Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
  • A61K31/5365—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines ortho- or peri-condensed with heterocyclic ring systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
  • A61K31/537—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines spiro-condensed or forming part of bridged ring systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/66—Phosphorus compounds
  • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/12—Antivirals
  • A61P31/14—Antivirals for RNA viruses
  • A61P31/18—Antivirals for RNA viruses for HIV
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
  • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
  • C07D471/04—Ortho-condensed systems

Definitions

• the invention relates to compounds, compositions, and methods for the treatment of human immunodeficiency virus (HIV) infection. More particularly, the invention provides novel Capsid inhibitors, pharmaceutical compositions containing such compounds, and methods for using these compounds in the treatment of HIV infection. The invention also relates to methods for making the compounds hereinafter described.
• HIV human immunodeficiency virus
• AIDS Acquired immunodeficiency syndrome
• agents are classified as either nucleotide reverse transcriptase inhibitors (NRTIs), non-nucleotide reverse transcriptase inhibitors (NNRTIs), protease inhibitors (Pis), integrase strand transfer inhibitors (INSTIs), or entry inhibitors (one, maraviroc, targets the host CCR5 protein, while the other, enfuvirtide, is a peptide that targets the gp41 region of the viral gpl60 protein).
• a pharmacokinetic enhancer cobicistat or ritonavir
• ARVs antiretroviral agents
• the present invention discloses a compound or salt selected from the group consisting of:
• the present invention discloses a compound or salt selected from the group consisting of:
• the present invention discloses a compound or salt selected from the group consisting of:
• the present invention discloses a compound or salt selected from the group consisting of: and pharmaceutically acceptable salts thereof. In another aspect, the present invention discloses a compound or salt selected from the group consisting of: and pharmaceutically acceptable salts thereof. In another aspect, the present invention discloses a composition comprising a compound or salt of the invention.
• the present invention discloses a method of treating HIV infection in a human comprising administering a compound or salt of the invention.
• the present invention discloses a compound or salt of the invention for use in therapy.
• the present invention discloses a compound or salt of the invention for use in treating HIV infection in a human.
• the present invention discloses the use of a compound or salt of the invention in the manufacture of a medicament for the treatment of HIV infection in a human.
• the salts of the invention are pharmaceutically acceptable. Such salts may be acid addition salts or base addition salts.
• suitable pharmaceutically acceptable salts see, for example, Berge et al, J. Pharm, Sci., 66, 1-19, 1977.
• Representative pharmaceutically acceptable acid addition salts include, but are not limited to, 4-acetamidobenzoate, acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate (besylate), benzoate, bisulfate, bitartrate, butyrate, calcium edetate, camphorate, camphorsulfonate (camsylate), caprate (decanoate), caproate (hexanoate), caprylate (octanoate), cinnamate, citrate, cyclamate, digluconate, 2,5-dihydroxybenzoate, disuccinate, dodecyl sulfate (estolate), edetate (ethylenediaminetetraacetate), estolate (lauryl sulfate), ethane-1, 2-disulfonate (edisylate), ethanesulfonate (esylate), formate, fumarate, galactarate
• Representative pharmaceutically acceptable base addition salts include, but are not limited to, aluminium, 2-amino-2-(hydroxymethyl)-1, 3-propanediol (TRIS, tromethamine), arginine, benethamine (N-benzylphenethylamine), benzathine N,N-dibenzylethylenediamine), bis-(2-hydroxyethyl)amine, bismuth, calcium, chloroprocaine, choline, clemizole (1 -p chlorobenzyl-2-pyrrolildine-1'-ylmethylbenzimidazole), cyclohexylamine, dibenzylethylenediamine, diethylamine, diethyltriamine, dimethylamine, dimethylethanolamine, dopamine, ethanolamine, ethylenediamine, L-histidine, iron, isoquinoline, lepidine, lithium, lysine, magnesium, meglumine (N-methylglucamine), piperazine, piperidine, potassium, proca
• compositions suitable for oral administration for example tablets
• compositions suitable for subcutaneous or intramuscular injection for example
• the present invention discloses methods of preventing HIV infection in a human or reducing the risk of infection, comprising administering a compound or salt of this invention.
• Pre-exposure prophylaxis or PrEP is when people at risk for HIV infection take daily medicine to lower their chances of getting HIV infection. PrEP has been shown to be effective in reducing the risk of infection.
• HIV or “Human Immunodeficiency Virus” refers to HIV-1 and/or to HIV-2.
• the compounds and salts of this invention are believed to have as their biological target the HIV capsid and thus their mechanism of action is to modify in one or more ways the function of the HIV capsid.
• Combination therapies according to the present invention thus comprise the administration of at least one compound or salt of the invention, and the administration of at least one other agent which may be useful in the treatment of HIV infection.
• a compound or salt of the present invention, and the other agent may be formulated and administered together in a single pharmaceutical composition or may be formulated and administered separately. When formulated and administered separately, administration may occur simultaneously or sequentially in any order.
• Suitable other agents include, for example, abacavir, atazanavir, bictegravir, cabotegravir, darunavir, delavirdine, didanosine, dideoxyinosine, dolutegravir, doravirine, efavirenz, elvitegravir, emtricitabine, etavirine, fosamprenavir, fostemsavir, GSK3640254, the antibody N6LS, GSK3739937/VH3739937 and GSK4000422/VH4000422, indinavir, lamivudine, lopinavir, maraviroc, nelfinavir, nevirapine, raltegravir, rilpiverine, ritonavir, saquinavir, slatravir, stavudine, tipranavir, tenofovir, tenofovir alafenamide, tenofovir disoprox
• Preferred agents include, for example, bictegravir, cabotegravir, dolutegravir, fostemsavir, islatravir, and lamivudine.
• Particularly preferred agents include, for example, bictegravir, cabotegravir, dolutegravir, fostemsavir, and lamivudine.
• the vial was sealed with a septum cap and then was purged with argon.
• THF: water (4:1) to afford a reaction volume 0.05M in boronic ester.
• the reaction mixture was stirred at room 20-60 °C for 16-24 h. Upon cooling to ambient temperature, the reaction mixture was concentrated in vacuo anti the resulting residue was subjected to HPLC purification to afforded the indicated product. Alternately, the reaction may be run under ambient atmosphere. Alternately, the reagents may be combined using stock solutions of THF and water to achieve the final concentrations indicated.
• the reaction mixture was degassed for 10 min with nitrogen bubbling. To the mixture was added dichloro[9,9-dimethyl-4,5- bis(diphenylphosphino)xanthene]palladium(II) (0.06 equiv). The mixture was stirred at room temperature for 8-16 h. The reaction mixture was filtered through a pad of Celite, extracting with ethyl acetate (30 mL). The organic layer was dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure to afford the crude product. The crude material was subjected to HPLC purification to afford the indicated product.
