NZ716794B2 - Polycyclic-carbamoylpyridone compounds and their use for the treatment of hiv infections - Google Patents
Polycyclic-carbamoylpyridone compounds and their use for the treatment of hiv infections Download PDFInfo
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- NZ716794B2 NZ716794B2 NZ716794A NZ71679414A NZ716794B2 NZ 716794 B2 NZ716794 B2 NZ 716794B2 NZ 716794 A NZ716794 A NZ 716794A NZ 71679414 A NZ71679414 A NZ 71679414A NZ 716794 B2 NZ716794 B2 NZ 716794B2
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- New Zealand
- Prior art keywords
- compound
- hydrogen
- independently
- saturated
- alkyl
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 282
- 208000005721 HIV Infections Diseases 0.000 title claims description 17
- 150000003839 salts Chemical class 0.000 claims abstract description 70
- 239000011780 sodium chloride Substances 0.000 claims abstract description 70
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 28
- 201000009910 diseases by infectious agent Diseases 0.000 claims abstract description 13
- -1 2,3- difluorophenyl Chemical group 0.000 claims description 120
- 239000000203 mixture Substances 0.000 claims description 112
- 229910052739 hydrogen Inorganic materials 0.000 claims description 105
- 239000001257 hydrogen Substances 0.000 claims description 103
- 125000000217 alkyl group Chemical group 0.000 claims description 80
- 125000005843 halogen group Chemical group 0.000 claims description 62
- 239000003814 drug Substances 0.000 claims description 52
- 150000002431 hydrogen Chemical class 0.000 claims description 48
- UFHFLCQGNIYNRP-UHFFFAOYSA-N hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 42
- 230000002401 inhibitory effect Effects 0.000 claims description 35
- 239000003112 inhibitor Substances 0.000 claims description 32
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 30
- 125000001188 haloalkyl group Chemical group 0.000 claims description 27
- 125000004435 hydrogen atoms Chemical group [H]* 0.000 claims description 24
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 19
- 102000033147 ERVK-25 Human genes 0.000 claims description 16
- 229910052736 halogen Inorganic materials 0.000 claims description 16
- 150000002367 halogens Chemical class 0.000 claims description 15
- 239000002777 nucleoside Substances 0.000 claims description 14
- 150000003833 nucleoside derivatives Chemical class 0.000 claims description 14
- 108010092799 EC 2.7.7.49 Proteins 0.000 claims description 13
- 201000001820 human immunodeficiency virus infectious disease Diseases 0.000 claims description 13
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- LDEKQSIMHVQZJK-CAQYMETFSA-N propan-2-yl (2S)-2-[[[(2R)-1-(6-aminopurin-9-yl)propan-2-yl]oxymethyl-phenoxyphosphoryl]amino]propanoate Chemical compound O([P@@](=O)(CO[C@H](C)CN1C2=NC=NC(N)=C2N=C1)N[C@@H](C)C(=O)OC(C)C)C1=CC=CC=C1 LDEKQSIMHVQZJK-CAQYMETFSA-N 0.000 claims description 12
- 239000003085 diluting agent Substances 0.000 claims description 11
- 239000003937 drug carrier Substances 0.000 claims description 10
- 239000002773 nucleotide Substances 0.000 claims description 9
- 125000003729 nucleotide group Chemical group 0.000 claims description 9
- 125000004215 2,4-difluorophenyl group Chemical group [H]C1=C([H])C(*)=C(F)C([H])=C1F 0.000 claims description 8
- 229960004556 Tenofovir Drugs 0.000 claims description 6
- 229960004693 Tenofovir disoproxil fumarate Drugs 0.000 claims description 6
- VCMJCVGFSROFHV-WZGZYPNHSA-N tenofovir disoproxil fumarate Chemical compound OC(=O)\C=C\C(O)=O.N1=CN=C2N(C[C@@H](C)OCP(=O)(OCOC(=O)OC(C)C)OCOC(=O)OC(C)C)C=NC2=C1N VCMJCVGFSROFHV-WZGZYPNHSA-N 0.000 claims description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
- 125000001153 fluoro group Chemical group F* 0.000 claims description 4
- 230000001225 therapeutic Effects 0.000 claims description 4
- 125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 claims description 3
- 125000004211 3,5-difluorophenyl group Chemical group [H]C1=C(F)C([H])=C(*)C([H])=C1F 0.000 claims description 3
- JTEGQNOMFQHVDC-NKWVEPMBSA-N 4-amino-1-[(2R,5S)-2-(hydroxymethyl)-1,3-oxathiolan-5-yl]-1,2-dihydropyrimidin-2-one Chemical compound O=C1N=C(N)C=CN1[C@H]1O[C@@H](CO)SC1 JTEGQNOMFQHVDC-NKWVEPMBSA-N 0.000 claims description 3
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 3
- 102000015084 HIV Reverse Transcriptase Human genes 0.000 claims description 3
- 108010078851 HIV Reverse Transcriptase Proteins 0.000 claims description 3
- 229960001627 Lamivudine Drugs 0.000 claims description 3
- 229960000531 abacavir sulfate Drugs 0.000 claims description 3
- WMHSRBZIJNQHKT-FFKFEZPRSA-N abacavir sulfate Chemical compound OS(O)(=O)=O.C=12N=CN([C@H]3C=C[C@@H](CO)C3)C2=NC(N)=NC=1NC1CC1.C=12N=CN([C@H]3C=C[C@@H](CO)C3)C2=NC(N)=NC=1NC1CC1 WMHSRBZIJNQHKT-FFKFEZPRSA-N 0.000 claims description 3
- 239000004030 hiv protease inhibitor Substances 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 239000002259 anti human immunodeficiency virus agent Substances 0.000 claims description 2
- 241000580858 Simian-Human immunodeficiency virus Species 0.000 claims 1
- SGOIRFVFHAKUTI-ZCFIWIBFSA-N Tenofovir Chemical compound N1=CN=C2N(C[C@@H](C)OCP(O)(O)=O)C=NC2=C1N SGOIRFVFHAKUTI-ZCFIWIBFSA-N 0.000 claims 1
- 230000000069 prophylaxis Effects 0.000 claims 1
- 241000725303 Human immunodeficiency virus Species 0.000 abstract description 35
- 238000002360 preparation method Methods 0.000 abstract description 18
- XEKOWRVHYACXOJ-UHFFFAOYSA-N acetic acid ethyl ester Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 117
- 239000011541 reaction mixture Substances 0.000 description 72
- 125000004432 carbon atoms Chemical group C* 0.000 description 59
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 46
- 235000019439 ethyl acetate Nutrition 0.000 description 46
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 46
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 46
- HEDRZPFGACZZDS-MICDWDOJSA-N cdcl3 Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 45
- 239000000460 chlorine Substances 0.000 description 44
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- 239000000243 solution Substances 0.000 description 43
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- 239000007787 solid Substances 0.000 description 28
- 230000035492 administration Effects 0.000 description 25
- RTZKZFJDLAIYFH-UHFFFAOYSA-N diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 25
- 239000003480 eluent Substances 0.000 description 25
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 24
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 23
- 239000000376 reactant Substances 0.000 description 22
- 125000002837 carbocyclic group Chemical group 0.000 description 20
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- 239000000741 silica gel Substances 0.000 description 20
- 229910002027 silica gel Inorganic materials 0.000 description 20
- YXFVVABEGXRONW-UHFFFAOYSA-N toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 20
- 238000006243 chemical reaction Methods 0.000 description 18
- 229910052757 nitrogen Inorganic materials 0.000 description 18
- 239000000047 product Substances 0.000 description 18
- 150000003254 radicals Chemical class 0.000 description 18
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- 239000000706 filtrate Substances 0.000 description 16
- 125000000623 heterocyclic group Chemical group 0.000 description 16
- UIIMBOGNXHQVGW-UHFFFAOYSA-M NaHCO3 Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 14
- 229910052799 carbon Inorganic materials 0.000 description 14
- KWYUFKZDYYNOTN-UHFFFAOYSA-M potassium hydroxide Inorganic materials [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 14
- 125000004122 cyclic group Chemical group 0.000 description 13
- 239000000727 fraction Substances 0.000 description 13
- JNWBBCNCSMBKNE-UHFFFAOYSA-N HATU Chemical compound F[P-](F)(F)(F)(F)F.C1=CN=C2N(OC(N(C)C)=[N+](C)C)N=NC2=C1 JNWBBCNCSMBKNE-UHFFFAOYSA-N 0.000 description 12
- 238000007792 addition Methods 0.000 description 12
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 12
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 11
- 238000004440 column chromatography Methods 0.000 description 11
- 229940079593 drugs Drugs 0.000 description 11
- AFVFQIVMOAPDHO-UHFFFAOYSA-N methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 11
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene dichloride Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 11
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 11
- 125000002947 alkylene group Chemical group 0.000 description 10
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine hydrate Chemical compound O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 10
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- 125000003118 aryl group Chemical group 0.000 description 9
- 125000004429 atoms Chemical group 0.000 description 9
- 125000001072 heteroaryl group Chemical group 0.000 description 9
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- 201000010099 disease Diseases 0.000 description 8
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- AFABGHUZZDYHJO-UHFFFAOYSA-N 2-Methylpentane Chemical class CCCC(C)C AFABGHUZZDYHJO-UHFFFAOYSA-N 0.000 description 5
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- WVLHHLRVNDMIAR-IBGZPJMESA-N N'-(1H-benzimidazol-2-ylmethyl)-N'-[(8S)-5,6,7,8-tetrahydroquinolin-8-yl]butane-1,4-diamine Chemical compound C1CCC2=CC=CN=C2[C@H]1N(CCCCN)CC1=NC2=CC=CC=C2N1 WVLHHLRVNDMIAR-IBGZPJMESA-N 0.000 description 5
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- 125000003282 alkyl amino group Chemical group 0.000 description 5
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- 101710011556 zfaA Proteins 0.000 description 1
Abstract
Compounds for use in the treatment of human immunodeficiency virus (HIV) infection are disclosed. The compounds have the following Formula (I): including stereoisomers and pharmaceutically acceptable salts thereof, wherein R1, X, Y1, Y2, or L are as defined herein. Methods associated with preparation and use of such compounds, as well as pharmaceutical compositions comprising such compounds, are also disclosed. n and use of such compounds, as well as pharmaceutical compositions comprising such compounds, are also disclosed.
Description
DCC-10/06/2021
POLYCYCLIC-CARBAMOYLPYRIDONE COMPOUNDS AND THEIR USE FOR
THE TREATMENT OF HIV INFECTIONS
This application claims the benefit of U.S. Provisional Application No. 61/845,806
filed July 12, 2013, the disclosure of which is hereby incorporated by reference herein in its
entirety.
BACKGROUND
Field
Compounds, compositions, and methods for the treatment of human
immunodeficiency virus (HIV) infection are disclosed. In particular, novel polycyclic
carbamoylpyridone compounds and methods for their preparation and use as therapeutic or
prophylactic agents are disclosed.
Description of the Related Art
Human immunodeficiency virus infection and related diseases are a major public
health problem worldwide. Human immunodeficiency virus type 1 (HIV-1) encodes three
enzymes which are required for viral replication: reverse transcriptase, protease, and
integrase. Although drugs targeting reverse transcriptase and protease are in wide use and
have shown effectiveness, particularly when employed in combination, toxicity and
development of resistant strains have limited their usefulness (Palella, et al. N. Engl. J Med.
(1998) 338:853 –860; Richman, D. D. Nature (2001) 410:995 –1001).
A goal of antiretroviral therapy is to achieve viral suppression in the HIV infected
patient. Current treatment guidelines published by the United States Department of Health
and Human Services provide that achievement of viral suppression requires the use of
combination therapies, i.e., several drugs from at least two or more drug classes. (Panel on
Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral
agents in HIVinfected adults and adolescents. Department of Health and Human Services.
Available at http://aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Section
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accessed March 14, 2013.) In addition, decisions regarding the treatment of HIV infected
patients are complicated when the patient requires treatment for other medical conditions (Id.
at E-12). Because the standard of care requires the use of multiple different drugs to suppress
HIV, as well as to treat other conditions the patient may be experiencing, the potential for
drug interaction is a criterion for selection of a drug regimen. As such, there is a need for
antiretroviral therapies having a decreased potential for drug interactions.
Accordingly, there is a need for new agents that inhibit the replication of HIV
and that minimize the potential for drug-drug interactions when co-administered with other
drugs.
BRIEF SUMMARY
The present invention is directed to novel polycyclic carbamoylpyridone
compounds, having antiviral activity, including stereoisomers and pharmaceutically
acceptable salts thereof, and the use of such compounds in the treatment of HIV infections.
The compounds of the invention may be used to inhibit the activity of HIV integrase and may
be used to reduce HIV replication.
In one embodiment of the present invention, compounds having the following
Formula (I) are provided:
or a stereoisomer or pharmaceutically acceptable salt thereof,
wherein:
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Y and Y are each, independently, hydrogen, C alkyl or C haloalkyl;
1-3 1-3
R is phenyl substituted with one to three halogens;
X is -O-, -NR -, -CHR - or a bond;
R and R are each, independently, hydrogen or C alkyl;
L is -C(R ) C(R ) -; and
each R is, independently, hydrogen, halo, hydroxyl, or C alkyl, and
wherein two R groups on adjacent carbon atoms, together with the carbon
atoms to which they are attached, form a carbocyclic ring having the following structure:
wherein each R is, independently, hydrogen or halo.
In another embodiment of the present invention, compounds having antiviral
activity are provided, the compounds having the following Formula (I):
or a stereoisomer or pharmaceutically acceptable salt thereof,
wherein:
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1 2 1
Y and Y are each, independently, hydrogen, C alkyl or C haloalkyl, or Y
1-3 1-3
and Y , together with the carbon atom to which they are attached, form a carbocyclic ring
having from 3 to 6 ring atoms or a heterocyclic ring having from 3 to 6 ring atoms, wherein
the carbocyclic or heterocyclic ring is optionally substituted with one or more R ;
each R is, independently, hydrogen, halo, hydroxyl or C alkyl, or wherein
two R groups, together with the carbon atom to which they are attached, form C=O;
R is optionally substituted aryl or optionally substituted heteroaryl;
X is -O-, -NR -, -CHR - or a bond;
R and R are each, independently, hydrogen or C alkyl;
L is -C(R ) C(R ) -; and
each R is, independently, hydrogen, halo, hydroxyl, or C alkyl, and
wherein two R groups on adjacent carbon atoms, together with the carbon
atoms to which they are attached, form a carbocyclic ring having the following structure:
wherein each R is, independently, hydrogen or halo.
In one embodiment of the present invention, compounds having the following
Formula (Ia) are provided:
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(Ia)
or a stereoisomer or pharmaceutically acceptable salt thereof,
wherein:
Y and Y are each, independently, hydrogen, C alkyl or C haloalkyl;
1-3 1-3
R is phenyl substituted with one to three halogen atoms;
X is -O-, -NR -, -CHR - or a bond;
R and R are each, independently, hydrogen or C alkyl; and
L is -C(R ) C(R ) -; and
each R is, independently, hydrogen, halo, hydroxyl, or C alkyl, and
wherein two R groups on adjacent carbon atoms, together with the carbon
atoms to which they are attached, form a carbocyclic ring having the following structure:
wherein each R is, independently, hydrogen or halo.
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In one embodiment of the present invention, compounds having the following
Formula (Ib) are provided:
(Ib)
or a stereoisomer or pharmaceutically acceptable salt thereof,
wherein:
Y and Y are each, independently, hydrogen, C alkyl or C haloalkyl;
1-3 1-3
R is phenyl substituted with one to three halogen atoms;
X is -O-, -NR -, -CHR - or a bond;
R and R are each, independently, hydrogen or C alkyl; and
L is -C(R ) C(R ) -; and
each R is, independently, hydrogen, halo, hydroxyl, or C alkyl, and
wherein two R groups on adjacent carbon atoms, together with the carbon atoms to
which they are attached, form a carbocyclic ring having the following structure:
,
wherein each R is, independently, hydrogen or halo.
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In one embodiment of the present invention, compounds having the following
Formula (Ic) are provided:
(Ic)
or a stereoisomer or pharmaceutically acceptable salt thereof,
wherein:
Y and Y are each, independently, hydrogen, C alkyl or C haloalkyl;
1-3 1-3
R is phenyl substituted with one to three halogen atoms;
X is -O-, -NR -, -CHR - or a bond;
R and R are each, independently, hydrogen or C alkyl; and
L is -C(R ) C(R ) -; and
each R is, independently, hydrogen, halo, hydroxyl, or C alkyl, and
wherein two R groups on adjacent carbon atoms, together with the carbon atoms to
which they are attached, form a carbocyclic ring having the following structure:
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wherein each R is, independently, hydrogen or halo.
In one embodiment of the present invention, compounds having the following
Formula (Id) are provided:
(Id)
or a stereoisomer or pharmaceutically acceptable salt thereof,
wherein:
Y and Y are each, independently, hydrogen, C alkyl or C haloalkyl;
1-3 1-3
R is phenyl substituted with one to three halogen atoms;
X is -O-, -NR -, -CHR - or a bond;
R and R are each, independently, hydrogen or C alkyl; and
L is -C(R ) C(R ) -; and
each R is, independently, hydrogen, halo, hydroxyl, or C alkyl, and
wherein two R groups on adjacent carbon atoms, together with the carbon atoms to
which they are attached, form a carbocyclic ring having the following structure:
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wherein each R is, independently, hydrogen or halo.
In one embodiment of the present invention, compounds having the following
Formula (Ie) are provided:
(Ie)
or a stereoisomer or pharmaceutically acceptable salt thereof,
wherein:
Y and Y are each, independently, hydrogen, C alkyl or C haloalkyl;
1-3 1-3
R is phenyl substituted with one to three halogen atoms;
X is -O-, -NR -, -CHR - or a bond;
R and R are each, independently, hydrogen or C alkyl; and
L is -C(R ) C(R ) -; and
each R is, independently, hydrogen, halo, hydroxyl, or C alkyl, and
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wherein two R groups on adjacent carbon atoms, together with the carbon atoms to
which they are attached, form a carbocyclic ring having the following structure:
wherein each R is, independently, hydrogen or halo.
In another embodiment, a pharmaceutical composition is provided comprising
a compound having Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), or a stereoisomer or
pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or
excipient.
The invention also provides the use of a pharmaceutical composition as
described hereinabove for the treatment of an HIV infection in a human being having or at
risk of having the infection.
In yet another embodiment compounds are provided having the following
structures:
;
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; and
In another embodiment, a method of using a compound having Formula (I),
(Ia), (Ib), (Ic), (Id), or (Ie) in therapy is provided. In particular, a method of treating the
proliferation of the HIV virus, treating AIDS, or delaying the onset of AIDS or ARC
symptoms in a mammal (e.g., a human) is provided, comprising administering to the mammal
a compound having Formula (I), (Ia), (Ib), (Ic), (Id), or (Ie), or a stereoisomer or
pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or
excipient.
In another embodiment, use of a compound of Formula (I), (Ia), (Ib), (Ic), (Id),
or (Ie) as described herein, or a pharmaceutically acceptable salt thereof, for the treatment of
an HIV infection in a human being having or at risk of having the infection is disclosed.
In another embodiment, the use of a compound of Formula (I), (Ia), (Ib), (Ic),
(Id), or (Ie) as described herein, or a pharmaceutically acceptable salt thereof, for the
manufacture of a medicament for the treatment of an HIV infection in a human being having
or at risk of having the infection is disclosed.
In another embodiment, an article of manufacture comprising a composition
effective to treat an HIV infection; and packaging material comprising a label which indicates
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that the composition can be used to treat infection by HIV is disclosed. Exemplary
compositions comprise a compound of Formula (I), (Ia), (Ib), (Ic), (Id), or (Ie) according to
this invention or a pharmaceutically acceptable salt thereof.
In still another embodiment, a method of inhibiting the replication of HIV is
disclosed. The method comprises exposing the virus to an effective amount of the compound
of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), or a salt thereof, under conditions where replication
of HIV is inhibited.
