clay, and i) lubricants such as talc, calcium stearate,
magnesium stearate, solid polyethylene glycols, sodium lauryl
sulfate, and mixtures thereof. In the case of capsules, tablets and
pills, the dosage form may also comprise buffering agents.
[0203] Solid compositions of a similar type may also be employed as
fillers in soft and hard-filled gelatin capsules using such
excipients as lactose or milk sugar as well as high molecular
weight polyethylene glycols and the like.
[0204] The solid dosage forms of tablets, dragees, capsules, pills,
and granules can be prepared with coatings and shells such as
enteric coatings and other coatings well known in the
pharmaceutical formulating art. They may optionally contain
opacifying agents and can also be of a composition that they
release the active ingredient(s) only, or preferentially, in a
certain part of the intestinal tract, optionally, in a delayed
manner. Examples of embedding compositions that can be used include
polymeric substances and waxes.
[0205] Dosage forms for topical or transdermal administration of a
compound of this invention include ointments, pastes, creams,
lotions, gels, powders, solutions, sprays, inhalants or
patches.
[0206] The active component is admixed under sterile conditions
with a pharmaceutically acceptable carrier and any needed
preservatives or buffers as may be required. Ophthalmic
formulation, ear drops, eye ointments, powders and solutions are
also contemplated as being within the scope of this invention.
[0207] The ointments, pastes, creams and gels may contain, in
addition to an active compound of this invention, excipients such
as animal and vegetable fats, oils, waxes, paraffins, starch,
tragacanth, cellulose derivatives, polyethylene glycols, silicones,
bentonites, silicic acid, talc and zinc oxide, or mixtures
thereof.
[0208] Powders and sprays can contain, in addition to the compounds
of this invention, excipients such as lactose, talc, silicic acid,
aluminum hydroxide, calcium silicates and polyamide powder, or
mixtures of these substances. Sprays can additionally contain
customary propellants such as chlorofluorohydrocarbons.
[0209] Transdermal patches have the added advantage of providing
controlled delivery of a compound to the body. Such dosage forms
can be made by dissolving or dispensing the compound in the proper
medium. Absorption enhancers can also be used to increase the flux
of the compound across the skin. The rate can be controlled by
either providing a rate controlling membrane or by dispersing the
compound in a polymer matrix or gel.
[0210] For pulmonary delivery, a therapeutic composition of the
invention is formulated and administered to the patient in solid or
liquid particulate form by direct administration e.g., inhalation
into the respiratory system. Solid or liquid particulate forms of
the active compound prepared for practicing the present invention
include particles of respirable size: that is, particles of a size
sufficiently small to pass through the mouth and larynx upon
inhalation and into the bronchi and alveoli of the lungs. Delivery
of aerosolized therapeutics, particularly aerosolized antibiotics,
is known in the art (see, for example U.S. Pat. No. 5,767,068 to
Van Devanter et al., U.S. Pat. No. 5,508,269 to Smith et al., and
WO 98/43650 by Montgomery, all of which are incorporated herein by
reference).
Antiviral Activity
[0211] In certain embodiments, the present invention provides a
method of treating or preventing a viral infection in a subject in
need thereof, comprising administering to the subject a
therapeutically effective amount of a compound of Formula (I) or a
pharmaceutically acceptable salt thereof. The viral infection is
preferably a coronavirus infection. In certain embodiments, the
coronavirus is SARS-CoV-1, SARS-CoV-2, or MERS-CoV. Preferably the
coronavirus is SARS-CoV-2.
[0212] A viral inhibitory amount or dose of the compounds of the
present invention may range from about 0.01 mg/Kg to about 500
mg/Kg, alternatively from about 1 to about 50 mg/Kg. Inhibitory
amounts or doses will also vary depending on route of
administration, as well as the possibility of co-usage with other
agents.
[0213] According to the methods of treatment of the present
invention, viral infections are treated or prevented in a patient
such as a human or another animal by administering to the patient a
therapeutically effective amount of a compound of the invention, in
such amounts and for such time as is necessary to achieve the
desired result.
[0214] By a "therapeutically effective amount" of a compound of the
invention is meant an amount of the compound which confers a
therapeutic effect on the treated subject, at a reasonable
benefit/risk ratio applicable to any medical treatment. The
therapeutic effect may be objective (i.e., measurable by some test
or marker) or subjective (i.e., subject gives an indication of or
feels an effect). A therapeutically effective amount of the
compound described above may range, for example, from about 0.1
mg/Kg to about 500 mg/Kg, preferably from about 1 to about 50
mg/Kg. Effective doses will also vary depending on route of
administration, as well as the possibility of co-usage with other
agents. It will be understood, however, that the total daily usage
of the compounds and compositions of the present invention will be
decided by the attending physician within the scope of sound
medical judgment. The specific therapeutically effective dose level
for any particular patient will depend upon a variety of factors
including the disorder being treated and the severity of the
disorder; the activity of the specific compound employed; the
specific composition employed; the age, body weight, general
health, sex and diet of the patient; the time of administration,
route of administration, and rate of excretion of the specific
compound employed; the duration of the treatment; drugs used in
combination or contemporaneously with the specific compound
employed; and like factors well known in the medical arts.
[0215] The total daily dose of the compounds of this invention
administered to a human or other animal in single or in divided
doses can be in amounts, for example, from 0.01 to 50 mg/kg body
weight or more usually from 0.1 to 25 mg/kg body weight. Single
dose compositions may contain such amounts or submultiples thereof
to make up the daily dose. In general, treatment regimens according
to the present invention comprise administration to a patient in
need of such treatment from about 10 mg to about 1000 mg of the
compound(s) of this invention per day in single or multiple
doses.
[0216] The compounds of the present invention described herein can,
for example, be administered by injection, intravenously,
intra-arterial, subdermally, intraperitoneally, intramuscularly, or
subcutaneously; or orally, buccally, nasally, transmucosally,
topically, in an ophthalmic preparation, or by inhalation, with a
dosage ranging from about 0.1 to about 500 mg/kg of body weight,
alternatively dosages between 1 mg and 1000 mg/dose, every 4 to 120
hours, or according to the requirements of the particular drug. The
methods herein contemplate administration of an effective amount of
compound or compound composition to achieve the desired or stated
effect. Typically, the pharmaceutical compositions of this
invention will be administered from about 1 to about 6 times per
day or alternatively, as a continuous infusion. Such administration
can be used as a chronic or acute therapy. The amount of active
ingredient that may be combined with pharmaceutically excipients or
carriers to produce a single dosage form will vary depending upon
the host treated and the particular mode of administration. A
typical preparation will contain from about 5% to about 95% active
compound (w/w). Alternatively, such preparations may contain from
about 20% to about 80% active compound.
[0217] Lower or higher doses than those recited above may be
required. Specific dosage and treatment regimens for any particular
patient will depend upon a variety of factors, including the
activity of the specific compound employed, the age, body weight,
general health status, sex, diet, time of administration, rate of
excretion, drug combination, the severity and course of the
disease, condition or symptoms, the patient's disposition to the
disease, condition or symptoms, and the judgment of the treating
physician.
[0218] Upon improvement of a patient's condition, a maintenance
dose of a compound, composition or combination of this invention
may be administered, if necessary. Subsequently, the dosage or
frequency of administration, or both, may be reduced, as a function
of the symptoms, to a level at which the improved condition is
retained when the symptoms have been alleviated to the desired
level. Patients may, however, require intermittent treatment on a
long-term basis upon any recurrence of disease symptoms.
Combination and Alternation Therapy
[0219] The compounds of the present invention may be used in
combination with one or more antiviral therapeutic agents or
anti-inflammatory agents useful in the prevention or treatment of
viral diseases or associated pathophysiology. Thus, the compounds
of the present invention and their salts, solvates, or other
pharmaceutically acceptable derivatives thereof, may be employed
alone or in combination with other antiviral or anti-inflammatory
therapeutic agents. The compounds herein and pharmaceutically
acceptable salts thereof may be used in combination with one or
more other agents which may be useful in the prevention or
treatment of respiratory disease, inflammatory disease, autoimmune
disease, for example; anti-histamines, corticosteroids, (e.g.,
fluticasone propionate, fluticasone furoate, beclomethasone
dipropionate, budesonide, ciclesonide, mometasone furoate,
triamcinolone, flunisolide), NSAIDs, Ieukotriene modulators (e.g.,
montelukast, zafirlukast.pranlukast), tryptase inhibitors, IKK2
inhibitors, p38 inhibitors, Syk inhibitors, protease inhibitors
such as elastase inhibitors, integrin antagonists (e.g., beta-2
integrin antagonists), adenosine A2a agonists, mediator release
inhibitors such as sodium chromoglycate, 5-lipoxygenase inhibitors
(zyflo), DP1 antagonists, DP2 antagonists, PI3K delta inhibitors,
ITK inhibitors, LP (Iysophosphatidic) inhibitors or FLAP
(5-lipoxygenase activating protein) inhibitors (e.g., sodium
3-(3-(tert-butylthio)-1-(4-(6-ethoxypyridin-3-yl)benzyl)-5-((5-eth-
ylpyridin-2-yl)methoxy)-1H-indol-2-yl)-2,2-dimethylpropanoate),
bronchodilators (e.g., muscarinic antagonists, beta-2 agonists),
methotrexate, and similar agents; monoclonal antibody therapy such
as anti-lgE, anti-TNF, anti-IL-5, anti-IL-6, anti-IL-12, anti-IL-1
and similar agents; cytokine receptor therapies e.g. etanercept and
similar agents; antigen non-specific immunotherapies (e.g.,
interferon or other cytokines/chemokines, chemokine receptor
modulators such as CCR3, CCR4 or CXCR2 antagonists, other
cytokine/chemokine agonists or antagonists, TLR agonists and
similar agents), suitable anti-infective agents including
antibiotic agents, antifungal agents, antheimintic agents,
antimalarial agents, antiprotozoal agents, antitubercuiosis agents,
and antiviral agents, including those listed at
https://www.drugs.com/drug-class/anti-infectives.html. In general,
combination therapy is typically preferred over alternation therapy
because it induces multiple simultaneous stresses on the virus.
[0220] When the compositions of this invention comprise a
combination of a compound of the Formula described herein and one
or more additional therapeutic or prophylactic agents, both the
compound and the additional agent should be present at dosage
levels of between about 1 to 100%, and more preferably between
about 5 to 95% of the dosage normally administered in a monotherapy
regimen. The additional agents may be administered separately, as
part of a multiple dose regimen, from the compounds of this
invention. Alternatively, those agents may be part of a single
dosage form, combined with a compound of this invention in a single
composition.
[0221] The "additional therapeutic or prophylactic agents" include
but are not limited to, immune therapies (e.g. interferon),
therapeutic vaccines, antifibrotic agents, anti-inflammatory agents
such as corticosteroids or NSAIDs, bronchodilators such as beta-2
adrenergic agonists and xanthines (e.g. theophylline), mucolytic
agents, anti-muscarinics, anti-leukotrienes, inhibitors of cell
adhesion (e.g. ICAM antagonists), anti-oxidants (e.g.
N-acetylcysteine), cytokine agonists, cytokine antagonists, lung
surfactants and/or antimicrobial and anti-viral agents (e.g.
ribavirin and amantidine). The compositions according to the
invention may also be used in combination with gene replacement
therapy.
Abbreviations
[0222] Abbreviations which may be used in the descriptions of the
scheme and the examples that follow are: Ac for acetyl; AcOH for
acetic acid; Boc.sub.2O for di-tert-butyl-dicarbonate; Boc for
t-butoxycarbonyl; Bz for benzoyl; Bn for benzyl; t-BuOK for
potassium tert-butoxide; Brine for sodium chloride solution in
water; CDI for carbonyldiimidazole; DCM or CH.sub.2C.sub.2 for
dichloromethane; CH.sub.3 for methyl; CH.sub.3CN for acetonitrile;
C.sub.s2CO.sub.3 for cesium carbonate; CuCl for copper (I)
chloride; CuI for copper (I) iodide; dba for dibenzylidene acetone;
DBU for 1,8-diazabicyclo[5.4.0]-undec-7-ene; DEAD for
diethylazodicarboxylate; DIAD for diisopropyl azodicarboxylate;
DIPEA or (i-Pr).sub.2EtN for N,N,-diisopropylethyl amine; DMP or
Dess-Martin periodinane for
1,1,2-tris(acetyloxy)-1,2-dihydro-1,2-benziodoxol-3-(1H)-one; DMAP
for 4-dimethylamino-pyridine; DME for 1,2-dimethoxyethane; DMF for
N,N-dimethylformamide; DMSO for dimethyl sulfoxide; EtOAc for ethyl
acetate; EtOH for ethanol; Et.sub.2O for diethyl ether; HATU for
O-(7-azabenzotriazol-2-yl)-N,N,N',N',-tetramethyluronium
Hexafluoro-phosphate; HCl for hydrogen chloride; K.sub.2CO.sub.3
for potassium carbonate; n-BuLi for n-butyl lithium; DDQ for
2,3-dichloro-5,6-dicyano-1,4-benzoquinone; LDA for lithium
diisopropylamide; LiTMP for lithium
2,2,6,6-tetramethyl-piperidinate; MeOH for methanol; Mg for
magnesium; MOM for methoxymethyl; Ms for mesyl or
--SO.sub.2--CH.sub.3; NaHMDS for sodium bis(trimethylsilyl)amide;
NaCl for sodium chloride; NaH for sodium hydride; NaHCO.sub.3 for
sodium bicarbonate or sodium hydrogen carbonate; Na.sub.2CO.sub.3
sodium carbonate; NaOH for sodium hydroxide; Na.sub.2SO.sub.4 for
sodium sulfate; NaHSO.sub.3 for sodium bisulfite or sodium hydrogen
sulfite; Na.sub.2S203 for sodium thiosulfate; NH.sub.2NH.sub.2 for
hydrazine; NH.sub.4C.sub.1 for ammonium chloride; Ni for nickel; OH
for hydroxyl; OsO.sub.4 for osmium tetroxide; OTf for triflate; PPA
for polyphosphoric acid; PTSA for p-toluenesulfonic acid; PPTS for
pyridinium p-toluenesulfonate; TBAF for tetrabutylammonium
fluoride; TEA or Et.sub.3N for triethylamine; TES for
triethylsilyl; TESCl for triethylsilyl chloride; TESOTf for
triethylsilyl trifluoromethanesulfonate; TFA for trifluoroacetic
acid; THE for tetrahydrofuran; TMEDA for
N,N,N',N'-tetramethylethylene-diamine; TPP or PPh.sub.3 for
triphenyl-phosphine; Tos or Ts for tosyl or
--SO.sub.2--C.sub.6H.sub.4CH.sub.3; Ts.sub.2O for tolylsulfonic
anhydride or tosyl-anhydride; TsOH for p-tolylsulfonic acid; Pd for
palladium; Ph for phenyl; Pd.sub.2(dba).sub.3 for
tris(diben-zylideneacetone) dipalladium (0); Pd(PPh.sub.3).sub.4
for tetrakis(triphenylphosphine)-palladium (0);
PdCl.sub.2(PPh.sub.3).sub.2 for
trans-dichlorobis-(triphenylphosphine)palladium (II); Pt for
platinum; Rh for rhodium; rt for room temperature; Ru for
ruthenium; TBS for tert-butyl dimethylsilyl; TMS for
trimethylsilyl; and TMSCl for trimethylsilyl chloride.
Synthetic Methods
[0223] The compounds and processes of the present invention will be
better understood in connection with the following synthetic
schemes that illustrate the methods by which the compounds of the
invention may be prepared, which are intended as an illustration
only and not to limit the scope of the invention. Various changes
and modifications to the disclosed embodiments will be apparent to
those skilled in the art and such changes and modifications
including, without limitation, those relating to the chemical
structures, substituents, derivatives, and/or methods of the
invention may be made without departing from the spirit of the
invention and the scope of the appended claims.
##STR00062## ##STR00063##
[0224] Scheme 1 illustrates a general method to prepare the
compound of formular (IV-1) from the amino ester compound (X-1),
wherein B is as previously defined and PG.sub.1 is C.sub.1-C.sub.4
alkyl or Bn. Treatment of amine (X-1) with formaldehyde affords the
cyclized amine (X-2), which is converted to (X-3) using appropriate
protecting group PG.sub.2 (e.g. Boc). Treatment of (X-3) with NBS
in solvents containing AcOH at low temperature provides the
rearranged spiral proline derivative (X-4). Examples of this
sequence of transformation has been reported in literature
(Pellegrini C. et al. "Synthesis of the Oxindole Alkaloid
(-)-Horsfiline" Tetrahedron Asymmetry, 1994, vol. 5, No. 10, pp
1979-1992; Efremov, I. V. et al. "Discovery and Optimization of a
Novel Spiropyrrolidine Inhibitor of .beta.-Secretase (BACE1)
through Fragment-Based Drug Design" Journal of Medicinal Chemistry,
2012, 55, 9069-9088). Treatment of ester (X-4) with NH.sub.3 (e. g.
ammonia in MeOH, NH.sub.3OH, etc.) affords the amide compound
(X-5), which is converted to amine compound (X-6) by removal of
protecting group PG.sub.2 (e.g. TFA, HCl, etc). Condensation of the
amine (X-6) with acid (X-7) wherein A, R.sub.1, R.sub.2, and
R.sub.3 are previously defined, under amide coupling conditions
(e.g. HATU, EDC, DCC, etc) provides amide compound (X-8). Amide
(X-8) is converted to the nitrile compound (IV-1) under dehydration
conditions, such as TFAA/Et.sub.3N, or
Pd(OCOCF.sub.3).sub.2/Cl.sub.2CHCN.
[0225] Alternatively, condensation of the amine (X-6) with acid
(X-9) wherein R.sub.1, R.sub.2, and R.sub.3 are previously defined
and PG.sub.3 is appropriate protecting group (e.g. Cbz), under
amide coupling conditions (e.g. HATU, EDC, DCC, etc) provides amide
compound (X-10). Removal of PG.sub.3 (e.g. hydrogenation) affords
amine compound (X-11). Condensation of amine (X-11) with acid
(A-COOH) wherein A is previously defined, under amide coupling
conditions (e.g. HATU, EDC, DCC, etc) or acylhalide generating
conditions (e.g. Ghosez's reagent), provides amide compound
(X-8)
##STR00064##
Scheme 2 illustrates a general method to synthesize the aldehyde
compound of formula (IV-2), wherein A, R.sub.1, R.sub.2, R.sub.3,
and B are previously defined. The ester compound of formula (X-4),
wherein B, PG.sub.1 and PG.sub.2 are previously defined, is reduced
to the alcohol compound (XI-1) employing reducing reagents such as,
but not limited to, LiBH.sub.4, NaBH.sub.4, or DIBAL-H. The
protecting group PG.sub.2 (e.g. Boc) of (XI-1) is removed under
acidic conditions using such as TFA, HCl, formic acid,
TMSOTf/lutidine, etc. Coupling of the amine compound (XI-2) with
the acid compound (X-7) wherein A, R.sub.1, R.sub.2, and R.sub.3
are previously defined, using coupling reagents such as HATU, EDC,
or DCC, provides compound (XI-3). Oxidation of the alcohol of
(XI-3) with mild oxidation reagents such as DMSO/Ac.sub.2O,
Dess-Martin periodinane, IBX, SO.sub.3-pyridine/DMSO/Et.sub.3N,
produces the aldehyde compound (IV-2).
##STR00065## ##STR00066##
Scheme 3 illustrates a general method to synthesize the
hydroxymethylketone compound of formula (IV-3). Hydrolysis of the
ester compound (X-4), wherein B, PG.sub.1 and PG.sub.2 are
previously defined, provides the acid compound (XII-1). Amide
(XII-2) can be obtained from the acid compound (XII-1) by coupling
with N,O-dimethylhydroxyamine using reagents such as HATU, EDC,
DCC, etc. Treatment of amide (XII-2) at low temperature (e.g.
-60.degree. C.) with an organometallic reagent generated by
BOM-C.sub.1, Mg, and HgCl.sub.2 affords the ketone compound
(XII-3). Removal of PG.sub.2 (e.g. PTSA if PG.sub.2 is BOC)
provides amine compound (XII-4). Coupling of amine (XII-4) with
acid (X-7), wherein A, R.sub.1, R.sub.2, and R.sub.3 are previously
defined, affords compound (XII-5) using amide coupling reagents
such as HATU, EDC, DCC, etc. Removal of the benzyl group in (XII-5)
under hydrogenation conditions (Pd/C, H.sub.2) provides compound of
formula (IV-3).
##STR00067##
Scheme 4 illustrates a general method to synthesize the
chloromethylketone compound of formula (IV-4). Treatment of the
ester compound (X-4) with an organometallic reagent generated by
ICH.sub.2Cl and appropriate base, such as LDA, MeLi/LiBr, or BuLi,
provides the chloroketone compound (XIII-1). Removal of PG.sub.2
(e.g. PTSA if PG.sub.2 is BOC) provides amine compound (XIII-2).
Coupling of amine (XIII-2) with acid (X-7), wherein A, R.sub.1,
R.sub.2, and R.sub.3 are previously defined, affords compound
(IV-4) using coupling reagents such as HATU, EDC, DCC, etc.
##STR00068##
Scheme 5 illustrates a general method to synthesize the
fluoromethylketone compound of formula (IV-5). Removal of the Bn
group of compound (XII-3) with Pd-catalyzed hydrogenation provides
alcohol compound (XIV-1). Alcohol (XIV-1) is converted to
fluoromethylketone compound (XIV-2) under conditions such as
SF.sub.4, Tf.sub.2O/lutidine/TBAF,
C.sub.4F.sub.9SO.sub.2F/HF-Et.sub.3N, etc. Removal of PG.sub.2
(e.g. PTSA if PG.sub.2 is BOC) provides amine compound (XIV-3).
Coupling of amine (XIV-3) with acid (X-7), wherein A, R.sub.2, and
R.sub.3 are previously defined, affords compound (IV-5) using amide
coupling reagents such as HATU, EDC, DCC, etc.
##STR00069##
Scheme 6 illustrates a general method to synthesize the
.alpha.-ketoamide compound of formula (IV-6). Treatment of the
aldehyde compound of formula (IV-2), wherein A, R.sub.1, R.sub.2,
R.sub.3, and B are previously defined, with isonitrile compound
(XV-1), wherein R.sub.13 is previously defined, affords
.alpha.-hydroxylamide (XV-2). Oxidation of compound (XV-2) with
appropriate oxidants such as Dess-Martin periodinane,
(COCl).sub.2/DMSO/Et.sub.3N, PCC, SO.sub.3-pyridine/DMSO/Et.sub.3N,
affords .alpha.-ketoamide of formula (IV-6').
