Bridged tricyclic carbamoylpyridone compounds and uses thereof

Abstract

The present disclosure relates generally to compounds of Formula (I): Pharmaceutical compositions comprising the compounds and methods of making the compounds are also disclosed. The compounds of the present disclosure are useful in the treatment or prevention of human immunodeficiency virus (HIV) infection.

Description

(19) State Intellectual Property Office (12) Invention Patent Application (10) Application Publication Number (43) Application Publication Date (21) Application Number 202480064943.2 (22) Application Date 2024.10.10 (30) Priority Data 63 / 543,700 2023.10.11 US 63 / 659,857 2024.06.14 US 63 / 702,723 2024.10.03 US (85) PCT International Application Entering National Phase Date 2026.04.09 (86) PCT International Application Application Data PCT / US2024 / 050832 2024.10.10 (87) PCT International Application Publication Data WO2025 / 080879 EN 2025.04.17 (71) Applicant Gilead Sciences, Inc. Address: California, USA (72) Inventors M.K. Armstrong, Zhou Jianhong, A.Z. Gonzalez Boonrostro, Han Xiaochun, Jiang Lan, Li Jiayao, M.L. Michel, G.M. Schwarzwald, A.B. Schödeinde, M. Subramaniam, Wu Qiaoyin, Yang Hai (74) Patent Agency: King & Wood Mallesons, Beijing 11256 Patent Attorney: Ma Hui (51) Int.Cl. C07F 9 / 6561 (2006.01) C07D 498 / 22 (2006.01) A61K 31 / 4995 (2006.01) A61K 31 / 675 (2006.01) A61P 31 / 18 (2006.01) (54) Invention Title: Bridged Tricyclic Carbamoylpyridinone Compound and Its Uses (57) Abstract: This disclosure relates in its entirety to compounds of formula (I): (I) also discloses pharmaceutical compositions comprising said compound and methods for preparing said compound. The compound disclosed herein can be used to treat or prevent human immunodeficiency virus (HIV) infection. Claims 47 pages, Description 189 pages, Drawings 2 pages, CN 122055373 A 2026.05.15 CN 1 22 05 53 73 A 1. A compound of formula I: Formula I or a pharmaceutically acceptable salt thereof, wherein: R1 is –(CR1AR1BO)a(Y)b(CR1CR1D)dX; wherein a is 0 or 1; b is 0 or 1; d is 0, 1, 2, 3, 4 or 5; R1A is H or C1-3 alkyl; R1B is H or C1-3 alkyl; each R1C is independently H or C1-3 alkyl; each R1D is independently H or C1-3 alkyl; or optionally, R1C and R1D on the same carbon atom are bonded to form a spirocyclopropyl group; Y is -C(O)-, -C(O)O-, -C(O)NH- or -C(O)NR1H-;R1H is a C1-4 alkyl group optionally substituted with one or two substituents independently selected from the group consisting of: –COOH, -OH, -NH2, –CONH2, -P(O)(OH)2, and -S(O)2(OH); X is selected from the group consisting of: (a) -O-P(O)(OR1E)2, wherein each R1E is independently H or phenyl; (b) -N(R1F)2, wherein each R1F is independently H, COO(CR1IR1J)eOPO(OH)2, or a C1-4 alkyl group; wherein the C1-4 alkyl group is optionally substituted with one or two substituents independently selected from the group consisting of: COOH, -S(O)2OH, -P(O)(OH)2, -OH, -NH2, and -CONH2; e is 1, 2, or 3; each R1I is independently H or a C1-3 alkyl group; Each R1J is independently H or C1-3 alkyl; or optionally, R1I and R1J on the same carbon atom are joined to form a spiropropyl group; and (c)-N+(R1G)3Z-, wherein each R1G is independently H or C1-4 alkyl; wherein the C1-4 alkyl is optionally substituted by one or two substituents independently selected from the group consisting of: -COOH, -OH, -NH2 and -CONH2; Z- is a counterion; R2 is C1-3 alkyl or C1-3 alkoxy; each R3, R4, R5, R6 and R7 is independently H or halogenated; and R8 is H or C1-3 alkyl. Claims 1 / 47 page 2 CN 122055373 A 2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein Z- is selected from the group consisting of: acetate, ascorbate, aspartate, benzenesulfonate, benzoate, bromide, bicarbonate, carbonate, cinnamate, citrate, chloride, formate, fumarate, gluconate, glutamate, glycolate, lactate, malate, maleate, malonic acid, mandelic acid, methanesulfonate, nicotinic acid, nitrate, oxalate, dihydrogen phosphate, hydrogen phosphate, phosphate, propionate, toluenesulfonate, pyroglutamate, salicylate, succinate, hydrogen sulfate, sulfate, tartrate, thiocyanate, trifluoromethanesulfonate, and trifluoroacetate. 3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein X is -O-P(O)(OR1E)2. 4. The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein each R1E is phenyl. 5. The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein each R1E is H. 6. The compound of any one of claims 1 or 2, or a pharmaceutically acceptable salt thereof, wherein X is -N(R1F)2.7. The compound of claim 6 or a pharmaceutically acceptable salt thereof, wherein each R1F is independently -COO(CR1IR1J)eOPO(OH)2 or a C1-4 alkyl group; wherein the C1-4 alkyl group is optionally substituted with one or two -COOH groups. 8. The compound of claim 6 or 7 or a pharmaceutically acceptable salt thereof, wherein each R1F is independently -COO(CR1IR1J)eOPO(OH)2 or a C1-4 alkyl group; wherein the C1-4 alkyl group is optionally substituted with one -COOH group. 9. The compound of any one of claims 6 to 8, wherein e is 1 or 2. 10. The compound of any one of claims 6 to 9, wherein each R1I and each R1J is H. 11. The compound of any one of claims 6 to 10 or a pharmaceutically acceptable salt thereof, wherein each R1F is independently -COOCH2OPO(OH)2 or a C1-4 alkyl group; wherein the C1-4 alkyl group is optionally substituted with one or two -COOH groups. 12. The compound of any one of claims 6 to 11 or a pharmaceutically acceptable salt thereof, wherein each R1F is independently -COOCH2OPO(OH)2 or a C1-4 alkyl group; wherein the C1-4 alkyl group is optionally substituted with a -COOH group. 13. The compound of any one of claims 6 to 12 or a pharmaceutically acceptable salt thereof, wherein each R1F is independently -COO(CH2)2OPO(OH)2, -COOCH2OPO(OH)2, -CH3, or -CH2COOH. 14. The compound of any one of claims 6 to 13 or a pharmaceutically acceptable salt thereof, wherein each R1F is independently -COOCH2OPO(OH)2, -CH3, or -CH2COOH. 15. The compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein X is -N+(R1G)3Z-. 16. The compound of claim 15 or a pharmaceutically acceptable salt thereof, wherein R1G is -CH3. 17. The compound of any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, wherein a is 0. 18. The compound of any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, wherein a is 1. 19. The compound of any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, wherein b is 0. 20. The compound of any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, wherein b is 1. 21. The compound of any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, wherein Y is -C(O)-, -C(O)O-, -C(O)NH-, or -C(O)NCH3-. 22. The compound of any one of claims 1 to 21, or a pharmaceutically acceptable salt thereof, wherein Y is -C23. The compound of any one of claims 1 to 22 or a pharmaceutically acceptable salt thereof, wherein Y is -C(O)-. 24. The compound of any one of claims 1 to 22 or a pharmaceutically acceptable salt thereof, wherein Y is -C(O)O-. Claims 2 / 47 pages 3 CN 122055373 A 25. The compound of any one of claims 1 to 22 or a pharmaceutically acceptable salt thereof, wherein Y is -C(O)NCH3-. 26. The compound of any one of claims 1 to 20 or a pharmaceutically acceptable salt thereof, wherein Y is -C(O)NR1H-. 27. The compound of claim 26 or a pharmaceutically acceptable salt thereof, wherein R1H is a C1-2 alkyl group optionally substituted with -COOH, -P(O)(OH)2 or -S(O)2(OH). 28. The compound of any one of claims 1 to 25 or a pharmaceutically acceptable salt thereof, wherein d is 1, 2 or 3. 29. The compound of any one of claims 1 to 28, or a pharmaceutically acceptable salt thereof, wherein d is 1. 30. The compound of any one of claims 1 to 28, or a pharmaceutically acceptable salt thereof, wherein d is 2. 31. The compound of any one of claims 1 to 28, or a pharmaceutically acceptable salt thereof, wherein d is 3. 32. The compound of any one of claims 1 to 31, or a pharmaceutically acceptable salt thereof, wherein R4, R5, and R7 are each H. 33. The compound of any one of claims 1 to 32, or a pharmaceutically acceptable salt thereof, wherein R3 and R6 are each independently halogenated. 34. The compound of any one of claims 1 to 33, or a pharmaceutically acceptable salt thereof, wherein R3 and R6 are each F. 35. The compound of any one of claims 1 to 34, or a pharmaceutically acceptable salt thereof, wherein R8 is a C1-3 alkyl group. 36. The compound of any one of claims 1 to 35, or a pharmaceutically acceptable salt thereof, wherein R8 is methyl. 37. The compound of any one of claims 1 to 36, or a pharmaceutically acceptable salt thereof, wherein R2 is methyl or methoxy. 38. The compound according to any one of claims 1 to 37, or a pharmaceutically acceptable salt thereof, wherein R2 is methyl. 39. The compound according to any one of claims 1 to 37, or a pharmaceutically acceptable salt thereof, wherein R2 is methoxy. 40. The compound according to any one of claims 1 to 39, or a pharmaceutically acceptable salt thereof, wherein R1 is selected from the group consisting of: (Claims 3 / 47, page 4, CN 122055373 A)41. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 39, wherein R1 is selected from the group consisting of: , , , , , , , , , , , , , , , , , , and. 42. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 39, wherein R1 is selected from the group consisting of: , , , , , , , , , , , , , , , , , , , , , and. 43. The compound according to any one of claims 1 to 42, wherein the compound is selected from the group consisting of: 7 CN 122055373 A, 8 CN 122055373 A, 9 CN 122055373 A, 10 CN 122055373 A, and 11 CN 122055373 A, or pharmaceutically acceptable salts thereof. 44. The compound according to any one of claims 1 to 42, wherein the compound is selected from the group consisting of: , ... 45. The compound according to any one of claims 1 to 42, wherein the compound is selected from the group consisting of: (Claims 12 / 47, page 13, CN 122055373 A, ..., Claims 13 / 47, page 14, CN 122055373 A, ..., Claims 14 / 47, page 15, CN 122055373 A, ..., Claims 15 / 47, page 16, CN 122055373 A, ..., Claims 16 / 47, page 17, CN 122055373 A, ..., and Claims 17 / 47, page 18...)CN 122055373 A, or a pharmaceutically acceptable salt thereof. 46. A pharmaceutical composition comprising a therapeutically effective amount of the compound according to any one of claims 1 to 45 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. 47. The pharmaceutical composition according to claim 46, further comprising one, two, three, or four additional therapeutic agents. 48. The pharmaceutical composition according to claim 47, wherein the one or more additional therapeutic agents are anti-HIV agents. 49. The pharmaceutical composition according to claim 47 or 48, wherein the one or more additional therapeutic agents are HIV protease inhibitors, non-nucleoside or non-nucleotide inhibitors of HIV reverse transcriptase, nucleoside or nucleotide inhibitors of HIV reverse transcriptase, HIV capsid inhibitors, gp41 inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5 inhibitors, latency reversal agents, capsid polymerization inhibitors, HIV bNAb, TLR7 agonists, pharmacokinetic enhancers, other drugs for treating HIV, or combinations thereof. 50. The pharmaceutical composition according to any one of claims 47 to 49, wherein the one or more adjunctive therapeutic agents are abacavir, tenofovir alafenamide, tenofovir disoproxil fumarate, N-((S)-1-(3-(4-chloro-3-(methylsulfonamide)-1-(2,2,2-trifluoroethyl)-1H-indazole-7-yl)-6-(3-methyl-3-(methylsulfonyl)but-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropyl[3,4]cyclopent[1,2-c]pyrazol-1-yl)acetamide or pharmaceutically acceptable salts thereof. 51. The pharmaceutical composition of any one of claims 46 to 50, wherein the pharmaceutical composition is for oral or parenteral administration. 52. A kit comprising a compound of any one of claims 1 to 45 or a pharmaceutically acceptable salt thereof and instructions for use. 53. The kit of claim 52, further comprising one, two, three, or four adjunctive therapeutic agents. 54. The kit of claim 53, wherein the one or more adjunctive therapeutic agents are anti-HIV agents. 55. The kit of claim 53 or 54, wherein the one or more adjunctive therapeutic agents are HIV protease inhibitors, non-nucleoside or non-nucleotide inhibitors of HIV reverse transcriptase, nucleoside or nucleotide inhibitors of HIV reverse transcriptase, HIV capsid inhibitors, gp41 inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5 inhibitors, latency reversal agents, capsid polymerization inhibitors, or HIV...bNAb, TLR7 agonists, pharmacokinetic enhancers, other HIV treatments, or combinations thereof. 56. The kit according to any one of claims 53 to 55, wherein the one or more additional therapeutic agents are abacavir, tenofovir alafenamide, tenofovir disoproxil fumarate, N-((S)-1-(3-(4-chloro-3-(methylsulfonamide)-1-(2,2,2-trifluoroethyl)-1H-indazole-7-yl)-6-(3-methyl-3-(methylsulfonyl)but-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropyl[3,4]cyclopent[1,2-c]pyrazol-1-yl)acetamide or pharmaceutically acceptable salts thereof. 57. A method of treating a person infected with HIV or at risk of HIV infection, the method comprising administering to the person a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 45, or a pharmaceutical composition according to any one of claims 46 to 51. 58. The method of claim 57, further comprising administering to the person a therapeutically effective amount of one, two, three, or four additional therapeutic agents. 59. The method of claim 58, wherein the one or more additional therapeutic agents are anti-HIV agents. 60. The method of claim 58 or 59, wherein the one or more additional therapeutic agents are HIV protease inhibitors, non-nucleoside or non-nucleotide inhibitors of HIV reverse transcriptase, nucleoside or nucleotide inhibitors of HIV reverse transcriptase, HIV capsid inhibitors, gp41 inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5 inhibitors, latency reversal agents, capsid polymerization inhibitors, HIV bNAb, TLR7 agonists, pharmacokinetic enhancers, other drugs for treating HIV, or combinations thereof. 61. The method according to any one of claims 58 to 60, wherein the one or more additional therapeutic agents are abacavir, tenofovir alafenamide, tenofovir disoproxil fumarate, N-((S)-1-(3-(4-chloro-3-(methylsulfonamide)-1-(2,2,2-trifluoroethyl)-1H-indazole-7-yl)-6-(3-methyl-3-(methylsulfonyl)but-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropyl[3,4]cyclopent[1,2-c]pyrazol-1-yl)acetamide or pharmaceutically acceptable salts thereof.62. The method of any one of claims 57 to 61, wherein the administration is oral, intravenous, subcutaneous, or intramuscular. 63. Use of the compound of any one of claims 1 to 45, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of any one of claims 46 to 51, for treating said infection in a person suffering from or at risk of HIV infection. 64. The compound of any one of claims 1 to 45, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of any one of claims 46 to 51, for use in a medical therapy. 65. The compound of any one of claims 1 to 45, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of any one of claims 46 to 51, for use in treating HIV infection. 66. Use of the compound of any one of claims 1 to 45, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of any one of claims 46 to 51, in the manufacture of a medicament for treating said infection in a person suffering from or at risk of HIV infection. 67. A combination comprising (i) a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof, or a compound of formula II or a pharmaceutically acceptable salt thereof, and (ii) a P-glycoprotein inhibitor: Claims 19 / 47 pages 20 CN 122055373 A Formula I Formula II Wherein: R1 is –(CR1AR1BO)a(Y)b(CR1CR1D)dX; Wherein a is 0 or 1; b is 0 or 1; d is 0, 1, 2, 3, 4 or 5; R1A is H or C1-3 alkyl; R1B is H or C1-3 alkyl; Each R1C is independently H or C1-3 alkyl; Each R1D is independently H or C1-3 alkyl; or optionally, R1C and R1D on the same carbon atom are bonded to form a spirocyclopropyl group; Y is -C(O)-, -C(O)O-, -C(O)NH-, or -C(O)NR1H-; R1H is a C1-4 alkyl group optionally substituted with one or two substituents independently selected from the group consisting of: –COOH, -OH, -NH2, –CONH2, -P(O)(OH)2, and -S(O)2(OH); X is selected from the group consisting of: (a) -O-P(O)(OR1E)2, wherein each R1E is independently H or phenyl; (b) -N(R1F)2, wherein each R1F is independently H, COO(CR1IR1J)eOPO(OH)2, or a C1-4 alkyl group; wherein the C1-4 alkyl group is optionally substituted with one or two substituents independently selected from the group consisting of: COOH, -S(O)2OH, -P(O)(OH)2, -OH, -NH2, and -CONH2; e is 1, 2, or 3;Each R1I is independently H or C1-3 alkyl; each R1J is independently H or C1-3 alkyl; or optionally, R1I and R1J on the same carbon atom are joined to form a spiropropyl group; and (c) -N+(R1G)3Z-, claim 20 / 47 page 21 CN 122055373 A wherein each R1G is independently H or C1-4 alkyl; wherein the C1-4 alkyl is optionally substituted by one or two substituents independently selected from the group consisting of: -COOH, -OH, -NH2 and -CONH2; Z- is a counterion; R2 is C1-3 alkyl or C1-3 alkoxy; each R3, R4, R5, R6 and R7 is independently H or halogenated; and R8 is H or C1-3 alkyl. 68. The combination according to claim 67, wherein the combination comprises a compound of formula I or a pharmaceutically acceptable salt thereof. 69. The combination according to claim 68, wherein Z is selected from the group consisting of: acetate, ascorbate, aspartate, benzenesulfonate, benzoate, bromide, bicarbonate, carbonate, cinnamate, citrate, chloride, formate, fumarate, gluconate, glutamate, glycolate, lactate, malate, maleate, malonic acid, mandelic acid, methanesulfonate, nicotinic acid, nitrate, oxalate, dihydrogen phosphate, hydrogen phosphate, phosphate, propionate, toluenesulfonate, pyroglutamate, salicylate, succinate, hydrogen sulfate, sulfate, tartrate, thiocyanate, trifluoromethanesulfonate, and trifluoroacetate. 70. The combination according to claim 68 or 69, wherein X is -O-P(O)(OR1E)2. 71. The combination according to any one of claims 68 to 70, wherein each R1E is phenyl. 72. The combination according to any one of claims 68 to 71, wherein each R1E is H. 73. The combination according to claim 68 or 69, wherein X is -N(R1F)2. 74. The combination according to claim 73, wherein each R1F is independently -COO(CR1IR1J)eOPO(OH)2 or a C1-4 alkyl group; wherein the C1-4 alkyl group is optionally substituted with one or two -COOH groups. 75. The combination according to claim 73 or 74, wherein each R1F is independently -COO(CR1IR1J)eOPO(OH)2 or a C1-4 alkyl group; wherein the C1-4 alkyl group is optionally substituted with one -COOH group. 76. The combination according to any one of claims 73 to 75, wherein e is 1 or 2. 77. The combination according to any one of claims 73 to 76, wherein each R1I and each R1J is H. 78. The combination according to any one of claims 73 to 77, wherein each R1F is independently -COOCH2OPO(OH)2.Or a C1-4 alkyl group; wherein the C1-4 alkyl group is optionally substituted with one or two -COOH groups. 79. The combination according to any one of claims 73 to 78, wherein each R1F is independently -COOCH2OPO(OH)2 or a C1-4 alkyl group; wherein the C1-4 alkyl group is optionally substituted with one -COOH group. 80. The combination according to any one of claims 73 to 79, wherein each R1F is independently -COO(CH2)2OPO(OH)2, -COOCH2OPO(OH)2, -CH3, or -CH2COOH. 81. The combination according to any one of claims 73 to 80, wherein each R1F is independently -COOCH2OPO(OH)2, -CH3, or -CH2COOH. 82. The combination according to claim 68 or 69, wherein X is -N+(R1G)3Z-. 83. The combination according to claim 82, wherein R1G is -CH3. 84. The combination according to any one of claims 68 to 83, wherein a is 0. 85. The combination according to any one of claims 68 to 83, wherein a is 1. 86. The combination according to any one of claims 68 to 85, wherein b is 0. 87. The combination according to any one of claims 68 to 85, wherein b is 1. 88. The combination according to any one of claims 68 to 87, wherein Y is -C(O)-, -C(O)O-, -C(O)NH-, or -C(O)NCH3-. Claims 21 / 47 pages 22 CN 122055373 A 89. The combination according to any one of claims 68 to 88, wherein Y is -C(O)-, -C(O)O-, or -C(O)NCH3-. 90. The combination according to any one of claims 68 to 89, wherein Y is -C(O)-. 91. The combination according to any one of claims 68 to 89, wherein Y is -C(O)O-. 92. The combination according to any one of claims 68 to 89, wherein Y is -C(O)NCH3-. 93. The combination according to any one of claims 68 to 87, wherein Y is -C(O)NR1H-. 94. The combination according to claim 93, wherein R1H is a C1-2 alkyl group optionally substituted with -COOH, -P(O)(OH)2, or -S(O)2(OH). 95. The combination according to any one of claims 68 to 92, wherein d is 1, 2, or 3. 96. The combination according to any one of claims 68 to 93, wherein d is 1. 97. The combination according to any one of claims 68 to 93, wherein d is 2. 98. The combination according to any one of claims 68 to 93, wherein d is 3.99. The combination according to any one of claims 67 to 98, wherein R4, R5, and R7 are each H. 100. The combination according to any one of claims 67 to 99, wherein R3 and R6 are each independently halogenated. 101. The combination according to any one of claims 67 to 100, wherein R3 and R6 are each F. 102. The combination according to any one of claims 67 to 101, wherein R8 is a C1-3 alkyl group. 103. The combination according to any one of claims 67 to 102, wherein R8 is methyl. 104. The combination according to any one of claims 67 to 103, wherein R2 is methyl or methoxy. 105. The combination according to any one of claims 67 to 104, wherein R2 is methyl. 106. The combination according to any one of claims 67 to 105, wherein R2 is methoxy. 107. The combination according to any one of claims 68 and 99 to 106, wherein R1 is selected from the group consisting of: (Claims 22 / 47, page 23, CN 122055373 A), (Claims 23 / 47, page 24, CN 122055373 A), and. 108. The combination according to any one of claims 68 and 99 to 106, wherein R1 is selected from the group consisting of: (Claims 22 / 47, page 23, CN 122055373 A), and. 109. The combination according to any one of claims 68 and 99 to 106, wherein R1 is selected from the group consisting of: , , , , , , , , , , , , , , , , , , CN 122055373 A, , , , , and. 110. The combination according to claim 68, wherein the compound of formula I is selected from the group consisting of: , , , , , , CN 122055373 A, ... 111. The combination according to claim 68, wherein the compound of formula I is selected from the group consisting of: (Claims 28 / 47, page 29, CN 122055373 A, ..., Claims)Page 29 / 47, 30 CN 122055373 A, 、 、 、 、 、 、 、 、 、 、 、 Claims 30 / 47, 31 CN 122055373 A, and, or pharmaceutically acceptable salts thereof. 112. The combination according to claim 68, wherein the compound of formula I is selected from the group consisting of: , , , , , claim 31 / 47 page 32 CN 122055373 A , , , claim 32 / 47 page 33 CN 122055373 A , , , , , claim 33 / 47 page 34 CN 122055373 A , , , , , claim 34 / 47 page 35 CN 122055373 A , , , , , , claim 35 / 47 page 36 CN 122055373 A , , , , , and claim 36 / 47 page 37 CN 122055373 A, or pharmaceutically acceptable salts thereof. 113. The combination according to claim 112, wherein the compound of formula I is selected from: and, or pharmaceutically acceptable salts thereof. 114. The combination according to claim 113, wherein the compound of formula I is: , or a pharmaceutically acceptable salt thereof. 115. The combination according to claim 113, wherein the compound of formula I is: , or a pharmaceutically acceptable salt thereof. 116. The combination according to any one of claims 68 to 115, wherein the combination comprises the compound of formula I. 117. The combination according to claim 116, wherein the compound of formula I is: . 118. The combination according to claim 116, wherein the compound of formula I is: . 119. The combination according to any one of claims 67 and 99 to 106, wherein the combination comprises the compound of formula II or a pharmaceutically acceptable salt thereof. Claims 38 / 47, page 39, CN 122055373 A 120. The combination according to claim 119, wherein the compound of formula II is: , or a pharmaceutically acceptable salt thereof.121. The combination of claim 119, wherein the compound of formula II is: , or a pharmaceutically acceptable salt thereof. 122. The combination of claim 119, wherein the combination comprises the compound of formula II. 123. The combination of claim 122, wherein the compound of formula II is: . 124. The combination of claim 122, wherein the compound of formula II is: . 125. The combination of any one of claims 67 to 124, wherein the P-glycoprotein inhibitor is selected from the group consisting of verapamil, dextrovertamil, cyclosporine, zoquine, laniquine, ecrimethamine, talicidamine, encequine, and pharmaceutically acceptable salts thereof. 126. The combination of any one of claims 67 to 125, wherein the P-glycoprotein inhibitor is encequine or a pharmaceutically acceptable salt thereof. 127. The combination of any one of claims 67 to 126, wherein the P-glycoprotein inhibitor is a salt of encequine. 128. The combination of claim 127, wherein the P-glycoprotein inhibitor is the mesylate of encequina. (Claims 39 / 47, page 40, CN 122055373 A) 129. The combination of claim 67, wherein the combination comprises a pharmaceutically acceptable salt thereof and encequina or a pharmaceutically acceptable salt thereof. 130. The combination of claim 67, wherein the combination comprises a pharmaceutically acceptable salt thereof and encequina or a pharmaceutically acceptable salt thereof. 131. The combination of claim 67, wherein the combination comprises a pharmaceutically acceptable salt thereof and encequina or a pharmaceutically acceptable salt thereof. 132. The combination of claim 67, wherein the combination comprises a pharmaceutically acceptable salt thereof and encequina or a pharmaceutically acceptable salt thereof. (Claims 40 / 47, page 41, CN 122055373 A) 133. The combination of claim 129, wherein the combination comprises a pharmaceutically acceptable salt thereof and a salt of encequina. 134. The combination of claim 130, wherein the combination comprises a pharmaceutically acceptable salt thereof and a salt of ensera. 135. The combination of claim 131, wherein the combination comprises a pharmaceutically acceptable salt thereof and a salt of ensera. Claims 41 / 47 pages 42 CN 122055373 A 136. The combination of claim 132, wherein the combination comprises a pharmaceutically acceptable salt thereof and a salt of ensera. 137. The combination of claim 133, wherein the combination comprises and a salt of ensera. 138. The combination of claim 134, wherein the combination comprises and a salt of ensera.139. The combination of claim 135, wherein the combination comprises a salt of ensequita. 140. The combination of claim 136, wherein the combination comprises a salt of ensequita. 141. The combination of claim 137, wherein the combination comprises a mesylate of ensequita. 142. The combination of claim 138, wherein the combination comprises a mesylate of ensequita. 143. The combination of claim 139, wherein the combination comprises a mesylate of ensequita. 144. The combination of claim 140, wherein the combination comprises a mesylate of ensequita. 145. A method of treating the infection in a person who is infected with HIV or at risk of becoming infected with HIV, the method comprising administering to the person the combination of any one of claims 67 to 144. 146. The method of claim 145, wherein (i) the compound of formula I or a pharmaceutically acceptable salt thereof, or the compound of formula II or a pharmaceutically acceptable salt thereof, and (ii) the P-glycoprotein inhibitor are administered together. 147. The method of claim 145 or 146, wherein (i) the compound of formula I or a pharmaceutically acceptable salt thereof, or the compound of formula II or a pharmaceutically acceptable salt thereof, and (ii) the P-glycoprotein inhibitor are administered as a co-preparation. 148. The method of claim 145, wherein (i) the compound of formula I or a pharmaceutically acceptable salt thereof, or the compound of formula II or a pharmaceutically acceptable salt thereof, and (ii) the P-glycoprotein inhibitor are administered alone. 149. The method of any one of claims 145 to 148, wherein (i) the compound of formula I or a pharmaceutically acceptable salt thereof, or the compound of formula II or a pharmaceutically acceptable salt thereof, and (ii) the P-glycoprotein inhibitor are administered orally. 150. The method of any one of claims 145 to 149, further comprising administering to the person a therapeutically effective amount of one, two, three, or four additional therapeutic agents. 151. The method of claim 150, wherein the one or more additional therapeutic agents are anti-HIV agents. 152. The method of claim 150 or 151, wherein the one or more additional therapeutic agents are HIV protease inhibitors, non-nucleoside or non-nucleotide inhibitors of HIV reverse transcriptase, nucleoside or nucleotide inhibitors of HIV reverse transcriptase, HIV capsid inhibitors, gp41 inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5 inhibitors, latency reversal agents, capsid polymerization inhibitors, or HIV...bNAb, TLR7 agonists, pharmacokinetic enhancers, other HIV treatments, or combinations thereof. 153. The method according to any one of claims 150 to 152, wherein the one or more additional therapeutic agents are abacavir, tenofovir alafenamide, tenofovir disoproxil fumarate, N-((S)-1-(3-(4-chloro-3-(methylsulfonamide)-1-(2,2,2-trifluoroethyl)-1H-indazole-7-yl)-6-(3-methyl-3-(methylsulfonyl)but-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropyl[3,4]cyclopent[1,2-c]pyrazol-1-yl)acetamide or pharmaceutically acceptable salts thereof. 154. The method according to any one of claims 150 to 153, wherein (i) the compound of formula I or a pharmaceutically acceptable salt thereof or the compound of formula II or a pharmaceutically acceptable salt thereof, (ii) the P-glycoprotein inhibitor and (iii) one or more additional therapeutic agents are administered as a co-formulation. 155. A pharmaceutical composition comprising the combination according to any one of claims 67 to 144 and a pharmaceutically acceptable excipient. 156. A kit comprising the combination according to any one of claims 67 to 144 and instructions for use. 157. The kit according to claim 156, comprising (i) a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof or a compound of formula II or a pharmaceutically acceptable salt thereof, (ii) a pharmaceutical composition comprising the P-glycoprotein inhibitor, and (iii) instructions for use. 158. The kit of claim 156, wherein the kit comprises (i) a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof, or a compound of formula II or a pharmaceutically acceptable salt thereof, and the P-glycoprotein inhibitor, and (ii) instructions for use. 159. The kit of any one of claims 156 to 158, wherein the kit further comprises one, two, three, or four additional therapeutic agents. 160. The kit of claim 159, wherein the one or more additional therapeutic agents are anti-HIV agents. 161. The kit of claim 159 or 160, wherein the one or more additional therapeutic agents are HIV protease inhibitors, non-nucleoside or non-nucleotide inhibitors of HIV reverse transcriptase, or nucleoside or nucleotide inhibitors of HIV reverse transcriptase.Drugs, HIV capsid inhibitors, gp41 inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5 inhibitors, latency reversal agents, capsid polymerization inhibitors, HIV bNAb, TLR7 agonists, pharmacokinetic enhancers, other drugs for the treatment of HIV, or combinations thereof. 162. The kit according to any one of claims 159 to 161, wherein the one or more additional therapeutic agents are abacavir, tenofovir alafenamide, tenofovir disoproxil fumarate, N-((S)-1-(3-(4-chloro-3-(methylsulfonamide)-1-(2,2,2-trifluoroethyl)-1H-indazole-7-yl)-6-(3-methyl-3-(methylsulfonyl)but-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropyl[3,4]cyclopent[1,2-c]pyrazol-1-yl)acetamide or pharmaceutically acceptable salts thereof. 163. The combination of any one of claims 67 to 144, the pharmaceutical composition of claim 155, or the kit of any one of claims 156 to 162, for use in a medical therapy. 164. The combination of any one of claims 67 to 144, the pharmaceutical composition of claim 155, or the kit of any one of claims 156 to 162, for use in the treatment of HIV infection. 165. A compound of formula I or a pharmaceutically acceptable salt thereof, or a compound of formula II or a pharmaceutically acceptable salt thereof, for use in a combination therapy for the treatment of HIV infection with a P-glycoprotein inhibitor, as defined in any one of the preceding claims. 166. A P-glycoprotein inhibitor, said P-glycoprotein inhibitor for use in a combination therapy for the treatment of HIV infection with a compound of formula I or a pharmaceutically acceptable salt thereof, or a compound of formula II or a pharmaceutically acceptable salt thereof, as defined in any one of the preceding claims. 167. Use in the manufacture of a medicament for treating a person suffering from or at risk of HIV infection, according to any one of claims 67 to 144, or according to any one of claims 155, or according to any one of claims 156 to 162. 168. The method according to any one of claims 145 to 154, the combination, compound, composition, or kit used according to any one of claims 163 to 166, or the use according to claim 167, wherein the use is relative to the use described on pages 45 / 47 of the claims, CN 122055373 A.Exposure to metabolites of the compound of Formula I or its pharmaceutically acceptable salt when administered in the absence of a P-glycoprotein inhibitor, and when co-administered with the P-glycoprotein inhibitor, the exposure to metabolites of the compound of Formula I or its pharmaceutically acceptable salt increases. 169. The method of any one of claims 145 to 154, the combination, compound, composition, or kit used according to any one of claims 163 to 166, or the use according to claim 167, wherein, relative to the CMAX of metabolites of the compound of Formula I or its pharmaceutically acceptable salt when administered in the absence of the P-glycoprotein inhibitor, the CMAX of metabolites of the compound of Formula I or its pharmaceutically acceptable salt increases when co-administered with the P-glycoprotein inhibitor. 170. The method of any one of claims 145 to 154, the combination, compound, composition, or kit used according to any one of claims 163 to 166, or the use according to claim 167, wherein the AUCINF of the metabolite of the compound of formula I or its pharmaceutically acceptable salt is increased when the compound of formula I or its pharmaceutically acceptable salt is co-administered with the P-glycoprotein inhibitor, relative to the AUCINF of the metabolite of the compound of formula I or its pharmaceutically acceptable salt when administered in the absence of the P-glycoprotein inhibitor. 171. The method of any one of claims 145 to 154, the combination, compound, composition, or kit used according to any one of claims 163 to 166, or the use according to claim 167, wherein the oral bioavailability of the metabolite of the compound of formula I or its pharmaceutically acceptable salt is increased when the compound of formula I or its pharmaceutically acceptable salt is co-administered with the P-glycoprotein inhibitor, relative to the oral bioavailability of the metabolite of the compound of formula I or its pharmaceutically acceptable salt when administered in the absence of the P-glycoprotein inhibitor. 172. The method, combination, compound, composition, or kit used according to any one of claims 168 to 171, or the use according to any one of claims 168 to 171, wherein the metabolite is a compound of formula II or its pharmaceutically acceptable salt. 173. The method of any one of claims 145 to 154, the combination, compound, composition, or kit used according to any one of claims 163 to 166, or the use according to claim 167, wherein the metabolite is a compound of formula II or its pharmaceutically acceptable salt.The method, combination, composition, or kit of claim 145 to 154, the combination, compound, composition, or kit of claim 163 to 166, or the use of claim 167, wherein the exposure of the compound of formula II or its pharmaceutically acceptable salt in the patient is increased when co-administered with the P-glycoprotein inhibitor, relative to the exposure when administered in the absence of the P-glycoprotein inhibitor. 174. The method of any one of claims 145 to 154, the combination, compound, composition, or kit of claim 163 to 166, or the use of claim 167, wherein the CMAX of the compound of formula II or its pharmaceutically acceptable salt in the patient is increased when co-administered with the P-glycoprotein inhibitor, relative to the CMAX of the compound of formula II or its pharmaceutically acceptable salt in the absence of the P-glycoprotein inhibitor. 175. The method according to any one of claims 145 to 154, the combination, compound, composition, or kit used according to any one of claims 163 to 166, or the use according to claim 167, wherein the AUCINF of the compound of formula II or its pharmaceutically acceptable salt thereof in the patient is increased when co-administered with the P-glycoprotein inhibitor, relative to the AUCINF of the compound of formula II or its pharmaceutically acceptable salt thereof when administered in the absence of the P-glycoprotein inhibitor. 176. The method according to any one of claims 145 to 154, the combination, compound, composition, or kit used according to any one of claims 163 to 166, or the use according to claim 167, wherein the oral bioavailability of the compound of formula II or its pharmaceutically acceptable salt thereof in the patient is increased when co-administered with the P-glycoprotein inhibitor, relative to the oral bioavailability of the compound of formula II or its pharmaceutically acceptable salt thereof when administered in the absence of the P-glycoprotein inhibitor. Claims 47 / 47 Page 48 CN 122055373 A Bridged Tricyclic Carbamoylpyridinone Compounds and Their Uses Cross-Reference to Related Applications

[0001] This application claims priority to U.S. Provisional Application No. 63 / 543,700, filed October 11, 2023; U.S. Provisional Application No. 63 / 659,857, filed June 14, 2024; and U.S. Provisional Application No. 63 / 702,723, filed October 3, 2024. The entire contents of these applications are incorporated herein by reference for all purposes. Technical Field

[0002] Compounds, compositions, and methods for treating or preventing human immunodeficiency virus (HIV) infection are disclosed. Specifically, novel spirocyclic-substituted bridged tricyclic carbamoylpyridinone compounds, their preparation methods, and their use as therapeutic or preventative agents are disclosed. Background Art

[0003] Human immunodeficiency virus infection and related diseases are a major public health problem worldwide. Human immunodeficiency virus encodes three enzymes required for viral replication: reverse transcriptase, protease, and integrase. Although drugs targeting reverse transcriptase and protease are widely used and have shown effectiveness, especially when used in combination, toxicity and the development of drug-resistant strains may limit their usefulness (Palella et al., N. Engl. J Med. (1998) 338:853-860; Richman, DD Nature (2001) 410:995-1001). Therefore, there is a need for new agents to inhibit HIV replication.

[0004] One goal of antiretroviral therapy is to achieve viral suppression in patients with HIV infection. Current treatment guidelines issued by the U.S. Department of Health and Human Services state that achieving viral suppression requires the use of combination therapy, i.e., several drugs from at least two or more drug classes (Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents Living with HIV. Department of Health and Human Services. See http: / / www.aidsinfo.nih.gov / ContentFiles / AdultandAdolescentGL.pdf. Accessed February 12, 2019). Furthermore, decisions regarding the treatment of HIV-infected patients are complex when they require treatment for other medical conditions (ibid., F-8). Because the standard of care requires the use of multiple different drugs to suppress HIV, and to treat other conditions the patient may be experiencing, the possibility of drug interactions is a criterion for selecting a drug regimen. Therefore, antiretroviral therapies with a reduced likelihood of drug interactions are needed.

[0005] Furthermore, it is known that the HIV virus can mutate in infected subjects (Tang et al. Drugs (2012) 72 (9) e1-e25). Due to the mutability of HIV, there is a need for anti-HIV drugs effective against a range of known HIV variants (Hurt et al. HIV / AIDS CID (2014) 58,423-431).

[0006] For some patients, such as those with difficulty or limited access to healthcare, adherence to daily oral treatment or prevention regimens can be challenging. Medications that provide favorable pharmaceutical properties (e.g., improved potency, long-acting pharmacokinetics, low clearance, and / or other properties) can reduce the frequency of administration and provide better patient compliance. For example, these favorable pharmaceutical properties can facilitate reduced doses, reduced pill size, and / or reduced pill counts for better patient compliance. Such improvements can in turn optimize drug exposure and limit the development of resistance.

[0007] In some cases, compatible combination agents may be required to modulate the PK properties of the drugs (such as dose, AUC, Cmax, and oral bioavailability) to achieve a target long-acting dosing regimen. Therefore, improved combination therapies are needed. Specification 1 / 189 pages 49 CN 122055373 A Summary of the Invention

[0008] This disclosure relates to novel compounds having antiviral activity and pharmaceutically acceptable salts thereof. In some embodiments, these compounds can be used to treat HIV infection, inhibit HIV integrase activity, and / or reduce HIV replication. In some embodiments, the compounds disclosed herein are effective against a range of known drug-resistant HIV mutants. In some embodiments, the compounds disclosed herein may have a reduced tendency to cause drug-drug interactions when administered in combination with other drugs. In some embodiments, the compounds disclosed herein may be administered at a less than daily frequency, such as once weekly, once monthly, once every three months, once every six months, or at longer intervals.

[0009] In one embodiment, this disclosure provides a compound of formula I: I or a pharmaceutically acceptable salt thereof, wherein: R1 is –(CR1AR1BO)a(Y)b(CR1CR1D)dX; wherein a is 0 or 1; b is 0 or 1; d is 0, 1, 2, 3, 4 or 5; R1A is H or C1-3 alkyl; R1B is H or C1-3 alkyl; each R1C is independently H or C1-3 alkyl; each R1D is independently H or C1-3 alkyl; or optionally, R1C and R1D on the same carbon atom are bonded to form a spirocyclopropyl group; Y is -C(O)-, -C(O)O-, -C(O)NH- or -C(O)NR1H-; R1H is a C1-4 alkyl group optionally substituted with one or two substituents independently selected from the group consisting of: –COOH, –OH, –NH2, –CONH2, –P(O)(OH)2, and –S(O)2(OH); X is selected from the group consisting of: (a) –O-P(O)(OR1E)2, wherein each R1E is independently H or phenyl; (b) –N(R1F)2,Each R1F is independently H, -COO(CR1IR1J)eOPO(OH)2, or a C1-4 alkyl group; wherein the C1-4 alkyl group is optionally substituted by one or two substituents independently selected from the group consisting of: COOH, -S(O)2OH, -P(O)(OH)2, -OH, -NH2, and -CONH2; e is 1, 2, or 3; each R1I is independently H or a C1-3 alkyl group; each R1J is independently H or a C1-3 alkyl group; or optionally, R1I and R1J on the same carbon atom are joined to form a spirocyclopropyl group; and specification 2 / 189 page 50 CN 122055373 A (c) -N+(R1G)3Z - , Each R1G is independently H or C1-4 alkyl; wherein the C1-4 alkyl is optionally substituted by one or two substituents independently selected from the group consisting of -COOH, -OH, -NH2 and -CONH2; Z- is a counterion; R2 is C1-3 alkyl or C1-3 alkoxy; each R3, R4, R5, R6 and R7 is independently H or halogenated; and R8 is H or C1-3 alkyl.

[0010] In one embodiment, a pharmaceutical composition is provided comprising a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0011] In another embodiment, a kit or article is provided comprising a compound of formula I or a pharmaceutically acceptable salt thereof and instructions for use.

[0012] In another embodiment, a method of treating or preventing HIV infection in a person who is infected with HIV or at risk of HIV infection is provided by administering to a person a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of a compound of formula I or a pharmaceutically acceptable salt thereof.

[0013] In another embodiment, use of a compound of formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of a compound of formula I or a pharmaceutically acceptable salt thereof, is provided for treating HIV infection in a person who is infected with HIV or at risk of HIV infection.

[0014] In another embodiment, use of a compound of formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of a compound of formula I or a pharmaceutically acceptable salt thereof, is provided in the manufacture of a medicament for treating HIV infection in a person who is infected with HIV or at risk of HIV infection.

[0015] In another embodiment, a compound of formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of a compound of formula I or a pharmaceutically acceptable salt thereof, is provided for use in a medical therapy.

[0016] In another embodiment, a compound of formula I or a pharmaceutically acceptable salt thereof or a compound of formula I is provided.Pharmaceutical compositions of compounds or pharmaceutically acceptable salts thereof, used in the treatment of HIV infection.

