tenofovir antiviral aliphatic ester compounds or pharmaceutically acceptable salts thereof, pharmace

专利摘要:
compounds of the formula i and their pharmaceutically acceptable salts are useful for the inhibition of hiv reverse transcriptase. the compounds may also be useful for the prophylaxis or treatment of HIV infection and for prophylaxis, delayed onset, or AIDS progression and treatment. the compounds and their salts can be used as ingredients in pharmaceutical compositions, optionally in combination with other antiviral agents, immunomodulators, antibiotics or vaccines.
公开号:BR112019013017A2
申请号:R112019013017
申请日:2017-12-20
公开日:2020-01-14
发明作者:Da Costa Daniel；Dukhan David；Rahali Houcine；Raheem Izaat；Paparin Jean-Lauret
申请人:Idenix Pharmaceuticals Llc；Merck Sharp & Dohme；
IPC主号:

专利说明:

TENOFOVIR ANTIVIRAL ALIFATIC ESTER COMPOUNDS OR PHARMACEUTICALLY ACCEPTABLE SALES OF THE SAME, PHARMACEUTICAL COMPOSITION AND USE OF THE SAME
BACKGROUND OF THE INVENTION [001] The retrovirus called human immunodeficiency virus (HIV), particularly strains known as HIV type-1 (HIV-1) and type-2 (HIV-2), have been etiologically linked to the immunosuppressive disease known as syndrome acquired immunodeficiency (AIDS). HIV-positive individuals are initially asymptomatic, but typically develop an AIDS-related complex (ARC) followed by AIDS. Affected individuals exhibit severe immunosuppression, which makes them highly susceptible to debilitating and ultimately fatal opportunistic infections. The replication of HIV by a host cell requires integration of the viral genome into the DNA of the host cell. Since HIV is a retrovirus, the HIV replication cycle requires transcription of the viral RNA genome into DNA using an enzyme known as reverse transcriptase (RT).
[002] Reverse transcriptase has three known enzyme functions: the enzyme acts as an RNA-dependent DNA polymerase, as a ribonuclease, and as a DNA-dependent DNA polymerase. In this role as an RNA-dependent DNA polymerase, RT transcribes a single-stranded DNA copy of the viral RNA. Like a ribonuclease, RT destroys the original viral RNA and releases the DNA produced only from the original RNA. During the viral RNA-dependent polymerization process, RT's ribonuclease activity is required to remove the RNA and leave the polyipurin tract preserved for the initiation of DNA-dependent polymerization. Like a DNA-dependent DNA polymerase, RT makes a second complementary DNA strand using the first DNA strand as a template. The two tapes
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2/84 form double-stranded DNA, which is integrated into the host cell genome by HIV integrase.
[003] It is known that compounds that inhibit the enzymatic functions of HIV RT will inhibit HIV replication in infected cells. These compounds are useful in the treatment of HIV infection in humans. Classes of RT inhibitors include non-nucleoside active site competitive RT inhibitors (NNRTIs), such as efavirenz (EFV), nevirapine (NVP), etravirine (ETR) and rilpivirine (RPV), and active site RT inhibitors that include nucleoside reverse transcriptase inhibitors (NsRTIs) and nucleotide reverse transcriptase inhibitors (NtRTIs), collectively referred to as NRTIs. Examples of NsRTIs include 3'-azido-3'-deoxythymidine (AZT), 2 ', 3'-didesoxy-inosine (ddl), 2 ', 3'-didesoxycytidine (ddC), 2', 3'-dideshydro-2 ', 3'-didesoxythymidine (d4T), 2', 3'didesoxy-3'-thiacitidine (3TC), abacavir , emtricitabine and 4'-ethynyl-2-fluoro-2'deoxyadenosine (EFdA) which are also known as a nucleoside reverse transcriptase inhibitor. Examples of NtRTIs include tenofovir (TFV, also known as PMPA, 9- (2-phosphonylmethoxypropyl) adenine), tenofovir disoproxil fumarate (VIREAD®, US Patent No. 5977089, 5935946) and tenofovir alafenamide fumarate (US Patent No. 7375791 .065).
[004] TFV belongs to a class of HIV antiretroviral agents (ARV) known as nucleotide reverse transcriptase inhibitors (NRTIs). Tenofovir is a mono-phosphonate:
[005] After being absorbed by the cells, the TFV is first converted to
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3/84 tenofovir-monophosphate (TFV-MP) by adenosine monophosphate kinase and then to active antiviral tenofovir-diphosphate (TFV-DP) by 5'-nucleoside diphosphate kinase.
ch ₃ o II Pnh ₂
No --- · Ά _ΚΙ o
II
HO I Ο I Ο I OH ‘‘
OH
O
II
P / O
I
Oh ch ₃
Tenofovir-monophosphate (TFV-MP)
Tenofovir-diphosphate (TFV-DP) [006] TFV-DP inhibits HIV DNA synthesis by competition with the natural substrate, deoxyadenosine triphosphate, for incorporation into the complementary DNA strand by HIV reverse transcriptase; after incorporation, TFV acts as a chain terminator due to the lack of a 3'-hydroxyl group that is required for addition of the next nucleotide. TFV has deficient cell permeability and thus has limited bioavailability. Tenofovir disoproxil fumarate (TDF) is approved to treat HIV infection and is marketed by Gilead under the trade name VIREAD ™. The disoproxil prodrug improves cell permeability and absorption after oral dosing, with the pro-portion being cleaved quickly after absorption to provide the precursor TFV. As a result, the circulating level of TFV is much higher than that of TDF. Tenofovir alafenamide fumarate (TAF) is currently approved by the USFDA as an active ingredient in combination with additional ARVs to treat HIV infection in GENVOYA® pharmaceuticals,
ODEFSEY® and DESCOVY®.
[007] While each of the previous drugs is effective in treating HIV infection and AIDS, there remains a need to develop additional HIV antiviral drugs including additional RT inhibitors. A particular problem is the development of mutant strains of HIV that are resistant
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4/84 to known inhibitors. The use of RT inhibitors to treat AIDS often leads to viruses that are less sensitive to inhibitors. This resistance is typically the result of mutations that occur in the reverse transcriptase segment of the pol gene. The continued use of antiviral compounds to prevent HIV infection will inevitably result in the emergence of new resistant strains of HIV. Consequently, there is a particular need for new RT inhibitors that are effective against mutant strains of HIV.
SUMMARY OF THE INVENTION [008] The present invention is directed to tenofovir aliphatic ester prodrugs and their use in inhibiting nucleotide reverse transcriptase. In addition to the use of said compounds in the inhibition of HIV reverse transcriptase, the invention is also directed to the use of said compounds for prophylaxis of HIV infection, treatment of HIV infection, and prophylaxis, treatment and / or delay in starting or progression of AIDS and / or ARC.
DETAILED DESCRIPTION OF THE INVENTION [009] The present invention is directed to compounds of Formula I:
NH
// U ~ R ^{1 ch} 3 ⁰ R ² | or a pharmaceutically acceptable salt thereof, where:
X ¹ is -O- or -S-;
X ² is -O- or -S-;
X ³ is -O- or -S-;
R ¹ is (a) -C1-4alkyl, (b) -C1-4alkyl substituted with -OH, -SH, -SCH3, -NH2,
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NH-C (= NH) -NH ₂ , (c) -CH ₂ -phenyl, (d) -CH ₂ -phenol, (e) - (CH ₂ ) i- ₂ -COOH, (f) - (CH ₂ ) i- ₂ CONH ₂ , (g) -CH ₂ -l / - / - indole, (h) -CH ₂ -imidazole, (i) aryl (eg, but not limited to phenyl or naphthyl) or (j) heteroaryl (for example, but not limited to pyridine);
R ² is (a) -C1-4alkyl, (b) -C1-4alkyl substituted with -OH, -SH, -SCH3, -NH ₂ , NH-C (= NH) -NH ₂ , (c) - CH ₂ -phenyl, (d) -CH ₂ -phenol, (e) - (CH ₂ ) i- ₂ -COOH, (f) - (CH ₂ ) i- ₂ CONH ₂ , (g) -CH ₂ -l / - / - indole, (h) -CH ₂ -imidazole, (i) aryl (eg, but not limited to phenyl or naphthyl) or (j) heteroaryl (eg, but not limited to pyridine);
or R ¹ and R ² are joined together with the carbon to which they are both attached to form C3-6 -cycloalkyl or a 4- to 6-membered heterocyclic ring;
R ³ is:
(a) -C1- ion alkyl substituted or substituted with one to three substituents, each substituent being independently fluorine, chlorine, bromine, -CN, -CF3, OR ^5a , -SH, -NR ⁶ R ⁷ , -C3 cycloalkyl -6 or C3-6 spirocycloalkyl, (b) -CH ₂ -phenyl unsubstituted or substituted with one to three substituents, where each substituent is independently fluorine, chlorine, bromine, -OR ^8a , -SH, -NR ⁶ R ⁷ or -C1-3alkyl, (c) -C3-8cycloalkyl unsubstituted or substituted with one to three substituents, where each substituent is independently fluorine, chlorine, bromine, -OR ^8a , -SH, - NR ⁶ R ⁷ or -C1-3 alkyl, (d) aryl unsubstituted or substituted with one to three substituents, each substituent being independently fluorine, chlorine, bromine, -OR ^8a , -SH, - NR ⁶ R ⁷ or -C1-3 alkyl , (e) -C1-5 alkyl-X-C1-5 alkyl where X is O, S or NH, (f) heteroaryl unsubstituted or substituted with one to three substituents, where each substituent is independently fluorine, c loro, bromo, -OR ^8a , -SH,
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- NR ⁶ R ⁷ or -C1-3alkyl, or (g) an unsubstituted or substituted heterocyclic ring with one to three substituents, where each substituent is independently fluorine, chlorine, bromine, -OR ^8a , -SH, -NR ⁶ R ⁷ or -C1-3alkyl;
R ⁴ is:
(a) -Ciononyl alkyl substituted or substituted with one to three substituents, each substituent being independently fluorine, chlorine, bromine, -CN, -CF3, OR ^5b , -SH, -NR ⁹ R ¹⁰ , -C3 cycloalkyl -6 or C3-6 spirocycloalkyl, (b) -CHz-phenyl unsubstituted or substituted with one to three substituents, where each substituent is independently fluorine, chlorine, bromine, -OR ^8b , -SH, -NR ⁹ R ¹⁰ or -C1-3alkyl, (c) -C3-8cycloalkyl unsubstituted or substituted with one to three substituents, where each substituent is independently fluorine, chlorine, bromine, -OR ^8b , -SH, -NR ⁹ R ¹⁰ or - C1-3alkyl, (d) aryl unsubstituted or substituted with one to three substituents, where each substituent is independently fluorine, chlorine, bromine, -OR ^8b , -SH, -NR ⁹ R ¹⁰ or -C1-3 alkyl, (e) -C1-5 alkyl-X-C1-5 alkyl wherein X is O, S or NH;
(f) heteroaryl unsubstituted or substituted with one to three substituents, where each substituent is independently fluorine, chlorine, bromine, -OR ^8b , -SH,
- NR ⁹ R ¹⁰ or -C1-3alkyl, or (g) an unsubstituted or substituted heterocyclic ring with one to three substituents, where each substituent is independently fluorine, chlorine, bromine, -OR ^8b , -SH, - NR ⁹ R ¹⁰ or -C1-3alkyl;
R ^5a and R ^5b are each independently -H or -C3-6 cycloalkyl;
R ⁶ and R ⁷ are each independently -H, -C1-3 alkyl or -C3-6 cycloalkyl;
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7/84
R ^8a and R ^8b are each independently -H, -C1-3alkyl or -cycloalkyl
C3-6;
R ⁹ and R ¹⁰ are each independently -H, -C1-3 alkyl or -cycloalkyl
C3-6;
where · is the connection point to -CH (R ¹⁴ ) and ·· is the connection point to C (O) X ³ R ⁴ ;
n is 0 (zero) or 1 (one);
mean (zero) or 1 (one);
R ^lla and R ^llb are each independently -H or -C1-3alkyl (for example, -CH3);
or R ^lla and R ^llb are joined together with the carbon to which they are both attached to form C3-6 spirocycloalkyl (e.g.);
R ^12a and R ^12b are each independently -H or -C1-3alkyl (for example, -CH3);
or R ^12a and R ^12b are joined together with the carbon to which they are both attached to form C3-6 spirocycloalkyl (for example,);
R ¹³ is H, -C1- alkyl, or halo (for example, F, Cl or Br); and
R ¹⁴ is H, -C1- alkyl, or halo (e.g., F, Cl, or Br).
or a pharmaceutically acceptable salt thereof.
[010] In one embodiment of this invention are compounds of Formula Ia,
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8/84
or pharmaceutically acceptable salts thereof, where the variables are as defined in Formula I.
[011] In another embodiment of this invention are compounds of the Formula
Ib:
or pharmaceutically acceptable salts thereof, where the variables are as defined in Formula I.
[012] In Mode 1 of this invention are compounds of Formula I or pharmaceutically acceptable salts thereof, where R ¹ and R ² are each independently selected from -C1-4alkyl. In a class of this modality, R ¹ and R ² are -C1-4alkyl and both are the same portion. In another class of this modality, R ¹ and R ² are both methyl, ethyl, propyl or i-propyl. In another class of this modality R ¹ and R ² are both methyl.
[013] In Mode 2 of this invention are compounds of Formula I, Ia or Ib, or Mode 1, or any class thereof, or pharmaceutically acceptable salts of the foregoing, where R ¹⁴ is H, -C1-3 alkyl or halo. In a class of Mode 2, R ¹⁴ is H, -CH3, or halo (for example, F, Cl or Br); or R ¹⁴ is H or
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-CH ₃ ; or R ¹⁴ is H.
[014] In Mode 3 of this invention are compounds of Formula I or Ia, or Mode 1 or 2, or any class thereof, or pharmaceutically acceptable salts of the foregoing, where n is zero (meaning that CR ^lla R ^llb is absent and CR ^12a R ^12b is directly linked to C (O) X ³ R ⁴ in Formula I or COOR ⁴ in Formula Ia), and R ^12a and R ^12b are as defined in Formula I.
[015] In Mode 4a of this invention are compounds of Formula I or Ia, or Mode 1 or 2, or any class thereof, or pharmaceutically acceptable salts of the foregoing, where n is one, and:
R ^lla and R ^llb are independently -H or -C _3- alkyl (for example, -CH 3), and
R ^12a and R ^12b are independently -H or -C1-3alkyl (for example, -CH3), or R ^12a and R ^12b are joined together with the carbon to which they are both attached to form C3-6 spirocycloalkyl (for example , spiro-cyclopropyl).
[016] In Mode 4b of this invention are compounds of Formula I or Ia, or Mode 1 or 2, or any class thereof, or pharmaceutically acceptable salts of the foregoing, where n is one, and:
R ^lla and R ^llb are independently -H or -C1-3 alkyl (for example, -CH3), or R ^lla and R ^llb are joined together with the carbon to which they are both attached to form C3-6 spirocycloalkyl (for example , spiro-cyclopropyl), and
R ^12a and R ^12b are independently -H or -C1-3alkyl (for example, -CH3).
[017] In Mode 5 of this invention are compounds of Formula I or Ib, or Mode 1 or 2, or any class thereof, or pharmaceutically acceptable salts of the foregoing, where m is zero (that is, (CFhJm is absent and CH ( R ¹⁴ ) is directly linked to the phenyl ring).
[018] In Mode 6 of this invention are compounds of Formula I or Ib, or Mode 1 or 2, or any class thereof, or pharmaceutically salts
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Acceptable 10/84 of the precedents, where m is one.
[019] In Mode 7 of this invention are compounds of Formula I or Ib, or Mode 1, 2, 5 or 6, or any class thereof, or pharmaceutically acceptable salts of the foregoing, where R ¹³ is H, -C1-3 alkyl or halo. In a class of Mode 7, R ¹³ is H, -CH3 or halo (for example, F, Cl or Br).
[020] In Mode 8 of this invention are compounds of Formula I, Ia or Ib, or Mode 1, 2, 3, 4, 5, 6 or 7, or any class thereof, or pharmaceutically acceptable salts of the foregoing, where R ³ is:
(a) Cl - ₈ -alkyl, -CH2CH2OH, -CH2CH2CH2OH, -CH2CH2SH, -CH2CH2CH2SH, CH2CH2NH2, -CH2CH2CH2NH2, -CH2CF2CH3 or -CH2CH2CF3;
(b) -CFh-phenyl unsubstituted or substituted with one to three substituents, where each substituent is independently fluorine, chlorine, bromine, -OR ^8a , -SH, -NR ⁶ R ⁷ or -C1-3alkyl, (c ) -C3-6 cycloalkyl unsubstituted or substituted with one to three substituents, where each substituent is independently fluorine, chlorine, bromine, -OR ^8a , -SH, - NR ⁶ R ⁷ or -C1-3 alkyl, (d) unsubstituted or substituted phenyl or naphthyl with one to three substituents, where each substituent is independently fluorine, chlorine, bromine, -OR ^8a , -SH, -NR ⁶ R ⁷ or -C1-3alkyl, (e) -CH2CH2OCH3, -CH2CH2CH2OCH3, -CH2CH2SCH3, -CH2CH2CH2SCH3, CH2CH2NHCH3, -CH2CH2CH2NHCH3, (f) unsubstituted pyridyl or substituted with one to three substituents, wherein each substituent is independently fluoro, chloro, bromo, -OR ^8a, SH, NR ⁶ R ⁷ or -C1-3alkyl, or (g) piperidinyl, pyrrolidinyl, tetrahydrofuranyl or tetrahydropyranyl unsubstituted or substituted with one to three substituents s, where each substituent is independently fluorine, chlorine, bromine, -OR ^8a , -SH, -NR ⁶ R ⁷ or -C1-3alkyl.
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11/84 [021] In a first class of Mode 8, R ³ is:
(a) Cl - ₈ -alkyl, -CH2CH2OH, -CH2CH2CH2OH, -CH2CH2SH, -CH2CH2CH2SH, CH2CH2NH2, -CH2CH2CH2NH2, -CH2CF2CH3 or -CH2CH2CF3;
(b) -CFE-phenyl unsubstituted or substituted with one to three substituents, where each substituent is independently fluorine, chlorine, bromine, -OR ^8a , -SH, -N NR ⁶ R ⁷ or -C1-3alkyl, or (c) -C3-6 -cycloalkyl unsubstituted or substituted with one to three substituents, wherein each substituent is independently fluoro, chloro, bromo, -OR ^8a , -SH, -NR ⁶ R ⁷ or -C1-3 alkyl.
[022] In a second class of Mode 8, R ³ is -C1-8 alkyl, and in a third class of this R ³ is -C2-6 alkyl.
[023] In Mode 9 of this invention are compounds of Formula I, Ia or Ib, or Mode 1, 2, 3, 4, 5, 6, 7 or 8, or any class thereof, or pharmaceutically acceptable salts of the foregoing, where ^R4 is (a) Cl - ₈ -alkyl, -CH2CH2OH, -CH2CH2CH2OH, -CH2CH2SH, -CH2CH2CH2SH, CH2CH2NH2, -CH2CH2CH2NH2, -CH2CF2CH3 or -CH2CH2CF3;
(b) -CH2-phenyl unsubstituted or substituted with one to three substituents, where each substituent is independently fluorine, chlorine, bromine, -OR ^8b , -SH, -NR ⁹ R ¹⁰ or -C1-3alkyl, (c ) -C3-6 cycloalkyl unsubstituted or substituted with one to three substituents, where each substituent is independently fluorine, chlorine, bromine, -OR ^8b , -SH, -NR ⁹ R ¹⁰ or -C1-3 alkyl, (d) phenyl or naphthyl unsubstituted or substituted with one to three substituents, where each substituent is independently fluorine, chlorine, bromine, -OR ^8b , -SH, -NR ⁹ R ¹⁰ or -C1-3alkyl, (e) -CH2CH2OCH3, -CH2CH2CH2OCH3, -CH2CH2SCH3, -CH2CH2CH2SCH3, CH2CH2NHCH3, -CH2CH2CH2NHCH3,
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12/84 (f) pyridyl unsubstituted or substituted with one to three substituents independently, where each substituent is independently of fluorine, chlorine, bromine, -OR ^8b , -SH, -NR ⁹ R ¹⁰ or -C1-3 alkyl, or (g) piperidinyl, pyrrolidinyl, tetrahydrofuranyl or tetrahydropyranyl, each unsubstituted or substituted with one to three substituents, each substituent being independently fluorine, chlorine, bromine, -OR ^8b , -SH, -NR ⁹ R ¹⁰ or alkyl C1-3.
[024] In a first class of Mode 9, R ⁴ is:
(a) Cl - ₈ -alkyl, -CH2CH2OH, -CH2CH2CH2OH, -CH2CH2SH, -CH2CH2CH2SH, CH2CH2NH2, -CH2CH2CH2NH2, -CH2CF2CH3 or -CH2CH2CF3;
(b) -CH2-phenyl unsubstituted or substituted with one to three substituents, where each substituent is independently fluorine, chlorine, bromine, -OR ^8b , -SH, -NR ⁹ R ¹⁰ or -C1-3alkyl, or ( c) -C3-6 -cycloalkyl unsubstituted or substituted with one to three substituents, where each substituent is independently fluorine, chlorine, bromine, -OR ^8b , -SH, -NR ⁹ R ¹⁰ or -C1-3 alkyl.
[025] In a second class of Mode 9, R ⁴ is -C1-8 alkyl, and in a third class of this R ⁴ -C2-6 alkyl.
[026] In Modality 10 of this invention are compounds of Formula I, Ia or Ib, or any of Modalities 1, 2, 3, 4, 5, 6 or 7, or any class thereof, or pharmaceutically acceptable salts of the foregoing, that R ³ and R ⁴ are each independently -C1-8 alkyl, -C3-6 cycloalkyl or -CH2-phenyl, and where each of R ³ and R ⁴ is unsubstituted or substituted as defined in Formula I In class (A) of these, R ³ is -C1-8 alkyl, -C3-6 cycloalkyl or -CH2-phenyl, and R ⁴ is -C1-8 alkyl or -C3-6 cycloalkyl. In class (B) of these, R ³ and R ⁴ are each independently selected from -C2-6alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or -CH2-phenyl. In class (C) of these, R ³ and R ⁴ are each
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13/84 independently selected from -C1-8 alkyl, or in a subclass thereof, R ³ and R ⁴ are each independently selected from -C2-6 alkyl.
[027] In Mode 11 of this invention are compounds of Formula I or a pharmaceutically acceptable salt thereof where one of X ¹ and X ² is -O- and the other is -O- or -S-. In a class like this, X ¹ and X ² are both -O-. In another class of this, X ¹ and X ² are both -S-.
[028] In Mode 12 of this invention are compounds of Formula I or a pharmaceutically acceptable salt of the same where X ³ is -0 [029] In Mode 13 of this invention are compounds of Formula I or a pharmaceutically acceptable salt of the same where:
one of X ¹ and X ² is -O- and the other is -O- or -S-;
X ³ is -O- or S;
R ¹ and R ² are both the same alkyl group in which the alkyl group is methyl, ethyl, propyl or i-propyl;
R ³ is -C1-6 alkyl;
R ⁴ is -C1-6 alkyl;
where · is the point of attachment to -CH (R ¹⁴ ) and ·· is the point of attachment to C (O) OR ⁴ ;
n is 0 or 1;
m is 0 or 1;
R ^lla and R ^llb are each independently -H or -C1-3 alkyl, or R ^lla and R ^llb are joined together with the carbon to which they are both attached to form C3-6 spirocycloalkyl;
R ^12a and R ^12b are each independently -H or -C1-3alkyl, or R ^12a and
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R ^12b are joined together with the carbon to which both are attached to form C3-6 spirocycloalkyl;
R ¹³ is H, -C 1-3 alkyl or halo; and
R ¹⁴ is -H or -C1-3alkyl.
[030] In Mode 14 of this invention are compounds of Formula I or a pharmaceutically acceptable salt thereof where:
X ¹ is -Ο-, X ² is -O- and X ³ is -O-;
R ¹ and R ² are both methyl;
R ³ is -C2-6alkyl;
R ⁴ is -C2-6alkyl;
where · is the point of attachment to -CH (R ¹⁴ ) and ·· is the point of attachment to C (O) OR ⁴ ;
when n is 0, R ^12a and R ^12b are each independently -H or -C1-3alkyl or R ^12a and R ^12b are joined together with the carbon to which they are both attached to form C3-6 spirocycloalkyl (for example example, spiro-cyclopropyl);
when n is 1, (a) R ^12a and R ^12b are each independently -H or -C1-3alkyl or R ^12a and R ^12b are joined together with the carbon to which they are both attached to form C3- spirocycloalkyl 6 (for example, spiro-cyclopropyl), and ^R1la and ^R11b are each independently -H or -C1-3alkyl; or (b) R ^12a and R ^12b are each independently -H or -C1-3alkyl; and R ^lla and R ^llb are each independently -H or -C1-3 alkyl or R ^lla and R ^llb are joined together with the carbon to which they are both attached to form C3-6 spirocycloalkyl (for example, spiro- cyclopropyl);
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15/84 m is 0 or 1;
R ¹³ is H, -C1-3alkyl, F, Cl or Br; and
R ¹⁴ is -H 0U-CH3.
[031] The reference to the compounds of Formula I in the present invention encompasses the compounds of Formula I, Ia and Ib, and all their modalities, classes and subclasses and includes the compounds of the Examples in the present invention.
[032] When a portion in a Formula I compound can be substituted with more than one substituent, the definition of each substituent is independently selected at each occurrence.
[033] As used in the present invention, alkyl refers to both straight or branched saturated aliphatic hydrocarbon groups having the specified number of carbon atoms in a specified range.
[034] For example, the term Ci-s alkyl means straight or branched chain alkyl groups, including all possible isomers, having 1, 2, 3, 4, 5, 7 or 8 carbon atoms, and includes each of the octyl, heptyl, hexyl and pentyl isomers as well as n-, iso-, see- and tert-butyl (butyl, / -butyl, s-butyl, t-butyl, collectively C4 alkyl; Bu = butyl), n- and / -propyl (propyl, / -propyl, collectively C3 alkyl; Pr = propyl), ethyl (Et) and methyl (Me). C 1-6 alkyl has 1, 2, 3, 4, 5 or 6 carbon atoms and includes each of the alkyl groups within C 1-8 alkyl except for those containing 7 or 8 carbon atoms. C1-4 alkyl has 1, 2, 3 or 4 carbon atoms and each includes n-, / -, s- and t-butyl, n- and / -propyl, ethyl and methyl. C1-3 alkyl has 1, 2 or 3 carbon atoms and each includes n-propyl, / -propyl, ethyl and methyl.
[035] Cycloalkyl refers to a cyclized alkyl ring having the indicated number of carbon atoms in a specified range. Thus, for example, C3-8 cycloalkyl each includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. C3-6 cycloalkyl each includes cyclopropyl,
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16/84 cyclobutyl, cyclopentyl and cyclohexyl. When cycloalkyl is a substituent on an alkyl group in a compound of Formula I, the cycloalkyl substituent can be attached to any carbon available in the alkyl group. The following are an illustration of C3-6 -cycloalkyl substituents in which the substituent is bold cyclopropyl:
[036] C3-6 spirocycloalkyl refers to a cycloalkyl ring attached to a non-terminal carbon atom in which the non-terminal carbon atom is shared with the cycloalkyl group. C3-6 spirocycloalkyl each includes spiro-cyclopropyl, spiro-cyclobutyl, spiro-cyclopentyl and spiro-cyclohexyl. The following is an illustration of a C3-6 spirocycloalkyl substituent in which the substituent is spiro-cyclopropyl in bold:
r ⁴ ooc
R ¹⁴ [037] Examples of -C1-5-X-C1-5 alkyl groups include, but are not limited to -CH2CH2OCH3, -CH2CH2OCH2CH3, -CH2CH2CH2OCH3, CH2CH2CH2OCH2CH3, -CH2CH2SCH3, -CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH , -CH2CH2NHCH2CH3, -CH2CH2CH2NHCH3 or CH2CH2CH2NHCH2CH3.
[038] Arila refers to (i) phenyl, (ii) 9 or 10 membered bicyclic fused carbocyclic ring systems, where at least one ring is aromatic, and (iii) 11 to fused tricyclic carbocyclic ring systems 14 members, where at least one ring is aromatic. Suitable aryls include, for example, substituted and unsubstituted phenyl and substituted and unsubstituted naphthyl. An aryl of particular interest is unsubstituted or substituted phenyl.
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17/84 [039] Halo or halogen refers to chlorine, fluorine, bromine or iodine; chlorine, fluorine and bromine are a class of halogens of interest and, particularly, chlorine and fluorine.
[040] Heteroaryl refers to (i) a 5- or 6-membered heteroaromatic ring containing from 1 to 4 heteroatoms independently selected from N, O and S, where each N is optionally in the form of an oxide, and (ii) a 9- or 10-membered bicyclic fused ring system, where the fused ring system of (ii) contains from 1 to 6 heteroatoms independently selected from N, O and S, where each ring in the fused ring system contains zero, one or more of a heteroatom, at least one ring is aromatic, each N is optionally in the form of an oxide, and each S in a non-aromatic ring is optionally S (O) or S (O) ₂ . Examples of 5-membered heteroaromatic rings include, but are not limited to, pyrrolyl, pyrazolyl, triazolyl (i.e., 1,2,3-triazolyl or 1,2,4-triazolyl), triazolinone (for example, 2,4- dihydro-3 / - / - 1,2,4-triazole-3-one), imidazolyl, tetrazolyl, furanyl, furanonyl (e.g., furan-2 (5 / - /) - one), thienyl, thiazolyl, isothiazolyl, oxazolyl, iso-oxazolyl, oxadiazolyl (i.e., the isomer 1,2,3-, 1,2,4-, l, 2,5- (furazanil) or 1,3,4-oxadiazolyl), oxatriazolyl and thiadiazolyl. Examples of 6-membered heteroaromatic rings include, but are not limited to, pyridyl (also referred to as pyridinyl), pyrimidinyl, pyrazinyl, pyridazinyl and triazinyl. Examples of 9- and 10-membered heteroaromatic bicyclic fused ring systems include, but are not limited to, benzofuranyl, indolyl, indazolyl, naphthyridinyl, isobenzofuranyl, benzopiperidinyl, benzisoxazolyl, benzoxazolyl, chromenyl, quinolinyl, isoquinolinyl, isoquinolinyl, isoquinolinyl, isoquinoline [1, 2a] pyridinyl, benzotriazolyl, indazolyl, indolinyl and isoindolinyl. A class of heteroaryl includes (1) thienyl, furyl, thiazolyl and oxazolyl, and (2) an unsubstituted or substituted 6-membered heteroaryl comprised of atoms of
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18/84 carbon and 1 or 2 N heteroatoms, for example, pyrimidinyl, pyrazinyl or pyridazinyl.
[041] The term heterocyclic ring refers to (i) a saturated 4- to 7-membered cyclized ring and (ii) an unsaturated non-aromatic 4- to 7-membered cyclized ring comprised of carbon atoms and 1 to 4 independently selected heteroatoms O, N and S. Heterocyclic rings within the scope of this invention include, for example, but are not limited to, azetidinyl, piperidinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, isoxazolidinyl, pyrrolidinyl, imidazolidinyl, tiperazyrinyl, tetraazolidinyl, tiperazolidinyl, tiperazolidinyl, tiperazolidinyl, tiperazolidinyl, tiperazolidinyl, tiperazolidinyl, tiperazolidinil , pyrazolidinyl, hexahydropyrimidinyl, thiazinanyl, thiazepanyl, azepanyl, diazepanyl, tetrahydropyranyl, tetrahydrothiopyranyl and dioxanyl. Examples of 4- to 7-membered unsaturated non-aromatic heterocyclic rings within the scope of this invention include mono-unsaturated heterocyclic rings that correspond to the saturated heterocyclic rings listed in the preceding sentence in which a single bond is replaced with a double bond (for example, a double bond simple carbon-carbon is replaced with a carbon-carbon double bond).
[042] In a class of heterocyclic rings are saturated monocyclic rings of 4 to 6 members comprised of carbon atoms and 1 or 2 hetero atoms, where the hetero atoms are selected from N, O and S. Examples of 4 to 6 heterocyclic rings members include, but are not limited to, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, tetrahydrofuranyl, tetrahydropyranyl and tetrahydrothiopyranil, and a subclass of these is piperidinyl, pyrrolidinyl, tetrahidranil, tetrahidrhydrinil, tetrahidrhydrilil, tetrahidrhydrilil, tetrahydrofuranil, tetrahydrofuranil, tetrahydrofuranil,
[043] The following is an illustration of R ¹ and R ² when they are joined to form a heterocyclic ring:
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[044] It is understood that specific rings and ring systems suitable for use in the present invention are not limited to those listed in the previous paragraphs. These rings and ring systems are merely representative.
[045] As would be recognized by one skilled in the art, certain compounds of the present invention may be able to exist as tautomers. All tautomeric forms of these compounds, whether individually or in mixtures, are within the scope of the present invention. For example, in cases where a -OH substituent is allowed on a heteroaromatic ring and keto-enolic tautomerism is possible, it is understood that the substituent may in fact be present, in whole or in part, in the oxo form (= 0).
[046] A stable compound is a compound that can be prepared and isolated and whose structure and properties remain or can be left essentially unchanged for a period of time sufficient to allow the use of the compound for the purposes described in the present invention (for example , therapeutic or prophylactic administration to an individual). The compounds of the present invention are limited to stable compounds covered by Formula I and its modalities. For example, certain moieties, as defined in Formula I, may be unsubstituted or substituted, and the latter is intended to cover substitution patterns (ie, number and type of substituents) that are chemically possible for the moiety and that result in a compound stable.
[047] Each compound of Formula I consists of a phosphonamide
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20/84 having a defined chiral center (/ ) In the alkyl ether linking group that binds the nucleobase to phosphorus as shown in Formula I, and may have one or more additional chiral centers depending on the selection of the substituent. For example, each of the compounds of Examples 1 to 14 here has an asymmetric phosphorus center. Consequently, a compound of Formula I can have multiple chiral centers (also referred to as asymmetric or stereogenic centers). This invention encompasses compounds of Formula I having stereo-configuration (/ ) Or (S) in an asymmetric phosphorus center and any additional asymmetric centers that may be present in a Formula I compound, as well as stereoisomeric mixtures thereof. .
[048] This invention includes individual diastereomers, particularly epimers, that is, compounds having the same chemical formula, but which differ in the spatial arrangement around a single atom. This invention also includes mixtures of diastereomers, particularly mixtures of epimers, in all proportions. The embodiments of this invention also include a mixture of epimers enriched with 51% or more of one epimer, including, for example, 60% or more, 70% or more, 80% or more or 90% or more of an epimer. A single epimer is preferred. An individual or single epimer refers to an epimer obtained by chiral synthesis and / or using commonly known separation and purification techniques, and which may be 100% of an epimer or may contain small amounts (for example, 10% or less) of the epimer opposite. Thus, individual diastereomers are an object of this invention in pure form, as levorotatory antipodes and as dextrorotatory antipodes, in the form of racemates and in the form of mixtures of two diastereomers in all proportions. In the case of a cis / trans isomerism, this invention includes both the cis and trans forms, as well as mixtures of these forms in all proportions.
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21/84 [049] The preparation of individual stereoisomers can be carried out, if desired, by separating a mixture by usual methods, for example by chromatography or crystallization, by using stereochemically uniform starting materials for synthesis or by stereoselective synthesis. Optionally, a derivation can be performed before a separation of stereoisomers. The separation of a mixture of stereoisomers can be carried out in an intermediate step during the synthesis of a compound of Formula I or it can be done in a final racemic product. The absolute stereochemistry can be determined by X-ray crystallography of crystalline products or crystalline intermediates that are derived, if necessary, with a reagent containing a stereogenic center of known configuration. Alternatively, the absolute stereochemistry can be determined by analysis of Vibrational Circular Dichroism (VCD) spectroscopy. The present invention includes all of these isomers, as well as salts, solvates (which includes hydrates), and solvated salts of such racemates, enantiomers, diastereomers and tautomers and mixtures thereof.
[050] Atoms in a Formula I compound may exhibit their natural isotopic abundances, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature. The present invention is intended to include all suitable isotopic variations of the compounds of Formula I; for example, different isotopic forms of hydrogen (H) include protium ( ^Χ Η) and deuterium ( ² H). The protium is the hydrogen isotope predominantly found in nature. Deuterium enrichment may provide certain therapeutic advantages, such as increasing in vivo half-life or reducing dosage requirements, or
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22/84 provide a compound useful as a standard for characterizing biological samples. The isotopically enriched compounds of Formula I can be prepared without undue experimentation by conventional techniques well known to those skilled in the art or by processes analogous to those described herein in the schemes and Examples using appropriate isotopically enriched reagents and / or intermediates.
[051] The compounds can be administered in the form of pharmaceutically acceptable salts. The term pharmaceutically acceptable salt refers to a salt that is not biologically or otherwise undesirable (for example, it is not toxic or otherwise harmful to its recipient). Since the compounds of Formula I contain, by definition, at least one basic group, this invention includes the corresponding pharmaceutically acceptable salts. When compounds of Formula I contain one or more acidic groups, the invention also includes the corresponding pharmaceutically acceptable salts. Thus, compounds of Formula I that contain acidic groups (for example, -COOH) can be used according to the invention as, for example, but not limited to alkali metal salts, alkaline earth metal salts or as ammonium salts. Examples of such salts include, but are not limited to, sodium salts, potassium salts, calcium salts, magnesium salts or salts with ammonia or organic amines such as, for example, ethylamine, ethanolamine, triethanolamine or amino acids. The compounds of Formula I, which contain one or more basic groups, that is, groups that can be protonated, can be used according to the invention in the form of their acid addition salts with organic or inorganic acids such as, for example, but not limited to salts with hydrogen chloride, hydrogen bromide, phosphoric acid, sulfuric acid, nitric acid, benzenesulfonic acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalenedisulfonic acids,
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23/84 oxalic acid, acetic acid, trifluoroacetic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, formic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pyelic acid, fumaric acid, maleic acid , malic acid, sulfaminic acid, phenylpropionic acid, glyconic acid, ascorbic acid, isonicotinic acid, citric acid, adipic acid, etc. If the compounds of Formula I contain both acidic and basic groups in the molecule, the invention also includes, in addition to the salt forms mentioned, internal salts or betaines (zwitterions). Salts can be obtained from the compounds of Formula I by usual methods that are known to the person skilled in the art, for example, by combining with an organic or inorganic acid or base in a solvent or dispersant, or by anionic or cationic exchange other salts. The present invention also includes all salts of the compounds of Formula I which, due to low physiological compatibility, are not directly suitable for use in pharmaceutical products, but which can be used, for example, as intermediates for chemical reactions or for the preparation of pharmaceutically acceptable salts.
