 benzyl amine phosphodiamide antiviral compounds, pharmaceutical composition and use of the compound
专利摘要:
The compounds of formula I and their pharmaceutically acceptable salts are useful for inhibiting hiv reverse transcriptase. The compounds may also be useful for the prophylaxis or treatment of HIV infection and prophylaxis, delayed onset or progression, and treatment of AIDS. The compounds and their salts may be used as ingredients in pharmaceutical compositions, optionally in combination with other antiviral agents, immunomodulators, antibiotics or vaccines. 公开号:BR112019012511A2 申请号:R112019012511-6 申请日:2017-12-19 公开日:2019-11-19 发明作者:RAHEEM Izzat；Paparin Jean-Laurent；Schreier John；De Lera Ruiz Manuel；J Hartingh Timothy 申请人:Idenix Pharmaceuticals Llc；Merck Sharp & Dohme； IPC主号:
专利说明:
ANTIVIRAL BENZYL-AMINE PHOSPHODIAMIDE COMPOUNDS, PHARMACEUTICAL COMPOSITION AND USE OF THE COMPOUND 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 that makes them highly susceptible to debilitating and basically 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 its 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 already produced from the original RNA. During the viral RNA-dependent polymerization process, RT ribonuclease activity is required to remove the RNA and leave the polyipurin tract preserved for the start of DNA-dependent polymerization. Like a DNA-dependent DNA polymerase, RT creates a secondary complementary DNA strand using the first DNA strand as a standard. The two strands form double-stranded DNA, which is integrated into the cell's genome Petition 870190056148, of 06/17/2019, p. 585/693 2/95 host by HIV integrase. [003] It is known that compounds that inhibit HIV RT enzymatic functions 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 NsRTI's include 3'-azido-3'-deoxythymidine (AZT), 2 ', 3'-didesoxyinosine (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 is also known as a nucleoside reverse transcriptase translocation inhibitor. Examples of NtRTIs include tenofovir (TFV, also known as PMPA, 9- (2-phosphonylmethoxypropyl) adenine), tenofovir disoproxyl fumarate (VIREAD®, U.S. Patent No. 5977089, US5935946) and tenofovir alafenamide fumarate (U.S. Patent N —7390791, 8,754,065). [004] TFV belongs to a class of HIV antiretroviral agents (ARV) known as nucleotide analog reverse transcriptase inhibitors (NRTIs). Tenofovir is a monophosphonate: [005] After being absorbed by cells, TFV is first converted to tenofovir-monophosphate (TFV-MP) by the adenosine monophosphate kinase and then Petition 870190056148, of 06/17/2019, p. 586/693 3/95 to active antiviral tenofovir-diphosphate (TFV-DP) by the 5'-nucleoside diphosphate kinase. Tenofovir-diphosphate (TFV-DP) Tenofovir-monophosphate (TFV-MP) [006] TFV-DP inhibits the synthesis of HIV DNA by competition with the natural substrate, deoxyadenosine triphosphate, for incorporation into the Complementary DNA by HIV reverse transcriptase; following incorporation, TFV acts as a chain terminator due to the lack of a 3'-hydroxyl group that is necessary for the addition of the next nucleotide. TFV has poor 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 disoproxyl prodrug improves cell permeability and absorption after oral dosing, with the pro-portion being cleaved quickly after absorption to produce 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 the pharmaceutical products GENVOYA®, ODEFSEY® and DESCOVY®. [007] Although each of the preceding 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 to known inhibitors. The use of RT inhibitors to treat Petition 870190056148, of 06/17/2019, p. 587/693 4/25 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 HIV strains. SUMMARY OF THE INVENTION [008] The present invention is directed to tenofovir benzylamine prodrugs and their use in nucleotide inhibition of reverse transcriptase. In addition to the use of said compounds in inhibiting HIV reverse transcriptase, the invention is also directed to the use of said compounds for the prophylaxis of HIV infection, the treatment of HIV infection, and the prophylaxis, treatment, and / or delay in onset or progression of AIDS and / or ARC. DETAILED DESCRIPTION OF THE INVENTION [009] The present invention is directed to compounds of Formula I: or a pharmaceutically acceptable salt thereof, where: R e-C 1-6 alkyl; R 2 is -C1- alkyl; 2 or R and R are bonded with the carbon to which they are both attached to form C3-6 spiro-cycloalkyl; Petition 870190056148, of 06/17/2019, p. 588/693 5/95 η 3 'R e: (a) -C1-10 alkyl unsubstituted or substituted with one, two or three of r C fi 7 fluorine, chlorine, bromine, -CN, -CF 3 , -OR, -SR, -NR R, -C3 cycloalkyl 6 or C3-6 spirocycloalkyl, (b) -CH 2 -phenyl unsubstituted or substituted with one, two or three of fluorine, chlorine, bromine, -OR 4 , -SR, -NR 6 R 7 or -C1-3 alkyl , (c) -C3-8 -cycloalkyl unsubstituted or substituted with one, two or three of fluorine, chlorine, bromine, -OR 4 , -SR, -NR 6 R 7 or -C1-3alkyl, (d) non-aryl substituted or substituted with one, two or three of fluorine, chlorine, bromine, -OR 4 , -SR, -NR 6 R 7 or -C1-3alkyl, (e) -C1-5-X-C1-5alkyl that X is O, S or NH, (f) heteroaryl unsubstituted or substituted with one, two or three of fluorine, chlorine, bromine, -OR 4 , -SR, -NR 6 R 7 or -C1-3alkyl, or (g) an unsubstituted or substituted heterocyclic ring with one, two or three of fluorine, chlorine, bromine, -OR 4 , -SR, -NR 6 R 7 or -C1-3 alkyl; R is -H, -CF 3 , -C1-3 alkyl or -C3-6 cycloalkyl; ç R eH, -CF 3 or C3-6-cycloalkyl; R 4 is -H, -CF 3 , -C1-3 alkyl or -C3-6 cycloalkyl; R 5 is -H, -CF 3 or -C3-6 cycloalkyl; β R is -H, -C1-3 alkyl or -C3-6 cycloalkyl; R 7 is -H, -C1-3 alkyl or -C3-6 cycloalkyl. The R is -H or -C 1-3 alkyl; g R e -H, -C1- alkyl or -C1- alkyl substituted with 1 to 3 of F; R e -H, -C1- alkyl or -C1- alkyl substituted with 1 to 3 of F; or R 9 and R 10 are linked with the carbon to which both are attached to Petition 870190056148, of 06/17/2019, p. 589/693 6/95 to form C3-6 spiro-cycloalkyl; R a is halo, -CN, -C1- alkyl, -C1- alkyl substituted with 1 to 3 of F, -O-C1-6 alkyl or -O-C1-6 alkyl substituted with 1 to 3 of F; and R is -H, halo, -CN, -C1- alkyl, -C1- alkyl substituted with 1 to 3 of F, -0C-alkyl or -O-C1-6 alkyl substituted with 1 to 3 of F. [010] In Mode 1 of this invention are the compounds of Formula I that have structural Formula Ia: or pharmaceutically acceptable salts thereof, wherein R 3 , R 8 , R 9 , R 10 , R a , R b and all additional variables are as defined in Formula I. [011] In Mode 2 of this invention are the compounds of Formula I, or pharmaceutically acceptable salts thereof, wherein R and R are independently selected from -C1-4alkyl, or R and R are joined together with the carbon to which they are attached. they are both bonded to form C3-6 spiro-cycloalkyl (e.g., spiro-cyclopropyl). In a class of this modality, R1 and R are the same selected portion of -Cl4 alkyl, or R and R are bonded with the carbon to which both are attached to form C3-6 spiro-cycloalkyl (for example, spiro-cyclopropyl ). In another class of this modality, R and R are the same portion where the portion is methyl, ethyl or propyl, or R and R are bonded with the carbon to which they are both attached to form spirocyclopropyl. In another class of this modality R and R are both methyl. Petition 870190056148, of 06/17/2019, p. 590/693 7/95 [012] In Mode 3 of this invention are the compounds of Formula I, Formula Ia, or Mode 2, or each class thereof, or pharmaceutically acceptable g salts of each of the foregoing, where R is -H or - CH 3 . [013] In Mode 4 of this invention are the compounds of Formula I, Formula Ia, or Mode 2 or 3, or each class thereof, or pharmaceutically acceptable salts of each of the foregoing, where R and R are independently -H, -C1-3alkyl or -C1-3alkyl substituted with 1 to 3 of F, or R 9 and R 10 are bonded with the carbon to which they are both attached to form C3-6 spiro-cycloalkyl (for example, spiro-cyclopropyl ). In a class thereof, R and R are independently -H, -CH 3 or -CF 3 , or R and R are bonded with the carbon to which they are both attached to form C3-6 spirocycloalkyl (for example, spiro-cyclopropyl) . [014] In Mode 5 of this invention are the compounds of Formula I, Formula Ia, or Mode 2, 3 or 4, or each class thereof, or pharmaceutically acceptable salts of each of the foregoing, where R is -H or - CH 3 , or R10 is joined with R 9 and the carbon to which both are attached to form C3-6 spiro-cycloalkyl (for example, spiro-cyclopropyl). [015] In Mode 6 of this invention are the compounds of Formula I, Formula Ia, or Mode 2, or 3, or each class thereof, or pharmaceutically acceptable salts of each of the foregoing, where R and R are the same portion selected from -C1- alkyl. In another class of this modality, R 9 and R 10 are the same portion in which the portion is methyl, ethyl or propyl. In another class of this modality R and R are both methyl. [016] In Mode 7 of this invention are the compounds of Formula I, Formula Ia, or Mode 2, 3, 4, 5 or 6, or each class thereof, or salts Petition 870190056148, of 06/17/2019, p. 591/693 8/95 pharmaceutically acceptable from each of the foregoing, where R a is halo, CN, -C1-3 alkyl, -C1-3 alkyl substituted with 1 to 3 of F, -O-C1-3 alkyl or -O- C1-3 alkyl substituted with 1 to 3 of F. In such a class, R a is F, Cl, Br, -CN, -C1-3 alkyl (for example, -CH 3 , / -Pr), -CF 3 , -OCH 3 or OCF 3 . [017] In Mode 8 of this invention are the compounds of Formula I, Formula Ia, or Mode 2, 3, 4, 5, 6 or 7, or each class thereof, or pharmaceutically acceptable salts of each of the foregoing, where R is H, halo, -CN, -C1-3 alkyl, -C1-3 alkyl substituted with 1 to 3 of F, -O-C1-3 alkyl or -O-C1-3 alkyl substituted with 1 to 3 of F In such a class, R is -H, F, Cl, -CN, -C1-3alkyl (for example, -CH3, / -Pr), -CF 3 , -OCH 3 or -OCF 3 . [018] In Mode 9 of this invention are the compounds of Formula I, Formula Ia, or Mode 2, 3, 4, 5, 6, 7 or 8, or each class thereof, or pharmaceutically acceptable salts of each of the foregoing, where R is: (a) -C 8 alkyl, -CH 2 CH 2 OH ; -CH 2 CH 2 CH 2 OH ; -CH 2 CH 2 SH ; -CH 2 CH 2 CH 2 SH ; CH 2 CH 2 NH 2 , -ch 2 ch 2 ch 2 nh 2 , (b) -CH 2 -phenyl, unsubstituted or substituted with one, two or three substituents independently selected from fluorine, chlorine, bromine, -OR 4 , SR, -NR 6 R 7 or -C1-3 alkyl, (c) -C3-6 cycloalkyl, unsubstituted or substituted with one, two or three substituents independently selected from fluorine, chlorine, bromine, -OR 4 , SR -NR 6 R 7 or -C1-3 alkyl, (d) phenyl or naphthyl, each unsubstituted or substituted with one, two or three substituents independently selected from fluorine, chlorine, bromine, OR4, -NR6R7 or -C1-3 alkyl, (e) -CH 2 CH 2 OCH 3; -CH 2 CH 2 OCH 2 CH 3 , -CH 2 CH 2 CH 2 OCH 3; -CH 2 CH 2 CH 2 OCH 2 CH 3 , Petition 870190056148, of 06/17/2019, p. 592/693 9/95 -CH 2 CH 2 SCH 3; -CH 2 CH 2 SCH 2 CH 3; -CH 2 CH 2 CH 2 SCH 3; -CH2CH2CH2SCH2CH3, CH2CH2NHCH3, -CH2CH2NHCH2CH3, -CH2CH2CH2NHCH3, or CH2CH2CH2NHCH2CH3; (f) pyridyl, unsubstituted or substituted with one, two or three substituents independently selected from fluorine, chlorine, bromine, OR 4 , SR, -NR 6 R 7 or -C1-3alkyl, or (g) piperidinyl, pyrrolidinyl, tetrahydrofuranyl, or tetrahydropyranyl, each unsubstituted or substituted with one, two or three substituents independently selected from fluorine, chlorine, bromine, OR, -SR, -NR R or C1-3 alkyl. (i) In a first class of Mode 9, R is -C1-8 alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or -C1-3-O-C1-3 alkyl. (ii) In a second class of Type 9, R is -C1- alkyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. (iii) In a third class of Mode 9, R is -C1-4alkyl (for example, propyl or / -propyl). [019] In Mode 10 of this invention are the compounds of Formula I, or pharmaceutically acceptable salts thereof, wherein R and R are both methyl, ethyl, propyl or / -propyl; R e-Ci-e alkyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; The R is -H or -C 1-3 alkyl; g R and -H, -C1-3 alkyl or -C1-3 alkyl substituted with 1 to 3 of F; R and -H, -C1-3 alkyl or -C1-3 alkyl substituted with 1 to 3 of F; or R 9 and R 10 are bonded with the carbon to which they are both attached to form C3-6 spiro-cycloalkyl; R a is halo, -CN, -C1-3 alkyl, -C1-3 alkyl substituted with 1 to 3 of F, -O-C1- alkyl alkyl 870190056148, of 06/17/2019, p. 593/693 10/95 or -O-C1-3 alkyl substituted with 1 to 3 of F; and R is -H, halo, -CN, -C1-3 alkyl, -C1-3 alkyl substituted with 1 to 3 of F, -O-C1-3 alkyl or -O-C1-3 alkyl substituted with 1 to 3 of F. [020] In Form 11 of this invention are the compounds of Formula I, or pharmaceutically acceptable salts thereof, where 2 R and R are both methyl, R is -C1-4 alkyl (e.g., propyl or i-propyl); R 8 is -H or -CH 3 ; R 9 is -H, -CH 3 or -CF 3 ; R 10 is -H or -CH 3 ; or R 9 and R 10 are joined with the carbon to which they are both attached to form spiro-cyclopropyl; R a is F, Cl, Br, -CN, -C1-3alkyl, -CF 3 , -OCH 3 or -OCF 3 ; and R b is -H, F, Cl, Br, -CN, -C1-3alkyl, -CF 3 , -OCH 3 or -OCF 3 . [021] Reference to the compounds of Formula I in the present invention encompasses the compounds of Formula I and Ia and all their modalities, classes and subclasses and includes the compounds of the Examples of the present invention. [022] 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. [023] As used here, alkyl refers to both straight and branched saturated aliphatic hydrocarbon groups having the specific number of carbon atoms in a specific range. For example, the term Cl-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 isomers , heptyl, hexyl and pentyl so Petition 870190056148, of 06/17/2019, p. 594/693 11/95 as n-, iso-, sec- and tert-butyl (butyl, / -butyl, s-butyl, t-butyl, collectively C 4 alkyl; Bu = butyl), n- and / -propyl (propyl, / -propyl, collectively C 3 alkyl; Pr = propyl), ethyl (Et) and methyl (Me). C1-6 alkyl has 1, 2, 3, 4, 5 or 6 carbon atoms and includes each of the alkyl groups within C1-8 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 ipropyl, ethyl and methyl. C1-3 alkyl has 1, 2 or 3 carbon atoms and each includes n-propyl, / -propyl, ethyl and methyl. [024] Cycloalkyl refers to a cyclized alkyl ring having the indicated number of carbon atoms in a specific range. Thus, for example, C3-8 cycloalkyl each includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloeptyl and cyclooctyl. C3-8 cycloalkyl each includes cyclopropyl, 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 illustrations of a C3-6 -cycloalkyl substituent on an alkyl group, where the substituent is bold cyclopropyl: the o o [025] Spiro-cycloalkyl C3-6 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. Spiro-cycloalkyl C3-6 each includes spiro-cyclopropyl, spiro-cyclobutyl, spiro-cyclopentyl and spirocyclohexyl. The following are illustrations of a C3-6 spirocycloalkyl substituent on an alkyl group in which the substituent is spiro-cyclopropyl in bold: Petition 870190056148, of 06/17/2019, p. 595/693 12/95 [026] Examples of -C1-5-X-C1-5alkyl groups include, but are not limited to, -CH 2 CH 2 OCH 3; -CH 2 CH 2 OCH 2 CH 3 , -CH 2 CH 2 CH 2 OCH 3; CH 2 CH 2 CH 2 OCH 2 CH 3 , -ch 2 ch 2 sch 3; -CH 2 CH 2 SCH 2 CH 3; -CH 2 CH 2 CH 2 SCH 3; ch 2 ch 2 ch 2 sch 2 ch 3; -ch 2 ch 2 nhch 3 , -ch 2 ch 2 nhch 2 ch 3 , -CH 2 CH 2 CH 2 NHCH 3 , or ch 2 ch 2 ch 2 nhch 2 ch 3 . [027] Arila (Ar) refers to (i) phenyl, (ii) bicyclic carbocyclic ring systems, fused of 9 or 10 members in which at least one ring is aromatic, and (iii) tricyclic carbocyclic ring systems, 11 to 14 member cast in which 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. [028] Halo or halogen refers to chlorine (Cl), fluorine (F), bromine (Br) or iodine (I); chlorine, fluorine and bromine are a class of halogens of interest, and particularly chlorine and fluorine. [029] Heteroaryl refers to (i) a 5- or 6-membered heteroaromatic ring