• HPLC purification was performed using one of the conditions indicated below, optionally followed by a second HPLC purification using a different condition indicated below. Based on analytical HPLC data obtained on the crude reaction mixture, the purification condition was optimized for each target compound by modifying the initial Solvent A: Solvent B ratio, the gradient time, the final Solvent A:Solvent B ratio, and the hold time at the final Solvent A: Solvent B concentration.
• the reaction mixture was filtered and the filter cake was extracted with EtOAc (1000 mL). The filtrate was washed with saturated aq. Na2S203 (2x500 mL); saturated aq. FeSO 4 (300 mL); and then brine (500 mL).
• the organic layer was dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure to obtain the crude title compound (150 g).
• the resulting solution was concentrated under reduced pressure and the resulting solids were dissolved in EtOAc, then twice washed with aq. citric acid (1M) followed by water followed by brine. The organic solution was dried over Na 2 SO 4 ; filtered; then concentrated in vacuo to afford the separated enantiomer in 80-90% recovery.
• Reaction is slightly exothermic (3-6 °C); so that addition is preferred at lower temperature].
• the reaction mixture was stirred at 5-10 °C for 2-3 h. After completion of the reaction (monitored by TLC), it was quenched with ice cold water (18.75 L, 15 V) at below 25 °C. Then the reaction mass was allowed warm to room temperature and stirred for 2 h. The solids were isolated by filtration and then were washed with water (2.5 L, 2.0 V). Bulk residual water was removed from the solids by maintaining vacuum filtration for 60-90 min.
• Step-2a To a solution of DMSO (5.9 L, 5.0 V)) in a round-bottom flask was added 2,6- dichloro-3-nitrobenzaldehyde (1.17 kg, 5.31 mol, 1.0 equiv.) at room temperature. After being stirred for 30 min at room temperature, hydroxylamine hydrochloride (0.63 kg, 9.04 mol, 1.70 equiv.) was added and the reaction mass was stirred at room temperature for 3 h. After completion of the reaction (monitored by TLC), the reaction mass was quenched by the addition of ice-cold water (18.0 L, 15.0 V) added at a rate sufficient to maintain the temperature below 30 °C (Observation: Solids formed upon water addition).
• the reaction mass was stirred at room temperature for 60-90 min.
• the solids were isolated by filtration; washed with water (2.5 L, 2.0 V); followed by washing with a mixture of acetone and hexanes (6.0 L, 1:1 ratio). Bulk residual water was removed from the solids by maintaining vacuum filtration for 60-90 min.
• the wet solid was initially air dried and then finally dried in a hot air oven at 50-55 °C for 10-12 h (until moisture content was not more than 1.0 %) to get the dried target product, 2,6-dichloro-3-nitrobenzaldehyde oxime (1.22 kg, 92% yield) as an off- white solid.
• the crude product (which contains 10-20% of 2,6-dichloro-3-nitrobenzonitrile) was used directly in the next step without further purification.
• Step-2b To a stirred solution of the crude oxime (preparation described above, 1.13 kg, 4.80 mol, 1.0 equiv.) in DCM (9.04 L, 8.0 V) at 0-5 °C was added triethylamine ("TEA", 1.02 kg, 10.09 mol, 2.1 equiv.). After being stirred for 5 min, methanesulfonyl chloride (0.60 kg, 5.29 mol, 1.1 equiv.) was added (Observation: An exotherm is noted during the addition) slowly at 15 °C. Then the reaction mass was stirred at room temperature for 30-45 min.
• TOA triethylamine
• reaction mass was diluted with water (6.78 L, 6.0 V); the organic layer was separated; and the aqueous layer was extracted with DCM (3.4 L, 3.0 V). The combined organic layers were washed with brine (5.65 L, 5.0 V); dried over Na 2 SO 4 ; and concentrated under vacuum. The resulting crude solids were triturated with hexanes (4.50 L, 4.0 V) at room temperature.
• the solids were isolated via filtration and then were washed with water (2.25 L, 3.0 V).
• the wet solid was washed with a 1:1 ratio mixture of acetone (1.875 L, 2.5 V) and hexanes (1.875 L, 2.5 V). Bulk residual water was removed from the solids by maintaining vacuum filtration for 60-90 min.
• the wet solid was finally dried in a hot air oven for 7-8 h at 50 °C (until moisture content reaches below 1.5%) to get the dried product, 4-chloro-7-nitro-1H- indazol-3-amine (549.0 g, 75% yield) as a brick red-colored solid.
• reaction temperature was slowly raised to room temperature and stirring was continued an additional 2 h at the same temperature.
• reaction mass was quenched by the addition of ice-cold water (15.0 L, 30.0 V) and the resulting mixture was then stirred for 6-8 h at room temperature.
• the solids were isolated via filtration and were then washed with water (1.5 L, 3.0 V).
• the wet solid was washed with IPA (1.5 L, 3.0 V) followed by hexanes (1.0 L, 2.0 V). Bulk residual water was removed from the solids by maintaining vacuum filtration for 60-90 min.
• Step 5a To a solution of 4-chloro-1-methyl-7-nitro-1H- indazol-3-amine (625.0 g, 2.76 mol, 1.0 equiv.) in DCM (6.25 L, 10.0 V) at 0-5 °C. was added triethylamine (TEA) (837.0 g, 8.27 mol, 3.0 equiv.); followed by the addition of 4-dimethylaminopyridine (DMAP) (20.60 g, 0.165 mol, 0.06 equiv.).
• TEA triethylamine
• DMAP 4-dimethylaminopyridine
• Step 6 Preparation of N-(4-chloro-1-methyl-7-nitro-1H- indazol-3-yl)-N-(4- methoxybenzyl)methanesulfonamide
• the mixture was poured into ice cold water (19.05 L, 30.0 V) [Note: Slow quenching with vigorous stirring is preferred to avoid clumping as the product precipitates].
• the resulting solids were isolated via filtration and washed with water (1.90 L, 3.0 V); then the solids were washed with hexanes (1.27 L, 2.0 V). Bulk residual water was removed from the solids by maintaining vacuum filtration for 60-90 min.
• the isolated solid was dissolved in Ethyl acetate (12.7 L, 20.0 V) and charcoal was added (63.5 g). The mixture was heated to 60-70 °C and then stirred for 30-45 min. at that temperature.
• Step 7 Preparation of N-(7-Amino-4-chloro-1-methyl-1H- indazol-3-yl)-N-(4- methoxybenzyl)methanesulfonamide
• Step 1 Preparation of methyl 2-nitro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate
• methyl 4-bromo-2-nitrobenzoate 600 g, 2307 mmol
• 1,4- dioxane 6 mL
• bis(pinacol)diborane 615 g, 2423 mmol
• potassium acetate 679 g, 6922 mmol
• the combined filtrate was partitioned, and the organic layer was isolated, dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure to afford the crude product.