##STR00070##
Alternatively, nitrile compound (IV-1) can be synthesized from
aldehyde compound (IV-2) using the method shown in Scheme 7.
Condensation of aldehyde (IV-2) with hydroxyamine hydrochloride in
appropriate solvents such as DMSO, i-PrOH, pyridine, etc. provides
oxime compound (XVI-1). Treatment of the oxime compound (XVI-1)
under acid-catalyzed dehydration conditions such as
(Cu(OAc).sub.2/MeCN, HCl, etc.) affords the nitrile compound
(IV-1).
##STR00071##
Scheme 8 illustrates a general method to synthesize functionalized
spirocycles of formula XX-2 (Qi defined as halogen or optionally
substituted alkyl). Treatment of the spirocyclic compound of
formula XX-1, wherein B, PG.sub.1, and PG.sub.2 are previously
defined, with an electrophilic reagent, including, but not limited
to: sulfuryl chloride, N-chlorosuccinimide, N-bromosuccinimide,
SelectFluor, or NFSI, can provide functionalized spirocycle
XX-2.
EXAMPLES
[0226] The compounds and processes of the present invention will be
better understood in connection with the following examples, which
are intended as an illustration only and not limiting of the scope
of the invention. Starting materials were either available from a
commercial vendor or produced by methods well known to those
skilled in the art.
General Conditions:
[0227] Mass spectra were run on LC-MS systems using electrospray
ionization. These were Agilent 1290 Infinity II systems with an
Agilent 6120 Quadrupole detector. Spectra were obtained using a
ZORBAX Eclipse XDB-C18 column (4.6.times.30 mm, 1.8 micron).
Spectra were obtained at 298K using a mobile phase of 0.1% formic
acid in water (A) and 0.1% formic acid in acetonitrile (B). Spectra
were obtained with the following solvent gradient: 5% (B) from
0-1.5 min, 5-95% (B) from 1.5-4.5 min, and 95% (B) from 4.5-6 min.
The solvent flowrate was 1.2 mL/min. Compounds were detected at 210
nm and 254 nm wavelengths. [M+H].sup.+ refers to mono-isotopic
molecular weights.
[0228] NMR spectra were run on a Bruker 400 MHz spectrometer.
Spectra were measured at 298K and referenced using the solvent
peak. Chemical shifts for .sup.1H NMR are reported in parts per
million (ppm).
[0229] Compounds were purified via reverse-phase high-performance
liquid chromatography (RPHPLC) using a Gilson GX-281 automated
liquid handling system. Compounds were purified on a Phenomenex
Kinetex EVO C18 column (250.times.21.2 mm, 5 micron), unless
otherwise specified. Compounds were purified at 298K using a mobile
phase of water (A) and acetonitrile (B) using gradient elution
between 0% and 100% (B), unless otherwise specified. The solvent
flowrate was 20 mL/min and compounds were detected at 254 nm
wavelength.
[0230] Alternatively, compounds were purified via normal-phase
liquid chromatography (NPLC) using a Teledyne ISCO Combiflash
purification system. Compounds were purified on a REDISEP silica
gel cartridge. Compounds were purified at 298K and detected at 254
nm wavelength.
Example 1
##STR00072## ##STR00073##
[0231] Step 1-1
[0232] methyl
(S)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylate
hydrochloride (500 mg, 1.875 mmol) was dissolved in
CH.sub.2Cl.sub.2 (10 ml). Triethylamine (523 .mu.l, 3.75 mmol) and
a 2.0 M solution of di-tert-butyl dicarbonate in DCM (1031 .mu.l,
2.062 mmol) was added. The mixture was stirred at rt for 3 h,
quenched with sat. NaHCO.sub.3, and extracted with DCM. The organic
layer was washed with brine, dried over MgSO.sub.4, and
concentrated in vacuo. Purification of the residue on silica gel
with 0-30% EtOAc/cyclohexane provided compound (1-1) (578 mg, 1.749
mmol, 93% yield).
Step 1-2
[0233] Compound (1-1) was dissolved in THE (15 ml), AcOH (10 ml),
and water (10 ml). The solution was cooled to -15.degree. C. A
solution of NBS (328 mg, 1.843 mmol) in THE (5 mL) was added
dropwise. The mixture was slowly warmed to 5.degree. C. over 1 h.
The reaction was quenched with Na.sub.2SO.sub.3 and sat.
NaHCO.sub.3, and extracted with DCM (2 x). The organic layer was
washed with brine, dried with MgSO.sub.4, and concentrated in
vacuo. Purification of the residue on silica gel with 0-50%
EtOAc/cyclohexane provided compound (1-2) (328 mg, 0.947 mmol,
53.9% yield).
Step 1-3
[0234] Compound (1-2) (328 mg, 0.947 mmol) was dissolved in MeOH (3
ml). A solution of 7 N ammonia in MeOH (5 mL, 35.0 mmol) was added.
The mixture was stirred at rt for 5 days. Solvent was removed in
vacuo. Purification of the residue on silica gel with 0-10%
MeOH/DCM, and on C18 column with 0-50% MeCN/H.sub.2O provided
compound (1-3) (101 mg, 0.305 mmol, 32.2% yield).
Step 1-4
[0235] Compound (1-3) (100 mg, 0.302 mmol) was dissolved in DCM and
trifluoroacetic acid (232 .mu.l, 3.02 mmol) was added. The mixture
was stirred at 0.degree. C. for 1 h, and at rt for 2 h. DCM (10 mL)
and toluene (10 mL) were added. Solvent was removed in vacuo. The
residue was dissolved in MeOH and 1 M HCl (0.6 mL, 2 eq) was added.
Solvent was removed. The obtained compound (1-4) (91 mg, 0.340
mmol, quantative yield) was used for next step.
Step 1-5
[0236] Compound (1-4) (15 mg, 0.056 mmol) and
((benzyloxy)carbonyl)-L-leucine (14.87 mg, 0.056 mmol) were
dissolved in THE (0.5 ml) and DMF (0.1 ml). DIPEA (30.0 .mu.l,
0.168 mmol) and HATU (21.30 mg, 0.056 mmol) were added. The mixture
was stirred at rt for 20 min, quenched with water, and extracted
with EtOAc (2 x). The organic layer was loaded on silica gel and
eluted with 0-70% acetone/cyclohexane to afford compound (1-5) (15
mg, 0.031 mmol, 55.9% yield).
Step 1-6
[0237] Compound (1-5) (60 mg, 0.125 mmol) was dissolved in DCM
(1.254 ml) (not soluble). Triethylamine (140 .mu.l, 1.003 mmol) and
TFAA (70.8 .mu.l, 0.502 mmol) was added. The mixture was stirred at
rt for 30 min. The reaction was diluted with DCM and quenched with
sat. NaHCO.sub.3. The organic layer was loaded on silica gel and
eluted with 0-50% acetone/cyclohexane, and on prep-HPLC with 20-85%
MeCN/H.sub.2O with 0.1% formic acid to afford Example 1 (14 mg,
0.056 mmol) as a white powder. .sup.1H NMR (400 MHz,
Acetone-d.sub.6) .delta. 9.70 (s, 1H), 7.42-7.31 (m, 5H), 7.28 (td,
J=7.7, 1.3 Hz, 1H), 7.12 (d, J=7.4 Hz, 1H), 7.04-6.96 (m, 2H), 6.65
(d, J=8.3 Hz, 1H), 5.17 (t, J=8.3 Hz, 1H), 5.06-4.94 (m, 2H), 4.48
(td, J=9.0, 5.0 Hz, 1H), 4.26 (d, J=10.4 Hz, 1H), 3.99 (d, J=10.3
Hz, 1H), 2.78-2.63 (m, 2H), 1.80 (dd, J=13.8, 6.9 Hz, 1H),
1.74-1.56 (m, 2H), 0.96 (dd, J=8.7, 6.6 Hz, 6H). [M+Na] m/e
483.18.
[0238] The following examples were prepared employing similar
protocol as described above.
TABLE-US-00001 Example # Structure MS NMR 2 ##STR00074## [M -
H].sup.- 471.16 .sup.1H NMR (400 MHz, Methanol-d.sub.4) .delta.
7.39-7.28 (m, 5H), 7.28 (td, J = 7.7, 1.2 Hz, 1H), 7.11 (d, J = 7.4
Hz, 1H), 7.06-6.93 (m, 2H), 5.14 (t, J = 8.0 Hz, 1H), 5.00 (d, J =
2.4 Hz, 2H), 4.28 (dd, J = 8.2, 6.2 Hz, 1H), 4.18 (d, J = 10.5 Hz,
1H), 3.95 (d, J = 10.5 Hz, 1H), 2.67 (dd, J = 7.9, 1.9 Hz, 2H),
2.44 (p, J = 7.9 Hz, 1H), 2.16-2.05 (m, 3H), 1.97- 1.62 (m, 5H). 3
##STR00075## [M - H].sup.- 459.17 .sup.1H NMR (400 MHz,
Acetone-d.sub.6) .delta. 9.55 (s, 1H), 7.28-7.15 (m, 5H), 7.15-7.07
(m, 1H), 6.89 (d, J = 7.5 Hz, 1H), 6.84 (d, J = 7.8 Hz, 1H), 6.80
(t, J = 7.5 Hz, 1H), 6.40 (d, J = 9.0 Hz, 1H), 5.04 (t, J = 8.4 Hz,
1H), 4.84 (s, 2H), 4.16 (dd, J = 17.5, 9.8 Hz, 2H), 3.95-3.84 (m,
1H), 2.64-2.48 (m, 2H), 0.97 (s, 9H). 4 ##STR00076## [M + Na].sup.+
481.16 .sup.1H NMR (500 MHz, Chloroform-d) .delta. 8.17 (s, 1H),
7.32-7.13 (m, 6H), 6.92- 6.74 (m, 3H), 5.53 (d, J = 8.3 Hz, 1H),
4.96-4.78 (m, 3H), 4.36 (q, J = 7.2 Hz, 1H), 3.92 (dd, J = 49.8,
10.4 Hz, 2H), 2.71 (dd, J = 13.2, 8.7 Hz, 1H), 2.40 (dd, J = 13.2,
8.3 Hz, 1H), 1.55 (ddt, J = 36.2, 13.7, 6.8 Hz, 2H), 0.60 (ddt, J =
10.2, 7.6, 3.7 Hz, 1H), 0.41 (t, J = 7.9 Hz, 2H), 0.00 (d, J = 4.9
Hz, 2H). 5 ##STR00077## [M + Na].sup.+ 497.19 .sup.1H NMR (400 MHz,
Chloroform-d) .delta. 8.26 (s, 1H), 7.32-7.16 (m, 6H), 6.95- 6.82
(m, 3H), 5.35 (d, J = 9.0 Hz, 1H), 5.01-4.73 (m, 3H), 4.41 (td, J =
8.5, 4.7 Hz, 1H), 4.19 (d, J = 10.2 Hz, 1H), 3.90 (d, J = 10.2 Hz,
1H), 2.79 (dd, J = 13.1, 9.0 Hz, 1H), 2.45 (dd, J = 13.1, 8.2 Hz,
1H), 1.72 (dd, J = 14.5, 4.8 Hz, 1H), 1.51 (dd, J = 14.5, 8.2 Hz,
1H), 0.90 (s, 9H). 6 ##STR00078## [M + Na].sup.+ 527.22 .sup.1H NMR
(400 MHz, Chloroform-d) .delta. 8.44 (s, 1H), 7.47-7.28 (m, 6H),
7.05 (t, J = 7.6 Hz, 1H), 6.96 (dd, J = 19.5, 7.7 Hz, 2H), 5.87 (d,
J = 7.9 Hz, 1H), 5.09 (s, 2H), 4.36 (dd, J = 8.0, 3.7 Hz, 1H),
4.21-4.07 (m, 1H), 4.07-3.92 (m, 2H), 2.87 (dd, J = 13.1, 9.0 Hz,
1H), 2.54 (dd, J = 13.1, 8.2 Hz, 1H), 1.23 (s, 9H), 1.21 (d, J =
6.3 Hz, 3H). 7 ##STR00079## [M + Na].sup.+ 501.19 .sup.1H NMR (400
MHz, Chloroform-d) .delta. 8.66 (s, 1H), 7.46-7.20 (m, 6H), 7.07-
6.86 (m, 3H), 5.71 (d, J = 8.3 Hz, 1H), 5.08-4.88 (m, 3H), 4.63
(td, J = 8.1, 4.7 Hz, 1H), 4.26-4.13 (m, 1H), 4.00 (d, J = 10.3 Hz,
1H), 2.83 (dd, J = 13.2, 8.4 Hz, 1H), 2.52 (dd, J = 13.2, 8.3 Hz,
1H), 2.08-1.86 (m, 1H), 1.41 (dd, J = 21.4, 4.6 Hz, 6H), 1.26 (s,
1H). 8 ##STR00080## [M + Na].sup.+ 523.24 .sup.1H NMR (400 MHz,
Acetone-d.sub.6) .delta. 9.69 (s, 1H), 7.38-7.17 (m, 5H), 7.15-7.06
(m, 1H), 7.06-6.92 (m, 2H), 6.56 (d, J = 8.4 Hz, 1H), 5.15 (t, J =
8.3 Hz, 1H), 4.42 (td, J = 9.2, 4.9 Hz, 1H), 4.23 (d, J = 10.3 Hz,
1H), 4.11 (d, J = 11.3 Hz, 1H), 4.10-3.93 (m, 2H), 2.83-2.56 (m,
2H), 1.84-1.53 (m, 3H), 0.94 (m, 8H), 0.92-0.81 (m, 2H). 9
##STR00081## [M - H].sup.- 521, 523 .sup.1H NMR (400 MHz,
Acetone-d.sub.6) .delta. 9.66 (s, 1H), 7.40 (t, J = 1.9 Hz, 1H),
7.38- 7.19 (m, 4H), 6.97 (dd, J = 7.5, 1.2 Hz, 2H), 6.93-6.84 (m,
1H), 6.66 (d, J = 8.7 Hz, 1H), 5.11 (t, J = 8.4 Hz, 1H), 4.35 (td,
J = 9.5, 4.7 Hz, 1H), 4.14 (d, J = 10.4 Hz, 1H), 3.93 (d, J = 10.3
Hz, 1H), 2.68 (m, 2H), 1.80 (m, 1H), 1.66 (m, 7H), 1.58 (m, 1H),
0.98 (d, J = 6.6 Hz, 3H), 0.91 (d, J = 6.5 Hz, 3H). 10 ##STR00082##
[M + Na].sup.+ 513.20
##STR00083## ##STR00084##
Step 1
[0239] 4-methoxy-1H-indole-2-carboxylic acid (1 g, 5.23 mmol) was
dissolved in THE (25 mL). ethyl L-leucinate hydrochloride (1.024 g,
5.23 mmol), hunig'sbase (2.3 mL, 13.08 mmol), DMAP (0.032 g, 0.262
mmol), and HATU (2.0 g, 5.23 mmol) were added sequentially.
[0240] The mixture was stirred at rt for 1.5 h, quenched with
water, and extracted with MTBE. The organic layer was washed with
brine, dried with MgSO.sub.4, and concentrated in vacuo.
Purification of the residue on silica gel with 0-50%
EtOAc/cyclohexane provided compound (11-1) (1.47 g, 4.42 mmol, 85%
yield).
Step 2
[0241] Compound (11-1) (1.47 g, 4.42 mmol) was dissolved in THF
(29.5 mL) and water (14.74 mL). At 0.degree. C. LiOH--H.sub.2O
(0.278 g, 6.63 mmol) was added. The mixture was stirred vigorously
at 0.degree. C. for 30 min, quenched with 1 M HCl (6.6 mL), and
extracted with EtOAc. The organic layer was washed with brine,
dried over MgSO.sub.4, and concentrated in vacuo. Purification of
the residue on silica gel with 0-15% MeOH/DCM provided compound
(11-2) (1.32 g).
Step 3
[0242] Compound (1-4) (50 mg, 0.187 mmol) and compound (11-2) (56.8
mg, 0.187 mmol) was dissolved in THE (1.6 mL) and DMF (0.3 mL).
hunig'sbase (98 .mu.l, 0.560 mmol) and HATU (56.8 mg, 0.149 mmol)
were added. The mixture was stirred at rt for 30 min, quenched with
water, and extracted with EtOAc. The organic layer was loaded on
silica gel and eluted with 0-50% acetone/cyclohexane to provide
compound (11-3) (75 mg, 0.145 mmol, 78% yield) as a mixture of two
diastereomers.
Step 4
[0243] To a suspension of compound (11-3) (67 mg, 0.129 mmol) in
DCM (1.3 mL) was added at 0.degree. C. triethylamine (144 .mu.l,
1.036 mmol) and TFAA (73.1 .mu.l, 0.518 mmol). The mixture was
warmed to rt and stirred for 10 min. The reaction mixture was
diluted with DCM and quenched with sat. NaHCO.sub.3. The organic
layer was loaded on silica gel and eluted with 0-50%
EtOAc/cyclohexane to afford compound (11-4) (48 mg, 0.096 mmol,
74.2% yield) as a mixture of two diastereomers.
Step 5
[0244] Purification of compound (11-4) (5 mg) on prep-HPLC with
20-85% MeCN/H.sub.2O with 0.1% formic acid provided Example 11 (1.8
mg) and Example 12 (1.9 mg).
[0245] Example 11: .sup.1H NMR (400 MHz, Acetone-d.sub.6) .delta.
10.47 (s, 1H), 9.56 (s, 1H), 7.74 (d, J=8.1 Hz, 1H), 7.21 (d, J=2.2
Hz, 1H), 7.10-6.89 (m, 5H), 6.85 (d, J=7.7 Hz, 1H), 6.76 (td,
J=7.5, 1.0 Hz, 1H), 6.41 (dd, J=7.3, 1.1 Hz, 1H), 5.03 (t, J=8.2
Hz, 1H), 4.84-4.74 (m, 1H), 4.23 (d, J=10.2 Hz, 1H), 3.91 (d,
J=10.3 Hz, 1H), 3.81 (s, 3H), 2.56 (td, J=13.5, 8.2 Hz, 2H), 1.71
(ddd, J=14.5, 9.9, 3.9 Hz, 2H), 1.58 (ddd, J=13.8, 9.7, 4.9 Hz,
1H), 0.86 (dd, J=11.9, 6.4 Hz, 6H). [M+Na] m/e 522.19.
[0246] Example 12: .sup.1H NMR (400 MHz, Acetone-d.sub.6) .delta.
10.75 (s, 0.33H), 10.59 (s, 0.67H), 9.58 (s, 0.67H), 9.54 (s,
0.33H), 8.10 (d, J=7.8 Hz, 0.33H), 7.90 (d, J=8.7 Hz, 0.67H),
7.34-6.71 (m, 8H), 6.42 (m, 1H), 5.90 (t, J=8.0 Hz, 0.33H), 5.06
(t, J=8.3 Hz, 0.67H), 4.98 (ddd, J=11.3, 7.7, 4.0 Hz, 0.33H), 4.83
(td, J=9.1, 4.7 Hz, 0.67H), 4.00 (dd, J=11.7, 1.4 Hz, 0.39H),
3.97-3.87 (m, 1.41H), 3.81 (m, 3H), 3.51 (d, J=11.7 Hz, 0.39H),
2.65-2.49 (m, 1H), 1.91 (s, 2H), 1.71-1.51 (m, 2H), 0.96-0.90 (m,
2H), 0.75 (dd, J=6.3, 4.1 Hz, 4H). [M+Na] m/e 522.19.
[0247] The following examples were prepared employing similar
protocol as described above.
TABLE-US-00002 Example # Structure MS NMR 13 ##STR00085## [M +
H].sup.+ 540.23 .sup.1H NMR (400 MHz, Chloroform-d) .delta. 8.92
(s, 1H), 7.86 (s, 1H), 7.18-7.08 (m, 2H), 7.04 (dd, J = 2.2, 0.9
Hz, 1H), 6.95-6.76 (m, 4H), 6.44 (d, J = 7.7 Hz, 1H), 4.99 (t, J =
8.6 Hz, 1H), 4.89-4.79 (m, 1H), 4.17 (t, J = 9.4 Hz, 1H), 3.95 (d,
J = 10.3 Hz, 1H), 3.89 (s, 3H), 2.82 (dd, J = 13.1, 8.9 Hz, 1H),
2.48 (dd, 13.1, 8.2 Hz, 1H), 1.77 (d, J = 12.8 Hz, 1H), 1.74-1.56
(m, 6H), 1.37 (s, 1H), 1.19 (d, J = 1.6 Hz, 4H), 1.14-1.01 (m, 1H),
0.89-0.76 (m, 1H). 14 ##STR00086## [M + H].sup.+ 540.26 15
##STR00087## [M + H].sup.+ 514.21 16 ##STR00088## [M + Na].sup.+
536.22
Example 17
##STR00089## ##STR00090##
[0248] Step 1
[0249] To a mixture of (2S)-2-amino-3-cyclobutylpropanoic acid
hydrochloride (0.359 g, 2 mmol) and NaOH (240 mg, 6.00 mmol) in
toluene/water (4 mL/4 mL) at 0.degree. C. was added Cbz-Cl (0.314
ml, 2.200 mmol). After stirring at rt for 2 h, the two layers were
separated and the aqueous layer was washed with MBTE. The aqueous
layer was then treated with 1 M HCl solution to PH.about.2. The
resulting mixture was extracted with EtOAc. The collected organic
layer was washed with brine, dry over Na.sub.2SO.sub.4, filtered,
and concentrated to give compound (17-1) (0.46 g, 1.659 mmol, 83%
yield).