containing 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 than one heteroatom, at least one ring is aromatic, each N is optionally in the form of an oxide, and each S in a ring that is non-aromatic is optionally S (O) or S (O) 2- Examples of rings Petition 870190056148, of 06/17/2019, p. 596/693 13/95 5-membered heteroaromatics include, but are not limited to, pyrrolyl, pyrazolyl, triazolyl (that is, 1,2,3-triazolyl or 1,2,4-triazolyl), triazolinone (for example, 2,4- dihydro-3 / - / - 1,2,4-triazol-3-one), imidazolyl, tetrazolyl, furanyl, furanonyl (e.g., furan-2 (5 / - /) - one), thienyl, thiazolyl, isothiazolyl, oxazolyl, isooxazolyl, oxadiazolyl (i.e., 1,2,3-, 1,2,4-, l, 2,5- (furazanil), or 1,3,4-oxadiazolyl isomer), 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 [1,2-a] pyridinyl, benzotriazolyl, indazolyl, indolinyl, and isoindolinyl. A class of heteroaryl includes (1) thienyl, furyl, thiazolyl and unsubstituted or substituted oxazolyl, and (2) a 6-membered heteroaryl comprised of carbon atoms and 1 or 2 N heteroatoms, for example, pyrimidinyl, pyrazinyl or pyridazinyl . [030] 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 heteroatoms independently selected from 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, tiperazolidinyl, tiperazolidinyl, tiperazine -hydrothienyl, pyrazolidinyl, hexahydropyrimidinyl, thiazinanil, thiazepanyl, azepanyl, diazepanyl, tetrahydropyranyl, tetrahydrothiopyranil, and dioxanil. Examples of 4 to 7 heterocyclic rings Petition 870190056148, of 06/17/2019, p. 597/693 14/95, unsaturated, non-aromatic members within the scope of this invention include monounsaturated heterocyclic rings corresponding to the saturated heterocyclic rings listed in the preceding sentence in which a single bond is replaced with a double bond (for example, a single carbonocarbon bond is replaced with a carbon-carbon double bond). [031] 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 heterocyclic rings from 4 to 6 members include, but are not limited to, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, tetrahydrofuranyl, tetrahydropyranyl and tetrahydrothiopyranyl, and a subclass of these is piperidinyl, pyrrolidinyl, tetrahydrofuran and tetrahydrofuran. [032] It is understood that specific rings and ring systems suitable for use in the present invention are not limited to those listed in the preceding paragraphs. These rings and ring systems are merely representative. [033] 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 isolated individually or in mixtures, are within the scope of the present invention. For example, in examples where a -OH substituent is allowed on a heteroaromatic ring and keto-enol tautomerism is possible, it is understood that the substituent could, in fact, be present, in whole or in part, in the form of oxo ( = 0). [034] A stable compound is a compound that can be prepared and isolated and whose structure and properties remain, or can be made with Petition 870190056148, of 06/17/2019, p. 598/693 15/95 which remain 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 adopted by Formula I and its modalities. For example, certain portions as defined in Formula I may be unsubstituted or substituted, and these are intended to cover substitution patterns (that is, the number and type of substituents) that are chemically possible for the portion and that result in a stable compound. [035] Each compound of Formula I is comprised of a phosphodiamide having a chiral center (/ ) Defined in the alkyl ether linking group that connects the nucleobase to phosphorus as shown in Formula I, and may have one or more chiral centers depending on the selection of the substituent. For example, each of the compounds of Examples 1 to 37 in the present invention 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 that have the stereo-configuration (/ ) Or (5) in an asymmetric phosphorus center and any additional asymmetric centers that may be present in a Formula I compound, as well as stereoisomeric mixtures of the themselves. [036] 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 ratios. The embodiments of this invention also include a blend of epimers enriched with 51% or more of one of the epimers, including Petition 870190056148, of 06/17/2019, p. 599/693 16/95 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 unique 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 opposite epimer. Thus, individual diastereomers are an object of the invention in pure form, both as levogyrous and dextrogyrous antipodes, in the form of racemates and in the form of mixtures of the two diastereomers in all reasons. In the case of a cis / trans isomerism the invention includes both the cis form and the trans form as well as mixtures of these forms in all ratios. [037] 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. Absolute stereochemistry can be determined by X-ray crystallography of crystalline products or crystalline intermediates which are derived, if necessary, with a reagent containing a stereogenic center of known configuration. Alternatively, the absolute stereochemistry can be determined by spectroscopic analysis by Vibrational Circular Dichroism (VCD). The present invention includes all such isomers, as well as salts, solvates (which includes hydrates) and solvated salts of such racemates, enantiomers, diastereomers and tautomers and mixtures thereof. Petition 870190056148, of 06/17/2019, p. 600/693 17/95 [038] Atoms in a Formula I compound can exhibit their natural isotopic abundances, or one or more of the atoms can be artificially enriched in a particular isotope that has 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, isotopic forms other than hydrogen (H) include protium (H) and deuterium (H). Procium is the predominant hydrogen isotope found in nature. Deuterium enrichment may provide certain therapeutic advantages, such as increased in vivo half-life or reduced dosage requirements, or it may provide a useful compound as a standard for the characterization of biological samples. Isotopically enriched compounds of Formula I can be prepared without undue experimentation by conventional techniques well known to the skilled artisan or by processes analogous to those described in the schemes and Examples in the present invention using appropriate isotopically enriched reagents and / or intermediates. [039] 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 by definition contain at least one basic group, the 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 Petition 870190056148, of 06/17/2019, p. 601/693 18/95 (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. 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 inorganic or organic acids such as, 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, 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, citric acid, adipic acid, etc. If the compounds of Formula I simultaneously contain 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 customary methods 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 from 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 Petition 870190056148, of 06/17/2019, p. 602/693 19/95 intermediates for chemical reactions or for the preparation of pharmaceutically acceptable salts. [040] 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 comprised of said associated compound together with one or more molecular components and / or additional ionic compounds that can be referred to as a co-crystal. The term cocrystal 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 non-ionic interactions including but not limited to hydrogen bonding, dipole-dipole interactions, dipole-quadrupole interactions or dispersion forces (van der Waals). There is no proton transfer between the dissimilar components and the solid phase is neither a simple salt nor a solvate. A discussion of co-crystals can be found, for example, in S. Aitipamula et a!., Cristal Growth and Design, 2012, 12 (5), pages 2147-2152. [041] More specifically with reference to this invention, a co-crystal is comprised 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, they are not toxic or otherwise harmful to their 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 techniques. 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 Petition 870190056148, of 06/17/2019, p. 603/693 20/95 an appropriate solvent to obtain dissolution and, for example, precipitating, lyophilizing or concentrating the solution to obtain the solid composition. The cocrystal may be, but is not limited to, a embodiment in which the composition is comprised 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 to cool and the crystals to grow. The present invention also includes all the 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, as intermediates for chemical reactions or for the preparation co-crystals or pharmaceutically acceptable salts. [042] In addition, the compounds of the present invention may 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. [043] Consequently, compounds of Formula I or salts thereof Petition 870190056148, of 06/17/2019, p. 604/693 21/95 including pharmaceutically acceptable salts thereof, modalities thereof and specific compounds described and claimed in the present invention, encompass stereoisomers, tautomers, physical forms (eg amorphous and crystalline forms), co-crystal forms, solvate forms and hydrate, and any combination of the preceding forms where such forms are possible. [044] The compounds of Formula I described in the present invention are prodrugs. A discussion of prodrugs is provided in (a) Stella, V. J .; Borchardt, R. T .; Hageman, M. J .; Oliyai, R .; Maag, H. et al. Prodrugs: 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 of the A.C.S. Symposium Series, and (d) Bioreversible Carriers in Drug Design, (1987) Edward B. Roche, ed., American 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 prodrug, which is a monophosphonate. The compounds described in the present invention 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 . Although 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 Petition 870190056148, of 06/17/2019, p. 605/693 22/95 compound of Formula I or a pharmaceutically acceptable salt thereof, to an individual. [045] 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 suitably means 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) consists of the compound or salt. The level of purity of the compounds and salts can be determined using a standard method of analysis 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 controls. 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. [046] Formula I compounds and pharmaceutically acceptable salts of Petition 870190056148, of 06/17/2019, p. 606/693 23/95 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 the polymerase function of HIV-1 reverse transcriptase. The testing of the compounds of the Examples of this invention in the Viking assay shown in Example 38 below, illustrates the ability of compounds of the invention to inhibit the HIV-1 reverse transcriptase RNA-dependent DNA polymerase activity. The compounds of Formula I can also be useful agents against HIV-2. The compounds of Examples 1 to 37 of the present invention can also exhibit activity against drug resistant forms of HIV (e.g., mutant strains associated with NNRTI K103N and / or Y181C; mutant strains associated with NRTI, mutants of M184V and M184I). [047] 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. [048] The invention further 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 anti-HIV 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, transcriptase inhibitors Petition 870190056148, of 06/17/2019, p. 607/693 24/95 HIV reverse, HIV integrase inhibitors, HIV fusion inhibitors, HIV entry inhibitors, and HIV maturation inhibitors. [049] 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 agents HIV antivirals, 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. [050] The compounds of this invention may also be useful for the 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. [051] The 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 delayed onset of AIDS in an individual in need of it. [052] Other embodiments of the present invention include the following (where the reference to Formula I covers the compounds of Formula I or Ia, and each Petition 870190056148, of 06/17/2019, p. 608/693 25/95 one of the modalities, classes and subclasses thereof, and each of the compounds of the Examples of the present 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 (e.g., 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-infective 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 HIV reverse transcriptase inhibitors, non-nucleoside inhibitors of HIV reverse transcriptase, 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 anti-HIV agents, immunomodulators, and anti-infective agents; wherein the compound and the anti-HIV agent are all 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 of, or delay onset or progression of AIDS. Petition 870190056148, of 06/17/2019, p. 609/693 26/95 (f) The combination of (e), where 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 , HIV integrase inhibitors, 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 (e.g., HIV-1) in an individual in need thereof that comprises administering to the individual an effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof. (i) The method of (h), wherein the Formula I compound 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 HIV protease inhibitors , HIV integrase inhibitors, non-nucleoside HIV reverse transcriptase inhibitors, nucleoside HIV 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, inhibitors Petition 870190056148, of 06/17/2019, p. 610/693 27/95 HIV integrase, non-nucleoside inhibitors of HIV reverse transcriptase, nucleoside inhibitors of HIV reverse transcriptase, HIV fusion inhibitors, HIV entry inhibitors and HIV maturation inhibitors. (l) A method for the inhibition of HIV reverse transcriptase in an individual in need of the same which comprises administering to the individual the pharmaceutical composition of (a), (b), (c) or (d) or the combination of (and ) 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 thereof that comprises administering to the individual the pharmaceutical composition of (a), (b), (c) or (d) or the combination of (e) or (f). [053] The present invention also includes compounds of Formula I or Ia and each of its modalities, classes and subclasses, and each of the compounds of the Examples of the present invention, or pharmaceutically acceptable salts of the foregoing (i) for use in, (ii) for use as a medicine for, or (iii) for use in the preparation of a medicine for: (a) therapy (for example, of the human body), (b) medicine, (c) reverse transcriptase inhibition of HIV, (d) treatment or prophylaxis of HIV infection, or (e) treatment, prophylaxis of, or delay in the 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 anti-HIV agents against HIV, anti-infective agents, and immunomodulators. [054] Additional embodiments of the present invention include each of the compounds of Formula I, and pharmaceutical compositions, combinations, and Petition 870190056148, of 06/17/2019, p. 611/693 28/95 methods and uses presented in the preceding paragraphs, in which the compound or its salt used in these 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 is in reference to a compound of Formula I or its salt per se. [055] Nevertheless, the additional 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) to (iii) (a) a (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 antiviral against HIV-1 selected from the group consisting of HIV protease inhibitors. -1, HIV-1 reverse transcriptase inhibitors, HIV-1 integrase inhibitors, HIV-1 fusion inhibitors, HIV-1 entry inhibitors and HIV-1 maturation inhibitors. The compounds of Formula I can also be useful agents against HIV-2. [056] In all embodiments etc., of the present invention, the compound can optionally be used in the form of a pharmaceutically acceptable salt. [057] The term administration and variants thereof (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 provided 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 Petition 870190056148, of 06/17/2019, p. 612/693 29/95 variants are all understood to include supplying the compound and other agents at the same time or at different times. When the 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. [058] As used here, the term composition is intended to cover a product comprising the specific ingredients, as well as any product that results from the combination of the specific 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 their receptor. [059] The term individual or patient as used here refers to an animal, preferably a mammal, most preferably a human being, who has been the object of treatment, observation or experiment. [060] The term effective amount as used herein means an amount of a compound sufficient to inhibit HIV reverse transcriptase, 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 foregoing that can also be referred to here as an effective amount of inhibition) , treat HIV infection, treat AIDS, delay the onset of AIDS, and / or slow the progression of ARC or AIDS in an HIV-infected patient. Another embodiment of the effective amount is a prophylactically effective amount which is an amount of the compound that is effective for the prophylaxis of HIV infection in an individual not infected with HIV, or prophylaxis of ARC or AIDS in an infected patient. Petition 870190056148, of 06/17/2019, p. 613/693 30/95 for HIV. 