RU2812128C2 - Human immunodeficiency virus replication inhibitors - Google Patents

Abstract

FIELD: organic chemistry; pharmaceuticals.

SUBSTANCE: group of inventions relates to a compound for the treatment of infection caused by the human immunodeficiency virus (HIV). A compound having the following structural formula, or a pharmaceutically acceptable salt thereof is disclosed. Besides, the following is disclosed: a pharmaceutical composition for use in the treatment of HIV infection containing the specified compound, and the use of this compound for the production of a medicinal product for the treatment of HIV infection.

EFFECT: group of inventions provides effective inhibition of human immunodeficiency virus replication.

4 cl, 2 tbl, 148 ex

Description

FIELD OF THE INVENTION

The invention relates to compounds, compositions and methods for treating infection caused by the human immunodeficiency virus (HIV). In particular, the present invention provides novel capsid inhibitors, pharmaceutical compositions containing such compounds, and methods of using these compounds for the treatment of HIV infection. The invention also relates to methods for preparing the compounds described below.

BACKGROUND OF THE ART

Acquired immunodeficiency syndrome (AIDS) is the result of infection with HIV. HIV remains a major health problem worldwide. An estimated 36.7 million people (including 1.8 million children) had HIV in 2015. global HIV prevalence was 0.8%. The vast majority of them live in low- and middle-income countries. That same year, 1.1 million people died from AIDS-related illnesses.

Currently, therapy for HIV-infected people consists of a combination of approved antiretroviral drugs. About four dozen drugs are currently approved for the treatment of HIV infection - in the form of monotherapy, fixed-dose combinations, or several drugs combined in one tablet; the last two options each contain 2-4 approved agents. These agents belong to a number of different classes and target either the viral enzyme or the function of the viral protein during the viral replication cycle. Agents are thus classified as nucleotide reverse transcriptase inhibitors (NRTIs), non-nucleotide reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), integrase strand transfer inhibitors (INSTIs), or entry inhibitors (one of which, maraviroc, targets the host CCR5 protein , and the other, enfuvirtide, is a peptide that targets the gp41 region of the viral gp160 protein). In addition, a pharmacokinetic booster (cobicistat or ritonavir) may be used in combination with antiretroviral drugs (ARVs) that require boosting.

Despite the currently available arsenal of agents and drug combinations, there is still a need in the medical field for new antiretroviral agents. High viral heterogeneity, drug toxicity, problems with drug tolerability, and poor adherence can all lead to treatment failure and the emergence of viruses with mutations that confer resistance to one or more antiretroviral agents or even multiple drugs from an entire class ( Beyer, S., Pozniak A. HIV drag resistance - an emerging threat to epidemic control. N. Engl. J. Med. 2017, 377, 1605-1607; Gupta, R. K., Gregson J., et al. HIV-1 drug resistance before initiation or reinitiation of first-line antiretroviral therapy in low-income and middle-income countries: a systematic review and meta-regression analysis. Lancet Infect. Dis. 2017, 18, 346-355; Zazzi, M., Hu, H ., Prosperi, M. The global burden of HIV-1 drug resistance in the past 20 years. PeerJ. 2018, DOI 10.7717/peerj.4848). Therefore, new drugs are needed that are easier to take, have high genetic barriers to resistance, and are safer than currently available agents. In choosing from this variety of options, novel mechanisms of action (MoA) may still play an important role and may be used as part of preferred antiretroviral therapy (APT), as they should be effective against viruses that are resistant to currently available agents.

Several compounds with potential therapeutic value have been described in the art; they are given in the works of Blair, Wade S. et. al. Antimicrobial Agents and Chemotherapy (2009), 53(12), 5080-5087, Blair, Wade S. et al. PLoS Pathogens (2010), 6(12), e1001220, Thenin-Houssier, Suzie; Valente, Susana T. Current HIV Research, 2016, 14, 270-282, and publications of international applications with the following numbers: WO 2012065062, WO 2013006738, WO 2013006792, WO 2014110296, WO 2014110297, WO 201411029 8, WO 2014134566, WO 2015130964, WO2015130966 , WO 2016033243, WO2018035359, WO2018203235, WO 2019161017 and WO 2019161280.

There is currently a need in the art for additional compounds that are new and suitable for the treatment of HIV. In addition, these compounds should provide advantages in terms of pharmaceutical use, for example, with respect to one or more of mechanisms of action, binding, inhibition efficiency, target selectivity, solubility, safety profiles, bioavailability or reduced dosing frequency. New formulations and methods of treatment using these compounds are also required.

BRIEF DESCRIPTION OF THE INVENTION

In general, in one aspect, the present invention discloses a compound of Formula I, or a pharmaceutically acceptable salt thereof:

Where:

G1 is phenyl substituted with one of -N(CH ₃ )S(O ₂ )CH ₃ , -S(O ₂ )C(CH ₃ ) ₃ , -CHF ₂ , -CF ₃ , -OCHF ₂ , -OCF ₃ or -C(CH ₃ ) ₂ OH, provided that when G1 is -CHF ₂ or CF ₃ , G1 is not in the para position or G1 is one of:

G ² and G ³ are independently selected from H or -CH ₃ ;

G ⁴ represents H, -CH ₃ or -OCH ₃ ;

G ^4a represents -CH ₃ or -OCH ₃ ;

G ⁵ represents -CH ₃ or CH ₂ CH ₃ ;

G ⁶ represents H, -CH ₃ or CH ₂ CH ₃ ;

G ⁷ is ethyl, isopropyl, tert-butyl, -CHF ₂ or -CF ₃ ;

G ⁸ represents H, methyl, ethyl, -CHF ₂ , -CF ₃ , -OCH ₃ or -OCH ₂ CH ₃ ;

G ⁹ represents ethyl, isopropyl, cyclopropyl, -CH ₂ OH, -OCH ₃ ;

G ¹⁰ is ethyl, isopropyl, cyclopropyl, tert-butyl, -CHF ₂ or -CF ₃ ;

G ¹¹ represents methyl, -OCH ₃ , -CHF ₂ , -CF ₃ , -S(O ₂ )CH ₃ ;

G ¹² represents F, -CH ₃ , -CHF ₂ , -CF ₃ , -OCH ₃ , -S(O ₂ )CH ₃ ;

G ¹³ represents C ₁ -C ₄ alkyl, C ₁ -C ₆ cycloalkyl, -CH ₂ O (C ₁ -C ₃ alkyl);

G ¹⁴ represents H, C ₁ -C ₄ alkyl, -CHF ₂ , -CF ₃ , -O(C ₁ -C ₃ alkyl);

G ¹⁵ represents H, F, -CH ₃ or OCH ₃ ;

R ³ represents H, F, Cl, -CH ₃ or -OCH ₃ ;

R ⁴ represents H or C ₁ -C ₃ alkyl, wherein the C ₁ -C ₃ alkyl is optionally substituted with 1-3 fluorine atoms;

R ⁵ represents C ₁ -C ₆ alkyl or C ₃ -C ₆ cycloalkyl;

W selected from:

where R ⁶ represents methyl, optionally substituted with 1-3 fluorine atoms.

In another aspect, the present invention discloses a composition containing a compound of Formula I or a pharmaceutically acceptable salt thereof.

In another aspect, the present invention discloses a method of treating HIV infection, comprising administering to a patient a composition containing a compound of Formula I or a pharmaceutically acceptable salt thereof.

In another aspect, the present invention discloses a compound of formula I or a pharmaceutically acceptable salt thereof for use in therapy.

In another aspect, the present invention discloses a compound of formula I or a pharmaceutically acceptable salt thereof for use in the treatment of HIV infection.

In another aspect, the present invention discloses the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment of HIV infection.

DETAILED DESCRIPTION OF THE INVENTION

In one embodiment, the present invention discloses a compound of Formula II or a pharmaceutically acceptable salt thereof:

where all variables have the same values as defined for formula I.

In one embodiment, the present invention discloses a compound of formula I or formula II, or a salt thereof, wherein W is

In another embodiment, the present invention discloses a compound of formula I or formula II, or a salt thereof, wherein W is

In another embodiment, the present invention discloses a compound of Formula I or Formula II, or a salt thereof, wherein W is one of:

In one embodiment, the present invention discloses a compound of Formula I or Formula II, or a salt thereof, wherein R ³ is Cl; R ⁴ represents -CH ₃ , -CH ₂ CHF ₂ , -CH ₂ CF ₃ ; and R ⁵ is methyl or cyclopropyl. In another embodiment, the present invention discloses a compound of Formula I or Formula II, or a salt thereof, wherein R ³ is -CH ₃ ; R ⁴ represents -CH ₃ , -CH ₂ CHF ₂ , -CH ₂ CF ₃ ; and R ⁵ is methyl or cyclopropyl. In another embodiment, the present invention discloses a compound of Formula I or Formula II, or a salt thereof, wherein R ³ is Cl; R ⁴ is -CH ₃ and R ⁵ is methyl.

In one embodiment, the present invention discloses a compound of Formula I or Formula II, or a salt thereof, wherein G ¹ is one of:

In another embodiment, the present invention discloses a compound of Formula I or Formula II, or a salt thereof, wherein G ¹ is one of:

In another embodiment, the present invention discloses a compound of Formula I or Formula II, or a salt thereof, wherein G ¹ is:

In another embodiment, the present invention discloses a compound of Formula I or Formula II, or a salt thereof, wherein G ¹ is one of:

In another embodiment, the present invention discloses a compound of Formula I or Formula II, wherein G ¹ is one of:

In another embodiment, the present invention discloses a compound of Formula I or Formula II, or a salt thereof, wherein G ¹ is one of:

In another embodiment, the present invention discloses a compound of Formula I or Formula II, or a salt thereof, wherein G ¹ is one of:

In another embodiment, the present invention discloses a compound of Formula I or Formula II, or a salt thereof, wherein G ¹ is one of:

In another embodiment, the present invention discloses a compound of Formula I or Formula II, or a salt thereof, wherein G ¹ is one of:

In another embodiment, the present invention discloses a compound of Formula I or Formula II, or a salt thereof, wherein G ¹ is one of:

In another embodiment, the present invention discloses a compound of formula I or formula II, or a salt thereof, wherein G ¹ contains a fluorine atom.

In another embodiment, the present invention discloses a compound of Formula I or Formula II, or a salt thereof, wherein G ¹ is

In another embodiment, the present invention discloses a compound of Formula I or Formula II, or a salt thereof, wherein G ¹ is:

In another embodiment, the present invention discloses a compound of Formula I or Formula II, or a salt thereof, wherein G ¹ is:

In another embodiment, the present invention discloses a compound of Formula I or Formula II, or a salt thereof, wherein G ¹ is:

In another embodiment, the present invention discloses a compound of Formula I or Formula II, or a salt thereof, wherein G ¹ is:

In another embodiment, the present invention discloses a compound of Formula I or Formula II, or a salt thereof, wherein G ¹ is:

In another embodiment, the present invention discloses a compound of Formula I or Formula II, or a salt thereof, wherein G ¹ is:

In another embodiment, the present invention discloses a compound of Formula I or Formula II, or a salt thereof, wherein G ¹ is:

In another embodiment, the present invention discloses a compound of Formula I, or a salt thereof, selected from the group consisting of:

their pharmaceutically acceptable salts.

In another embodiment, the present invention discloses a compound or salt selected from the group consisting of:

and their pharmaceutically acceptable salts.

In another embodiment, the present invention discloses a compound or salt selected from the group consisting of:

their pharmaceutically acceptable salts.

In another embodiment, the present invention discloses a compound or salt selected from the group consisting of:

their pharmaceutically acceptable salts.

In another embodiment, the present invention discloses a compound or salt selected from the group consisting of:

their pharmaceutically acceptable salts.

In another embodiment, the present invention discloses a compound or salt selected from the group consisting of:

and their pharmaceutically acceptable salts.

In another embodiment, the present invention discloses a compound or salt selected from the group consisting of:

and their pharmaceutically acceptable salts.

In another embodiment, the present invention discloses a compound or salt selected from the group consisting of:

and their pharmaceutically acceptable salts.

In another embodiment, the present invention discloses a compound or salt selected from the group consisting of:

and their pharmaceutically acceptable salts.

In another embodiment, the present invention discloses a compound or salt selected from the group consisting of:

and their pharmaceutically acceptable salts.

In another embodiment, the present invention discloses a compound or salt selected from the group consisting of:

and their pharmaceutically acceptable salts.

In another embodiment, the present invention discloses a compound or salt selected from the group consisting of:

and their pharmaceutically acceptable salts.

In another embodiment, the present invention discloses a compound or salt selected from the group consisting of:

and their pharmaceutically acceptable salts.

In another embodiment, the present invention discloses a compound of Formula II, or a salt thereof, selected from the group consisting of:

and their pharmaceutically acceptable salts.

In another embodiment, the present invention discloses a compound or salt selected from the group:

and their pharmaceutically acceptable salts.

In another embodiment, the present invention discloses a compound of Formula II, or a salt thereof, selected from the group consisting of:

and their pharmaceutically acceptable salts.

In another embodiment, the present invention discloses a compound of Formula I, or a salt thereof, selected from the group consisting of:

and their pharmaceutically acceptable salts.

Salts of the compounds of formula I and formula II are pharmaceutically acceptable. Such salts may be acid addition salts or base addition salts. For a review of suitable pharmaceutically acceptable salts, see Berge et al, J. Pharm, Sci., 66, 1-19, 1977. In one embodiment, the acid addition salts are selected from hydrochloride, hydrobromide, hydroiodide, sulfate, bisulfate, nitrate, phosphate , hydrogen phosphate, acetate, benzoate, succinate, sucrose, fumarate, maleate, lactate, citrate, tartrate, gluconate, camsylate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate. In one embodiment, base addition salts include metal salts (such as sodium, potassium, aluminum, calcium, magnesium and zinc salts) and ammonium salts (such as isopropylamine, diethylamine, diethanolamine salts). Other salts (such as trifluoroacetates, oxalates and choline salts) can be used to prepare the compounds of formula I and formula II and their pharmaceutically acceptable salts and are included within the scope of the present invention. All possible stoichiometric and non-stoichiometric salt forms of the compounds of formula I and formula II are included within the scope of the present invention. Acid and base addition salts can be prepared by a skilled chemist by treating a compound of formula I and formula II with the appropriate acid or base in a suitable solvent, followed by crystallization and filtration.

Some compounds of the present invention exist in stereoisomeric forms. The invention includes all stereoisomeric forms of compounds, including enantiomers and diastereomers, including atropoisomers. The term "homochiral" is used in accordance with conventional terminology to describe a structure that is a single stereoisomer. Absolute stereochemistry is not indicated in all cases. Thus, in the structural formula of a compound, the stereochemistry at the chiral center is not indicated, but the compound is labeled as homochiral, and in the procedures it is identified by its properties, such as, for example, first elution through a normal or chiral column, as is known to chemical specialists. It should be noted that the experimental procedures presented show how to prepare a specific compound, even if its structural formula does not indicate the absolute configuration. Methods for preparing and separating stereoisomers are known in the art. The invention includes all tautomeric forms of the compounds. The invention includes atropisomers and rotary isomers.

For compounds of Formula I and Formula II, the volume of the variable substituent for any value thereof may be used independently with the volume of the variable substituent for another value. Thus, the present invention includes combinations of various embodiments. In some examples, atropoisomers may be formed; they may undergo transformation slowly or rapidly, or not at all, depending on the handling conditions of the compound. When they mutually transform into one another at ambient temperature, they are called mixtures of atropisomers, and when they are isolated, they are called atropisomer 1 and atropisomer 2. Since compounds are identified by their properties and not by an exact indication of the structure based on the crystal structure, in this It is clear from the art that, unless otherwise specified, atropisomers are included within the scope of the chemical structure.

In the method of the present invention, the preferred routes of administration are oral and injection for subcutaneous delivery. Therefore, preferred pharmaceutical compositions include a composition suitable for oral administration (eg, tablets) and compositions suitable for injection, including intramuscular injection.

The biological target of the compounds and salts of the present invention is believed to be the HIV capsid and therefore their mechanism of action is to modify in one or more ways the function of the HIV capsid.

The compounds of the present invention and their salts, solvates or other pharmaceutically acceptable derivatives can be used alone or in combination with other therapeutic agents. The compounds and salts of the present invention and any other pharmaceutically active agent(s) can be administered together or separately, and when administered separately, said administration can be carried out simultaneously or sequentially, in any order. The amounts of the compounds and salts of the present invention and the other pharmaceutically active agent(s), and the timing of their administration relative to each other, will be selected to achieve the desired combination therapeutic effect. Administration of the compound of the present invention and its salts, solvates or other pharmaceutically acceptable derivatives in combination with other therapeutic agents can be accomplished by simultaneous administration as: (1) a single pharmaceutical composition containing multiple compounds; or (2) separate pharmaceutical compositions, each of which contains one of the compounds. Alternatively, the combination may be administered separately in a sequential manner, with one of the therapeutic agents administered first and the other second, or vice versa, and different agents may be administered according to different schedules if desired. Such sequential administration may be close in time or spaced apart in time. The amounts of the compound(s) of formulas I or P, or salts thereof, and other pharmaceutically active agent(s) and the timing of their administration relative to each other will be selected to achieve the desired combination therapeutic effect.

Thus, the compounds and salts of the present invention can be used in combination with one or more agents suitable for the prevention or treatment of HIV.

In another aspect, the present invention discloses a compound of formula I or formula II, or a pharmaceutically acceptable salt thereof, for use in the treatment of HIV infection, wherein said method further comprises administering at least one other agent used for the treatment of AIDS or HIV infection, selected from the group consisting of nucleoside HIV reverse transcriptase inhibitors, non-nucleoside HIV reverse transcriptase inhibitors, HIV protease inhibitors, HIV fusion inhibitors, HIV attachment inhibitors, CCR5 inhibitors, CXCR4 inhibitors, HIV budding or maturation inhibitors, and HIV integrase inhibitors.

In another aspect, the present invention discloses a compound of Formula I or Formula II, or a pharmaceutically acceptable salt thereof, for use in the treatment of HIV infection, wherein said method further comprises administering at least one other agent selected from the group consisting of dolutegravir, lamivudine , fostemsavir, cabotegravir, maraviroc, rilpiverine, reyataz, tenofovir, afenamide, EfDA, doravirine and Preziata.

In another aspect, the present invention discloses a compound of Formula I or Formula II, or a pharmaceutically acceptable salt thereof, for use in the treatment of HIV infection, wherein said method further comprises administering at least one other agent selected from the group consisting of dolutegravir, lamivudine , fostemsavir and cabotegravir.

EXAMPLES

General synthesis methods:

General Method D:

Pd(OAc) ₂ (0.1 eq.), dicyclohexyl(2',6'-dimethoxy-[1,1'-biphenyl]-2-yl)phosphane ( 0.2 eq.), potassium orthophosphate (3 eq.), N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol- 7-yl)-4-oxo-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-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]pyrazol-1-yl)acetamide (1 eq., typically 25-50 mg) and a suitable aryl/heteroaryl halide (3 eq.). The vessel was hermetically sealed with a stopper with a membrane. THF:water (4:1) was added to the vessel to obtain a reaction volume of 0.05 M in boronic acid ester. The reaction mixture was degassed with argon, then the reaction mixture was stirred at ambient temperature or at 45°C for 16-48 hours. After cooling to room temperature, the reaction mixture was concentrated in vacuo and the resulting residue was purified by HPLC to obtain the title product.

HPLC Purification:

HPLC purification was performed using one of the conditions listed below, optionally followed by a second HPLC purification using another condition listed below. Based on HPLC data obtained for the crude reaction mixture, purification conditions were optimized for each target compound by modifying the initial solvent A:solvent B ratio, gradient time, final solvent A:solvent B ratio, and dwell time at final solvent A:solvent concentration. IN.

HPLC Condition A: Column: Zorbax Eclipse Plus C18, 21.2×100 mm, 5 µm particles; solvent A = 0.1% formic acid in 100% water. Solvent B = acetonitrile. Flow = 40 ml/min. Wavelength = 215 and 254 nm. ESI+ range: 150 to 1500 daltons.

HPLC Condition: Column: Sunfire Prep CI8 OBD, 30x100 mm, 5 µm particles; Solvent A: water: MeCN 95:5 wt/ 0.1% TFA, Solvent B: MeCN: water 95:5 wt/ 0.1% TFA. Flow = 42 ml/min. Wavelength = 220 and 254 nm.

HPLC Condition C: Column: Waters Xterra C18, 19×100 mm, 10 µm particles; solvent A = 0.1% NH ₄ OH in 100% water. Solvent B = acetonitrile. Flow = 40 ml/min. Wavelength = 215 and 254 nm. ESI+ range: 150 to 1500 daltons.

General methods of LC-MS analysis:

Method C LC-MS:

Column: Acquity UPLC VEN C18, 2.1×30 mm, 1.7 µm particles; solvent A = 0.1% formic acid in 100% water. Solvent B = 0.1% formic acid in 100% acetonitrile. Flow=0.8 ml/min. Initial % B=5. Final % B=95. Gradient time = 1.6 min, then hold for 0.25 min at 95% V. Wavelength = 215 nm.

LC-MS Method F:

Column: Acquity VEN C18, 2.1×30 mm, 1.7 µm particles; solvent A = 0.1% formic acid in 100% water. Solvent B = 0.1% formic acid in 100% acetonitrile. Flow = 0.8 ml/min. Initial %V = 5. Final %V = 95. Gradient time = 1.7 min, then hold for 0.2 min at 95% V. Wavelength = 215 and 254 nm.

Preparation of 3-bromo-6-chloro-2-fluorobenzaldehyde

To a solution of 1-bromo-4-chloro-2-fluorobenzene (200 g, 0.955 mol, 1.0 eq.) in anhydrous THF (2.0 L) was added a solution of LDA in THF (2.0 M) with stirring , 620 ml, 1.24 mol, 1.3 eq.) at -50°C. The reaction mixture was left to warm to -20°C and stirred for 1 hour. The mixture was cooled to -50°C, and DMF (184.8 ml, 2.48 mol, 2.6 eq.) was slowly added to the mixture, maintaining the temperature at -50°C. The mixture was allowed to warm to 0°C and stirred for 30-45 minutes at this temperature (0°C). The mixture was quenched by slowly adding ice water (2.0 L). The reaction mixture was diluted with ethyl acetate (2.0 L) and stirred for 15 minutes at room temperature. The organic layer was separated and set aside; the aqueous layer was extracted with ethyl acetate (2×1.0 L). The combined organic layers were washed with water (2×1.0 L); 1.0 n. HCl (1.0 L), and then 15% NaCl solution (2.0 L). The organic solution was dried over Na ₂ SO ₄ , filtered and then concentrated in vacuo. The resulting crude solid was directly used in the next step without further purification. Yield of crude product: (210.0 g, 93%).

Preparation of 3-bromo-6-chloro-2-fluorobenzonitrile

Hydroxylamine-O-sulfonic acid ( 175.15 g, 1.55 mol, 1.75 eq.). The reaction mixture was heated to 50°C and stirred for 18 hours. The mixture was cooled to room temperature and stirred for 1-1.5 hours. Solids were isolated by filtration and then washed with water. The wet solid was dried under vacuum at 50°C for 12-15 hours to obtain 3-bromo-6-chloro-2-fluorobenzaldehyde, 190.0 g (91%).

Preparation of 7-bromo-4-chloro-1H-indazol-3-amine

3-Bromo-6-chloro-2-fluorobenzonitrile (100 g, 427 mmol) and ethanol (500 ml) were added to a 3 L three-neck round bottom flask equipped with a water condenser, thermometer and mechanical stirrer. Hydrazine hydrate (104 mL, 2133 mmol) was added to the solution at room temperature. The solution was heated to 80°C and maintained at this temperature for 1 hour, after which the mixture became a homogeneous solution and LC-MS analysis indicated that the reaction was complete. The solution was allowed to cool to 45°C and then water (1 L) was slowly added to obtain a white precipitate in the form of a thick suspension. After addition, the mixture was stirred for 30 minutes. The solid was isolated by filtration. The solids were washed with water (1 L) and then dried under vacuum at 45°C to give 7-bromo-4-chloro-1H-indazol-3-amine as a pale orange solid, 103 g (98%) . ^1H NMR (400 MHz, DMSO-d6): δ 12.21 (bs, 1H), 7.41 (d, J=7.8 Hz, 1H), 6.84 (d, J=7.8 Hz , 1H), 5.34 (bs, 2H) ppm.

Preparation of 7-bromo-4-chloro-1-methyl-1H-indazol-3-amine

To a solution of 3-bromo-6-chloro-2-fluorobenzonitrile (360.0 g, 1.55 mol, 1.0 eq.) in ethanol (1.08 L) was added methylhydrazine sulfate (1.11 kg, 7.73 mol , 5.0 eq.) followed by the addition of triethylamine (1.3 L, 9.3 mol, 6.0 eq.) at 25-35°C. The mixture was heated to 110°C and kept at this temperature for 15 hours. The mixture was cooled to room temperature and water (3.0 L) was added to the mixture. The mixture was stirred at room temperature for 1 hour. Solids were isolated by filtration and washed with water. The wet solid was dried under vacuum at 50°C for 12-15 hours. The product was subjected to silica gel column chromatography (hexanes:EtOAc 90:10→60:40) to give 7-bromo-4-chloro-1-methyl-1H-indazol-3-amine as a pale yellow solid, 185.0 g (46%).

Preparation of 7-bromo-4-chloro-1-(2,2-difluoroethyl)-1H-indazol-3-amine

To a solution of 7-bromo-4-chloro-1H-indazol-3-amine (128.0 g, 0.52 mol, 1.0 eq.) in dry THF (1.92 L) with stirring at 0°C in portions ^t BuOK (76 g, 0.67 mol, 1.3 eq.) was added. The reaction mixture was stirred for 10 min at 0°C; then 2,2-difluoroethyltrifluoromethanesulfonate (122.5 g, 0.57 mol, 1.1 eq.) was slowly added to the solution at 0°C. The mixture was slowly warmed to room temperature and then stirred for 2 hours. The mixture was diluted with ice water (3.0 L) and MTBE (2 x 1.5 L). The organic layer was separated, washed with water (2×1.2 L), dried over Na ₂ SO ₄ , filtered, and then concentrated in vacuo. The resulting crude material was subjected to silica gel chromatography (hexanes:EtOAc 95:5→90:10). Product containing fractions contaminated with the undesired regioisomer were concentrated and then triturated with DCM (5 ml/g) to obtain pure title product, which was then combined with pure material fractions. The result was 7-bromo-4-chloro-1-(2,2-difluoroethyl)-1H-indazol-3-amine as a light yellow solid, 110 g (68%). ^1H NMR (DMSO- _d6 , 500 MHz) δ 7.55 (d, 1H, J=7.9 Hz), 6.96 (d, 1H, J=7.9 Hz), 6.1-6 .5 (m, 1H), 5.62 (s, 2H), 4.94 (dt, 2H, 7=3.8, 14.1 Hz).

Preparation of 7-bromo-4-chloro-1-(2,2,2-trifluoroethyl)-1H-indazol-3-amine

Cs ₂ CO ₃ (184 g, 568 mmol, 2 equiv.). The reaction mixture was stirred for 10 min at room temperature. 2,2,2-trifluoroethyltrifluoromethanesulfonate (72.5 g, 312 mmol, 1.10 eq.) was slowly added to the reaction mixture at room temperature. After completion of the reaction (monitored by TLC), the mixture was diluted with ice-cold water (700 ml), after which a precipitate formed. The mixture was allowed to warm to room temperature and then stirred for 30 minutes at room temperature. Solids were isolated by filtration and then washed with water (500 ml). The wet product was dissolved in DMF (350 ml) and then diluted with water (350 ml) at room temperature. The resulting mass was stirred for 30 minutes, then the solids were collected by filtration and washed with water (200 ml) and then with hexanes (700 ml). The wet solids were dried under vacuum at 50-55°C for 18-20 hours to give 7-bromo-4-chloro-1-(2,2,2-trifluoroethyl)-1H-indazol-3-amine(4) as a light yellow solid, 64.0 g (69%).

Preparation of N-(7-bromo-4-chloro-1-methyl-1H-indazol-3-yl)methanesulfonamide

To a solution of 7-bromo-4-chloro-1-methyl-1H-indazol-3-amine (90 g, 0.34 mol, 1.0 eq.) in CH ₂ Cl ₂ (900 ml) was added diisopropylethylamine ("DIPEA ", 180.4 ml, 1.04 mol, 3.0 eq.) and 4-dimethylaminopyridine ("DMAP", 2.07 g, 0.017 mol, 0.05 eq.). The mixture was stirred for 5 min, then cooled to 0° C. and methanesulfonyl chloride (67.7 ml, 0.87 mol, 2.5 eq.) was added, resulting in a noticeable exothermic effect. The reaction mixture was warmed to room temperature and stirred at this temperature for 3 hours, resulting in the formation of a precipitate. The mixture was then diluted with dichloromethane (1.0 L) and then washed with water (2.0 L) followed by the addition of aq. HCl (1.0 M, 1.0 L) and then brine (1.5 L). The organic solution was dried over Na ₂ SO ₄ , filtered and then concentrated in vacuo. The crude residue was dissolved in EtOH (1.8 L). An aqueous NaOH solution (20%, 650 ml) was added to this solution at room temperature, resulting in a slight exothermic effect. The resulting mixture was stirred for 2 hours, as a result of which the mixture turned into a homogeneous solution. The solution was diluted with water (2.0 L), and the pH was adjusted to pH 2-3 using an aqueous solution of HCl (1.0 M, ca. 3.0 L). The resulting precipitate was collected by filtration. The solids were washed with water and then dried under vacuum to provide N-(7-bromo-4-chloro-1-methyl-1H-indazol-3-yl)methanesulfonamide as an off-white solid, 96 g (82% ). ¹ H NMR (500 MHz, CDCl ₃ ) δ 7.48 (d, J=7.9 Hz, 1H), 7.24 (br s, 1H), 6.95 (d, J=7.9 Hz, 1H), 4.38 (s, 3H), 3.42 (s, 3H). LC/MS (M+H) ⁺ =337.80.

Preparation of N-(7-bromo-4-chloro-1-(2,2-difluoroethyl)-1H-indazol-3-yl)methanesulfonamide

To a solution of 7-bromo-4-chloro-1-(2,2-difluoroethyl)-1H-indazol-3-amine (40.0 g, 0.12 mol, 1.0 eq.) in dry DCM (400 ml ) DIPEA (67 ml, 0.38 mol, 3.0 eq) and DMAP (0.78 g, 0.0064 mol, 0.05 eq) were added with stirring. The solution was stirred for 5 minutes, then the reaction mixture was cooled to 0°C, and methanesulfonyl chloride (31.0 ml, 0.38 mol, 3.0 eq.) was slowly added to the mixture. The reaction mixture was allowed to warm to room temperature and then stirred for 2 hours. After completion of the reaction (monitored by TLC), the mixture was diluted with DCM (2 x 2.5 L) and water (2.0 L). The organic layer was separated and washed with water (2×1.5 L), brine (1.5 L); dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The resulting residue was dissolved in ethanol (320 ml), and an aqueous NaOH solution (20% w/w, 320 ml) was added to the solution. The reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction (monitored by TLC), the mixture was diluted with water (1.0 L) and acidified to pH 2-3 using water. HCl (1.0 M). The resulting solids were filtered off. The solids were triturated with hexanes:EtOAc (95:5, 10 vol.) and again separated by filtration. The wet solids were dried under vacuum at 50°C to give N-(7-bromo-4-chloro-1-(2,2-difluoroethyl)-1H-indazol-3-yl)methanesulfonamide (5) as light yellow solids, 45.7 g (91%). ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.52 (d, J=8.0 Hz, 1H), 7.41 (bs, 1H), 7.00 (d, J=8.0 Hz, 1H), 6.16 (tt, J ₁ =4.3 Hz, J ₂ =8.6 Hz, J ₃ =55.4 Hz, 1H), 5.15 (td, J ₁ =4.3 Hz, J ₂ =12.7 Hz, 2H), 3.41 (s, 3H).

Preparation of N-(7-bromo-4-chloro-1-(2,2-difluoroethyl)-1H-indazol-3-yl)cyclopropanesulfonamide

To a solution of 7-bromo-4-chloro-1-(2,2-difluoroethyl)-1H-indazol-3-amine (10 g, 0.032 mol, 1.0 eq.) in dry pyridine (100 ml) was added with stirring cyclopropylsulfonyl chloride (18.1 g, 0.128 mol, 4.0 eq.). The reaction mixture was stirred at room temperature for 48 hours. The mixture was diluted with water (400 ml) and extracted with MTBE (2×100 ml). The combined organic layers were washed with water (3×300 ml), brine (300 ml), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The resulting crude material was triturated with hexanes (15 vol) to give N-(7-bromo-4-chloro-1-(2,2-difluoroethyl)-1H-indazol-3-yl)cyclopropanesulfonamide as a light red solid , 11.1 g (82%).

Preparation of N-(7-bromo-4-chloro-1-(2,2,2-trifluoroethyl)-1H-indazol-3-yl)methanesulfonamide

To a solution of 7-bromo-4-chloro-1-(2,2,2-trifluoroethyl)-1H-indazol-3-amine (60 g, 182.64 mmol, 1.0 eq.) in dry DCM (600 ml , 10 vol.) DIPEA (94.8 ml, 547.92 mmol, 3.0 eq.) and DMAP (1.11 g, 9.13 mmol, 0.05 eq.) were added with stirring. After stirring for 15 minutes, the solution was cooled to 0°C. Methanesulfonyl chloride (52.3 g, 456.6 mmol, 3.0 eq.) was slowly added to the solution. The reaction mixture was then allowed to warm to room temperature and stirred at room temperature for 2 hours. The progress of the reaction (bis-mesylation) was monitored by TLC. After completion of the reaction, the mixture was diluted with DCM (200 ml) and water (200 ml). The organic layer was separated and washed with water (500 ml), brine (300 ml), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The resulting residue was dissolved in ethanol (600 ml), and an aqueous NaOH solution (20% w/w, 600 ml) was added to the solution. The reaction mixture was stirred for 2 hours at room temperature. After completion of the reaction (mono-demesylation, monitored by TLC), the solution was diluted with water (300 ml) and acidified to pH 2-3 with aqueous HCl (1.0 M). The resulting solids were isolated by filtration and then washed with water. The solids were dried under vacuum at 50-55°C. The solid was further purified by trituration with hexanes:EtOAc (95:5, 15 vol) to give N-(7-bromo-4-chloro-1-(2,2,2-trifluoroethyl)-1H-indazol-3- yl)methanesulfonamide as a light yellow solid, 55.1 g (75%).

Preparation of N-(7-bromo-4-chloro-1-methyl-1H-indazol-3-yl)-N-(4-methoxybenzyl)methanesulfonamide

To a mixture of N-(7-bromo-4-chloro-1-methyl-1H-indazol-3-yl)methanesulfonamide (49 g, 0.144 mol, 1.0 eq.) in DMF (980 ml) was added 1-(chloromethyl )-4-methoxybenzene (23.54 ml, 0.17 mol, 1.2 eq.). Cesium carbonate (61.3 g, 0.18 mol, 1.3 eq.) was added to the mixture. The mixture was heated to 80°C and kept at this temperature for 2 hours. After completion of the reaction (monitored by TLC), the mixture was poured into water (2.0 L). The mixture was extracted with EtOAc (2×1.5 L). The combined organic layers were washed with brine (1.0 L), dried over Na2SO4, filtered and then concentrated in vacuo. The residue was crystallized from hexanes: EtOAc (9:1.120 ml) to obtain the target product, N-(7-bromo-4-chloro-1-methyl-1H-indazol-3-yl)-N-(4-methoxybenzyl)methanesulfonamide, in the form of a white solid. Yield: (62 g, 94%). ¹ H NMR (500 MHz, CDCl ₃ ) δ 7.44 (d, J=7.9 Hz, 1H), 7.31 (d, J=8.5 Hz, 2H), 6.99 (d, J =7.9 Hz, 1H), 6.84 (d, J=8.5 Hz, 2H), 4.99 (br s, 1H), 4.76 (br s, 1H), 4.40 (s , 3H), 3.80 (s, 3H), 3.01 (s, 3H).

Preparation of N-(7-bromo-4-chloro-1-(2,2-difluoroethyl)-1H-indazol-3-yl)-N-(4-methoxybenzyl)methanesulfonamide

To a solution of N-bromo-4-chloro-1-(2,2-difluoroethyl)-1H-indazol-3-yl)methanesulfonamide (45.7 g, 0.117 mol, 1.0 eq.) and 1-(chloromethyl) -4-methoxybenzene (22.1 g, 0.141 mol, 1.2 eq.) in DMF (460 ml, 10 vol.) was added with stirring cesium carbonate (49.8 g, 0.152 mol, 1.3 eq.). The reaction mixture was heated to 80°C and stirred for 2 hours at this temperature. After completion of the reaction (monitored by TLC), the mixture was cooled to room temperature and then poured into water (2.0 L). The mixture was extracted with EtOAc (2×1.5 L). The combined organic layers were washed with brine (1.0 L), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The resulting crude material was purified by silica gel column chromatography (eluting with hexanes: EtOAc 85:15→75:25) to give N-(7-bromo-4-chloro-1-(2,2-difluoroethyl)-1H-indazole-3 -yl)-N-(4-methoxybenzyl)methanesulfonamide as a light yellow solid, 56 g (93%).

Preparation of N-(7-bromo-4-chloro-1-(2,2-difluoroethyl)-1H-indazol-3-yl)-N-(4-methoxybenzyl)cyclopropanesulfonamide

To a mixture of N-(7-bromo-4-chloro-1-(2,2-difluoroethyl)-1H-indazol-3-yl)cyclopropanesulfonamide (15 g, 0.036 mol, 1.0 eq.) and 1-(chloromethyl )-4-methoxybenzene (6.79 g, 0.043 mol, 1.2 eq.) in DMF (150 ml), cesium carbonate (15.32 g, 0.047 mol, 1.3 eq.) was added with stirring. The reaction mixture was heated to 80°C and stirred at this temperature for 2 hours. After completion of the reaction (monitored by TLC), the mixture was poured into water (300 ml) and the product was extracted with MTBE (2 x 200 ml). The combined organic layers were washed with brine (300 ml), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The resulting crude material was purified by silica gel column chromatography (hexanes:EtOAc 80:20→75:25) to give N-(7-bromo-4-chloro-1-(2,2-difluoroethyl)-1H-indazole-3- yl)-N-(4-methoxybenzyl)methanesulfonamide as a viscous liquid, 16.5 g (86%).