Step 2
[0250] To a mixture of compound (17-1) (104 mg, 0.374 mmol),
compound (1-4) (80 mg, 0.299 mmol), and DIPEA (183 .mu.l, 1.046
mmol) in DCM/DMF (1.0/0.5 mL) at rt was added HATU (136 mg, 0.359
mmol). The mixture was stirred at rt for 20 h, quenched with water,
and extracted with EtOAc. The collected organic layer was washed
with 1 N HCl, sat NaHCO.sub.3, brine, and dried over
Na.sub.2SO.sub.4 and filtered. The filtrate was concentrated in
vacuo. Purification of the residue on silica gel column provided
compound (17-2) (98 mg, 0.200 mmol, 66.9% yield). [M-H].sup.-
489.16
Step 3
[0251] A suspension of (17-2) (25 mg, 0.051 mmol) and Pd--C (5.42
mg, 5.10 .mu.mol) in MeOH (1 mL) was treated with 1 atm H.sub.2 for
40 mins. The mixture was diluted with DCM, filtered through celite,
washed with DCM, and concentrated in vacuo. The product (17-3) was
used in next step directly. [M-H].sup.-, 355.15 Step 4 To a
suspension of 4-methoxy-1H-indole-2-carboxylic acid (15 mg, 0.077
mmol), compound (17-3) (18 mg, 0.051 mmol) and HATU (0.029 g, 0.077
mmol) in DCM (0.3 mL) was added DIPEA (0.031 ml, 0.179 mmol) in DMF
(0.3 ML). The mixture was stirred at rt for 1 h, quenched with
water, and extracted with EtOAc. The organic layer was washed with
1 N HCl, sat NaHCO.sub.3, brine, dried over Na.sub.2SO.sub.4, and
concentrated in vacuo. Purification of the residue with silica gel
column conc afforded compound (17-4) (19 mg, 0.036 mmol, 70.3%
yield). [M-H].sup.-, 528.18
Step 5
[0252] To a mixture of compound (17-4) (19 mg, 0.036 mmol) and
Et.sub.3N (60.0 .mu.l, 0.431 mmol) in DCM (0.6 mL) at 0.degree. C.
was added TFAA (30.4 .mu.l, 0.215 mmol). The mixture was warmed to
rt and stirred for 1 h. The reaction was quenched with cold sat.
NaHCO.sub.3 and extracted with EtOAc. The organic layer was washed
with 1 N HCl, sat NaHCO.sub.3 and brine, dried over
Na.sub.2SO.sub.4, and concentrated. Purification of the residue
with silica gel column provided Example 17 (12 mg, 0.023 mmol,
65.4% yield). [M-H].sup.- 510.17; .sup.1H NMR (400 MHz,
Methanol-d.sub.4) .delta. 7.26 (d, J=0.9 Hz, 1H), 7.22-7.10 (m,
3H), 7.02 (d, J=8.3 Hz, 1H), 6.99-6.89 (m, 2H), 6.53 (d, J=7.7 Hz,
1H), 5.17 (t, J=7.9 Hz, 1H), 4.71 (dd, J=8.0, 6.4 Hz, 1H), 4.30 (d,
J=10.5 Hz, 1H), 4.08 (d, J=10.5 Hz, 1H), 3.96 (s, 3H), 2.75-2.62
(m, 2H), 2.52 (hept, J=7.7 Hz, 1H), 2.20-2.12 (m, 3H), 2.15-2.02
(m, 1H), 2.05-1.88 (m, 2H), 1.90-1.80 (m, 1H), 1.83-1.70 (m,
1H).
[0253] The following examples were prepared employing similar
protocol as described above.
TABLE-US-00003 Example # Structure MS NMR 18 ##STR00091## [M -
H].sup.- 486.15 .sup.1H NMR (400 MHz, Acetone-d.sub.6) .delta.
10.79 (s, 1H), 9.55 (s, 1H), 7.51 (d, J = 9.0 Hz, 1H), 7.34 (dd, J
= 2.2, 0.9 Hz, 1H), 7.21 (dd, J = 8.3, 0.8 Hz, 1H), 7.13- 6.96 (m,
2H), 6.94-6.87 (m, 1H), 6.83 (dt, J = 7.8, 0.9 Hz, 1H), 6.72-6.62
(m, 2H), 5.06 (t, J = 8.2 Hz, 1H), 4.71 (d, J = 9.0 Hz, 1H), 4.20
(dd, J = 10.6, 1.0 Hz, 1H), 3.96 (d, J = 10.5 Hz, 1H), 2.69-2.50
(m, 2H), 1.04 (s, 9H). 19 ##STR00092## [M + Na].sup.+ 520.17
.sup.1H NMR (500 MHz, Chloroform-d) .delta. 9.28 (s, 1H), 8.51 (s,
1H), 7.44-7.25 (m, 1H), 7.05-6.92 (m, 3H), 6.82 (d, J = 8.3 Hz,
1H), 6.76-6.60 (m, 3H), 6.31 (d, J = 7.7 Hz, 1H), 4.93 (t, J = 8.4
Hz, 1H), 4.78 (q, J = 7.1 Hz, 1H), 4.05 (d, J = 10.4 Hz, 1H), 3.88
(d, J = 10.4 Hz, 1H), 3.76 (s, 3H), 2.69 (dd, J = 13.2, 8.7 Hz,
1H), 2.35 (dd, J = 13.2, 8.3 Hz, 1H), 1.66 (ddt, J = 46.7, 13.5,
6.9 Hz, 2H), 0.64 (dq, J = 12.7, 7.4, 6.3 Hz, 1H), 0.47-0.30 (m,
2H), 0.00 (d, J = 4.9 Hz, 2H). 20 ##STR00093## [M + Na].sup.+
542.18 .sup.1H NMR (400 MHz, Acetone-d.sub.6) .delta. 7.39 (d, J =
0.9 Hz, 1H), 7.35-7.25 (m, 1H), 7.25-7.11 (m, 2H), 7.11-7.02 (m,
1H), 6.95 (d, J = 7.8 Hz, 1H), 6.82 (td, J = 7.6, 1.1 Hz, 1H), 5.16
(t, J = 8.3 Hz, 1H), 4.98 (dd, J = 8.6, 4.1 Hz, 1H), 4.38 (d, J =
10.3 Hz, 1H), 4.05 (d, J = 10.3 Hz, 1H), 3.27 (d, J = 2.2 Hz, 1H),
2.77-2.62 (m, 2H), 1.96-1.74 (m, 2H), 1.03 (s, 9H). 21 ##STR00094##
[M + H].sup.+ 502.20 22 ##STR00095## [M + H].sup.+ 544.25
Example 23
##STR00096## ##STR00097##
[0254] Step 1
[0255] To a solution of compound (1-2) (2.5 g, 7.22 mmol) in THE
(24.06 mL) was added dropwise a solution of 2M LiBH.sub.4 in THE
(10.83 mL, 21.65 mmol). The mixture was stirred at rt for 2 hrs and
the majority of THE was removed in vacuo. The reaction was quenched
carefully with 1N HCl to pH=5-6 (.about.22 mL) and extracted with
EtOAc (3.times.40 mL). The combined organic layers were washed with
sat NaHCO.sub.3, brine, dried and concentrated. Purification of the
residue on silica gel with 0-50% EtOAc/Cyclohexane provided the
desired alcohol (23-1) (1.54 g, 67% yield).
Step 2
[0256] Compound (23-1) (0.5 g, 1.570 mmol) was dissolved in a
solution of 4M HCl in dioxane (3.93 mL, 15.70 mmol. The mixture was
stirred at rt for 1 hrs and concentrated to dryness. Compound
(23-2) (492 mg, 80% yield) was obtained as a yellow solid. LC-MS,
ES+: 218.85 [M+1].
Step 3
[0257] To a solution of compound (23-2) (960 mg, 3.13 mmol) and
((benzyloxy)carbonyl)-L-leucine (913 mg, 3.44 mmol) in dry DMF
(15.64 mL) at 0.degree. C. was added HATU (1546 mg, 4.07 mmol) and
Hunig's base (1912 .mu.l, 10.95 mmol). The resulting mixture was
stirred at 0.degree. C. for 1 h, diluted with EtOAc, and washed
with 10% citric acid, water, and brine. The organic layer was dried
and concentrated. Purification of the residue on silica gel with
0-40% EtOAc/Cyclohexane provided 1.2 g of compound (23-3). LC-MS,
ES+: 466.19 [M+1].
Step 4
[0258] Compound (23-3) (800 mg, 1.718 mmol) was dissolved in MeOH
(17 mL). 10% Pd on carbon (40 mg, 0.038 mmol) was added. The
mixture was stirred under hydrogen for 2.5 h, and filtered through
a pad of Celite. Solvent was removed and the crude product (23-4)
(543 mg, 1.638 mmol, 95% yield), was used for next step. [M+1]
332.20.
Step 5
[0259] Compound (23-4) (195 mg, 0.588 mmol) and
4-methoxy-1H-indole-2-carboxylic acid (118 mg, 0.618 mmol) was
dissolved in CH.sub.2Cl.sub.2 (5.9 mL). At 0.degree. C.,
hunig'sbase (308 .mu.l, 1.765 mmol) and HATU (235 mg, 0.618 mmol)
were added. The mixture was stirred at 0.degree. C. for 30 min. The
reaction was quenched with water and extracted with DCM. The
organic layer was loaded on silica gel and eluted with 0-50%
acetone/cyclohexane to afford compound (23-5) (213 mg, 0.422 mmol,
71.7% yield).
Step 6
[0260] In a flame dried flask, acetic anhydride (422 .mu.l, 4.46
mmol) was added to anhydrous DMSO (3.10 mL) at rt. After stirring
for 10 mins, compound (23-5) (150 mg, 0.297 mmol) was added in one
portion. The mixture was stirred at rt for 6 h. The reaction was
cooled to 0.degree. C. and diluted with water (.about.8 mL). The
white precipitate was collected by filtration, rinsed with water,
and dried under vacuum. Purification of the solid on silica gel
with 0-45% acetone/cyclohexane provided Example 23 as a colorless
solid (112 mg, 75% yield). [M+H].sup.+ 503.16. .sup.1H NMR (500
MHz, DMSO-d.sub.6) .delta. 11.52 (d, J=2.3 Hz, 1H), 10.66 (s, 1H),
9.52 (d, J=2.1 Hz, 1H), 8.61 (d, J=7.7 Hz, 1H), 7.40-7.32 (m, 1H),
7.26 (d, J=7.9 Hz, 1H), 7.26-7.18 (m, 1H), 7.17-7.02 (m, 1H),
7.04-6.97 (m, 2H), 6.89 (d, J=8.9 Hz, 1H), 6.52 (t, J=8.4 Hz, 1H),
4.75 (s, 1H), 4.62 (td, J=8.1, 7.1, 3.8 Hz, 1H), 4.11 (d, J=10.5
Hz, 1H), 3.97 (d, J=10.5 Hz, 1H), 3.89 (s, 3H), 3.88 (d, J=7.4 Hz,
1H), 2.41 (dd, J=13.0, 9.0 Hz, 1H), 2.21 (dd, J=13.2, 6.2 Hz, 1H),
1.77 (m, 1H), 1.60 (m, 1H), 0.96 (d, J=7.0 Hz, 3H), 0.89 (d, J=7.0
Hz, 3H).
[0261] The following examples were prepared employing similar
protocol as described above.
TABLE-US-00004 Example # Structure MS NMR 24 ##STR00098## [M -
H].sup.- 476.2 25 ##STR00099## [M + H].sup.+ 491.19 .sup.1H NMR
(400 MHz, Acetone-d.sub.6) .delta. 10.99 (s, 1H), 9.65 (d, J = 1.9
Hz, 1H), 9.64 (s, 1H), 8.06-7.96 (m, 1H), 7.42-7.32 (m, 3H),
7.32-7.17 (m, 2H), 7.12-6.90 (m, 2H), 6.81 (dd, J = 10.6, 7.8 Hz,
1H), 5.15-4.98 (m, 1H), 4.80-4.65 (m, 1H), 4.28 (d, J = 10.4 Hz,
1H), 4.13 (d, J = 10.4 Hz, 1H), 2.51 (dd, J = 13.1, 9.1 Hz, 1H),
2.37 (dd, J = 13.1, 6.1 Hz, 1H), 1.92-1.70 (m, 2H), 1.44 (s, 1H),
1.00 (dd, J = 6.5, 4.8 Hz, 6H).
Example 26
##STR00100## ##STR00101##
[0262] Step 1
[0263] Compound 23-4 (45 mg, 0.136 mmol) was dissolved in DCM
(1.358 mL). DIPEA (48.5 .mu.l, 0.272 mmol),
6-cyano-4-methoxy-1H-indole-2-carboxylic acid (32.3 mg, 0.149
mmol), and HATU (51.6 mg, 0.136 mmol) were added. The mixture was
stirred at rt for 1 h, quenched with water, and extracted with DCM.
The organic layer was loaded on silica gel and eluted with 0-50%
acetone/cyclohexane to afford Compound 26-1 (22 mg, 0.042 mmol,
30.6% yield). [M-OH]+, 512.20.
Step 2
[0264] Acetic anhydride (78 .mu.l, 0.831 mmol) was added to DMSO
(0.415 mL) at rt. The mixture was stirred at rt for 5 min, and
transferred to a vial containing compound 26-1 (22 mg, 0.042 mmol).
The reaction mixture was stirred at rt for 6 h, quenched with water
at 0.degree. C., and extracted with EtOAc. The organic layer was
washed with water, brine, and concentrated. Purification of the
residue on silica gel with 0-50% acetone/cyclohexane provided
compound 26-2 (15 mg, 0.028 mmol, 68.4% yield). [M+H].sup.+,
528.21.
Step 3
[0265] Compound 26-2 (15 mg, 0.028 mmol) was dissolved in
2-propanol. A 1 M solution of hydroxylamine hydrochloride (56.9
.mu.l, 0.057 mmol) in t-BuOH/H.sub.2O (1:1) was added. The mixture
was stirred at rt for 30 min, quenched with aq NaHCO.sub.3, and
extracted with EtOAc. The organic layer was dried over
Na.sub.2SO.sub.4, and concentrated in vacuo. The crude product,
compound 26-3 (14 mg, 0.026 mmol, 91% yield) was used in the next
step. [M+H].sup.+, 543.22
Step 4
[0266] To a vial containing compound 26-3 (14 mg, 0.026 mmol) was
added MeCN (0.516 mL) and copper (II) acetate (1.406 mg, 7.74
.mu.mol). The resulting mixture was stirred at 70.degree. C. for 2
h, and concentrated in vacuo. Purification of the residue on silica
gel with 0-50% EtOAc/cyclohexane, followed by prep-HPLC, provided
Example 26 (2.8 mg, 5.34 .mu.mol, 20.69% yield). [M+H].sup.+,
525.22; .sup.1H NMR (400 MHz, Acetone-d.sub.6) .delta. 11.06 (s,
1H), 9.57 (s, 1H), 7.96 (d, J=8.3 Hz, 1H), 7.45 (s, 1H), 7.32 (d,
J=1.9 Hz, 1H), 7.08-6.92 (m, 2H), 6.84 (d, J=7.8 Hz, 1H), 6.77-6.68
(m, 2H), 5.03 (t, J=8.3 Hz, 1H), 4.84-4.75 (m, 1H), 4.23 (d, J=10.4
Hz, 1H), 3.91 (m, 5H), 2.58 (qd, J=13.3, 8.4 Hz, 2H), 1.72 (m, 2H),
1.61 (m, 1H), 0.85 (m, 6H).
[0267] The following examples were prepared employing similar
protocol as described above.
TABLE-US-00005 Example # Structure MS NMR 27 ##STR00102## [M +
H].sup.+ 488.19 .sup.1H NMR (400 MHz, Acetone-d.sub.6) .delta.
10.78 (s, 1H), 9.56 (s, 1H), 7.90 (d, J = 8.2 Hz, 1H), 7.29- 7.19
(m, 2H), 7.12-6.93 (m, 3H), 6.83 (dt, J = 7.8, 0.8 Hz, 1H), 6.73
(td, J = 7.6, 1.1 Hz, 1H), 6.70-6.62 (m, 1H), 5.03 (t, J = 8.3 Hz,
1H), 4.81 (ddd, J = 9.6, 8.2, 4.7 Hz, 1H), 4.21 (dd, J = 10.5, 1.0
Hz, 1H), 3.97-3.87 (m, 1H), 2.66-2.49 (m, 2H), 1.78-1.64 (m, 2H),
1.58 (ddd, J = 13.8, 9.6, 5.0 Hz, 1H), 0.85 (m, 6H). 28
##STR00103## [M + H].sup.+ 505.93 .sup.1H NMR (500 MHz,
Acetone-d.sub.6) .delta. 10.90 (s, 1H), 10.10 (s, 1H), 8.01 (d, J =
8.2 Hz, 1H), 7.37-7.34 (m, 1H), 7.21 (m, 1H), 7.03-6.97 (m, 1H),
6.95 (d, J = 7.4 Hz, 1H), 6.85 (ddd, J = 8.4, 7.5, 4.8 Hz, 1H),
6.82-6.77 (m, 1H), 5.17 (t, J = 8.3 Hz, 1H), 4.93 (ddd, J = 9.6,
8.3, 4.7 Hz, 1H), 4.42 (dd, J = 10.6, 1.2 Hz, 1H), 4.06 (d, J =
10.5 Hz, 1H), 2.80-2.76 (m, 1H), 2.70 (dd, J = 13.3, 8.1 Hz, 1H),
1.86-1.78 (m, 2H), 1.71 (m, 1H), 0.97 (m, 6H).
Example 29
##STR00104##
[0269] To a solution of Example 23 (45 mg, 0.090 mmol) in EtOH (2
mL) and water (0.2 mL) was added sodium bisulfite (9.32 mg, 0.090
mmol). The mixture was stirred at rt for 4 h and then concentrated.
DCM was added to the residue and white solid precipitated. The
collected solid was washed with acetone and dried to afford Example
29 as a white solid. [M-Na].sup.- 583.0. .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 11.42 (s, 1H), 10.57 (d, J=7.9 Hz, 1H), 9.88
(s, 1H), 8.47 (d, J=8.2 Hz, 1H), 7.35-7.31 (m, 1H), 7.14-7.05 (m,
2H), 7.02-6.96 (m, 1H), 6.86 (ddt, J=24.0, 15.0, 8.1 Hz, 3H), 6.50
(d, J=7.7 Hz, 1H), 5.65 (d, J=5.5 Hz, 1H), 4.83-4.78 (m, 1H), 4.70
(t, J=9.3 Hz, 2H), 3.96 (d, J=9.3 Hz, 1H), 3.90 (s, 3H), 3.61 (d,
J=9.8 Hz, 1H), 2.79 (dd, J=13.1, 9.8 Hz, 1H), 1.81-1.67 (m, 3H),
0.99 (td, J=15.4, 7.0 Hz, 1H), 0.90 (d, J=6.4 Hz, 3H), 0.85 (d,
J=6.1 Hz, 3H).
[0270] The following example was prepared employing similar
protocol as described above.
TABLE-US-00006 Example Structure MS 30 ##STR00105## [M - H].sup.-
585.1
Example 31
##STR00106##
[0271] Step 1
[0272] To Example 23 (18 mg, 0.036 mmol) at 0.degree. C. was added
acetic acid (2.4 .mu.l, 0.041 mmol) and a solution of
isocyanocyclopropane (2.64 mg, 0.039 mmol) in DCM (0.20 mL). The
mixture was stirred at 0.degree. C. to rt for 5 h. The reaction
mixture was concentrated to dryness and redissolved in MeOH (0.35
mL). A 0.5 M solution of K.sub.2CO.sub.3 in water (179 .mu.l, 0.090
mmol) was added. The mixture was stirred at rt for 2 h. MeOH was
removed in vacuo and the aqueous layer was extracted with EtOAc
(3.times.). The combined organic layer was washed with water and
brine, dried, and concentrated. The crude product (31-1) was
directly used in the next step. [M+1], 588.2.
Step 2
[0273] To a solution of compound (31-1) in DCM (0.360 mL) at
0.degree. C. was added Dess-Martin Periodinane (0.023 g, 0.054
mmol). The mixture was stirred at 0.degree. C. for 2.5 h. At
0.degree. C., the reaction mixture was diluted with DCM, quenched
with 10% Na.sub.2S203, and washed with 5% NaHCO.sub.3. The
collected organic layer was washed with water and brine, dried, and
concentrated. Purification of the residue on silica gel with 0-60%
acetone/cyclohexane provided Example 31 (6.5 mg). [M-1].sup.-
584.07. .sup.1H NMR (400 MHz, Acetone-d.sub.6) .delta. 10.62 (s,
1H), 9.67 (s, 1H), 7.90 (d, J=4.9 Hz, 1H), 7.78 (d, J=8.2 Hz, 1H),
7.31 (dd, J=2.3, 0.8 Hz, 1H), 7.29-7.10 (m, 4H), 7.14-6.95 (m, 2H),
6.92 (td, J=7.6, 1.1 Hz, 1H), 6.53 (dd, J=7.2, 1.2 Hz, 1H),
5.69-5.54 (m, 1H), 4.93 (td, J=8.4, 6.0 Hz, 1H), 4.34 (d, J=9.9 Hz,
1H), 4.02 (d, J=9.9 Hz, 1H), 3.94 (s, 3H), 4.00-3.86 (m, 1H),
2.92-2.78 (m, 1H), 2.52-2.38 (m, 2H), 1.89 (dt, J=12.9, 6.5 Hz,
1H), 1.72 (ddd, J=8.1, 5.7, 2.3 Hz, 2H), 1.13-0.93 (m, 6H),
0.83-0.65 (m, 4H).
[0274] The following examples were prepared employing similar
protocol as described above.