• This material was triturated with diethyl ether as follows: First, the material was triturated with Et 2 O (2400 mL) and the resulting off-white solid was collected via filtration, washed with Et 2 O (2 x 900 mL), and reserved (480 g isolated). The combined filtrate was concentrated under a stream of N 2 gas to half of the original volume, upon which the solution cooled to below ambient temperature and an off-white solid precipitated. The precipitate was collected via filtration, washed with Et 2 O (2 x 600 mL), and reserved (90 g isolated).
• Step 2 Preparation of methyl 2-nitro-4-(4-(trifluoromethyl)pyrimidin-2-yl)benzoate
• methyl 2-nitro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)benzoate 600 g, 1954 mmol
• 2-chloro-4-(trifluoromethyl)pyrimidine 357 mL, 2931 mmol
• THF tetrahydrofuran
• the reaction mixture was degassed by bubbling N 2 gas through the mixture for 10 min.
• dichloro[9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene]palladium(II) 73.8 g, 98 mmol
• the reaction mixture was concentrated under reduced pressure and the resulting residue was diluted with ethyl acetate (5000 mL) and then washed with water (2 x 2000 mL).
• Step 3 Preparation of methyl 2-amino-4-(4-(trifluoromethyl)pyrimidin-2-yl)benzoate
• Step 1 Preparation of tert-butyl (S)-(1-(3-(4-chloro-3-(N-(4- methoxybenzyl)methylsulfonamido)-1-methyl-1H-indazol-7-yl)-4-oxo-7-(4- (trifluoromethyl)pyrimidin-2-yl)-3,4-dihydroquinazolin-2-yl)-2-(3,5- d if I uorophenyl)ethyl)ca rba mate
• reaction mixture was stirred at -5 °C for 2 hr, then to the mixture was added N-(7-amino-4-chloro-1- methyl-1H-indazol-3-yl)-N-(4-methoxybenzyl)methanesulfonamide (100 g, 253 mmol) in one portion.
• the mixture was slowly warmed to 25 °C and was stirred for 18 hr.
• Step 2 Preparation of (S)-N-((6P)-7-(2-(1-amino-2-(3,5-difluorophenyl)ethyl)-4-oxo-7-(4-
• the solids were isolated via filtration and were then washed with water (540 mL, 3.0 V). The wet solid was washed with hexanes (0.9 L, 5.0 V). Bulk residual water was removed from the solids by maintaining vacuum filtration for 60-90 min. The wet solid was dried in a hot air oven for 7-8 h at 50 °C (until the moisture content was below 1.0%). The isolated material, 4-chloro-1-(2,2-difluoroethyl)-7-nitro-1H-indazol-3-amine (160 g, 71% yield), was used in the next step without further purification.
• Step 2 Preparation of N-(4-chloro-1-(2,2-difluoroethyl)-7-nitro-1H-indazol-3-yl)methane sulfonamide
• Step 2a To a solution of 4-chloro-1-(2,2-difluoroethyl)-7-nitro-1H- indazol-3-amine
• Step 2b To a stirred solution of N-(4-chloro-1-(2,2-difluoroethyl)-7-nitro-1H- indazol-3- yl)-N-(methylsulfonyl) methanesulfonamide (entirety of material prepared above) in ethanol (1.7 L, 10.0 V) at room temperature was added slowly aq. 5% NaOH solution (1.19 L, 7.0 V) [Note: Slow addition is preferred via dropping funnel]. The reaction mass was stirred at the same temperature for 3 h. After completion of the reaction [Sample preparation for TLC analysis: an aliquot of reaction solution ( ⁇ 1 mL) was acidified with aq.
• the wet material was dried in a hot air oven at 50 °C for 6-7 h (until the moisture content was below 1.0%) to afford the dried product, N-(4-chloro-1-(2,2- difluoroethyl)-7-nitro-1H- indazol-3-yl)methanesulfonamide (170.0 g, 75%) as a yellow solid.
• Step 3 Preparation of N-(4-chloro-1-(2,2-difluoroethyl)-7-nitro-1H-indazol-3-yl)- N-(4-methoxy benzyl)methanesulfonamide
• the mixture was poured into ice cold water (4.8 L, 60.0 V) [Note: Slow quenching with vigorous stirring is preferred to avoid clumping as the product precipitates].
• the resulting solids were isolated via filtration and washed with water (480 mL, 3.0 V); then the solids were washed with hexanes (320 mL, 2.0 V). Bulk residual water was removed from the solids by maintaining vacuum filtration for 1-2 h.
• the isolated solid was dissolved in ethyl acetate (1.6 L, 10.0 V) and charcoal was added (16.0 g). The mixture was heated to 60-70 °C and then stirred for 30-45 min. at that temperature.
• the mixture was filtered while hot (40-50 °C) through a pad of Celite and the Celite pad was then extracted with ethyl acetate (800 mL, 5.0 V).
• the combined filtrates were concentrated to dryness under reduced pressure at below 50 °C.
• ethyl acetate 160 mL, 1.0 V.
• the suspension was stirred for 30 min.
• the solids were isolated via filtration and then were washed with hexanes (320 mL, 2.0 V). Residual water was removed from the solids by maintaining vacuum filtration for 45-60 min.
• Step 4 Preparation of N-(7-amino-4-chloro-1-(2,2-difluoroethyl)-1H- indazol-3-yl)-N-(4- methoxybenzyl)methanesulfonamide
• the reaction mixture was heated to 60 °C and then stirred for 2 h. After completion of the reaction (monitored by in-process TLC/HPLC), the mixture was cooled to room temperature and diluted with ethyl acetate (1.3 L, 10.0 V) and water (390 mL, 3.0 V). The mixture was stirred for 15 min. The mixture was filtered through a pad of Celite and the Celite pad was then extracted with ethyl acetate (650 mL, 5.0 V). The bi-phasic filtrate was partitioned, and the organic phase was reserved while the aqueous layer was extracted with ethyl acetate (650 mL, 5.0 V).
• Step 1 Preparation of N-(4-chloro-1-(2,2-difluoroethyl)-7-nitro-1H-indazol-3- yl)cyclopropanesulfonamide
• 4-chloro-1-(2,2-difluoroethyl)-7-nitro-1H- indazol-3-amine 150.0 g, 0.54 mol, 1.0 equiv.
• acetonitrile 600 mL, 4.0 V
• pyridine 600 mL, 4.0 V
• 4-dimethylaminopyridine 30.0 g, 0.27 mol, 0.5 equiv.
• the reaction mass was stirred for 5-10 min., then cyclopropylsulfonyl chloride (114 mL, 1.08 mol, 2.0 equiv.) was added at room temperature.
• the reaction mixture was heated to 50 °C and then stirred at that temperature for 3 days.
• the mixture was cooled to room temperature and diluted with water (1.5 L, 10.0 V) and ethyl acetate (1.5 L, 10.0 V), then stirred at room temperature for 15 min.
• the organic layer was separated, and the aqueous layer was extracted with EtOAc (300 mL, 2.0 V). The combined organic layers were washed with aq.