Preparation of N-(7-bromo-4-chloro-1-(2,2,2-trifluoroethyl)-1H-indazol-3-yl)-N-(4-methoxybenzyl)methanesulfonamide

To a solution of N-(7-bromo-4-chloro-1-(2,2,2-trifluoroethyl)-1H-indazol-3-yl)methanesulfonamide (6.0 g, 14.77 mmol, 1.0 eq. ) in dry DMF (60 ml, 10 vol.) with stirring at room temperature, Cs ₂ CO ₃ (6.25 g, 19.20 mmol, 1.3 eq.) was added in portions. The mixture was stirred for 10 minutes at room temperature, then 1-(chloromethyl)-4-methoxybenzene (2.77 g, 17.724 mmol, 1.2 eq.) was slowly added to the mixture. The reaction mixture was heated to 80°C and kept at this temperature for 2 hours. After completion of the reaction (monitored by TLC), the mixture was cooled to room temperature and then diluted with ice water (60 ml) and ethyl acetate (60 ml). The organic layer was separated, washed with water (40 ml), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The resulting crude material was triturated with hexanes:EtOAc (97:3, 15 vol.) to give N-(7-bromo-4-chloro-1-(2,2,2-trifluoroethyl)-1H-indazol-3-yl )-N-(4-methoxybenzyl)methanesulfonamide as a light yellow solid, 7.0 g (90%).

Preparation of N-(7-amino-4-chloro-1-methyl-1H-indazol-3-yl)-N-(4-methoxybenzyl)methanesulfonamide

To a solution of N-(7-bromo-4-chloro-1-methyl-1-H-indazol-3-yl)-N-(4-methoxybenzyl)methanesulfonamide (55 g, 0.12 mol, 1.0 eq. ) in N-methylpyrrolidone (NMP) (900 ml), copper (I) iodide (4.57 g, 0.024 mol, 0.2 eq.), sodium ascorbate (47.4 g, 0.24 eq.) was added with stirring at room temperature mol, 2 eq.) and (1R, 2R)-N ₁ ,N ₂ -dimethylcyclohexane-1,2-diamine (8.52 g, 0.06 mol, 0.5 eq.) at room temperature. Then a solution of sodium azide (23.3 g, 0.36 mol, 3.0 eq.) in water (182 ml). The mixture was heated to 100°C and maintained at this temperature for 12 hours. The reaction mixture was cooled to room temperature and diluted with ethyl acetate (1.5 L), then filtered through a pad of celite. The filter layer was extracted with EtOAc (500 ml). The combined filtrate was diluted with water (2.0 L), and the organic layer was separated and set aside. The aqueous phase was extracted with EtOAc (2×1.0 L). The combined organic layers were washed with water (1.0 L), brine (1.0 L); dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude material was purified by silica gel column chromatography (hexanes:EtOAc 100:0→80:20) to give the title compound, N-(7-amino-4-chloro-1-methyl-1H-indazol-3-yl )-N-(4-methoxybenzyl)methanesulfonamide, as an off-white solid, 27.0 g (57%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.33-7.29 (m, 2H), 6.89 (d, J=7.8 Hz, 1H), 6.85-6.79 (m, 2H), 6.48 (d, J=7.8 Hz, 1H), 5.11 (br.s, 1H), 4.81 (br.s, 1H), 4.30 (s, 3H), 3.80 (br s, 2H), 3.79 (s, 3H), 2.99 (s, 3H). LC/MS (M+H) ⁺ =395.00.

Preparation of N-(7-amino-4-chloro-1-(2,2-difluoroethyl)-1H-indazol-3-yl)-N-(4-methoxybenzyl)methanesulfonamide

To a solution of N-(7-bromo-4-chloro-1-(2,2-difluoroethyl)-1H-indazol-3-yl)-N-(4-methoxybenzyl)methanesulfonamide (62 g, 0.12 mol, 1 .0 eq.) in NMP (745 ml) with stirring at room temperature, copper (I) iodide (4.64 g, 0.024 mol, 0.2 eq.), sodium ascorbate (48.3 g, 0.24 mol) was added , 2 eq.) and (1R, 2R)-N ₁ , N ₂ -dimethylcyclohexane-1,2-diamine (8.7 g, 0.06 mol, 0.5 eq.). A solution of sodium azide (23.8 g, 0.36 mol, 3.0 eq) in water (204 ml) was added to the mixture. The mixture was heated to 100°C and maintained at this temperature for 15 hours. The mixture was cooled to room temperature and then diluted with ethyl acetate (1.5 L). The mixture was filtered through a pad of celite and the filter pad was extracted with EtOAc (500 ml). The combined filtrate was diluted with water (2.0 L), the organic layer was separated, and the aqueous layer was extracted with EtOAc (2×1.0 L). The combined organic layers were washed with water (1.2 L), brine (1.0 L), dried over Na ₂ SO ₄ , filtered and then concentrated in vacuo. The resulting residue was subjected to silica gel column chromatography (hexanes:EtOAc 100:0→75:25) to give the title compound, N-(7-amino-4-chloro-1-(2,2-difluoroethyl)-1H-indazole -3-yl)-N-(4-methoxybenzyl)methanesulfonamide, as an off-white solid, 23.0 g, (44%).

Preparation of N-(7-amino-4-chloro-1-(2,2-difluoroethyl)-1H-indazol-3-yl)-N-(4-methoxybenzyl)cyclopropanesulfonamide

To a solution of N-(7-bromo-4-chloro-1-(2,2-difluoroethyl)-1H-indazol-3-yl)-N-(4-methoxybenzyl)cyclopropanesulfonamide (32 g, 0.059 mol, 1.0 eq.) in NMP (512 ml) with stirring at room temperature, copper (I) iodide (2.27 g, 0.012 mol, 0.2 eq.), sodium ascorbate (23.7 g, 0.12 mol, 2 eq.) and (1R, 2R)-N ₁ ,N ₂ -lymethylcyclohexane-1,2-diamine (4.25 g, 0.03 mol, 0.5 eq.). A solution of sodium azide (11.6 g, 0.18 mol, 3.0 eq) in water (112 ml) was added to the mixture. The reaction mixture was heated to 100°C and stirred for 18 hours at this temperature. The mixture was cooled to room temperature and diluted with ethyl acetate (1.2 L). The mixture was filtered through a pad of celite, extracting with EtOAc (300 ml). The combined filtrate was poured into water (1.5 L) and the organic layer was separated and set aside. The aqueous layer was extracted with EtOAc (2×0.8 L). The combined organic layers were washed with water (0.8 L), brine (0.8 L), dried over Na ₂ SO ₄ , filtered and then concentrated in vacuo. The crude residue was subjected to silica gel column chromatography (hexanes:EtOAc 100:0→80:20) to give the title compound, N-(7-amino-4-chloro-1-(2,2-dafluoroethyl)-1H-indazole -3-yl)-N-(4-methoxybenzyl)cyclopropanesulfonamide, as an off-white solid, 14.2 g (50%).

Preparation of N-(7-amino-4-chloro-1-(2,2,2-trifluoroethyl)-1H-indazol-3-yl)-N-(4-methoxybenzyl)methanesulfonamide

To a solution of N-(7-bromo-4-chloro-1-(2,2,2-trifluoroethyl)-1H-indazol-3-yl)-N-(4-methoxybenzyl)methanesulfonamide (3 g, 5.69 mmol , 1.0 eq.) in NMP (45 ml) with stirring at room temperature, copper (I) iodide (0.22 g, 1.13 mmol, 0.2 eq.), sodium ascorbate (2.25 g, 11.38 mmol, 2 eq.) and (1R, 2R)-N ₁ ,N ₂ -dimethylcyclohexane-1,2-diamine (0.4 g, 2.84 mmol, 0.5 eq.). A solution of sodium azide (1.1 g, 17.07 mmol) in water (15 ml) was added to the mixture. The mixture was heated to 100°C and maintained at this temperature for 13 hours. The reaction mixture was cooled to room temperature and then diluted with ethyl acetate (50 ml). The mixture was filtered through a pad of celite, extracting with EtOAc (30 ml). The combined filtrate was poured into water (50 ml) and the organic layer was separated and set aside. The aqueous phase was extracted with EtOAc (2×30 ml). The combined organic phases were washed with water (50 ml), brine (40 ml), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The resulting residue was subjected to silica gel column chromatography (hexanes: EtOAc 100:0→75:25) to give the title compound, N-(7-amino-4-chloro-1-(2,2,2-trifluoroethyl)-1H -indazol-3-yl)-N-(4-methoxybenzyl)methanesulfonamide as an off-white solid, 1.6 g (61%).

Preparation of bicyclo[3.1.0]hexan-3-ol

To a solution of cyclopent-3-enol (130 g, 1545 mmol) in DCM (1200 ml) was added dropwise a solution of diethylzinc in hexane (1.0 M, 3091 ml, 3091 mmol) with stirring in an atmosphere of N ₂ at 0-5°C ) for 3 hours. A solution of diiodomethane (249 ml, 3091 mmol) in DCM (300 ml) was added dropwise to this solution at 0° C. over 1 hour. The reaction mixture was left to warm to 27°C, and the formation of a white precipitate was observed. The mixture was stirred for 16 hours. The progress of the reaction was monitored by TLC (SiO ₂ , 20% EtOAc/pet, Rf = 0.3, UV-inactive, PMA-active). The reaction mixture was quenched by careful addition of an aqueous saturated solution of NH ₄ Cl (1.5 L). The mixture was filtered through a pad of celite. The aqueous layer was extracted with DCM (2×1 L). The combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered and then concentrated under reduced pressure to give crude bicyclo[3.1.0]hexan-3-ol as a red liquid, 180 g. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 4.41-4.35 (m, 1H), 2.18-2.05 (m, 2H), 1.73 (d, J = 13.9 Hz, 2H), 1.35-1, 25 (m, 2H), 1.21-1.14 (m, 1H), 0.57-0.43 (m, 2H). GC-MS: m/z = 98.1.

Preparation of bicyclo[3.1.0]hexan-3-one

Dess-Martin periodinane (954 g, 225 mmol) was added piecemeal to a solution of bicyclo[3.1.0]hexan-3-ol (210 g, 2054 mmol) in DCM (5000 ml) with stirring in an atmosphere of N ₂ at 0°C. . The mixture was allowed to warm to 27°C and then stirred for 16 hours. The progress of the reaction was monitored by TLC (SiO ₂ , 20% acetone/hexane, Rf = 0.3, UV inactive, PMA active). The reaction mixture was filtered through a pad of celite, and the filtrate was washed with aq. NaOH (1 N, 8×1 L). The combined aqueous phases were extracted with DCM (5X1 L). The combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered and then concentrated under reduced pressure (bath temperature: 20°C) to obtain crude bicyclo[3.1.0]hexan-3-one as a brown liquid. This liquid was further purified by distillation at 70° C. to obtain bicyclo[3.1.0]hexan-3-one as a pale yellow viscous liquid, 125 g (62%). ^1H NMR (400 MHz, CDCl ₃ ) δ = 2.61-2.54 (m, 2H), 2.17-2.12 (m, 2H), 1.54-1.46 (m, 2H) , 0.92-0.86 (m, 1H), -0.01--0.08 (m, 1H); GC-MS: M/Z = 96.1.

Preparation of 2-(2,2-difluoroacetyl)bicyclo[3.1.0]hexan-3-one

To a solution of bicyclo[3.1.0]hexan-3-one (125 g, 1274 mmol) in THF ( ₁₅₀₀ ml), lithium diisopropylamide (LDA) (2.0 M in THF , 0.701 l, 1402 mmol). The solution was stirred for 1 hour at -78°C. A solution of ethyl difluoroacetate (174 g, 1402 mmol) in THF (300 ml) was slowly added to the solution over 30 minutes, maintaining the temperature at -78°C. The reaction mixture was left to warm to 27°C and then stirred for 1 hour. The progress of the reaction was monitored by TLC (SiO ₂ , 20% acetone/hexane, Rf = 0.3, UV active). The reaction mixture was quenched by adding waves. HCl (1 N, 2000 ml). The mixture was stirred for 30 minutes and then extracted with EtOAc (3×1000 ml). The combined organic layers were washed with brine (1000 ml), dried over anhydrous Na ₂ SO ₄ and filtered. The filtrate was concentrated under reduced pressure to give 2-(2,2-difluoroacetyl)bicyclo[3.1.0]hexan-3-one as a pale yellow viscous liquid, 180 g (71%). ^1H NMR (400 MHz, CDCl ₃ ) δ = 6.18 (t, J = 54.8 Hz, 1H), 2.70-2.62 (m, 1H), 2.35 (d, J = 19 .4 Hz, 1H), 2.14 (brs, 1H), 1.26-1.21 (m, 1H), 1.04-1.03 (m, 1H), 0.22-0.21 ( m, 1H), LC-MS: M/Z = 173.17.

Preparation of ethyl 2-(3-(difluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetate

Ethyl- _2- hydrazinyl acetate hydrochloride (422 g, 2729 mmol) and then sulfuric acid (20 ml, 375 mmol). The mixture was stirred for 30 minutes and then heated to 100°C and stirred for 16 hours. The progress of the reaction was monitored by TLC (SiO ₂ , 20% acetone/hexane, Rf = 0.3, UV active). The reaction mixture was concentrated under reduced pressure. The residue was dissolved in EtOAc (2000 ml) and washed with water (2×1 L), brine (1.0 L), dried over anhydrous Na ₂ SO ₄ , filtered and then concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography (petroleum ether (pet.) : acetone 100:0→98:2) to obtain ethyl 2-(3-(difluoromethyl)-3b,4,4a,5-tetrahydro-1H-cycloprop [3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetate as an off-white solid, 110 g (46%). ^1H NMR (400 MHz, DMSO- _d6 ) δ = 6.86 (t, J = 54.8 Hz, 1H), 4.93 (s, 2H), 4.14 (q, J = 7.2 Hz, 2H), 2.88-2.79 (m, 1H), 2.76-2.68 (m, 1H), 2.14-2.04 (m, 2H), 1.19 (t, J = 7.2 Hz, 3H), 1.10-1.03 (m, 1H), 0.14 (q, J = 4.3 Hz, 1H).

Preparation of ethyl 2-(3-(difluoromethyl)-5-oxo-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetate

To a solution of ethyl 2-(3-(difluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetate (110 g, 422 mmol) and celite (395 g) in cyclohexane (3.5 l) with stirring at 0°C, pyridinium dichromate (794 g, 2110 mmol) was added in portions. To this mixture, tert-butyl hydroperoxide (355 mL, 2130 mmol) was added dropwise under nitrogen atmosphere over 10 minutes. The reaction mixture was heated to 27°C and then stirred at this temperature for 48 hours. The progress of the reaction was monitored by TLC (SiO ₂ , 30% acetone/Pet, Rf = 0.4, UV active). The reaction mixture was filtered and the filter residue was extracted with EtOAc (1000 ml). The filtrate was washed with saturated water. Na ₂ S ₂ O ₃ (2x500 ml), saturated aqueous FeSO ₄ solution (300 ml) and then saline (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).

Preparation of ethyl-(3-(difluoromethyl)-4,4a-dihydrospiro[cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-5,2'-[1,3]dithiolane]-1(3bH)- yl)acetate

To a solution of ethyl 2-(3-(difluoromethyl)-5-oxo-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetate (75 g, 269 mmol) in DCM (1500 ml) with stirring at 27°C under nitrogen atmosphere was added ethane-1,2-dithiol (43.0 ml, 511 mmol) followed by the addition of acetic acid boron trifluoride (72.6 ml , 511 mmol). The solution was stirred for 16 hours. The progress of the reaction was monitored by TLC (SiO ₂ , 20% acetone/Pet, Rf = 0.35, UV active). After completion, the reaction mixture was cooled to 0°C and quenched by adding saturated water. NaHCO ₃ (500 ml). The mixture was then extracted with DCM (2×1000 ml). The combined organic solutions were washed with brine (1000 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to obtain a brown liquid. This material was subjected to silica gel column chromatography (Pet.: EtOAc 95:5→90:10) to give ethyl 2-(3-(difluoromethyl)-4,4a-dihydrospiro[cyclopropa[3,4]cyclopenta[1,2 -c]pyrazol-5,2'-[1,3]dithiolane]-1(3bH)-yl)acetate as an off-white solid, 80 g (74%). ¹ H-NMR (400 MHz, CDCl ₃ ) δ = 6.61 (t, J = 55.2 Hz, 1H), 5.00-4.85 (m, 2H), 4.29-4.19 ( m, 2H), 3.55-3.46 (m, 4H), 2.63-2.53 (m, 1H), 2.49-2.38 (m, 1H), 1.30-1, 24 (m, 4H), 0.65-0.60 (m, 1H). LC-MS M+H = 346.9.

Preparation of ethyl 2-(3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl) acetate

HF _- pyridine ( 2.460 g, 24.83 mmol). Solution for 30 minutes. A solution of ethyl 2-(3-(difluoromethyl)-4,4a-dihydrospiro[cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-5,2'-1,3]dithiolane]- 1(3bH)-yl)acetate (10 g, 25 mmol) in DCM (20 ml). The reaction mixture was allowed to warm to -40°C and then stirred at this temperature for 1 hour. The progress of the reaction was monitored by TLC (SiO2, 30% EtOAc/Pet, Rf = 0.3, UV inactive). The reaction mixture was quenched by adding saturated aqueous NaHCO ₃ solution (200 ml). The mixture was warmed to room temperature and then extracted with EtOAc (2×100 ml). The combined organic solutions were washed with brine (50 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to obtain a brown solid. This product was subjected to silica gel column chromatography (Pet.: EtOAc 100:0→75-25) to give ethyl 2-(3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H -cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetate as a pale yellow solid, 8.5 g (91%). ^1H NMR (400 MHz, CDCl ₃ ) δ = 6.62 (t, J = 55.2 Hz, 1H), 4.82 (s, 2H), 4.30-4.18 (m, 2H), 2.51-2.37 (m, 2H), 1.42-1.35 (m, 1H), 1.31-1.23 (m, 3H), 1.14-1.08 (m, 1H ). LC-MS M+H = 293.07.

Preparation of 2-(3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetic acid

To a solution of ethyl 2-(3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl )acetate (15 g, 50 mmol) in THF (17 ml) and MeOH (66 ml), a solution of LiOH (1.788 g, 74.7 mmol) in water (66 ml) was added with stirring at 0°C under N ₂ atmosphere. The reaction mixture was left to warm to 27°C and then stirred for 3 hours at this temperature. The progress of the reaction was monitored by TLC (SiO ₂ , 5% MeOH/DCM, Rf = 0.2, UV active). After completion of the reaction, the reaction mixture was concentrated under reduced pressure, diluted with water (50 ml) and washed with EtOAc (2×250 ml) to remove impurities. The pH of the aqueous layer was adjusted to 2-3 using aqueous HCl (1M), then extracted with EtOAc (3×1000 ml). The combined organic solutions were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give 2-(3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa [3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetic acid as an off-white solid, 14 g (98%). LC-MS M+H = 265.15.

Resolution to give 2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c] pyrazol-1-yl)acetic acid and 2-((3bR,4aS)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[ 1,2-c]pyrazol-1-yl)acetic acid

2-(3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetic acid ( 5.5 g) were dissolved in isopropanol (20 ml). The solution was subjected to chiral separation using supercritical fluid chromatography (SFC) as follows: Instrument = Thar 80; column = Chiralpak IC 30x250 mm, 5 µm; solvent A = supercritical CO ₂ ; solvent B = isopropanol with 0.5% isopropylamine (v/v); eluent composition = 70%A : 30%B; flow rate = 65 g/min; back pressure = 100 bar; temperature = 30°C; injection volume = 2.5 ml; detection = 220 nm. 2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropane[3,4]cyclopenta[1,2-c]pyrazol- 1-yl)acetic acid; it corresponded to the peak eluting at 7.5 min. up to 14 minutes; and 2-((3bR,4aS)-3-(difluorometal)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol- 1-yl)acetic acid, which corresponded to the peak eluting at 2.7 min. up to 5.8 min. For each enantiomer, the resulting solution was concentrated under reduced pressure and the resulting solid was dissolved in EtOAc, then washed twice with aqueous citric acid (1 M), then with water, and then with brine. The organic solution was dried over Na ₂ SO ₄ , filtered, then concentrated in vacuo to obtain the isolated enantiomer with a recovery of 80-90%.

Preparation of ethyl 2-(3,5-bis(difluoromethyl)-1H-pyrazol-1-yl)acetate

_Sulfuric acid (1.394 ml, 26.2 mmol), followed by ethyl aminoglycinate hydrochloride (16.17 g, 105 mmol). The reaction mixture was heated to 100°C and then stirred for 3 hours at this temperature. The progress of the reaction was monitored by TLC (SiO ₂ , 30% EtOAc/pet, Rf = 0.4, UV active). After completion of the reaction, the reaction mixture was cooled to room temperature and then concentrated under reduced pressure. The resulting residue was dissolved in water (100 ml) and then extracted with EtOAc (2X100 ml). The combined organic layers were washed with brine (50 ml), dried over anhydrous Na ₂ SO ₄ , filtered and then concentrated under reduced pressure to give ethyl 2-(3,5-bis(difluoromethyl)-1H-pyrazol- 1-yl)acetate as a pale yellow solid, 22.0 g (86%). ^1H NMR (400 MHz, CDCl ₃ ) δ = 6.91-6.52 (m, 3H), 5.03 (s, 2H), 4.30-4.20 (m, 2H), 1.32 -1.25 (m, 3H). LC-MS: (M+H) = 255.21, purity according to LC-MS = 86.6%.

Preparation of 2-(3,5-bis(difluoromethyl)-1H-pyrazol-1-yl)acetic acid

To a solution of ethyl 2-(3,5-bis(difluoromethyl)-1H-pyrazol-1-yl)acetate (22 g, 75 mmol) in THF (50 ml) and methanol (25 ml) with stirring under N ₂ atmosphere At 0°C, a solution of lithium hydroxide (5.41 g, 226 mmol) in water (25 ml) was added dropwise. The reaction mixture was allowed to warm to 27°C and then stirred for 16 hours at this temperature. The progress of the reaction was monitored by TLC (SiO ₂ , 50% EtOAc/pet, Rf = 0.2, UV active). After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The resulting residue was dissolved in water (100 ml), and the pH of the solution was adjusted to 3 using water. HCl (2 N). The solution was extracted with EtOAc (4X50 ml). The combined organic layers were washed with brine (50 ml), dried over anhydrous Na ₂ SO ₄ , filtered and then concentrated under reduced pressure to give 2-(3,5-bis(difluoromethyl)-1H-pyrazol-1-yl)acetic acid. acid as a pale yellow solid, 15 g (87%). ^1H NMR (400 MHz, DMSO- _d6 ) δ = 13.53-13.24 (m, 1H), 7.46-7.07 (m, 3H), 5.14 (s, 2H). LC-MS: (M-H) = 225.15; purity according to LC-MS = 98.7%.

Preparation of 1-cyclopropyl-4,4-difluorobutane-1,3-dione

To a solution of 1-cyclopropylethan-1-one (20 g, 238 mmol) in diethyl ether (2000 ml), NaHMDS (119 ml, 238 mmol) was slowly added with stirring under N ₂ at -78°C over 20 minutes. The solution was then stirred for 45 minutes at -78°C. Ethyl 2,2-difluoroacetate (75 mL, 713 mmol) was added to the solution. The reaction mixture was slowly heated to 27°C and then stirred for 16 hours. Once complete, the reaction mixture was quenched with water (80 ml) and washed with diethyl ether (100 ml). The aqueous layer was acidified with water. HCl (1 N, 20 ml) and extracted with diethyl ether (2 x 100 ml). The combined organic layers were washed with brine (50 ml), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give 1-cyclopropyl-4,4-difluorobutane-1,3-dione as a pale yellow oil 25 g (65%). ^1H NMR (400 MHz, CDCl ₃ ) δ = 6.07-5.87 (m, 2H), 1.84-1.75 (m, 1H), 1.28-1.19 (m, 2H) , 1.10-1.05 (m, 2H).

Preparation of 5-cyclopropyl-3-(difluoromethyl)-1H-pyrazole

Hydrazine was added to a solution of 1-cyclopropyl-4,4-difluorobutane-1,3-dione (25 g, 154 mmol) in ethanol (250 ml) with stirring at 27°C. H ₂ O (16.13 ml, 385 mmol) followed by dropwise addition of hydrochloric acid (0.18 ml, 5.92 mmol). The reaction mixture was heated to 80°C and stirred at this temperature for 6 hours. The reaction was monitored by TLC (50% EtOAc in petroleum ether; RF: 0.2; Detection: KMnO ₄ active). After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The resulting residue was dissolved in water (250 ml) and extracted with ethyl acetate (3×200 ml). The combined organic layers were washed with brine (50 ml), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give 5-cyclopropyl-3-(difluoromethyl)-1H-pyrazole as a yellow liquid 20 g (79 %). ^1H NMR (400 MHz, CDCl ₃ ) δ = 6.79-6.49 (m, 1H), 6.24-6.08 (m, 1H), 1.96-1.82 (m, 1H) , 1.09-0.91 (m, 2H), 0.79-0.56 (m, 2H) LC-MS: M+H = 159.11, purity = 96.91%.

Preparation of ethyl 2-(5-cyclopropyl-3-(difluoromethyl)-1H-pyrazol-1-yl)acetate:

To a solution of 5-cyclopropyl-3-(difluoromethyl)-1H-pyrazole (20 g, 123 mmol) in acetonitrile (200 ml) was added DIPEA (53.5 ml, 306 mmol) with stirring at 27°C under N ₂ atmosphere. and then ethyl bromoacetate (27.3 ml, 245 mmol). The reaction mixture was stirred at 65°C for 48 hours. The progress of the reaction was monitored by TLC (SiO ₂ , mobile phase: 30% ethyl acetate in petroleum ether; RF: 0.5 and KMnO ₄ active). Once complete, the reaction mixture was diluted with water (20 ml) and extracted with ethyl acetate (2×500 ml). The combined organic layers were washed with brine (500 ml) and dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to give the crude compound as a brown oil (30 g). This material was chromatographed on silica gel (Pet.: EtOAc 80:20→70:30) to obtain ethyl 2-(5-cyclopropyl-3-(difluoromethyl)-1H-pyrazol-1-yl)acetate as a mixture of regioisomers, 25 g. The product was further purified by HPLC using the following conditions: Column = KROMOSIL PHENYL, 25x150 mm, 10 µm; mobile phase A: 10 mM ammonium bicarbonate in water; mobile phase B: acetonitrile; flow = 25 ml/min; temperature = ambient; gradient (min/%V) = 0/10, 2/10, 10/30, 15/30, 15.2/100, 18/100, 18.2/10. Fractions containing the desired product were combined and then concentrated under reduced pressure to obtain an aqueous mixture. This mixture was extracted with ethyl acetate (3×100 ml). The combined organic solutions were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give ethyl 2-(5-cyclopropyl-3-(difluoromethyl)-1H-pyrazol-1-yl) acetate as a pale yellow oil. 2.1 g (24%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 7.05-6.69 (m, 1H), 6.24-6.14 (m, 1H), 5.21-5.10 (m, 2H), 4.21-4.09 (m, 2H), 1.92-1.76 (m, 1H), 1.27-1.13 (m, 3H), 0.98-0.86 ( m, 2H), 0.70-0.56 (m, 2H). LC-MS: M+H = 245.31, purity = 98.89%.

Preparation of 2-(5-cyclopropyl-3-(difluoromethyl)-1H-pyrazol-1-yl)acetic acid

To a solution of ethyl 2-(5-cyclopropyl-3-(difluoromethyl)-1H-pyrazol-1-yl)acetate (2.1 g, 8.60 mmol) in THF:methanol (5 ml: 2 ml) with stirring a solution of LiOH (1.647 g, 68.8 mmol) in water (2 ml) was added at 27°C. The reaction mixture was stirred at 27°C for 16 hours. The progress of the reaction was monitored by TLC (SiO ₂ , ethyl acetate; Rf: 0.1, UV inactive and KMnO ₄ active). After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The resulting aqueous mixture was diluted with water (50 ml) and then washed with ethyl acetate (3×50 ml). The aqueous layer was cooled to 0°C and then the pH was adjusted to 2 by adding water. HCl (2 N). The precipitated solid was collected by filtration and then dried under vacuum to give 2-(5-cyclopropyl-3-(difluoromethyl)-1H-pyrazol-1-yl)acetic acid as an off-white solid, 1 .3 g (70%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 13.27-13.10 (m, 1H), 7.02-6.72 (m, 1H), 6.21-6.10 (m, 1H), 5.08-4.93 (m, 2H), 1.86-1.77 (m, 1H), 0.97-0.87 (m, 2H), 0.71-0.58 ( m, 2H). LC-MS: M+H = 217.20, purity = 99.52%.

Preparation of tert-butyl-(S)-(1-(7-bromo-3-(4-chloro-3-(N-(4-methoxybenzyl)methylsulfonamido)-1-methyl-1H-indazol-7-yl)- 4-oxo-3,4-dihydroquinazolin-2-yl)-2-(3,5-difluorophenyl)ethyl)carbamate

To a solution of (S)-2-((tert-butoxycarbonyl)amino)-3-(3,5-difluorophenyl)propanoic acid (3.82 g, 12.66 mmol), 2-amino-4-bromobenzoic acid (3 .01 g, 13.93 mmol) and N-(7-amino-4-chloro-1-methyl-1H-indazol-3-yl)-N-(4-methoxybenzyl)methanesulfonamide (5 g, 12.66 mmol ) in pyridine (50 ml) was added diphenylphosphite (9.80 ml, 50.6 mmol). The resulting mixture was placed in a preheated oil bath (70°C) and heated at 70°C for 16 hours. The mixture was cooled to room temperature and then concentrated under reduced pressure. The mixture was then diluted with EtOAc (ca. 500 mL) and washed with aqueous citric acid (0.5 M, 2 x 50 mL), then aqueous NaOH (1 M, 3 x 50 mL), dried over Na ₂ SO ₄ , filtered and concentrated. The residue was then purified by silica gel chromatography (330 g silica gel column, hexanes:EtOAc gradient 0:100→50:50) to give tert-butyl-(S)-(1-(7-bromo-3- (4-chloro-3-(N-(4-methoxybenzyl)methylsulfonamido)-1-methyl-1H-indazol-7-yl)-4-oxo-3,4-dihydroquinazolin-2-yl)-2-(3 ,5-difluorophenyl)ethyl)carbamate (6.2 g, 7.22 mmol, 57.1% yield) as a pale yellow solid foam (inseparable mixture of atropisomers). LC/MS: m/z = 801.10 [M-tBu].

Preparation of (S)-N-((6P)-7-(2-(1-amino-2-(3,5-difluorophenyl)ethyl)-7-bromo-4-oxoquinazolin-3(4H)-yl)- 4-chloro-1-methyl-1H-indazol-3-yl)methanesulfonamide

To a solution of tert-butyl-(S)-(1-(7-bromo-3-(4-chloro-3-(N-(4-methoxybenzyl)methylsulfonamido)-1-methyl-1H-indazol-7-yl) -4-oxo-3,4-dihydroquinazolin-2-yl)-2-(3,5-difluorophenyl)ethyl)carbamate (6.2 g, 7.22 mmol) in dichloromethane (DCM) (50 ml) with stirring trifluoroacetic acid (20 mL, 260 mmol) was added followed by trifluoromethanesulfonic acid (0.770 mL, 8.67 mmol). The resulting dark red solution was stirred at room temperature for 1 hour. LC-MS at this point showed two peaks containing the desired mass of product, consistent with the presence of two diastereomeric atropisomers (approximately 30:70 ratio). The mixture was concentrated in vacuo and the resulting residue was partitioned between EtOAc (300 ml) and water. NaOH (1 M, 30 ml). The aqueous phase was checked and found to have a pH >= 8.0. The organic phase was isolated and dried over Na ₂ SO ₄ , filtered and then concentrated in vacuo. The residue was purified in three approximately equal parts by C18 column chromatography (275 g on a RediSep Gold column, mobile phase A: 5:95 acetonitrile: water with 0.1% TFA; mobile phase B: 95:5 acetonitrile: water with 0. 1% TFA; gradient 10-60% B over 30 minutes). Fractions containing the main atropisomer (second elution) were combined, adjusted to pH 8 by adding aqueous 1 M NaOH, extracted with ethyl acetate, washed with brine (saturated water. NaCl), dried over Na ₂ SO ₄ , filtered and then concentrated to obtain the target main atropoisomer (S)-N-((6P)-7-(2-(1-amino-2-(3,5-difluorophenyl)ethyl)-7-bromo-4-oxoquinazoline-3(4H) -yl)-4-chloro-1-methyl-1H-indazol-3-yl)methanesulfonamide (2.4 g, 3.76 mmol, 52% yield). ¹ H NMR (500 MHz, DMSO-d ₆ ) δ ppm 8.11 (d, J = 8.55 Hz, 1 N), 8.06 (d, J = 1.53 Hz, 1 N), 7.81 (dd, J = 8.55, 1.83 Hz , 1 N), 7.33 (s, 2 N), 6.96-7.05 (m, 1 N), 6.75 (br d, J = 7.02 Hz, 2 N), 3.67 (s, 3 N), 3.56 (dd, J = 7.63, 5.19 Hz, 1 N), 3.25-3.29 (m, 1 N), 3.21 (s, 3 N ), 2.81 (dd, J = 13.43, 8.24 Hz, 1 N). LC-MS: m/z = 637.05 [M+H] ⁺ .

Preparation of N-((S)-1-((3P)-7-bromo-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-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

To a solution of (S)-R-((6P)-7-(2-(1-amino-2-(3,5-difluorophenyl)ethyl)-7-bromo-4-oxoquinazolin-3(4H)-yl) -4-chloro-1-methyl-1H-indazol-3-yl)methanesulfonamide (2.08 g, 3.26 mmol), 2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro -3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetic acid (0.861 g, 3.26 mmol) and diisopropylethylamine ("DIPEA" ) (1.709 ml, 9.78 mmol) in tetrahydrofuran (THF) (30 ml) was added O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) (1.364 g , 3.59 mmol). The resulting mixture was stirred at room temperature for 3 hours. Ammonia in methanol (2 M, 3 ml) was added to the mixture. The mixture was stirred at room temperature for 30 minutes. Water was then added and the mixture was extracted with ethyl acetate, washed with brine, dried over Na ₂ SO ₄ , filtered, and concentrated in vacuo. The resulting residue was chromatographed on silica gel (hexanes: EtOAc 100:0→30:70) to give N-((S)-1-((3P)-7-bromo-3-(4-chloro-1-methyl-3 -(methylsulfonamido)-1H-indazol-7-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 (2.5 g , 2.83 mmol, yield 87%). ¹ H NMR (500 MHz, CDCl ₃ ) δ ppm 8.18 (d, J = 8.24 Hz, 1 N), 7.88 (d, J = 1.53 Hz, 1 N), 7.72 (dd, J = 8.55, 1.83 Hz , 1 N), 7.33 (s, 1 N), 7.16 (d, J = 7.63 Hz, 1 N), 6.57-6.83 (m, 4 N), 6.38 ( br d, J = 5.80 Hz, 2 N), 4.71-4.80 (m, 1 N), 4.63 (d, J = 6.71 Hz, 2 N), 3.56 (s , 3 N), 3.40 (s, 3 N), 3.18 (dd, J = 13.73, 6.10 Hz, 1 N), 2.86 (dd, J = 13.58, 7, 48 Hz, 1 N), 2.52-2.61 (m, 1 N), 2.41-2.50 (m, 1 N), 1.42-1.50 (m, 1 N), 1 .09-1.16 (m, 1 N). LC-MS: m/z = 883.05 [M+H] ⁺ .

Preparation of tert-butyl-(S)-(1-(7-bromo-3-(4-chloro-1-(2,2-difluoroethyl)-3-(N-(4-methoxybenzyl)methylsulfonamido)-1H-indazole -7-yl)-4-oxo-3,4-dihydroquinazolin-2-yl)-2-3,5-difluorophenyl)ethyl)carbamate

To a solution of (S)-2-((tert-butoxycarbonyl)amino)-3-(3,5-difluorophenyl)propanoic acid (15 g, 49.8 mmol) and 2-amino-4-bromobenzoic acid (10.76 g, 49.8 mmol) in pyridine (150 ml), diphenylphosphite (9.64 ml, 49.8 mmol) was added with stirring at 27°C. The mixture was purged with argon, and then the flask was sealed. The reaction mixture was heated to 80°C and stirred at this temperature for 2 hours. The reaction mixture was cooled to 27°C, and 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 hours. The progress of the reaction was monitored by TLC (SiO ₂ , 30% EtOAc/Pet., Rf = 0.4, UV active). The reaction mixture was allowed to cool to 27°C and then concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography (Pet.: EtOAc 80:20→70:30) to give tert-butyl-(S)-(1-(7-bromo-3-(4-chloro-1-(2, 2-difluoroethyl)-3-(H-(4-methoxybenzyl)methylsulfonamido)-1H-indazol-7-yl)-4-oxo-3,4-dihydroquinazolin-2-yl)-2-(3,5-dafluorophenyl) )ethyl)carbamate as an off-white solid, 18 g (35%). The isolated material is a mixture of stereoisomers. LC-MS: M+H = 907.18 and 909.12; purity = 89%.