[052] The present invention encompasses any composition comprised of a compound of Formula I or a compound that is a salt thereof, including, for example, but not limited to a composition comprising said compound associated together with one or more molecular components and / or additional ions that can be referred to as a co-crystal. The term co-crystal, as used in the present invention, refers to a solid phase (which may or may not be crystalline) in which two or more different molecular and / or ionic components (usually in a stoichiometric ratio) are held together by nonionic interactions including, but not limited to, hydrogen bonding, dipole-dipole interactions, dipole-quadrupole interactions or dispersion forces
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24/84 (van der Waals). There is no transfer of protons between the dissimilar components and the solid phase, it is not a simple salt or a solvate. A discussion of co-crystals can be found, for example, in S. Aitipamula et al., Crystal Growth and Desing, 2012, 12 (5), pages 2147 - 2152.
[053] More specifically with reference to this invention, a co-crystal consists of a compound of Formula I or a pharmaceutically acceptable salt thereof, and one or more non-pharmaceutically active components that are not biologically or otherwise undesirable (for example, example, it is not toxic or otherwise harmful to its recipient). Co-crystals can be obtained from a compound of Formula I, or a pharmaceutically acceptable salt thereof, by usual methods known in the chemical arts. For example, co-crystals comprised of a compound of this invention can be prepared by adding an acid or neutral molecule in the desired stoichiometry to the compound, adding an appropriate solvent to obtain dissolution and, for example, precipitating, lyophilizing or concentrating the solution to obtain the solid composition. The co-crystal can be, but is not limited to, a modality in which the composition consists of a neutral compound (i.e., not a salt form) of Formula I and one or more non-pharmaceutically active components; and in another embodiment, the co-crystal composition is crystalline. Crystalline compositions can be prepared, for example, by adding an acid or neutral molecule in the desired stoichiometry to the compound of Formula I, adding an appropriate solvent and heating to obtain complete dissolution, and then allowing the solution cool and crystallize to grow. The present invention also includes all co-crystals of the compounds of this invention which, due to low physiological compatibility, are not directly suitable for use in pharmaceutical products, but which can be used, for example,
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25/84 example, as intermediates for chemical reactions or for the preparation of co-crystals or pharmaceutically acceptable salts.
[054] In addition, the compounds of the present invention can exist in amorphous form and / or one or more crystalline forms, and as such, all amorphous and crystalline forms, and mixtures thereof, of the compounds of Formula I, and salts thereof , are intended to be included within the scope of the present invention. In addition, some of the compounds of the present invention can form solvates with water (i.e., a hydrate) or common organic solvents. Such solvates and hydrates, particularly the pharmaceutically acceptable solvates and hydrates, of the compounds of this invention are likewise included within the scope of the compounds defined by Formula I and the pharmaceutically acceptable salts thereof, together with unsolvated and anhydrous forms of such compounds.
[055] Consequently, the compounds of Formula I or salts thereof, including pharmaceutically acceptable salts thereof, their modalities and specific compounds described and claimed in the present invention, encompass stereoisomers, tautomers, physical forms (for example, amorphous and crystalline forms) , co-crystal forms, solvate and hydrate forms, and any combination of the above forms where such forms are possible.
[056] The compounds of Formula I described here are prodrugs. A debate on prodrugs is provided in (a) Stella, V. J .; Borchardt, R. T .; Hageman, M. J .; Oliyai, R .; Maag, H. et al. Pro-drugs: Challenges and Rewards Part 1 and Part 2; Springer, p. 726: New York, NY, USA, 2007, (b) Rautio, J .; Kumpulainen, H .; Heimbach, T .; Oliyai, R .; Oh, D. et al. Prodrugs: design and clinical applications. Nat. Rev. Drug Discov. 2008, 7, 255, (c) T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems (1987) 14 by A.C.S. Symposium Series, and (d) Bioreversible Carriers in Drug Design, (1987) Edward B. Roche, ed., American
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Pharmaceutical Association and Pergamon Press. More specifically, the compounds of Formula I and pharmaceutically acceptable salts thereof (or any modality thereof) are modifications of tenofovir prodrugs, which is a monophosphonate. The compounds described herein can be converted intracellularly (in vivo or in vitro) to the corresponding tenofovir monophosphate or diphosphate. Conversion can take place by one or more mechanisms, for example, an enzyme-catalyzed chemical reaction, a metabolic chemical reaction and / or a spontaneous chemical reaction (eg, solvolysis), such as, for example, through hydrolysis in the blood. While not wishing to be bound by any particular theory, tenofovir diphosphate is generally understood to be responsible for inhibiting the HIV RT enzyme and for the resulting antiviral activity after administration of the Formula I compound, or a pharmaceutically acceptable salt thereof, to a individual.
[057] Another embodiment of the present invention is a compound of Formula I in which the compound or its salt is in a substantially pure form. As used in the present invention substantially pure means suitably at least about 60% by weight, typically at least about 70% by weight, preferably at least about 80% by weight, more preferably at least about 90% by weight (e.g. for example, from about 90% by weight to about 99% by weight), even more preferably at least about 95% by weight (for example, from about 95% by weight to about 99% by weight, or about 98% by weight to 100% by weight), and most preferably at least about 99% by weight (e.g., 100% by weight) of a product containing a compound of Formula I or its salt (e.g. the product isolated from a reaction mixture providing the compound or salt) consisting of the compound or salt. The level of purity of the compounds and salts can be determined using a standard method of analysis
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27/84 such as, high performance liquid chromatography and / or mass spectrometry or NMR techniques. If more than one method of analysis is used and the methods provide experimentally significant differences in the determined purity level, then the method that provides the highest purity level governs. A 100% pure compound or salt is one that is free of detectable impurities as determined by a standard method of analysis. With respect to a compound of the invention that has one or more asymmetric centers and can occur as mixtures of stereoisomers, a substantially pure compound can be a substantially pure mixture of the stereoisomers or a substantially pure individual stereoisomer.
[058] The compounds of Formula I and the pharmaceutically acceptable salts thereof are useful for inhibiting HIV reverse transcriptase and for inhibiting HIV replication in vitro and in vivo. More particularly, the compounds of Formula I are useful for inhibiting HIV-1 reverse transcriptase polymerase function. The testing of the compounds of the Examples of this invention in the Viking assay shown in Example 15 below, illustrates the ability of the compounds of the invention to inhibit the RNA-dependent DNA polymerase activity of HIV-1 reverse transcriptase. The compounds of Formula I can also be useful agents against HIV-2. The compounds of Examples 1 to 14 of the present invention may also exhibit activity against forms resistant to HIV drugs (for example, NNRTI-associated K103N and / or Y181C mutant strains; NRTI-associated mutant M184V and M184I mutant strains).
[059] This invention also encompasses methods for the treatment or prophylaxis of HIV infection, for the inhibition of HIV reverse transcriptase, for the treatment, prophylaxis or delay in the onset of AIDS in an individual in need thereof, which comprise administering to the individual an effective amount of a compound of the invention or a pharmaceutically salt
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28/84 acceptable.
[060] This invention also encompasses methods for the treatment or prophylaxis of HIV infection, for the inhibition of HIV reverse transcriptase, for the treatment, prophylaxis or delay in the onset of AIDS in an individual in need thereof, which comprise administering to the individual an effective amount of a compound of the invention or a pharmaceutically acceptable salt thereof in combination with an effective amount of one or more additional anti-HIV agents selected from the group consisting of HIV antiviral agents, immunomodulators and anti-infective agents. Within this modality, the anti-HIV agent is an antiviral selected from the group consisting of HIV protease inhibitors, HIV reverse transcriptase inhibitors, HIV integrase inhibitors, HIV fusion inhibitors, HIV entry inhibitors and inhibitors of maturation of HIV.
[061] This invention encompasses a pharmaceutical composition comprising an effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. The invention also encompasses a pharmaceutical composition comprising an effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier further comprising an effective amount of one or more additional anti-HIV agents selected from the group consisting of HIV antiviral agents, immunomodulators and anti-infectious agents. Within this modality, the anti-HIV agent is an antiviral selected from the group consisting of HIV protease inhibitors, HIV reverse transcriptase inhibitors, HIV integrase inhibitors, HIV fusion inhibitors, HIV entry inhibitors and inhibitors of maturation of HIV.
[062] The compounds of this invention can also be useful for the
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29/84 inhibition of HBV reverse transcriptase. Accordingly, this invention also encompasses methods for the treatment of chronic hepatitis B which comprise administering to the individual an effective amount of a compound of the invention or a pharmaceutically acceptable salt thereof.
[063] This invention also encompasses a compound of the invention, or a pharmaceutically acceptable salt thereof, for use in the preparation of a medicament for the treatment or prophylaxis of HIV infection, for the inhibition of HIV reverse transcriptase, or for the treatment, prophylaxis or delay in the onset of AIDS in an individual in need.
[064] Other embodiments of the present invention include the following (where the reference to Formula I covers the compounds of Formula I, Ia or Ib and each of the modalities, classes and subclasses thereof, and each of the compounds of the Examples contained herein invention):
(a) a pharmaceutical composition comprising an effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
(b) a pharmaceutical composition comprising the product prepared by combining (for example, mixing) an effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
(c) the pharmaceutical composition of (a) or (b), further comprising an effective amount of one or more anti-HIV agents selected from the group consisting of HIV antiviral agents, immunomodulators and anti-infectious agents.
(d) the pharmaceutical composition of (c), wherein the anti-HIV agent is selected from one or more of an antiviral selected from the group consisting of HIV protease inhibitors, nucleoside transcriptase inhibitors
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30/84 HIV reverse, non-nucleoside HIV reverse transcriptase inhibitors, HIV integrase inhibitors, HIV fusion inhibitors, HIV entry inhibitors and HIV maturation inhibitors.
(e) A combination that is (i) a compound of Formula I or a pharmaceutically acceptable salt thereof and (ii) an anti-HIV agent selected from the group consisting of HIV antiviral agents, immunomodulators and anti-infective agents; wherein the compound and the anti-HIV agent are each used in an amount that makes the combination effective for inhibiting HIV reverse transcriptase, for the treatment or prophylaxis of HIV infection, or for the treatment, prophylaxis or delayed onset or progression of AIDS.
(f) The combination of (e), wherein the anti-HIV agent is an antiviral selected from the group consisting of HIV protease inhibitors, nucleoside HIV reverse transcriptase inhibitors, non-nucleoside HIV reverse transcriptase inhibitors, inhibitors of HIV integrase, HIV fusion inhibitors, HIV entry inhibitors and HIV maturation inhibitors.
(g) A method for inhibiting HIV reverse transcriptase in an individual in need thereof, which comprises administering to the individual an effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof.
(h) A method for the prophylaxis or treatment of HIV infection (for example, HIV-1) in an individual in need thereof, which comprises administering to the individual an effective amount of a Formula I compound or pharmaceutically acceptable salt of the same.
(i) The method of (h), wherein the compound of Formula I or a pharmaceutically acceptable salt thereof is administered in combination with an effective amount of at least one other HIV antiviral selected from the group consisting of protease inhibitors of the HIV, integrase inhibitors of
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HIV, non-nucleoside HIV reverse transcriptase inhibitors, HIV nucleoside reverse transcriptase inhibitors, HIV fusion inhibitors, HIV entry inhibitors and HIV maturation inhibitors.
(j) A method for the prophylaxis, treatment or delay in the onset or progression of AIDS in an individual in need thereof, which comprises administering to the individual an effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof.
(k) The method of (j), wherein the compound is administered in combination with an effective amount of at least one other HIV antiviral selected from the group consisting of HIV protease inhibitors, HIV integrase inhibitors, non-HIV inhibitors HIV reverse transcriptase nucleosides, HIV reverse transcriptase nucleosides, HIV fusion inhibitors, HIV entry inhibitors and HIV maturation inhibitors.
(l) A method for inhibiting HIV reverse transcriptase in an individual in need thereof, which comprises administering to the individual the pharmaceutical composition of (a), (b), (c) or (d) or the combination of (e) or (f).
(m) A method for the prophylaxis or treatment of HIV infection (for example, HIV-1) in an individual in need thereof, which comprises administering to the individual the pharmaceutical composition of (a), (b), (c) or (d) or the combination of (e) or (f).
(n) A method for the prophylaxis, treatment, or delay in the onset or progression of AIDS in an individual in need of it, which comprises administering to the individual the pharmaceutical composition of (a), (b), (c) or ( d) or the combination of (e) or (f).
[065] The present invention also includes compounds of Formula I, Ia or Ib and each of its modalities, classes and subclasses, and each of
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32/84 compounds of the Examples contained herein, or pharmaceutically acceptable salts of the foregoing, (i) for use in, (ii) for use as a medicament for, or (iii) for use in the preparation of a medicament for: ( a) therapy (for example, from the human body), (b) medication, (c) inhibition of HIV reverse transcriptase, (d) treatment or prophylaxis of HIV infection, or (e) treatment, prophylaxis or delay in onset or progression of AIDS. In these uses, the compounds of the present invention can optionally be used in combination with one or more anti-HIV agents selected from HIV antiviral agents, anti-infective agents and immunomodulators.
[066] Additional embodiments of the present invention include each of the compounds of Formula I, and pharmaceutical compositions, combinations, methods and uses presented in the preceding paragraphs, wherein the compound or its salt used in it is substantially pure. With respect to a pharmaceutical composition comprising a compound of Formula I or its salt and a pharmaceutically acceptable carrier and optionally one or more excipients, it is understood that the term substantially pure refers to a compound of Formula I or its own salt.
[067] Still further embodiments of the present invention include the pharmaceutical compositions, combinations and methods presented in (a) to (n) above and the uses (i) (a) to (e) through (iii) (a) to (e ) presented above, where the HIV of interest is HIV-1. Thus, for example, in the pharmaceutical composition (d), the compound of Formula I is used in an amount effective against HIV-1 and the anti-HIV agent is an HIV-1 antiviral selected from the group consisting of HIV protease inhibitors. HIV-1, HIV-1 reverse transcriptase inhibitors, HIV-1 integrase inhibitors, HIV-1 fusion inhibitors, HIV-1 entry inhibitors and HIV-1 maturation inhibitors.
[068] In all modalities etc., contained in the present invention, the
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The compound can optionally be used in the form of a pharmaceutically acceptable salt.
[069] The term administration and its variants (for example, administering a compound) in reference to a compound of Formula I means providing the compound to the individual in need of treatment or prophylaxis and includes both self-administration and administration to the patient by another person. When a compound is supplied in combination with one or more other active agents (for example, antiviral agents useful for the treatment or prophylaxis of HIV or AIDS infection), administration and its variants are understood to include delivery of the compound and other agents at the same time or at different times. When agents of a combination are administered at the same time, they can be administered together in a single composition or they can be administered separately.
[070] As used in the present invention, the term composition is intended to encompass a product comprising the specified ingredients, as well as any product that results from the combination of the specified ingredients. Suitable ingredients for inclusion in a pharmaceutical composition are pharmaceutically acceptable ingredients, which means that the ingredients must be compatible with each other and not harmful to your recipient.
[071] The term individual or patient, as used in the present invention, refers to an animal, preferably a mammal, most preferably a human, that has been the object of treatment, observation or experiment.
[072] The term effective amount, as used in the present invention, means an amount of a compound sufficient to inhibit transcriptase
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34/84 HIV, inhibit HIV replication, exert a prophylactic effect and / or exert a therapeutic effect after administration. An effective amount modality is a therapeutically effective amount which is an amount of a compound that is effective to inhibit HIV reverse transcriptase, inhibit HIV replication (any of the above which can also be referred to here as an effective inhibition amount ), treat HIV infection, treat AIDS, delay the onset of AIDS and / or delay the progression of ARC or AIDS in an HIV-infected patient. Another embodiment of an effective amount is a prophylactically effective amount which is an amount of the compound that is effective for prophylaxis of HIV infection in an individual not infected with HIV or prophylaxis of ARC or AIDS in an HIV-infected patient. It is understood that an effective amount can be both a therapeutically effective amount, for example, for the treatment of HIV infection, and a prophylactically effective amount, for example, for preventing or reducing the risk of developing AIDS in an HIV-infected individual. . The term prevention, as used in the present invention, with respect to a viral infection with HIV or AIDS, refers to reducing the likelihood or severity of HIV or AIDS infection. When the compound of Formula I is administered as a salt, reference to an amount of the compound in milligrams or grams is based on the free form (i.e., the non-saline form) of the compound. In the combination therapies of the present invention, an effective amount can refer to each individual agent or the combination as a whole, where the amounts of all agents administered in the combination are effective together, but where an agent component of the combination may or may not be present individually in an effective amount with reference to what is considered effective for that component agent if administered alone.
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35/84 [073] In the method of the present invention (i.e., inhibiting HIV reverse transcriptase, HIV infection treatment or prophylaxis, inhibiting HIV replication, AIDS treatment or prophylaxis, delaying the onset of AIDS or delaying or slow the progression of AIDS), the compounds of this invention, optionally in the form of a salt, can be administered by means that produce contact between the active agent and the agent's site of action. They can be administered by conventional means available for use in conjunction with pharmaceutical products, as individual therapeutic agents or in a combination of therapeutic agents. They can be administered alone, but are typically administered with a pharmaceutical carrier selected based on the chosen route of administration and standard pharmaceutical practice. The compounds of the invention can, for example, be administered orally (for example, via tablet or capsule), parenterally (including subcutaneous, intravenous, intramuscular injections or intrasternal injection, or infusion techniques), by inhalation spray, or rectally, into a unit dosage form of a pharmaceutical composition containing an effective amount of the compound and conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles. The compound can also be administered via an implantable drug delivery device adapted to provide an effective amount of the compound or a pharmaceutical composition of the compound over an extended period of time, for example, but not limited to, over the course of a month, 3 months, 6 months or a year.
[074] Solid preparations suitable for oral administration (for example, powders, pills, capsules and tablets) can be prepared according to techniques known in the art and can use such solid excipients as starches, sugars, kaolin, lubricants, binders, disintegrating agents and
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36/84 similar. Liquid preparations suitable for oral administration (for example, suspensions, syrups, elixirs and the like) can be prepared according to techniques known in the art and can use any of the usual means, such as water, glycols, oils, alcohols and the like . Parenteral compositions can be prepared according to techniques known in the art and typically use sterile water as a carrier and, optionally, other ingredients, such as a solubility aid. Injectable solutions can be prepared according to methods known in the art in which the carrier comprises a saline solution, a glucose solution or a solution containing a mixture of saline and glucose. Implantable compositions can be prepared according to methods known in the art in which the vehicle comprises the active chemical ingredient with polymers as suitable excipients, or using an implantable drug delivery device. Other descriptions of suitable methods for use in the preparation of pharmaceutical compositions for use in the present invention and of ingredients suitable for use in said compositions is provided in Remington's Pharmaceutical Sciences, 18th edition, edited by AR Gennaro, Mack Publishing Co., 1990 and in Remington - The Science and Practice of Pharmacy, 22- Edition, published by Pharmaceutical Press and Philadelphia College of Pharmacy at University of the Sciences, 2012, ISBN 978 0 85711-062-6 and earlier editions.
[075] Formulations of the compounds described by Formula I that result in drug supersaturation and / or rapid dissolution can be used to facilitate absorption of the oral drug. Formulation methods for causing drug supersaturation and / or rapid dissolution include, but are not limited to, nanoparticulate systems, amorphous systems, solid solutions, solid dispersions and lipid systems. Such formulation methods and techniques
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37 / ZA for its preparation are well known in the art. For example, solid dispersions can be prepared using excipients and processes as described in the reviews (for example, A.T.A. Serajuddin, J Pharm Sei, 88:10, pages 1058 1066 (1999)). Nanoparticulate systems based on friction and direct synthesis have also been described in reviews such as Wu et al. (F. Kesisoglou, S. Panmai, Y. Wu, Advanced Drug Delivery Reviews, 59: 7 pages 631 - 644 (2007)).
[076] Formula I compounds can be administered in a dosage range of 0.001 to 1,000 mg / kg of mammalian body weight (eg, human) per day, or at longer intervals on non-consecutive days as appropriate, in a single dose or in divided doses. An example of a dosage range is 0.01 to 500 mg / kg of body weight per day or at other intervals as appropriate, administered orally or via other routes of administration in a single dose or in divided doses. Another example of a dosage range is 0.1 to 100 mg / kg body weight per day or at other intervals as appropriate, administered orally or via other routes of administration in single or divided doses. Another example of a dosage range is 50 mg to 1 g per day, in a single dose or divided doses.
[077] Daily or weekly administration or less frequent dosing regimens with longer time intervals on non-consecutive days (as discussed below), can be via any suitable route of administration, for example, but not limited to, oral or parenteral. Daily or weekly administration is preferably via oral administration. For a daily or weekly dosing regimen, on each day (calendar day or about a 24-hour time period) of drug administration (the day of administration), the desired dosage amount can be administered once daily administration or in divided dosage amounts
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38/84 administered at two or more times staggered during the day of administration, for example, a first administration followed about 12 hours later with a second administration over the course of a day of administration (the time (s) ) dosage). The desired dosage amount at each of one or more dosing times in a day of administration can be administered via an oral dosing unit such as a tablet, or more than one oral dosing unit as appropriate. Preferably administration is through a single oral dosage unit, for example, a tablet, once a day of administration.
[078] For weekly or less frequent dosing regimens with longer time intervals on non-consecutive days, a parenteral route of administration can be used. Examples of dosing regimens with longer time intervals on non-consecutive days include, but are not limited to, weekly administration (every seventh day with tolerance for the exact dosing date), fortnightly (every two weeks with tolerance for the date exact dosage), monthly (for example, every 30 days, or the same calendar day every month with tolerance for the exact dosing date), bimonthly (for example, every 60 days, or the same calendar day every two months with tolerance for the exact dosage date), every 3 months (for example, every 90 days, or the same calendar day every three months with tolerance for the exact dosage date), every six months (for example, every 180 days, or the same calendar day every six months with tolerance for the exact dosing date) or annually (for example, every 12 months with tolerance for the exact annual dosing date). Tolerance is intended to mean that the dosage regimens described herein also cover those in which the patient generally follows the time intervals between days of administration including when
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39/84 interval is not always strictly followed by the patient, for example, a weekly dosing regimen where the patient can take the drug product the day before or the day after the seventh day after the day of the previous administration for one or more weeks . The tolerance time may increase as the dosing regimen interval increases.
[079] For oral use (eg, tablets or capsules) or other routes of administration, dosage units may contain 1.0 mg to 1,000 mg of the active ingredient, for example, but not limited to, 1, 5, 10 , 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, 900 or 1,000 milligrams of the active ingredient for symptomatic adjustment of the dosage to the patient to be treated. In addition, the compound can be formulated into oral formulations for immediate or modified release such as prolonged or controlled release.
[080] The favorable pharmacokinetic profile of the tested compounds of this invention can also make the compounds suitable for less frequent dosages. Thus, the compounds of the invention can be administered orally, weekly or parenterally at longer intervals as described above. For parenteral administration, the compositions can be administered, for example, intravenously (IV) or intramuscularly (IM) via injection, or using other infusion techniques. One or more of such injections or infusions can be administered at each dosing time interval as needed to provide the appropriate amount of active agent. The compound can also be administered subcutaneously using an implantable device. For parenteral administration including implantable devices using long-term dosing intervals such as monthly intervals, every 3 months, every 6 months, yearly or longer, the dosage amount would be adjusted upward as needed to
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40/84 provide effective treatment during the time intervals between the administration of each dose.
[081] The specific dose level and dosing frequency for any particular patient can be varied and will depend on a variety of factors including the activity of the specific compound used, the metabolic stability and duration of action of that compound, age, weight body weight, general health, sex, diet, mode and time of administration, rate of excretion, combination of drugs, the severity of the particular condition and the host in therapy. In some cases, depending on the potency of the compound or the individual response, it may be necessary to deviate upwards or downwards from the given dose. The amount and frequency of administration will be regulated according to the judgment of the attending physician considering such factors.
[082] As noted above, the present invention is also directed to the use of a compound of Formula I with one or more anti-HIV agents. An anti-HIV agent is any agent that is directly or indirectly effective in inhibiting HIV, the treatment or prophylaxis of HIV infection and / or the treatment, prophylaxis or delay in the onset or progression of AIDS. An anti-HIV agent is understood to be effective in treating, preventing or delaying the onset or progression of HIV or AIDS infection and / or associated or associated diseases or conditions. For example, the compounds of this invention can be effectively administered, either in periods of pre-exposure and / or post-exposure to HIV, in combination with effective amounts of one or more anti-HIV agents selected from HIV antiviral agents, immunomodulators, anti- infectious or vaccines useful to treat HIV infection or AIDS. HIV antivirals suitable for use in combination with the compounds of the present invention include, for example, those listed in Table A as follows:
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Table A: Antiviral agents to treat HIV or AIDS infection
Name Type abacavir, abacavir sulfate, ABC, Ziagen® nRTI abacavir + lamivudine, Epzicom® nRTI abacavir + lamivudine + zidovudine, Trizivir® nRTI amprenavir, Agenerase® PI atazanavir, atazanavir sulfate, Reyataz® PI AZT, zidovudine, azidothymidine, Retrovir® nRTI capravirin nnRTI darunavir, Prezista® PI ddC, zalcitabine, didesoxycytidine, Hivid® nRTI ddl, didanosine, didesoxy-inosine, Videx® nRTI ddl (enterically coated), Videx EC® nRTI delavirdine, delavirdine mesylate, DLV, Rescriptor® nnRTI dolutegravir, Tivicay® Inl doravirin, MK-1439 nnRTI efavirenz, EFV, Sustiva®, Stocrin® nnRTI EFdA (4'-ethynyl-2-fluoro-2'-deoxyadenosine) nRTI elvitegravir Inl emtricitabine, FTC, Emtriva® nRTI emivirine, Coactinon® nnRTI enfuvirtide, Fuzeon® Fl enterically coated didanosine, Videx EC® nRTI etravirine, TMC-125 nnRTI fosamprenavir calcium, Lexiva® PI indinavir, indinavir sulfate, Crixivan® PI
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lamivudine, 3TC, Epivir® nRTI lamivudine + zidovudine, Combivir® nRTI lopinavir PI lopinavir + ritonavir, Kaletra® PI maraviroc, Selzentry® El nelfinavir, nelfinavir mesylate, Viracept® PI nevirapine, NVP, Viramune® nnRTI PPL-100 (also known as PL-462) (Ambrilia) PI raltegravir, MK-0518, Isentress ™ Inl rilpivirine nnRTI ritonavir, Norvir® PI saquinavir, saquinavir mesylate, Invirase®, Fortovase® PI stavudine, d4T, dideshydrodeoxythymidine, Zerit® nRTI tipranavir, Aptivus® PI vicriviroc El
El = entry inhibitor; Fl = fusion inhibitor; Ini = integrase inhibitor; PI = protease inhibitor; nRTI = nucleoside reverse transcriptase inhibitor; nnRTI = non-nucleoside reverse transcriptase inhibitor. Some of the drugs listed in the table are used in a salt form; for example, abacavir sulfate, delavirdine mesylate, indinavir sulfate, atazanavir sulfate, nelfinavir mesylate, saquinavir mesylate.
[083] It is understood that the scope of combinations of the compounds of this invention with anti-HIV agents is not limited to the HIV antivirals listed in Table A, but in principle includes any combination with any pharmaceutical composition useful for the treatment or prophylaxis of AIDS. HIV antiviral agents and other agents will typically be used in these combinations in their conventional ranges and dosing regimens as reported
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43/84 in the art, including, for example, the dosages described in the Physicians' Desk Reference current, Thomson PDR, 70 edition (2016), Montvale, NJ: PDR Network, or earlier editions thereof. The dosage ranges for a compound of the invention in these combinations can be the same as those shown above.
[084] The compounds of this invention are also useful in the preparation and execution of screening assays for antiviral compounds. For example, the compounds of this invention may be useful for isolating enzyme mutants, which are excellent screening tools for more powerful antiviral compounds. In addition, the compounds of this invention may be useful in establishing or determining the binding site of other antivirals to HIV reverse transcriptase, for example, by competitive inhibition.
[085] Abbreviations and acronyms used here include the following:
B.C Acetyl mg milligrams aq Aqueous MHz megahertz AUC Area under the curve min minute Bu Butila μί microliters Bz Benzoyl mL milliliters DBU 1.8-Diazabicycle [5.4.0] undec-7-eno mmol millimol DCM dichloromethane MS spectrometrypastas DHP 3,4-dihydro-2H-pyran NHS normal human serum DlEAouDIPEAorbasis of Λ /, / V-diisopropylethylamine NMR nuclear magnetic resonance spectroscopy
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Hünig DMF dimethylformamide PBMC mononuclear cell ofperipheral blood DMAP 4-Dimethylaminopyridine DMSO dimethyl sulfoxide Ph phenyl EDCI orEDC / / - Ethyl - / / '- (3dimethylaminopropyl) carbodiimide hydrochloride POWDER. oral PE Petroleum ether Et Ethyl PTSA acid para-toluenesulfonic EtOH Ethanol Pr propyl EtOAc ethyl acetate RT or rt room temperature(environment, about 25° C) e.g. for example sat orsat'd saturated g grams Gl gastrointenstinal ACN acetonitrile H Hour SFC supercritical fluid chromatography HIV human immunodeficiency virus tBu tert-butyl HPBCD Hydroxypropyl-βcyclodextrin TEA triethylamine (EtsN) HPLC liquid chromatographyhigh performance TEMED tetramethylethylenediamine Hz hertz TFA trifluoroacetic acid IPA isopropanol TFV Tenofovir
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IV intravenous TFV-MP Tenofovir monophosphate iPr isopropyl TFV-DP Tenofovir diphosphate L liter THF tetrahydrofuran LC liquid chromatography TMS tetramethylsilane LC / MS liquid chromatography coupled to mass spectrometry UPLC liquid chromatographyultra high pressure Me methyl UV ultraviolet MeOH methanol UV / VIS ultraviolet / visible
[086] Various methods for preparing the compounds of this invention are described in the following Schemes and Examples. The starting materials and intermediates were purchased commercially from common catalog sources or were manufactured using known procedures or, as otherwise illustrated. Some routes frequently applied to compounds of Formula I are described in the schemes that follow. In some cases, the order of carrying out the reaction steps in the schemes can be varied to facilitate the reaction or to avoid unwanted reaction products.
SCHEME 1