• Step 2 Preparation of N-(4-chloro-1-(2,2-difluoroethyl)-7-nitro-1H-indazol-3-yl)-N-(4- methoxybenzyl)cyclopropanesulfonamide
• the mixture was poured into ice cold water (3.0 L, 30.0 V) [Note: Slow quenching with vigorous stirring is preferred to avoid clumping as the product precipitates].
• the resulting solids were isolated via filtration and washed with water (300 mL, 3.0 V); then the solids were washed with hexanes (300 mL, 3.0 V). Bulk residual water was removed from the solids by maintaining vacuum filtration for 1-2 h.
• the wet solid was dissolved in ethyl acetate (500 mL, 5.0 V) and charcoal was added (10.0 g). The mixture was heated to 60-70 °C and then stirred for 30-45 minutes at that temperature.
• Step 3 Preparation of N-(7-amino-4-chloro-1-(2,2-difluoroethyl)-1H-indazol-3-yl)-N-(4- methoxybenzyl)cyclopropanesulfonamide
• the mixture was stirred for 5-10 min, then to the stirred mixture at 10-15 °C was added 2,2,2- trifluoroethyl trifluoromethanesulfonate (60.18 g, 0.26 mol, 1.1 equiv.) at a rate sufficient to maintain the reaction mass below 20 °C (Note: slow addition is preferred for obtaining more favorable regio-selectivity).
• the reaction mass was allowed to slowly warm to room temperature and was then stirred at the same temperature for 2 h. After completion of the reaction (monitored by TLC), the reaction mass was quenched via the addition of ice-cold water (1.5 L, 30.0 V) and the resulting mixture was allowed to warm to room temperature with stirring for 6-8 h.
• the solids were isolated via filtration and were then washed with water (150 mL, 3.0 V). The wet solid was washed with hexanes (250 mL, 5.0 V) and then bulk residual water was removed from the solids by maintaining vacuum filtration for 60-90 min. The wet solid was dried in a hot air oven for 7-8 h at 50 °C (until the moisture content was below 1.0%).
• the isolated material 4-chloro-7-nitro-1-(2,2,2-trifluoroethyl)-1H-indazol-3- amine (45.0 g, 60% yield), was used directly in the next step without further purification.
• Step 2 Preparation of N-(4-chloro-7-nitro-1-(2,2,2-trifluoroethyl)-1H-indazol-3- yl)methanesulfonamide
• Step 2a To a solution of 4-chloro-7-nitro-1-(2,2,2-trifluoroethyl)-1H- indazol-3-amine
• the mixture was diluted with water (200 mL, 10.0 V) and then stirred at room temperature for 15 min.
• the organic layer was separated, and the aqueous layer was extracted with DCM (200 mL, 10.0 V).
• the combined organic layers were washed with 10% brine solution (60 mL, 3.0 V), dried over Na 2 SO 4 , filtered, and concentrated to afford the crude solids.
• Step 2b To a stirred solution of N-(4-chloro-7-nitro-1-(2,2,2-trifluoroethyl)-1H- indazol-
• Step 3 Preparation of N-(4-chloro-7-nitro-1-(2,2,2-trifluoroethyl)-1H-indazol-3-yl)-N-(4- methoxybenzyl)methanesulfonamide
• the mixture was poured into ice cold water (2.0 L, 40.0 V) [Note: Slow quenching with vigorous stirring is preferred to avoid clumping as the product precipitates].
• the resulting solids were isolated via filtration and washed with water (150 mL, 3.0 V); then the solids were washed with hexanes (150 mL, 3.0 V). Bulk residual water was removed from the solids by maintaining vacuum filtration for 1-2 h.
• the solids were dissolved in ethyl acetate (500 mL, 10.0 V) and to the solution was added charcoal (5.0 g). The mixture was heated to 60-70 °C and then stirred at that temperature for 30-45 min.
• the mixture was filtered while hot (40-50 °C) through a pad of Celite and the Celite pad was extracted with ethyl acetate (250 mL, 5.0 V).
• the combined filtrate was concentrated to dryness under reduced pressure at below 50 °C.
• the solids were combined with ethyl acetate (50 mL, 1.0 V) at room temperature. The resulting suspension was stirred for 30 min.
• the solids were isolated via filtration and then were washed with hexanes (100 mL, 2.0 V). Residual water was removed from the solids by maintaining vacuum filtration for 45-60 min.
• Step 4 Preparation of N-(7-amino-4-chloro-1-(2,2,2-trifluoroethyl)-1H- indazol-3-yl)-N-(4- methoxybenzyl)methanesulfonamide
• the reaction mixture was stirred at room temperature for 3 h. After completion of the reaction (monitored by in-process TLC/HPLC), the mixture was diluted with ethyl acetate (1.0 L, 20.0 V) and water (250 mL, 5.0 V). The mixture was stirred for 15 min. The mixture was filtered through a pad of Celite and the Celite pad was extracted with ethyl acetate (250 mL, 5.0 V). The bi-phasic filtrate was partition and the organic layer was reserved while the aqueous layer was extracted with ethyl acetate (500 mL, 10.0 V).
• the major atropisomer was chirally purified by SFC chromatography on a Chiralpak ID, 25 mm x 250 mm, 5u column, using a A:B gradient, solvent A 80 % heptane, 0.1% TFA solvent B 20% ethanol, 0.1% TFA to provide the desired product (176 mg, 18%, chiral purity 98.2%).
• LC/MS: m/z 654.15 [M+1] + .
• the mixture was cooled to rt and then was diluted with EtOAc and washed with aq. 0.5 M citric acid, dried over Na 2 SO 4 , filtered, and then concentrated under reduced pressure.
• the resulting residue was purified by silica gel chromatography (80g RediSep column) eluting with 0-45% ethyl acetate in hexanes over 25 CV.
• the mixture was cooled to room temperature and then concentrated under reduced pressure.
• the mixture was then diluted with EtOAc (approximately 500 mL) and washed with aqueous citric acid (0.5M, 2 x 50 mL), then aqueous NaOH (1M, 3 x 50 mL), dried over Na 2 SO 4 , filtered, and concentrated.
• reaction mixture was cooled to 27 °C and to the mixture was added N-(7-amino-4-chloro-1-(2,2-difluoroethyl)-1H-indazol- 3-yl)-N-(4-methoxybenzyl)methanesulfonamide.
• the flask was sealed and the mixture was heated at 80 °C for 16 hr.
• the reaction mixture was allowed to cool to 27 °C and then was concentrated under reduced pressure.
• the solution was stirred at 27 °C for 36 h.
• the reaction mixture was diluted with ice cold water (50 mL), and stirred for 15 min.
• the precipitated solid was isolated via filtration, washed with water (50 mL), and dried under vacuum to obtain the crude product.
• reaction mixture was cooled to 26 °C, then N-(7-amino-4-chloro-1-(2,2-difluoroethyl)-1H-indazol-3-yl)- N-(4-methoxybenzyl)cyclopropanesulfonamide (N66734-90-A2, 20.49 g, 34.9 mmol) was added.