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 infected individual. with HIV. The term prevent, as used in the present invention with respect to an HIV or AIDS viral infection, 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-salt 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 simultaneously effective, but where an agent component of the combination can to be present or not individually in an effective amount with reference to what is considered effective for the component agent if it has been administered alone. [061] In the method of the present invention (i.e., inhibition of HIV reverse transcriptase, treatment or prophylaxis of HIV infection, inhibition of HIV replication, treatment or prophylaxis of AIDS, delayed onset of AIDS, or delayed or reduced progression of AIDS), the compounds of this invention, optionally in the form of a salt, can be administered by means that produce contact of the active agent with the agent's site of action. They can be administered by conventional means available for use in combination 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 carrier Petition 870190056148, of 06/17/2019, p. 614/693 31/95 pharmacist selected from the basis of 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 injections, intravenous, intramuscular or intrasternal injection, or infusion techniques), by inhalation spray, or rectally , in the form of a unit dosage 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. [062] 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, agents disintegrating and the like. 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 solution Petition 870190056148, of 06/17/2019, p. 615/693 32/95 saline, 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 carrier comprises the active chemical ingredient with polymers as suitable excipients, or using an implantable device for drug delivery. Another description of methods suitable 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. [063] Formulations of compounds described by Formula I that result in rapid supersaturation and / or dissolution of drug can be used to facilitate oral drug absorption. Formulation methods for causing supersaturation and / or rapid drug dissolution include, but are not limited to, nanoparticulate systems, amorphous systems, solid solutions, solid dispersions, and lipid systems. Such formulation methods and techniques for preparing them are well known in the art. For example, solid dispersions can be prepared using excipients and processes as described in reviews (for example, A.T.M. Serajuddin, J Pharm Sei, 88:10, pages 1058 - 1066 (1999)). Nanoparticulate systems based on both 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)) . [064] Formula I compounds can be administered in a dosage range of 0.001 to 1000 mg / kg of mammalian body weight (for example, Petition 870190056148, of 06/17/2019, p. 616/693 33/95 example, 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 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 gram per day, in a single dose or divided doses. [065] Daily or weekly administration or less frequent dosing regimens with longer time intervals on non-consecutive days (as discussed below), can be through any suitable route of administration, for example, but not limited to, oral or parenteral. Daily or weekly administration is preferably by 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 administered over two or more staggered times during the day of administration, for example, a first administration followed about 12 hours later with a second administration during the course of a day of administration (the) dosing time (s)). The desired dosage amount for each one or more dosing times in a day of administration can be administered via an oral dosing unit such as a tablet, or Petition 870190056148, of 06/17/2019, p. 617/693 34/95 more than one oral dosage unit as appropriate. Preferably, administration is by means of a single oral dosage unit, for example, a tablet, once a day of administration. [066] 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 seven days with a margin as to the exact dosing date), biweekly (every two weeks with a margin as to the exact dosing date), monthly (for example, every 30 days, or the same calendar day each month with a margin as until the exact dosing date), bimonthly (for example, every 60 days, or the same running day every two months with a margin as to the exact dosing date), every 3 months (for example, every 90 days, or the same calendar day every three months with a margin as to the exact dosing date), every six months (for example, every 180 days, or the same calendar day every six months with a margin as until the exact dosing date), or yearly (for example, every 12 months with a margin as until the exact dosing date Yearly). Margin is intended to mean that the dosage regimes described in the present invention also cover those in which the patient generally follows the time intervals between the days of administration including when the interval is not always strictly followed by the patient, for example, a weekly dosage where the patient can take the drug product the day before or the day after the seventh day after the previous administration day for one or more weeks. The margin time may increase as the dosing interval increases. [067] For oral administration routes (for example, tablets or Petition 870190056148, of 06/17/2019, p. 618/693 35/95 capsules) or other routes of administration, the dosage units may contain 1.0 mg to 1000 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 1000 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. [068] 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 release the appropriate amount of active agent. The compound can also be administered subcutaneously using an implantable device. For parenteral administration including implantable devices using longer duration dosing intervals such as monthly, every 3 months, every 6 months, annually or longer intervals, the dosage amount would be adjusted upward as needed to provide effective treatment during the time intervals between the administration of each dose. [069] 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, stability Petition 870190056148, of 06/17/2019, p. 619/693 36/95 metabolic rate and duration of action of this compound, age, 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 that passes by 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. [070] 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, in the treatment or prophylaxis of HIV infection, and / or in 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 diseases or conditions that arise from or are associated with them. For example, the compounds of this invention can be effectively administered, if 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 anti-HIV agents, immunomodulators, anti-HIV infectious, or vaccines useful to treat HIV infection or AIDS. Antivirals suitable against HIV for use in combination with the compounds of the present invention include, for example, those listed in table A as follows: Table A: Antiviral agents to treat HIV or AIDS infection Name Type abacavir, abacavir sulfate, ABC, Ziagen® nRTI abacavir + lamivudine, Epzicom® nRTI Petition 870190056148, of 06/17/2019, p. 620/693 37/95 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, didesoxyinosine, Videx® nRTI ddl (enteric 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 enteric coated didanosine, Videx EC® nRTI etravirine, TMC-125 nnRTI fosamprenavir calcium, Lexiva® PI indinavir, indinavir sulfate, Crixivan® PI lamivudine, 3TC, Epivir® nRTI lamivudine + zidovudine, Combivir® nRTI Lopinavir PI Petition 870190056148, of 06/17/2019, p. 621/693 38/95 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, didehydrodesoxythymidine, 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. [071] 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. Antiviral agents against HIV and other agents will typically be used in these combinations in their conventional ranges and dosing regimes as reported in the art, including, for example, the dosages described in Petition 870190056148, of 06/17/2019, p. 622/693 39/95 Work Reference of the current Physician, Thomson PDR, 70- edition (2016), Montvale, NJ: PDR Network, or in previous editions of the same. The dosage ranges for a compound of the invention in these combinations can be the same as those shown above. [072] 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 potent antiviral compounds. In addition, the compounds of this invention may be useful in establishing or determining the binding site of other antivirals for HIV reverse transcriptase, for example, by competitive inhibition. [073] The abbreviations and acronyms used here include the following: B.C acetyl MeOH methanol aq aqueous mg milligrams AOP hexafluorophosphatetris (dimethylamino) (3H-1, 2,3-triazolo [4,5-b] pyridin-3-yloxy) phosphorus MHz mega-hertz PyAOP (7- hexafluorophosphateazabenzotriazole-1-iloxy) tripyrrolidinophosphonium min minute Air aryl (e.g. phenyl) AUC area under the curve rl microliters Bu Butila mL milliliters Bz benzoyl DBU 1,8-Diazabiciclo [5.4.0] undec-7-eno mmol millimoles DCM dichloromethane MS mass spectrometry Petition 870190056148, of 06/17/2019, p. 623/693 40/95 Dl EA, DIPEA or Hünig's base Λ /, / V-diisopropylethylamine NMR nuclear magnetic resonance spectroscopy DMF dimethylformamide PBMC peripheral blood mononuclear cell DMSO dimethyl sulfoxide Ph phenyl Et ethyl POWDER. oral EtOH ethanol Pr propyl EtOAc ethyl acetate RT or rt room temperature (room temperature, around 25 ° C) e.g. for example sat orsat'd saturated g grams H hour SFC supercritical fluid chromatography HIV human immunodeficiency virus tBu tert-butyl HPBCD hydroxypropyl β-cyclodextrin TEA triethylamine (Et 3 N) HPLC high performance liquid chromatography TFA trifluoroacetic acid Hz hertz TFV Tenofovir IPA isopropanol TFV-MP monophosphateTenofovir IV intravenous TFV-DP Tenofovir diphosphate iPr isopropyl THF tetrahydrofuran L liter TMS tetramethylsilane Petition 870190056148, of 06/17/2019, p. 624/693 41/95 LC liquid chromatography UPLC ultra high pressure liquid chromatography LC / MS liquid chromatography and mass spectrometry UV Ultraviolet Me methyl UV / VIS ultraviolet / visible [074] Various methods for preparing the compounds of this invention are described in the following Schemes and Examples. 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 S-1 [075] The intermediate compounds of Formula S-1 are prepared from (R (- ((1- (6-amino-9H-purin-9-yl) propan-2-yl) oxy) methyl) phosphonic acid , Petition 870190056148, of 06/17/2019, p. 625/693 42/95 referred to in the present invention as TFV, after treatment with thionyl chloride or oxalyl. Treatment of Sl in a double-step condensation reaction of single step first with amines of Formula S-2, followed by the addition of amines of Formula S-4 in the presence of a base such as triethylamine, pyridine, tributylamine or diisopropylethylamine produces the Formula S-5 products. SCHEME 2 [076] The treatment of Sl in a double-step condensation reaction of single step, first with amines of Formula S-4, followed by the addition of amines of Formula S-2 in the presence of a base such as triethylamine, pyridine, tributylamine or diisopropylethylamine, produces the products of Formula S-5. Petition 870190056148, of 06/17/2019, p. 626/693 43/95 SCHEME 3 ο [077] Formula S-8 intermediate compounds are prepared from TFV, with phenols variably substituted in a single-step condensation reaction with 2,2'-dipyridyldisulfide (aldrithiol), triphenylphosphine, and a base, with phenols such as p-chlorophenol and m-cyanophenol. The Formula S-9 intermediates are obtained by hydrolysis of the corresponding Formula S-8 intermediates by treatment with water in the presence of a base such as DBU. Finally, treatment of Formula S9 intermediates with Formula S-4 benzylamines with a binding reagent such as AOP and PyAOP and base produces the products of Formula S-5. SCHEME 4 aldritiol, PhaP base Petition 870190056148, of 06/17/2019, p. 627/693 44/95 [078] The Formula S-5 compounds of the present invention are prepared from TFV in a single-step condensation reaction with 2,2'-dipyridyldisulfide (aldrithiol), triphenylphosphine, a base, and amines S-2 and S-4. [079] The reactions sensitive to humidity or air were carried out inside a glove box or under nitrogen or argon using solvents and anhydrous reagents. The progress of the reactions was determined by analytical thin layer chromatography (TLC) usually performed with TLC plates pre-coated with E. Merck, silica gel 60F-254, layer thickness 0.25 mm or liquid chromatography-mass spectrometry ( LC / MS). [080] Typically the analytical LC-MS system used consisted of a Waters ZQ ™ platform with electrospray ionization in positive ion detection mode with an Agilent 1100 series HPLC with autosampler. The column was commonly a Waters Xterra MS C18, 3.0 x 50 mm, 5 pm or a Waters Acquity UPLC BEH C18 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 changing to 100% solvent B for 3.75 min, maintained for 1.1 min, then reverting to 100% solvent A for 0.2 min. [081] Preparative HPLC purifications were usually performed using 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: single Waters ZQ ™ quadrilateral MS system with electrospray ionization, Waters 2525 gradient pump, Injector / Collector Petition 870190056148, of 06/17/2019, p. 628/693 Waters 2767, Waters 996 PDA Detector, MS Conditions: 150 to 750 amu, Positive Electrospray, MS Collection, and a 5 micron, 30 mm (id) x 100 mm Waters SUNFIRE C-18 column. 