R = m-CN or p-CI [087] Intermediate compounds of Formula Sl are prepared from (/ ) - (((l- (6-amino-9H-purin-9-yl) propan-2-yl) oxy) methyl) phosphonic, referred to here as TFV, with variably substituted phenols (for example, meta-CN or
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46/84 para-CI) in a one-step one-pot condensation reaction with 2,2'dipyridyldisulfide (aldrithiol), triphenylphosphine, and base, with p-chlorophenol and mycophenol being preferred. Amino esters that are not commercially available can be easily prepared by condensing the corresponding amino acid and alcohols with thionyl chloride.
SCHEME 2
[088] The subsequent reaction of S-1 with a corresponding hydroxy ester or mercapto ester in the presence of DBU base produces the products of Formula S2 of the present invention. The Formula S-2 products of the present invention can also be obtained in a two-step sequence. First, the intermediate compounds of Formula S-3 are prepared from intermediate compounds of Formula S-1 in the presence of DBU and H2O. Then, the subsequent reaction of S-3 with a corresponding hydroxy ester or mercapto ester in the presence of SOCI2 produces the products of Formula S-2 of the present invention.
[089] Reactions sensitive to moisture or air were carried out under nitrogen or argon using solvents and anhydrous reagents. The progress of the reactions was
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47/84 determined by analytical thin layer chromatography (TLC) usually performed with pre-coated E. Merck TLC plates, silica gel 60F-254, layer thickness 0.25 mm or liquid chromatography coupled to mass spectrometry (LC / MS).
[090] Typically, the analytical LC-MS system used consisted of a Waters ZQ ™ platform with electrospray ionization in positive ion detection mode with an Agilent HPLC 1100 with automatic sampler. The column was commonly a Waters C18 MS Xterra, 3.0 x 50 mm, 5 pm or a C18 BEH Waters Acquity UPLC® 1.0 x 50 mm, 1.7 pm. The flow rate was 1 mL / min, and the injection volume was 10 pL. The UV detection was in the range of 210 to 400 nm. The mobile phase consisted of solvent A (water plus 0.05% TFA) and solvent B (MeCN plus 0.05% TFA) with a gradient of 100% solvent A for 0.7 min changeable to 100% solvent B for 3.75 min, maintained for 1.1 min, then reverting to 100% solvent A for 0.2 min.
[091] Preparative HPLC purifications were usually performed using either a mass spectrometry-driven system or a non-mass guided system. Usually, they were performed in a Waters Chromatography Workstation configured with LC-MS System consisting of: ZQ ™ Waters single quad MS system with electrospray ionization, Waters2525 Gradient Pump, Waters 2767 Injector / Collector, Waters PDA 996 Detector, the MS Conditions: 150 to 750 amu, Positive Electrospray, Collection Triggered by MS, and a Waters C-18 SUNFIRE® column, 5 microns, 30 mm (id) x 100 mm. The mobile phases consisted of mixtures of acetonitrile (10 to 100%) in water containing 0.1% TFA. Flow rates were maintained at 50 mL / min, the injection volume was 1,800 pL, and the UV detection range was 210 to 400 nm. An alternate preparative HPLC system used was a Gilson Workstation consisting of: Gilson GX-281 Injector / Collector, UV / VIS Detector
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Gilson 155, Gilson 333 and 334 Pumps, and a Phenomenex C-18 GeminiNX column, 5 microns, 50 mm (id) x 250 mm or a Waters C-18 XBridge ™ column, 5 microns OBD ™, 30 mm (id) x 250 mm. The mobile phases consisted of mixtures of acetonitrile (0 to 75%) in water containing 5 mmol (NHziJHCOs. Flow rates were maintained at 50 mL / min for the Waters Xbridge ™ column and 90 mL / min for the Phenomenex Gemini column. The injection volume ranged from 1,000 to 8,000 μΙ_, and the UV detection range was 210 to 400 nm. Mobile phase gradients were optimized for individual compounds. Reactions performed using microwave irradiation were normally performed using an Optimizer Emrys manufactured by Personal Chemistry, or an Initiator manufactured by Biotage. The concentration of solutions was performed on a rotary evaporator under reduced pressure. Flash chromatography was usually performed using a Biotage® flash chromatography device (Dyax Corp.), an RF device CombiFlash® ISCO, or a Companion XL CombiFlash® ISCO in silica gel (32 to 63 μΜ, pore size 60 Å) in pre-packaged cartridges of the observed size. ¹ H NMR samples were acquired on 500 MHz spectrometers in CCD solutions unless otherwise noted. Chemical substitutions have been reported in parts per million (ppm). Tetramethylsilane (TMS) was used as an internal reference in CD3CI solutions, and residual CH3OH peak or TMS was used as an internal reference in CD3OD solutions. Coupling constants (J) have been reported in hertz (Hz). Chiral analytical chromatography was most commonly performed on CHIRALPAK® AS, CHIRALPAK® AD, CHIRALCEL® OD, CHIRALCEL® la or CHIRALCEL® OJ (250 x 4.6 mm) columns (Daicel Chemical Industries, Ltd.) with observed percentage of ethanol in hexane (% Et / Hex) or isopropanol in heptane (% IPA / Hep) as isocratic solvent systems. Preparative chiral chromatography was conducted on CHIRALPAK® AS, CHIRALPAK® AD, CHIRALCEL® OD,
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CHIRALCEL® IA, CHIRALCEL® OJ (20 x 250 mm) (Daicel Chemical Industries, Ltd.) with desired isocratic solvent systems identified in chiral analytical chromatography or by supercritical fluid (SFC) conditions.
[092] It is understood that a chiral center in a compound can exist in the S or R stereo configuration, or as a mixture of both. Within a molecule, each bond drawn as a straight line from a chiral center includes both stereoisomers (/ ) And (S) as well as mixtures of these. The compounds of the invention contained herein including those in Examples 1 to 14 contain a chiral phosphorus center. The isomer mixture in each of Examples 1 to 14 was separated, providing an Isomer #A, for example, Isomer IA (isomer with faster elution) and an Isomer #B, for example, Isomer 1B (isomer with slower elution ), based on their observed elution order resulting from the separation as performed in the Example. The time and / or order of elution of separate isomers may differ if performed under conditions other than those used here. The absolute stereochemistry (/ Or S) of the chiral phosphorus center in each of the separate stereoisomers A and B in Examples 1 to 6 and 8 to 14 has not been determined, and A and B refer only to the order of elution. The absolute stereochemistry (/ Or S) of the chiral phosphorus center was determined for each of the separate isomers A and B in Example 7. An asterisk (*) can be used in the associated chemical structure drawings of the exemplary compounds to indicate the center phosphorus chiral.
INTERMEDIATE A
NHo I NH ₂ HCI ^H0 ^ ~ ---------- y ° yV
SOC SOCI ₂ / -50 ° C ~ 80 ° C, 16h T Π ^X O ¹ O
INTERMEDIATE A [093] Isopropyl 2-amino-2-methylpropanoate hydrochloride: To a
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50/84 solution of 2-amino-2-methylpropanoic acid (20 g, 194 mmol) in propan-2-ol (200 mL) was added to the drops of thionyl chloride (98 g, 833 mmol) at -50 ° C. The reaction mixture was stirred at 80 ° C for 16 hours. The resulting reaction mixture was cooled to RT, and then concentrated under reduced pressure to provide a residue, which was triturated with diethyl ether to provide the title compound: ^{Å 8} NMR (400 MHz, DMSO-cfc) δ 8, 55 (brs, 3H), 4.98 (heptuplet, J = 6.25 Hz, 1H), 1.45 (s, 6H), 1.44 (s, 1H), 1.24 (d, J = 6 , 25 Hz, 6H).
INTERMEDIATE B
INTERMEDIATE B [094] Propyl 2-amino-2-methylpropanoate hydrochloride: To a solution of 2-amino-2-methylpropanoic acid (5 g, 48.5 mmol) in propan-l-ol (150 mL) at 0 ° C thionyl chloride (11.54 g, 97 mmol) was added to the drops. The reaction mixture was heated to 80 ° C overnight. The resulting reaction mixture was concentrated under reduced pressure to give a residue, which was triturated with diethyl ether to give the title compound: NMR H (400 MHz, DMSO-c / e) δ 8 61 (brs, 3H ), 4.13 (t, J = 6.40 Hz, 2H), 1.68 - 1.59 (m, 2H), 1.48 (s, 6H), 0.91 (t, J = 7, 43 Hz, 3H).
INTERMEDIATE C
INTERMEDIATE C [095] Pentyl 2-amino-2-methylpropanoate hydrochloride: To a solution of 2-amino-2-methylpropanoic acid (6 g, 58.2 mmol) in pentan-l-ol (100 mL) was added dropwise on RT thionyl chloride (17.31 g, 145 mmol). The mixture was heated to 95 ° C overnight. The resulting reaction mixture was
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51/84 concentrated under reduced pressure to provide a residue, which was triturated with diethyl ether to provide the title compound: ^Ã H NMR (400 MHz, DMSO-cfc) δ 8.68 (brs, 3H), 4.15 (t, J = 6.50 Hz, 2H), 1.65 - 1.58 (m, 2H), 1.48 (s, 6H), 1.33 - 1.29 (m, 4H), 0, 88 (t, J = 7.12 Hz, 3H).
INTERMEDIATE D
Method 1:
INTERMEDIATE D r _{1 =}
[096] Isopropyl 3-hydroxypropanoate: Step 1: To a solution of 3- (benzyloxy) propanoic acid (10.0 g, 55.5 mmol) in propan-2-ol (84 mL) in RT was added to the drops thionyl chloride (4.46 ml, 61 mmol). The reaction mixture was stirred at RT overnight. The reaction mixture was concentrated under reduced pressure and used directly in the next step without further purification. Step 2: To a solution of isopropyl 3- (benzyloxy) propanoate (11.99 g, 53.9 mmol) in propan-2-ol (130 mL) was added palladium hydroxide on carbon (1.8 g, 16 , 91 mmol). After 3 times of vacuum / nitrogen, the reaction mixture was stirred under hydrogen at RT overnight. The resulting mixture was filtered on a pad of CELITE® (diatomaceous earth), the filtrate was partially concentrated under reduced pressure, and then additional carbon palladium hydroxide (1.8 g, 16.91 mmol) was added. The reaction mixture was stirred under hydrogen at RT for 4 days. The resulting mixture was filtered on a CELITE® pad. The filtrate was concentrated under reduced pressure to provide the title compound. H NMR (400 MHz, DMSO-d ₆₎ δ 4.89 (heptupleto, J = 6.27 Hz, 1H), 4.64 (brs, 1H), 3.62 (t, J = 6.19 Hz, 2H), 2.38 (t, J = 6.19 Hz, 2H), 1.18 (d, J = 6.27 Hz, 6H).
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Method 2:
2 ^^^ ΟΗ K ₂ CO ₃ , Kl, DMF, 60 ° C, 16 h ^{0 0H}
INTERMEDIATE D [097] To a solution of 3-hydroxypropanoic acid (15 g, 167 mmol) in DMF (100 mL) were added 2-bromopropane (27 g, 216 mmol), potassium carbonate (58 g, 416 mmol) and potassium iodide (1 g, 8 mmol) in RT. The reaction mixture was stirred at 60 ° C for 16 hours. After cooling to RT, the reaction mixture was filtered and the filtrate was diluted with water (200 ml) and extracted with EtOAc (3 x 400 ml). The combined organic layers were washed with brine (3 x 100 ml), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the crude residue was purified by silica gel column chromatography (petroleum ether / EtOAc: 10% to 20%) to provide the title compound. H NMR (300 MHz, CDCH) δ 5.07 4.99 (m, 1H), 3.83 (t, J = 5.7 Hz, 2H), 2.51 (t, J = 5.7 Hz, 2H), 1.23 (d, J = 6.3 Hz, 6H).
INTERMEDIATE AND
[098] Isopropyl 3-hydroxy-2,2-dimethylpropanoate: Step 1: To a solution of 2,2-dimethyl-3- (trityloxy) propanoic acid (10 g, 27.7 mmol) and potassium carbonate (4 , 60 g, 33.3 mmol) in DMF (100 mL) at 0 ° C under nitrogen 2-bromopropane (3.13 mL, 33.3 mmol) was added. The reaction mixture was stirred at 60 ° C for 24 h, and then concentrated under reduced pressure. The crude residue was dissolved in water and ethyl acetate. The aqueous layer was washed three times with ethyl acetate, and the organic layers combined
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53/84 were dried and concentrated under reduced pressure to provide the expected compound. Step 2: To a solution of isopropyl 2,2-dimethyl-3- (trityloxy) propanoate (11 g, 27.3 mmol) in dioxane (10 mL) was added hydrochloric acid, 4M in dioxane (13.66 mL, 54.7 mmol). The reaction mixture was stirred at RT for 2 h, and then concentrated under reduced pressure. The crude residue was purified by flash chromatography on silica gel (DCM / MeOH) to provide the title compound. ^X H NMR (400 MHz, DMSO-c / e) δ 4.85 (heptuplet, J = 6.29 Hz, 1H), 4.74 (brs, 1H), 3.38 (s, 2H), 1 , 16 (d, J = 6.29 Hz, 6H), 1.04 (s, 6H).
INTERMEDIATE F
O
HO
ΌΗ
Potassium carbonate
2-bromopropane
DMF
HO ’
INTERMEDIATE F [099] l- (Hydroxymethyl) cyclopropane-l-carboxylate ______ of______isopropyl:
INTERMEDIATE F was synthesized according to the previous scheme and to that step 1 of the method described for the synthesis of INTERMEDIARY E starting from l- (hydroxymethyl) cyclopropane-l-carboxylic acid to provide the title compound. ^X H NMR (400 MHz, DMSO-cfc) δ 4.85 (heptuplet, J = 6.24 Hz, 1H), 4.56 (t, J = 5.76 Hz, 1H), 3.54 (d , J = 5.76 Hz, 2H), 1.15 (d, J = 6.24 Hz, 6H), 0.99 0.96 (m, 2H), 0.85 - 0.83 (m, 2H ).
INTERMEDIATE G
OH
H ₂ SO ₄ EtOH
Pd (OH) ₂ / C EtOAc
O
HO.
INTERMEDIATE G [0100] ethyl l- (2-hydroxyethyl) cyclopropane-l-carboxylate: Step 1: To a suspension of l- (2- (benzyloxy) ethyl) cyclopropane-l-carboxylic acid (5 g, 22.70 mmol) in EtOH (113 mL, 22.70 mmol) was added to the drops sulfuric acid
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54/84 (4.84 mL, 91 mmol). The reaction mixture was stirred at 80 ° C for 4 hours. The resulting reaction mixture was then cooled to RT, diluted with dichloromethane and washed with saturated aqueous sodium bicarbonate solution. The organic layer was dried, filtered and concentrated under reduced pressure to provide the expected intermediate. Step 2: To a solution of ethyl 1- (2 (benzyloxy) ethyl) cyclopropane-1-carboxylate (5.54 g, 22.31 mmol) in EtOAc (80 mL) was added palladium hydroxide on carbon (1.567 g , 2.23 mmol). The reaction mixture was stirred at RT under hydrogen pressure for 2 hours. The resulting reaction mixture was filtered through a CELITE® pad and washed with EtOAc. The resulting solution was concentrated under reduced pressure at RT to provide the title compound. ^X H NMR (400 MHz, CDCh) δ 4.11 (q, J = 7.14 Hz, 2H), 3.78 (t, J = 6.12 Hz, 2H), 1.82 (t, J = 6.12 Hz, 2H), 1.28 -1.24 (m, 2H), 1.23 (d, J = 7.14 Hz, 3H), 0.78 - 0.75 (m, 2H) .
INTERMEDIATE H soci ₂
I O ________ / PrOH I Ο I
OH ΗΟ ' ^Λ ''' ^/ χ / ^Χ
INTERMEDIATE H [0101] (5) isopropyl-3-hydroxybutanoate: To a solution of (S) -3-hydroxybutanoic acid (0.565 g, 5.43 mmol) in propan-2-ol (5.52 mL) was added to the drops thionyl chloride (0.79 mL, 10.85 mmol). The reaction mixture was stirred at 80 ° C overnight, and then concentrated under reduced pressure. The crude residue was diluted with EtOAc, washed with saturated aqueous NaHCOs, dried and concentrated under reduced pressure to provide the title compound. ¹ H NMR (400 MHz, CDCh) δ 5.06 (heptuplet, J = 6.26 Hz, 1H), 4.22 4.14 (m, 1H), 2.47 (dd, J = 16.40 Hz, 3.44 Hz, 1H), 2.38 (dd, J = 16.40 Hz, 8.68 Hz, 1H), 1.25 (d, J = 6.26 Hz, 6H), 1.22 (d, J = 6.33 Hz, 3H).
INTERMEDIATE I
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[0102] Isopropyl 5-fluoro-2- (hydroxymethyl) benzoate: Step 1: To a solution of 5-fluoro-2-methylbenzoic acid (20 g, 130 mmol) in DCM (200 mL) / V hydrochloride was added -ethyl- / V '- (3-dimethylaminopropyl) carbodiimide (36 g, 188 mmol), 4-dimethylaminopyridine (45 g, 368 mmol) and propan-2-ol (23 g, 390 mmol) in RT. The resulting reaction mixture was stirred at RT for 5 hours, and then it was concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (PE / EtOAc: 2 to 5%) to provide the expected intermediate: ^Ã H NMR (400 MHz, CDCh) δ 7.59 7.56 (m, 1H ), 7.20 - 7.17 (m, 1H), 7.10 - 7.06 (m, 1H), 5.26 - 5.20 (m, 1H), 2.55 (s, 3H), 1.37 (d, J = 6.4 Hz, 6H). Step 2: To a solution of 5-fluoro-2-methylbenzoate isopropyl (5.0 g, 25.5 mmol) in carbon tetrachloride (100 mL) was added / V-bromosuccinimide (13.6 g, 76.4 mmol) and azodiisobutyronitrile (1.3 g, 7.7 mmol). The reaction mixture was refluxed for 16 hours. After cooling to RT, the resulting reaction mixture was concentrated under reduced pressure and the crude residue was purified by silica gel column chromatography (PE / EtOAc: 2 to 3%) to provide the expected intermediate: ^Å NMR H (400 MHz, CDCh) δ 8.18 - 8.14 (m, 1H), 7.99 (s, 1H), 7.56 - 7.53 (m, 1H), 7.33 - 7.29 (m, 1H), 5.31 - 5.25 (m, 1H), 1.41 (d, J = 6.4 Hz, 6H). Step 3: A solution of isopropyl 2- (dibromomethyl) -5-fluorobenzoate (2.0 g, 6.0 mmol) in isopropanol (60 mL) and water (15 mL) was treated with silver nitrate (3.0 g, 18.0 mmol) for 30 min. in RT. The resulting reaction mixture was diluted with
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DCM (200 mL) and filtration was performed. The filtrate was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (ΡΕ / EtOAc: 1 to 5%) to provide the expected intermediate: ^X H NMR (400 MHz, CDCh) δ 10.56 (s, 1H), 8 .00 - 7.97 (m, 1H), 7.63 - 7.60 (m, 1H), 7.33 - 7.28 (m, 1H), 5.34 - 5.28 (m, 1H) , 1.40 (d, J = 6.4 Hz, 6H). Step 4: To a solution of isopropyl 5-fluoro-2-formylbenzoate (1.10 g, 5.24 mmol) in THF (20 mL) was added 1 M solution of borane in THF (7.86 mL, 7, 86 mmol) at 0 ° C. The reaction mixture was stirred at RT for 30 min, and then cooled with water (50 ml) and extracted with DCM (3 x 30 ml). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (ΡΕ / EtOAc: 1 to 10%) to provide the title compound: ^Ã H NMR (400 MHz, CDCI ₃ ) δ 7.71 - 7.68 ( m, 1H), 7.47 7.43 (m, 1H), 7.26 - 7.21 (m, 1H), 5.32 - 5.26 (m, 1H), 4.77 (s, 2H ), 1.42 (d, J = 6.4 Hz, 6H).
INTERMEDIATE J
INTERMEDIATE J [0103] Isopropyl 3- (2-hydroxyethyl) benzoate: Step 1: To a solution of
2- (3-bromophenyl) ethanol (5.0 g, 25.0 mmol) in DCM (50 mL) were added
3,4-dihydro-2H-pyran (12.5 g, 62.0 mmol) and 4-methylbenzenesulfonic acid
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57/84 (0.3 g, 0.10 mmol) at RT. The reaction mixture was stirred for 2 hours, and then concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (PE / EtOAc: 2 to 4%) to provide the expected intermediate: ^X H NMR (400 MHz, CDCh) δ 7.47 - 7.31 (m, 2H), 7.26 - 7.13 (m, 2H), 4.61 (m, 1H), 4.07 - 3.43 (m, 4H), 2.91 (m, 2H), 1.97 -1.46 (m, 6H). Step 2: To a solution of 2- (3-bromophenotoxy) tetrahydro-2H-pyran (1.30 g, 4.56 mmol) in THF (15 mL) was added tetramethylethylenediamine (1.06 g, 9.12 mmol) at RT. The resulting solution was cooled to -78 ° C followed by the addition of n-butyl lithium (2.0 ml, 5.0 mmol, 2.5 M in hexane). After stirring for an additional 2 hours at -78 ° C, isopropyl carbonochloridate (0.56 g, 4.56 mmol) was added. The temperature was allowed to warm up to RT spontaneously and after stirring for an additional 3 hours at RT, the resulting reaction mixture was concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (PE / EtOAc: 1 to 5%) to provide the expected intermediate: ^X H NMR (400 MHz, CDCh) δ 7.93 - 7.87 (m, 2H), 7.44 - 7.33 (m, 2H), 5.30 - 5.22 (m, 1H), 4.61 - 4.59 (m, 1H), 3.97 - 3.93 ( m, 1H), 3.74 - 3.60 (m, 2H), 3.46 - 3.43 (m, 1H), 2.98 - 2.94 (m, 2H), 1.82 - 1, 43 (m, 6H), 1.37 (d, J = 6.4 Hz, 6H). Step 3: To a solution of isopropyl 3- (2 - ((tetrahydro-2H-pyran-2yl) oxy) ethyl) benzoate (0.80 g, 2.74 mmol) in methanol (10 mL) 4-methylbenzenesulfonic acid (0.10 g, 0.58 mmol). The reaction mixture was stirred at RT for 1 hour. The resulting solution was concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography, eluting with (PE / EtOAc: 5 to 50%) to provide the title compound: ^Å H NMR (400 MHz, CDCh) δ 7,96 - 7, 93 (m, 2H), 7.49 - 7.36 (m, 2H), 5.33 - 5.25 (m, 1H), 3.93 (d, J = 6.4 Hz, 2H), 2 , 96 (t, J = 6.4 Hz, 2H), 1.40 (d, J = 6.4 Hz, 6H).
INTERMEDIATE K
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ΌΗ
Br
HO '
H ₂ SO ₄ , 80 ° C
1 / NaHCO ₃ DMSO / H ₂ O, 110 ° C 2 / BH ₃ -THF THF, 0 ° C ~ RT
INTERMEDIATE K [0104] Isopropyl 3- (hydroxymethyl) benzoate: Step 1: To a solution of 3- (bromomethyl) benzoic acid (3.01 g, 14.00 mmol) in propan-2-ol (42.10 g ) concentrated sulfuric acid (1.36 g, 13.95 mmol) was added. The reaction mixture was stirred for 16 hours at 80 ° C. The resulting reaction mixture was cooled to RT and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (ΡΕ / EtOAc: 1 to 2%) to provide the expected intermediate: ^Ã H NMR (400 MHz, CDCb) δ 8.05 7.97 (m, 2H ), 7.60 - 7.54 (m, 1H), 7.44 - 7.39 (m, 1H), 5.29 - 5.24 (m, 1H), 4.52 (s, 2H), 1.37 (d, J = 6.4 Hz, 6H). Step 2: To a solution of isopropyl 3- (bromomethyl) benzoate (1.0 g, 3.89 mmol) in DMSO (20 mL) was added sodium hydrogen carbonate (0.98 g, 11.67 mmol) and water (1 mL) at RT. The reaction mixture was stirred for 16 hours at 110 ° C under a nitrogen atmosphere. Upon completion, the resulting reaction mixture was cooled to RT and diluted with water (100 mL). The reaction mixture was extracted with EtOAc (2 x 100 ml) and the organic layer was washed with brine, dried, filtered and concentrated under reduced pressure. The crude residue was dissolved in THF (30 ml) followed by the addition of 1 M solution of borane in THF (3.89 ml, 3.89 mmol) at 0 ° C. After stirring for 30 min at RT, the reaction was cooled with water (1 mL) and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (PE / EtOAc: 5 to 10%) to provide the title compound: ¹ H NMR (400 MHz, CDCb) δ 8.03 - 8.02 (m , 1H), 7.98 - 7.93 (m, 1H), 7.58 - 7.54 (m, 1H), 7.45 - 7.41 (m, 1H), 5.30 - 5.23 (m, 1H), 4.76 (s, 2H), 1.38 (d, J = 6.4 Hz, 6H).
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INTERMEDIATE L
Propan-2-ol
EDC.HCI Pd (OH) ₂ / C
INTERMEDIATE L [0105] (5) -4-Hydroxy-2-methylbutanoate isopropyl: Step 1: To a solution of (S) -4- (benzyloxy) -2-methylbutanoic acid (12 g, 57.6 mmol) in DCM (222 ml) were added propan-2-ol (22.06 ml, 288 mmol), EDC (13.26 g, 69.1 mmol) and DMAP (0.704 g, 5.76 mmol). The reaction mixture was stirred at RT for 20 h. The resulting mixture was washed with water, 10% citric acid solution and brine. The organic layer was dried, filtered and concentrated under reduced pressure. The crude residue was used directly in the next step without further purification. Step 2: To a solution of isopropyl (S) -4- (benzyloxy) -2methylbutanoate (12.26 g, 49.0 mmol) in propan-2-ol (240 ml) was added palladium hydroxide on carbon (5 , 16 g, 7.35 mmol). The reaction mixture was flowed 3 times with vacuum and nitrogen and then stirred under hydrogen for 22 h. The reaction mixture was filtered through a CELITE® pad and the filtrate was concentrated under reduced pressure (T <40 ° C) to provide the title compound. H NMR (400 MHz, CDCH) δ 5.01 (heptupleto, J = 6.28 Hz, 1H), 3.73 to 3.64 (m, 2H), 2.63 to 2.54 (m, 1H), 1.96 -1.88 (m, 1H), 1.73 - 1.65 (m, 1H), 1.24 (d, J = 6.28 Hz, 3H), 1.23 (d , J = 6.28 Hz, 3H), 1.18 (d, J = 7.09 Hz, 3H).
INTERMEDIATE M
[0106] Isopropyl 3-mercaptopropanoate: INTERMEDIATE M is commercially available, and was purchased from TCI.
INTERMEDIATE N
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O OH ^P OH
N
3-hydroxybenzonitrile, Et ₃ N
Pyridine, 60 ° C
2 / Aldritiol, PPh ₃ Pyridine, 60 ° C, 16h / O Z // γ'ΝΗ'Ρχ O ⁰
NH ·
N