[0017] Other embodiments, objectives, features, and advantages are set forth in the following detailed description of the embodiments and may be apparent in part from the description of the claimed embodiments or may be learned by practice. These objectives and advantages may be realized and obtained by methods and compositions particularly pointed out in the specification and its claims. The foregoing summary is to be understood as a brief and general summary of some embodiments disclosed herein, provided for the benefit and convenience of the reader, and is not intended to limit in any way the scope or equivalents legally enjoyed by the appended claims.

[0018] In another embodiment, a combination therapy comprising a compound having antiviral activity and a pharmaceutically acceptable salt thereof and a PGP inhibitor is provided. As shown in the Examples section, administration of the combination of the invention increases the exposure and bioavailability of the compound having antiviral activity. In some embodiments, this disclosure provides a method of treating or preventing HIV infection in a patient, the method comprising administering to the patient a combination of a compound of formula I or a pharmaceutically acceptable salt thereof, as disclosed herein, wherein when the compound of formula I or a pharmaceutically acceptable salt thereof is co-administered with a P-glycoprotein inhibitor, the exposure to metabolites of the compound of formula I or a pharmaceutically acceptable salt thereof is increased relative to the exposure to metabolites of the compound of formula I or a pharmaceutically acceptable salt thereof when administered at the same dose but in the absence of a P-glycoprotein inhibitor. Specification 3 / 189 pages 51 CN 122055373 A Brief Description of the Drawings

[0019] Figure 1 shows the plasma concentration of intermediate B in beagle dogs after oral administration of intermediate B with and without encequina mesylate pretreatment.

[0020] Figure 2 shows the plasma concentration of intermediate C in beagle dogs after oral administration of intermediate C with and without encequina mesylate pretreatment.

[0021] Figure 3 shows the plasma concentrations of intermediate C in beagle dogs after oral administration of compound C with and without pretreatment with encequina mesylate. Detailed Description

[0022] In the following description, certain specific details are set forth in order to provide a thorough understanding of the various embodiments disclosed herein. However, those skilled in the art will understand that the embodiments disclosed herein can be practiced without these details. Several embodiments are described below while understanding that this disclosure is to be regarded as an illustration of the claimed subject matter and not intended to limit the appended claims to the specific embodiments shown. The headings used throughout this disclosure are provided for convenience only and should not be construed as limiting the claims in any way. Embodiments illustrated under any heading may be combined with embodiments illustrated under any other heading.

[0023] I.Definitions Unless the context otherwise requires, throughout this disclosure and claims, the word “comprising” and its variations such as “including” and “containing” shall be interpreted in an open, inclusive sense, meaning “including but not limited to”.

[0024] The phrase “one embodiment” or “in an embodiment” as used throughout this specification means that a particular feature, structure, or characteristic described in connection with that embodiment is included in at least one embodiment disclosed herein. Therefore, the phrases “in one embodiment” or “in an embodiment” appearing in various places throughout this specification do not necessarily refer to the same embodiment. Furthermore, in one or more embodiments, a particular feature, structure, or characteristic may be combined in any suitable manner.

[0025] “Amino” refers to an -NH2 group.

[0026] “Hydroxy” refers to an -OH group.

[0027] As used herein, the term “C1-n alkyl”, where n is an integer, alone or in combination with another group, is intended to mean a non-cyclic, straight-chain, or branched alkyl group containing 1 to n carbon atoms. "C1-6 alkyl" includes, but is not limited to, methyl, ethyl, propyl (n-propyl), butyl (n-butyl), 1-methylethyl (isopropyl), 1-methylpropyl (sec-butyl), 2-methylpropyl (isobutyl), 1,1-dimethylethyl (tert-butyl), pentyl, and hexyl. The abbreviations Me represent methyl; Et represent ethyl, Pr represent propyl, iPr represent 1-methylethyl, Bu represent butyl, and tBu represent 1,1-dimethylethyl.

[0028] "alkyl" is a hydrocarbon containing primary, secondary, or tertiary atoms. For example, an alkyl group may have 1 to 20 carbon atoms (i.e., C1-C20 alkyl), 1 to 10 carbon atoms (i.e., C1-C10 alkyl), 1 to 8 carbon atoms (i.e., C1-C8 alkyl), or 1 to 6 carbon atoms (i.e., C1-C6 alkyl). Examples of alkyl groups include, but are not limited to, methyl (Me, -CH3), ethyl (Et, CH2CH3), 1-propyl (n-Pr, n-propyl, -CH2CH2CH3), 2-propyl (i-Pr, isopropyl, CH(CH3)2), 1-butyl (n-Bu, n-butyl, -CH2CH2CH2CH3), 2-methyl-1-propyl (i-Bu, isobutyl, -CH2CH(CH3)2), 2-butyl (s-Bu, sec-butyl, CH(CH3)2CH3), 2-methyl-2-propyl (t-Bu, tert-butyl, C(CH3)3), 1-pentyl (n-pentyl, CH2CH2CH2CH2CH3), 2-pentyl (CH(CH3)2CH2CH3), 3-pentyl (CH(CH2CH3)2), 2-methyl-2-butyl (C(CH3)2CH2CH3), 3-methyl-2-butyl3-Methyl-1-butyl (CH(CH3)CH(CH3)2), 2-Methyl-1-butyl (CH2CH2CH(CH3)2), 1-Hexyl (CH2CH2CH2CH2CH2CH3), 2-Hexyl (CH(CH3)2CH2CH2CH3), 3-Hexyl (CH(CH2CH3)(CH2CH2CH3)), 2-Methyl-2-pentyl (C(CH3)2CH2CH2CH3), 3-Methyl-2-pentyl (CH(CH3)CH(CH3)2CH3), 4-Methyl-2-pentyl (CH(CH3)2CH(CH3)2) (Specification 4 / 189 pages 52 CN 122055373 A (CH(CH3)2CH(CH3)2), 3-Methyl-3-pentyl (-C(CH3)(CH2CH3)2), 2-Methyl-3-pentyl (-CH(CH2CH3)CH (CH3)2), 2,3-dimethyl-2-butyl (C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3), and octyl ((CH2)7CH3). "Alkyl" also refers to a saturated, branched, or straight-chain hydrocarbon group having two monovalent groups at its center derived by removing two hydrogen atoms from the same or two different carbon atoms of the parent alkane. For example, an alkyl group may have 1 to 10 carbon atoms (i.e., C1-10 alkyl), 1 to 6 carbon atoms (i.e., C1-6 alkyl), or 1 to 3 carbon atoms (i.e., C1-3 alkyl). Typical alkyl groups include, but are not limited to, methylene (CH2), 1,1-ethyl (CH(CH3)), 1,2-ethyl (CH2CH2), 1,1-propyl (CH(CH2CH3)), 1,2-propyl (CH2CH(CH3)), 1,3-propyl (CH2CH2CH2), 1,4-butyl (CH2CH2CH2CH2), etc.

[0029] As used herein, the term "alkenyl" refers to a straight-chain or branched hydrocarbon containing a primary, secondary, or tertiary carbon atom and having at least one unsaturated site (i.e., a carbon-carbon sp2 double bond). For example, an alkenyl group may have 2 to 20 carbon atoms (i.e., C2-C20 alkenyl or C2-20 alkenyl), 2 to 8 carbon atoms (i.e., C2-C8 alkenyl or C2-8), or 2 to 6 carbon atoms (i.e., C2-C6 alkenyl or C2-6 alkenyl). Examples of suitable alkenyl groups include, but are not limited to, ethylene or vinyl (-CHCH2), allyl (CH2CH=CH2), cyclopentenyl (C5H7), and 5-hexenyl (CH2CH2CH2CH2CH=CH2).

[0030] As used herein, the term “C2-n alkenyl,” where n is an integer, alone or in combination with another group, is intended to refer to an unsaturated, acyclic straight-chain or branched group containing two to n carbon atoms, wherein at least two carbon atoms are bonded to each other by double bonds.Examples of such groups include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, and 1-butenyl. Unless otherwise stated, the term “C2-n alkenyl” should be understood to include, where possible, individual stereoisomers, including but not limited to (E) and (Z) isomers and mixtures thereof. Unless otherwise stated, when a C2-n alkenyl group is substituted, it should be understood to substitute it at any carbon atom on which it will have a hydrogen atom, such that the substitution will produce a chemically stable compound, as recognized by those skilled in the art.

[0031] As used herein, the term “halogen” or “halogen” refers to fluorine, chlorine, bromine, and iodine.

[0032] As used herein, the term “C3-m cycloalkyl,” where m is an integer, alone or in combination with another group, is intended to mean a cycloalkyl substituent containing 3 to m carbon atoms, and includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. The term includes fully saturated and partially unsaturated rings.

[0033] It should be understood that when a variable is substituted, for example, as described by the phrase “C1-6 alkyl, alone or as part of a group, optionally substituted,” the phrase means that the variable C1-6 alkyl can be substituted alone, and that the variable “C1-6 alkyl” can also be substituted as part of a larger group. Similarly, other variables can also be substituted “alone or as part of a group” when stated.

[0034] The term “chiral” refers to a molecule having the property that its mirror-coupled counterparts cannot overlap, while the term “achiral” refers to a molecule that can overlap with its mirror-coupled counterpart.

[0035] The term “stereoisomer” refers to a compound having the same chemical composition but with different spatial arrangements of atoms or groups.

[0036] “Diabeta-isomer” refers to a stereoisomer having two or more chiral centers or axes and whose molecules are not mirror images of each other. Diabeta-isomers typically have different physical properties, such as melting point, boiling point, spectral properties, and reactivity. Mixtures of diastereomers can be separated using high-resolution analytical methods such as electrophoresis and chromatography.

[0037] "Enantiomer" refers to two stereoisomers of a compound that are non-overlapping mirror images of each other.

[0038] The term "treatment" includes, to the extent that it relates to a disease or condition, preventing the occurrence of a disease or condition, inhibiting or improving a disease or condition (e.g., suppressing or slowing its development), eliminating a disease or condition (e.g., resolving or curing a disease or condition), and / or alleviating one or more symptoms of a disease or condition. In the case of HIV, treatment includes reducing the HIV viral load level in a patient. Specification 5 / 189 pages 53 CN 122055373 A

[0039] In some embodiments, the term "treatment" refers to the application of a compound or composition according to the invention to alleviate orEliminating symptoms of HIV infection and / or reducing viral load in patients. The term “treatment” also encompasses the administration of a compound or composition according to the invention before an individual is exposed to the virus, after an individual is exposed to the virus but before the onset of disease symptoms and / or before the virus is detected in the blood, to prevent the onset of disease symptoms and / or to prevent the virus from reaching detectable levels in the blood, and the administration of a compound or composition according to the invention to prevent perinatal transmission of HIV from mother to infant by administration to the mother before delivery and to the child in the first few days of life.

[0040] As used herein, the term “combination therapy” refers to the use of two or more treatments, such as pharmaceutical active agents (i.e., “combination”), to treat or prevent a single disease or condition. Pharmaceutical active agents may be administered together or alone, and simultaneously or sequentially, generally such that they function synergistically and have overlapping effects on the patient, thereby producing the desired therapeutic or preventive effect on the patient. In some embodiments, the pharmaceutical active agents are derived from at least two or more drug classes.

[0041] “Protective group” refers to a portion of a compound that masks or alters the properties of a functional group or the properties of the compound as a whole. Chemical protecting groups and strategies for protection / deprotection are well known in the art. See, for example, *Protective Groups in Organic Chemistry*, Theodora W. Greene, John Wiley & Sons, Inc., New York, 1991. Protecting groups are often used to mask the reactivity of certain functional groups to contribute to the efficiency of desired chemical reactions, such as the orderly and planned formation and breaking of chemical bonds. Functional group protection of a compound alters other physical properties besides the reactivity of the protected functional group, such as polarity, lipophilicity (hydrophobicity), and other properties that can be measured by commonly used analytical tools. Chemically protected intermediates can themselves be biologically active or inactive.

[0042] Protected compounds may also exhibit altered, in some cases optimized, properties, such as cross-membrane penetration and resistance to enzymatic degradation or chelation, both in vitro and in vivo. In this role, a protected compound with the intended therapeutic effect may be referred to as a prodrug. Another function of protecting groups is to convert a parent drug into a prodrug, thereby releasing the parent drug during prodrug conversion in vivo. Because the active prodrug may be absorbed more efficiently than the parent drug, it may have greater potency in vivo than the parent drug. In the case of chemical intermediates, the protecting group is removed in vitro, while in the case of prodrugs, the protecting group is removed in vivo. For chemical intermediates, whether the resulting product (e.g., an alcohol) after deprotection is physiologically acceptable is not particularly important, but generally, it is preferable if the product is pharmacologically harmless.

[0043] The protecting group is available, generally known and used, and optionally used to prevent the formation of protective groups during the synthesis process.Side reactions of the protecting group (i.e., the route or method for preparing the compounds of the present invention). In most cases, the decision regarding which groups to protect, when to do so, and the nature of the chemical protecting group "PG" will depend on the chemical nature of the reaction to be protected (e.g., acidic, basic, oxidative, reducing, or other conditions) and the intended synthetic direction. If the compound is substituted by multiple PGs, the PGs are not required and are usually not the same. Typically, PGs will be used to protect functional groups such as carboxyl, hydroxyl, thio, or amino groups to prevent side reactions or otherwise promote synthetic efficiency. The deprotection sequence that produces free deprotected groups depends on the intended synthetic direction and the reaction conditions encountered, and can occur in any order determined by a person skilled in the art.

[0044] Various functional groups of the compounds of the present invention can be protected. For example, the protecting group of the -OH group (whether hydroxyl, carboxylic acid, phosphate, or other functional group) includes "ether or ester forming groups". In the synthetic schemes described herein, ether or ester forming groups can act as chemical protecting groups. However, as will be understood by those skilled in the art, some hydroxyl and thio protecting groups are not ether or ester forming groups and are included in amides, as described below.

[0045] Protective Groups in Organic Synthesis, Theodora W. Greene (John Wiley & Sons, Inc., New York, 1991, ISBN 0-471-62301-6) (“Greene”) describes a very large number of hydroxyl protecting groups and amide forming groups and the corresponding chemical cleavage reactions. See also Kocienski, Philip J.; Protecting Groups (Georg Thieme Verlag Stuttgart, New York, 1994), specification 6 / 189 pages 54 CN 122055373 A, the entire contents of which are incorporated herein by reference. Specifically, Chapter 1, Protecting Groups: An Overview, pp. 1-20; Chapter 2, Hydroxyl Protecting Groups, pp. 21-94; Chapter 3, Diol Protecting Groups, pp. 95-117; Chapter 4, Carboxyl Protecting Groups, pp. 118-154; and Chapter 5, Carbonyl Protecting Groups, pp. 155-184. For protecting groups of carboxylic acids, phosphonic acids, phosphonates, sulfonic acids, and other protecting groups of acids, see Greene as described below.

[0046] The term "solvent" refers to a crystalline solid containing a certain amount of solvent incorporated into its crystal structure. As used herein, the term "solvent" includes hydrates.

[0047] The term "nonsolvent" refers to a crystalline solid in which no solvent molecules occupy specific crystallization sites.

[0048] As used herein, the term "pharmaceutically acceptable" with respect to a substance means a substance that, within reasonable medical judgment, is suitable for contact with tissues of humans and lower animals without undue toxicity, irritation, allergic reactions, etc., in proportion to a reasonable benefit / risk ratio, and is effective for its intended use when used in a pharmaceutical composition.

[0049] As used herein, the term "pharmaceutically acceptable salt" is intended to mean a salt of a compound according to the invention that, within reasonable medical judgment, is suitable for contact with tissues of humans and lower animals without undue toxicity, irritation, allergic reactions, etc., in proportion to a reasonable benefit / risk ratio, is generally water-soluble or oil-soluble or dispersible, and is effective for its intended use. This term includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts. A list of suitable salts can be found, for example, SM Birge et al., J. Pharm. Sci., 1977, 66, pp. 1–19.

[0050] As used herein, the term "pharmaceutically acceptable acid addition salt" is intended to mean those salts formed from inorganic and organic acids that retain the bioavailability and properties of the free base and are not biologically or otherwise undesirable, including but not limited to hydrochloric acid, hydrobromic acid, sulfuric acid, aminosulfonic acid, nitric acid, phosphoric acid, etc., and organic acids including but not limited to acetic acid, trifluoroacetic acid, adipic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, butyric acid, camphoric acid, camphorsulfonic acid, cinnamic acid, citric acid, digluconic acid, ethanesulfonic acid, glutamic acid, glycolic acid, glycerophosphate, hemisulfonic acid, hexanoic acid, formic acid, fumaric acid, 2-hydroxyethanesulfonic acid (isoethanesulfonic acid), lactic acid, hydroxymaleic acid, malic acid, malonic acid, mandelic acid, mesitylenesulfonic acid, methanesulfonic acid, Naphthalenesulfonic acid, nicotinic acid, 2-naphthalenesulfonic acid, oxalic acid, dihydroxynaphthalic acid, pectic acid, phenylacetic acid, 3-phenylpropionic acid, neopentanoic acid, propionic acid, pyruvic acid, salicylic acid, stearic acid, succinic acid, p-aminobenzenesulfonic acid, tartaric acid, p-toluenesulfonic acid, undecanoic acid, etc.

[0051] As used herein, the term "pharmaceutically acceptable base addition salt" is intended to mean those salts formed from inorganic bases that retain the bioavailability and properties of the free acid and are not biologically or otherwise undesirable, including but not limited to hydroxides, carbonates, or bicarbonates of ammonia or ammonium or metal cations (such as sodium, potassium, lithium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, etc.). Ammonium salts, potassium salts, sodium salts, calcium salts, and magnesium salts are particularly preferred. Salts derived from pharmaceutically acceptable nontoxic organic bases include, but are not limited to, primary amines, secondary and tertiary amines, quaternary amine compounds, and substituted amines (including naturally occurring substituted amines).Salts of amines, cyclic amines, and basic ion exchange resins, such as methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, isopropylamine, tripropylamine, tributylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, heparin, choline, betaine, ethylenediamine, glucosamine, methylglucosamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, tetramethylammonium compounds, tetraethylammonium compounds, pyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, dicyclohexylamine, dibenzylamine, N,N-dibenzylphenethylamine, 1-diphenylhydroxymethylamine, N,N'-dibenzylethylenediamine, polyamine resins, etc. Particularly preferred non-toxic organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine.

[0052] As used herein, the term “antiviral agent” is intended to mean an agent that effectively inhibits the formation and / or replication of a virus in mammals, including but not limited to agents that interfere with the host or viral mechanisms necessary for the formation and / or replication of a virus in mammals. The term "antiviral agent" includes, for example, HIV integrase catalytic site inhibitors selected from the group consisting of: Retegvir (ISENTRESS®; Merck); Aviravir (Gilead); Soltegravir (GSK; ViiV); GSK 1265744 (GSK; ViiV) and Dulutegravir; HIV nucleoside reverse transcriptase inhibitors selected from the group consisting of: Abacavir (ZIAGEN®; GSK); Didanoxin (VIDEX®; BMS); Tenofovir (VIREAD®; Gilead); Emtricitabine (EMTRIVA®; Gilead); Lamivudine (EPIVIR®; GSK / Shire); Stavudine (ZERIT®; BMS); Zidovudine (RETROVIR®). (GSK); Avtabin (Achillion); Fertinavir (Oncolys); HIV non-nucleoside reverse transcriptase inhibitors, selected from the group consisting of: Nevirapine (VIRAMUNE®; BI); Efavirenz (SUSTIVA®; BMS); Etravirine (INTELENCE®; J&J); Rilpivirine (TMC278, R278474; J&J); Folicidiline (GSK / ViiV); and Lesvirine (Pfizer / ViiV); HIV protease inhibitors, selected from the group consisting of: Atazanavir (REYATAZ®; BMS); Derrenavir (PREZISTA®; J&J); Indinavir (CRIXIVAN®; Merck); Lopinavir (KELETRA®; Abbott);Nefernavir (VIRACEPT®; Pfizer); Saquinavir (INVIRASE®; Hoffmann-LaRoche); Titranavir (APTIVUS®; BI); Ritonavir (NORVIR®; Abbott); and phosxanavir (LEXIVA®; GSK / Vertex); HIV entry inhibitors selected from: Maraviro (SELZENTRY®; Pfizer); Enfuvirtide (FUZEON®; Trimeris); and BMS-663068 (BMS); and HIV maturation inhibitors selected from: Bevirimil (Myriad Genetics).

[0053] As used herein, the term “HIV replication inhibitor” is intended to mean an agent capable of reducing or eliminating HIV replication in host cells, whether in vitro, ex vivo, or in vivo.

[0054] Unless otherwise stated, the term “substituent” as used herein is intended to mean an atom, group, or group that can bond to a carbon atom, heteroatom, or any other atom that is originally bonded to at least one hydrogen atom. Substituents considered in the context of a particular molecule or fragment thereof are those that produce chemically stable compounds, such as those recognized by those skilled in the art.

[0055] As used herein, the term “heteroatom” is intended to mean O, S, or N.

[0056] The terms “O-C1-n alkyl” or “C1-n alkoxy”, which are used interchangeably herein, where n is an integer, alone or in combination with another group, are intended to mean an oxygen atom further bonded to an alkyl group having 1 to n carbon atoms as defined above. Examples of C1-n alkoxy groups include, but are not limited to, methoxy (CH3O-), ethoxy (CH3CH2O-), propoxy (CH3CH2CH2O-), 1-methylethoxy (isopropoxy; (CH3)2CHO), and 1,1-dimethylethoxy (tert-butoxy; (CH3)3CO). When a C1-n alkoxy group is substituted, it should be understood that substitution is performed on its alkyl moiety such that the substitution will produce a chemically stable compound, as is recognized by those skilled in the art.

[0057] As used herein, the term “mammal” is intended to cover humans, as well as non-human mammals susceptible to HIV infection. Non-human mammals include, but are not limited to, domesticated animals such as cattle, pigs, horses, dogs, cats, rabbits, rats, and mice, as well as non-domesticated animals.

[0058] The embodiments disclosed herein are also intended to cover all pharmaceutically acceptable compounds of formula I or formula II that are isotopically labeled having one or more atoms substituted with atoms having different atomic masses or mass numbers. Examples of isotopes that can be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, such as...2H, 3H, 11C, 13C, 14C, 13N, 15N, 15O, 17O, 18O, 31P, 32P, 35S, 18F, 36Cl, 123I, and 125I. In some embodiments, these radiolabeled compounds can be used to help determine or measure the effectiveness of a compound by characterizing, for example, the site or pattern of action or the binding affinity to a pharmacologically important site of action. Certain isotope-labeled compounds of Formula I or II, such as those incorporating radioisotopes, can be used for drug and / or substrate tissue distribution studies. Radioisotopes tritium (i.e., 3H) and carbon-14 (i.e., 14C) are particularly suitable for this purpose because they are easy to incorporate and readily detectable.

[0059] In some embodiments, substitution with a heavier isotope such as deuterium (i.e., 2H) may provide certain therapeutic advantages due to greater metabolic stability. For example, the in vivo half-life may be increased or the dosage requirement may be reduced. Therefore, in some cases, heavier isotopes than those specified on page 8 / 189 of the specification, CN 122055373 A, may be preferred.

[0060] Substitution with positron-emitting isotopes such as 11C, 18F, 15O, and 13N can be used in positron emission tomography (PET) studies to examine substrate acceptor occupancy. The isotopically labeled compounds of the compounds disclosed herein can generally be prepared by techniques known to those skilled in the art, or by methods similar to those described in the examples listed below, using suitable isotopically labeled reagents instead of previously used unlabeled reagents.

[0061] The methods, compositions, kits, and articles provided herein use or include compounds of formula I or II or pharmaceutically acceptable salts thereof, wherein 1 to n hydrogen atoms attached to a carbon atom may be substituted with deuterium or D, where n is the number of hydrogen atoms in the molecule. As known in the art, a deuterium atom is a non-radioactive isotope of a hydrogen atom. Such compounds increase resistance to metabolism and are therefore used to increase the half-life of the compound or its pharmaceutically acceptable salts when administered to mammals. See, for example, Foster, “Deuterium Isotope Effects in Studies of Drug Metabolism”, Trends Pharmacol.Sci., 5(12):524-527 (1984). Such compounds can be synthesized by means known in the art, for example by using starting materials in which one or more hydrogen atoms have been replaced by deuterium.

[0062] The embodiments disclosed herein are also intended to cover in vivo metabolites of the disclosed compounds of Formula I or II. Such products can be generated, for example, by oxidation, reduction, hydrolysis, amidation, esterification, etc., of the administered compound, primarily byProduced by an enzymatic process. Therefore, embodiments disclosed herein include compounds of formula I or II produced by a process comprising administering a compound according to an embodiment disclosed herein to a mammal for a period sufficient to produce its metabolites. Such products are typically identified by administering a radiolabeled compound according to an embodiment disclosed herein to an animal (such as a rat, mouse, guinea pig, monkey, or human) at a detectable dose, allowing sufficient time for metabolism and separation of its transformation products from urine, blood, or other biological samples.

[0063] Compounds of formula I or II disclosed herein, or pharmaceutically acceptable salts thereof, may comprise one or more asymmetric centers and thus may produce enantiomers, diastereomers, and other stereoisomers that may be defined by absolute stereochemistry as (R)- or (S)- or for amino acids as (D)- or (L)-. This disclosure is intended to include all such possible isomers as well as their racemic, non-racemic, and optically pure forms. Optically active (+) and (-), (R)- and (S)-, or (D)- and (L)- isomers can be prepared using chiral synthons or chiral reagents, or resolved using methods such as chromatography and fractional crystallization. Techniques for preparing / separating individual enantiomers include chiral synthesis from suitable optically pure precursors or resolution of racemic mixtures (or racemic mixtures of salts or derivatives) using, for example, chiral high-performance liquid chromatography (HPLC). When the compounds described herein contain alkene double bonds or other geometrically asymmetric centers, and unless otherwise stated, the compounds are intended to include E and Z geometric isomers. Similarly, all tautomer forms are also intended to be included.

[0064] "Optional" or "optionally" means that the events or conditions described below may or may not occur, and the description includes instances where said events or conditions occur and instances where said events or conditions do not occur. For example, "optionally substituted heterocyclic group" means that the heterocyclic group may or may not be substituted, and the description includes substituted heterocyclic groups and unsubstituted heterocyclic groups.

[0065] II. Compound of Formula I In some embodiments, this disclosure provides a compound of Formula I: Specification 9 / 189 page 57 CN 122055373 AI or a pharmaceutically acceptable salt thereof, wherein: R1 is –(CR1AR1BO)a(Y)b(CR1CR1D)dX; wherein a is 0 or 1; b is 0 or 1; d is 0, 1, 2, 3, 4 or 5; R1A is H or C1-3 alkyl; R1B is H or C1-3 alkyl; each R1C is independently H or C1-3 alkyl; each R1D is independently H or C1-3 alkyl; or optionally, R1C and R1D on the same carbon atom are bonded to form a spirocyclopropyl group; Y is -C(O)-, -C(O)O-, -C(O)NH- or -C(O)NR1H-;R1H is a C1-4 alkyl group optionally substituted with one or two substituents independently selected from the group consisting of: –COOH, –OH, –NH2, –CONH2, –P(O)(OH)2, and –S(O)2(OH); X is selected from the group consisting of: (a) –O-P(O)(OR1E)2, wherein each R1E is independently H or phenyl; (b) –N(R1F)2, wherein each R1F is independently H, –COO(CR1IR1J)eOPO(OH)2, or a C1-4 alkyl group; wherein the C1-4 alkyl group is optionally substituted with one or two substituents independently selected from the group consisting of: COOH, –S(O)2OH, –P(O)(OH)2, –OH, –NH2, and –CONH2; e is 1, 2, or 3; each R1I is independently H or a C1-3 alkyl group; Each R1J is independently H or C1-3 alkyl; or optionally, R1I and R1J on the same carbon atom are bonded to form a spiropropyl group; and (c)-N+(R1G)3Z-, wherein each R1G is independently H or C1-4 alkyl; wherein the C1-4 alkyl is optionally substituted by one or two substituents independently selected from the group consisting of: -COOH, -OH, -NH2 and -CONH2; Z- is a counterion; R2 is C1-3 alkyl or C1-3 alkoxy; each R3, R4, R5, R6 and R7 is independently H or halogenated; and R8 is H or C1-3 alkyl.

[0066] In some embodiments, a is 0. In some embodiments, a is 1. Specification 10 / 189 pages 58 CN 122055373 A

[0067] In some embodiments, b is 0. In some embodiments, b is 1.

[0068] In some embodiments, d is 1, 2, 3, or 4. In some embodiments, d is 1, 2, or 3. In some embodiments, d is 1. In some embodiments, d is 2. In some embodiments, d is 3. In some embodiments, d is 4.

[0069] In some embodiments, each R1A is H. In some embodiments, each R1B is H. In some embodiments, each R1A and R1B is H.

[0070] In some embodiments, each R1A is a C1-3 alkyl group, and each R1B is H. In some embodiments, each R1A is methyl. In some embodiments, each R1A is methyl, and each R1B is H.

[0071] In some embodiments, each R1C is H. In some embodiments, each R1D is H. In some embodiments, each R1C and R1D is H. In some embodiments, each R1C is independently H or methyl. In some embodiments, eachEach R1D is independently H or methyl. In some embodiments, each R1C is independently H or methyl, and each R1D is H.

[0072] In some embodiments, Y is -C(O)-, -C(O)O-, -C(O)NH-, or -C(O)NCH3-. In some embodiments, Y is -C(O)-, -C(O)O-, or -C(O)NCH3-. In some embodiments, Y is -C(O)-. In some embodiments, Y is -C(O)O-. In some embodiments, Y is -C(O)NCH3-.

[0073] In some embodiments, Y is -C(O)NR1H-. In some embodiments, R1H is a C1-2 alkyl group optionally substituted with -COOH, -P(O)(OH)2, or -S(O)2(OH).

[0074] In some embodiments, X is -O-P(O)(OR1E)2. In some embodiments, each R1E is phenyl. In some embodiments, each R1E is H.

[0075] In some embodiments, X is -N(R1F)2. In some embodiments, each R1F is independently -COO(CR1IR1J)eOPO(OH)2 or C1-4 alkyl; wherein the C1-4 alkyl is optionally substituted with one or two -COOH. In some embodiments, each R1F is independently -COO(CR1IR1J)eOPO(OH)2 or C1-4 alkyl; wherein the C1-4 alkyl is optionally substituted with one -COOH.

[0076] In some embodiments, e is 1 or 2. In some embodiments, e is 1. In some embodiments, e is 2.

[0077] In some embodiments, each R1I is H. In some embodiments, each R1J is H. In some embodiments, each R1I and each R1J are H. In some embodiments, each R1J is a 1-3 alkyl group, and each R1I is H.

[0078] In some embodiments, each R1F is independently -COOCH2OPO(OH)2 or a C1-4 alkyl group; wherein the C1-4 alkyl group is optionally substituted with one or two -COOH groups. In some embodiments, each R1F is independently -COOCH2OPO(OH)2 or a C1-4 alkyl group; wherein the C1-4 alkyl group is optionally substituted with one -COOH group.

[0079] In some embodiments, each R1F is independently -COO(CH2)2OPO(OH)2, -COOCH2OPO(OH)2, -CH3, or -CH2COOH. In some embodiments, each R1F is independently -COOCH2OPO(OH)2, -CH3, or -CH2COOH.

[0080] In some embodiments, X is -N+(R1G)3Z-.

[0081] In some embodiments, Z is selected from the group consisting of: acetate, ascorbate, aspartate, benzenesulfonate, benzoate, bromide, bicarbonate, carbonate, cinnamate, citrate, chloride, formate, fumarate, gluconate, glutamate, glycolate, lactate, malate, maleate, malonic acid, mandelic acid, methanesulfonate, nicotinic acid, nitrate, oxalate, dihydrogen phosphate, hydrogen phosphate, phosphate, propionate, toluenesulfonate, pyroglutamate, salicylate, succinate, hydrogen sulfate, sulfate, tartrate, thiocyanate, trifluoromethanesulfonate, and trifluoroacetate.

[0082] In some embodiments, each R1G is independently a C1-4 alkyl group. In some embodiments, each R1G is -CH3.

[0083] In some embodiments, R1 is selected from the group consisting of: (Page 59, Specification 11 / 189, CN 122055373 A), , , , , , , , , , , , , , , , , , and.

[0084] In some embodiments, R1 is selected from the group consisting of: , , , , (Page 60, Specification 12 / 189, CN 122055373 A), , ...

[0085] In some embodiments, R1 is selected from the group consisting of: , , , , , , , , , , , , , , , , and.

[0086] In some embodiments, R2 is methyl or methoxy. In some embodiments, R2 is methyl. In some embodiments, R2 is methoxy.

[0087] In some embodiments, R3 and R6 are each independently halogenated. In some embodiments, R3 and R6 are each F. Specification 14 / 189 pages 62 CN 122055373 A

[0088] In some embodiments, R4, R5 and R7 are each H.

[0089] In some embodiments, R8 is C1-3 alkyl. In some embodiments, R8 is methyl.

[0090] In some embodiments, the compounds of formula I are selected from the group consisting of: , , , , , , , CN 122055373 A, , , , , , CN 122055373 A, , , , , , CN 122055373 A, , , , , , CN 122055373 A, , and, or pharmaceutically acceptable salts thereof.

[0091] In some embodiments, the compound of formula I is selected from the group consisting of: , , Specification 18 / 189 page 66 CN 122055373 A, , , , , Specification 19 / 189 page 67 CN 122055373 A, , Specification 20 / 189 page 68 CN 122055373 A, , , Specification 21 / 189 page 69 CN 122055373 A, , , , , Specification 22 / 189 page 70 CN 122055373 A, , , , , , Specification 23 / 189 page 71 CN 122055373 A, , , , , , Specification 24 / 189 page 72 CN 122055373 A, , And, or pharmaceutically acceptable salts thereof.

[0092] In some embodiments, the compounds of Formula I are selected from the group consisting of: , ...

[0095] In some embodiments, the compound of formula I is: , or a pharmaceutically acceptable salt thereof.

[0096] In some embodiments, the compounds disclosed herein have therapeutic activity. In some embodiments, the compounds disclosed herein are prodrugs that can be converted into compounds with therapeutic activity when administered to the human body. In some embodiments, the compounds disclosed herein are prodrugs of certain compounds disclosed in U.S. Applications No. 18 / 296,285, 18 / 334,588, and 18 / 334,611, and PCT Application No. PCT / US2023 / 065401, the disclosures of which are incorporated herein by reference in their entirety. For example, the compound of formula I disclosed herein can be converted into a compound of formula II: Specification 29 / 189 pages 77 CN 122055373 A IIOr a pharmaceutically acceptable salt thereof, wherein R2, R3, R4, R5, R6, R7, and R8 are as defined according to any other embodiments described herein.

[0097] In some embodiments, the compound of formula II is, or a pharmaceutically acceptable salt thereof.

[0098] In some embodiments, the compound of formula II is.

[0099] In some embodiments, the compound of formula II is, or a pharmaceutically acceptable salt thereof.

[0100] In some embodiments, the compound of formula II is.

[0101] The present invention includes a method for converting a compound of formula I or a pharmaceutically acceptable salt thereof into a compound of formula II or a pharmaceutically acceptable salt thereof. A compound of Formula I or a pharmaceutically acceptable salt thereof may be converted into a compound of Formula II or a pharmaceutically acceptable salt thereof by: (1) contacting a compound of Formula I or a pharmaceutically acceptable salt thereof with a cellular aqueous medium capable of converting -OR1 to -OH (e.g., by enzymatic or chemical means, via acid or alkaline hydrolysis); or (2) administering the compound to a patient, thereby converting a compound of Formula I or a pharmaceutically acceptable salt thereof into a compound of Formula II or a pharmaceutically acceptable salt thereof via a biological route (e.g., enzymes) or by contacting a biological fluid and / or tissue conducive to converting -OR1 to -OH (e.g., via acid or alkaline hydrolysis).

[0102] The present invention also provides for treating or preventing HIV infection in a patient in need by contacting a patient with a compound of Formula II or a pharmaceutically acceptable salt thereof, thereby generating a compound of Formula II or a pharmaceutically acceptable salt thereof in the patient's body after administration of a compound of Formula I or a pharmaceutically acceptable salt thereof to the patient. In some embodiments, the compound of Formula II generated in the patient's body is intermediate B or intermediate C, as described in the Examples section below. In some embodiments, the compound of formula II disclosed herein, or a combination of its pharmaceutically acceptable salts, is typically administered as a treatment or prevention of HIV infection in a patient in need.

[0103] III. Pharmaceutical Compositions The compounds provided herein are generally administered as pharmaceutical compositions. Therefore, pharmaceutical compositions comprising one or more of the compounds provided herein or their pharmaceutically acceptable salts, isomers, or mixtures, and one or more pharmaceutically acceptable solvents selected from carriers, adjuvants, and excipients are also provided herein. The compounds provided herein may be the sole active ingredient or one of the active ingredients of a pharmaceutical composition. Suitable pharmaceutically acceptable solvents may include, for example, inert solid diluents and fillers, diluents including sterile aqueous solutions and various organic solvents, permeation enhancers, solubilizers, and adjuvants. Such compositions are prepared in a manner well known in the pharmaceutical field. See, for example, Remington's PharmaceuticalSciences, Mace Publishing Co., Philadelphia, Pa., 17th edition, (1985); and Modern Pharmaceutics, Marcel Dekker, Inc., 3rd edition (edited by GSBanker and CTRhodes).

[0104] In one aspect, pharmaceutical compositions are provided herein comprising a compound provided herein (e.g., a compound of formula I or II) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier. In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of a compound provided herein or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier.

[0105] In some embodiments, the pharmaceutical compositions provided herein further comprise one or more (e.g., one, two, three, four, one or two, one to three, or one to four) additional therapeutic agents or pharmaceutically acceptable salts thereof. In some embodiments, the pharmaceutical composition further comprises a therapeutically effective amount of one or more (e.g., one, two, three, four, one or two, one to three, or one to four) additional therapeutic agents or pharmaceutically acceptable salts thereof. In some embodiments, the pharmaceutical composition further comprises one, two, three, or four additional therapeutic agents.

[0106] The pharmaceutical composition may be administered in single or multiple doses. The pharmaceutical composition may be administered by various methods, including, for example, rectal, buccal, intranasal, and transdermal routes. In some embodiments, the pharmaceutical composition may be administered by intra-arterial injection, intravenous, intraperitoneal, parenteral, intramuscular, subcutaneous, oral, topical, or as an inhalant.

[0107] One route of administration is parenteral, for example, by injection. Forms in which the pharmaceutical composition described herein may be incorporated for administration by injection include, for example, aqueous or oil suspensions or emulsions, with sesame oil, corn oil, cottonseed oil, or peanut oil, as well as elixirs, mannitol, dextrose, or sterile aqueous solutions and similar pharmaceutical solvents.

[0108] Oral administration may be another route of administration for the compounds provided herein. Administration may be via, for example, capsules or enteric-coated tablets. In preparing pharmaceutical compositions comprising at least one compound provided herein or a pharmaceutically acceptable salt, isomer, or mixture thereof, the active ingredient (such as the compounds provided herein) is typically diluted with an excipient and / or encapsulated in a carrier, which may be in the form of capsules, sachets, paper, or other containers. When the excipient is used as a diluent, it may be in the form of a solid, semi-solid, or liquid material, acting as a solvent, carrier, or medium for the active ingredient. Thus, pharmaceutical compositions may be in the form of tablets, pills, powders, lozenges, capsules, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft gelatin capsules, and...The pharmaceutical composition may be in the form of hard gelatin capsules, sterile injectable solutions, and sterile packaged powders.

[0109] Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starch, gum arabic, calcium phosphate, alginate, tragacanth gum, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup and methylcellulose, vitamin E-tocopherol polyethylene glycol succinate (vitamin E-TPGS), and polyethoxylated castor oil (also known as Cremophor EL or Kolliphor EL). Or any combination thereof. The pharmaceutical composition may additionally include lubricants such as talc, magnesium stearate and mineral oil; wetting agents; emulsifiers and suspending agents; preservatives such as methyl benzoate and propylparaben; sweeteners; and flavoring agents; or any combination thereof.

[0110] Pharmaceutical compositions comprising at least one compound described herein or a pharmaceutically acceptable salt, isomer, or mixture thereof may be formulated to provide a rapid, sustained, or delayed release of an active ingredient, such as a compound provided herein, upon administration to a subject using procedures known in the art. Controlled-release drug delivery systems for oral administration include osmotic pump systems and dissolution systems containing polymer-coated reservoirs or drug-polymer matrix formulations. Examples of controlled-release systems are given in U.S. Patent Nos. 3,845,770, 4,326,525, 4,902,514, and 5,616,345. Another formulation used in the methods of this disclosure employs a transdermal delivery device (“patch”). Such transdermal patches can be used to provide a controlled amount of a compound provided herein for continuous or discontinuous infusion. The construction and use of transdermal patches for delivering pharmaceutical agents are well known in the art. See, for example, U.S. Patents 5,023,252, 4,992,445, and 5,001,139. Such patches can be configured for continuous, pulsatile, or on-demand delivery of pharmaceutical preparations.

[0111] To prepare solid compositions (such as tablets), a major active ingredient may be mixed with a pharmaceutical excipient to form a solid preformed composition containing a homogeneous mixture of the compounds described herein or their pharmaceutically acceptable salts, isomers, or mixtures thereof. When these preformed compositions are referred to as homogeneous, the active ingredient is uniformly dispersed throughout the composition, making it easy to subdivide the composition into equivalent unit dosage forms, such as tablets, pills, and capsules.

[0112] Tablets or pills of the compounds described herein may be coated or otherwise compounded to provide a dosage form with the advantage of prolonged action or protection against the acidic conditions of the stomach. For example, tablets or pills may contain an inner dose component and an outer dose component, the latter being in the form of a coating over the former. These two components may be separated by an enteric coating layer, which...The layer is designed to resist disintegration in the stomach and allow the internal components to enter the duodenum intact or delay release. A variety of materials can be used for such enteric coatings or coatings, including a variety of polymeric acids and mixtures of polymeric acids with materials such as shellac, cetyl alcohol, and cellulose acetate.

[0113] Pharmaceutical compositions for inhalation or inhalation may include solutions and suspensions or mixtures thereof in pharmaceutically acceptable aqueous or organic solvents, as well as powders. Liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described above. In some embodiments, the composition is administered via oral or nasal inhalation to achieve a local or systemic effect. In other embodiments, the composition may be nebulized in a pharmaceutically acceptable solvent using an inert gas. The nebulized solution may be inhaled directly from a nebulizer, or the nebulizer may be attached to a face mask tent or intermittent positive pressure ventilation machine. Solution, suspension, or powder compositions may be administered orally or nasally from a device that delivers the formulation in a suitable manner.

[0114] In some embodiments, compounds of formula I or II described herein, or their pharmaceutically acceptable salts and PGP inhibitors, are provided as pharmaceutical compositions.

[0115] The compounds of Formula I or II described herein, or pharmaceutically acceptable salts thereof, may be present in the same pharmaceutical composition as the PGP inhibitor, or may be present in a different pharmaceutical composition. In one embodiment, the compounds of Formula I or II, or pharmaceutically acceptable salts thereof, are formulated, for example, as a fixed combination in the same pharmaceutical composition as the PGP inhibitor.