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 1800 μΙ_, and the UV detection range was 210 to 400 nm. An alternative preparative HPLC system used was a Gilson Workstation consisting of: Gilson GX-281 Injector / Collector, Gilson UV / VIS-155 Detector, Gilson 333 and 334 Pumps, and a Phenomenex Gemini-NX C-18 column of 5 micron, 50 mm (id) x 250 mm or a Waters XBridge ™ C-18 5 micron OBD ™ column, 30 mm (id) x 250 mm. The mobile phases consisted of mixtures of acetonitrile (0 to 75%) in water containing 5 mmol of (NH ^ HCOs. Flow rates were maintained at 50 mL / min for the Waters Xbridge ™ column and 90 mL / min for the column Phenomenex Gemini The injection volume ranged from 1000 to 8000 μί, and the UV detection range was 210 to 400 nm. Mobile phase gradients were optimized for the individual compounds. Reactions performed using microwave radiation were normally performed using an Optimizer Emrys manufactured by Personal Chemistry, or an Initiator manufactured by Biotage The concentration of the solutions was carried out in a rotary evaporator under reduced pressure. Scintillation chromatography was usually performed using a Biotage scintillation chromatography device (Dyax Corp.), an ISCO CombiFlash® device Rf, or an ISCO CombiFlash® Companion XL silica gel (32-63 μΜ, pore size 60 Å) in pre-packed cartridges of the size noted. NMR spectra 1 H were acquired on 500 MHz spectrometers in CDCI 3 solutions unless otherwise noted. Chemical substitutions have been reported in parts per million (ppm). Tetramethylsilane (TMS) was used as an internal reference in Petition 870190056148, of 06/17/2019, p. 629/693 46/95 CD3CI, and residual CH3OH peak or TMS was used as an internal reference in CD3OD solutions. Binding constants (J) have been reported in hertz (Hz). Chiral analytical chromatography was most commonly performed on one of the CHIRALPAK AS, CHIRALPAK AD, CHIRALCEL OD, CHIRALCEL IA, or CHIRALCEL OJ (250 x 4.6 mm) columns (Daicel Chemical Industries, Ltd.) with an observed percentage of ethanol in hexane (% Et / Hex) or isopropanol in heptane (% IPA / Hep) as isocratic solvent systems. Preparative chiral chromatography was conducted on one of the CHIRALPAK AS, CHIRALPAK AD, CHIRALCEL OD, CHIRALCEL IA, CHIRALCEL OJ (20 x 250 mm) columns (Daicel Chemical Industries, Ltd.) with desired isocratic solvent systems identified in chiral analytical chromatography or by supercritical fluid (SFC) conditions. [082] It is understood that a chiral center in a compound can exist in the stereo-configuration S or R, 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 herein including those in Examples 1 to 37 contain a chiral phosphorus center. The mixture of isomers in each of Examples 1 to 37 was separated, providing an Isomer #A, for example, Isomer IA (fastest eluting isomer) and an Isomer #B, for example, Isomer 1B (slowest eluting isomer ), 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 5) of the chiral phosphorus center in each of the separate stereoisomers of A and B in Examples 1 to 37 has not been determined. An asterisk (*) can be used in drawings associated with the chemical structure of Petition 870190056148, of 06/17/2019, p. 630/693 47/95 compounds of the Example to indicate the chiral phosphorus center. INTERMEDIATE A soci 2 MeCN HCI INTERMEDIATE A [083] Dichloride (/ ) - ((((l- (6-amino-9/7-purin-9-yl) propan-2yl) oxy) methyl) phosphonic hydrochloride: To a stirred suspension of acid ( R) - (((l- (6-amino-9Hpurin-9-yl) propan-2-yl) oxy) methyl) phosphonic (30 g) in acetonitrile (600 ml) was added thionyl chloride (27.1 ml ) and the mixture was heated to 75 ° C for 8 h. The mixture was cooled to room temperature and connected to a distillation apparatus. The reaction mixture was then heated to 40 ° C under vacuum to perform distillation. Distillation continued until the volume of the reaction mixture reached 150 ml. The resulting slurry was stirred at room temperature overnight. The flask was transferred to a glove box and the solid was filtered. The solid was washed with 2-MeTHF (100 ml). The solid was then vacuum dried in the glove box to provide the title compound as a solid. [084] For the characterization by 31 P NMR, INTERMEDIATE A was dissolved in anhydrous MeOH to prepare the bis-methoxy adduct of A: 31 P NMR (202.5 MHz; CD3OD) δ 24.55; LCMS: [(M + 1)] + = 316.11. INTERMEDIATE B INTERMEDIATE B [085] Isopropyl 2-amino-2-methylpropanoate hydrochloride: One Petition 870190056148, of 06/17/2019, p. 631/693 48/95 pure 2-propanol solution (89 L 1164 mmol) was treated slowly with thionyl chloride (15.57 mL, 213 mmol) at room temperature over a period of 2 min (exotherm to ~ 60 ° C). The mixture was treated with 2-amino-2-methylpropanoic acid (20 g, 194 mmol) and adapted with a reflux condenser. This suspension was heated to 85 ° C (reflux) and stirred for 3 days. The resulting clear solution was concentrated to dryness. The resulting oil was crystallized by trituration in diethyl ether and hexanes. The solids were isolated by filtration and dried under high vacuum to provide the title compound: LC / MS: [(M + 1)] + = 146.1. INTERMEDIATE C INTERMEDIATE C [086] Isobutyl 2-amino-2-methylpropanoate hydrochloride: INTERMEDIATE C was prepared on a 142 mmol scale in a similar manner to that described for the synthesis of INTERMEDIATE B starting from 2 amino-2- methylpropanoic acid, except using 1-propanol in place of 2-propanol to provide the title compound: LC / MS: [(M + 1)] + = 145.8. EXAMPLE 1 INTERMEDIATE A INTERMEDIATE C DIPEA, DCM, 23 ° C 2 - (((/ ) - ((((/ ) - 1- (6-amino-9H-purin-9-yl) propan-2-yl) oxy) methyl) (((/ ) - l - (4Petition 870190056148, of 06/17/2019, page 632/693 Propyl 49/95 chlorophenyl) ethyl) amino) phosphoryl) amino) -2-methylpropanoate and 2 - (((5) ((((/ ) - 1- (6-amino-9H-purin-9-yl) propan-2-yl) oxy) methyl) (propyl ((/ ) - 1- (4-chlorophenyl) ethyl) amino) phosphoryl) amino) -2-methylpropanoate (1A and IB): [087] In a glove box, Hunig's base (0.19 mL, 1.1 mmol) was added to a stirred mixture of INTERMEDIATE A (100 mg, 0.28 mmol) and INTERMEDIATE C (45 mg, 0, 25 mmol) in anhydrous DCM (0.92 mL) and the mixture was stirred at 23 ° C for 10 minutes. (R) -1- (4-chlorophenyl) ethanamine (86 mg, 0.56 mmol) was added to the solution followed by additional Hunig's base (0.15 mL, 0.83 mmol) and the mixture was stirred at 23 ° C for 10 minutes. The reaction mixture was concentrated and the residue was dissolved in MeCN / water 1: 1 (2 mL) and purified by reverse phase chromatography (XBridge column 10 pm C18 30 x 250 mm; 25 to 55% CH3CN in a solution 5 mM NH4CO3 for 30 min) and the pure fractions were lyophilized to provide: Example IA isomer (faster eluting): H NMR (500 MHz, CDCl3) δ 8.33 (s, 1H), 7.99 (s, 1H), 7.25 (s, 4H), 5, 70 (br s, 2H), 4.52 - 4.43 (m, 1H), 4.32 (dd, J = 14.4, 3.0 Hz, 1H), 4.18 - 4.11 (m , 2H), 4.11 - 4.02 (m, 1H), 3.70 (m, 1H), 3.32 - 3.28 (m, 2H), 3.28 - 3.18 (m, 1H ), 3.14 (d, J = 12.4 Hz, 1H), 1.69 (q, J = 7.1 Hz, 2H), 158 (s, 3H), 1.46 (s, 3H), 1.40 (d, J = 6.9 Hz, 3H), 1.01 - 0.94 (m, 6H); 31 P NMR (162 MHz; CDCI3) δ 18.54; LC / MS: [(M + 1)] + = 552.4; and Isomer from Example 1B (slower eluting): H NMR (500 MHz, CDCl3) δ 8.33 (s, 1H), 8.04 (s, 1H), 7.24 (d, J = 12.2 , 2H), 7.16 (d, J = 12.2 Hz, 2H), 5.72 (br s, 2H), 4.41 - 4.35 (m, 2H), 4.13 - 4.00 (m, 3H), 3.85 (dd, J = 9.7, 4.7 Hz, 1H), 3.77 (dd, J = 12.7, 8.4 Hz, 1H), 3.33 - 3.22 (m, 2H), 2.98 (t, J = 10.5 Hz, 1H), 1.62 (p, J = 7.1 Hz, 2H), 1.48 (s, 3H), 1.46 (s, 3H), 1.24 (d, J = 6.2 Hz, 3H), 1.14 (d, J = 6.9 Hz, 3H), 0.91 (t, J = 7 , 4 Hz, 3H); 31 P NMR (162 MHz; CDCI3) δ 18.56; LC / MS: [(M + 1)] + = 552.4. Petition 870190056148, of 06/17/2019, p. 633/693 50/95 EXAMPLE 2 INTERMEDIATE A INTERMEDIATE C DIPEA, DCM, 23 ° C DIPEA, DCM, 23 ° C 2 - ((((R) - (((((R) -l- (6-amino-9H-purin-9-yl) propan-2-yl) oxy) methyl) ((((R) -l- (4chlorophenyl ) propyl ethyl) (methyl) amino) phosphoryl) amino) -2-methylpropanoate and 2 (((S) - ((((R) -1- (6-amino-9H-purin-9-yl) propan- Propyl 2-yl) oxy) methyl) (((R) -1- (4-chlorophenyl) ethyl) (methyl) amino) phosphoryl) amino) -2-methylpropanoate (2A and 2B): [088] In a glove box, Hunig's base (0.19 mL, 1.1 mmol) was added to a stirred mixture of INTERMEDIATE A (100 mg, 0.28 mmol) and INTERMEDIATE C (45 mg, 0, 25 mmol) in anhydrous DCM (0.92 mL) and the mixture was stirred at 23 ° C for 10 minutes. (R) -1- (4-chlorophenyl) -N-methylethylamine hydrochloride (114 mg, 0.56 mmol) was added to the solution followed by additional Hunig's base (0.15 mL, 0.83 mmol) and the mixture was stirred at 23 ° C for 10 minutes. The reaction mixture was concentrated and the residue was dissolved in MeCN / water 1: 1 (2 mL) and purified by reverse phase chromatography (XBridge column 10 pm C18 30 x 250 mm; 25 to 55% CH3CN in a solution 5 mM NH4CO3 for 30 min) and the pure fractions were lyophilized to provide: Isomer from Example 2A (faster eluting): H NMR (500 MHz, CDCH) δ 8.32 (s, 1H), 7.96 (s, 1H), 7.25 (s, 4H), 5, 60 (br s, 2H), 5.02 (m, 1H), 4.33 (dd, J = 14.5, 3.1 Hz, 1H), 4.25 - 4.04 (m, 3H), 3.96 (m, 1H), 3.75 (m, 2H), 3.40 (dd, J = 12.5, 8.4 Hz, 1H), 2.19 (d, J = 9.7 Hz , 3H), 1.66 (q, J = 7.0 Hz, 2H), 1.55 (s, 3H), 1.45 (s, 3H), 1.32 (d, J = 6.6 Hz , 3H), 1.26 (d, J = 6.8 Hz, 3H), 0.94 (t, J = 7.4 Petition 870190056148, of 06/17/2019, p. 634/693 51/95 Hz, 3H); 31 P NMR (162 MHz; CDCI 3 ) δ 20.77; LC / MS: [(M + 1)] + = 566.4; and Example 2B isomer (slower eluting): H NMR (500 MHz, CDCH) δ 8.33 (s, 1H), 7.96 (s, 1H), 7.26 (s, 4H), 5, 77 (br s, 2H), 5.11 (dq, J = 8.6, 7.1 Hz, 1H), 4.34 (dd, J = 14.5, 3.2 Hz, 1H), 4, 21 - 4.00 (m, 3H), 3.89 (m, 1H), 3.65 (d, J = 12.4 Hz, 1H), 3.58 (dd, J = 12.6, 8, 3 Hz, 1H), 3.43 (dd, J = 12.5, 10.2 Hz, 1H), 2.37 (d, J = 9.7 Hz, 3H), 1.66 (h, J = 7.2 Hz, 2H), 1.57 (s, 3H), 1.53 (s, 3H), 1.45 (d, J = 7.1 Hz, 3H), 1.06 (d, J = 6.2 Hz, 3H), 0.93 (t, J = 7.4 Hz, 3H); 31 P NMR (162 MHz; CDCh) δ 21.08; LC / MS: [(M + 1)] + = 566.4. EXAMPLE 3 2 - ((((R) - (((((R) -1- (6-amino-9H-purin-9-yl) propan-2-yl) oxy) methyl) ((((R) -2,2, Propyl 2trifluoro-1- (4- (trifluoromethoxy) phenyl) ethyl) amino) phosphoryl) amino) -2-methylpropanoate and 2 - (((S) - ((((R) -l- (6-amino-9H-purin -9-yl) propan-2yl) oxy) methyl) (propyl (((R) -2,2,2-trifluoro-1- (4 (trifluoromethoxy) phenyl) ethyl) amino) phosphoryl) amino) -2-methylpropanoate (3A and 3B): [089] In a glove box, Hunig's base (0.19 mL, 1.1 mmol) was added to a stirred mixture of INTERMEDIATE A (100 mg, 0.28 mmol) and INTERMEDIATE C (45 mg, 0, 25 mmol) in anhydrous DCM (0.92 mL) and the mixture was stirred at 23 ° C for 10 minutes. (R) -1- (4 (trifluoromethoxy) phenyl) ethanamine hydrochloride (134 mg, 0.56 mmol) was added to the solution followed by additional Hunig's base (0.19 mL, 1.1 mmol) and the mixture was agitated Petition 870190056148, of 06/17/2019, p. 635/693 52/95 at 23 ° C for 10 minutes. The reaction mixture was concentrated and the residue was dissolved in MeCN / water 1: 1 (2 mL) and purified by reverse phase chromatography (XBridge column 10 pm C18 30 x 250 mm; 25 to 55% CH3CN in a solution 5 mM NH4CO3 for 30 min) and the pure fractions were lyophilized to provide: Example 3A isomer (faster eluting): H NMR (500 MHz, CDCl3) δ 8.32 (s, 1H), 8.00 (s, 1H), 7.30 (d, J = 12.2 Hz, 2H), 7.10 (d, J = 12.2 Hz, 2H), 5.76 (br s, 2H), 4.51 (h, J = 7.1 Hz, 1H), 4.31 (dd, J = 14.5, 2.9 Hz, 1H), 4.13 (qt, J = 10.6, 6.6 Hz, 2H), 4.11 (m, 1H), 3.68 ( m, 1H), 3.33 (t, J = 10.1 Hz, 1H), 3.28 - 3.18 (m, 2H), 3.16 (d, J = 14.5 Hz, 1H), 1.70 (dt, J = 14.1, 7.1 Hz, 2H), 1.63 (s, 3H), 1.48 (s, 3H), 1.46 (d, J = 7.1 Hz , 3H), 1.0 (t, J = 7.0 Hz, 3H), 0.90 (d, J = 7.1 Hz, 3H); 31 P NMR (162 MHz; CDCI3) δ 18.52; LC / MS: [(M + 1)] + = 602.4; and Isomer of Example 3B (slower elution): NMR Ã H (500 MHz, CDCl3) δ 8.20 (s, 1H), 7.25 (m, 3H), 7.15 (d, J = 12.2 Hz , 2H), 5.75 (br s, 2H), 4.47 - 4.30 (m, 2H), 4.19 - 4.01 (m, 3H), 3.85 - 3.75 (m, 2H), 3.30 - 3.18 (m, 2H), 3.02 (m, 1H), 1.65 (dt, J = 14.1, 7.1 Hz, 2H), 1.48 (s , 3H), 1.47 (s, 3H), 1.26 (d, J = 7.0 Hz, 3H), 1.18 (d, J = 7.0 Hz, 3H), 0.90 (t , J = 7.0 Hz, 3H); 31 P NMR (162 MHz; CDCl 3) δ 18.59; LC / MS: [(M + 1)] + = 602.4. EXAMPLE 4 DIPEA, DCM, 23 ° C 2 - ((((S) - (((((R) -3- (6-amino-9H-purin-9-yl) -1, 1,1-trifluoropropan-2yl) oxy) methyl) (((R) -2,2,2-trifluoro-l- (4Petition 870190056148, of 6/17/2019, page 636/693 Propyl 53/95 (trifluoromethoxy) phenyl) ethyl) amino) phosphoryl) amino) -2-methylpropanoate and 2 - (((R) - ((((R) -3- (6-amino-9H-purin-9 -yl) -l, 1,1-trifluoropropan-2 yl) oxy) methyl) ((((R) -2,2,2-trifluoro-l- (4 (trifluoromethoxy) phenyl) ethyl) amino) phosphoryl) amino) Propyl -2-methylpropanoate (4Ae4B): [090] In a glove box, Hunig's base (0.29 mL, 1.67 mmol) was added to a stirred mixture of INTERMEDIATE A (150 mg, 0.42 mmol) and INTERMEDIATE C (68 mg, 0, 37 mmol) in anhydrous DCM (1.4 mL) and the mixture was stirred at 23 ° C for 10 minutes. (R) -2,2,2-trifluoro-1- (4 (trifluoromethoxy) phenyl) ethanamine hydrochloride (184 mg, 0.62 mmol) was added to the solution followed by additional Hunig's base (0.29 mL, 1 , 67 mmol) and the mixture was stirred at 23 ° C for 10 minutes. The reaction mixture was concentrated and the residue was dissolved in MeCN / water 1: 1 (3 mL) and purified by reverse phase chromatography (XBridge 10 pm C18 column 30 x 250 mm; 30 to 60% CH3CN in a solution 5 mM NH4CO3 for 30 min) and the pure fractions were lyophilized to provide: Example 4A isomer (faster eluting): H NMR (500 MHz, CDCl3) δ 8.11 (s, 1H), 7.26 (s, 1H), 7.02 (d, J = 8.6 Hz, 2H), 6.91 (d, J = 8.2 Hz, 2H), 5.79 (br s, 2H), 4.88 (h, J = 8.1 Hz, 1H), 4.36 (dd, J = 14.5, 2.9 Hz, 1H), 4.26 - 4.08 (m, 2H), 4.01 (dd, J = 14.5, 8.1 Hz, 1H), 3.86 (t, J = 10.8 Hz, 1H), 3.69 (dd, J = 12.6, 7.8 Hz, 1H), 3.60 (d, J = 13.8 Hz, 1H ), 3.53 (m, 1H), 3.35 (m, 1H), 2.67 (t, J = 12.5 Hz, 1H), 1.70 (m, 2H), 1.52 (s , 3H), 1.13 (d, J = 6.2 Hz, 3H), 0.98 (t, J = 7.4 Hz, 3H); 31 P NMR (162 MHz; CDCI3) δ 18.35; LC / MS: [(M + 1)] + = 656.4; and Example 4B isomer (slower eluting): H NMR (500 MHz, CDCl3) δ 8.35 (s, 1H), 8.01 (s, 1H), 7.39 (d, J = 8.5 Hz, 2H), 7.21 (d, J = 8.3 Hz, 2H), 5.56 (br s, 2H), 4.96 (m, 1H), 4.42 (dd, J = 14, 4, 2.9 Hz, 1H), 4.20 - 4.10 (m, 2H), 4.05 (dt, J = 10.6, 6.6 Hz, 1H), 3.97 (dt, J = 10.6, 6.6 Hz, 1H), 3.94 - 3.82 (m, 1H), 3.75 Petition 870190056148, of 06/17/2019, p. 637/693 54/95 (t, J = 12.1 Hz, 1H), 3.43 (dd, J = 12.5, 8.7 Hz, 1H), 3.12 (d, J = 14.1 Hz, 1H ), 1.59 (ddd, J = 13.8, 8.7, 6.9 Hz, 2H), 1.40 (s, 3H), 1.30 (s, 3H), 1.24 (d, J = 6.2 Hz, 3H), 0.89 (t, J = 7.4 Hz, 3H); 31 P NMR (162 MHz; CDCI 3 ) δ 18.61; LC / MS: [(M + 1)] + = 656.4. [091] The compounds in Table 1 were prepared in a form analogous to that described for the previous Examples. The isomers were separated by preparative HPLC or / and preparative chiral SFC. The intermediate used to prepare each compound is observed under the structure of the compound. Refers to the exchange 31 P NMR 31 P (ppm). TABLE 1 Structure Name EXAMPLE 5 HN 0 -0 / Pt O, NN Intermediate: C Isomer separation / purification conditions: Preparative RP-Scintillant - Prep C18 330 g, 20 to 35 µm; Mobile phase A: 0.1 M ammonium carbonate / water, Mobile phase B: ACN; Flow rate: 80 mL / min; Gradient: 10% B to 50% B in 45 min; Detector: 2 - ((((R) - ((((R) -l- (6-amino-9H-purin-9-il) propan-2-yl) oxy) methyl) ((4-isopropylbenzyl) amino) phosphoryl) amino) -2-propyl methylpropanoateand2 - (((S) - ((((R) -l- (6-amino-9H-purin-9-il) propan-2-yl) oxy) methyl) ((4-isopropylbenzyl) amino) phosphoryl) amino) -2-propyl methylpropanoate Petition 870190056148, of 06/17/2019, p. 638/693 55/95 254/210 nm, Rt: 43 min. Preparative Chiral SFC: Chiralpak AD-H, 2 x 25 cm (5 µm); Mobile phase A: CO2: 60, Mobile phase B: IPA: 40; Flow rate: 40 mL / min; Detector: 220 nm; Rti: 3.53 min; Rtz: 4.41 min Ex. LC / MS (M + l) + 31 P NMR 5A 546.3 (162 MHz;DMSO-c / e) δ20.97 ppm 5B 546.3 (162 MHz;DMSO-c / e) δ20.92 ppm EXAMPLE 6 AT THE Intermediate: C Isomer separation / purification conditions: Preparative HPLC Waters XBridge C18 10 pm OBD column, 19 mm x 250 mm; Phase 2 - ((((R) - (((((R) -1- (6-amino-9H-purin-9yl) propan-2-yl) oxy) methyl) (((4-cyanobenzyl) amino) phosphoryl) amino) -2methylpropanoate propyl and 2 - ((((S) - (((((R) -1-- (6-amino-9H-purin-9yl) propan-2-yl) oxy) methyl) (((4-cyanobenzyl) amino) phosphoryl) amino) -2methylpropanoate of propyl Petition 870190056148, of 06/17/2019, p. 639/693 56/95 mobile A: 0.1 M ammonium