TABLE-US-00007 Example # Structure MS NMR 32 ##STR00107## [M -
H].sup.- 634.0 .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 11.49
(d, J = 2.4 Hz, 1H), 10.74 (s, 1H), 9.37 (t, J = 6.4 Hz, 1H), 8.53
(d, J = 7.5 Hz, 1H), 7.40-7.26 (m, 4H), 7.28-7.20 (m, 3H), 7.15 (d,
J = 7.3 Hz, 1H), 7.10 (t, J = 8.0 Hz, 1H), 7.06-6.88 (m, 3H), 6.51
(d, J = 7.7 Hz, 1H), 5.44 (dd, J = 10.5, 7.7 Hz, 1H), 4.71-4.63 (m,
1H), 4.39-4.28 (m, 2H), 4.19 (d, J = 10.2 Hz, 1H), 3.89 (s, 3H),
3.88-3.80 (m, 1H), 2.35-2.27 (m, 1H), 2.25 (dd, J = 12.6, 10.4 Hz,
1H), 1.80-1.64 (m, 2H), 1.50 (ddd, J = 13.5, 8.8, 4.3 Hz, 1H), 0.94
(d, J = 6.5 Hz, 3H), 0.88 (d, J = 6.5 Hz, 3H). 33 ##STR00108## [M -
H].sup.- 626.1 .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 11.48
(d, J = 2.3 Hz, 1H), 10.73 (s, 1H), 8.64 (d, J= 8.4 Hz, 1H), 8.52
(d, J = 7.4 Hz, 1H), 7.35 (dd, J = 2.4, 0.9 Hz, 1H), 7.22 (qd, J =
7.5, 1.2 Hz, 1H), 7.13 (d, J = 7.5 Hz, 1H), 7.09 (t, J = 7.9 Hz,
1H), 7.03-6.90 (m, 3H), 6.50 (d, J = 7.7 Hz, 1H), 5.37 (dd, J =
10.3, 7.8 Hz, 1H), 4.66 (ddd, J = 10.6, 7.3, 4.1 Hz, 1H), 4.17 (d,
J = 10.1 Hz, 1H), 3.89 (s, 3H), 3.87-3.79 (m, 1H), 3.56 (s, 1H),
2.34-2.21 (m, 2H), 1.77 (s, 1H), 1.70 (d, J = 12.1 Hz, 6H),
1.61-1.46 (m, 2H), 1.33 (q, J = 11.3 Hz, 2H), 1.26 (s, 3H), 0.94
(d, J = 6.6 Hz, 3H), 0.88 (d, J = 6.5 Hz, 3H). 34 ##STR00109## [M -
H].sup.- 640.2 .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 11.44
(s, 1H), 10.70 (s, 1H), 8.69 (d, J = 8.4 Hz, 1H), 7.12 (dt, J =
24.9, 8.1 Hz, 3H), 6.93 (q, J = 7.6, 6.8 Hz, 2H), 6.85 (d, J = 7.8
Hz, 1H), 6.70 (s, 1H), 6.50 (d, J = 7.6 Hz, 1H), 5.40 (dd, J =
10.2, 8.0 Hz, 1H), 5.33 (s, 1H), 3.93 (s, 1H), 3.89 (s, 3H), 3.84
(d, J = 10.0 Hz, 1H), 3.57 (d, J = 10.5 Hz, 2H), 3.25 (s, 3H), 2.34
(dd, J = 12.9, 8.2 Hz, 1H), 1.71 (s, 6H), 1.57 (s, 3H), 1.35-1.22
(m, 5H), 0.96 (d, J = 6.3 Hz, 3H), 0.90 (d, J = 6.1 Hz, 3H). 35
##STR00110## [M - H].sup.- 628.02 36 ##STR00111## [M - H].sup.-
586.12 1H NMR (500 MHz, Acetone-d6) 8 10.72 (s, 1H), 9.64 (s, 1H),
7.95 (d, J = 4.9 Hz, 1H), 7.32 (d, J = 8.3 Hz, 1H), 7.23-7.15 (m,
2H), 7.11 (t, J = 7.7 Hz, 1H), 6.96-6.86 (m, 3H), 6.79 (dd, J =
10.5, 7.7 Hz, 1H), 5.60 (dd, J = 10.3, 8.1 Hz, 1H), 5.53 (t, J =
7.5 Hz, 1H), 4.21 (d, J = 9.5 Hz, 1H), 3.96 (d, J = 10.1 Hz, 1H),
3.44 (s, 3H), 2.93-2.87 (m, 1H), 2.44 (dd, J = 8.1, 1.4 Hz, 1H),
2.38 (dd, J = 12.7, 10.3 Hz, 1H), 1.82 (dt, J = 14.0, 7.2 Hz, 1H),
1.79-1.67 (m, 2H), 1.67-1.58 (m, 1H), 0.99 (dd, J = 27.9, 6.6 Hz,
6H), 0.84-0.69 (m, 4H).
Example 37
##STR00112##
[0276] To a mixture of Example 23 (105 mg, 0.209 mmol) in
tert-butanol (2.79 mL) at rt was added 2-methyl-2-butene, 2M in THE
(2.09 mL, 4.18 mmol) to achieve a clear solution. A solution of
sodium chlorite (236 mg, 2.089 mmol) and sodium phosphate monobasic
(251 mg, 2.089 mmol) in water (1.39 mL) was added dropwise over 10
minutes. After stirring at rt for 1 h, the reaction mixture was
concentrated to remove most of the volatiles. The resulting mixture
was diluted with EtOAc, washed with water, brine, dried and
concentrated. Purification of the residue on silica gel
chromatography with 0-10% MeOH/DCM provided Example 37 (40 mg, 36%
yield). LC-MS, ES: 516.94 [M-H].sup.-.
Example 38
##STR00113##
[0278] A solution of Example 37 (18 mg, 0.035 mmol),
cyclopropanesulfonamide (8.41 mg, 0.069 mmol), EDCI (7.2 mg, 0.038
mmol) and DMAP (4.59 mg, 0.038 mmol) in dry DCM was stirred at rt
for 4 hrs. The reaction mixture was diluted with DCM, washed with
brine, dried, and concentrated. The residue was purified by
chromatography on silica gel using 0 to 50% acetone/cyclohexane to
give Example 38 (3.5 mg, 16% yield) as a white solid. LC-MS, ES-:
619.80 [M-H].sup.-.
Example 39
##STR00114##
[0279] Step 1
[0280] Compound (1-4) (300 mg, 1.121 mmol) and
N-((benzyloxy)carbonyl)-N-methyl-L-leucine (344 mg, 1.233 mmol) was
taken up in CH.sub.2Cl.sup.2 (5 ml) and DMF (1 ml).
4-methylmorpholine (246 .mu.l, 2.241 mmol) and HATU (469 mg, 1.233
mmol) were added. The mixture was stirred at rt for 1 h, diluted
with DCM (30 mL), and washed with sat. NaHCO.sub.3. The collected
organic layer was washed with 1 M HCl and brine, filtered through
Na.sub.2SO.sub.4, and concentrated in vacuo.
[0281] Purification of the residue on silica gel with 0-100%
acetone/cyclohexane provided compound (39-1) (417 mg, 0.847 mmol,
76% yield). [M-1].sup.-, 491.02.
Step 2
[0282] To a suspension of (39-1) (28 mg, 0.057 mmol) in DCM (0.6
mL) at 0.degree. C. was added Et.sub.3N (79 .mu.l, 0.568 mmol) and
TFAA (40.1 .mu.l, 0.284 mmol). The mixture was warmed to rt and
stirred for 1 h. The reaction was quenched with cold NaHCO.sub.3
solution and extracted with EtOAc. The organic layer was washed
with water, 1N HCl, sat NaHCO.sub.3 and brine, dried over
Na.sub.2SO.sub.4, filtered, and concentrated. Purification of the
residue on silica gel column provided Example 39 (24 mg, 0.051
mmol, 89% yield). [M-H].sup.- 473.17. .sup.1H NMR (400 MHz,
Methanol-d.sub.4) .delta. 7.35-7.15 (m, 5H), 7.07-6.88 (m, 4H),
5.21-4.88 (m, 2H), 4.77 (dd, J=12.1, 3.8 Hz, 1H), 4.19-4.07 (m,
1H), 3.92 (d, J=10.7 Hz, 1H), 3.71 (p, J=10.8 Hz, 1H), 2.93 (d,
J=4.8 Hz, 3H), 2.75-2.57 (m, 2H), 1.79 (ddt, J=14.4, 9.2, 5.0 Hz,
1H), 1.67 (dq, J=14.8, 7.2, 6.6 Hz, 1H), 1.56-1.47 (m, 1H),
1.05-0.88 (m, 6H).
[0283] The following examples were prepared employing similar
protocol as described above.
TABLE-US-00008 Example # Structure MS 40 ##STR00115## [M +
Na].sup.+ 511.21 41 ##STR00116## [M - H].sup.- 507.20
Example 42
##STR00117##
[0284] Step 1
[0285] Compound (39-1) (1323 mg, 2.69 mmol) was dissolved in MeOH
(30 ml). 10% Pd--C (143 mg, 0.134 mmol) was added. The mixture was
stirred under H.sub.2 (balloon) for 1 h and filtered through a pad
of Celite. The filtrate was concentrated in vacuo to provide
compound (42-1). [M+H].sup.+ 359.2.
Step 2
[0286] To a suspension of 4-methoxy-1H-indole-2-carboxylic acid
(0.111 g, 0.583 mmol), compound (42-1) (0.182 g, 0.507 mmol) and
HATU (0.212 g, 0.558 mmol) in DCM (0.3 mL) was added DIPEA (0.266
ml, 1.521 mmol) in DMF (0.35 mL). The mixture was stirred at rt for
1 h, quenched with water, and extracted with EtOAc. The organic
layer was washed with 1 N HCl, sat NaHCO.sub.3 and brine, dried
over Na.sub.2SO.sub.4, filtered, and concentrated. Purification of
the residue on silica gel column afforded compound (42-2) (160 mg,
0.301 mmol, 59.4% yield). [M-H].sup.- 530.18.
Step 3
[0287] Compound (42-2) (150 mg, 0.282 mmol) was dissolved in
CH.sub.2C.sub.2 (1.9 ml). At 0.degree. C., Et.sub.3N (0.32 mL, 2.26
mmol) and TFAA (0.16 mL, 1.13 mmol) was added. The mixture was
stirred at 0.degree. C. for 20 min, quenched with aq. NaHCO.sub.3,
and extracted with DCM (2 x). The combined organic layer was dried
over Na.sub.2SO.sub.4 and concentrated in vacuo. Purification of
the residue on silica gel with 0-40% acetone/cyclohexane provided
Example 42 (114 mg, 0.222 mmol, 79% yield). [M-H].sup.- 512.18;
.sup.1H NMR (400 MHz, Methanol-d.sub.4) .delta. 7.15 (t, J=8.0 Hz,
1H), 7.05 (t, J=7.8 Hz, 1H), 7.01-6.94 (m, 2H), 6.90 (s, 1H), 6.85
(dd, J=15.4, 7.7 Hz, 2H), 6.52 (d, J=7.7 Hz, 1H), 5.53 (brs, 1H),
5.19 (t, J=8.0 Hz, 1H), 4.21 (d, J=11.0 Hz, 1H), 3.99 (d, J=11.0
Hz, 1H), 3.96 (s, 3H), 3.40 (s, 3H), 2.75-2.60 (m, 2H), 1.96-1.76
(m, 2H), 1.63 (ddt, J=14.6, 13.0, 6.6 Hz, 1H), 1.47 (s, 1H), 1.26
(t, J=7.1 Hz, 1H), 1.01 (m, 6H).
[0288] The following examples were prepared employing similar
protocol as described above.
TABLE-US-00009 Example Structure MS NMR 43 ##STR00118## [M +
Na].sup.+ 575.11 .sup.1H NMR (400 MHz, Acetone-d.sub.6) .delta.
9.58 (s, 1H), 7.77-7.68 (m, 2H), 7.27 (td, J = 8.9, 2.3 Hz, 1H),
7.17 (t, J = 7.6 Hz, 1H), 7.03 (d, J = 7.3 Hz, 1H), 6.91 (t, J =
7.2 Hz, 2H), 5.36 (dd, J = 9.7, 5.2 Hz, 1H), 5.08 (t, J = 8.2 Hz,
1H), 4.10 (d, J = 10.5 Hz, 1H), 3.96 (d, J = 10.5 Hz, 1H), 3.00 (s,
3H), 2.71-2.56 (m 2H), 1.82 (m, 1H), 1.74-1.61 (m, 2H), 0.89 (m,
6H). 44 ##STR00119## [M + Na].sup.+ 524.19 .sup.1H NMR (400 MHz,
Acetone-d.sub.6) .delta. 10.70 (s, 1H), 9.67 (s, 1H), 7.33 (d, J =
8.2 Hz, 1H), 7.22 (td, J = 8.0, 5.2 Hz, 1H), 7.03 (d, J = 7.7 Hz,
2H), 6.96-6.88 (m, 2H), 6.87-6.76 (m, 2H), 5.59 (dd, J = 9.5, 5.6
Hz, 1H), 5.21 (t, J = 8.2 Hz, 1H), 4.28 (d, J = 10.7 Hz, 1H), 4.00
(d, J = 10.6 Hz, 1H), 3.46 (s, 3H), 2.83-2.64 (m, 2H), 1.94 (ddd, J
= 14.5, 9.6, 5.2 Hz, 1H), 1.79 (ddd, J = 14.2, 8.7, 5.6 Hz, 1H),
1.64 (dtd, J = 8.7, 6.7, 5.1 Hz, 1H), 0.99 (m, 6H). 45 ##STR00120##
[M + Na].sup.+ 546.23 .sup.1H NMR (400 MHz, Acetone-d.sub.6)
.delta. 10.39 (s, 1H), 9.67 (s, 1H), 7.29 (d, J = 8.3 Hz, 1H),
7.17-7.03 (m, 4H), 6.95-6.84 (m, 2H), 6.65 (d, J = 7.2 Hz, 1H),
5.61 (m, 1H), 5.20 (t, J = 8.2 Hz, 1H), 4.27 (d, J = 10.7 Hz, 1H),
4.01 (d, J = 10.6 Hz, 1H), 3.47 (s, 3H), 2.83-2.63 (m, 2H), 2.32
(br s, 1H), 1.92 (ddd, J = 14.3, 9.3, 5.2 Hz, 1H), 1.86-1.74 (m,
1H), 1.64 (dt, J = 13.7, 6.8 Hz, 1H), 1.01 (m, 8H), 0.84- 0.78 (m,
2H). 46 ##STR00121## [M + Na].sup.+ 542.17 .sup.1H NMR (400 MHz,
Acetone-d.sub.6) .delta. 10.79 (s, 1H), 9.67 (s, 1H), 7.04 (m, 3H),
6.96 (s, 1H), 6.91 (d, J = 7.7 Hz, 1H), 6.85- 6.70 (m, 2H), 5.59
(dd, J = 9.5, 5.6 Hz, 1H), 5.21 (t, J = 8.3 Hz, 1H), 4.30 (d, J =
10.8 Hz, 1H), 3.98 (d, J = 10.6 Hz, 1H), 3.45 (s, 3H), 2.78-2.66
(m, 2H), 1.95 (td, J = 9.4, 4.7 Hz, 1H), 1.78 (ddd, J = 14.2, 8.7,
5.5 Hz, 1H), 1.63 (dt, J = 13.8, 6.4 Hz, 1H), 0.98 (m, 6H). 47
##STR00122## [M + Na].sup.+ 556.18 .sup.1H NMR (500 MHz,
Acetone-d.sub.6) .delta. 10.47 (s, 1H), 9.71 (s, 1H), 7.28 (td, J =
7.7, 1.2 Hz, 1H), 7.16 (d, J = 7.4 Hz, 1H), 7.02 (t, J = 7.3 Hz,
2H), 6.96 (s, 1H), 6.66 (ddd, J = 11.3, 10.1, 2.1 Hz, 1H), 5.37 (s,
1H), 5.19 (t, J = 8.3 Hz, 1H), 4.32 (br s, 1H), 4.07 (br s, 1H),
3.20 (s, 3H), 2.82-2.66 (m, 2H), 2.27 (s, 3H), 2.00-1.91 (m, 1H),
1.81 (s, 1H), 1.72 (s, 1H), 1.05 (d, J = 6.5 Hz, 3H), 0.99 (br s,
3H). 48 ##STR00123## [M + Na].sup.+ 582.22 .sup.1H NMR (500 MHz,
Acetone-d.sub.6) .delta. 10.37 (s, 1H), 9.72 (s, 1H), 7.73 (d, J =
8.0 Hz, 1H), 7.55-7.46 (m, 5H), 7.39 (tt, J = 5.8, 2.9 Hz, 1H),
7.31-7.23 (m, 2H), 7.15 (t, J = 7.6 Hz, 1H), 7.11 (d, J = 7.5 Hz,
1H), 7.04 (d, J = 7.8 Hz, 1H), 6.94 (t, J = 7.5 Hz, 1H), 5.31 (dd,
J = 10.7, 4.9 Hz, 1H), 5.15 (t, J = 8.3 Hz, 1H), 4.34 (d, J = 10.5
Hz, 1H), 4.05 (d, J = 10.5 Hz, 1H), 2.77 (s, 3H), 2.70 (m, 2H),
1.82-1.72 (m, 1H), 1.62 (ddd, J = 14.4, 9.6, 4.9 Hz, 1H), 1.41 (m,
1H), 0.99 (d, J = 6.5 Hz, 3H), 0.93 (d, J = 6.7 Hz, 3H). 49
##STR00124## [M + Na].sup.+ 590.20 .sup.1H NMR (400 MHz,
Acetone-d.sub.6) .delta. 10.81 (s, 1H), 9.66 (s, 1H), 7.53 (d, J =
8.3 Hz, 1H), 7.31 (t, J = 8.0 Hz, 1H), 7.10-6.96 (m, 4H), 6.91 (d,
J = 7.4 Hz, 1H), 6.81 (t, J = 7.5 Hz, 1H), 5.60 (dd, J = 9.4, 5.8
Hz, 1H), 5.21 (t, J = 8.2 Hz, 1H), 4.28 (d, J = 10.6 Hz, 1H), 4.00
(d, J = 10.6 Hz, 1H), 3.46 (s, 3H), 2.82-2.60 (m, 2H), 2.00- 1.90
(m, 1H), 1.85-1.74 (m, 1H), 1.64 (dt, J = 13.8, 6.6 Hz, 1H), 0.99
(m, 6H). 50 ##STR00125## [M + Na].sup.+ 524.22 .sup.1H NMR (400
MHz, Acetone-d.sub.6) .delta. 10.51 (s, 1H), 9.67 (s, 1H), 7.66 (s,
1H), 7.24- 7.16 (m, 1H), 7.08-6.98 (m, 2H), 6.92 (d, J = 8.3 Hz,
3H), 6.82 (s, 1H), 5.59 (dd, J = 9.5, 5.7 Hz, 1H), 5.21 (t, J = 8.3
Hz, 1H), 4.29 (d, J = 10.8 Hz, 1H), 3.99 (d, J = 10.6 Hz, 1H), 3.43
(s, 3H), 2.78-2.63 (m, 2H), 2.00-1.91 (m, 1H), 1.77 (m, 1H), 1.61
(m, 1H), 0.98 (m, 6H). 51 ##STR00126## [M + Na].sup.+ 572.22
.sup.1H NMR (400 MHz, Acetone-d.sub.6) .delta. 10.69 (s, 1H), 9.66
(s, 1H), 7.39 (d, J = 8.3 Hz, 1H), 7.25 (t, J = 8.0 Hz, 1H), 7.15
(s, 1H), 7.03 (d, J = 7.6 Hz, 2H), 6.97-6.79 (m, 4H), 5.59 (dd, J =
9.4, 5.6 Hz, 1H), 5.21 (t, J = 8.2 Hz, 1H), 4.28 (d, J = 10.8 Hz,
1H), 4.00 (d, J = 10.6 Hz, 1H), 3.46 (s, 3H), 2.78-2.66 (m, 2H),
2.00-1.90 (m, 1H), 1.79 (ddd, J = 14.2, 8.8, 5.7 Hz, 1H), 1.64 (dt,
J = 14.0, 6.8 Hz, 1H), 0.99 (m, 6H). 52 ##STR00127## [M + Na].sup.+
560.20 .sup.1H NMR (400 MHz, Acetone-d.sub.6) .delta. 9.67 (s, 1H),
7.04 (dd, J = 14.4, 7.4 Hz, 2H), 6.93 (ddd, J = 10.6, 8.9, 5.1 Hz,
3H), 6.84 (t, J = 7.5 Hz, 1H), 5.61-5.53 (m, 1H), 5.22 (t, J = 8.3
Hz, 1H), 4.25 (d, J = 10.6 Hz, 1H), 3.99 (d, J = 10.7 Hz, 1H), 3.43
(s, 3H), 2.82-2.73 (m, 5H), 2.76-2.64 (m, 1H), 1.80 (ddd, J = 14.2,
8.7, 5.6 Hz, 1H), 1.64 (dt, J = 13.7, 6.6 Hz, 1H), 1.44 (s, 3H),
0.99 (dd, J = 18.3, 6.6 Hz, 5H). 53 ##STR00128## [M + Na].sup.+
550.25 .sup.1H NMR (400 MHz, Acetone-d.sub.6) .delta. 9.72 (s, 1H),
7.26 (td, J = 7.7, 1.3 Hz, 1H), 7.19 (t, J = 8.1 Hz, 1H), 7.13 (s,
1H), 7.05-6.95 (m, 3H), 6.63-6.55 (m, 2H), 5.56 (br s, 1H), 5.24
(t, J = 8.3 Hz, 1H), 4.40 (d, J = 10.9 Hz, 1H), 4.05 (d, J = 10.6
Hz, 1H), 3.95 (s, 3H), 3.47 (s, 3H), 2.83 (d, J = 0.5 Hz, 4H),
2.78-2.66 (m, 2H), 1.98 (ddd, J = 14.1, 9.6, 4.8 Hz, 1H), 1.79
(ddd, J = 13.8, 8.7, 5.6 Hz, 1H), 1.71 (br s, 1H), 1.05 (d, J = 6.5
Hz, 3H), 1.00 (d, J = 6.2 Hz, 3H). 54 ##STR00129## [M + Na].sup.+
582.26 .sup.1H NMR (400 MHz, Acetone-d.sub.6) .delta. 10.50 (s,
1H), 9.67 (s, 1H), 7.91 (s, 1H), 7.69 (d, J = 7.7 Hz, 2H), 7.58 (s,
2H), 7.47 (t, J = 7.7 Hz, 2H), 7.38-7.29 (m, 1H), 7.07 (s, 2H),
6.94 (d, J = 9.1 Hz, 2H), 6.88 (s, 1H), 5.59 (br s, 1H), 5.22 (t, J
= 7.9 Hz, 1H), 4.29 (br s, 1H), 4.01 (d, J = 10.5 Hz, 1H),
2.77-2.66 (m, 2H), 1.94 (br s, 1H), 1.85-1.73 (m, 1H), 1.63 (br s,
1H), 1.02 (d, J = 6.6 Hz, 3H), 0.97 (br s, 3H). 55 ##STR00130## [M
+ Na].sup.+ 582.26 .sup.1H NMR (500 MHz, Acetone-d.sub.6) .delta.