In another embodiment, the use of a compound of Formula (I), (Ia), (Ib), (Ic),
(Id), or (Ie) to inhibit the activity of the HIV integrase enzyme is disclosed.
In another embodiment, the use of a compound of Formula (I), (Ia), (Ib), (Ic),
(Id), (Ie), or a salt thereof, to inhibit the replication of HIV is disclosed.
Other embodiments, objects, features and advantages will be set forth in the
detailed description of the embodiments that follows, and in part will be apparent from the
description, or may be learned by practice, of the claimed invention. These objects and
advantages will be realized and attained by the processes and compositions particularly
pointed out in the written description and claims hereof. The foregoing Summary has been
made with the understanding that it is to be considered as a brief and general synopsis of
some of the embodiments disclosed herein, is provided solely for the benefit and convenience
of the reader, and is not intended to limit in any manner the scope, or range of equivalents, to
which the appended claims are lawfully entitled.
DETAILED DESCRIPTION
In the following description, certain specific details are set forth in order to
provide a thorough understanding of various embodiments of the invention. However, one
skilled in the art will understand that the invention may be practiced without these details.
The description below of several embodiments is made with the understanding that the
present disclosure is to be considered as an exemplification of the claimed subject matter, and
is not intended to limit the appended claims to the specific embodiments illustrated. The
headings used throughout this disclosure are provided for convenience only and are not to be
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construed to limit the claims in any way. Embodiments illustrated under any heading may be
combined with embodiments illustrated under any other heading.
Definitions
Unless the context requires otherwise, throughout the present specification and
claims, the word “comprise” and variations thereof, such as, “comprises” and “comprising”
are to be construed in an open, inclusive sense, that is as “including, but not limited to”.
Reference throughout this specification to “one embodiment” or “an
embodiment” means that a particular feature, structure or characteristic described in
connection with the embodiment is included in at least one embodiment of the present
invention. Thus, the appearances of the phrases “in one embodiment” or “in an embodiment”
in various places throughout this specification are not necessarily all referring to the same
embodiment. Furthermore, the particular features, structures, or characteristics may be
combined in any suitable manner in one or more embodiments.
“Amino” refers to the -NH radical.
“Cyano” refers to the -CN radical.
“Hydroxy” or “hydroxyl” refers to the -OH radical.
“Imino” refers to the =NH substituent.
“Nitro” refers to the -NO radical.
“Oxo” refers to the =O substituent.
“Thioxo” refers to the =S substituent.
“Alkyl” refers to a straight or branched hydrocarbon chain radical consisting
solely of carbon and hydrogen atoms, which is saturated or unsaturated (i.e., contains one or
more double and/or triple bonds), having from one to twelve carbon atoms (C -C alkyl),
1 12
preferably one to eight carbon atoms (C -C alkyl) or one to six carbon atoms (C -C alkyl),
1 8 1 6
and which is attached to the rest of the molecule by a single bond, e.g., methyl, ethyl,
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n-propyl, 1-methylethyl (iso-propyl), n-butyl, n-pentyl, 1,1-dimethylethyl (t-butyl),
3-methylhexyl, 2-methylhexyl, ethenyl, propenyl, butenyl, pentenyl,
penta-1,4-dienyl, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. In certain
embodiments, “Alkyl” refers to a straight or branched hydrocarbon chain radical consisting
solely of carbon and hydrogen atoms, which is saturated, having from one to twelve carbon
atoms (C -C alkyl), or from one to eight carbon atoms (C -C alkyl), or from one to six
1 12 1 8
carbon atoms (C -C alkyl), or from one to four carbon atoms (C -C alkyl), and which is
1 6 1 4
attached to the rest of the molecule by a single bond Unless stated otherwise specifically in
the specification, an alkyl group may be optionally substituted.
“Alkylene” or “alkylene chain” refers to a straight or branched divalent
hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of
carbon and hydrogen, which is saturated or unsaturated (i.e., contains one or more double
and/or triple bonds), and having from one to twelve carbon atoms, e.g., methylene, ethylene,
propylene, n-butylene, ethenylene, propenylene, n-butenylene, propynylene, n-butynylene,
and the like. The alkylene chain is attached to the rest of the molecule through a single or
double bond and to the radical group through a single or double bond. The points of
attachment of the alkylene chain to the rest of the molecule and to the radical group can be
through one carbon or any two carbons within the chain. Unless stated otherwise specifically
in the specification, an alkylene chain may be optionally substituted.
“Alkoxy” refers to a radical of the formula –OR where R is an alkyl radical
as defined above containing one to twelve carbon atoms. Unless stated otherwise specifically
in the specification, an alkoxy group may be optionally substituted.
“Alkylamino” refers to a radical of the formula –NHR or –NR R where
A A A
each R is, independently, an alkyl radical as defined above containing one to twelve carbon
atoms. Unless stated otherwise specifically in the specification, an alkylamino group may be
optionally substituted.
“Thioalkyl” refers to a radical of the formula –SR where R is an alkyl
radical as defined above containing one to twelve carbon atoms. Unless stated otherwise
specifically in the specification, a thioalkyl group may be optionally substituted.
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“Aryl” refers to a hydrocarbon ring system radical comprising hydrogen, 6 to
18 carbon atoms and at least one aromatic ring. For purposes of this invention, the aryl
radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include
fused or bridged ring systems. In a preferred embodiment, the aryl radical is a monocyclic
ring system. Aryl radicals include, but are not limited to, aryl radicals derived from
aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene,
fluoranthene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, phenalene,
phenanthrene, pleiadene, pyrene, and triphenylene. Unless stated otherwise specifically in the
specification, the term “aryl” or the prefix “ar-“ (such as in “aralkyl”) is meant to include aryl
radicals that are optionally substituted.
“Aralkyl” refers to a radical of the formula –R -R where R is an alkylene
B C B
chain as defined above and R is one or more aryl radicals as defined above, for example,
benzyl, diphenylmethyl and the like. Unless stated otherwise specifically in the specification,
an aralkyl group may be optionally substituted.
“Cycloalkyl” or “carbocyclic ring” refers to a stable non-aromatic monocyclic
or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, which
may include fused or bridged ring systems, having from three to fifteen carbon atoms,
preferably having from three to ten carbon atoms, and which is saturated or unsaturated and
attached to the rest of the molecule by a single bond. In certain preferred embodiments,
“Cycloalkyl” or “carbocyclic ring” refers to a stable non-aromatic monocyclic hydrocarbon
radical consisting solely of carbon and hydrogen atoms, having from three to fifteen carbon
atoms, or having from three to ten carbon atoms, or having from three to eight carbon atoms
and which is saturated or unsaturated and attached to the rest of the molecule by a single
bond. Monocyclic radicals include, for example, cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic radicals include, for example, adamantyl,
norbornyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. Unless otherwise
stated specifically in the specification, a cycloalkyl group may be optionally substituted.
“Cycloalkylalkyl” refers to a radical of the formula –R R where R is an
B D B
alkylene chain as defined above and R is a cycloalkyl radical as defined above. Unless
stated otherwise specifically in the specification, a cycloalkylalkyl group may be optionally
substituted.
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“Fused” refers to any ring structure described herein which is fused to an
existing ring structure in the compounds of the invention. When the fused ring is a
heterocyclyl ring or a heteroaryl ring, any carbon atom on the existing ring structure which
becomes part of the fused heterocyclyl ring or the fused heteroaryl ring may be replaced with
a nitrogen atom.
“Halo” or “halogen” refers to bromo, chloro, fluoro or iodo.
“Haloalkyl” refers to an alkyl radical, as defined above, that is substituted by
one or more halo radicals, as defined above, e.g., trifluoromethyl, difluoromethyl,
trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromofluoropropyl,
1,2-dibromoethyl, and the like. Unless stated otherwise specifically in the specification, a
haloalkyl group may be optionally substituted.
“Heterocyclyl” or “heterocyclic ring” refers to a stable 3- to 18-membered
non-aromatic ring radical which consists of two to twelve carbon atoms and from one to six
heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. Unless stated
otherwise specifically in the specification, the heterocyclyl radical may be a monocyclic,
bicyclic, tricyclic or tetracyclic ring system, which may include fused or bridged ring
systems; and the nitrogen, carbon or sulfur atoms in the heterocyclyl radical may be
optionally oxidized; the nitrogen atom may be optionally quaternized; and the heterocyclyl
radical may be partially or fully saturated. Examples of such heterocyclyl radicals include,
but are not limited to, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl,
imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl,
octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl,
piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl,
thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl,
thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. Unless stated
otherwise specifically in the specification, a heterocyclyl group may be optionally
substituted.
“N-heterocyclyl” refers to a heterocyclyl radical as defined above containing
at least one nitrogen and where the point of attachment of the heterocyclyl radical to the rest
of the molecule is through a nitrogen atom in the heterocyclyl radical. Unless stated
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otherwise specifically in the specification, an N-heterocyclyl group may be optionally
substituted.
“Heterocyclylalkyl” refers to a radical of the formula –R R where R is an
B E B
alkylene chain as defined above and R is a heterocyclyl radical as defined above, and if the
heterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl may be attached to the
alkyl radical at the nitrogen atom. Unless stated otherwise specifically in the specification, a
heterocyclylalkyl group may be optionally substituted.
“Heteroaryl” refers to a 5- to 14-membered ring system radical comprising
hydrogen atoms, one to thirteen carbon atoms, one to six heteroatoms selected from the group
consisting of nitrogen, oxygen and sulfur, and at least one aromatic ring. For purposes of this
invention, the heteroaryl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring
system, which may include fused or bridged ring systems; the nitrogen, carbon or sulfur
atoms in the heteroaryl radical may be optionally oxidized; and the nitrogen atom may be
optionally quaternized. In certain preferred embodiments, the heteroaryl radical may be a
monocyclic ring system; the nitrogen, carbon or sulfur atoms in the heteroaryl radical may be
optionally oxidized; and the nitrogen atom may be optionally quaternized. Examples include,
but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl,
benzodioxolyl, benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl,
benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl,
benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl,
benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl,
benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl,
dibenzothiophenyl, furanyl, furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl,
isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl,
oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-
oxidopyrazinyl, 1-oxidopyridazinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl,
phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl,
pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl,
tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl
(i.e. thienyl). Unless stated otherwise specifically in the specification, a heteroaryl group may
be optionally substituted.
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“N-heteroaryl” refers to a heteroaryl radical as defined above containing at
least one nitrogen and where the point of attachment of the heteroaryl radical to the rest of the
molecule is through a nitrogen atom in the heteroaryl radical. Unless stated otherwise
specifically in the specification, an N-heteroaryl group may be optionally substituted.
“Heteroarylalkyl” refers to a radical of the formula –R R where R is an
B F B
alkylene chain as defined above and R is a heteroaryl radical as defined above. Unless stated
otherwise specifically in the specification, a heteroarylalkyl group may be optionally
substituted.
The term “substituted” used herein means any of the above groups (i.e., alkyl,
alkylene, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, haloalkyl,
heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl, N-heteroaryl and/or
heteroarylalkyl) wherein at least one hydrogen atom is replaced by a bond to a non-hydrogen
atoms such as, but not limited to: a halogen atom such as F, Cl, Br, and I; an oxygen atom in
groups such as hydroxyl groups, alkoxy groups, and ester groups; a sulfur atom in groups
such as thiol groups, thioalkyl groups, sulfone groups, sulfonyl groups, and sulfoxide groups;
a nitrogen atom in groups such as amines, amides, alkylamines, dialkylamines, arylamines,
alkylarylamines, diarylamines, N-oxides, imides, and enamines; a silicon atom in groups such
as trialkylsilyl groups, dialkylarylsilyl groups, alkyldiarylsilyl groups, and triarylsilyl groups;
and other heteroatoms in various other groups. “Substituted” also means any of the above
groups in which one or more hydrogen atoms are replaced by a higher-order bond (e.g., a
double- or triple-bond) to a heteroatom such as oxygen in oxo, carbonyl, carboxyl, and ester
groups; and nitrogen in groups such as imines, oximes, hydrazones, and nitriles. For example,
“substituted” includes any of the above groups in which one or more hydrogen atoms are
replaced with –
NR R , -NR C(=O)R , -NR C(=O)NR R , -NR C(=O)OR , -NR C(=NR )NR R , -NR
G H G H G G H G H G g G H G
SO R , -OC(=O)NR R , -OR , -SR , -SOR , -SO R , -OSO R , -SO OR , =NSO R ,
2 H G H G G G 2 G 2 G 2 G 2 G
and -SO NR R . “Substituted also means any of the above groups in which one or more
2 G H
hydrogen atoms are replaced
with -C(=O)R , -C(=O)OR , -C(=O)NR R , -CH SO R , -CH SO NR R . In the
G G G H 2 2 G 2 2 G H
foregoing, R and R are the same or different and independently hydrogen, alkyl, alkoxy,
alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocyclyl, N-
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heterocyclyl, heterocyclylalkyl, heteroaryl, N-heteroaryl and/or heteroarylalkyl. “Substituted”
further means any of the above groups in which one or more hydrogen atoms are replaced by
a bond to an amino, cyano, hydroxyl, imino, nitro, oxo, thioxo, halo, alkyl, alkoxy,
alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocyclyl, N-
heterocyclyl, heterocyclylalkyl, heteroaryl, N-heteroaryl and/or heteroarylalkyl group. In
addition, each of the foregoing substituents may also be optionally substituted with one or
more of the above substituents.
The term “protecting group,” as used herein, refers to a labile chemical moiety
which is known in the art to protect reactive groups including without limitation, hydroxyl
and amino groups, against undesired reactions during synthetic procedures. Hydroxyl and
amino groups protected with a protecting group are referred to herein as “protected hydroxyl
groups” and “protected amino groups”, respectively. Protecting groups are typically used
selectively and/or orthogonally to protect sites during reactions at other reactive sites and can
then be removed to leave the unprotected group as is or available for further reactions.
Protecting groups as known in the art are described generally in Greene and Wuts, Protective
Groups in Organic Synthesis, 3rd edition, John Wiley & Sons, New York (1999). Generally,
groups are protected or present as a precursor that will be inert to reactions that modify other
areas of the parent molecule for conversion into their final groups at an appropriate time.
Further representative protecting or precursor groups are discussed in Agrawal, et al.,
Protocols for Oligonucleotide Conjugates, Eds, Humana Press; New Jersey, 1994; Vol. 26 pp.
1–72. Examples of “hydroxyl protecting groups” include, but are not limited to, t-butyl, t-
butoxymethyl, methoxymethyl, tetrahydropyranyl, 1-ethoxyethyl, 1-(2-chloroethoxy)ethyl, 2-
trimethylsilylethyl, p-chlorophenyl, 2,4-dinitrophenyl, benzyl, 2,6-dichlorobenzyl, diphenyl-
methyl, p-nitrobenzyl, triphenylmethyl, trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, t-
butyldiphenylsilyl (TBDPS), triphenylsilyl, benzoylformate, acetate, chloroacetate,
trichloroacetate, trifluoroacetate, pivaloate, benzoate, p-phenylbenzoate, 9-fluorenylmethyl
carbonate, mesylate and tosylate. Examples of “amino protecting groups” include, but are not
limited to, carbamate-protecting groups, such as 2-trimethylsilylethoxycarbonyl (Teoc), 1-
methyl(4-biphenylyl)ethoxycarbonyl (Bpoc), t-butoxycarbonyl (BOC), allyloxycarbonyl
(Alloc), 9-fluorenylmethyloxycarbonyl (Fmoc), and benzyloxycarbonyl (Cbz); amide
protecting groups, such as formyl, acetyl, trihaloacetyl, benzoyl, and nitrophenylacetyl;
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sulfonamide-protecting groups, such as 2-nitrobenzenesulfonyl; and imine and cyclic imide
protecting groups, such as phthalimido and dithiasuccinoyl.
The invention disclosed herein is also meant to encompass all
pharmaceutically acceptable compounds of Formulas (I), (Ia), (Ib), (Ic), (Id), and (Ie), being
isotopically-labeled by having one or more atoms replaced by an atom having a different
atomic mass or mass number. Examples of isotopes that can be incorporated into the
disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous,
2 3 11 13 14 13 15 15 17 18 31 32
fluorine, chlorine, and iodine, such as H, H, C, C, C, N, N, O, O, O, P, P,
18 36 123 125
S, F, Cl, I, and I, respectively. These radiolabeled compounds could be useful to
help determine or measure the effectiveness of the compounds, by characterizing, for
example, the site or mode of action, or binding affinity to pharmacologically important site of
action. Certain isotopically-labeled compounds of Formulas (I), (Ia), (Ib), (Ic), (Id), and (Ie),
for example, those incorporating a radioactive isotope, are useful in drug and/or substrate
3 14
tissue distribution studies. The radioactive isotopes tritium, i.e. H, and carbon-14, i.e. C,
are particularly useful for this purpose in view of their ease of incorporation and ready means
of detection.
Substitution with heavier isotopes such as deuterium, i.e. H, may afford
certain therapeutic advantages resulting from greater metabolic stability. For example, in vivo
half-life may increase or dosage requirements may be reduced. Thus, heavier isotopes may be
preferred in some circumstances.
11 18 15 13
Substitution with positron emitting isotopes, such as C, F, O and N, can
be useful in Positron Emission Topography (PET) studies for examining substrate receptor
occupancy. Isotopically-labeled compounds of Formulas (I), (Ia), (Ib), (Ic), (Id), and (Ie), can
generally be prepared by conventional techniques known to those skilled in the art or by
processes analogous to those described in the Examples as set out below using an appropriate
isotopically-labeled reagent in place of the non-labeled reagent previously employed.
The invention disclosed herein is also meant to encompass the in vivo
metabolic products of the disclosed compounds. Such products may result from, for example,
the oxidation, reduction, hydrolysis, amidation, esterification, and the like of the administered
compound, primarily due to enzymatic processes. Accordingly, the invention includes
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compounds produced by a process comprising administering a compound of this invention to
a mammal for a period of time sufficient to yield a metabolic product thereof. Such products
are typically identified by administering a radiolabeled compound of the invention in a
detectable dose to an animal, such as rat, mouse, guinea pig, monkey, or to human, allowing
sufficient time for metabolism to occur, and isolating its conversion products from the urine,
blood or other biological samples.
“Stable compound” and “stable structure” are meant to indicate a compound
that is sufficiently robust to survive isolation to a useful degree of purity from a reaction
mixture, and formulation into an efficacious therapeutic agent.
“Mammal” includes humans and both domestic animals such as laboratory
animals and household pets (e.g., cats, dogs, swine, cattle, sheep, goats, horses, rabbits), and
non-domestic animals such as wildlife and the like.
“Optional” or “optionally” means that the subsequently described event of
circumstances may or may not occur, and that the description includes instances where said
event or circumstance occurs and instances in which it does not. For example, “optionally
substituted aryl” means that the aryl radical may or may not be substituted and that the
description includes both substituted aryl radicals and aryl radicals having no substitution.
“Pharmaceutically acceptable carrier, diluent or excipient” includes without
limitation any adjuvant, carrier, excipient, glidant, sweetening agent, diluent, preservative,
dye/colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent,
stabilizer, isotonic agent, solvent, or emulsifier which has been approved by the United States
Food and Drug Administration as being acceptable for use in humans or domestic animals.
Examples of “pharmaceutically acceptable salts” of the compounds disclosed
herein include salts derived from an appropriate base, such as an alkali metal (for example,
sodium), an alkaline earth metal (for example, magnesium), ammonium and NX (wherein
X is C C alkyl). Pharmaceutically acceptable salts of a nitrogen atom or an amino group
include for example salts of organic carboxylic acids such as acetic, benzoic, lactic, fumaric,
tartaric, maleic, malonic, malic, isethionic, lactobionic and succinic acids; organic sulfonic
acids, such as methanesulfonic, ethanesulfonic, benzenesulfonic and p-toluenesulfonic acids;
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and inorganic acids, such as hydrochloric, hydrobromic, sulfuric, phosphoric and sulfamic
acids. Pharmaceutically acceptable salts of a compound of a hydroxy group include the anion
of said compound in combination with a suitable cation such as Na and NX (wherein X is
independently selected from H or a C C alkyl group).