Preparation of (S)-N-((6P)-7-(2-(1-amino-2-(3,5-difluorophenyl)ethyl)-7-bromo-4-oxoquinazolin-3(4H)-yl)- 4-chloro-1-(2,2-difluoroethyl)-1H-indazol-3-yl)methanesulfonamide

To a solution of tert-butyl-(S)-(1-(7-bromo-3-(4-chloro-1-(2,2-difluoroethyl)-3-(N-(4-methoxybenzyl)methylsulfonamido)-1H- indazol-7-yl)-4-oxo-3,4-dihydroquinazolin-2-yl)-2-(3,5-difluorophenyl)ethyl)carbamate (N68085-33-A2.15 g, 14.70 mmol) in DCM (150 ml) was added with TFA (150 ml, 1947 mmol) with stirring at 27°C under N ₂ atmosphere. The solution was stirred for 10 minutes. Trifluoromethanesulfonic acid (15 mL, 169 mmol) was added to the reaction mixture. The solution was stirred for 1 hour at 27°C. The progress of the reaction was monitored by TLC (SiO ₂ , 5% MeOH/DCM, Rf = 0.4, UV active). Once completed, the solvent was removed under a gentle stream of nitrogen. The residue was dissolved in EtOAc (500 ml), washed with saturated water. NaHCO ₃ (2×250 ml), saline (150 ml), dried over Na ₂ SO ₄ and filtered. The filtrate was concentrated under reduced pressure to obtain an off-white solid. LC-MS analysis of the said solid showed a diastereomer ratio of 75.42%:21.47%. The crude solid was subjected to reverse phase column chromatography on a C18 column (mobile phase: A: 0.1% TFA in water and B: 0.1% TFA in MeCN). Pure fractions containing the major diastereomer (atropoisomer) were combined and concentrated under reduced pressure. The resulting aqueous solution was made alkaline by adding aqueous saturated NaHCO ₃ ; then extracted with EtOAC (2×500 ml). The combined organic layers were washed with brine (200 ml), dried over Na ₂ SO ₄ , filtered and concentrated to give (S)-N-((6P)-7-(2-(1-amino-2-( 3,5-difluorophenyl)ethyl)-7-bromo-4-oxoquinazolin-3(4H)-yl)-4-chloro-1-(2,2-difluoroethyl)-1H-indazol-3-yl)methanesulfonamide in the form off-white solid, 8.0 g (76%). LC-MS: M+H = 687.34, purity = 96%. This product was further purified to isolate the main enantiomer as follows: (S)-N-((6P)-7-(2-(1-amino-2-(3,5-difluorophenyl)ethyl)-7-bromo-4- Oxoquinazolin-3(4H)-yl)-4-chloro-1-(2,2-difluoroethyl)-1H-indazol-3-yl)methanesulfonamide (4.5 g, 6.28 mmol) was dissolved in MeOH: MeCN ( 1:1, 170 ml). The solution was subjected to chiral separation using SFC in portions as follows: column = (R, R) WHELK-01, 30×250 mm, 5 μm; solvent A = supercritical CO ₂ ; solvent B = methanol); eluent composition = 50%A : 50%B; flow rate = 100 g/min; back pressure = 90 bar; injection volume = 1.1 ml; detection = 214 nm; stacking time = 6.8 min. For each enantiomer isolated, the resulting solution was concentrated under reduced pressure to obtain an off-white solid. (S)-N-((6P)-7-(2-(1-amino-2-(3,5-difluorophenyl)ethyl)-7-bromo-4-oxoquinazolin-3(4H)-yl)-4 -Chloro-1-(2,2-difluoroethyl)-1H-indazol-3-yl)methanesulfonamide was isolated as a peak eluting from 6 min to 8 min to give 2.1 g (48%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.11-8.05 (m, 2H), 7.83-7.78 (m, 1H), 7.47-7.41 (m, 2H), 7.03-6.97 (m, 1H), 6.76-6.69 (m, 2H), 6.41-6.14 (m, 1H), 4.47-4.22 ( m, 2H), 3.54-3.49 (m, 1H), 3.25-3.21 (m, 4H), 2.83-2.76 (m, 1H). LC-MS: M+H = 687.04, purity = 99%, chiral HPLC purity = 96%.

Preparation of N-((S)-1-((3P)-7-bromo-3-(4-chloro-1-(2,2-difluoroethyl)-3-(methylsulfonamido)-1H-indazol-7-yl) -4-oxo-3,4-dihydroquinazolin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(diftormethyl)-5,5-difluoro-3b ,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide

To a solution of (S)-N-((6P)-7-(2-(1-amino-2-(3,5-difluorophenyl)ethyl)-7-bromo-4-oxoquinazolin-3(4H)-yl) -4-chloro-1-(2,2-difluoroethyl)-1H-indazol-3-yl)methanesulfonamide (1.75 g, 2.52 mmol), 2-((3bS,4aR)-3-(difluoromethyl) -5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetic acid (0.739 g, 2.77 mmol) , HOBt hydrate (0.424 g, 2.77 mmol) and EDC.HCl (0.579 g, 3.02 mmol) in DMF (15 ml) at 27°C under a nitrogen atmosphere was added N-methylmorpholine (2.215 ml, 20.15 mmol ). The solution was stirred at 27°C for 36 hours. The progress of the reaction was monitored by TLC (SiO ₂ , 50% EtOAc/Pet. Rf = 0.5, UV active). The reaction mixture was diluted with ice cold water (50 ml) and stirred for 15 minutes. The precipitated solid was isolated by filtration, washed with water (50 ml) and dried under vacuum to obtain the crude product. This product was treated with EtOAc (20 ml), stirred for 15 min and then the solids were isolated by filtration and dried under vacuum to give R-((S)-1-((3P)-7-bromo-3-(4- chloro-1-(2,2-difluoroethyl)-3-(methylsulfonamido)-1H-indazol-7-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 as an off-white solid, 1.6 g (64%). ^1H NMR (400 MHz, DMSO- _d6 ) δ = 10.00 (brs, 1H), 9.23 (d, J = 8.1 Hz, 1H), 8.13 (d, J = 8.6 Hz, 1H), 7.98 (d, J = 2.0 Hz, 1H), 7.85 (dd, J = 2.0, 2.1 Hz, 1H), 7.78 (d, J = 7 .9 Hz, 1H), 7.54 (d, J = 7.9 Hz, 1H), 7.07-6.99 (m, 1H), 6.92 (t, J = 51.7 Hz, 1H ), 6.61 (d, J = 6.3 Hz, 2H), 6.11 (t, J = 54.6 Hz, 1H), 4.72-4.57 (m, 2H), 4.38 (tt, J = 107, 2.9 Hz, 1H), 4.31-4.19 (m, 1H), 3.96-3.83 (m, 1H), 3.44-3.37 (m , 1H), 3.19 (s, 3H), 3.00-2.92 (m, 1H), 2.49-2.45 (m, 2H), 1.39-1.31 (m, 1H ), 0.87-0.82 (m, 1H). LC-MS: M+H = 933.13, LC-MS purity = 95%, HPLC purity = 96%, chiral HPLC purity = 97%.

Preparation of tert-butyl-(S)-(1-(7-bromo-3-(4-chloro-1-(2,2-difluoroethyl)-3-(N-(4-methoxybenzyl)cyclopropanesulfonamido)-1H-indazole -7-yl)-4-oxo-3,4-dihydroquinazolin-2-yl)-2-(3,5-difluorophenyl)ethyl)carbamate

To a solution of (S)-2-((tert-butoxycarbonyl)amino)-3-(3,5-difluorophenyl)propanoic acid (15 g, 49.8 mmol) and 2-amino-4-bromobenzoic acid (12.91 g, 59.7 mmol) in pyridine (150 ml), diphenylphosphite (35.7 ml, 184 mmol) was added with stirring in a sealed tube at 26°C. The reaction mixture was degassed by bubbling N ₂ with each addition of reagents. The reaction mixture was heated to 80°C and stirred for 2 hours. The reaction mixture was cooled to 26°C, then N-(7-amino-4-chloro-1-(2,2-difluoroethyl)-1H-indazole-3 -yl)-N-(4-methoxybenzyl)cyclopropanesulfonamide (N66734-90-A2, 20.49 g, 34.9 mmol). The mixture was heated at 80°C for 16 hours. The progress of the reaction was monitored by TLC (SiO ₂ , 30% EtOAc/Pet. Rf = 0.3). The reaction mixture was cooled to 26°C and then concentrated under reduced pressure. The residue was diluted with water (150 ml) and extracted with ethyl acetate (2X500 ml). The combined organic layers were washed with aqueous citric acid (5% w/v, 2×150 ml), then with brine (250 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to obtain a brown viscous liquid (40 g). The above procedure was repeated and the crude product from both iterations was combined. This material was then subjected to silica gel column chromatography (Pet.: EtOAc, 60:40→55:45) to give tert-butyl-(S)-(1-(7-bromo-3-(4-chloro-1-( 2,2-difluoroethyl)-3-(N-(4-methoxybenzyl)cyclopropanesulfonamido)-1H-indazol-7-yl)-4-oxo-3,4-dihydroquinazolin-2-yl)-2-(3,5 -difluorophenyl)ethyl)carbamate (mixture of diastereomers) as a yellow solid (42 g, 98%). LC-MS: M+H = 933.88 and 935.88; purity = 76.91%.

Preparation of (S)-N-((6P)-7-(2-(1-amino-2-(3,5-difluorophenyl)ethyl)-7-bromo-4-oxoquinazolin-3(4H)-yl)- 4-chloro-1-(2,2-difluoroethyl)-1H-indazol-3-yl)cyclopropanesulfonamide

To a solution of tert-butyl-(S)-(1-(7-bromo-3-(4-chloro-1-(2,2-difluoroethyl)-3-(N-(4-methoxybenzyl)cyclopropanesulfonamido)-1H- indazol-7-yl)-4-oxo-3,4-dihydroquinazolin-2-yl)-2-(3,5-difluorophenyl)ethyl)carbamate (14 g, 11.53 mmol) in DCM (140 ml) at TFA (140 ml) was added while stirring at 27°C under N ₂ atmosphere. The solution was stirred for 10 minutes. Trifluoromethanesulfonic acid (7.16 mL, 81 mmol) was added to the solution. The reaction mixture was stirred for 1 hour at 27°C. The progress of the reaction was monitored by TLC (SiO ₂ , 50% EtOAc/pet, Rf = 0.2). The solvent was removed under a gentle stream of nitrogen. The residue was dissolved in EtOAc (500 ml), and the organic layer was washed with saturated aqueous NaHCO ₃ (2 x 150 ml), brine (50 ml), dried over Na ₂ SO ₄ , filtered and concentrated to dryness to obtain the crude compound as a solid off-white substances (12 g). The above procedure was repeated twice more and additional crude solids (2×14 g) were combined with the above. The combined product was dissolved in dichloromethane (500 ml) and concentrated to give a homogeneous crude solid. This material was washed with petroleum ether:EtOAc (80:20) and then dried under vacuum to give a brown solid (30 g). This product was then subjected to reverse phase chromatography on a C18 column under the following conditions: Column = RediSep Gold HP C18 275 g; mobile phase A = water: MeCN: TFA (950:50:1); mobile phase B = water: MeCN: TFA (50:950:1); flow = 80 ml/min; gradient profile (time/%V) = 5/5, 5/10, 5/15, 10/20, 15/30, 20/40, 15/45, 10/50; temperature = ambient. Fractions corresponding to the main peak were combined and concentrated under reduced pressure to remove the non-aqueous solvent. The resulting aqueous solution was neutralized by adding saturated aqueous NaHCO3 (1000 ml), then extracted with EtOAC (4 x 500 ml). The combined organic layers were washed with brine (500 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to give (S)-N-((6P)-7-(2-(1-amino-2-(3, 5-difluorophenyl)ethyl)-7-bromo-4-oxoquinazolin-3(4H)-yl)-4-chloro-1-(2,2-difluoroethyl)-1H-indazol-3-yl)cyclopropanesulfonamide (sole diastereomer) as an off-white solid. The product was then purified using SFC under the following conditions: Column/Dimensions = Chiralpak OX-H (30 x 250 mm), 5 µm; solvent A = liquid CO ₂ ; solvent B = methanol with 0.5% diethylamine; eluent = A:B (70:30); flow rate = 100.0 g/min; back pressure = 100.0 bar; detection = UV (214 nm); injection volume = 1.3 ml (93 mg/injection); 160 injections. The two peaks were collected separately and the main peak was concentrated under reduced pressure to obtain (S)-N-((6P)-7-(2-(1-amino-2-(3,5-difluorophenyl)ethyl)- 7-bromo-4-oxoquinazolin-3(4H)-yl)-4-chloro-1-(2,2-difluoroethyl)-1H-indazol-3-yl)cyclopropanesulfonamide (single stereoisomer) as a pale yellow solid , 7.5 g (20%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.11-8.04 (m, 2H), 7.82-7.78 (m, 1H), 7.47-7.39 (m, 2H), 7.02-6.95 (m, 1H), 6.76-6.69 (m, 2H), 6.38-6.19 (m, 1H), 4.48-4.37 ( m, 1H), 4.32-4.24 (m, 1H), 3.54-3.48 (m, 1H), 3.3-3.20 (m, 1H), 2.97-2, 90 (m, 1H), 2.83-2.76 (m, 1H), 1.05-0.99 (m, 4H). LC-MS: M+H = 712.94 and 714.94; purity = 98.37%, chiral HPLC purity = 96%.

Preparation of N-((S)-1-((3P)-7-bromo-3-(4-chloro-3-(cyclopropanesulfonamido)-1-(2,2-difluoroethyl)-1H-indazol-7-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

To a solution of (S)-N-((6P)-7-(2-(1-amino-2-(3,5-difluorophenyl)ethyl)-7-bromo-4-oxoquinazolin-3(4H)-yl) -4-chloro-1-(2,2-difluoroethyl)-1H-indazol-3-yl)cyclopropanesulfonamide (500 mg, 0.700 mmol), 2-((3bS,4aR)-3-(difluoromethyl)-5,5 -difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetic acid (N68084-15-A1, 185 mg, 0.700 mmol) and HOBt (42.9 mg, 0.280 mmol) in DMF (5 ml) with stirring at 27°C, N-methylmorpholine (0.308 ml, 2.80 mmol) and N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride were added (242 mg, 1.261 mmol). The reaction mixture was stirred at 27°C for 16 hours. The completeness of the reaction was monitored by TLC (SiO ₂ , 50% EtOAc/Pet., Rf = 0.3, UV active). After completion of the reaction, the reaction mixture was diluted with ice water (70 ml) and then stirred for 15 minutes 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 crude compound was subjected to chromatography on silica gel (Pet.: EtOAc (98:2→50:50) to give N-((S)-1-((3P)-7-bromo-3-(4-chloro-3-( cyclopropanesulfonamido)-1-(2,2-difluoroethyl)-1H-indazol-7-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]pyrazole-1- yl)acetamide as an off-white solid, 550 mg (80%) ^1H NMR (400 MHz, DMSO- _d6 ) δ = 9.99 (s, 1H), 9.24 (d, J = 8 ,1 Hz, 1H), 8.13 (d, J = 8.8 Hz, 1H), 7.97 (d, J = 1.8 Hz, 1H), 7.87-7.83 (m, 1H ), 7.77 (d, J = 7.9 Hz, 1H), 7.54 (d, J = 7.9 Hz, 1H), 7.06-6.79 (m, 2H), 6.64 -6.58 (m, 2H), 6.23-5.98 (m, 1H), 4.74-4.57 (m, 2H), 4.41-4.35 (m, 1H), 4 .29-4.16 (m, 1H), 3.94-3.84 (m, 1H), 3.38-3.34 (m, 1H), 3.02-2.93 (m, 1H) , 2.90-2.83 (m, 1H), 2.48-2.35 (m, 2H), 1.37-1.30 (m, 1H), 1.02-0.90 (m, 4H), 0.87-0.82 (m, 1H). Method F analysis using LC-MS: RT = 6.74 min, (M+H) = 959.0 and 961.0; purity according to LC- MS = 98%; purity by chiral HPLC = 98%.

Preparation of (S)-2-(3,5-bis(difluoromethyl)-1H-pyrazol-1-yl)-N-(1-((3P)-7-bromo-3-(4-chloro-3-( cyclopropanesulfonamido)-1-(2,2-difluoroethyl)-1H-indazol-7-yl)-4-oxo-3,4-dihydroquinazolin-2-yl)-2-(3,5-difluorophenyl)ethyl)acetamide

To a solution of (S)-R-((6P)-7-(2-(1-amino-2-(3,5-difluorophenyl)ethyl)-7-bromo-4-oxoquinazolin-3(4H)-yl) -4-chloro-1-(2,2-difluoroethyl)-1H-indazol-3-yl)cyclopropanesulfonamide (500 mg, 0.690 mmol), 2-(3,5-bis(difluoromethyl)-1H-pyrazol-1- yl)acetic acid (236 mg, 1.035 mmol) and HOBt (190 mg, 1.242 mmol) in DMF (10 ml) at 27°C were added N-methylmorpholine (0.152 ml, 1.380 mmol) and N-(3-dimethylaminopropyl)- N'-ethylcarbodiimide hydrochloride (238 mg, 1.242 mmol). The reaction mixture was then degassed for 10 min with nitrogen gas. The reaction mixture was stirred at 27°C for 16 hours; the completeness of the reaction was monitored using TLC (SiO ₂ , 50% EtOAc/Pet. Rf = 0.2). After completion of the reaction, the reaction mixture was diluted with ethyl acetate (50 ml) and washed with ice water (2×30 ml) and then with brine (20 ml). The organic layer was separated, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness to give the crude compound as an off-white solid (700 mg). This product was subjected to silica gel column chromatography (PET:EtOAc, 100:0→50:50) to give (S)-2-(3,5-bis(difluoromethyl)-1H-pyrazol-1-yl)-N-( 1-((3P)-7-bromo-3-(4-chloro-3-(cyclopropanesulfonamido)-1-(2,2-difluoroethyl)-1H-indazol-7-yl)-4-oxo-3,4 -dihydroquinazolin-2-yl)-2-(3,5-difluorophenyl)ethyl)acetamide as an off-white solid, 500 mg (76%). ^1H NMR (400 MHz, DMSO- _d6 ) δ = 9.99-9.94 (m, 1H), 9.31-9.25 (m, 1H), 8.14 (d, J = 8, 6 Hz, 1H), 7.99 (d, J = 1.8 Hz, 1H), 7.88-7.83 (m, 1H), 7.75 (d, J = 8.1 Hz, 1H) , 7.52 (d, J = 7.9 Hz, 1H), 7.07-6.82 (m, 4H), 6.65-6.57 (m, 2H), 6.19-5.99 (m, 1H), 4.94-4.81 (m, 2H), 4.45-4.38 (m, 1H), 4.31-4.19 (m, 1H), 3.97-3 .87 (m, 1H), 3.39-3.34 (m, 1H), 3.01-2.94 (m, 1H), 2.89-2.82 (m, 1H), 1.00 -0.92 (m, 4H). LC-MS: M+H = 921.24 and 923.12; purity = 98.3%, chiral HPLC purity = 99.46%.

Preparation of (S)-N-(1-((3P)-7-bromo-3-(4-chloro-3-(cyclopropanesulfonamido)-1-(2,2-difluoroethyl)-1H-indazol-7-yl) -4-oxo-3,4-dihydroquinazolin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-(5-cyclopropyl-3-(difluoromethyl)-1H-pyrazol-1-yl)acetamide

To a solution of (S)-N-((6P)-7-(2-(1-amino-2-(3,5-difluorophenyl)ethyl)-7-bromo-4-oxoquinazolin-3(4H)-yl) -4-chloro-1-(2,2-difluoroethyl)-1H-indazol-3-yl)cyclopropanesulfonamide (600 mg, 0.826 mmol), 2-(3-cyclopropyl-5-(difluoromethyl)-1H-pyrazole-1 -yl)acetic acid (179 mg, 0.826 mmol) and HOBt (50.6 mg, 0.330 mmol) in DMF (5 ml) at 27°C was added N-methylmorpholine (0.363 ml, 3.30 mmol) and N-( 3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (285 mg, 1.487 mmol). The reaction mixture was then degassed for 10 minutes with nitrogen gas and then stirred at 27°C for 16 hours. The progress of the reaction was monitored by TLC (SiO ₂ , 50% EtOAc/Pet. Rf = 0.3). The reaction mixture was diluted with ice water (70 ml) and then stirred for 30 min at 27°C. The precipitated solid was isolated by filtration and then dried under vacuum to give (S)-N-(1-((3P)-7-bromo-3-(4-chloro-3-(cyclopropanesulfonamido)-1-(2, 2-difluoroethyl)-1H-indazol-7-yl)-4-oxo-3,4-dihydroquinazolin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-(5-cyclopropyl-3- (difluoromethyl)-!H-pyrazol-1-yl)acetamide as a pale yellow solid, 550 mg (68%). ^1H NMR (400 MHz, DMSO- _d6 ) δ = 10.02-9.85 (m, 1H), 9.17-9.10 (m, 1H), 8.14 (d, J = 8, 3 Hz, 1H), 7.99-7.95 (m, 1H), 7.87-7.84 (m, 1H), 7.77 (d, J = 7.9 Hz, 1H), 7, 52 (d, J = 7.9 Hz, 1H), 7.07-7.00 (m, 1H), 6.86-6.59 (m, 3H), 6.20-5.98 (m, 2H), 4.77-4.67 (m, 2H), 4.50-4.43 (m, 1H), 4.33-4.22 (m, 1H), 4.00-3.87 ( m, 1H), 3.39-3.32 (m, 1H), 3.06-2.94 (m, 2H), 2.60-2.55 (m, 1H), 1.46-1, 38 (m, 1H), 1.00-0.91 (m, 4H), 0.75-0.64 (m, 2H), 0.57-0.46 (m, 2H). LC-MS: M+H = 910.89 and 912.91; purity = 93.59%.

Preparation of N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-4-oxo-7-(4, 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-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

N-((S)-1-((3P)-7-bromo-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl) was added to a round bottom flask equipped with a stirrer )-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 (1.00 g, 1.13 mmol), 4,4,4 ',4',5,5',5'-octamethyl-2,2"-bi(1,3,2-dioxaborolane) (431 mg, 1.70 mmol), potassium acetate (333 mg, 3.39 mmol ) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II) ("Pd(dppf)Cl ₂ "), (83 mg, 0.113 mmol). The flask was sealed with a rubber membrane and then placed in an argon atmosphere. Dioxane (23 ml) was added to the flask. The reaction mixture was degassed with argon, then the reaction mixture was stirred at 60°C for 16 hours. The reaction mixture was concentrated under vacuum and adsorbed on celite. The resulting powder was subjected to chromatography on silica gel (hexanes: EtOAc 100:0 →0:100 in 10 column volumes) to obtain N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl) -4-oxo-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-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 (1.2 g, quantitative yield). LC-MS: LC-MS analysis detected both boric acid and boronate. Conditions: Wavelength 1: 220 nm, Wavelength 2: 254 nm, Injection Volume: 5.00 µl, Stop Time: 4.00, Degree Time: 3.0, Start %V: 0, End %V: 100, Total flow: 0.80 ml/min, solvent A: 95:5 Water: MeCN 0.1% TFA, solvent B: 5:95 Bofla: MeCN 0.1% TFA, column: Acquity UPLC VEN C18 1, 7 µm; Result: retention time (boronic acid): 2.112 min, mass detected: 849.15 (M+H); retention time (boronic acid ester): 2.733 min., mass detected: 931.25 (M+H). ^1H NMR ( _CDCl3 , 500 MHz) δ 8.26 (d, 1H, J = 7.6 Hz), 8.11 (s, 1H), 7.95 (d, 1H, J = 7.6 Hz ), 7.3-7.3 (m, 1H), 7.14 (d, 1H, J = 7.9 Hz), 6.7-6.7 (m, 3H), 6.35 (d, 2H, J = 6.8 Hz), 4.7-4.8 (m, 1H), 4.1-4.2 (m, 1H), 3.70 (s, 1H), 3.47 (s , 3H), 3.37 (s, 3H), 3.1-3.2 (m, 1H), 2.8-2.9 (m, 1H), 2.6-2.7 (m, 1H ), 2.3-2.5 (m, 1H), 1.8-1.9 (m, 2H), 1.24 (s, 12H), 1.1-1.2 (m, 1H)

Preparation of N-((S)-1-((3P)-3-(4-chloro-1-(2,2-difluoroethyl)-3-(methylsulfonamido)-1H-indazol-7-yl)-4-oxo -7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-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]pyrazole-1 -yl)acetamide

N-((S)-1-((3P)-7-bromo-3-(4-chloro-1-(2,2-difluoroethyl)-3-(methylsulfonamido)- 1H-indazol-7-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 (500 mg, 0.535 mmol), 4, 4,4',4',5,5,5',5"-octamethyl-2,2"-bi(1,3,2-dioxaborolane) (204 mg, 0.803 mmol), potassium acetate (158 mg, 1.606 mmol) and PdCl ₂ (dppf) (39.2 mg, 0.054 mmol). The flask was sealed with a membrane and then placed in an argon atmosphere (vacuum/fill ×3). 1,4-dioxane (14 ml) was added to the flask. The mixture was degassed (vacuum/argon filling ×3). The mixture was then stirred at 60°C overnight (16 hours). The reaction mixture was concentrated under reduced pressure. The resulting residue was adsorbed onto celite. The resulting powder was subjected to silica gel column chromatography (40 g silica gel column, hexanes: EtOAc 100:0→50:50 in 10 column volumes). Fractions containing the product were collected and concentrated in vacuo to give N-((S)-1-((3P)-3-(4-chloro-1-(2,2-difluoroethyl)-3-(methylsulfonamido)-1H -indazol-7-yl)-4-oxo-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-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, 520 mg (99%). ^1H NMR (METHANOL-d4, 500 MHz) δ 8.2-8.3 (m, 2H), 7.97 (d, 1H, J = 7.7 Hz), 7.40 (d, 1H, J = 8.0 Hz), 7.28 (d, 1H, J = 8.0 Hz), 6.5-6.9 (m, 4H), 6.00 (tt, 1H, J = 4.1, 55.2 Hz), 4.75 (dd, 1H, J = 4.8, 9.2 Hz), 4.6-4.7 (m, 2H), 4.38 (dtd, 1H, J = 4 ,2, 13.3, 15.2 Hz), 4.12 (q, 1H, J = 7.2 Hz), 3.9-4.0 (m, 1H), 3.3-3.5 ( m, 1H), 3.3-3.3 (m, 3H), 3.06 (dd, 1H, J = 9.2, 14.0 Hz), 2.4-2.5 (m, 2H) , 2.0-2.0 (m, 2H), 1.3-1.4 (m, 2H), 1.22 (s, 12H), 1.0-1.1 (m, 1H)

Preparation of N-((S)-1-((3P)-3-(4-chloro-3-(cyclopropanesulfonamido)-1-(2,2-difluoroethyl)-1H-indazol-7-yl)-4-oxo -7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-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]pyrazole-1 -yl)acetamide

N-((S)-1-((3P)-7-bromo-3-(4-chloro-3-(cyclopropanesulfonamido)-1-(2,2-difluoroethyl)- 1H-indazol-7-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 (300 mg, 0.312 mmol), 4, 4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (119 mg, 0.469 mmol), potassium acetate (92 mg, 0.937 mmol) and PdCl ₂ (dppf) (22.86 mg, 0.031 mmol). The flask was sealed with a membrane and then placed in an argon atmosphere (vacuum/fill ×3). Dioxane (6.3 ml) was added to the flask. The flask was again placed under argon (vacuum/fill ×3). The resulting mixture was stirred at 60°C for 16 hours overnight. After cooling to room temperature, the reaction mixture was concentrated in vacuo and the resulting residue was adsorbed onto celite. The resulting powder was subjected to silica gel column chromatography (hexanes: EtOAc 100:0→0:100, 10 column volumes) to obtain N-((S)-1-((3P)-3-(4-chloro-3-(cyclopropanesulfonamido )-1-(2,2-difluoroethyl)-1H-indazol-7-yl)-4-oxo-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -3,4-dihydroquinazolin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(dafluoromethyl)-5,5-difluoro-3b,4,4a ,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide, 220 mg (70%). ^1H NMR (METHANOL-d4, 500 MHz) δ 8.27 (d, 2H, J = 6.2 Hz), 8.26 (s, 1H), 7.97 (dd, 1H, J = 1.0 , 7.9 Hz), 7.41 (d, 1H, J = 7.7 Hz), 7.29 (d, 1H, J = 7.7 Hz), 6.8-6.8 (m, 1H ), 6.70 (br t, 1H, J = 54.8 Hz), 6.55 (dd, 2H, J = 2.1, 8.0 Hz), 6.01 (t, 1H, J = 55 .3 Hz), 4.74 (dd, 1H, J = 4.8, 9.5 Hz), 4.68 (d, 1H, J = 16.4 Hz), 4.59 (d, 1H, J = 16.4 Hz), 4.38 (dd, 1H, J = 4.2, 15.2 Hz), 4.12 (q, 1H, J = 7.2 Hz), 3.91 (dd, 1H , J = 3.9, 15.2 Hz), 3.68 (s, 1H), 3.06 (dd, 1H, J = 9.4, 14.2 Hz), 2.9-2.9 ( m, 1H), 2.4-2.5 (m, 2H), 2.03 (s, 2H), 1.45 (s, 12H), 1.1-1.1 (m, 2H), 1 .0-1.0 (m, 2H).

Preparation of N-((S)-1-((3P)-7-bromo-3-(4-chloro-3-(N-(4-methoxybenzyl)methylsulfonamido)-1-methyl-1H-indazol-7-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

1-(chloromethyl)-4-methoxybenzene (0.276 ml, 2.036 mmol) was added to the stirred solution of N-((S)-1-((3P)-7-bromo-3-(4-chloro-1-methyl-3 -(methylsulfonamido)-1H-indazol-7-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 (1.5 g , 1.697 mmol) and cesium carbonate (0.553 g, 1.697 mmol) in N,N-dimethylformamide (DMF) (10 ml), and the resulting mixture was stirred at room temperature for 16 hours. Water was then added and the mixture was extracted with ethyl acetate, washed saline solution, dried (Na ₂ SO ₄ ), filtered and concentrated. The residue was then subjected to silica gel column chromatography (hexanes: EtOAc 95:5→70:30) to give N-((S)-1-((3P)-7-bromo-3-(4-chloro-3-(N -(4-methoxybenzyl)methylsulfonamido)-1-methyl-1H-indazol-7-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]pyrazole-1- yl)acetamide, 1.4 g (82%). LC-MS analysis conditions: Wavelength 1: 220 nm; Wavelength 2: 254 nm; volume of injected sample: 5.00 µl; stopping time: 4.50 min; Deg time: 3.50 min; Initial %B: 0; final %B: 100; Total flow: 0.80 ml/min; solvent A: 95:5 Bofla: MeCN with 0.1% TFA; Solvent B: 5:95 Bofla: MeCN with 0.1% TFA; Column = Acquity UPLC VEN C18, 2.1×100 mm, 1.7 µm. Result of LC-MS analysis: retention time: 3.536 min, M+H: 1003.05.

Preparation of N-((S)-1-((3P)-3-(4-chloro-3-(N-(4-methoxybenzyl)methylsulfonamido)-1-methyl-1H-indazol-7-yl)-4- oxo-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-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

N-((S)-1-((3P)-7-bromo-3-(4-chloro-3-(N-(4-methoxybenzyl)methylsulfonamido)-1-methyl-1H-indazol-7-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 (954 mg, 0.950 mmol), 4,4,4",4", 5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (362 mg, 1.425 mmol), potassium acetate (280 mg, 2.85 mmol) and PdCl ₂ ( dppf) (69.5 mg, 0.095 mmol) were combined dry and degassed with Ar. They were then placed in dioxane (19 ml) and again degassed with argon, and the resulting mixture was stirred at 60°C overnight (16 hours). The reaction mixture was concentrated, adsorbed onto celite, and the resulting powder was subjected to silica gel column chromatography (hexanes: EtOAc 100:0→0:100, 10 column volumes) to give N-((S)-1-((3P)-3- (4-chloro-3-(N-(4-methoxybenzyl)methylsulfonamido)-1-methyl-1H-indazol-7-yl)-4-oxo-7-(4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl)-3,4-dihydroquinazolin-2-yl)-2-(3,5-dafluorophenyl)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, 709 mg (71%). MS analysis shows both boronic acid ester and boronic acid. However, 1H-NMR shows that the product is entirely boronic acid ester. LC-MS analysis conditions: Wavelength 1: 220 nm; Wavelength 2: 254 nm; injected sample volume: 5.00 µl; stop time: 2.50 min; Graduation time: 1.50 min; Initial %V: 0; final %V: 100; Total flow: 0.80 ml/min; Solvent A: 95:5 Bofla: MeCN with 0.1% TFA; Solvent B: 5:95 Bofla: MeCN with 0.1% TFA; Column = Acquity UPLC VEN C18, 2.1x50 mm, 1.7 µm. Result of LC-MS analysis: retention time: 1.495 min, M+H: 969.15; retention time: 1.760 min, M+H: 1051.25.

Preparation of Example 1: N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7-(4,6 -dimethylpyridin-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.

The title compound was prepared according to General Procedure D using 2-bromo-4,6-dimethylpyridine as the coupling partner. As a result of the experiment, we obtained the title compound, N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7 -(4,6-dimethylpyridin-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. The sample was analyzed using LC-MS method C: retention time = 1.36 min; observed ion = 910.8 (M+H). 1H NMR (METHANOL-d4, 500 MHz) δ 8.46 (d, 1H, J = 1.2 Hz), 8.38 (d, 1H, J = 8.3 Hz), 8.24 (dd, 1H , J = 1.8, 8.3 Hz), 7.71 (s, 1H), 7.31 (d, 1H, J = 7.7 Hz), 7.23 (s, 1H), 7.20 (d, 1H, J = 7.7 Hz), 6.8-6.8 (m, 1H), 6.64 (dd, 2H, J = 2.2, 8.2 Hz), 6.71 ( t, 1H, J = 54.8 Hz), 4.9-4.9 (m, 1H), 4.55 (d, 2H, J = 2.1 Hz), 3.64 (s, 3H), 3.5-3.5 (m, 1H), 3.2-3.3 (m, 4H), 3.1-3.2 (m, 2H), 2.64 (s, 3H), 2, 4-2.5 (m, 5H)

Preparation of Example 2: N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7-(4-methylpyridine -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.

The title compound was prepared according to General Procedure D using 2-bromo-4-methylpyridine as a coupling agent. As a result of the experiment, we obtained the title compound, N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7 -(4-methylpyridin-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. The sample was analyzed using LC-MS method C: retention time = 1.37 min; observed ion = 896.7 (M+H). 1H NMR (METHANOL-d4, 500 MHz) δ 8.62 (d, 1H, J = 5.7 Hz), 8.48 (d, 1H, J = 1.5 Hz), 8.40 (d, 1H , J = 8.3 Hz), 8.25 (dd, 1H, J = 1.8, 8.3 Hz), 7.95 (d, 1H, J = 1.5 Hz), 7.37 (d , 1H, J = 5.1 Hz), 7.31 (d, 1H, J = 7.7 Hz), 7.20 (d, 1H, J = 7.7 Hz), 6.8-6.8 (m, 1H), 6.6-6.7 (m, 2H), 6.70 (t, 1H, J = 54.8 Hz), 4.88 (d, 1H, J = 5.1 Hz) , 4.54 (s, 2H), 3.64 (s, 3H), 3.5-3.5 (m, 1H), 3.2-3.3 (m, 3H), 3.1-3 .2 (m, 1H), 2.55 (s, 3H), 2.4-2.5 (m, 2H), 1.3-1.4 (m, 1H), 1.0-1.0 (m, 1H)

Preparation of Example 3: N-((S)-1-((3P)-3-(4-chloro-l-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-4-oxo-7- (4-(trifluoromethyl)pyrimidin-2-yl)-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.

The title compound was prepared according to General Procedure D using 2-chloro-4-(trifluoromethyl)pyrimidine as the coupling agent. As a result of the experiment, we obtained the title compound, N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-4 -oxo-7-(4-(trifluoromethyl)pyrimidin-2-yl)-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. The sample was analyzed using LC-MS method C: retention time = 1.48 min; observed ion 951.7 (M+H). 1H NMR (METHANOL-d4, 500 MHz) δ 9.31 (d, 1H, J = 5.1 Hz), 9.02 (d, 1H, J = 1.2 Hz), 8.76 (dd, 1H , J = 1.8, 8.3 Hz), 8.46 (d, 1H, J = 8.3 Hz), 7.92 (d, 1H, J = 4.8 Hz), 7.33 (d , 1H, J = 7.7 Hz), 7.25 (d, 1H, J = 8.0 Hz), 6.8-6.8 (m, 1H), 6.70 (s, 1H), 6 .63 (dd, 2H, J = 2.2, 8.2 Hz), 6.69 (t, 1H, J = 54.7 Hz), 4.89 (t, 1H, J = 4.6 Hz) , 4.5-4.6 (m, 2H), 3.6-3.7 (m, 3H), 3.5-3.5 (m, 1H), 3.26 (s, 3H), 3 .14 (dd, 1H, J = 9.2, 14.0 Hz), 2.4-2.5 (m, 1H), 1.3-1.4 (m, 1H), 1.01 (dt , 1H, J = 1.9, 3.7 Hz)

Preparation of Example 4: N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7-(4-( methylsulfonyl)pyridin-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.

The title compound was prepared according to General Procedure D using 2-chloro-4-(methylsulfonyl)pyridine as the coupling agent. As a result of the experiment, we obtained the title compound, N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7 -(4-(methylsulfonyl)pyridin-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. The sample was analyzed using LC-MS method C: retention time = 1.3 min; observed ion = 960.8 (M+H). 1H NMR (METHANOL-d4, 500 MHz) δ 9.11 (dd, 1H, J = 0.9, 5.1 Hz), 8.65 (s, 1H), 8.59 (s, 1H), 8 ,4-8.5 (m, 2H), 8.00 (dd, 1H, J = 1.6, 4.9 Hz), 7.32 (d, 1H, J = 7.7 Hz), 7, 23 (d, 1H, J = 7.7 Hz), 6.7-6.8 (m, 1H), 6.64 (dd, 2H, J = 2.1, 8.0 Hz), 6.70 (t, 1H, J = 54.7 Hz), 4.9-4.9 (m, 2H), 4.5-4.6 (m, 2H), 3.65 (s, 3H), 3, 5-3.5 (m, 1H), 3.4-3.4 (m, 1H), 3.2-3.3 (m, 4H), 3.1-3.2 (m, 1H), 2.4-2.5 (m, 2H), 1.3-1.4 (m, 1H), 1.0-1.0 (m, 1H)

Preparation of Example 5: N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7-(6-methoxy -2-methylpyridin-3-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.

The title compound was prepared according to General Procedure D using 3-bromo-6-methoxy-2-methylpyridine as a coupling agent. As a result of the experiment, we obtained the title compound, N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7 -(6-methoxy-2-methylpyridin-3-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. The sample was analyzed using LC-MS method C: retention time = 1.46 min; observed ion = 926.8 (M+H). 1H NMR (METHANOL, 500 MHz) δ 8.36 (d, 1H, J = 8.0 Hz), 7.85 (d, 1H, J = 1.8 Hz), 7.69 (d, 1H, J = 8.6 Hz), 7.6-7.7 (m, 1H), 7.32 (d, 1H, J = 7.7 Hz), 7.22 (d, 1H, J = 8.0 Hz ), 6.6-6.8 (m, 5H), 4.9-4.9 (m, 1H), 4.5-4.6 (m, 2H), 4.00 (s, 3H), 3.65 (s, 3H), 3.5-3.5 (m, 1H), 3.2-3.3 (m, 3H), 3.11 (dd, 1H, J = 9.2, 14 .0 Hz), 2.51 (s, 3H), 2.43 (ddd, 2H, J = 4.0, 7.6, 11.3 Hz), 1.3-1.4 (m, 1H) , 1.0-1.0 (m, 1H)

Preparation of Example 6: N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7-(2,4 -dimethylthiazol-5-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.