10.48 (s, 1H), 9.67 (s, 1H), 7.76 (s, 1H), 7.73- 7.67 (m, 2H), 7.48
(dd, J = 8.4, 7.1 Hz, 2H), 7.41 (d, J = 8.4 Hz, 1H), 7.39-7.33 (m,
1H), 7.09 (s, 2H), 7.05 (s, 1H), 6.94 (d, J = 7.8 Hz, 2H), 6.87 (s,
1H), 5.61 (d, J = 9.5 Hz, 1H), 5.22 (t, J = 8.2 Hz, 1H), 4.29 (d, J
= 10.1 Hz, 1H), 4.01 (d, J = 10.6 Hz, 1H), 3.46 (s, 3H), 2.78-2.65
(m, 2H), 1.94 (m, 1H), 1.79 (m, 1H), 1.64 (dt, J = 13.8, 6.7 Hz,
1H), 1.02 (d, J = 6.7 Hz, 3H), 0.97 (d, J = 6.3 Hz, 3H). 56
##STR00131## [M - H].sup.- 538.1 .sup.1H NMR (400 MHz,
Acetone-d.sub.6) .delta. 10.28 (s, 1H), 9.67 (s, 1H), 7.62 (s, 1H),
7.45- 7.34 (m, 2H), 7.12 (s, 1H), 7.06 (s, 1H), 6.94 (d, J = 7.8
Hz, 1H), 6.87 (d, J = 15.3 Hz, 2H), 5.57 (dd, J = 9.6, 5.5 Hz, 1H),
5.21 (t, J = 8.1 Hz, 1H), 4.27 (br s, 1H), 4.01 (d, J = 10.5 Hz,
1H), 3.43 (s, 3H), 2.68 (m, 2H), 1.93 (m, 1H), 1.83-1.72 (m, 1H),
1.61 (dd, J = 13.8, 6.7 Hz, 1H), 1.38 (s, 9H), 1.01 (d, J = 6.6 Hz,
3H), 0.95 (br s, 3H). 57 ##STR00132## [M - H].sup.- 538.1 .sup.1H
NMR (400 MHz, Acetone-d.sub.6) .delta. 10.25 (s, 1H), 9.66 (s, 1H),
7.55 (s, 1H), 7.50 (d, J = 1.5 Hz, 1H), 7.21 (d, J = 8.5 Hz, 1H),
7.11 (s, 1H), 7.06 (s, 1H), 6.94 (d, J = 7.8 Hz, 1H), 6.89 (s, 1H),
6.82 (s, 1H), 5.58 (dd, J = 9.5, 5.6 Hz, 1H), 5.21 (t, J = 8.2 Hz,
1H), 4.24 (br s, 1H), 4.01 (d, J = 10.6 Hz, 1H), 3.42 (s, 3H), 2.83
(d, J = 0.8 Hz, 3H), 2.78-2.63 (m, 2H), 1.91 (m, 1H), 1.78 (ddd, J
= 14.1, 8.7, 5.6 Hz, 1H), 1.62 (dt, J = 13.8, 6.7 Hz, 1H), 1.37 (s,
9H), 0.98 (d, J = 6.4 Hz, 3H), 0.95 (br s, 3H). 58 ##STR00133## [M
+ Na].sup.+ 531.15, 533.10 .sup.1H NMR (500 MHz, Methanol-d.sub.4)
.delta. 7.38- 7.29 (m, 2H), 7.07-6.94 (m, 5H), 5.52 (t, J = 7.5 Hz,
1H), 5.21 (q, J = 8.0 Hz, 1H), 4.17 (d, J = 11.8 Hz, 1H), 4.07 (dd,
J = 19.0, 10.5 Hz, 1H), 3.82-3.73 (m, 3H), 3.23 (s 3 H), 2.72 (qd,
J = 13.2, 8.4 Hz, 2H), 1.85 (m, 3H), 1.05 (m, 6H). 59 ##STR00134##
[M + Na].sup.+ 480.27, 450.10 .sup.1H NMR (500 MHz,
Acetone-d.sub.6) .delta. 9.70 (s, 1H), 8.49 (dd, J = 4.7, 1.4 Hz,
1H), 7.91 (dd, J = 8.2, 1.4 Hz, 1H), 7.47 (dd, J = 8.3, 4.7 Hz,
1H), 7.39-7.13 (m, 2H), 7.06- 6.97 (m, 2H), 5.60 (dd, J = 9.7, 5.1
Hz, 1H), 5.23-5.16 (m, 1H), 4.26 (dd, J = 10.5, 1.0 Hz, 1H), 4.11
(d, J = 10.6 Hz, 1H), 2.82 (s, 3 H), 2.82-2.76 (m, 1H), 2.70 (dd, J
= 13.2, 7.6 Hz, 1H), 2.00- 1.87 (m, 1H), 1.83-1.70 (m, 3H), 1.03
(t, J = 6.5 Hz, 6H). 60 ##STR00135## [M + H].sup.+ 471.24 .sup.1H
NMR (400 MHz, Acetone-d.sub.6) .delta. 9.79 (s, 1H), 8.99 (d, J =
2.0 Hz, 1H), 8.50 (d, J = 2.1 Hz, 1H), 7.71 (t, J = 2.1 Hz, 1H),
7.33 (td, J = 7.7, 1.4 Hz, 1H), 7.13-7.05 (m, 2H), 7.01 (td, J =
7.5, 1.1 Hz, 1H), 5.54 (dd, J = 9.0, 6.0 Hz, 1H), 5.24 (t, J = 8.5
Hz, 1H), 4.38 (dd, J = 10.7, 1.3 Hz, 1H), 4.12-3.96 (m, 1H), 3.04
(s, 3H), 2.82-2.67 (m, 2H), 1.92 (ddd, J = 14.0, 8.9, 5.4 Hz, 1H),
1.82 (ddd, J = 14.0, 8.5, 6.1 Hz, 1H), 1.78-1.65 (m, 1H), 1.01 (dd,
J = 14.7, 6.5 Hz, 6H). 61 ##STR00136## [M + Na].sup.+ 519.04,
521.08 .sup.1H NMR (400 MHz, Acetone-d.sub.6) .delta. 9.79 (s, 1H),
7.49-7.23 (m, 3H), 7.20-6.90 (m, 4H), 5.59 (dd, J = 8.6, 6.3 Hz,
1H), 5.23 (br, 1H), 4.21 (d, J = 10.8 Hz, 1H), 4.08 (br, 1H), 2.85
(s, 3 H)2.74 (td, J = 14.0, 13.0, 8.5 Hz, 2H), 1.97-1.61 (m, 3H),
1.01 (t, J = 6.3 Hz, 6H). 62 ##STR00137## [M + Na].sup.+ 519.19,
521.11 .sup.1H NMR (400 MHz, Acetone-d.sub.6) .delta. 9.80 (s, 1H),
7.50 (s, 1H), 7.31 (d, J = 21.4 Hz, 1H), 7.22 (td, J = 8.6, 3.1 Hz,
1H), 7.07 (d, J = 26.1 Hz, 4H), 5.58 (t, J = 7.4 Hz, 1H), 5.22 (d,
J = 9.0 Hz, 1H), 4.23 (d, J = 10.6 Hz, 1H), 4.16-3.97 (m, 1H), 2.82
(s, 3 H), 2.80-2.67 (m, 2H), 1.94-1.64 (m, 3H), 1.01 (t, J = 6.4
Hz, 6H). 63 ##STR00138## [M + Na].sup.+ 519.13, 521.02 .sup.1H NMR
(400 MHz, Acetone-d.sub.6) .delta. 9.78 (s, 1H), 7.35 (td, J = 7.6,
1.5 Hz, 1H), 7.28 (t, J = 8.9 Hz, 1H), 7.18-7.03 (m, 4H), 7.04-6.94
(m, 2H), 5.51 (dd, J = 8.9, 6.0 Hz, 1H), 5.23 (t, J = 8.5 Hz, 1H),
4.42-4.26 (m, 1H), 4.00 (d, J = 10.7 Hz, 1H), 2.97 (s, 3H),
2.82-2.60 (m, 2H), 1.89 (ddd, J = 14.2, 10.9, 5.5 Hz, 1H), 1.79
(ddd, J = 14.0, 8.4, 6.1 Hz, 1H), 1.69 (dq, J = 13.9, 6.6 Hz, 1H),
1.00 (dd, J = 14.5, 6.5 Hz, 6H). 64 ##STR00139## [M + Na].sup.+
535.11, 537.00 .sup.1H NMR (400 MHz, Acetone-d.sub.6) .delta. 9.73
(s, 1H), 7.49 (ddt, J = 7.3, 3.9, 1.9 Hz, 1H), 7.46-7.42 (m, 2H),
7.28 (tt, J = 7.7, 1.1 Hz, 1H), 7.15 (d, J = 7.5 Hz, 1H), 7.01 (dt,
J = 7.5, 3.7 Hz, 2H), 5.62-5.54 (m, 1H), 5.20 (t, J = 8.4 Hz, 1H),
4.27 (d, J = 10.3 Hz, 1H), 4.15 (d, J = 10.3 Hz, 1H), 2.90 (s, 3H),
2.79-2.61 (m, 2H), 1.98- 1.68 (m, 3H), 1.03 (dd, J = 8.9, 6.5 Hz,
6H). 65 ##STR00140## [M + Na].sup.+ 540.13, 542.10 .sup.1H NMR (400
MHz, Acetone-d.sub.6) .delta. 10.77 (s, 1H), 9.67 (s, 1H), 7.47 (d,
J = 8.2 Hz, 1H), 7.23 (t, J = 7.9 Hz, 1H), 7.14 (dd, J = 7.5, 0.8
Hz, 1H), 7.04 (d, J = 7.4 Hz, 2H), 6.95-6.89 (m, 2H), 6.84 (t, J =
7.5 Hz, 1H), 5.60 (dd, J = 9.5, 5.7 Hz, 1H), 5.22 (t, J = 8.2 Hz,
1H), 4.27 (d, J = 10.7 Hz, 1H), 4.01 (d, J = 10.6 Hz, 1H), 3.47 (s,
3H), 2.81-2.63 (m, 2H), 1.94 (td, J = 9.3, 4.7 Hz, 1H), 1.80 (ddd,
J = 14.2, 8.7, 5.7 Hz, 1H), 1.65 (dpd, J = 8.6, 6.6, 5.2 Hz, 1H),
0.99 (m, 6H). 66 ##STR00141## [M - H].sup.- 594.05, 596.03 .sup.1H
NMR (400 MHz, Acetone-d.sub.6) .delta. 9.69 (s, 1H), 7.61 (d, J =
8.2 Hz, 1H), 7.49 (d, J = 8.2 Hz, 1H), 7.39 (s, 1H), 7.19-7.08 (m,
2H), 7.08-6.97 (m, 1H), 6.93 (t, J = 8.7 Hz, 1H), 5.44 (dd, J =
9.7, 5.4 Hz, 1H), 5.22 (td, J = 8.3, 3.9 Hz, 1H), 4.13- 3.97 (m,
2H), 3.62 (s, 3H), 2.84-2.61 (m, 2H), 1.86 (ddd, J = 14.5, 9.0, 5.5
Hz, 1H), 1.79-1.58 (m, 2H), 1.10-0.90 (m, 6H). 67 ##STR00142## [M +
H].sup.+ 509.22 .sup.1H NMR (400 MHz, Acetone-d.sub.6) .delta.
11.02 (s, 1H), 9.67 (s, 1H), 7.84 (d, J = 8.3 Hz, 1H), 7.59 (dd, J
= 7.3, 0.9 Hz, 1H), 7.41 (dd, J = 8.4, 7.3 Hz, 1H), 7.13-6.94 (m,
3H), 6.96-6.77 (m, 2H), 5.60 (dd, J = 9.4, 5.7 Hz, 1H), 5.23 (t, J
= 8.2 Hz, 1H), 4.26 (d, J = 10.7 Hz, 1H), 4.00 (d, J = 10.7 Hz,
1H), 3.49 (s, 3H), 2.81-2.66 (m, 2H), 2.00-1.88 (m, 1H), 1.81 (ddd,
J = 14.2, 8.6, 5.7 Hz, 1H), 1.66 (dtd, J = 8.4, 6.6, 5.1 Hz, 1H),
1.00 (dd, J = 16.8, 6.6 Hz, 6H). 68 ##STR00143## [M + H].sup.+
509.22 .sup.1H NMR (400 MHz, Acetone-d.sub.6) .delta. 10.75 (s,
1H), 9.68 (s, 1H), 7.21 (d, J = 9.2 Hz, 1H), 7.13-6.99 (m, 2H),
6.96 (d, J = 9.7 Hz, 2H), 6.88 (s, 2H), 5.56 (br, 1H), 5.22 (t, J =
8.3 Hz, 1H), 4.24 (d, J = 10.7 Hz, 1H), 3.99 (d, J = 10.6 Hz, 1H),
3.40 (s, 3H), 2.77-2.60 (m, 2H), 1.98 (s, 1H), 1.87-1.70 (m, 1H),
1.63 (s, 1H), 0.99 (dd, J = 17.8, 6.5 Hz, 6H). 69 ##STR00144## [M +
Na].sup.+ 542.22 .sup.1H NMR (400 MHz, Acetone-d.sub.6) .delta.
10.61 (s, 1H), 9.67 (s, 1H), 7.54 (s, 1H), 7.38 (dd, J = 11.0, 6.9
Hz, 1H), 7.16-6.96 (m, 2H), 6.93 (br, 2H), 6.81 (br, 1H), 5.57 (d,
J = 9.3 Hz, 1H), 5.21 (t, J = 8.3 Hz, 1H), 4.29 (d, J = 10.8 Hz,
1H), 3.99 (d, J = 10.6 Hz, 1H), 3.42 (s, 3H), 2.72 (qd, J = 13.2,
8.3 Hz, 2H), 1.99-1.89 (m, 1H), 1.77 (ddd, J = 14.2, 8.8, 5.5 Hz,
1H), 1.62 (dq, J = 14.1, 6.7 Hz, 1H), 0.98 (dd, J = 20.8, 6.5 Hz,
6H). 70 ##STR00145## [M + Na].sup.+ 524.20 .sup.1H NMR (400 MHz,
Acetone-d.sub.6) .delta. 10.53 (s, 1H), 9.68 (s, 1H), 7.50 (dd, J =
9.0, 4.5 Hz, 1H), 7.33 (d, J = 9.6 Hz, 1H), 7.16- 6.98 (m, 3H),
6.89 (dd, J = 26.7, 10.6 Hz, 3H), 5.64-5.46 (m, 1H), 5.21 (t, J =
8.2 Hz, 1H), 4.27 (d, J = 10.6 Hz, 1H), 4.00 (d, J = 10.6 Hz, 1H),
3.43 (s, 3H), 2.71 (tt, J = 13.3, 6.4 Hz, 2H), 1.97-1.88 (m, 1H),
1.78 (ddd, J = 14.2, 8.8, 5.6 Hz, 1H), 1.63 (dd, J = 13.7, 7.0 Hz,
1H), 0.98 (dd, J = 20.0, 6.5 Hz, 6H). 71 ##STR00146## [M +
Na].sup.+ 542.21 .sup.1H NMR (400 MHz, Acetone-d.sub.6) .delta.
10.96 (s, 1H), 9.67 (s, 1H), 7.04 (d, J = 7.6 Hz, 2H), 7.00-6.89
(m, 3H), 6.85 (t, J = 7.5 Hz, 1H), 6.77 (ddd, J = 9.8, 8.5, 3.0 Hz,
1H), 5.57 (dd, J = 9.5, 5.7 Hz, 1H), 5.22 (t, J = 8.3 Hz, 1H), 4.26
(d, J = 10.7 Hz, 1H), 4.00 (d, J = 10.7 Hz, 1H), 2.80- 2.64 (m,
2H), 1.00 (dd, J = 18.1, 6.6 Hz, 6H). 72 ##STR00147## [M + H].sup.+
536.11 .sup.1H NMR (400 MHz, Acetone-d.sub.6) .delta. 10.84 (s,
1H), 9.67 (s, 1H), 7.27-7.14 (m, 1H), 7.11-6.98 (m, 3H), 6.98-6.87
(m, 2H), 6.82 (t, J = 7.5 Hz, 1H), 5.59 (dd, J = 9.5, 5.6 Hz, 1H),
5.21 (t, J = 8.3 Hz, 1H), 4.29 (d, J = 10.7 Hz, 1H), 3.99 (d, J =
10.6 Hz, 1H), 3.47 (s, 3H), 2.79-2.62 (m, 2H), 1.99-1.87 (m, 1H),
1.79 (ddd, J = 14.2, 8.8, 5.7 Hz, 1H), 1.63 (dddd, J = 13.2, 11.7,
8.8, 6.5 Hz, 1H), 0.99 (dd, J = 19.1, 6.6 Hz, 6H). 73 ##STR00148##
[M - H].sup.- 534.24, 535.68 .sup.1H NMR (400 MHz, Acetone-d.sub.6)
.delta. 10.87 (s, 1H), 9.68 (s, 1H), 7.36 (d, J = 8.7 Hz, 1H), 7.28
(dd, J = 8.8, 6.9 Hz, 1H), 7.03 (dd, J = 11.8, 7.4 Hz, 2H), 6.97
(s, 1H), 6.91 (d, J = 7.7 Hz, 1H), 6.82 (t, J = 7.5 Hz, 1H), 5.59
(dd, J = 9.4, 5.7 Hz, 1H), 5.22 (t, J = 8.3 Hz, 1H), 4.28 (d, J =
10.7 Hz, 1H), 3.99 (d, J = 10.6 Hz, 1H), 3.46 (s, 3H), 2.78-2.65
(m, 2H),
1.99-1.89 (m, 1H), 1.79 (ddd, J = 14.2, 8.7, 5.6 Hz, 1H), 1.72-1.44
(m, 1H), 0.99 (m, 6H). 74 ##STR00149## [M - H].sup.- 550.13, 552.14
.sup.1H NMR (400 MHz, Acetone-d.sub.6) .delta. 10.89 (s, 1H), 9.67
(s, 1H), 7.52 (s, 1H), 7.19 (d, J = 1.7 Hz, 1H), 7.08-6.97 (m, 2H),
6.97- 6.88 (m, 2H), 6.82 (t, J = 7.5 Hz, 1H), 5.59 (dd, J = 9.5,
5.6 Hz, 1H), 5.22 (t, J = 8.3 Hz, 1H), 4.29 (d, J = 10.7 Hz, 1H),
3.99 (d, J = 10.6 Hz, 1H), 3.47 (s, 3H), 2.79-2.63 (m, 2H),
2.02-1.87 (m, 1H), 1.79 (ddd, J = 14.2, 8.7, 5.6 Hz, 1H), 1.64
(dtd, J = 8.7, 6.7, 5.1 Hz, 1H), 0.99 (m, 6H). 75 ##STR00150## [M -
H].sup.- 483.16 76 ##STR00151## [M - H].sup.- 550.07, 551.95
.sup.1H NMR (400 MHz, Acetone-d.sub.6) .delta. 10.31 (s, 1H), 9.67
(s, 1H), 7.63 (s, 1H), 7.32 (s, 1H), 7.14-6.88 (m, 3H), 6.82 (d, J
= 13.9 Hz, 2H), 5.53 (s, 1H), 5.20 (t, J = 8.4 Hz, 1H), 4.25 (d, J
= 10.8 Hz, 1H), 3.95 (d, J = 10.6 Hz, 1H), 3.36 (s, 3H), 2.68 (td,
J = 14.1, 13.3, 8.4 Hz, 2H), 1.85 (br, 1H), 1.79 (m, J1H), 1.61 (m,
1H), 0.96 (dd, J = 16.7, 6.6 Hz, 6H). 77 ##STR00152## [M + H].sup.+
536.15, 538.06 .sup.1H NMR (400 MHz, Acetone-d.sub.6) .delta. 10.80
(s, 1H), 9.72 (s, 1H), 7.51 (dd, J = 9.1, 4.3 Hz, 1H), 7.25 (t, J =
7.9 Hz, 2H), 7.18 (d, J = 7.4 Hz, 1H), 7.16-7.08 (m, 1H), 6.99 (dd,
J = 17.6, 7.9 Hz, 2H), 5.47-5.30 (m, 1H), 5.21 (t, J = 8.1 Hz, 1H),
4.26 (d, J = 10.5 Hz, 1H), 4.09 (d, J = 10.5 Hz, 1H), 3.24 (s, 3H),
2.86-2.63 (m, 2H), 2.03- 1.93 (m, 1H), 1.82 (d, J = 15.3 Hz, 2H),
1.02 (dd, J = 23.0, 6.0 Hz, 6484.20 H). 78 ##STR00153## [M +
H].sup.+ 484.20 .sup.1H NMR (400 MHz, Acetone-d.sub.6) .delta.