TFV
INTERMEDIATE N [0107] 2 - (((((((((R) -l- (6-Amino-9H-purin-9-yl) propan-2-yl) oxy) methyl) (3 cyanophenoxy) phosphoryl) -amino) Propyl -2-methylpropanoate: To a mixture of propyl 2-amino-2-methylpropanoate hydrochloride (15 g, 83 mmol), 3 hydroxybenzonitrile (12 g, 99 mmol), acid (/ ) - (((l - (6-amino-9/7-purin-9 yl) propan-2-yl) oxy) methyl) phosphonic (hereinafter referred to as TFV, 24 g, 83 mmol) and triethylamine (67 g, 661 mmol) in pyridine ( 700 ml) triphenylphosphine (87 g, 330 mmol) el, 2-di (pyridin-2-yl) disulfane (73 g, 330 mmol) was added at RT. The reaction mixture was stirred at 60 ° C for 16 hours under nitrogen. After cooling to RT, the resulting mixture was concentrated under reduced pressure and the crude residue was purified by silica gel column chromatography (DCM / MeOH: 2 to 10%) to provide the title compound. NMR of ^Ã H (400
MHz, CD ₃ OD) δ 8.18 - 8.15 (m, 2H), 7.55 - 7.40 (m, 3H), 7.33 - 7.32 (m, 1H), 4.41
- 4.36 (m, 1H), 4.27 - 4.22 (m, 1H), 4.09 - 3.99 (m, 4H), 3.88 - 3.80 (m, 1H), 1 , 65
1.57 (m, 2H), 1.43 - 1.38 (m, 6H), 1.28 - 1.24 (m, 3H), 0.96 - 0.89 (m, 3H); ³¹ P NMR (162 MHz, CD ₃ OD): 25.41, 25.30; LC / MS: [(M + 1)] ⁺ = 516.2.
INTERMEDIATE O
TFV
3-hydroxybenzonitrile, Et ₃ N
Pyridine, 60 ° C
2 / Aldritiol, PPh ₃ Pyridine, 60 ° C, 16h
INTERMEDIATE O [0108] 2 - (((((((((R) -l- (6-Amino-9H-purin-9-yl) propan-2-yl) oxy) methyl) (3Petition 870190087906, 06/06/09 / 2019, page 65/105
61/84 isopropyl cyanophenoxy) phosphoryl) amino) -2-methylpropanoate: To a mixture of isopropyl 2-amino-2-methylpropanoate hydrochloride (15 g, 83 mmol), 3 hydroxybenzonitrile (10 g, 87 mmol), TFV ( 24 g, 83 mmol) and triethylamine (67 g, 661 mmol) in pyridine (1 L) were added triphenylphosphine (87 g, 330 mmol) and 1.2di (pyridin-2-yl) dissuphane (73 g, 330 mmol) in RT. The reaction mixture was stirred at 60 ° C for 16 hours under nitrogen. After cooling to RT, the resulting mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (DCM / MeOH: 2 to 10%) to provide the title compound. ^X H NMR (400 MHz, CDCh) δ 8.31 (d, J = 4.0 Hz, 1H), 7.97 (d, J = 4.4 Hz, 1H), 7.53 - 7.20 (m, 3H), 7.15 - 7.03 (m, 1H), 5.99 (br s, 2H), 5.11 - 4.92 (m, 1H), 4.41 - 4.39 ( m, 1H), 4.20 - 4.07 (m, 1H), 4.05 - 3.85 (m, 3H), 3.81 - 3.57 (m, 1H), 1.51 -1, 28 (m, 15H); ³¹ P NMR (162 MHz, CDCh): 22.82, 22.76; LC / MS: [(M + 1)] ⁺ = 516.0.
INTERMEDIATE P o
TFV INTERMEDIATE P [0109] 2 - (((((((R) -l- (6-Amino-9H-purin-9-yl) propan-2-yl) oxy) methyl) (3-cyanophenoxy) phosphoryl) amino) - Pentyl 2-methylpropanoate: To a mixture of pentyl 2-amino-2-methylpropanoate hydrochloride (1.92 g, 9.14 mmol), 3-hydroxybenzonitrile (1.09 g, 9.14 mmol), TFV (2, 5 g, 8.70 mmol) and DIPEA (13.50 g, 104 mmol) in pyridine (25 mL), stirred and heated to 60 ° C, triphenylphosphine (15.98 g, 60.9 mmol) and 1, 2-di (pyridin-2-yl) disulfan (13.42 g, 60.9 mmol). The reaction mixture was stirred at 60 ° C overnight under nitrogen. After cooling to RT, the resulting mixture was concentrated under pressure
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INTERMEDIATE Q
INTERMEDIATE THE INTERMEDIARY Q [0110] Acid P - (((((R) -l- (6-amino-9H-purin-9-yl) propan-2-yl) oxy) methyl) -N- (smoothpropoxy-2- methyl-1-oxopropan-2-yl) phosphonamide: To a solution of 2 - (((((((R) 1- (6-amino-9H-purin-9-yl) propan-2-yl) oxy) methyl ) Isopropyl (3-cyanophenoxy) phosphoryl) amino) -2-methylpropanoate (2.5 g, 4.85 mmol) in THF (13.86 mL) was added H2O (1.747 mL, 97 mmol) and DBU (1.096 mL, 7 , 27 mmol). The reaction mixture was stirred at RT for 2 hours, and then concentrated under reduced pressure. The crude residue was dissolved in water and extracted many times with DCM. The aqueous layer was lyophilized to provide the title compound. LC / MS: [(M + 1)] ⁺ = 415.7.
INTERMEDIATE R
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1/
HO '
NHBoc
Step 1
SH
CDI, DCM, -10 ° C, RT, 16h
S'
NHBoc
Step 2
HCI / Dioxane, RT, lh
NH ₂ HCI
3-hydroxybenzonitrile, Et ₃ N, Pyridine, 60 ° C
OH'J ³ '
OH
2 / Aldritiol, PPh ₃ , Pyridine, 60 ° C, 16h
Step 3
TFV
CN
INTERMEDIATE R [0111] 2 - (((((((((R) -l- (6-Amino-9H-purin-9-yl) propan-2-yl) oxy) methyl) (3-cyanophenoxy) phosphoryl) amino) -2 -S-propyl methylpropanothioate:
[0112] Step 1: 2 - ((tert-butoxycarbonyl) amino) -2-Spropila-methylpropanothioate: To a solution of 2 - ((tert-butoxycarbonyl) amino) -2-methylpropanoic acid (2.67 g, 13.13 mmol) in DCM (30 mL) CDI (2.13 g, 13.13 mmol) was added at -10 ° C. The reaction mixture was stirred at RT for 1 hour followed by the addition of propane-1-thiol (1.01 g, 13.13 mmol) in 5 min at 0 ° C. After stirring for 16 hours at RT, the resulting reaction mixture was concentrated under reduced pressure and the crude residue was purified by silica gel column chromatography (petroleum ether / EtOAc: 9/1) to provide the expected intermediate. ^X H NMR (300 MHz, CDCb) δ 5.02 - 4.97 (brs, 1H), 2.84 (t, J = 7.2 Hz, 2H), 1.66 - 1.57 (m, 2H), 1.49 (s, 6H), 1.45 (s, 9H), 0.97 (t, J = 7.2 Hz, 3H); LC / MS: [(M + 1)] ⁺ = 262.2.
[0113] Step 2: S-propyl 2-Amino-2-methylpropanothioate S-propyl 2 ((tert-Butoxycarbonyl) amino) -2-methylpropanothioate (1.8 g, 6.9 mmol) was treated with 4M HCI (gas) in 1,4-dioxane (20 mL) at RT for 1 hour. Volatiles were evaporated under reduced pressure to provide the
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64/84 expected intermediate. H NMR (400 MHz, CDCH) δ 8.98 (brs, 3H), 2.97 (t, J = 7.2 Hz, 2H), 1.81 (s, 6H), 1.70 -1 , 60 (m, 2H), 0.99 (t, J = 7.2 Hz, 3H). LC / MS: [(M + 1)] ⁺ = 162.1.
[0114] Step 3: 2 - (((((((/ ) - 1- (6-Amino-9/7-purin-9-yl) propan-2-yl) oxy) methyl) (3-cyanophenoxy) phosphoryl) amino) S-propyl -2-methylpropanothioate: To a mixture of TFV (1.45 g, 5.06 mmol), Spropila 2-amino-2-methylpropanothioate hydrochloride (1.01 g, 5.06 mmol) , 3-hydroxybenzonitrile (0.91 g, 7.59 mmol) and triethylamine (4.09 g, 40.51 mmol) in pyridine (50 mL) were added triphenylphosphine (5.31 g, 20.23 mmol) and aldrithiol (4.46 g, 20.23 mmol) at RT. The reaction mixture was stirred for 16 hours at 60 ° C under a nitrogen atmosphere. After cooling to RT, the resulting reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (DCM / MeOH: 2 to 10%) to provide the title compound. H NMR (300 MHz, CDCH) δ 8.31 (s, 1H), 7.98 (s, 1H), 7.55 to 7.09 (m, 4H), 5.89 (br s, 2H ), 4.48 - 4.38 (m, 1H), 4.18 - 4.11 (m, 1H), 4.09 - 3.95 (m, 3H), 3.73 - 3.63 (m , 1H), 2.88 - 2.75 (m, 2H), 1.69 - 1.51 (m, 9H), 1.27 - 1.22 (m, 2H), 0.99 - 0.92 (m, 3H); ³¹ P NMR (121 MHz, CDCl 3): 22.51, 22.32; LC / MS: [(M + 1)] ⁺ = 532.2.
EXAMPLE 1
[0115] Step 1: 2 - (((((((/ ) - 1- (6-Amino-9/7-purin-9-yl) propan-2-yl) oxy) methyl) (3isopropoxy-3- propyl oxopropoxy) phosphoryl) amino) -2-methylpropanoate
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65/84 [0116] To a stirred solution of INTERMEDIATE N (17.5 g, 33.9 mmol) in DCM (25 mL) were added INTERMEDIATE D (6.7 g, 50.9 mmol) and DBU (5, 2 g, 33.9 mmol). The reaction mixture was stirred at RT for 1 hour, then cooled by the addition of saturated aqueous ammonium chloride (30 ml) and extracted with EtOAc (3 x 150 ml). The combined organic layers were washed with brine (3 x 100 ml), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the crude residue was purified by silica gel column chromatography (DCM / MeOH: 5% to 10%) to provide a mixture of two diastereomers.
[0117] Step______2: 2 - (((/ ) - ((((/ ) - 1- (6-Amino-9 / - / - purin-9-yl) propan-2yl) oxy) methyl) (3 propyl-isopropoxy-3-oxopropoxy) phosphoryl) amino) -2-methylpropanoate and 2 - (((5) - ((((/ ) - l- (6-amino-9 / - / - purin-9- propyl yl) propan-2-yl) oxy) methyl) (3isopropoxy-3-oxopropoxy) phosphoryl) amino) -2-methylpropanoate:
[0118] The two diastereomers were separated by preparative chiral SFC with the following condition: Column: CHIRALPAK-AD, 20 x 250 mm; Mobile Phase A: CO ₂ ; Mobile Phase B: MeOH; Gradient: 20% B in 10 min; flow rate: 40 mL / min; Detector: UV 254 nm; IA to afford isomer (faster eluting, Rt = 3.63 min): H NMR (300 MHz, CD3 OD) δ 8.18 (s, 1H), 8.16 (s, 1H), 4.99 - 4.95 (m, 1H), 4.35 (dd, J = 14.7, 3.3 Hz, 1H), 4.25 - 4.11 (m, 3H), 4.01 (t, J =
6.6 Hz, 2H), 3.92 - 3.86 (m, 1H), 3.80 (dd, J = 13.2, 8.7 Hz, 1H), 3.57 (dd, J = 13.2 ,
9.6 Hz, 1H), 2.59 (t, J = 6.0 Hz, 2H), 1.65 - 1.58 (m, 2H), 1.44 (s, 3H), 1.39 (s, 3H), 1.21 -1.16 (m, 9H), 0.91 (t, J = 7.2 Hz, 3H); ³¹ P NMR (121 MHz, CD3OD) δ 26.24; LC / MS: [(M + 1)] ⁺ = 529.1; and Isomer 1B (slower elution, Rt = 4.26 min): ^Ã H NMR (300 MHz, CD3OD) δ 8.18 (s, 1H), 8.15 (s, 1H), 4.96 - 4 , 93 (m, 1H), 4.34 (dd, J = 14.7, 3.3 Hz, 1H), 4.23 - 4.11 (m, 3H), 4.05 (t, J = 6 , 6 Hz, 2H), 3.94 - 3.89 (m, 1H), 3.80 (dd, J = 13.5, 8.7 Hz, 1H), 3.60 (dd, J = 13, 5, 9.3 Hz, 1H), 2.59 - 2.54 (m, 2H), 1.68 - 1.60 (m, 2H), 1.45 (d, J = 5.4 Hz, 6H ), 1.20 - 1.16 (m, 9H), 0.93 (t, J =
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7.2 Hz, 3H); ³¹ P NMR (121 MHz, CD ₃ OD) δ 26.23; LC / MS: [(M + 1)] ⁺ = 529.0.
EXAMPLE 2
INTERMEDIATE The ^after chiral ^chromate ^ A _{2 E E 2β} [0119] Step 1: 2 - (((((((/ ) - l- (6-Amino-9 / - / - purin-9-yl) propan-2 -yl) oxy) methyl) (3isopropoxy-3-oxopropoxy) phosphoryl) amino) -2-isopropyl methylpropanoate [0120] To a stirred solution of INTERMEDIATE O (18.0 g, 34.9 mmol) in DCM (30 mL ) INTERMEDIATE D (6.9 g, 52.4 mmol) and DBU (5.3 g, 34.9 mmol) were added. The reaction mixture was stirred at RT for 2 hours and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (DCM / MeOH: 2% to 10%) to provide a mixture of two diastereomers.
[0121] Step______2: 2 - (((/ ) - ((((/ ) - 1- (6-Amino-9 / - / - purin-9-yl) propan-2yl) oxy) methyl) (3 -isopropoxy-3-oxopropoxy) phosphoryl) amino) -2-isopropyl methylpropanoate and 2 - (((S) - ((((/ ) - l- (6-amino-9 / - / - purin-9- il) propan-2-yl) oxy) methyl) (3isopropoxy-3-oxopropoxy) phosphoryl) amino) isopropyl -2-methylpropanoate:
[0122] The two diastereomers were separated by preparative chiral SFC with the following condition: Column: CHIRALPAK-IC, 5 x 25 cm, 5 μηη; Mobile Phase A: CO2; Mobile Phase B: IPA (0.2% DEA); flow rate: 180 mL / min; Gradient: 50% B in 8 min; Detector: UV 254 nm; 2A to afford isomer (faster eluting, Rt = 4.75 min): H NMR (300 MHz, CD3 OD) δ 8.18 (s, 1H), 8.15 (s, 1H), 4.99 - 4.91 (m, 2H), 4.32 (dd, J = 11.1, 3.3 Hz, 1H), 4.22 - 4.13 (m, 3H), 3.97 3.89 (m , 1H), 3.77 (dd, J = 8.4, 4.8 Hz, 1H), 3.63 (dd, J = 9.3, 4.2 Hz, 1H), 2.59 2.54 (m, 2H), 1.43 (d, J = 4.8 Hz, 6H), 1.23 -1.16 (m, 15H); ³¹ P NMR (121 MHz,
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CDsOD) δ 26.14; LC / MS: [(Μ + 1)] ⁺ = 529.0; 2B and isomer (slower eluting Rt = 6.53 min): H NMR (300 MHz, CD ₃ OD) δ 8.18 (s, 1H), 8.15 (s, 1H), 4.98 - 4.90 (m, 2H), 4.32 (dd, J = 11.4, 3.0 Hz, 1H), 4.28 - 4.09 (m, 3H), 3.93 - 3.87 (m, 1H), 3.81 (dd, J = 8.4, 4.8 Hz, 1H), 3.57 (dd, J = 9.3, 4.2 Hz, 1H), 2.58 - 2.54 (m, 2H), 1.42 (s, 3H), 1.39 (s, 3H), 1.17 - 1.13 (m, 15H); ³¹ P NMR (121 MHz, CD3OD) δ 26.13; LC / MS: [(M + 1)] ⁺ = 529.1.
EXAMPLE 3
INTERMEDIATE Ο 3A AND 3B [0123] Step________1: l - (((((((( ) - l- (6-Amino-9 / - / - purin-9-yl) propan-2yl) oxy) methyl) ( (isopropyl l-isopropoxy-2-methyl-l-oxopropan-2yl) amino) phosphoryl) oxy) methyl) cyclopropane-l-carboxylate [0124] To a solution of INTERMEDIATE O (10.0 g, 19.4 mmol) in THF (40 mL) INTERMEDIATE F (4.6 g, 29.1 mmol) and DBU (2.9 g, 19.4 mmol) were added. The reaction mixture was stirred at RT for 3 hours, then the resulting solution was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (DCM / MeOH: 2% to 10%) to provide a mixture of two diastereomers.
[0125] Step 2: l - ((((/ ) - ((((/ ) - l- (6-Amino-9 / - / - purin-9-yl) propan-2yl) oxy) methyl) ((l-isopropoxy-2-methyl-1-oxopropan-2yl) amino) phosphoryl) oxy) methyl) isopropyl cyclopropane-l-carboxylate and 1 - (((((5) ((((/ ) - l- (6-amino-9 / - / - purin-9-yl) propan-2-yl) oxy) methyl) ((l-isopropoxy-2-methyl-loxopropan-2-yl) amino) phosphoryl) oxy) methyl) isopropyl __________ cyclopropane-l-carboxylate:
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68/84 [0126] The two diastereomers were separated by preparative chiral SFC with the following condition: Column: CHIRALPAK IA, 5 x 25 cm, 5 pm; Mobile Phase A: CO2; Mobile Phase B: EtOH; Gradient: 30% B in 7 min; flow rate: 150 mL / min; Detector: UV 254 nm; 3A to afford isomer (faster eluting, Rt = 4.27 min): H NMR (300 MHz, DMSO-cfc) δ 8.14 (s, 1H), 8.11 (s, 1H), 7. 20 (brs, 2H), 4.91 - 4.76 (m, 3H), 4.29 - 4.06 (m, 3H), 3.99 - 3.90 (m, 2H), 3.72 - 3.56 (m, 2H), 1.34 (d, J = 8.1 Hz, 6H), 1.18 - 1.14 (m, 12H), 1.14 - 1.07 (m, 5H) , 1.05 - 0.95 (m, 2H); ³¹ P NMR (121 MHz, DMSO-cfc) δ 24.09; LC / MS: [(M +
1)] ⁺ = 555.2; 3B and isomer (slower eluting Rt = 4.88 min): H NMR (300 MHz, DMSO-cfc) δ 8.13 (s, 1H), 8.09 (s, 1H), 7.18 (brs, 2H), 4.90 - 4.81 (m, 3H), 4.27 - 4.12 (m, 2H), 4.07 - 3.92 (m, 3H), 3.70 - 3 .65 (m, 2H), 1.35 (s, 6H), 1.23
1.15 (m, 12H), 1.13 - 1.11 (m, 2H), 1.08 - 1.05 (m, 3H), 0.98 - 0.95 (m, 2H); ³¹ P NMR (121 MHz, DMSO-cfc) δ 24.08; LC / MS: [(M + 1)] ⁺ = 555.1.
EXAMPLE 4
INTERMEDIATE O
íBu-MgCI, THF, RT, 90 min after chiral chromatography
[0127] Step_______1: l- (2 - ((((((( ) - l- (6-Amino-9 / - / - purin-9-yl) propan-2 yl) oxy) methyl) ((l ethyl -isopropoxy-2-methyl-1-oxopropan-2yl) amino) phosphoryl) oxy) ethyl) cyclopropane-1-carboxylate [0128] To a stirred solution of INTERMEDIATE O (2 g, 3.88 mmol) and
INTERMEDIATE G (1.228 g, 7.76 mmol) in THF (25.9 mL) tert-butylmagnesium chloride (8.54 mL, 8.54 mmol) was added. The reaction was carried out in a sealed flask. The reaction mixture was stirred at RT for 90 min. The resulting mixture was purified by silica gel column chromatography (DCM / MeOH: 0 to 10%) to provide a mixture of two diastereomers.
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69/84 [0129] Step 2: 1- (2 - (((/ ) - (((((/ ) - 1- (6-Amino-9 / - / - purin-9-yl) propan-2il ) oxy) methyl) (ethyl (l-isopropoxy-2-methyl-l-oxopropan-2yl) amino) phosphoryl) oxy) ethyl) cyclopropane-l-carboxylate and l- (2 - (((S) - (( ((/ ) - 1 (6-amino-9 / - / - purin-9-yl) propan-2-yl) oxy) methyl) ((1-isopropoxy-2-methyl-loxopropan-2-yl) amino ) ethyl phosphoryl) oxy) ethyl) cyclopropane-1-carboxylate:
[0130] The two diastereomers were separated by preparative chiral SFC with the following condition: Column: CHIRALPAK ID, 2 x 25 cm, 5 pm; Mobile Phase A: CO2; Mobile Phase Β: IPA (0.1% DEA); flow rate: 60 g / min; Gradient: 40% B in 6 min; Detector: UV 254 nm; to provide Isomer 4A (fastest elution, Rt = 3.89 min): ^X H NMR (500 MHz, DMSO-cfc) δ 8.13 (s, 1H), 8.10 (s, 1H), 7, 17 (s, 2H), 4.84 (heptuplet, J = 6.5 Hz, 1H), 4.74 - 4.72 (m, 1H), 4.27 - 4.24 (m, 1H), 4 , 17 - 4.13 (m, 1H), 4.05 - 3.89 (m, 5H), 3.70 - 3.54 (m, 2H), 1.81 - 1.78 (m, 2H) , 1.35 (s, 3H), 1.31 (s, 3H), 1.18 - 1.07 (m, 14H), 0.83 - 0.82 (m, 2H); ³¹ P NMR (243 MHz, DMSO-cfc) δ 23.84; LC / MS: [(M + 1)] ⁺ = 555.4; and Isomer 4B (slower elution, Rt = 4.33 min): ^X H NMR (500 MHz, DMSO-c / e) δ 8.13 (s, 1H), 8.10 (s, 1H), 7 , 16 (s, 2H), 4.85 (heptuplet, J = 6.0 Hz, 1H), 4.76 - 4.74 (m, 1H), 4.26 - 4.22 (m, 1H), 4.18 - 4.13 (m, 1H), 4.05 - 3.92 (m, 5H), 3.65 - 3.63 (m, 2H), 1.78 - 1.75 (m, 2H ), 1.36 - 1.34 (m, 6H), 1.18 -1.05 (m, 14H), 0.84 - 0.78 (m, 2H); ³¹ P NMR (243 MHz, DMSO-cfc) δ 23.91; LC / MS: [(M + 1)] ⁺ = 555.3.
EXAMPLE 5
INTERMEDIATE O
then chiral chromatography
[0131] Stage
1:
(S) -4 - (((((((( ) - 1- (6-Amino-9 / - / - purin-9-yl) propan-2yl) oxy) methyl) ((l-isopropoxy-2- methyl-1-oxopropan-2-yl) amino) phosphoryl) oxy) -2 Petition 870190087906, of 9/6/2019, p. 74/105
70/84 isopropyl methylbutanoate [0132] To a solution of INTERMEDIATE 0 (6.0 g, 12.0 mmol) in THF (100 mL) were added INTERMEDIATE L (3.8 g, 24.0 mmol) and DBU ( 2.7 g, 18.9 mmol) at RT. The reaction mixture was stirred at 45 ° C for 4 hours, and then concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (DCM / MeOH: 5% to 10%) to provide a mixture of two diastereomers.
[0133] Step 2: (S) -4 - (((/ ) - ((((/ ) - 1- (6-Amino-9 / - / - purin-9-yl) propan-2yl) oxy ) methyl) ((l-isopropoxy-2-methyl-l-oxopropan-2-yl) amino) phosphoryl) oxy) -2-isopropyl methylbutanoate and (S) -4 - ((((S) - (((( ) -l- (6-amino-9 / - / - purin-9il) propan-2-yl) oxy) methyl) ((l-isopropoxy-2-methyl-l-oxopropan-2yl) amino) phosphoryl) oxy) Isopropyl -2-methylbutanoate:
[0134] The two diastereomers were separated by preparative chiral SFC with the following condition: Column: CHIRALPAK IC, 2 x 25 cm, 5 μηη; Mobile Phase A: CO2; Mobile Phase Β: IPA (plus 0.5% (2M NH3 in MeOH), v / v); Gradient: 40% B in 10 min; flow rate: 150 mL / min; Detector: 254 nm; to afford: Isomer 5A (faster eluting, Rt = 6.27 min): H NMR (400 MHz, DMSO-d6) δ 8.11 (s, 1H), 8.09 (s, 1H), 7.17 (brs, 2H), 4.86 - 4.80 (m, 3H), 4.22 - 4.15 (m, 2H), 3.85 - 3.82 (m, 3H), 3.63 (d , J = 8.4 Hz, 2H), 2.49 - 2.45 (m, 1H), 1.88 - 1.81 (m, 1H), 1.58 - 1.51 (m, 1H), 1.32 (d, J = 4.4 Hz, 6H), 1.16 - 1.13 (m, 12H), 1.06 1.03 (m, 6H); ³¹ P NMR (162 MHz, DMSO-cfc) δ 24.15; LC / MS: [(M + 1)] ⁺ = 557.3; and isomer 5B (slower eluting Rt = 7.95 min): H NMR (400 MHz, DMSO-d6) δ 8.11 (s, 1H), 8.09 (s, 1H), 7.17 (brs , 2H), 4.87 - 4.73 (m, 3H), 4.25 - 4.10 (m, 2H), 3.90 - 3.83 (m, 3H), 3.66 (dd, J = 13.2, 4.8 Hz, 1H), 3.55 (dd, J = 13.2, 9.2 Hz, 1H), 2.49 - 2.45 (m, 1H), 1.89 - 1.84 (m, 1H), 1.58 -1.53 (m, 1H), 1.33 (s, 3H), 1.29 (s, 3H), 1.15 - 1.13 (m, 12H), 1.06 - 1.04 (m, 6H); ³¹ P NMR (162 MHz, DMSOd ₆ ) δ 24.12; LC / MS: [(M + 1)] ⁺ = 557.3.
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EXAMPLE 6
[0135] Step______1: (S) -4 - ((((((( ) - 1- (6-Amino-9 / - / - purin-9-yl) propan-2yl) oxy) methyl) ((2 isopropyl-methyl-1-oxo-l-propoxypropan-2-yl) amino) phosphoryl) oxy) -2methylbutanoate [0136] To a solution of INTERMEDIATE N (6.34 g, 12.67 mmol) in THF (100 mL ) INTERMEDIATE L (4.06 g, 25.30 mmol) and DBU (2.88 g, 19.00 mmol) were added at RT. The reaction mixture was stirred at 45 ° C for 4 hours, and then concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (DCM / MeOH: 5% to 10%) to provide a mixture of two diastereomers.
[0137] Step 2: (S) -4 - (((/ ) - ((((/ ) - 1- (6-Amino-9 / - / - purin-9-yl) propan-2yl) oxy ) methyl) (isopropyl (2-methyl-1-oxo-l-propoxypropan-2-yl) amino) phosphoryl) oxy) -2methylbutanoate and (5) -4 - (((5) - (((( ) -l- (6-amino-9H-purin-9yl) propan-2-yl) oxy) methyl) ((2-methyl-1-oxo-1-propoxypropan-2yl) amino) phosphoryl) oxy) -2- isopropyl methylbutanoate:
[0138] The two diastereomers were separated by preparative chiral SFC with the following condition: Column: Chiralpak SE, 2 * 25 cm, 5 qm; Mobile Phase A:
CO ₂ ; Mobile Phase B: IPA; Gradient: 30% B in 10 min; flow rate: 40 mL / min; Detector: UV 254 nm; to afford: Isomer 6A (faster eluting, Rt = 5.57 min): ^X H NMR (400 MHz, DMSO-Cl ₆₎ δ 8.13 (s, 1H), 8.10 (s,
1H), 7.17 (brs, 2H), 4.90 - 4.78 (m, 2H), 4.24 (dd, J = 14.8, 3.6 Hz, 1H), 4.15 (dd , J = 14.4, 6.4 Hz, 1H), 3.97 - 3.85 (m, 5H), 3.68 (dd, J = 13.2, 8.4 Hz, 1H), 3, 57 (dd, J = 12.8, 9.2 Hz, 1H), 2.50 - 2.47 (m, 1H), 1.92 - 1.84 (m, 1H), 1.62 - 1, 53 (m, 3H),
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1.35 (d, J = 8.4 Hz, 6H), 1.14 -1.12 (m, 6H), 1.09 -1.07 (m, 6H), 0.85 (t, J = 7.2 Hz, 3H); ³¹ P NMR (162 MHz, DMSO-cfc) δ 24.15; LC / MS: [(M + 1)] ⁺ = 557.3; and Isomer 6B (slower elution, Rt = 6.72 min): ^Ã H NMR (400 MHz, DMSO-c / e) δ 8.13 (s, 1H), 8.10 (s, 1H), 7 , 17 (brs, 2H), 4.90 - 4.84 (m, 2H), 4.25 (dd, J = 14.0,
3.2 Hz, 1H), 4.15 (dd, J = 14.4, 6.0 Hz, 1H), 3.98 - 3.92 (m, 3H), 3.87 - 3.81 (m, 2H ), 3.65 (d, J = 8.8 Hz, 2H), 2.50 - 2.45 (m, 1H), 1.88 - 1.83 (m, 1H), 1.60 - 1, 53 (m, 3H), 1.36 (d, J = 4.0 Hz, 6H), 1.17 - 1.13 (m, 6H), 1.09 - 1.07 (m, 6H), 0 , 87 (t, J =
7.2 Hz, 3H); ³¹ P NMR (162 MHz, DMSO-cfc) δ 24.17; LC / MS: [(M + 1)] ⁺ = 557.3.
EXAMPLE 7
[0139] Step_______1: 2 - (((((((((( ) - 1- (6-Amino-9H-purin-9-yl) propan-2yl) oxy) methyl) ((2-methyl-1-oxo) -l-propoxypropan-2-yl) amino) phosphoryl) oxy) methyl) -5 isopropyl fluorobenzoate [0140] To a solution of INTERMEDIATE N (331 mg, 0.64 mmol) in THF (4 mL) INTERMEDIATE I ( 407 mg, 1.92 mmol) and DBU (97.4 mg, 0.64 mmol) at RT. The reaction mixture was stirred at RT overnight, and then concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (DCM / MeOH: 2% to 10%) followed by RP-18 chromatography (H2O + NHziHCOsJ / ACN to provide a mixture of two diastereomers.
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73/84 [0141] Step 2: 2 - (((((/ ) - ((((/ ) - 1- (6-Amino-9H-purin-9-yl) propan-2yl) oxy) methyl) Isopropyl (2-methyl-1-oxo-1-propoxypropan-2-yl) amino) phosphoryl) oxy) methyl) -5 fluorobenzoate (7A); and 2 - (((((5) - ((((/ ) - 1- (6-amino-9H-purin-9yl) propan-2-yl) oxy) methyl) ((2-methyl-1-oxo isopropyl-1-propoxypropan-2yl) amino) phosphoryl) oxy) methyl) -5-fluorobenzoate (7B):
[0142] The two diastereomers were separated by preparative chiral HPLC with the following condition: Column: Chiralpak IF, 2 * 25 cm, 5 μιτι; Mobile Phase A: Hexane; Mobile Phase B: IPA; Gradient: 50% B in 31 min; flow rate: 13 mL / min; Detector: UV 254 nm; to provide: Isomer 7A (fastest elution, Rt = 19.96 min): ^X H NMR (400 MHz, DMSO-cfc) δ 8.13 (s, 1H), 8.11 (s, 1H), 7 , 65 - 7.60 (m, 2H), 7.50 - 7.46 (m, 1H), 7.20 (br s, 2H), 5.27 (d, J = 7.2 Hz, 2H) , 5.12 - 5.05 (m, 2H), 4.27 - 4.23 (m, 1H), 4.18 - 4.13 (m, 1H), 3.96 - 3.92 (m, 3H), 3.77 (dd, J = 13.2, 8.8 Hz, 1H), 3.68 (dd, J = 13.2, 8.8 Hz, 1H), 1.55 - 1.49 (m, 2H), 1.38 - 1.30 (m, 12H), 1.06 (d, J = 6.0 Hz, 3H), 0.82 (t, J = 7.6 Hz, 3H) ; ³¹ P NMR (162 MHz, DMSO-cfc) δ 24.89; LC / MS: [(M + 1)] ⁺ = 609.3; and Isomer 7B (slower elution, Rt = 25.29 min): ^X H NMR (400 MHz, DMSO-cfc) δ 8.13 (s, 1H), 8.11 (s, 1H), 7.65 - 7.60 (m, 2H), 7.50 - 7.45 (m, 1H), 7.19 (br s, 2H), 5.29 - 5.27 (m, 2H), 5.14 - 5.07 (m, 2H), 4.27 - 4.14 (m, 2H), 3.98 - 3.94 (m, 3H), 3.76 (d, J = 8.8 Hz, 2H) , 1.56 -1.49 (m, 2H), 1.38 - 1.30 (m, 12H), 1.04 (d, J = 6.4 Hz, 3H), 0.83 (t, J = 7.6 Hz, 3H); ³¹ P NMR (162 MHz, DMSO-cfc) δ 24.88; LC / MS: [(M + 1)] ⁺ = 609.3.
[0143] The compounds in Examples 8 to 14 were prepared in a form analogous to that described by Examples 1 to 7 above, i.e., Step 1 describes the preparation of the compound as a mixture of diastereoisomers and Step 2 describes the separation of diastereoisomers. The Intermediaries seen in Examples 8 to 14 refer to the exemplary letters of the intermediary that represent each of the two intermediates that have been
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74/84 used in Step 1 of each Example. The isomers were separated by preparative HPLC, preparative chiral HPLC or preparative chiral SFC. The observed 'isomer separation / purification conditions' provides the separation conditions used to obtain each diastereoisomer.
Example 8 ^H 2 ^N Up in the air 2 - ((((S) - ((((/ ) - 1- (6-Amino-9H-purin-9yl) propan-2-yl) oxy) methyl) (3-isopropoxy-3oxopropoxy) phosphoryl) amino) -2 pentyl methylpropanoate; and 2 - (((/ ) - ((((/ ) - 1- (6-Amino-9H-purin-9yl) propan-2-yl) oxy) methyl) (3-isopropoxy-3oxopropoxy) phosphoryl) amino) -2-pentyl methylpropanoate Intermediates: P and D.Isomer separation / purification conditions: SFC Prep. Chiral - CHIRALPAK IC 2 x 25 cm, 5 pm; Mobile Phase A: CO2: 60%, Mobile Phase B: IPA: 40% (12 min); flow rate: 60 mL / min; Detector 254 nm Isomer ³¹ P NMR (ppm) LC / MS (M + 1) ⁺ Elution order 8A CDCb, 162 MHz: 24.11 557.2 Faster elution 8B CDCb, 162 MHz: 23.97 557.2 Slower elution Example 9 1 h ₂ n ΗΝ _Χ * ^ ° N ^N OV> w ^r 3 - ((((S) - ((((/ ) - 1- (6-Amino-9H-purin-9-il) propan-2-yl) oxy) methyl) (isopropyl (1-isopropoxy-2methyl-1-oxopropan-2-yl) amino) phosphoryl) oxy) 2,2-dimethylpropanoate; and3 - (((/ ) - ((((/ ) - 1- (6-Amino-9H-purin-9yl) propan-2-yl) oxy) methyl) ((l-isopropoxy-2-
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methyl-1-oxopropan-2-yl) amino) phosphoryl) oxy) -Isopropyl 2,2-dimethylpropanoate Intermediaries: 0 and EIsomer separation / purification conditions: HPLC Prep. Chiral - ChiralpakAD-H 2 x 25 cm, 5 pm; Mobile Phase: Heptane / EtOH (85/15) in 20 min; flow rate: 50 g / min; Detector: 254 nm Isomer ³¹ P NMR (ppm) LC / MS (M + 1) ⁺ Elution order 9A DMSO-c / e, 243 MHz: 23.97 557.4 Faster elution 9B DMSO-c / e, 243 MHz: 23.98 557.4 Slower elution Example 10 1 H ₂ N A / ΧΊ ΗΝ ^ Ζ / θ N ^ ^N o WY (S) -3 - ((((S) - ((((/ ) - 1- (6-Amino-9 / - / - purin-9yl) propan-2-yl) oxy) methyl) ((l- isopropyl-2methyl-1-oxopropan-2yl) amino) phosphoryl) oxy) isopropyl butanoate; and(S) -3 - ((((/ ) - ((((/ ) - 1- (6-Amino-9 / - / - purin-9yl) propan-2-yl) oxy) methyl) ((l -isopropoxy-2methyl-l-oxopropan-2-il) amino) phosphoryl) oxy) isopropyl butanoate Intermediates: Q and HIsomer separation / purification conditions: SFC Prep .: Chiralpak AD-H, 2 x 25 cm, 5 μηη; Mobile Phase A: CO2; Mobile Phase B: MeOH; Gradient: 30% B in 8 min; flow rate: 40 mL / min; Detector: UV 254 nm;Followed by: SFC Prep .: Chiralpak IC, 2 x 25 cm, 5 μηη; Mobile Phase A: CO2; Mobile Phase B: MeOH; Gradient: 30% B in 10 min; flow rate: 40 mL / min; Detector: UV 254 nm
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Isomer ³¹ P NMR (ppm) LC / MS (M + 1) ⁺ Elution order 10A DMSO-c / e, 162 MHz: 23.57 543.2 Faster elution 10B DMSO-c / e, 162 MHz: 23.38 543.2 Slower elution Example 11 nh ₂ 1 θ < ^z 1 J o ₇ c ° Y HN i 0 3- (2 - (((/ ) - ((((/ ) - 1- (6-Amino-9 / - / - purin-9yl) propan-2-yl) oxy) methyl) ((2- methyl-l-oxo-lpropoxypropan-2-yl) amino) phosphoryl) oxy) ethyl) isopropyl benzoate, and 3- (2 - (((S) - ((((/ ) l- (6-Amino- 9 / - / - purin-9-yl) propan-2yl) oxy) methyl) ((2-methyl-1-oxo-lpropoxypropan-2-yl) amino) phosphoryl) oxy) ethyl) isopropyl benzoate Intermediates: N and JIsomer separation / purification conditions: HPLC Prep. Chiral:CHIRALPAK-AD-H, 20 * 250 mm; Mobile Phase A: Hex .; Mobile Phase B: EtOH; flow rate: 20 mL / min; Gradient: 30% B in 35 min; Detector: UV 254 nm Isomer ³¹ P NMR (ppm) LC / MS (M + 1) ⁺ Elution order 11A DMSO-c / e, 162 MHz: 24.24 605.3 Faster elution 11B DMSO-c / e, 162 MHz: 24.18 605.3 Slower elution Example 12 nh ₂ / <Ά s _x * _z oy HN | O 2 - (((S) - ((((/ ) - 1- (6-Amino-9H-purin-9-yl) propan-Propyl 2-yl) oxy) methyl) ((3-isopropoxy-3-oxopropyl) thio) phosphoryl) amino) -2-methylpropanoate; and2 - (((/ ) - ((((/ ) - 1- (6-Amino-9H-purin-9-il) propan-2-yl) oxy) methyl) ((3-isopropoxy-3-
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oxopropyl) thio) phosphoryl) amino) -2-propyl methylpropanoate Intermediates: N and MIsomer separation / purification conditions: HPLC Prep. Chiral:CHIRALPAK-IC, 5 x 25 cm, 5 pm; Mobile Phase A: Hex .; Mobile Phase B: EtOH; flow rate: 16 mL / min; Gradient: 50% B in 16 min; Detector: UV 254 nm Isomer ³¹ P NMR (ppm) LC / MS (M + 1) ⁺ Elution order 12A DMSO-cfc, 162 MHz: 39.14 545.2 Faster elution 12B DMSO-c / e, 162 MHz: 39.39 545.2 Slower elution Example 13 NH ₂ / <· Ά ° _X * / O HN j O 3 - ((((S) - ((((/ ) - 1- (6-Amino-9H-purin-9yl) propan-2-yl) oxy) methyl) ((2-methyl-1-oxo-1 isopropyl (propylthio) propan-2-yl) amino) phosphoryl) oxy) propanoate; and 3 - (((/ ) ((((/ ) - 1- (6-Amino-9/7-purin-9-yl) propan-2yl) oxy) methyl) ((2-methyl-l- oxo-l-(propylthio) propan-2-yl) amino) phosphoryl) oxy) isopropyl propanoate Intermediates: R and DIsomer separation / purification conditions: HPLC Prep. Chiral: ChiralpakIC, 2 x 25 cm, 5 pm; Mobile Phase A: Hex .; Mobile Phase B: EtOH; Gradient: 30B% in 24 min; flow rate: 20 mL / min; Detector 254 nm Isomer ³¹ P NMR (ppm) LC / MS (M + 1) ⁺ Elution order 13A DMSO-c / e, 162 MHz: 23.64 545.1 Faster elution 13B DMSO-c / e, 162 MHz: 23.53 545.1 Slower elution
Example 14
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nh ₂ VyA with CM, P f ^N HN i 0 3 - ((((/ ) - ((((/ ) - 1- (6-Amino-9H-purin-9yl) propan-2-yl) oxy) methyl) ((2-methyl-1-oxo -lpropoxypropan-2-yl) amino) phosphoryl) oxy) methyl) isopropyl benzoate; and 3 - (((((5) ((((/ ) - 1- (6-Amino-9 / - / - purin-9-yl) propan-2yl) oxy) methyl) ((2-methyl-1 -oxo-lpropoxypropan-2-yl) amino) phosphoryl) oxy) methyl) isopropyl benzoate Intermediates: N and KIsomer separation / purification conditions: HPLC Prep. Chiral:CHIRALPAK-AD-H, 20 * 250 mm; Mobile Phase A: Hex .; Mobile Phase B: EtOH; flow rate: 20 mL / min; Gradient: 50% B in 32 min; Detector: UV 254 nm Isomer ³¹ P NMR (ppm) LC / MS (M + 1) ⁺ Elution order 14A CD ₃ OD, 162 MHz: 26.64 591.3 Faster elution 14B CD3OD, 162 MHz: 26.63 591.3 Slower elution
EXAMPLE 15
Evaluation of antiviral potency in a Multi-Round HIV-1 Infection Assay (Vikina Assay) [0144] The antiviral activity of the tenofovir prodrugs in the Examples contained herein was assessed in an assay that measures the rate of HIV replication in culture cells, called the Viking Assay (Viral KINetics in Green cells) (viral kinetics in green cells) and performed as follows. HIV1 replication was monitored using D3 clone MT4-gag-GFP (hereinafter referred to as MT4-GFP), which are MT-4 cells modified to harbor a GFP reporter gene, the expression of which is dependent on proteins expressed by HIV -1 is tat and rev. The productive infection of an MT4-GFP cell with HIV-1 results
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79/84 in GFP expression approximately 24 h after infection. MT4GFP cells were maintained at 37 ° C / 5% CO2 / 90% relative humidity in RPMI 1640 supplemented with 10% fetal bovine serum, 100 U / ml penicillin / streptomycin and 400 μg / ml G418 to maintain the reporter gene. For infections, MT4-GFP cells were placed in the same medium without G418 and infected overnight with HIV-1 (strain H9 / IIIB) at an approximate multiplicity of infection of 0.01 under the same incubation conditions. The cells were then washed and resuspended in RPMI 1640 supplemented with 10% or 50% normal human serum (NHS) at 1.6 x 105 cells / ml (10% NHS or 50% NHS, respectively) . Compound plates were prepared by dispensing compounds dissolved in DMSO in wells of plates coated with 384-well poly-D-lysine (0.2 μΙ / well) using an ECHO acoustic dispenser. Each compound was tested in a 10-fold serial dilution of 3 times (typical final concentrations: 8.4 μΜ at 0.42 nM). Controls included in the inhibitor (DMSO only) and a combination of three antiviral agents (efavirenz, indinavir, an internal integrase tape transfer inhibitor at final concentrations of 4 μΜ each). The cells were added (50 μΕ / well) to the compound plates and the infected cells were maintained at 37 ° C / 5% CO2 / 90% relative humidity.
[0145] Infected cells were quantified at two points in time, ~ 48 h and ~ 72 h after infection, by counting the number of green cells in each well using an Acumen eX3 scanner. The increase in the number of green cells over a ~ 24 h period provides the reproductive ratio, R0, which is typically 5 to 15 and has been shown experimentally in the logarithmic phase (data not shown). The inhibition of R0 is calculated for each well, and the IC50s determined by adjusting a 4-parameter non-linear curve. The results of the IC50 assay are shown in Table 1.
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EXAMPLE 16
Pro-drug stability test in bio-relevant media [0146] The following test was used to assess the stability of prodrugs under simulated gastrointestinal tract conditions. The preparation of simulated fasting intestinal fluid (FaSSIF) using Powder SIF Phares was performed according to the protocols of Phare Drug Delivery AG (Baselland, Switzerland). For sample preparation, 10 μί of stock solutions (10 mM) of prodrug substance in DMSO were added to 990 μί of 0.5 mg / mL pancreatin solution (Fisher CAS # 8049-47-6) in FaSSIF. Two samples were prepared for each compound. If the sample was a clear solution, it was directly analyzed by HPLC. If the sample was not clear, the sample was diluted with 100% MeCN, maintained at 37 ° C and observed 5 h later. If the sample was clear, the HPLC analysis was performed directly. If the sample is still unclear, the sample was diluted with 100% ACN and evaluated by HPLC. All samples were vortexed for 3 min and observed before injection. For diluted samples, the area is multiplied by a dilution factor when the data is analyzed. The analysis was performed with an Agilent 1100 HPLC with automatic sampler. The column was a Poroshell EC-C18 120, 4.6 x 50 mm, 2.7 μηη. The flow rate was 1.8 mL / min, and the injection volume was 5 or 10 μί. The UV detection was in the range of 210 to 400 nm. The mobile phase consisted of solvent A (water plus 10 mM tetrabutylammonium bromide) and solvent B (acetonitrile) with a gradient of: 90% solvent A at 0 min, changeable to 95% solvent B for 6 min, keeping for 1 , 5 min, then reverting to 90% solvent A for 1.6 min. The peak HPLC area of the prodrug at 5 h was divided by the peak HPLC area of the prodrug at 0 h, to generate the% of the claimed precursor ratio, which is summarized in Table 1 for tract stability gastrointestinal (Gl).
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EXAMPLE 17
Pharmacokinetic Studies in Dogs - Dog PK In Vivo [0147] The prodrugs were administered to beagle dogs through intravenous (IV) and oral (P.O.) administrations in a non-crossed manner. Dose IV was prepared in hydroxypropyl-3-cyclodextrin (HPBCD) at 20% and was administered through the cephalic or saphenous vein. The P.O. dose was prepared in 10% polysorbate 80 (Tween 80) and was administered by gavage. Blood samples were collected in series after administration of the dose for up to 48 h and the plasma was separated by centrifugation. Dog plasma concentrations of prodrugs were determined by an LC-MS / MS assay after a protein precipitation step and the addition of an appropriate internal standard (labetalol, imipramine or diclofenac). Quantification was performed by determining the peak area ratios of the prodrugs and tenofovir to the internal standard. Additional blood samples were collected after administration of the dose for up to 24 h. Peripheral blood mononuclear cells (PBMCs) were isolated by centrifugation, using test tubes and specific reagents for such application. The concentrations of tenofovir and / or its phosphate conjugates in PBMCs were determined by an LC-MS / MS assay after a protein precipitation step and the addition of an appropriate internal standard (labetalol, imipramine or diclofenac). Quantification was performed by determining the peak area ratios of tenofovir and / or its phosphate conjugates for the internal standard.
[0148] The pharmacokinetic parameters were obtained using non-compartmental methods (Watson®). The area under plasma concentration-time plasma (AUCo-t) was calculated from the first point in time (0 min) to the last point in time with measurable drug concentration using the linear trapezoidal rule or linear trapezoidal / log- linear. Plasma clearance IV was calculated by dividing the dose by AUCo-inf. The terminal elimination half-life was determined by unweighted linear regression analysis
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82/84 of the data logged. Time points for determining half-life were selected by visual inspection of the data. The volume of distribution at steady state (Vd _ss ) was obtained from the plasma clearance product and mean residence time (determined by dividing the area under the first moment curve by the area under the curve). The maximum plasma concentration (Cmax) and the time at which the maximum concentration occurred (Tmax) were obtained by inspecting the plasma concentration-time data. The absolute oral bioavailability (F (%)) was determined from the AUC ratios adjusted by dose IV and PO of the prodrug. Table 1 shows the dog PK data in vivo as TFV-DP concentrations (μ) in dog PBMCs at 24 h after a PO dose of 10 mg / kg of the indicated prodrug.
TABLE 1
Example Viking, IC50(NHSa 10%)(nM) Viking, IC50(50% NHS)(nM) Gl Tract Stability (%) Dog In PKAlive (μΜ) IA 23.19 102.50 IB 5.09 13.75 99.35 29.96 2A 22.45 69.78 100.30 23.29 2B 601.30 622.40 3A 88.67 521.30 3B 16.77 70.8812.46 4A 252.40 756.40 4B 7.84 22.67 99.725A 7.52 33.6415.27 5B 540.20 2224.00 6A 5.54 15.4645.66 6B 73.10 246.00 7A 107.30 654.40
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7B 1.08 5.55 95.0 59.5 8A 0.92 11.35 92.12 4.67 8B 7.59 49.76 99.59 9.55 9A 173.30 562.00 9B 8.34 26.37 98.18 5.57 10A 11.38 71.71 99.7510B 283.70 1071.00 11A 2.18 6.39 88.5811B 45.77 301.60 12A 75.44 321.80 96.6912B 13.00 38.60 54.8313A 5.08 21.85 76.99 55.4 13B 99.61 248.00 14A 1.71 7.58 96.7114B 16.74 114.40
[0149] The data for stereoisomers of compounds 15,16 and 17 in the Table are for comparison with the data provided for the stereoisomers of compounds 1, 6 and 7, respectively.
TABLE 2
L-WingCompound / Structure No. Isomer Viking,IC50 (10% NHSa) (nM) Viking,IC50 (NHSa 50%) (nM) Gl Tract Stability(%) Dog In PKLive(μΜ) 15 nh ₂ ^. _o j ° < ⁿ í5 ^{n N} ^ o- ^ o 15A 10160.1 1.9 15B 340 1220
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16 nh ₂ ΆΆ Y / o ^H ° 0 16A 21351.3 1.5 16B 730 1830 17 ^F X Γ AAe ° ϊ ^N A hn ^z I 0 17A 3520.3 2.6 17B 570 2230
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权利要求:
Claims (22)
[1]
1. Compound, characterized by the fact that it presents Formula I:

[2]
2/13 substituents, where each substituent is independently fluorine, chlorine, bromine, -OR ^8a , -SH, -NR ⁶ R ⁷ or -C1-3alkyl, (d) unsubstituted or substituted aryl with one to three substituents, where each substituent is independently fluorine, chlorine, bromine, -OR ^8a , -SH, -NR ⁶ R ⁷ or -C1-3 alkyl, (e) -C1-5 alkyl-X-C1-5 alkyl where X is O, S or NH, (f) heteroaryl unsubstituted or substituted with one to three substituents, where each substituent is independently fluorine, chlorine, bromine, -OR ^8a , -SH, -NR ⁶ R ⁷ or -C1-3 alkyl , or (g) an unsubstituted or substituted heterocyclic ring with one to three substituents, wherein each substituent is independently fluorine, chlorine, bromine, -OR ^8a , -SH, -NR ⁶ R ⁷ or -C1-3 alkyl;
R ⁴ is:
(a) -C1-10 alkyl unsubstituted or substituted with one to three substituents, each substituent being independently fluorine, chlorine, bromine, -CN, -CF3, OR ^5b , -SH, -NR ⁹ R ¹⁰ , -cycloalkyl C3-6 or C3-6 spiro-cycloalkyl, (b) -CHz-phenyl unsubstituted or substituted with one to three substituents, where each substituent is independently fluorine, chlorine, bromine, -OR ^8b , -SH, -NR ⁹ R ¹⁰ or -C1-3 alkyl, (c) -C3-8 cycloalkyl unsubstituted or substituted with one to three substituents, where each substituent is independently fluorine, chlorine, bromine, -OR ^8b , -SH, -NR ⁹ R ¹⁰ or -C1-3alkyl, (d) aryl unsubstituted or substituted with one to three substituents, where each substituent is independently fluorine, chlorine, bromine, -OR ^8b , -SH, -NR ⁹ R ¹⁰ or -C1 alkyl -3, (e) -C1-5-X-C1-5alkyl where X is O, S or NH;
(f) heteroaryl unsubstituted or substituted with one to three substituents,
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[3]
3/13 where each substituent is independently fluorine, chlorine, bromine, -OR ^8b , -SH, -NR ⁹ R ¹⁰ or -C1-3alkyl, or (g) an unsubstituted or substituted heterocyclic ring with one to three substituents , wherein each substituent is independently fluorine, chlorine, bromine, -OR ^8b , -SH, -NR ⁹ R ¹⁰ or -C1-3alkyl;
R ^5a and R ^5b are each independently -H or -C3-6 cycloalkyl;
R ⁶ and R ⁷ are each independently -H, -C1-3alkyl or -cycloalkyl
C3-6;
R ^8a and R ^8b are each independently -H, -C1-3alkyl or -cycloalkyl
C3-6;
R ⁹ and R ¹⁰ are each independently -H, -C1-3 alkyl or -cycloalkyl
C3-6;