The title compound was prepared according to General Procedure D using 5-bromo-2,4-dimethylthiazole as a coupling agent. As a result of the experiment, we obtained the title compound, N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7 -(2,4-dimethylthiazol-5-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. The sample was analyzed using LC-MS method C: retention time = 1.37 min; observed ion = 916.8 (M+H). 1H NMR (METHANOL, 500 MHz) δ 8.35 (d, 1H, J = 8.1 Hz), 7.95 (d, 1H, J = 1.5 Hz), 7.76 (dd, 1H, J = 1.8, 8.3 Hz), 7.32 (d, 1H, J = 8.0 Hz), 7.23 (d, 1H, J = 7.7 Hz), 6.8-6.8 (m, 1H), 6.63 (dd, 2H, J = 2.2, 8.2 Hz), 6.69 (t, 1H, J = 54.7 Hz), 4.9-4.9 ( m, 1H), 4.5-4.6 (m, 2H), 3.63 (s, 3H), 3.5-3.5 (m, 1H), 3.2-3.3 (m, 3H), 3.11 (dd, 1H, J = 9.2, 14.0 Hz), 2.76 (s, 3H), 2.59 (s, 3H), 2.43 (ddd, 2H, J = 3.9, 7.6, 11.2 Hz), 1.3-1.4 (m, 1H), 1.00 (td, 1H, J = 2.1, 3.6 Hz)

Preparation of Example 7: N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7-(6-methoxypyridazine -3-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.

The title compound was prepared according to General Procedure D using 3-bromo-6-methoxypyridazine as the coupling agent. As a result of the experiment, we obtained the title compound, N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7 -(6-methoxypyridazin-3-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. The sample was analyzed using LC-MS method C: retention time = 1.33 min; observed ion 913.7 (M+H). 1H NMR (METAHOJI-d4, 500 MHz) δ 8.54 (d, 1H, J = 1.2 Hz), 8.44 (d, 1H, J = 8.3 Hz), 8.29 (t, 2H , J = 8.9 Hz), 7.39 (d, 1H, J = 9.2 Hz), 7.32 (d, 1H, J = 7.7 Hz), 7.21 (d, 1H, J = 8.0 Hz), 6.8-6.8 (m, 1H), 6.64 (dd, 2H, J = 2.2, 8.2 Hz), 6.69 (br t, 2H, J = 54.7 Hz), 4.54 (s, 2H), 4.23 (s, 3H), 3.64 (s, 3H), 3.51 (dd, 1H, J = 5.2, 13, 9 Hz), 3.26 (s, 3H), 3.13 (dd, 1H, J = 9.1, 14.2 Hz), 2.43 (br dd, 2H, J = 3.7, 6, 1 Hz), 1.3-1.4 (m, 1H), 1.0-1.0 (m, 1H)

Preparation of Example 8: N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7-(3-( methylsulfonyl)pyridin-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.

The title compound was prepared according to General Procedure D using 2-chloro-3-(methylsulfonyl)pyridine as the coupling agent. As a result of the experiment, we obtained the title compound, N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7 -(3-(methylsulfonyl)pyridin-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. The sample was analyzed using LC-MS method C: retention time = 1.27 min; observed ion 960.8 (M+H). 1H NMR (METHANOL-d4, 500 MHz) δ 8.98 (dd, 1H, J = 1.8, 4.8 Hz), 8.7-8.7 (m, 1H), 8.41 (d, 1H, J = 8.6 Hz), 8.11 (d, 1H, J = 2.1 Hz), 7.83 (s, 1H), 7.8-7.8 (m, 1H), 7, 33 (d, 1H, J = 7.7 Hz), 7.23 (d, 1H, J = 8.0 Hz), 6.8-6.8 (m, 1H), 6.63 (dd, 2H , J = 2.2, 8.2 Hz), 6.69 (t, 1H, J = 54.8 Hz), 4.8-4.9 (m, 1H), 4.52 (d, 2H, J = 1.5 Hz), 3.67 (s, 3H), 3.5-3.5 (m, 1H), 3.26 (s, 3H), 3.11 (dd, 1H, J = 9 ,2, 14.0 Hz), 3.01 (s, 3Н), 2.43 (ddd, 2Н, J = 4.2, 7.7, 11.4 Hz), 1.3-1.4 ( m, 1H), 1.0-1.0 (m, 1H)

Preparation of Example 9: N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7-(5-methoxy -2-methylpyrimidin-4-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.

The title compound was prepared according to General Procedure D using 4-chloro-5-methoxy-2-methylpyrimidine as a coupling agent. As a result of the experiment, we obtained the title compound, N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7 -(5-methoxy-2-methylpyrimidin-4-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. The sample was analyzed using LC-MS method C: retention time = 1.32 min; observed ion = 927.9 (M+H). ^1H NMR (METHANOL-d4, 500 MHz) δ 8.65 (s, 1H), 8.60 (s, 1H), 8.4-8.4 (m, 1H), 8.3-8.3 (m, 1H), 7.32 (d, 1H, J = 8.0 Hz), 7.24 (d, 1H, J = 8.0 Hz), 6.7-6.8 (m, 1H) , 6.64 (dd, 2H, J = 2.1, 8.0 Hz), 6.69 (br t, 2H, J = 54.8 Hz), 4.5-4.6 (m, 2H) , 4.10 (s, 3H), 3.64 (s, 3H), 3.5-3.5 (m, 1H), 3.26 (s, 3H), 3.12 (dd, 1H, J = 9.2, 14.0 Hz), 2.76 (s, 3H), 2.4-2.5 (m, 2H), 1.3-1.4 (m, 1H), 1.0- 1.0 (m, 1H)

Preparation of Example 10: N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7-(2-methylpyrimidine -4-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.

The title compound was prepared according to General Procedure D using 4-chloro-2-methylpyrimidine as the coupling agent. As a result of the experiment, we obtained the title compound, N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7 -(2-methylpyrimidin-4-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. The sample was analyzed using LC-MS method C: retention time = 1.32 min; observed ion = 897.8 (M+H). 1H NMR (METHANOL-d4, 500 MHz) δ 8.86 (d, 1H, J = 5.4 Hz), 8.70 (d, 1H, J = 1.5 Hz), 8.4-8.5 (m, 2H), 8.01 (d, 1H, J = 5.1 Hz), 7.32 (d, 1H, J = 8.0 Hz), 7.24 (d, 1H, J = 7, 7 Hz), 6.8-6.8 (m, 1H), 6.6-6.7 (m, 2H), 6.70 (t, 1H, J = 54.8 Hz), 4.9- 4.9 (m, 1H), 4.5-4.6 (m, 2H), 3.64 (s, 3H), 3.5-3.5 (m, 1H), 3.26 (s, 3H), 3.13 (dd, 1H, J = 9.2, 14.0 Hz), 2.85 (s, 3H), 2.4-2.5 (m, 2H), 1.3-1 .4 (m, 1H), 1.01 (td, 1H, J = 2.1, 3.6 Hz)

Preparation of Example 11: N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7-(3-methoxypyridine -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.

The title compound was prepared according to General Procedure D using 2-chloro-3-methoxypyridine as the coupling agent. As a result of the experiment, we obtained the title compound, N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7 -(3-methoxypyridin-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. The sample was analyzed using LC-MS method C: retention time = 1.35 min; observed ion = 912.8 (M+H). 1H NMR (METHANOL-d4, 500 MHz) δ 8.3-8.4 (m, 3H), 8.12 (dd, 1H, J = 1.6, 8.2 Hz), 7.71 (dd, 1H, J = 1.2, 8.3 Hz), 7.53 (dd, 1H, J = 4.8, 8.3 Hz), 7.32 (d, 1H, J = 7.7 Hz), 7.21 (d, 1H, J = 8.0 Hz), 6.79 (tt, 1H, J = 2.3, 9.1 Hz), 6.6-6.7 (m, 2H), 6 .69 (br t, 2H, J = 54.7 Hz), 4.54 (d, 2H, J = 1.8 Hz), 4.00 (s, 3H), 3.64 (s, 3H), 3.5-3.5 (m, 1H), 3.26 (s, 3H), 3.12 (dd, 1H, J = 9.1, 13.9 Hz), 2.43 (ddd, 2H, J = 4.0, 7.6, 11.3 Hz), 1.3-1.4 (m, 1H), 1.0 (m, 1H)

Preparation of Example 12: N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7-(2-( difluoromethyl)phenyl)-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.

The title compound was prepared according to General Procedure D using 1-bromo-2-(difluoromethyl)benzene as a coupling agent. As a result of the experiment, we obtained the title compound, N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7 -(2-(difluoromethyl)phenyl)-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. The sample was analyzed using LC-MS method C: retention time = 1.49 min; observed ion = 931.8 (M+H). 1H NMR (METHANOL-d4, 500 MHz) δ 8.39 (d, 1H, J = 8.0 Hz), 7.88 (d, 1H, J = 1.2 Hz), 7.86 (d, 1H , J = 7.5 Hz), 7.6-7.7 (m, 3H), 7.53 (d, 1H, J = 7.5 Hz), 7.33 (d, 1H, J = 8, 0 Hz), 7.25 (d, 1H, J = 8.0 Hz), 6.6-6.9 (m, 5H), 4.8-4.8 (m, 1H), 4.5- 4.6 (m, 2H), 3.6-3.7 (m, 3H), 3.5-3.5 (m, 1H), 3.26 (s, 3H), 3.12 (dd, 1H, J = 9.2, 14.0 Hz), 2.42 (ddd, 2H, J = 4.0, 7.7, 11.5 Hz), 1.3-1.4 (m, 1H) , 1.00 (dt, 1H, J = 1.9, 3.8 Hz)

Preparation of Example 13: N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7-(2-( 2-hydroxypropan-2-yl)phenyl)-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.

The title compound was prepared according to General Procedure D using 2-(2-bromophenyl)propan-2-ol as a coupling agent. As a result of the experiment, we obtained the title compound, N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7 -(2-(2-hydroxypropan-2-yl)phenyl)-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. The sample was analyzed using LC-MS method C: retention time = 1.42 min; observed ion = 939.9 (M+H). 1H NMR (METHANOL-d4, 500 MHz) δ 8.26 (d, 1H, J = 8.6 Hz), 7.79 (d, 1H, J = 8.2 Hz), 7.77 (d, 1H , J = 1.5 Hz), 7.59 (dd, 1H, J = 1.6, 8.2 Hz), 7.45 (t, 1H, J = 7.6 Hz), 7.33 (dt , 1H, J = 1.2, 7.5 Hz), 7.25 (br d, 1H, J = 8.0 Hz), 7.17-7.2 (m, 1H), 7.11 (dd , 1H, J = 1.3, 7.6 Hz), 6.8-6.8 (m, 1H), 6.69 (s, 1H), 6.6-6.6 (m, 1H), 6.69 (br t, 1H, J = 54.7 Hz), 4.9-5.0 (m, 1H), 4.5-4.6 (m, 2H), 3.62 (s, 3H ), 3.4-3.5 (m, 1H), 3.2-3.2 (m, 3H), 3.09 (dd, 1H, J = 9.1, 13.9 Hz), 2, 4-2.5 (m, 2H), 1.4-1.5 (m, 6H), 1.3-1.4 (m, 1H), 1.0-1.0 (m, 1H)

Preparation of Example 14: N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-4-oxo-7- (2-(trifluoromethoxy)phenyl)-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.

The title compound was prepared according to General Procedure D using 1-bromo-2-(trifluoromethoxy)benzene as a coupling agent. As a result of the experiment, we obtained the title compound, N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-4 -oxo-7-(2-(trifluoromethoxy)phenyl)-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. The sample was analyzed using LC-MS method C: retention time = 1.54 min; observed ion = 965.8 (M+H). 1H NMR (METHANOL, 500 MHz) Shift 8.38 (br d, 1H, J = 8.3 Hz), 7.99 (s, 1H), 7.77 (br d, 1H, J = 8.0 Hz ), 7.67 (br d, 1H, J = 7.2 Hz), 7.5-7.6 (m, 3H), 7.31 (br d, 1H, J = 7.7 Hz), 7 .2-7.3 (m, 1H), 6.6-6.8 (m, 4H), 4.89 (br d, 1H, J = 6.0 Hz), 4.54 (br s, 2H ), 3.65 (s, 3H), 3.4-3.5 (m, 1H), 3.2-3.3 (m, 3H), 3.11 (br d, 1H, J = 0, 9 Hz), 2.4-2.5 (m, 2H), 1.3-1.4 (m, 1H), 1.01 (br d, 1H, J = 3.6 Hz)

Preparation of Example 15: N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7-(3-methoxypyrazine -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.

The title compound was prepared according to General Procedure D using 2-chloro-3-methoxypyrazine as the coupling agent. As a result of the experiment, we obtained the title compound, N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7 -(3-methoxypyrazin-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. The sample was analyzed using LC-MS method C: retention time = 1.4 min; observed ion = 913.6 (M+H). 1H NMR (METHANOL-d4, 500 MHz) δ 8.61 (s, 1H), 8.3-8.4 (m, 3H), 8.30 (d, 1H, J = 2.4 Hz), 7 .32 (d, 1H, J = 7.7 Hz), 7.22 (d, 1H, J = 7.7 Hz), 6.8-6.8 (m, 1H), 6.64 (dd, 2H, J = 2.2, 8.2 Hz), 6.69 (br t, 2H, J = 54.8 Hz), 4.90 (br d, 1H, J = 5.1 Hz), 4, 5-4.6 (m, 2H), 4.16 (s, 3H), 3.6-3.7 (m, 3H), 3.5-3.5 (m, 1H), 3.26 ( s, 3H), 2.4-2.5 (m, 2H), 1.3-1.4 (m, 1H), 1.0-1.0 (m, 1H)

Preparation of Example 16: N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7-(3-isopropylpyrazine) -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.

The title compound was prepared according to General Procedure D using 2-chloro-3-isopropylpyrazine as the coupling agent. As a result of the experiment, we obtained the title compound, N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7 -(3-isopropylpyrazin-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. The sample was analyzed using LC-MS method C: retention time = 1.41 min; observed ion = 925.8 (M+H). 1H NMR (METHANOL-d4, 500 MHz) δ 8.71 (d, 1H, J=2.4 Hz), 8.60 (d, 1H, J=2.4 Hz). 8.44 (d, 1H, J=8.0 Hz), 8.01 (d, 1H, J=1.8 Hz), 7.80 (dd, 1H, J=1.6, 8.2 Hz ), 7.33 (d, 1H, J=7.7 Hz), 7.26 (d, 1H, J=7.7 Hz), 6.8-6.8 (m, 1H), 6.63 (dd, 2H, J=2.2, 8.2 Hz), 6.68 (t, 2H, J=54.8 Hz), 4.8-4.8 (m, 1H), 4.5- 4.6 (m, 2H), 3.66 (s, 3H), 3.3-3.4 (m, 2H), 3.2-3.3 (m, 3H), 3.11 (dd, 1H, J=9.2, 14.0 Hz), 2.4-2.5 (m, 2H), 1.33 (d, 6H, J=6.9 Hz), 1.0-1.0 (m, 1H)

Preparation of Example 17: N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7-(3-ethylpyrazine) -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.

The title compound was prepared according to General Procedure D using 2-chloro-3-ethylpyrazine as the coupling agent. As a result of the experiment, we obtained the title compound, N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7 -(3-ethylpyrazin-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. The sample was analyzed using LC-MS method C: retention time = 1.35 min; observed ion = 911.8 (M+H). 1H NMR (METHANOL-d4, 500 MHz) δ 8.68 (d, 1H, J=2.7 Hz), 8.63 (d, 1H, J=2.7 Hz), 8.44 (d, 1H , J=8.0 Hz), 8.06 (d, 1H, J=1.8 Hz), 7.84 (dd, 1H, J=1.6, 8.2 Hz), 7.33 (d , 1H, J=7.7 Hz), 7.25 (d, 1H, J=7.7 Hz), 6.6-6.8 (m, 4H), 4.8-4.8 (m, 1H), 4.5-4.6 (m, 3H), 3.70 (s, 1H), 3.66 (s, 3H), 3.5-3.5 (m, 1H), 3.2 -3.3 (m, 3H), 3.00 (q, 2H, J=7.5 Hz), 2.4-2.5 (m, 2H), 1.3-1.3 (m, 3H ), 1.00 (dt, 1H, J=1.8, 3.7 Hz)

Preparation of Example 18: N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7-(3-( Hydroxymethyl)pyrazin-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.

The title compound was prepared according to General Procedure D using (3-chloropyrazin-2-yl)methanol as the coupling agent. As a result of the experiment, we obtained the title compound, N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7 -(3-(hydroxymethyl)pyrazin-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. The sample was analyzed using LC-MS method C: retention time = 1.21 min; observed ion = 913.8 (M+H). 1H NMR (METHANOL-d4, 500 MHz) δ 8.75 (s, 2H), 8.43 (br d, 1H, J=8.3 Hz), 8.26 (s, 1H), 7.99 ( br d, 1H, J=8.0 Hz), 7.32 (br d, 1H, J=8.0 Hz), 7.23 (br d, 1H, J=8.3 Hz), 6.5 -6.8 (m, 4H), 4.90 (br d, 1H, J=1.5 Hz), 4.5-4.6 (m, 3H), 3.65 (s, 3H), 3 .4-3.5 (m, 1H), 3.4-3.4 (m, 1H), 3.2-3.3 (m, 4H), 3.1-3.2 (m, 1H) , 2.4-2.5 (m, 2H), 1.3-1.4 (m, 1H), 1.00 (br d, 1H, J=3.3 Hz)

Preparation of Example 19: N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7-(3-methoxyquinoxaline -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.

The title compound was prepared according to General Procedure D using 2-chloro-3-methoxyquinoxaline as a coupling agent. As a result of the experiment, we obtained the title compound, N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7 -(3-methoxyquinoxalin-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. The sample was analyzed using LC-MS method C: retention time = 1.54 min; observed ion = 963.8 (M+H). 1H NMR (METHANOL-d4, 500 MHz) δ 8.67 (s, 1H), 8.41 (s, 2H), 8.15 (dd, 1H, J=1.5, 8.3 Hz), 7 .97 (dd, 1Н, J=1.5, 8.3 Hz), 7.81 (t, 1Н, J=7.6 Hz), 7.71 (ddd, 1Н, J=1.3, 7 ,0, 8.3 Hz), 7.33 (d, 1H, J=7.7 Hz), 7.24 (d, 1H, J=7.7 Hz), 6.8-6.8 (m , 1H), 6.65 (dd, 2H, J=2.2, 8.2 Hz), 6.70 (br t, 2H, J=54.7 Hz), 4.9-4.9 (m , 1H), 4.5-4.6 (m, 3H), 4.27 (s, 3H), 3.66 (s, 3H), 3.52 (dd, 1H, J=5.2, 14 ,2 Hz), 3.1-3.2 (m, 2H), 2.4-2.5 (m, 2H), 1.3-1.4 (m, 1H), 1.0-1, 0 (m, 1H)

Preparation of Example 20: N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7-(3-methylpyridine -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.

The title compound was prepared according to General Procedure D using 2-bromo-3-methylpyridine as a coupling agent. As a result of the experiment, we obtained the title compound, N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7 -(3-methylpyridin-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. The sample was analyzed using LC-MS method C: retention time = 1.29 min; observed ion = 896.7 (M+H). 1H NMR (METHANOL-d4, 500 MHz) δ 8.5-8.6 (m, 1H), 8.42 (d, 1H, J=8.6 Hz), 8.00 (d, 1H, J= 1.2 Hz), 7.90 (d, 1H, J=7.9 Hz), 7.79 (dd, 1H, J=1.6, 8.2 Hz), 7.47 (dd, 1H, J=5.1, 7.7 Hz), 7.33 (d, 1H, J=7.7 Hz), 7.23 (d, 1H, J=8.0 Hz), 6.6-6.8 ( m, 4H), 4.54 (d, 2H, J=2.1 Hz), 3.71 (s, 1H), 3.66 (s, 3H), 3.5-3.5 (m, 1H ), 3.2-3.3 (m, 4H), 3.11 (dd, 1H, J=9.1, 14.2 Hz), 2.4-2.5 (m, 5H), 1, 0-1.0 (m, 1H)

Preparation of Example 21: N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7-(3-fluoropyridine -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.

The title compound was prepared according to General Procedure D using 2-chloro-3-fluoropyridine as the coupling agent. As a result of the experiment, we obtained the title compound, N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7 -(3-fluoropyridin-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. The sample was analyzed using LC-MS method C: retention time = 1.38 min; observed ion = 900.7 (M+H). 1H NMR (METHANOL-d4, 500 MHz) δ 8.64 (td, 1H, J=1.5, 4.7 Hz), 8.46 (t, 1H, J=1.5 Hz), 8.42 (d, 1H, J=8.3 Hz), 8.24 (td, 1H, J=1.5, 8.3 Hz), 7.84 (ddd, 1H, J=1.5. 8.4 , 11.3 Hz), 7.6-7.6 (m, 1H), 7.32 (d, 1H, J=7.7 Hz), 7.23 (d, 1H, J=8.0 Hz ), 6.8-6.8 (m, 1H), 6.63 (dd, 2H, J=2.2, 8.2 Hz), 6.69 (br t, 2H, J=54.7 Hz ), 4.9-4.9 (m, 2H), 4.5-4.6 (m, 2H), 3.6-3.7 (m, 3H), 3.5-3.5 (m , 1H), 3.3-3.3 (m, 3H), 2.4-2.5 (m, 2H), 1.0-1.0 (m, 1H)

Preparation of Example 22: N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7-(3-fluoro -6-methylpyridin-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.

The title compound was prepared according to General Procedure D using 2-chloro-3-fluoro-6-methylpyridine as a coupling agent. As a result of the experiment, we obtained the title compound, N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7 -(3-fluoro-6-methylpyridin-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. The sample was analyzed using LC-MS method C: retention time = 1.44 min; observed ion = 914.8 (M+H). 1H NMR (METHANOL-d4, 500 MHz) δ 8.44 (t, 1H, J=1.3 Hz), 8.40 (d, 1H, J=8.3 Hz), 8.23 (td, 1H , J=1.5, 8.3 Hz), 7.69 (dd, 1H, J=8.5, 10.9 Hz), 7.42 (dd, 1H, J=3.3, 8.6 Hz), 7.32 (d, 1H, J=8.0 Hz), 7.22 (d, 1H, J=7.7 Hz), 6.8-6.8 (m, 1H), 6, 63 (dd, 2H, J=2.2, 8.2 Hz), 6.69 (t, 2H, J=54.8 Hz), 4.55 (d, 2H, J=5.1 Hz), 3.6-3.7 (m, 3H), 3.5-3.5 (m, 1H), 3.26 (s, 3H), 3.12 (dd, 1H, J=9.1, 14 ,2 Hz), 2.67 (s, 3H), 2.43 (td, 2H, J=3.6, 7.4 Hz), 1.3-1.4 (m, 1H), 1.0 -1.0 (m, 1H)

Preparation of Example 23: N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7-(2-isopropylphenyl) )-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.

The title compound was prepared according to General Procedure D using 1-bromo-2-isopropylbenzene as the coupling agent. As a result of the experiment, we obtained the title compound, N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7 -(2-isopropylphenyl)-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. The sample was analyzed using LC-MS method C: retention time = 1.59 min; observed ion = 923.8 (M+H). 1H NMR (METHANOL-d4, 500 MHz) δ 8.35 (d, 1H, J=8.6 Hz), 7.79 (d, 1H, J=1.8 Hz), 7.6-7.6 (m, 1H), 7.5-7.5 (m, 1H), 7.46 (dt, 1H, J=1.3, 7.5 Hz), 7.2-7.3 (m, 4H ), 6.6-6.8 (m, 4H), 4.9-4.9 (m, 1H), 4.5-4.6 (m, 2H), 3.66 (s, 3H), 3.5-3.5 (m, 1H), 3.26 (s, 3H), 3.1-3.1 (m, 2H), 2.42 (ddd, 2H, J=4.0, 7 ,7, 11.3 Hz), 1.3-1.4 (m, 1H), 1.24 (d, 6H, J=6.9 Hz), 1.0-1.0 (m, 1H)

Preparation of Example 24: N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-4-oxo-7- (2-(trifluoromethyl)phenyl)-3,4-dihydroquinazolin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5 -difluoro-3b4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.

The title compound was prepared according to General Procedure D using 1-bromo-2-(trifluoromethyl)benzene as a coupling agent. As a result of the experiment, we obtained the title compound, N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-4 -oxo-7-(2-(trifluoromethyl)phenyl)-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. The sample was analyzed using LC-MS method C: retention time = 1.51 min; observed ion = 949.9 (M+H). 1H NMR (METHANOL-d4, 500 MHz) δ 8.35 (d, 1H, J=8.0 Hz), 7.91 (d, 1H, J=7.5 Hz), 7.85 (d, 1H , J=1.5 Hz), 7.78 (t, 1H, J=7.5 Hz), 7.70 (t, 1H, J=7.6 Hz), 7.62 (dd, 1H, J =1.5, 8.3 Hz), 7.53 (d, 1H, J=7.7 Hz), 7.32 (d, 1H, J=7.7 Hz), 7.25 (d, 1H , J=8.0 Hz), 6.6-6.8 (m, 4H), 4.9-4.9 (m, 1H), 4.5-4.6 (m, 2H), 3, 66 (s, 3H), 3.4-3.5 (m, 1H), 3.2-3.3 (m, 3H), 3.11 (dd, 1H, J=9.4, 14.2 Hz), 2.4-2.5 (m, 2H), 1.3-1.4 (m, 1H), 1.00 (td, 1H, J=2.1, 3.6 Hz)

Preparation of Example 25: N-((5)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7-(2-( difluoromethoxy)phenyl)-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.

The title compound was prepared according to General Procedure D using 1-bromo-2-(difluoromethoxy)benzene as a coupling agent. As a result of the experiment, we obtained the title compound, N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7 -(2-(difluoromethoxy)phenyl)-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. The sample was analyzed using LC-MS method C: retention time = 1.46 min; observed ion = 947.8 (M+H). 1H NMR (METHANOL-d4, 500 MHz) δ 8.35 (d, 1H, J=8.6 Hz), 8.02 (d, 1H, J=1.8 Hz), 7.79 (dd, 1H , J=1.6, 8.2 Hz), 7.62 (dd, 1H, J=1.6,7.6 Hz), 7.5-7.6 (m, 1H), 7.45 ( dt, 1H, J=1.2, 7.6 Hz), 7.40 (d, 1H, J=7.9 Hz), 7.32 (d, 1H, J=7.7 Hz), 7, 22 (d, 1H, J=7.7 Hz), 6.6-7.0 (m, 5H), 4.87 (s, 1H), 4.53 (d, 2H, J=2.4 Hz ), 3.6-3.7 (m, 3H), 3.5-3.5 (m, 1H), 3.26 (s, 3H), 3.12 (dd, 1H, J=9.2 , 14.0 Hz), 2.42 (ddd, 2H, J=4.0, 7.7, 11.5 Hz), 1.3-1.4 (m, 1H), 1.0-1, 0 (m, 1H)

Preparation of Example 26: N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7-(2-methylthiazole -5-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.

The title compound was prepared according to General Procedure D using 5-bromo-2-methylthiazole as the coupling agent. As a result of the experiment, we obtained the title compound, N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7 -(2-methylthiazol-5-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. The sample was analyzed using LC-MS method C: retention time = 1.34 min; observed ion = 902.7 (M+H). 1H NMR (METHANOL-d4, 500 MHz) δ 8.32 (br d, 1H, J=8.0 Hz), 8.22 (s, 1H), 8.06 (s, 1H), 7.94 ( br d, 1H, J=8.0 Hz), 7.30 (br d, 1H, J=7.2 Hz), 7.20 (br d, 1H, J=8.0 Hz), 6.6 -6.8 (m, 4H), 4.5-4.6 (m, 3H), 3.62 (s, 3H), 3.5-3.5 (m, 1H), 3.2-3 .3 (m, 3H), 3.1-3.1 (m, 1H), 2.82 (s, 3H), 2.44 (br dd, 2H, J=3.0, 6.0 Hz) , 1.37 (br d, 1H, J=6.3 Hz), 1.0-1.0 (m, 1H)

Preparation of Example 27: N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7-(2-( N-methylmethylsulfonamido)phenyl)-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.

The title compound was prepared according to General Procedure D using N-(2-bromophenyl)-N-methylmethanesulfonamide as the coupling agent. As a result of the experiment, we obtained the title compound, N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7 -(2-(N-methylmethylsulfonamido)phenyl)-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. The sample was analyzed using LC-MS method C: retention time = 1.35 min; observed ion = 988.9 (M+H). 1H NMR (METHANOL-d4, 500 MHz) δ 8.34 (d, 1H, J=8.1 Hz), 7.99 (d, 1H, J=1.2 Hz), 7.74 (dd, 1H , J=1.6, 8.2 Hz), 7.6-7.7 (m, 1H), 7.6-7.6 (m, 3H), 7.31 (d, 1H, J=7 ,7 Hz), 7.20 (d, 1H, J=8.0 Hz), 6.8-6.8 (m, 1H), 6.63 (dd, 2H, J=2.2, 8, 2 Hz), 6.69 (br t, 1H,.1=54.8 Hz), 4.8-4.8 (m, 1H), 4.54 (d, 2H, J=3.0 Hz) , 3.6-3.7 (m, 3H), 3.5-3.5 (m, 1H), 3.2-3.3 (m, 6H), 3.11 (dd, 1H, J= 9.1, 13.9 Hz), 2.9-3.0 (m, 3H), 2.4-2.5 (m, 2H), 1.36 (br d, 1H, J=7.5 Hz), 1.0-1.0 (m, 1H)

Preparation of Example 28: N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7-(3-( N-methylmethylsulfonamido)phenyl)-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.

The title compound was prepared according to General Procedure D using N-(3-bromophenyl)-N-methylmethanesulfonamide as the coupling agent. As a result of the experiment, we obtained the title compound, N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7 -(3-(N-methylmethylsulfonamido)phenyl)-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. The sample was analyzed using LC-MS method C: retention time = 1.36 min; observed ion = 988.8 (M+H). 1H NMR (METHANOL-d4, 500 MHz) δ 8.39 (d, 1H, J=8.3 Hz), 8.14 (d, 1H, J=1.5 Hz), 7.97 (dd, 1H , J=1.8, 8.3 Hz), 7.90 (t, 1H, J=1.8 Hz), 7.80 (d, 1H, J=7.4 Hz), 7.64 (t , 1H, J=7.7 Hz), 7.6-7.6 (m, 1H), 7.32 (d, 1H, J=7.7 Hz), 7.22 (d, 1H, J= 7.7 Hz), 6.8-6.8 (m, 1H), 6.63 (dd, 2H, J=2.2, 8.2 Hz), 6.70 (br t, 1H, J= 54.7 Hz), 4.8-4.8 (m, 1H), 4.55 (d, 2H, J=6.0 Hz), 3.6-3.6 (m, 3H), 3, 4-3.5 (m, 4H), 3.26 (s, 3H), 3.1-3.2 (m, 1H), 2.99 (s, 3H), 2.4-2.5 ( m, 2H), 1.36 (br d, 1H, J=7.5 Hz), 1.0-1.0 (m, 1H)

Preparation of Example 29: N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7-(4-( N-methylmethylsulfonamido)phenyl)-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.

The title compound was prepared according to General Procedure D using N-(4-bromophenyl)-N-methylmethanesulfonamide as the coupling agent. As a result of the experiment, we obtained the title compound, N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7 -(4-(N-methylmethylsulfonamido)phenyl)-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. The sample was analyzed using LC-MS method C: retention time = 1.35 min; observed ion = 988.8 (M+H). 1H NMR (METHANOL-d4, 500 MHz) δ 8.37 (d, 1H, J=8.3 Hz), 8.14 (d, 1H, J=1.8 Hz), 7.97 (dd, 1H , J=1.8, 8.3 Hz). 7.9-7.9 (m, 2H), 7.6-7.7 (m, 2H), 7.31 (d, 1H, J=7.7 Hz), 7.20 (d, 1H, J=7.7 Hz), 6.8-6.8 (m, 1H), 6.64 (dd, 2H, J=2.2, 8.2 Hz), 6.69 (br t, 1H, J=54.7 Hz), 4.8-4.8 (m, 1H), 4.54 (d, 2H, J=3.6 Hz), 3.63 (s, 3H), 3.5- 3.5 (m, 1H), 3.42 (s, 3H), 3.2-3.3 (m, 3H), 3.12 (dd, 1H, J=9.1, 14.2 Hz) , 2.99 (s, 3H), 2.43 (ddd, 2H, J=4.0, 7.7, 11.5 Hz), 1.36 (br d, 1H, J=7.5 Hz), 1 .01 (td, 1H, J=2.1, 3.6 Hz)

Preparation of Example 30: N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-4-oxo-7- (3-(trifluoromethyl)pyridin-2-yl)-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.

The title compound was prepared according to General Procedure D using 2-chloro-3-(trifluoromethyl)pyridine as the coupling agent. As a result of the experiment, we obtained the title compound, N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-4 -oxo-7-(3-(trifluoromethyl)pyridin-2-yl)-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. The sample was analyzed using LC-MS method C: retention time = 1.4 min; observed ion = 950.8 (M+H). 1H NMR (METHANOL-d4, 500 MHz) δ 8.95 (br d, 1H, J=4.5 Hz), 8.40 (br t, 2H, J=7.6 Hz), 7.99 (s , 1H), 7.7-7.8 (m, 2H), 7.32 (d, 1H, J=7.6 Hz), 7.2-7.3 (m, 1H), 6.5- 6.8 (m, 4H), 4.5-4.6 (m, 2H), 3.66 (s, 3H), 3.4-3.5 (m, 1H), 3.2-3, 3 (m, 3H), 3.19 (s, 1H), 3.1-3.1 (m, 1H), 2.4-2.5 (m, 2H), 1.3-1.4 ( m, 1H), 1.0-1.0 (m, 1H)

Preparation of Example 31: N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-4-oxo-7- (pyridazin-4-yl)-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.

The title compound was prepared according to General Procedure D using 4-bromopyridazine as the coupling agent. As a result of the experiment, we obtained the title compound, N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-4 -oxo-7-(pyridazin-4-yl)-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. The sample was analyzed using LC-MS method C: retention time = 1.2 min; observed ion = 883.5 (M+H). 1H NMR (METHANOL-d4, 500 MHz) δ 9.74 (dd, 1H, J=1.2, 2.4 Hz), 9.39 (dd, 1H, J=1.3, 5.5 Hz) , 8.49 (d, 1H, J=8.6 Hz), 8.37 (d, 1H, J=1.8 Hz), 8.21 (dd, 1H, J=2.5, 5.5 Hz), 8.13 (dd, 1H, J=1.8, 8.3 Hz), 7.32 (d, 1H, J=7.7 Hz), 7.22 (d, 1H, J=7 ,7 Hz), 6.8-6.8 (m, 1H), 6.64 (dd, 2H, J=2.2, 8.2 Hz), 6.69 (t, 1H, J=54, 7 Hz), 4.9-4.9 (m, 1H), 4.53 (s, 2H), 3.63 (s, 3H), 3.51 (dd, 1H, J=5.2, 14 ,2 Hz), 3.25 (s, 3H), 3.1-3.2 (m, 1H), 2.43 (ddd, 2H, J=3.9, 7.7, 11.3 Hz) , 1.37 (br d, 1H, J=7.5 Hz), 1.0-1.0 (m, 1H)

Preparation of Example 32: N-((S)-1-(7-(2-(tert-butylsulfonyl)phenyl)-(3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H- indazol-7-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.

The title compound was prepared according to General Procedure D using 1-bromo-2-(tert-butylsulfonyl)benzene as the coupling agent. As a result of the experiment, we obtained the title compound, N-((S)-1-(7-(2-(tert-butylsulfonyl)phenyl)-(3P)-3-(4-chloro-1-methyl-3-( methylsulfonamido)-1H-indazol-7-yl)-4-oxo-3,4-dihydroquinazolin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3- (difluoromethyl)-5,5-difluoro-3b4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide. The sample was analyzed using LC-MS method C: retention time = 1.44 min; observed ion = 999.5 (M+H). 1H NMR (METHANOL-d4, 500 MHz) δ 8.43 (d, 1H, J=8.3 Hz), 8.28 (t, 1H, J=1.6 Hz), 8.24 (td, 1H , J=1.1, 8.5 Hz), 8.17 (d, 1H, J=1.5 Hz), 8.03 (td, 1H, J=1.5, 7.8 Hz), 8 .00 (dd, 1H, J=1.8, 8.3 Hz), 7.89 (t, 1H, J=7.9 Hz), 7.3-7.3 (m, 1H), 7. 25 (d, 1H, J=8.0 Hz), 6.6-6.8 (m, 4H), 4.8-4.9 (m, 1H), 4.57 (d, 2H, J= 7.2 Hz), 3.63 (s, 3H), 3.47 (s, 1H), 3.2-3.3 (m, 3H), 3.19 (s, 1H), 2.45 ( br s, 2H), 1.42 (s, 9H), 1.3-1.4 (m, 1H), 1.0-1.0 (m, 1H)

Preparation of Example 33: N-((S)-1-(7-(3-(tert-butylsulfonyl)phenyl)-(3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H- indazol-7-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-piclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.