10.43 (s, 1H), 9.67 (s, 1H), 7.64 (s, 1H), 7.49 (d, J = 8.3 Hz,
1H), 7.23 (ddd, J = 8.2, 6.9, 1.1 Hz, 1H), 7.06 (q, J = 9.4, 8.4
Hz, 3H), 6.89 (dd, J = 20.9, 11.6 Hz, 3H), 5.59 (dd, J = 9.5, 5.6
Hz, 1H), 5.21 (t, J = 8.2 Hz, 1H), 4.27 (d, J = 10.6 Hz, 1H), 4.01
(d, J = 10.6 Hz, 1H), 3.44 (s, 3H), 2.79-2.63 (m, 2H), 1.94 (ddd, J
= 19.1, 9.7, 4.9 Hz, 1H), 1.78 (ddd, J = 14.2, 8.7, 5.6 Hz, 1H),
1.71-1.55 (m, 1H), 0.98 (dd, J = 20.7, 6.5 Hz, 6H). 79 ##STR00154##
[M - H].sup.- 560.00, 562.00 .sup.1H NMR (400 MHz, Acetone-d.sub.6)
.delta. 10.79 (s, 1H), 9.67 (s, 1H), 7.52 (d, J = 8.2 Hz, 1H), 7.31
(d, J = 7.5 Hz, 1H), 7.17 (t, J = 7.9 Hz, 1H), 7.04 (d, J = 7.6 Hz,
2H), 6.97- 6.78 (m, 3H), 5.60 (dd, J = 9.4, 5.7 Hz, 1H), 5.21 (t, J
= 8.2 Hz, 1H), 4.33-4.02 (m, 1H), 4.00 (d, J = 10.6 Hz, 1H), 3.47
(s, 3H), 2.79-2.63 (m, 2H), 1.94 (ddd, J = 14.4, 9.5, 5.2 Hz, 1H),
1.80 (ddd, J = 14.2, 8.6, 5.6 Hz, 1H), 1.72-1.57 (m, 1H), 0.99 (dd,
J = 18.4, 6.5 Hz, 6H). 80 ##STR00155## [M - H].sup.- 534.19 .sup.1H
NMR (400 MHz, Acetone-d.sub.6) .delta. 10.59 (s, 1H), 9.64 (s, 1H),
7.42-7.35 (m, 2H), 7.32-7.21 (m, 3H), 7.24-7.13 (m, 2H), 7.02 (dt,
J = 7.4, 1.9 Hz, 2H), 6.92-6.85 (m, 1H), 6.85-6.74 (m, 3H), 5.76
(dd, J = 8.6, 6.7 Hz, 1H), 5.21 (t, J = 8.3 Hz, 1H), 4.24 (d, J =
10.6 Hz, 1H), 3.73 (d, J = 10.6 Hz, 1H), 3.53 (s, 3H), 3.40 (dd, J
= 14.0, 6.7 Hz, 1H), 3.26 (dd, J = 14.1, 8.6 Hz, 1H), 2.72 (ddd, J
= 13.3, 8.5, 1.1 Hz, 1H), 2.62 (dd, J = 13.2, 8.0 Hz, 1H). 81
##STR00156## [M - H].sup.- 552.18 .sup.1H NMR (400 MHz,
Acetone-d.sub.6) .delta. 10.69 (s, 1H), 9.65 (s, 1H), 7.41-7.34 (m,
2H), 7.29-7.21 (m, 2H), 7.24-7.13 (m, 1H), 7.07-6.97 (m, 3H), 6.89
(d, J = 7.6 Hz, 1H), 6.85 (s, 1H), 6.79 (t, J = 7.5 Hz, 1H), 6.72
(td, J = 10.3, 2.1 Hz, 1H), 5.76 (dd, J = 8.8, 6.6 Hz, 1H), 5.21
(t, J = 8.3 Hz, 1H), 4.25 (d, J = 10.7 Hz, 1H), 3.73 (d, J = 10.6
Hz, 1H), 3.52 (s, 3H), 3.39 (dd, J = 14.1, 6.7 Hz, 1H), 3.26 (dd, J
= 14.1, 8.8 Hz, 1H), 2.72 (ddd, J = 13.2, 8.5, 1.2 Hz, 1H), 2.63
(dd, J = 13.3, 8.1 Hz, 1H). 82 ##STR00157## [M + Na].sup.+ 562.24
.sup.1H NMR (400 MHz, Acetone-d.sub.6) .delta. 10.39 (s, 1H), 9.67
(s, 1H), 7.17 (t, J = 7.9 Hz, 1H), 7.13-6.96 (m, 3H), 6.87 (td, J =
18.4, 16.6, 7.2 Hz, 5H), 5.58 (d, J = 9.4 Hz, 1H), 5.20 (t, J = 8.2
Hz, 1H), 4.27 (d, J = 10.8 Hz, 1H), 4.03-3.92 (m, 1H), 3.43 (s,
3H), 3.38 (d, J = 7.2 Hz, 1H), 2.78-2.62 (m, 2H), 1.99-1.85 (m,
1H), 1.77 (dt, J = 14.2, 7.2 Hz, 1H), 1.63 (dd, J = 14.3, 7.7 Hz,
1H), 1.45-1.35 (m, 2H), 1.34-1.28 (m, 1H), 1.19 (q, J = 8.0, 7.3
Hz, 1H), 1.01 (d, J = 6.7 Hz, 3H), 0.95 (d, J = 6.6 Hz, 3H). 83
##STR00158## [M + Na].sup.+ 560.19 .sup.1H NMR (400 MHz,
Acetone-d.sub.6) .delta. 10.87 (s, 1H), 9.69 (s, 1H), 7.31-7.20 (m,
1H), 7.09-6.95 (m, 3H), 6.91 (d, J = 7.7 Hz, 1H), 6.80 (t, J = 7.5
Hz, 1H), 5.58 (dd, J = 9.5, 5.6 Hz, 1H), 5.21 (t, J = 8.3 Hz, 1H),
4.29 (d, J = 10.7 Hz, 1H), 3.98 (d, J = 10.6 Hz, 1H), 3.46 (s, 3H),
2.81-2.58 (m, 2H), 1.94 (ddd, J = 14.4, 9.6, 5.0 Hz, 1H), 1.78
(ddd, J = 14.2, 8.8, 5.6 Hz, 1H), 1.70-1.55 (m, 1H), 1.01 (d, J =
6.6 Hz, 3H), 0.96 (d, J = 6.5 Hz, 3H). 84 ##STR00159## [M +
Na].sup.+ 548.26 .sup.1H NMR (400 MHz, Acetone-d.sub.6) .delta.
10.28 (s, 1H), 9.68 (s, 1H), 7.54 (s, 1H), 7.20- 6.97 (m, 3H),
6.97-6.72 (m, 3H), 5.58 (dd, J = 9.4, 5.6 Hz, 1H), 5.21 (t, J = 8.2
Hz, 1H), 4.25 (d, J = 10.6 Hz, 1H), 4.01 (d, J = 10.6 Hz, 1H), 3.43
(s, 3H), 3.01 (td, J = 13.5, 6.6 Hz, 1H), 2.81-2.60 (m, 2H),
2.01-1.85 (m, 1H), 1.78 (ddd, J = 14.2, 8.7, 5.6 Hz, 1H), 1.63 (dq,
J = 13.6, 6.6 Hz, 1H), 1.29 (d, J = 6.9 Hz, 6H), 1.01 (d, J = 6.6
Hz, 3H), 0.99-0.89 (m, 3H). 85 ##STR00160## [M + Na].sup.+ 550.24
.sup.1H NMR (400 MHz, Chloroform-d) .delta. 8.81 (s, 1H), 8.14 (s,
1H), 7.20 (t, J = 8.0 Hz, 1H), 7.04-6.89 (m, 3H), 6.83 (d, J = 7.8
Hz, 1H), 6.73-6.58 (m, 2H), 6.50 (d, J = 7.8 Hz, 1H), 5.59 (t, J =
6.4 Hz, 1H), 5.00 (t, J = 8.6 Hz, 1H), 4.65 (d, J = 10.4 Hz, 1H),
4.01-3.91 (m, 1H), 3.99 (s, 3H), 3.49 (s, 3H), 2.94-2.78 (m, 1H),
2.51 (dd, J = 13.2, 8.5 Hz, 1H), 2.11 (q, J = 6.5, 5.3 Hz, 1H),
1.74 (dd, J = 14.3, 6.0 Hz, 1H), 0.99 (s, 9H). 86 ##STR00161## [M +
Na].sup.+ 556.21 .sup.1H NMR (500 MHz, Chloroform-d) .delta. 9.21
(s, 1H), 8.67 (s, 1H), 7.10 (ddd, J = 10.6, 8.9, 7.3 Hz, 1H),
7.07-6.89 (m, 2H), 6.89-6.74 (m, 2H), 6.74-6.54 (m, 2H), 5.55 (t, J
= 6.4 Hz, 1H), 5.03 (t, J = 8.5 Hz, 1H), 4.48 (d, J = 10.5 Hz, 1H),
3.98 (d, J = 10.5 Hz, 1H), 3.48 (s, 3H), 2.86 (dd, J = 13.3, 8.7
Hz, 1H), 2.52 (ddd, J = 13.3, 8.4, 1.3 Hz, 1H), 2.20-2.13 (m, 1H),
1.73 (dd, J = 14.3, 6.0 Hz, 1H), 0.99 (s, 9H). 87 ##STR00162## [M +
Na].sup.+ 538.22 88 ##STR00163## [M + Na].sup.+ 556.21 .sup.1H NMR
(400 MHz, Chloroform-d) .delta. 9.34 (s, 1H), 8.79 (s, 1H), 6.96
(t, J = 7.6 Hz, 1H), 6.89-6.79 (m, 3H), 6.73-6.54 (m, 3H), 5.57 (t,
J = 6.4 Hz, 1H), 5.03 (t, J = 8.5 Hz, 1H), 4.51 (d, J = 10.5 Hz,
1H), 3.97 (d, J = 10.5 Hz, 1H), 3.47 (s, 3H), 2.85 (dd, J = 13.3,
8.5 Hz, 1H), 2.52 (dd, J = 13.3, 8.5 Hz, 1H), 2.21-2.11 (m, 1H),
1.76 (d, J = 6.2 Hz, 1H), 0.99 (s, 9H).
Example 89
##STR00164##
[0289] Step 1
[0290] To a mixture of
(S)-2-(((benzyloxy)carbonyl)amino)-3-cyclobutylpropanoic acid (2.68
g, 9.66 mmol) and MeI (4.83 mL, 77 mmol) in THE (30 mL) at
0.degree. C. was added NaH (1.16 g, 29 mmol) portionwise. The
resulting mixture was stirred at rt for 2 days, quenched with
ice-water, and washed with MBTE (2.times.). The aqueous layer was
acidified with 1 N HCl to PH .about.2 and extracted with EtOAc. The
collected organic layer was washed with brine, dried over
Na.sub.2SO.sub.4, filtered, and concentrated give the desired
compound (89-1) (2.54 g, 90% yield). ESI-MS m/z=290.12
[M-H].sup.-.
Step 2
[0291] To a solution of compound (1-4) (2.33 g, 6.96 mmol),
compound (89-1) (2.54 g, 8.70 mmol) and 4-methylmorpholine (3.06
mL, 27.9 mmol) in DCM/DMF (5/5 mL) was added HATU (2.78 g, 7.31
mmol). The mixture was stirred at rt for 2 h, quenched with water,
and extracted with EtOAc. The collected organic layer was washed
with water, 1N HCl, sat NaHCO.sub.3 and brine, dried over
Na.sub.2SO.sub.4, filtered, and concentrated. Purification of the
residue on silica gel column provided compound (89-2) (3.16 g, 90%
yield). ESI-MS m/z=503.19 [M-H].sup.-.
Step 3
[0292] To a mixture of compound (89-2) (45 mg, 0.089 mmol) and
Et.sub.3N (99 .mu.l, 0.713 mmol) in DCM (1 mL) at 0.degree. C. was
added dropwise TFAA (50.4 .mu.l, 0.357 mmol). The resulting mixture
was stirred at rt for 30 min, quenched with cold sat. NaHCO.sub.3
solution, and extracted with EtOAc. The collected organic layer was
washed with water, 1N HCl, sat NaHCO.sub.3, and brine, dried over
Na.sub.2SO.sub.4, filtered, and concentrated. Purification of the
residue on silica gel column provided Example 89 (23 mg, 53%
yield). ESI-MS m/z=485.19 [M-H].sup.-.
[0293] The following example was prepared employing similar
protocol as described above.
TABLE-US-00010 Example # Structure MS 90 ##STR00165## [M - H]
487.19
Example 91
##STR00166##
[0294] Step 1
[0295] A mixture of compound (89-2) (65 mg, 0.13 mmol) and Pd--C
(13.7 mg, 0.013 mmol) in MeOH (1 mL) was treated with H.sub.2 using
a hydrogen balloon. After 1 h, the mixture was diluted with DCM,
filtered through celite, and concentrated to give compound (91-1)
(48 mg, 100%). ESI-MS m/z=369.19 [M-H].sup.-.
Step 2
[0296] To a mixture of compound (91-1) (0.032 g, 0.086 mmol),
4,6-difluoro-1H-indole-2-carboxylic acid (0.021 g, 0.108 mmol),
DIPEA (0.045 mL, 0.258 mmol) in DCM/DMF (0.5/0.5 mL) at rt was
added HATU (39 mg, 0.103 mmol). The resulting mixture was stirred
at rt for 20 h, quenched water, and extracted with EtOAc. The
collected organic layer was washed with water and brine, dried over
Na.sub.2SO.sub.4, filtered, and concentrated. Purification of the
residue on silica gel column provided compound (91-2) (34 mg, 72%
yield). ESI-MS m/z=548.21 [M-H].sup.-.
Step 3
[0297] To a mixture of compound (91-2) (34 mg, 0.062 mmol) and
Et.sub.3N (86 .mu.l, 0.619 mmol) in DCM (1 mL) at 0.degree. C. was
added TFAA (44 .mu.l, 0.31 mmol). The mixture was stirred at rt for
30 min, quenched with cold sat. NaHCO.sub.3, and extracted with
EtOAc. The collected organic layer was washed with 1 N HCl, sat.
NaHCO.sub.3, brine, dried over Na.sub.2SO.sub.4, filtered, and
concentrated. Purification of the residue on silica gel
chromatography with 0-40% acetone/cyclohexane provided Example 91
(17 mg, 52% yield). ESI-MS m/z=530.20 [M-H].sup.-. H NMR (400 MHz,
Acetone-d.sub.6) .delta. 10.65 (s, 1H), 9.51 (s, 1H), 6.97-6.83 (m,
3H), 6.81-6.72 (m, 2H), 6.67 (t, J=7.6 Hz, 1H), 6.60 (td, J=10.3,
2.1 Hz, 1H), 5.28 (t, J=7.4 Hz, 1H), 5.05 (t, J=8.2 Hz, 1H), 4.08
(d, J=10.7 Hz, 1H), 3.82 (d, J=10.6 Hz, 1H), 3.28 (s, 3H), 2.69 (s,
1H), 2.67-2.48 (m, 2H), 2.22 (hept, J=7.7 Hz, 1H), 1.89 (d, J=7.4
Hz, 3H), 1.74-1.53 (m, 4H).
[0298] The following examples were prepared employing similar
protocol as described above.
TABLE-US-00011 Example # Structure MS NMR 92 ##STR00167## [M -
H].sup.- 524.23 .sup.1H NMR (400 MHz, Acetone-d.sub.6) .delta.
10.25 (s, 1H), 9.50 (s, 1H), 7.05-6.97 (m, 1H), 6.96-6.85 (m, 3H),
6.75 (dd, J = 4.9, 2.7 Hz, 2H), 6.68 (t, J = 7.5 Hz, 1H), 6.43-6.36
(m, 1H), 5.28 (t, J = 7.5 Hz, 1H), 5.04 (t, J = 8.1 Hz, 1H), 4.09
(d, J = 10.6 Hz, 1H), 3.83 (d, J = 9.9 Hz, 4H), 3.28 (s, 3H), 2.69
(s, 1H), 2.60 (ddd, J = 13.3, 8.6, 1.0 Hz, 1H), 2.53 (dd, J = 13.3,
7.6 Hz, 1H), 2.22 (dt, J = 15.0, 7.7 Hz, 1H), 1.89 (d, J = 7.6 Hz,
2H), 1.89 (s, 1H), 1.74-1.63 (m, 1H), 1.66-1.53 (m, 3H). 93
##STR00168## [M - H].sup.- 512.18 .sup.1H NMR (400 MHz,
Acetone-d.sub.6) .delta. 10.72 (s, 1H), 9.66 (s, 1H), 7.33 (d, J =
8.3 Hz, 1H), 7.21 (td, J = 8.0, 5.2 Hz, 1H), 7.04 (d, J = 7.6 Hz,
2H), 6.94-6.87 (m, 2H), 6.87-6.76 (m, 2H), 5.44 (t, J = 7.5 Hz,
1H), 5.21 (t, J = 8.2 Hz, 1H), 4.22 (d, J = 10.6 Hz, 1H), 3.98 (d,
J = 10.6 Hz, 1H), 3.44 (s, 3H), 2.76 (ddd, J = 13.3, 8.6, 1.0 Hz,
1H), 2.68 (dd, J = 13.3, 7.8 Hz, 1H), 2.38 (p, J = 7.7 Hz, 1H),
2.04 (m, 2H), 2.03 (s, 1H), 1.98 (s, 1H), 1.89-1.68 (m, 4H). 94
##STR00169## [M + Na].sup.+ 574.25 95 ##STR00170## [M - H].sup.-
514.22
Example 96
##STR00171##
[0299] Step 1
[0300] To a solution of ((benzyloxy)carbonyl)-L-leucine (1.56 g,
5.88 mmol) and 3-iodoprop-1-ene (0.807 mL, 8.82 mmol) in THE (30
mL) at 0.degree. C. was added NaH (0.706 g, 17.64 mmol) in
portions. The mixture was stirred at rt for 4 days, quenched with
ice-water, and washed with MBTE twice. The aqueous layer was
acidified with 1 N HCl to PH .about.2, and extracted with EtOAc.
The collected organic layer was washed with brine, dry over
Na.sub.2SO.sub.4, filtered, and concentrated to afford compound
(96-1) (1.15 g, 64.0% yield). ESI-MS m/z=304.12 [M-H].sup.-.
Step 2
[0301] To a mixture of compound (1-4) (221 mg, 0.826 mmol),
compound (96-1) (265 mg, 0.868 mmol) and DIPEA (577 .mu.l, 3.31
mmol) in DCM/DMF (0.8/0.8 mL) was added HATU (314 mg, 0.826 mmol).
The resulting mixture was stirred at rt for 16 h, quenched with
water, and extracted with EtOAc. The organic layer was washed with
water, 1N HCl, sat NaHCO.sub.3 and brine, dried over
Na.sub.2SO.sub.4, filtered, and concentrated. Purification of the
residue by silica gel chromatography with 0-10% MeOH/DCM provided
compound (96-2) (262 mg, 61.1% yield). ESI-MS m/z=517.20
[M-H].sup.-.
Step 3
[0302] To a mixture of compound (96-2) (22 mg, 0.042 mmol) and
Et.sub.3N (59.1 .mu.l, 0.424 mmol) in DCM (1 mL) at 0.degree. C.
was added TFAA (30.0 .mu.l, 0.212 mmol). The mixture was stirred at
rt for 30 min, quenched with cold sat. NaHCO.sub.3 solution, and
extracted with EtOAc. The organic layer was washed with water, 1N
HCl, sat NaHCO.sub.3 and brine, dried over Na.sub.2SO.sub.4,
filtered, and concentrated. Purification of the residue on silica
gel chromatography with 0-50% acetone/cyclohexane provided Example
96 (20 mg, 94% yield). ESI-MS m/z=499.20 [M-H].sup.-.
Example 97
##STR00172##
[0303] Step 1
[0304] A mixture of compound (96-2) (105 mg, 0.202 mmol) and Pd--C
(21.55 mg, 0.020 mmol) in MeOH (3 mL) was stirred under H.sub.2
using a hydrogen balloon. After 1 h, the mixture was diluted with
DCM, filtered through celite, and concentrated to give compound
(97-1) (79 mg, 100%). ESI-MS m/z=385.19 [M-H].sup.-.
Step 2
[0305] To a mixture of compound (97-1) (0.039 g, 0.10 mmol) in
DCM/DMF (0.5/0.5 mL) and Et.sub.3N (0.098 mL, 0.70 mmol) was added
Cbz-Cl (0.042 mL, 0.30 mmol). The mixture was stirred at rt for 16
h, quenched with aqueous NH.sub.3, and extracted with EtOAc. The
organic layer was washed with water and brine, dried over
N.sub.2SO.sub.4, filtered, and concentrated. Purification of the
residue by silica gel chromatography with 0-10% MeOH/DCM provided
(97-2) (10 mg, 19% yield). ESI-MS m/z=519.22 [M-H].sup.-.
Step 3
[0306] To a mixture compound (97-2) (10 mg, 0.019 mmol) and
Et.sub.3N (53.5 .mu.l, 0.384 mmol) in DCM (0.5 mL) was added TFAA
(27.1 .mu.l, 0.192 mmol) at 0.degree. C. quenched with cold sat.
NaHCO.sub.3 solution, and extracted with EtOAc. The organic layer
was washed with 1 N HCl, sat. NaHCO.sub.3 solution and brine, dried
over Na.sub.2SO.sub.4, filtered, and concentrated. Purification of
the residue by silica gel chromatography with 0-50%
acetone/cyclohexane provided Example 97 (7.0 mg, 72.5% yield)
ESI-MS m/z=501.22 [M-H].sup.-.
Example 98
##STR00173##
[0307] Step 1
[0308] A mixture of 4-fluoro-1H-indole-2-carboxylic acid (0.054 g,
0.30 mmol) and 1-chloro-N,N,2-trimethylprop-1-en-1-amine (0.044 mL,
0.330 mmol) in DCM (1 mL) was stirred at rt for 1 h. The resulting
mixture was added to a solution of compound (97-1) and Et.sub.3N
(0.108 mL, 0.85 mmol) in DCM/DMF (0.5/0.5 mL). The resulting
mixture was stirred rt for 20 h, quenched aqueous NH.sub.3, and
extracted with EtOAc. The organic layer was washed with water and
brine, dried over Na.sub.2SO.sub.4, filtered, and concentrated.
Purification of the residue by silica gel chromatography with 0-10%
MeOH/DCM provided compound (98-1)(40 mg, 69% yield). ESI-MS
m/z=546.23 [M-H].sup.-.
Step 2
[0309] To a mixture of compound (98-1) (40 mg, 0.073 mmol) and
Et.sub.3N (10.18 .mu.l, 0.073 mmol) in DCM (1 mL) at 0.degree. C.
was added TFAA (10.32 .mu.l, 0.073 mmol). The mixture was stirred
at rt for 30 min, quenched with cold sat. NaHCO.sub.3, and
extracted with EtOAc. The organic layer was washed with 1 N HCl,
sat. NaHCO.sub.3 and brine, dried over Na.sub.2SO.sub.4, filtered,
and concentrated. Purification of the residue by silica gel
chromatography with 0-50% acetone/cyclohexane provided Example 98
(35 mg, 90% yield) ESI-MS m/z=528.20 [M-H].sup.-.
[0310] The following example was prepared employing similar
protocol as described above.
TABLE-US-00012 Example # Structure MS 99 ##STR00174## [M - H]
546.23
Example 100
##STR00175##
[0311] Synthesis of
(S)-2-(((benzyloxy)carbonyl)(methyl)amino)-5-methylhexanoic
acid
Step 1
[0312] To a mixture of (S)-2-amino-5-methylhexanoic acid (0.9 g,
6.20 mmol) in toluene/water (12.4 mL/3 mL) at 0.degree. C. was
added 2N NaOH (9.30 mL, 18.59 mmol), followed by addition of Cbz-Cl
(0.973 mL, 6.82 mmol). After stirring at rt for 2 hrs, the two
layers were separated, and the aqueous layer was washed with MBTE
(2.times.), and then acidified to pH .about.2 with 1 N HCl solution
at 0.degree. C. The mixture was extracted with EtOAc (3.times.).
The combined organics were washed with brine, dried over
Na.sub.2SO.sub.4, and concentrated to give
(S)-2-(((benzyloxy)carbonyl)amino)-5-methylhexanoic acid (1.42 g,
5.08 mmol, 82% yield), which was used in the next step without
further purification. LC-MS, ES-: 277.77 [M-1].