For therapeutic use, salts of active ingredients of the compounds disclosed
herein will typically be pharmaceutically acceptable, i.e. they will be salts derived from a
physiologically acceptable acid or base. However, salts of acids or bases which are not
pharmaceutically acceptable may also find use, for example, in the preparation or purification
of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), or another compound of the
invention. All salts, whether or not derived from a physiologically acceptable acid or base,
are within the scope of the present invention.
Metal salts typically are prepared by reacting the metal hydroxide with a
compound of this invention. Examples of metal salts which are prepared in this way are salts
+ + +
containing Li , Na , and K . A less soluble metal salt can be precipitated from the solution
of a more soluble salt by addition of the suitable metal compound.
In addition, salts may be formed from acid addition of certain organic and
inorganic acids, e.g., HCl, HBr, H SO H PO or organic sulfonic acids, to basic centers,
4, 3 4
typically amines. Finally, it is to be understood that the compositions herein comprise
compounds disclosed herein in their un-ionized, as well as zwitterionic form, and
combinations with stoichiometric amounts of water as in hydrates.
Often crystallizations produce a solvate of the compound of the invention. As
used herein, the term “solvate” refers to an aggregate that comprises one or more molecules
of a compound of the invention with one or more molecules of solvent. The solvent may be
water, in which case the solvate may be a hydrate. Alternatively, the solvent may be an
organic solvent. Thus, the compounds of the present invention may exist as a hydrate,
including a monohydrate, dihydrate, hemihydrate, sesquihydrate, trihydrate, tetrahydrate and
the like, as well as the corresponding solvated forms. The compound of the invention may be
true solvates, while in other cases, the compound of the invention may merely retain
adventitious water or be a mixture of water plus some adventitious solvent.
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A “pharmaceutical composition” refers to a formulation of a compound of the
invention and a medium generally accepted in the art for the delivery of the biologically
active compound to mammals, e.g., humans. Such a medium includes all pharmaceutically
acceptable carriers, diluents or excipients therefor.
“Effective amount” or “therapeutically effective amount” refers to an amount
of a compound according to the invention, which when administered to a patient in need
thereof, is sufficient to effect treatment for disease-states, conditions, or disorders for which
the compounds have utility. Such an amount would be sufficient to elicit the biological or
medical response of a tissue system, or patient that is sought by a researcher or clinician. The
amount of a compound according to the invention which constitutes a therapeutically
effective amount will vary depending on such factors as the compound and its biological
activity, the composition used for administration, the time of administration, the route of
administration, the rate of excretion of the compound, the duration of the treatment, the type
of disease-state or disorder being treated and its severity, drugs used in combination with or
coincidentally with the compounds of the invention, and the age, body weight, general health,
sex and diet of the patient. Such a therapeutically effective amount can be determined
routinely by one of ordinary skill in the art having regard to their own knowledge, the state of
the art, and this disclosure.
The term "treatment" as used herein is intended to mean the administration of
a compound or composition according to the present invention to alleviate or eliminate
symptoms of HIV infection and/or to reduce viral load in a patient. The term "treatment" also
encompasses the administration of a compound or composition according to the present
invention post-exposure of the individual to the virus but before the appearance of symptoms
of the disease, and/or prior to the detection of the virus in the blood, to prevent the
appearance of symptoms of the disease and/or to prevent the virus from reaching detectible
levels in the blood, and the administration of a compound or composition according to the
present invention to prevent perinatal transmission of HIV from mother to baby, by
administration to the mother before giving birth and to the child within the first days of life.
The term "antiviral agent" as used herein is intended to mean an agent
(compound or biological) that is effective to inhibit the formation and/or replication of a virus
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in a human being, including but not limited to agents that interfere with either host or viral
mechanisms necessary for the formation and/or replication of a virus in a human being.
The term "inhibitor of HIV replication" as used herein is intended to mean an
agent capable of reducing or eliminating the ability of HIV to replicate in a host cell, whether
in vitro, ex vivo or in vivo.
The compounds of the invention, or their pharmaceutically acceptable salts
may contain one or more asymmetric centers and may 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.
Optically active (+) and (-), (R)- and (S)-, or (D)- and (L)- isomers may be prepared using
chiral synthons or chiral reagents, or resolved using conventional techniques, for example,
chromatography and fractional crystallization. Conventional techniques for the
preparation/isolation of individual enantiomers include chiral synthesis from a suitable
optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative)
using, for example, chiral high pressure liquid chromatography (HPLC). When the
compounds described herein contain olefinic double bonds or other centres of geometric
asymmetry, and unless specified otherwise, it is intended that the compounds include both E
and Z geometric isomers. Likewise, all tautomeric forms are also intended to be included.
A “stereoisomer” refers to a compound made up of the same atoms bonded by
the same bonds but having different three-dimensional structures, which are not
interchangeable. The present invention contemplates various stereoisomers and mixtures
thereof and includes “enantiomers”, which refers to two stereoisomers whose molecules are
nonsuperimposeable mirror images of one another.
A “tautomer” refers to a proton shift from one atom of a molecule to another
atom of the same molecule. The present invention includes tautomers of any said compounds.
Compounds
As noted above, in one embodiment of the present invention, compounds
having antiviral activity are provided, the compounds having the following Formula (I):
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or a stereoisomer or pharmaceutically acceptable salt thereof,
wherein:
Y and Y are each, independently, hydrogen, C alkyl or C haloalkyl;
1-3 1-3
R is phenyl substituted with one to three halogens;
X is -O-, -NR -, -CHR - or a bond;
R and R are each, independently, hydrogen or C alkyl;
L is -C(R ) C(R ) -; and
each R is, independently, hydrogen, halo, hydroxyl, or C alkyl, and
wherein two R groups on adjacent carbon atoms, together with the carbon atoms to
which they are attached, form a carbocyclic ring having the following structure:
wherein each R is, independently, hydrogen or halo.
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In one embodiment of the present invention, compounds having the following
Formula (Ia) are provided:
(Ia)
or a stereoisomer or pharmaceutically acceptable salt thereof,
wherein:
Y and Y are each, independently, hydrogen, C alkyl or C haloalkyl;
1-3 1-3
R is phenyl substituted with one to three halogen atoms;
X is -O-, -NR -, -CHR - or a bond;
R and R are each, independently, hydrogen or C alkyl; and
L is -C(R ) C(R ) -; and
each R is, independently, hydrogen, halo, hydroxyl, or C alkyl, and
wherein two R groups on adjacent carbon atoms, together with the carbon
atoms to which they are attached, form a carbocyclic ring having the following structure:
,
wherein each R is, independently, hydrogen or halo.
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In one embodiment of the present invention, compounds having the following
Formula (Ib) are provided:
(Ib)
or a stereoisomer or pharmaceutically acceptable salt thereof,
wherein:
Y and Y are each, independently, hydrogen, C alkyl or C haloalkyl;
1-3 1-3
R is phenyl substituted with one to three halogen atoms;
X is -O-, -NR -, -CHR - or a bond;
R and R are each, independently, hydrogen or C alkyl; and
L is -C(R ) C(R ) -; and
each R is, independently, hydrogen, halo, hydroxyl, or C alkyl, and
wherein two R groups on adjacent carbon atoms, together with the carbon atoms to
which they are attached, form a carbocyclic ring having the following structure:
,
wherein each R is, independently, hydrogen or halo.
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In one embodiment of the present invention, compounds having the following
Formula (Ic) are provided:
(Ic)
or a stereoisomer or pharmaceutically acceptable salt thereof,
wherein:
Y and Y are each, independently, hydrogen, C alkyl or C haloalkyl;
1-3 1-3
R is phenyl substituted with one to three halogen atoms;
X is -O-, -NR -, -CHR - or a bond;
R and R are each, independently, hydrogen or C alkyl; and
L is -C(R ) C(R ) -; and
each R is, independently, hydrogen, halo, hydroxyl, or C alkyl, and
wherein two R groups on adjacent carbon atoms, together with the carbon atoms to
which they are attached, form a carbocyclic ring having the following structure:
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wherein each R is, independently, hydrogen or halo.
In one embodiment of the present invention, compounds having the following
Formula (Id) are provided:
(Id)
or a stereoisomer or pharmaceutically acceptable salt thereof,
wherein:
Y and Y are each, independently, hydrogen, C alkyl or C haloalkyl;
1-3 1-3
R is phenyl substituted with one to three halogen atoms;
X is -O-, -NR -, -CHR - or a bond;
R and R are each, independently, hydrogen or C alkyl; and
L is -C(R ) C(R ) -; and
each R is, independently, hydrogen, halo, hydroxyl, or C alkyl, and
wherein two R groups on adjacent carbon atoms, together with the carbon atoms to
which they are attached, form a carbocyclic ring having the following structure:
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wherein each R is, independently, hydrogen or halo.
In one embodiment of the present invention, compounds having the following
Formula (Ie) are provided:
(Ie)
or a stereoisomer or pharmaceutically acceptable salt thereof,
wherein:
Y and Y are each, independently, hydrogen, C alkyl or C haloalkyl;
1-3 1-3
R is phenyl substituted with one to three halogen atoms;
X is -O-, -NR -, -CHR - or a bond;
R and R are each, independently, hydrogen or C alkyl; and
L is -C(R ) C(R ) -; and
each R is, independently, hydrogen, halo, hydroxyl, or C alkyl, and
wherein two R groups on adjacent carbon atoms, together with the carbon atoms to
which they are attached, form a carbocyclic ring having the following structure:
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wherein each R is, independently, hydrogen or halo.
In another embodiment, X is -O-. In another embodiment, X is -NH-. In
another embodiment, X is -CH -. In another embodiment, X is a bond.
In another embodiment, Y is C alkyl and Y is hydrogen. In another
1 2 1
embodiment, Y is methyl and Y is hydrogen. In another embodiment, Y is
C haloalkyl and Y is hydrogen. In another embodiment, Y is
CF and Y is hydrogen. In another embodiment, Y is
2 1 2
hydrogen, methyl or CF and Y is hydrogen. In another embodiment, Y and Y are both
hydrogen.
In another embodiment, R is substituted with one halogen. In a further
embodiment, R is 4-fluorophenyl or 2-fluorophenyl.
In another embodiment, R is substituted with two halogens. In a further
embodiment, R is 2,4-difluorophenyl, 2,3-difluorophenyl, 2,6-difluorophenyl, 3-fluoro
chlorophenyl, 3,4-difluorophenyl, 2-fluorochlorophenyl, or 3,5-difluorophenyl. In still a
further embodiment, R is 2,4-difluorophenyl.
In another embodiment, R is substituted with three halogens. In a further
embodiment, R is 2,4,6-trifluorophenyl or 2,3,4-trifluorophenyl. In still a further
embodiment, R is 2,4,6-trifluorophenyl.
In another embodiment, each R is independently hydrogen. In another
embodiment, each R is independently halogen. In a further embodiment, each R is fluoro.
In one embodiment, a pharmaceutical composition is provided comprising a
compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), or a stereoisomer or pharmaceutically
acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or excipient.
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Another embodiment is provided comprising a method of treating or
preventing an HIV infection in a human having or at risk of having the infection by
administering to the human a therapeutically effective amount of a compound of Formula (I),
(Ia), (Ib), (Ic), (Id), (Ie), or a pharmaceutical composition thereof.
In another embodiment, the use of a compound of Formula (I), (Ia), (Ib), (Ic),
(Id), (Ie), or a pharmaceutical composition thereof for the treatment or prevention of an HIV
infection in a human having or at risk of having the infection.
As further noted above, in another embodiment of the present invention,
compounds having antiviral activity are provided, the compounds having the following
Formula (I):
or a stereoisomer or pharmaceutically acceptable salt thereof,
wherein:
1 2 1
Y and Y are each, independently, hydrogen, C alkyl or C haloalkyl, or Y
1-3 1-3
and Y , together with the carbon atom to which they are attached, form a carbocyclic ring
having from 3 to 6 ring atoms or a heterocyclic ring having from 3 to 6 ring atoms, wherein
the carbocyclic or heterocyclic ring is optionally substituted with one or more R ;
each R is, independently, hydrogen, halo, hydroxyl or C alkyl, or wherein
two R groups, together with the carbon atom to which they are attached, form C=O;
R is optionally substituted aryl or optionally substituted heteroaryl;
X is -O-, -NR -, -CHR - or a bond;
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R and R are each, independently, hydrogen or C alkyl;
L is -C(R ) C(R ) -; and
each R is, independently, hydrogen, halo, hydroxyl, or C alkyl, and
wherein two R groups on adjacent carbon atoms, together with the carbon
atoms to which they are attached, form a carbocyclic ring having the following structure:
wherein each R is, independently, hydrogen or halo.
In another embodiment, compounds are provided having one of the following
Formulas (II-A), (II-B), (II-C) or (II-D):
;
(II–A)
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(II–B)
; or
(II–C)
(II–D)
In another embodiment, compounds are provided having one of the following
Formulas (II-E), (II-F), (II-G), or (II-H):
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(II–E)
(II–F)
; or
(II–G)
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(II–H)
In another embodiment, X is -O-. In another embodiment, X is -NH-. In
another embodiment, X is -CH -. In another embodiment, X is a bond.
In another embodiment, R is phenyl. In another embodiment, R is pyridinyl.
In another embodiment, R is substituted with at least one halogen.
In another embodiment, R is substituted with one halogen. In a further
embodiment, R is 4-fluorophenyl or 2-fluorophenyl.
In another embodiment, R is substituted with two halogens. In a further
embodiment, R is 2,4-difluorophenyl, 2,3-difluorophenyl, 2,6-difluorophenyl, 3-fluoro
chlorophenyl, 3,4-difluorophenyl, 2-fluorochlorophenyl, or 3,5-difluorophenyl. In still a
further embodiment, R is 2,4-difluorophenyl.
In another embodiment, R is substituted with three halogens. In a further
embodiment, R is 2,4,6-trifluorophenyl or 2,3,4-trifluorophenyl. In still a further
embodiment, R is 2,4,6-trifluorophenyl.
In another embodiment, each R is independently hydrogen. In another
embodiment, each R is independently halogen. In a further embodiment, each R is fluoro.
In one embodiment, a pharmaceutical composition is provided comprising a
compound of any one of Formulas (I), (Ia), (Ib), (Ic), (Id), (Ie), (II–A), (II–B), (II–C), (II–D),
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(II–E), (II–F), (II–G), and (II–H), or a stereoisomer or pharmaceutically acceptable salt
thereof, and a pharmaceutically acceptable carrier, diluent or excipient.
Another embodiment is provided comprising a method of treating or
preventing an HIV infection in a human having or at risk of having the infection by
administering to the human a therapeutically effective amount of a compound of any one of
Formulas (I), (Ia), (Ib), (Ic), (Id), (Ie), (II–A), (II–B), (II–C), (II–D), (II–E), (II–F), (II–G),
and (II–H), or a pharmaceutical composition thereof.
In another embodiment, the use of a compound of Formula any one of
Formulas (I), (Ia), (Ib), (Ic), (Id), (Ie), (II–A), (II–B), (II–C), (II–D), (II–E), (II–F), (II–G),
and (II–H), or a pharmaceutical composition thereof for the treatment or prevention of an
HIV infection in a human having or at risk of having the infection.
It is understood that any embodiment of the compounds of any one of
Formulas (I), (Ia), (Ib), (Ic), (Id), (Ie), (II–A), (II–B), (II–C), (II–D), (II–E), (II–F), (II–G),
1 2 3
and (II–H), as set forth above, and any specific substituent set forth herein for a R , R , R ,
a b c 1 2
R , R , R , X, Y , Y , or L group in the compounds of Formulas (I), (Ia), (Ib), (Ic), (Id), or
(Ie), as set forth above, may be independently combined with other embodiments and/or
substituents of compounds of any one of Formulas (I), (Ia), (Ib), (Ic), (Id), (Ie), (II–A), (II–
B), (II–C), (II–D), (II–E), (II–F), (II–G), and (II–H), to form embodiments of the inventions
not specifically set forth above. In addition, in the event that a list of substitutents is listed for
1 2 3 a b c 1 2
any particular R , R , R , R , R , R , X, Y , Y , or L in a particular embodiment and/or claim,
it is understood that each individual substituent may be deleted from the particular
embodment and/or claim and that the remaining list of substituents will be considered to be
within the scope of the invention.
Pharmaceutical Compositions
For the purposes of administration, in certain embodiments, the compounds
described herein are administered as a raw chemical or are formulated as pharmaceutical
compositions. Pharmaceutical compositions of the present invention comprise a compound of
Formulas (I), (Ia), (Ib), (Ic), (Id), (Ie), and a pharmaceutically acceptable carrier, diluent or
excipient. The compound of Formulas (I), (Ia), (Ib), (Ic), (Id), (Ie), is present in the
composition in an amount which is effective to treat a particular disease or condition of
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interest. The activity of compounds of Formulas (I), (Ia), (Ib), (Ic), (Id), (Ie), can be
determined by one skilled in the art, for example, as described in the Examples below.
Appropriate concentrations and dosages can be readily determined by one skilled in the art.
Administration of the compounds of the invention, or their pharmaceutically
acceptable salts, in pure form or in an appropriate pharmaceutical composition, can be carried
out via any of the accepted modes of administration of agents for serving similar utilities. The
pharmaceutical compositions of the invention can be prepared by combining a compound of
the invention with an appropriate pharmaceutically acceptable carrier, diluent or excipient,
and may be formulated into preparations in solid, semi-solid, liquid or gaseous forms, such as
tablets, capsules, powders, granules, ointments, solutions, suppositories, injections, inhalants,
gels, microspheres, and aerosols. Typical routes of administering such pharmaceutical
compositions include, without limitation, oral, topical, transdermal, inhalation, parenteral,
sublingual, buccal, rectal, vaginal, and intranasal. Pharmaceutical compositions of the
invention are formulated so as to allow the active ingredients contained therein to be
bioavailable upon administration of the composition to a patient. Compositions that will be
administered to a subject or patient take the form of one or more dosage units, where for
example, a tablet may be a single dosage unit, and a container of a compound of the invention
in aerosol form may hold a plurality of dosage units. Actual methods of preparing such
dosage forms are known, or will be apparent, to those skilled in this art; for example, see
Remington: The Science and Practice of Pharmacy, 20th Edition (Philadelphia College of
Pharmacy and Science, 2000). The composition to be administered will, in any event, contain
a therapeutically effective amount of a compound of the invention, or a pharmaceutically
acceptable salt thereof, for treatment of a disease or condition of interest in accordance with
the teachings of this invention.
The pharmaceutical compositions of the invention may be prepared by
methodology well known in the pharmaceutical art. For example, a pharmaceutical
composition intended to be administered by injection can be prepared by combining a
compound of the invention with sterile, distilled water so as to form a solution. A surfactant
may be added to facilitate the formation of a homogeneous solution or suspension.
Surfactants are compounds that non-covalently interact with the compound of the invention
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so as to facilitate dissolution or homogeneous suspension of the compound in the aqueous
delivery system.
The compounds of the invention, or their pharmaceutically acceptable salts,
are administered in a therapeutically effective amount, which will vary depending upon a
variety of factors including the activity of the specific compound employed; the metabolic
stability and length of action of the compound; the age, body weight, general health, sex, and
diet of the patient; the mode and time of administration; the rate of excretion; the drug
combination; the severity of the particular disorder or condition; and the subject undergoing
therapy.