[0116] In one embodiment, the compounds of Formula I or II, or pharmaceutically acceptable salts thereof, and the PGP inhibitor are formulated in different pharmaceutical compositions for, for example, to be administered alone, simultaneously, or sequentially. When formulated alone, the compounds of Formula I or II, or pharmaceutically acceptable salts thereof, and the PGP inhibitors provided herein may be the sole active ingredients of the pharmaceutical composition.

[0117] Each pharmaceutical composition may contain one or more pharmaceutically acceptable solvents selected from carriers, adjuvants, and excipients.

[0118] V. Treatment Method Instructions 32 / 189 pages 80 CN 122055373 A In one embodiment, a method is provided for treating a person infected with HIV (e.g., HIV-1 and / or HIV-2) or at risk of HIV infection, the method comprising administering to the person a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of a compound of formula I or a pharmaceutically acceptable salt thereof.

[0119] In some embodiments, the method further comprises administering to the person a therapeutically effective amount of one, two, three, or four additional therapeutic agents. In some embodiments, one or more additional therapeutic agents are anti-HIV agents. In specific embodiments,One or more adjunctive therapeutic agents are HIV protease inhibitors, non-nucleoside or non-nucleotide inhibitors of HIV reverse transcriptase, nucleoside or nucleotide inhibitors of HIV reverse transcriptase, HIV capsid inhibitors, gp41 inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5 inhibitors, latency reversal agents, capsid polymerization inhibitors, HIV bNAb (broadly neutralizing HIV antibodies), TLR7 agonists, pharmacokinetic enhancers, other drugs for treating HIV, or combinations thereof.

[0120] In some embodiments, one or more adjunctive therapeutic agents are HIV protease inhibitors, non-nucleoside or non-nucleotide inhibitors of HIV reverse transcriptase, HIV reverse transcriptase and / or translocated nucleoside or nucleotide inhibitors, HIV capsid inhibitors, gp41 inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5 inhibitors, latency reversal agents, capsid polymerization inhibitors, HIV bNAb (broadly neutralizing HIV antibodies), TLR7 agonists, pharmacokinetic enhancers, other drugs for treating HIV, or combinations thereof.

[0121] In some embodiments, one or more adjunctive therapeutic agents are abacavir, tenofovir alafenamide, tenofovir disoproxil fumarate, N-((S)-1-(3-(4-chloro-3-(methylsulfonamide)-1-(2,2,2-trifluoroethyl)-1H-indazole-7-yl)-6-(3-methyl-3-(methylsulfonyl)but-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropyl[3,4]cyclopent[1,2-c]pyrazol-1-yl)acetamide or their pharmaceutically acceptable salts. In one embodiment, the one or more adjunctive therapeutic agents are abacavir, tenofovir alafenamide, tenofovir disoproxil fumarate, lenakapavir, or pharmaceutically acceptable salts thereof. In one embodiment, the one or more adjunctive therapeutic agents are abacavir, tenofovir alafenamide, tenofovir disoproxil fumarate, lenakapavir, GS-5894, islatravir, or pharmaceutically acceptable salts thereof. In some embodiments, the one or more adjunctive therapeutic agents are lenakapavir or islatravir. In some embodiments, the adjunctive therapeutic agent is lenakapavir. In some embodiments, the adjunctive therapeutic agent is islatravir.

[0122] In another embodiment, a pharmaceutical composition of a compound of formula I or a pharmaceutically acceptable salt thereof, or a compound of formula I or a pharmaceutically acceptable salt thereof, is provided for the treatment of a person who has HIV (e.g., HIV-1 and / or HIV-2) infection or is at risk of HIV infection.

[0123] In another embodiment, a compound of formula I or a pharmaceutically acceptable salt thereof is provided, or aPharmaceutical compositions of compounds of Formula I or pharmaceutically acceptable salts thereof, used in medical therapies.

[0124] In another embodiment, a compound of Formula I or pharmaceutically acceptable salt thereof, or a pharmaceutical composition of Formula I or pharmaceutically acceptable salt thereof, is provided for use in treating HIV infection.

[0125] In another embodiment, a compound of Formula I or pharmaceutically acceptable salt thereof, or a pharmaceutical composition of a compound of Formula I or pharmaceutically acceptable salt thereof, is provided for use in a method of treating the infection in a person who has HIV infection or is at risk of HIV infection.

[0126] In another embodiment, a compound of Formula I or pharmaceutically acceptable salt thereof, or a pharmaceutical composition of a compound of Formula I or pharmaceutically acceptable salt thereof, is provided for use in a method of treating the infection in a person who has HIV infection or is at risk of HIV infection, wherein the method further includes administering one, two, three, or four additional therapeutic agents to the person.

[0127] In another embodiment, a compound of formula I or a pharmaceutically acceptable salt thereof is provided, or a pharmaceutical composition of a compound of formula I or a pharmaceutically acceptable salt thereof, as specified in specification 33 / 189 pages 81 CN 122055373 A, for use in a method of treating a person with HIV infection or at risk of HIV infection, wherein said method further includes administering to a person one, two, three or four additional therapeutic agents selected from the group consisting of: HIV protease inhibitors, non-nucleoside or non-nucleotide inhibitors of HIV reverse transcriptase, nucleoside or nucleotide inhibitors of HIV reverse transcriptase, HIV capsid inhibitors, gp41 inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5 inhibitors, latency reversal agents, capsid polymerization inhibitors, HIV bNAb, TLR7 agonists, pharmacokinetic enhancers, other drugs for treating HIV, or combinations thereof. In one embodiment, one, two, three, or four additional therapeutic agents are selected from HIV protease inhibitors, non-nucleoside inhibitors of HIV reverse transcriptase, nucleoside or nucleotide inhibitors of HIV reverse transcriptase, latency reversal agents, HIV capsid inhibitors, HIV bNAb, TLR7 agonists, and combinations thereof.

[0128] In another embodiment, a compound of formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of a compound of formula I or a pharmaceutically acceptable salt thereof, is provided for use in a method of treating a person with HIV infection or at risk of HIV infection, wherein the method further comprises administering to the person a therapeutically effective amount of tenofovir disoproxil fumarate and emtricitabine.

[0129] In another embodiment, a compound of formula I or a pharmaceutically acceptable salt thereof, or a...Pharmaceutical compositions of a compound of Formula I or a pharmaceutically acceptable salt thereof, used in a method of treating the infection in a person who is infected with HIV or at risk of contracting HIV infection, wherein the method further comprises administering to the person a therapeutically effective amount of tenofovir disoproxil fumarate and emtricitabine.

[0130] In another embodiment, a pharmaceutical composition of a compound of Formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of a compound of Formula I or a pharmaceutically acceptable salt thereof, is provided for use in a method of treating the infection in a person who is infected with HIV or at risk of contracting HIV infection, wherein the method further comprises administering to the person a therapeutically effective amount of tenofovir disoproxil fumarate.

[0131] In another embodiment, a pharmaceutical composition of a compound of Formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of a compound of Formula I or a pharmaceutically acceptable salt thereof, is provided for use in a method of treating the infection in a person who is infected with HIV or at risk of contracting HIV infection, wherein the method further comprises administering to the person a therapeutically effective amount of tenofovir disoproxil fumarate.

[0132] In another embodiment, a method of using a compound of Formula I in a therapy is provided. Specifically, a method is provided for treating HIV viral replication in mammals (e.g., humans), treating AIDS, or delaying the onset of AIDS or ARC symptoms, the method comprising administering to the mammal a compound of Formula I or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0133] In another embodiment, a composition comprising a compound of Formula I or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, is provided for use in a method for treating HIV viral replication in mammals (e.g., humans), treating AIDS, or delaying the onset of AIDS or ARC symptoms.

[0134] In one embodiment, a pharmaceutical composition of a compound of Formula I or a pharmaceutically acceptable salt thereof, or a compound of Formula I or a pharmaceutically acceptable salt thereof, is provided for use in the prevention of HIV infection.

[0135] In some embodiments, a compound of formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of a compound of formula I or a pharmaceutically acceptable salt thereof, is provided for use before and / or after an event that exposes an individual to HIV or otherwise increases the individual's risk of acquiring HIV (e.g., as pre-exposure prophylaxis (PrEP) and / or post-exposure prophylaxis (PEP)).

[0136] For example, in one embodiment, a compound of formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of a compound of formula I or a pharmaceutically acceptable salt thereof, is provided for use before exposure prophylaxis (PrEP) (i.e., before an individual is exposed to HIV or otherwise increases the individual's risk of acquiring HIV).

[0137] In another embodiment, a compound of formula I or a pharmaceutically acceptable salt thereof is provided, or a composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof, for use in post-exposure prophylaxis (PEP) (i.e., after an individual has been exposed to HIV) to prevent HIV infection from taking root and / or to prevent the establishment of a permanent infection and / or to prevent the appearance of disease symptoms and / or to prevent the virus from reaching a detectable level in the blood.

[0138] In another embodiment, the use of a compound of formula I or a pharmaceutically acceptable salt thereof is disclosed in the preparation of a medicament for treating a person who has HIV infection or is at risk of developing HIV infection.

[0139] In another embodiment, the use of a compound of formula I or a pharmaceutically acceptable salt thereof as a research tool is disclosed.

[0140] In another embodiment, an article of manufacture is disclosed comprising a composition effective in treating HIV infection; and packaging material including a label indicating that the composition can be used to treat an infection caused by HIV. Exemplary compositions comprise a compound of formula I or a pharmaceutically acceptable salt thereof.

[0141] In another embodiment, a method of inhibiting HIV replication is disclosed. The method comprises exposing a virus to an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof under conditions that inhibit HIV replication.

[0142] In another embodiment, the use of a compound of formula I or a pharmaceutically acceptable salt thereof to inhibit the activity of HIV integrase is disclosed.

[0143] In another embodiment, the use of a compound of formula I or a pharmaceutically acceptable salt thereof to inhibit HIV replication is disclosed.

[0144] VI. The compounds disclosed herein may be administered via any route suitable for the condition to be treated. Suitable routes include oral, rectal, nasal, topical (including buccal and sublingual), transdermal, vaginal, and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal, and epidural) administration. In some embodiments, administration is oral, intravenous, subcutaneous, or intramuscular. It should be understood that the preferred route may vary depending on, for example, the recipient's condition. An advantage of some of the compounds disclosed herein is that they are orally bioavailable and can be administered orally.

[0145] The compounds of this disclosure can be administered to an individual for the period or duration required for an effective dosing regimen, such as at least about 1 month, at least about 2 months, at least about 3 months, at least about 6 months, or at least about 12 months or longer. In some embodiments, the compounds are administered on a daily or intermittent schedule throughout the individual's life.

[0146] The specific dose level of the compounds disclosed herein for any particular subject will depend on a variety of factors, including the activity of the specific compound used, the age, weight, general health condition, sex, diet, time of administration, route of administration and excretion rate, drug combination, and severity of the specific disease. For example, the dose may be expressed as milligrams (mg / kg) of the compound described herein per kilogram of subject body weight. A dose between about 0.1 mg / kg and 150 mg / kg may be appropriate. In some embodiments, a dose between about 0.1 mg / kg and 100 mg / kg may be appropriate. In other embodiments, a dose between 0.5 mg / kg and 60 mg / kg may be appropriate. Normalization based on the subject's weight is particularly useful when adjusting for doses among subjects with large differences in size, such as when using the drug in children and adults, or when converting an effective dose for a non-human subject, such as a dog, to a dose suitable for a human subject.

[0147] The dose may also be described as the total amount of the compound described herein administered per dose. The dosage of an acceptable salt or pharmaceutically acceptable tautomer of a compound of formula I or thereof may be between about 1 mg and 4,000 mg, between about 2,000 mg and 4,000 mg, between about 1 mg and 2,000 mg, between about 1 mg and 1,000 mg, between about 1 mg and 1,000 mg, between about 10 mg and 500 mg, between about 20 mg and 500 mg, between about 50 mg and 300 mg, between about 75 mg and 200 mg, or between about 15 mg and 150 mg.

[0148] The dosage of the compound of Formula II or its pharmaceutically acceptable salt or pharmaceutically acceptable tautomer may be between about 1 mg and 4,000 mg, between about 2,000 mg and 4,000 mg, between about 1 mg and 2,000 mg, between about 1 mg and 1,000 mg, between about 10 mg and 500 mg, between about 20 mg and 500 mg, between about 50 mg and 300 mg, between about 75 mg and 200 mg, or between about 15 mg and 150 mg.

[0149] The dosage of the PGP inhibitor may be between about 1 mg and 4,000 mg, between about 2,000 mg and 4,000 mg, between about 1 mg and 2,000 mg, between about 1 mg and 1,000 mg, between about 1 mg and 500 mg, between about 10 mg and 500 mg, between about 20 mg and 500 mg, between about 1 mg and 300 mg, between about 10 mg and 300 mg, etc.The dosage may be between about 20 mg and 300 mg, between about 1 mg and 200 mg, between about 10 mg and 200 mg, between about 20 mg and 200 mg, between about 1 mg and 100 mg, between about 10 mg and 100 mg, between about 20 mg and 100 mg, between about 50 mg and 300 mg, between about 75 mg and 200 mg, or between about 15 mg and 150 mg. For example, the dosage of a PGP inhibitor may be about 15 mg.

[0150] The dosage or frequency of administration of the compounds disclosed herein may be adjusted during treatment at the discretion of the administering physician.

[0151] The compounds disclosed herein may be administered in a therapeutically effective amount to an individual (e.g., a human). In some embodiments, the compound is administered once daily. In some embodiments, the compound is administered once weekly. In some embodiments, the compound is administered once monthly. In some embodiments, the compound is administered every two months. In some embodiments, the compound is administered every three months. In some embodiments, the compound is administered every four months. In some embodiments, the compound is administered every five months. In some embodiments, the compound is administered every six months. In some embodiments, the compound is administered every seven months. In some embodiments, the compound is administered every eight months. In some embodiments, the compound is administered every nine months. In some embodiments, the compound is administered every ten months. In some embodiments, the compound is administered every eleven months. In some embodiments, the compound is administered annually.

[0152] The compounds provided herein may be administered by any useful route and means, such as by oral or parenteral (e.g., intravenous) administration. Therapeuticly effective amounts of the compound may include from about 0.00001 mg / kg body weight / day to about 10 mg / kg body weight / day, such as from about 0.0001 mg / kg body weight / day to about 10 mg / kg body weight / day, or such as from about 0.001 mg / kg body weight / day to about 1 mg / kg body weight / day, or such as from about 0.01 mg / kg body weight / day to about 1 mg / kg body weight / day, or such as from about 0.05 mg / kg body weight / day to about 0.5 mg / kg body weight / day. In some embodiments, therapeutically effective amounts of the compounds provided herein include about 0.3 mg / dose to about 30 mg / dose, or about 30 mg / dose to about 300 mg / dose, or about 0.3 μg / dose to about 30 mg / dose, or about 30 μg / dose to about 300 μg / dose.

[0153] The compounds of this disclosure may be combined with one or more additional therapeutic agents at any dose of the compounds of this disclosure (e.g., 1 mg to 1000 mg of the compound). Therapeuticly effective amounts may include about 0.1 mg / dose to about 1000 mg / dose, such as about 50 mg / dose.The dosage is approximately 500 mg / dose, or such as approximately 100 mg / dose to approximately 400 mg / dose, or such as approximately 150 mg / dose to approximately 350 mg / dose, or such as approximately 200 mg / dose to approximately 300 mg / dose, or such as approximately 0.01 mg / dose to approximately 1000 mg / dose, or such as approximately 0.01 mg / dose to approximately 100 mg / dose, or such as approximately 0.1 mg / dose to approximately 100 mg / dose, or such as approximately 1 mg / dose to approximately 100 mg / dose, or such as approximately 1 mg / dose to approximately 100 mg / dose, or such as approximately 1 mg / dose to approximately 1000 mg / dose. Other therapeutically effective doses of the compounds of Formula I are about 1 mg / dose, or about 2 mg / dose, 3 mg / dose, 4 mg / dose, 5 mg / dose, 6 mg / dose, 7 mg / dose, 8 mg / dose, 9 mg / dose, 10 mg / dose, 15 mg / dose, 20 mg / dose, 25 mg / dose, 30 mg / dose, 35 mg / dose, 40 mg / dose, 45 mg / dose, 50 mg / dose, 55 mg / dose, 60 mg / dose, 65 mg / dose, 70 mg / dose, 75 mg / dose, 80 mg / dose, 85 mg / dose, 90 mg / dose, 95 mg / dose, or about 100 mg / dose. Other therapeutically effective doses of the disclosed compounds are approximately 100 mg / dose, 125 mg / dose, 150 mg / dose, 175 mg / dose, 200 mg / dose, 225 mg / dose, 250 mg / dose, 275 mg / dose, 300 mg / dose, 325 mg / dose, 350 mg / dose, 375 mg / dose, 400 mg / dose, 425 mg / dose, 450 mg / dose, 475 mg / dose, 500 mg / dose, 525 mg / dose, 550 mg / dose, 575 mg / dose, 600 mg / dose, 625 mg / dose, 650 mg / dose, 675 mg / dose, 700 mg / dose, 725 mg / dose, 750 mg / dose, 775 mg / dose, 800 mg / dose, 825 mg / dose. 850 mg / dose, 875 mg / dose, 900 mg / dose, 925 mg / dose, 950 mg / dose, 975 mg / dose, or about 1000 mg / dose.

[0154] In some embodiments, the method described herein comprises administering to a subject an initial daily dose of about 1 mg to 500 mg of the compound disclosed herein, and gradually increasing the dose until clinical efficacy is achieved. Increments of about 5 mg, 10 mg, 25 mg, 50 mg, or 100 mg may be used to increase the dose. The dose may be increased daily, every other day, twice a week, once a week, once every two weeks, once every three weeks, or once a month.

[0155] When administered orally, the total daily dose to a human subject may be between about 1 mg and 1,000 mg, between about 10 mg / dose.The total daily dose for human subjects may be between 500 mg / day, between about 50 mg / day and 300 mg / day, between about 75 mg / day and 200 mg / day, or between about 100 mg / day and 150 mg / day. In some embodiments, the total daily dose for human subjects may be about 100 mg / day, 200 mg / day, 300 mg / day, 400 mg / day, 500 mg / day, 600 mg / day, 700 mg / day, 800 mg / day, 900 mg / day, or 1000 mg / day, administered as a single dose. In some embodiments, the total daily dose for human subjects may be about 200 mg / day, 300 mg / day, 400 mg / day, 500 mg / day, 600 mg / day, 700 mg / day, or 800 mg / day, administered as a single dose. In some embodiments, the total daily dose of a human subject may be about 300 mg / day, 400 mg / day, 500 mg / day, or 600 mg / day, administered as a single dose.

[0156] In some embodiments, the total daily dose of a human subject may be about 100 mg / day, administered as a single dose. In some embodiments, the total daily dose of a human subject may be about 150 mg / day, administered as a single dose. In some embodiments, the total daily dose of a human subject may be about 200 mg / day, administered as a single dose. In some embodiments, the total daily dose of a human subject may be about 250 mg / day, administered as a single dose. In some embodiments, the total daily dose of a human subject may be about 300 mg / day, administered as a single dose. In some embodiments, the total daily dose of a human subject may be about 350 mg / day, administered as a single dose. In some embodiments, the total daily dose of a human subject may be about 400 mg / day, administered as a single dose. In some embodiments, the total daily dose of a human subject may be about 450 mg / day, administered as a single dose. In some embodiments, the total daily dose of the human subject may be about 500 mg / day administered as a single dose. In some embodiments, the total daily dose of the human subject may be about 550 mg / day administered as a single dose. In some embodiments, the total daily dose of the human subject may be about 600 mg / day administered as a single dose. In some embodiments, the total daily dose of the human subject may be about 650 mg / day administered as a single dose. In some embodiments, the total daily dose of the human subject may be about 700 mg / day administered as a single dose. In some embodiments, the total daily dose of the human subject may be about 750 mg / day administered as a single dose. In some embodiments, the total daily dose of the human subject may be about 800 mg / day administered as a single dose. In some embodiments, the total daily dose of the human subject may be about 850 mg / day administered as a single dose. In some embodiments, the total daily dose of the human subject may be about 900 mg / day administered as a single dose. In some embodiments, the total daily dose of the human subject may be about 500 mg / day administered as a single dose.The dosage is approximately 950 mg / day. In some embodiments, the total daily dose for a human subject may be approximately 1000 mg / day administered as a single dose.

[0157] A single dose may be administered hourly, daily, weekly, or monthly. For example, a single dose may be administered every 1 hour, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 12 hours, 16 hours, or every 24 hours. A single dose may also be administered every 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, or every 7 days. A single dose may also be administered every 1 week, 2 weeks, 3 weeks, or every 4 weeks. In some embodiments, a single dose may be administered weekly. A single dose may also be administered monthly once a month. In some embodiments, the compounds disclosed herein are administered once daily in the methods disclosed herein. In some embodiments, the compounds disclosed herein are administered twice daily in the methods disclosed herein.

[0158] In some embodiments, the compound disclosed herein is applied every 10 days. In some embodiments, the compound disclosed herein is applied every 15 days. In some embodiments, the compound disclosed herein is applied every 20 days. In some embodiments, the compound disclosed herein is applied every 10-15 days. In some embodiments, the compound disclosed herein is applied every 15-20 days. In some embodiments, the compound disclosed herein is applied every 10-20 days. In some embodiments, the compound disclosed herein is applied once a month. In some embodiments, the compound disclosed herein is applied once every 2 months. In some embodiments, the compound disclosed herein is applied once every 3 months. In some embodiments, the compound disclosed herein is applied once every 4 months. In some embodiments, the compound disclosed herein is applied once every 5 months. In some embodiments, the compound disclosed herein is applied once every 6 months. In some embodiments, the compound disclosed herein is applied once every 8 months. In some embodiments, the compound disclosed herein is applied once every 10 months. In some embodiments, the compound disclosed herein is applied once a year.

[0159] The frequency of administration of the compounds disclosed herein will be determined by the individual patient's needs and may be, for example, once daily, once weekly, once every two weeks, once monthly, once every two months, once every three months, once every four months, once every six months, or less. Administration of the compounds continues as long as treatment of HIV infection is required.

[0160] VII. Kits and Articles In one aspect, kits are provided herein comprising the compounds provided herein (e.g., compounds of Formula I) or pharmaceutically acceptable salts, stereoisomers, prodrugs, or solvates thereof, and suitable packaging. In some embodimentsThe kit also includes instructions for use. In some embodiments, the kit includes a compound provided herein (e.g., a compound of Formula I) or a pharmaceutically acceptable salt, stereoisomer, prodrug, or solvate thereof, and a label and / or instructions for using the compound to treat the indications (including diseases or conditions) described herein.

[0161] In some embodiments, the kit also includes one or more (e.g., one, two, three, four, one or two, one to three, or one to four) additional therapeutic agents or pharmaceutically acceptable salts thereof.

[0162] In one aspect, an article is provided herein containing a compound described herein or a pharmaceutically acceptable salt, isomer, or mixture thereof in a suitable container. In some embodiments, the container may be a vial, wide-mouth bottle, ampoule, pre-filled syringe, or intravenous bag.

[0163] In one aspect, a kit is provided herein containing (i) a compound of Formula I or II provided herein (e.g., a compound of Formula I) or a pharmaceutically acceptable salt, stereoisomer, prodrug, or solvate thereof, (ii) a P-glycoprotein, and suitable packaging. In some embodiments, the kit also includes instructions for use. In some embodiments, the kit contains (i) a compound of formula I or formula II provided herein (e.g., a compound of formula I) or a pharmaceutically acceptable salt, stereoisomer, prodrug, or solvate thereof, (ii) a P-glycoprotein inhibitor and a label and / or instructions for using the compound to treat the indications (including diseases or conditions) described herein.

[0164] In some embodiments, the kit contains (i) a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof, or a compound of formula II or a pharmaceutically acceptable salt thereof, (ii) a pharmaceutical composition comprising a P-glycoprotein inhibitor, and (iii) instructions for use.

[0165] In some embodiments, the kit contains (i) a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof, or a compound of formula II or a pharmaceutically acceptable salt thereof, and a P-glycoprotein inhibitor, and (ii) instructions for use.

[0166] In some embodiments, the kit further comprises one or more (e.g., one, two, three, four, one or two, one to three, or one to four) additional therapeutic agents or pharmaceutically acceptable salts thereof. Specification 38 / 189 pages 86 CN 122055373 A

[0167] In one aspect, articles thereof are provided in a suitable container comprising (i) a compound of formula I or II described herein, or a pharmaceutically acceptable salt, isomer, or mixture thereof, and (ii) a P-glycoprotein inhibitor. In some embodiments, the container may be a vial, wide-mouth bottle, ampoule, pre-filled syringe, or intravenous bag.

[0168] VII. Combination TherapyIn some embodiments, a method for treating HIV infection is provided, the method comprising administering to a person a therapeutically effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one, two, three, or four additional therapeutic agents. In one embodiment, a method for treating HIV infection is provided, the method comprising administering to a person a therapeutically effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one, two, three, or four additional therapeutic agents.

[0169] In one embodiment, a pharmaceutical composition is provided comprising a compound disclosed herein or a pharmaceutically acceptable salt thereof, in combination with one, two, three, or four additional therapeutic agents, and a pharmaceutically acceptable carrier, diluent, or excipient.

[0170] In some embodiments, this disclosure provides a method for treating HIV infection, the method comprising administering to a subject in need a therapeutically effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one, two, three, or four additional therapeutic agents suitable for treating HIV infection.

[0171] In some embodiments, the compounds disclosed herein or pharmaceutically acceptable salts thereof are combined with one, two, three, four, or more adjunctive therapeutic agents. In some embodiments, the compounds disclosed herein or pharmaceutically acceptable salts thereof are combined with one, two, three, or four adjunctive therapeutic agents. In some embodiments, the compounds disclosed herein or pharmaceutically acceptable salts thereof are combined with two adjunctive therapeutic agents. In other embodiments, the compounds disclosed herein or pharmaceutically acceptable salts thereof are combined with three adjunctive therapeutic agents. In still other embodiments, the compounds disclosed herein or pharmaceutically acceptable salts thereof are combined with four adjunctive therapeutic agents. The one, two, three, four, or more adjunctive therapeutic agents may be different therapeutic agents selected from the same class of therapeutic agents, and / or they may be selected from different classes of therapeutic agents.

[0172] Administration of HIV combination therapy In some embodiments, the compounds disclosed herein are administered together with one, two, three, or four adjunctive therapeutic agents. Co-administration of the compounds disclosed herein with one, two, three, or four additional therapeutic agents generally refers to the simultaneous or sequential administration of the compounds disclosed herein and one, two, three, or four additional therapeutic agents such that therapeutically effective amounts of the compounds disclosed herein and one, two, three, or four additional therapeutic agents are present in the patient. When administered sequentially, the combination may be administered in two or more doses.

[0173] Co-administration includes administering a unit dose of the compounds disclosed herein before or after administering a unit dose of one, two, three, or four additional therapeutic agents. For example, it may be administered with one, two, three, or four additional therapeutic agents.The compound disclosed herein may be administered within seconds, minutes, or hours. In some embodiments, a unit dose of the compound disclosed herein is administered first, followed by a unit dose of one, two, three, or four additional therapeutic agents within seconds or minutes. Alternatively, a unit dose of one, two, three, or four additional therapeutic agents is administered first, followed by a unit dose of the compound disclosed herein within seconds or minutes. In other embodiments, a unit dose of the compound disclosed herein is administered first, followed by a unit dose of one, two, three, or four additional therapeutic agents after several hours (e.g., 1-12 hours). In other embodiments, a unit dose of one, two, three, or four additional therapeutic agents is administered first, followed by a unit dose of the compound disclosed herein after several hours (e.g., 1-12 hours).

[0174] In some embodiments, a kit is provided comprising a compound disclosed herein (e.g., a compound of formula I, e.g., page 39 / 189 of specification, 87 CN 122055373 A) and a pharmaceutically acceptable salt thereof, and one or more (e.g., one, two, three, or four) adjunctive therapeutic agents.

[0175] In one specific embodiment, the kit comprises a compound disclosed herein or a pharmaceutically acceptable salt thereof, a nucleoside or nucleotide inhibitor of HIV reverse transcriptase, and an HIV capsid inhibitor or an HIV capsid polymerization inhibitor.

[0176] HIV Combination Therapy In the above embodiments, one or more adjunctive therapeutic agents may be anti-HIV agents. In some cases, adjunctive therapy may include HIV protease inhibitors, non-nucleoside or non-nucleotide inhibitors of HIV reverse transcriptase, nucleoside or nucleotide inhibitors of HIV reverse transcriptase, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, HIV entry inhibitors, HIV maturation inhibitors, HIV capsid inhibitors, nucleocapsid protein 7 (NCp7) inhibitors, HIV Tat or Rev inhibitors, Tat-TAR-P-TEFb inhibitors, immunomodulators, immunotherapeutic agents, antibody-drug conjugates, gene modifiers, gene editing products (such as CRISPR / Cas9, zinc finger nucleases, homing nucleases, synthetic nucleases, TALEN), cell therapies (such as chimeric antigen receptor T cells, CAR-T and engineered T cell receptors, TCR-T, autologous T cell therapy, engineered B cells, NK cells), latency reversal agents, immunotherapy-based therapies, phosphatidylinositol 3-kinase (PI3K) inhibitors, HIV antibodies, bispecific antibodies and "antibody-like" therapeutic proteins, HIV p17 matrix protein inhibitors, IL-13 antagonists, peptidyl prolyl cis-trans isomerase A regulators, protein disulfide isomerase inhibitors, complement C5a receptor antagonists, DNA methyltransferase inhibitors, and lipids.HIV synthase inhibitors, HIV vif gene regulators, Vif dimerization antagonists, HIV-1 viral infectivity factor inhibitors, HIV-1 Nef regulators, TNF-α ligand inhibitors, HIV Nef inhibitors, Hck tyrosine kinase regulators, mixed lineage kinase-3 (MLK-3) inhibitors, HIV-1 splicing inhibitors, integrin antagonists, nucleoprotein inhibitors, splicing factor regulators, COMM domain-containing protein 1 regulators, HIV ribonuclease H inhibitors, IFN antagonists, retrocycline regulators, CD3 antagonists, CDK-4 inhibitors, CDK-6 inhibitors, CDK-9 inhibitors, cytochrome P450 3 inhibitors, CXCR4 regulators, dendritic cell ICAM-3-extracting non-integrin 1 inhibitors, HIV GAG protein inhibitors, HIV POL protein inhibitors, complement factor H regulators, ubiquitin ligase inhibitors, deoxycytidine kinase inhibitors, cyclin-dependent kinase inhibitors. HPK1 (MAP4K1) inhibitors, proprotein convertase PC9 stimulators, ATP-dependent RNA helicase DDX3X inhibitors, reverse transcriptase initiation complex inhibitors, G6PD and NADH-oxidase inhibitors, mTOR complex 1 inhibitors, mTOR complex 2 inhibitors, P-glycoprotein regulators, RNA polymerase regulators, TAT protein inhibitors, prolyl endopeptidase inhibitors, phospholipase A2 inhibitors, pharmacokinetic enhancers, HIV gene therapy, HIV vaccines, anti-HIV peptides, and combinations thereof.

[0177] In some embodiments, one or more additional therapeutic agents are selected from combination drugs for HIV, other drugs for treating HIV, HIV protease inhibitors, HIV reverse transcriptase inhibitors, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, HIV entry (fusion) inhibitors, HIV maturation inhibitors, latency reversal agents, capsid inhibitors, immune-based therapies, PI3K inhibitors, HIV antibodies and bispecific antibodies and "antibody-like" therapeutic proteins, and combinations thereof.

[0178] In some embodiments, the adjunctive therapeutic agent is selected from the group consisting of: combination drugs for HIV, other drugs for treating HIV, HIV protease inhibitors, HIV reverse transcriptase inhibitors, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, HIV entry (fusion) inhibitors, HIV maturation inhibitors, latency reversal agents, capsid inhibitors, immune-based therapies, PI3K inhibitors, HIV antibodies and bispecific antibodies and "antibody-like" therapeutic proteins, and combinations thereof.

[0179] In some embodiments, one or more adjunctive therapeutic agents are selected from HIV protease inhibitors, HIV reverse transcriptase inhibitors, and other similar drugs.Non-nucleoside or non-nucleotide inhibitors, nucleoside or nucleotide inhibitors of HIV reverse transcriptase, HIV integrase inhibitors, HIV capsid inhibitors, gp41 inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5 inhibitors, Nef inhibitors, latency reversal agents, HIV bNAb, TLR7, TLR8 and TLR9 agonists, HIV vaccines, cytokines, immune checkpoint inhibitors, FLT3 ligands, bispecific antibodies that recruit T cells and NK cells, chimeric T cell receptors that target HIV antigens, pharmacokinetic enhancers and other drugs for the treatment of HIV, and combinations thereof.

[0180] In some embodiments, one or more adjunctive therapeutic agents are selected from dulutegravir, cabotevir, islatrevir, direravir, bicagvir, issavirline, rilpivirline and lenacapavir, and combinations thereof.

[0181] Examples of HIV combination therapies include, but are not limited to, ATRIPLA® (efavirenz, tenofovir disoproxil fumarate, and emtricitabine); COMPLERA® (EVIPLERA®; rilpivirine, tenofovir disoproxil fumarate, and emtricitabine); STRIBILD® (erteiravir, cobistat, tenofovir disoproxil fumarate, and emtricitabine); TRUVADA® (tenofovir disoproxil fumarate and emtricitabine; TDF+FTC); DESCOVY® (tenofovir alafenamide and emtricitabine); ODEFSEY® (tenofovir alafenamide, emtricitabine, and rilpivirine); GENVOYA® (Tenofovir alafenamide, emtricitabine, cobistat, and ertirapvir); direravir, tenofovir alafenamide hemifumarate, emtricitabine, and cobistat; efavirenz, lamivudine, and tenofovir disoproxil fumarate; lamivudine and tenofovir disoproxil fumarate; tenofovir and lamivudine; tenofovir alafenamide and emtricitabine; tenofovir alafenamide hemifumarate and emtricitabine; tenofovir alafenamide hemifumarate, emtricitabine, and rilpivirine; tenofovir alafenamide hemifumarate, emtricitabine, cobistat, and ertirapvir; tenofovir analogues; COMBIVIR® (zidovudine and lamivudine; AZT+ 3TC); EPZICOM® (LIVEXA®) Abacavir sulfate and lamivudine; ABC+3TC); KALETRA® (ALUVIA®; lopinavir and ritonavir); TRIUMEQ® (durutexvir, abacavir and lamivudine); BIKTARVY® (bikagvir + emtricitabine + tenofovir alafenamide), DOVATO® (durutexvir + lamivudine), TRIZIVIR®(Abacavir sulfate, zidovudine, and lamivudine; ABC+AZT+3TC); Atazanavir and cobistat; Atazanavir sulfate and cobistat; Atazanavir sulfate and ritonavir; Deruravir and cobistat; Dulutegravir and rilpivirine; Dulutegravir and rilpivirine hydrochloride; Dulutegravir, abacavir sulfate, and lamivudine; Lamivudine, nevirapine, and zidovudine; Rettagvir and lamivudine; Doravirine, lamivudine, and tenofovir disoproxil fumarate; Doravirine, lamivudine, and tenofovir disoproxil fumarate; Dulutegravir + lamivudine, Lamivudine + abacavir + zidovudine, Lamivudine + abacavir, Lamivudine + Tenofovir disoproxil fumarate, lamivudine + zidovudine + nevirapine, lopinavir + ritonavir, lopinavir + ritonavir + abacavir + lamivudine, lopinavir + ritonavir + zidovudine + lamivudine, tenofovir + lamivudine, and tenofovir disoproxil fumarate + emtricitabine + rilpivirine hydrochloride, lopinavir, ritonavir, zidovudine, lopinavir + ritonavir + abacavir + lamivudine, lamivudine, cabotevir + rilpivirine, 3-BNC117 + ibevitra, elpida (esavilin, VM-1500) and VM-1500A, lenakapavir + isratrivir (oral, injectable) and dual-targeting HIV-1 reverse transcriptase / nucleocapsid protein 7 inhibitors.

[0182] Examples of other HIV medications used to treat HIV include, but are not limited to, aspergillin C, acemannan, alisporivir, BanLec, deferiprone, gamimune, metenkefalin, naltrexone, prolastin, REP 9, RPI-MN, VSSP, H1viral, SB-728-T, 1,5-dicaffeoylquinic acid, rHIV7-shl-TAR-CCR5RZ, AAV-eCD4-Ig gene therapy, MazF gene therapy, BlockAide, bevirimat derivatives, ABBV-382, ABX-464, AG-1105. APH-0812, APH0202, Bryozoin-1, Bryozoin analogs, BIT-225, BRII-732, BRII-778, CYT-107, CS-TATI-1, Fluoro-β-D-arabinonucleotide (FANA) modified antisense oligonucleotides, FX-101, Gravelson product manual, page 41 / 189, CN 122055373 A(griffithsin), GSK-3739937, GSK-3739937 (long-acting), HGTV-43, HPH-116, HS-10234, hydroxychloroquine, IMB-10035, IMO-3100, IND-02, JL-18008, LADAVRU, MK-1376, MK-2048, MK-4250, MK-8507, MK-8558, MK-8591 (isratrovir), NOV-205, OB-002H, ODE-Bn-TFV, PA-1050040 (PA-040), PC- 707, PGN-007, QF-036, S-648414, SCY-635, SB-9200, SCB-719, TR-452, TEV-90110, TEV-90112, TEV-90111, TEV-90113, RN-18, DIACC-1010, Fasnall, Immuglo, 2-ClIPS peptide, HRF-4467, thrombospondin analog, TBL-1004HI, VG-1177, XL-081, AVI-CO- 004, rfhSP-D, [18F]-MC-225, URMC-099-C, RES-529, Verdinexor, IMC-M113V, IML-106, antiviral fc conjugate (AVC), WP-1096, WP-1097, Gammora, ISR-CO48, ISR-48, ISR-49, MK-8527, cannabinoids, ENOB-HV-32, HiviCide-I, T-1144, VIR-576, nipamovir, Covimro, and ABBV-1882.

[0183] Examples of HIV protease inhibitors include, but are not limited to, ampravir, atazanavir, becanavir, drenavir, forosanavir, forosanavir calcium, indinavir, indinavir sulfate, lopinavir, nelfinavir, nelfinavir mesylate, ritonavir, saquinavir, saquinavir mesylate, telanavir, ASC-09+ritonavir, AEBL-2, DG-17, GS-1156, TMB-657 (PPL-100), T-169, BL-008, MK-8122, TMB-607, GRL-02031, and TMC-310911.

[0184] Additional examples of HIV protease inhibitors are described, for example, in U.S. Patent Nos. 10,294,234 and U.S. Patent Application Publications Nos. US2020030327 and US2019210978.

[0185] HIVExamples of HIV Gag protein inhibitors include, but are not limited to, HRF-10071.

[0186] Examples of HIV ribonuclease H inhibitors include, but are not limited to, NSC-727447.

[0187] Examples of HIV Nef inhibitors include, but are not limited to, FP-1.

[0188] Examples of non-nucleoside or non-nucleotide inhibitors of HIV reverse transcriptase include, but are not limited to, dapirine, delavudine mesylate, doravirine, efavirenz, iletravirine, lentinan, nevirapine, rilpivirine, ACC-007, ACC-008, AIC-292, F-18, KM-023, PC-1005, M1-TFV, M2-TFV, VM-1500A-LAI, PF-3450074, isavirin (sustained-release oral, for HIV infection), doravirine + isavirin (fixed-dose combination / oral tablet formulation, for HIV-1 infection), isavirin (long-acting injectable nanosuspension, for HIV infection), and isavirin (VM-1500).

[0189] Examples of nucleoside or nucleotide inhibitors of HIV reverse transcriptase include, but are not limited to, adefovir, adefovir dipivoxil, azavudine, emtricitabine, tenofovir, tenofovir alafenamide, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, tenofovir disoproxil fumarate, tenofovir disoproxil fumarate, tenofovir octadecyloxyethyl ester (AGX-1009), tenofovir disoproxil fumarate, VIDEX® and VIDEX EC® (desoxyinosine, ddl), abacavir, abacavir sulfate, alovudine, aripipridine, cilsavudine, doxaviridine, evitabine, fetinaviridine, fosalvudine tidoxil, CMX-157, dapoxil, doravirin, ectaviridine, OCR- 5753, orofovir disoproxil fumarate, fozivudine dipropionate, lamivudine, azidophosphine, stavudine, zalcitabine, zidovudine, rovafovir estarafenamide (GS-9131), GS-9148, MK-8504, isratravir, MK-8583, VM- (Instructions for Use, 42 / 189 pages, 90 CN 122055373 A 2500 and KP-1461).

[0190] Additional examples of nucleoside or nucleotide inhibitors of HIV reverse transcriptase include, but are not limited to, those described in patent publications US2007049754, US2016250215, US2016237062, US2016251347, US2002119443.Those listed in US2013065856, US2013090473, US2014221356, and WO04096286.

[0191] Examples of HIV integrase inhibitors include, but are not limited to, erteiravir, erteiravir (extended-release microcapsules), curcumin, curcumin derivatives, chicoric acid, chicoric acid derivatives, 3,5-dicaffeoylquinic acid, 3,5-dicaffeoylquinic acid derivatives, ginsenoside tricarboxylic acid, ginsenoside tricarboxylic acid derivatives, caffeic acid phenethyl ester, caffeic acid phenethyl ester derivatives, tyrphostin, tyrphostin derivatives, quercetin, quercetin derivatives, retegvir, pegylated retegvir, dulutegravir, JTK-351, bicagvir, AVX-15567, cabotevir (long-acting injectable), diketoquinoline-4-1 derivatives, integrase-LEDGF inhibitors, ledgins, M-522, M-532. MK-0536, NSC-310217, NSC-371056, NSC-48240, NSC-642710, NSC-699171, NSC-699172, NSC-699173, NSC-699174, stilbenedisulfonic acid, T169, STP-0404, VM-3500, XVIR-110, and ACC-017.

[0192] Examples of HIV non-catalytic site or allosteric integrase inhibitors (NCINIs) include, but are not limited to, CX-05045, CX-05168, and CX-14442.

[0193] Additional examples of HIV capsid inhibitors include, but are not limited to, those described in U.S. Patent Application Publications US20200317689, US20210284642, US2014221356, and US2016016973.

[0194] Examples of HIV infectious agent inhibitors include, but are not limited to, 2-amino-N-(2-methoxyphenyl)-6-((4-nitrophenyl)thio)benzamide derivatives and Irino-L.

[0195] Examples of HIV entry inhibitors include, but are not limited to, AAR-501, LBT-5001, cineviro, CCR5 inhibitors, gp41 inhibitors, CD4 attachment inhibitors, gp120 inhibitors, gp160 inhibitors, and CXCR4 inhibitors.

[0196] Examples of CCR5 inhibitors include, but are not limited to, apravirone, vevicvirone, maraviro, and maraviro (long-acting).Injectable nanoemulsions), senevirol, lerolimusab (PRO-140), adatavir (RAP-101), nifevirol (TD-0232), anti-GP120 / CD4 or CCR5 bispecific antibody, B-07, MB-66, peptide C25P, TD-0680, celavirol, and vMIP (Haimipu).

[0197] Examples of gp41 inhibitors include, but are not limited to, epfuvirtide, grefterone (gp41 / gp120 / gp160 inhibitor), BMS-986197, enfuvirtide biomodification, enfuvirtide biosimilar, HIV-1 fusion inhibitor (P26-Bapc), ITV-1, ITV-2, ITV-3, ITV-4, CPT-31, Cl3hmAb, lipuvirtide, PIE-12 trimer, and sifvirtide.