• the mixture was heated at 80 °C for 16 h.
• the reaction mixture was cooled to 26 °C and then was concentrated under reduced pressure.
• reaction mixture was stirred at 27 °C for 16 h.
• the reaction mixture was diluted with ice cold water (70 mL) and then stirred for 15 min at 27 °C.
• the precipitated solids were collected by filtration and then dried under vacuum to obtain the crude compound as an off-white solid.
• the flask was sealed with a septum and then placed under argon atmosphere (vac/fill x 3). To the flask was added dioxane (6.3 mL). The flask was again placed under argon atmosphere (vac/fill x 3). The resulting mixture was stirred at 60 °C for 16 h overnight. Upon cooling to ambient temperature the reaction was concentrated in vacuo anti the resulting residue was adsorbed onto Celite.
• reaction mixture was degassed for 10 min with nitrogen gas and then stirred at 27 °C for 16 h.
• the reaction mixture was diluted with ice cold water (70 mL) and then was stirred for 30 min at 27 °C.
• the title compound was prepared according to General Procedure B using 2-chloro-3- methylpyrazine as the coupling partner.
• the vessel was sealed and then placed under Ar atmosphere (vacuum evacuation followed by refill with argon, repeated three times).
• dioxane (16 ml)
• the resulting mixture was degassed (brief vacuum evacuation followed by refill with argon, repeated three times).
• the mixture was stirred at 60 °C for 16 h.
• the mixture was concentrated and the resulting residue was adsorbed on Celite.
• the resulting powder was subjected to silica gel chromatography eluting with 0-100% ethyl acetate in hexanes over 10 CVs.
• the vessel was sealed with a septum cap and then placed under Ar atmosphere (vacuum evacuation followed by refill with argon, repeated three times).
• To the vessel was added THF (5.2 ml) and Water (1.3 ml), and the mixture was degassed (brief vacuum evacuation followed by refill with argon, repeated three times). The mixture was stirred at 60 °C for 12 hr.
• the vial was sealed with a setum cap and then placed under Ar atmosphere (vacuum evacuation followed by refill with argon, repeated three times).
• To the vial was added THF (4 ml) and Water (1 ml). The mixture was degassed (brief vacuum evacuation followed by refill with argon, repeated three times). The mixture was stirred at 45°C for 5 hr. The mixture was concentrated in vacuo and the resulting residue was purified by silica chromatography using a gradient of 0-100% ethyl acetate in hexanes over 10 CVs followed by 100 % methanol.
• Step 2 To a solution of 3-(difluoromethyl)-1H-indazole (275 mg, 1.635 mmol) and methyl 2- bromoacetate (0.186 mL, 1.963 mmol) in DMF (10 mL) was added potassium carbonate (271 mg, 1.963 mmol) and the mixture was stirred at ambient temperature for 18 h. The mixture was diluted with water and extracted with EtOAc.
• 2-(1-isopropyl-1H-indol-3-yl)acetic acid was prepared according to the literature procedure (CN107151223, 2017).
• 2-(3-cyclopropyl-5-(difluoromethyl)-1H-pyrazol-1-yl)acetic acid, 2-(3- cyclopropyl-1H-pyrazol-1-yl)-2-methylpropanoic acid, 2-(3-cyclopropyl-1H-pyrazol-1-yl)-3- methyl butanoic acid, and 2-(1H-indol-1-yl)acetic acid were purchased from Enamine.
• Example 1 (S)-2-(3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl)-N-(1-((3P)-3-(4- chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7-(3-methylpyrazin-2-yl)-4-oxo-3,4- dihydroquinazolin-2-yl)-2-(3,5-difluorophenyl)ethyl)acetamide.
• the title compound was prepared according to General Procedure C using 2-(3,5- bis(trifluoromethyl)-1H-pyrazol-1-yl)acetic acid as the coupling partner.
• Example 2 (S)-N-(1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H- indazol-7-yl)-7-(3-methylpyrazin-2-yl)-4-oxo-3,4-dihydroquinazolin-2-yl)-2-(3,5- difluorophenyl)ethyl)-2-(3-cyclopropyl-1H-indazol-1-yl)acetamide.
• the title compound was prepared according to General Procedure C using 2-(3- cyclopropyl-1H-indazol-1-yl)acetic acid as the coupling partner modified as follows: the HATU coupling was stirred for 5 h instead of 18 h.
• Example 3 (S)-2-(3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl)-N-(1-((3P)-3-(4- chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7-(4, 6-dimethyl pyrimidin-2-yl)-4-oxo- 3,4-dihydroquinazolin-2-yl)-2-(3,5-difluorophenyl)ethyl)acetamide.
• the title compound was prepared according to General Procedure C using 2-(3,5- bis(trifluoromethyl)-1H-pyrazol-1-yl)acetic acid as the coupling partner modified as follows: the amine used was (S)-N-(7-(2-(1-amino-2-(3,5-difluorophenyl)ethyl)-7-(4,6- dimethylpyrimidin-2-yl)-4-oxoquinazolin-3(4H)-yl)-4-chloro-1-methyl-1H-indazol-3- yl)methanesulfonamide.
• Example 4 Preparation of Example 4: (S)-N-(1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H- indazol-7-yl)-7-(4, 6-dimethyl pyrimidin-2-yl)-4-oxo-3,4-dihydroquinazolin-2-yl)-2-(3, 5- difluorophenyl)ethyl)-2-(3-cyclopropyl-1H-indazol-1-yl)acetamide.
• the title compound was prepared according to General Procedure C using 2-(3- cyclopropyl-1H-indazol-1-yl)acetic acid as the coupling partner modified as follows: the amine used was (S)-N-(7-(2-(1-amino-2-(3,5-difluorophenyl)ethyl)-7-(4,6-dimethylpyrimidin-2-yl)-4- oxoquinazolin-3(4H)-yl)-4-chloro-1-methyl-1H-indazol-3-yl)methanesulfonamide.
• the title compound was prepared according to General Procedure C using 2-(3-(tert- butyl)-1H-pyrazol-1-yl)acetic acid as the coupling partner.
• Example 6 2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro- 1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)-N-((S)-2-(3,5-difluorophenyl)-1-(3-(1,4- dimethyl-3-(methylsulfonamido)-1H-indazol-7-yl)-(3P)-7-(3-methylpyrazin-2-yl)-4-oxo-3,4- dihydroquinazolin-2-yl)ethyl)acetamide.
• the vial was degassed (brief vacuum evacuation followed by refill with argon, repeated three times) and then to the vial was added dioxane (0.5 ml) and Water (0.1 ml). The vial was again degassed (brief vacuum evacuation followed by refill with argon, repeated three times), then the mixture was stirred at 100°C for 3 hrs.