Combination Therapy
In one embodiment, a method for treating or preventing an HIV infection in a
human having or at risk of having the infection is provided, comprising administering to the
human a therapeutically effective amount of a compound disclosed herein, or a
pharmaceutically acceptable salt thereof, in combination with a therapeutically effective
amount of one or more (e.g., one, two, three, one or two, or one to three) additional
therapeutic agents. In one embodiment, a method for treating an HIV infection in a human
having or at risk of having the infection is provided, comprising administering to the human a
therapeutically effective amount of a compound disclosed herein, or a pharmaceutically
acceptable salt thereof, in combination with a therapeutically effective amount of one or more
(e.g., one, two, three, one or two, or one to three) additional therapeutic agents.
In one embodiment, pharmaceutical compositions comprising a compound
disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with one or
more (e.g., one, two, three, one or two, or one to three) additional therapeutic agents, and a
pharmaceutically acceptable carrier, diluent or excipient are provided.
In one embodiment, combination pharmaceutical agents comprising a
compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination
with one or more (e.g., one, two, three, one or two, or one to three) additional therapeutic
agents are provided.
In the above embodiments, the additional therapeutic agent may be an anti-
HIV agent. For example, in some embodiments, the additional therapeutic agent is selected
from the group consisting of HIV protease inhibitors, HIV non-nucleoside inhibitors of
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reverse transcriptase, HIV nucleoside or nucleotide inhibitors of reverse transcriptase, HIV
integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, entry inhibitors
(e.g., CCR5 inhibitors, gp41 inhibitors (i.e., fusion inhibitors) and CD4 attachment
inhibitors), CXCR4 inhibitors, gp120 inhibitors, G6PD and NADH-oxidase inhibitors,
compounds that target the HIV capsid (“capsid inhibitors”; e.g., capsid polymerization
inhibitors or capsid disrupting compounds such as those disclosed in
(Gilead Sciences), US 2013/0165489 (University of Pennsylvania), and
(Pharma Resources), pharmacokinetic enhancers, and other drugs for treating HIV, and
combinations thereof. In further embodiments, the additional therapeutic agent is selected
from one or more of:
(1) HIV protease inhibitors selected from the group consisting of amprenavir,
atazanavir, fosamprenavir, indinavir, lopinavir, ritonavir, nelfinavir, saquinavir, tipranavir,
brecanavir, darunavir, TMC-126, TMC-114, mozenavir (DMP-450), JE-2147 (AG1776), L-
756423, RO0334649, KNI-272, DPC-681, DPC-684, GW640385X, DG17, PPL-100, DG35,
and AG 1859;
(2) HIV non-nucleoside or non-nucleotide inhibitors of reverse transcriptase
selected from the group consisting of capravirine, emivirine, delaviridine, efavirenz,
nevirapine, (+) calanolide A, etravirine, GW5634, DPC-083, DPC-961, DPC-963, MIV-150,
TMC-120, rilpivirene, BILR 355 BS, VRX 840773, lersivirine (UK-453061), RDEA806,
KM023 and MK-1439;
(3) HIV nucleoside or nucleotide inhibitors of reverse transcriptase selected
from the group consisting of zidovudine, emtricitabine, didanosine, stavudine, zalcitabine,
lamivudine, abacavir, abavavir sulfate, amdoxovir, elvucitabine, alovudine, MIV-210, -
FTC, D-d4FC, emtricitabine, phosphazide, fozivudine tidoxil, apricitibine (AVX754), KP-
1461, GS-9131 (Gilead Sciences) and fosalvudine tidoxil (formerly HDP 99.0003), tenofovir,
tenofovir disoproxil fumarate, tenofovir alafenamide (Gilead Sciences), tenofovir
alafenamide hemifumarate (Gilead Sciences), GS-9148 (Gilead Sciences), adefovir, adefovir
dipivoxil, CMX-001 (Chimerix) or CMX-157 (Chimerix);
(4) HIV integrase inhibitors selected from the group consisting of curcumin,
derivatives of curcumin, chicoric acid, derivatives of chicoric acid, 3,5-dicaffeoylquinic acid,
derivatives of 3,5-dicaffeoylquinic acid, aurintricarboxylic acid, derivatives of
aurintricarboxylic acid, caffeic acid phenethyl ester, derivatives of caffeic acid phenethyl
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ester, tyrphostin, derivatives of tyrphostin, quercetin, derivatives of quercetin, S-1360, AR-
177, L-870812, and L-870810, raltegravir, BMS-538158, GSK364735C, BMS-707035, MK-
2048, BA 011, elvitegravir, dolutegravir and GSK-744;
(5) HIV non-catalytic site, or allosteric, integrase inhibitors (NCINI)
including, but not limited to, BI-224436, CX0516, CX05045, CX14442, compounds
disclosed in (Boehringer Ingelheim), (Boehringer
Ingelheim), (Gilead Sciences), (Gilead Sciences), WO
2012/003497 (Gilead Sciences), (Gilead Sciences) each of which is
incorporated by references in its entirety herein;
(6) gp41 inhibitors selected from the group consisting of enfuvirtide,
sifuvirtide, albuvirtide, FB006M, and TRI-1144;
(7) the CXCR4 inhibitor AMD-070;
(8) the entry inhibitor SP01A;
(9) the gp120 inhibitor BMS-488043;
(10) the G6PD and NADH-oxidase inhibitor immunitin;
(11) CCR5 inhibitors selected from the group consisting of aplaviroc,
vicriviroc, maraviroc, cenicriviroc, PRO-140, INCB15050, PF-232798 (Pfizer), and
CCR5mAb004;
(12) CD4 attachment inhibitors selected from the group consisting of
ibalizumab (TMB-355) and BMS-068 (BMS-663068);
(13) pharmacokinetic enhancers selected from the group consisting of
cobicistat and SPI-452; and
(14) other drugs for treating HIV selected from the group consisting of BAS-
100, SPI-452, REP 9, SP-01A, TNX-355, DES6, ODN-93, ODN-112, VGV-1, PA-457
(bevirimat), HRG214, VGX-410, KD-247, AMZ 0026, CYT 99007A-221 HIV, DEBIO-025,
BAY 50-4798, MDX010 (ipilimumab), PBS 119, ALG 889, and PA-1050040 (PA-040),
and combinations thereof
In certain embodiments, a compound disclosed herein, or a pharmaceutically
acceptable salt thereof, is combined with one, two, three, four or more additional therapeutic
agents. In certain embodiments, a compound disclosed herein, or a pharmaceutically
acceptable salt thereof, is combined with two additional therapeutic agents. In other
embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is
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combined with three additional therapeutic agents. In further embodiments, a compound
disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with four
additional therapeutic agents. The two, three, four or more additional therapeutic agents can
be different therapeutic agents selected from the same class of therapeutic agents, or they can
be selected from different classes of therapeutic agents. In a specific embodiment, a
compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with
an HIV nucleoside or nucleotide inhibitor of reverse transcriptase and an HIV non-nucleoside
inhibitor of reverse transcriptase. In another specific embodiment, a compound disclosed
herein, or a pharmaceutically acceptable salt thereof, is combined with an HIV nucleoside or
nucleotide inhibitor of reverse transcriptase, and an HIV protease inhibiting compound. In a
further embodiment, a compound disclosed herein, or a pharmaceutically acceptable salt
thereof, is combined with an HIV nucleoside or nucleotide inhibitor of reverse transcriptase,
an HIV non-nucleoside inhibitor of reverse transcriptase, and an HIV protease inhibiting
compound. In an additional embodiment, a compound disclosed herein, or a pharmaceutically
acceptable salt thereof, is combined with an HIV nucleoside or nucleotide inhibitor of reverse
transcriptase, an HIV non-nucleoside inhibitor of reverse transcriptase, and a
pharmacokinetic enhancer. In another embodiment, a compound disclosed herein, or a
pharmaceutically acceptable salt thereof, is combined with two HIV nucleoside or nucleotide
inhibitor of reverse transcriptase.
In a particular embodiment, a compound disclosed herein, or a
pharmaceutically acceptable salt thereof, is combined with abacavir sulfate, tenofovir,
tenofovir disoproxil fumarate, tenofovir alafenamide, or tenofovir alafenamide hemifumarate.
In a particular embodiment, a compound disclosed herein, or a
pharmaceutically acceptable salt thereof, is combined with tenofovir, tenofovir disoproxil
fumarate, tenofovir alafenamide, or tenofovir alafenamide hemifumarate.
In a particular embodiment, a compound disclosed herein, or a
pharmaceutically acceptable salt thereof, is combined with a first additional therapeutic agent
selected from the group consisting of: abacavir sulfate, tenofovir, tenofovir disoproxil
fumarate, tenofovir alafenamide, and tenofovir alafenamide hemifumarate and a second
additional therapeutic agent selected from the group consisting of emtricitibine and
lamivudine.
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In a particular embodiment, a compound disclosed herein, or a
pharmaceutically acceptable salt thereof, is combined with a first additional therapeutic agent
selected from the group consisting of: tenofovir, tenofovir disoproxil fumarate, tenofovir
alafenamide, and tenofovir alafenamide hemifumarate and a second additional therapeutic
agent, wherein the second additional therapeutic agent is emtricitibine.
In certain embodiments, when a compound disclosed herein is combined with
one or more additional therapeutic agents as described above, the components of the
composition are administered as a simultaneous or sequential regimen. When administered
sequentially, the combination may be administered in two or more administrations.
In certain embdoiments, a compound disclosed herein is combined with one or
more additional therapeutic agents in a unitary dosage form for simultaneous administration
to a patient, for example as a solid dosage form for oral administration.
In certain embodiments, a compound disclosed herein is administered with
one or more additional therapeutic agents. Co-administration of a compound disclosed herein
with one or more additional therapeutic agents generally refers to simultaneous or sequential
administration of a compound disclosed herein and one or more additional therapeutic agents,
such that therapeutically effective amounts of the compound disclosed herein and one or
more additional therapeutic agents are both present in the body of the patient.
Co-administration includes administration of unit dosages of the compounds
disclosed herein before or after administration of unit dosages of one or more additional
therapeutic agents, for example, administration of the compound disclosed herein within
seconds, minutes, or hours of the administration of one or more additional therapeutic agents.
For example, in some embodiments, a unit dose of a compound disclosed herein is
administered first, followed within seconds or minutes by administration of a unit dose of one
or more additional therapeutic agents. Alternatively, in other embodiments, a unit dose of
one or more additional therapeutic agents is administered first, followed by administration of
a unit dose of a compound disclosed herein within seconds or minutes. In some
embodiments, a unit dose of a compound disclosed herein is administered first, followed,
after a period of hours (e.g., 1-12 hours), by administration of a unit dose of one or more
additional therapeutic agents. In other embodiments, a unit dose of one or more additional
therapeutic agents is administered first, followed, after a period of hours (e.g., 1-12 hours), by
administration of a unit dose of a compound disclosed herein.
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The following Examples illustrate various methods of making compounds of
this invention, i.e., compound of Formula (I):
(I)
1 1 2
wherein R , X, W, Y , Y , or L are as defined above. It is understood that one skilled in the
art may be able to make these compounds by similar methods or by combining other methods
known to one skilled in the art. It is also understood that one skilled in the art would be able
to make, in a similar manner as described below, other compounds of Formulas (I), (Ia), (Ib),
(Ic), (Id), (Ie), not specifically illustrated below by using the appropriate starting components
and modifying the parameters of the synthesis as needed. In general, starting components
may be obtained from sources such as Sigma Aldrich, Lancaster Synthesis, Inc., Maybridge,
Matrix Scientific, TCI, and Fluorochem USA, etc. or synthesized according to sources known
to those skilled in the art (see, for example, Advanced Organic Chemistry: Reactions,
Mechanisms, and Structure, 5th edition (Wiley, December 2000)) or prepared as described
herein.
The following examples are provided for purposes of illustration, not
limitation.
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EXAMPLES
REPRESENTATIVE COMPOUNDS
Example 1
Preparation of Compound 1
(1aS,2S,3aR,12R,12aR)-N-((S)(2,4-difluorophenyl)-2,2,2-trifluoroethyl)hydroxy-8,10-
dioxo-1a,2,3a,4,8,10,12,12a-octahydro-1H-2,12-
methanocyclopropa[e]pyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepinecarboxamide
Step 1
A 50-mL 1-neck round bottom flask was charged with reactant 1-A (0.11 g,
0.22 mmol) in acetonitrile (1.5 mL) and acetic acid (0.2 mL) was treated with
methanesulfonic acid (0.05 mL), sealed with a yellow cap, and heated to 70 °C. After 16
hours, the mixture was cooled to afford a crude solution of intermediate 1-B. LCMS-ESI
(m/z): [M+H] calculated for C H F N O : 481; found: 481.
18 19 2 2 7
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Step 2
The crude mixture from the previous step contains reactant 1-B in acetonitrile
(1.5 mL) and acetic acid (0.2 mL). 1-C (WO2013090929A1, 0.032 g, 0.22 mmol) and K CO
(0.15 g, 1.1 mmol) were added to the reaction mixture. The reaction mixture was sealed and
heated to 70 °C. After 3 hours, the reaction mixture was diluted with EtOAc (50 mL), washed
with saturated NaHCO and dried over Na SO . After concentration, the crude was purified
by column chromatography on silica gel with hexane-EtOAc to obtain 1-D. LCMS-ESI
(m/z): [M+H] calculated for C H F N O : 526; found: 526.
21 20 2 3 5
Step 3
A 50-mL 1-neck round bottom flask was charged with reactant 1-D (0.02 g,
0.038 mmol) and magnesium bromide (0.02 g, 0.10mmol) in acetonitrile (2 mL). The
reaction mixture was heated to 50 °C. After 10 minutes, the reaction mixture was cooled to
0 °C and 1 N hydrochloric acid (0.5 mL) was added in. There were some solids formed and
stuck on the flask wall. Add more water (~ 5 mL). The solid was filtrated and washed with
water. Then the solid was transferred to the barcode vial and under lyophilization overnight
to afford compound 1. H NMR (400 MHz, Chloroform-d) δ 12.38 (s, 1H), 11.25 (d, J = 9.3
Hz, 1H), 8.24 (s, 1H), 7.48 (q, J = 7.8 Hz, 1H), 7.06 - 6.69 (m, 2H), 6.30 - 5.98 (m, 1H), 5.85
(s, 1H), 4.18 (s, 1H), 3.93 (d, J = 34.6 Hz, 2H), 2.04 - 1.35 (m, 5H), 0.80 (d, J = 7.3 Hz, 1H),
0.63 - 0.43 (m, 1H). F NMR (377 MHz, Chloroform-d) δ -75.29 (t, J = 7.5 Hz, 3 F), -
107.18 - -109.52 (m, 1F), -113.01 (m, 1F). LCMS-ESI (m/z): [M+H] calculated for
C H F N O : 512.; found: 512.
21 20 2 3 5
Example 2
Preparation of Compound 2
(1aR,2R,3aS,12S,12aS)-N-((S)(2,4-difluorophenyl)-2,2,2-trifluoroethyl)hydroxy-8,10-
dioxo-1a,2,3a,4,8,10,12,12a-octahydro-1H-2,12-
methanocyclopropa[e]pyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepinecarboxamide
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Step 1
A 50-mL 1-neck round bottom flask was charged with reactant 1-A (0.11 g,
0.22 mmol) in acetonitrile (1.5 mL) and acetic acid (0.2 mL) was treated with
methanesulfonic acid (0.05 mL), sealed with a yellow cap, and heated to 70 °C. After 16
hours, the mixture was cooled to afford a crude solution of intermediate 1-B. LCMS-ESI
(m/z): [M+H] calculated for C H F N O : 481; found: 481.
18 19 2 2 7
Step 2
The crude mixture from the previous step contains reactant 1-B in acetonitrile
(1.5 mL) and acetic acid (0.2 mL). 2-A (0.032 g, 0.22 mmol) and K CO (0.15 g, 1.1 mmol)
were added to the reaction mixture. The reaction mixture was sealed and heated to 70 °C.
After 3 hours, the reaction mixture was diluted with EtOAc (50 mL), washed with saturated
NaHCO and dried over Na SO . After concentration, the crude was purified by column
chromatography on silica gel with hexane-EtOAc to obtain 2-B. LCMS-ESI (m/z): [M+H]
calculated for C H F N O : 526; found: 526.
21 20 2 3 5
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Step 3
A 50-mL 1-neck round bottom flask was charged with reactant 2-B (0.03 g,
0.058 mmol) and magnesium bromide (0.03 g, 0.15 mmol) in acetonitrile (2 mL). The
reaction mixture was heated to 50 °C. After 10 minutes, the reaction mixture was cooled to
0 °C and 1 N hydrochloric acid (0.5 mL) was added in. There were some solid formed and
stuck on the flask wall. Add more water (~ 5 mL). The solid was filtrated and washed with
water. Then the solid was transferred to the barcode vial and under lyophilization overnight
to afford compound 2. H NMR (400 MHz, Chloroform-d) δ 12.44 (s, 1H), 11.32 (d, J = 9.4
Hz, 1H), 8.29 (s, 1H), 7.81 - 7.39 (m, 1H), 7.19 - 6.67 (m, 2H), 6.42 - 6.04 (m, 1H), 5.94 (d, J
= 9.3 Hz, 1H), 4.84 - 4.43 (m, 1H), 4.26 (d, J = 12.6 Hz, 1H), 4.02 (t, J = 10.5 Hz, 1H), 2.08 -
1.38 (m, 5H), 0.88 (q, J = 7.2 Hz, 1H), 0.60 (dd, J = 6.3, 3.3 Hz, 1H). F NMR (377 MHz,
Chloroform-d) δ -75.25 (t, J = 6.5 Hz, 3 F), -106.94 - -109.63 (m, 1F), -112.11 (m, 1F).
LCMS-ESI (m/z): [M+H] calculated for C H F N O : 512.; found: 512.
21 20 2 3 5
Example 3
Preparation of Compound 3
(1aS,2S,3aR,12R,12aR)-N-((R)(2,4-difluorophenyl)ethyl)hydroxy-8,10-dioxo-
1a,2,3a,4,8,10,12,12a-octahydro-1H-2,12-
methanocyclopropa[e]pyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepinecarboxamide
3
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Step 1
A 50-mL 1-neck round bottom flask was charged with reactant 3-A (0.11 g,
0.24 mmol) in acetonitrile (1.5 mL) and acetic acid (0.2 mL) was treated with
methanesulfonic acid (0.05 mL), sealed with a yellow cap, and heated to 70 °C. After 16
hours, the mixture was cooled to afford a crude solution of intermediate 3-B. LCMS-ESI
(m/z): [M+H] calculated for C H F N O : 427; found: 427.
18 19 2 2 7
Step 2
The crude mixture from the previous step contains reactant 3-B in acetonitrile
(1.5 mL) and acetic acid (0.2 mL). 1-C (0.036 g, 0.24 mmol) and K CO (0.167 g, 1.2 mmol)
were added to the reaction mixture. The reaction mixture was sealed and heated to 70 °C.
After 3 hours, the reaction mixture was diluted with EtOAc (50 mL), washed with saturated
NaHCO and dried over Na SO . After concentration, the crude was purified by column
chromatography on silica gel with hexane-EtOAc to obtain 3-C. LCMS-ESI (m/z): [M+H]
calculated for C H F N O : 472; found: 472.
21 20 2 3 5
Step 3
A 50-mL 1-neck round bottom flask was charged with reactant 3-C (0.03 g,
0.058 mmol) and magnesium bromide (0.03 g, 0.15 mmol) in acetonitrile (2 mL). The
reaction mixture was heated to 50 °C. After 10 minutes, the reaction mixture was cooled to
0 °C and 1 N hydrochloric acid (0.5 mL) was added in. There were some solid formed and
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stuck on the flask wall. Add more water (~ 5 mL). The solid was filtrated and washed with
water. Then the solid was transferred to the barcode vial and under lyophilization overnight
to afford compound 3. H NMR (400 MHz, Chloroform-d) δ 12.35 (s, 1H), 10.57 (s, 1H),
8.26 (s, 1H), 7.61 - 7.28 (m, 1H), 7.00 - 6.65 (m, 2H), 5.89 (s, 1H), 5.45 (d, J = 10.2 Hz, 1H),
5.34 - 5.13 (m, 1H), 4.58 (d, J = 2.0 Hz, 1H), 4.20 (s, 1H), 4.02 (d, J = 7.2 Hz, 2H), 2.12 -
1.43 (m, 6H), 0.87 (d, J = 7.5 Hz, 1H), 0.60 (s, 1H).. F NMR (376 MHz, Methanol-d ) δ -
113.03 (m, 1F), -114.92 (m, 1F). LCMS-ESI (m/z): [M+H] calculated for C H F N O :
21 20 2 3 5
458.; found: 458.