[4]
4/13
2. A compound or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that R ¹ and R ² are both the same and are selected from methyl, ethyl, propyl or i-propyl.
A compound or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that R ¹ and R ² are both methyl.
A compound or a pharmaceutically acceptable salt thereof according to claim 3, characterized in that X ¹ is -O- and X ² is -O- or -S-.
[5]
A compound or a pharmaceutically acceptable salt thereof according to claim 3, characterized in that X ¹ is -O- or -S- and X ² is -O-.
[6]
6. A compound or a pharmaceutically acceptable salt thereof according to claim 3, characterized in that R ³ is (a) Cl - ₈ -alkyl, -CH2CH2OH, -CH2CH2CH2OH, -CH2CH2SH, -CH 2 CH ₂ CH 2 _SH; CH2CH2NH2, -CH2CH2CH2NH2, -CH2CF2CH3 or -CH2CH2CF3;
(b) -CFh-phenyl unsubstituted or substituted with one to three substituents, wherein each substituent is independently fluorine, chlorine, bromine, -OR ^8a , -SH, -NR ⁶ R ⁷ or -C1-3 alkyl;
(c) -C3-6 cycloalkyl unsubstituted or substituted with one to three substituents, each substituent being independently fluorine, chlorine, bromine, -OR ^8a , -SH, -NR ⁶ R ⁷ or -C1-3 alkyl;
(d) phenyl or naphthyl unsubstituted or substituted with one to three substituents, wherein each substituent is independently fluorine, chlorine, bromine, -OR ^8a , -SH, -NR ⁶ R ⁷ or -C1-3 alkyl;
(e) -CH2CH2OCH3, -CH2CH2CH2OCH3, -CH2CH2SCH3, -CH2CH2CH2SCH3, CH2CH2NHCH3, -CH2CH2CH2NHCH3;
(f) pyridyl unsubstituted or substituted with one to three substituents, wherein each substituent is independently fluorine, chlorine, bromine, -OR ^8a , -SH, NR ⁶ R ⁷ or -C1-3 alkyl; or
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5/13 (g) piperidinyl, pyrrolidinyl, tetrahydrofuranyl or tetrahydropyranyl unsubstituted or substituted with one to three substituents, where each substituent is independently fluorine, chlorine, bromine, -OR ^8a , -SH, - NR ⁶ R ⁷ or -alkyl C1-3.
[7]
A compound or a pharmaceutically acceptable salt thereof according to claim 6, characterized in that R ⁴ is (a) -C ₈ alkyl, -CH ₂ CH ₂ OH _; -CHzCHzCHzOH, -CH ₂ CH2SH _; -CH2CH2CH2SH, CH2CH2NH2, -CH2CH2CH2NH2, -CH2CF2CH3 or -CH2CH2CF3;
(b) -CH2-phenyl unsubstituted or substituted with one to three substituents, wherein each substituent is independently fluorine, chlorine, bromine, -OR ^8b , -SH, -NR ⁹ R ¹⁰ or -C1-3alkyl;
(c) -C3-6 -cycloalkyl unsubstituted or substituted with one to three substituents, each substituent being independently fluorine, chlorine, bromine, -OR ^8b , -SH, -NR ⁹ R ¹⁰ or -C1-3 alkyl;
(d) phenyl or naphthyl unsubstituted or substituted with one to three substituents, wherein each substituent is independently fluorine, chlorine, bromine, -OR ^8b , -SH, -NR ⁹ R ¹⁰ or -C1-3 alkyl;
(e) -CH2CH2OCH3, -CH2CH2CH2OCH3, -CH2CH2SCH3, -CH2CH2CH2SCH3, CH2CH2NHCH3, -CH2CH2CH2NHCH3;
(f) pyridyl unsubstituted or substituted with one to three substituents independently, wherein each substituent is independently fluorine, chlorine, bromine, -OR ^8b , -SH, -NR ⁹ R ¹⁰ or -C1-3 alkyl; or (g) piperidinyl, pyrrolidinyl, tetrahydrofuranyl or tetrahydropyranyl, each unsubstituted or substituted with one to three substituents, each substituent being independently fluorine, chlorine, bromine, -OR ^8b , -SH, -NR ⁹ R ¹⁰ or alkyl C1-3.
[8]
A compound or a pharmaceutically acceptable salt thereof according to claim 7, characterized by the fact that R ³ is:
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6/13 (a) -C ₈ alkyl, -CH ₂ CH ₂ OH _; -CHzCHzCHzOH, -CH ₂ CH2SH _; -CHzCHzCHzSH, -
CH2CH2NH2, -CH2CH2CH2NH2, -CH2CF2CH3 or -CH2CH2CF3;
(b) -CHz-phenyl unsubstituted or substituted with one to three substituents, where each substituent is independently fluorine, chlorine, bromine, -OR ^8a , -SH,
-N NR ⁶ R ⁷ or -C1-3alkyl; or (c) -C3-6 -cycloalkyl unsubstituted or substituted with one to three substituents, where each substituent is independently fluorine, chlorine, bromine, -OR ^8a , -SH, -NR ⁶ R ⁷ or -C1-3 alkyl, and R ⁴ is:
(a) Cl - ₈ -alkyl, -CHzCHzOH, -CHzCHzCHzOH, -CHzCHzSH, -CH2CH2CH2SH, -
CH2CH2NH2, -CH2CH2CH2NH2, -CH2CF2CH3 or -CH2CH2CF3;
(b) -CHz-phenyl unsubstituted or substituted with one to three substituents, where each substituent is independently fluorine, chlorine, bromine, -OR ^8b , -SH,
-NR ⁹ R ¹⁰ or -C1-3alkyl, or (c) -C3-6cycloalkyl unsubstituted or substituted with one to three substituents, where each substituent is independently fluorine, chlorine, bromine, -OR ^8b , -SH, -NR ⁹ R ¹⁰ or -C1-3alkyl.
[9]
Compound according to any one of claims 1, 6, 7 or 8, characterized by the fact that it presents Formula Ia:
R ^12a R ¹⁴
I / ^ 0 θ _R 12b //
HN ^X
CH ₃ ch ₃ íl CH ₃ o