• Example 7 (S)-N-(1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H- indazol-7-yl)-7-(3-methylpyrazin-2-yl)-4-oxo-3,4-dihydroquinazolin-2-yl)-2-(3,5- difluorophenyl)ethyl)-2-(3-(difluoromethyl)-1H-indazol-1-yl)acetamide.
• the title compound was prepared according to General Procedure C using 2-(3- (difluoromethyl)-1H-indazol-1-yl)acetic acid as the coupling partner.
• Example 8 (S)-N-(1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H- indazol-7-yl)-7-(3-methylpyrazin-2-yl)-4-oxo-3,4-dihydroquinazolin-2-yl)-2-(3,5- difluorophenyl)ethyl)-2-(1-isopropyl-1H-indol-3-yl)acetamide.
• the title compound was prepared according to General Procedure C using 2-(1- isopropyl-1H-indol-3-yl)acetic acid as the coupling partner modified as follows: the amine used was (S)-N-(7-(2-(1-amino-2-(3,5-difluorophenyl)ethyl)-7-(3-methylpyrazin-2-yl)-4- oxoquinazolin-3(4H)-yl)-4-chloro-1-methyl-1H-indazol-3-yl)methanesulfonamide .
• the title compound was prepared according to General Procedure C using 2-(5- cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetic acid as the coupling partner modified as follows: the amine used was (S)-N-(7-(2-(1-amino-2-(3,5-difluorophenyl)ethyl)-7-(4,6- dimethylpyrimidin-2-yl)-4-oxoquinazolin-3(4H)-yl)-4-chloro-1-methyl-1H-indazol-3- yl)methanesulfonamide.
• Example 10 (S)-N-(1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H- indazol-7-yl)-7-(3-methylpyrazin-2-yl)-4-oxo-3,4-dihydroquinazolin-2-yl)-2-(3,5- difluorophenyl)ethyl)-2-(3-cyclopropyl-5-methyl-1H-pyrazol-1-yl)acetamide.
• the title compound was prepared according to General Procedure C using 2-(3- cyclopropyl-5-methyl-1H-pyrazol-1-yl)acetic acid as the coupling partner.
• Example 11 (S)-N-(1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H- indazol-7-yl)-7-(3-methylpyrazin-2-yl)-4-oxo-3,4-dihydroquinazolin-2-yl)-2-(3,5- difluorophenyl)ethyl)-2-(3-cyclobutyl-1H-pyrazol-1-yl)acetamide.
• the title compound was prepared according to General Procedure C using 2-(3- cyclobutyl-1H-pyrazol-1-yl)acetic acid as the coupling partner.
• the title compound was prepared according to General Procedure C using 2-(5- methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetic acid as the coupling partner.
• Example 13 (S)-N-(1-((3P)-3-(4-chloro-3-(cyclopropanesulfonamido)-1-(2,2- difluoroethyl)-1H-indazol-7-yl)-7-(2-fluorophenyl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2- yl)-2-(3,5-difluorophenyl)ethyl)-2-(3-cyclopropyl-1H-indazol-1-yl)acetamide.
• Example 14 (S)-2-(3-(tert-butyl)-1H-pyrazol-1-yl)-N-(1-((3P)-3-(4-chloro-1- methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7-(2-fluorophenyl)-4-oxo-3,4- dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)acetamide.
• Example 15 (S)-N-(1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H- indazol-7-yl)-7-(2-fluorophenyl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5- difluorophenyl)ethyl)-2-(3-cyclopropyl-1H-indazol-1-yl)acetamide.
• the title compound was prepared according to General Procedure A using 2-(3- cyclopropyl-1H-indazol-1-yl)acetic acid as the coupling partner modified as follows: the reaction time was lh.
• Example 16 (S)-N-(1-((3P)-3-(4-chloro-1-(2,2-difluoroethyl)-3- (methylsulfonamido)-1H-indazol-7-yl)-7-(2-fluorophenyl)-4-oxo-3,4-dihydropyrido[2,3- d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-(5-cyclopropyl-3-(difluoromethyl)-1H-pyrazol- 1-yl)acetamide.
• the title compound was prepared according to General Procedure A using 2-(5- cyclopropyl-3-(difluoromethyl)-1H-pyrazol-1-yl)acetic acid as the coupling partner modified as follows: the amine coupling partner was (S)-N-(7-(2-(1-amino-2-(3,5-difluorophenyl)ethyl)-7- (2-fluorophenyl)-4-oxopyrido[2,3-d]pyrimidin-3(4H)-yl)-4-chloro-1-(2,2-difluoroethyl)-1H- indazol-3-yl)methanesulfonamide.
• Example 17 (S)-N-(1-((3P)-3-(4-chloro-1-(2,2-difluoroethyl)-3- (methylsulfonamido)-1H-indazol-7-yl)-7-(2-fluorophenyl)-4-oxo-3,4-dihydropyrido[2,3- d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-(3-cyclopropyl-5-(difluoromethyl)-1H-pyrazol- 1-yl)acetamide.
• the title compound was prepared according to General Procedure A using 2-(3- cyclopropyl-5-(difluoromethyl)-1H-pyrazol-1-yl)acetic acid as the coupling partner modified as follows: the amine coupling partner was (S)-N-(7-(2-(1-amino-2-(3,5-difluorophenyl)ethyl)-7- (2-fluorophenyl)-4-oxopyrido[2,3-d]pyrimidin-3(4H)-yl)-4-chloro-1-(2,2-difluoroethyl)-1H- indazol-3-yl)methanesulfonamide.
• the title compound was prepared according to General Procedure A using 2-(3- cyclopropyl-1H-indazol-1-yl)acetic acid as the coupling partner modified as follows: the amine coupling partner was (S)-N-(7-(2-(1-amino-2-(3,5-difluorophenyl)ethyl)-7-(2-fluorophenyl)-4- oxopyrido[2,3-d]pyrimidin-3(4H)-yl)-4-chloro-1-(2,2-difluoroethyl)-1H-indazol-3- yl)methanesulfonamide and the reaction time was 1h.
• Example 19 (S)-N-(1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H- indazol-7-yl)-7-(2-fluorophenyl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5- difluorophenyl)ethyl)-2-(3-cyclopropyl-1H-pyrazol-1-yl)-2-methylpropanamide.
• the title compound was prepared according to General Procedure A using 2-(3- cyclopropyl-1H-pyrazol-1-yl)-2-methylpropanoic acid as the coupling partner modified as follows: the reaction solvent was tetrahydrofuran (1 mL) : N,N-Dimethylformamide (0.250 mL).
• Example 20 (S)-N-(1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H- indazol-7-yl)-7-(2-fluorophenyl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5- difluorophenyl)ethyl)-2-(3-cyclopropyl-1H-pyrazol-1-yl)-2-methylpropanamide.