[0198] Examples of CD4 attachment inhibitors include, but are not limited to, ibalizumab and CADA analogs.

[0199] Examples of gp120 inhibitors include, but are not limited to, anti-HIV microbestocides, Radha-108 (receptol) 3B3-PE38, BMS818251, BanLec, bentonite-based nanomedicines, fostemsavir (aminobutyric acid), IQP-0831, VVX-004, and BMS-663068.

[0200] Examples of gp160 inhibitors include, but are not limited to, tetrandrine.

[0201] Examples of CXCR4 inhibitors include, but are not limited to, praxavir, ALT-1188, N15 peptide, and vMIP (Haimipu).

[0202] HIV maturation inhibitor specification 43 / 189 pages 91 CN 122055373 A Examples of HIV maturation inhibitors include, but are not limited to, BMS-955176, GSK-3640254 and GSK-2838232.

[0203] Examples of latency reversal agents include, but are not limited to, toll-like receptor (TLR) agonists (including TLR7 agonists, such as GS-9620, TLR8 agonists, and TLR9 agonists), histone deacetylase (HDAC) inhibitors, proteasome inhibitors such as velcade, protein kinase C (PKC) activators, Smyd2 inhibitors, BET-bromodomain 4 (BRD4) inhibitors (such as ZL-0580, apabelon), ionomycin, IAP antagonists (inhibitors of apoptosis proteins, such as APG-1387, LBW-242), and SMAC mimics (including TL32711, LCL161, GDC-0917, HGS1029, AT-406, Debio-1143).PMA, SAHA (aminosuccinate or succinyl, aniline and isohydroxamic acid), NIZ-985, IL-15 modulating antibodies (including IL-15, IL-15 fusion proteins and IL-15 receptor agonists), JQ1, disulfiram, amphotericin B and ubiquitin inhibitors (such as lagazole analogs, APH-0812 and GSK-343). Examples of PKC activators include, but are not limited to, indolelactam, prostratin, styraxol B and DAG-lactone.

[0204] Additional examples of TLR7 agonists include, but are not limited to, those described in U.S. Patent Application Publication No. US2010143301.

[0205] Additional examples of TLR8 agonists include, but are not limited to, those described in U.S. Patent Application Publication No. US2017071944.

[0206] Histone deacetylase (HDAC) inhibitors, in some embodiments, combine the agents as described herein with histone deacetylases such as histone deacetylase 1, histone deacetylase 9 (HDAC9, HD7, HD7b, HD9, HDAC, HDAC7, HDAC7B, HDAC9B, HDAC9FL, HDRP, MITR; gene ID: 9734). Examples of HDAC inhibitors include, but are not limited to, abexinostat, ACY-241, AR-42, BEBT-908, belinostat, CKD-581, CS-055 (HBI-8000), CT-101, CUDC-907 (fimepinostat), entinostat, givinostat, mocetinostat, panobinostat, pracinostat, quisinostat (JNJ-26481585), remixitar, ricolinostat, romidesin, and SHP- 141. TMB-ADC, valproic acid (VAL-001), vorinostat, tinostamustine, remetinostat, and entinostat.

[0207] Capsid inhibitors Examples of capsid inhibitors include, but are not limited to, capsid polymerization inhibitors or capsid-destructive compounds, HIV nucleocapsid p7 (NCp7) inhibitors (such as azodicarbonamide), HIV p24 capsid protein inhibitors, lenakapavir (GS-6207), and others.And their prodrugs, GS-CA1, AVI-621, AVI-101, AVI-201, AVI-301 and the AVI-CAN1-15 series, PF-3450074, HIV-1 capsid inhibitors (HIV-1 infection, Shandong University), and compounds described in (GSK WO2019 / 087016).

[0208] Additional examples of capsid inhibitors include, but are not limited to, those described in U.S. Patent Application Publication Nos. US2018051005 and US2016108030.

[0209] Cytochrome P450 3 inhibitors Examples of cytochrome P450 3 inhibitors include, but are not limited to, those described in U.S. Patent No. 7,939,553.

[0210] RNA polymerase regulators Examples of RNA polymerase regulators include, but are not limited to, those described in U.S. Patent Nos. 10,065,958 and 8,008,264. Instructions for Use, 44 / 189 pages, 92 CN 122055373 A

[0211] Immune checkpoint modulators, in various embodiments, combine the agent as described herein with one or more blockers or inhibitors of inhibitory immune checkpoint proteins or receptors and / or with one or more stimulators, activators, or agonists of one or more stimulating immune checkpoint proteins or receptors. Blocking or inhibiting inhibitory immune checkpoints can positively modulate T cell or NK cell activation and prevent immune escape of infected cells. Stimulating or activating immune checkpoints can enhance the efficacy of immune checkpoint inhibitors in the treatment of infections. In various embodiments, immune checkpoint proteins or receptors modulate T cell responses (e.g., as reviewed in the following literature: Xu et al., J Exp Clin Cancer Res. (2018) 37:110). In various implementations, immune checkpoint proteins or receptors regulate NK cell responses (e.g., as reviewed in the following literature: Davis et al., Semin Immunol. (2017) 31:64–75; and Chiossone et al., Nat Rev Immunol. (2018) 18 (11):671–688).

[0212] Examples of immune checkpoint proteins or receptors include, but are not limited to, CD27, CD70; CD40, CD40LG; CD47, CD48 (SLAMF2), 2 containing transmembrane and immunoglobulin domains (TMIGD2, CD28H), CD84 (LY9B, SLAMF5), CD96, CD160, MS4A1 (CD20), CD244 (SLAMF4); CD276 (B7H3); and T cell activation inhibitors containing V-set domains.(VTCN1, B7H4); V-set immunomodulatory receptors (VSIR, B7H5, VISTA); Immunoglobulin superfamily member 11 (IGSF11, VSIG3); Natural killer cell cytotoxic receptor 3 ligand 1 (NCR3LG1, B7H6); HERV-H LTR-associated 2 (HHLA2, B7H7); Inducible T cell costimulatory factors (ICOS, CD278); Inducible T cell costimulatory ligands (ICOSLG, B7H2); TNF receptor superfamily member 4 (TNFRSF4, OX40); TNF superfamily member 4 (TNFSF4, OX40L); TNFRSF8 (CD30), TNFSF8 (CD30L); TNFRSF10A (CD261, DR4, TRAILR1), TNFRSF9 (CD137) TNFSF9 (CD137L); TNFRSF10B (CD262, DR5, TRAILR2), TNFRSF10 (TRAIL); TNFRSF14 (HVEM, CD270), TNFSF14 (HVEML); CD272 (B and T lymphocyte-associated (BTLA)); TNFRSF17 (BCMA, CD269), TNFSF13B (BAFF); TNFRSF18 (GITR), TNFSF18 (GITRL); MHC class I peptide-associated sequence A (MICA); MHC class I peptide-associated sequence B (MICB); CD274 (CD274, PDL1, PD-L1); programmed cell death 1 (PDCD1, PD1, PD-L1) 1) Cytotoxic T-lymphocyte-associated proteins 4 (CTLA4, CD152); CD80 (B7-1), CD28; nectin cell adhesion molecule 2 (NECTIN2, CD112); CD226 (DNAM-1); poliovirus receptor (PVR) cell adhesion molecules (PVR, CD155); containing PVR-associated immunoglobulin domains (PVRIG, CD112R); T-cell immune receptor with Ig and ITIM domains (TIGIT); containing T-cell immunoglobulin and mucin domains 4 (TIMD4; TIM4); hepatitis A virus cell receptor 2 (HAVCR2, TIMD3, TIM3); galactoglobulin 9 (LGALS9); lymphocyte activation 3 (LAG3, CD223); signal transduction lymphocyte activation molecule family member 1 (SLAMF1, SLAM, CD150); lymphocyte antigen 9 (LY9, CD229, SLAMF3). SLAM family member 6 (SLAMF6, CD352); SLAM family member 7 (SLAMF7, CD319); UL16 binding protein 1 (ULBP1);UL16-binding protein 2 (ULBP2); UL16-binding protein 3 (ULBP3); Early retinoic acid transcript 1E (RAET1E; ULBP4); Early retinoic acid transcript 1G (RAET1G; ULBP5); Early retinoic acid transcript 1L (RAET1L; ULBP6); Lymphocyte activation 3 (CD223); Cytokine immunoglobulin-like receptor, three Ig domains and long cytoplasmic tail 1 (KIR, CD158E1); Cytokine lectin-like receptor C1 (KLRC1, NKG2A, CD159A); Cytokine lectin-like receptor K1 (KLRK1, NKG2D, CD314); Cytokine lectin-like receptor C2 (KLRC2, CD159c, NKG2C); Cytokine lectin-like receptor C3 (KLRC3, NKG2E); cytotoxic cell lectin-like receptor C4 (KLRC4, NKG2F); cytotoxic cell immunoglobulin-like receptor, two Ig domains and long cytoplasmic tail 1 (KIR2DL1); cytotoxic cell immunoglobulin-like receptor, two Ig domains and long cytoplasmic tail 2 (KIR2DL2); cytotoxic cell immunoglobulin-like receptor, two Ig domains and long cytoplasmic tail 3 (KIR2DL3); cytotoxic cell immunoglobulin-like receptor, three Ig domains and long cytoplasmic tail 1 (KIR3DL1); cytotoxic cell lectin-like receptor D1 (KLRD1); SLAM family member 7 (SLAMF7); and hematopoietic progenitor cell kinase 1 (HPK1, MAP4K1). Specification 45 / 189 pages 93 CN 122055373 A

[0213] In various embodiments, the agents described herein are combined with one or more blockers or inhibitors of one or more T cell inhibitory immune checkpoint proteins or receptors. Exemplary T-cell suppressor immune checkpoint proteins or receptors include, but are not limited to, CD274 (CD274, PDL1, PD-L1); programmed cell death 1 ligand 2 (PDCD1LG2, PD-L2, CD273); programmed cell death 1 (PDCD1, PD1, PD-1); cytotoxic T-lymphocyte-associated protein 4 (CTLA4, CD152); CD276 (B7H3); V-set domain-containing T-cell activation inhibitor 1 (VTCN1, B7H4); V-set immunomodulatory receptors (VSIR, B7H5, VISTA); immunoglobulin superfamily member 11 (IGSF11, VSIG3); TNFRSF14 (HVEM, ... CD270), TNFSF14 (HVEML); CD272 (B and T lymphocyte-associated receptor (BTLA)); containing PVR-associated immunoglobulin domains (PVRIG, CD112R); T cell immune receptor with Ig and ITIM domains (TIGIT); lymphocyte activation 3 (LAG3, ...CD223); Hepatitis A virus cell receptor 2 (HAVCR2, TIMD3, TIM3); Galactoglobulin 9 (LGALS9); Cytokine immunoglobulin-like receptor with three Ig domains and a long cytoplasmic tail 1 (KIR, CD158E1); Cytokine immunoglobulin-like receptor with two Ig domains and a long cytoplasmic tail 1 (KIR2DL1); Cytokine immunoglobulin-like receptor with two Ig domains and a long cytoplasmic tail 2 (KIR2DL2); Cytokine immunoglobulin-like receptor with two Ig domains and a long cytoplasmic tail 3 (KIR2DL3); and Cytokine immunoglobulin-like receptor with three Ig domains and a long cytoplasmic tail 1 (KIR3DL1). In various embodiments, the reagents as described herein are combined with one or more agonists or activators of one or more T cell-stimulated immune checkpoint proteins or receptors. Exemplary T-cell stimulating immune checkpoint proteins or receptors include, but are not limited to, CD27, CD70; CD40, CD40LG; inducible T-cell costimulators (ICOS, CD278); inducible T-cell costimulator ligands (ICOSLG, B7H2); TNF receptor superfamily member 4 (TNFRSF4, OX40); TNF superfamily member 4 (TNFSF4, OX40L); TNFRSF9 (CD137), TNFSF9 (CD137L); TNFRSF18 (GITR), TNFSF18 (GITRL); CD80 (B7-1), CD28; nectin cell adhesion molecule 2 (NECTIN2, CD112); CD226 (DNAM-1); CD244 (2B4, SLAMF4); poliovirus receptor (PVR) cell adhesion molecule (PVR, CD155). See, for example, Xu et al., J Exp Clin Cancer Res. (2018) 37:110.

[0214] In various embodiments, the agents described herein are combined with one or more blockers or inhibitors of one or more NK cell inhibitory immune checkpoint proteins or receptors. Exemplary NK cell inhibitory immune checkpoint proteins or receptors include, but are not limited to, cytotoxic cell immunoglobulin-like receptors with three Ig domains and a long cytoplasmic tail 1 (KIR, CD158E1); cytotoxic cell immunoglobulin-like receptors with two Ig domains and a long cytoplasmic tail 1 (KIR2DL1); cytotoxic cell immunoglobulin-like receptors with two Ig domains and a long cytoplasmic tail 2 (KIR2DL2); cytotoxic cell immunoglobulin-like receptors with two Ig domains and a long cytoplasmic tail 3 (KIR2DL3); cytotoxic cell immunoglobulin-like receptors with three Ig domains and a long cytoplasmic tail 1 (KIR3DL1); cytotoxic cell lectin-like receptors C1 (KLRC1, NKG2A, CD159A); and cytotoxic cell lectin-like receptor D1.(KLRD1, CD94). In various embodiments, the agents described herein are combined with one or more agonists or activators of one or more NK cell-stimulating immune checkpoint proteins or receptors. Exemplary NK cell-stimulating immune checkpoint proteins or receptors include, but are not limited to, CD16, CD226 (DNAM-1); CD244 (2B4, SLAMF4); cytotoxic lectin-like receptor K1 (KLRK1, NKG2D, CD314); and SLAM family member 7 (SLAMF7). See, for example, Davis et al., Semin Immunol. (2017) 31:64–75; Fang et al., Semin Immunol. (2017) 31:37–54; and Chiossone et al., Nat Rev Immunol. (2018) 18(11):671–688.

[0215] In some embodiments, one or more immune checkpoint inhibitors include protein (e.g., antibody or fragment thereof or antibody mimic) inhibitors of PD-L1 (CD274), PD-1 (PDCD1), or CTLA4. In some embodiments, one or more immune checkpoint inhibitors include small organic molecule inhibitors of PD-L1 (CD274), PD-1 (PDCD1), or CTLA4. In some embodiments, the small molecule inhibitors of CD274 or PDCD1 are selected from the group consisting of GS-4224, GS-4416, INCB086550, and MAX10181. In some embodiments, the small molecule inhibitor of CTLA4 includes BPI-002. Instructions for Use, pages 46 / 189, CN 122055373 A

[0216] Examples of CTLA4 inhibitors that can be co-administered include, but are not limited to, ipilimumab, trimemumab, BMS-986218, AGEN1181, AGEN1884, BMS-986249, MK-1308, REGN-4659, ADU-1604, CS-1002, BCD-145, APL-509, JS-007, BA-3071, ONC-392, AGEN-2041, JHL-1155, KN-044, CG-0161, ATOR-1144, PBI-5D3H5, BPI-002, and multispecific inhibitors FPT-155 (CTLA4 / PD-L1 / CD28), PF- 06936308 (PD‑1 / CTLA4), MGD‑019 (PD‑1 / CTLA4), KN‑046 (PD‑1 / CTLA4), MEDI‑5752 (CTLA4 / PD-1), XmAb-20717 (PD-1 / CTLA4) and AK-104 (CTLA4 / PD-1).

[0217] Examples of PD-L1 (CD274) or PD-1 (PDCD1) inhibitors that can be co-administered include, but are not limited to, pembrolizumab, nivolumab, cimetizumab, pildizumab, AMP-224, MEDI0680 (AMP-514), spartazumab, atezolizumab, avelumab, durvalumab, BMS-936559, CK-301, PF-06801591, BGB-A317 (tislelizumab), GLS-010 (WBP-3055), AK-103 (HX-008), AK-105, CS-1003, HLX-10, MGA-012, BI- 754091, AGEN-2034, JS-001 (Toripalimab), JNJ-63723283, Genomeamarab (CBT-501), LZM-009, BCD-100, LY-3300054, SHR-1201, SHR-1210 (Camrelizumab), Sym-021, ABBV-181 (Buglimab), PD1-PIK, BAT-1306 (MSB0010718C), CX-072, CBT-502, TSR-042 (Dotalimab), MSB-2311, JTX-4014, BGB-A333, SHR-1316, CS-1001 (WBP-3155, KN-035, IBI-308 (Sintilimab)) HLX-20, KL-A167, STI-A1014, STI-A1015 (IMC-001), BCD-135, FAZ-053, TQB-2450, MDX1105-01, GS-4224, GS-4416, INCB086550, MAX10181, and multispecific inhibitors FPT-155 (CTLA4 / PD-L1 / CD28), PF-06936308 (PD-1 / CTLA4), MGD-013 (PD-1 / LAG-3), FS-118 (LAG-3 / PD-L1), MGD-019 (PD-1 / CTLA4), KN-046 (PD-1 / CTLA4), MEDI-5752 (CTLA4 / PD-1), RO-7121661 (PD-1 / TIM-3). XmAb-20717 (PD-1 / CTLA4), AK-104 (CTLA4 / PD-1), M7824 (PD-L1 / TGFβ-EC domain), CA-170(PD-L1 / VISTA), CDX-527 (CD27 / PD-L1), LY-3415244 (TIM3 / PDL1), and INBRX-105 (4-1BB / PDL1).

[0218] In various embodiments, the agents as described herein are combined with anti-TIGIT antibodies such as BMS-986207, RG-6058, and AAGEN-1307.

[0219] In various embodiments, the agent as described herein is combined with an agonist of one or more members of the TNF receptor superfamily (TNFRSF) such agonist as one or more of the following: TNFRSF1A (NCBI gene ID: 7132), TNFRSF1B (NCBI gene ID: 7133), TNFRSF4 (OX40, CD134; NCBI gene ID: 7293), TNFRSF5 (CD40; NCBI gene ID: 958), TNFRSF6 (FAS, NCBI gene ID: 355), TNFRSF7 (CD27, NCBI gene ID: 939), TNFRSF8 (CD30, NCBI gene ID: 943), TNFRSF9 (4-1BB, CD137, NCBI gene ID: 3604). TNFRSF10A (CD261, DR4, TRAILR1, NCBI gene ID: 8797), TNFRSF10B (CD262, DR5, TRAILR2, NCBI gene ID: 8795), TNFRSF10C (CD263, TRAILR3, NCBI gene ID: 8794), TNFRSF10D (CD264, TRAILR4, NCBI gene ID: 8793), TNFRSF11A (CD265, RANK, NCBI gene ID: 8792), TNFRSF11B (NCBI gene ID: 4982), TNFRSF12A (CD266, NCBI gene ID: 51330), TNFRSF13B (CD267, NCBI gene ID: 8797), TNFRSF10B (CD262, DR5, TRAILR2, NCBI gene ID: 8795), TNFRSF10C (CD263, TRAILR3, ...8794), TNFRSF10D (CD264, TRAILR4, NCBI gene ID: 8793), TNFRSF11A (CD265, RANK, NCBI gene ID: 8792), TNFRSF11B (CD267, NCBI gene ID: 8795), TNFRSF10B (CD266 TNFRSF13C (CD268, NCBI gene ID: 115650), TNFRSF16 (NGFR, CD271, NCBI gene ID: 4804), TNFRSF17 (BCMA, CD269, NCBI gene ID: 608), TNFRSF18 (GITR, CD357, NCBI gene ID: 8784), TNFRSF19 (NCBI gene ID: 55504), TNFRSF21 (CD358, DR6, NCBI gene ID: 27242) andTNFRSF25 (DR3, NCBI gene ID: 8718).

[0220] Examples of anti-TNFRSF4 (OX40) antibodies that can be co-administered include, but are not limited to, MEDI6469, MEDI6383, MEDI0562 (tavorizumab), MOXR0916, PF-04518600, RG-7888, GSK-3174998, INCAGN1949, ABMS-986178, GBR-8383, ABBV-368, and those described in WO2016179517, WO2017096179, WO2017096182, WO2017096281 and WO2018089628.

[0221] Examples of anti-TNFRSF5 (CD40) antibodies that can be co-administered include, but are not limited to, RG7876, SEA-CD40, APX-005M, and ABBV-428.

[0222] In some embodiments, the anti-TNFRSF7 (CD27) antibody varigramab (CDX-1127) is co-administered.

[0223] Examples of anti-TNFRSF9 (4-1BB, CD137) antibodies that can be co-administered include, but are not limited to, urigramab, utolumab (PF-05082566), AAGEN2373, and ADG-106.

[0224] Examples of anti-TNFRSF18 (GITR) antibodies that can be co-administered include, but are not limited to: MEDI1873, FPA-154, INCAGN-1876, TRX-518, BMS-986156, MK-1248, GWN-323, and those described in WO2017096179, WO2017096276, WO2017096189, and WO2018089628. In some embodiments, antibodies or fragments thereof that co-target TNFRSF4 (OX40) and TNFRSF18 (GITR) are co-administered. Such antibodies are described, for example, in WO2017096179 and WO2018089628.

[0225] Bispecific and trispecific natural killer (NK) cell adaptors, in various embodiments, combine the agent as described herein with a bispecific NK cell adaptor (BiKE) or a trispecific NK cell adaptor (TriKE) (e.g., without Fc) or a bispecific antibody against (e.g., with Fc) of: NK cell activation receptors, such as CD16A, type C lectin receptors (CD94 / NKG2C, NKG2D, NKG2E / H, and NKG2F).Natural cytotoxic receptors (NKp30, NKp44, and NKp46), cytotoxic cell C-type lectin-like receptors (NKp65, NKp80), Fc receptor FcγR (which mediates antibody-dependent cytotoxicity), SLAM family receptors (e.g., 2B4, SLAM6, and SLAM7), cytotoxic cell immunoglobulin-like receptors (KIRs) (KIR-2DS and KIR-3DS), DNAM-1, and CD137 (41BB). Depending on the case, anti-CD16 binding bispecific molecules may or may not have an Fc. Exemplary bispecific NK cell adaptors that can be co-administered target CD16 and one or more HIV-associated antigens as described herein. BiKE and TriKE are described, for example, in: Felices et al., Methods Mol Biol. (2016) 1441:333–346; Fang et al., Semin Immunol. (2017) 31:37–54. Examples of trispecific NK cell adaptors (TRiKE) include, but are not limited to, OXS-3550, HIV-TriKE, and CD16-IL-15-B7H3 TriKe.

[0226] Indoleamine-pyrrole-2,3-dioxygenase (IDO1) inhibitors In various embodiments, an agent as described herein is combined with an inhibitor of indoleamine 2,3-dioxygenase 1 (IDO1; NCBI gene ID: 3620). Examples of IDO1 inhibitors include, but are not limited to, BLV-0801, icardolstat, F-001287, GBV-1012, GBV-1028, GDC-0919, indomod, NKTR-218, NLG-919-based vaccines, PF-06840003, pyranoquinone derivatives (SN-35837), remixstat, SBLK-200802, BMS-986205, shIDO-ST, EOS-200271, KHK-2455, and LY-3381916.

[0227] In various embodiments, Toll-like receptor (TLR) agonists combine an agent as described herein with an agonist of a Toll-like receptor (TLR), such agonist as TLR1 (NCBI gene ID: 7096), TLR2 (NCBI gene ID: 7097), TLR3 (NCBI gene ID: 7098), TLR4 (NCBI gene ID: 7099), TLR5 (NCBI gene ID: 7100), TLR6 (NCBI gene ID: 10333), TLR7 (NCBI gene ID: 51284), TLR8 (NCBI gene ID: 51311), TLR9 (NCBI gene ID: 54106), and / or TLR10 (NCBI gene ID: 54106) and / or TLR10 (NCBI gene ID: 7099).Due to the agonist (ID: 81793). Examples of TLR7 agonists that can be co-administered include, but are not limited to, AL-034, DSP-0509, GS-9620 (vesamote), vesamote analogs, LHC-165, TMX-101 (imiquimod), GSK-2245035, remiquimod, DSR-6434, DSP-3025, IMO-4200, MCT-465, MEDI-9197, 3M-051, SB-9922, 3M-052, Limtop, TMX-30X, TMX-202, RG-7863, RG-7854, RG-7795, and US20100143301 (Gilead Sciences), product information 48 / 189 pages 96 CN 122055373 A US20110098248 (Gilead). Sciences) and US20090047249 (Gilead Sciences), US20140045849 (Janssen), US20140073642 (Janssen), WO2014 / 056953 (Janssen), WO2014 / 076221 (Janssen), WO2014 / 128189 (Janssen), US20140350031 (Janssen), WO2014 / 023813 (Janssen), US20080234251 (Array Biopharma), US20080306050 (Array Biopharma), US20100029585 (Ventirx Pharma), US20110092485 (Ventirx Pharma), US20110118235 (Ventirx Compounds disclosed in US20120082658 (Ventirx Pharma), US20120219615 (Ventirx Pharma), US20140066432 (Ventirx Pharma), US20140088085 (Ventirx Pharma), US20140275167 (Novira Therapeutics), and US20130251673 (Novira Therapeutics). TLR7 / TLR8 agonists include, but are not limited to, NKTR-262, teiramod, and BDB-001. TLR8 agonists include, but are not limited to, E-6887, IMO-4200, IMO-8400, IMO-9200, MCT-465, MEDI-9197, Motolimod, Requimod, GS-9688, VTX-1463, VTX-763, 3M-051, 3M-052, and US20140045849 (Janssen), US20140073642 (Janssen), WO2014 / 056953 (Janssen), WO2014 / 076221 (Janssen), WO2014 / 128189 (Janssen), US20140350031 (Janssen), WO2014 / 023813 (Janssen), US20080234251 (Array) Compounds disclosed in US20080306050 (Array Biopharma), US20100029585 (Ventirx Pharma), US20110092485 (Ventirx Pharma), US20110118235 (Ventirx Pharma), US20120082658 (Ventirx Pharma), US20120219615 (Ventirx Pharma), US20140066432 (Ventirx Pharma), US20140088085 (Ventirx Pharma), US20140275167 (Novira Therapeutics) and US20130251673 (Novira Therapeutics). TLR9 agonists include, but are not limited to, AST-008, cobitolimod, CMP-001, IMO-2055, IMO-2125, S-540956, litenimod, MGN-1601, BB-001, BB-006, IMO-3100, IMO-8400, IR-103, IMO-9200, agatolimod, DIMS-9054, DV-1079, DV-1179, AZD-1419, lefitolimod (MGN-1703), CYT-003, CYT-003-QbG10, tilsotolimod, and PUL-042. Examples of TLR3 agonists include rapamod, polyICLC, RIBOXXON®, Apoxxim, RIBOXXIM®, and IPH-.33. MCT-465, MCT-475, and ND-1.1. TLR4 agonists include, but are not limited to, G-100 and GSK-1795091.

[0228] CDK inhibitors or antagonists In some embodiments, the agents described herein are combined with CDK inhibitors or antagonists. In some embodiments, the CDK inhibitors or antagonists are selected from the group consisting of VS2-370.

[0229] STING agonists, RIG-I, and NOD2 regulators In some embodiments, the agents described herein are combined with interferon gene stimulators (STING). In some embodiments, the STING receptor agonist or activator is selected from the group consisting of ADU-S100 (MIW-815), SB-11285, MK-1454, SR-8291, AdVCA0848, GSK-532, SYN-STING, MSA-1, SR-8291, STING agonist (latent HIV), 5,6-dimethylxanthonone-4-acetic acid (DMXAA), cyclic GAMP (cGAMP), and cyclic diAMP. In some embodiments, the agents described herein are combined with RIG-I modulators (such as RGT-100) or NOD2 modulators (such as SB-9200 and IR-103).

[0230] In some embodiments, LAG-3 and TIM-3 inhibitors are combined with agents as described herein and anti-TIM-3 antibodies (such as TSR-022, LY-3321367, MBG-453, INCAGN-2390).

[0231] In some embodiments, antibodies or antigen-binding fragments as described herein are combined with anti-LAG-3 (lymphocyte activation) antibodies (such as relatlimab (ONO-4482), LAG-525, MK-4280, REGN-3767, INCAGN2385).

[0232] In some embodiments, the interleukin agonist combines the agent as described herein with the following substances: interleukin agonists (such as IL-2, IL-7, IL-15, IL-10, IL-12) agonists; examples of IL-2 agonists, such as proleukin (aldeleukin, IL-2); BC-IL (Cel-Sci), polyethylene glycol-modified IL-2 (e.g., NKTR-214); modified variants of IL-2 (e.g., THOR-707), bepepedin, AIC-284, ALKS-4230, CUI-101, Neo-2 / 15; examples of IL-15 agonists, such as...ALT-803, NKTR-255 and hetIL-15, interleukin-15 / Fc fusion protein, AM-0015, NIZ-985, SO-C101, IL-15 Synthorin (pegylated IL-15), P-22339 and IL-15-PD-1 fusion protein N-809; examples of IL-7 include, but are not limited to, CYT-107.

[0233] Examples of additional immunotherapy that can be combined with the agents of this disclosure include, but are not limited to, interferon α, interferon α-2b, interferon α-n3, pegylated interferon α, interferon γ; FLT3 agonists such as CDX-301, GS-3583, gepon, nomoflon, pegylated interferon α-2a, pegylated interferon α-2b and RPI-MN.

[0234] Examples of phosphatidylinositol 3-kinase (PI3K) inhibitors include, but are not limited to, edalixib, avocadolixib, bupalixib, orotic acid CAI, copanlixib, duvelixib, gladellixib, neratinib, panolixib, perifoxine, idalixib, piracexib, praquitinib mesylate, regoratinib, regoratinib sodium, sonolixib, tacelilixib, AMG-319, AZD-8186, BAY-1082439, CLR-1401, CLR-457, CUDC-907, DS-7423, EN-3342, GSK- 2126458, GSK-2269577, GSK-2636771, INCB-040093, LY-3023414, MLN-1117, PQR-309, RG-7666, RP-6530, RV-1729, SAR-245409, SAR-260301, SF-1126, TGR-1202, UCB-5857, VS-5584, XL-765, and ZSTK-474.

[0235] Examples of α-4 / β-7 antagonists integrin α-4 / β-7 antagonists include, but are not limited to, PTG-100, TRK-170, alirubumab, itralizumab, methylcarograss, and vedolizumab.

[0236] Examples of HPK1 inhibitors include, but are not limited to, ZYF-0272 and ZYF-0057.

[0237] Examples of HIV-targeting antibodies, bispecific antibodies, and “antibody-like” therapeutic proteins include, but are not limited to, DARTs®, DUOBODIES®, BITES®, XmAbs®, TandAbs®, Fab derivatives, bNAb (broadly neutralizing HIV-1 antibody), TMB-360, TMB-370, and those antibodies targeting HIV gp120 or gp41, antibody recruitment molecules targeting HIV, and anti-CD63 monoclonal antibodies.Anti-GB virus C antibody, anti-GP120 / CD4, gp120 bispecific monoclonal antibody, CCR5 bispecific antibody, anti-Nef single domain antibody, anti-Rev antibody, camelid-derived anti-CD18 antibody, camelid-derived anti-ICAM-1 antibody, DCVax-001, gp140 targeting antibody, gp41-based HIV therapeutic antibody, human recombinant mAb (PGT-121), PGT121.414.LS, ibalizumab, ibalizumab (second generation), Immuglo, MB-66, clone 3 human monoclonal antibody targeting KLIC (HIV infection), GS-9721, BG-HIV, VRC-HIVMAB091-00-AB.

[0238] Various bNAb can be used. Examples include, but are not limited to, those described in U.S. Patent Nos. 8,673,307, 9,493,549, 9,783,594, 10,239,935, US2018371086, US2020223907, WO2014 / 063059, WO2012 / 158948, WO2015 / 117008, PCT / US2015 / 41272, and WO2017 / 096221, including antibodies 12A12, 12A21, NIH45-46, bANC131, 8ANC134, IB2530, INC9, 8ANC195, 8ANC196, 10-259, 10-303, 10-410, 10- 847, 10-996, 10-1074, 10-1121, 10-1130, 10-1146, 10-1341, 10-1369 and 10-1074GM. The other instructions, page 50 / 189, 98 CN 122055373 A, include examples from those described in the following literature: Klein et al., Nature, 492(7427): 118-22 (2012); Horwitz et al., Proc Natl Acad Sci USA, 110(41): 16538-43 (2013); Scheid et al., Science, 333: 1633-1637 (2011); Scheid et al., Nature, 458: 636-640 (2009); Eroshkin et al., Nucleic Acids Res., 42 (Database Special): Dl 133-9 (2014); Mascola et al., Immunol Rev., 254(l): 225-44 (2013), such as 2F5, 4E10, M66.6, CAP206-CH12, 10E81 (all of them are knotted)MPER of gp41); PG9, PG16, CH01-04 (all of which bind to V1V2-glycans), 2G12 (which binds to the outer domain glycan); b12, HJ16, CH103-106, VRC01-03, VRC-PG04, 04b, VRC-CH30-34, 3BNC62, 3BNC89, 3BNC91, 3BNC95, 3BNC104, 3BNC176 and 8ANC131 (all of which bind to the CD4 binding site).

[0239] Further broadly neutralizing antibodies that can be used as a second therapeutic agent in combination therapy are described, for example, in U.S. Patent Nos. 8,673,307, 9,493,549, 9,783,594, and WO 2012 / 154312, WO2012 / 158948, WO 2013 / 086533, WO 2013 / 142324, WO2014 / 063059, WO 2014 / 089152, WO 2015 / 048462, WO 2015 / 103549, WO 2015 / 117008, WO2016 / 014484, WO 2016 / 154003, WO 2016 / 196975, WO 2016 / The following documents are incorporated herein by reference in their entirety for all purposes: 149710, WO2017 / 096221, WO 2017 / 133639, and WO 2017 / 133640. Additional examples include, but are not limited to, those mentioned in the following literature: Sajadi et al., Cell. (2018) 173(7):1783-1795; Sajadi et al., J Infect Dis. (2016) 213(1):156-64; Klein et al., Nature, 492(7427): 118-22 (2012); Horwitz et al., Proc Natl Acad Sci USA, 110(41): 16538-43 (2013); Scheid et al., Science, 333: 1633-1637 (2011); Scheid et al., Nature, 458:636-640 (2009); Eroshkin et al., Nucleic Acids Res., 42 (Database Special):Dl 133-9 (2014); Mascola et al., Immunol Rev., 254(l):225-44 (2013), such as 2F5, 4E10, M66.6, CAP206-CH12, 10E8, 10E8v4, 10E8-5R-100cF, DH511.11P, 7b2, 10-1074 and LN01 (all of which are bound to gp41 MPER).

[0240] Examples of additional antibodies include, but are not limited to, bavituximab, UB-421, BF520.1, BiIA-SG, CH01, CH59, C2F5, C4E10, C2F5+C2G12+C4E10, CAP256V2LS, 3BNC117, 3BNC117-LS, 3BNC60, DH270.1, DH270.6, D1D2, 10-1074-LS, C13hmAb, GS-9722 (epavivir), DH411-2, BG18, GS-9721, GS-9723, PGT145, PGT121, PGT-121.60, PGT-121.66, PGT122, PGT-123, PGT- 124, PGT-125, PGT-126, PGT-151, PGT-130, PGT-133, PGT-134, PGT-135, PGT-128, PGT-136, PGT-137, PGT-138, PGT-139, MDX010 (Ipilimumab), DH511, DH511-2, N6, N6LS, N49P6, N49P7, N49P7.1, N49P9, N49P11, N60P1.1, N60P25.1, N60P2.1, N60P31.1, N60P22, NIH 45-46 PGC14, PGG14, PGT-142, PGT-143, PGT-144, PGDM1400, PGDM12, PGDM21, PCDN-33A, 2Dm2m, 4Dm2m, 6Dm2m, PGDM1400, MDX010 (Ipilimumab), VRC01, VRC-01-LS, A32, 7B2, 10E8, VRC-07-523, VRC07-523LS, VRC24, VRC41.01, 10E8VLS, 3810109, 10E8v4, IMC-HIV, iMabm36, eCD4- Ig, IOMA, CAP256-VRC26.25, DRVIA7, VRC-HIVMAB080-00-AB, VRC-HIVMAB060-00-AB, P2G12, VRC07, 354BG8, 354BG18, 354BG42, 354BG33, 354BG129, 354BG188, 354BG411, 354BG426, VRC29.03, CAP256, CAP256-VRC26.08, CAP256-VRC26.09, CAP256-VRC26.25, PCT64-24E andVRC38.01, PGT-151, CAP248-2B, 35O22, ACS202, VRC34 and VRC34.01, 10E8, 10E8v4, 10E8-5R-100cF, 4E10, DH511.11P, 2F5, 7b2 and LN01.

[0241] Examples of HIV bispecific and trispecific antibodies include, but are not limited to, MGD014, B12BiTe, BiIA-SG, TMB-bispecific, SAR-441236, VRC-01 / PGDM-1400 / 10E8v4, 10E8.4 / iMab, 10E8v4 / PGT121-VRC01. Instructions for Use, pages 51 / 189, 99 CN 122055373 A

[0242] Examples of in vivo delivered bNAb include, but are not limited to, AAV8-VRC07; mRNA encoding the anti-HIV antibody VRC01; and engineered B cells encoding 3BNC117 (Hartweger et al., J. Exp. Med., 2019, 1301).

[0243] Pharmacokinetic enhancers Examples of pharmacokinetic enhancers include, but are not limited to, cobistat and ritonavir.

[0244] Additive Therapeutic Agents Examples of additive therapeutic agents include, but are not limited to, WO 2004 / 096286 (Gilead Sciences), WO 2006 / 015261 (Gilead Sciences), WO 2006 / 110157 (Gilead Sciences), WO 2012 / 003497 (Gilead Sciences), WO 2012 / 003498 (Gilead Sciences), WO 2012 / 145728 (Gilead Sciences), WO 2013 / 006738 (Gilead Sciences), WO 2013 / 159064 (Gilead Sciences), WO 2014 / 100323 (Gilead Sciences), US 2013 / 0165489 (University of Pennsylvania), US 2014 / 0221378 (Japan Tobacco), US 2014 / 0221380 (Japan Tobacco), WO 2009 / 062285 (Boehringer Ingelheim), WO 2010 / 130034 (Boehringer Ingelheim), WO 2013 / 006792 (Pharma Resources), US 20140221356 (Gilead Sciences), USCompounds disclosed in 20100143301 (Gilead Sciences) and WO 2013 / 091096 (Boehringer Ingelheim).

[0245] Examples of HIV vaccines include, but are not limited to, peptide vaccines, recombinant subunit protein vaccines, live vector vaccines, DNA vaccines, HIV MAG DNA vaccines, CD4-derived peptide vaccines, vaccine combinations, adenovirus vector vaccines (adenovirus vectors, such as Ad5, Ad26, or Ad35), simian adenovirus (chimpanzee, gorilla, rhesus monkey, i.e., rhAd), adeno-associated virus vector vaccines, and chimpanzee adenovirus vaccines (e.g., ChAdOX1, ChAd68, ChAd3, ChAd63, ChAd83, ChAd155, ChAd157, Pan5, Pan6, ... Pan7, Pan9), Coxsackievirus-based vaccines, enterovirus-based vaccines, chimpanzee adenovirus vaccines, lentiviral vector-based vaccines, arenavirus vaccines (such as LCMV, Pichinde), bisegmented or trisegmented arenavirus-based vaccines, trimer-based HIV-1 vaccines, measles virus-based vaccines, flavivirus-based vaccines, tobacco mosaic virus-based vaccines, varicella-zoster virus-based vaccines, human parainfluenza virus 3 (PIV3)-based vaccines, poxvirus-based vaccines (modified vaccinia virus Ankara (MVA), orthopox virus-derived NYVAC, and fowlpox virus-derived ALVAC (canarypox virus) strains); fowlpox virus-based vaccines, rhabdovirus-based vaccines, such as VSV and Malabar virus; recombinant human CMV (rhCMV)-based vaccines, and A virus-based vaccines, such as Simelik Forest virus, Venezuelan equine encephalitis virus, and Sindbis virus; (see Lauer, Clinical and Vaccine) Immunology, 2017, :DOI 10.1128 / CVI.00298-16); mRNA-based therapeutic vaccines formulated by LNP; self-replicating RNA / self-amplifying RNA vaccines formulated by LNP.

[0246] Examples of vaccines include: AAVLP-HIV vaccine, AE-298p, anti-CD40 Env-gp140 vaccine, Ad4-EnvC150, BG505 SOSIP .664gp140 adjuvanted vaccine, BG505SOSIP .GT1 .1 gp140 adjuvanted vaccine, ChAdOx1 .tHIVconsv1 vaccine, CMV-MVA trivalent vaccine, ChAdOx1 .HTI, Chimigen HIV vaccine, ConM SOSIP.v7 gp140, ALVAC HIV (vCP1521), AIDSVAXB / E (gp120), monomeric gp120 HIV-1 C subtype vaccine, MPER-656 liposomal subunit vaccine, Remune, ITV-1, Contre Vir, Ad5-ENVA-48, DCVax-001 (CDX-2401), Vacc-4x, Vacc-C5, VAC-3S, multi-branched DNA recombinant adenovirus-5 (rAd5), rAd5 gag-pol env A / B / C vaccine, Pennvax-G, Pennvax-GP, Pennvax-G / MVA-CMDR, HIV-TriMix-mRNA vaccine, HIV-LAMP-vax, Ad35, Ad35-GRIN, NAcGM3 / VSSP ISA-51, poly-ICLC adjuvanted vaccine, TatImmune, GTU- multiHIV (FIT-06), ChAdV63.HIVconsv, gp140[δ]V2.TV1+MF-59, rVSVIN HIV-1 gag vaccine, SeV-EnvF, SeV-Gag vaccine, AT-20, DNK-4, ad35-Grin / ENV, TBC-M4, HIVAX, HIVAX-2, HIV vaccine based on N123-VRC-34.01 inducible epitope, NYVAC-HIV-PT1, NYVAC-HIV-PT4, DNA-HIV-PT123, rAAV1-PG9DP, GOVX-B11, GOVX-B21, GOVX-C55, TVI-HIV-1, Ad-4 (Ad4-env clade C+Ad4-mGag), Paxvax, EN41-UGR7C, EN41-FPA2, ENOB-HV-11, ENOB-HV-12, PreVaxTat, AE-H, MYM-V101, CombiHIVvac, ADVAX, MYM-V201, MVA-CMDR, MagaVax, DNA-Ad5 gag / pol / nef / nev (HVTN505), MVATG-17401, ETV-01, CDX-1401, DNA and Sev vector vaccines expressing SCaVII, rcAD26.MOS1.HIV-Env, Ad26.Mod.HIV vaccine, Ad26.Mod.HIV + MVA mosaic vaccine + gp140, AGS-004,AVX-101, AVX-201, PEP-6409, SAV-001, ThV-01, TL-01, TUTI-16, VGX-3300, VIR-1111, IHV-001 and virus-like particle vaccines (such as pseudovirion vaccines), CombiVICHvac, LFn-p24 B / C fusion vaccine, GTU-based DNA vaccines, HIV gag / pol / nef / env DNA vaccines, anti-TAT HIV vaccines, conjugated peptide vaccines, dendritic cell vaccines (such as DermaVir), gag-based DNA vaccines, GI-2010, gp41 HIV-1 vaccine, HIV vaccine (PIKA adjuvant), i-key / MHC class II epitope heterozygous peptide vaccine, ITV-2, ITV-3, ITV-4, LIPO-5, multi-branch Env vaccine, MVA vaccine, Pennvax-GP, pp71 defective HCMV vector HIV GAG vaccine, rgp160 HIV vaccine, RNActive HIV vaccine, SCB-703, Tat Oyi vaccine, TBC-M4, UBI HIV gp120, Vacc-4x+romidesin, variant gp120 peptide vaccine, rAd5 gag-pol env A / B / C vaccine, DNA.HTI and MVA.HTI, VRC-HIVDNA016-00-VP + VRC-HIVADV014-00-VP, INO-6145, JNJ-9220, gp145 C.6980; eOD-GT8 60mer-based vaccine, PD-201401, env(A, B, C, A / E) / gag(C) DNA vaccine, gp120(A, B, C, A / E) protein vaccine, PDPHV-201401, Ad4-EnvCN54, EnvSeq-1 Envs HIV-1 vaccine (GLA-SE adjuvanted), HIV p24gag primary-boost plasmid DNA vaccine, HIV-1 iglb12 neutralizing VRC-01 antibody-stimulated anti-CD4 vaccine, isanoplasmic virus vector-based vaccines (Vaxwave, TheraT), MVA-BN HIV-1 vaccine regimen, mRNA-based prophylactic vaccines, VPI-211, multimeric HIV gp120 vaccine (Fred Hutchinson Cancer Center), TBL-1203HI, CH505 TF chTrimer, CD40.HIVRI.Env vaccine, Drep-HIV-PT-1, mRNA-1644 and mRNA-1574.