carbonate / water, Mobile phase B: ACN; Flow rate: 20 mL / min; Gradient: 35% B to 52% B in 6 min; 254/210 nm; Rt: 5.33 min. Preparative Chiral HPLC: CHIRALPAK IF, 2 x 25 cm, 5 µm; Mobile phase A: Hex, Mobile phase B: EtOH; Flow rate: 20 mL / min; Gradient: 30% B to 30% B in 29 min; Detector: 254/220 nm; Rti: 19.36 min; Rt 2 : 23.87 min.Ex. LC / MS (M + l) + 31P NMR 6A 529.3 (162 MHz;DMSO-c / e) δ21.26 ppm 6B 529.3 (162 MHz;DMSO-c / e) δ21.17 ppm EXAMPLE 7 2 - ((((R) - ((((R) -l- (6-amino-9H-purin-9- Petition 870190056148, of 06/17/2019, p. 640/693 57/95 Isomer separation / purification conditions: Preparative HPLC Column Waters XBridge C18 10 pm OBD, 19 mm x 250 mm; Mobile phase A: 0.1 M ammonium carbonate / water, Mobile phase B: ACN; Flow rate: 20 mL / min; Gradient: 40% B to 65% B in 8 min; 254/210 nm; Rt: 6.48 min. Preparative Chiral HPLC: Chiralpak IC, 2 x 25 cm, 5 µm; Mobile phase A: Hex, Mobile phase B: IPA; Flow rate: 20 mL / min; Gradient: 30% B to 30% B in 25 min; Detector: 254/220 nm; Rti: 16.12 min; Rtz: 19.44 min. il) propan-2-yl) oxy) methyl) ((4 (trifluoromethoxy) benzyl) amino) phosphoryl) amin o) propyl -2-methylpropanoate and 2 - ((((S) - (((((R) -1- (6-amino-9H-purin-9yl) propan-2-yl) oxy) methyl) ((4 (trifluoromethoxy) benzyl) amino) phosphoryl) amin o) Propyl -2-methylpropanoate Ex. LC / MS (M + l) + 31 P NMR 7A 588.3 (162 MHz; Petition 870190056148, of 06/17/2019, p. 641/693 58/95 7B 588.3 DMSO-c / δ) δ 21.14 ppm (162 MHz; DMSO-c / δ) δ 21.07 ppm EXAMPLE 8 Intermediate: C Isomer separation / purification conditions: Preparative HPLC Waters XBridge Prep C18 5 pm OBD, 30 x 250 mm; Mobile phase A: acetonitrile; Mobile phase B: ammonium carbonate at 0.50 M / water; Flow rate: 50 mL / min; Gradient 20 to 50% A over 30 min; Detector 260 2 - ((((R) - (((((R) -1- (6-amino-9H-purin-9yl) propan-2-yl) oxy) methyl) (((3 fluorobenzyl) amino) phosphoryl) amino) -2methylpropanoate propyl and 2 - ((((S) - (((((R) -1- (6-amino-9H-purin-9yl) propan-2-yl) oxy) methyl) (((3 fluorobenzyl) amino) phosphoryl) amino) -2methylpropanoate nm propyl Ex. LC / MS (M + l) + 31 P NMR 8A 522.4 (162 MHz;CDCh) δ Petition 870190056148, of 06/17/2019, p. 642/693 59/95 522.4 20.22 ppm (162 MHz; CDCb) δ 20.05 ppm EXAMPLE 9 Isomer separation / purification conditions: Preparative HPLC Waters XBridge Prep C18 5 pm OBD, 30 x 250 mm; Mobile phase A: acetonitrile; Mobile phase B: ammonium carbonate at 0.50 M / water; Flow rate: 50 mL / min; Gradient 20 to 50% A over 30 min; Detector 260 2 - ((((R) - (((((R) -1- (6-amino-9H-purin-9yl) propan-2-yl) oxy) methyl) ((((R) -1- (3 fluorophenyl) ethyl ) propyl amino) phosphoryl) amino) -2-methylpropanoate and 2 - ((((S) - (((((R) -1- (6-amino-9H-purin-9yl) propan-2-yl) oxy) methyl) ((((R) -1- (3-fluorophenyl) ethyl ) amino) phosphoryl) amino) -2 propyl methylpropanoate nm Ex. LC / MS (M + l) + 31 P NMR 9A 536.4 (162 MHz;CDCb) δ18.53 ppm Petition 870190056148, of 06/17/2019, p. 643/693 60/95 9B 536.4 (162 MHz; CDCb) δ 18.60 ppm EXAMPLE 10 2 - ((((R) - ((((R) -l- (6-amino-9H-purin-9- ^^ 9 nh 2 <Tfj N HN * OA P z n N F HN yl) propan-2-yl) oxy) methyl) (((S) -l- (3-fluorophenyl) ethyl) amino) phosphoryl) amino) -2-propyl methylpropanoateand2 - (((S) - ((((R) -l- (6-amino-9H-purin-9- Intermediate: C yl) propan-2-yl) oxy) methyl) (((S) -l- (3- Conditions of fluorophenyl) ethyl) amino) phosphoryl) amino) -2- separation / purification of isomer: Preparative HPLC - propyl methylpropanoate XBridge Prep C18 5 pm OBD Waters, 30 x 250 mm; Mobile phase A: acetonitrile; Mobile phase B: ammonium carbonate at 0.50 M / water; Flow rate: 50 mL / min; Gradient 20 to 50% A over 30 min; 260 nm detector Ex. LC / MS (M + l) + 31 P NMR 10A 536.4 (162 MHz;CDCh) δ 18.24ppm 10B 536.4 (162 MHz; Petition 870190056148, of 06/17/2019, p. 644/693 61/95 CDCh) δ 18.76 ppm EXAMPLE 11 Isomer separation / purification conditions: Preparative HPLC Waters XBridge Prep C18 5 pm OBD, 30 x 250 mm; Mobile phase A: acetonitrile; Mobile phase B: ammonium carbonate at 0.50 M / water; Flow rate: 50 mL / min; Gradient 25 to 55% A over 30 min; Detector 260 2 - ((((R) - (((((R) -1- (6-amino-9H-purin-9yl) propan-2-yl) oxy) methyl) ((((S) -1- (4 (trifluoromethyl ) phenyl) ethyl) amino) phosphoryl) amin o) propyl -2-methylpropanoate and 2 - ((((S) - ((((/ ) - 1- (6-amino-9H-purin-9yl) propan-2-yl) oxy) methyl) ((((S) -l- (4 ( propyl trifluoromethyl) phenyl) ethyl) amino) phosphoryl) amino) -2-methylpropanoate nm Ex. LC / MS (M + l) + 31 P NMR 11A 586.4 (162 MHz;CDCh) δ 18.04ppm 11B 586.4 (162 MHz; CDCh) δ Petition 870190056148, of 06/17/2019, p. 645/693 62/95 18.78 ppm EXAMPLE 12 Isomer separation / purification conditions: Preparative HPLC Waters XBridge Prep C18 5 pm OBD, 30 x 250 mm; Mobile phase A: acetonitrile; Mobile phase B: ammonium carbonate at 0.50 M / water; Flow rate: 50 mL / min; Gradient 25 to 55% A over 30 min; Detector 260 2 - ((((R) - (((((R) -1- (6-amino-9H-purin-9yl) propan-2-yl) oxy) methyl) ((((R) -1- (4 (trifluoromethyl ) phenyl) ethyl) amino) phosphoryl) amin o) propyl -2-methylpropanoate and 2 - ((((S) - (((((R) -l- (6-amino-9H-purin-9yl) propan-2-yl) oxy) methyl) ((((R) -l- (4 (trifluoromethyl ) phenyl) ethyl) amino) phosphoryl) amin o) propyl -2-methylpropanoate nm Ex. LC / MS (M + l) + 31 P NMR 12A 586.4 (162 MHz;CDCh) δ 18.45 ppm 12B 586.4 (162 MHz; CDCh) δ 18.62 ppm Petition 870190056148, of 06/17/2019, p. 646/693 63/95 EXAMPLE 13 ci Intermediate: C Isomer separation / purification conditions: Preparative HPLC Waters XBridge Prep C18 5 pm OBD, 30 x 250 mm; Mobile phase A: acetonitrile; Mobile phase B: ammonium carbonate at 0.50 M / water; Flow rate: 50 mL / min; Gradient 25 to 55% A over 30 min; Detector 260 2 - ((((R) - (((((R) -1- (6-amino-9H-purin-9yl) propan-2-yl) oxy) methyl) ((((S) -1- (4-chlorophenyl) ethyl ) propyl amino) phosphoryl) amino) -2-methylpropanoate and 2 - ((((S) - (((((R) -1- (6-amino-9H-purin-9yl) propan-2-yl) oxy) methyl) ((((S) -1- (4-chlorophenyl) ethyl ) amino) phosphoryl) amino) -2 propyl methylpropanoate nm Ex. LC / MS (M + l) + 31 P NMR13A 552.4 (162 MHz;CDCh) δ 18.54ppm 13B 552.5 (162 MHz;CDCh) δ 18.56ppm EXAMPLE 14 2 - ((((R) - ((((R) -l- (6-amino-9H-purin-9- Petition 870190056148, of 06/17/2019, p. 647/693 64/95 Intermediate: C Isomer separation / purification conditions: Preparative HPLC Waters XBridge Prep C18 5 pm OBD, 30 x 250 mm; Mobile phase A: acetonitrile; Mobile phase B: ammonium carbonate at 0.50 M / water; Flow rate: 50 mL / min; Gradient 25 to 55% A over 30 min; Detector 260 nm il) propan-2-yl) oxy) methyl) ((((S) -1- (4methoxyphenyl) ethyl) amino) phosphoryl) amino) -2-propyl methyl propanoate and 2 - ((((S) - (((((R) -1- (6-amino-9H-purin-9yl) propan-2-yl) oxy) methyl) ((((S) -1- (4methoxyphenyl) ethyl ) amino) phosphoryl) amino) -2-propyl methylpropanoate Ex. LC / MS (M + l) + 3 1P NMR 14A 548.4 (162 MHz;CDCh) δ 18.45ppm 14B 548.4 (162 MHz;CDCh) δ18.69 ppm EXAMPLE 15 2 - ((((R) - (((((R) -l- (6-amino-9H-purin-9Petition 870190056148, dated 06/17/2019, page 648/693 65/95 Intermediate: C Isomer separation / purification conditions: Preparative HPLC Waters XBridge Prep C18 5 pm OBD, 30 x 250 mm; Mobile phase A: acetonitrile; Mobile phase B: ammonium carbonate at 0.50 M / water; Flow rate: 50 mL / min; Gradient 25 to 55% A over 30 min; Detector 260 nm il) propan-2-yl) oxy) methyl) (((R) -1- (4methoxyphenyl) ethyl) amino) phosphoryl) amino) -2 methyl propanoate and 2 - ((((S) - (((((R) -1- (6-amino-9H-purin-9yl) propan-2-yl) oxy) methyl) ((((R) -1- (4methoxyphenyl) ethyl ) amino) phosphoryl) amino) -2-propyl methylpropanoate Ex. LC / MS (M + l) + 31 P NMR 15A 548.4 (162 MHz;CDCh) δ 18.76ppm 15B 548.4 (162 MHz;CDCh) δ18.49 ppm EXAMPLE 16 2 - ((((R) - (((((R) -l- (6-amino-9H-purin-9Petition 870190056148, of 6/17/2019, page 649/693 66/95 Intermediate: C Isomer separation / purification conditions: Preparative HPLC Waters XBridge Prep C18 5 μηη OBD, 30 x 250 mm; Mobile phase A: acetonitrile; Mobile phase B: ammonium carbonate at 0.50 M / water; Flow rate: 50 mL / min; Gradient 25 to 55% A over 30 min; Detector 260 nm il) propan-2-yl) oxy) methyl) ((((R) -1- (ptolyl) ethyl) amino) phosphoryl) amino) -2 propyl methylpropanoate and 2 - ((((S) - (((((R) -1- (6-amino-9H-purin-9yl) propan-2-yl) oxy) methyl) ((((R) -1- (ptolyl) ethyl ) amino) phosphoryl) amino) -2-propyl methylpropanoate Ex. LC / MS (M + l) + 31 P NMR 16A 532.4 (162 MHz;CDCh) δ 18.74ppm 16B 532.4 (162 MHz;CDCh) δ18.50 ppm EXAMPLE 17 2 - ((((R) - (((((R) -l- (6-amino-9H-purin-9Petition 870190056148, of 6/17/2019, page 650/693 67/95 Intermediate: C Isomer separation / purification conditions: Preparative HPLC Waters XBridge Prep C18 5 pm OBD, 30 x 250 mm; Mobile phase A: acetonitrile; Mobile phase B: ammonium carbonate at 0.50 M / water; Flow rate: 50 mL / min; Gradient 25 to 55% A over 30 min; Detector 260 nm il) propan-2-yl) oxy) methyl) ((((S) -1- (2methoxyphenyl) ethyl) amino) phosphoryl) amino) -2 propyl methyl propanoate and 2 - ((((S) - (((((R) -1- (6-amino-9H-purin-9yl) propan-2-yl) oxy) methyl) ((((S) -1- (2methoxyphenyl) ethyl ) amino) phosphoryl) amino) -2-propyl methylpropanoate Ex. LC / MS (M + l) + 31 P NMR 17A 548.4 (162 MHz;CDCh) δ 18.54ppm 17B 548.4 (162 MHz;CDCh) δ18.76 ppm EXAMPLE 18 2 - ((((R) - (((((R) -l- (6-amino-9H-purin-9Petition 870190056148, of 6/17/2019, page 651/693 68/95 Isomer separation / purification conditions: Preparative HPLC Waters XBridge Prep C18 5 pm OBD, 30 x 250 mm; Mobile phase A: acetonitrile; Mobile phase B: ammonium carbonate at 0.50 M / water; Flow rate: 50 mL / min; Gradient 25 to 55% A over 30 min; Detector 260 il) propan-2-yl) oxy) methyl) (((S) -1- (ptolyl) ethyl) amino) phosphoryl) amino) -2 propyl methylpropanoate and 2 - ((((S) - (((((R) -l- (6-amino-9H-purin-9yl) propan-2-yl) oxy) methyl) ((((S) -l- (ptolyl) ethyl ) amino) phosphoryl) amino) -2 propyl methylpropanoate nm Ex. LC / MS (M + l) + 31 P NMR18A 532.4 (162 MHz;CDCh) δ 18.45ppm 18B 532.4 (162 MHz;CDCh) δ18.68 ppm EXAMPLE 19 2 - ((((R) - ((((R) -l- (6-amino-9H-purin-9- Petition 870190056148, of 06/17/2019, p. 652/693 69/95 Isomer separation / purification conditions: Preparative HPLC Waters XBridge Prep C18 5 pm OBD, 30 x 250 mm; Mobile phase A: acetonitrile; Mobile phase B: ammonium carbonate at 0.50 M / water; Flow rate: 50 mL / min; Gradient 25 to 55% A over 30 min; Detector 260 il) propan-2-yl) oxy) methyl) ((((S) -1- (4 (trifluoromethoxy) phenyl) ethyl) amino) phosphoryl) amine) -2-methylpropanoate and 2 - ((((S) - (((((R) -l- (6-amino-9H-purin-9yl) propan-2-yl) oxy) methyl) ((((S) -l- (4 (trifluoromethoxy ) propyl phenyl) ethyl) amino) phosphoryl) amine) -2-methylpropanoate nm Ex. LC / MS (M + l) + 31 P NMR19A 602.4 (162 MHz;CDCh) δ 18.20ppm 19B 602.4 (162 MHz;CDCh) δ18.78 ppm EXAMPLE 20 2 - ((((R) - ((((R) -l- (6-amino-9H-purin-9- Petition 870190056148, of 06/17/2019, p. 653/693 70/95 Intermediate: C Isomer separation / purification conditions: Preparative HPLC Waters XBridge Prep C18 5 pm OBD, 30 x 250 mm; Mobile phase A: acetonitrile; Mobile phase B: ammonium carbonate at 0.50 M / water; Flow rate: 50 mL / min; Gradient 25 to 55% A over 30 min; Detector 260 nm il) propan-2-yl) oxy) methyl) ((((R) -1- (2methoxyphenyl) ethyl) amino) phosphoryl) amino) -2 methyl propanoate and 2 - ((((S) - (((((R) -1- (6-amino-9H-purin-9yl) propan-2-yl) oxy) methyl) ((((R) -1- (2methoxyphenyl) ethyl ) amino) phosphoryl) amino) -2-propyl methylpropanoate Ex. LC / MS (M + l) + 31 P NMR 20A 548.4 (162 MHz;CDCh) δ 18.97ppm 20B 548.4 (162 MHz;CDCh) δ18.64 ppm EXAMPLE 21 2 - ((((R) - (((((R) -l- (6-amino-9H-purin-9Petition 870190056148, of 6/17/2019, page 654/693 71/95 F 3 CO ^ ^ Intermediate: C Isomer separation / purification conditions: Preparative HPLC Waters XBridge Prep C18 5 pm OBD, 30 x 250 mm; Mobile phase A: acetonitrile; Mobile phase B: ammonium carbonate at 0.50 M / water; Flow rate: 50 mL / min; Gradient 30 to 60% of A over 30 min; Detector 260 yl) propan-2-yl) oxy) methyl) ((((R) -1- (2-methyl-4 (trifluoromethoxy) phenyl) ethyl) amino) phosphoryl) amine) -2-methylpropanoate and 2 - ((((S) - (((((R) -l- (6-amino-9H-purin-9yl) propan-2-yl) oxy) methyl) ((((R) -l- (2-methyl -4 propyl (trifluoromethoxy) phenyl) ethyl) amino) phosphoryl) amine) -2-methylpropanoate nm Ex. LC / MS (M + l) + 31 P NMR21A 616.4 (162 MHz;CDCh) δ 18.40ppm 21B 616.4 (162 MHz;CDCh) δ18.57 ppm EXAMPLE 22 2 - ((((R) - ((((R) -l- (6-amino-9H-purin-9- Petition 870190056148, of 06/17/2019, p. 655/693 72/95 Isomer separation / purification conditions: Preparative HPLC Waters XBridge Prep C18 5 pm OBD, 30 x 250 mm; Mobile phase A: acetonitrile; Mobile phase B: ammonium carbonate at 0.50 M / water; Flow rate: 50 mL / min; Gradient 20 to 50% A over 30 min; Detector 260 il) propan-2-yl) oxy) methyl) (((R) -2,2,2-trifluoro- 1- (3-fluorophenyl) ethyl) amino) phosphoryl) amino) - 2- propyl methylpropanoate and 2 - ((((S) - (((((R) -1- (6-amino-9H-purin-9yl) propan-2-yl) oxy) methyl) ((((R) -2,2,2- trifl uoro- 1- (3-fluorophenyl) ethyl) amino) phosphoryl) amino) - 2- propyl methylpropanoate nm Ex. LC / MS (M + l) + 31 P NMR22A 590.4 (162 MHz;CDCh) δ 18.47ppm 22B 590.4 (162 MHz;CDCh) δ18.65 ppm EXAMPLE 23 2 - ((((R) - ((((R) -l- (6-amino-9H-purin-9- Petition 870190056148, of 06/17/2019, p. 656/693 73/95 Intermediate: C Isomer separation / purification conditions: Preparative HPLC Waters XBridge Prep C18 5 pm OBD, 30 x 250 mm; Mobile phase A: acetonitrile; Mobile phase B: ammonium carbonate at 0.50 M / water; Flow rate: 50 mL / min; Gradient 20 to 50% A over 30 min; Detector 260 il) propan-2-yl) oxy) methyl) ((((R) -1- (4-cyanophenyl) -2,2,2trifluoroethyl) amino) phosphoryl) amino) -2-propyl methyl propanoate and 2 - ((((S) - (((((R) -1- (6-amino-9H-purin-9yl) propan-2-yl) oxy) methyl) ((((R) -1- (4cyanophenyl) - 2,2,2trifluoroethyl) amino) phosphoryl) amino) -2 propyl methylpropanoate nm Ex. LC / MS (M + l) + 31 P NMR23A 597.4 (162 MHz;CDCh) δ 18.16ppm 23B 597.4 (162 MHz;CDCh) δ18.43 ppm EXAMPLE 24 2 - ((((R) - ((((R) -l- (6-amino-9H-purin-9- Petition 870190056148, of 06/17/2019, p. 657/693 74/95 Intermediate: C Isomer separation / purification conditions: Preparative HPLC Waters XBridge Prep C18 5 pm OBD, 30 x 250 mm; Mobile phase A: acetonitrile; Mobile phase B: ammonium carbonate at 0.50 M / water; Flow rate: 50 mL / min; Gradient 20 to 50% A over 30 min; Detector 260 yl) propan-2-yl) oxy) methyl) ((((S) -1- (4-cyanophenyl) -2,2,2trifluoroethyl) amino) phosphoryl) amino) -2-propyl methyl propanoate and 2 - ((((S) - (((((R) -l- (6-amino-9H-purin-9yl) propan-2-yl) oxy) methyl) ((((S) -l- (4cyanophenyl) - 2,2,2trifluoroethyl) amino) phosphoryl) amino) -2 propyl methylpropanoate nm Ex. LC / MS (M + l) + 31 P NMR24A 597.4 (162 MHz;CDCh) δ 18.63ppm 24B 597.4 (162 MHz;CDCh) δ18.44 ppm EXAMPLE 25 2 - ((((R) - ((((R) -l- (6-amino-9H-purin-9- Petition 870190056148, of 06/17/2019, p. 658/693 75/95 Isomer separation / purification conditions: Preparative HPLC Waters XBridge Prep C18 5 pm OBD, 30 x 250 mm; Mobile phase A: acetonitrile; Mobile phase B: ammonium carbonate at 0.50 M / water; Flow rate: 50 mL / min; Gradient 20 to 50% A over 30 min; 260 nm detector Ex. LC / MS (M + l) + 31 P NMR 25A 602.4 (162 MHz;CDCh) δ 18.74ppm 25B 602.4 (162 MHz;CDCh) δ18.54 ppm il) propan-2-yl) oxy) methyl) (((R) -2,2,2-trifluoro- 1- (3-methoxyphenyl) ethyl) amino) phosphoryl) amino) - 2- propyl methylpropanoate and 2 - ((((S) - (((((R) -1-- (6-amino-9H-purin-9yl) propan-2-yl) oxy) methyl) ((((R) -2,2,2- trifl uoro- 1- (3-methoxyphenyl) ethyl) amino) phosphoryl) amino) - 2- propyl methylpropanoate EXAMPLE 26 2 - ((((R) - (((((R) -l- (6-amino-9H-purin-9Petition 870190056148, of 6/17/2019, page 659/693 76/95 Intermediate: C Isomer separation / purification conditions: Preparative HPLC Waters XBridge Prep C18 5 pm OBD, 30 x 250 mm; Mobile phase A: acetonitrile; Mobile phase B: ammonium carbonate at 0.50 M / water; Flow rate: 50 mL / min; Gradient 25 to 55% A over 30 min; Detector 