The title compound was prepared according to General Procedure D using 1-bromo-3-(tert-butylsulfonyl)benzene as the coupling agent. As a result of the experiment, we obtained the title compound, N-((S)-1-(7-(3-(tert-butylsulfonyl)phenyl)-(3P)-3-(4-chloro-1-methyl-3-( methylsulfonamido)-1H-indazol-7-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. The sample was analyzed using LC-MS method C: retention time = 1.44 min; observed ion = 1001.3 (M+H). 1H NMR (METHANOL-d4, 500 MHz) δ 8.27 (d, 1H, J=8.3 Hz), 8.18 (dd, 1H, J=1.2, 8.0 Hz), 7.9 -7.9 (m, 2H), 7.78 (dt, 1H, J=1.5, 7.7 Hz), 7.6-7.7 (m, 1H), 7.52 (dd, 1H , J=1.2, 7.7 Hz), 7.31 (br d, 1H, J=7.7 Hz), 6.8-6.8 (m, 1H), 6.63 (br d, 1H, J=6.0 Hz), 6.69 (br t, 2H, J=54.8 Hz), 4.9-5.0 (m, 1H), 4.8-4.9 (m, 1H), 4.53 (s, 2H), 3.66 (s, 3H), 3.5-3.5 (m, 1H), 3.2-3.3 (m, 3H), 3.09 (dd, 1H, J=8.9, 14.0 Hz), 2.4-2.5 (m, 2H), 1.37 (br d, 1H, J=7.5 Hz), 1.21 (s, 9H), 1.0-1.0 (m, 1H)

Preparation of Example 34: N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7-(5-methoxypyrimidine -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.

The title compound was prepared according to General Procedure D using 2-chloro-5-methoxypyrimidine as the coupling agent. As a result of the experiment, we obtained the title compound, N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7 -(5-methoxypyrimidin-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. The sample was analyzed using LC-MS method C: retention time = 1.4 min; observed ion = 913.4 (M+H). 1H NMR (METHANOL-d4, 500 MHz) δ 8.86 (s, 1H), 8.70 (s, 2H), 8.63 (dd, 1H, J=1.8, 8.3 Hz), 8 .37 (d, 1H, J=8.0 Hz), 7.31 (d, 1H, J=7.7 Hz), 7.22 (d, 1H, J=8.0 Hz), 6.6 -6.8 (m, 4H), 4.9-4.9 (m, 1H), 4.55 (d, 2H, J=2.7 Hz), 4.08 (s, 3H), 3, 64 (s, 3H), 3.5-3.5 (m, 1H), 3.2-3.3 (m, 3H), 3.1-3.2 (m, 1H), 2.4- 2.5 (m, 2H), 1.3-1.4 (m, 1H), 1.02 (tdd, 1H, J=2.0, 3.8, 5.6 Hz)

Preparation of Example 35: N-((S)-1-(7-(6-(tert-butyl)pyridin-2-yl)-(3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido )-1H-indazol-7-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.

The title compound was prepared according to General Procedure D using 2-(tert-butyl)-6-chloropyridine as the coupling agent. As a result of the experiment, we obtained the title compound, N-((S)-1-(7-(6-(tert-butyl)pyridin-2-yl)-(3P)-3-(4-chloro-1-methyl -3-(methylsulfonamido)-1H-indazol-7-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. The sample was analyzed using LC-MS method C: retention time = 1.65 min; observed ion = 938.4 (M+H). 1H NMR (METHANOL-d4, 500 MHz) δ 8.69 (d, 1H, J=1.5 Hz), 8.4-8.4 (m, 2H), 7.9-7.9 (m, 2H), 7.54 (dd, 1H, J=1.2, 7.5 Hz), 7.32 (d, 1H, J=7.7 Hz), 7.23 (d, 1H, J=7 ,7 Hz), 6.8-6.8 (m, 1H), 6.6-6.7 (m, 2H), 6.69 (t, 1H, J=54.7 Hz), 4.8 -4.9 (m, 1H), 4.5-4.6 (m, 2H), 3.63 (s, 3H), 3.5-3.5 (m, 1H), 3.2-3 .3 (m, 3H), 3.1-3.2 (m, 1H), 2.4-2.5 (m, 2H), 1.51 (s, 9H), 1.3-1.4 (m, 1H), 1.01 (td, 1H, J=2.0, 3.7 Hz)

Preparation of Example 36: N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7-(4-ethyl) -6-methylpyrimidin-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.

The title compound was prepared according to General Procedure D using 2-chloro-4-ethyl-6-methylpyrimidine as a coupling agent. As a result of the experiment, we obtained the title compound, N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7 -(4-ethyl-6-methylpyrimidin-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. The sample was analyzed using LC-MS method C: retention time = 1.55 min; observed ion = 925.4 (M+H). 1H NMR (METHANOL-d4, 500 MHz) δ 8.95 (d, 1H, J=1.5 Hz), 8.70 (dd, 1H, J=1.5, 8.3 Hz), 8.39 (d, 1H, J=8.3 Hz), 7.32 (d, 1H, J=8.0 Hz), 7.29 (s, 1H), 7.23 (d, 1H, J=7, 7 Hz), 6.8-6.8 (m, 1H), 6.64 (dd, 2H, J=2.2, 8.2 Hz), 6.71 (br t, 1H, J=54, 8 Hz), 4.9-4.9 (m, 1H), 4.56 (d, 2H, J=6.0 Hz), 3.64 (s, 3H), 3.5-3.5 ( m, 1H), 3.2-3.3 (m, 3H), 3.13 (dd, 1H, J=9.2, 14.0 Hz), 2.92 (q, 2H, J=7, 7 Hz), 2.65 (s, 3H), 2.4-2.5 (m, 2H), 1.4-1.5 (m, 3H), 1.3-1.4 (m, 1H ), 1.02 (td, 1H, J=2.0, 3.7 Hz)

Preparation of Example 37: N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7-(4-isopropyl) -6-methylpyrimidin-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.

The title compound was prepared according to General Procedure D using 2-chloro-4-isopropyl-6-methylpyrimidine as a coupling agent. As a result of the experiment, we obtained the title compound, N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7 -(4-isopropyl-6-methylpyrimidin-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. The sample was analyzed using LC-MS method C: retention time = 1.61 min; observed ion = 939.4 (M+H). 1H NMR (METHANOL-d4, 500 MHz) δ 8.97 (s, 1H), 8.72 (dd, 1H, J=1.5, 8.3 Hz), 8.40 (d, 1H, J= 8.0 Hz), 7.2-7.3 (m, 3H), 6.8-6.8 (m, 1H), 6.6-6.7 (m, 2H), 6.70 (br t, 1H, J=54.7 Hz), 4.8-4.9 (m, 1H), 4.6-4.6 (m, 2H), 3.64 (s, 3H), 3.5 -3.5 (m, 1H), 3.2-3.3 (m, 3H), 3.1-3.2 (m, 1H), 2.65 (s, 3H), 2.44 (br s, 2H), 1.43 (d, 6H, J=7.2 Hz), 1.3-1.4 (m, 2H), 1.02 (td, 1H, J=2.0, 3, 5 Hz)

Preparation of Example 38: N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7-(4,6 -diethylpyrimidin-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.

The title compound was prepared according to General Procedure D using 2-chloro-4,6-diethylpyrimidine as a coupling agent. As a result of the experiment, we obtained the title compound, N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7 -(4,6-diethylpyrimidin-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. The sample was analyzed using LC-MS method C: retention time = 1.62 min; observed ion = 939.5 (M+H). 1H NMR (METHANOL-d4, 500 MHz) δ 8.97 (d, 1H, J=1.2 Hz), 8.73 (dd, 1H, J=1.5, 8.3 Hz), 8.40 (d, 1H, J=8.3 Hz), 7.2-7.3 (m, 3H), 6.8-6.8 (m, 1H), 6.64 (dd, 2H, J=2 ,2, 8.2 Hz), 6.71 (brt, 1H, J=54.8 Hz), 4.8-4.9 (m, 1H), 4.5-4.6 (m, 2H) , 3.64 (s, 3H), 3.5-3.5 (m, 1H), 3.2-3.3 (m, 3H), 3.1-3.2 (m, 1H), 2 .93 (q, 4H, J=7.5 Hz), 2.4-2.5 (m, 2H), 1.44 (t, 6H, J=7.6 Hz), 1.3-1, 4 (m, 1H), 1.0-1.0 (m, 1H)

Preparation of Example 39: N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7-(2-methoxypyrimidine -5-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.

The title compound was prepared according to General Procedure D using 5-bromo-2-methoxypyrimidine as a coupling agent. As a result of the experiment, we obtained the title compound, N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7 -(2-methoxypyrimidin-5-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. The sample was analyzed using LC-MS method C: retention time = 1.33 min; observed ion = 913.4 (M+H). 1H NMR (METHANOL-d4, 500 MHz) δ 9.07 (s, 2H), 8.41 (d, 1H, J=8.1 Hz), 8.18 (d, 1H, J=1.5 Hz ), 7.98 (dd, 1H, J=1.8, 8.3 Hz), 7.31 (d, 1H, J=8.0 Hz), 7.21 (d, 1H, J=7, 7 Hz), 6.6-6.8 (m, 4H), 4.9-5.0 (m, 1H), 4.5-4.5 (m, 2H), 4.14 (s, 3H ), 3.63 (s, 3H), 3.5-3.5 (m, 1H), 3.2-3.3 (m, 3H), 3.1-3.2 (m, 1H), 2.44 (ddd, 2H, J=4.0, 7.7, 11.5 Hz), 1.3-1.4 (m, 1H), 1.0-1.0 (m, 1H)

Preparation of Example 40: N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7-(4,6 -dimethylpyrimidin-5-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.

The title compound was prepared according to General Procedure D using 5-bromo-4,6-dimethylpyrimidine as a coupling agent. As a result of the experiment, we obtained the title compound, N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7 -(4,6-dimethylpyrimidin-5-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. The sample was analyzed using LC-MS method C: retention time = 1.264 min; observed ion = 911.4 (M+H). 1H NMR (METHANOL-d4, 500 MHz) δ 8.98 (s, 1H), 8.45 (d, 1H, J=8.0 Hz), 7.83 (d, 1H, J=1.2 Hz ), 7.59 (dd, 1H, J=1.6. 8.2 Hz), 7.3-7.3 (m, 2H), 6.8-6.8 (m, 1H), 6, 63 (dd, 2H, J=2.2, 8.2 Hz), 6.69 (br t, 1H, J=54.7 Hz), 4.9-4.9 (m, 1H), 4, 54 (d, 2H, J=4.2 Hz), 3.67 (s, 3H), 3.4-3.5 (m, 1H), 3.2-3.3 (m, 3H), 3 .11 (dd, 1H, J=9.4, 14.2 Hz), 2.4-2.4 (m, 8H), 1.3-1.4 (m, 1H), 1.0-1 .0 (m, 1H)

Preparation of Example 41: N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7-(6-cyclopropylpyridine -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.

The title compound was prepared according to General Procedure D using 2-chloro-6-cyclopropylpyridine as a coupling agent. As a result of the experiment, we obtained the title compound, N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7 -(6-cyclopropylpyridin-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. The sample was analyzed using LC-MS method C: retention time = 1.55 min; observed ion = 922.4 (M+H). 1H NMR (METHANOL-d4, 500 MHz) δ 8.58 (d, 1H, J=1.8 Hz), 8.4-8.4 (m, 1H), 8.3-8.3 (m, 1H), 7.8-7.9 (m, 2H), 7.3-7.4 (m, 2H), 7.22 (d, 1H, J=8.0 Hz), 6.5-6 .8 (m, 4H), 4.5-4.6 (m, 3H), 3.63 (s, 3H), 3.5-3.5 (m, 1H), 3.2-3.3 (m, 3H), 3.13 (dd, 1H, J=9.4, 14.2 Hz), 2.43 (dt, 2H, J=2.1,4.9 Hz), 2.2- 2.2 (m, 1H), 1.3-1.4 (m, 1H), 1.1-1.2 (m, 2H), 1.1-1.1 (m, 2H), 1, 0-1.0 (m, 1H)

Preparation of Example 42: N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7-(4-methylpyrimidine -5-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.

The title compound was prepared according to General Procedure D using 5-bromo-4-methylpyrimidine as a coupling agent. As a result of the experiment, we obtained the title compound, N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7 -(4-methylpyrimidin-5-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. The sample was analyzed using LC-MS method C: retention time = 1.27 min; observed ion = 897.4 (M+H). 1H NMR (METHANOL-d4, 500 MHz) δ 9.13 (s, 1H), 8.76 (s, 1H), 8.44 (d, 1H, J=8.0 Hz), 7.97 (d , 1H, J=1.8 Hz), 7.74 (dd, 1H, J=1.6, 8.2 Hz), 7.33 (d, 1H, J=7.7 Hz), 7.25 (d, 1H, J=7.7 Hz), 6.8-6.8 (m, 1H), 6.63 (dd, 2H, J=2.2, 8.2 Hz), 6.69 ( t, 1H, J=54.7 Hz), 4.8-4.9 (m, 1H), 4.53 (d, 2H, J=2.7 Hz), 3.65 (s, 3H), 3.5-3.5 (m, 1H), 3.2-3.3 (m, 3H), 3.12 (dd, 1H, J=9.2, 14.3 Hz), 2.63 ( s, 3H), 2.43 (ddd, 2H, J=4.0, 7.7, 11.5 Hz), 1.3-1.4 (m, 1H), 1.0-1.0 ( m, 1H)

Preparation of Example 43: N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7-(4-ethylpyrimidine -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.

The title compound was prepared according to General Procedure D using 2-chloro-4-ethylpyrimidine as a coupling agent. As a result of the experiment, we obtained the title compound, N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7 -(4-ethylpyrimidin-2-yl)-4-oxo-3,4-digadroquinazolin-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. The sample was analyzed using LC-MS method F: retention time = 1.48 min; observed ion = 911.4 (M+H). 1H NMR (METHANOL-d4, 500 MHz) Shift 8.96 (s, 1H), 8.84 (d, 1H, J=5.1 Hz), 8.71 (dd, 1H, J=1.8, 8.3 Hz), 8.41 (d, 1H, J=8.0 Hz), 7.41 (d, 1H, J=5.1 Hz), 7.32 (br d, 1H, J=7 ,4 Hz), 7.24 (d, 1H, J=7.7 Hz), 6.6-6.8 (m, 4H), 4.56 (d, 3H, J=5.4 Hz), 3.6-3.7 (m, 3H), 3.5-3.5 (m, 1H), 3.25 (s, 3H), 3.13 (dd, 1H, J=9.2, 14 ,0 Hz), 2.98 (q, 2H, J=7.6 Hz), 2.43 (br d, 2H, J=4.5 Hz), 1.46 (t, 3H, J=7, 6 Hz), 1.35 (s, 1H), 1.0-1.0 (m, 1H)

Preparation of Example 44: N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7-(2,6 -dimethylpyrimidin-4-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.

The title compound was prepared according to General Procedure D using 4-chloro-2,6-dimethylpyrimidine as the coupling agent. As a result of the experiment, we obtained the title compound, N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7 -(2,6-dimethylpyrimidin-4-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. The sample was analyzed using LC-MS method F: retention time = 1.35 min; observed ion = 911.4 (M+H). 1H NMR (METHANOL-d4, 500 MHz) Shift 8.67 (s, 1H), 8.4-8.4 (m, 2H), 7.91 (s, 1H), 7.32 (d, 1H, J=7.7 Hz), 7.23 (d, 1H, J=8.0 Hz), 6.7-6.8 (m, 1H), 6.71 (br t, 1H, J=54, 8 Hz), 6.64 (br dd, 2H, J=2.2, 8.2 Hz), 4.54 (d, 2H, J=2.7 Hz), 3.64 (s, 3H), 3.4-3.5 (m, 1H), 3.2-3.3 (m, 3H), 3.1-3.2 (m, 1H), 2.81 (s, 2H), 2, 67 (d, 3H, J=11.0 Hz), 2.44 (br dd, 2H, J=4.3, 8.2 Hz), 1.7-1.8 (m, 1H), 1, 3-1.5 (m, 1H), 1.1-1.2 (m, 1H), 1.01 (brdd, 1H, J=1.9, 3.7 Hz)

Preparation of Example 45: N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7-(5-methoxypyridine -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.

The title compound was prepared according to General Procedure D using 2-chloro-5-methoxypyridine as the coupling agent. As a result of the experiment, we obtained the title compound, N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7 -(5-methoxypyridin-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. The sample was analyzed using LC-MS method F: retention time = 1.4 min; observed ion = 912.4 (M+H). 1H NMR (METHANOL-d4, 500 MHz) Shift 8.46 (s, 1H), 8.47 (d, 2H, J=4.4 Hz), 8.36 (d, 1H, J=8.3 Hz ), 8.25 (dd, 1H, J=1.8, 8.3 Hz), 8.07 (d, 1H, J=8.3 Hz), 7.59 (dd, 1H, J=3, 0, 8.6 Hz), 7.31 (d, 1H, J=7.7 Hz), 7.20 (d, 1H, J=7.7 Hz), 6.79 (br t, 1H, J =2.4 Hz), 6.64 (dd, 2H, J=2.1, 8.0 Hz), 6.70 (t, 1H, J=54.8 Hz), 4.54 (s, 2H ), 4.00 (s, 3H), 3.64 (s, 3H), 3.5-3.5 (m, 1H), 3.2-3.3 (m, 3H), 3.12 ( dd, 1H, 9.1, 14.2 Hz), 2.43 (br dd, J=4.8, 6.9 Hz), 1.3-1.4 (m, 1H), 1.0- 1.0 (m, 1H)

Preparation of Example 46: N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7-(6-isopropylpyridine -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.

The title compound was prepared according to General Procedure D using 2-chloro-6-isopropylpyridine as the coupling agent. As a result of the experiment, we obtained the title compound, N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7 -(6-isopropylpyridin-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. The sample was analyzed using LC-MS method F: retention time = 1.58 min; observed ion = 924.5 (M+H). 1H NMR (METHANOL-d4, 500 MHz) Shift 8.62 (d, 1H, J=1.5 Hz), 8.3-8.4 (m, 2H), 7.91 (s, 1H), 7 .90 (d, 1H, J=2.4 Hz), 7.4-7.4 (m, 1H), 7.31 (d, 1H, J=7.7 Hz), 7.22 (d, 1H, J=7.7 Hz), 6.80 (br t, 1H, J=2.4 Hz), 6.64 (dd, 2H, J=2.1, 8.0 Hz), 6.69 (br t, 1H, J=54.7 Hz), 4.8-4.9 (m, 1H), 4.56 (d, 2H, J=5.7 Hz), 3.63 (s, 3H ), 3.51 (dd, 1H, J=4.9, 14.2 Hz), 3.1-3.3 (m, 5H), 2.4-2.5 (m, 2H), 1, 43 (d, 6H, J=7.2 Hz), 1.36 (br d, 1H, J=5.7 Hz), 1.0-1.0 (m, 1H)

Preparation of Example 47: N-((S)-1-(7-(4-(tert-butyl)pyrimidin-2-yl)-(3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido )-1H-indazol-7-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.

The title compound was prepared according to General Procedure D using 4-(tert-butyl)-2-chloropyrimidine as a coupling agent. As a result of the experiment, we obtained the title compound, N-((S)-1-(7-(4-(Tper-butyl)pyrimidin-2-yl)-(3P)-3-(4-chloro-1-methyl -3-(methylsulfonamido)-1H-indazol-7-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. The sample was analyzed using LC-MS method F: retention time = 1.59 min; observed ion = 939.4 (M+H). 1H NMR (METHANOL-d4, 500 MHz) Shift 8.62 (d, 1H, J=1.2 Hz), 8.4-8.4 (m, 2H), 8.17 (s, 1H), 7 .67 (s, 1H), 7.31 (d, 1H, J=7.7 Hz), 7.23 (d, 1H, J=7.7 Hz), 6.8-6.8 (m, 1H), 6.64 (dd, 2H, J=2.1, 8.0 Hz), 6.71 (br t, 1H, J=54.8 Hz), 4.56 (d, 2H, J= 4.8 Hz), 3.64 (s, 3H), 3.5-3.5 (m, 1H), 3.2-3.3 (m, 3H), 3.1-3.2 (m , 1H), 2.80 (s, 3H), 2.68 (s, 1H), 2.4-2.5 (m, 2H), 1.3-1.4 (m, 1H), 1, 0-1.0 (m, 1H)

Preparation of Example 48: N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7-(6-methyl -4-(trifluoromethyl)pyridin-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.

The title compound was prepared according to General Procedure D using 2-chloro-6-methyl-4-(trifluoromethyl)pyridine as the coupling agent. As a result of the experiment, we obtained the title compound, N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7 -(6-methyl-4-(trifluoromethyl)pyridin-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. The sample was analyzed using LC-MS method F: retention time = 1.57 min; observed ion = 964.4 (M+H). 1H NMR (METHANOL-d4, 500 MHz) Shift 8.62 (d, 1H, J=1.2 Hz), 8.4-8.4 (m, 2H), 8.17 (s, 1H), 7 .67 (s, 1H), 7.31 (d, 1H, J=7.7 Hz), 7.23 (d, 1H, J=7.7 Hz), 6.8-6.8 (m, 1H), 6.64 (dd, 2H, J=2.1, 8.0 Hz), 6.71 (br t, 1H, J=54.8 Hz), 4.56 (d, 2H, J= 4.8 Hz), 3.64 (s, 3H), 3.5-3.5 (m, 1H), 3.2-3.3 (m, 3H), 3.1-3.2 (m , 1H), 2.80 (s, 3H), 2.68 (s, 1H), 2.4-2.5 (m, 2H), 1.3-1.4 (m, 1H), 1, 0-1.0 (m, 1H)

Preparation of Example 49: N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-4-oxo-7- (pyridazin-3-yl)-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.

The title compound was prepared according to General Procedure D using 3-chloropyridazine as the coupling agent. As a result of the experiment, we obtained the title compound, N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-4 -oxo-7-(pyridazin-3-yl)-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. The sample was analyzed using LC-MS method F: retention time = 1.25 min; observed ion = 883.4 (M+H). 1H NMR (METHANOL-d4, 500 MHz) Shift 9.28 (dd, 1H, J=1.5,4.8 Hz), 8.63 (d, 1H, J=1.8 Hz), 8.45 (d, 1H, J=8.3 Hz), 8.37 (dd, 1H, J=6.9, 18.8 Hz), 8.38 (dd, 1H, J=10.3, 18.9 Hz), 7.92 (dd, 1H, J=5.1, 8.6 Hz), 7.29 (d, 1H, J=7.7 Hz), 7.20 (d, 1H, J=8 ,0 Hz), 6.77 (br t, 1H, J=2.4 Hz), 6.62 (dd, 2H, J=2.2, 8.2 Hz), 6.67 (br t, 1H , J=54.8 Hz), 4.9-4.9 (m, 1H), 4.52 (d, 2H, 2.4 Hz), 3.62 (s, 3H), 3.4-3 .6 (m, 1H), 3.23 (s, 3H), 3.12 (dd, 1H, 9.2, 14.0 Hz), 2.4-2.0 (m, 2H), 1, 33 (s, 1H), 1.0-1.0 (m, 1H)

Preparation of Example 50: N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7-(6-methylpyridazine -3-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.

The title compound was prepared according to General Procedure D using 3-chloro-6-methylpyridazine as the coupling agent. As a result of the experiment, we obtained the title compound, N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7 -(6-methylpyridazin-3-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. The sample was analyzed using LC-MS method F: retention time = 1.27 min; observed ion = 897.4 (M+H). 1H NMR (METHANOL-d4, 500 MHz) Shift 8.63 (d, 1H, J=1.5 Hz), 8.46 (d, 1H, J=8.3 Hz), 8.36 (dd, 1H , J=1.8, 8.3 Hz), 8.31 (d, 1H, J=8.6 Hz), 7.82 (d, 1H, J=8.6 Hz), 7.31 (d , 1H, J=7.7 Hz), 7.23 (d, 1H, J=7.7 Hz), 6.8-6.8 (m, 1H), 6.64 (dd, 2H, J= 2.1, 8.0 Hz), 6.70 (br t, 1H, J=54.7 Hz), 4.9-5.0 (m, 1H), 4.8-4.9 (m, 1H), 4.54 (d, 2H, J=1.5 Hz), 3.64 (s, 3H), 3.5-3.5 (m, 1H), 3.14 (dd, 1H, J =9.4, 13.9 Hz), 2.82 (s, 3H), 2.68 (s, 2H), 2.4-2.5 (m, 2H), 1.3-1.4 ( m, 1H), 1.0-1.0 (m, 1H)

Preparation of Example 51: N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7-(4-methylpyridazine -3-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.

The title compound was prepared according to General Procedure D using 3-chloro-4-methylpyridazine as the coupling agent. As a result of the experiment, we obtained the title compound, N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7 -(4-methylpyridazin-3-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. The sample was analyzed using LC-MS method F: retention time = 1.25 min; observed ion = 897.4 (M+H). 1H NMR (METHANOL-d4, 500 MHz) δ 9.15 (d, 1H, J=5.4 Hz), 8.47 (d, 1H, J=8.1 Hz), 8.1-8.1 (m, 1H), 7.88 (d, 1H, J=8.1 Hz), 7.80 (d, 1H, J=5.6 Hz). 7.33 (d, 1H, J=7.7 Hz), 7.25 (d, 1H, J=7.7 Hz), 6.6-6.8 (m, 4H), 4.8-4 .8 (m, 1H), 4.53 (d, 2H, J=2.7 Hz), 3.6-3.7 (m, 3H), 3.4-3.5 (m, 1H), 3.2-3.3 (m, 3H), 3.12 (dd, 1H, J=9.2, 14.0 Hz), 2.51 (s, 3H), 2.4-2.5 ( m, 2H), 1.36 (s, 1H),1.0-1.0(m, 1H)

Preparation of Example 52: N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7-(4,6 -dimethyl-3-(trifluoromethyl)pyridin-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.

The title compound was prepared according to General Procedure D using 2-chloro-4,6-dimethyl-3-(trifluoromethyl)pyridine as the coupling agent. As a result of the experiment, we obtained the title compound, N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7 -(4,6-dimethyl-3-(trifluoromethyl)pyridin-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 The sample was analyzed using LC-MS method F: retention time = 1.51 min; observed ion = 978.4 (M+H). 1H NMR (METHANOL-d4, 500 MHz) Shift 8.37 (d, 1H, J=8.0 Hz), 7.87 (d, 1H, J=1.8 Hz), 7.67 (dd, 1H , J=1.8, 8.0 Hz), 7.46 (s, 1H), 7.31 (d, 1H, J=7.7 Hz), 7.23 (d, 1H, J=8, 0 Hz), 6.7-6.8 (m, 1H), 6.69 (brt, 1H, J=54.7 Hz), 6.62 (br dd, 2H, J=2.2, 8, 2 Hz), 4.54 (d, 2H, J=4.5 Hz), 3.64 (s, 3H), 3.4-3.5 (m, 1H), 3.25 (s, 3H) , 3.10 (dd, 1H, J=9.2, 14.0 Hz), 2.6-2.7 (m, 7H), 2.42 (td, 2H, J=3.7, 7, 5 Hz), 1.3-1.4 (m, 1H), 1.01 (br dd, 1H, J=1.6, 3.7 Hz)

Preparation of Example 53: N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7-(4-methyl -6-(trifluoromethyl)pyrimidin-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.

The title compound was prepared according to General Procedure D using 2-chloro-4-methyl-6-(trifluoromethyl)pyrimidine as a coupling agent. As a result of the experiment, we obtained the title compound, N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7 -(4-methyl-6-(trifluoromethyl)pyrimidin-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. The sample was analyzed using LC-MS method F: retention time = 1.54 min; observed ion = 963.4 (M+H). 1H NMR (METHANOL-d4, 500 MHz) Shift 9.01 (d, 1H, J=1.8 Hz), 8.75 (dd, 1H, J=1.8,8.3 Hz), 8.44 (d, 1H, J=8.3 Hz), 7.83 (s, 1H), 7.32 (d, 1H, J=8.0 Hz), 7.25 (d, 1H, J=7, 7 Hz), 6.8-6.8 (m, 1H), 6.70 (br t, 1H, J=54.7 Hz), 6.64 (dd, 2H, J=2.2, 8, 2 Hz), 4.5-4.6 (m, 2H), 3.64 (s, 3H), 3.5-3.5 (m, 1H), 3.2-3.3 (m, 3H ), 3.1-3.2 (m, 1H), 2.82 (s, 3H), 2.68 (s, 1H), 2.4-2.5 (m, 2H), 1.36 ( br dd, 1H, J=1.3, 7.0 Hz), 1.02 (td, 1H, J=2.0, 3.5 Hz)

Preparation of Example 54: N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7-(4-methoxy -6-(trifluoromethyl)pyrimidin-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.

The title compound was prepared according to General Procedure D using 2-chloro-4-methoxy-6-(trifluoromethyl)pyrimidine as a coupling agent. As a result of the experiment, we obtained the title compound, N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7 -(4-methoxy-6-(trifluoromethyl)pyrimidin-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. The sample was analyzed using LC-MS method F: retention time = 1.58 min; observed ion = 979.4 (M-H). 1H NMR (METHANOL-d4, 500 MHz) Shift 9.0-9.0 (m, 1H), 8.71 (dd, 1H, J=1.8, 8.3 Hz), 8.42 (d, 1H, J=8.0 Hz), 7.3-7.3 (m, 1H), 7.2-7.2 (m, 1H), 6.7-6.8 (m, 1H), 6 .67 (br t, 1H, J=54.7 Hz), 6.60 (br dd, 2H, J=2.1, 8.0 Hz), 4.5-4.6 (m, 2H), 4.27 (s, 2H), 3.61 (s, 4H), 3.4-3.5 (m, 2H), 3.3-3.4 (m, 1H), 3.22 (s, 2H), 3.1-3.1 (m, 1H), 2.4-2.5 (m, 2H), 1.34 (br dd, 1H, J=1.3, 6.7 Hz), 0.99 (br dd, 1H, J=1.8, 3.3 Hz), 0.0-0.0 (m, 1H)

Preparation of Example 55: N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7-(5,6 -dimethyl-1,2,4-triazin-3-yl)-4-oxo-3,4-dihydroquinazolin-2-yl)-2-(3,5-difluorophenyl)ztyl)-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.

The title compound was prepared according to General Procedure D using 3-chloro-5,6-dimethyl-1,2,4-triazine as a coupling agent. As a result of the experiment, we obtained the title compound, N-((S)-1-((3 P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)- 7-(5,6-dimethyl-1,2,4-triazin-3-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]pyrazole-1- yl)acetamide. The sample was analyzed using LC-MS method F: retention time = 1.36 min; observed ion = 910.3 (M-H). 1H NMR (METHANOL-d4, 500 MHz) Shift 8.95 (d, 1H, J=1.8 Hz), 8.69 (dd, 1H, J=1.8, 8.3 Hz), 8.42 (d, 1H, J=8.0 Hz), 7.28 (d, 1H, J=8.0 Hz), 7.21 (d, 1H, J=8.0 Hz), 6.7-6 .8 (m, 1H), 6.68 (br t, 2H, J=54.8 Hz), 6.61 (dd, 2H, J=2.2, 8.2 Hz), 4.5-4 .6 (m, 2H), 3.61 (s, 3H), 3.4-3.5 (m, 1H), 3.22 (s, 3H), 3.10 (dd, 1H, J=9 ,1, 14.2 Hz), 2.78 (s, 3H), 2.73 (s, 3H), 2.42 (br d, 1H, J=4.5 Hz), 1.34 (br dd , 2H, J=1.2, 6.9 Hz), 0.99 (td, 1H, J=2.1, 3.6 Hz)

Preparation of Example 56: N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7-(4-( difluoromethyl)pyrimidin-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.

The title compound was prepared according to General Procedure D using 2-chloro-4-(difluoromethyl)pyrimidine as the coupling agent. As a result of the experiment, we obtained the title compound, N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7 -(4-(difluoromethyl)pyrimidin-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. The sample was analyzed using LC-MS method F: retention time = 1.43 min; observed ion = 933.4 (M+H). 1H NMR (METHANOL-d4, 500 MHz) Shift 9.19 (d, 1H, J=5.1 Hz), 8.98 (s, 1H), 8.73 (dd, 1H, J=1.8, 8.3 Hz), 8.41 (d, 1H, J=8.0 Hz), 7.76 (d, 1H, J=5.1 Hz), 7.29 (d, 1H, J=7, 7 Hz), 7.21 (d. 1H, J=7.7 Hz), 6.6-7.0 (m, 5H), 4.9-4.9 (m, 1H), 4.54 ( d, 2H, J=6.3 Hz), 3.61 (s, 3H), 3.4-3.5 (m, 1H), 3.23 (s, 3H), 3.11 (dd, 1H , J=9.4, 14.2 Hz), 2.4-2.5 (m, 2H), 1.34 (br dd, 1H,.1=1.2,6.9 Hz), 1, 0-1.0 (m, 1H)

Preparation of Example 57: N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7-(4-methoxy -6-methylpyridin-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.

The title compound was prepared according to General Procedure D using 2-chloro-4-methoxy-6-methylpyridine as a coupling agent. As a result of the experiment, we obtained the title compound, N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7 -(4-methoxy-6-methylpyridin-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. The sample was analyzed using LC-MS method F: retention time = 1.2 min; observed ion = 926.4 (M+H). 1H NMR (METHANOL-d4, 500 MHz) Shift 8.41 (d, 1H, J=1.8 Hz), 8.36 (d, 1H, J=8.1 Hz), 8.19 (dd, 1H , J=1.5, 8.3 Hz), 7.37 (d, 1H, J=2.4 Hz), 7.28 (d, 1H, J=8.0 Hz), 7.1-7 ,2 (m, 1H), 6.94 (d, 1H, J=1.8 Hz), 6.77 (br d, 1H, J=2.4 Hz), 6.68 (br t, 1H, J=54.7 Hz), 6.61 (br dd, 2H, J=2.4, 8.3 Hz), 4.8-4.9 (m, 1H), 4.7-4.8 ( m, 1H), 4.5-4.6 (m, 2H), 3.98 (s, 2H), 3.6-3.6 (m, 3H), 3.4-3.5 (m, 1H), 3.2-3.2 (m, 3H), 3.09 (dd, 1H, J=9.1, 14.2 Hz), 2.63 (d, 3H, J=17.6 Hz ), 2.41 (br dd, 2H, J=4.0, 7.6 Hz), 1.34 (br d, 1H, J=5.7 Hz), 0.99 (br dd, 1H, J =1.8, 3.3 Hz)

Preparation of Example 58: N-((S)-1-(7-(4,6-bis(trifluoromethyl)pyridin-2-yl)-(3P)-3-(4-chloro-1-methyl-3-( methylsulfonamido)-1H-indazol-7-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.

The title compound was prepared according to General Procedure D using 2-chloro-4,6-bis(trifluoromethyl)pyridine as the coupling agent. As a result of the experiment, we obtained the title compound, N-((S)-1-(7-(4,6-bis(trifluoromethyl)pyridin-2-yl)-(3P)-3-(4-chloro-1- methyl-3-(methylsulfonamido)-1H-indazol-7-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. The sample was analyzed using LC-MS method F: retention time = 1.6 min; observed ion = 1016.5 (M-H). 1H NMR (METHANOL-d4, 500 MHz) Shift 8.72 (t, 1H, J=1.2 Hz), 8.70 (s, 1H), 8.45 (d, 2H, J=1.2 Hz ), 8.19 (s, 1H), 7.27 (d, 1H, J=7.9 Hz), 7.20 (d, 1H, J=7.7 Hz), 6.7-6.8 (m, 1H), 6.67 (br t, 1H, J=54.7 Hz), 6.61 (dd, 2H, J=2.1, 8.0 Hz), 4.9-4.9 (m, 1H), 4.54 (d, 2H, J=7.2 Hz), 3.61 (s, 3H), 3.4-3.5 (m, 1H), 3.22 (s, 3H), 3.11 (dd, 1H, J=9.2, 14.3 Hz), 2.41 (br dd, 2H, J=3.6, 7.2 Hz), 1.3-1, 4 (m, 1H), 0.99 (br dd, 1H, J=1.8, 3.9 Hz)

Preparation of Example 59: N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-4-oxo-7- (6-(trifluoromethyl)pyridin-2-yl)-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.

The title compound was prepared according to General Procedure D using 2-chloro-6-(trifluoromethyl)pyridine as the coupling agent. As a result of the experiment, we obtained the title compound, N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-4 -oxo-7-(6-(trifluoromethyl)pyridin-2-yl)-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. The sample was analyzed using LC-MS method F: retention time = 1.51 min; observed ion = 948.4 (M-H). 1H NMR (METHANOL-d4, 500 MHz) Shift 8.66 (s, 1H), 8.4-8.4 (m, 3H), 8.22 (t, 1H, J=7.9 Hz), 7 .88 (d, 1H, J=7.7 Hz), 7.28 (br d, 1H, J=8.0 Hz), 7.20 (d, 1H, J=7.7 Hz), 6, 7-6.8 (m, 1H), 6.61 (dd, 2H, J=2.2, 8.2 Hz), 6.67 (br t, 2H, J=54.7 Hz), 4, 5-4.6 (m, 2H), 3.61 (s, 3H), 3.4-3.5 (m, 1H), 3.2-3.2 (m, 3H), 3.1- 3.2 (m, 1H), 2.41 (br dd, 2H, J=3.7, 7.3 Hz), 1.34 (br d, 1H, J=5.4 Hz), 0.99 (br dd, 1H, J=1.9, 3.7 Hz)

Preparation of Example 60: N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7-(4-ethylpyrimidine -5-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.

The title compound was prepared according to General Procedure D using 5-bromo-4-ethylpyrimidine as a coupling agent. As a result of the experiment, we obtained the title compound, N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7 -(4-ethylpyrimidin-5-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. The sample was analyzed using LC-MS method F: retention time = 1.32 min; observed ion = 911.4 (M+H). 1H NMR (METHANOL-d4, 500 MHz) Shift 9.16 (s, 1H), 8.70 (s, 1H), 8.41 (br d, 1H, J=8.3 Hz), 7.90 ( s, 1H), 7.69 (br d, 1H, J=7.7 Hz), 7.29 (br s, 1H), 7.2-7.3 (m, 1H), 6.6-6 .8 (m, 4H), 4.52 (br s, 2H), 3.62 (s, 3H), 3.4-3.5 (m, 1H), 3.23 (br s, 3H), 3.1-3.1 (m, 1H), 2.89 (br d, 2H, J=7.7 Hz), 2.4-2.4 (m, 2H), 1.34 (br d, 1H, J=6.0 Hz), 1.28 (brt, 4H, J=7.5 Hz), 1.0-1.0 (m, 1H)

Preparation of Example 61: N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7-(3-cyclopropylpyrazine -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.