[0247] Contraceptive combination therapyIn some embodiments, the agents described herein are combined with contraceptive or birth control regimens. Therapeutic agents for birth control (contraceptives) that can be combined with the agents disclosed herein include, but are not limited to, cyproterone acetate, desogestrel, dinogest, drospirenone, estradiol valerate, ethinylestradiol, norethindrone, etoposide, levonorgestrel, levofloxacin, levonorgestrel, linegestrel, medroxyprogesterone acetate, ethinylestradiol methyl ether, mifepristone, misoprostol, normethylenetetrahydrofolate, norethindrone, isethindrone, norgestrel, olmexifen, sigmason acetate, ulipristal acetate, and any combination thereof.

[0248] In one specific embodiment, the compounds disclosed herein or pharmaceutically acceptable salts thereof are combined with one, two, three, or four additional therapeutic agents selected from the group consisting of: ATRIPLA® (efavirenz, tenofovir disoproxil fumarate, and emtricitabine); COMPLERA® (EVIPLERA®; rilpivirine, tenofovir disoproxil fumarate, and emtricitabine); STRIBILD® (erteiravir, cobistat, tenofovir disoproxil fumarate, and emtricitabine); TRUVADA® (tenofovir disoproxil fumarate and emtricitabine; TDF+FTC); DESCOVY® (tenofovir alafenamide and emtricitabine); ODEFSEY® (tenofovir alafenamide, emtricitabine, and rilpivirine); GENVOYA® (Tenofovir alafenamide, emtricitabine, cobistatin, and ertirapvir); BIKTARVY® (bicagvir + emtricitabine + tenofovir alafenamide), adefovir; adefovir dipivoxil; cobistatin; emtricitabine; tenofovir; tenofovir alafenamide and ertirapvir; tenofovir alafenamide + ertirapvir (rectal preparation, HIV infection); tenofovir disoproxil fumarate; tenofovir disoproxil fumarate; tenofovir alafenamide; tenofovir alafenamide hemifumarate; TRIUMEQ® (durutexvir, abacavir, and lamivudine); dulutexvir, abacavir sulfate, and lamivudine; retigvir; polyethylene glycol-modified retigvir; retigvir package insert 53 / 189 pages 101 CN 122055373 A Lamivudine and lopinavir; Lamivudine + lopinavir + ritonavir + abacavir; Maraviro; Tenofovir + emtricitabine + maraviro, enfuvirtide; ALUVIA® (KALETRA®; lopinavir and ritonavir); COMBIVIR® (zidovudine and lamivudine; AZT + 3TC); EPZICOM® (LIVEXA®; abacavir sulfate and lamivudine; ABC + 3TC); TRIZIVIR® (abacavir sulfate, zidovudine and lamivudine; ABC + AZT + 3TC); Rilpivirine; Rilpivirine hydrochloride; Atazanavir sulfateand cobistat; atazanavir and cobistat; darirapvir and cobistat; atazanavir; atazanavir sulfate; dulutegravir; ertirapvir; ritonavir; atazanavir sulfate and ritonavir; darirapvir; lamivudine; prastin; fosanavir; fosanavir calcium efavirenz; etravirline; nelfinavir; nelfinavir mesylate; interferon; norinosine; stavudine; indinavir; indinavir sulfate; tenofovir and lamivudine; zidovudine; nevirapine; saquinavir; saquinavir mesylate; adeleukin; zalcitabine; telanavir; ampravir; dilavudine; dilavudine mesylate; Radha- 108 (receptor alcohol); lamivudine and tenofovir disoproxil fumarate; efavirenz, lamivudine and tenofovir disoproxil fumarate; zizonil; lamivudine, nevirapine and zidovudine; abacavir; and abacavir sulfate.

[0249] In some embodiments, the pharmaceutical agents or pharmaceutical compositions thereof disclosed herein are combined with HIV nucleoside or nucleotide inhibitors of reverse transcriptase and HIV non-nucleoside inhibitors of reverse transcriptase. In another specific embodiment, the pharmaceutical agents or pharmaceutical compositions thereof disclosed herein are combined with HIV nucleoside or nucleotide inhibitors of reverse transcriptase and HIV protease inhibitory compounds. In further embodiments, the pharmaceutical agents or pharmaceutical compositions thereof disclosed herein are combined with HIV nucleoside or nucleotide inhibitors of reverse transcriptase, HIV non-nucleoside inhibitors of reverse transcriptase, and pharmacokinetic enhancers. In some embodiments, the pharmaceutical agents or pharmaceutical compositions thereof disclosed herein are combined with at least one HIV nucleoside inhibitor of reverse transcriptase, an integrase inhibitor, and a pharmacokinetic enhancer. In another embodiment, the agent or pharmaceutical composition disclosed herein is combined with two HIV nucleoside or nucleotide inhibitors of reverse transcriptase.

[0250] In another embodiment, the agent or pharmaceutical composition disclosed herein is combined with a first adjunctive therapy and a second adjunctive therapy, the first adjunctive therapy being selected from dulutegravir, cabotevir, isratrovir, direravir, bicagvir, issavirline, rilpivirline, and lenapapvir, and the second adjunctive therapy being selected from emtricitabine and lamivudine.

[0251] In some embodiments, the agents or pharmaceutical compositions disclosed herein are combined with a first adjunctive therapeutic agent (contraceptive), the first adjunctive therapeutic agent being selected from the group consisting of: cyproterone acetate, desogestrel, dinogest, drospirenone, estradiol valerate, ethinylestradiol, norethindrone, etoposide, levonorgestrel, levofloxacin, levonorgestrel, linegestrel, medroxyprogesterone acetate, ethinylestradiol methyl ether, mifepristone, misoprostol, nomenoprogesterone acetate, norgestrel, norethindrone, isethindrone, norgestrel, olmexifen, sigmason acetate, ulipristal acetate, and any combination thereof.

[0252] Gene therapy and cell therapyIn some implementations, the agents described herein are combined with gene therapy or cell therapy regimens. Gene therapy and cell therapy include, but are not limited to, gene modifications that silence genes; gene methods that directly kill infected cells; infusion of immune cells designed to replace most of the patient's own immune system to enhance the immune response to infected cells, or to activate the patient's own immune system to kill infected cells, or to locate and kill infected cells; and gene methods that modify cell activity to further alter the endogenous immune response to infection. Examples of cell therapies include, but are not limited to, LB-1903, ENOB-HV-01, ENOB-HV-21, ENOB-HV-31, GOVX-B01, HSPCs overexpressing ALDH1 (LV-800, HIV infection), AGT103-T, and SupT1 cell-based therapies. Examples of dendritic cell therapies include, but are not limited to, AGS-004. CCR5 gene editing agents include, but are not limited to, SB-728T and SB-728-HSPC. CCR5 gene inhibitors include, but are not limited to, autologous CD34-positive hematopoietic progenitor cells (HIV-infected / HIV-related lymphoma) transduced with Cal-1 and lentiviral vector CCR5 shRNA / TRIM5α / TAR decoys. In some embodiments, CD4-positive T cells expressing C34-CCR5 / C34-CXCR4 are co-administered with one or more multispecific antigen-binding molecules. In some embodiments, the pharmaceutical product described herein (page 54 / 189, CN 122055373 A) is co-administered with autologous T-cell therapy transduced with AGT-103 or AAV-eCD4-Ig gene therapy.

[0253] Gene editing products: In some embodiments, the pharmaceutical products described herein are combined with a gene editor (e.g., an HIV-targeting gene editor). In various embodiments, the genome editing system may be selected from the group consisting of: CRISPR / Cas9 complexes, zinc finger nuclease complexes, TALEN complexes, homing endonuclease complexes, and broad-spectrum nuclease complexes. Exemplary HIV-targeting CRISPR / Cas9 systems include, but are not limited to, EBT-101.

[0254] In some embodiments, CAR-T cell therapy may involve co-administering the agents described herein with a population of immune effector cells engineered to express a chimeric antigen receptor (CAR), wherein the CAR contains an HIV antigen-binding domain. The HIV antigen includes an HIV envelope protein or a portion thereof, gp120 or a portion thereof, a CD4 binding site on gp120, a CD4-induced binding site on gp120, an N-glycan on gp120, V2 of gp120, and a proximal membrane region on gp41. The immune effector cells are T cells or NK cells. In some embodiments, the T cells are CD4+.T cells, CD8+ T cells, or combinations thereof. The cells may be autologous or allogeneic. Examples of HIV CAR-T include A-1801, A-1902, convertible CAR-T, VC-CAR-T, CMV-N6-CAR, anti-HIV duoCAR-T, anti-CD4 CAR-T cell therapy, CD4 CAR+C34-CXCR4+CCR5 ZFN T cells, dual anti-CD4 CAR-T cell therapy (CD4 CAR+C34-CXCR4 T cells), anti-CD4 MicAbody antibody + anti-MicAbody CAR T cell therapy (iNKG2D CAR, HIV infection), GP-120 CAR-T therapy, and autologous hematopoietic stem cells genetically engineered to express CD4 CAR and C46 peptide.

[0255] In some embodiments, TCR T cell therapy combines the agents described herein with a TCR-T cell population. TCR-T cells are engineered to target HIV-derived peptides, such as ImmTAV, present on the surface of virus-infected cells.

[0256] In some embodiments of B-cell therapy, an antibody or antigen-binding fragment described herein is combined with a population of B cells genetically modified to express a broadly neutralizing antibody, such as 3BNC117 (Hartweger et al., J. Exp. Med. 2019, 1301; Moffett et al., Sci. Immunol. 4, eaax0644 (2019) May 17, 2019).

[0257] Compounds disclosed herein (e.g., any compound of formula I) may be combined with one, two, three, or four additional therapeutic agents at any dose of the compound of formula I (e.g., 1 mg to 500 mg of the compound).

[0258] In one embodiment, a kit is provided comprising a combination of a compound disclosed herein or a pharmaceutically acceptable salt thereof with one or more (e.g., one, two, three, one or two, or one to three) additional therapeutic agents.

[0259] In one embodiment, one or more additional therapeutic agents in the kit are anti-HIV agents selected from HIV protease inhibitors, non-nucleoside or non-nucleotide inhibitors of HIV reverse transcriptase, nucleoside or nucleotide inhibitors of HIV reverse transcriptase, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, HIV entry inhibitors, HIV maturation inhibitors, immunomodulators, immunotherapeutic agents, antibody-drug conjugates, gene modifiers, gene-editing products (such as CRISPR / Cas9, zinc finger nucleases, homing nucleases, synthetic nucleases, TALEN), and cell therapies (such as chimeric antigen receptor T cells).CAR-T and engineered T-cell receptors, TCR-T, autologous T-cell therapy), compounds targeting the HIV capsid, latency reversal agents, HIV bNAb, immunotherapy, phosphatidylinositol 3-kinase (PI3K) inhibitors, HIV antibodies, broadly neutralizing HIV antibodies, bispecific antibodies and "antibody-like" therapeutic proteins, HIV p17 matrix protein inhibitors, IL-13 antagonists, peptidyl prolyl cis-trans isomerase A modulators, protein disulfide isomerase inhibitors, complement C5a receptor antagonists, DNA methyltransferase inhibitors, HIV vif gene modulators, Vif dimerization antagonists, HIV viral infectivity factor inhibitors, TAT protein inhibitors, product information 55 / 189 pages 103 CN 122055373 A HIV Nef modulators, Hck tyrosine kinase modulators, mixed lineage kinase-3 (MLK-3) inhibitors, HIV splicing inhibitors, Rev protein inhibitors, integrin antagonists, nucleoprotein inhibitors, splicing factor regulators, COMM domain-containing protein 1 regulators, HIV ribonuclease H inhibitors, retrocyclin regulators, CDK-9 inhibitors, dendritic cell ICAM-3-extracting non-integrin 1 inhibitors, HIV GAG protein inhibitors, HIV POL protein inhibitors, complement factor H regulators, ubiquitin ligase inhibitors, deoxycytidine kinase inhibitors, cyclin-dependent kinase inhibitors, proprotein convertase PC9 stimulators, ATP-dependent RNA helicase DDX3X inhibitors, reverse transcriptase initiation complex inhibitors, G6PD and NADH oxidase inhibitors, pharmacokinetic enhancers, HIV gene therapy, HIV vaccines, and combinations thereof.

[0260] In some embodiments, one or more additional therapeutic agents in the kit are selected from combination drugs for HIV, other drugs for treating HIV, HIV protease inhibitors, HIV reverse transcriptase inhibitors, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, HIV entry (fusion) inhibitors, HIV maturation inhibitors, latency reversal agents, capsid inhibitors, immunotherapy-based therapies, PI3K inhibitors, HIV antibodies and bispecific antibodies and "antibody-like" therapeutic proteins, and combinations thereof.

[0261] In one specific embodiment, the kit comprises a compound disclosed herein or a pharmaceutically acceptable salt thereof, and a nucleoside or nucleotide inhibitor of HIV reverse transcriptase. In another specific embodiment, the kit comprises a compound disclosed herein or a pharmaceutically acceptable salt thereof, and a nucleoside or nucleotide inhibitor of HIV reverse transcriptase and a non-nucleoside inhibitor of HIV reverse transcriptase. In yet another specific embodiment, the kit comprises a compound disclosed herein or a pharmaceutically acceptable salt thereof, and a nucleoside or nucleotide inhibitor of HIV reverse transcriptase and an HIV protease inhibitory compound.In another embodiment, the kit comprises a compound disclosed herein or a pharmaceutically acceptable salt thereof, a nucleoside or nucleotide inhibitor of HIV reverse transcriptase, a non-nucleoside inhibitor of HIV reverse transcriptase, and a pharmacokinetic enhancer. In some embodiments, the kit comprises a compound disclosed herein or a pharmaceutically acceptable salt thereof, at least one HIV nucleoside inhibitor of reverse transcriptase, an integrase inhibitor, and a pharmacokinetic enhancer. In another embodiment, the kit comprises a compound disclosed herein or a pharmaceutically acceptable salt thereof, and two HIV nucleoside or nucleotide inhibitors of reverse transcriptase. In one specific embodiment, the kit comprises a compound disclosed herein or a pharmaceutically acceptable salt thereof, a nucleoside or nucleotide inhibitor of HIV reverse transcriptase, and an HIV capsid inhibitor. In one specific embodiment, the kit comprises a compound disclosed herein or a pharmaceutically acceptable salt thereof, a nucleoside inhibitor of HIV reverse transcriptase, and an HIV capsid inhibitor. In one specific embodiment, the kit comprises a compound disclosed herein or a pharmaceutically acceptable salt thereof, and one, two, three, or four HIV bNAb. In one specific embodiment, the kit comprises the compounds disclosed herein or pharmaceutically acceptable salts thereof, one, two, three, or four HIV bNAb and HIV capsid inhibitors. In one specific embodiment, the kit comprises the compounds disclosed herein or pharmaceutically acceptable salts thereof, one, two, three, or four HIV bNAb, HIV capsid inhibitors, and nucleoside inhibitors of HIV reverse transcriptase.

[0262] Examples of drugs being developed as long-acting HIV therapies include, but are not limited to, cabozantvir, rilpivirine, any integrase LA, VM-1500 LAI, maraviro (LAI), tenofovir implant, islatravir implant, doravirine, retegvir, and long-acting durutivir.

[0263] Combination with PGP Inhibitors In some embodiments, the compounds described herein may be used in combination with P-glycoprotein (PGP) inhibitors. Examples of PGP inhibitors include, but are not limited to, verapamil, dextrovertamil, cyclosporine, zoquine, laniquine, ectelida, talicidil, and encequine. In some embodiments, the compounds described herein may be used in combination with encequina. In some embodiments, the compounds described herein may be used in combination with pharmaceutically acceptable salts of encequina. In some embodiments, the compounds described herein may be used in combination with mesylates of encequina.

[0264] In some embodiments, the compounds of formula I or II described herein may be used in combination with P-glycoprotein (PGP) inhibitors.Co-administration. Examples of PGP inhibitors include, but are not limited to, verapamil, dexverapamil, cyclosporine, zoquine, laniquine, ecridia, talichda, and encequine. In some embodiments, the compounds described herein may be co-administered with encequine. In some embodiments, the compounds described herein may be co-administered with a pharmaceutically acceptable salt of encequine. In some embodiments, the compounds described herein may be co-administered with the mesylate of encequine.

[0265] Increased intestinal expression of P-glycoprotein can reduce the absorption of drugs that are P-glycoprotein substrates. Therefore, PGP inhibitors can be used to modulate the PK properties of the compounds disclosed herein.

[0266] In one embodiment, the PGP inhibitor is selected from the group consisting of verapamil, dexverapamil, cyclosporine, zoquine, laniquine, ecridia, talichda, encequine, and their pharmaceutically acceptable salts. In one embodiment, the PGP inhibitor is encequine or a pharmaceutically acceptable salt thereof. In one embodiment, the PGP inhibitor is a salt of encequina. In another embodiment, the PGP inhibitor is the mesylate of encequina.

[0267] In some embodiments, this disclosure provides a combination comprising (i) a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof, or a compound of formula II or a pharmaceutically acceptable salt thereof, and (ii) a P-glycoprotein inhibitor. In some embodiments, the combination comprises a compound of formula I or a pharmaceutically acceptable salt thereof.

[0268] In some embodiments of the combination, the compounds of Formula I are selected from the group consisting of: CN 122055373 A (page 57 / 189), CN 122055373 A (page 58 / 189), CN 122055373 A (page 59 / 189), CN 122055373 A (page 60 / 189), or pharmaceutically acceptable salts thereof.

[0269] In some embodiments of the combination, the compound of formula I is selected from the group consisting of: (Examples provided in the original text are provided in the original text, but are not translated here as they are not part of the main text.)Specification 66 / 189 page 114 CN 122055373 A, , , , , , , Specification 67 / 189 page 115 CN 122055373 A, and, or pharmaceutically acceptable salts thereof.

[0270] In some embodiments of the combination, the compound of formula I is selected from the group consisting of: and, or pharmaceutically acceptable salts thereof. Specification 68 / 189 page 116 CN 122055373 A

[0271] In some embodiments of the combination, the compound of formula I is: , or a pharmaceutically acceptable salt thereof.

[0272] In some embodiments of the combination, the compound of formula I is: , or a pharmaceutically acceptable salt thereof.

[0273] In some embodiments, the combination comprises a compound of formula I.

[0274] In some embodiments of the combination, the compound of formula I is: . Specification 69 / 189 pages 117 CN 122055373 A

[0275] In some embodiments of the combination, the compound of formula I is: .

[0276] In some embodiments, the combination comprises a compound of formula II or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of formula II is: , or a pharmaceutically acceptable salt thereof.

[0277] In some embodiments of the combination, the compound of formula II is: , or a pharmaceutically acceptable salt thereof.

[0278] In some embodiments, the combination comprises a compound of formula II. In some embodiments, the compound of formula II is: .

[0279] In some embodiments, the compound of formula II is: .

[0280] In some embodiments, the P-glycoprotein inhibitor in the combination is selected from the group consisting of: verapamil, dextrovertapamil, cyclosporine, zoquine, laniquine, ecrizotinib, talicidin, encequine, and pharmaceutically acceptable salts thereof. In some embodiments, the P-glycoprotein inhibitor is encequine or a pharmaceutically acceptable salt thereof. In some embodiments, the P-glycoprotein inhibitor is a salt of encequine. In some embodiments, the P-glycoprotein inhibitor is the mesylate of encequine.

[0281] In some embodiments, the combination comprises or a pharmaceutically acceptable salt thereof and encequine or a pharmaceutically acceptable salt thereof.

[0282] In some embodiments, the combination comprises or a pharmaceutically acceptable salt thereof and encequine or a pharmaceutically acceptable salt thereof.

[0283] In some embodiments, the combination comprises or a pharmaceutically acceptable salt thereof and encequine or a pharmaceutically acceptable salt thereof. Instruction manual, 71 / 189 pages, 119 CN122055373 A

[0284] In some embodiments, the combination comprises a pharmaceutically acceptable salt thereof and ensicalin or a pharmaceutically acceptable salt thereof.

[0285] In some embodiments, the combination comprises a pharmaceutically acceptable salt thereof and a salt of ensicalin.

[0286] In some embodiments, the combination comprises a pharmaceutically acceptable salt thereof and a salt of ensicalin.

[0287] In some embodiments, the combination comprises a pharmaceutically acceptable salt thereof and a salt of ensicalin. Specification 72 / 189 pages 120 CN 122055373 A

[0288] In some embodiments, the combination comprises a pharmaceutically acceptable salt thereof and a salt of ensicalin.

[0289] In some embodiments, the combination comprises and a salt of ensicalin.

[0290] In some embodiments, the combination comprises and a salt of ensicalin.

[0291] In some embodiments, the combination comprises and a salt of ensicalin. Specification 73 / 189 pages 121 CN 122055373 A

[0292] In some embodiments, the combination comprises a salt of encequine.

[0293] In some embodiments, the combination comprises a mesylate of encequine.

[0294] In some embodiments, the combination comprises a mesylate of encequine.

[0295] In some embodiments, the combination comprises a mesylate of encequine. Specification 74 / 189 pages 122 CN 122055373 A

[0296] In some embodiments, the combination comprises a mesylate of encequine.

[0297] In some embodiments, this disclosure provides a method of treating HIV infection in a person who has or is at risk of HIV infection, the method comprising administering to the person a combination comprising: (i) a compound of formula I or a pharmaceutically acceptable salt thereof or a compound of formula II or a pharmaceutically acceptable salt thereof, and (ii) a P-glycoprotein inhibitor. In some embodiments, (i) a compound of formula I or a pharmaceutically acceptable salt thereof, or a compound of formula II or a pharmaceutically acceptable salt thereof, and (ii) a P-glycoprotein inhibitor are administered together. In some embodiments, (i) a compound of formula I or a pharmaceutically acceptable salt thereof, or a compound of formula II or a pharmaceutically acceptable salt thereof, and (ii) a P-glycoprotein inhibitor are administered together. In some embodiments, (i) a compound of formula I or a pharmaceutically acceptable salt thereof, or a compound of formula II or a pharmaceutically acceptable salt thereof, and (ii) a P-glycoprotein inhibitor are administered as a co-formulation (i.e., a compound of formula I or formula II or a pharmaceutically acceptable salt thereof is formulated with a PGP inhibitor in the same pharmaceutical composition). In some embodiments, (i) a compound of formula I or a pharmaceutically acceptable salt thereof...The compound of Formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, and (ii) a P-glycoprotein inhibitor are administered alone. In some embodiments, the compound of Formula I or a pharmaceutically acceptable salt thereof, or the compound of Formula II or a pharmaceutically acceptable salt thereof, and (ii) a P-glycoprotein inhibitor are administered orally.

[0298] In some embodiments, the methods disclosed herein further include administering to a person a therapeutically effective amount of one, two, three, or four additional therapeutic agents. In some embodiments, one or more additional therapeutic agents are anti-HIV agents. In some embodiments, one or more additional therapeutic agents are HIV protease inhibitors, non-nucleoside or non-nucleotide inhibitors of HIV reverse transcriptase, nucleoside or nucleotide inhibitors of HIV reverse transcriptase, HIV capsid inhibitors, gp41 inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5 inhibitors, latency reversal agents, capsid polymerization inhibitors, HIV bNAb, TLR7 agonists, pharmacokinetic enhancers, other drugs for treating HIV, or combinations thereof. In some embodiments, one or more adjunctive therapeutic agents are abacavir, tenofovir alafenamide, tenofovir disoproxil fumarate, N-((S)-l-(3-(4-chloro-3-(methylsulfonamide)-l-(2,2,2-trifluoroethyl)-lH-indazole-7-yl)-6-(3-methyl-3-(methylsulfonyl)but-l-yn-l-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-lH-cyclopropyl[3,4]cyclopent[1,2-c]pyrazol-l-yl)acetamide or their pharmaceutically acceptable salts.

[0299] In some embodiments, a method for treating HIV infection is provided, the method comprising administering to a person (i) a therapeutically effective amount of a compound of formula I or II disclosed herein or a pharmaceutically acceptable salt thereof, and (ii) a combination of a PGP inhibitor and one, two, three, or four additional therapeutic agents in a therapeutically effective amount. In one embodiment, a method for treating HIV infection is provided, the method comprising administering to a person (i) a therapeutically effective amount of a compound of formula I or II disclosed herein or a pharmaceutically acceptable salt thereof, and (ii) a combination of a PGP inhibitor and one, two, three, or four additional therapeutic agents in a therapeutically effective amount.

[0300] In one embodiment, a pharmaceutical composition is provided comprising (i) a compound of formula I or II disclosed herein or a pharmaceutically acceptable salt thereof, and (ii) a combination of a P-glycoprotein inhibitor and one, two, three, or four additional therapeutic agents, and a pharmaceutically acceptable carrier, diluent, or excipient.

[0301] In some embodiments, this disclosure provides a method for treating HIV infection, the method comprising administering to a subject in need (i) a therapeutically effective amount of a compound of formula I or II disclosed herein or a pharmaceutically acceptable salt thereof, and (ii) a P-glycoprotein inhibitor in combination with a therapeutically effective amount of one, two, three, or four additional therapeutic agents suitable for treating HIV infection.

[0302] In some embodiments, (i) a compound of formula I or II disclosed herein or a pharmaceutically acceptable salt thereof, and (ii) a PGP inhibitor are combined with one, two, three, four, or more additional therapeutic agents. In some embodiments, (i) a compound of formula I or II disclosed herein or a pharmaceutically acceptable salt thereof, and (ii) a PGP inhibitor are combined with one, two, three, or four additional therapeutic agents. In some embodiments, (i) a compound of formula I or II disclosed herein or a pharmaceutically acceptable salt thereof, and (ii) a PGP inhibitor are combined with two additional therapeutic agents. In other embodiments, (i) a compound of formula I or formula II disclosed herein, or a pharmaceutically acceptable salt thereof, and (ii) a PGP inhibitor are combined with three additional therapeutic agents. In further embodiments, (i) a compound of formula I or formula II disclosed herein, or a pharmaceutically acceptable salt thereof, and (ii) a PGP inhibitor are combined with four additional therapeutic agents. One, two, three, four or more additional therapeutic agents may be different therapeutic agents selected from the same class of therapeutic agents, and / or they may be selected from different classes of therapeutic agents.

[0303] In some embodiments, (i) a compound of formula I or a pharmaceutically acceptable salt thereof or a compound of formula II or a pharmaceutically acceptable salt thereof, (ii) a P-glycoprotein inhibitor and (iii) one or more additional therapeutic agents are administered as a co-preparation.

[0304] In some embodiments, this disclosure provides a pharmaceutical composition comprising (i) a compound of formula I or a pharmaceutically acceptable salt thereof or a compound of formula II or a pharmaceutically acceptable salt thereof, (ii) a P-glycoprotein inhibitor, and (iii) a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition further comprises (iv) one or more additional therapeutic agents.

[0305] In some embodiments, this disclosure provides a kit comprising a combination of: (i) a compound of formula I or a pharmaceutically acceptable salt thereof, or a compound of formula II or a pharmaceutically acceptable salt thereof, and (ii) a P-glycoprotein inhibitor. In some embodiments, the kit comprises (i) a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof, or a compound of formula II or a pharmaceutically acceptable salt thereof, (ii) a pharmaceutical composition comprising a P-glycoprotein inhibitor, and (iii) instructions for use.

[0306] In some embodiments, the kit comprises (i) a pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable salt thereof, or a compound of Formula II or a pharmaceutically acceptable salt thereof, and a P-glycoprotein inhibitor, and (ii) instructions for use. In some embodiments, the kit also comprises one, two, three, or four additional therapeutic agents. In some embodiments, one or more additional therapeutic agents are anti-HIV agents. In some embodiments, one or more additional therapeutic agents are HIV protease inhibitors, non-nucleoside or non-nucleotide inhibitors of HIV reverse transcriptase, nucleoside or nucleotide inhibitors of HIV reverse transcriptase, HIV capsid inhibitors, gp41 inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5 inhibitors, latency reversal agents, capsid polymerization inhibitors, HIV bNAb, TLR7 agonists, pharmacokinetic enhancers, other drugs for treating HIV, or combinations thereof. In some embodiments, one or more adjunctive therapeutic agents are abacavir, tenofovir alafenamide, tenofovir disoproxil fumarate, N-((S)-l-(3-(4-chloro-3-(methylsulfonamide)-l-(2,2,2-trifluoroethyl)-lH-indazole-7-yl)-6-(3-methyl-3-(methylsulfonyl)but-l-yn-l-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-lH-cyclopropyl[3,4]cyclopent[1,2-c]pyrazol-l-yl)acetamide, or pharmaceutically acceptable salts thereof.

[0307] In some embodiments, this disclosure provides a compound of formula I or a pharmaceutically acceptable salt thereof, or a compound of formula II or a pharmaceutically acceptable salt thereof, for use in combination therapy for treating HIV infection with a P-glycoprotein inhibitor.

[0308] In some embodiments, this disclosure provides a P-glycoprotein inhibitor for use in combination therapy for treating HIV infection with a compound of formula I or a pharmaceutically acceptable salt thereof, or a compound of formula II or a pharmaceutically acceptable salt thereof, as defined in any of the preceding claims.

[0309] In some embodiments, this disclosure provides the use of (i) a compound of formula I or a pharmaceutically acceptable salt thereof, or a compound of formula II or a pharmaceutically acceptable salt thereof, and (ii) a P-glycoprotein inhibitor or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating HIV infection in a person who has or is at risk of developing HIV infection.

[0310] In some embodiments, the use of a compound of formula I relative to when a P-glycoprotein inhibitor is administered...Exposure to metabolites of Formula I or its pharmaceutically acceptable salts is increased when a compound of Formula I or its pharmaceutically acceptable salts is co-administered with a P-glycoprotein inhibitor. In some embodiments, the CMAX of the metabolites of Formula I or its pharmaceutically acceptable salts is increased when co-administered with a P-glycoprotein inhibitor, relative to the CMAX of the metabolites of Formula I or its pharmaceutically acceptable salts when administered in the absence of a P-glycoprotein inhibitor. In some embodiments, the AUCINF of the metabolites of Formula I or its pharmaceutically acceptable salts is increased when co-administered with a P-glycoprotein inhibitor, relative to the AUCINF of the metabolites of Formula I or its pharmaceutically acceptable salts when administered in the absence of a P-glycoprotein inhibitor. In some embodiments, the oral bioavailability of the metabolite of the compound of Formula I or its pharmaceutically acceptable salt is increased when co-administered with a P-glycoprotein inhibitor, relative to the oral bioavailability of the metabolite of the compound of Formula I or its pharmaceutically acceptable salt when administered in the absence of a P-glycoprotein inhibitor. In some embodiments, the metabolite is a compound of Formula II or its pharmaceutically acceptable salt.

[0311] In some embodiments, the patient's exposure to the compound of Formula II or its pharmaceutically acceptable salt is increased when co-administered with a P-glycoprotein inhibitor, relative to the exposure to the compound of Formula II or its pharmaceutically acceptable salt when administered in the absence of a P-glycoprotein inhibitor. In some embodiments, the CMAX of the compound of Formula II or its pharmaceutically acceptable salt is increased when co-administered with a P-glycoprotein inhibitor, relative to the CMAX of the compound of Formula II or its pharmaceutically acceptable salt when administered in the absence of a P-glycoprotein inhibitor. In some embodiments, when administered in the absence of a P-glycoprotein inhibitor, the compound of formula II or a pharmaceutically acceptable salt thereof is AUCINF. In some embodiments, the oral bioavailability of the compound of formula II or a pharmaceutically acceptable salt thereof in patients is increased when co-administered with a P-glycoprotein inhibitor, relative to the oral bioavailability of the compound of formula II or a pharmaceutically acceptable salt thereof when administered in the absence of a P-glycoprotein inhibitor.

[0312] In the above embodiments, (i) a compound of formula I or a pharmaceutically acceptable salt thereof or a compound of formula II or a pharmaceutically acceptable salt thereof and (ii) may be provided in the pharmaceutical composition described herein.P-glycoprotein inhibitors. For example, compounds of formula I or II, or pharmaceutically acceptable salts thereof, and PGP inhibitors may be present in the same pharmaceutical composition. Alternatively, compounds of formula I or II, or pharmaceutically acceptable salts thereof, and PGP inhibitors may be present in different pharmaceutical compositions.

[0313] In some embodiments, this disclosure provides a method of treating HIV infection in a person who has or is at risk of HIV infection, the method comprising administering to the person (i) a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, and (ii) a P-glycoprotein inhibitor. In some embodiments, a compound of formula I is administered. In some embodiments, a pharmaceutically acceptable salt of a compound of formula I disclosed herein is administered.

[0314] In some embodiments, this disclosure provides a method of treating HIV infection in a person who has or is at risk of HIV infection, the method comprising administering to the person (i) a therapeutically effective amount of a compound of formula II or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof and (ii) a P-glycoprotein inhibitor. In some embodiments, a compound of formula II is administered. In some embodiments, a pharmaceutically acceptable salt of a compound of formula II disclosed herein is administered.

[0315] In some embodiments, the P-glycoprotein inhibitor is selected from the group consisting of verapamil, dextrovertamil, cyclosporine, zoquine, laniquine, ectelida, talicidil, encequine, and pharmaceutically acceptable salts thereof. In some embodiments, the P-glycoprotein inhibitor is encequine or a pharmaceutically acceptable salt thereof. In some embodiments, the P-glycoprotein inhibitor is a salt of encequine. In some embodiments, the P-glycoprotein inhibitor is a mesylate of encequine.

[0316] In some embodiments of the methods disclosed herein, (i) a compound of formula I or a pharmaceutically acceptable salt thereof, or a compound of formula II or a pharmaceutically acceptable salt thereof, and (ii) a P-glycoprotein inhibitor are administered together. In some embodiments, (i) a compound of formula I or a pharmaceutically acceptable salt thereof, or a compound of formula II or a pharmaceutically acceptable salt thereof, and (ii) a P-glycoprotein inhibitor are administered as a co-preparation.

[0317] In some embodiments, (i) a compound of formula I or a pharmaceutically acceptable salt thereof, or a compound of formula I or a pharmaceutically acceptable salt thereof, and (ii) a P-glycoprotein inhibitor are administered alone.

[0318] In some embodiments, (i) a compound of formula I or a pharmaceutically acceptable salt thereof, or a compound of formula I or a pharmaceutically acceptable salt thereof, and (ii) a P-glycoprotein inhibitor are administered orally.

[0319] In some embodiments, (i) a compound of formula I or a pharmaceutically acceptable salt thereof, or a compound of formula II or a pharmaceutically acceptable salt thereof, and (ii) a P-glycoprotein inhibitor are administered orally.Pharmaceutically acceptable salts and (ii) P-glycoprotein inhibitors are administered to humans in combination with one, two, three, or four additional therapeutic agents in therapeutically effective amounts. In some embodiments, one or more additional therapeutic agents are anti-HIV agents. In some embodiments, one or more additional therapeutic agents are HIV protease inhibitors, non-nucleoside or non-nucleotide inhibitors of HIV reverse transcriptase, nucleoside or nucleotide inhibitors of HIV reverse transcriptase, HIV capsid inhibitors, gp41 inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5 inhibitors, latency reversal agents, capsid polymerization inhibitors, HIV bNAb, TLR7 agonists, pharmacokinetic enhancers, other drugs for treating HIV, or combinations thereof. In some embodiments, one or more adjunctive therapeutic agents are abacavir, tenofovir alafenamide, tenofovir disoproxil fumarate, N-((S)-l-(3-(4-chloro-3-(methylsulfonamide)-l-(2,2,2-trifluoroethyl)-lH-indazole-7-yl)-6-(3-methyl-3-(methylsulfonyl)but-l-yn-l-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-lH-cyclopropyl[3,4]cyclopent[1,2-c]pyrazol-l-yl)acetamide or their pharmaceutically acceptable salts.

[0320] In some embodiments, one or more adjunctive therapeutic agents are HIV protease inhibitors, non-nucleoside or non-nucleotide inhibitors of HIV reverse transcriptase, HIV reverse transcriptase and / or translocated nucleoside or nucleotide inhibitors, HIV capsid inhibitors, gp41 inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5 inhibitors, latency reversal agents, capsid polymerization inhibitors, HIV bNAb, TLR7 agonists, pharmacokinetic enhancers, other medicines for treating HIV, or combinations thereof. (See specification 78 / 189 pages 126 CN 122055373 A). In another embodiment, this disclosure provides the use of (i) a compound of formula I or a pharmaceutically acceptable salt thereof, or a compound of formula II or a pharmaceutically acceptable salt thereof, and (ii) a P-glycoprotein inhibitor for treating HIV infection in a person who has HIV infection or is at risk of developing HIV infection.

[0321] In another embodiment, this disclosure provides (i) a compound of formula I or a pharmaceutically acceptable salt thereof, or a compound of formula II or a pharmaceutically acceptable salt thereof, and (ii) a P-glycoprotein inhibitor, for use in a medical therapy.

[0322] In another embodiment, this disclosure provides (i) a compound of formula I or a pharmaceutically acceptable salt thereof, or a compound of formula II or a pharmaceutically acceptable salt thereof, and (ii) a P-glycoprotein inhibitor, for use in the treatment of HIV infection.

[0323] In another embodiment, this disclosure provides the use of (i) a compound of formula I or a pharmaceutically acceptable salt thereof or a compound of formula II or a pharmaceutically acceptable salt thereof and (ii) a P-glycoprotein inhibitor in the preparation of a medicament for treating HIV infection in a person who has or is at risk of HIV infection.

[0324] An advantage of the combination disclosed herein is that the use of a PGP inhibitor in combination with a compound of formula I or II or a pharmaceutically acceptable salt thereof disclosed herein can modulate (e.g., increase) the PK properties of the compound, such as AUC, Cmax, and oral bioavailability. Thus, in some embodiments, (i) a compound of formula I or a pharmaceutically acceptable salt thereof or a compound of formula II or a pharmaceutically acceptable salt thereof and (ii) a P-glycoprotein inhibitor are administered orally.

[0325] A compound of formula I or II or a pharmaceutically acceptable salt thereof and a PGP inhibitor disclosed herein may be administered simultaneously or sequentially such that an effective amount of a compound of formula I or II or a pharmaceutically acceptable salt thereof and a PGP inhibitor are present in the patient. When administered sequentially, the combination may be administered in a manner of two or more administrations.

[0326] A unit dose of the compound of formula I or II disclosed herein, or a pharmaceutically acceptable salt thereof, may be administered before or after administration of a unit dose of the PGP inhibitor. For example, the compound of formula I or II disclosed herein, or a pharmaceutically acceptable salt thereof, may be administered within seconds, minutes, or hours after administration of the PGP inhibitor. In some embodiments, a unit dose of the compound of formula I or II disclosed herein, or a pharmaceutically acceptable salt thereof, is administered first, followed by administration of the PGP inhibitor within seconds or minutes. Alternatively, a unit dose of the PGP inhibitor is administered first, followed by administration of a unit dose of the compound of formula I or II disclosed herein, or a pharmaceutically acceptable salt thereof, within seconds or minutes. In other embodiments, a unit dose of the compound of formula I or II disclosed herein, or a pharmaceutically acceptable salt thereof, is administered first, followed by administration of a unit dose of the PGP inhibitor after a period of several hours (e.g., 0.1 hours to 12 hours). In other embodiments, a unit dose of the PGP inhibitor is administered first, followed by a unit dose of the compound of formula I or II disclosed herein, or a pharmaceutically acceptable salt thereof, after a period of several hours (e.g., 0.1 hours to 12 hours). In some embodiments, a unit dose of the PGP inhibitor is administered first, followed by a unit dose of the compound of formula I or II disclosed herein, or a pharmaceutically acceptable salt thereof, after a period of 10 minutes to 40 minutes. In some embodiments, a unit dose of the PGP inhibitor is administered first, followed by a unit dose of the compound of formula I or II disclosed herein, after a period of 30 minutes.The compound or a pharmaceutically acceptable salt thereof. In some embodiments, a unit dose of the PGP inhibitor is administered concurrently with a unit dose of a compound of formula I or II disclosed herein or a pharmaceutically acceptable salt thereof.

[0327] VII. Intermediate A in the examples: (3S,7S)-12-(benzyloxy)-N-(2,4-difluorobenzyl)-3-methyl-6-methylene-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-bridged methylenepyrido[1,2-a][1,4]diazacyclic nonene-10-carboxamide (A): Specification 79 / 189 pages 127 CN 122055373 A Step 1: Synthesis of (3S,7R)-N-(2,4-difluorobenzyl)-12-hydroxy-3-methyl-1,6,11-trioxo-1,4,5,6,7,11-hexahydro-3H-2,7-bridged methylenepyrido[1,2-a][1,4]diazacyclic nonene-10-carboxamide: At room temperature, EtOH (400 mL) was added to a solution of (3S,7R)-12-(benzyloxy)-N-(2,4-difluorobenzyl)-3-methyl-1,6,11-trioxo-1,6,7,11-tetrahydro-3H-2,7-bridged methylenepyrido[1,2-a][1,4]diazacyclic nonene-10-carboxamide (17 g, 32.7 mmol) in EtOAc (200 mL), followed by the addition of 20% Pd(OH)2 / C (50 wt% water, 7.6 g). The resulting mixture was degassed and purged three times with nitrogen, then degassed and purged three times with hydrogen, and then hydrogenated under a hydrogen balloon for 4 hours. The reaction mixture was then degassed and purged with nitrogen, diluted with DCM, filtered through a Celite® filter, concentrated, and used directly in the next step. MS (m / z) 432.124 [M+H]+.

[0328] Step 2: Synthesis of (3S,7R)-12-(benzyloxy)-N-(2,4-difluorobenzyl)-3-methyl-1,6,11-trioxo-1,4,5,6,7,11-hexahydro-3H-2,7-bridged methylenepyrido[1,2-a][1,4]diazacyclic nonene-10-carboxamide: The (3S,7R)-N-(2,4-difluorobenzyl)-12-hydroxy-3-methyl-1,6,11-trioxo-1,4,5,6,7,11-hexahydro-3H-2,7-bridged methylenepyrido[1,2-a][1]diazacyclic nonene-10-carboxamide from step 1 was used. [4] Diazacyclononene-10-carboxamide (33.1 g, 76.7 mmol) was dissolved in DMF (300 mL) at room temperature, and K2CO3 (16.0 g, 115.0 mmol) and benzyl bromide (13.1 g, 76.7 mmol) were added. The resulting mixture was then heated to 50 °C for 4.5 hours and then cooled to room temperature.The mixture was filtered through a Celite® pad, and the filter cake was rinsed with DMF (100 mL). The combined filtrate was used directly for the next step. MS (m / z) 554.086 [M+H+MeOH]+.