260 il) propan-2-yl) oxy) methyl) (((R) -2,2,2-trifluoro- Propyl 1- (p-tolyl) ethyl) amino) phosphoryl) amino) -2-methylpropanoate and 2- ((((S) - (((((R) -1- (6-amino-9H-purin-9-yl) propan-2-yl) oxy) methyl) ((((R) -2,2, Propyl 2-trifluoro- (p-tolyl) ethyl) amino) phosphoryl) amino) -2 methylpropanoate nm Ex. LC / MS (M + l) + 31 P NMR26A 586.4 (162 MHz;CDCh) δ 18.67ppm 26B 586.4 (162 MHz;CDCh) δ18.52 ppm EXAMPLE 27 2 - ((((R) - ((((R) -l- (6-amino-9H-purin-9- Petition 870190056148, of 06/17/2019, p. 660/693 77/95 Intermediate: C Isomer separation / purification conditions: Preparative HPLC Waters XBridge Prep C18 5 μηη OBD, 30 x 250 mm; Mobile phase A: acetonitrile; Mobile phase B: ammonium carbonate at 0.50 M / water; Flow rate: 50 mL / min; Gradient 25 to 55% A over 30 min; Detector 260 il) propan-2-yl) oxy) methyl) (((R) -2,2,2-trifluoro- Propyl 1- (4- (trifluoromethoxy) phenyl) ethyl) amino) phosphoryl) amine) -2-methylpropanoate and 2- ((((S) - (((((R) -1- (6-amino-9H-purin-9-yl) propan-2-yl) oxy) methyl) ((((R) -2,2, Propyl 2-trifluorol- (4 (trifluoromethoxy) phenyl) ethyl) amino) phosphoryl) amine) -2-methylpropanoate nm Ex. LC / MS (M + l) + 31 P NMR27A 656.4 (162 MHz;CDCh) δ 18.35ppm 27B 656.4 (162 MHz;CDCh) δ18.61 ppm EXAMPLE 28 2 - ((((R) - ((((R) -l- (6-amino-9H-purin-9- Petition 870190056148, of 06/17/2019, p. 661/693 78/95 Intermediate: C Isomer separation / purification conditions: Preparative HPLC Waters XBridge Prep C18 5 pm OBD, 30 x 250 mm; Mobile phase A: acetonitrile; Mobile phase B: ammonium carbonate at 0.50 M / water; Flow rate: 50 mL / min; Gradient 20 to 50% A over 30 min; Detector 260 il) propan-2-yl) oxy) methyl) (((S) -2,2,2-trifluoro- 1- (3-methoxyphenyl) ethyl) amino) phosphoryl) amino) - 2- propyl methylpropanoate and 2 - ((((S) - (((((R) -1- (6-amino-9H-purin-9yl) propan-2-yl) oxy) methyl) ((((S) -2,2,2- trifluoro- 1- (3-methoxyphenyl) ethyl) amino) phosphoryl) amino) - 2- propyl methylpropanoate nm Ex. LC / MS (M + l) + 31 P NMR28A 602.4 (162 MHz;CDCh) δ 18.52ppm 28B 602.4 (162 MHz;CDCh) δ18.99 ppm EXAMPLE 29 2 - ((((R) - ((((R) -l- (6-amino-9H-purin-9- Petition 870190056148, of 06/17/2019, p. 662/693 79/95 Isomer separation / purification conditions: Preparative HPLC Waters XBridge Prep C18 5 pm OBD, 30 x 250 mm; Mobile phase A: acetonitrile; Mobile phase B: ammonium carbonate at 0.50 M / water; Flow rate: 50 mL / min; Gradient 20 to 50% A over 30 min; Detector 260 yl) propan-2-yl) oxy) methyl) ((((R) -1- (4-chloro-2methylphenyl) ethyl) amino) phosphoryl) amino) -2 methyl propanoate and 2 - ((((S) - (((((R) -1- (6-amino-9H-purin-9yl) propan-2-yl) oxy) methyl) ((((R) -1- (4-chlorine -2methylphenyl) ethyl) amino) phosphoryl) amino) -2 propyl methylpropanoate nm Ex. LC / MS (M + l) + 31 P NMR29A 566.4 (162 MHz;CDCh) δ 18.40ppm 29B 566.4 (162 MHz;CDCh) δ18.52 ppm EXAMPLE 30 2 - ((((R) - ((((R) -l- (6-amino-9H-purin-9- Petition 870190056148, of 06/17/2019, p. 663/693 80/95 Intermediate: C Isomer separation / purification conditions: Preparative HPLC Waters XBridge Prep C18 5 pm OBD, 30 x 250 mm; Mobile phase A: acetonitrile; Mobile phase B: ammonium carbonate at 0.50 M / water; Flow rate: 50 mL / min; Gradient 20 to 50% A over 30 min; Detector 260 nm il) propan-2-yl) oxy) methyl) ((((S) -1- (4-chloro-2methylphenyl) ethyl) amino) phosphoryl) amino) -2 methyl propanoate and 2 - ((((S) - (((((R) -l- (6-amino-9H-purin-9yl) propan-2-yl) oxy) methyl) ((((S) -l- (4-chlorine -2methylphenyl) ethyl) amino) phosphoryl) amino) -2 propylmethylpropanoate Ex. LC / MS (M + l) + 31 P NMR 30A 566.4 (162 MHz; CDCI 3 ) δ 18.10 ppm 30B 566.4 (162 MHz;CDCh) δ18.66 ppm EXAMPLE 31 2 - ((((R) - (((((R) -l- (6-amino-9H-purin-9Petition 870190056148, of 6/17/2019, page 664/693 81/95 Intermediate: C Isomer separation / purification conditions: Preparative HPLC Waters XBridge Prep C18 5 pm OBD, 30 x 250 mm; Mobile phase A: acetonitrile; Mobile phase B: ammonium carbonate at 0.50 M / water; Flow rate: 50 mL / min; Gradient 20 to 50% A over 30 min; Detector 260 il) propan-2-yl) oxy) methyl) (propyl (((R) -1- (4-cyanophenyl) ethyl) amino) phosphoryl) amino) -2-methylpropanoate and 2 - ((((S) - (((((R) -1- (6-amino-9H-purin-9yl) propan-2-yl) oxy) methyl) ((((R) -1- (4cyanophenyl) ethyl ) amino) phosphoryl) amino) -2 propyl methylpropanoate nm Ex. LC / MS (M + l) + 31 P NMR31A 543.4 (162 MHz;CDCh) δ 18.33ppm 31B 543.4 (162 MHz;CDCh) δ18.73 ppm EXAMPLE 32 2 - ((((R) - ((((R) -l- (6-amino-9H-purin-9- Petition 870190056148, of 06/17/2019, p. 665/693 82/95 Intermediate: C Isomer separation / purification conditions: Preparative HPLC Waters XBridge Prep C18 5 μηη OBD, 30 x 250 mm; Mobile phase A: acetonitrile; Mobile phase B: ammonium carbonate at 0.50 M / water; Flow rate: 50 mL / min; Gradient 20 to 60% A over 30 min; 260 nm detector Ex. LC / MS (M + l) + 31 P NMR 32A 560.47 (162 MHz;CDCh) δ21.49 ppm 32B 560.48 (162 MHz;CDCh) δ21.72 ppm il) propan-2-yl) oxy) methyl) ((4isopropylbenzyl) (methyl) amino) phosphoryl) amino) -2-propyl methylpropanoate and 2 - ((((S) - (((((R) -1-- (6-amino-9H-purin-9yl) propan-2-yl) oxy) methyl) ((4isopropylbenzyl) (methyl) amino) phosphoryl) amino ) Propyl -2-methylpropanoate EXAMPLE 33 2 - ((((R) - (((((R) -l- (6-amino-9H-purin-9Petition 870190056148, of 6/17/2019, page 666/693 83/95 Isomer separation / purification conditions: Preparative HPLC Waters XBridge Prep C18 5 pm OBD, 30 x 250 mm; Mobile phase A: acetonitrile; Mobile phase B: ammonium carbonate at 0.50 M / water; Flow rate: 50 mL / min; Gradient 20 to 60% A over 30 min; Detector 260 il) propan-2-yl) oxy) methyl) (methyl ((R) -1- (4 (trifluoromethoxy) phenyl) ethyl) amino) phosphoryl) amine) -2-methylpropanoate and 2 - ((((S) - (((((R) -l- (6-amino-9H-purin-9yl) propan-2-yl) oxy) methyl) (methyl ((R) -l- (4 ( propyl trifluoromethoxy) phenyl) ethyl) amino) phosphoryl) amine) -2-methylpropanoate nm Ex. LC / MS (M + l) + 31 P NMR33A 616.43 (162 MHz;CDCh) δ21.07 ppm 33B 616.40 (162 MHz;CDCh) δ20.89 ppm EXAMPLE 34 2 - ((((R) - ((((R) -l- (6-amino-9H-purin-9- Petition 870190056148, of 06/17/2019, p. 667/693 84/95 nh 2 r < z Ύ i HN * 0 Xi-A. > n / NN HN rvtf 'I do-A ^ Intermediate: B Isomer separation / purification conditions: Preparative HPLC Waters XBridge Prep C18 5 pm OBD, 30 x 250 mm; Mobile phase A: acetonitrile; Mobile phase B: ammonium carbonate at 0.50 M / water; Flow rate: 50 mL / min; Gradient 20 to 60% A over 30 min; 260 nm detector il) propan-2-yl) oxy) methyl) (((R) -l- (4-(trifluoromethoxy) phenyl) ethyl) amino) phosphoryl) amino) isopropyl -2-methylpropanoateand2 - (((S) - ((((R) -l- (6-amino-9H-purin-9-il) propan-2-yl) oxy) methyl) (((R) -l- (4-(trifluoromethoxy) phenyl) ethyl) amino) phosphoryl) amino) isopropyl -2-methylpropanoate Ex. LC / MS (M + l) + 31 P NMR 34A 602.43 (162 MHz;CDCh) δ18.54 ppm 34B 602.43 (162 MHz;CDCh) δ18.57 ppm EXAMPLE 35 2 - ((((R) - ((((R) -l- (6-amino-9H-purin-9- Petition 870190056148, of 06/17/2019, p. 668/693 85/95 nh 2 ci-X ^^ Intermediate: B Isomer separation / purification conditions: Preparative HPLC Waters XBridge Prep C18 5 pm OBD, 30 x 250 mm; Mobile phase A: acetonitrile; Mobile phase B: ammonium carbonate at 0.50 M / water; Flow rate: 50 mL / min; Gradient 20 to 60% A over 30 min; 260 nm detector il) propan-2-yl) oxy) methyl) (((R) -l- (4-chlorophenyl) ethyl) amino) phosphoryl) amino) -2-isopropyl methylpropanoateand2 - (((S) - ((((R) -l- (6-amino-9H-purin-9-il) propan-2-yl) oxy) methyl) (((R) -l- (4-chlorophenyl) ethyl) amino) phosphoryl) amino) -2-isopropyl methylpropanoate Ex. LC / MS (M + l) + 31 P NMR 35A 552.38 (162 MHz;CDCh) δ18.57 ppm 35B 552.4 (162 MHz;CDCh) δ18.60 ppm EXAMPLE 36 2 - ((((R) - ((((R) -l- (6-amino-9H-purin-9- Petition 870190056148, of 06/17/2019, p. 669/693 86/95 Intermediate: C Isomer separation / purification conditions: Preparative HPLC Waters XBridge Prep C18 5 pm OBD, 30 x 250 mm; Mobile phase A: acetonitrile; Mobile phase B: ammonium carbonate at 0.50 M / water; Flow rate: 50 mL / min; Gradient 20 to 60% A over 30 min; Detector 260 il) propan-2-yl) oxy) methyl) (isopropyl (2- (4-chlorophenyl) propan-2yl) amino) phosphoryl) amino) -2-methylpropanoate and 2 - ((((S) - (((((R) -1-- (6-amino-9H-purin-9yl) propan-2-yl) oxy) methyl) ((2- (4-chlorophenyl) propan-2yl) amino ) isopropyl phosphoryl) amino) -2-methylpropanoate nm Ex. LC / MS (M + l) + 31 P NMR36A 566.40 (162 MHz; CDCI 3 ) δ 17.29 ppm 36B 566.41 (162 MHz;CDCh) δ17.27 ppm EXAMPLE 37 2 - ((((R) - ((((R) -l- (6-amino-9H-purin-9- Petition 870190056148, of 06/17/2019, p. 670/693 87/95 Intermediate: C Isomer separation / purification conditions: Preparative HPLC Waters XBridge Prep C18 5 pm OBD, 30 x 250 mm; Mobile phase A: acetonitrile; Mobile phase B: ammonium carbonate at 0.50 M / water; Flow rate: 50 mL / min; Gradient 20 to 60% A over 30 min; Detector 260 il) propan-2-yl) oxy) methyl) ((1- (4-chlorophenyl) cyclopropyl) amino) phosphoryl) amino) Isopropyl -2-methylpropanoate and 2 - ((((S) - (((((R) -l- (6-amino-9H-purin-9yl) propan-2-yl) oxy) methyl) ((l- (4-chlorophenyl) cyclopropyl) amino) phosphoryl ) amino) Isopropyl -2-methylpropanoate nm Ex. LC / MS (M + l) + 31 P NMR 37A 564.38 (162 MHz;CDCb) δ18.94 ppm 37B 564.41 (162 MHz; CDCb) δ 19.17 ppm EXAMPLE 38 Evaluation of antiviral potency in an HIV-1 Infection Assay Petition 870190056148, of 06/17/2019, p. 671/693 88/95 multiple round (Viking Assay) [092] The antiviral activity of the tenofovir prodrugs in the Examples of the present invention was evaluated in an assay that measures the rate of HIV replication in cell culture, called the Viking assay ( Viral KINetics in Green cells) and performed as follows. HIV-1 replication was monitored using the 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 protein dependent expressed by HIV-1 tat and rev. The productive infection of an MT4-GFP cell with HIV-1 results in GFP expression approximately 24 h after infection. MT4-GFP cells were maintained at 37 ° C / 5% CO 2 /90% relative humidity in RPMI 1640 supplemented with 10% fetal bovine serum, 100 U / mL penicillin / streptomycin, and 400 pg / mL G418 to keep the reporter gene. For infections, MT4-GFP cells were placed in the same medium lacking G418 and infected overnight with HIV-1 virus (strain H9 / IIIB) in 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) in 1.6 x 10 5 cells / ml (10% NHS or 50% NHS, respectively). Compound plates were prepared by dispensing compounds dissolved in DMSO in wells of 384-well poly-D-lysine coated plates (0.2 µl / well) using an ECHO acoustic dispenser. Each compound was tested in a 10-fold serial 3-fold dilution (typical final concentrations: 8.4 pM to 0.42 nM). Controls did not include any inhibitors (DMSO only) and a combination of three antiviral agents (efavirenz, indinavir, an internal integrase tape transfer inhibitor at final concentrations of 4 pM each). The cells were added (50 pL / well) to compound plates and the Petition 870190056148, of 06/17/2019, p. 672/693 89/95 infected cells were maintained at 37 ° C / 5% CO 2 /90% relative humidity. [093] 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 during the ~ 24 h period provides the reproductive ratio, R o , which is typically 5 to 15 and has been experimentally shown to be in the logarithmic phase (data not shown). The inhibition of R o is calculated for each well, and the IC50S determined by non-linear curve fitting of 4 parameters. The IC 50 results of the assay are shown in Table 2. EXAMPLE 39 Pro-drug stability test in bio-relevant media [094] The following test was used to assess the stability of prodrugs under simulated conditions of the gastrointestinal tract. The preparation of simulated fasted intestinal fluid (FaSSIF) using Phares SIF Powder was performed according to protocols of Phare Drug Delivery AG (Baselland, Switzerland). For sample preparation, stock solutions of 10 pL (10 mM) of prodrug substance in DMSO were added to 990 pL 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 swirled 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 a Petition 870190056148, of 06/17/2019, p. 673/693 90/95 Agilent 1100 series HPLC with autosampler. The column was a Poroshell 120 EC-C18, 4.6 χ 50 mm, 2.7 pm. The flow rate was 1.8 ml / min, and the injection volume was 5 or 10 pL. 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 in 0 min, changing to 95% solvent B for 6 min, maintaining for 1.5 min, then reverting to 90% solvent A for 1.6 min. The peak HPLC area of the prodrug in 5 h was divided by the peak HPLC area of the prodrug in 0 h, to generate the% of claimed precursor ratio, which is summarized in Table 2 for gastrointestinal tract stability ( Gl). EXAMPLE 40 Pharmacokinetic Studies in Dogs - Dog PK in vivo [095] Prodrugs were administered to beagle dogs through intravenous (IV) and oral (P.O.) administrations in a non-crossover manner. Dose IV was prepared in 20% hydroxypropyl β-cyclodextrin (HPBCD) or polyethylene glycol 200: ethanol: water (70:10:20 v / v / v). The dose was administered through the cephalic or saphenous vein. The P.O. dose was prepared in 10% polysorbate 80 (Tween 80) and was administered via gavage. [096] Blood samples were collected serially after administration of the dose for up to 48 h and the plasma was separated by centrifugation. Canine plasma prodrug concentrations were determined by an LC-MS / MS assay following 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. Blood sample (s) Petition 870190056148, of 06/17/2019, p. 674/693 Additional 91/95 (s) were collected after dose administration for up to 24 h. Peripheral blood mononuclear cells (PBMCs) were isolated by centrifugation, using specific tubes and reagents for such application. The concentrations of tenofovir and / or its phosphate conjugate (s) in PBMCs were determined by an LC-MS / MS assay following 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 conjugate (s) for the internal standard. [097] Pharmacokinetic parameters were obtained using non-compartmental methods (Watson). The area under the plasma concentration-time curve (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 the logarithmic linear / linear trapezoids. Plasma IV clearance was calculated by dividing the dose by AUCo-inf. The terminal elimination half-life was determined by non-weighted linear regression analysis of the log data. The 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 the mean residence time (determined by dividing the area under the first 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 (% of F) was determined from AUC IV and PO ratios adjusted for prodrug dose. Table 2 shows the PK data of dogs in vivo in the form of TFV-DP concentrations (μΜ) in canine PBMCs within 24 h following a Petition 870190056148, of 06/17/2019, p. 675/693 92/95 P.O. dose of 10 mg / kg of the indicated prodrug. TABLE 2 Example Viking, IC50 (10% NHS) (nM) Viking, IC50 (50% NHS) (nM) Gl tract stability (%) PK of dogs in vivo (μΜ) IA 120 710 1B 4.7 36 98.7 15.4 2A 43 130 2B 2.0 9.619.9 3A 80 780 3B 1.8 8.6 99.4 16.5 4A 3.5 29 95.84B 16 160 5A 3.1 17 96.3 7.7 5B 48 240 6A 70 660 6B 250 850 7A 4.5 27 96.07B 45 300 8A 110 680 8B 76 680 9A 89 940 9B 12 130 90.910A 68 560 10B 99 490 11A 4.6 42 Petition 870190056148, of 06/17/2019, p. 676/693 93/95 Example Viking, IC50 (10% NHS) (nM) Viking, IC50 (50% NHS) (nM) Gl tract stability (%) PK of dogs in vivo (μΜ) 11B 16 84 12A 96 680 12B 2.2 11 99.113A 8.4 75 98.5 15.9 13B 73 310 14A 25 140 14B 52 280 15A 74 410 15B 7.4 40 16A 83 440 16B 4.6 27 17A 24 310 17B 84 510 18A 13 140 18B 37 520 19A 2.7 12 98.119B 84 360 20A 61 590 20B 9.5 53 21A 150 800 21B 1.0 5.8 71.522A 8.1 74 22B 42 330 Petition 870190056148, of 06/17/2019, p. 677/693 94/95 Example Viking, IC50 (10% NHS) (nM) Viking, IC50 (50% NHS) (nM) Gl tract stability (%) PK of dogs in vivo (μΜ) 23A 6.1 37 23B 47 140 24A 6.3 30 24B 22 170 25A 4.6 54 70.325B 15 97 26A 4.7 45 75.326B 34 200 27A 1.4 6.7 79.5 0.8 27B 52 250 28A 29 330 28B 17 120 29A 260 2,300 29B 2.5 21 12.130A 24 350 30B 56 750 31A 83 770 31B 8.8 110 90.632A 1.7 6.7 32B 10 41 33A 25 84 33B 2.2 7.1 97.234A 760 4,200 Petition 870190056148, of 06/17/2019, p. 678/693 95/95 Example Viking, IC50 (10% NHS) (nM) Viking, IC50 (50% NHS) (nM) Gl tract stability (%) PK of dogs in vivo (μΜ) 34B 1.5 7.9 67.435A 280 1,600 35B 2.9 22 70.536A 3.2 37 20.236B 200 1,100 37A 110 720 37B 5.1 30 21.1 Petition 870190056148, of 06/17/2019, p. 679/693