The title compound was prepared according to General Procedure D using 2-chloro-3-cyclopropylpyrazine as the coupling agent. As a result of the experiment, we obtained the title compound, N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7 -(3-cyclopropylpyrazin-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. The sample was analyzed using LC-MS method F: retention time = 1.44 min; observed ion = 923.3 (M+H). 1H NMR (METHANOL-d4, 500 MHz) Shift 8.5-8.6 (m, 1H), 8.47 (d, 1H, J=2.4 Hz), 8.42 (d, 1H, J= 8.1 Hz), 8.18 (d, 1H, J=1.8 Hz), 7.9-8.0 (m, 1H), 7.28 (d, 1H, J=7.7 Hz) , 7.21 (d, 1H, J=7.7 Hz), 6.7-6.8 (m, 1H), 6.61 (dd, 2H, J=2.4, 8.0 Hz), 6.66 (t, 1H, J=54.8 Hz), 4.8-4.9 (m, 1H), 4.53 (d, 2H, J=4.2 Hz), 3.62 (s , 3H), 3.4-3.5 (m, 1H), 3.22 (s, 3H), 3.09 (dd, 1H, J=9.2, 14.0 Hz), 2.40 ( br dd, 2H, J=4.3, 7.3 Hz), 2.24 (s, 1H), 1.34 (br d, 1H, J=5.7 Hz), 1.25 (qd, 2H , J=3.2, 4.7 Hz), 1.0-1.1 (m, 2H), 0.9-1.0 (m, 1H)

Preparation of Example 62: N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7-(6-ethyl) -2-methylpyrimidin-4-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.

The title compound was prepared according to General Procedure D using 4-chloro-6-ethyl-2-methylpyrimidine as a coupling agent. As a result of the experiment, we obtained the title compound, N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7 -(6-ethyl-2-methylpyrimidin-4-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. The sample was analyzed using LC-MS method F: retention time = 1.43 min; observed ion = 925.4 (M+H). 1H NMR (METHANOL-d4, 500 MHz) δ 8.65 (s, 1H), 8.4-8.4 (m, 2H), 7.87 (s, 1H), 7.28 (d, 1H, J=7.5 Hz), 7.21 (d, 1H, J=7.7 Hz), 6.6-6.8 (m, 4H), 4.52 (d, 2H, J=3.3 Hz), 3.61 (s, 3H), 3.48 (br dd, 3H, J=4.9, 14.2 Hz), 3.23 (s, 2H), 3.0-3.1 ( m, 1H), 2.9-2.9 (m, 2H), 2.79 (s, 3H), 2.4-2.5 (m, 2H), 1.40 (t, 4H, J= 7.6 Hz), 0.9-1.0 (m, 1H)

Preparation of Example 63: N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7-(2-methyl -6-(trifluoromethyl)pyrimidin-4-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.

The title compound was prepared according to General Procedure D using 4-chloro-2-methyl-6-(trifluoromethyl)pyrimidine as the coupling agent. As a result of the experiment, we obtained the title compound, N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7 -(2-methyl-6-(trifluoromethyl)pyrimidin-4-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. The sample was analyzed using LC-MS method F: retention time = 1.51 min; observed ion = 963.3 (M-H). 1H NMR (METHANOL-d4, 500 MHz) Shift 8.75 (s, 1H), 8.4-8.5 (m, 2H), 8.36 (s, 1H), 7.28 (br d, 1H , J=8.0 Hz), 7.21 (d, 1H, J=8.0 Hz), 6.6-6.8 (m, 4H), 4.52 (d, 2H, J=4, 2 Hz), 3.60 (s, 3H), 3.48 (dd, 1H, J=4.9, 14.2 Hz), 3.26 (br s, 1H), 3.22 (s, 3H ), 3.11 (dd, 1H, J=9.2, 14.3 Hz), 2.92 (s, 3H), 2.42 (br dd, 2H, J=4.0, 8.2 Hz ), 1.3-1.4 (m, 1H), 1.0-1.0(m, 1H)

Preparation of Example 64: N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7-(5-fluoro -2-methylpyrimidin-4-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.

The title compound was prepared according to General Procedure D using 4-chloro-5-fluoro-2-methylpyrimidine as a coupling agent. As a result of the experiment, we obtained the title compound, N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7 -(5-fluoro-2-methylpyrimidin-4-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. The sample was analyzed using LC-MS method F: retention time = 1.39 min; observed ion = 913.4 (M-H). 1H NMR (METHANOL-d4, 500 MHz) Shift 8.78 (d, 1H, J=3.3 Hz), 8.59 (s, 1H), 8.4-8.4 (m, 1H), 8 .35 (d, 1H, J=8.3 Hz), 7.30 (d, 1H, J=7.7 Hz), 7.23 (d, 1H, J=7.7 Hz), 6.7 -6.8 (m, 1H), 6.67 (br t, 1H, J=54.7 Hz), 6.61 (dd, 2H, J=2.2, 8.2 Hz), 4.8 -4.8 (m, 1H), 4.52 (d, 2H, J=5.7 Hz), 3.6-3.6 (m, 3H), 3.48 (dd, 1H, J=4 ,8, 14.0 Hz), 3.2-3.3 (m, 3H), 3.11 (dd, 1H, J=9.4, 14.2 Hz), 2.81 (d. 3H, J=0.9 Hz), 2.41 (br dd, 2H, J=3.9, 7.5 Hz), 1.34 (br d, 1H, J=5.7 Hz), 1.0- 1.0 (m, 1H)

Preparation of Example 65: N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-4-oxo-7- (2,5,6-trimethylpyrimidin-4-yl)-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.

The title compound was prepared according to General Procedure D using 4-chloro-2,5,6-trimethylpyrimidine as the coupling agent. As a result of the experiment, we obtained the title compound, N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-4 -oxo-7-(2,5,6-trimethylpyrimidin-4-yl)-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. The sample was analyzed using LC-MS method F: retention time = 1.32 min; observed ion = 925.4 (M+H). 1H NMR (METHANOL-d4, 500 MHz) Shift 8.40 (d, 1H, J=7.9 Hz), 8.00 (s, 1H), 7.77 (dd, 1H, J=1.5, 8.0 Hz), 7.30 (d, 1H, J=7.7 Hz), 7.21 (d, 1H, J=7.7 Hz), 6.77 (br d, 1H, J=2 ,4 Hz), 6.67 (br t, 1H, J=54.7 Hz), 6.6-6.6 (m, 2H), 4.51 (d, 2H, J=2.7 Hz) , 3.62 (s, 3H), 3.4-3.5 (m, 2H), 3.2-3.2 (m, 3H), 3.1-3.1 (m, 1H), 2 .69 (s, 3H), 2.6-2.6 (m, 3H), 2.40 (br d, 2H, J=3.9 Hz), 2.33 (s, 3H), 1.33 (s, 1H), 0.98 (br d, 1H, J=3.3 Hz)

Preparation of Example 66: N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7-(6-isopropyl) -2-methylpyrimidin-4-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.

The title compound was prepared according to General Procedure D using 4-chloro-6-isopropyl-2-methylpyrimidine as a coupling agent. As a result of the experiment, we obtained the title compound, N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7 -(6-isopropyl-2-methylpyrimidin-4-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. The sample was analyzed using LC-MS method F: retention time = 1.51 min; observed ion = 939.4 (M+H). 1H NMR (METHANOL-d4, 500 MHz) Shift 8.63 (s, 1H), 8.4-8.4 (m, 2H), 7.84 (s, 1H), 7.29 (d, 1H, J=7.7 Hz), 7.21 (d, 1H, J=7.8 Hz), 6.6-6.8 (m, 4H), 4.8-4.8 (m, 1H), 4.52 (d, 2H, J=3.6 Hz), 3.61 (s, 3H), 3.48 (dd, 2H, J=4.9, 14.2 Hz), 3.2-3 ,2 (m, 3H), 3.1-3.1 (m, 1H), 2.80 (s, 3H), 2.42 (br dd, 2H, J=4.3, 8.2 Hz) , 1.40 (d, 6H, J=6.9 Hz), 1.3-1.4 (m, 1H), 0.99 (dd, 1H, J=1.9, 3.4 Hz)

Preparation of Example 67: N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7-(2-isopropylpyrimidine -4-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.

The title compound was prepared according to General Procedure D using 4-chloro-2-isopropylpyrimidine as the coupling agent. As a result of the experiment, we obtained the title compound, N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7 -(2-isopropylpyrimidin-4-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. The sample was analyzed using LC-MS method F: retention time=1.47 min; observed ion=925.4 (M+H). 1H NMR (METHANOL-d4, 500 MHz) Shift 8.86 (d, 1H, J=5.4 Hz), 8.74 (t, 1H, J=1.2 Hz), 8.42 (d, 2H , J=1.2 Hz), 7.99 (d, 1H, J=5.4 Hz), 7.3-7.3 (m, 1H), 7.22 (d, 1H, J=7, 7 Hz), 6.6-6.8 (m, 4H), 4.8-4.8 (m, 1H), 4.53 (d, 2H, J=6.0 Hz), 3.61 ( s, 3H), 3.4-3.5 (m, 2H), 3.2-3.2 (m, 3H), 3.12 (dd, 1H, J=9.4, 14.2 Hz) , 2.4-2.4 (m, 2H), 1.46 (d, 6H, J=6.9 Hz), 1.33 (s, 1H), 1.0-1.0 (m, 1H )

Preparation of Example 68: N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7-(2,6 -diethylpyrimidin-4-yl)-4-oxo-3,4-dihydroquinazolin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3b8,4aR)-3-(difluoromethyl)- 5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.

The title compound was prepared according to General Procedure D using 4-chloro-2,6-diethylgrimidine as a coupling agent. As a result of the experiment, we obtained the title compound, N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7 -(2,6-diethylpyrimidin-4-yl)-4-oxo-3,4-dihydroquinazolin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3b8,4aR)-3 -(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide. The sample was analyzed using LC-MS method F: retention time=1.51 min; observed ion 939.5 (M+H). 1H NMR (METHANOL-d4, 500 MHz) Shift 8.7-8.7 (m, 1H), 8.4-8.4 (m, 2H), 7.87 (s, 1H), 7.29 ( d, 1H, J=7.7 Hz), 7.21 (d, 1H, J=8.0 Hz), 6.6-6.8 (m, 4H), 4.53 (d, 2H, J =5.1 Hz), 3.61 (s, 3H), 3.48 (br dd, 2H, J=4.9, 14.2 Hz), 3.2-3.2 (m, 3H), 3.0-3.1 (m, 3H), 2.91 (q, 2H, J=7.5 Hz), 2.41 (br dd, 2H, J=4.0, 7.9 Hz), 1.3-1.5 (m, 7H), 0.99 (br dd, 1H, J=2.1, 3.6 Hz)

Preparation of Example 69: N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7-(6-ethoxy -2-methylpyrimidin-4-yl)-4-oxo-3,4-dihydroquinazolin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3b8,4aR)-3-(difluoromethyl )-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.

The title compound was prepared according to General Procedure D using 4-chloro-6-ethoxy-2-methylpyrimidine as a coupling agent. As a result of the experiment, we obtained the title compound, N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7 -(6-ethoxy-2-methylpyrimidin-4-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. The sample was analyzed using LC-MS method F: retention time=1.53 min; observed ion=941.4 (M+H). 1H NMR (METHANOL-d4, 500 MHz) Shift 8.55 (d, 1H, J=1.2 Hz), 8.4-8.4 (m, 1H), 8.2-8.3 (m, 1H), 7.28 (br d, 1H, J=7.7 Hz), 7.26 (s, 1H), 7.19 (d, 1H, J=8.0 Hz), 6.6-6 .8 (m, 4H), 4.9-4.9 (m, 1H), 4.7-4.8 (m, 2H), 4.5-4.5 (m, 3H), 3.6 -3.7 (m, 3H), 3.48 (br d, 1H, J=19.4 Hz), 3.3-3.4 (m, 1H), 3.2-3.2 (m, 3H), 3.10 (s, 1H), 2.70 (s, 2H), 2.42 (ddd, 2H, J=2.2, 3.9, 5.8 Hz), 1.45 (t , 2H, J=7.2 Hz), 1.34 (s, 1H), 0.9-1.0 (m, 1H)

Preparation of Example 70: N-((1S)-1-(7-(2-(sec-butyl)pyrimidin-4-yl)-(3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido )-1H-indazol-7-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.

The title compound was prepared according to General Procedure D using 2-(sec-butyl)-4-chloropyrimidine as the coupling agent. As a result of the experiment, we obtained the title compound, N-((1S)-1-(7-(2-(sec-butyl)pyrimidin-4-yl)-(3P)-3-(4-chloro-1-methyl -3-(methylsulfonamido)-1H-indazol-7-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. The sample was analyzed using LC-MS method F: retention time=1.52 min; observed ion=939.4 (M+H). 1H NMR (METHANOL-d4, 500 MHz) Shift 8.86 (d, 1H, J=5.4 Hz), 8.7-8.7 (m, 1H), 8.42 (t, 2H, J= 1.3 Hz), 7.99 (d, 1H, J=5.4 Hz), 7.29 (d, 1H, J=7.7 Hz), 7.22 (d, 1H, J=7, 5 Hz), 6.7-6.8 (m, 1H), 6.61 (dd, 2H, J=2.1, 8.0 Hz), 6.67 (br t, 1H, J=54, 8 Hz), 4.9-4.9 (m, 1H), 4.54 (d, 2H, J=6.9 Hz), 3.6-3.6 (m, 3H), 3.46 ( d, 1H, J=4.8 Hz), 3.2-3.2 (m, 3H), 3.1-3.2 (m, 2H), 2.41 (br dd, 2H, J=3 ,9, 7.5 Hz), 2.01 (s, 1H), 1.79 (s, 1H), 1.43 (d, 3H, J=7.2 Hz), 1.3-1.4 (m, 1H), 0.9-1.0 (m, 4H)

Preparation of Example 71: N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7-(2-ethylpyrimidine -4-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.

The title compound was prepared according to General Procedure D using 4-chloro-2-ethylpyrimidine as the coupling agent. As a result of the experiment, we obtained the title compound, N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7 -(2-ethylpyrimidin-4-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. The sample was analyzed using LC-MS method F: retention time=1.4 min; observed ion=911.4 (M+H). 1H NMR (METHANOL-d4, 500 MHz) Shift 8.85 (d, 1H, J=5.1 Hz), 8.71 (s, 1H), 8.42 (s, 2H), 8.00 (d , 1H, J=5.1 Hz), 7.29 (br d, 1H, J=7.7 Hz), 7.21 (br d, 1H, J=7.7 Hz), 6.6-6 .8 (m, 4H), 4.53 (br d, 2H, J=4.2 Hz), 3.61 (s, 3H), 3.46 (br s, 1H), 3.2-3, 2 (m, 3H), 3.1-3.2 (m, 4H), 2.4-2.4 (m, 2H), 1.47 (t, 3H, J=7.7 Hz), 1 .34 (br d, 1H, J=6.0 Hz), 0.99 (br s, 1H)

Preparation of Example 72: N-((S)-1-(7-(2-(tert-butyl)pyrimidin-4-yl)-(3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido )-1H-indazol-7-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.

The title compound was prepared according to General Procedure D using 2-(tert-butyl)-4-chloropyrimidine as the coupling agent. As a result of the experiment, we obtained the title compound, N-((S)-1-(7-(2-(tert-butyl)pyrimidin-4-yl)-(3P)-3-(4-chloro-1-methyl -3-(methylsulfonamido)-1H-indazol-7-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. The sample was analyzed using LC-MS method F: retention time=1.56 min; observed ion=939.4 (M+H). 1H NMR (METHANOL-d4, 500 MHz) Shift 8.87 (d, 1H, J=5.4 Hz), 8.8-8.8 (m, 1H), 8.4-8.4 (m, 2H), 7.96 (d, 1H, J=5.4 Hz), 7.2-7.3 (m, 1H), 7.21 (d, 1H, J=8.0 Hz), 6, 6-6.8 (m, 4H), 4.5-4.6 (m, 2H), 3.60 (s, 3H), 3.48 (dd, 1H, J=4.8, 14.0 Hz), 3.3-3.4 (m, 1H), 3.22 (s, 3H), 3.12 (dd, 1H, J=9.4, 14.2 Hz), 2.4-2 .4 (m, 2H), 1.5-1.5 (m, 9H), 1.3-1.4 (m, 1H), 1.0-1.0 (m, 1H)

Preparation of Example 73: N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7-(2-cyclopentylpyrimidine -4-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.

The title compound was prepared according to General Procedure D using 4-chloro-2-cyclopentylpyrimidine as a coupling agent. As a result of the experiment, we obtained the title compound, N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7 -(2-cyclopentylpyrimidin-4-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. The sample was analyzed using LC-MS method F: retention time=1.55 min; observed ion=951.5 (M+H). 1H NMR (METHANOL-d4, 500 MHz) Shift 8.84 (d, 1H, J=5.1 Hz), 8.72 (s, 1H), 8.41 (s, 2H), 7.97 (d , 1H, J=5.4 Hz), 7.29 (d, 1H, J=7.7 Hz), 7.22 (d, 1H, J=7.7 Hz), 6.6-6.8 (m, 4H), 4.54 (d, 2H, J=6.6 Hz), 3.61 (s, 3H), 3.4-3.6 (m, 3H), 3.2-3, 2 (m, 3H), 3.12 (dd, 1H, J=9.5, 14.0 Hz), 2.41 (br dd, 2H, J=4.0, 7.3 Hz), 2, 2-2.2 (m, 2H), 2.0-2.1 (m, 2H), 1.95 (br dd, 2H, J=3.3, 5.1 Hz), 1.8-1 .8 (m, 2H), 1.33 (br d, 1H, J=5.7 Hz), 0.98 (br dd, 1H, J=1.8, 3.6 Hz)

Preparation of Example 74: N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7-(2-( methoxymethyl)pyrimidin-4-yl)-4-oxo-3,4-dihydroquinazolin-2-yl)-2-(3,5-dafluorophenyl)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.

The title compound was prepared according to General Procedure D using 4-chloro-2-(methoxymethyl)pyrimidine as the coupling agent. As a result of the experiment, we obtained the title compound, N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7 -(2-(methoxymethyl)pyrimidin-4-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. The sample was analyzed using LC-MS method F: retention time=1.3 min; observed ion=927.4 (M+H). 1H NMR (METHANOL-d4, 500 MHz) Shift 8.94 (d, 1H, J=5.4 Hz), 8.72 (s, 1H), 8.43 (d, 2H, J=1.2 Hz ), 8.10 (d, 1H, J=5.4 Hz), 7.29 (d, 1H, J=8.0 Hz), 7.20 (d, 1H, J=7.9 Hz), 6.6-6.8 (m, 4H), 4.9-4.9 (m, 1H), 4.52 (d, 2H, J=3.3 Hz), 3.6-3.6 ( m, 7H), 3.4-3.5 (m, 2H), 3.2-3.2 (m, 3H), 3.11 (dd, 1H, J=9.2, 14.3 Hz) , 2.41 (br dd, 2H, J=4.0, 8.2 Hz), 1.33 (s, 1H), 0.98 (br dd, 1H, J=2.1, 3.6 Hz )

Preparation of Example 75: N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7-(2-( methoxymethyl)-6-methylpyrimidin-4-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.

The title compound was prepared according to General Procedure D using 4-chloro-2-(methoxymethyl)-6-methylpyrimidine as a coupling agent. As a result of the experiment, we obtained the title compound, N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7 -(2-(methoxymethyl)-6-methylpyrimidin-4-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. The sample was analyzed using LC-MS method F: retention time=1.34 min; observed ion=941.4 (M+H). 1H NMR (METHANOL-d4, 500 MHz) Shift 8.70 (t, 1H, J=1.0 Hz), 8.41 (s, 2H), 7.99 (s, 1H), 7.29 (d , 1H, J=7.7 Hz), 7.20 (d, 1H, J=8.0 Hz), 6.6-6.8 (m, 4H), 4.9-4.9 (m, 1H), 4.75 (s, 2H), 4.52 (d, 2H, J=3.3 Hz), 3.6-3.6 (m, 6H), 3.48 (dd, 1H, J =5.1, 14.0 Hz), 3.2-3.2 (m, 3H), 3.11 (dd, 1H, J=9.1, 13.9 Hz), 2.7-2, 7 (m, 3H), 2.41 (br dd, 2H, J=4.2, 8.0 Hz), 1.3-1.4 (m, 1H), 0.99 (br dd, 1H, J=1.9, 3.4 Hz)

Preparation of Example 76: N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7-(2-cyclobutylpyrimidine -4-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.

The title compound was prepared according to General Procedure D using 4-chloro-2-cyclobutylpyrimidine as a coupling agent. As a result of the experiment, we obtained the title compound, N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7 -(2-cyclobutylpyrimidin-4-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. The sample was analyzed using LC-MS method F: retention time=1.49 min; observed ion 937.4 (M+H). 1H NMR (METHANOL-d4, 500 MHz) Shift 8.85 (d, 1H, J=5.4 Hz), 8.76 (s, 1H), 8.43 (d, 2H, J=1.5 Hz ), 7.98 (d, 1H, J=5.1 Hz), 7.29 (d, 1H, J=8.0 Hz), 7.22 (d, 1H, J=8.0 Hz), 6.6-6.8 (m, 4H), 4.54 (d, 2H, J=6.6 Hz), 3.9-4.0 (m, 1H), 3.6-3.7 ( m, 4H), 3.48 (br dd, 2H, J=4.8, 14.0 Hz), 3.3-3.4 (m, 2H), 3.2-3.2 (m, 3H ), 2.4-2.5 (m, 2H), 2.4-2.4 (m, 2H), 2.2-2.2 (m, 1H), 2.06 (br d, 1H, J=1.2 Hz), 1.33 (br d, 1H, J=5.4 Hz), 1.0-1.0 (m, 1H)

Preparation of Example 77: N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7-(2.5 -dimethylpyrimidin-4-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.

The title compound was prepared according to General Procedure D using 4-chloro-2,5-dimethylpyrimidine as the coupling agent. As a result of the experiment, we obtained the title compound, N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7 -(2,5-dimethylpyrimidin-4-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. The sample was analyzed using LC-MS method F: retention time=1.32 min; observed ion 911.4 (M+H). 1H NMR (METHANOL, 500 MHz) Shift 8.70 (s, 1H), 8.42 (d, 1H, J=8.1 Hz), 8.08 (d, 1H, J=1.5 Hz), 7.87 (dd, 1H, J=1.6, 8.2 Hz), 7.29 (d, 1H, J=7.7 Hz), 7.21 (d, 1H, J=7.7 Hz ), 6.7-6.8 (m, 1H), 6.67 (br t, 1H, J=54.7 Hz), 6.61 (dd, 2H, J=2.1, 8.0 Hz ), 4.9-4.9 (m, 1H), 4.52 (d, 2H, J=3.6 Hz), 3.62 (s, 3H), 3.47 (dd, 1H, J= 5.1, 14.0 Hz), 3.2-3.2 (m, 3H), 3.09 (dd, 1H, J=9.2, 14.0 Hz), 2.75 (s, 3H ), 2.4-2.4 (m, 5H), 1.3-1.4 (m, 1H), 1.0-1.0 (m, 1H)

Preparation of Example 78: N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7-(2-cyclopropylpyrimidine -4-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-tetrapadro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.

The title compound was prepared according to General Procedure D using 4-chloro-2-cyclopropylpyrimidine as a coupling agent. As a result of the experiment, we obtained the title compound, N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7 -(2-cyclopropylpyrimidin-4-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. The sample was analyzed using LC-MS method F: retention time=1.43 min; observed ion=923.6 (M+H). 1H NMR (METHANOL-d4, 500 MHz) Shift 8.75 (d, 1H, J=5.4 Hz), 8.66 (s, 1H), 8.3-8.4 (m, 2H), 7 .90 (d, 1H, J=5.4 Hz), 7.3-7.3 (m, 1H), 7.21 (d, 1H, J=7.7 Hz), 6.6-6, 8 (m, 4H), 4.8-4.9 (m, 1H), 4.53 (d, 2H, J=6.0 Hz), 3.6-3.6 (m, 3H), 3 .5-3.5 (m, 1H), 3.3-3.4 (m, 1H), 3.2-3.2 (m, 3H), 2.37 (s, 3H), 1.2 -1.4 (m, 3H), 1.1-1.2 (m, 2H), 1.0-1.0 (m, 1H)

Preparation of Example 79: N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7-(6-ethylpyridine -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.

The title compound was prepared according to General Procedure D using 2-bromo-6-ethylpyridine as a coupling agent. As a result of the experiment, we obtained the title compound, N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7 -(6-ethylpyridin-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. The sample was analyzed using LC-MS method F: retention time=1.51 min; observed ion=910.4 (M+H). 1H NMR (METHANOL-d4, 500 MHz) Shift 8.53 (d, 1H, J=1.5 Hz), 8.37 (d, 1H, J=8.2 Hz), 8.29 (dd, 1H , J=1.8, 8.3 Hz), 7.9-7.9 (m, 2H), 7.36 (dd, 1H, J=2.2, 6.4 Hz), 7.28 ( d, 1H, J=7.7 Hz), 7.18 (d, 1H, J=8.0 Hz), 6.7-6.8 (m, 1H), 6.68 (br t, 1H, J=54.7 Hz), 6.61 (dd, 2H, J=2.2, 8.2 Hz), 4.9-4.9 (m, 1H), 4.53 (d, 2H, J =4.2 Hz), 3.61 (s, 3H), 3.4-3.5 (m, 1H), 3.2-3.2 (m, 3H), 3.10 (dd, 1H, J=9.2, 14.0 Hz), 2.95 (q, 2H, J=7.5 Hz), 2.41 (br dd, 2H, J=4.0, 7.6 Hz), 1 .41 (t, 3H, J=7.6 Hz), 1.34 (br d, 1H, J=5.7 Hz), 1.0-1.0 (m, 1H)

Alternative preparation of N-(7-amino-4-chloro-1-methyl-1H-indazol-3-yl)-N-(4-methoxybenzyl)methanesulfonamide.

Synthesis scheme:

Step 1: Preparation of 2,6-dachloro-3-nitrobenzaldehyde

2,6-Dichlorobenzaldehyde ( _1.25 kg, _7.10 mol, 1 .0 eq.) at temperatures below 15°C. The reaction mass was stirred at 0-5°C for 30 minutes. A solution of freshly prepared nitrating mixture [prepared from conc. H ₂ SO ₄ (0.425 L, 0.34 vol.) and 70% HNO ₃ (0.85 kg, 13.49 mol, 1.30 eq.) at 0°C] were added to the above reaction mixture at a temperature below 10°C [Note: the reaction is slightly exothermic (3-6°C), so addition is preferably carried out at a reduced temperature]. The reaction mixture was stirred at 5-10°C for 2-3 hours. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with ice water (18.75 L, 15 vol.) at a temperature below 25°C. The reaction mixture was then allowed to warm to room temperature and stirred for 2 hours. Solids were isolated by filtration and then washed with water (2.5 L, 2.0 vol). The bulk of the residual water was removed from said solids by vacuum filtration for 60-90 minutes. The crude wet solid was first dried in air and then in a hot air oven at 50-55°C for 10-12 hours (to a moisture content of not more than 5.0%) to obtain the dried title product, 2,6- dichloro-3-nitrobenzaldehyde (1.44 kg, 92% yield) as a yellow solid. ^1H NMR (400 MHz, CDCl ₃ ): δ 10.44 (s, 1H), 7.88 (d, J=8.4 Hz, 1H), 7.56 (d, J=8.8 Hz, 1H).

Step 2: Preparation of 2,6-dichloro-3-nitrobenzonitrile

(Step-2a) To a solution of DMSO (5.9 L, 5.0 vol) in a round bottom flask was added 2,6-dichloro-3-nitrobenzaldehyde (1.17 kg, 5.31 mol, 1.0 eq. ) at room temperature. After stirring for 30 minutes at room temperature, hydroxylamine hydrochloride (0.63 kg, 9.04 mol, 1.70 eq.) was added and the reaction was stirred at room temperature for 3 hours. After completion of the reaction (monitored by TLC ) the reaction mixture was quenched by adding ice water (18.0 L, 15.0 vol.) at a rate sufficient to maintain the temperature below 30°C (observation: solids formed when water was added. The reaction mixture was stirred at room temperature for 60 -90 min The solids were isolated by filtration, washed with water (2.5 L, 2.0 vol.), then washed with a mixture of acetone and hexanes (6.0 L, 1:1 ratio). water by filtering under vacuum for 60-90 minutes.The wet solid was first air dried and then finally dried in a hot air oven at 50-55°C for 10-12 hours (to a moisture content of no more than 1.0 %) to obtain the dried target product, 2,6-dichloro-3-nitrobenzaldehyde oxime (1.22 kg, 92% yield) as an off-white solid. The crude product (containing 10-20% 2,6-dichloro-3-nitrobenzonitrile) was directly used in the next step without further purification.

(Step-2b) To a solution of crude oxime (preparation described above, 1.13 kg, 4.80 mol, 1.0 eq.) in DCM (9.04 L, 8.0 vol.) with stirring at 0-5 °C triethylamine ("TEA", 1.02 kg, 10.09 mol, 2.1 eq.) was added. After stirring for 5 minutes, methanesulfonyl chloride (0.60 kg, 5.29 mol, 1.1 eq.) was slowly added at 15° C. (observation: addition generated heat). Then the reaction mass was stirred at room temperature for 30-45 minutes. After completion of the reaction (monitored by TLC; mobile phase: 20% ethyl acetate in hexanes), the reaction mixture was diluted with water (6.78 L, 6.0 vol), the organic layer was separated, and the aqueous layer was extracted with DCM (3.4 l, 3.0 vol.). The combined organic layers were washed with brine (5.65 L, 5.0 vol), dried over Na ₂ SO ₄ and concentrated in vacuo. The resulting crude solids were triturated with hexanes (4.50 L, 4.0 vol.) at room temperature. The wet product was dried in a hot air oven at 50-55°C for 5-6 hours to obtain the dried product, 2,6-dichloro-3-nitrobenzonitrile (0.95 kg, 91% yield), as a yellow solid colors. ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.07 (d, J=8.8 Hz, 1H), 7.63 (d, J=8.8 Hz, 1H).

Step 3: Preparation of 4-chloro-7-nitro-1H-indazol-3-amine

To a solution of 2,6-dichloro-3-nitrobenzonitrile (750.0 g, 3.45 mol, 1.0 eq.) in ethanol (7.5 L, 10.0 vol.) with stirring at 15-20 ° C Hydrazine hydrate (519.0 g, 10.36 mol, 3.0 eq.) was slowly added while maintaining the reaction temperature below 25° C. (observation: addition produces a small amount of heat and precipitates). The temperature of the reaction mixture was slowly raised to room temperature, and then the mixture was stirred for 3 hours (observation: during this time, the amount of solids will increase). After completion of the reaction (monitored by TLC), the mixture was diluted with water (7.5 L, 10.0 vol.) and further stirred for 1 hour at room temperature. Solids were isolated by filtration and then washed with water (2.25 L, 3.0 vol). The wet solid was washed with a 1:1 mixture of acetone (1.875 L, 2.5 vol.) and hexanes (1.875 L, 2.5 vol.). The bulk of the residual water was removed from said solids by vacuum filtration for 60-90 minutes. The wet solid was finally dried in a hot air oven for 7-8 hours at 50°C (to less than 1.5% moisture content) to obtain the dried product, 4-chloro-7-nitro-1H-indazol-3-amine (549.0 g, 75% yield) as a brick-red solid. ^1H NMR (400 MHz, CDCl ₃ ): δ 10.36 (bs, 1H), 8.20 (d, J=8.4 Hz, 1H), 7.07 (d, J=8.40 Hz, 1H), 4.73 (bs, 2H).

Step 4: Preparation of 4-chloro-1-methyl-7-nitro-1H-indazol-3-amine

To a solution of 4-chloro-7-nitro-1H-indazol-3-amine (500 g, 0.42 mol, 1.0 eq.) in DMF (5.0 L, 10.0 vol.) with stirring at 5 -10°C, cesium carbonate (Cs ₂ CO ₃ ) (1.91 kg, 5.88 mol, 2.5 eq.) was slowly added while maintaining the reaction temperature below 10°C. After stirring for 5-10 min, dimethyl sulfate (326.3 g, 2.59 mol, 1.1 eq.) was added while maintaining the reaction temperature below 10°C (note: slow addition is preferred for best regioselectivity). The reaction temperature was then slowly raised to room temperature and stirring was continued for an additional 2 hours at this temperature. After completion of the reaction (monitored by TLC), the reaction mass was quenched by adding ice water (15.0 L, 30.0 vol.), and then the resulting mixture was stirred for 6-8 hours at room temperature. Solids were collected by filtration and then washed with water (1.5 L, 3.0 vol). The wet solid was washed with isopropyl alcohol (IPA) (1.5 L, 3.0 vol.) and then with hexanes (1.0 L, 2.0 vol.). The bulk of the residual water was removed from said solids by vacuum filtration for 60-90 minutes. The wet solid was dried in a hot air oven for 7-8 hours at 50°C (until the moisture content was below 1.0%). The isolated material, 4-chloro-1-methyl-7-nitro-1H-indazol-3-amine (319.0 g, 60% yield), was used in the next step without further purification. ^1H NMR (400 MHz, CDCl ₃ ): δ 7.97 (d, J=8.32 Hz, 1H), 6.97 (d, J=8.24 Hz, 1H), 4.63 (bs, 2H), 3.96 (s, 3H).

Step 5: Preparation of N-(4-chloro-1-methyl-7-nitro-1H-indazol-3-yl)methanesulfonamide

(Step 5a) To a solution of 4-chloro-1-methyl-7-nitro-1H-indazol-3-amine (625.0 g, 2.76 mol, 1.0 eq.) in DCM (6.25 L, 10.0 vol.) at 0-5°C, triethylamine (TEA) (837.0 g, 8.27 mol, 3.0 eq.) was added followed by the addition of 4-dimethylaminopyridine (DMAP) (20.60 g, 0.165 mol, 0.06 eq.). The reaction mass was stirred for 5-10 minutes, then methanesulfonyl chloride (MsCl) (790.0 g, 6.89 mol, 2.5 eq.) was slowly added, maintaining the temperature of the reaction mass below 10°C. The reaction mixture was allowed to warm to room temperature and then stirred for 1.5-2.0 hours. After completion of the reaction (monitored by TLC), the mixture was diluted with water (6.25 L, 10.0 vol.) and then stirred at room temperature for 15 minutes. The organic layer was separated and the aqueous layer was extracted with DCM (6.25 L, 10.0 vol). The combined organic layers were washed with brine (1.25 L, 2.0 vol), dried over Na ₂ SO ₄ and concentrated to give crude solids. The above solids were triturated with hexanes (1.25 L, 2.0 vol) at room temperature to give the intermediate, N-(4-chloro-1-methyl-7-nitro-1H-indazol-3-yl)- N-(methylsulfonyl)methanesulfonamide, which was directly used in the next step.

(ii) To a solution of N-(4-chloro-1-methyl-7-nitro-1H-indazol-3-yl)-N-(methylsulfonyl)methanesulfonamide (prepared above) in ethanol (10.5 L, 20.0 vol.) while stirring at room temperature, waves were slowly added. 5% NaOH solution (4.38 L, 7.0 vol) [note: slow addition via addition funnel is preferred]. The reaction mass was stirred at this temperature for 3 hours. After completion of the reaction (monitored by TLC) [sample preparation for TLC analysis: ~1.0 ml of sample, acidified with aq. 2.0 n. HCl until pH 2-3 is reached, extracted with ethyl acetate and the organic layer is analyzed by TLC], the reaction mass was cooled to 0-5°C and the pH was adjusted to 2-3 by adding aq. 2.0 n. HCl (3.13 L, 5.0 vol) while maintaining the reaction temperature below 10°C [note: when HCl was added, precipitation occurred and increased with stirring]. The reaction mixture was warmed to room temperature and then stirred for 1.5-2.0 hours. The resulting solids were isolated by filtration and then washed with water (1.25 L, 2.0 vol.), followed by hexanes (1. 25 l, 2.0 rpm). The bulk of the residual water was removed from said solids by vacuum filtration for 60-90 minutes. The wet material was dried in a hot air oven at 50°C for 6-7 hours (until the moisture content was less than 1.0%) to obtain the dried product, N-(4-chloro-1-methyl- 7-nitro-1H-indazol-3-yl)methanesulfonamide (640.0 g, 76%) as a yellow solid. ^1H NMR (400 MHz, CDCl ₃ ): δ 8.05 (d, J=8.32 Hz, 1H), 7.32 (bs, 1H), 7.17 (d, J=8.28 Hz, 1H), 4.15 (s, 3H), 3.45 (s, 3H).

Step 6: Preparation of N-(4-chloro-1-methyl-7-nitro-1H-indazol-3-yl)-N-(4-methoxybenzyl)methanesulfonamide

To a mixture of N-(4-chloro-1-methyl-7-nitro-1H-indazol-3-yl)methanesulfonamide (635.0 g, 2.08 mol, 1.0 eq.) and 1-(chloromethyl)- 4-methoxybenzene (359.0 g, 2.30 mol, 1.1 eq.) in DMF (6.35 L, 10.0 vol.) was added potassium carbonate (374.7 g, 2.70 mol) at room temperature , 1.3 eq.). The reaction mixture was heated to 80-90°C and maintained at this temperature for 3 hours. After completion of the reaction (monitored by TLC), the mixture was poured into ice water (19.05 L, 30.0 vol.) [note: preferably slow quenching with vigorous stirring to avoid clumping as the product settles]. The resulting solids were isolated by filtration and washed with water (1.90 L, 3.0 vol); the solids were then washed with hexanes (1.27 L, 2.0 vol). The bulk of the residual water was removed from said solids by vacuum filtration for 60-90 minutes. The isolated solid was dissolved in ethyl acetate (12.7 L, 20.0 vol) and charcoal (63.5 g) was added. The mixture was heated to 60-70°C and then stirred for 30-45 minutes. at this temperature. The mixture was filtered while still hot (40-50°C) through a pad of celite, and then the celite pad was extracted with ethyl acetate (3.17 L, 5.0 vol). The combined filtrates were concentrated to dryness under reduced pressure at a temperature below 50°C. Ethyl acetate (0.635 L, 1.0 vol) was added to the solids at room temperature. The resulting solid suspension was stirred for 30 minutes. Solids were isolated by filtration and then washed with hexanes (1.27 L, 2.0 vol). Residual water was removed from these solids by vacuum filtration for 45-60 minutes to give the product, N-(4-chloro-1-methyl-7-nitro-1H-indazol-3-yl)-N-(4- methoxybenzyl)methanesulfonamide (705.0 g, 80% yield) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.99 (d, J=8.24 Hz, 1H), 7.27 (d, J=8.68 Hz, 2H), 7.19 (d, J=8.24 Hz, 1H), 6.80 (d, J=8.44 Hz, 2H), 4.95-4.76 (m, 2H), 4.17 (s, 3H), 3, 76 (s, 3H), 3.01 (s, 3H).