• the title compound was prepared according to General Procedure A using 2-(3- cyclopropyl-1H-pyrazol-1-yl)-2-methylpropanoic acid as the coupling partner modified as follows: the amine coupling partner was (S)-N-(7-(2-(1-amino-2-(3,5-difluorophenyl)ethyl)-7- (2-fluorophenyl)-4-oxopyrido[2,3-d]pyrimidin-3(4H)-yl)-4-chloro-1-(2,2-difluoroethyl)-1H- indazol-3-yl)methanesulfonamide and the reaction solvent was tetrahydrofuran (1 mL) : N,N- Dimethylformamide (0.250 mL).
• Example 21 (S)-N-(1-((3P)-3-(4-chloro-3-(cyclopropanesulfonamido)-1-(2,2- difluoroethyl)-1H-indazol-7-yl)-7-(2-fluorophenyl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2- yl)-2-(3,5-difluorophenyl)ethyl)-2-(3-cyclopropyl-1H-pyrazol-1-yl)-2-methylpropanamide.
• the title compound was prepared according to General Procedure A using 2-(3- cyclopropyl-1H-pyrazol-1-yl)-2-methylpropanoic acid as the coupling partner modified as follows: the amine coupling partner was (S)-N-(7-(2-(1-amino-2-(3,5-difluorophenyl)ethyl)-7- (2-fluorophenyl)-4-oxopyrido[2,3-d]pyrimidin-3(4H)-yl)-4-chloro-1-(2,2-difluoroethyl)-1H- indazol-3-yl)cyclopropanesulfonamide and the reaction solvent was tetrahydrofuran (1 mL) : N,N-Dimethylformamide (0.250 mL).
• the title compound was prepared according to General Procedure A using 2-(3- cyclopropyl-1H-pyrazol-1-yl)-2-methylpropanoic acid as the coupling partner modified as follows: the amine coupling partner was (S)-N-(7-(2-(1-amino-2-(3,5-difluorophenyl)ethyl)-7- (2-fluorophenyl)-4-oxopyrido[2,3-d]pyrimidin-3(4H)-yl)-4-chloro-1-(2,2,2-trifluoroethyl)-1H- indazol-3-yl)methanesulfonamide and the reaction solvent was tetrahydrofuran (1 mL) : N,N- Dimethylformamide (0.250 mL). The experiment afforded the title compound, (S)-N-(1-((3P)-
• Example 23 N-((S)-1-((3P)-3-(4-chloro-3-(methylsulfonamido)-1-(2,2,2- trifluoroethyl)-1H-indazol-7-yl)-7-(2-fluorophenyl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2- yl)-2-(3,5-difluorophenyl)ethyl)-2-(3-cyclopropyl-1H-pyrazol-1-yl)-3-methylbutanamide.
• the title compound was prepared according to General Procedure A using 2-(3- cyclopropyl-1H-pyrazol-1-yl)-3-methylbutanoic acid as the coupling partner modified as follows: the amine coupling partner was (S)-N-(7-(2-(1-amino-2-(3,5-difluorophenyl)ethyl)-7- (2-fluorophenyl)-4-oxopyrido[2,3-d]pyrimidin-3(4H)-yl)-4-chloro-1-(2,2,2-trifluoroethyl)-1H- indazol-3-yl)methanesulfonamide and the reaction solvent was tetrahydrofuran (1 mL) : N,N- Dimethylformamide (0.250 mL). The experiment afforded the title compound, N-((S)-1-((3P)-
• Example 24 N-((S)-1-((3P)-3-(4-chloro-3-(cyclopropanesulfonamido)-1-(2,2- difluoroethyl)-1H-indazol-7-yl)-7-(2-fluorophenyl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2- yl)-2-(3,5-difluorophenyl)ethyl)-2-(3-cyclopropyl-1H-pyrazol-1-yl)-3-methylbutanamide.
• the title compound was prepared according to General Procedure A using 2-(3- cyclopropyl-1H-pyrazol-1-yl)-3-methylbutanoic acid as the coupling partner modified as follows: the amine coupling partner was (S)-N-(7-(2-(1-amino-2-(3,5-difluorophenyl)ethyl)-7- (2-fluorophenyl)-4-oxopyrido[2,3-d]pyrimidin-3(4H)-yl)-4-chloro-1-(2,2-difluoroethyl)-1H- indazol-3-yl)cyclopropanesulfonamide and the reaction solvent was tetrahydrofuran (1 mL) : N,N-Dimethylformamide (0.250 mL).
• Example 25 N-((S)-1-((3P)-3-(4-chloro-1-(2,2-difluoroethyl)-3- (methylsulfonamido)-1H-indazol-7-yl)-7-(2-fluorophenyl)-4-oxo-3,4-dihydropyrido[2,3- d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-(3-cyclopropyl-1H-pyrazol-1-yl)-3- methylbutanamide.
• the title compound was prepared according to General Procedure A using 2-(3- cyclopropyl-1H-pyrazol-1-yl)-3-methylbutanoic acid as the coupling partner modified as follows: the amine coupling partner was (S)-N-(7-(2-(1-amino-2-(3,5-difluorophenyl)ethyl)-7- (2-fluorophenyl)-4-oxopyrido[2,3-d]pyrimidin-3(4H)-yl)-4-chloro-1-(2,2-difluoroethyl)-1H- indazol-3-yl)methanesulfonamide and the reaction solvent was tetrahydrofuran (1 mL) : N,N- Dimethylformamide (0.250 mL).
• Example 26 N-((S)-1-((3P)-3-(4-chloro-3-(methylsulfonamido)-1-(2,2,2- trifluoroethyl)-1H-indazol-7-yl)-7-(2-fluorophenyl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2- yl)-2-(3,5-difluorophenyl)ethyl)-2-(3-cyclopropyl-1H-pyrazol-1-yl)-3-methylbutanamide.
• the title compound was prepared according to General Procedure A using 2-(3- cyclopropyl-1H-pyrazol-1-yl)-3-methylbutanoic acid as the coupling partner modified as follows: the amine coupling partner was (S)-N-(7-(2-(1-amino-2-(3,5-difluorophenyl)ethyl)-7- (2-fluorophenyl)-4-oxopyrido[2,3-d]pyrimidin-3(4H)-yl)-4-chloro-1-(2,2,2-trifluoroethyl)-1H- indazol-3-yl)methanesulfonamide and the reaction solvent was tetrahydrofuran (1 mL) : N,N- Dimethylformamide (0.250 mL). The experiment afforded the title compound, N-((S)-1-((3P)-
• Example 27 N-((S)-1-((3P)-3-(4-chloro-1-(2,2-difluoroethyl)-3- (methylsulfonamido)-1H-indazol-7-yl)-7-(2-fluorophenyl)-4-oxo-3,4-dihydropyrido[2,3- d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-(3-cyclopropyl-1H-pyrazol-1-yl)-3- methylbutanamide (0.0014 g, 1.565 ⁇ mol, 2.329 % yield).