[0329] Step 3: Synthesis of (3S,7S)-12-(benzyloxy)-N-(2,4-difluorobenzyl)-3-methyl-6-methylene-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-bridged methylenepyrido[1,2-a][1,4]diazacyclic nonene-10-carboxamide (A): (3S,7R)-12-(benzyloxy)-N-(2,4-difluorobenzyl)-3-methyl-1,6,11-trioxo-1,4,5,6,7,11-hexahydro-3H-2,7-bridged methylenepyrido[1,2-a][1,4]diazacyclic nonene-10-carboxamide (39.7g, 76g) A solution of 1-methyl-2-(methanesulfonyl)-1H-benzi[d]imidazole (20.81 g, 99.0 mmol) in DMF (350 mL) was immersed in a water bath at room temperature. Potassium tert-butoxide (21.36 g, 190 mmol) was added in a single addition, followed by five fractions. The reaction mixture was removed from the water bath and stirred at room temperature for 1.5 h. The reaction was then slowly quenched with an aqueous solution of 0.5 N HCl (180 mL) and extracted three times with EtOAc. The combined organic layers were washed with water and brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by normal-phase silica gel chromatography (eluting with 0%–100% EtOAc / hexane) to give intermediate A. MS (m / z) 520.060 [M+H]+.

[0330] Intermediate B: (3'S,5S,7'R)-N-(2,4-difluorobenzyl)-12'-hydroxy-3,3'-dimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]bridged methylenepyrido[1,2-a] [1,4]diazacyclic nonene]-10'-formamide (B): Step 1: Preparation of (3'S,5S,7'R)-12'-(benzyloxy)-N-(2,4-difluorobenzyl)-3,3'-dimethyl-1',11'- Preparation of dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]bridged methylenepyrido[1,2-a][1,4]diazacyclic nonene]-10'-formamide: N-chlorosuccinimide (1.51 g, 11 mmol) was added to a solution of acetaldehyde oxime (666 mg, 11.3 mmol) in DMF (50 ml) at room temperature.0.3 mmol), then heated to 60 °C and held for 1 hour. After cooling to room temperature, (3S,7S)-12-(benzyloxy)-N-(2,4-difluorobenzyl)-3-methyl-6-methylene-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-bridged methylenepyrido[1,2-a][1,4]diazacyclic nonene-10-carboxamide (intermediate A) (1.58 g, 3.04 mmol) and triethylamine (1.539 g, 15.2 mmol) were added at room temperature. After stirring overnight at room temperature, the reaction was quenched by adding saturated NaHCO3 solution. The mixture was extracted with EtOAc, the organic phase was separated and dried over MgSO4, filtered, concentrated and purified by silica gel column chromatography (eluting with 0%–100% EtOAc / hexane). MS (m / z) 577.135 [M+H]+ Step 2: Preparation of (3'S,5S,7'R)-N-(2,4-difluorobenzyl)-12'-hydroxy-3,3'-dimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazo-5,6'-[2,7]bridged methylenepyrido[1,2-a][1,4]diazacyclic nonene]-10'-formamide (B): TFA (0.5 mL) was added to a solution of (3'S,5S,7'R)-12'-(benzyloxy)-N-(2,4-difluorobenzyl)-3,3'-dimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazo-5,6'-[2,7]bridged methylenepyrido[1,2-a][1,4]diazacyclononene]-10'-formamide (64.7 mg, 0.112 mmol) in toluene (2 mL). The reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated, and the residue was purified by reversed-phase HPLC, eluting with 10%–90% aqueous acetonitrile solution to give intermediate B. MS (m / z) 487.12 [M+H]+. 1H NMR (400MHz, chloroform‑d) δ 10.53 (s, 1H) , 8.43 (s, 1H) , 7.37 (td, J = 8.6, 6.3Hz, 1H) , 6.92 – 6.78 (m, 2H) , 4.82 – 4.70 (m, 1H) , 4.67 (t, J = 4.8Hz, 2H) , 4.18 (d, J = 2.2Hz, 1H) , 3.86 (dd ,J = 14.9, 1.9Hz, 1H) , 3.72 (dd , J = 14.9, 2.7Hz, 1H) , 2.94 (d, J = 17.8Hz,1H) , 2.53 (d, J = 17.7Hz, 1H) , 2.06 (s, 3H) , 2.04 – 1.88 (m, 3H) , 1.56 (dd, J = 14.3, 11.2Hz,1H) , 1.32 (d, J = 6.6Hz, 3H).

[0331] Intermediate C: Synthesis of (3'S,5S,7'R)-N-(2,4-difluorobenzyl)-12'-hydroxy-3-methoxy-3'-methyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazo-5,6'-[2,7]bridged methylenepyrido[1,2-a][1,4]diazacyclic nonene]-10'-formamide: Specification 81 / 189 pages 129 CN 122055373 A Step 1: (3'S,5S,7'R)-12'-(benzyloxy)-3-bromo-N-(2,4-difluorobenzyl)-3'-methyl-1',11'- Synthesis of dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]bridged methylenepyrido[1,2-a][1,4]diazacyclic nonene]-10'-carboxamide: At 0°C, dibromoformaldehyde oxime (21.199 g, 34.8 mmol) was added to a solution of (3S,7S)-12-(benzyloxy)-N-(2,4-difluorobenzyl)-3-methyl-6-methylene-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-bridged methylenepyrido[1,2-a][1,4]diazacyclic nonene-10'-carboxamide (intermediate A) (18.1 g, 34.8 mmol) in EtOAc (350 mL). 105 mmol), followed by the addition of potassium carbonate (28.846 g, 209 mmol). The resulting mixture was stirred overnight and then diluted with water (300 mL). The layers were separated. The aqueous layer was extracted with EtOAc (200 mL), and the combined organic phases were washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by normal-phase silica gel chromatography, eluting with 0%–80% EtOAc / hexane to give the title compound. MS (m / z) 640.904 [M+H]+. 1H NMR (400MHz, DMSO) δ 10.41 (t, J = 6.0Hz, 1H), 8.89 (s, 1H), 7.54 – 7.21 (m, 7H), 7.13 – 7.05 (m, 1H), 5.30 (d, J = 10.5Hz, 1H), 5.04 (d, J = 10.5Hz, 1H), 4.78 (s, 1H), 4.72 – 4.54 (m, 3H) , 3.75 – 3.62 (m , 2H) , 3.39 (d , J = 17 .6Hz, 1H) , 3.07 (d , J = 17 .7Hz, 1H) , 1 .92 – 1.73 (m, 3H) , 1.41 (t, J = 12.9Hz, 1H), 1.15 (d, J = 6.7Hz, 3H).

[0332] Step 2: Synthesis of (3'S,5S,7'R)-12'-(benzyloxy)-N-(2,4-difluorobenzyl)-3-methoxy-3'-methyl-1', 11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazo-5,6'-[2,7]bridged methylenepyrido[1,2-a][1,4]diazacyclic nonene]-10'-carboxamide: Synthesis of (3'S,5S,7'R)-12'-(benzyloxy)-3-bromo-N-(2,4-difluorobenzyl)-3'-methyl-1', 11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]bridged methylenepyrido[1,2-a][1,4]diazacyclononene]-10'-formamide (23.2 g, 36.2 mmol) was reacted with potassium carbonate (12.496 g, 90.4 mmol) in a mixture of MeOH (450 mL) and DMF (100 mL). The reaction was stirred for 3 hours and then cooled to room temperature. Water (1100 mL) was added to the stirred mixture and stirring was continued for 30 minutes. The mixture was filtered, and the filter cake was washed with water, collected, and dried to give the title compound. MS (m / z) 593.207 [M+H]+. 1H NMR (400MHz, DMSO) δ 10.41 (t, J = 6.0Hz, 1H), 8.73 (s, 1H), 7.53 – 7.48 (m, 2H), 7.47 – 7.30 (m, 4H), 7.25 (ddd, J = 10.5, 9.3, 2.6Hz, 1H), 7.08 (tdd, J = 8.5, 2.6, 1.0Hz, 1H), 5.30 (d, J = 10.5Hz, 1H), 5.03 (d, J = 10.5Hz, 1H), 4.73 – 4.63 (m, 2H) , 4.63 – 4 .49 (m, 2H), 3.82 (s, 3H), 3.65 (d, J = 2.0Hz, 2H), 3.08(d, J = 16.8Hz, 1H), 2.77 (d, J = 16.9Hz, 1H), 1.96 – 1.71 (m, 3H), 1.38 (dd, J = 15.5, 10.2Hz, 1H), 1.15 (d, J = 6.6Hz, 3H).

[0333] Step 3: Synthesis of (3'S,5S,7'R)-N-(2,4-difluorobenzyl)-12'-hydroxy-3-methoxy-3'-methyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazo-5,6'-[2,7]bridged methylenepyrido[1,2-a][1,4]diazacyclic nonene]-10'-carboxamide (C): Synthesis of (3'S,5S,7'R)-12'-(benzyloxy)-N-(2,4-difluorobenzyl)-3-methoxy-3 A solution of '-methyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]bridged methylenepyrido[1,2-a][1,4]diazacyclononene]-10'-formamide (19 g, 32.1 mmol) in toluene (64 mL) was mixed with TFA (32 mL) and stirred for 16 h. The solvent was removed by rotary evaporator. The resulting residue was treated with EtOAc (60 mL) and concentrated, repeated three times. The residue was mixed with a mixture of toluene (42 mL) / MeOH (42 mL) / EtOAc (42 mL) and stirred at 70 °C for 1 h, followed by stirring at room temperature for 2 h. The mixture was then filtered, and the filter cake was washed with EtOAc, collected, and dried to give the title compound. MS (m / z) 503.263 [M+H]+. 1H NMR (400MHz, DMSO) δ 10.99 (s, 1H) , 10.34 (t, J = 5.9Hz, 1H) , 8.64 (s, 1H) , 7.42 (td , J = 8.7, 6.6Hz, 1H) , 7.25 (ddd , J = 10.5 , 9.3 , 2.6Hz , 1H) , 7.08 (tdd , J = 8.6 , 2.6 ,1.0Hz , 1H) , 4.74 (s , 1H) , 4.63 – 4.47 (m , 3H) , 3.81 (s , 3H) , 3.80 – 3.67 (m , 2H) , 2.93 (d , J = 16.9Hz, 1H) ,2.70 (d, J = 16.9Hz, 1H), 1.95 – 1.76 (m, 3H), 1.41 – 1.31 (m, 1H), 1.19 (d, J = 6.8Hz, 3H).

[0334] Intermediate D: Synthesis of (((3'S,5S,7'R)-10'-((2,4-difluorobenzyl)carbamoyl)-3,3'-dimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazo-5,6'-[2,7]bridged methylenepyrido[1,2-a][1,4]diazacyclononene]-12'-yl)oxy)methyl(4-nitrophenyl) carbonate: The (3'S,5S,7'R)-N-(2,4-difluorobenzyl)-12'-hydroxy-3,3'- Dimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazol-5,6'-[2,7]bridged methylenepyrido[1,2-a][1,4]diazacyclononene]-10'-formamide (intermediate B, 3.06 g, 6.29 mol) and (4-nitrophenyl) methyl iodide carbonate (4.23 g, 13.1 mmol) were mixed with acetonitrile (73 mL). Ag₂CO₃ (5.29 g, 19.2 mmol) was added in a single batch. The slurry was stirred overnight at room temperature and filtered through diatomaceous earth. The filtrate was collected and concentrated to dryness. The residue was purified on a silica gel column using 0%–20% MeOH / DCM to obtain crude material after concentration. The crude product was then dissolved in EtOAc (200 mL) and treated with water (200 mL) under stirring. The organic phase was separated, dried over Na2SO4, and filtered. The filtrate was concentrated to give intermediate D. C32H29F2N5O10 Calculated value: 681.19, Measured value MS (ESI+): 682.01 [M+H]+.

[0335] Intermediate E: (((3'S,5S,7'R)-10'-((2,4-difluorobenzyl)carbamoyl)-3-methoxy-3'-methyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazo-5,6'-[2,7]bridged methylenepyridine specification 83 / 189 pages 131 CN 122055373 A diazo[1,2-a][1,4]diazacyclononene]-12'-yl)oxy)methyl(4-nitrophenyl)carbonate Synthesis: The title compound was prepared by a method similar to that of intermediate D, except that intermediate C was used instead of intermediate B. LCMS-ESI+(m / z): The theoretical value of H+ calculated for C32H29F2N5O11 is 697.18, and the measured value is 697.845.

[0336] Example 1: Synthesis of (((3'S,5S,7'R)-10'-((2,4-difluorobenzyl)carbamoyl)-3-methoxy-3'-methyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazo-5,6'-[2,7]bridged methylenepyrido[1,2-a][1,4]diazacyclononene]-12'-yl)oxy)methyl phosphate dihydrogen ester (1): Step 1: (( ...-10'-((2,4-difluorobenzyl)-10'-((2,4-difluorobenzyl)-10'-((2,4-difluorobenzyl)-10'-((2,4-difluorobenzyl)-10'-((2,4-difluorobenzyl)-10'-((2,4-difluorobenzyl)-10'-((2,4-di '-((2,4-difluorobenzyl)carbamoyl)-3-methoxy-3'-methyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxaazole-5,6'-[2,7]bridged methylenepyrido[1,2-a][1,4]diazacyclic nonene]-12'-yl)oxy)methyl)phosphobis(3'S,5S,7'R)-10'-((2,4-difluorobenzyl)carbamoyl)-3-methoxy-3'-methyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxaazole-5,6'-[2,7]bridged methylenepyrido[1 Synthesis of [2-a][1,4]diazacyclononene]-12'-yl)oxy)methyl)hydrobenzyl phosphate: At room temperature, tetrabutylammonium iodide (14.7 mg, 0.0398 mmol) and potassium carbonate (11.0 mg, 0.0796 mmol) were added to a solution of (3'S,5S,7'R)-N-(2,4-difluorobenzyl)-12'-hydroxy-3-methoxy-3'-methyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazo-5,6'-[2,7]bridged methylenepyrido[1,2-a][1,4]diazacyclononene]-10'-carboxamide (intermediate C, 30 mg, 0.0597 mmol) in DMF (0.5 mL). The resulting mixture was heated at 63°C. Dibenzylchloromethyl phosphate (19.5 mg, 0.0597 mmol) was added to the heated mixture, and the mixture was stirred for 30 minutes. The reaction was then cooled to room temperature and filtered. The mother liquor was purified by reversed-phase preparative chromatography, and the fractions with the desired mass were collected and lyophilized. LCMS-ESI+ (m / z): Theoretical H+ value of C39H39F2N4O10P: 792.24, Measured value: 792.697. LCMS-ESI+(m / z): Theoretical H+ value of C32H33F2N4O10P: 702.19, measured value: 702.722.

[0337] Step 2: Synthesis of (((3'S,5S,7'R)-10'-((2,4-difluorobenzyl)carbamoyl)-3-methoxy-3'-methyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazo-5,6'-[2,7]bridged methylenepyrido[1,2-a][1,4]diazacyclononene]-12'-yl)oxy)methyl phosphate dihydrogen ester (1): At room temperature, ((((3'S,5S,7'R)-10'-((2,4-difluorobenzyl)carbamoyl)-3-methoxy-3'- Methyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazo-5,6'-[2,7]bridged methylenepyrido[1,2-a][1,4]diazacyclic nonene]-12'-yl)oxy)methyl)phosphodiester and ((((3'S,5S,7'R)-10'-((2,4-difluorobenzyl)carbamoyl)-3-methoxy-3'-methyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazo-5,6'-[2,7]bridged methylenepyrido[1,2-a][1,4]diazacyclic nonene]- A mixture of 12'-yl)oxy)methyl)hydrogen phosphate was dissolved in THF (10 mL). Platinum oxide (6.0 mg) was added, and the resulting mixture was degassed and purged three times with nitrogen. The reaction mixture was then degassed and purged three times with hydrogen, followed by hydrogenation under a hydrogen balloon for 45 min. The reaction mixture was then degassed and purged with nitrogen, filtered, and concentrated. The residue was redissolved in DMF, filtered, and purified by reversed-phase preparative chromatography (5% to 100% MeCN / H2O containing 0.1% TFA). ¹H NMR (400MHz, acetonitrile-d³) δ 9.85 (t, J = 6.0Hz, 1H), 8.68 (s, 1H), 7.50–7.38 (m, 1H), 7.03–6.92 (m, 2H), 5.70–5.57 (m, 2H), 4.86–4.72 (m, 1H), 4.61 (d, J = 5.5Hz, 2H), 4.49 (s, 1H), 3.88 (s, 3H), 3.80–3.69 (m, 2H), 2.98 (d, J = 17.3Hz, 1H), 2.70 (d, J = 17.3Hz, 1H), 2.07 –1.81 (m, 3H), 1.60 – 1.48 (m, 1H), 1.23 (d, J = 6.7Hz, 3H). LCMS-ESI+ (m / z): Theoretical calculated value of H+ for C25H27F2N4O10P: 612.14, measured value: 612.662.

[0338] Example 2: Synthesis of N-(4-(((3'S,5S,7'R)-10'-((2,4-difluorobenzyl)carbamoyl)-3,3'-dimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazo-5,6'-[2,7]bridged methylenepyrido[1,2-a][1,4]diazacyclononene]-12'-yl)oxy)-3,3-dimethyl-4-oxobutyl)-N-(((phosphono)methoxy)carbonyl)glycine (2): Specification 85 / 189 pages 133 CN 122055373 A Step 1: Synthesis of 4-((2-(tert-butoxy)-2-oxoethyl)((((di-tert-butoxyphosphoryl)oxy)methoxy)carbonyl)amino)-2,2-dimethylbutyric acid: At room temperature, a solution of benzyl 4-((2-(tert-butoxy)-2-oxoethyl)((((di-tert-butoxyphosphoryl)oxy)methoxy)carbonyl)amino)-2,2-dimethylbutyrate (prepared according to WO2023102239) (200 mg, 0.332 mmol) in MeOH (20.0 mL) was treated with platinum oxide (20.0 mg, 0.088 mmol). The resulting mixture was degassed and purged three times with nitrogen, then degassed and purged three times with hydrogen, followed by hydrogenation under a hydrogen balloon for 4 hours. The reaction mixture was then degassed and purged with nitrogen, diluted with DCM, filtered, concentrated, and used directly in the next step. LCMS-ESI+ (m / z): Theoretical value of H+ in C22H42NO10P: 511.25, measured value: 511.512.

[0339] Step 2: Synthesis of (3'S,5S,7'R)-10'-((2,4-difluorobenzyl)carbamoyl)-3,3'-dimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazo-5,6'-[2,7]bridged methylenepyrido[1,2-a][1,4]diazacyclononene]-12'-yl 4-((2-(tert-butoxy)-2-oxoethyl)((((di-tert-butoxyphosphoryl)oxy)methoxy)carbonyl)amino)-2,2-dimethylbutyrate: At room temperature, the ester was synthesized into (3'S,5S,7'R)-N-(2,4-difluorobenzyl)-12'-hydroxy-3,3'-dimethyl-1',11'-Dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]bridged methylenepyrido[1,2-a] Instructions for Use 86 / 189 pages 134 CN 122055373 A [1,4]diazacyclononene]-10'-formamide (intermediate B, 60 mg, 0.123 mmol) and 4-((2-(tert-butoxy)-2-oxoethyl)((((di-tert-butoxyphosphoryl)oxy)methoxy)carbonyl)amino)-2,2-dimethylbutyric acid (75.7 mg, 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (30.6 mg, 0.16 mmol), DMAP (19.6 mg, 0.16 mmol), and triethylamine (25.0 mg, 0.247 mmol) were added to a mixture of 0.148 mmol DMF (0.5 mL). After stirring for 16 hours, the reaction mixture was diluted with EtOAc, washed with 0.5 N HCl aqueous solution, water, and brine, dried over sodium sulfate, filtered, concentrated, and purified by normal phase chromatography. MS (m / z) 979.529 [M]+.

[0340] Step 3: Synthesis of N-(4-(((3'S,5S,7'R)-10'-((2,4-difluorobenzyl)carbamoyl)-3,3'-dimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazol-5,6'-[2,7]bridged methylenepyrido[1,2-a][1,4]diazacyclononene]-12'-yl)oxy)-3,3-dimethyl-4-oxobutyl)-N-(((phosphono)methoxy)carbonyl)glycine (2): At room temperature, (3'S,5S,7'R)-10'-((2,4-difluorobenzyl)carbamoyl)-3,3'-dimethyl-1', 11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazo-5,6'-[2,7]bridged methylenepyrido[1,2-a][1,4]diazacyclononene]-12'-yl 4-((2-(tert-butoxy)-2-oxoethyl)((((di-tert-butoxyphosphoryl)oxy)methoxy)carbonyl)amino)-2,2-dimethylbutyrate (60 mg) was dissolved in DCM (3.0 mL) and slowly treated with TFA (1.0 mL). After stirring for 30 minutes, the reaction was concentrated, dissolved in DMF, filtered, and purified by reversed-phase preparative HPLC (5% to 100% MeCN / H2O containing 0.1% TFA) to give the title compound. ¹H NMR (400 MHz, acetone-d6) δ 10.23 (s, ¹H), 8.68 (d, J = 7.1 Hz, ¹H), 7.48(td , J = 8.6, 6.2Hz, 1H) , 7.09 – 6.89 (m , 2H) , 5.72 – 5.53 (m , 2H) , 4.86 – 4.72 (m , 1H) , 4.72 – 4.55 (m, 3H) , 4.36 – 4.13 (m, 2H) ,4.07 – 3.77 (m, 2H) , 3.74 – 3.44 (m, 2H) , 3.29 – 3.16 (m, 1H) , 2.85 – 2.69 (m, 1H) , 2.01 (s, 5H) , 1.97 – 1.83 (m, 3H) , 1.67 – 1.43 (m, 1H), 1.36 (s, 6H), 1.26 (d, J = 6.6Hz, 3H). LCMS-ESI+ (m / z): Theoretical calculated value of H+ for C34H40F2N5O14P: 811.23, measured value: 811.769.

[0341] Example 3: Preparation of (((3'S,5S,7'R)-10'-((2,4-difluorobenzyl)carbamoyl)-3-methoxy-3'-methyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazo-5,6'-[2,7]bridged methylenepyrido[1,2-a][1,4]diazacyclononene]-12'-yl)oxy)methyl(2-(phosphono)ethyl)carbonate (3): Specification 87 / 189 pages 135 CN 122055373 A Step 1: Preparation of 2-((bis(benzyloxy)phosphoryl)oxy)ethyl((((3'S,5S,7'R)-10'-((2,4-difluorobenzyl)carbamoyl)-3-methoxy-3'-methyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazo-5,6'-[2,7]bridged methylenepyrido[1,2-a][1,4]diazacyclononene]-12'-yl)oxy)methyl)carbonate: To (((3'S,5S,7'R)-10'-((2,4-difluorobenzyl)carbamoyl)-3-methoxy-3'-methyl-1', 11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazol-5,6'-[2,7]bridged methylenepyrido[1,2-a][1,4]diazacyclononene]-12'-yl)oxy)methyl(4-nitrophenyl)carbonate (intermediate E) (11.9 g, 17.1 mmol) was added to a solution of 11'-dioxo-1',4',5',11'-tetrahydro-3'H,4'H,7'H-spiro[isoxazol-5,6'-[2,7]bridged methylenepyrido[1,2-a][1,4]diazacyclononene]-12'-yl)oxy)methyl(4-nitrophenyl)carbonate (intermediate E) (11.9 g, 17.1 mmol) in MeCN (250 mL)0.13 mL (51.2 mmol) and DMAP (0.208 g, 1.71 mmol) were added, followed by the addition of (2-hydroxyethyl) dibenzyl phosphate (16.5 g, 51.2 mmol) prepared according to WO2010039474. The reaction mixture was stirred at room temperature for 16 hours and concentrated. The residue was purified by silica gel column chromatography (0% to 100% EtOAc / hexane, then 0% to 20% MeOH / DCM, and again 50% to 100% EtOAc / hexane) to give the title compound. MS (m / z) 880.82 [M+H]+.

[0342] Step 2: Preparation of (((3'S,5S,7'R)-10'-((2,4-difluorobenzyl)carbamoyl)-3-methoxy-3'-methyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazo-5,6'-[2,7]bridged methylenepyrido[1,2-a][1,4]diazacyclononene]-12'-yl)oxy)methyl(2-(phosphono)ethyl)carbonate (3): Add 10% Pd / C (0.834 g, 0.783 mmol) to a solution of 2-((bis(benzyloxy)phosphoryl)oxy)ethyl((((3'S,5S,7'R)-10'-((2,4-difluorobenzyl)carbamoyl)-3-methoxy-3'-methyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazo-5,6'-[2,7]bridged methylenepyrido[1,2-a][1,4]diazacyclononene]-12'-yl)oxy)methyl)carbonate (6.90 g, 7.83 mmol) in THF (500 mL). Evacuate the flask and backfill with hydrogen (2×), then aerate with hydrogen for 2 minutes. Stir the reaction mixture under a hydrogen balloon atmosphere for 4 hours. Instructions for Use, pages 88 / 189, 136, CN 122055373 A: The reaction mixture was filtered through diatomaceous earth and concentrated. The residue was dissolved in 1:1 MeCN / water and lyophilized to give the title compound. MS (m / z) 700.90 [M+H]+. 1H NMR (400MHz, DMSO‑d6) δ 10.26 (t, J = 6.0Hz, 1H) , 8.74 (s, 1H) , 7.41 (td , J = 8.7, 6.7Hz, 1H) , 7.24 (td , J = 9.9, 2.6Hz, 1H) , 7 .07 (td, J = 8.5, 2.5Hz, 1H), 5.80 (d, J = 6.3Hz, 1H), 5.64 (d, J =6.4Hz, 1H), 4.71 (s, 1H), 4.62 (dq, J = 14.5, 6.9Hz, 1H), 4.55 (t, J = 5.7Hz, 2H), 4.23 (q, J = 4.3Hz, 2H), 4.00 (dt, J = 7.1 , 4.7Hz, 2H) , 3.81 (s , 3H) , 3.75 – 3.59 (m, 2H) , 3.05 (d, J = 16.8Hz, 1H) , 2.75 (d, J = 16.9Hz, 1H) , 1.98 – 1.65 (m, 3H) , 1.37 – 1.29 (m, 1H), 1.15 (d, J = 6.7Hz, 3H).

[0343] Example 4: Preparation of (((3'S,5S,7'R)-10'-((2,4-difluorobenzyl)carbamoyl)-3,3'-dimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazo-5,6'-[2,7]bridged methylenepyrido[1,2-a][1,4]diazacyclononene]-12'-yl)oxy)methyl(2-(phosphono)ethyl)carbonate (4): Step 1: Preparation of 2-((bis(benzyloxy)phosphoryl)oxy)ethyl((((3'S,5S,7'R)-10'-((2,4-difluorobenzyl)carbamoyl)-3,3'-dimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazo-5,6'-[2,7]bridged methylenepyrido[1,2-a][1,4]diazacyclic nonene]-12'-yl)oxy)methyl)carbonate: To (((3'S,5S,7'R)-10'-((2,4-difluorobenzyl)carbamoyl)-3,3'-dimethyl-1',11'-dioxo-1',4',5',11) '-Tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]bridged methylenepyrido[1,2-a][1,4]diazacyclononene]-12'-yl)oxy)methyl(4-nitrophenyl)carbonate (intermediate D) (2.50 g, 3.67 mmol) in a solution in MeCN (95 mL) was supplemented with Et3N (2.56 mL, 18.3 mmol), DMAP (0.045 g, 0.367 mmol), and (2-hydroxyethyl) dibenzyl phosphate (2.36 g, 7.34 mmol) prepared according to WO2010039474. The reaction was carried out...The mixture was stirred at room temperature for 16 hours, then diluted with EtOAc and quenched with an aqueous solution of NaHCO3. The phases were separated, and the aqueous phase was extracted with EtOAc. The combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (20% to 100% EtOAc / hexane) and reversed-phase preparative HPLC (5% to 100% MeCN / H2O) to give the title compound. MS (m / z) 864.87 [M+H]+.

[0344] Step 2: Preparation of (((3'S,5S,7'R)-10'-((2,4-difluorobenzyl)carbamoyl)-3,3'-dimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazo-5,6'-[2,7]bridged methylenepyrido[1,2-a][1,4]diazacyclononene]-12'-yl)oxy)methyl(2-(phosphono)ethyl)carbonate (4): Add 5% Pd / C (0.083 g, 0.039 mmol) to a solution of 2-((bis(benzyloxy)phosphoryl)oxy)ethyl((((3'S,5S,7'R)-10'-((2,4-difluorobenzyl)carbamoyl)-3,3'-dimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazo-5,6'-[2,7]bridged methylenepyrido[1,2-a][1,4]diazacyclononene]-12'-yl)oxy)methyl)carbonate (0.336 g, 0.389 mmol) in THF (42 mL). Evacuate the flask and backfill with hydrogen (2×), then aerate with hydrogen for 2 minutes. Stir the reaction mixture under a hydrogen balloon atmosphere for 2 hours. The reaction mixture was filtered through diatomaceous earth and concentrated. The residue was dissolved in 1:1 MeCN / water and lyophilized to give the title compound. MS (m / z) 684.82 [M+H]+. 1H NMR (400MHz, DMSO‑d6) δ 10.27 (t, J = 6.0Hz, 1H) , 8.70 (s, 1H) , 7.42 (td , J = 8.7, 6.6Hz, 1H) , 7.24 (ddd , J = 10.5, 9.3, 2.6Hz, 1H) , 7.07 (ddd , J = 10.3, 8.2, 2.6Hz, 1H) , 5.81 (d , J = 6.4Hz, 1H) , 5.65 (d , J = 6.4Hz, 1H) , 4.64 (d , J = 11.0Hz, 2H) , 4.59 – 4.46 (m, 2H) ,4.22 (q, J = 4.3Hz, 2H) , 3.99 (dd , J = 7.2, 4.5Hz, 2H) , 3.76 – 3.61 (m, 2H) , 3.00 (d , J = 17.5Hz, 1H) , 2.63 (d , J = 17.6Hz, 1H) , 1.94 (s, 3H) , 1.89 – 1.67 (m, 3H) , 1.35 – 1.22 (m, 1H) , 1.15 (d, J = 6.7Hz, 3H).

[0345] Example 5: Preparation of 1-(((3'S,5S,7'R)-10'-((2,4-difluorobenzyl)carbamoyl)-3,3'-dimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazo-5,6'-[2,7]bridged methylenepyrido[1,2-a][1,4]diazacyclononene]-12'-yl)oxy)ethyl(2-(phosphonooxy)ethyl)carbonate (5): Specification 90 / 189 pages 138 CN 122055373 A Step 1: Preparation of (4-nitrophenyl)carbonate 1-iodoethyl ester: Sodium iodide (8.54 g, 57.0 mmol) was added to a solution of (4-nitrophenyl)carbonate 1-iodoethyl ester (2.00 g, 8.14 mmol) in MeCN (16 mL) and heated to 50 °C. After 16 hours, the mixture was concentrated and suspended in EtOAc. The organic phase was washed with brine, Na₂S₂O₃, NaHCO₃ (2×), and brine. The organic phase was dried over Na₂SO₄, filtered, and concentrated to give a residue, which was purified by silica gel column chromatography (0% to 100% EtOAc / hexane) to give the title compound. MS (m / z) 336.02 [M]⁺.

[0346] Step 2: Preparation of 1-(((3'S,5S,7'R)-10'-((2,4-difluorobenzyl)carbamoyl)-3,3'-dimethyl-1', 11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazo-5,6'-[2,7]bridged methylenepyrido[1,2-a][1,4]diazacyclononene]-12'-yl)oxy)ethyl(4-nitrophenyl)carbonate: Add (3'S,5S,7'R)-N-(2,4-difluorobenzyl)-12'-hydroxy-3,3'-dimethyl-1 ',11 '-dioxo-1 ',4 ',5 ',11'-Tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]bridged methylenepyrido[1,2-a][1,4]diazacyclononene]-10'-formamide (intermediate B, 0.400 g, 0.822 mmol) and silver carbonate (0.680 g, 2.47 mmol). The mixture was stirred at 50 °C for 16 h and concentrated. The residue was purified by reversed-phase preparative HPLC (10% to 100% MeCN / H2O containing 0.1% TFA) to give the title compound. MS (m / z) 695.39 [M]+.

[0347] Step 3: Preparation of 2-((bis(benzyloxy)phosphoryl)oxy)ethyl(1-(((3'S,5S,7'R)-10'-((2,4-difluorobenzyl)carbamoyl)-3,3'-dimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazo-5,6'-[2,7]bridged methylenepyrido[1,2-a][1,4]diazacyclononene]-12'-yl)oxy)ethyl)carbonate: To 1-(((3'S,5S,7'R)-10'-((2,4-difluorobenzyl)carbamoyl)-3,3'-dimethyl-1',11'- A solution of dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazol-5,6'-[2,7]bridged methylenepyrido[1,2-a][1,4]diazacyclononen]-12'-yl)oxy)ethyl(4-nitrophenyl) carbonate (0.171 g, 0.246 mmol) in MeCN (10 mL) was sequentially supplemented with dibenzyl phosphate (0.238 g, 0.737 mmol), Et3N (0.10 mL, 0.737 mmol), and DMAP (0.003 g, 0.025 mmol) prepared according to WO2010039474. The mixture was stirred at room temperature for 16 hours and then concentrated. The residue was redissolved in MeCN and purified by reversed-phase preparative HPLC (10% to 100% MeCN / water containing 0.1% TFA) to obtain the title compound. MS (m / z) 878.71 [M+H]+.

[0348] Step 4: 1-(((3'S,5S,7'R)-10'-((2,4-difluorobenzyl)carbamoyl)-3,3'-dimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]bridged methylenepyrido[1,Preparation of 2-a][1,4]diazacyclononene]-12'-yl)oxy)ethyl(2-(phosphono)ethyl)carbonate (5): 10% of 2-((bis(benzyloxy)phosphono)oxy)ethyl(1-(((3'S,5S,7'R)-10'-((2,4-difluorobenzyl)carbamoyl)-3,3'-dimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazo-5,6'-[2,7]bridged methylenepyrido[1,2-a][1,4]diazacyclononene]-12'-yl)oxy)ethyl)carbonate (0.070 g, 0.080 mmol) in a solution of 2-((bis(benzyloxy)phosphono)oxy)ethyl(1-(((3'S,5S,7'R)-10'-((2,4-difluorobenzyl)carbamoyl)-3,3'-dimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazo-5,6'-[2,7]bridged methylenepyrido[1,2-a][1,4]diazacyclononene]-12'-yl)oxy)ethyl)carbonate (0.070 g, 0.080 mmol) in THF (5 mL) was added. Pd / C (0.008 g, 0.008 mmol). The flask was evacuated and backfilled with hydrogen (2×), then aerated with hydrogen for 2 minutes. The reaction mixture was stirred for 4 hours under a hydrogen balloon atmosphere. The reaction mixture was filtered through diatomaceous earth and concentrated. The residue was dissolved in 1:1 MeCN / water and lyophilized to give the title compound. MS (m / z) 698.80 [M+H]+. 1H NMR (400MHz, DMSO‑d6) δ 10.28 (t, J = 6.0Hz, 1H) , 8.70 (s, 1H) , 7.42 (td , J = 8.6, 6.5Hz, 1H) , 7.29 – 7.18 (m, 1H) , 7.07 (td , J = 8.6, 2.7Hz, 1H), 6.50 (q, J = 5.2Hz, 1H), 4.71 – 4.60 (m, 2H), 4.60 – 4.48 (m, 2H), 4.11 (dt, J = 10.6, 5.1Hz, 1H), 4 .07 – 4 .01 (m, 1H), 3.94 (dd, J = 7.1, 4.6Hz, 2H), 3.81 (dt, J = 7.4, 5.4Hz, 1H), 3.53 (d, J = 10.8Hz, 1H), 2.97 (d, J = 17.5Hz, 1H), 2.58 (d, J = 17.3Hz, 1H), 1.95 (d, J = 3.4Hz, 3H), 1.87 – 1.73 (m, 3H), 1.60 (d, J = 5.3Hz, 3H), 1.19 (d, J = 7.2Hz, 1H), 1.14 (d, J = 6.6Hz, 3H).

[0349] Example 6: (3'S, 5S, 7Preparation of 'R)-10'-((2,4-difluorobenzyl)carbamoyl)-3,3'-dimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]bridged methylenepyrido[1,2-a][1,4]diazacyclononene]-12'-yl(2-(phosphono)ethyl)carbonate (6): Instructions 92 / 189, page 140, CN 122055373 A. Step 1: Preparation of 2-((bis(benzyl)phosphono)oxy)ethyl chloroformate: Add pyridine (0.024 mL, 0.116 mmol) to a solution of triphosgene (0.034 g, 0.116 mmol) in THF (1.5 mL). 0.303 mmol), and the suspension was cooled to 0 °C. A solution of (2-hydroxyethyl) dibenzyl phosphate (0.075 g, 0.233 mmol) prepared according to WO2010039474 in THF (1.5 mL) was added to the mixture. The mixture was heated to room temperature and stirred for 4 hours. The reaction mixture was filtered through diatomaceous earth and washed with DCM. The organic filtrate was washed with 1N HCl, dried over Na2SO4, filtered, and concentrated to give the title compound. MS (m / z) 366.80 [M+H2O–Cl]+.

[0350] Step 2: Preparation of 2-((bis(benzyloxy)phosphoryl)oxy)ethyl((3'S,5S,7'R)-10'-((2,4-difluorobenzyl)carbamoyl)-3,3'-dimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazo-5,6'-[2,7]bridged methylenepyrido[1,2-a][1,4]diazacyclic nonene]-12'-yl)carbonate: At 0°C, the (3'S,5S,7'R)-N-(2,4-difluorobenzyl)-12'-hydroxy-3,3'-dimethyl-1',11'- Dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]bridged methylenepyrido[1,2-a][1,4]diazacyclononene]-10'-formamide (intermediate B, 0.075 g, 0.154 mmol) and DIPEA (0.081 mL, 0.463 mmol) in a mixture of DMF (1 mL) was added to 2-((bis(benzyloxy)phosphoryl)oxy)ethyl chloroformate (0.089 g, 0.231 mmol). The reaction mixture was warmed to room temperature and stirred for 16 hours. Additional portions of 2-((bis(benzyloxy)phosphoryl)oxy)ethyl chloroformate (0.089 g, 0.231 mmol) and DIPEA (0.081 mL, 0.463 mmol) were added and stirred.Stir for 16 hours. Dilute the reaction mixture with EtOAc and wash with 5% LiCl (aqueous solution), water, and brine. Dry the organic phase over Na2SO4, filter, and concentrate to obtain the residue, which is purified by column chromatography (0% to 100% EtOAc / hexane) and reversed-phase preparative HPLC (5% to 100% MeCN / water) to give the title compound. MS (m / z) 834.89 [M+H]+.

[0351] Step 3: Preparation of (3'S,5S,7'R)-10'-((2,4-difluorobenzyl)carbamoyl)-3,3'-dimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazo-5,6'-[2,7]bridged methylenepyrido[1,2-a][1,4]diazacyclic nonene]-12'-yl(2-(phosphono)ethyl)carbonate (6): To 2-((bis(benzyl)phosphono)oxy)ethyl((3'S,5S,7'R)-10'-((2,4-difluorobenzyl)carbamoyl)-3,3'-dimethyl-1',11'-dioxo-1',4',5',11 '-Tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]bridged methylenepyrido[1,2-a][1,4]diazacyclononene]-12'-yl) carbonate (0.014 g, 0.017 mmol) was added to a solution of THF (2 mL) with 5% Pd / C (0.004 g, 0.002 mmol). The vial was evacuated and backfilled with hydrogen (2×), then aerated with hydrogen for 2 minutes. The reaction mixture was stirred for 2 hours under a hydrogen balloon atmosphere. The reaction mixture was filtered through diatomaceous earth, washed with THF, and concentrated. The residue was dissolved in 1:1 MeCN / water and lyophilized to give the title compound. MS (m / z) 654.99 [M+H]+. 1H NMR (400MHz, DMSO‑d6) δ 10.12 (t, J = 6.0Hz, 1H) , 8.85 (s, 1H) , 7.47 – 7.37 (m, 1H) , 7.25 (td , J = 10.0, 2.6Hz, 1H) , 7.14 – 7 .02 (m, 1H), 4.72 (s, 1H), 4.56 (dq, J = 15.3, 9.0, 7.7Hz, 3H), 4.39 – 4.26 (m, 2H), 4.05 (d, J = 6.2Hz, 2H), 3.83 (d, J = 15.8Hz, 1H),3.71 (d, J = 15.2Hz, 1H), 3.03 (d, J = 17.4Hz, 1H), 2.67 (d, J = 17.7Hz, 1H), 1.95 (s, 3H), 1.78 (d, J = 19.4Hz, 3H), 1.30 – 1.24 (m, 1H), 1.17 (d, J = 6.6Hz, 3H).

[0352] Example 7: Preparation of N-(2-((((3'S,5S,7'R)-10'-((2,4-difluorobenzyl)carbamoyl)-3,3'-dimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazol-5,6'-[2,7]bridged methylenepyrido[1,2-a][1,4]diazacyclononene]-12'-yl)oxy)carbonyl)oxy)ethyl)-N-(((phosphono)methoxy)carbonyl)glycine (7): Step 1: Preparation of (2-((tert-butyldimethylsilyl)oxy)ethyl)glycine benzyl ester: Under argon at 0°C, 2-((tert-butyldimethylsilyl)oxy)ethyl-1-amine (100g, 571.4 mmol) of benzyl 2-bromoacetate (64.85 g, 285.7 mmol) was added to a stirred solution in DCM (3.0 L), followed by the addition of DIPEA (81.0 g, 628.1 mmol). The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with DCM and washed with water. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (10% to 15% petroleum ether solution of EtOAc) to give the title compound. MS (m / z) 324.25 [M+H]+.

[0353] Step 2: Preparation of N-(2-((tert-butyldimethylsilyl)oxy)ethyl)-N-((chloromethoxy)carbonyl)glycine benzyl ester: Chloromethyl chloroformate (41.5 g, 321.9 mmol) was added to a stirred solution of (2-((tert-butyldimethylsilyl)oxy)ethyl)glycine benzyl ester (80 g, 247.6 mmol) in DCM (2.4 L) at 0 °C under argon atmosphere, followed by the addition of Et3N (62.5 g, 619 mmol). The mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with DCM and washed with water. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (20% to 30% petroleum ether solution of EtOAc) to give the title compound. MS (m / z)416.56 [M+H]+.

[0354] Step 3: Preparation of N-((((bis(benzyloxy)phosphoryl)oxy)methoxy)carbonyl)-N-(2-((tert-butyldimethylsilyl)oxy)ethyl)glycine benzyl ester: Dibenzyl silver phosphate (37 g, 96.08 mmol) was added to a stirred solution of N-(2-((tert-butyldimethylsilyl)oxy)ethyl)-N-((chloromethoxy)carbonyl)glycine benzyl ester (20 g, 48.08 mmol) in toluene (200 mL) under argon at room temperature. The mixture was stirred under reflux for 16 hours. The reaction mixture was cooled to room temperature and filtered, and the solids were washed with toluene (5V). The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (20% to 30% petroleum ether solution of EtOAc) to give the title compound. MS (m / z) 658.21 [M+H]+.