Step 7: Preparation of N-(7-amino-4-chloro-1-methyl-1H-indazol-3-yl)-N-(4-methoxybenzyl)methanesulfonamide

To a suspension of zinc powder (540.0 g, 8.23 mol, 10.0 eq.) in a mixture of THF (3.50 L, 10.0 vol.) and water (7.0 L, 20.0 vol.) Ammonium chloride (NH ₄ Cl) (449.0 g, 8.23 mol, 10.0 eq.) was added with stirring at room temperature. N-(4-chloro-1-methyl-7-nitro-1H-indazol-3-yl)-N-(4-methoxybenzyl)methanesulfonamide (350 g, 0.823 mol, 1.0 eq) in THF was added to the mixture (7.0 l, 20.0 rpm). The reaction mixture was stirred at room temperature for 3-4 hours. After completion of the reaction (monitored by TLC/HPLC during the process), the mixture was diluted with ethyl acetate (3.5 L, 10.0 vol.) and water (1.12 L, 2 ,5 vol.). The mixture was stirred for 15 minutes. The reaction mass was filtered through a pad of celite, washing with ethyl acetate (1.75 L, 5.0 vol.). The two-phase filtrate was collected and the phases were separated. The aqueous layer was extracted with ethyl acetate (3.50 L, 10.0 vol). The combined organic layers were washed with brine (3.50 L, 10 vol), dried over Na ₂ SO ₄ and then concentrated in vacuo to give a crude solid. MTBE (3.25 L, 10 vol) was added to the crude product and the suspension was stirred for 30 min at room temperature. Solids were isolated by filtration. The bulk of the residual water was removed from said solids by vacuum filtration for 30-45 minutes. The wet product was dried in a hot air oven (50° C.) for 2 hours to obtain the title product, N-(7-amino -4-chloro-1-methyl-1H-indazol-3-yl)-N-(4-methoxybenzyl)methanesulfonamide (276.0 g, 85% yield) as an off-white solid. ^1H NMR (400 MHz, CDCl ₃ ): δ 7.29-7.26 (m, 2H), 6.86-6.79 (m, 2H), 6.42 (d, J=7.80 Hz , 1H), 4.99-4.70 (m, 2H), 4.25 (s, 3H), 3.77 (s, 5H), 2.98 (s, 3H).

Alternative preparation of N-(7-amino-4-chloro-1-(2,2-difluoroethyl)-1H-indazol-3-yl)-N-(4-methoxybenzyl)methanesulfonamide:

Synthesis scheme:

Step 1: Preparation of 4-chloro-1-(2,2-difluoroethyl)-7-nitro-1H-indazol-3-amine

To a solution of 4-chloro-7-nitro-1H-indazol-3-amine (180 g, 0.85 mol, 1.0 eq.) in DMF (1.8 L, 10.0 vol.) with stirring at 10 -15°C, cesium carbonate (Cs ₂ CO ₃ ) (551 g, 1.70 mol, 2.0 eq.) was added at a rate necessary to maintain the reaction temperature below 20°C. The mixture was stirred for 5-10 min, then 2,2-difluoroethyltrifluoromethanesulfonate (133 ml, 0.93 mol, 1.1 eq.) was added to the mixture with stirring at 10-15°C at a rate necessary to maintain the temperature of the reaction mass below 20°C (note: for best regioselectivity, slow addition is preferred). The reaction mass was allowed to slowly warm to room temperature and then stirred at this temperature for 3 hours. After completion of the reaction (monitored by TLC), the reaction mass was quenched by adding ice water (5.4 L, 30.0 vol.), and the resulting the mixture was allowed to warm to room temperature with stirring for 6-8 hours. Solids were isolated by filtration and then washed with water (540 ml, 3.0 vol). The wet solid was washed with hexanes (0.9 L, 5.0 vol). The bulk of the residual water was removed from said solids by vacuum filtration for 60-90 minutes. The wet solid was dried in a hot air oven for 7-8 hours at 50°C (until the moisture content was less than 1.0%). The isolated product, 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. ^1H NMR (400 MHz, CDCl ₃ ): δ 8.05 (d, J=8.4 Hz, 1H), 7.07 (d, J=8.4 Hz, 1H), 6.00 (tt, J ₁ =3.9 Hz, J ₂ =7.7 Hz, 1H), 4.76-4.84 (m, 4H).

Step 2: Preparation of N-(4-chloro-1-(2,2-difluoroethyl)-7-nitro-1H-indazol-3-yl)methanesulfonamide

Step 2a: To a solution of 4-chloro-1-(2,2-difluoroethyl)-7-nitro-1H-indazol-3-amine (170.0 g, 0.96 mol, 1.0 eq.) in DCM ( 1.7 L, 10.0 vol.) at 0-5°C, triethylamine (264 ml, 2.88 mol, 3.0 eq.) was added, followed by 4-dimethylaminopyridine (3.4 g, 0.048 mol, 0 .05 eq.). The reaction mass was stirred for 5-10 minutes, then methanesulfonyl chloride (120 ml, 2.4 mol, 2.5 eq.) was slowly added, maintaining the temperature of the reaction mass below 10°C. The reaction mixture was allowed to warm to room temperature and then stirred for 1.5-2.0 hours. After completion of the reaction (monitored by TLC), the mixture was diluted with water (1.7 L, 10.0 vol.) and then stirred at room temperature for 15 minutes. The organic layer was separated and the aqueous layer was extracted with DCM (1.7 L, 10.0 vol). The combined organic layers were washed with 10% brine (340 mL, 2.0 vol), dried over Na ₂ SO ₄ and concentrated to provide the product as a crude solid. The solids were triturated with hexanes (340 ml, 2.0 vol.) at room temperature to give N-(4-chloro-1-(2,2-difluoroethyl)-7-nitro-1H-indazol-3-yl)- N-(methylsulfonyl)methanesulfonamide, which was directly used in the next step.

Step 2b: To a solution of N-(4-chloro-1-(2,2-difluoroethyl)-7-nitro-1H-indazol-3-yl)-N-(methylsulfonyl)methanesulfonamide (whole amount of product obtained above) in ethanol (1.7 L, 10.0 vol.) While stirring at room temperature, aqueous 5% NaOH solution (1.19 L, 7.0 vol.) was slowly added [note: slow addition via addition funnel is preferred]. The reaction mass was stirred at this temperature for 3 hours. After completion of the reaction [sample preparation for TLC analysis: an aliquot of the reaction solution (~1 ml) was acidified with water. 2.0 n. HCl to pH 2-3; then the mixture was extracted with ethyl acetate and the organic layer was analyzed by TLC; the reaction mass was cooled to 0-5°C and the pH was adjusted to 2-3 by adding water. 2.0 n. HCl (850 ml, 5.0 vol.) at a temperature below 10°C [note: upon addition of HCl, a precipitate occurred, which gradually increased with stirring]. The reaction mixture was warmed to room temperature and then stirred for 1.5-2.0 hours. The resulting solids were isolated by filtration and then washed with water (340 ml, 2.0 vol.), followed by hexanes (340 ml, 2 ,0 vol.). The bulk of the residual water was removed from said solids by vacuum filtration for 60-90 minutes. The wet material was dried in a hot air oven at 50°C for 6-7 hours (until the moisture content was less than 1.0%), resulting in 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. ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.15 (d, J=8.3 Hz, 1H), 7.52 (bs, 1H), 7.24 (d, J=8.3 Hz, 1H), 6.04 (tt, J ₁ =3.7 Hz, J ₂ =7.9 Hz, 1H), 5.02 (td, J ₁ =3.9 Hz, J ₂ =14.3 Hz, 2H), 3.42 (s, 4H).

Step 3: Preparation of N-(4-chloro-1-(2,2-difluoroethyl)-7-nitro-1H-indazol-3-yl)-N-(4-methoxybenzyl)methanesulfonamide

To a mixture of N-(4-chloro-1-(2,2-difluoroethyl)-7-nitro-1H-indazol-3-yl)methanesulfonamide (160.0 g, 0.45 mol, 1.0 eq.) and 1-(chloromethyl)-4-methoxybenzene (67.6 ml, 0.5 mol, 1.1 eq.) in DMF (1.6 L, 10.0 vol.) was added potassium carbonate (93.8 g, 0.59 mol, 1.3 eq.). The reaction mixture was heated to 80-90°C and maintained at this temperature for 3 hours. After completion of the reaction (monitored by TLC), the mixture was poured into ice water (4.8 L, 60.0 vol.) [note: preferably slow quenching with vigorous stirring to avoid clumping as the product settles]. The resulting solids were isolated by filtration and washed with water (480 ml, 3.0 vol); the solids were then washed with hexanes (320 mL, 2.0 vol). Residual water was removed from said solids by vacuum filtration for 1-2 hours. The isolated solid was dissolved in ethyl acetate (1.6 L, 10.0 vol.) and charcoal (16.0 g) was added. The mixture was heated to 60-70°C and then stirred for 30-45 minutes. at this temperature. The mixture was filtered while still hot (40-50°C) through a pad of celite, and then the celite pad was subjected to extraction with ethyl acetate (800 ml, 5.0 vol). The combined filtrates were concentrated to dryness under reduced pressure at a temperature below 50°C. Ethyl acetate (160 mL, 1.0 vol.) was added to the resulting solids at room temperature. The suspension was stirred for 30 minutes. Solids were isolated by filtration and then washed with hexanes (320 ml, 2.0 vol). Residual water was removed from these solids by vacuum filtration for 45-60 minutes to give the product, N-(4-chloro-1-(2,2-difluoroethyl)-7-nitro-1H-indazol-3-yl) -N-(4-methoxybenzyl)methanesulfonamide (180.0 g, 92% yield) as a yellow solid. ^1H NMR (400 MHz, CDCl ₃ ): δ 8.06 (d, J=8.4 Hz, 1H), 7.52 (bs, 1H), 7.27-7.21 (m, 4H), 6.77 (d, J=8.3 Hz, 2H), 6.01 (tt, J ₁ =3.8 Hz, J ₂ =7.9 Hz, 1H), 5.12-4.78 (m , 4H), 3.74 (s, 3H), 3.02 (s, 3H).

Step 4: Preparation of N-(7-amino-4-chloro-1-(2,2-difluoroethyl)-1H-indazol-3-yl)-N-(4-methoxybenzyl)methanesulfonamide

To a suspension of iron powder (76.5 g, 1.37 mol, 5.0 eq.) in a mixture of EtOH (650 ml, 5.0 vol.) and water (780 ml, 6.0 vol.) with stirring at room temperature ammonium chloride (118.0 g, 2.18 mol, 8.0 eq.) was added at temperature. N-(4-chloro-1-(2,2-difluoroethyl)-7-nitro-1H-indazol-3-yl)-N-(4-methoxybenzyl)methanesulfonamide (130 g, 0.27 mol) was added to the mixture. 1.0 eq.) in EtOH (520 ml, 4.0 vol.). The reaction mixture was heated to 60°C and then stirred for 2 hours. After completion of the reaction (monitored by TLC/HPLC during the process), the mixture was cooled to room temperature and diluted with ethyl acetate (1.3 L, 10.0 vol.) and water (390 ml, 3.0 vol.). The mixture was stirred for 15 minutes. The mixture was filtered through a pad of celite, and then the celite layer was extracted with ethyl acetate (650 ml, 5.0 vol.). The two-phase filtrate was separated and the organic phase was set aside and the aqueous layer was extracted with ethyl acetate (650 ml, 5.0 vol). The combined organic layers were washed with brine (1.3 L, 10 vol), dried over Na ₂ SO ₄ and then concentrated in vacuo to give a crude solid. MTBE (650 mL, 5.0 vol) was added to the crude product and the suspension was stirred for 30 min at room temperature. Solids were isolated by filtration. The bulk of the residual water was removed from said solids by vacuum filtration for 30-45 minutes. The wet product was dried in a hot air oven (50° C.) for 2 hours to give the title compound, N-(7-amino -4-chloro-1-(2,2-difluoroethyl)-1H-indazol-3-yl)-N-(4-methoxybenzyl)methanesulfonamide (100.0 g, 70% yield), as an off-white solid colors. ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.21 (d, J=8.5 Hz, 2H), 6.87 (d, J=8.4 Hz, 1H), 6.78 (d, J=8.5 Hz, 2H), 6.52 (d, J=8.3 Hz, 1H), 6.01 (tt, J ₁ =3.8 Hz, J2=7.7 Hz, 1H), 4, 98-4.69 (m, 4H), 3.75 (s, 3H), 2.98 (s, 3H).

Alternative preparation of N-(7-amino-4-chloro-1-(2,2-difluoroethyl)-1H-indazol-3-yl)-N-(4-methoxybenzyl)cyclopropanesulfonamide

Synthesis scheme:

Step 1: Preparation of N-(4-chloro-1-(2,2-difluoroethyl)-7-nitro-1H-indazol-3-yl)cyclopropanesulfonamide

To a solution of 4-chloro-1-(2,2-difluoroethyl)-7-nitro-1H-indazol-3-amine (150.0 g, 0.54 mol, 1.0 eq.) in acetonitrile (600 ml, 4.0 vol.), pyridine (600 ml, 4.0 vol.) was added with stirring at room temperature, followed by the addition of 4-dimethylaminopyridine (30.0 g, 0.27 mol, 0.5 eq.). The reaction mass was stirred for 5-10 minutes, then cyclopropylsulfonyl chloride (114 ml, 1.08 mol, 2.0 eq.) was added at room temperature. The reaction mixture was heated to 50°C and then stirred at this temperature for 3 days. After completion of the reaction (monitored by TLC), the mixture was cooled to room temperature and diluted with water (1.5 L, 10.0 vol.) and ethyl acetate (1.5 L, 10.0 vol.), then stirred at room temperature in for 15 minutes. The organic layer was separated and the aqueous layer was extracted with EtOAc (300 ml, 2.0 vol). The combined organic layers were washed with water. 1.0 n. HCl (600 ml, 4.0 vol.), followed by 10% saline solution (1.5 L, 10.0 vol.). The organic layer was dried over Na ₂ SO ₄ , filtered and then concentrated under reduced pressure to give N-(4-chloro-1-(2,2-difluoroethyl)-7-nitro-1H-indazol-3-yl )cyclopropanesulfonamide (124.0 g, 61%) as a viscous liquid. ^1H NMR (400 MHz, CDCl ₃ ): δ 8.11 (d, J=8.5 Hz, 1H), 7.25 (d, J=8.5 Hz, 1H), 6.04 (tt, J ₁ =3.8 Hz, J ₂ =7.7 Hz, 1H), 5.05 (td, J ₁ =3.8 Hz, J ₂ =14.4 Hz, 2H), 3.06-3, 00 (m, 1H), 1.65-1.42 (m, 2H), 1.19-1.13 (m, 2H).

Step 2: Preparation of N-(4-chloro-1-(2,2-difluoroethyl)-7-nitro-1H-indazol-3-yl)-N-(4-methoxybenzyl)cyclopropanesulfonamide

To a mixture of N-(4-chloro-1-(2,2-difluoroethyl)-7-nitro-1H-indazol-3-yl)cyclopropanesulfonamide (100.0 g, 0.20 mol, 1.0 eq.) and Potassium carbonate (128 g, 0.33 mol, 1.3 eq.). The reaction mixture was heated to 80-90°C and maintained at this temperature for 3 hours. After completion of the reaction (monitored by TLC), the mixture was poured into ice water (3.0 L, 30.0 vol.) [note: preferably slow quenching with vigorous stirring to avoid clumping as the product settles]. The resulting solids were isolated by filtration and washed with water (300 ml, 3.0 vol); the solids were then washed with hexanes (300 ml, 3.0 vol). Residual water was removed from said solids by vacuum filtration for 1-2 hours. The wet solid was dissolved in ethyl acetate (500 ml, 5.0 vol.) and charcoal (10.0 g) was added. The mixture was heated to 60-70°C and then stirred for 30-45 minutes at this temperature. The mixture was filtered while still hot (40-50°C) through a pad of celite, and the celite pad was extracted with ethyl acetate (500 ml, 5.0 vol). The combined filtrates were concentrated to dryness under reduced pressure at temperatures below 50°C to give N-(4-chloro-1-(2,2-difluoroethyl)-7-nitro-1H-indazol-3-yl)-N-(4- methoxybenzyl)piclopropanesulfonamide (122.0 g, 92% yield) as a yellow solid. ^1H NMR (400 MHz, CDCl ₃ ): δ 8.05 (d, J=8.6 Hz, 1H), 7.26-7.22 (m, 3H), 6.73 (d, J=8 .5 Hz, 2H), 5.98 (tt, J ₁ =3.7 Hz, J ₂ =7.8 Hz, 1H), 5.09-4.88 (m, 4H), 3.72 (s , 3H), 2.65-2.60 (m, 1H), 1.15-1.06 (m, 2H), 0.89-0.86 (m, 2H).

Step 3: Preparation of N-(7-amino-4-chloro-1-(2,2-difluoroethyl)-1H-indazol-3-yl)-N-(4-methoxybenzyl)cyclopropanesulfonamide

To a suspension of zinc powder (156.0 g, 2.4 mol, 10.0 eq.) in a mixture of THF (1.2 L, 10.0 vol.) and water (2.4 L, 20.0 vol.) Ammonium chloride (129.0 g, 2.40 mol, 10.0 eq.) was added with stirring at room temperature. N-(4-chloro-1-(2,2-difluoroethyl)-7-nitro-1H-indazol-3-yl)-N-(4-methoxybenzyl)cyclopropanesulfonamide (120 g, 0.2 mol, 1.0 eq) in THF (2.4 L, 20.0 vol). The reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction (monitored by TLC/HPLC during the process), the mixture was diluted with ethyl acetate (1.2 L, 10.0 vol.) and water (360 ml, 3.0 vol. ). The mixture was stirred for 15 minutes. The mixture was filtered through a pad of celite, and the celite pad was extracted with ethyl acetate (600 ml, 5.0 vol). The two-phase filtrate was separated and the organic phase was set aside and the aqueous layer was extracted with ethyl acetate (600 ml, 5.0 vol). The combined organic layers were washed with 10% brine (1.2 L, 10 vol), dried over Na ₂ SO ₄ , filtered and then concentrated in vacuo to give a crude solid. MTBE (600 ml, 5.0 vol) was added to the crude product and the suspension was stirred for 30-45 min at room temperature. The solids were isolated by filtration, and then the bulk of the residual water was removed from said solids by vacuum filtration for 30-45 minutes. The wet product was dried in a hot air oven (50°C) for 2 hours to obtain the product, N- (7-amino-4-chloro-1-(2,2-difluoroethyl)-1H-indazol-3-yl)-N-(4-methoxybenzyl)cyclopropanesulfonamide (81.0 g, 73% yield), as solid off-white substances. ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.25 (d, J=8.5 Hz, 2H), 6.93 (d, J=8.4 Hz, 1H), 6.75 (d, J=8.3 Hz, 2H), 6.57 (d, J=8.4 Hz, 1H), 6.03 (tt, J ₁ =3.7 Hz, J ₂ =7.9 Hz, 1H) , 4.80-4.95 (m, 4H), 3.74 (s, 3H), 2.67-2.61 (m, 1H), 1.14 (d, J=2.4 Hz, 2H ), 0.96 (d, J=2.3 Hz, 2H).

Alternative preparation of N-(7-amino-4-chloro-1-(2,2,2-trifluoroethyl)-1H-indazol-3-yl)-N-(4-methoxybenzyl)methanesulfonamide

Synthesis scheme:

Step 1: Preparation of 4-chloro-7-nitro-1-(2,2,2-trifluoroethyl)-1H-indazol-3-amine

To a solution of 4-chloro-7-nitro-1H-indazol-3-amine (50 g, 0.23 mol, 1.0 eq.) in DMF (500 ml, 10.0 vol.) with stirring at 10-15 °C cesium carbonate (Cs ₂ CO ₃ ) (153.3 g, 0.47 mol, 2.0 eq.) was added at a rate sufficient to maintain the temperature of the reaction mass below 20 °C. The mixture was stirred for 5-10 minutes, then 2,2,2-trifluoroethyltrifluoromethanesulfonate (60.18 g, 0.26 mol, 1.1 eq.) was added to the mixture with stirring at 10-15°C at a rate sufficient to maintaining the temperature of the reaction mass below 20°C (note: for better regioselectivity, slow addition is preferable). The reaction mass was allowed to slowly warm to room temperature and then stirred at this temperature for 2 hours. After completion of the reaction (monitored by TLC), the reaction mass was quenched by adding ice water (1.5 L, 30.0 vol.), and the resulting the mixture was allowed to warm to room temperature with stirring for 6-8 hours. Solids were isolated by filtration and then washed with water (150 ml, 3.0 vol). The wet solid was washed with hexanes (250 ml, 5.0 vol) and then most of the residual water was removed from said solids by vacuum filtration for 60-90 minutes. The wet solid was dried in a hot air oven for 7 -8 hours at 50°C (until the moisture content is less than 1.0%). The isolated material, 4-chloro-7-nitro-1-(2,2,2-trifluoroethyl)-1H-indazol-3-amine (45.0 g, 60% yield), was directly used in the next step without further purification. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 8.09 (d, J=8.40 Hz, 1H), 7.12 (d, J=8.40 Hz, 1H), 5.14 (q , J=8.52 Hz, 2H), 4.77 (bs, H).

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 (20.0 g, 0.068 mol, 1.0 eq.) in DCM (200 ml, 10.0 vol.) at 0-5°C was added triethylamine (29.0 ml, 0.204 mol, 3.0 eq.) followed by the addition of 4-dimethylaminopyridine (415 mg, 0.03 mol, 0 .05 eq.). The reaction mass was stirred for 5-10 minutes, then methanesulfonyl chloride (13.25 ml, 0.17 mol, 2.5 eq.) was added to the mixture at a rate sufficient to maintain the temperature of the reaction mass below 10°C. The reaction mixture was allowed to warm to room temperature with stirring for 12 hours. After completion of the reaction (monitored by TLC), the mixture was diluted with water (200 ml, 10.0 vol) and then stirred at room temperature for 15 minutes. The organic layer was separated and the aqueous layer was extracted with DCM (200 ml, 10.0 vol). The combined organic layers were washed with 10% brine (60 mL, 3.0 vol), dried over Na ₂ SO ₄ , filtered and concentrated to give crude solids. The above solids were triturated with hexanes (60 mL, 3.0 vol) at room temperature to give the intermediate, N-(4-chloro-7-nitro-1-(2,2,2-trifluoroethyl)-1H-indazole -3-yl)-N-(methylsulfonyl)methanesulfonamide, which was directly used in the next step.

(Step 2b): To a solution of N-(4-chloro-7-nitro-1-(2,2,2-trifluoroethyl)-1H-indazol-3-yl)-N-(methylsulfonyl)methanesulfonamide (whole amount obtained above product) in ethanol (200 ml, 10.0 vol.), aqueous 5% NaOH solution (140 ml, 7.0 vol.) was slowly added with stirring at room temperature [note: slow addition via addition funnel is preferred]. The reaction mass was stirred at this temperature for 2 hours. After completion of the reaction [sample preparation for TLC analysis: an aliquot of the reaction solution (~1.0 ml) was acidified by adding water. 2.0 n. HCl to pH 2-3; then the mixture was extracted with ethyl acetate and the organic phase was analyzed by TLC; the reaction mass was cooled to 0-5°C and the pH was adjusted to 2-3 by adding water. 2.0 n. HCl (100 ml, 5.0 vol.), maintaining the temperature below 10°C [note: when HCl was added, precipitation occurred and increased with stirring]. The reaction mixture was warmed to room temperature and then stirred for 1.5-2.0 hours. Solids were isolated by filtration and then washed with water (60 ml, 3.0 vol.) followed by washing with hexanes (60 ml, 3.0 vol. .). The bulk of the residual water was removed from said solids by vacuum filtration for 60-90 minutes. The wet material was dried in a hot air oven at 50°C for 6-7 hours (until the moisture content was less than 1.0%) to obtain N-(4-chloro-7-nitro-1-( 2,2,2-trifluoroethyl)-1H-indazol-3-yl)methanesulfonamide (22.1 g, 87%) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.19 (d, J=8.40 Hz, 1H), 7.56 (bs, 1H), 7.30 (d, J=8.40 Hz, 1H), 5.34 (q, J=8.30 Hz, 2H), 3.46 (s, 3H).

Step 3: Preparation of N-(4-chloro-7-nitro-1-(2,2,2-trifluoroethyl)-1H-indazol-3-yl)-N-(4-methoxybenzyl)methanesulfonamide

To a mixture of N-(4-chloro-7-nitro-1-(2,2,2-trifluoroethyl)-1H-indazol-3-yl)methanesulfonamide (50.0 g, 0.134 mol, 1.0 eq.) and 1-(chloromethyl)-4-methoxybenzene (23.0 g, 0.147 mol, 1.1 eq.) in DMF (500 ml, 10.0 vol.) was added potassium carbonate (27.8 g, 0.201 mol) at room temperature , 1.5 eq.). The reaction mixture was heated to 80-90°C and maintained at this temperature for 3 hours. After completion of the reaction (monitored by TLC), the mixture was poured into ice water (2.0 L, 40.0 vol.) [note: preferably slow quenching with vigorous stirring to avoid clumping as the product settles]. The resulting solids were isolated by filtration and washed with water (150 ml, 3.0 vol); the solids were then washed with hexanes (150 ml, 3.0 vol). Residual water was removed from said solids by vacuum filtration for 1-2 hours. The solids were dissolved in ethyl acetate (500 ml, 10.0 vol.) and charcoal (5.0 g) was added to the solution. The mixture was heated to 60-70°C and then stirred at this temperature for 30-45 minutes. The mixture was filtered while still hot (40-50°C) through a pad of celite, and the celite layer was extracted with ethyl acetate (250 ml, 5.0 vol). The combined filtrate was concentrated to dryness under reduced pressure at a temperature below 50°C. The solids were combined with ethyl acetate (50 ml, 1.0 vol.) at room temperature. The resulting suspension was stirred for 30 minutes. Solids were isolated by filtration and then washed with hexanes (100 ml, 2.0 vol). Residual water was removed from these solids by vacuum filtration for 45-60 minutes to give N-(4-chloro-7-nitro-1-(2,2,2-trifluoroethyl)-1H-indazol-3-yl) -N-(4-methoxybenzyl)methanesulfonamide (56.0 g, 85% yield) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.12 (d, J=8.36 Hz, 1H), 7.31 (d, J=8.36 Hz, 1H), 7.22 (d, J=8.44 Hz, 2H), 6.77 (d, J=8.44 Hz, 2H), 5.50-5.25 (m, 2H), 4.94-4.79 (m, 2H ), 3.75 (s, 3H), 3.02 (s, 3H).

Step 4: Preparation of N-(7-amino-4-chloro-1-(2,2,2-trifluoroethyl)-1H-indazol-3-yl)-N-(4-methoxybenzyl)methanesulfonamide

To a suspension of zinc powder (66.31 g, 1.01 mol, 10.0 eq.) in THF (500 ml, 10.0 vol.) and water (1.0 L, 20.0 vol.) with stirring at Ammonium chloride (54.78 g, 1.01 mol, 10.0 eq.) was added at room temperature. A solution of N-(4-chloro-7-nitro-1-(2,2,2-trifluoroethyl)-1H-indazol-3-yl)-N-(4-methoxybenzyl)methanesulfonamide (50.0 g, 0.101 mol, 1.0 eq) in THF (1.0 L, 20.0 vol). The reaction mixture was stirred at room temperature for 3 hours. After completion of the reaction (monitored by TLC/HPLC during the process), the mixture was diluted with ethyl acetate (1.0 L, 20.0 vol.) and water (250 ml, 5.0 vol. ). The mixture was stirred for 15 minutes. The mixture was filtered through a pad of celite, and the celite layer was extracted with ethyl acetate (250 ml, 5.0 vol). The two-phase filtrate was separated and the organic layer was set aside and the aqueous layer was extracted with ethyl acetate (500 ml, 10.0 vol). The combined organic layers were washed with 10% brine (500 mL, 10.0 vol), dried over Na ₂ SO ₄ , filtered, and then concentrated in vacuo to give a crude solid. MTBE (250 mL, 5.0 vol) was added to the crude product and the resulting suspension was stirred for 30 min at room temperature. The solids were isolated by filtration, and then the bulk of the residual water was removed from said solids by vacuum filtration for 30-45 minutes. The wet product was dried in a hot air oven (50°C) for 2 hours to obtain the title product, N-(7-amino-4-chloro-1-(2,2,2-trifluoroethyl)-1H-indazole -3-yl)-N-(4-methoxybenzyl)methanesulfonamide (39.0 g, 83% yield) as an off-white solid. ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.25 (d, J=8.48 Hz, 2H), 6.98 (d, J=7.80 Hz, 1H), 6.79 (d, J=8.48 Hz, 2H), 6.66 (d, J=7.84 Hz, 1H), 5.35-4.75 (m, 4H), 3.77 (s, 3H), 3, 56 (bs, 2H), 2.98 (s, 3H).

The general procedures, general analytical methods, and general purification methods used to prepare Examples 80-151 are described above or described in detail below. The experimental procedure presented for each specific example identifies the general method used to prepare and purify this compound.

General Method I:

Pd(OAc) ₂ (0.1 eq.), dicyclohexyl (2',6'-dimethoxy-[1,1'-biphenyl]-2-yl)phosphane (0.2 eq.) was added to a vessel equipped with a stirrer. ), K ₃ PO ₄ (3 eq.) and N-((S)-1-(3-(4-chloro-1-(2,2-difluoroethyl)-3-(methylsulfonamido)-1H-indazole-7 -yl)-4-oxo-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-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 (1 eq., usually 50-100 mg). A suitable aryl halide or heteroaryl halide (3 eq.) was added to the vessel. The vessel was sealed with a septum stopper and then placed in an argon atmosphere (vacuum/fill x 3). THF:water (4:1) was added to the vessel to give a reaction volume of 0.05 M in boronic acid ester. The reaction mixture was degassed by evacuation/filling (x3) with argon. The reaction mixture was stirred at ambient temperature, 45°C or 60°C overnight (~18 hours). After cooling to room temperature, the reaction mixture was concentrated and the residue was purified by HPLC to give the title product.

General Method J:

Pd(OAc) ₂ (0.1 eq.), dicyclohexyl (2',6'-dimethoxy-[1,1'-biphenyl]-2-yl)phosphane (0.2 eq.) was added to a vessel equipped with a stirrer. ), K ₃ PO ₄ (3 eq.) and N-((S)-1-(3-(4-chloro-3-(cyclopropanesulfonamido)-1-(2,2-difluoroethyl)-1H-indazole-7 -yl)-4-oxo-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-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 (1 eq., usually 50-100 mg). A suitable aryl halide or heteroaryl halide (3 eq.) was added to the vessel. The vessel was sealed with a septum stopper and then placed in an argon atmosphere (vacuum/fill x 3). THF:water (4:1) was added to the vessel to give a reaction volume of 0.05 M in boronic acid ester. The reaction mixture was degassed by evacuation/filling (x3) with argon. The reaction mixture was stirred at ambient temperature, 45°C or 60°C overnight (~18 hours). After cooling to room temperature, the reaction mixture was concentrated and the residue was purified by HPLC to give the title product.

General Method Q:

In a dry reaction vessel equipped with a stirrer, Pd(OAc) ₂ (0.1 eq.), dicyclohexyl(2',6'-dimethoxy-[1,1'-biphenyl]-2-yl)phosphane ( 0.2 eq.), potassium orthophosphate (3 eq.) and N-((S)-1-(3-(4-chloro-3-(methylsulfonamido)-1-(2,2,2-trifluoroethyl)- 1H-indazol-7-yl)-4-oxo-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-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 (1 eq.). A suitable aryl halide or heteroaryl halide (3 eq.) was added to the vessel. The vessel was degassed with argon and THF/water (4:1, 0.05 M) was added. The mixture was degassed with argon and then stirred at ambient temperature, 45°C or 60°C overnight (approximately 18 hours). After cooling to ambient temperature, the mixture was purified by HPLC to obtain the desired product.

Method A LC-MS:

Column: Acquity VEN C18, 2.1 × 100 mm, 1.7 µm particles; solvent A=0.05% TFA in water; solvent B=acetonitrile; flow=0.45 ml/min; Gradient {time (min) / %V at time (%)}=0/3, 0.4/3, 7.5/98, 9.5/98, 9.6/3, 10/3 ; Column temperature=35°C.

Method B LC-MS:

Column: Acquity VEN C18, 2.1 × 50 mm, 1.7 µm particles; solvent A = 0.1% solution of formic acid in water; solvent B = 0.1% solution of formic acid in acetonitrile; flow=0.6 ml/min; Gradient {time (min) / %V at time (%)}=0/3, 0.4/3, 3.2/98, 3.8/98, 4.2/3, 4.5 /3; Column temperature=35°C.

LC-MS Method D:

Column: Acquity VEN C18, 2.1 × 50 mm, 1.7 µm particles; solvent A = 0.1% solution of formic acid in water; solvent B = 0.1% solution of formic acid in acetonitrile; flow=0.6 ml/min; Gradient {time (min) / %V at time (%)}=0/3, 0.4/3, 7.5/98, 9.5/98, 9.6/3, 10/3 ; Column temperature=35°C.

LC-MS Method G:

Column: Acquity UPLC VEN C18, 2.1 × 100 mm, 1.7 µm particles; solvent A=95:5 water: MeCN with 0.1% formic acid; solvent B=5:95 water: MeCN with 0.1% formic acid; flow=0.8 ml/min; Gradient {time (min) / %V at time (%)}=0/0, 3.5/100, 4.5/100; UV detection=220 nm and 254 nm.

Preparation of Example 80: N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-4-oxo-7- (4-(trifluoromethyl)pyridin-2-yl)-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

The title compound was prepared according to General Procedure Q using 2-chloro-4-(trifluoromethyl)pyridine as a coupling agent. As a result of the experiment, we obtained the title compound, N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-4 -oxo-7-(4-(trifluoromethyl)pyridin-2-yl)-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. The sample was analyzed using LC-MS method F: retention time=1.59 min; observed ion=950.2 (M+H). ¹ H NMR (500 MHz, METHANOL-d4) δ ppm 9.02 (d, J=5.07 Hz, 1 N), 8.61 (d, J=1.19 Hz, 1 N), 8.35-8.47 (m, 3 N), 7, 77 (dd, J=5.07, 0.89 Hz, 1 N), 7.17-7.32 (m, 2 N), 6.57-6.81 (m, 4 H), 4.46 -4.57 (m, 2 H), 3.61 (s, 3 H), 3.49 (dd, J=14.01, 5.07 Hz, 1 H), 3.23 (s, 3 N ), 3.11 (dd, J=14.16, 9.39 Hz, 1 N), 2.37-2.46 (m, 2 N), 1.31-1.37 (m, 1 N) , 0.96-1.03 (m, 1 N).

Preparation of Example 81: N-((S)-1-((3P)-3-(4-chloro-3-(cyclopropanesulfonamido)-1-(2,2-difluoroethyl)-1H-indazol-7-yl)- 7-(2-methylpyrimidin-4-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.

The title compound was prepared according to General Procedure J using 4-chloro-2-methylpyrimidine as a coupling agent. As a result of the experiment, we obtained the title compound, N-((S)-1-((3P)-3-(4-chloro-3-(cyclopropanesulfonamido)-1-(2,2-difluoroethyl)-1H-indazol- 7-yl)-7-(2-methylpyrimidin-4-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. The sample was analyzed using LC-MS method F: retention time=1.38 min; observed ion 973.3 (M+H). 1H NMR (METHANOL-d4, 500 MHz) Shift 8.86 (d, 1H, J=5.4 Hz), 8.69 (s, 1H), 8.4-8.4 (m, 2H), 8 .02 (d, 1H, J=5.4 Hz), 7.40 (br d, 1H, J=7.7 Hz), 7.31 (d, 1H, J=8.0 Hz), 6, 80 (tt, 1H, J=2.2, 9.1 Hz), 6.70 (br t, 1H, J=54.8 Hz), 6.57 (br dd, 2H, J=2.1, 7.7 Hz), 6.04 (t, 1H, J=55.3 Hz), 4.77 (dd, 1H, J=4.8, 9.2 Hz), 4.6-4.7 ( m, 2H), 4.4-4.5 (m, 1H), 3.9-4.0 (m, 1H), 3.4-3.5 (m, 1H), 3.09 (dd, 1H, J=9.5, 14.0 Hz), 2.9-2.9 (m, 1H), 2.86 (s, 3H), 2.4-2.5 (m, 2H), 1 .3-1.4 (m, 1H), 1.1-1.2 (m, 2H), 0.9-1.0 (m, 3H)

Preparation of Example 82: N-((S)-1-((3P)-3-(4-chloro-3-(cyclopropanesulfonamido)-1-(2,2-difluoroethyl)-1H-indazol-7-yl)- 7-(4-ethyl-6-methylpyrimidin-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.

The title compound was prepared according to General Procedure J using 2-chloro-4-ethyl-6-methylpyramidine as a coupling agent. As a result of the experiment, we obtained the title compound, N-((S)-1-((3P)-3-(4-chloro-3-(cyclopropanesulfonamido)-1-(2,2-difluoroethyl)-1H-indazol- 7-yl)-7-(4-ethyl-6-methylpyrimidin-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. The sample was analyzed using LC-MS method F: retention time=1.5 min; observed ion=1001.3 (M+H). 1H NMR (METHANOL-d4, 500 MHz) Shift 8.94 (s, 1H), 8.70 (d, 1H, J=8.2 Hz), 8.39 (d, 1H, J=8.2 Hz ), 7.2-7.3 (m, 2H), 6.6-6.8 (m, 4H), 6.04 (br t, 1H, J=55.3 Hz), 4.8-4 .9 (m, 1H), 4.77 (dd, 1H, J=4.8, 9.5 Hz), 4.6-4.7 (m, 2H), 4.3-4.5 (m , 1H), 3.9-4.0 (m, 1H), 3.4-3.5 (m, 1H), 3.09 (dd, 1H, J=9.2, 14.3 Hz), 2.9-3.0 (m, 3H), 2.65 (s, 2H), 2.4-2.5 (m, 2H), 1.4-1.5 (m, 2H), 1, 3-1.4 (m, 2H), 1.1-1.2 (m, 2H), 0.9-1.1 (m, 4H)

Preparation of Example 83: N-((S)-1-((3P)-3-(4-chloro-3-(cyclopropanesulfonamido)-1-(2,2-difluoroethyl)-1H-indazol-7-yl)- 7-(4,6-dimethylpyridin-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.