Step 2
[0313] To a solution of
(S)-2-(((benzyloxy)carbonyl)amino)-5-methylhexanoic acid (660 mg,
2.363 mmol) and paraformaldehyde (426 mg, 14.18 mmol)) in dry
acetonitrile (11.8 mL) was added 4-methylbenzenesulfonic acid
hydrate (44.9 mg, 0.236 mmol). The resulting mixture was heated
under microwave at 130.degree. C. for 10 min. After cooling to rt,
the mixture was filtered through celite, concentrated, and chased
with DCM to give the crude benzyl
(S)-4-isopentyl-5-oxooxazolidine-3-carboxylate as a sticky oil,
which was used in the next step without further purification.
Step 3
[0314] To the crude benzyl
(S)-4-isopentyl-5-oxooxazolidine-3-carboxylate from previous step
was added DCM (24 mL), triethylsilane (1.89 mL, 11.81 mmol), and
2,2,2-trifluoroacetic acid (7.28 mL, 95 mmol). The mixture was
stirred at rt for 2 hrs, concentrated, and chased with DCM
(3.times.). The residue was basified with 1N NaOH at 0.degree. C.
to pH .about.10, and washed with EtOAc (1.times.) and MBTE
(1.times.). The aqueous layer was acidified to pH .about.2 with 1N
HCl, and extracted with EtOAc (2.times.). The combined organics
were washed with brine, dried, and concentrated to give
(S)-2-(((benzyloxy)carbonyl)(methyl)amino)-5-methylhexanoic acid
(715 mg, 92% yield for 2 steps). 1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 12.56 (s, 1H), 7.41-7.27 (m, 5H), 5.17-5.00 (m, 2H), 4.48
(ddd, J=27.4, 11.1, 4.7 Hz, 1H), 2.81 (s, 2H, N-Me rotamer), 2.78
(s, 1H, N-Me rotamer), 1.84 (tq, J=9.6, 4.6, 4.1 Hz, 1H), 1.70
(ddd, J=14.4, 9.6, 4.5 Hz, 1H), 1.52 (dt, J=12.8, 6.5 Hz, 1H),
1.21-0.99 (m, 2H), 0.84 (dd, J=9.2, 6.6 Hz, 6H).
##STR00176##
Synthesis of Example 100
Step 1
[0315] To a mixture of
(S)-2-(((benzyloxy)carbonyl)(methyl)amino)-5-methylhexanoic acid
(300 mg, 1.023 mmol) and (1-4) (261 mg, 0.974 mmol) in dry
CH.sub.2Cl.sub.2 (2.96 mL) at 0.degree. C. was added DIPEA (510
.mu.l, 2.92 mmol) and HATU (481 mg, 1.266 mmol). The resulting
mixture was stirred at rt for 2 hrs. The mixture was diluted with
DCM, washed with water (2.times.), brine, dried, and concentrated.
Purification of the residue on silica gel chromatography with 0-10%
MeOH/DCM provided benzyl
((S)-1-((3R,5'S)-5'-carbamoyl-2-oxospiro[indoline-3,3'-pyrrolidin]-1'-yl)-
-5-methyl-1-oxohexan-2-yl)(methyl)carbamate (100-1) (189 mg, 38%
yield).
[0316] LC-MS, ES-: 505.0 [M-1].
Step 2
[0317] To a mixture of compound (100-1) (31 mg, 0.061 mmol) and
Et.sub.3N (85 .mu.L, 0.612 mmol) in dry DCM (0.8 mL) at 0.degree.
C. was added TFAA (43.2 .mu.l, 0.306 mmol). After stirring at rt
for 1 h, the reaction mixture was diluted with DCM, washed with sat
NaHCO.sub.3, water, brine, dried and concentrated. Purification of
the residue by silica gel chromatography with 0-40%
acetone/cyclohexane provided Example 100 (25 mg, 84% yield). LC-MS,
ES.sup.+: 488.96 [M+1]. The following examples were prepared
employing similar protocol as described above.
TABLE-US-00013 Example # Structure MS 100 ##STR00177## above 101
##STR00178## [M + Na].sup.+ 515.20 102 ##STR00179## [M + Na].sup.+
495.19 103 ##STR00180## [M + H].sup.+ 533.33
Example 104
##STR00181##
[0318] Step 1
[0319] A mixture of compound (100-1) (152 mg, 0.300 mmol) and 10%
Pd--C (31.9 mg, 0.030 mmol) in MeOH (3.00 mL) was stirred at rt
under a hydrogen balloon. After 1 h, the reaction mixture was
filtered through celite, rinsed with MeOH, and concentrated to give
the crude
(3R,5'S)-1'-((S)-5-methyl-2-(methylamino)hexanoyl)-2-oxospiro[indoline-3,-
3'-pyrrolidine]-5'-carboxamide (104-1) (112 mg, 0.301 mmol, 100%
yield), which was used in the next step directly. LC-MS, ES+:
372.99 [M+H].sup.+.
Step 2
[0320] To a mixture of compound (104-1) (85 mg, 0.228 mmol) and
4,6-difluoro-1H-indole-2-carboxylic acid (47.2 mg, 0.240 mmol) in
dry DMF (1.14 mL) at 0.degree. C. were added Hunig's base (122
.mu.L, 0.685 mmol) and HATU (113 mg, 0.297 mmol). The resulting
mixture was then stirred at rt for 1 h, diluted with DCM, washed
with water (2.times.) and brine. The organic layer was dried and
concentrated. The crude product (104-2) was used in the next step
without further purification. LC-MS, ES-: 550.2 [M-H].sup.-.
Step 3
[0321] A mixture of crude
(3R,5'S)-1'-((S)-2-(4,6-difluoro-N-methyl-1H-indole-2-carboxamido)-5-meth-
ylhexanoyl)-2-oxospiro[indoline-3,3'-pyrrolidine]-5'-carboxamide
(104-2) (0.121 g, 0.22 mmol) and Et.sub.3N (0.307 mL, 2.20 mmol) in
DCM (2.9 mL) at 0.degree. C. was treated with TFAA (0.155 mL, 1.100
mmol). After stirring at rt for 30 min, the reaction mixture was
diluted with DCM, washed with sat NaHCO.sub.3, water and brine,
dried, and concentrated. Purification of the residue by silica gel
chromatography with 0-40% acetone/cyclohexane provided Example 104
(62 mg, 53% yield for 3 steps). LC-MS, ES-: 532.01 [M-H].sup.-. 1H
NMR (400 MHz, Acetone-d.sub.6) .delta. 10.84 (s, 1H), 9.69 (s, 1H),
7.12-6.99 (m, 3H), 6.97-6.93 (m, 1H), 6.90 (d, J=7.6 Hz, 1H),
6.86-6.78 (m, 1H), 6.74 (td, J=10.3, 2.1 Hz, 1H), 5.45 (dd, J=8.8,
6.4 Hz, 1H), 5.22 (t, J=8.2 Hz, 1H), 4.26 (d, J=10.7 Hz, 1H), 3.99
(d, J=10.7 Hz, 1H), 3.46 (s, 3H), 2.74-2.64 (m, 2H), 2.04-1.91
[0322] The following examples were prepared employing similar
protocol as described above.
TABLE-US-00014 Example # Structure MS NMR 105 ##STR00182## [M +
H].sup.+ 528.00 106 ##STR00183## [M + H].sup.+ 539.97 1H NMR (400
MHz, Acetone-d6) .delta. 10.39 (s, 1H), 9.65 (s, 1H), 7.20-7.12 (m,
1H), 7.12-6.99 (m, 3H), 6.95-6.87 (m, 2H), 6.82 (t, J = 7.5 Hz,
1H), 6.54 (dd, J = 7.7, 0.7 Hz, 1H), 5.55 (dd, J = 9.1, 5.7 Hz,
1H), 5.20 (t, J = 8.2 Hz, 1H), 4.29 (d, J = 10.7 Hz, 1H), 3.99 (d,
J = 10.6 Hz, 1H), 3.96 (s, 3H), 3.45 (s, 3H), 2.81-2.63 (m, 2H),
2.05-1.98 (m, 1H), 1.96-1.90 (m, 1H), 1.88-1.79 (m, 3H), 1.67-1.58
(m, 2H), 1.52-1.45 (m, 2H), 1.31-1.14 (m, 2H). 107 ##STR00184## [M
+ H].sup.+ 545.95 1H NMR (400 MHz, Acetone-d6) .delta. 10.80 (s,
1H), 9.67 (s, 1H), 7.08 (dd, J = 9.4, 2.0 Hz, 1H), 7.05-6.97 (m,
2H), 6.96 (s, 1H), 6.91 (d, J = 7.7 Hz, 1H), 6.80 (dd, J = 13.7,
6.1 Hz, 1H), 6.77-6.68 (m, 1H), 5.55 (dd, J = 9.1, 5.7 Hz, 1H),
5.21 (t, J = 8.3 Hz, 1H), 4.29 (d, J = 10.7 Hz, 1H), 3.98 (d, J =
10.6 Hz, 1H), 3.46 (s, 3H), 2.75-2.64 (m, 2H), 2.06-1.99 (m, 1H),
1.99-1.89 (m, 1H), 1.83 (p, J = 6.3 Hz, 3H), 1.63 (q, J = 6.9, 5.8
Hz, 2H), 1.51 (dt, J = 14.5, 5.3 Hz, 2H), 1.32-1.11 (m, 2H). 108
##STR00185## [M - H].sup.- 592.00 1H NMR (400 MHz, Acetone-d6)
.delta. 10.82 (s, 1H), 9.65 (s, 1H), 7.50 (d, J = 8.3 Hz, 1H), 7.28
(t, J = 8.0 Hz, 1H), 7.07-6.93 (m, 4H), 6.87 (d, J = 7.7 Hz, 1H),
6.78 (t, J = 7.5 Hz, 1H), 5.54 (dd, J = 9.1, 5.9 Hz, 1H), 5.19 (t,
J = 8.2 Hz, 1H), 4.25 (d, J = 10.7 Hz, 1H), 3.98 (d, J = 10.6 Hz,
1H), 2.72-2.62 (m, 2H), 1.99 (dd, J = 8.9, 5.1 Hz, 1H), 1.92 (dt, J
= 13.6, 6.3 Hz, 1H), 1.86-1.76 (m, 3H), 1.64-1.56 (m, 2H),
1.53-1.43 (m, 2H), 1.27-1.16 (m, 2H). 109 ##STR00186## [M -
H].sup.- 561.99 1H NMR (400 MHz, Acetone-d6) .delta. 11.10 (s, 1H),
9.60 (s, 1H), 6.98-6.91 (m, 2H), 6.84 (tt, J = 9.0, 4.0 Hz, 3H),
6.74 (t, J = 7.5 Hz, 1H), 5.45 (dd, J = 9.0, 5.8 Hz, 1H), 5.14 (t,
J = 8.3 Hz, 1H), 4.17 (d, J = 10.7 Hz, 1H), 3.91 (d, J = 10.6 Hz,
1H), 3.36 (s, 3H), 2.65-2.55 (m, 2H), 1.97- 1.91 (m, 1H), 1.91-1.83
(m, 1H), 1.80- 1.72 (m, 3H), 1.59-1.51 (m, 2H), 1.49- 1.38 (m, 2H),
1.24-1.09 (m, 2H). 110 ##STR00187## [M + Na].sup.+ 564.20 .sup.1H
NMR (400 MHz, Acetone-d.sub.6) .delta. 10.73 (s, 1H), 9.67 (s, 1H),
7.33 (d, J = 8.2 Hz, 1H), 7.22 (td, J = 8.0, 5.2 Hz, 1H), 7.04 (d,
J = 7.9 Hz, 2H), 6.99-6.89 (m, 2H), 6.91-6.75 (m, 2H), 5.62 (dt, J
= 9.5, 4.6 Hz, 1H), 5.21 (t, J = 8.2 Hz, 1H), 4.27 (d, J = 10.6 Hz,
1H), 3.99 (d, J = 10.6 Hz, 1H), 3.47 (s, 3H), 2.79-2.62 (m, 2H),
1.87 (dddd, J = 38.4, 18.2, 9.6, 4.4 Hz, 4H), 1.76-1.56 (m, 3H),
1.42-0.82 (m, 6H). 111 ##STR00188## [M - H].sup.- 558.26 .sup.1H
NMR (400 MHz, Acetone-d.sub.6) .delta. 10.83 (s, 1H), 9.68 (s, 1H),
7.17-6.93 (m, 4H), 6.91 (d, J = 7.7 Hz, 1H), 6.82 (t, J = 7.5 Hz,
1H), 6.75 (td, J = 10.3, 2.1 Hz, 1H), 5.71-5.56 (m, 1H), 5.21 (t, J
= 8.3 Hz, 1H), 4.28 (d, J = 10.7 Hz, 1H), 3.99 (d, J = 10.6 Hz,
1H), 3.47 (s, 3H), 2.81-2.63 (m, 2H), 1.98-1.78 (m, 4H), 1.75-1.54
(m, 3H), 1.37-0.84 (m, 6H). 112 ##STR00189## [M + H].sup.+ 560.15
.sup.1H NMR (400 MHz, Acetone-d.sub.6) .delta. 10.80 (s, 1H), 9.68
(s, 1H), 7.31 (dd, J = 9.0, 3.5 Hz, 1H), 7.20 (ddd, J = 11.2, 8.9,
7.5 Hz, 1H), 7.13-6.95 (m, 3H), 6.91 (d, J = 7.7 Hz, 1H), 6.84 (t,
J = 7.6 Hz, 1H), 5.66- 5.49 (m, 1H), 5.21 (t, J = 8.2 Hz, 1H), 4.26
(d, J = 10.7 Hz, 1H), 3.99 (d, J = 10.6 Hz, 1H), 3.47 (s, 3H),
2.79-2.64 (m, 2H), 1.94-1.76 (m, 4H), 1.76-1.55 (m, 3H), 1.38-0.89
(m, 6H). 113 ##STR00190## [M - H].sup.- 552.08 .sup.1H NMR (400
MHz, Methanol-d.sub.4) .delta. 7.16 (t, J = 8.0 Hz, 1H), 7.06 (t, J
= 7.7 Hz, 1H), 7.02-6.94 (m, 2H), 6.93-6.80 (m, 3H), 6.53 (d, J =
7.7 Hz, 1H), 5.54 (m, 1H), 5.18 (t, J = 7.9 Hz, 1H), 4.61 (s, 0H),
4.20 (d, J = 10.7 Hz, 1H), 3.96 (s, 3H), 3.95 (d, J = 2.8 Hz, 1H),
3.40 (s, 3H), 2.70 (dd, J = 12.0, 6.0 Hz, 1H), 2.67 (m, 1H),
1.86-1.67 (m, 7H), 1.25-0.93 (m, 6H). 114 ##STR00191## [M +
Na].sup.+ 534.21 .sup.1H NMR (500 MHz, Chloroform-d) .delta. 8.98
(s, 1H), 8.27 (s, 1H), 7.20 (t, J = 8.0 Hz, 1H), 7.10-7.04 (m, 1H),
7.02-6.88 (m, 2H), 6.88-6.76 (m, 3H), 6.50 (d, J = 7.8 Hz, 1H),
5.42 (t, J = 7.5 Hz, 1H), 5.02 (t, J = 8.5 Hz, 1H), 4.56 (d, J =
10.5 Hz, 1H), 4.03 (d, J = 10.5 Hz, 1H), 3.96 (s, 3H), 3.51 (s,
3H), 2.85 (dd, J = 13.2, 8.6 Hz, 1H), 2.52 (ddd, J = 13.2, 8.3, 1.2
Hz, 1H), 1.92 (tq, J = 13.8, 7.4 Hz, 2H), 0.73 (qq, J = 7.6, 5.2,
3.8 Hz, 1H), 0.64-0.43 (m, 2H), 0.20 (ddt, J = 14.6, 9.0, 4.7 Hz,
2H). 115 ##STR00192## [M + Na].sup.+ 540.18 .sup.1H NMR (400 MHz,
Chloroform-d) .delta. 9.38 (s, 1H), 8.51 (s, 1H), 7.26 (s, 1H),
7.08 (td, J = 7.4, 6.5, 2.1 Hz, 1H), 6.91- 6.74 (m, 5H), 6.62 (td,
J = 10.0, 2.0 Hz, 1H), 5.39 (t, J = 7.6 Hz, 1H), 5.05 (t, J = 8.4
Hz, 1H), 4.46 (d, J = 10.4 Hz, 1H), 4.04 (d, J = 10.4 Hz, 1H), 3.50
(s, 3H), 2.85 (dd, J = 13.3, 8.3 Hz, 1H), 2.53 (dd, J = 13.3, 8.4
Hz, 1H), 1.92 (h, J = 6.6 Hz, 2H), 0.88-0.66 (m, 1H), 0.66-0.45 (m,
2H), 0.21 (p, J = 4.5 Hz, 2H). 116 ##STR00193## [M + Na].sup.+
522.19 117 ##STR00194## [M + Na] 554.23 .sup.1H NMR (400 MHz,
Chloroform-d) .delta. 9.32 (s, 1H), 9.03 (s, 1H), 7.18 (t, J = 8.0
Hz, 1H), 7.05-6.86 (m, 3H), 6.79 (d, J = 7.8 Hz, 1H), 6.68 (dd, J =
21.4, 7.4 Hz, 2H), 6.47 (d, J = 7.8 Hz, 1H), 5.75 (t, J = 6.5 Hz,
1H), 5.02 (t, J = 8.2 Hz, 1H), 4.48 (d, J = 10.7 Hz, 1H), 4.00 (d,
J = 10.8 Hz, 1H), 3.95 (s, 3H), 3.47 (s, 3H), 2.82 (dd, J = 13.4,
8.1 Hz, 1H), 2.55-2.42 (m, 2H), 2.37-2.21 (m, 1H), 1.45 (s, 3H),
1.39 (s, 3H). 118 ##STR00195## [M + Na] 560.19
Example 119
##STR00196##
[0323] Step 1
[0324] To a solution of compound (23-5) (64 mg, 0.127 mmol) in dry
acetone (0.634 mL) was added K.sub.2CO.sub.3 (26.3 mg, 0.190 mmol)
and dimethyl sulfate (18.04 .mu.L, 0.190 mmol) at rt. The reaction
mixture was then heated and refluxed for 2 hrs. After 2 hrs,
another portion of dimethyl sulfate (6.0 .mu.L, 0.06 mmol) was
added and the mixture was heated for another 3 hrs. The reaction
mixture was concentrated to dryness. The residue was diluted with
EtOAc, washed with water, brine, dried, and concentrated.
Purification of the residue by silica gel chromatography with 0-50%
acetone/cyclohexane provided compound (119-1) (53 mg, 81% yield).
LC-MS, ES+: 519.14 [M+H].sup.+.
Step 2
[0325] To a solution of compound (119-1) (51 mg, 0.098 mmol) in dry
DCM (0.98 mL) at 0.degree. C. was added Dess-Martin periodinane
(62.6 mg, 0.148 mmol). The mixture was stirred at 0.degree. C. for
3 hrs. Purification of the crude reaction mixture on silica gel
chromatography with 0-55% EtOAc/cyclohexane provided Example 119
(28 mg, 55% yield). LC-MS, ES+: 517.06 [M+H].sup.+. .sup.1H NMR
(400 MHz, Acetone-d.sub.6) .delta. 10.52 (s, 1H), 9.52 (d, J=1.9
Hz, 1H), 7.75-7.69 (m, 1H), 7.23-7.16 (m, 3H), 7.03-6.95 (m, 2H),
6.92-6.85 (m, 2H), 6.40 (dd, J=7.2, 1.2 Hz, 1H), 4.84 (ddd, J=9.7,
8.3, 4.8 Hz, 1H), 4.54 (ddd, J=9.2, 6.1, 2.0 Hz, 1H), 4.12 (d,
J=10.4 Hz, 1H), 3.96 (d, J=10.4 Hz, 1H), 3.79 (s, 3H), 3.07 (s,
3H), 2.37-2.29 (m, 1H), 2.20 (dd, J=13.1, 6.1 Hz, 1H), 1.71 (ddd,
J=14.5, 9.8, 4.2 Hz, 2H), 1.66-1.58 (m, 1H), 0.84 (dd, J=10.7, 6.4
Hz, 6H).
Example 120
##STR00197##
[0326] Step 1
[0327] To a solution of Example 119 (24 mg, 0.046 mmol) in dry DMSO
(0.186 mL) was added hydroxylamine hydrochloride (4.36 mg, 0.063
mmol). After stirring at rt for 1 h, the reaction mixture was
diluted with EtOAc, washed with water (2.times.), brine, dried, and
concentrated to provide the crude oxime intermediate (118-1) (21
mg), which was directly used in the next step.
[0328] LC-MS, ES+: 532.13 [M+H].sup.+.
Step 2
[0329] To a solution of the crude oxime intermediate (120-1) (21
mg, 0.046 mmol) in dry acetonitrile (0.79 mL) was added
Cu(OAc).sub.2 (1.4 mg, 7.9 .mu.mol). The reaction mixture was
heated at 70.degree. C. for 1 h and concentrated. Purification of
the residue by silica gel chromatography using 0 to 50%
acetone/cyclohexane afforded Example 120 (8 mg, 40% yield). LC-MS,
ES+: 514.09 [M+H].sup.+. .sup.1H NMR (400 MHz, Acetone-d.sub.6)
.delta. 10.60 (s, 1H), 7.88 (d, J=8.2 Hz, 1H), 7.35 (dd, J=2.3, 0.8
Hz, 1H), 7.29 (td, J=7.7, 1.2 Hz, 1H), 7.20-7.08 (m, 3H), 7.02 (d,
J=7.8 Hz, 1H), 6.95 (td, J=7.6, 1.0 Hz, 1H), 6.55 (dd, J=7.4, 1.0
Hz, 1H), 5.17 (t, J=8.3 Hz, 1H), 4.91 (ddd, J=9.8, 8.2, 4.6 Hz,
1H), 4.34 (d, J=10.3 Hz, 1H), 4.05 (d, J=10.4 Hz, 1H), 3.95 (s,
3H), 3.24 (s, 3H), 2.70 (dd, J=8.3, 3.9 Hz, 2H), 1.85 (ddd, J=12.7,
9.4, 4.7 Hz, 2H), 1.73 (dt, J=9.4, 5.3 Hz, 1H), 0.99 (dd, J=15.9,
6.4 Hz, 6H).
Example 121
##STR00198##
[0330] Step 1
[0331] To a solution of Example 42 (30 mg, 0.058 mmol) in dry
acetone (0.29 mL) was added K.sub.2CO.sub.3 (12.11 mg, 0.088 mmol)
and dimethyl sulfate (8.31 .mu.L, 0.088 mmol) at rt. The reaction
mixture was then heated to reflux for 3 hrs. The mixture was then
concentrated to remove acetone, diluted with EtOAc, washed with
water and brine, dried and concentrated. Purification of the
residue on silica gel with 0-50% acetone/cyclohexane provided
Example 121 (16 mg, 81% yield). LC-MS, ES-: 526.03 [M-1]. .sup.1H
NMR (400 MHz, Acetone-d.sub.6) .delta. 10.36 (s, 1H), 7.20-7.10 (m,
2H), 7.10-7.03 (m, 2H), 7.00-6.91 (m, 2H), 6.87 (t, J=7.5 Hz, 1H),
6.55 (d, J=7.7 Hz, 1H), 5.57 (dd, J=9.6, 5.6 Hz, 1H), 5.20 (t,
J=8.1 Hz, 1H), 4.25 (d, J=10.7 Hz, 1H), 4.00 (d, J=10.6 Hz, 1H),
3.97 (s, 3H), 3.45 (s, 3H), 3.22 (s, 3H), 2.77-2.63 (m, 2H), 1.93
(ddd, J=14.4, 9.6, 5.1 Hz, 1H), 1.77 (ddd, J=14.2, 8.7, 5.6 Hz,
1H), 1.62 (dtd, J=8.6, 6.6, 5.0 Hz, 1H), 0.98 (dd, J=23.1, 6.6 Hz,
6H).