Example 4
Preparation of Compound 4
(1aR,2R,3aS,12S,12aS)-N-((R)(2,4-difluorophenyl)ethyl)hydroxy-8,10-dioxo-
1a,2,3a,4,8,10,12,12a-octahydro-1H-2,12-
methanocyclopropa[e]pyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepinecarboxamide
4
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Step 1
A 50-mL 1-neck round bottom flask was charged with reactant 3-A (0.11 g,
0.24 mmol) in acetonitrile (1.5 mL) and acetic acid (0.2 mL) was treated with
methanesulfonic acid (0.05 mL), sealed with a yellow cap, and heated to 70 °C. After 16
hours, the mixture was cooled to afford a crude solution of intermediate 3-B. LCMS-ESI
(m/z): [M+H] calculated for C H F N O : 427; found: 427.
18 19 2 2 7
Steps 2
The crude mixture from the previous step contains reactant 3-B in acetonitrile
(1.5 mL) and acetic acid (0.2 mL). 2-A (0.036 g, 0.24 mmol) and K CO (0.167 g, 1.2 mmol)
were added to the reaction mixture. The reaction mixture was sealed and heated to 70 °C.
After 3 hours, the reaction mixture was diluted with EtOAc (50 mL), washed with sat
NaHCO and dried over Na SO . After concentration, the crude was purified by column
chromatography on silica gel with hexane-EtOAc to obtain 4-A. LCMS-ESI (m/z): [M+H]
calculated for C H F N O : 472; found: 472.
21 20 2 3 5
Steps 3
A 50-mL 1-neck round bottom flask was charged with reactant 4-A (0.03 g,
0.058 mmol) and magnesium bromide (0.03 g, 0.15mmol) in acetonitrile (2 mL). The
reaction mixture was heated to 50 °C. After 10 minutes, the reaction mixture was cooled to
0 °C and 1 N hydrochloric acid (0.5 mL) was added in. There were some solid formed and
stuck on the flask wall. Add more water (~ 5 mL). The solid was filtrated and washed with
water. Then the solid was transferred to the barcode vial and under lyophilization overnight
to afford compound 4. H NMR (400 MHz, Chloroform-d) δ 12.35 (s, 1H), 10.56 (s, 1H),
8.26 (s, 1H), 7.37 (s, 1H), 7.00 - 6.63 (m, 2H), 5.89 (s, 1H), 5.45 (d, J = 11.0 Hz, 1H), 5.34 -
.00 (m, 1H), 4.58 (d, J = 2.4 Hz, 1H), 4.21 (s, 1H), 4.03 (s, 2H), 2.10 - 1.43 (m, 6H), 0.87 (d,
J = 7.5 Hz, 1H), 0.60 (s, 1H). F NMR (376 MHz, Chloroform-d) δ -113.00 (m, 1F), -115.00
(m, 1F). LCMS-ESI (m/z): [M+H] calculated for C H F N O : 458.; found: 458.
21 20 2 3 5
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Example 5
Preparation of Compound 5
(1aR,2R,12S,12aS)-N-(2,4-difluorobenzyl)-1,1-difluorohydroxy-8,10-dioxo-
1a,2,3a,4,8,10,12,12a-octahydro-1H-2,12-
methanocyclopropa[e]pyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepinecarboxamide
Step 1
A mixture of compound 5-A (1252 mg, 6.796 mmol), phthalimide (1631 mg,
11.09 mmol), and PPh (3939 mg, 15.02 mmol) in THF (75 mL) was stirred at 0 C bath as
DIAD (3.0 mL, 15.24 mmol) was added. After addition, the mixture was stirred at room
temperature. After 3 hours, the mixture was concentrated and the residue was triturated with
ethyl ether (~100 mL) at 0 C bath for 10 minutes before filtration. After the filtrate was
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concentrated, the residue was dissolved in ethyl ether (~50 ml) again and the insoluble
material was filtered off. The filtrate was concentrated, and the residue was purified by
CombiFlash using hexanes-ethyl acetate as eluents to obtain compound 5-B. H NMR (400
MHz, CDCl ) δ 7.91 - 7.75 (m, 2H), 7.75 - 7.64 (m, 2H), 6.06 (dt, J = 5.8, 2.0 Hz, 1H), 5.99
(dt, J = 5.7, 1.7 Hz, 1H), 5.64 (ddq, J = 7.4, 5.5, 1.6 Hz, 1H), 5.25 (tq, J = 6.7, 2.1 Hz, 1H),
2.90 (dt, J = 13.6, 8.1 Hz, 1H), 2.22 - 2.00 (m, 1H), 1.21 (d, J = 1.3 Hz, 9H).
Step 2
A mixture of compound 5-B (750 mg, 2.394 mmol) and NaF (1.0 mg, 0.024
mmol) in toluene (1 mL) was stirred at 110 C as FSO CF COOTMS (0.95 mL, 4.821 mmol)
was added using syringe drive over 5 hours. The reaction mixture was treated with NaHCO
solution and the organic soluble material was extracted with CH Cl (x 2). After the
combined extracts were dried (Na SO ) and concentrated, the residue was separated with
Combiflash using hexanes-ethyl acetate as eluents to get partially pure compound 5-C and
the reactant.
The recovered reactant (577 mg) with NaF (1.0 mg, 0.024 mmol) in toluene (1
mL) was again stirred at 110 C as FSO CF COOTMS (3 mL, 15.22 mmol) was added using
syringe drive over 15 hours. The reaction mixture was worked up as described previously and
the residue was purified by Combiflash using hexanes-ethyl acetate as eluents to get partially
pure compound 5-C (205 mg). Two partially pure compound 5-C were combined and
purified again by CombiFlash using hexanes- ethyl acetate as eluents to get compound 5-C.
H NMR (400 MHz, CDCl ) δ 7.95 - 7.81 (m, 2H), 7.82 - 7.67 (m, 2H), 5.26 (d, J = 6.5 Hz,
1H), 4.99 - 4.84 (m, 1H), 2.67 (ddd, J = 35.4, 14.5, 8.0 Hz, 3H), 2.13 - 1.91 (m, 1H), 1.15 (d,
J = 0.9 Hz, 9H). F NMR (376 MHz, Chloroform-d) δ -126.81 (dt, J = 170.9, 14.5 Hz, 1 F),
-129.43 - -130.54 (m, 0.15F), -137.42 - -138.86 (m, 0.15F), -148.12 (dt, J = 171.0, 4.2 Hz, 1
F), -150.85 ~ -152.25 (m, 0.15F).
Step 3
A solution of compound 5-C (330 mg, 0.908 mmol) and hydrazine hydrate
(0.18 mL, 3.7 mmol) in ethanol (10 mL) was stirred at 70 C bath for 2 hours. After being
cooled to room temperature, the mixture was diluted with ethyl ether (30 mL) and the solids
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filtered off. After the filtrate was concentrated, the residue was triturated with CH Cl , and
filtered off some solids present. After the filtrate was concentrated, compound 5-D was
obtained. H NMR (400 MHz, CDCl ) δ 5.29 - 5.24 (m, 1H), 3.65 - 3.51 (m, 1H), 2.41 -
2.09 (m, 4H), 1.93 - 1.52 (m, 2H), 1.21 (s, 9H). F NMR (376.1 MHz, CDCl ) δ -124.67 (dt,
J = 172.1, 15.1 Hz, 1F), -126.97 (d, J = 14.8 Hz, 0.1F), -129.38 (dt, J = 150.2, 11.8 Hz, 0.1F),
-147.22 (dt, J = 172.2, 4.6 Hz, 1F), -155.11 (dd, J = 149.9, 2.6 Hz, 0.1F). LCMS-ESI (m/z):
[M+H] calculated for C H F NO : 234.13; found: 233.9.
11 18 2 2
Step 4
A solution of compound 5-D (205 mg, 0.879 mmol) in 1 N KOH (3 mL), THF
(3 mL), and water (3 mL) was stirred at 50 C for 16 hours before concentration to ~1/3
volume. The resulting solution was cooled to 0 C and neutralized with 1N HCl (~3.2 mL).
After the solution was diluted with saturated NaHCO (3 mL) and THF (5 mL), the solution
was stirred at 0 C and as Boc O (613 mg, 2.809 mmol) was added. After 2 hours, additional
Boc O (450 mg, 2.062 mmol) was added. After 1.5 hours more at 0 C, the mixture was
diluted with water and extracted with ethyl acetate (x 2). The extracts were washed with
water (x 1), combined, dried (Na SO ), and concentrated. The residue was purified by
CombiFlash using hexanes- ethyl acetate as eluents to get compound 5-E. H NMR (400
MHz, CDCl ) δ 5.27 (br, 1H), 4.51 - 4.38 (d, J = 7.4 Hz, 1H), 4.17 (d, J = 7.4 Hz, 1H), 2.88
(br, 1H), 2.24 (m, 3H), 1.84 - 1.70 (m, 1H), 1.44 (s, 9H). F NMR (376.1 MHz, CDCl ) δ -
125.18 (d, J = 172.5 Hz, 1F), -147.57 (d, J = 171.8 Hz, 1F). LCMS-ESI (m/z): [M+H]
calculated for C H F NO : 234.13; found: 233.9.
11 18 2 2
Step 5
A solution of compound 5-E (173 mg, 0.694 mmol) in CH2Cl2 (2 mL) was
stirred at room temperature as 4 N HCl in dioxane (2 mL) was added. After 1 hour, additional
4 N HCl in dioxane (2 mL) was added and the resulting mixture was stirred at room
temperature for 1 hour. The mixture was concentrated and the residue was co-evaporated
with toluene (x 1) before drying in high vacuum for 1 hour.
A mixture of the resulting residue, compound 5-F (285 mg, 0.691 mmol), and
K CO (191 mg, 1.382 mmol) in MeCN (2.7 mL) and AcOH (0.3 mL) was stirred at 90 C
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bath. After 2 hours, the reaction mixture was stirred at 0 C, quenched with 1 N HCl (~ 4
mL), and diluted with water before extraction with CH Cl (x 3). The combined extracts were
dried (Na SO ), and concentrated. The residue was purified by preparative HPLC to get 67
mg of the partially purified cyclic product.
To a solution of the partially purified cyclic product in MeCN (3 mL) was
added MgBr (65 mg, 0.353 mmol) and the resulting mixture was stirred at 50 C for 1 hour,
and cooled to 0 C before addition of 1 N HCl. After the mixture was diluted with water, the
product was extracted with CH Cl (x 3) and the combined extracts were dried (Na SO ), and
2 2 2 4
concentrated. The residue was purified by preparative HPLC and the product containing
fraction was freeze-dried to get compound 5 as a 1:1 mixture with TFA. H NMR (400 MHz,
CDCl ) δ 10.48 (t, J = 6.0 Hz, 1H), 8.49 (s, 1H), 7.43 - 7.29 (m, 1H), 6.91 - 6.73 (m, 2H),
.80 (dd, J = 9.8, 4.0 Hz, 1H), 5.47 (t, J = 3.6 Hz, 1H), 4.80 (s, 1H), 4.72 - 4.52 (m, 2H), 4.35
(dd, J = 13.0, 4.1 Hz, 1H), 4.09 (dd, J = 12.9, 9.8 Hz, 1H), 2.50 (dd, J = 14.7, 7.3 Hz, 1H),
2.40 - 2.29 (m, 1H), 2.11 (dq, J = 13.9, 3.4 Hz, 1H), 2.03 - 1.89 (m, 1H). F NMR (376.1
MHz, CDCl ) δ -76.38 (s, 3F), -111.32 (p, J = 7.8 Hz, 1F), -114.54 (q, J = 8.6 Hz, 1F), -
117.70 (dt, J = 174.1, 14.5 Hz, 1F), -139.72 ~ -142.02 (m, 1F). LCMS-ESI (m/z): [M+H]
calculated for C H F N O : 480.12; found: 480.2.
22 18 4 3 5
Example 6
Preparation of Compound 6
(1aR,2R,3aS,12S,12aS)-N-(2,4-difluorobenzyl)hydroxy-8,10-dioxo-1a,2,3a,4,8,10,12,12a-
octahydro-1H-2,12-methanocyclopropa[e]pyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepine
carboxamide
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Step 1
To a solution of compound 6-A (4.272 g, 30.053 mmol), PPh (15.785 g,
60.18 mmol), and pivaloic acid (3.5 mL, 30.446 mmol) in THF (200 mL) was stirred at 0 C
as diisopropyl azodicarboxylate (11.9 mL, 60.439 mmol) was added over 5 min. After 10
min, the mixture was warmed to room temperature and stirred for 30 min. The mixture was
concentrated and resulting syrup was dissolved in ethyl ether. After the mixture was filtered
and the filtrate was concentrated, the residue was purified by CombiFlash to obtain
compound 6-B. H NMR (400 MHz, CDCl ) δ 6.11 (s, 2H), 5.80 (m, 2H), 2.29 – 2.11 (m,
2H), 2.04 (s, 3H), 1.17 (s, 9H).
Step 2
A suspension of compound 6-B (4.875 g, 21.545 mmol) and K CO (3.265 g,
23.623 mmol) in methanol (100 mL) was stirred at room temperature for 2 hours. After the
reaction mixture was diluted with CH Cl (~150 mL), the mixture was filtered and the filtrate
was concentrated. The residue was triturated with CH Cl and the supernatant was purified by
CombiFlash to obtain compound 6-C. H NMR (400 MHz, CDCl ) δ 6.11 (br d, J = 5.7Hz,
1H), 6.02 (br d, J = 5.7 Hz, 1H), 5.82 – 5.72 (m, 1H), 5.14 – 4.98 (m, 1H), 2.28 – 2.06 (m,
2H), 1.57 (s, 1H), 1.17 (s, 9H).
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Step 3
A solution of compound 6-C (1.503 g, 8.158 mmol) in CH Cl (50 mL) was
stirred at 0 C as 1 M solution of ZnEt in toluene (9 mL) was added. After 15 min, CH I
2 2 2
(1.45 mL, 18 mmol) followed by 1 M solution of ZnEt in toluene (9 mL) were added. After
the mixture was stirred for 30 min, additional CH I (1.45 mL, 18 mmol) was added. After 30
min, the mixture was warmed to room temperature and stirred for 2 hours before additional 1
M solution of ZnEt in toluene (9 mL) and CH I (1.45 mL, 18 mmol) were added. The
2 2 2
resulting mixture was stirred at room temperature for 18 hours. The reaction mixture was
poured into 0 C cold saturated NH Cl and the product was extracted with ethyl acetate (x 2).
The combined extracts were dried (Na SO ), and concentrated before purification by
CombiFlash to get compound 6-D. H NMR (400 MHz, CDCl ) δ 5.12 (d, J = 5.2 Hz, 1H),
4.78 (td, J = 8.3, 4.6 Hz, 1H), 2.00 – 1.87 (m, 1H), 1.75 – 1.65 (m, 1H), 1.56 (s, 1H), 1.51 (m,
1H), 1.38 (m, 1H), 1.19 (s, 9H), 0.58 (m, 2H).
Step 4
A mixture of compound 6-D (1291 mg, 6.512 mmol) and PPh (3794 mg,
14.47 mmol) in THF (70 mL) was stirred at 0 C bath as DIAD (2.9 mL, 14.73 mmol) was
added. After addition, the mixture was stirred at 0 C for 30 min and then at room
temperature overnight. The mixture was concentrated to syrup and dissolved in ether (~70
mL) and stirred at 0 C bath for ~1 hour before filtration. After the filtrate was concentrated,
the residue was purified by CombiFlash using hexanes-ethyl acetate as eluents to
obtain compound 6-E. H NMR (400 MHz, Chloroform-d) δ 7.81 (dd, J = 5.4, 3.0 Hz, 2H),
7.70 (dd, J = 5.5, 3.0 Hz, 2H), 5.15 (d, J = 5.8 Hz, 1H), 4.70 – 4.57 (m, 1H), 2.24 ~ 2.08 (m,
2H), 1.92 (dt, J = 8.6, 4.4 Hz, 1H), 1.84 (d, J = 16.3 Hz, 1H), 1.05 (s, 9H), 0.81 (tdd, J = 8.6,
.9, 1.3 Hz, 1H), 0.11 (dt, J = 6.0, 4.0 Hz, 1H).
Step 5
A solution of compound 6-E (890 mg, 2.719 mmol) and hydrazine hydrate
(0.53 mL, 10.89 mmol) in ethanol (15 mL) was stirred at 70 C bath for 2 hours. After cooled
to room temperature, the mixture was diluted with ethyl ether (50 mL) and the resulting
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mixture was stirred at 0 C bath for 1 hour before filter the solids. After the filtrate was
concentrated, the residue was triturated with CH Cl , and filtered off some solids present.
After the filtrate was concentrated, compound 6-F was obtained. H NMR (400 MHz,
CDCl ) δ 5.15 (d, J = 5.2 Hz, 1H), 3.33 (d, J = 6.2 Hz, 1H), 1.90 (br, 2H), 1.77 (dt, J = 15.8,
5.7 Hz, 1H), 1.64 - 1.55 (m, 2H), 1.55 - 1.47 (m, 1H), 1.20 (s, 9H), 0.60 - 0.48 (m, 1H), -0.01
(dt, J = 5.9, 3.8 Hz, 1H).
Step 6
A solution of compound 6-F (522 mg, 2.646 mmol) in 1 N KOH (9.1 mL),
THF (9 mL), and water (9 mL) was stirred at 50 C for 15 hours and at 70 C for 7 hours
before concentration to ~1/3 volume. The resulting solution was cooled to 0 C and
neutralized with 1N HCl (~9.2 mL). After the solution was diluted with saturated NaHCO
(10 mL) and THF (10 mL), the solution was stirred at 0 C and as Boc O (1846 mg, 8.412
mmol) was added. After 1 hour, the mixture was warmed to room temperature and stirred for
hours before addition of Boc O (1846 mg, 8.412 mmol). After 6 hours, the mixture was
diluted with water and extracted with ethyl acetate (x 2). The extracts were washed with
water (x 1), combined, dried (Na SO ), and concentrated. The residue was purified by
CombiFlash using hexanes- ethyl acetate as eluents to get compound 6-G. H NMR (400
MHz, CDCl ) δ 5.3 (br, 1H), 4.26 (d, J = 4.4 Hz, 1H), 4.03 (d, J = 6.3 Hz, 1H), 2.5 (br, 1H),
1.64 (ddd, J = 15.5, 6.4, 4.6 Hz, 1H), 1.59 - 1.49 (m, 3H), 1.42 (s, 9H), 0.60 - 0.37 (m, 1H), -
0.08 (dt, J = 5.9, 3.7 Hz, 1H).
Step 7
A solution of compound 6-G (457 mg, 2.143 mmol) in CH Cl (5.5 mL) was
stirred at room temperature as 4 N HCl in dioxane (5.5 mL) was added. After 1 hour,
additional 4 N HCl in dioxane (5.5 mL) was added and the resulting mixture was stirred at
room temperature for 1 hour. The mixture was concentrated and the residue was dried in high
vacuum overnight.
A mixture of the resulting residue (320 mg), compound 5-F (881 mg, 2.137
mmol), and K CO (592 mg, 4.183 mmol) in MeCN (10 mL) and AcOH (1 mL) was stirred
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at 65 C bath. After 3 hours, the reaction mixture was stirred at 0 C, quenched with 1 N HCl
(~ 2 mL), and diluted with water before extraction with CH Cl (x 3). The combined extracts
were dried (Na SO ), and concentrated. The residue was purified by CombiFlash (40 g
column) using hexanes – ethyl acetate - 20% MeOH/ ethyl acetate as eluents to get 433 mg of
the partially purified cyclic product.