[0355] Step 4: Preparation of N-((((bis(benzyloxy)phosphoryl)oxy)methoxy)carbonyl)-N-(2-hydroxyethyl)glycine benzyl ester: At 0°C under argon, a 1,4-dioxane solution (9.8 mL, 39.2 mmol) of 4M HCl in 1,4-dioxane was added to a stirred solution of N-((((bis(benzyloxy)phosphoryl)oxy)methoxy)carbonyl)-N-(2-((tert-butyldimethylsilyl)oxy)ethyl)glycine benzyl ester (13 g, 19.76 mmol) in 1,4-dioxane (390 mL) under argon. The mixture was stirred at room temperature for 4 hours and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (50% EtOAc in petroleum ether solution). The pure fraction was collected and concentrated under reduced pressure. The substance was ground with n-pentane, filtered, and dried under vacuum to obtain the title compound. MS (m / z) 544.25 [M+H]+.

[0356] Step 5: Preparation of N-((((bis(benzyloxy)phosphoryl)oxy)methoxy)carbonyl)-N-(2-(((chlorocarbonyl)oxy)ethyl)glycine benzyl ester): Pyridine (0.289 mL, 3.59 mmol) was added to a solution of triphosgene (0.409 g, 1.38 mmol) in THF (12 mL), and the suspension was cooled to 0 °C. A solution of N-((((bis(benzyloxy)phosphoryl)oxy)methoxy)carbonyl)-N-(2-hydroxyethyl)glycine benzyl ester (1.50 g, 2.76 mmol) in THF (12 mL) was added to the solution. The suspension was heated to room temperature and stirred for 4 hours. The reaction mixture was filtered through diatomaceous earth and washed with DCM. The organic filtrate was washed with 1N HCl, dried over Na2SO4, filtered, and concentrated. MS (m / z) 605.70 [M+H]+.

[0357] Step 6: Preparation of N-((((bis(benzyloxy)phosphoryl)oxy)methoxy)carbonyl)-N-(2-(((((3'S,5S,7'R)-10'-((2,4-difluorobenzyl)carbamoyl)-3,3'-dimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazo-5,6'-[2,7]bridged methylenepyrido[1,2-a][1,4]diazacyclic nonene]-12'-yl)oxy)carbonyl)oxy)ethyl)glycine benzyl ester: At 0°C, the (3'S,5S,7'R)-N-(2,4-difluorobenzyl)-12'-hydroxy-3,3'-dimethyl-1',11'- Dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]bridged methylenepyrido[1,2-a] [1,4]diazacyclononene]-10'-formamide (intermediate B, 0.895 g, 1.84 mmol) and DIPEA (0.96 mL, 5.52 mmol) in a suspension in DMF (8 mL) was supplemented with N-((((bis(benzyloxy)phosphoryl)oxy)methoxy)carbonyl)-N-(2-((chlorocarbonyl)oxy)ethyl)glycine benzyl ester (1.67 g, 2.76 mmol). The reaction mixture was warmed to room temperature and stirred for 16 hours. The reaction mixture was diluted with EtOAc and washed with 5% LiCl (aqueous solution), water, and brine. The organic phase was dried over Na₂SO₄, filtered, and concentrated to obtain a residue, which was purified by silica gel column chromatography (0% to 100% EtOAc / hexane). The residue was then purified by reversed-phase preparative HPLC (5% to 100% MeCN / water) to obtain the title compound. MS (m / z) 1055.96 [M+H]+.

[0358] Step 7: Preparation of N-(2-(((((3'S,5S,7'R)-10'-((2,4-difluorobenzyl)carbamoyl)-3,3'-dimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazo-5,6'-[2,7]bridged methylenepyrido[1,2-a][1,4]diazacyclic nonene]-12'-yl)oxy)carbonyl)oxy)ethyl)-N-(((phosphono)methoxy)carbonyl)glycine (7): To N-((((bis(benzyloxy)phosphono)oxy)methoxy)carbonyl)-N-(2-((((3'S,5S,7'R)-10'- ((2,4-difluorobenzyl)carbamoyl)-3,3'-dimethyl-1',11'-dioxo-1',4',5',11'-Tetrahydro-3'H,4H,7'H-spiro[isoxazo-5,6'-[2,7]bridged methylenepyrido[1,2-a][1,4]diazacyclononene]-12'-yl)oxy)carbonyl)oxy)ethyl)glycine benzyl ester (1.32 g, 1.25 mmol) was added to a solution of 10% Pd / C (0.133 g, 0.125 mmol) in THF (100 mL). The flask was evacuated and backfilled with hydrogen (2×), then aerated with hydrogen for 2 min. The reaction mixture was stirred for 4 h under a hydrogen balloon atmosphere. The reaction mixture was filtered, washed with THF, and concentrated to give the title compound. MS (m / z) 785.88 [M+H]+. 1H NMR (400MHz, DMSO‑d6) δ 10 .12 (t , J = 6 .0Hz , 1H) , 8.85 (s, 1H) , 7.42 (td , J = 8.7, 6.5Hz, 1H) , 7.25 (ddd , J = 10.4, 9.3, 2.6Hz, 1H) , 7.08 (td, J = 8.7, 2.7Hz, 1H) , 5.54 – 5.38 (m, 2H) , 4.72 (s, 1H) , 4.56 (qt, J = 14.9, 6.7Hz, 3H) , 4.32 (dt, J = 14.7, 5.8Hz, 2H), 4.04 (d, J = 25.5Hz, 2H), 3.82 (d, J = 16.5Hz, 1H), 3.71 (d, J = 14.8Hz, 1H). 3.67 – 3.51 (m, 2H), 3.03 (d, J = 17.5Hz, 1H), 2.66 (d, J = 17.5Hz, 1H), 1.95 (s, 3H), 1.87 – 1.72 (m, 3H), 1.25 (dd, J = 15.8, 9.3Hz, 1H), 1.17 (d, J = 6.7Hz, 3H).

[0359] Example 8: Preparation of N-(2-(((((3'S,5S,7'R)-10'-((2,4-difluorobenzyl)carbamoyl)-3-methoxy-3'-methyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazo-5,6'-[2,7]bridged methylenepyrido[1,2-a][1,4]diazacyclic nonene]-12'-yl)oxy)methoxy)carbonyl)oxy)ethyl)-N-(((phosphono)methoxy)carbonyl)glycine (8): Specification96 / 189 Page 144 CN 122055373 A Step 1: Preparation of N-((((bis(benzyloxy)phosphoryl)oxy)methoxy)carbonyl)-N-(2-((((((3'S,5S,7'R)-10'-((2,4-difluorobenzyl)carbamoyl)-3-methoxy-3'-methyl-1',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazo-5,6'-[2,7]bridged methylenepyrido[1,2-a][1,4]diazacyclononene]-12'-yl)oxy)methoxy)carbonyl)oxy)ethyl)glycine benzyl ester: To (((3'S,5S,7'R)-10'-((2,4-difluorobenzyl)carbamoyl)-3-methoxy-3'-methyl-1', A solution of 11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazol-5,6'-[2,7]bridged methylenepyrido[1,2-a][1,4]diazacyclononene]-12'-yl)oxy)methyl(4-nitrophenyl) carbonate (intermediate E, 0.100 g, 0.143 mmol) in MeCN (2 mL) was supplemented with Et3N (0.060 mL, 0.430 mmol) and DMAP (0.002 g, 0.014 mmol), followed by N-((((bis(benzyloxy)phosphoryl)oxy)methoxy)carbonyl)-N-(2-hydroxyethyl)glycine benzyl ester (0.234 g, 0.430 mmol) prepared according to step 4 of Example 7. The reaction mixture was stirred at room temperature for 16 hours and concentrated. The residue was purified by silica gel column chromatography (0% to 100% EtOAc / hexane, followed by 0% to 20% MeOH / DCM) to obtain the title compound. MS (m / z) 1101.92 [M+H]+.

[0360] Step 2: Preparation of N-(2-(((((3'S,5S,7'R)-10'-(((2,4-difluorobenzyl)carbamoyl)-3-methoxy-3'-methyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazo-5,6'-[2,7]bridged methylenepyrido[1,2-a][1,4]diazacyclononene]-12'-yl)oxy)methoxy)carbonyl)oxy)ethyl)-N-(((phosphono)methoxy)carbonyl)glycine (8): To N-((((bis(benzyloxy)phosphono)oxy)methoxy)carbonyl)-N-(2-(((((3'S,5S,7'R)- 10'-((2,4-difluorobenzyl)carbamoyl)-3-methoxy-3'-methyl-1',11'-tetrahydro-3'H,4H,7'H-spiro[iso]Oxazol-5,6'-[2,7]bridged methylenepyrido[1,2-a][1,4]diazacyclononene]-12'-yl)oxy)methoxy)carbonyl (C)carboxylic acid benzyl ester (0.063 g, 0.057 mmol) was added to a solution of THF (5 mL) with 5% Pd / C (0.012 g, 0.006 mmol). The vial was evacuated and backfilled with hydrogen (2×), then aerated with hydrogen for 2 min. The reaction mixture was stirred for 2 h under a hydrogen balloon atmosphere. The reaction mixture was filtered and concentrated to give a crude residue, which was dissolved in 1:1 MeCN / water and purified by reversed-phase preparative HPLC (10% to 100% MeCN / water containing 0.1% TFA) to give the title compound after lyophilization. MS (m / z) 831.82 [M+H]+. 1H NMR (400MHz, DMSO‑d6) δ 10.26 (t, J = 6.0Hz, 1H), 8.75 (s, 1H), 7.42 (q, J = 8.3Hz, 1H), 7.24 (td, J = 9.9, 2.7Hz, 1H) , 7.07 (td, J = 8.5, 2.5Hz, 1H) , 5.82 (d, J = 6.5Hz, 1H) , 5.64 (dd, J = 6.5, 2.7Hz, 1H) , 5.44 (dd, J = 14.8, 13.0Hz, 2H) , 4.71 (s, 1H) , 4.58 (dt, J = 20.7, 7.7Hz, 3H), 4.20 (t, J = 6.5Hz, 2H), 4.04 (s, 1H), 3.98 (s, 1H), 3.82 (s, 3H), 3.68 (d, J = 6.5Hz, 2H), 3.54 (t, J = 5.2Hz, 2H) , 3.05 (d , J = 16.8Hz, 1H) , 2.75 (d, J = 16.9Hz, 1H) , 1.98 – 1.69 (m, 3H) ,1.32 (s, 1H) , 1.15 (d, J = 6.6Hz, 3H).

[0361] Example 9: (((3'S,5S,7'R)-10'-((2,4-difluorobenzyl)carbamoyl)-3,3'-dimethyl-1',Preparation of 11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]bridged methylenepyrido[1,2-a][1,4]diazacyclononene]-12'-yl)oxy)methyl((phosphono)methyl)ethane-1,2-dimethylbis(methylcarbamate) (9): Instruction manual 98 / 189 pages 146 CN 122055373 A Step 1: Preparation of tert-butyl(chloromethyl)ethane-1,2-dimethylbis(methylcarbamate): 0.500 g, 2.66 mmol of methyl (2-(methylamino)ethyl)carbamate tert-butyl ester) was added to DCM at 0 °C. DIPEA (0.694 mL, 3.98 mmol) and chloromethyl chloroformate (0.283 mL, 3.19 mmol) were added to a solution in (3 mL). The reaction mixture was stirred at 0 °C for 2 hours and concentrated. The residue was purified by silica gel column chromatography (10% to 100% EtOAc / hexane) to give the title compound. MS (m / z) 180.99 [M-Boc+H]+.

[0362] Step 2: Preparation of ((bis(benzyloxy)phosphoryl)oxy)methyl tert-butylethane-1,2-dimethylbis(methylcarbamate): Dibenzylsilver phosphate (0.412 g, 1.07 mmol) was added to a solution of tert-butyl(chloromethyl)ethane-1,2-dimethylbis(methylcarbamate) (0.100 g, 0.356 mmol) in toluene (12 mL), and the reaction mixture was heated to reflux for 2 hours. The reaction mixture was cooled to room temperature and concentrated. The residue was purified by silica gel column chromatography (10% to 100% EtOAc / hexane) to give the title compound. MS (m / z) 545.03 [M+Na]+.

[0363] Step 3: Preparation of ((bis(benzyloxy)phosphoryl)oxy)methylmethyl(2-(methylamino)ethyl)carbamate; Specification 99 / 189 pages 147 CN 122055373 A fluoroacetic acid adduct: A solution of TFA (0.872 mL, 11.4 mmol) in DCM (1 mL) was added to a solution of ((bis(benzyloxy)phosphoryl)oxy)methyl tert-butylethane-1,2-dimethylbis(methylcarbamate) (0.186 g, 0.356 mmol) in DCM (2.5 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 1 hour. The reaction mixture was concentrated to dryness, then dissolved in 1 mL of DCM and concentrated again. The residue was dried under high vacuum to give the title compound, a 2,2,2-trifluoroacetic acid adduct. MS (m / z) 423.03 [M+H]+.

[0364] Step 4: Preparation of ((bis(benzyloxy)phosphoryl)oxy)methyl((((3'S,5S,7'R)-10'-((2,4-difluorobenzyl)carbamoyl)-3,3'-dimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazo-5,6'-[2,7]bridged methylenepyrido[1,2-a][1,4]diazacyclic nonene]-12'-yl)oxy)methyl)ethane-1,2-dimethylbis(methylcarbamate): At room temperature, to (((3'S,5S,7'R)-10'-((2,4-difluorobenzyl)carbamoyl)-3,3'-dimethyl- 1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazo-5,6'-[2,7]bridged methylenepyrido[1,2-a][1,4]diazacyclononene]-12'-yl)oxy)methyl(4-nitrophenyl)carbonate (intermediate D) (0.130 g, 0.191 mmol) and ((bis(benzyloxy)phosphoryl)oxy)methylmethyl(2-(methylamino)ethyl)carbamate trifluoroacetic acid adduct) (0.153 g, 0.286 mmol) in a solution of DCM (8 mL) were supplemented with Et3N (0.798 mL, 5.72 mmol). The reaction mixture was concentrated and purified by reversed-phase preparative HPLC (5% to 100% MeCN / water containing 0.1% TFA) and lyophilized to give the title compound. MS (m / z) 964.76 [M+H]+.

[0365] Step 5: Preparation of (((3'S,5S,7'R)-10'-((2,4-difluorobenzyl)carbamoyl)-3,3'-dimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazol-5,6'-[2,7]bridged methylenepyrido[1,2-a][1,4]diazacyclononene]-12'-yl)oxy)methyl((phosphono)methyl)ethane-1,2-dimethylbis(methylcarbamate) (9): To ((bis(benzyl)phosphono)oxy)methyl((((3'S,5S,7'R)-10'-((2,4-difluorobenzyl)carbamoyl)-3,3'-dimethyl-1',11) '-Dioxo-1',4',5',11'-Tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]bridged methylenepyrido[1,2-a][1,4]diazacyclononene]-12'-yl)oxy)methyl)ethane-1,2-dimethylbis(methylcarbamate) (0.084 g, 0.087 mmol) was added to a solution of 5% Pd / C (0.018 g, 0.018 mmol) in THF (8 mL).0.009 mmol). The vial was evacuated and backfilled with hydrogen (2×), then aerated with hydrogen for 2 minutes. The reaction mixture was stirred for 2 hours under a hydrogen balloon atmosphere. The reaction mixture was filtered through diatomaceous earth, washed with THF, and concentrated. The residue was dissolved in 1:1 MeCN / water and lyophilized to give the title compound. MS (m / z) 784.80 [M+H]+. 1H NMR (400MHz, DMSO‑ d6) δ 10.32 (t, J = 6.0Hz, 1H) , 8.67 (d , J = 1.8Hz, 1H) , 7.43 (td , J = 8.6, 6.6Hz, 1H) , 7.25 (ddd , J = 10.5, 9.3, 2.6Hz, 1H) , 7.08 (td , J = 8.6, 2.6Hz, 1H) , 5.76 – 5.56 (m, 2H) , 5.48 – 5.33 (m, 2H) , 4.64 (d, J = 10.9Hz, 2H) , 4.59 – 4.50 (m, 2H) , 3.69 (d , J = 13.9Hz, 1H) , 3.65 (s, 1H) , 3.33 (s, 4H) , 3.03 – 2.93 (m, 1H) , 2.88 – 2.74 (m, 6H) , 2.63 (dd , J = 17.9, 4.8Hz, 1H), 1.95 (s, 3H), 1.77 (dd, J = 16.9, 9.8Hz, 3H), 1.37 – 1.20 (m, 1H), 1.15 (d, J = 6.6Hz, 3H).

[0366] Example 10: Preparation of (((3'S,5S,7'R)-10'-((2,4-difluorobenzyl)carbamoyl)-3,3'-dimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazo-5,6'-[2,7]bridged methylenepyrido[1,2-a][1,4]diazacyclononene]-12'-yl)oxy)methyl(3-(phosphono)propyl)carbonate (10): Specification 100 / 189 pages 148 CN 122055373 A Step 1: Preparation of (3-hydroxypropyl)dibenzyl phosphate: N was added to a solution of propane-1,3-diol (0.22 g, 2.89 mmol) N-Diisopropylethylamine (0.79 ml, 4.4 mmol), followed by the sequential addition of tetrabenzyl pyrophosphate (0.95 g, 1.76 mmol) and titanium isopropoxide (IV) (0.085 g, 4.4 mmol).0.3 mmol). The resulting mixture was stirred at room temperature for 4 hours. The reaction mixture was then filtered through a silica gel / magnesium sulfate mixture (20:1) pad, and the solids were washed with ethyl acetate / hexane. The filtrate was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by normal-phase silica gel chromatography to give the title compound. MS (m / z) 337.2 [M+H]+.

[0367] Step 2: Preparation of 3-((bis(benzyloxy)phosphoryl)oxy)propyl(chloromethyl) carbonate: 3-hydroxypropyl dibenzyl phosphate (0.5 g, 1.5 mmol) was added to a stirred mixture of chloromethyl chloroformate (0.145 mL, 1.64 mmol) in CH2Cl2 (10 mL), followed by the dropwise addition of pyridine (0.14 mL, 1.87 mmol) at room temperature. The reaction was stirred overnight, then diluted with DCM and washed sequentially with HCl (0.5 M) and water. The organic layer was dried over magnesium sulfate, filtered, and evaporated to give the title compound. MS (m / z) 428.9 [M+H]+.

[0368] Step 3: Preparation of 3-((bis(benzyloxy)phosphoryl)oxy)propyl((((3'S,5S,7'R)-10'-((2,4-difluorobenzyl)carbamoyl)-3,3'-dimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazo-5,6'-[2,7]bridged methylenepyrido[1,2-a][1,4]diazacyclononene]-12'-yl)oxy)methyl)carbonate: To (3'S,5S,7'R)-N-(2,4-difluorobenzyl)-12'-hydroxy-3,3'-dimethyl-1',11'-dioxo- 1',4',5',11'-Tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]bridged methylenepyrido[1,2-a][1,4]diazacyclononene]-10'-carboxamide (intermediate B, 0.08 g, 0.164 mmol) was added to a solution of acetone (20 mL) with KI (0.036 mg, 0.21 mmol) and K2CO3 (0.046 g, 0.329 mmol), followed by the addition of 3-((bis(benzyloxy)phosphoryl)oxy)propyl(chloromethyl)carbonate (0.085 g, 0.197 mmol). The resulting mixture was stirred overnight at room temperature and then concentrated. The residue was purified by silica gel column chromatography (0%–100% EtOAc / hexane) to obtain the title compound. MS (m / z) 878.9 [M+H]+.

[0369] Step 4: (((3'S,5S,7'R)-10Preparation of '-((2,4-difluorobenzyl)carbamoyl)-3,3'-dimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazo-5,6'-[2,7]bridged methylenepyrido[1,2-a][1,4]diazacyclic nonene]-12'-yl)oxy)methyl(3-(phosphono)propyl)carbonate (10): Pd / C (5% by weight) (0.020 g, 0.0009 mmol) was added to a solution of 3-((bis(benzyloxy)phosphoryl)oxy)propyl((((3'S,5S,7'R)-10'-((2,4-difluorobenzyl)carbamoyl)-3,3'-dimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazo-5,6'-[2,7]bridged methylenepyrido[1,2-a][1,4]diazacyclononene]-12'-yl)oxy)methyl)carbonate (0.08 g, 0.009 mmol) in THF (20 ml). The resulting mixture was purged three times with hydrogen and then stirred under hydrogen for 1 hour. The reaction was then filtered through a Celite® filter and concentrated. The residue was purified by reversed-phase preparative HPLC to obtain the title compound. MS (m / z) 698.88 [M+ H]+. 1H NMR (400MHz, DMSO‑d6) δ 10.28 (t, J = 6.0Hz, 1H) , 8.71 (s, 1H) , 7.43 (td , J = 8.7, 6.6Hz, 1H) , 7.25 (ddd , J = 10.6, 9.3, 2.6Hz, 1H), 7.13 – 7.03 (m, 1H), 5.83 (d, J = 6.5Hz, 1H), 5.64 (d, J = 6.5Hz, 1H), 4.71 – 4.47 (m, 5H), 4.14 (ddt, J = 10.9, 6 .3, 4.4Hz, 2H), 3.88 (dt, J = 7.5, 6.3Hz, 2H), 3.68 (t, J = 2.3Hz, 2H), 3.01 (d, J = 17.5Hz, 1H), 2.63 (d, J = 17.6Hz, 1H), 1.97 – 1.86 (m, 4H), 1.91 – 1.75 (m, 2H), 1.79 – 1.69 (m, 1H), 1.35 – 1.23 (m, 1H), 1.16(d, J = 6.7Hz, 3H).

[0370] Example 11: Preparation of (3'S,5S,7'R)-10'-((2,4-difluorobenzyl)carbamoyl)-3,3'-dimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]bridged methylenepyrido[1,2-a][1,4]diazacyclononene]-12'-yl(3-(phosphono)propyl)carbonate (11): Specification 102 / 189 pages 150 CN 122055373 A Step 1: Preparation of 3-((bis(benzyl)phosphono)oxy)propyl chloroformate: To triphosgene (0.088g, 0 Add pyridine (90.062 mL, 0.773 mmol) to a solution of (0.297 mmol) in THF (1 mL), and cool the resulting suspension to 0 °C. Add a solution of (3-hydroxypropyl)dibenzyl phosphate (0.2 g, 0.595 mmol) in THF (1 mL) to the mixture. Heat the suspension to room temperature and stir for 4 hours. Filter the mixture through diatomaceous earth and wash with DCM. Wash the filtrate with 1N HCl, dry with Na2SO4, filter, concentrate, and use directly in the next step.

[0371] Step 2: Preparation of 3-((bis(benzyloxy)phosphoryl)oxy)propyl((3'S,5S,7'R)-10'-((2,4-difluorobenzyl)carbamoyl)-3,3'-dimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazo-5,6'-[2,7]bridged methylenepyrido[1,2-a][1,4]diazacyclic nonene]-12'-yl)carbonate: At 0°C, the (3'S,5S,7'R)-N-(2,4-difluorobenzyl)-12'-hydroxy-3,3'-dimethyl-1',11'- Dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]bridged methylenepyrido[1,2-a][1,4]diazacyclononene]-10'-carboxamide (intermediate B, 0.1 g, 0.21 mmol) and DIPEA (0.11 mL, 0.62 mmol) were added to a suspension in DMF (1 mL) with 3-((bis(benzyloxy)phosphoryl)oxy)propyl chloroformate (0.123 g, 0.31 mmol). The reaction mixture was then warmed to room temperature and stirred overnight. The reaction mixture was diluted with EtOAc and washed with 5% LiCl (aqueous solution), water, and brine. The organic phase was dried over MgSO4, filtered, and concentrated to give a residue, which was purified by silica gel column chromatography (0% to 100% EtOAc / hexane) to give the title compound.(m / z) 849.40 [M+ H]+.

[0372] Step 3: Preparation of (3'S,5S,7'R)-10'-((2,4-difluorobenzyl)carbamoyl)-3,3'-dimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]bridged methylenepyrido[1,2-a][1,4]diazacyclic nonene]-12'-yl(3-(phosphono)propyl)carbonate (11): The title compound was prepared by the same method as in step 4 of Example 10, except that 3-((bis(benzyl)phosphono)oxy)propyl((3'S,5S,7'R)-10'-((2,4-difluorobenzyl)carbamoyl)-3, 3'-Dimethyl-1',11'-Dioxo-1',4',5',11'-Tetrahydro-3'H,4H,7'H-Spiro[isoxazole-5,6'-[2,7]bridge Specification 103 / 189 pages 151 CN 122055373 A Methylpyrido[1,2-a][1,4]diazacyclic nonene]-12'-yl)carbonate substituted for 3-((bis(benzyloxy)phosphoryl)oxy)propyl((((3'S,5S,7'R)-10'-((2,4-difluorobenzyl)carbamoyl)-3,3'-dimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazo-5,6'-[2,7]bridged methylenepyrido[1,2-a][1,4]diazacyclic nonene]-12'-yl)oxy)methyl)carbonate. MS (m / z) 668.88 [M+H]+. 1H NMR (400MHz, chloroform‑d) δ 10.27 (s , 1H) , 8.59 (s , 1H) , 7.42 – 7.32 (m , 1H) , 6.94 – 6.75 (m, 2H) , 4.74 (d, J = 8.5Hz, 1H) , 4.61 (d, J = 5.7Hz, 2H), 4.43 (s, 2H), 4.22 (d, J = 34.6Hz, 3H), 3.81 (s, 2H), 3.09 (d, J = 17.8Hz, 1H), 2.63 (d, J = 17.9Hz, 1H) , 2.08 (m , 5H), 2.01 – 1.81 (m, 3H), 1.57 (t, J = 10.3Hz, 1H), 1.25 (d, J = 6.5Hz, 3H).

[0373] Example 12: (((3'S,5S,7Preparation of 'R)-10'-((2,4-difluorobenzyl)carbamoyl)-3,3'-dimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazo-5,6'-[2,7]bridged methylenepyrido[1,2-a][1,4]diazacyclononene]-12'-yl)oxy)methyl(2,2-dimethyl-3-(phosphonooxy)propyl)carbonate (12): The title compound was prepared by the same method as in Example 10, except that in step 1, propane-1,3-diol was replaced by 2,2-dimethylpropane-1,3-diol. MS (m / z) 726.91 [M+H]+. 1H NMR (400MHz, chloroform‑d) δ 10.28 (s, 1H) , 8.43 (s, 1H) , 7.38 (q, J = 7.9Hz, 1H) , 6.82 (q , J = 9.3Hz, 2H) , 5.93 (d , J = 6.6Hz, 1H) , 5.79 (d , J = 6.7Hz, 1H) , 4.85 (d , J = 8.9Hz, 1H) , 4.62 (q, J = 14.2, 12.8Hz, 2H) , 4.22 (s, 1H) , 3.98 (d , J = 10.4Hz, 1H) , 3.90 (d , J = 10.3Hz, 1H) , 3.77 (m, 4H) , 3.03 (d , J = 17.8Hz, 1H) , 2.60 (d, J = 17.8Hz, 1H) , 2.08 (s, 3H) , 1.94 (s, 3H) , 1.52 (m, 1H) , 1.30 – 1.23 (m, 3H), 0.97 (d, J = 7.3Hz, 6H).

[0374] Example 13: Preparation of (3'S,5S,7'R)-10'-((2,4-difluorobenzyl)carbamoyl)-3,3'-dimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazo-5,6'-[2,7]bridged methylenepyrido[1,2-a][1,4]diazacyclononene]-12'-yl(2,2-dimethyl-3-(phosphono)propyl) carbonate (13): Specification 104 / 189 pages 152 CN 122055373 A The title compound was prepared by the same method as in Example 11, except that in step 1, propane-1,3-diol was replaced by 2,2-dimethylpropane-1,3-diol. MS (m / z)696.9 [M+H]+. 1H NMR (400MHz, chloroform‑d) δ 10.23 (t, J = 6.0Hz, 1H), 8.56 (s, 1H), 7.35 (td, J = 8.5, 6.3Hz, 1H), 6.90 – 6.76 (m, 2H), 4.79 – 4.68 (m, 1H), 4.62 (d, J = 5.9Hz, 2H), 4.25 (d, J = 2.2Hz, 1H), 4.12 (s, 2H), 3.88 – 3.76 (m, 4H), 3.08 (d, J = 17.9Hz, 1H) , 2.62 (d , J = 17.9Hz, 1H), 2.07 (s, 3H), 1.99 – 1.85 (m, 3H), 1.59 – 1.50 (m, 1H), 1.25 (d, J = 6.6Hz, 3H), 1.00 (d, J = 4.5Hz, 6H).

[0375] Example 14: Preparation of (((3'S,5S,7'R)-10'-((2,4-difluorobenzyl)carbamoyl)-3,3'-dimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazol-5,6'-[2,7]bridged methylenepyrido[1,2-a][1,4]diazacyclononene]-12'-yl)oxy)methyl(2-(dimethylamino)ethyl)carbonate (14): (((3'S,5S,7'R)-10'-((2,4-difluorobenzyl)carbamoyl)-3,3'-dimethyl- 1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazol-5,6'-[2,7]bridged methylenepyrido[1,2-a][1,4]diazacyclononene]-12'-yl)oxy)methyl(4-nitrophenyl)carbonate (intermediate D, 32 mg, 0.0467 mmol) and 2-(dimethylamino)ethanol (21 mg, 0.233 mmol) were mixed with acetonitrile (1 ml). Et3N (23.6 mg, 0.233 mmol) and DMAP (0.854 mg, 0.007 mmol) were then added. The resulting reaction mixture was then stirred at room temperature for 17 hours. The reaction mixture was purified by reversed-phase preparative HPLC (using an aqueous solution of 0% to 100% acetonitrile containing 0.1% TFA) to give the title compound as a TFA salt after lyophilization. Calculated value of C30H35F2N5O8: 631.25, Measured MS (ESI+): 632.41 [M+H]+; 1H NMR (400MHz, acetonitrile-d3) δ 10.23 (s, 1H), 8.52 (s, 1H), 7.58 – 7.30 (m, 1H), 6.98 (ddt, J = 13.5, 8.5, 3.1Hz, 2H), 5.97 (d, J = 6.5Hz, 1H), 5.76 (d, J = 6.6Hz, 1H), 4.86 – 4.68 (m, 1H), 4.61 (d, J = 5.9Hz, 2H), 4.51 (qt, J = 13.3, 5.0Hz, 2H) , 4.31 (s, 1H) , 3.70 (d,J= 2.3Hz, 2H) , 3.43 (t,J= 5.0Hz, 2H) , 3.06 (d ,J= 17.9Hz, 1H) , 2.85 (s, 6H) , 2.61 (d,J= 17.8Hz, 1H), 1.99 (s, 3H), 1.94 – 1.78 (m, 3H), 1.43 (dd,J= 15.4, 10.8Hz, 1H), 1.21 (d,J= 6.7Hz, 3H).

[0376] Example 15: Preparation of 2-(((((3'S,5S,7'R)-10'-((2,4-difluorobenzyl)carbamoyl)-3,3'-dimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazo-5,6'-[2,7]bridged methylenepyrido[1,2-a][1,4]diazacyclononene]-12'-yl)oxy)methoxy)carbonyl)oxy)-N,N,Ntrimethylethyl-1-ammonium trifluoroacetic acid (15): Specification 105 / 189 pages 153 CN 122055373 A At room temperature, (((3'S,5S,7'R)-10'-((2,4-difluorobenzyl)carbamoyl)-3,3'-dimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazo-5,6'-[2,7]bridged methylenepyrido[1,2-a][1,4]diazacyclononene]-12'-yl)oxy)methyl(4-nitrophenyl) carbonate (intermediate D, 33 mg, 0.0484 mmol) and 2-hydroxy-N,N,N-trimethylethyl-1-ammonium chloride (33.8 mg, 0.242 mmol) were mixed with acetonitrile (1 ml).Then Et3N (24.5 mg, 0.242 mmol) and DMAP (0.854 mg, 0.007 mmol) were added. The resulting reaction mixture was then stirred at room temperature for 17 hours. The reaction mixture was purified by reversed-phase preparative HPLC (using 0% to 100% aqueous acetonitrile containing 0.1% TFA) to give the title compound as a TFA salt after lyophilization. Calculated value of C31H38F2N5O8+: 646.27, Found MS (ESI+): 646.14 [M]+. 1H NMR (400MHz, CD3CN) δ 10.25 (t, J = 5.8Hz, 1H), 8.54 (s, 1H), 7.44 (td, J = 8.8, 6.4Hz, 1H), 7.04 – 6.93 (m, 2H), 6.03 (d, J = 6.6Hz, 1H), 5.79 (d, J = 6.6Hz, 1H), 4.72 (dt, J = 9.9, 6.9Hz, 1H), 4.61 (d, J = 6.0Hz, 2H), 4.67-4.48 (m, 2H), 4 .32 (s, 1H) , 3.70 (t, J = 2.0Hz, 2H), 3.67 (t, J = 4.7Hz, 2H), 3.14 (s, 9H), 3.07 – 3.03 (dd, J = 17.8, 1.1Hz, 1H), 2.61 (dd, J = 17.8, 1.1Hz, 1H), 1.99 (d, J = 1.1Hz, 3H), 1.94 – 1.79 (m, 3H), 1.45 – 1.34 (m, 1H), 1.22 (d, J = 6.7Hz, 3H).

[0377] Example 16: Preparation of 2-((((3'S,5S,7'R)-10'-((2,4-difluorobenzyl)carbamoyl)-3,3'-dimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazo-5,6'-[2,7]bridged methylenepyrido[1,2-a][1,4]diazacyclononene]-12'-yl)oxy)methoxy)carbonyl)oxy)-N,N,N-trimethylethyl-1-ammonium trifluoroacetic acid (16): Specification 106 / 189 pages 154 CN 122055373 A Step 1: Synthesis of 2-((chlorocarbonyl)oxy)-N,N,N-trimethylethyl-1-ammonium chloride: At room temperature, 2-hydroxy-N,N,N-trimethylethyl-1-ammonium chloride (1 g, 7.16 mmol) was mixed with THF (50 mL) to obtain a slurry. Triphosgene (2.34 g, 7.88 mmol) was added in four portions at 0 °C. The reaction mixture was then warmed to room temperature and stirred for 24 hours. The reaction mixture was filtered and the solid was collected. The solid was washed with hexane (3 × 30 mL). The solid product 2-((chlorocarbonyl)oxy)-N,N,N-trimethylethyl-1-ammonium chloride was placed under high vacuum for 3 hours and used directly in the next step. MS (m / z) 166.10 [M]+.

[0378] Step 2: Synthesis of 2-(((((3'S,5S,7'R)-10'-((2,4-difluorobenzyl)carbamoyl)-3,3'-dimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazol-5,6'-[2,7]bridged methylenepyrido[1,2-a][1,4]diazacyclononene]-12'-yl)oxy)methoxy)carbonyl)oxy)-N,N,N-trimethylethyl-1-ammonium trifluoroacetate (16): At room temperature, (3'S,5S,7'R)-N-(2,4-difluorobenzyl)-12'-hydroxy-3,3'-dimethyl-1',11'- Dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazol-5,6'-[2,7]bridged methylenepyrido[1,2-a][1,4]diazacyclononene]-10'-carboxamide (intermediate B, 103 mg, 0.212 mmol) was dissolved in DMF (3 mL). DIPEA (137 mg, 1.06 mmol) and 2-((chlorocarbonyl)oxy)-N,N,N-trimethylethyl-1-ammonium chloride (66 mg, 0.327 mmol) were added sequentially at room temperature. The reaction mixture was stirred for 17 hours. The compound was purified directly by reversed-phase preparative HPLC with ACN / water (containing 0.1% TFA) to give the title compound (16). Calculated value of C30H36F2N5O7+: 616.26, measured value (MS (M+): 616.37); 1H NMR (400MHz, CD3CN) δ 10.11 (t, J = 5.9Hz, 1H), 8.63 (s, 1H), 7.44 (td, J = 8.8, 6.5Hz, 1H), 7.04 – 6.93 (m, 2H), 4.76 – 4.66 (m, 3H), 4.61 (d, J = 6.0Hz, 2H), 4.40 (d, J = 2.5Hz, 1H), 3.75 (d, J = 2.3Hz, 2H), 3.74 – 3.70 (m,2H), 3.17 (s, 9H), 3.06 (d, J = 17.8Hz, 1H), 2.62 (d, J = 17.8Hz, 1H), 1.99 (s, 3H), 1.95 – 1.82 (m, 3H), 1.38 (ddt, J = 13.2, 10.0, 5.0Hz, 1H), 1.22 (d, J = 6.7Hz, 3H).

[0379] Example 17: Preparation of (((3'S,5S,7'R)-10'-((2,4-difluorobenzyl)carbamoyl)-3,3'-dimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazo-5,6'-[2,7]bridged methylenepyrido[1,2-a][1,4]diazacyclononene]-12'-yl)oxy)methyl((S)-2-(phosphonooxy)propyl)carbonate (17): Specification 107 / 189 pages 155 CN 122055373 A Step 1: Preparation of (S)-dibenzyl(1-hydroxypropyl-2-yl)phosphate and (S)-dibenzyl(2-hydroxypropyl)phosphate: DIPEA (1.66 mL, 9.25 mmol) was added to a mixture of (S)-propane-1,2-diol (0.44 mL, 4.16 mmol) and DCM (2.7 mL), followed by the addition of tetrabenzyl pyrophosphate (2.00 g, 3.71 mmol) and Ti(i-PrO)₄ (0.19 mL, 0.631 mmol). The mixture was stirred at room temperature for 16 hours. MgSO₄ and silica gel were added to the reaction mixture, stirred for 10 minutes, and filtered, washed with 4:3 EtOAc / hexane. The filtrate was concentrated and purified by reversed-phase preparative HPLC (10% to 100% MeCN / water) to give the title compound as an inseparable mixture of regioisomers (rr = 1.1:1) by NMR. MS (m / z) 336.99 [M+H]⁺.

[0380] Step 2: Preparation of (S)-2-((bis(benzyloxy)phosphoryl)oxy)propyl((((3'S,5S,7'R)-10'-((2,4-difluorobenzyl)carbamoyl)-3,3'-dimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazo-5,6'-[2,7]bridged methylenepyrido[1,2-a][1,4]diazacyclononene]-12'-yl)oxy)methyl)carbonate:Add Et3N (0.153 mL, 1.10 mmol) and DMAP (0.004 g, 0.367 mmol) to a solution of (((3'S,5S,7'R)-10'-((2,4-difluorobenzyl)carbamoyl)-3,3'-dimethyl-1',11'-dioxane-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]bridged methylenepyrido[1,2-a][1,4]diazacyclononene]-12'-yl)oxy)methyl(4-nitrophenyl)carbonate (intermediate D) (0.250 g, 0.367 mmol) in MeCN (5 mL) to a solution of (((3'S,5S,7'R)-10'-((2,4-difluorobenzyl)carbamoyl)-3,3'-dimethyl-1',11'-dioxane-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]bridged methylenepyrido[1,2-a][1,4]diazacyclononene]-12'-yl)oxy)methyl(4-nitrophenyl)carbonate (intermediate D) (0.250 g, 0.367 mmol) in MeCN (5 mL). 0.037 mmol was added, followed by a mixture of (S)-dibenzyl (1-hydroxypropyl-2-yl) phosphate and (S)-dibenzyl (2-hydroxypropyl) phosphate prepared in step 1 (0.370 g, 1.10 mmol). The reaction mixture was stirred at room temperature for 16 hours and concentrated. The residue was purified by silica gel column chromatography (0% to 100% EtOAc / hexane, then 0% to 20% MeOH / DCM) to give the title compound. MS (m / z) 878.88 [M+H]+.

[0381] Step 3: Preparation of (((3'S,5S,7'R)-10'-((2,4-difluorobenzyl)carbamoyl)-3,3'-dimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazo-5,6'-[2,7]bridged methylenepyrido[1,2-a][1,4]diazacyclononene]-12'-yl)oxy)methyl((S)-2-(phosphono)propyl)carbonate (17): Add 10% Pd / C (0.008 g, 0.008 mmol) to a solution of (S)-2-((bis(benzyloxy)phosphoryl)oxy)propyl((((3'S,5S,7'R)-10'-((2,4-difluorobenzyl)carbamoyl)-3,3'-dimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazo-5,6'-[2,7]bridged methylenepyrido[1,2-a][1,4]diazacyclononene]-12'-yl)oxy)methyl)carbonate (0.068 g, 0.077 mmol) in THF (5 mL). Evacuate the vial and backfill with hydrogen (2×), then aerate with hydrogen for 2 minutes. Stir the reaction mixture under a hydrogen balloon atmosphere for 2 hours. Filter and concentrate the reaction mixture. The crude residue was dissolved in a 1:1 MeCN / water solution and analyzed by reversed-phase preparative HPLC (containing 0.1% TFA, ranging from 10% to 100%).The compound was purified by MeCN and then lyophilized to give the title compound. MS (m / z) 698.91 [M+H]+. 1H NMR (400MHz, DMSO‑d6) δ 10.28 (t, J = 5.9Hz, 1H), 8.71 (s, 1H), 7.42 (td, J = 8.6, 6.7Hz, 1H), 7.29 – 7.20 (m, 1H), 7.08 (td, J = 8.5, 2.7Hz, 1H) , 5.84 (d , J = 6.4Hz, 1H) , 5.64 (d , J = 6.4Hz, 1H) , 4.63 (d , J = 3.2Hz, 2H) , 4.61 – 4.48 (m , 2H) , 4.42 (dq , J = 11 .9, 5.5Hz, 1H), 4.13 (dd, J = 11.2, 5.2Hz, 1H), 4.04 (dd, J = 11.2, 4.7Hz, 1H), 3.78 – 3.58 (m, 2H), 3.00 (d, J = 17.5Hz , 1H) , 2.64 (d , J = 17.6Hz , 1H) , 1.95 (s , 3H) , 1.88 – 1.66 (m , 3H) , 1.36 – 1.24 (m, 1H) , 1.22 (d, J = 6.3Hz, 3H) , 1.16 (d, J = 6.7Hz, 3H).

[0382] Example 18: Preparation of (((3'S,5S,7'R)-10'-((2,4-difluorobenzyl)carbamoyl)-3,3'-dimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazo-5,6'-[2,7]bridged methylenepyrido[1,2-a][1,4]diazacyclononene]-12'-yl)oxy)methyl((R)-1-(phosphono)propyl-2-yl)carbonate (18): Specification 109 / 189 pages 157 CN 122055373 A Step 1: Preparation of (R)-dibenzyl(2-((tert-butyldimethylsilyl)oxy)propyl)phosphate: DIPEA (0.83 mL, 4.62 mmol) was added to a mixture of (R)-2-((tert-butyldimethylsilyl)oxy)prop-1-ol (0.396 g, 2.08 mmol) and DCM (1.35 mL), followed by the addition of tetrabenzyl pyrophosphate (1.00 g).1.86 mmol) and Ti(i-PrO)4 (0.094 mL, 0.316 mmol). The mixture was stirred at room temperature for 16 hours. MgSO4 and silica gel were added to the reaction, stirred for 10 minutes, and filtered, washed with 4:3 EtOAc / hexane. The filtrate was concentrated and purified by reversed-phase preparative HPLC (10% to 100% MeCN / water) to give the title compound. MS (m / z) 451.66 [M+H]+.