Example 122
##STR00199##
[0332] Step 1
[0333] Compound (1-3) (425 mg, 1.38 mmol) was suspended in DCM (5
mL). Et.sub.3N (0.54 mL, 3.9 mmol) and TFAA (0.36 mL, 2.57 mmol)
were added dropwise. The mixture was stirred at rt for 30 mins. The
2nd portion of Et.sub.3N (0.2 mL) was added, followed by TFAA (0.12
mL). The mixture was stirred at rt for 20 min and concentrated.
Purification of the residue on silica gel afforded compound (122-1)
(320 mg, 80%). ESI-MS m/z=314.05 [M+H].sup.+.
Step 2
[0334] Lutidine (0.18 mL, 1.05 mmol) in DCM (1 mL) was cooled to
0.degree. C. TMSOTf (0.2 mL, 0.95 mmol) was added and the mixture
was stirred at 0.degree. C. for 5 mins. In another tube, compound
(122-1) (100 mg, 0.32 mmol) in DCM (1 mL) was cooled to 0.degree.
C. The TMSOTf/lutidine solution (1.9 mL) was added dropwise and the
resulting mixture was stirred at 0.degree. C. for 20 mins. Aq.
NaHCO.sub.3(4 mL) was added and the mixture was stirred for 10 min
and extracted with DCM (2.times.). The combined organic layer was
washed with aq. CsF (0.5 M) and brine, dried with Na.sub.2SO.sub.4,
and concentrated to afford compound (122-2) (68 mg, 100%) as a
yellow solid. ESI-MS m/z=213.88 [M+H].sup.+.
##STR00200##
Step 3
[0335] Leucine t-butyl ester hydrochloride salt (1.0 g, 4.47 mmol)
and benzyl isocyanate (595 mg, 4.47 mmol) was mixed in DCM (6 mL).
At 0.degree. C. TEA (1.25 mL, 8.95 mmol) was added. The mixture was
stirred at rt for 3 h and concentrated. Purification of the residue
on silica provided the compound (122-3) (1.5 g) as a colorless
syrup. ESI-MS m/z=321.07 [M+H].sup.+.
Step 4
[0336] To a solution of compound (122-3) (1.5 g) in DCM (12 mL) was
added TFA (1.27 mL, 23 mmol). The mixture was stirred at rt
overnight and concentrated. Purification of the residue on silica
provided compound (122-4) (301 mg, 25% for two steps) as light
yellow oil. ESI-MS m/z=265.02 [M+H].sup.+.
Step 5
[0337] To a solution of compound (122-2) (20 mg, 0.094 mmol) and
compound (122-4) (32 mg, 1.122 mol) in DMF (1 mL) was added TCFH
(39 mg, 0.14 mmol) and methyl imidazole (23 mg, 0.38 mmol). The
reaction was stirred at rt for 15 mins, diluted with EtOAc, and
washed with water and brine. The organic layer was dried over
Na.sub.2SO.sub.4 and concentrated. Purification of the residue on
silica provided Example 122 (30 mg, 70%) as a yellow solid. ESI-MS
m/z=460.31 [M+H].sup.+; .sup.1H NMR (400 MHz, Chloroform-d) .delta.
9.06 (br, 1H), 7.21 (d, J=4.3 Hz, 4H), 7.18-7.11 (m, 1H), 7.06 (t,
J=7.8 Hz, 1H), 6.85 (d, J=7.6 Hz, 1H), 6.83-6.73 (m, 1H), 6.65 (d,
J=7.9 Hz, 1H), 6.03 (br, 1H), 5.61 (br, 1H), 4.63 (d, J=7.8 Hz,
1H), 4.45 (t, J=8.3 Hz, 1H), 4.33 (d, J=14.6 Hz, 1H), 4.20 (dd,
J=20.2, 12.6 Hz, 2H), 3.85 (d, J=10.3 Hz, 1H), 2.72-2.58 (m, 1H),
2.24 (dd, J=13.0, 8.0 Hz, 1H), 1.80-1.46 (m, 3H), 0.98-0.81 (m,
6H).
Example 123
##STR00201## ##STR00202##
[0338] Step 1
[0339] Compound (1-2) (5.00 g) was dissolved in acetic acid (115
mL). Sulfuryl chloride (2.09 g) was slowly added to the resulting
solution at room temperature. The mixture was stirred overnight at
room temperature. Then, the reaction mixture was concentrated. The
crude residue was dissolved in methylene chloride (100 mL) and
triethylamine (5.84 g, 8.05 mL, 4.0 equiv) was added, followed by
tert-butyl dicarbonate (4.73 g, 1.5 equiv). Then, the organic layer
was washed with 1M HCl (2.times.50 mL), then brine (100 mL), then
dried over magnesium sulfate. Upon concentration, the crude residue
was purified by RPHPLC, affording compound (123-1) (2.81 g, 51%
yield). [M+H].sup.-, 381.1.
Step 2
[0340] Compound (123-1) (2.81 g) was dissolved in 7M methanolic
ammonia (36.1 mL) in a 100 mL pressure vessel. The mixture was
heated at 60.degree. C. for 36 h. Upon concentration, the crude
residue was triturated with acetonitrile to afford compound (123-2)
as a colorless solid (1.92 g, 71% yield). [M+H].sup.-, 366.1.
Step 3
[0341] Compound (123-2) (1.61 g) was dissolved in 4M
HCl/1,4-dioxane (22.0 mL). The resulting mixture was stirred at
room temperature for 2 h. Concentration afforded compound (123-4)
(1.33 g) as a white solid which was used without further
purification. [M+H].sup.+, 266.1.
Step 4
[0342] Compound (123-3) (103.0 mg), compound (123-3b) (98.0 mg),
and HATU (149.0 mg) were combined in a 40 mL vial equipped with a
stir bar. DMF (2.27 mL) was added, followed by DIPEA (179 .mu.L).
The resulting mixture was stirred at room temperature overnight.
Upon completion, the reaction mixture was diluted with ethyl
acetate (50 mL), washed with 1M HCl (2.times.20 mL) and brine (20
mL), then dried over magnesium sulfate. Upon concentration, the
crude residue was purified by silica gel column chromatography (0
to 10% MeOH/DCM) affording compound (123-4) (58.1 mg, 34% yield).
[M+H].sup.+, 497.2.
Step 5
[0343] Compound (123-4) (58.1 mg) was dissolved in 4M
HCl/1,4-dioxane (585 .mu.L). The resulting mixture was stirred for
1.5 h. The reaction mixture was concentrated to afford compound
(123-5) (51.0 mg) which was used in the next step without
purification. [M+H].sup.+, 397.2.
Step 6
[0344] Compound (123-5) (51.0 mg), compound (121-5b) (26.7 mg), and
HATU (51.5 mg) were combined in 40 mL vial equipped with a stir
bar. DMF (785 .mu.L) was added, followed by DIPEA (62 .mu.L). The
resulting mixture was stirred 2.5 h at room temperature. The
reaction mixture was diluted with ethyl acetate (100 mL) and washed
with 1M HCl (3.times.20 mL) and brine (20 mL).
[0345] The organic layer was dried over magnesium sulfate then
concentrated. Purification of the crude residue by silica gel
column chromatography (0 to 10% MeOH/DCM) afforded compound (123-6)
(26.9 mg, 40% yield). [M+H].sup.+, 576.1.
Step 7
[0346] Compound (123-6) (26.9 mg) was dissolved in a mixture of
MeCN (500 .mu.L) and water (500 .mu.L) in a 20 mL vial. Next,
2,2-dichloroacetonitrile (56 .mu.L) was added, followed by
palladium(II) trifluoroacetate (1.5 mg). The vial was sealed and
the mixture was heated at 65.degree. C. for 2 h. Additional
2,2-dichloroacetonitrile (56 .mu.L) and palladium(II)
trifluoroacetate (1.5 mg) were added, and the mixture was heated at
70.degree. C. for 20 min. Upon cooling to room temperature, the
mixture was purified by RPHPLC to afford Example 123 as a white
solid (10.0 mg, 38% yield). ESI MS m/z=558.1 [M+H].sup.+. .sup.1H
NMR (400 MHz, acetone-d.sub.6, .delta. ppm): .delta. 10.96 (s, 1H),
9.80 (s, 1H), 8.18-8.16 (m, 1H), 7.35-7.34 (m, 1H), 7.15-7.09 (m,
3H), 6.97-6.95 (m, 1H). 6.77-6.72 (m, 1H), 5.23 (app t, J=8.2, 8.2
Hz, 1H), 5.15-5.09 (m, 1H), 4.46 (d, J=10.5 Hz, 1H), 4.06 (10.5
Hz), 2.85-2.67 (m, 2H), 2.42-2.18 (m, 2H), 1.47 (d,
J.sub.19F-1H=3.2 Hz, 3H), 1.41 (d, J.sub.19F-1H=3.2 Hz, 3H).
Example 124
##STR00203##
[0347] Step 1
[0348] To a mixture of
(S)-2-(((benzyloxy)carbonyl)amino)-3-cyclopropylpropanoic acid (2.4
g, 9.12 mmol) and MeI (10.5 g, 72.9 mmol) in THE (30 mL) at
0.degree. C. was added NaH (1.09 g, 27.3 mmol) portion wise and
stirred at rt for 2 days. it was quenched with ice-water, extracted
with MBTE twice. The aqueous layer was acidified with 1 N HCl to pH
.about.2, extracted with EtOAc, washed with brine, dry over
Na.sub.2SO.sub.4, filtered, concentrated to give the desired
compound (1-1) (2.3 g, 90% yield). ESI-MS m/z=276.12
[M-H].sup.-.
Step 2
[0349] To a solution of intermediate 1-5 (5.75 g, 17.18 mmol),
compound (1-1) (5.24 g, 18.9 mmol) and N-methyl morpholine (6.08 g,
60.1 mmol) in DCM/DMF (30/10 mL) was added HATU (6.55 g, 17.18
mmol) and stirred at rt for 2 h. It was quenched with water,
extracted with EtOAc, washed with water, 1N HCl, sat NaHCO.sub.3,
brine, dry over Na.sub.2SO.sub.4, filtered, concentrated, silica
gel column purification to give the desired compound (1-2) (5.94 g,
70% yield). ESI-MS m/z=489.21 [M-H].sup.-.
Step 3
[0350] A mixture of compound (1-2) (5.65 g, 11.52 mmol) and Pd--C
(10%) (1.23 g, 1.15 mmol) in MeOH (30 mL) was treated with H.sub.2
using a hydrogen balloon. After 1 h, it was diluted with DCM,
filtered through celite, concentrated to give desired compound
(1-3) (4.1 g, 100%). ESI-MS m/z=355.18 [M-H].sup.-.
Step 4
[0351] A mixture of compound (1-3) (50 mg, 0.14 mmol),
1-(2-(trifluoromethyl)phenyl)-1H-pyrazole-4-carboxylic acid (35.9
mg, 0.140 mmol), N-methyl morpholine (35.5 mg, 0.35 mmol) in
DCM/DMF (0.5/0.5 mL) at rt was added HATU (53 mg, 0.14 mmol) and
stirred rt for 20 h. It was quenched water, extracted with EtOAc,
washed with water, brine, dry over Na.sub.2SO.sub.4, filtered.
concentrated, silica gel column purification to give desired
compound (1-4) (60 mg, 72% yield). ESI-MS m/z=593.21
[M-H].sup.-.
Step 5
[0352] A mixture of compound (1-4) (60 mg, 0.10 mmol) and Et.sub.3N
(113 .mu.l, 0.80 mmol) in DCM (1 mL) at 0.degree. C. was treated
with TFAA (57 .mu.l, 0.40 mmol). After 30 mins at rt, it was
quenched with cold Sat. NaHCO.sub.3, extracted with EtOAc, washed
with 1 N HCl, Sat. NaHCO.sub.3, brine, dry over Na.sub.2SO.sub.4,
filtered, concentrated, silica gel column purification to give the
compound of example 1 (32 mg, 55% yield) ESI-MS m/z=575.28
[M-H].sup.-. .sup.1H NMR (400 MHz, Acetone-d.sub.6) .delta. 9.50
(s, 1H), 7.86 (s, 1H), 7.80-7.74 (m, 1H), 7.70 (t, J=7.6 Hz, 1H),
7.59 (dd, J=14.9, 5.8 Hz, 2H), 7.45 (d, J=8.0 Hz, 1H), 6.95 (td,
J=7.7, 1.3 Hz, 1H), 6.87 (ddd, J=7.5, 1.4, 0.7 Hz, 1H), 6.74 (dd,
J=8.0, 7.0 Hz, 2H), 5.28 (t, J=7.7 Hz, 1H), 5.00 (t, J=8.3 Hz, 1H),
4.21 (d, J=10.7 Hz, 1H), 3.78 (d, J=10.6 Hz, 1H), 3.10 (s, 3H),
2.64-2.44 (m, 2H), 1.66 (dd, J=15.1, 7.7 Hz, 2H), 0.64-0.54 (m,
1H), 0.33-0.23 (m, 2H), 0.05-0.00 (m, 2H).
Example 125
##STR00204##
[0354] The compound of example 125 was prepared employing similar
protocol as example 1. ESI-MS m/z=490.27 [M-H].sup.-. .sup.1H NMR
(400 MHz, Acetone-d.sub.6) .delta. 9.51 (s, 1H), 7.63 (s, 1H), 7.40
(s, 1H), 7.02 (t, J=7.7 Hz, 1H), 6.88-6.82 (m, 1H), 6.77 (dd,
J=14.0, 7.5 Hz, 2H), 5.27 (s, 1H), 4.99 (t, J=8.3 Hz, 1H), 4.22 (d,
J=10.5 Hz, 1H), 3.77 (d, J=10.7 Hz, 1H), 2.59-2.46 (m, 2H 1.65-1.56
(m, 2H), 1.39 (s, 9H), 0.62-0.54 (m, 1H), 0.34-0.25 (m, 2H),
0.06-0.00 (m, 2H).
Biological Activity
[0355] SARS-CoV-2 3C-like (3CL) protease fluorescence assay (FRET):
Recombinant SARS-CoV-2 3CL-protease was expressed and purified.
TAMRA-SITSAVLQSGFRKMK-Dabcyl-OH peptide 3CLpro substrate was
synthesized. Black, low volume, round-bottom, 384 well microplates
were used. In a typical assay, 0.85 .mu.L of test compound was
dissolved in DMSO then incubated with SARS-CoV-2 3CL-protease (10
nM) in 10 .mu.L assay buffer (50 mM HEPES [pH 7.5], 1 mM DTT, 0.01%
BSA, 0.01% Triton-X 100) for 30 min at RT. Next, 10 .mu.L of
3CL-protease substrate (40 .mu.M) in assay buffer was added and the
assays were monitored continuously for 1 h in an Envision multimode
plate reader operating in fluorescence kinetics mode with
excitation at 540 nm and emission at 580 nm at RT. No compound
(DMSO only) and no enzyme controls were routinely included in each
plate. All experiments were run in duplicate. Data Analysis:
SARS-CoV-2 3CL-protease enzyme activity was measured as initial
velocity of the linear phase (RFU/s) and normalized to controlled
samples DMSO (100% activity) and no enzyme (0% activity) to
determine percent residual activity at various concentrations of
test compounds (0-10 .mu.M). Data were fitted to normalized
activity (variable slope) versus concentration fit in GraphPad
Prism 7 to determine IC.sub.50. All experiments were run in
duplicate, and IC.sub.50 ranges are reported as follows: A<0.1
.mu.M; B 0.1-1 .mu.M; C>1 .mu.M.
TABLE-US-00015 TABLE 1 Summary of Activities FRET FRET Compound
IC.sub.50 Compound IC.sub.50 1 B 2 A 3 C 4 A 5 A 6 C 7 A 8 A 9 B 10
B 11 A 12 C 13 A 14 B 15 A 16 B 17 A 18 C 19 A 20 A 21 A 22 B 23 A
24 B 25 A 26 B 27 A 28 A 29 A 30 A 31 B 32 A 33 A 34 C 35 C 36 B 37
B 38 C 39 A 40 A 41 A 42 A 43 B 44 A 45 A 46 A 47 A 48 B 49 A 50 A
51 A 52 A 53 A 54 A 55 A 56 A 57 A 58 A 59 A 60 A 61 A 62 A 63 A 64
A 65 A 66 A 67 A 68 A 69 A 70 A 71 A 72 A 73 A 74 A 75 A 76 A 77 B
78 A 79 A 80 A 81 A 82 A 83 A 84 A 85 A 86 A 87 A 88 A 89 A 90 A 91
A 92 A 93 A 94 A 95 A 96 A 97 A 98 A 99 A 100 A 101 A 102 A 103 A
104 A 105 A 106 A 107 A 108 A 109 A 110 A 111 A 112 A 113 A 114 A
115 A 116 A 117 -- 118 -- 119 A 120 B 121 A 122 A 123 A 124 A 125
A
229E Assay protocol
[0356] Viral stock preparation: MRC-5 cells, (a diploid cell
culture line composed of fibroblasts, originally developed from the
lung tissue of a 14-week-old aborted Caucasian male fetus), were
used for the culturing of 229E human corona virus (hCoV). Flasks
were inoculated with hCoV-229E and viral stocks were collected once
cytopathic effect (CPE) was greater than 70%. Viral stocks in
Growth Media (EMEM, 1% Penn/Strep, 1% nonessential amino acids, 10%
heat-inactivated FBS) plus 5% glycerol were snap frozen using
liquid nitrogen and stored at -80.degree. C. Viral stock titers
were quantified by a TCID.sub.50 (50% median tissue culture
infectious dose) assay, as described elsewhere.
[0357] 229E live virus assay: 384-well black cell-culture-treated
plastic clear-bottom plates are used in this assay. Using an ECHO
liquid dispenser, 3-fold serial dilutions of control and test
compounds suspended in DMSO are added to the plate wells in
duplicate in a total volume of 125 nL per well. MRC-5 cells below
passage 17 are seeded into the inner 240 wells of the 384-well
plate at 1,500 cells per well in a volume of 12.5 .mu.L using
Growth Media. Viral stock is then added to the wells at a
multiplicity of infection (MOI) of 0.05 in a volume of 12.5 .mu.L
per well, bringing the total volume of each well to .about.25
.mu.L. Each plate has a control row of 20 wells with cells plus
DMSO and virus but no compound (positive control, max CPE, minimum
ATPlite signal), and a row with cells plus DMSO but no compound or
virus (negative control, minimum CPE, maximum ATPlite signal), and
a row with no cells or virus or compound (background plate/reagent
control). The control wells with cells but no virus are given an
additional 12.5 .mu.L of growth media containing an equal quantity
of glycerol as those wells receiving the viral stock in order to
keep consistent in media and volume conditions. The outer 2
rows/columns of wells are filled with 30 .mu.L of moat media (DMEM,
1% Penn/Strep) to act as a thermal and evaporative barrier around
the test wells. Following addition of all components, the sides of
the plates are gently tapped by hand to promote even cell
distribution across the wells. Upon confirmation of cell
distribution, plates are incubated at 34.degree. C. in a C.sub.02
humidity-controlled incubator for 6 days. Following the 6-day
incubation period, the plates are read using ATPlite (12.5 .mu.L
added per well), which quantifies the amount of ATP (a measure of
cell health) present in each well. Assay plates are read using an
Envision luminometer. These data are used to calculate the percent
cell health per well relative to the negative control wells and the
EC.sub.50 of each compound is calculated using ExcelFit software
and 4-parameter logistical curve fitting analysis.
[0358] All experiments were run in duplicate, and EC.sub.50 ranges
are reported as follows: A<0.1 .mu.M; B 0.1-1 .mu.M; C>1
.mu.M.
TABLE-US-00016 TABLE 2 Summary of Activities 229E 229E Compound
EC.sub.50 Compound EC.sub.50 1 B 2 B 3 C 4 B 5 B 6 -- 7 -- 8 -- 9
-- 10 -- 11 A 12 B 13 A 14 A 15 A 16 B 17 A 18 B 19 A 20 A 21 A 22
-- 23 A 24 A 25 A 26 A 27 A 28 A 29 A 30 A 31 B 32 B 33 C 34 C 35 C
36 B 37 B 38 -- 39 C 40 B 41 C 42 A 43 A 44 A 45 A 46 A 47 B 48 B
49 A 50 A 51 A 52 A 53 -- 54 -- 55 -- 56 -- 57 -- 58 B 59 C 60 B 61
C 62 C 63 C 64 C 65 A 66 A 67 -- 68 -- 69 -- 70 -- 71 -- 72 -- 73
-- 74 -- 75 -- 76 -- 77 -- 78 -- 79 -- 80 -- 81 -- 82 A 83 -- 84 --
85 A 86 A 87 A 88 A 89 B 90 B 91 A 92 A 93 A 94 -- 95 B 96 B 97 C
98 B 99 -- 100 B 101 -- 102 C 103 B 104 A 105 A 106 -- 107 -- 108
-- 109 -- 110 -- 111 -- 112 -- 113 A 114 A 115 A 116 A 117 -- 118
-- 119 B 120 C 121 B 122 B 123 A 124 A 125 A
[0359] While this invention has been particularly shown and
described with references to preferred embodiments thereof, it will
be understood by those skilled in the art that various changes in
form and details may be made therein without departing from the
scope of the invention encompassed by the appended claims.
* * * * *
References