To a solution of the partially purified cyclic product in MeCN (5 mL) was
added MgBr (453 mg, 2.46 mmol) and MeCN (2 mL) at room temperature. The resulting
mixture was stirred at 50 C for 20 min, and cooled to 0 C before addition of 1 N HCl. After
the mixture was diluted with water, the product was extracted with CH Cl (x 3) and the
combined extracts were dried (Na SO ), and concentrated. The residue was purified by
CombiFlash using CH Cl -20%MeOH/CH Cl as eluents. After the combined product
2 2 2 2
containing fractions were concentrated, the residue was triturated with MeCN (5 mL) for 15
min, filtered, and the solids collected were dried in vacuum to obtain compound 6. H NMR
(400 MHz, CDCl ) δ 10.51 (t, J = 6.0 Hz, 1H), 8.47 (s, 1H), 7.40 – 7.29 (m, 1H), ~7 (br, 1H),
6.90 – 6.76 (m, 2H), 5.94 (dd, J = 9.8, 4.0 Hz, 1H), 5.21 (d, J = 3.8 Hz, 1H), 4.63 (dd, J =
.9, 2.7 Hz, 2H), 4.61 – 4.53 (m, 1H), 4.32 (dd, J = 13.0, 4.1 Hz, 1H), 4.04 (dd, J = 12.9, 9.9
Hz, 1H), 1.86 – 1.64 (m, 2H), 1.61 (p, J = 4.0 Hz, 1H), 1.52 (dt, J = 13.6, 3.4 Hz, 1H), 0.87
(q, J = 7.5 Hz, 1H), 0.60 (dt, J = 6.7, 3.4 Hz, 1H). F NMR (376.1 MHz, CDCl ) δ -76.43 (s,
3F), -111.61 (p, J = 7.7 Hz, 1F), -114.58 (q, J = 8.5 Hz, 1F). LCMS-ESI (m/z): [M+H]
calculated for C H F N O : 444.14; found: 444.2.
22 20 2 3 5
Example 7
Preparation of Compound 7
(1aS,2S,3aR,12R,12aR)-N-(2,4-difluorobenzyl)hydroxy-8,10-dioxo-1a,2,3a,4,8,10,12,12a-
octahydro-1H-2,12-methanocyclopropa[e]pyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepine
carboxamide
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Step 1
A 500-mL 1-neck round bottom flask was charged with reactant 7-A (5.0 g, 35
mmol) and DCM (100 ml). The reaction mixture was cooled to 0 C with stirring. 1 N
diethylzinc in hexane (39 ml) was added to the reaction mixture slowly. The reaction mixture
was stirred at 0 C for 15 minutes. Diiodomethane (4.25 mL) was added followed by 1N
diethylzinc in hexane (39 mL). After stirring another 15 minutes, additional diiodomethane
(4.25 ml) was added to the reaction mixture. Then the reaction mixture was warmed to room
temperature and stirred for overnight. The reaction mixture was poured onto a cold aqueous
solution of NH Cl and extracted with ethyl acetate. The organic layer was dried and
evaporated in vacuo. The residue was purified by column chromatography on silica gel with
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hexane-EtOAc to afford 7-B. H NMR (400 MHz, Chloroform-d) δ 5.34 - 5.02 (m, 1H), 4.45
(ddd, J = 8.7, 7.7, 4.7 Hz, 1H), 2.31 (dt, J = 13.4, 7.8 Hz, 1H), 2.02 (s, 3H), 1.84 - 1.59 (m,
2H), 1.25 - 1.07 (m, 2H), 0.92 (dt, J = 5.4, 3.9 Hz, 1H), 0.54 (td, J = 7.7, 5.5 Hz, 1H).
Step 2
A 500-mL 1-neck round bottom flask was charged with reactant 7-B (5.5 g, 35
mmol), triphenylphosphine (20.3 g, 77 mmol), phthalimide (8.3 g, 56 mmol) and THF (200
ml). The reaction mixture was cooled to 0 C with stirring. Diisopropyl azodicarboxylate
(DIAD) (15.3 ml, 77 mmol) was added to the reaction mixture slowly. The reaction mixture
was stirred at room temperature overnight. The reaction mixture was concentrated down, re-
dissolved in ether and stirred at 0 C for 10 minutes. Solid (triphenylphosphine oxide) was
filtered away. The filtrate was concentrated and purified by column chromatography on silica
gel with hexane-EtOAc to obtain 7-C. H NMR (400 MHz, Acetonitrile-d3) δ 8.06 - 7.61 (m,
4H), 5.84 (d, J = 5.1 Hz, 1H), 4.88 - 4.50 (m, 1H), 2.29 (dd, J = 15.1, 8.7 Hz, 1H), 2.01(s, 3
H), 1.98 (m, 1H), 1.94 (d, J = 2.4 Hz, 1H), 1.49 (m, 1H), 0.68 (td, J = 8.2, 5.5 Hz, 1H), 0.56
(s, 1H).
Steps 3 and 4
A 250-mL 1-neck round bottom flask was charged with reactant 7-C (1.0 g,
3.5 mmol), hydrazine monohydrate (~2ml) and EtOH (20 ml). The reaction mixture was
stirred at 70 C for 30 minutes. The reaction mixture was concentrated under high vacuum for
1 hour to afford 7-D. The crude reaction mixture was re-dissolved in THF (20 mL). Saturated
NaHCO (20 mL) and di-tert-butyl dicarbonate (8g, 36.7 mmol) were added and the reaction
mixture was stirred over 24 hours. The reaction mixture was extracted with EtOAc (2 x 100
mL) and dried over Na SO . After concentration, the crude was purified by column
chromatography on silica gel with hexane-EtOAc to obtain 7-E. H NMR (400 MHz,
Chloroform-d) δ 4.63 (td, J = 8.3, 4.6 Hz, 1H), 4.01 - 3.81 (m, 1H), 2.17 (s, 1H), 1.81 (dd, J =
14.4, 7.8 Hz, 1H), 1.55 (ddt, J = 8.0, 5.6, 4.2 Hz, 1H), 1.39 (s, 9H), 1.38 - 1.31 (m, 2H), 0.68
- 0.33 (m, 2H).
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Step 5
A 100-mL 1-neck round bottom flask was charged with reactant 7-E (0.5 g,
2.34 mmol), triphenylphosphine (1.35g, 5.1mmol), benzoic acid (0.46g, 3.8m mol) and THF
(20 ml). The reaction mixture was cooled to 0 C with stirring. DIAD (1.01 ml, 5.1 mmol)
was added to the reaction mixture slowly. The reaction mixture was stirred at room
temperature for overnight. The reaction mixture was concentrated down, re-dissolved in ether
and stirred at 0 C for 10 minutes. Solid (triphenylphosphine oxide) was filtered away. The
crude was purified was purified by column chromatography on silica gel with hexane-EtOAc
to obtain 7-F. H NMR (400 MHz, Chloroform-d) δ 8.16 - 7.77 (m, 2H), 7.58 (dd, J = 7.1,
1.6 Hz, 1H), 7.54 - 7.36 (m, 2H), 4.99 - 4.76 (m, 1H), 4.02 (dt, J = 8.7, 3.2 Hz, 1H), 1.70 (d, J
= 3.3 Hz, 1H), 1.62 (ddd, J = 8.7, 5.1, 3.6 Hz, 1H), 1.53 - 1.44 (m, 1H), 1.30 (s, 9H), 0.96
(dd, J = 6.3, 2.6 Hz, 2H), 0.63 - 0.47 (m, 1H), 0.00 (dd, J = 6.3, 3.4 Hz, 1H).
Step 6
A 100-mL 1-neck round bottom flask was charged with 7-F (0.7 g, 2.2 mmol),
THF (10 mL) and MeOH (5 mL). 1 N KOH (4.4 mL) was added to the reaction mixture. The
reaction mixture was stirred at room temperature for 30 minutes. After acidification with 1 N
HCl to pH = 4, the reaction mixture was extracted with EtOAc (2x 50 ml). The combined
organic layers were dried by Na SO . After concentration, the crude was purified by column
chromatography on silica gel with hexane-EtOAc to obtain the Boc protected product. The
Boc protected product in DCM was stirred at room temperature as 5.5 mL of 4 N HCl in
dioxane was added in. After stirred at room temperature for 2 hours, the reaction mixture
was concentrated and the residue was dried under high vacuum for overnight. The resulting
7-G was used for the next reaction without further purification.
Step 7
A 100-mL 1-neck round bottom flask was charged with 7-G (0.22 g, 1.47
mmol), H (0.60 g, 1.47 mmol), potassium carbonate (0.40 g, 2.90 mmol), acetic acid (0.71 g,
11.83 mmol) and acetonitrile (10 mL). The reaction mixture was stirred at 65 C bath for 2
hours. After cooling to room temperature, the reaction mixture was diluted with EtOAc (100
mL), washed with saturated NaHCO and dried over Na SO After concentration, the crude
2 4.
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was purified by column chromatography on silica gel with hexane-EtOAc to obtain 7-I.
[M+H] calculated for C H F N O : 458.; found: 458.
21 20 2 3 5
Step 8
A 50-mL 1-neck round bottom flask was charged with 7-I (0.20 g, 0.44
mmol), magnesium bromide (0.21 g, 1.14 mmol) and acetonitrile (5 mL). The resulting
mixture was stirred at 50 C for 10 minutes. Then the mixture was stirred at 0 C bath and 1
N HCl (~4 mL) was added, followed by addition of water (~ 5 mL). The solid was filtered
and washed with water. After drying under high vacuum overnight, compound 7 was
obtained. H NMR (400 MHz, Chloroform-d) δ 12.33 (s, 1H), 10.36 (s, 1H), 8.29 (s, 1H),
7.44 - 7.30 (m, 1H), 6.89 - 6.66 (m, 2H), 5.89 (d, J = 10.0 Hz, 1H), 5.25 - 5.13 (m, 1H), 4.75 -
4.43 (m, 3H), 4.20 (s, 1H), 4.10 - 3.84 (m, 1H), 1.90 - 1.30 (m, 4 H), 0.86 (t, J = 7.5 Hz, 1H),
0.58 (dd, J = 6.6, 3.3 Hz, 1H). F NMR (376 MHz, Chloroform-d) δ -112.30 , -114.74 .
[M+H] calculated for C H F N O : 444; found: 444.
21 20 2 3 5
Example 8
Preparation of Compound 8
(1aS,2S,10aS,11R,11aR)-N-(2,4-difluorobenzyl)hydroxy-4,6-dioxo-
1a,2,4,6,10,10a,11,11a-octahydro-1H-2,11-methanocyclopropa[4,5]pyrido[1,2-a]pyrido[1,2-
d]pyrazinecarboxamide
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Step 1
A mixture of the compound 8-A (1.002 g, 3.894 mmol) and Pd(OAc) (15.0
mg, 0.067 mmol) in ether (15 mL) was stirred at 0 C as diazomethane in ether (10 mL) was
added over ~3 min. After 30 min at 0 C, additional diazomethane in ether (10 mL) was
added and the mixture was stirred at 0 C for 30 min. The mixture was filtered through celite
pad and concentrated. The residue was purified by Combiflash (40 g column) using
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hexanes-ethyl acetate as eluents to provide compound 8-B. H NMR (400 MHz, Chloroform-
d) δ 7.35 - 7.28 (m, 2H), 7.26 - 7.21 (m, 2H), 7.21 - 7.14 (m, 1H), 3.82 (d, J = 1.8 Hz, 1H),
3.78 (q, J = 6.7 Hz, 1H), 3.28 (s, 3H), 2.64 (s, 1H), 2.44 (d, J = 2.0 Hz, 1H), 1.63 (d, J = 11.1
Hz, 1H), 1.48 ( m, 1H), 1.46 (d, J = 6.5 Hz, 3H), 1.08 (d, J = 11.1 Hz, 1H), 1.01 (t, J = 6.9
Hz, 1H), 0.54 (dt, J = 6.1, 3.0 Hz, 1H), 0.18 (q, J = 7.0 Hz, 1H). LCMS-ESI (m/z): [M+H]
calculated for C H NO : 272.17; found: 272.1.
17 22 2
Step 2
A mixture of compound 8-B (3720 mg, 11.7 mmol) and 10% Pd/C (711 mg)
in EtOH (60 mL) was stirred under H atmosphere. After 20 hours, the mixture was filtered
through celite and the filtrate was concentrated, and the residue was used for the Boc
protection. LCMS-ESI (m/z): [M+H] calculated for C H NO : 168.10; found: 168.0.
9 14 2
The residue was stirred in THF (50 mL) at room temperature as Boc2O (6.00
g, 27.49 mmol) and DIEA (6 mL, 34.45 mmol) were added. After ~30 min, the reaction
mixture was concentrated to ~1/3 volume, diluted with ethyl acetate, and washed with water
(twice). After the aqueous fractions were extracted with ethyl acetate, the organic fractions
were combined, dried (Na2SO4) and concentrated. The residue was purified by CombiFlash
(120 g column) using hexanes - ethyl acetate as eluents to obtain compound 8-C. H NMR
(400 MHz, Chloroform-d) δ 4.39 (s, 0.5H), 4.25 (s, 0.5H), 3.86 (s, 0.5H), 3.77 (s, 0.5H), 3.73
(s, 1.5H), 3.71 (s, 1.5H), 2.74 (m, 1H), 1.48 (s, 4.5H), 1.44 - 1.42 (m, 1H), 1.41 (s, 4.5H),
1.36 - 1.21 (m, 1H), 1.06 (m, 2H), 0.50 (dt, J = 5.9, 3.0 Hz, 1H), 0.27 (qd, J = 7.2, 2.8 Hz,
1H). LCMS-ESI+ (m/z): [M+H]+ calculated for C H NO : 268.15; found: 267.7.
14 22 4
Step 3
A solution of compound 8-C (400 mg, 1.496 mmol) in THF (3 mL) was
stirred at 0 C as 2.0 M LiBH in THF (1.5 mL) was added. After 5 min, the mixture was
stirred at room temperature. After 66 hours, the reaction mixture was diluted with ethyl
acetate and added water slowly. After two phases were separated, the aqueous fraction was
extracted with ethyl acetate and the two organic fractions were washed with water, combined,
dried (Na SO ), and concentrated. The residue was purified by CombiFlash (40 g column)
using hexanes - ethyl acetate as eluents to yield compound 8-D. H NMR (400 MHz,
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Chloroform-d) δ 4.14 (dd, J = 2.3, 1.3 Hz, 1H), 3.68 - 3.53 (m, 2H), 3.50 - 3.41 (m, 1H), 2.61
(s, 1H), 2.39 (d, J = 2.1 Hz, 1H), 1.49 (s, 9H), 1.30 (td, J = 6.8, 6.2, 2.3 Hz, 1H), 1.16 (dt, J =
11.1, 1.8 Hz, 1H), 1.10 - 1.03 (m, 1H), 0.99 (td, J = 7.0, 3.0 Hz, 1H), 0.46 (dt, J = 6.5, 3.2 Hz,
1H), 0.22 (q, J = 7.1 Hz, 1H). LCMS-ESI (m/z): [M+H] calculated for C H NO : 240.16;
13 22 3
found: 239.7.
Step 4
A solution of compound 8-D (345 mg, 1.442 mmol), phthalimide (351 mg,
2.386 mmol), and PPh (852 mg, 3.248 mmol) in THF (20 mL) was stirred at 0 C as DIAD
(0.65 mL, 3.301 mmol) was added. After addition, the mixture was stirred at 0 C for 30 min
and then at rt. After 16 hours, the solution was concentrated to syrup and the residue was
stirred in ether (50 mL) at 0 C for 1.5 hours before filtration. The filtrate was concentrated,
and the residue was purified using CombiFlash (40 g column) with hexane- ethyl acetate as
eluents to obtain compound 8-E. 1H NMR (400 MHz, Chloroform-d) δ 7.84 (ddt, J = 10.3,
7.8, 3.8 Hz, 2H), 7.78 - 7.61 (m, 2H), 4.23 (s, 0.5H), 4.11 (m, 0.5H), 3.99 (dd, J = 13.1, 4.1
Hz, 0.5H), 3.88 (dd, J = 12.7, 6.7 Hz, 0.5H), 3.73 - 3.43 (m, 2H), 2.41 (d, J = 2.1 Hz, 1H),
1.49 (s, 4.5H), 1.49 – 1.2 (m, 2H), 1.31 (s, 4.5H), 1.09 (d, J = 11.5 Hz, 1H), 0.94 - 0.86 (m,
0.5H), 0.85 - 0.77 (m, 0.5H), 0.44 (m, 1H), 0.17 (m, 1H). LCMS-ESI (m/z): [M+H]
calculated for C H N O : 369.18; found: 368.9.
21 25 2 4
Step 5 and Step 6
To a solution of compound 8-E (516 mg, 1.401 mmol) in EtOH (30 mL) was
added hydrazine hydrate (0.29 mL) at rt and the resulting solution was stirred at 70 C. After
4.5 hours, the mixture was cooled to room temperature and diluted with ethyl ether (30 mL)
and stirred at 0 C for 30 min before filtration. The filtrate was concentrated and the residue
was dissolved in CH Cl before filtration to remove some insoluble material. The resulting
filtrate was concentrated to obtain crude compound 8-F. LCMS-ESI (m/z): [M+H]
calculated for C H N O : 239.18; found: 238.9.
13 23 2 2
The mixture of crude compound 8-F, compound 8-G (341 mg, 1.408 mmol),
and NaHCO (240 mg, 2.857 mmol) in water (4 mL) and EtOH (4 mL) was stirred at
rt. After 15 hours, the mixture was diluted with water and extracted with ethyl acetate
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(twice). The extracts were washed with water, combined, dried (Na SO ), concentrated. To
the crude residue in CH Cl (5 mL) was added 4 N HCl in dioxane (10 mL) at room
temperature and the resulting mixture was stirred at room temperature for 2 hours. The
mixture was concentrated, co-evaporated with toluene, and dried under vacuum for 30 min.
A suspension of the residue and DBU (1.06 mL, 7.088 mmol) in toluene (10
mL) was stirred at 110 C bath. After 30 min, the mixture was concentrated and the residue
was dissolved in CH Cl (~50 mL) and washed with aqueous NH Cl (twice). After the
2 2 4
aqueous fractions were extracted with CH Cl (twice), the three organic fractions were
combined, dried (Na SO ), and concentrated. The residue was purified by CombiFlash (24 g
column) using ethyl acetate - 20% MeOH/ethyl acetate as eluents to obtain compound 8-H.
H NMR (400 MHz, Chloroform-d) δ 8.17 (s, 1H), 5.04 (s, 1H), 4.09 (s, 1H), 4.08 (s, 3H),
3.91 (s, 3H), 3.86 – 3.71 (m, 2H), 2.73 (d, J = 1.8 Hz, 1H), 1.43 – 1.21 (m, 2H), 1.13 (d, J =
12.1 Hz, 2H), 0.60 (dt, J = 6.7, 3.1 Hz, 1H), 0.40 (q, J = 7.3 Hz, 1H). LCMS-ESI (m/z):
[M+H] calculated for C H N O : 331.13; found: 331.2.
17 19 2 5
Step 7
A mixture of compound 8-H (40 mg, 0.121 mmol) in THF (1 mL) and MeOH
(1 mL) was stirred at room temperature as 1 N KOH (1 mL) was added. After 30 min, the
reaction mixture was acidified with 1 N HCl (~1.1 mL), concentrated to ~ 2 mL, and diluted
with brine before extraction with CH Cl (x 3). The combined extracts was dried (Na SO )
2 2 2 4
and concentrated.