[10]
10. Compound or a pharmaceutically acceptable salt thereof according to
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7/13 with claim 9, characterized by the fact that n is 0; or n is 1 and (a) R ^lla and R ^llb are independently -H or -C1-3alkyl, and
R ^12a and R ^12b are independently -H or -C1-3alkyl, or R ^12a and R ^12b are joined together with the carbon to which they are both attached to form C3-6 spirocycloalkyl; or (c) R ^lla and R ^llb are independently -H or -C1-3 alkyl, or R ^lla and R ^llb are joined together with the carbon to which they are both attached to form C3-6 spirocycloalkyl, and
R ^12a and R ^12b are independently -H or -C1-3alkyl.
[11]
A compound according to any one of claims 1, 6, 7 or 8, characterized by the fact that it presents Formula Ib:

[12]
12. A compound or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that:
one of X ¹ and X ² is -O- and the other is -O- or -S-;
X ³ is -O- or S;
R ¹ and R ² are both the same alkyl group in which the alkyl group is methyl, ethyl, propyl or i-propyl;
R ³ is -C1-6 alkyl;
R ⁴ is -C1-6 alkyl;
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[13]
13. Compound according to claim 1, characterized by the fact that it is:
2 - (((/ ) - ((((/ ) - 1- (6-amino-9H-purin-9-yl) propan-2-yl) oxy) methyl) (3-isopropoxy-3oxopropoxy) phosphoryl ) propyl amino) -2-methylpropanoate;
2 - ((((S) - ((((/ ) - 1- (6-amino-9H-purin-9-yl) propan-2-yl) oxy) methyl) (3-isopropoxy-3oxopropoxy) phosphoryl) amino) propyl -2-methylpropanoate;
2 - (((/ ) - ((((/ ) - 1- (6-amino-9H-purin-9-yl) propan-2-yl) oxy) methyl) (3-isopropoxy-3oxopropoxy) phosphoryl ) isopropyl amino) -2-methylpropanoate;
2 - ((((S) - ((((/ ) - 1- (6-amino-9H-purin-9-yl) propan-2-yl) oxy) methyl) (3-isopropoxy-3oxopropoxy) phosphoryl) amino) isopropyl -2-methylpropanoate;
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1- ((((/ ) - ((((/ ) - 1- (6-amino-9H-purin-9-yl) propan-2-yl) oxy) methyl) ((l-isopropoxy-
Isopropyl 2-methyl-1-oxopropan-2-yl) amino) phosphoryl) oxy) methyl) cyclopropane-1-carboxylate;
l ^_ (((((S) - ((((/ ) - l- (6-amino-9 / - / - purin-9-yl) propan-2-yl) oxy) methyl) ((l-isopropoxy2 isopropyl-methyl-1-oxopropan-2-yl) amino) phosphoryl) oxy) methyl) cyclopropane-lcarboxylate;
l- (2 - (((/ ) - ((((/ ) - l- (6-amino-9 / - / - purin-9-yl) propan-2-yl) oxy) methyl) (( lysopropoxy-2-ethyl-1-oxopropan-2-yl) amino) phosphoryl) oxy) ethyl) cyclopropane-ethyl carboxylate;
1- (2 - ((((S) - ((((/ ) - 1- (6-amino-9 / - / - purin-9-yl) propan-2-yl) oxy) methyl) ((smoothpropoxy -2-methyl-1-oxopropan-2-yl) amino) phosphoryl) oxy) ethyl) cyclopropane-ethyl carboxylate;
(S) -4 - (((/ ) - ((((/ ) - 1- (6-amino-9 / - / - purin-9-yl) propan-2-yl) oxy) methyl) ( isopropyl (smoothpropoxy-2-methyl-1-oxopropan-2-yl) amino) phosphoryl) oxy) -2-methylbutanoate;
(S) -4 - ((((S) - ((((/ ) - 1- (6-amino-9 / - / - purin-9-yl) propan-2-yl) oxy) methyl) (( isopropyl lysopropoxy-2-methyl-1-oxopropan-2-yl) amino) phosphoryl) oxy) -2-methylbutanoate;
(S) -4 - (((/ ) - ((((/ ) - 1- (6-amine-9 / - / - pu rin-9-yl) propan-2-yl) oxy) methyl Isopropyl ((2-methyl-loxo-1-propoxypropan-2-yl) amino) phosphoryl) oxy) -2-methylbutanoate;
(S) -4 - ((((S) - ((((/ ) - 1- (6-amino-9H-purin-9-yl) propan-2-yl) oxy) methyl) ((2-methyl isopropyl-loxo-1-propoxypropan-2-yl) amino) phosphoryl) oxy) -2-methylbutanoate;
2- ((((( ) - ((((/ ) - 1- (6-amino-9H-purin-9-yl) propan-2-yl) oxy) methyl) ((2-methyl-loxo isopropyl-1-propoxypropan-2-yl) amino) phosphoryl) oxy) methyl) -5-fluorobenzoate;
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2 - (((((S) - ((((/ ) - 1- (6-amino-9H-purin-9-yl) propan-2-yl) oxy) methyl) ((2-methyl-l- isopropyl oxo-1-propoxypropan-2-yl) amino) phosphoryl) oxy) methyl) -5-fluorobenzoate;
2 - ((((S) - ((((/ ) - 1- (6-amino-9H-purin-9-yl) propan-2-yl) oxy) methyl) (3-isopropoxy-3oxopropoxy) phosphoryl) amino) pentyl -2-methylpropanoate;
2- (((/ ) - ((((/ ) - 1- (6-amino-9H-purin-9-yl) propan-2-yl) oxy) methyl) (3-isopropoxy-3-oxopropoxy ) phosphoryl) pentyl) -2-methylpropanoate of pentyl;
3- ((((S) - ((((( ) - 1- (6-amino-9H-purin-9-yl) propan-2-yl) oxy) methyl) ((l-isopropoxy-
Isopropyl 2-methyl-1-oxopropan-2-yl) amino) phosphoryl) oxy) -2,2-dimethylpropanoate;
3- (((( ) - ((((/ ) - 1- (6-amino-9H-purin-9-yl) propan-2-yl) oxy) methyl) ((l-isopropoxy-
Isopropyl 2-methyl-1-oxopropan-2-yl) amino) phosphoryl) oxy) -2,2-dimethylpropanoate;
(S) -3 - ((((S) - ((((/ ) - 1- (6-amino-9 / - / - purin-9-yl) propan-2-yl) oxy) methyl) (( isopropyl lysopropoxy-2-methyl-1-oxopropan-2-yl) amino) phosphoryl) oxy) butanoate;
(S) -3 - (((/ ) - ((((/ ) - 1- (6-amino-9 / - / - purin-9-yl) propan-2-yl) oxy) methyl) ( isopropyl (smoothpropoxy-2-methyl-1-oxopropan-2-yl) amino) phosphoryl) oxy) butanoate;
3- (2 - (((/ ) - ((((/ ) - 1- (6-amino-9 / - / - purin-9-yl) propan-2-yl) oxy) methyl) (( Isopropyl 2-methyl-loxo-1-propoxypropan-2-yl) amino) phosphoryl) oxy) ethyl) benzoate;
3- (2 - ((((S) - ((((/ ) - 1- (6-amine-9 / - / - pyrin-9-yl) propan-2-yl) oxy) methyl) ( Isopropyl (2-methyl-loxo-1-propoxypropan-2-yl) amino) phosphoryl) oxy) ethyl) benzoate;
2- ((((S) - ((((( ) - 1- (6-amino-9H-purin-9-yl) propan-2-yl) oxy) methyl) ((3-isopropoxy-
Propyl 3-oxopropyl) thio) phosphoryl) amino) -2-methylpropanoate;
2- (((( ) - ((((/ ) - 1- (6-amino-9H-purin-9-yl) propan-2-yl) oxy) methyl) ((3-isopropoxy-
Propyl 3-oxopropyl) thio) phosphoryl) amino) -2-methylpropanoate;
Petition 870190087906, of 09/06/2019, p. 99/105
11/13
3 - ((((S) - ((((/ ) - 1- (6-amino-9H-purin-9-yl) propan-2-yl) oxy) methyl) ((2-methyl-1-oxol) - isopropyl (propylthio) propan-2-yl) amino) phosphoryl) oxy) propanoate;
3 - (((/ ) - ((((/ ) - 1- (6-amino-9H-purin-9-yl) propan-2-yl) oxy) methyl) ((2-methyl-l- isopropyl oxol- (propylthio) propan-2-yl) amino) phosphoryl) oxy) propanoate;
3 - ((((/ ) - ((((/ ) - 1- (6-amino-9H-purin-9-yl) propan-2-yl) oxy) methyl) ((2-methyl-loxo isopropyl-1-propoxypropan-2-yl) amino) phosphoryl) oxy) methyl) benzoate;
or
3 - (((((S) - ((((/ ) - 1- (6-amino-9H-purin-9-yl) propan-2-yl) oxy) methyl) ((2-methyl-loxo- isopropyl 1-propoxypropan-2-yl) amino) phosphoryl) oxy) methyl) benzoate;
or a pharmaceutically acceptable salt thereof.
[14]
Pharmaceutical composition, characterized in that it comprises an effective amount of the compound or a pharmaceutically acceptable salt thereof defined in any one of claims 1 to 8, 12 or 13, and a pharmaceutically acceptable carrier.
[15]
Pharmaceutical composition according to claim 14, characterized in that it additionally comprises an effective amount of one or more additional HIV antiviral agents selected from HIV protease inhibitors, HIV integrase inhibitors, non-nucleoside reverse transcriptase inhibitors HIV, nucleoside inhibitors of HIV reverse transcriptase, HIV fusion inhibitors and HIV entry inhibitors.
[16]
16. Pharmaceutical composition according to claim 14, characterized in that it additionally comprises an effective amount of one or more additional HIV antiviral agents selected from abacavir, abacavir sulfate, abacavir + lamivudine, abacavir + lamivudine + zidovudine, amprenavir, atazanavir, atazanavir sulfate, AZT, capravirin, darunavir, didesoxycytidine, didesoxy-inosine, delavirdine, mesylate
Petition 870190087906, of 09/06/2019, p. 100/105
12/13 delavirdine, dolutegravir, doravirine, efavirenz, 4'-ethinyl-2-fluoro-2'deoxyadenosine, elvitegravir, emtricitabine, emivirine, enfuvirtide, etravirine, fosamprenavir calcium, indinavir, indinavirina lamivudine, lamivudine, lamivudine, lamivine, lamivine , lopinavir + ritonavir, maraviroc, nelfinavir, nelfinavir mesylate, nevirapine, PPL-1OO, raltegravir, rilpivirine, ritonavir, saquinavir, saquinavir, stavudine, tipranavir or vicriviroc mesylate.
[17]
17. Use of a compound or a pharmaceutically acceptable salt thereof as defined in any one of claims 1 to 8, 12 or 13, and optionally of one or more additional HIV antiviral agents, characterized in that it is in the manufacture of a single composition or separate compositions for the prophylaxis or treatment of HIV infection or for the prophylaxis, treatment, or delay in the onset of AIDS in an individual in need of it.
[18]
18. Use according to claim 17, characterized by the fact that one or more additional HIV antiviral agents are selected from HIV protease inhibitors, HIV integrase inhibitors, non-nucleoside HIV reverse transcriptase inhibitors, nucleoside inhibitors of HIV HIV reverse transcriptase, HIV fusion inhibitors and HIV entry inhibitors.
[19]
19. Use according to claim 18, characterized in that one or more additional HIV antiviral agents are selected from abacavir, abacavir sulfate, abacavir + lamivudine, abacavir + lamivudine + zidovudine, amprenavir, atazanavir, atazanavir sulfate, AZT, capravirin, darunavir, didesoxycytidine, didesoxy-inosine, delavirdine, delavirdine mesylate, dolutegravir, doravirine, efavirenz, 4'-ethinyl-2-fluoro-2'-deoxyadenosine, elvitegravir, emtricitabine, emtricitabine, emiricitin , indinavir, indinavir sulfate, lamivudine, lamivudine + zidovudine, lopinavir, lopinavir + ritonavir, maraviroc, nelfinavir, nelfinavir mesylate, nevirapine, PPL-1OO, raltegravir, rilavivine, ritonavirine, ritonavirquin, ritonavirquin, ritonavirquin
Petition 870190087906, of 09/06/2019, p. 101/105
13/13 saquinavir, stavudine, tipranavir or vicriviroc.
[20]
20. Use according to any one of claims 17 to 19, characterized by the fact that the individual is human.
[21]
21. A compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 8.12 or 13, characterized in that it is for use in the preparation of a medicament for the prophylaxis or treatment of HIV infection or for prophylaxis , treatment or delay in the onset of AIDS in an individual in need.
[22]
22. Invention of a product, process, system, kit or use, characterized by the fact that it comprises one or more elements described in the present patent application.

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同族专利:

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公开号 | 公开日

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CN110099912B|2021-10-15|

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US10519159B2|2019-12-31|

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CA3047573A1|2018-06-28|

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US20180179208A1|2018-06-28|

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AU2017379850A1|2019-06-13|

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TW201829412A|2018-08-16|

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RU2759902C2|2021-11-18|

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JP6938637B2|2021-09-22|

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MA47094A|2021-05-26|

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MX2019007585A|2019-09-09|

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CN110099912A|2019-08-06|

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RU2019122414A|2021-01-25|

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EP3559011A1|2019-10-30|

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WO2018119013A1|2018-06-28|

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RU2019122414A3|2021-04-26|

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JP2020504733A|2020-02-13|

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KR20190100250A|2019-08-28|

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法律状态:
2021-10-13| B350| Update of information on the portal [chapter 15.35 patent gazette]|

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2022-02-15| B06W| Patent application suspended after preliminary examination (for patents with searches from other patent authorities) chapter 6.23 patent gazette]|

优先权:

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申请号 | 申请日 | 专利标题

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US201662437753P| true| 2016-12-22|2016-12-22|

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US201762574493P| true| 2017-10-19|2017-10-19|

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PCT/US2017/067470|WO2018119013A1|2016-12-22|2017-12-20|Antiviral aliphatic ester prodrugs of tenofovir|

---