• the title compound was prepared according to General Procedure A using 2-(3- cyclopropyl-1H-pyrazol-1-yl)-3-methylbutanoic acid as the coupling partner modified as follows: the amine coupling partner was (S)-N-(7-(2-(1-amino-2-(3,5-difluorophenyl)ethyl)-7- (2-fluorophenyl)-4-oxopyrido[2,3-d]pyrimidin-3(4H)-yl)-4-chloro-1-(2,2-difluoroethyl)-1H- indazol-3-yl)methanesulfonamide and the reaction solvent was tetrahydrofuran (1 mL) : N,N- Dimethylformamide (0.250 mL).
• Example 28 (S)-N-(1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H- indazol-7-yl)-7-(2-fluorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)-2-(3,5- difluorophenyl)ethyl)-2-(5-cyclopropyl-3-(difluoromethyl)-1H-pyrazol-1-yl)acetamide.
• the title compound was prepared according to General Procedure I using 2-(5- cyclopropyl-3-(difluoromethyl)-1H-pyrazol-1-yl)acetic acid as the coupling partner modified as follows: the amine used was (S)-N-(7-(2-(1-amino-2-(3,5-difluorophenyl)ethyl)-7-(2- fluorophenyl)-4-oxoquinazolin-3(4H)-yl)-4-chloro-1-methyl-1H-indazol-3- yl)methanesulfonamide and immediately prior to HPLC purification the crude residue was stirred with ammonia in methanol (2M, 0.3 mL) for 10 min at room temperature.
• Example 29 (S)-N-(1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H- indazol-7-yl)-7-(2-fluorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)-2-(3,5- difluorophenyl)ethyl)-2-(3-cyclopropyl-5-(difluoromethyl)-1H-pyrazol-1-yl)acetamide.
• the title compound was prepared according to General Procedure I using 2-(3- cyclopropyl-5-(difluoromethyl)-1H-pyrazol-1-yl)acetic acid as the coupling partner modified as follows: the amine used was (S)-N-(7-(2-(1-amino-2-(3,5-difluorophenyl)ethyl)-7-(2- fluorophenyl)-4-oxoquinazolin-3(4H)-yl)-4-chloro-1-methyl-1H-indazol-3- yl)methanesulfonamide and immediately prior to HPLC purification the crude residue was stirred with ammonia in methanol (2M, 0.3 mL) for 10 min at room temperature.
• Example 30 (S)-N-(1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H- indazol-7-yl)-7-(2-fluorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)-2-(3,5- difluorophenyl)ethyl)-2-(1H-indol-1-yl)acetamide.
• the title compound was prepared according to General Procedure I using 2-(1H-indol- 1-yl)acetic acid as the coupling partner modified as follows: the amine used was (S)-N-(7-(2- (1-amino-2-(3,5-difluorophenyl)ethyl)-7-(2-fluorophenyl)-4-oxoquinazolin-3(4H)-yl)-4-chloro-1- methyl-1H-indazol-3-yl)methanesulfonamide and immediately prior to HPLC purification the crude residue was stirred with ammonia in methanol (2M, 0.3 mL) for 10 min at room temperature.
• Example 31 2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro- 1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)-N-((S)-2-(3,5-difluorophenyl)-1-(3-(1,4- dimethyl-3-(methylsulfonamido)-1H-indazol-7-yl)-(3P)-7-(4-fluoro-2-methylphenyl)-4-oxo-3,4- dihydroquinazolin-2-yl)ethyl)acetamide.
• Example 32 N-((S)-1-(3-(1-(2,2-difluoroethyl)-4-methyl-3- (methylsulfonamido)-1H-indazol-7-yl)-(3P)-7-(3-methylpyrazin-2-yl)-4-oxo-3,4- dihydroquinazolin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5- difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.
• Example 33 (S)-N-(1-((3P)-3-(4-chloro-3-(cyclopropanesulfonamido)-1-(2,2- difluoroethyl)-1H-indazol-7-yl)-4-oxo-7-(pyridin-2-yl)-3,4-dihydroquinazolin-2-yl)-2-(3,5- difluorophenyl)ethyl)-2-(5-cyclopropyl-3-(difluoromethyl)-1H-pyrazol-1-yl)acetamide.
• Example 34 (S)-N-(1-((3P)-3-(4-chloro-3-(cyclopropanesulfonamido)-1-(2,2- difluoroethyl)-1H-indazol-7-yl)-4-oxo-7-(pyrimidin-2-yl)-3,4-dihydroquinazolin-2-yl)-2-(3,5- difluorophenyl)ethyl)-2-(5-cyclopropyl-3-(difluoromethyl)-1H-pyrazol-1-yl)acetamide.
• Example 35 (S)-N-(1-((3P)-3-(4-chloro-3-(cyclopropanesulfonamido)-1-(2,2- difluoroethyl)-1H-indazol-7-yl)-7-(3-methylpyrazin-2-yl)-4-oxo-3,4-dihydroquinazolin-2-yl)-2- (3,5-difluorophenyl)ethyl)-2-(5-cyclopropyl-3-(difluoromethyl)-1H-pyrazol-1-yl)acetamide.
• the mixture was degassed with nitrogen gas for 10 min. Then to the mixture was added at 26°C under nitrogen atmosphere dichloro[9,9- dimethyl-4,5-bis(diphenylphosphino)xanthene]palladium(II) (1.683 mg, 2.226 ⁇ mol).
• HIV cell culture assay - MT-2 cells, 293T cells and the proviral DNA clone of NU-3 virus were obtained from the NIH AIDS Research and Reference Reagent Program.
• MT-2 cells were propagated in RPMI 1640 media supplemented with 10% heat inactivated fetal bovine serum (FBS), 100 mg/ml penicillin G and up to 100 units/mL streptomycin.
• FBS heat inactivated fetal bovine serum
• the 293T cells were propagated in DMEM media supplemented with 10% heat inactivated FBS, 100 mg/mL penicillin G and 100 mg/mL streptomycin.
• the recombinant virus was prepared through transfection of the recombinant NL4-3 proviral clone into 293T cells using Transit-293 Transfection Reagent from Mirus Bio LLC (Madison, WI). Supernatent was harvested after 2-3 days and the amount of virus present was titered in MT-2 cells using luciferase enzyme activity as a marker by measuring luciferase enzyme activity.
• Luciferase was quantitated using the EnduRen Live Cell Substrate from Promega (Madison, WI). Antiviral activities of compounds toward the recombinant virus were quantified by measuring luciferase activity in MT-2 cells infected for 4-5 days with the recombinant virus in the presence of serial dilutions of the compound.
• cytotoxicity and the corresponding CC50 values were determined using the same protocol as described in the antiviral assay except that uninfected cells were used. Cytotoxicity was assessed on day 4 in uninfected MT2 cells by using a XTT (2,3-bis[2- Methoxy-4-nitro-5-sulfophenyl]-2H-tetrazolium-5-carboxyanilide inner salt)-based colorimetric assay (Sigma-Aldrich, St Louis, Mo).

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