To the solution of crude acid were added 2,4-difluorobenzylamine (26 mg,
0.182 mmol), and HATU (56 mg, 0.147 mmol) at room temperature followed by DIEA (0.32
mL, 1.835 mmol). After 1 hour, additional 2,4-difluorobenzylamine (26 mg, 0.182 mmol)
and HATU (56 mg, 0.147 mmol) were added. After 1 hour, the reaction mixture was diluted
with water and the product was extracted with CH Cl (x 2). The extracts were washed with
water, combined, dried (Na SO ) and concentrated.
The residue was purified by CombiFlash (24 g column) using ethyl acetate-
%MeOH/ethyl acetate as eluents to obtain compound 8-I. H NMR (400 MHz,
Chloroform-d) δ 10.44 (t, J = 6.0 Hz, 1H), 8.36 (s, 1H), 7.34 (td, J = 8.6, 6.8 Hz, 1H), 6.87 -
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6.69 (m, 2H), 5.02 (s, 1H), 4.60 (qd, J = 15.2, 5.9 Hz, 2H), 4.16 - 4.07 (m, 1H), 4.04 (s, 3H),
3.83 (t, J = 12.0 Hz, 1H), 3.76 (dd, J = 12.2, 2.7 Hz, 1H), 2.72 (d, J = 1.7 Hz, 1H), 1.39 - 1.21
(m, 2H), 1.18 - 1.07 (m, 2H), 0.59 (dt, J = 6.6, 3.2 Hz, 1H), 0.39 (q, J = 7.3 Hz, 1H). F
NMR (376 MHz, Chloroform-d) δ -112.08 (p, J = 7.7 Hz), -114.77 (q, J = 8.6 Hz). LCMS-
ESI (m/z): [M+H] calculated for C H F N O : 442.16; found: 442.3.
23 22 2 3 4
Step 8
A suspension of compound 8-I (47 mg, 0.106 mmol) in MeCN (2 mL) was
stirred at 50 C as MgBr (49 mg, 0.266 mmol) was added. After 30 min, the reaction
mixture was stirred at 0 C and added 1 N HCl to make the mixture a solution (~2 mL). After
the mixture was diluted with CH Cl and water, two fractions were separated and the aqueous
fraction was extracted with CH Cl (twice). The combined organic fractions were dried
(Na SO ) and concentrated. The residue was purified by CombiFlash (24 g column) using
CH Cl and 20% MeOH in CH Cl as eluents to obtain compound 8. The residue was
2 2 2 2
triturated in MeCN at 0 C for 30 min and filtered. The collected solids were dried in
vacuum to obtain additional compound 8. H NMR (400 MHz, Chloroform-d) δ 11.68 (s,
1H), 10.43 (s, 1H), 8.28 (s, 1H), 7.36 (td, J = 8.6, 6.4 Hz, 1H), 6.86 - 6.75 (m, 2H), 4.96 (s,
1H), 4.64 (d, J = 6.0 Hz, 2H), 4.12 (d, J = 7.9 Hz, 1H), 3.81 (d, J = 7.6 Hz, 2H), 2.79 (d, J =
1.7 Hz, 1H), 1.42 (d, J = 11.0 Hz, 2H), 1.17 (d, J = 12.3 Hz, 2H), 0.65 (dt, J = 6.7, 3.2 Hz,
1H), 0.46 (q, J = 7.3 Hz, 1H). F NMR (376 MHz, Chloroform-d) δ -112.36 (p, J = 7.5 Hz),
-114.76 (q, J = 8.6 Hz). LCMS-ESI (m/z): [M+H] calculated for C H F N O : 428.14;
22 20 2 3 4
found: 428.3.
Example 9
Preparation of Compound 9
(1aS,2S,10aS,11R,11aR)hydroxy-4,6-dioxo-N-(2,4,6-trifluorobenzyl)-
1a,2,4,6,10,10a,11,11a-octahydro-1H-2,11-methanocyclopropa[4,5]pyrido[1,2-a]pyrido[1,2-
d]pyrazinecarboxamide
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Step 1
A mixture of compound 8-H (84 mg, 0.254 mmol) in THF (2 mL) and MeOH
(2 mL) was stirred at room temperature as 1 N KOH (1 mL) was added. After 30 min, the
reaction mixture was concentrated to ~ 2 mL, acidified with 1 N HCl (~1.1 mL), concentrated
to ~2 mL, and diluted with brine before extraction with CH Cl (thrice). The combined
extracts was dried (Na SO ) and the solution was used for the next reaction.
To the crude acid solution were added 2,4,6-trifluorobenzylamine (57 mg,
0.354 mmol), and HATU (157 mg, 0.413 mmol) at room temperature followed by DIEA
(0.31 mL, 1.780 mmol). After ~30 min, additional DIEA (0.31 mL, 1.78 mmol) was
added. After 1 hour, the reaction mixture was washed with saturated NH Cl and
water. After the aqueous fractions were extracted with CH Cl , the two organic fractions
were combined, dried (Na SO ) and concentrated. The residue was purified by CombiFlash
(24 g column) using ethyl acetate - 20%MeOH/ethyl acetate as eluents to obtain compound 9-
A. H NMR (400 MHz, Chloroform-d) δ 10.37 (t, J = 5.7 Hz, 1H), 8.36 (s, 1H), 6.74 - 6.57
(m, 2H), 5.03 (s, 1H), 4.64 (qd, J = 14.5, 5.7 Hz, 2H), 4.11 - 4.06 (m, 1H), 4.04 (s, 3H), 3.83
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(t, J = 12.0 Hz, 1H), 3.76 (dd, J = 12.2, 2.8 Hz, 1H), 2.74 (d, J = 1.8 Hz, 1H), 1.33 (dd, J =
13.7, 2.8 Hz, 2H), 1.19 - 1.08 (m, 2H), 0.60 (dt, J = 6.6, 3.1 Hz, 1H), 0.40 (q, J = 7.2 Hz, 1H).
F NMR (376 MHz, Chloroform-d) δ -108.39 - -109.90 (m, 1F), -111.99 (t, J = 6.9 Hz, 2F).
LCMS-ESI (m/z): [M+H] calculated for C H F N O : 460.15; found: 460.3.
23 21 3 3 4
Step 2
A suspension of compound 9-A (106 mg, 0.231 mmol) in MeCN (4 mL) was
stirred at 50 C and MgBr (107 mg, 0.581 mmol) was added. After 30 min, the reaction
mixture was stirred at 0 C and 1 N HCl was added to obtain a solution (~2 mL) After the
mixture was diluted with CH Cl and water, two fractions were separated and the aqueous
fraction was extracted with CH Cl (twice). The combined organic fractions were dried
(Na2SO4) and concentrated. The residue was purified by CombiFlash (12 g column) using
CH Cl and 20% MeOH in CH Cl as eluents to get 85 mg of compound 12. The residue was
2 2 2 2
triturated in MeCN at 0 C for 30 min and filtered. The collected solids were dried in
vacuum to obtain compound 9. H NMR (400 MHz, Chloroform-d) δ 10.35 (s, 1H), 8.27 (s,
1H), 6.65 (dd, J = 8.7, 7.6 Hz, 2H), 4.96 (s, 1H), 4.66 (dd, J = 5.7, 4.0 Hz, 2H), 4.09 (d, J =
8.3 Hz, 1H), 3.80 (d, J = 8.1 Hz, 2H), 2.79 (s, 1H), 1.41 (d, J = 11.1 Hz, 2H), 1.18 (t, J = 10.6
Hz, 2H), 0.65 (dt, J = 6.8, 3.2 Hz, 1H), 0.46 (q, J = 7.3 Hz, 1H). F NMR (376 MHz,
Chloroform-d) δ -109.13 - -109.32 (m, 1F), -111.99 (t, J = 7.0 Hz, 2F). LCMS-ESI (m/z):
[M+H] calculated for C H F N O : 446.13; found: 446.3.
22 19 3 3 4
Example 10
Preparation of Compound 10
(1aS,2S,3aR,12R,12aR)hydroxy-8,10-dioxo-N-(2,4,6-trifluorobenzyl)-
1a,2,3a,4,8,10,12,12a-octahydro-1H-2,12-
methanocyclopropa[e]pyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepinecarboxamide
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Step 1
A 100-mL 1-neck round bottom flask was charged with 7-G (0.26 g, 1.74
mmol), 10-A (0.8 g, 1.74 mmol), potassium carbonate (0.97 g, 7.03 mmol), acetic acid (2.55
g, 42.5 mmol) and acetonitrile (30 mL). The reaction mixture was stirred at 65 C for 2
hours. After cooled back to room temperature, the reaction mixture was diluted with EtOAc
(100 mL), washed with sat NaHCO and dried over Na SO After concentration, the crude
2 4.
was purified by column chromatography on silica gel with hexane-EtOAc to obtain 10-B.
[M+H] calculated for C H F N O : 476.; found: 476.
21 20 2 3 5
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Step 2
A 50-mL 1-neck round bottom flask was charged with 10-B (0.30 g, 0.63
mmol), magnesium bromide (0.30 g, 1.63 mmol) and acetonitrile (5 mL). The resulting
mixture was stirred at 50 C for 10 minutes. Then the mixture was stirred at 0 C while 1 N
HCl (~4 mL) was added. Additional water (~ 5 mL) was added to wash down solids forming
on the flask walls. The resulting solid was filtrated and washed with water. After drying
under high vacuum overnight, Compound 10 was obtained. H NMR (400 MHz,
Chloroform-d) δ 12.31 (s, 1H), 10.32 (s, 1H), 8.31 (s, 1H), 6.83 - 6.54 (m, 2H), 5.90 (d, J =
9.2 Hz, 1H), 5.22 (d, J = 3.9 Hz, 1H), 4.79 - 4.47 (m, 4H), 4.22 (s, 1H), 4.08 - 3.86 (m, 1H),
1.92 - 1.64 (m, 2H), 1.65 - 1.43 (m, 2H), 0.86 (q, J = 7.4 Hz, 1H), 0.59 (dt, J = 6.6, 3.2 Hz,
1H). F NMR (376 MHz, Chloroform-d) δ -109.17 , -111.95 . [M+H] calculated for
C H F N O : 462; found: 462.
21 20 2 3 5
Example 11
Preparation of Compound 11
(1aR,2R,10aR,11S,11aS)hydroxy-4,6-dioxo-N-(2,4,6-trifluorobenzyl)-
1a,2,4,6,10,10a,11,11a-octahydro-1H-2,11-methanocyclopropa[4,5]pyrido[1,2-a]pyrido[1,2-
d]pyrazinecarboxamide
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Step 1
A suspension of compound 11-A (965 mg, 3.061 mmol), 2,4,6-
trifluorobenzylamine (493 mg, 3.06 mmol), and HATU (1402 mg, 3.688 mmol) in CH Cl
(15 mL) was stirred in 0 C as DIEA (2 mL, 11.48 mmol) was added.
After 1.5 hours at 0 C, the reaction mixture was diluted with ethyl acetate,
and washed with water (twice). After the aqueous fractions were extracted with ethyl acetate,
the organic fractions were combined, dried (Na SO ), and concentrated. The residue was
purified by CombiFlash (40 g column) using hexanes-ethyl acetate as eluents to obtain
compound 11-B. H NMR (400 MHz, Chloroform-d) δ 10.30 (t, J = 5.9 Hz, 1H), 8.40 (s,
1H), 6.79 - 6.51 (m, 2H), 4.65 (d, J = 5.6 Hz, 2H), 4.48 (t, J = 4.8 Hz, 1H), 4.01 (d, J = 4.8
Hz, 2H), 3.97 (s, 3H), 3.94 (s, 3H), 3.38 (s, 6H). F NMR (376 MHz, Chloroform-d) δ -
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109.07 - -109.35 (m, 1F), -111.93 (t, J = 6.9 Hz, 2F). LCMS-ESI (m/z): [M+H] calculated
for C H F N O : 459.14; found: 459.2.
22 3 2 7
Step 2
A mixture of the compound 11-B (300 mg, 0.654 mmol) and methanesulfonic
acid (63 mg, 0.655 mmol) in MeCN (3 mL) and acetic acid (0.3 mL) was heated to 75 C for
2 hours. After cooling the solution, aminoalcohol 11-D (98 mg, 0.655 mmol), and K CO
(272 mg, 1.968 mmol) were added and the mixture was diluted with MeCN (10 mL) and
stirred at 65 C for 21 hours. The reaction mixture was concentrated to remove most of
MeCN, diluted with water (~30 mL) and extracted with ethyl acetate (~30 mL, twice). The
extracts were washed with water, combined, dried (Na SO ), and concentrated. The residue
was purified by CombiFlash (40 g column) using hexanes - ethyl acetate as eluents to obtain
compound 11-E. H NMR (400 MHz, Chloroform-d) δ 10.27 (t, J = 5.7 Hz, 1H), 8.37 (s,
1H), 6.73 - 6.56 (m, 2H), 5.81 (dd, J = 9.9, 3.8 Hz, 1H), 5.25 (d, J = 3.9 Hz, 1H), 4.71 - 4.57
(m, 2H), 4.53 - 4.48 (m, 1H), 4.21 (dd, J = 12.8, 3.8 Hz, 1H), 4.02 (s, 3H), 3.98 (dd, J = 12.7,
9.9 Hz, 1H), 1.67 (dt, J = 13.5, 1.1 Hz, 2H), 1.54 (ddd, J = 7.5, 5.4, 3.6 Hz, 1H), 1.48 (dt, J =
13.5, 3.4 Hz, 1H), 0.79 (td, J = 8.0, 6.7 Hz, 1H), 0.54 (dt, J = 6.7, 3.4 Hz, 1H). F NMR
(376 MHz, Chloroform-d) δ -108.89 - -109.13 (m, 1F), -111.96 (t, J = 7.0 Hz, 2F). LCMS-
ESI (m/z): [M+H] calculated for C H F N O : 476.14; found: 476.3.
23 21 3 3 5
Step 3
A suspension of compound 11-E (151 mg, 0.318 mmol) in MeCN (4 mL) was
stirred at 50 C and MgBr (146 mg, 0.793 mmol) was added. After 30 min, the reaction
mixture was stirred at 0 C 1 N HCl and was added to obtain a solution (~2 mL). The
solution was diluted with water, and the product was extracted with CH2Cl2 (thrice). The
combined organic extracts were dried (Na SO ) and concentrated. The residue was purified
by CombiFlash (24 g column) using CH Cl and 20% MeOH in CH Cl as eluents, then
2 2 2 2
further purified by trituration in MeOH (~2 mL). After the mixture was stored in the freezer,
the solids were filtered and washed with MeOH. The collected solids were dried in vacuum
to obtain compound 11. H NMR (400 MHz, Chloroform-d) δ 12.28 (s, 1H), 10.29 (t, J = 5.7
Hz, 1H), 8.27 (s, 1H), 6.72 – 6.58 (m, 2H), 5.89 (dd, J = 9.8, 4.1 Hz, 1H), 5.22 (d, J = 3.9 Hz,
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1H), 4.73 – 4.59 (m, 2H), 4.59 – 4.54 (m, 1H), 4.19 (dd, J = 12.8, 4.1 Hz, 1H), 3.99 (ddd, J =
12.7, 9.9, 0.7 Hz, 1H), 1.79 – 1.74 (m, 1H), 1.72 (d, J = 13.5 Hz, 1H), 1.63 – 1.59 (m, 1H),
1.51 (dt, J = 13.6, 3.5 Hz, 1H), 0.90 – 0.81 (m, 1H), 0.59 (dt, J = 6.7, 3.4 Hz, 1H). F NMR
(376 MHz, Chloroform-d) δ -109.21 (tt, J = 8.8, 6.3 Hz, 1F), -111.98 (t, J = 6.9 Hz, 2F).
LCMS-ESI (m/z): [M+H] calculated for C H F N O : 462.13; found: 462.3.
22 19 3 3 5
Example 12
Preparation of Compound 12
(1aR,2R,10aR,11S,11aS)hydroxy-4,6-dioxo-N-(2,4,6-trifluorobenzyl)-
1a,2,4,6,10,10a,11,11a-octahydro-1H-2,11-methanocyclopropa[4,5]pyrido[1,2-a]pyrido[1,2-
d]pyrazinecarboxamide
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Step 1
2,2-dihydroxyacetic acid (12-A) in MeOH was refluxed for 24h. After the
reaction was cooled to room temperature and concentrated under vacuum, it was diluted with
DCM (25 mL) and concentrated again to provide methyl 2-hydroxymethoxyacetate (12-
1H NMR (400 MHz, Chloroform-d) δ 4.86 (s, 1H), 3.82 (s, 3H), 3.48 (s, 3H).
Step 2
A solution of Compound 12-B in toluene was cooled to 0 C under N . L(-)-
alpha-Methylbenzylamine, 99+%, (99% ee) was added via syringe slowly. The reaction was
warmed to room temperature and stirred for 1.5 hours. The presence of the starting material
was monitored by thin layer chromatography (TLC).
The reaction was quenched with water and the aqueous and organic layers
separated. The aqueous layer was extracted with EtOAc. The organic layers were combined
and washed with brine, dried (Na SO ), and concentrated to provide compound 12-C.
Step 3
A solution of compound 12-C in N, N-dimethylformamide was cooled to -
C under N . TFA was added via syringe slowly over 15 min. After stirring for 10 min,
freshly cracked cyclopentadiene (6.76g, 0.102 mol) was added via syringe over 10 min. The
reaction was stirred for 1.5 hours at -15 to -10 C and monitored via TLC and LCMS.
The reaction mixture was diluted with heptane (100mL), quenched with
saturated aqueous Na CO , and stirred for 10 min. The layers were separated, the organic
layer was washed with brine, dried (MgSO ), and concentrated. The crude mixture was
purified from the organic layer by CombiFlash on silica gel with 0-50% EtOAc/Hexane to
obtain compound 12-D.
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H NMR (400 MHz, Chloroform-d) δ 7.32 - 7.11 (m, 5H), 6.42 (ddd, J = 5.6,
3.1, 1.3 Hz, 1H), 6.27 (dd, J = 5.6, 1.9 Hz, 1H), 4.31 (q, J = 1.6 Hz, 1H), 3.35 (s, 3H), 3.03 (q,
J = 6.5 Hz, 1H), 2.93 - 2.88 (m, 1H), 2.22 (s, 1H), 1.42 (t, J = 5.8 Hz, 4H).
Step 4
The mixture of 12-D (1.77 g, 6.878 mmol) and Pd(OAc) (31 mg, 0.138
mmol) in ether (30 mL) was stirred at 0 C as diazomethane in ether (freshly made) (10 mL)
was added slowly. After the addition, the mixture was stirred for ~30 min and TLC
indicated a mixture of the starting material and the product. Additional diazomethane was
added every 30 min until no starting material was detected via TLC. The reaction was
quenched with AcOH (5mL) at 0 C and stirred for about 20 min, concentrated, and purified
by Combiflash using silica gel column with Hexanes-EtOAc as eluent to obtain compound
12-E.
H NMR (400 MHz, Chloroform-d) δ 7.36 - 7.10 (m, 5H), 3.88 - 3.67 (m,
2H), 3.26 (s, 3H), 2.63 (s, 1H), 2.47 - 2.36 (m, 1H), 1.68 - 1.54 (m, 1H), 1.45 (d, J = 6.5 Hz,
4H), 1.13 - 0.94 (m, 2H), 0.54 (dt, J = 6.2, 3.1 Hz, 1H), 0.17 (q, J = 7.1 Hz, 1H).
Step 5
The mixture of compound 12-E (1 g, 3.7 mmol) and 10% Pd/C (1 g) in EtOH
(150 mL) was stirred under H atmosphere for 36 hours. The reaction mixture was filtered
through Celite and the filtrate was concentrated.
The residue obtained from the above hydrogenation was stirred in THF
(20mL) at room temperature as Boc O (1.7 g, 7.7 mmol) and DIPEA (2 mL, 11.6 mmol)
were added and allowed to continue for one hour. The reaction mixture was concentrated, and
the resulting residue was purified by CombiFlash on silica gel column using hexanes - EtOAc
as eluents to obtain compound 12-F. LCMS: m/z=267.6.