权利要求:
Claims (21) [1] 1. Compound, characterized by the fact that it presents Structural Formula I: [2] 2/13 (g) an unsubstituted or substituted heterocyclic ring with one, two or three of fluorine, chlorine, bromine, -OR 4 , -SR, -NR 6 R 7 or -C1-3alkyl; R is -H, -CF3, -C1-3 alkyl or -C3-6 cycloalkyl; R c is -H, -CF3 or -C3-6 cycloalkyl; R 4 is -H, -CF3, -C1-3 alkyl or -C3-6 cycloalkyl; R 5 is -H, -CF3 or -C3-6 cycloalkyl; R 6 is -H, -C1-3 alkyl or -C3-6 cycloalkyl; R 7 is -H, -C1-3 alkyl or -C3-6 cycloalkyl. R 8 is -H or -C1-3alkyl; R 9 is -H, -C1- alkyl or -C1- alkyl substituted with 1 to 3 of F; R 10 is -H, -C1- alkyl, or -C1- alkyl, substituted with 1 to 3 of F; or R 9 and R 10 are bonded with the carbon to which they are both attached to form C3-6 spiro-cycloalkyl; R a is halo, -CN, -C1- alkyl, -C1- alkyl substituted with 1 to 3 of F, -O-C1-6 alkyl or -O-C1-6 alkyl substituted with 1 to 3 of F; and R b is -H, halo, -CN, -C1- alkyl, -C1- alkyl substituted with 1 to 3 of F, -O-C1-6 alkyl or -O-C1-6 alkyl substituted with 1 to 3 from F. 2. A compound or a pharmaceutically acceptable salt thereof, according to claim 1, characterized in that R 1 and R 2 are independently selected from -C1-4alkyl, or R 1 and R 2 are bonded with carbon to the which both are linked to form C3-6 spiro-cycloalkyl. [3] 3. A compound or a pharmaceutically acceptable salt thereof, according to claim 2, characterized by the fact that R 1 and R 2 are the same selected portion of -C1-4alkyl, or R 1 and R 2 are united with the carbon to which both are attached to form C3-6 spiro-cycloalkyl. [4] 4. A compound or a pharmaceutically acceptable salt thereof, according to claim 2, characterized by the fact that R 9 and R 10 are Petition 870190056148, of 06/17/2019, p. 681/693 3/13 independently -H, -C1-3 alkyl or -C1-3 alkyl substituted with 1 to 3 of F, or R 9 and R 10 are bonded with the carbon to which they are both attached to form C3-6 spiro-cycloalkyl . [5] A compound or a pharmaceutically acceptable salt thereof, according to claim 4, characterized in that R 9 and R 10 are independently -H, -CH3 or -CF3, or R 9 and R 10 are bonded with carbon to which both are attached to form C3-6 spiro-cycloalkyl. [6] 6. A compound or a pharmaceutically acceptable salt thereof, according to claim 5, characterized in that R 9 and R 10 are the same selected portion of -C 1- alkyl. [7] A compound or a pharmaceutically acceptable salt thereof, according to claim 2, characterized in that R a is halo, -CN, -C 3 alkyl, -C 1-3 alkyl substituted with 1 to 3 of F, -O -C1-3alkyl or -O-C1-3alkyl substituted with 1 to 3 of F. [8] A compound or a pharmaceutically acceptable salt thereof, according to claim 7, characterized in that R b is -H, halo, -CN, -C1-3 alkyl, -C1-3 alkyl substituted with 1 to 3 of F, -O-C1-3 alkyl or -O-C1-3 alkyl substituted with 1 to 3 of F. [9] Compound or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 8, characterized by the fact that R 3 is: (a) Cl - 8 -alkyl, -CH2CH2OH, -CH2CH2CH2OH, -CH2CH2SH, -CH2CH2CH2SH, CH2CH2NH2, -CH2CH2CH2NH2, (b) -CFh-phenyl unsubstituted or substituted with one, two or three substituents independently selected from fluoro, chloro , bromine, -OR 4 , -SR, -NR 6 R 7 or C1-3 alkyl, Petition 870190056148, of 06/17/2019, p. 682/693 4/13 (c) -C3-6 cycloalkyl unsubstituted or substituted with one, two or three substituents independently selected from fluorine, chlorine, bromine, -OR 4 , -SR -NR 6 R 7 or -C1-3 alkyl, ( d) phenyl or naphthyl each unsubstituted or substituted with one, two or three substituents independently selected from fluorine, chlorine, bromine, -OR 4 , -NR 6 R 7 or -C1-3alkyl, (e) -CH2CH2OCH3, - CH2CH2OCH2CH3, -CH2CH2CH2OCH3, -CH2CH2CH2OCH2CH3, CH2CH2SCH3, -CH2CH2SCH2CH3, -CH2CH2CH2SCH3, -CH2CH2CH2SCH2CH3, CH2CH2NHCH3, -CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2 (f) pyridyl unsubstituted or substituted with one, two or three substituents independently selected from fluorine, chlorine, bromine, OR 4 , -SR, -NR 6 R 7 or C1-3 alkyl, or (g) piperidinyl, pyrrolidinyl, tetrahydrofuranyl , or tetrahydropyranyl, each unsubstituted or substituted with one, two or three substituents independently selected from fluorine, chlorine, bromine, OR 4 , -SR, -NR 6 R 7 or C1-3 alkyl. [10] A compound or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 8, characterized in that R 3 is -C1-8 alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or -C1-3 alkyl O-C1-3 alkyl. [11] A compound or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 8, characterized in that R 3 is -C1- alkyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. [12] 12. A compound or a pharmaceutically acceptable salt thereof, according to claim 1, characterized by the fact that: R 1 and R 2 are both methyl, ethyl, propyl or / -propyl; Petition 870190056148, of 06/17/2019, p. 683/693 5/13 R 3 is -C1- alkyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; R 8 is -H or -C1-3alkyl; R 9 is -H, -C1-3 alkyl or -C1-3 alkyl substituted with 1 to 3 of F; R 10 is -H, -C1-3 alkyl or -C1-3 alkyl substituted with 1 to 3 of F; or R 9 and R 10 are bonded with the carbon to which they are both attached to form C3-6 spiro-cycloalkyl; R a is halo, -CN, -C1-3 alkyl, -C1-3 alkyl substituted with 1 to 3 of F, -O-C1-3 alkyl or -O-C1-3 alkyl substituted with 1 to 3 of F; and R b is -H, halo, -CN, -C1-3 alkyl, -C1-3 alkyl substituted with 1 to 3 of F, -O-C1-3 alkyl or -O-C1-3 alkyl substituted with 1 to 3 from F. [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) (((/ ) - l - propyl (4chlorophenyl) ethyl) amino) phosphoryl) amino) -2-methylpropanoate; 2 - ((((S) - ((((/ ) - 1- (6-amino-9H-purin-9-yl) propan-2-yl) oxy) methyl) (((/ ) - 1- Propyl (4chlorophenyl) ethyl) amino) phosphoryl) amino) -2-methylpropanoate; 2 - (((/ ) - ((((/ ) - 1- (6-amino-9H-purin-9-yl) propan-2-yl) oxy) methyl) (((/ ) - l - propyl (4chlorophenyl) ethyl) (methyl) amino) phosphoryl) amino) -2-methylpropanoate; 2 - ((((S) - ((((/ ) - 1- (6-amino-9H-purin-9-yl) propan-2-yl) oxy) methyl) (((/ ) - 1- Propyl (4-chlorophenyl) ethyl) (methyl) amino) phosphoryl) amino) -2-methylpropanoate; 2 - (((/ ) - ((((/ ) - 1- (6-amino-9H-purin-9-yl) propan-2-yl) oxy) methyl) (((/ ) - 2 , 2,2-trifluoro- Propyl 1- (4- (trifluoromethoxy) phenyl) ethyl) amino) phosphoryl) amino) -2-methylpropanoate; 2- ((((S) - ((((/ ) - 1- (6-amino-9H-purin-9-yl) propan-2-yl) oxy) methyl) (((/ ) - 2, Propyl 2,2-trifluorol- (4- (trifluoromethoxy) phenyl) ethyl) amino) phosphoryl) amino) -2-methylpropanoate; Petition 870190056148, of 06/17/2019, p. 684/693 6/13 2 - ((((S) - ((((/ ) - 3- (6-amino-9 / - / - purin-9-yl) -1,1-trifluoropropan-2-yl) oxy) methyl ) Propyl (((/ ) 2,2,2-trifluoro-1- (4- (trifluoromethoxy) phenyl) ethyl) amino) phosphoryl) amino) -2-methylpropanoate; 2 - (((/ ) - ((((/ ) - 3- (6-amino-9 / - / - purin-9-yl) -1,1-trifluoropropan-2-yl) ox) propyl methyl) (((/ ) 2,2,2-trifluoro-1- (4- (trifluoromethoxy) phenyl) ethyl) amino) phosphoryl) amino) -2-methylpropanoate; 2 - (((( ) - ((((/ ) - 1- (6-amino-9H-purin-9-yl) propan-2-yl) oxy) methyl) ((4isopropylbenzyl) amino) phosphoryl) amino) propyl -2-methylpropanoate; 2 - ((((S) - ((((/ ) - 1- (6-amino-9H-purin-9-yl) propan-2-yl) oxy) methyl) ((4isopropylbenzyl) amino) phosphoryl) amino ) Propyl -2-methylpropanoate; 2 - (((( ) - ((((/ ) - 1- (6-amino-9H-purin-9-yl) propan-2-yl) oxy) methyl) ((4-cyanobenzyl) amino) phosphoryl) amino) propyl -2-methylpropanoate; 2 - ((((S) - ((((/ ) - 1- (6-amino-9H-purin-9-yl) propan-2-yl) oxy) methyl) ((4-cyanobenzyl) amino) phosphoryl) amino ) Propyl -2-methylpropanoate; 2 - (((/ ) - ((((/ ) - 1- (6-amino-9H-purin-9-yl) propan-2-yl) oxy) methyl) ((4 (trifluoromethoxy) benzyl) propyl amino) phosphoryl) amino) -2-methylpropanoate; 2 - ((((S) - ((((/ ) - 1- (6-amino-9H-purin-9-yl) propan-2-yl) oxy) methyl) ((4 (trifluoromethoxy) benzyl) amino ) propyl phosphoryl) amino) -2-methylpropanoate; 2 - (((/ ) - ((((/ ) - 1- (6-amino-9H-purin-9-yl) propan-2-yl) oxy) methyl) ((3-fluorobenzyl) amino) phosphoryl) amino) propyl -2-methylpropanoate; 2 - ((((S) - ((((/ ) - 1- (6-amino-9H-purin-9-yl) propan-2-yl) oxy) methyl) ((3-fluorobenzyl) amino) phosphoryl) amino ) Propyl -2-methylpropanoate; 2 - (((/ ) - ((((/ ) - 1- (6-amino-9H-purin-9-yl) propan-2-yl) oxy) methyl) ((((R) -l- Propyl (3-fluorophenyl) ethyl) amino) phosphoryl) amino) -2-methylpropanoate; 2 - ((((S) - ((((/ ) - 1- (6-amino-9H-purin-9-yl) propan-2-yl) oxy) methyl) ((((R) -l- ( Propyl 3 fluorophenyl) ethyl) amino) phosphoryl) amino) -2-methylpropanoate; Petition 870190056148, of 06/17/2019, p. 685/693 7/13 2 - (((/ ) - ((((/ ) - 1- (6-amino-9H-purin-9-yl) propan-2-yl) oxy) methyl) ((((S) -l- Propyl (3-fluorophenyl) ethyl) amino) phosphoryl) amino) -2-methylpropanoate; 2 - ((((S) - ((((/ ) - 1- (6-amino-9H-purin-9-yl) propan-2-yl) oxy) methyl) ((((S) -l- ( Propyl 3 fluorophenyl) ethyl) amino) phosphoryl) amino) -2-methylpropanoate; 2 - (((/ ) - ((((/ ) - 1- (6-amino-9H-purin-9-yl) propan-2-yl) oxy) methyl) ((((S) -l- Propyl (4 (trifluoromethyl) phenyl) ethyl) amino) phosphoryl) amino) -2-methylpropanoate; 2 - ((((S) - ((((/ ) - 1- (6-amino-9H-purin-9-yl) propan-2-yl) oxy) methyl) ((((S) -l- ( Propyl 4 (trifluoromethyl) phenyl) ethyl) amino) phosphoryl) amino) -2-methylpropanoate; 2 - (((/ ) - ((((/ ) - 1- (6-amino-9H-purin-9-yl) propan-2-yl) oxy) methyl) (((/ ) - l - propyl (4 (trifluoromethyl) phenyl) ethyl) amino) phosphoryl) amino) -2-methylpropanoate; 2 - ((((S) - ((((/ ) - 1- (6-amino-9H-purin-9-yl) propan-2-yl) oxy) methyl) (((/ ) - 1- Propyl (4 (trifluoromethyl) phenyl) ethyl) amino) phosphoryl) amino) -2-methylpropanoate; 2 - (((/ ) - ((((/ ) - 1- (6-amino-9H-purin-9-yl) propan-2-yl) oxy) methyl) ((((S) -l- Propyl (4chlorophenyl) ethyl) amino) phosphoryl) amino) -2-methylpropanoate; 2 - ((((S) - ((((/ ) - 1- (6-amino-9H-purin-9-yl) propan-2-yl) oxy) methyl) ((((S) -l- ( Propyl 4-chlorophenyl) ethyl) amino) phosphoryl) amino) -2-methylpropanoate; 2 - (((/ ) - ((((/ ) - 1- (6-amino-9H-purin-9-yl) propan-2-yl) oxy) methyl) ((((S) -l- Propyl (4methoxyphenyl) ethyl) amino) phosphoryl) amino) -2-methylpropanoate; 2 - ((((S) - ((((/ ) - 1- (6-amino-9H-purin-9-yl) propan-2-yl) oxy) methyl) ((((S) -l- ( Propyl 4methoxyphenyl) ethyl) amino) phosphoryl) amino) -2-methylpropanoate; 2 - (((/ ) - ((((/ ) - 1- (6-amino-9H-purin-9-yl) propan-2-yl) oxy) methyl) (((/ ) - l - propyl (4methoxyphenyl) ethyl) amino) phosphoryl) amino) -2-methylpropanoate; 2 - ((((S) - ((((/ ) - 1- (6-amino-9H-purin-9-yl) propan-2-yl) oxy) methyl) (((/ ) - 1- Propyl (4methoxyphenyl) ethyl) amino) phosphoryl) amino) -2-methylpropanoate; 2 - (((/ ) - ((((/ ) - 1- (6-amino-9H-purin-9-yl) propan-2-yl) oxy) methyl) (((/ ) - l - propyl (ptolyl) ethyl) amino) phosphoryl) amino) -2-methylpropanoate; Petition 870190056148, of 06/17/2019, p. 686/693 8/13 2 - ((((S) - ((((/ ) - 1- (6-amino-9H-purin-9-yl) propan-2-yl) oxy) methyl) (((/ ) - 1- propyl (ptolyl) ethyl) amino) phosphoryl) amino) -2-methylpropanoate; 2 - (((/ ) - ((((/ ) - 1- (6-amino-9H-purin-9-yl) propan-2-yl) oxy) methyl) ((((S) -l- Propyl (2methoxyphenyl) ethyl) amino) phosphoryl) amino) -2-methylpropanoate; 2 - ((((S) - ((((/ ) - 1- (6-amino-9H-purin-9-yl) propan-2-yl) oxy) methyl) ((((S) -l- ( Propyl 2methoxyphenyl) ethyl) amino) phosphoryl) amino) -2-methylpropanoate; 2 - (((/ ) - ((((/ ) - 1- (6-amino-9H-purin-9-yl) propan-2-yl) oxy) methyl) ((((S) -l- propyl (ptolyl) ethyl) amino) phosphoryl) amino) -2-methylpropanoate; 2 - ((((S) - ((((/ ) - 1- (6-amino-9H-purin-9-yl) propan-2-yl) oxy) methyl) ((((S) -l- ( ptolyl) ethyl) amino) phosphoryl) propyl) -2-methylpropanoate; 2 - (((/ ) - ((((/ ) - 1- (6-amino-9H-purin-9-yl) propan-2-yl) oxy) methyl) ((((S) -l- Propyl (4 (trifluoromethoxy) phenyl) ethyl) amino) phosphoryl) amino) -2-methylpropanoate; 2 - ((((S) - ((((/ ) - 1- (6-amino-9H-purin-9-yl) propan-2-yl) oxy) methyl) ((((S) -l- ( Propyl 4 (trifluoromethoxy) phenyl) ethyl) amino) phosphoryl) amino) -2-methylpropanoate; 2 - (((/ ) - ((((/ ) - 1- (6-amino-9H-purin-9-yl) propan-2-yl) oxy) methyl) (((/ ) - l - propyl (2methoxyphenyl) ethyl) amino) phosphoryl) amino) -2-methylpropanoate; 2 - ((((S) - ((((/ ) - 1- (6-amino-9H-purin-9-yl) propan-2-yl) oxy) methyl) (((/ ) - 1- Propyl (2methoxyphenyl) ethyl) amino) phosphoryl) amino) -2-methylpropanoate; 2 - (((/ ) - ((((/ ) - 1- (6-amino-9H-purin-9-yl) propan-2-yl) oxy) methyl) (((/ ) - l - propyl (2-methyl-4 (trifluoromethoxy) phenyl) ethyl) amino) phosphoryl) amino) -2-methylpropanoate; 2 - ((((S) - ((((/ ) - 1- (6-amino-9H-purin-9-yl) propan-2-yl) oxy) methyl) (((/ ) - 1- Propyl (2-methyl-4 (trifluoromethoxy) phenyl) ethyl) amino) phosphoryl) amino) -2-methylpropanoate; 2 - (((/ ) - ((((/ ) - 1- (6-amino-9H-purin-9-yl) propan-2-yl) oxy) methyl) (((/ ) - 2 , 2,2-trifluoro- Propyl 1- (3-fluorophenyl) ethyl) amino) phosphoryl) amino) -2-methylpropanoate; 2- ((((5) - ((((/ ) - 1- (6-amino-9 / - / - purin-9-yl) propan-2-yl) oxy) methyl) (((/ ) -2,2,2-trifluorol- (3-fluorophenyl) ethyl) amino) phosphoryl) amino) -2-propyl methylpropanoate; Petition 870190056148, of 06/17/2019, p. 687/693 9/13 2 - (((/ ) - ((((/ ) - 1- (6-amino-9H-purin-9-yl) propan-2-yl) oxy) methyl) (((/ ) - l - propyl (4-cyanophenyl) -2,2,2-trifluoroethyl) amino) phosphoryl) amino) -2-methylpropanoate; 2 - ((((S) - ((((/ ) - 1- (6-amino-9H-purin-9-yl) propan-2-yl) oxy) methyl) (((/ ) - 1- Propyl (4-cyanophenyl) -2,2,2-trifluoroethyl) amino) phosphoryl) amino) -2-methylpropanoate; 2 - (((/ ) - ((((/ ) - 1- (6-amino-9H-purin-9-yl) propan-2-yl) oxy) methyl) ((((S) -l- Propyl (4-cyanophenyl) -2,2,2-trifluoroethyl) amino) phosphoryl) amino) -2-methylpropanoate; 2 - ((((S) - ((((/ ) - 1- (6-amino-9H-purin-9-yl) propan-2-yl) oxy) methyl) ((((S) -l- ( Propyl 4-cyanophenyl) -2,2,2-trifluoroethyl) amino) phosphoryl) amino) -2-methylpropanoate; 2 - (((/ ) - ((((/ ) - 1- (6-amino-9H-purin-9-yl) propan-2-yl) oxy) methyl) (((/ ) - 2 , 2,2-trifluoro- Propyl 1- (3-methoxyphenyl) ethyl) amino) phosphoryl) amino) -2-methylpropanoate; 2- ((((5) - ((((/ ) - 1- (6-amino-9 / - / - purin-9-yl) propan-2-yl) oxy) methyl) (((/ ) -2,2,2-trifluoro- Propyl 1- (3-methoxyphenyl) ethyl) amino) phosphoryl) amino) -2-methylpropanoate; 2- (((/ ) - (((((R) -1- (6-amino-9H-purin-9-yl) propan-2-yl) oxy) methyl) (((/ ) - 2, 2,2-trifluoro- Propyl 1- (p-tolyl) ethyl) amino) phosphoryl) amino) -2-methylpropanoate; 2- ((((5) - ((((/ ) - 1- (6-amino-9 / - / - purin-9-yl) propan-2-yl) oxy) methyl) (((/ ) -2,2,2-trifluoro- Propyl 1- (p-tolyl) ethyl) amino) phosphoryl) amino) -2-methylpropanoate; 2- (((/ ) - ((((/ ) - 1- (6-amino-9H-purin-9-yl) propan-2-yl) oxy) methyl) (((/ ) - 2 , 2,2-trifluoro- Propyl 1- (4- (trifluoromethoxy) phenyl) ethyl) amino) phosphoryl) amino) -2-methylpropanoate; 2- ((((5) - ((((/ ) - 1- (6-amino-9 / - / - purin-9-yl) propan-2-yl) oxy) methyl) (((/ ) -2,2,2-trifluoro-1- (4- (trifluoromethoxy) phenyl) ethyl) amino) phosphoryl) amino) -2-propyl methylpropanoate; Petition 870190056148, of 06/17/2019, p. 688/693 10/13 2 - (((/ ) - ((((/ ) - 1- (6-amino-9 / - / - purin-9-yl) propan-2-yl) oxy) methyl) (((S) -2,2,2-trifluoro- Propyl 1- (3-methoxyphenyl) ethyl) amino) phosphoryl) amino) -2-methylpropanoate; 2- ((((5) - ((((/ ) - 1- (6-amino-9 / - / - purin-9-yl) propan-2-yl) oxy) methyl) (((S) - 2,2,2-trifluoro- Propyl 1- (3-methoxyphenyl) ethyl) amino) phosphoryl) amino) -2-methylpropanoate; 2- (((/ ) - ((((/ ) - 1- (6-amino-9H-purin-9-yl) propan-2-yl) oxy) methyl) (((/ ) - 1 - propyl (4-chloro-2-methylphenyl) ethyl) amino) phosphoryl) amino) -2-methylpropanoate; 2 - ((((S) - ((((/ ) - 1- (6-amino-9H-purin-9-yl) propan-2-yl) oxy) methyl) (((/ ) - 1- Propyl (4-chloro-2methylphenyl) ethyl) amino) phosphoryl) amino) -2-methylpropanoate; 2 - (((/ ) - ((((/ ) - 1- (6-amino-9H-purin-9-yl) propan-2-yl) oxy) methyl) ((((S) -l- Propyl (4-chloro-2methylphenyl) ethyl) amino) phosphoryl) amino) -2-methylpropanoate; 2 - ((((S) - ((((/ ) - 1- (6-amino-9H-purin-9-yl) propan-2-yl) oxy) methyl) ((((S) -l- ( Propyl 4-chloro-2methylphenyl) ethyl) amino) phosphoryl) amino) -2-methylpropanoate; 2 - (((/ ) - ((((/ ) - 1- (6-amino-9H-purin-9-yl) propan-2-yl) oxy) methyl) (((/ ) - l - propyl (4-cyanophenyl) ethyl) amino) phosphoryl) amino) -2-methylpropanoate; 2 - ((((S) - ((((/ ) - 1- (6-amino-9H-purin-9-yl) propan-2-yl) oxy) methyl) (((/ ) - 1- Propyl (4-cyanophenyl) ethyl) amino) phosphoryl) amino) -2-methylpropanoate; 2 - (((/ ) - ((((/ ) - 1- (6-amino-9H-purin-9-yl) propan-2-yl) oxy) methyl) ((4isopropylbenzyl) (methyl) amino ) propyl phosphoryl) amino) -2-methylpropanoate; 2 - ((((S) - ((((/ ) - 1- (6-amino-9H-purin-9-yl) propan-2-yl) oxy) methyl) ((4isopropylbenzyl) (methyl) amino) phosphoryl) propyl amino) -2-methylpropanoate; 2 - (((/ ) - ((((/ ) - 1- (6-amino-9H-purin-9-yl) propan-2-yl) oxy) methyl) (methyl ((/ ) - propyl 1- (4 (trifluoromethoxy) phenyl) ethyl) amino) phosphoryl) amino) -2-methylpropanoate; 2 - ((((S) - ((((/ ) - 1- (6-amino-9H-purin-9-yl) propan-2-yl) oxy) methyl) (methyl ((/ ) - l - propyl (4 (trifluoromethoxy) phenyl) ethyl) amino) phosphoryl) amino) -2-methylpropanoate; 2 - (((/ ) - ((((/ ) - 1- (6-amino-9H-purin-9-yl) propan-2-yl) oxy) methyl) (((/ ) - l - isopropyl (4 (trifluoromethoxy) phenyl) ethyl) amino) phosphoryl) amino) -2-methylpropanoate; Petition 870190056148, of 06/17/2019, p. 689/693 11/13 2 - ((((S) - ((((/ ) - 1- (6-amino-9H-purin-9-yl) propan-2-yl) oxy) methyl) (((/ ) - 1- Isopropyl (4 (trifluoromethoxy) phenyl) ethyl) amino) phosphoryl) amino) -2-methylpropanoate; 2 - (((/ ) - ((((/ ) - 1- (6-amino-9H-purin-9-yl) propan-2-yl) oxy) methyl) (((/ ) - l - isopropyl (4chlorophenyl) ethyl) amino) phosphoryl) amino) -2-methylpropanoate; 2 - ((((S) - ((((/ ) - 1- (6-amino-9H-purin-9-yl) propan-2-yl) oxy) methyl) (((/ ) - 1- Isopropyl (4chlorophenyl) ethyl) amino) phosphoryl) amino) -2-methylpropanoate; 2 - (((/ ) - ((((/ ) - 1- (6-amino-9H-purin-9-yl) propan-2-yl) oxy) methyl) ((2- (4-chlorophenyl) propan Isopropyl -2-yl) amino) phosphoryl) amino) -2-methylpropanoate; 2 - ((((S) - ((((/ ) - 1- (6-amino-9H-purin-9-yl) propan-2-yl) oxy) methyl) ((2- (4-chlorophenyl) propan- Isopropyl 2-yl) amino) phosphoryl) amino) -2-methylpropanoate; 2 - (((/ ) - ((((/ ) - 1- (6-amino-9H-purin-9-yl) propan-2-yl) oxy) methyl) ((l- (4-chlorophenyl) cyclopropyl ) isopropyl amino) phosphoryl) amino) -2-methylpropanoate; or 2 - ((((S) - ((((/ ) - 1- (6-amino-9H-purin-9-yl) propan-2-yl) oxy) methyl) ((l- (4-chlorophenyl) cyclopropyl) isopropyl amino) phosphoryl) amino) -2-methylpropanoate; or a pharmaceutically acceptable salt thereof. [14] Pharmaceutical composition, characterized in that it comprises an effective amount of the compound defined in any one of claims 1 to 8, 12 or 13, or a pharmaceutically acceptable salt thereof, 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 agent selected from HIV protease inhibitors, HIV integrase inhibitors, non-nucleoside transcriptase inhibitors reverse HIV, nucleoside HIV reverse transcriptase inhibitors, HIV fusion inhibitors and HIV entry inhibitors. Petition 870190056148, of 06/17/2019, p. 690/693 12/13 [16] 16. Pharmaceutical composition according to claim 14, characterized in that it additionally comprises an effective amount of one or more additional HIV antiviral agent selected from: abacavir, abacavir sulfate, abacavir + lamivudine, abacavir + lamivudine + zidovudine, amprenavir, atazanavir, atazanavir sulphate, AZT, capravirine, darunavir, didesoxycytidine, didesoxyinosine, delavirdine, delavirdine mesylate, dolutegravir, doravirine, efavirenz, 4'-ethinyl-2-fluoro-2'-deoxydehyde and 3-deoxydehyde enfuvirtide, etravirine, fosamprenavir calcium, indinavir, indinavir sulphate, lamivudine, lamivudine + zidovudine, lopinavir, lopinavir + ritonavir, maraviroc, nelfinavir, nelfinavir mesylate, nevirapine, raltin, pPL-1OO , stavudine, tipranavir or vicriviroc. [17] 17. Use of a compound defined in any one of claims 1 to 8.12 or 13, or a pharmaceutically acceptable salt thereof, and optionally of one or more additional HIV antiviral agent, characterized in that it is for 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 agent is selected from HIV protease inhibitors, HIV integrase inhibitors, non-nucleoside HIV reverse transcriptase inhibitors, nucleoside inhibitors of HIV reverse transcriptase, HIV fusion inhibitors and HIV entry inhibitors. [19] 19. Use according to claim 17, characterized by the fact that one or more additional HIV antiviral agent is selected from: abacavir, abacavir sulfate, abacavir + lamivudine, abacavir + lamivudine + zidovudine, amprenavir, atazanavir, atazanavir, sulfate atazanavir, AZT, capravirin, darunavir, Petition 870190056148, of 06/17/2019, p. 691/693 13/13 didesoxycytidine, didesoxyinosine, delavirdine, delavirdine mesylate, dolutegravir, doravirine, efavirenz, 4'-ethinyl-2-fluoro-2'-deoxyadenosine, elvitegravir, emtricitabine, emivirine, enfuvirtide, etraviravine, etraviravine, etraviravine indinavir, lamivudine, lamivudine + zidovudine, lopinavir, lopinavir + ritonavir, maraviroc, nelfinavir, nelfinavir mesylate, nevirapine, PPL-1OO, raltegravir, rilpivirine, ritonavir, saquinavir, saquinavir, vicin, serquinirate [20] A compound according to any one of claims 1 to 8.12 or 13, or a pharmaceutically acceptable salt thereof, characterized in that it is for use in the preparation of a medicament 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. [21] 21. Invention of a product, process, system or use, characterized by the fact that it comprises one or more elements described in the present patent application.
类似技术:
公开号 | 公开日 | 专利标题 BR112019012511A2|2019-11-19|benzyl amine phosphodiamide antiviral compounds, pharmaceutical composition and use of the compound BR112019013017A2|2020-01-14|tenofovir antiviral aliphatic ester compounds or pharmaceutically acceptable salts thereof, pharmaceutical composition and use thereof US10745428B2|2020-08-18|Antiviral phosphodiamide prodrugs of tenofovir JP6563585B2|2019-08-21|Antiviral beta-amino acid ester phosphodiamide compounds US10736908B2|2020-08-11|Antiviral aryl-amide phosphodiamide compounds WO2017007701A1|2017-01-12|Antiviral phosphodiamide compounds EP3390413B1|2020-08-19|Antiviral oxime phosphoramide compounds EP3503895B1|2021-09-15|Antiviral prodrugs of tenofovir BR112019010924A2|2019-10-01|tetracyclic heterocyclic compounds useful as hiv integrase inhibitors, pharmaceutically acceptable salts thereof, pharmaceutical compositions and uses of said compounds US20210260082A1|2021-08-26|Phosphinic amide prodrugs of tenofovir
同族专利:
公开号 | 公开日 MX2019007262A|2019-09-05| CA3046029A1|2018-06-28| MA47131A|2021-05-12| KR20190100249A|2019-08-28| RU2019122625A|2021-01-22| WO2018118826A1|2018-06-28| EP3558322B1|2021-09-29| JP2020504734A|2020-02-13| EP3558322A4|2020-05-06| US11123355B2|2021-09-21| AU2017378893A1|2019-05-16| CN110035760A|2019-07-19| US20190321380A1|2019-10-24| EP3558322A1|2019-10-30|
引用文献:
公开号 | 申请日 | 公开日 | 申请人 | 专利标题 EP0719273B1|1993-09-17|2010-11-03|Gilead Sciences, Inc.|Nucleotide analogs| US5977061A|1995-04-21|1999-11-02|Institute Of Organic Chemistry And Biochemistry Of The Academy Of Sciences Of The Czech Republic|N6 - substituted nucleotide analagues and their use| US5922695A|1996-07-26|1999-07-13|Gilead Sciences, Inc.|Antiviral phosphonomethyoxy nucleotide analogs having increased oral bioavarilability| US5935946A|1997-07-25|1999-08-10|Gilead Sciences, Inc.|Nucleotide analog composition and synthesis method| CN1740182A|1999-12-22|2006-03-01|症变治疗公司|Novel bisamidate phosphonate prodrugs| PL213214B1|2000-07-21|2013-01-31|Gilead Sciences|Prodrugs of phosphonate nucleotide analogues and methods for selecting and making same| US7388002B2|2001-11-14|2008-06-17|Biocryst Pharmaceuticals, Inc.|Nucleosides, preparation thereof and use as inhibitors of RNA viral polymerases| NZ540728A|2003-01-14|2008-08-29|Gilead Sciences Inc|Compositions and methods for combination antiviral therapy| WO2007002912A2|2005-06-29|2007-01-04|Gilead Sciences, Inc.|Anti-proliferative compounds, compositions, and methods of use thereof| DK1716162T3|2003-12-30|2011-01-10|Gilead Sciences Inc|Phosphonates, amidomonophosphonates, amidobis phosphonates for the treatment of viral diseases| CA2585353A1|2004-10-26|2006-05-04|Gilead Sciences, Inc.|Phosphonate derivatives of mycophenolic acid| SI2038290T1|2006-07-07|2014-01-31|Gilead Sciences, Inc.|Modulators of toll-like receptor 7| TWI444384B|2008-02-20|2014-07-11|Gilead Sciences Inc|Nucleotide analogues and their use in the treatment of malignancies| WO2011123586A1|2010-04-01|2011-10-06|Idenix Pharmaceuticals, Inc.|Compounds and pharmaceutical compositions for the treatment of viral infections| EP2569291B1|2010-05-11|2016-04-06|Simon Fraser University|Selective glycosidase inhibitors and uses thereof| JP2014514295A|2011-03-31|2014-06-19|アイディニックスファーマシューティカルズインコーポレイテッド|Compounds and pharmaceutical compositions for the treatment of viral infections| UA115311C2|2011-08-16|2017-10-25|Гіліад Сайєнсіз, Інк.|Tenofovir alafenamide hemifumarate| EP2794624B1|2011-12-22|2019-05-15|Geron Corporation|Guanine analogs as telomerase substrates and telomere length affectors| CN107312039B|2012-08-30|2019-06-25|江苏豪森药业集团有限公司|A kind of preparation method of tenofovir prodrug| CN103435672A|2013-04-25|2013-12-11|刘沛|Structure and synthesis of novel nucleoside phosphate prodrug containing substituted benzyl| CN111808136A|2014-09-15|2020-10-23|加利福尼亚大学董事会|Nucleotide analogs| WO2017007701A1|2015-07-07|2017-01-12|Merck Sharp & Dohme Corp.|Antiviral phosphodiamide compounds| JP6563585B2|2015-08-10|2019-08-21|メルク・シャープ・アンド・ドーム・コーポレーションＭｅｒｃｋ Ｓｈａｒｐ ＆ Ｄｏｈｍｅ Ｃｏｒｐ．|Antiviral beta-amino acid ester phosphodiamide compounds| CN106167504A|2015-11-04|2016-11-30|洛阳聚慧医药科技有限公司|Acyclonucleosides phosphamide D amino acid ester derivative and the preparation of salt thereof and in the application of anti-virus aspect| EP3386512A4|2015-12-10|2019-05-29|Merck Sharp & Dohme Corp.|Antiviral phosphodiamide prodrugs of tenofovir| WO2017106069A1|2015-12-15|2017-06-22|Merck Sharp & Dohme Corp.|Antiviral oxime phosphoramide compounds| US10449208B2|2016-08-25|2019-10-22|Merck Sharp & Dohme Corp.|Antiviral prodrugs of tenofovir| US10736908B2|2016-10-26|2020-08-11|Merck Sharp & Dohme Corp.|Antiviral aryl-amide phosphodiamide compounds| EP3559011A1|2016-12-22|2019-10-30|Merck Sharp & Dohme Corp.|Antiviral aliphatic ester prodrugs of tenofovir| AU2017378893A1|2016-12-22|2019-05-16|Idenix Pharmaceuticals Llc|Antiviral benzyl-amine phosphodiamide compounds|EP3386512A4|2015-12-10|2019-05-29|Merck Sharp & Dohme Corp.|Antiviral phosphodiamide prodrugs of tenofovir| WO2017106069A1|2015-12-15|2017-06-22|Merck Sharp & Dohme Corp.|Antiviral oxime phosphoramide compounds| US10449208B2|2016-08-25|2019-10-22|Merck Sharp & Dohme Corp.|Antiviral prodrugs of tenofovir| SG10201914029RA|2016-10-14|2020-03-30|Precision Biosciences Inc|Engineered meganucleases specific for recognition sequences in the hepatitis b virus genome| US10736908B2|2016-10-26|2020-08-11|Merck Sharp & Dohme Corp.|Antiviral aryl-amide phosphodiamide compounds| EP3559011A1|2016-12-22|2019-10-30|Merck Sharp & Dohme Corp.|Antiviral aliphatic ester prodrugs of tenofovir| AU2017378893A1|2016-12-22|2019-05-16|Idenix Pharmaceuticals Llc|Antiviral benzyl-amine phosphodiamide compounds| US11203610B2|2017-12-20|2021-12-21|Institute Of Organic Chemistry And Biochemistry Ascr, V.V.I.|2′3′ cyclic dinucleotides with phosphonate bond activating the sting adaptor protein| US10966999B2|2017-12-20|2021-04-06|Institute Of Organic Chemistry And Biochemistry Ascr, V.V.I.|3′3′ cyclic dinucleotides with phosphonate bond activating the sting adaptor protein| KR20200124716A|2018-02-26|2020-11-03|길리애드 사이언시즈, 인코포레이티드|Substituted pyrrolysine compounds as inhibitors of HBV replication| EP3774883A1|2018-04-05|2021-02-17|Gilead Sciences, Inc.|Antibodies and fragments thereof that bind hepatitis b virus protein x| TW202010503A|2018-04-06|2020-03-16|捷克科學院有機化學與生物化學研究所|3’3’－cyclic dinucleotides| TW202005655A|2018-04-06|2020-02-01|捷克科學院有機化學與生物化學研究所|2'3'-cyclic dinucleotides| TW202005654A|2018-04-06|2020-02-01|捷克科學院有機化學與生物化學研究所|2'2'-cyclic dinucleotides| TW201945388A|2018-04-12|2019-12-01|美商精密生物科學公司|Optimized engineered meganucleases having specificity for a recognition sequence in the hepatitis B virus genome| TW202014193A|2018-05-03|2020-04-16|捷克科學院有機化學與生物化學研究所|2’3’-cyclic dinucleotides comprising carbocyclic nucleotide| WO2020028097A1|2018-08-01|2020-02-06|Gilead Sciences, Inc.|Solid forms of -11--12--3,3-dimethyl-8-0x0-2,3,8,13b-tetrahydro-1h-pyrido[2,1-a]pyrrolo[1,2-c] phthalazine-7-c arboxylic acid| CR20210215A|2018-10-31|2021-06-17|Gilead Sciences Inc|Substituted 6-azabenzimidazole compounds as hpk1 inhibitors| EP3873608A1|2018-10-31|2021-09-08|Gilead Sciences, Inc.|Substituted 6-azabenzimidazole compounds having hpk1 inhibitory activity| WO2020178769A1|2019-03-07|2020-09-10|Institute Of Organic Chemistry And Biochemistry Ascr, V.V.I.|2'3'-cyclic dinucleotides and prodrugs thereof| WO2020178768A1|2019-03-07|2020-09-10|Institute Of Organic Chemistry And Biochemistry Ascr, V.V.I.|3'3'-cyclic dinucleotide analogue comprising a cyclopentanyl modified nucleotide as sting modulator| WO2020178770A1|2019-03-07|2020-09-10|Institute Of Organic Chemistry And Biochemistry Ascr, V.V.I.|3'3'-cyclic dinucleotides and prodrugs thereof| WO2020214663A1|2019-04-17|2020-10-22|Gilead Sciences, Inc.|Solid forms of a toll-like receptor modulator| EP3956329A1|2019-04-17|2022-02-23|Gilead Sciences, Inc.|Solid forms of a toll-like receptor modulator| WO2020237025A1|2019-05-23|2020-11-26|Gilead Sciences, Inc.|Substituted exo-methylene-oxindoles which are hpk1/map4k1 inhibitors| CA3142513A1|2019-06-25|2020-12-30|Gilead Sciences, Inc.|Flt3l-fc fusion proteins and methods of use| WO2021034804A1|2019-08-19|2021-02-25|Gilead Sciences, Inc.|Pharmaceutical formulations of tenofovir alafenamide| WO2021067181A1|2019-09-30|2021-04-08|Gilead Sciences, Inc.|Hbv vaccines and methods treating hbv| WO2021113765A1|2019-12-06|2021-06-10|Precision Biosciences, Inc.|Optimized engineered meganucleases having specificity for a recognition sequence in the hepatitis b virus genome| CN111157638A|2019-12-31|2020-05-15|济南康和医药科技有限公司|Method for detecting oxalic acid content in vitamin C| WO2021188959A1|2020-03-20|2021-09-23|Gilead Sciences, Inc.|Prodrugs of 4'-c-substituted-2-halo-2'-deoxyadenosine nucleosides and methods of making and using the same| WO2022031894A1|2020-08-07|2022-02-10|Gilead Sciences, Inc.|Prodrugs of phosphonamide nucleotide analogues and their pharmaceutical use|
法律状态:
2021-03-30| B11A| Dismissal acc. art.33 of ipl - examination not requested within 36 months of filing| 2021-06-15| B11Y| Definitive dismissal - extension of time limit for request of examination expired [chapter 11.1.1 patent gazette]| 2021-10-13| B350| Update of information on the portal [chapter 15.35 patent gazette]|
优先权:
[返回顶部]
申请号 | 申请日 | 专利标题 US201662437745P| true| 2016-12-22|2016-12-22| US201762540748P| true| 2017-08-03|2017-08-03| PCT/US2017/067159|WO2018118826A1|2016-12-22|2017-12-19|Antiviral benzyl-amine phosphodiamide compounds| 相关专利
Sulfonates, polymers, resist compositions and patterning process
Washing machine
Washing machine
Device for fixture finishing and tension adjusting of membrane
Structure for Equipping Band in a Plane Cathode Ray Tube
Process for preparation of 7 alpha-carboxyl 9, 11-epoxy steroids and intermediates useful therein an
国家/地区
|