[0383] Step 2: Preparation of (R)-dibenzyl(2-hydroxypropyl)phosphate: At room temperature, a solution of (R)-dibenzyl(2-((tert-butyldimethylsilyl)oxy)propyl)phosphate (0.344 g, 0.763 mmol) in MeOH (3.4 mL) was added to a solution of (R)-dibenzyl(2-((tert-butyldimethylsilyl)oxy)propyl)phosphate (0.344 g, 0.763 mmol) in MeOH (3.4 mL) with 50 W x 8 of Dowex resin (hydrogen form) (3.40 g). After 6 hours, the mixture was filtered, concentrated, and purified by silica gel column chromatography (0% to 100% EtOAc / hexane) to give the title compound. MS (m / z) 336.74 [M+H]+.

[0384] Step 3: Preparation of (R)-1-((bis(benzyloxy)phosphoryl)oxy)propyl-2-yl(chloromethyl)carbonate: Chloromethyl chloroformate (0.184 mL, 2.07 mmol) was added to a solution of (R)-dibenzyl(2-hydroxypropyl) phosphate (0.316 g, 0.940 mmol) in DCM (22 mL) at 0 °C, followed by the addition of pyridine (0.190 mL, 2.35 mmol). The reaction mixture was heated to room temperature and stirred for 1 hour. The reaction mixture was quenched with water and 1N HCl. The phases were separated, and the aqueous phase was extracted with DCM (3 ×). The combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (0% to 100% EtOAc / hexane) as per the specification page 110 / 189, CN 122055373 A, to give the title compound. MS (m / z) 428.78 [M+H]+.

[0385] Step 4: Preparation of (R)-1-((bis(benzyloxy)phosphoryl)oxy)propyl-2-yl((((3'S,5S,7'R)-10'-((2,4-difluorobenzyl)carbamoyl)-3,3'-dimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazo-5,6'-[2,7]bridged methylenepyrido[1,2-a][1,4]diazacyclononene]-12'-yl)oxy)methyl)carbonate: To (R)-1-((bis(benzyloxy)phosphoryl)oxy)propyl-2-yl(chloromethyl)carbonate (0.15 g, 0.35 mmol)Intermediate B (0.142 g, 0.292 mmol), KI (0.063 g, 0.379 mmol), and K₂CO₃ (0.081 g, 0.584 mmol) were added to a solution in acetone (3.4 mL). The reaction mixture was stirred overnight at room temperature. The reaction mixture was partitioned between EtOAc and water, and the phases were separated. The aqueous phase was extracted with EtOAc, and the combined organic phases were washed with brine, dried over Na₂SO₄, filtered, and concentrated. The residue was suspended in MeCN and purified by reversed-phase preparative HPLC (10% to 100% MeCN / water). The collected fractions were concentrated to remove MeCN and extracted with EtOAc (3×). The combined organic phases were dried over Na₂SO₄, filtered, and concentrated. The residue was purified by silica gel column chromatography (0% to 100% EtOAc / hexane) to give the title compound. MS (m / z) 878.77 [M+H]⁺.

[0386] Step 5: Preparation of (((3'S,5S,7'R)-10'-((2,4-difluorobenzyl)carbamoyl)-3,3'-dimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazo-5,6'-[2,7]bridged methylenepyrido[1,2-a][1,4]diazacyclononene]-12'-yl)oxy)methyl((R)-1-(phosphono)propyl-2-yl)carbonate (18): Add 10% Pd / C (0.004 g, 0.004 mmol) to a solution of (R)-1-((bis(benzyloxy)phosphoryl)oxy)propyl-2-yl((((3'S,5S,7'R)-10'-((2,4-difluorobenzyl)carbamoyl)-3,3'-dimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazo-5,6'-[2,7]bridged methylenepyrido[1,2-a][1,4]diazacyclononene]-12'-yl)oxy)methyl)carbonate (0.035 g, 0.040 mmol) in THF (4 mL). Evacuate the flask and backfill with hydrogen (2×), then aerate with hydrogen for 2 minutes. Stir the reaction mixture under a hydrogen balloon atmosphere for 4 hours. The reaction mixture was filtered through diatomaceous earth and concentrated. The residue was dissolved in 1:1 MeCN / water and lyophilized to give the title compound. MS (m / z) 698.96 [M+H]+. 1H NMR (400MHz, DMSO-d6) δ 10.28 (t, J = 5.9Hz, 1H), 8.71 (s, 1H), 7.43 (td, J = 8.6, 6.5Hz, 1H), 7.25 (ddd, J = 10.5, J = 10.5, J = 10.5Hz ...9.3, 2.6Hz, 1H) , 7.15 – 6.99 (m, 1H) , 5.86 (d , J = 6.4Hz, 1H) , 5.59 (d , J = 6.4Hz, 1H) , 4.89 – 4.73 (m , 1H) , 4.73 – 4.60 (m , 2H), 4.60 – 4.45 (m, 2H), 3.87 (dt, J = 6.4, 4.6Hz, 2H), 3.69 (dd, J = 4.7, 2.3Hz, 2H), 3.00 (d, J = 17.6Hz, 1H), 2.63 (d , J = 17 .6Hz, 1H), 1.95 (s, 3H), 1.88 – 1.67 (m, 3H), 1.37 – 1.22 (m, 2H), 1.20 (d, J = 6.4Hz, 3H), 1.16 (d, J = 6.7Hz, 3H).

[0387] Example 19: Preparation of (((3'S,5S,7'R)-10'-((2,4-difluorobenzyl)carbamoyl)-3,3'-dimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazo-5,6'-[2,7]bridged methylenepyrido[1,2-a][1,4]diazacyclononene]-12'-yl)oxy)methyl((S)-1-(phosphono)propyl-2-yl)carbonate (19): Specification 111 / 189 pages 159 CN 122055373 A The title compound was prepared in a manner similar to Example 18, except that (S)- 2-((tert-butyldimethylsilyl)oxy)prop-1-ol replaces (R)-2-((tert-butyldimethylsilyl)oxy)prop-1-ol. MS (m / z) 698.83 [M+H]+. 1H NMR (400MHz, DMSO‑d6) δ 10 .27 (t , J = 5.9Hz, 1H) , 8.70 (s, 1H) , 7.42 (td, J = 8.6, 6.5Hz, 1H) , 7.29 – 7.20 (m, 1H) , 7.07 (td, J = 8.6, 2.6Hz, 1H), 5.88 – 5.73 (m, 1H), 5.72 – 5.55 (m, 1H), 4.79 (dq, J = 11.7, 6.2, 5.6Hz, 1H), 4.61(d, J = 12.2Hz, 2H), 4.59 – 4.47 (m, 2H), 3.85 (t, J = 5.9Hz, 2H), 3.68 (d, J = 2.3Hz, 2H), 3.00 (d, J = 17.5Hz, 1H), 2.64 (d, J = 17.7Hz, 1H) , 1.94 (s, 3H) , 1.85 – 1.70 (m, 3H) , 1.33 – 1.22 (m, 1H) , 1.20 (d, J = 6.4Hz, 3H) , 1.15 (d, J = 6.7Hz, 3H).

[0388] Example 20: Preparation of (((3'S,5S,7'R)-10'-((2,4-difluorobenzyl)carbamoyl)-3,3'-dimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazo-5,6'-[2,7]bridged methylenepyrido[1,2-a][1,4]diazacyclononene]-12'-yl)oxy)methyl 5-(phosphonoyloxy)valerate (20): Specification 112 / 189 pages 160 CN 122055373 A Step 1: Preparation of methyl 5-((di-tert-butoxyphosphono)oxy)valerate: A mixture of methyl 5-bromopentanoate (1 g, 5.13 mmol) and tetrabutylammonium di-tert-butylphosphate (2.78 g, 6.15 mmol) in dimethoxyethane (10 mL) was stirred at 80 °C for 3 hours. The reaction was cooled to ambient temperature, quenched with brine, and extracted with ethyl acetate (2×). The combined organic phases were dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound. MS (m / z) 324.7 [M+H]+.

[0389] Step 2: Preparation of 5-((di-tert-butoxyphosphoryl)oxy)pentanoic acid: A solution of 5-((di-tert-butoxyphosphoryl)oxy)pentanoic acid ester (1.32 g, 4.07 mmol) in tetrahydrofuran (15 mL) and methanol (10 mL) was treated with a solution of lithium hydroxide monohydrate (2.5N) (3.58 mL, 8.95 mmol). The mixture was stirred for 3 hours, and then most of the solvent was evaporated under reduced pressure. The residue was diluted with 2 mL of water and acidified to pH 5 with 5% citric acid. The resulting emulsion was extracted with ethyl acetate (2×). The combined organic phases were washed with brine, dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure to give the title compound. MS (m / z) 311.1 [M+H]+.

[0390] Step 3: Preparation of methyl 5-((di-tert-butoxyphosphoryl)oxy)valerate:A two-phase mixture of 5-di-tert-butoxyphosphoryloxyvalerate (1.8 g, 5.8 mmol), tetrabutylammonium bisulfate (0.197 g, 0.58 mmol), and sodium bicarbonate (2.92 g, 34.8 mmol) in water (9 mL) and DCM (18 mL) was cooled to 0 °C. While stirring, methyl chlorosulfate (1.9 g, 11.6 mmol) was added dropwise. The reaction mixture was stirred for 4 hours and slowly heated to room temperature. Water was added, and the aqueous phase was extracted with DCM (3×). The combined organic phases were washed with sodium bicarbonate and brine, dried over Na₂SO₄, filtered, and concentrated. The crude product was purified by column chromatography (0% to 100% EtOAc / hexane) to give the title compound. MS (m / z) 358.8 [M+H]+.

[0391] Step 4: Preparation of (((3'S,5S,7'R)-10'-((2,4-difluorobenzyl)carbamoyl)-3,3'-dimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazo-5,6'-[2,7]...

Claims

1. A compound of formula I: Formula I Or its pharmaceutically acceptable salt, wherein: R 1 is –(CR 1A R 1B O) a (Y) b (CR 1C R 1D ) d X; Where a is 0 or 1; b is 0 or 1; d can be 0, 1, 2, 3, 4, or 5; R 1A For H or C 1-3 alkyl; R 1B For H or C 1-3 alkyl; Each R 1C Independently H or C 1-3 alkyl; Each R 1D Independently H or C 1-3 Alkyl; or Optionally, R on the same carbon atom 1C and R 1D To combine and form a spirocyclopropyl group; Y is -C(O)-, -C(O)O-, -C(O)NH-, or -C(O)NR 1H -; R 1H C is a C that is optionally substituted by one or two substituents independently selected from the group consisting of the following items. 1-4 Alkyl groups: –COOH, -OH, -NH2, –CONH2, -P(O)(OH)2 and -S(O)2(OH); X selects a group consisting of the following items: (a) -O-P(O)(OR 1E )2, Each R 1E Independently, it can be H or phenyl; (b) -N(R 1F )2, Each R 1F Independently H, COO (CR) 1I R 1J ) e OPO(OH)2 or C 1-4 Alkyl; wherein the C 1-4 The alkyl group is optionally substituted by one or two independent substituents selected from the group consisting of: COOH, -S(O)2OH, -P(O)(OH)2, -OH, -NH2 and -CONH2; e is 1, 2, or 3; Each R 1I Independently H or C 1-3 alkyl; Each R 1J Independently H or C 1-3 Alkyl; or Optionally, R on the same carbon atom 1I and R 1J To combine and form a spirocyclopropyl group; as well as (c) -N + (R 1G 3Z - , Each R 1G Independently H or C 1-4 Alkyl; wherein the C 1-4 The alkyl group is optionally substituted by one or two independent substituents selected from the group consisting of: -COOH, -OH, -NH2 and -CONH2; Z - To counteract ions; R 2 C 1-3 Alkyl or C 1-3 Alkoxy; Each R 3 R 4 R 5 R 6 and R 7 Independently H or halogenated; and R 8 For H or C 1-3 alkyl.

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein Z is selected from the group consisting of: acetate, ascorbate, aspartate, benzenesulfonate, benzoate, bromide, bicarbonate, carbonate, cinnamate, citrate, chloride, formate, fumarate, gluconate, glutamate, glycolate, lactate, malate, maleate, malonic acid, mandelic acid, methanesulfonate, nicotinic acid, nitrate, oxalate, dihydrogen phosphate, hydrogen phosphate, phosphate, propionate, toluenesulfonate, pyroglutamate, salicylate, succinate, hydrogen sulfate, sulfate, tartrate, thiocyanate, trifluoromethanesulfonate, and trifluoroacetate.

3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein X is -OP(O)(OR) 1E )2.

4. The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein each R 1E It is a phenyl group.

5. The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein each R 1E For H.

6. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein X is -N(R) 1F )2.

7. The compound of claim 6 or a pharmaceutically acceptable salt thereof, wherein each R 1F Independently for -COO(CR) 1I R 1J ) e OPO(OH)2 or C 1-4 Alkyl; wherein the C 1-4 The alkyl group may optionally be replaced by one or two -COOH groups.

8. The compound according to claim 6 or 7, or a pharmaceutically acceptable salt thereof, wherein each R 1F Independently for -COO(CR) 1I R 1J ) e OPO(OH)2 or C 1-4 Alkyl; wherein the C 1-4 The alkyl group is optionally replaced by a -COOH group.

9. The compound according to any one of claims 6 to 8, wherein e is 1 or 2.

10. The compound according to any one of claims 6 to 9, wherein each R 1I and each R 1J For H.

11. The compound according to any one of claims 6 to 10, or a pharmaceutically acceptable salt thereof, wherein each R 1F Independently -COOCH2OPO(OH)2 or C 1-4 Alkyl; wherein the C 1-4 The alkyl group may optionally be replaced by one or two -COOH groups.

12. The compound according to any one of claims 6 to 11, or a pharmaceutically acceptable salt thereof, wherein each R 1F Independently -COOCH2OPO(OH)2 or C 1-4 Alkyl; wherein the C 1-4 The alkyl group is optionally replaced by a -COOH group.

13. The compound according to any one of claims 6 to 12, or a pharmaceutically acceptable salt thereof, wherein each R 1F It can be independently -COO(CH2)2OPO(OH)2, -COOCH2OPO(OH)2, -CH3, or -CH2COOH.

14. The compound according to any one of claims 6 to 13, or a pharmaceutically acceptable salt thereof, wherein each R 1F It can be independently -COOCH2OPO(OH)2, -CH3, or -CH2COOH.

15. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein X is -N + (R 1G )3Z - .

16. The compound of claim 15 or a pharmaceutically acceptable salt thereof, wherein R 1G It is -CH3.

17. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 16, wherein a is 0.

18. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 16, wherein a is 1.

19. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 18, wherein b is 0.

20. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 18, wherein b is 1.

21. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 20, wherein Y is -C(O)-, -C(O)O-, -C(O)NH- or -C(O)NCH3-.

22. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 21, wherein Y is -C(O)-, -C(O)O- or -C(O)NCH3-.

23. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 22, wherein Y is -C(O)-.

24. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 22, wherein Y is -C(O)O-.

25. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 22, wherein Y is -C(O)NCH3-.

26. The compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, wherein Y is -C(O)NR 1H - 27. The compound of claim 26 or a pharmaceutically acceptable salt thereof, wherein R 1H C is optionally substituted with -COOH, -P(O)(OH)2 or -S(O)2(OH) 1-2 alkyl.

28. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 25, wherein d is 1, 2 or 3.

29. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 28, wherein d is 1.

30. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 28, wherein d is 2.

31. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 28, wherein d is 3.

32. The compound according to any one of claims 1 to 31, or a pharmaceutically acceptable salt thereof, wherein R 4 R 5 and R 7 Each is represented by H.

33. The compound according to any one of claims 1 to 32, or a pharmaceutically acceptable salt thereof, wherein R 3 and R 6 Each is an independent halogenation.

34. The compound according to any one of claims 1 to 33, or a pharmaceutically acceptable salt thereof, wherein R 3 and R 6 Each is F.

35. The compound according to any one of claims 1 to 34, or a pharmaceutically acceptable salt thereof, wherein R 8 C 1-3 alkyl.

36. The compound according to any one of claims 1 to 35, or a pharmaceutically acceptable salt thereof, wherein R 8 It is a methyl group.

37. The compound according to any one of claims 1 to 36, or a pharmaceutically acceptable salt thereof, wherein R 2 It is methyl or methoxy.

38. The compound according to any one of claims 1 to 37, or a pharmaceutically acceptable salt thereof, wherein R 2 It is a methyl group.

39. The compound according to any one of claims 1 to 37, or a pharmaceutically acceptable salt thereof, wherein R 2 It is a methoxy group.

40. The compound according to any one of claims 1 to 39, or a pharmaceutically acceptable salt thereof, wherein R 1 Choose from the following groups: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 , , , , , , , , and .

41. The compound according to any one of claims 1 to 39, or a pharmaceutically acceptable salt thereof, wherein R 1 Choose from the following groups: , , , , , , , , , , , , , , , and .

42. The compound according to any one of claims 1 to 39, or a pharmaceutically acceptable salt thereof, wherein R 1 Choose from the following groups: , , , , , , , , , , , , , , , , , , and .

43. The compound according to any one of claims 1 to 42, wherein the compound is selected from the group consisting of: 、 、 、 、 、 、 、 、 、 、 、 、 , , , , , , , and , or their pharmaceutically acceptable salts.

44. The compound according to any one of claims 1 to 42, wherein the compound is selected from the group consisting of: , , , , , , , , , , , , , , , , , , , , , , , , , , , , and , or their pharmaceutically acceptable salts.

45. The compound according to any one of claims 1 to 42, wherein the compound is selected from the group consisting of: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 , and , or their pharmaceutically acceptable salts.

46. ​​A pharmaceutical composition comprising a therapeutically effective amount of the compound according to any one of claims 1 to 45 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

47. The pharmaceutical composition of claim 46, wherein the pharmaceutical composition further comprises one, two, three or four additional therapeutic agents.

48. The pharmaceutical composition of claim 47, wherein one or more additional therapeutic agents are anti-HIV agents.

49. The pharmaceutical composition according to claim 47 or 48, wherein the one or more additional therapeutic agents are HIV protease inhibitors, non-nucleoside or non-nucleotide inhibitors of HIV reverse transcriptase, nucleoside or nucleotide inhibitors of HIV reverse transcriptase, HIV capsid inhibitors, gp41 inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5 inhibitors, latency reversal agents, capsid polymerization inhibitors, HIV bNAb, TLR7 agonists, pharmacokinetic enhancers, other drugs for treating HIV, or combinations thereof.

50. The pharmaceutical composition according to any one of claims 47 to 49, wherein one or more of the adjunctive therapeutic agents are abacavir, tenofovir alafenamide, tenofovir disoproxil fumarate, N-(( S )-l-(3-(4-chloro-3-(methylsulfonamide)-l-(2,2,2-trifluoroethyl)-l H -Indazole-7-yl)-6-(3-methyl-3-(methylsulfonyl)but-l-yn-l-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3b S ,4a R )-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-l H -Cyclopropyl[3,4]cyclopentyl[1,2- c Pyrazole-l-yl)acetamide or their pharmaceutically acceptable salts.

51. The pharmaceutical composition according to any one of claims 46 to 50, wherein the pharmaceutical composition is for oral or parenteral administration.

52. A kit comprising a compound according to any one of claims 1 to 45 or a pharmaceutically acceptable salt thereof and instructions for use.

53. The kit according to claim 52, wherein the kit further comprises one, two, three or four additional therapeutic agents.

54. The kit according to claim 53, wherein one or more additional therapeutic agents are anti-HIV agents.

55. The kit according to claim 53 or 54, wherein the one or more additional therapeutic agents are HIV protease inhibitors, non-nucleoside or non-nucleotide inhibitors of HIV reverse transcriptase, nucleoside or nucleotide inhibitors of HIV reverse transcriptase, HIV capsid inhibitors, gp41 inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5 inhibitors, latency reversal agents, capsid polymerization inhibitors, HIV bNAb, TLR7 agonists, pharmacokinetic enhancers, other drugs for treating HIV, or combinations thereof.

56. The kit according to any one of claims 53 to 55, wherein the one or more additional therapeutic agents are abacavir, tenofovir alafenamide, tenofovir disoproxil fumarate, N-(( S )-l-(3-(4-chloro-3-(methylsulfonamide)-l-(2,2,2-trifluoroethyl)-l H -Indazole-7-yl)-6-(3-methyl-3-(methylsulfonyl)but-l-yn-l-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3b S ,4a R )-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-l H -Cyclopropyl[3,4]cyclopentyl[1,2- c Pyrazole-l-yl)acetamide or their pharmaceutically acceptable salts.

57. A method of treating the infection in a person who is infected with HIV or at risk of becoming infected with HIV, the method comprising administering to the person a therapeutically effective amount of a compound according to any one of claims 1 to 45 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to any one of claims 46 to 51.

58. The method of claim 57, further comprising administering to the person a therapeutically effective amount of one, two, three, or four additional therapeutic agents.

59. The method of claim 58, wherein one or more additional therapeutic agents are anti-HIV agents.

60. The method according to claim 58 or 59, wherein the one or more additional therapeutic agents are HIV protease inhibitors, non-nucleoside or non-nucleotide inhibitors of HIV reverse transcriptase, nucleoside or nucleotide inhibitors of HIV reverse transcriptase, HIV capsid inhibitors, gp41 inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5 inhibitors, latency reversal agents, capsid polymerization inhibitors, HIV bNAb, TLR7 agonists, pharmacokinetic enhancers, other drugs for treating HIV, or combinations thereof.

61. The method according to any one of claims 58 to 60, wherein the one or more additional therapeutic agents are abacavir, tenofovir alafenamide, tenofovir disoproxil fumarate, N-(( S )-l-(3-(4-chloro-3-(methylsulfonamide)-l-(2,2,2-trifluoroethyl)-l H -Indazole-7-yl)-6-(3-methyl-3-(methylsulfonyl)but-l-yn-l-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3b S ,4a R )-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-l H -Cyclopropyl[3,4]cyclopentyl[1,2- c Pyrazole-l-yl)acetamide or their pharmaceutically acceptable salts.

62. The method according to any one of claims 57 to 61, wherein the administration is oral, intravenous, subcutaneous, or intramuscular.

63. Use of the compound of any one of claims 1 to 45 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of any one of claims 46 to 51, for the treatment of a person suffering from or at risk of HIV infection.

64. The compound of any one of claims 1 to 45 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of any one of claims 46 to 51, for use in medical therapy.

65. The compound of any one of claims 1 to 45 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of any one of claims 46 to 51, for use in the treatment of HIV infection.

66. Use of the compound of any one of claims 1 to 45 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of any one of claims 46 to 51, in the manufacture of a medicament for treating a person suffering from or at risk of HIV infection.

67. A combination comprising (i) a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof, or a compound of formula II or a pharmaceutically acceptable salt thereof, and (ii) a P-glycoprotein inhibitor: Formula I Formula II in: R 1 is –(CR 1A R 1B O) a (Y) b (CR 1C R 1D ) d X; Where a is 0 or 1; b is 0 or 1; d can be 0, 1, 2, 3, 4, or 5; R 1A For H or C 1-3 alkyl; R 1B For H or C 1-3 alkyl; Each R 1C Independently H or C 1-3 alkyl; Each R 1D Independently H or C 1-3 Alkyl; or Optionally, R on the same carbon atom 1C and R 1D To combine and form a spirocyclopropyl group; Y is -C(O)-, -C(O)O-, -C(O)NH-, or -C(O)NR 1H -; R 1H C is a C that is optionally substituted by one or two substituents independently selected from the group consisting of the following items. 1-4 Alkyl groups: –COOH, -OH, -NH2, –CONH2, -P(O)(OH)2 and -S(O)2(OH); X selects a group consisting of the following items: (a) -O-P(O)(OR 1E )2, Each R 1E Independently, it can be H or phenyl; (b) -N(R 1F )2, Each R 1F Independently H, COO (CR) 1I R 1J ) e OPO(OH)2 or C 1-4 Alkyl; wherein the C 1-4 The alkyl group is optionally substituted by one or two independent substituents selected from the group consisting of: COOH, -S(O)2OH, -P(O)(OH)2, -OH, -NH2 and -CONH2; e is 1, 2, or 3; Each R 1I Independently H or C 1-3 alkyl; Each R 1J Independently H or C 1-3 Alkyl; or Optionally, R on the same carbon atom 1I and R 1J To combine and form a spirocyclopropyl group; as well as (c) -N + (R 1G 3Z - , Each R 1G Independently H or C 1-4 Alkyl; wherein the C 1-4 The alkyl group is optionally substituted by one or two independent substituents selected from the group consisting of: -COOH, -OH, -NH2 and -CONH2; Z - To counteract ions; R 2 C 1-3 Alkyl or C 1-3 Alkoxy; Each R 3 R 4 R 5 R 6 and R 7 Independently H or halogenated; and R 8 For H or C 1-3 alkyl.

68. The combination according to claim 67, wherein the combination comprises a compound of formula I or a pharmaceutically acceptable salt thereof.

69. The combination according to claim 68, wherein Z is selected from the group consisting of: acetate, ascorbate, aspartate, benzenesulfonate, benzoate, bromide, bicarbonate, carbonate, cinnamate, citrate, chloride, formate, fumarate, gluconate, glutamate, glycolate, lactate, malate, maleate, malonic acid, mandelic acid, methanesulfonate, nicotinic acid, nitrate, oxalate, dihydrogen phosphate, hydrogen phosphate, phosphate, propionate, toluenesulfonate, pyroglutamate, salicylate, succinate, hydrogen sulfate, sulfate, tartrate, thiocyanate, trifluoromethanesulfonate, and trifluoroacetate.

70. The combination according to claim 68 or 69, wherein X is -OP(O)(OR) 1E )2.

71. The combination according to any one of claims 68 to 70, wherein each R 1E It is a phenyl group.

72. The combination according to any one of claims 68 to 71, wherein each R 1E For H.

73. The combination according to claim 68 or 69, wherein X is -N(R) 1F )2.

74. The combination according to claim 73, wherein each R 1F Independently for -COO(CR) 1I R 1J ) e OPO(OH)2 or C 1-4 Alkyl; wherein the C 1-4 The alkyl group may optionally be replaced by one or two -COOH groups.

75. The combination according to claim 73 or 74, wherein each R 1F Independently for -COO(CR) 1I R 1J ) e OPO(OH)2 or C 1-4 Alkyl; wherein the C 1-4 The alkyl group is optionally replaced by a -COOH group.

76. The combination according to any one of claims 73 to 75, wherein e is 1 or 2.

77. The combination according to any one of claims 73 to 76, wherein each R 1I and each R 1J For H.

78. The combination according to any one of claims 73 to 77, wherein each R 1F Independently -COOCH2OPO(OH)2 or C 1-4 Alkyl; wherein the C 1-4 The alkyl group may optionally be replaced by one or two -COOH groups.

79. The combination according to any one of claims 73 to 78, wherein each R 1F Independently -COOCH2OPO(OH)2 or C 1-4 Alkyl; wherein the C 1-4 The alkyl group is optionally replaced by a -COOH group.

80. The combination according to any one of claims 73 to 79, wherein each R 1F It can be independently -COO(CH2)2OPO(OH)2, -COOCH2OPO(OH)2, -CH3, or -CH2COOH.

81. The combination according to any one of claims 73 to 80, wherein each R 1F It can be independently -COOCH2OPO(OH)2, -CH3, or -CH2COOH.

82. The combination according to claim 68 or 69, wherein X is -N + (R 1G )3Z - .

83. The combination according to claim 82, wherein R 1G It is -CH3.

84. The combination according to any one of claims 68 to 83, wherein a is 0.

85. The combination according to any one of claims 68 to 83, wherein a is 1.

86. The combination according to any one of claims 68 to 85, wherein b is 0.

87. The combination according to any one of claims 68 to 85, wherein b is 1.

88. The combination according to any one of claims 68 to 87, wherein Y is -C(O)-, -C(O)O-, -C(O)NH- or -C(O)NCH3-.

89. The combination according to any one of claims 68 to 88, wherein Y is -C(O)-, -C(O)O-, or -C(O)NCH3-.

90. The combination according to any one of claims 68 to 89, wherein Y is -C(O)-.

91. The combination according to any one of claims 68 to 89, wherein Y is -C(O)O-.

92. The combination according to any one of claims 68 to 89, wherein Y is -C(O)NCH3-.

93. The combination according to any one of claims 68 to 87, wherein Y is -C(O)NR 1H - 94. The combination according to claim 93, wherein R 1H C is optionally substituted with -COOH, -P(O)(OH)2 or -S(O)2(OH) 1-2 alkyl.

95. The combination according to any one of claims 68 to 92, wherein d is 1, 2 or 3.

96. The combination according to any one of claims 68 to 93, wherein d is 1.

97. The combination according to any one of claims 68 to 93, wherein d is 2.

98. The combination according to any one of claims 68 to 93, wherein d is 3.

99. The combination according to any one of claims 67 to 98, wherein R 4 R 5 and R 7 Each is represented by H.

100. The combination according to any one of claims 67 to 99, wherein R 3 and R 6 Each is an independent halogenation.

101. The combination according to any one of claims 67 to 100, wherein R 3 and R 6 Each is F.

102. The combination according to any one of claims 67 to 101, wherein R 8 C 1-3 alkyl.

103. The combination according to any one of claims 67 to 102, wherein R 8 It is a methyl group.

104. The combination according to any one of claims 67 to 103, wherein R 2 It is methyl or methoxy.

105. The combination according to any one of claims 67 to 104, wherein R 2 It is a methyl group.

106. The combination according to any one of claims 67 to 105, wherein R 2 It is a methoxy group.

107. The combination of any one of claims 68 and 99 to 106, wherein R 1 Choose from the following groups: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 , , , , , , , , and .

108. The combination of any one of claims 68 and 99 to 106, wherein R 1 Choose from the following groups: , , , , , , , , , , , , , , , and .

109. The combination of any one of claims 68 and 99 to 106, wherein R 1 Choose from the following groups: , , , , , , , , , , , , , , , , , , and .

110. The combination according to claim 68, wherein the compound of formula I is selected from the group consisting of: 、 、 、 、 、 、 、 、 、 、 、 、 , , , , , , , and , or their pharmaceutically acceptable salts.

111. The combination according to claim 68, wherein the compound of formula I is selected from the group consisting of: , , , , , , , , , , , , , , , , , , , , , , , , , , , , and , or their pharmaceutically acceptable salts.

112. The combination according to claim 68, wherein the compound of formula I is selected from the group consisting of: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 , and , or their pharmaceutically acceptable salts.

113. The combination according to claim 112, wherein the compound of formula I is selected from: and , or their pharmaceutically acceptable salts.

114. The combination according to claim 113, wherein the compound of formula I is: Or, or a pharmaceutically acceptable salt thereof.

115. The combination according to claim 113, wherein the compound of formula I is: Or, or a pharmaceutically acceptable salt thereof.

116. The combination according to any one of claims 68 to 115, wherein the combination comprises a compound of formula I.

117. The combination according to claim 116, wherein the compound of formula I is: .

118. The combination according to claim 116, wherein the compound of formula I is: .

119. The combination according to any one of claims 67 and 99 to 106, wherein the combination comprises a compound of formula II or a pharmaceutically acceptable salt thereof.

120. The combination according to claim 119, wherein the compound of formula II is: Or, or a pharmaceutically acceptable salt thereof.

121. The combination according to claim 119, wherein the compound of formula II is: Or, or a pharmaceutically acceptable salt thereof.

122. The combination according to claim 119, wherein the combination comprises a compound of formula II.

123. The combination according to claim 122, wherein the compound of formula II is: 。 124. The combination according to claim 122, wherein the compound of formula II is: 。 125. The combination of any one of claims 67 to 124, wherein the P-glycoprotein inhibitor is selected from the group consisting of verapamil, dexverapamil, cyclosporine, zoquine, laniquine, ecridia, talicidia, encequine, and pharmaceutically acceptable salts thereof.

126. The combination according to any one of claims 67 to 125, wherein the P-glycoprotein inhibitor is encequina or a pharmaceutically acceptable salt thereof.

127. The combination of any one of claims 67 to 126, wherein the P-glycoprotein inhibitor is a salt of encequina.

128. The combination according to claim 127, wherein the P-glycoprotein inhibitor is the mesylate of encequina.

129. The combination of claim 67, wherein the combination comprises Or a pharmaceutically acceptable salt thereof, or ensecidium or a pharmaceutically acceptable salt thereof.

130. The combination of claim 67, wherein the combination comprises Or a pharmaceutically acceptable salt thereof, or ensecidium or a pharmaceutically acceptable salt thereof.

131. The combination of claim 67, wherein the combination comprises Or a pharmaceutically acceptable salt thereof, or ensecidium or a pharmaceutically acceptable salt thereof.

132. The combination of claim 67, wherein the combination comprises Or a pharmaceutically acceptable salt thereof, or ensecidium or a pharmaceutically acceptable salt thereof.

133. The combination of claim 129, wherein the combination comprises Or its pharmaceutically acceptable salts and salts of ensequita.

134. The combination of claim 130, wherein the combination comprises Or its pharmaceutically acceptable salts and salts of ensequita.

135. The combination of claim 131, wherein the combination comprises Or its pharmaceutically acceptable salts and salts of ensequita.

136. The combination of claim 132, wherein the combination comprises Or its pharmaceutically acceptable salts and salts of ensequita.

137. The combination of claim 133, wherein the combination comprises And salt from Ensequida.

138. The combination of claim 134, wherein the combination comprises And salt from Ensequida.

139. The combination of claim 135, wherein the combination comprises And salt from Ensequida.

140. The combination of claim 136, wherein the combination comprises And salt from Ensequida.

141. The combination of claim 137, wherein the combination comprises And ensequida mesylate.

142. The combination of claim 138, wherein the combination comprises And ensequida mesylate.

143. The combination of claim 139, wherein the combination comprises And ensequida mesylate.

144. The combination of claim 140, wherein the combination comprises And ensequida mesylate.

145. A method of treating said infection in a person who has or is at risk of developing HIV infection, the method comprising administering to said person the combination of any one of claims 67 to 144.

146. The method of claim 145, wherein (i) the compound of formula I or a pharmaceutically acceptable salt thereof or the compound of formula II or a pharmaceutically acceptable salt thereof is administered together with (ii) the P-glycoprotein inhibitor.

147. The method according to claim 145 or 146, wherein (i) the compound of formula I or a pharmaceutically acceptable salt thereof or the compound of formula II or a pharmaceutically acceptable salt thereof and (ii) the P-glycoprotein inhibitor are administered as a co-preparation.

148. The method of claim 145, wherein (i) the compound of formula I or a pharmaceutically acceptable salt thereof or the compound of formula II or a pharmaceutically acceptable salt thereof and (ii) the P-glycoprotein inhibitor are administered alone.

149. The method according to any one of claims 145 to 148, wherein (i) the compound of formula I or a pharmaceutically acceptable salt thereof or the compound of formula II or a pharmaceutically acceptable salt thereof is administered orally and (ii) the P-glycoprotein inhibitor is administered orally.

150. The method according to any one of claims 145 to 149, the method further comprising administering to the person a therapeutically effective amount of one, two, three, or four additional therapeutic agents.

151. The method of claim 150, wherein the one or more additional therapeutic agents are anti-HIV agents.

152. The method according to claim 150 or 151, wherein the one or more additional therapeutic agents are HIV protease inhibitors, non-nucleoside or non-nucleotide inhibitors of HIV reverse transcriptase, nucleoside or nucleotide inhibitors of HIV reverse transcriptase, HIV capsid inhibitors, gp41 inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5 inhibitors, latency reversal agents, capsid polymerization inhibitors, HIV bNAb, TLR7 agonists, pharmacokinetic enhancers, other drugs for treating HIV, or combinations thereof.

153. The method according to any one of claims 150 to 152, wherein the one or more additional therapeutic agents are abacavir, tenofovir alafenamide, tenofovir disoproxil fumarate, N-(( S )-l-(3-(4-chloro-3-(methylsulfonamide)-l-(2,2,2-trifluoroethyl)-l H -Indazole-7-yl)-6-(3-methyl-3-(methylsulfonyl)but-l-yn-l-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3b S ,4a R )-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-l H -Cyclopropyl[3,4]cyclopentyl[1,2- c Pyrazole-l-yl)acetamide or their pharmaceutically acceptable salts.

154. The method according to any one of claims 150 to 153, wherein (i) the compound of formula I or a pharmaceutically acceptable salt thereof or the compound of formula II or a pharmaceutically acceptable salt thereof, (ii) the P-glycoprotein inhibitor and (iii) one or more additional therapeutic agents are administered as a co-preparation.

155. A pharmaceutical composition comprising the combination of any one of claims 67 to 144 and a pharmaceutically acceptable excipient.

156. A kit comprising the combination and instructions for use according to any one of claims 67 to 144.

157. The kit according to claim 156, wherein the kit comprises (i) a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof or a compound of formula II or a pharmaceutically acceptable salt thereof, (ii) a pharmaceutical composition comprising the P-glycoprotein inhibitor, and (iii) instructions for use.

158. The kit according to claim 156, wherein the kit comprises (i) a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof or a compound of formula II or a pharmaceutically acceptable salt thereof and the P-glycoprotein inhibitor, and (ii) instructions for use.

159. The kit according to any one of claims 156 to 158, wherein the kit further comprises one, two, three or four additional therapeutic agents.

160. The kit of claim 159, wherein one or more additional therapeutic agents are anti-HIV agents.

161. The kit according to claim 159 or 160, wherein the one or more additional therapeutic agents are HIV protease inhibitors, non-nucleoside or non-nucleotide inhibitors of HIV reverse transcriptase, nucleoside or nucleotide inhibitors of HIV reverse transcriptase, HIV capsid inhibitors, gp41 inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5 inhibitors, latency reversal agents, capsid polymerization inhibitors, HIV bNAb, TLR7 agonists, pharmacokinetic enhancers, other drugs for treating HIV, or combinations thereof.

162. The kit according to any one of claims 159 to 161, wherein the one or more additional therapeutic agents are abacavir, tenofovir alafenamide, tenofovir disoproxil fumarate, N-(( S )-l-(3-(4-chloro-3-(methylsulfonamide)-l-(2,2,2-trifluoroethyl)-l H -Indazole-7-yl)-6-(3-methyl-3-(methylsulfonyl)but-l-yn-l-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3b S ,4a R )-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-l H -Cyclopropyl[3,4]cyclopentyl[1,2- c Pyrazole-l-yl)acetamide or their pharmaceutically acceptable salts.

163. The combination of any one of claims 67 to 144, the pharmaceutical composition of claim 155, or the kit of any one of claims 156 to 162, for use in medical therapy.

164. The combination of any one of claims 67 to 144, the pharmaceutical composition of claim 155, or the kit of any one of claims 156 to 162, for use in the treatment of HIV infection.

165. A compound of Formula I or a pharmaceutically acceptable salt thereof, or a compound of Formula II or a pharmaceutically acceptable salt thereof, used in combination therapy for the treatment of HIV infection in conjunction with a P-glycoprotein inhibitor, as defined in any of the preceding claims.

166. A P-glycoprotein inhibitor, said P-glycoprotein inhibitor being used in combination therapy for treating HIV infection with a compound of Formula I or a pharmaceutically acceptable salt thereof, or a compound of Formula II or a pharmaceutically acceptable salt thereof, as defined in any of the preceding claims.

167. Use in the manufacture of a medicament for treating a person suffering from or at risk of HIV infection, based on any combination of claims 67 to 144, a pharmaceutical composition according to claim 155, or a kit according to any one of claims 156 to 162.

168. The method of any one of claims 145 to 154, the combination, compound, composition, or kit used according to any one of claims 163 to 166, or the use according to claim 167, wherein the exposure of the metabolites of the compound of formula I or its pharmaceutically acceptable salt is increased when the compound of formula I or its pharmaceutically acceptable salt is co-administered with the P-glycoprotein inhibitor, relative to the exposure of the metabolites of the compound of formula I or its pharmaceutically acceptable salt when administered in the absence of a P-glycoprotein inhibitor.

169. The method according to any one of claims 145 to 154, the combination, compound, composition, or kit used according to any one of claims 163 to 166, or the use according to claim 167, wherein the C of the metabolite of the compound of formula I or its pharmaceutically acceptable salt is relative to the amount of the compound of formula I or its pharmaceutically acceptable salt when administered in the absence of the P-glycoprotein inhibitor. MAX When a compound of Formula I or a pharmaceutically acceptable salt thereof is co-administered with the P-glycoprotein inhibitor, the C of the metabolite of the compound of Formula I or a pharmaceutically acceptable salt thereof... MAX Increase.

170. The method according to any one of claims 145 to 154, the combination, compound, composition, or kit used according to any one of claims 163 to 166, or the use according to claim 167, wherein the metabolite of the compound of formula I or a pharmaceutically acceptable salt thereof is present relative to the AUC of the metabolite of the compound of formula I or a pharmaceutically acceptable salt thereof when administered in the absence of the P-glycoprotein inhibitor. INF When a compound of Formula I or a pharmaceutically acceptable salt thereof is co-administered with the P-glycoprotein inhibitor, the AUC of the metabolite of the compound of Formula I or a pharmaceutically acceptable salt thereof is... INF Increase.

171. The method according to any one of claims 145 to 154, the combination, compound, composition, or kit used according to any one of claims 163 to 166, or the use according to claim 167, wherein the oral bioavailability of the metabolite of the compound of formula I or its pharmaceutically acceptable salt is increased when the compound of formula I or its pharmaceutically acceptable salt is co-administered with the P-glycoprotein inhibitor, relative to the oral bioavailability of the metabolite of the compound of formula I or its pharmaceutically acceptable salt when administered in the absence of the P-glycoprotein inhibitor.

172. The method, combination, compound, composition, or kit used according to any one of claims 168 to 171, or the use according to any one of claims 168 to 171, wherein the metabolite is a compound of formula II or a pharmaceutically acceptable salt thereof.

173. The method of any one of claims 145 to 154, the combination, compound, composition, or kit used according to any one of claims 163 to 166, or the use according to claim 167, wherein when co-administered with the P-glycoprotein inhibitor, the patient's exposure to the compound of formula II or its pharmaceutically acceptable salt is increased relative to the exposure when administered in the absence of the P-glycoprotein inhibitor.

174. The method according to any one of claims 145 to 154, the combination, compound, composition, or kit used according to any one of claims 163 to 166, or the use according to claim 167, wherein the C of the compound of formula II or a pharmaceutically acceptable salt thereof is relative to the amount of the compound when administered in the absence of the P-glycoprotein inhibitor. MAX When co-administered with the P-glycoprotein inhibitor, the C-value of the compound of formula II or a pharmaceutically acceptable salt thereof in the patient is [not specified]. MAX Increase.

175. The method according to any one of claims 145 to 154, the combination, compound, composition, or kit used according to any one of claims 163 to 166, or the use according to claim 167, wherein the AUC of the compound of formula II or a pharmaceutically acceptable salt thereof when administered in the absence of the P-glycoprotein inhibitor is... INF When co-administered with the P-glycoprotein inhibitor, the AUC of the compound of formula II or its pharmaceutically acceptable salt in the patient is... INF Increase.

176. The method of any one of claims 145 to 154, the combination, compound, composition, or kit used according to any one of claims 163 to 166, or the use according to claim 167, wherein the oral bioavailability of the compound of formula II or a pharmaceutically acceptable salt thereof in the patient is increased when co-administered with the P-glycoprotein inhibitor, relative to the oral bioavailability of the compound of formula II or a pharmaceutically acceptable salt thereof when administered in the absence of the P-glycoprotein inhibitor.

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