LCMS-ESI (m/z): [M+H] calculated for Chemical Formula: C14H21NO4,
Molecular Weight: 267.32; found: 267.67.
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H NMR (400 MHz, Chloroform-d) δ 4.32 (dd, J = 55.7, 2.2 Hz, 1H), 3.82 (d,
J = 43.3 Hz, 1H), 3.72 (d, J = 3.6 Hz, 3H), 2.78 - 2.68 (m, 1H), 1.52 - 1.36 (m, 11H), 1.29
(dq, J = 20.6, 7.0, 6.5 Hz, 1H), 1.13 - 0.97 (m, 1H), 0.50 (dt, J = 5.5, 3.0 Hz, 1H), 0.33 - 0.21
(m, 1H).
Step 6
Compound 12-F (850 mg, 3.18 mmol) in THF (6 mL) was stirred at 0 C as 2.0
M LiBH in THF (3.2 mL, 6.4 mmol) was added. After 5 min, the temperature was raised to
room temperature and the reaction was allowed to proceed for 7 hours. The reaction was
quenched with ice and diluted with EtOAc and saturated NH Cl. The aqueous and organic
phases were separated. The aqueous fraction was extracted with EtOAc and the two organic
fractions were washed with water, combined, dried (Na SO ), and concentrated. The crude
product alcohol was used as is for the next step.
LCMS-ESI (m/z): [M+H] calculated for Chemical Formula: C13H21NO3
Molecular Weight: 239.31; found: 239.72.
A solution of the above alcohol (760mg, 3.18 mmol), phthalimide (701 mg,
4.77 mmol), and PPh (1.67 g, 6.36 mmol) in THF (20 mL) was stirred at 0 C as DIAD (1.3
mL, 6.36 mmol) was added. After addition, the mixture was stirred at 0 C for 30 min and
then at room temperature overnight. The reaction was diluted with EtOAc and washed with
saturated NH Cl twice. After the aqueous and organic phases were separated, the aqueous
fraction was extracted with EtOAcand the two organic fractions were combined, dried
(Na SO ), and concentrated. The crude product was purified using CombiFlash (silica gel
column) with 0-50%EtOAc/Hexane as eluents to provide compound 12-G. 1H NMR
indicated a mixture of two rotamers.
LCMS-ESI (m/z): [M+H] calculated for Chemical Formula: C21H24N2O4,
Molecular Weight: 368.43; found: 368.81.
H NMR (400 MHz, Chloroform-d) δ 7.95 - 7.58 (m, 4H), 4.32 - 4.05 (m,
1H), 4.07 - 3.79 (m, 1H), 3.66 (s, 2H), 2.42 (d, J = 2.2 Hz, 1H), 1.65 - 1.15 (m, 11H), 1.10 (d,
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J = 11.5 Hz, 1H), 0.87 (d, J = 40.7 Hz, 1H), 0.45 (dt, J = 6.5, 3.2 Hz, 1H), 0.18 (q, J = 7.0 Hz,
1H).
Step 7
Hydrazine hydrate was added to a solution of the compound 12-G in EtOH at
room temperature; the reaction was stirred at 75 C for ~3 hours. The resulting mixture was
cooled to room temperature and diluted with ethyl ether (30 mL) and stirred at 0 C for 60 min
before filtration. The resulting filtrate was concentrated to provide compound 12-H. LCMS-
ESI (m/z): [M+H] calculated for Chemical Formula: C13H22N2O2, Molecular Weight:
238.33 found: 238.87.
Step 8
A mixture of 12-H 2.85mmol), 12-I (913mg, 2.87mmol), and NaHCO (482
mg, 5.74mmol) in water (10 mL) and EtOH (20 mL) was stirred at room temperature
overnight. The mixture was diluted with brine and extracted with EtOAc (twice). The extracts
were combined, dried (MgSO ), concentrated, and dried under vacuum for 30 min.
To a solution of the above crude reactant (1.6g) in CH Cl (10 mL) was added
4 N HCl in dioxane (10 mL). The reaction was stirred for about 2 hours, concentrated to
dryness, co-evaporated with toluene, and dried under vacuum for 30 min.
The mixture of the above crude reactant (2.87 mmol) and DBU (4.3 mL,
28.7mmol) in MeOH (30 mL) was stirred at 60 C bath for 120 min. The mixture was
concentrated and the residue was purified by CombiFlash on silica gel using 0-20%
MeOH/EtOAc as eluents to provide 12-J.
H NMR (400 MHz, Chloroform-d) δ 8.05 (s, 1H), 7.65 (s, 1H), 7.34 (s, 2H),
.56 (d, J = 9.7 Hz, 1H), 5.14 (d, J = 9.9 Hz, 1H), 5.02 (s, 1H), 4.39 (d, J = 7.2 Hz, 2H), 3.96
(d, J = 11.6 Hz, 1H), 3.74 (d, J = 29.1 Hz, 1H), 2.68 (s, 1H), 2.04 (s, 1H), 1.56 (d, J = 4.6 Hz,
2H), 1.45 - 1.20 (m, 4H), 1.11 (d, J = 14.1 Hz, 2H), 0.58 (s, 1H), 0.38 (s, 1H).
LCMS-ESI (m/z): [M+H] calculated for Chemical Formula: C24H24N2O5,
Molecular Weight: 420.46; found: 421.29.
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Step 9
A mixture of 12-J (752 mg, 1.841 mmol) in THF (4 mL) and MeOH (4 mL)
was stirred at room temperature as 1N KOH (3.75 mL) was added. After 1 hour, the reaction
mixture was acidified with 3N HCl (1mL), and diluted with brine before extraction with
EtOAc. The combined extracts was dried (MgSO ) and concentrated.
To the mixture of the above crude reactant (158mg, 0.403 mmol) in DCM
(4mL) were added 2,4,6-trifluorobenzyl amine (85 mg, 0.52 mmol), and HATU (230 mg,
0.604 mmol) at room temperature followed by DIPEA (0.3 mL, 1.6 mmol). After about 60
min, the reaction mixture was diluted with DCM, washed with saturated NaHCO , dried
(MgSO ), and concentrated. The residue was purified by CombiFlash on silica gel using 0-
%MeOH/EtOAc to provide compound 12-H.
Step 10
Compound 12-H (174mg, 0.325 mmol) was dissolved in TFA (2 mL) at room
temperature and stirred for 30 min. The solution was concentrated and the residue was
purified by CombiFlash (silica gel column) using 0-20% MeOH in CH Cl to provide
compound 12.
H NMR (400 MHz, Chloroform-d) δ 10.37 (t, J = 5.5 Hz, 1H), 8.29 (s, 1H),
6.65 (dd, J = 8.8, 7.4 Hz, 2H), 4.94 (s, 1H), 4.65 (d, J = 5.7 Hz, 2H), 4.13 (s, 1H), 3.81 (d, J =
.2 Hz, 2H), 2.79 (s, 1H), 1.40 (d, J = 10.9 Hz, 2H), 1.18 (d, J = 12.5 Hz, 2H), 0.64 (dt, J =
6.7, 3.1 Hz, 1H), 0.45 (q, J = 7.3 Hz, 1H).
F NMR (376 MHz, cdcl3) δ -109.13 to -109.21 (1F), -111.98 to -112.02
(2F).
LCMS-ESI (m/z): [M+H] calculated for Chemical Formula:
C22H18F3N3O4, Molecular Weight: 445.39.; found: 446.26.
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Example 13
Preparation of Compound 13
(1aR,2R,10aR,11S,11aS)hydroxy-4,6-dioxo-N-(2,4,5-trifluorobenzyl)-
1a,2,4,6,10,10a,11,11a-octahydro-1H-2,11-methanocyclopropa[4,5]pyrido[1,2-a]pyrido[1,2-
d]pyrazinecarboxamide
Step 1
A mixture of 12-J (752 mg, 1.841 mmol) in THF (4 mL) and MeOH (4 mL)
was stirred at room temperature as 1N KOH (3.75 mL) was added. After 1 hour, the reaction
mixture was acidified with 3N HCl (1mL), and diluted with brine before extraction with
EtOAc. The combined extracts was dried (MgSO ) and concentrated.
To the mixture of the above crude reactant (158mg, 0.403 mmol) in DCM
(4mL) were added the benzyl amine (85 mg, 0.52 mmol), and HATU (230 mg, 0.604 mmol)
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at room temperature followed by DIPEA (0.3 mL, 1.6 mmol). After about 60 min, the
reaction mixture was diluted with DCM, washed with saturated NaHCO , dried (MgSO ),
and concentrated. The residue was purified by CombiFlash on silica gel using 0-
%MeOH/EtOAc to provide compound 13-A.
Step 2
Compound 13-A (118mg, 0.22 mmol) was dissolved in TFA (2 mL) at room
temperature and stirred for 30 min. The solution was concentrated and the residue was
purified by CombiFlash (silica gel column) using 0-20% MeOH in CH Cl to provide
compound 13.
H NMR (400 MHz, Chloroform-d) δ 11.74 (s, 1H), 10.45 (s, 1H), 8.29 (s,
1H), 7.25 - 7.16 (m, 1H), 6.90 (td, J = 9.5, 6.4 Hz, 1H), 4.95 (s, 1H), 4.60 (d, J = 6.0 Hz, 2H),
4.23 - 4.05 (m, 1H), 3.84 (dd, J = 4.2, 2.4 Hz, 2H), 2.80 (d, J = 3.2 Hz, 2H), 1.42 (d, J = 10.9
Hz, 2H), 1.29 - 1.12 (m, 2H), 0.65 (dt, J = 6.8, 3.2 Hz, 1H), 0.46 (q, J = 7.3 Hz, 1H).
F NMR (376 MHz, cdcl3) δ -120.67, -136.05, -143.22 to -143.36.
LCMS-ESI (m/z): [M+H] calculated for Chemical Formula:
C22H18F3N3O4, Molecular Weight: 445.39.; found: 446.29.
ANTIVIRAL ASSAY
Example 14
Antiviral Assays in MT4 Cells
For the antiviral assay utilizing MT4 cells, 0.4 µL of 189X test concentration
of 3-fold serially diluted compound in DMSO was added to 40 µL of cell growth medium
(RPMI 1640, 10% FBS, 1% penicillin/streptomycin, 1% L-Glutamine, 1% HEPES) in each
well of 384-well assay plates (10 concentrations) in quidruplicate.
1 mL aliquots of 2 × 10 MT4 cells are pre-infected for 1 and 3 hours
respectively at 37 °C with 25 µL (MT4) or of either cell growth medium (mock-infected) or a
fresh 1:250 dilution of an HIV-IIIb concentrated ABI stock (0.004 m.o.i. for MT4 cells).
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Infected and uninfected cells are diluted in cell growth medium and 35 µL of 2000 (for MT4)
cells is added to each well of the assay plates.
Assay plates were then incubated in a 37 °C incubator. After 5 days of
incubation, 25 µL of 2X concentrated CellTiter-Glo™ Reagent (catalog # G7573, Promega
Biosciences, Inc., Madison, WI) was added to each well of the assay plate. Cell lysis was
carried out by incubating at room temperature for 2–3 minutes, and then chemiluminescence
was read using the Envision reader (PerkinElmer).
Compounds of the present invention demonstrate antiviral activity in this
assay as depicted in Table 1 below. Accordingly, the compounds of the invention may be
useful for treating the proliferation of the HIV virus, treating AIDS, or delaying the onset of
AIDS or ARC symptoms.
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Table 1
nM in MT-4
Compound Number
EC CC
50 50
1 9.6 14113
2 10.7 7804
3 9.9 4099
4 8.4 12829
1.6 50481
6 1.5 14062
7 2.7 4826
8 1.4 8843
9 1.4 10677
1.7 7587
11 1.5 10977
12 2.9 22792
13 2.3 7051
The data in Table 1 represent an average over time for each compound. For
certain compounds, multiple assays have been conducted over the life of the project.
All of the U.S. patents, U.S. patent application publications, U.S. patent
applications, foreign patents, foreign patent applications and non-patent publications referred
to in this specification are incorporated herein by reference, in their entirety to the extent not
inconsistent with the present description.
From the foregoing it will be appreciated that, although specific embodiments
of the invention have been described herein for purposes of illustration, various modifications
may be made without deviating from the spirit and scope of the invention. Accordingly, the
invention is not limited except as by the appended claims.
108849907 v1
Claims (38)
1. A compound having the following Formula (I): or a stereoisomer or pharmaceutically acceptable salt thereof, wherein: Y and Y are each, independently, hydrogen, saturated or unsaturated C alkyl or saturated or unsaturated C haloalkyl; 1-3 1-3 R is phenyl substituted with one to three halogen atoms; X is -O-, -NR -, -CHR - or a bond; R and R are each, independently, hydrogen or saturated or unsaturated C alkyl; and L is a linker of formula: , wherein each R is independently hydrogen, halo, hydroxyl, or saturated or unsaturated C alkyl, and each R is, independently, hydrogen or halo.
2. A compound of claim 1 having the following Formula (Ia): (Ia) or a stereoisomer or pharmaceutically acceptable salt thereof, wherein: Y and Y are each, independently, hydrogen, saturated or unsaturated C alkyl or saturated or unsaturated C haloalkyl; 1-3 1-3 R is phenyl substituted with one to three halogen atoms; X is -O-, -NR -, -CHR - or a bond; R and R are each, independently, hydrogen or saturated or unsaturated C alkyl; and L is a linker of formula: , wherein each R is independently hydrogen, halo, hydroxyl, or saturated or unsaturated C alkyl, and each R is, independently, hydrogen or halo.
3. A compound of claim 1 having the following Formula (Ib): (Ib) or a stereoisomer or pharmaceutically acceptable salt thereof, wherein: Y and Y are each, independently, hydrogen, saturated or unsaturated C alkyl or saturated or unsaturated C haloalkyl; 1-3 1-3 R is phenyl substituted with one to three halogen atoms; X is -O-, -NR -, -CHR - or a bond; R and R are each, independently, hydrogen or saturated or unsaturated C alkyl; and L is a linker of formula: , wherein each R is independently hydrogen, halo, hydroxyl, or saturated or unsaturated C alkyl, and each R is, independently, hydrogen or halo.
4. A compound of claim 1 having the following Formula (Ic): (Ic) or a stereoisomer or pharmaceutically acceptable salt thereof, wherein: Y and Y are each, independently, hydrogen, saturated or unsaturated C alkyl or saturated or unsaturated C haloalkyl; 1-3 1-3 R is phenyl substituted with one to three halogen atoms; X is -O-, -NR -, -CHR - or a bond; R and R are each, independently, hydrogen or saturated or unsaturated C alkyl; and L is a linker of formula: , wherein each R is independently hydrogen, halo, hydroxyl, or saturated or unsaturated C alkyl, and each R is, independently, hydrogen or halo.
5. A compound of claim 1 having the following Formula (Id): (Id) or a stereoisomer or pharmaceutically acceptable salt thereof, wherein: Y and Y are each, independently, hydrogen, saturated or unsaturated C alkyl or saturated or unsaturated C haloalkyl; 1-3 1-3 R is phenyl substituted with one to three halogen atoms; X is -O-, -NR -, -CHR - or a bond; R and R are each, independently, hydrogen or saturated or unsaturated C alkyl; and L is a linker of formula: , wherein each R is independently hydrogen, halo, hydroxyl, or saturated or unsaturated C alkyl, and each R is, independently, hydrogen or halo.
6. A compound of claim 1 having the following Formula (Ie): (Ie) or a stereoisomer or pharmaceutically acceptable salt thereof, wherein: Y and Y are each, independently, hydrogen, saturated or unsaturated C alkyl or saturated or unsaturated C haloalkyl; 1-3 1-3 R is phenyl substituted with one to three halogen atoms; X is -O-, -NR -, -CHR - or a bond; R and R are each, independently, hydrogen or saturated or unsaturated C alkyl; and L is a linker of formula: , wherein each R is independently hydrogen, halo, hydroxyl, or saturated or unsaturated C alkyl, and each R is, independently, hydrogen or halo.
7. A compound of any one of claims 1 –6 wherein X is -O-.
8. A compound of any one of claims 1 –6 wherein X is -NH-.
9. A compound of any one of claims 1 –6 wherein X is -CH -.
10. A compound of any one of claims 1 –6 wherein X is a bond.
11. A compound of any one of claims 1 –10 wherein Y is saturated or unsaturated C alkyl and Y is hydrogen. 1 –3
12. A compound of claim 11 wherein Y is methyl and Y is hydrogen.
13. A compound of any one of claims 1 –5 wherein Y is saturated or unsaturated C haloalkyl and Y is hydrogen. 1 –3
14. A compound of claim 13 wherein Y is CF and Y is hydrogen.
15. A compound of any one of claims 1 –10 wherein Y is hydrogen, methyl or CF and Y is hydrogen.
16. A compound of any one of claims 1 –10 wherein Y and Y are both hydrogen.
17. A compound of any one of claims 1 –16 wherein R is substituted with one halogen.
18. A compound of claim 17 wherein R is 4-fluorophenyl or 2- fluorophenyl.
19. A compound of any one of claims 1 –16 wherein R is substituted with two halogens.
20. A compound of claim 19 wherein R is 2,4-difluorophenyl, 2,3- difluorophenyl, 2,6-difluorophenyl, 3-fluorochlorophenyl, 3,4-difluorophenyl, 2- fluorochlorophenyl, or 3,5-difluorophenyl.
21. A compound of claim 20 wherein R is 2,4-difluorophenyl.
22. A compound of any one of claims 1 –16 wherein R is substituted with three halogens.
23. A compound of claim 22 wherein R is 2,4,6-trifluorophenyl, 2,3,4-trifluorophenyl, or 2,4,5-trifluorophenyl.
24. A compound of claim 22 wherein R is 2,4,6-trifluorophenyl or 2,3,4-trifluorophenyl.
25. A compound of claim 24 wherein R is 2,4,6-trifluorophenyl.
26. A compound of claim 23 wherein R is 2,4,5-trifluorophenyl.
27. A compound of any one of claims 1 –26 wherein each R is independently hydrogen.
28. A compound of any one of claims 1 –26 wherein each R is independently halogen.
29. A compound of claim 28 wherein each R is fluoro.
30. A compound of claim 1 that is: ; or
31. A compound of claim 1 that is: ; or
32. A pharmaceutical composition comprising a compound of any one of claims 1 –31, or a stereoisomer or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or excipient.
33. A pharmaceutical composition of claim 32 further comprising one to three additional therapeutic agents.
34. A pharmaceutical composition of claim 33 wherein the one to three one additional therapeutic agents is an anti-HIV agent.
35. A pharmaceutical composition of claim 33 wherein the one to three additional therapeutic agents is selected from the group consisting of HIV protease inhibitors, HIV non-nucleoside inhibitors of reverse transcriptase, HIV nucleoside or nucleotide inhibitors of reverse transcriptase, and combinations thereof.
36. A pharmaceutical composition of claim 32, further comprising a first additional therapeutic agent selected from the group consisting of: abacavir sulfate, tenofovir, tenofovir disoproxil fumarate, tenofovir alafenamide, and tenofovir alafenamide hemifumarate and a second additional therapeutic agent selected from the group consisting of emtricitibine and lamivudine.
37. Use of a compound of any one of claims 1 –31 or a pharmaceutical composition of any one of claims 32 to 36 in the manufacture of a medicament for the treatment of an HIV infection in a human having or at risk of having the infection.
38. A compound as described in any one of claims 1 –31, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of any one of claims 32 to 36 for use in the prophylactic or therapeutic treatment of an HIV infection.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
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US201361845806P | 2013-07-12 | 2013-07-12 | |
US61/845,806 | 2013-07-12 | ||
PCT/US2014/046413 WO2015006731A1 (en) | 2013-07-12 | 2014-07-11 | Polycyclic-carbamoylpyridone compounds and their use for the treatment of hiv infections |
Publications (2)
Publication Number | Publication Date |
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NZ716794A NZ716794A (en) | 2021-06-25 |
NZ716794B2 true NZ716794B2 (en) | 2021-09-28 |
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