The title compound was prepared according to General Procedure J using 2-bromo-4,6-dimethylpyridine as the coupling agent. As a result of the experiment, we obtained the title compound, N-((S)-1-((3P)-3-(4-chloro-3-(cyclopropanesulfonamido)-1-(2,2-difluoroethyl)-1H-indazol- 7-yl)-7-(4,6-dimethylpyridin-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 . The sample was analyzed using LC-MS method F: retention time=1.46 min; observed ion=986.2 (M+H). 1H NMR (METHANOL-d4, 500 MHz) Shift 8.45 (d, 1H, J=1.5 Hz), 8.38 (d, 1H, J=8.3 Hz), 8.23 (dd, 1H , J=1.5, 8.3 Hz), 7.72 (s, 1H), 7.39 (brd, 1H, J=7.7 Hz), 7.27 (d, 1H, J=8, 0 Hz), 7.24 (s, 1H), 6.8-6.8 (m, 1H), 6.71 (brt, 1H, J=54.8 Hz), 6.5-6.6 ( m, 2H), 6.04 (t, 1H, J=55.4 Hz), 4.77 (dd, 1H, J=5.1, 9.2 Hz), 4.6-4.7 (m , 2H), 4.39 (br dd, 1H, J=4.0, 14.5 Hz), 3.9-4.0 (m, 1H), 3.4-3.5 (m, 1H) , 3.08 (dd, 1H=9.2, 14.0 Hz), 2.92 (tt, 1H, J=4.9, 7.9 Hz), 2.64 (s, 3H), 2, 4-2.5 (m, 5H), 1.36 (dt, 1H, J=5.5, 7.5 Hz), 1.1-1.1 (m, 2H), 0.9-1, 1 (m, 3H)

Preparation of Example 84: N-((S)-1-((3P)-3-(4-chloro-3-(cyclopropanesulfonamido)-1-(2,2-difluoroethyl)-1H-indazol-7-yl)- 4-oxo-7-(4-(trifluoromethyl)pyrimidin-2-yl)-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.

The title compound was prepared according to General Procedure J using 2-chloro-4-(trifluoromethyl)pyrimidine as the coupling agent. As a result of the experiment, we obtained the title compound, N-((S)-1-((3P)-3-(4-chloro-3-(cyclopropanesulfonamido)-1-(2,2-difluoroethyl)-1H-indazol- 7-yl)-4-oxo-7-(4-(trifluoromethyl)pyrimidin-2-yl)-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 The sample was analyzed using LC-MS method F: retention time=1.33 min; observed ion=1027.2 (M+H). 1H NMR (METHANOL-d4, 500 MHz) Shift 9.32 (d, 1H, J=5.1 Hz), 9.03 (s, 1H), 8.77 (dd, 1H, J=1.8, 8.3 Hz), 8.45 (d, 1H, J=8.3 Hz), 7.92 (d, 1H, J=5.1 Hz), 7.41 (br d, 1H, J=7 ,7 Hz), 7.33 (d, 1H, J=8.0 Hz), 6.8-6.8 (m, 1H), 6.69 (t, 1H, J=54.8 Hz), 6.57 (br dd, 2H, J=2.1, 8.0 Hz), 6.04 (t, 1H, J=55.3 Hz), 4.7-4.8 (m, 2H), 4.6-4.7 (m, 1H), 4.3-4.5 (m, 1H), 3.96 (br dd, 1H, J=2.8, 13.9 Hz), 3.4 -3.5 (m, 1H), 3.09 (dd, 1H, J=9.5, 14.0 Hz), 2.92 (tt, 1H, J=4.8, 8.0 Hz), 2.4-2.5 (m, 2H), 1.36 (dt, 1H, J=6.6, 7.3 Hz), 1.1-1.1 (m, 2H), 1.0- 1.0 (m, 3H)

Preparation of Example 85: N-((S)-1-((3P)-3-(4-chloro-3-(cyclopropanesulfonamido)-1-(2,2-difluoroethyl)-1H-indazol-7-yl)- 7-(2,6-dimethylpyrimidin-4-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.

The title compound was prepared according to General Procedure J using 4-chloro-2,6-dimethylpyrimidine as the coupling agent. As a result of the experiment, we obtained the title compound, N-((S)-1-((3P)-3-(4-chloro-3-(cyclopropanesulfonamido)-1-(2,2-difluoroethyl)-1H-indazol- 7-yl)-7-(2,6-dimethylpyrimidin-4-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 . The sample was analyzed using LC-MS method F: retention time=1.61 min; observed ion=987.3 (M+H). 1H NMR (METHANOL, 500 MHz) Shift 8.67 (d, 1H, J=1.2 Hz), 8.4-8.4 (m, 2H), 7.91 (s, 1H), 7.40 (br d, 1H, J=8.0 Hz), 7.30 (d, 1H, J=7.7 Hz), 6.8-6.8 (m, 1H), 6.71 (br t, 1H, J=54.8 Hz), 6.5-6.6 (m, 2H), 6.04 (br t, 1H, J=55.3 Hz), 4.77 (dd, 1H, J= 4.8, 9.2 Hz), 4.6-4.7 (m, 2H), 4.3-4.4 (m, 1H), 3.9-4.0 (m, 1H), 3 ,4-3.5 (m, 1H), 3.09 (dd, 1H, J=9.4, 13.9 Hz), 2.92 (tt, 1H, J=4.8, 8.0 Hz ), 2.81 (s, 3H), 2.66 (s, 3H), 2.4-2.5 (m, 2H), 1.3-1.4 (m, 1H), 1.1- 1.1 (m, 2H), 1.0-1.0 (m, 3H)

Preparation of Example 86: N-((S)-1-((3P)-3-(4-chloro-3-(cyclopropanesulfonamido)-1-(2,2-difluoroethyl)-1H-indazol-7-yl)- 7-(4-(difluoromethyl)pyrimidin-2-yl)-4-oxo-3,4-detidroquinazolin-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.

The title compound was prepared according to General Procedure J using 2-chloro-4-(difluoromethyl)pyrimidine as the coupling agent. As a result of the experiment, we obtained the title compound, N-((S)-1-((3P)-3-(4-chloro-3-(cyclopropanesulfonamido)-1-(2,2-difluoroethyl)-1H-indazol- 7-yl)-7-(4-(difluoromethyl)pyrimidin-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 The sample was analyzed using LC-MS method F: retention time=1.49 min; observed ion=1009.2 (M+H). 1H NMR (METHANOL-d4, 500 MHz) Shift 9.21 (d, 1H, J=5.1 Hz), 9.01 (d, 1H, J=1.8 Hz), 8.76 (dd, 1H , J=1.5, 8.3 Hz), 8.43 (d, 1H, J=8.3 Hz), 7.78 (d, 1H, J=5.1 Hz), 7.41 (br d, 1H, J=7.7 Hz), 7.32 (d, 1H, J=8.0 Hz), 6.5-7.0 (m, 5H), 6.05 (br t, 1H, J=55.3 Hz), 4.77 (dd, 1H, J=4.8, 9.5 Hz), 4.6-4.7 (m, 2H), 4.4-4.5 (m , 1H), 3.96 (br dd, 1H, J=3.4, 14.8 Hz), 3.4-3.5 (m, 1H), 3.09 (dd, 1H, J=9, 5, 14.3 Hz), 2.92 (tt, 1H, J=4.8, 8.0 Hz), 2.4-2.5 (m, 2H), 1.3-1.4 (m , 1H), 1.1-1.1 (m, 2H), 0.9-1.0 (m, 3H)

Preparation of Example 87: N-((S)-1-((3P)-3-(4-chloro-3-(cyclopropanesulfonamido)-1-(2,2-difluoroethyl)-1H-indazol-7-yl)- 7-(5,6-dimethyl-1,2,4-triazin-3-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]pyrazole-1- yl)acetamide.

The title compound was prepared according to General Procedure J using 3-chloro-5,6-dimethyl-1,2,4-triazine as the coupling agent. As a result of the experiment, we obtained the title compound, N-((S)-1-((3P)-3-(4-chloro-3-(cyclopropanesulfonamido)-1-(2,2-difluoroethyl)-1H-indazol- 7-yl)-7-(5,6-dimethyl-1,2,4-triazin-3-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. The sample was analyzed using LC-MS method F: retention time=1.54 min; observed ion=988.3 (M+H). 1H NMR (METHANOL-d4, 500 MHz) Shift 8.98 (d, 1H, J=1.5 Hz), 8.73 (dd, 1H, J=1.8, 8.3 Hz), 8.44 (d, 1H, J=8.4 Hz), 7.41 (br d, 1H, J=8.0 Hz), 7.32 (d, 1H, J=8.0 Hz), 6.6- 6.8 (m, 4H), 6.04 (br t, 1H, J=55.3 Hz), 4.77 (dd, 1H, J=4.8, 9.5 Hz), 4.6- 4.7 (m, 2H), 4.3-4.5 (m, 1H), 3.9-4.0 (m, 1H), 3.43 (dd, 1H, J=4.6,14 ,2 Hz), 3.09 (dd, 1H, J=9.5, 14.3 Hz), 2.9-2.9 (m, 1H), 2.81 (s, 3H), 2.75 (s, 3H), 2.4-2.5 (m, 2H), 1.3-1.4 (m, 1H), 1.1-1.2 (m, 2H), 0.9-1 ,1 (m, 3H)

Preparation of Example 88: R-((S)-1-((3P)-3-(4-chloro-3-(cyclopropanesulfonamido)-1-(2,2-difluoroethyl)-1H-indazol-7-yl)- 7-(6-methylpyridazin-3-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.

The title compound was prepared according to General Procedure J using 3-chloro-6-methylpyridazine as the coupling agent. As a result of the experiment, we obtained the title compound, N-((S)-1-((3P)-3-(4-chloro-3-(cyclopropanesulfonamido)-1-(2,2-difluoroethyl)-1H-indazol- 7-yl)-7-(6-methylpyridazin-3-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. The sample was analyzed using LC-MS method F: retention time=1.49 min; observed ion=973.4 (M+H). 1H NMR (METHANOL-d4, 500 MHz) Shift 8.63 (d, 1H, J=1.8 Hz), 8.45 (d, 1H, J=8.3 Hz), 8.36 (dd, 1H , J=1.5, 8.3 Hz), 8.31 (d, 1H, J=8.9 Hz), 7.83 (d, 1H, J=8.9 Hz), 7.40 (d , 1H, J=7.7 Hz), 7.31 (d, 1H, J=8.0 Hz), 6.5-6.8 (m, 4H), 6.05 (t, 1H, J= 55.4 Hz), 4.7 (dd, 1H, J=4.8, 9.2 Hz), 4.6-4.7 (m, 2H), 4.4-4.4 (m, 1H ), 3.96 (br d, 1H, J=11.3 Hz), 3.4-3.5 (m, 1H), 3.10 (dd, 1H, J=9.5, 14.0 Hz ), 2.9-3.0 (m, 1H), 2.82 (s, 3H), 2.4-2.5 (m, 2H), 1.3-1.4 (m, 1H), 1.1-1.2 (m, 2H), 0.9-1.1 (m, 3H)

Preparation of Example 89: R-((S)-1-((3P)-3-(4-chloro-3-(cyclopropanesulfonamido)-1-(2,2-difluoroethyl)-1H-indazol-7-yl)- 4-oxo-7-(pyridazin-3-yl)-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.

The title compound was prepared according to General Procedure J using 3-chloropyridazine as the coupling agent. As a result of the experiment, we obtained the title compound, N-((S)-1-((3P)-3-(4-chloro-3-(cyclopropanesulfonamido)-1-(2,2-difluoroethyl)-1H-indazol- 7-yl)-4-oxo-7-(pyridazin-3-yl)-3,4-dihydroquinazolin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR) -3-(difluoromethyl)-5,5-dafluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide. The sample was analyzed using LC-MS method F: retention time=1.41 min; observed ion=959.2 (M+H). 1H NMR (METHANOL-d4, 500 MHz) Shift 9.31 (dd, 1H, J=1.5,4.8 Hz), 8.66 (d, 1H, J=1.2 Hz), 8.4 -8.5 (m, 3H), 7.9-8.0 (m, 1H), 7.4-7.4 (m, 1H), 7.31 (d, 1H, J=8.0 Hz ), 6.5-6.8 (m, 4H), 6.05 (br t, 1H, J=55.4 Hz), 4.78 (dd, 1H, J=4.8, 9.5 Hz ), 4.6-4.7 (m, 2H), 4.4-4.4 (m, 1H), 3.9-4.0 (m, 1H), 3.4-3.5 (m , 1H), 3.10 (dd, 1H, J=9.5, 14.0 Hz), 2.9-2.9 (m, 1H), 2.4-2.5 (m, 2H), 1.2-1.4 (m, 1H), 1.1-1.1 (m, 2H), 0.9-1.1 (m, 3H)

Preparation of Example 90: N-((S)-1-((3P)-3-(4-chloro-3-(cyclopropanesulfonamido)-1-(2,2-difluoroethyl)-1H-indazol-7-yl)- 7-(6-methoxypyridazin-3-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.

The title compound was prepared according to General Procedure J using 3-chloro-6-methoxypyridazine as the coupling agent. As a result of the experiment, we obtained the title compound, N-((S)-1-((3P)-3-(4-chloro-3-(cyclopropanesulfonamido)-1-(2,2-difluoroethyl)-1H-indazol- 7-yl)-7-(6-methoxypyridazin-3-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. The sample was analyzed using LC-MS method F: retention time = 1.4 min; observed ion = 989.2 (M+H). 1H NMR (METHANOL-d4, 500 MHz) Shift 8.5-8.6 (m, 1H), 8.43 (d, 1H, J=8.2 Hz), 8.30 (s, 1H), 8 ,3-8.3 (m, 1H), 7.39 (d, 2H, J=9.2 Hz), 7.29 (d, 1H, J=8.0 Hz), 6.5-6, 9 (m, 4H), 6.05 (t, 1H, J=55.3 Hz), 4.77 (dd, 1H, J=4.9, 9.4 Hz), 4.6-4.7 (m, 2H), 4.3-4.4 (m, 1H), 4.23 (s, 3H), 3.95 (br dd, 1H, J=3.6, 14.9 Hz), 3 ,4-3.5 (m, 1H), 3.09 (dd, 1H, J=9.2, 14.0 Hz), 2.9-2.9 (m, 1H), 2.4-2 .5 (m, 2H), 1.3-1.4 (m, 1H), 1.1-1.1 (m, 2H), 1.0-1.1 (m, 3H)

Preparation of Example 91: N-((S)-1-((3P)-3-(4-chloro-3-(cyclopropanesulfonamido)-1-(2,2-difluoroethyl)-1H-indazol-7-yl)- 7-(2-isopropylpyrimidin-4-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.

The title compound was prepared according to General Procedure J using 4-chloro-2-isopropylpyrimidine as the coupling agent. As a result of the experiment, we obtained the title compound, N-((S)-1-((3P)-3-(4-chloro-3-(cyclopropanesulfonamido)-1-(2,2-difluoroethyl)-1H-indazol- 7-yl)-7-(2-isopropylpyrimidin-4-yl)-4-oxo-3,4-dihydroquinazolin-2-yl)-2-(3,5-difluorophene)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. The sample was analyzed using LC-MS method F: retention time = 11.49 min; observed ion = 1001.3 (M+H). 1H NMR (METHANOL-d4, 500 MHz) Shift 8.88 (d, 1H, J=5.4 Hz), 8.8-8.8 (m, 1H), 8.44 (s, 2H), 8 .02 (d, 1H, J=5.4 Hz), 7.41 (br d, 1H, J=7.5 Hz), 7.32 (d, 1H, J=7.7 Hz), 6, 5-6.8 (m, 4H), 6.04 (t, 1H, J=55.4 Hz), 4.77 (dd, 1H, J=4.8, 9.5 Hz), 4.6 -4.7 (m, 2H), 4.40 (br dd, 1H, J=3.6, 14.6 Hz), 3.9-4.0 (m, 1H), 3.4-3, 5 (m, 1H), 3.3-3.4 (m, 1H), 3.10 (dd, 1H, J=9.5, 14.0 Hz), 2.9-2.9 (m, 1H), 2.4-2.5 (m, 2H), 1.49 (d, 6H, J=6.9 Hz, 1.3-1.4 (m, 1H), 1.1-1, 1 (m, 2H), 0.9-1.0 (m, 3H)

Preparation of Example 92: N-((S)-1-((3P)-3-(4-chloro-3-(cyclopropanesulfonamido)-1-(2,2-difluoroethyl)-1H-indazol-7-yl)- 4-oxo-7-(2,5,6-trimethylpyrimidin-4-yl)-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.

The title compound was prepared according to General Procedure J using 4-chloro-2,5,6-trimethylpyrimidine as the coupling agent. As a result of the experiment, we obtained the title compound, N-((S)-1-((3P)-3-(4-chloro-3-(cyclopropanesulfonamido)-1-(2,2-difluoroethyl)-1H-indazol- 7-yl)-4-oxo-7-(2,5,6-trimethylpyrimidin-4-yl)-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. The sample was analyzed using LC-MS method F: retention time = 11.42 min; observed ion = 1001.2 (M+H). 1H NMR (METHANOL-d4, 500 MHz) Shift 8.42 (d, 1H, J=7.7 Hz), 8.02 (d, 1H, J=1.2 Hz), 7.8-7.8 (m, 1H), 7.41 (br d, 1H, J=7.7 Hz), 7.32 (d, 1H, J=8.0 Hz), 6.5-6.8 (m, 4H ), 6.05 (t, 1H, J=55.4 Hz), 4.76 (dd, 1H, J=4.8, 9.2 Hz), 4.6-4.7 (m, 2H) , 4.40 (br dd, 1H, J=4.0, 14.5 Hz), 3.9-4.0 (m, 1H), 3.4-3.5 (m, 1H), 3, 07 (dd, 1H, J=9.5, 14.0 Hz), 2.92 (tt, 1H, J=4.8, 8.0 Hz), 2.72 (s, 3H), 2.65 (s, 3H), 2.4-2.5 (m, 2H), 2.36 (s, 3H), 1.2-1.4 (m, 1H), 1.1-1.2 (m , 2H), 0.9-1.0 (m, 3H)

Preparation of Example 93: N-((S)-1-((3P)-3-(4-chloro-3-(cyclopropanesulfonamido)-1-(2,2-difluoroethyl)-1H-indazol-7-yl)- 7-(4-ethylpyrimidin-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.

The title compound was prepared according to General Procedure J using 2-chloro-4-ethylpyrimidine as a coupling agent. As a result of the experiment, we obtained the title compound, N-((S)-1-((3P)-3-(4-chloro-3-(cyclopropanesulfonamido)-1-(2,2-difluoroethyl)-1H-indazol- 7-yl)-7-(4-ethylpyrimidin-2-yl)-4-oxo-3,4-dagadroquinazolin-2-yl)-2-(3,5-dafluorophenyl)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. The sample was analyzed using LC-MS method F: retention time = 11.33 min; observed ion = 987.2 (M+H). 1H NMR (METHANOL-d4, 500 MHz) Shift 8.96 (s, 1H), 8.85 (d, 1H, J=5.1 Hz), 8.71 (dd, 1H, J=1.5, 8.3 Hz), 8.40 (d, 1H, J=8.3 Hz), 7.4-7.4 (m, 2H), 7.31 (d, 1H, J=7.7 Hz) , 6.8-6.8 (m, 1H), 6.70 (br t, 1H, J=54.8 Hz), 6.5-6.6 (m, 2H), 6.04 (br t, 1H , J=55.3 Hz), 4.77 (dd, 1H, J=4.8, 9.5 Hz), 4.6-4.7 (m, 2H), 4.3-4.4 ( m, 1H), 3.9-4.0 (m, 1H), 3.43 (dd, 1H, J=4.8, 14.0 Hz), 3.09 (dd, 1H, J=9.5, 14.3 Hz), 2.9-3.0 (m, 3H), 2.4-2.5 (m, 2H), 1.46 (t, 3H, J=7.6 Hz), 1, 3-1.4 (m, 1H), 1.1-1.1 (m, 2H), 0.9-1.1 (m, 3H)

Preparation of Example 94: N-((S)-1-((3P)-3-(4-chloro-3-(cyclopropanesulfonamido)-1-(2,2-difluoroethyl)-1H-indazol-7-yl)- 7-(6-ethyl-2-methylpyrimidin-4-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.

The title compound was prepared according to General Procedure J using 4-chloro-6-ethyl-2-methylpyrimidine as a coupling agent. As a result of the experiment, we obtained the title compound, N-((S)-1-((3P)-3-(4-chloro-3-(cyclopropanesulfonamido)-1-(2,2-difluoroethyl)-1H-indazol- 7-yl)-7-(6-ethyl-2-methylpyrimidin-4-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. The sample was analyzed using LC-MS method F: retention time = 11.49 min; observed ion = 1001.2 (M+H). 1H NMR (METAHOJI-d4, 500 MHz) Shift 8.66 (d, 1H, J=1.8 Hz), 8.4-8.4 (m, 2H), 7.90 (s, 1H), 7 ,4-7.4 (m, 1H), 7.31 (d, 1H, J=7.7 Hz), 6.8-6.8 (m, 1H), 6.71 (br t, 1H, J=54.8 Hz), 6.5-6.6 (m, 2H), 6.04 (t, 1H, J=55.3 Hz), 4.77 (dd, 1H, J=4.8 , 9.5 Hz), 4.6-4.7 (m, 2H), 4.40 (br dd, 1H, J=3.3, 14.6 Hz), 3.95 (br dd, 1H, J=3.6, 14.9 Hz), 3.4-3.5 (m, 1H), 3.09 (dd, 1H, J=9.5, 14.0 Hz), 2.9-3 .0 (m, 3H), 2.82 (s, 3H), 2.4-2.5 (m, 2H), 1.3-1.4 (m, 4H), 1.1-1.1 (m, 2H), 0.9-1.0 (m, 3H)

Preparation of Example 95: N-((S)-1-((3P)-3-(4-chloro-3-(cyclopropanesulfonamido)-1-(2,2-difluoroethyl)-1H-indazol-7-yl)- 7-(3-(methylsulfonyl)pyridin-2-yl)-4-oxo-3,4-dihydroquinazootn-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.

The title compound was prepared according to General Procedure J using 2-chloro-3-(methylsulfonyl)pyridine as the coupling agent. As a result of the experiment, we obtained the title compound, N-((S)-1-((3P)-3-(4-chloro-3-(cyclopropanesulfonamido)-1-(2,2-difluoroethyl)-1H-indazol- 7-yl)-7-(3-(methylsulfonyl)pyridin-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 The sample was analyzed using LC-MS method F: retention time = 11.34 min; observed ion = 1036.3 (M+H). 1H NMR (METHANOL-d4, 500 MHz) Shift 8.98 (dd, 1H, J=1.5, 4.8 Hz), 8.69 (dd, 1H, J=1.6, 8.2 Hz) , 8.41 (d, 1H, J=8.3 Hz), 8.13 (d, 1H, J=2.1 Hz), 7.8-7.9 (m, 2H), 7.41 ( d, 1H, J=7.8 Hz), 7.34 (d, 1H, J=7.7 Hz), 6.7-6.8 (m, 1H), 6.69 (br t, 1H, J=54.8 Hz), 6.5-6.6 (m, 2H), 6.06 (t, 1H, J=55.3 Hz), 4.79 (dd, 1H, J=4.8 , 9.5 Hz), 4.6-4.6 (m, 2H), 4.4-4.5 (m, 1H), 3.9-4.0 (m, 1H), 3.4- 3.5 (m, 1H), 3.08 (dd, 1H, J=9.4, 14.2 Hz), 2.9-3.0 (m, 4H), 2.43 (ddd, 2H, J=4.0, 7.6, 11.3 Hz), 1.7-1.8 (m, 1H), 1.1-1.2 (m, 2H), 0.9-1.1 ( m, 3H)

Preparation of Example 96: N-((S)-1-((3P)-3-(4-chloro-3-(cyclopropanesulfonamido)-1-(2,2-difluoroethyl)-1H-indazol-7-yl)- 7-(3-fluoro-6-methylpyridin-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.

The title compound was prepared according to General Procedure J using 2-chloro-3-fluoro-6-methylpyridine as the coupling agent. As a result of the experiment, we obtained the title compound, N-((S)-1-((3P)-3-(4-chloro-3-(cyclopropanesulfonamido)-1-(2,2-difluoroethyl)-1H-indazol- 7-yl)-7-(3-fluoro-6-methylpyridin-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. The sample was analyzed using LC-MS method F: retention time = 11.46 min; observed ion 990.3 (M+H). 1H NMR (METHANOL-d4, 500 MHz) Shift 8.44 (t, 1H, J=1.3 Hz), 8.40 (d, 1H, J=8.3 Hz), 8.23 (d, 1H , J=8.1 Hz), 7.70 (dd, 1H, J=8.5, 10.9 Hz), 7.4-7.5 (m, 2H), 7.30 (d, 1H, J=8.0 Hz), 6.8-6.8 (m, 1H), 6.69 (t, 1H, J=54.8 Hz), 6.5-6.6 (m, 2H), 6.05 (t, 1H, J=55.4 Hz), 4.77 (dd, 1H, J=4.8, 9.5 Hz), 4.6-4.7 (m, 2H), 4 .40 (br dd, 1H, J=3.9, 15.2 Hz), 3.9-4.0 (m, 1H), 3.4-3.5 (m, 1H), 3.08 ( dd, 1H, J=9.5, 14.0 Hz), 2.92 (tt, 1H, J=4.8, 8.0 Hz), 2.67 (s, 3H), 2.4-2 .5 (m, 2H), 1.36 (dt, 1H, J=5.4, 7.5 Hz), 1.1-1.1 (m, 2H), 0.9-1.0 (m , 3H)

Preparation of Example 97: N-((S)-1-((3P)-3-(4-chloro-3-(cyclopropanesulfonamido)-1-(2,2-difluoroethyl)-1H-indazol-7-yl)- 7-(2-methylthiazol-5-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.

The title compound was prepared according to General Procedure J using 5-bromo-2-methylthiazole as the coupling agent. As a result of the experiment, we obtained the title compound, N-((S)-1-((3P)-3-(4-chloro-3-(cyclopropanesulfonamido)-1-(2,2-difluoroethyl)-1H-indazol- 7-yl)-7-(2-methylthiazol-5-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. The sample was analyzed using LC-MS method F: retention time = 11.44 min; observed ion 978.3 (M+H). 1H NMR (METHANOL-d4, 500 MHz) Shift 8.37 (d, 1H, J=1.8 Hz), 8.35 (d, 1H, J=8.3 Hz), 8.17 (dd, 1H , J=1.8, 8.3 Hz), 7.73 (s, 1H), 7.40 (br d, 1H, J=7.7 Hz), 7.30 (d, 1H, J=7 ,7 Hz), 6.80 (tt, 1H, J=2.4, 9.2 Hz), 6.69 (t, 1H, J=54.8 Hz), 6.5-6.6 (m , 2H), 6.04 (t, 1H, J=55.3 Hz), 4.7-4.8 (m, 2H), 4.6-4.6 (m, 1H), 4.3- 4.4 (m, 1H), 3.95 (br dd, 1H, J=3.0, 14.0 Hz), 3.4-3.5 (m, 1H), 3.08 (dd, 1H , J=9.5,14.0 Hz), 2.92 (tt, 1H, J=4.8, 8.0 Hz), 2.64 (d, 3H, J=1.2 Hz), 2 .4-2.5 (m, 2H), 1.3-1.4 (m, 1H), 1.1-1.1 (m, 2H), 0.9-1.1 (m, 3H)

Preparation of Example 98: N-((S)-1-((3P)-3-(4-chloro-3-(cyclopropanesulfonamido)-1-(2,2-difluoroethyl)-1H-indazol-7-yl)- 7-(5-methoxypyrimidin-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.

The title compound was prepared according to General Procedure J using 2-chloro-5-methoxypyrimidine as the coupling agent. As a result of the experiment, we obtained the title compound, N-((S)-1-((3P)-3-(4-chloro-3-(cyclopropanesulfonamido)-1-(2,2-difluoroethyl)-1H-indazol- 7-yl)-7-(5-methoxypyrimidin-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. The sample was analyzed using LC-MS method F: retention time = 11.47 min; observed ion = 989.2 (M+H). 1H NMR (METHANOL-d4, 500 MHz) Shift 8.86 (s, 1H), 8.70 (s, 2H), 8.64 (dd, 1H, J=1.8, 8.3 Hz), 8 .36 (d, 1H, J=8.1 Hz), 7.40 (d, 1H, J=7.5 Hz), 7.29 (d, 1H, J=7.7 Hz), 6.8 -6.8 (m, 1H), 6.70 (brt, 1H, J=54.8 Hz), 6.5-6.6 (m, 2H), 6.04 (t, 1H, J=55 ,3 Hz), 4.77 (dd, 1H, J=4.8, 9.5 Hz), 4.69 (d, 1H, J=16.7 Hz), 4.61 (d, 1H, J =16.7 Hz), 4.3-4.4 (m, 1H), 4.08 (s, 3H), 3.9-4.0 (m, 1H), 3.4-3.5 ( m, 1H), 3.09 (dd, 1H, 9.4, J=14.2 Hz), 2.92 (tt, 1H=4.8, 8.0 Hz), 2.4-2.5 (m, 2H), 1.3-1.4 (m, 1H), 1-1.1 (m, 2H), 0.9-1.0 (m, 3H)

Preparation of Example 99: N-((S)-1-((3P)-3-(4-chloro-3-(cyclopropanesulfonamido)-1-(2,2-difluoroethyl)-1H-indazol-7-yl)- 7-(2-methoxypyrimidin-5-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.

The title compound was prepared according to General Procedure J using 5-bromo-2-methoxypyrimidine as the coupling agent. As a result of the experiment, we obtained the title compound, N-((S)-1-((3P)-3-(4-chloro-3-(cyclopropanesulfonamido)-1-(2,2-difluoroethyl)-1H-indazol- 7-yl)-7-(2-methoxypyrimidin-5-yl)-4-oxo-3,4-dihydroquinazolin-2-yl)-2-(3,5-difluorofegosh)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. The sample was analyzed using LC-MS method F: retention time = 11.56 min; observed ion = 989.2 (M+H). 1H NMR (METAHOJI-d4, 500 MHz) Shift 9.08 (s, 2H), 8.41 (d, 1H, J=8.1 Hz), 8.18 (d, 1H, J=1.8 Hz ), 7.99 (dd, 1H, J=1.8, 8.3 Hz), 7.39 (br d, 1H, J=7.5 Hz), 7.27 (d, 1H, J=8 ,0 Hz), 6.8-6.8 (m, 1H), 6.69 (t, 1H, J=54.8 Hz), 6.5-6.6 (m, 2H), 6.04 (t, 1H, J=55.4 Hz), 4.8-4.9 (m, 1H), 4.76 (dd, 1H, J=4.8, 9.2 Hz), 4.6- 4.7 (m, 2H), 4.3-4.4 (m, 1H), 4.14 (s, 2H), 3.9-4.0 (m, 1H), 3.4-3, 5 (m, 1H), 3.08 (dd, 1H, J=9.4, 14.2 Hz), 2.92 (tt, 1H, J=4.8, 8.0 Hz), 2.44 (ddd, 2H, J=4.0, 7.7, 11.2 Hz), 1.2-1.4 (m, 1H), 1.1-1.2 (m, 2H), 0.9 -1.1 (m, 3H)

Preparation of Example 100: N-((S)-1-((3P)-3-(4-chloro-3-(methylsulfonamido)-1-(2,2,2-trifluoroethyl)-1H-indazol-7-yl )-7-(2-methylpyrimidin-4-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.

The title compound was prepared according to General Procedure Q using 4-chloro-2-methylpyrimidine as a coupling agent. As a result of the experiment, we obtained the title compound, N-((S)-1-((3P)-3-(4-chloro-3-(methylsulfonamido)-1-(2,2,2-trifluoroethyl)-1H- indazol-7-yl)-7-(2-methylpyrimidin-4-yl)-4-oxo-3,4-digadroquinazolin-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 . The sample was analyzed using LC-MS method F: retention time = 11.4 min; observed ion = 963 (M-H). 1H NMR (METHANOL-d14, 500 MHz) Shift 8.86 (d, 1H, J=5.4 Hz), 8.68 (t, 1H, J=1.0 Hz), 8.42 (d, 2H , J=1.2 Hz), 8.01 (d, 1H, J=4.8 Hz), 7.4-7.5 (m, 2H), 6.7-6.8 (m, 1H) , 6.71 (br t, 1H, J=54.8 Hz), 6.5-6.5 (m, 2H), 4.7-4.8 (m, 3H), 4.66 (s, 1H), 4.21 (br d, 1H, J=7.7 Hz), 3.3-3.4 (m, 1H), 3.25 (s, 3H), 3.04 (dd, 1H, J=9.4, 14.2 Hz), 2.86 (s, 3H), 2.45 (br dd, 2H, J=4.2, 8.3 Hz), 1.37 (br dd, 1H , J=1.0, 6.7 Hz), 1.0-1.0 (m, 1H)

Preparation of Example 101: N-((S)-1-((3P)-3-(4-chloro-3-(methylsulfonamido)-1-(2,2,2-trifluoroethyl)-1H-indazol-7-yl )-7-(4,6-dimethylpyridin-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-cyclo1fopa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.

The title compound was prepared according to General Procedure Q using 2-bromo-4,6-dimethylpyridine as the coupling agent. As a result of the experiment, we obtained the title compound, N-((S)-1-((3P)-3-(4-chloro-3-(methylsulfonamido)-1-(2,2,2-trifluoroethyl)-1H- indazol-7-yl)-7-(4,6-dimethylpyridin-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. The sample was analyzed using LC-MS method F: retention time = 11.48 min; observed ion = 978.2 (M+H). 1H NMR (METHANOL-d4, 500 MHz) Shift 8.42 (d, 1H, J=1.2 Hz), 8.33 (d, 1H, J=8.3 Hz), 8.20 (dd, 1H , J=1.8, 8.3 Hz), 7.69 (s, 1H), 7.41 (br d, 1H, J=7.7 Hz), 7.32 (d, 1H, J=8 ,0 Hz), 7.22 (s, 1H), 6.4-6.8 (m, 4H), 4.6-4.8 (m, 4H), 4.18 (dd, 1H, J= 8.3, 16.1 Hz), 3.3-3.4 (m, 1H), 3.2-3.2 (m, 3H), 3.01 (dd, 1H, J=9.2, 14.0 Hz), 2.62 (s, 3H), 2.47 (s, 3H), 2.4-2.4 (m, 2H), 1.35 (br dd, 1H, J=1, 8, 8.0 Hz), 0.99 (dt, 1H, J=1.8, 3.7 Hz)

Preparation of Example 102: N-((S)-1-((3P)-3-(4-chloro-3-(methylsulfonamido)-1-(2,2,2-trifluoroethyl)-1H-indazol-7-yl )-4-oxo-7-(4-(trifluoromethyl)pyrimidin-2-yl)-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.

The title compound was prepared according to General Procedure Q using 2-chloro-4-(trifluoromethyl)pyrimidine as the coupling agent. As a result of the experiment, we obtained the title compound, N-((S)-1-((3P)-3-(4-chloro-3-(methylsulfonamido)-1-(2,2,2-trifluoroethyl)-1H- indazol-7-yl)-4-oxo-7-(4-(trifluorometal)pyrimidin-2-yl)-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]pyrazole-1- yl)acetamide. The sample was analyzed using LC-MS method F: retention time = 11.56 min; observed ion = 1019.2 (M+H). 1H NMR (METHANOL-d4, 500 MHz) Shift 9.29 (d, 1H, J=5.1 Hz), 8.99 (d, 1H, J=1.8 Hz), 8.74 (dd, 1H , J=1.8, 8.3 Hz), 8.40 (d, 1H, J=8.0 Hz), 7.90 (d, 1H, J=5.1 Hz), 7.4-7 ,4 (m, 2H), 6.7-6.8 (m, 1H), 6.67 (brt, 1H, J=54.8 Hz), 6.4-6.5 (m, 2H), 4.6-4.8 (m, 4H), 4.20 (dd, 1H, J=8.5, 16.2 Hz), 3.3-3.4 (m, 1H), 3.22 ( s, 3H), 3.02 (dd, 1H, J=9.5, 14.3 Hz), 2.4-2.5 (m, 2H), 1.3-1.4 (m, 1H) , 0.99 (dt, 1H, 2.2, 3.7 Hz)

Preparation of Example 103: N-((S)-1-((3P)-3-(4-chloro-3-(methylsulfonamido)-1-(2,2,2-trifluoroethyl)-1H-indazol-7-yl )-7-(2,6-dimethylpyrimidin-4-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.

The title compound was prepared according to General Procedure Q using 4-chloro-2,6-dimethylpyrimidine as the coupling agent. As a result of the experiment, we obtained the title compound, N-((S)-1-((3P)-3-(4-chloro-3-(methylsulfonamido)-1-(2,2,2-trifluoroethyl)-1H- indazol-7-yl)-7-(2,6-damethylpyrimidin-4-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. The sample was analyzed using LC-MS method F: retention time = 11.42 min; observed ion = 979.2 (M+H). 1H NMR (METHANOL-d4, 500 MHz) Shift 8.63 (d, 1H, J=1.5 Hz), 8.37 (s, 1H), 8.3-8.4 (m, 1H), 7 .88 (s, 1H), 7.4-7.5 (m, 1H), 7.35 (d, 1H, J=8.0 Hz), 6.7-6.8 (m, 1H), 6.69 (br t, 1H, J=54.8 Hz), 6.5-6.5 (m, 2H), 4.6-4.8 (m, 4H), 4.1-4.2 (m, 1H), 3.3-3.4 (m, 1H), 3.22 (s, 3H), 3.01 (dd, 1H, J=9.5, 14.0 Hz), 2, 79 (s, 3H), 2.63 (s, 3H), 2.4-2.5 (m, 2H), 1.3-1.4 (m, 1H), 0.99 (td, 1H, J=2,1,3,6 Hz)

Preparation of Example 104: N-((S)-1-((3P)-3-(4-chloro-3-(methylsulfonamido)-1-(2,2,2-trifluoroethyl)-1H-indazol-7-yl )-7-(4-(difluoromethyl)pyrimidin-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.

The title compound was prepared according to General Procedure Q using 2-chloro-4-(difluoromethyl)pyrimidine as the coupling agent. As a result of the experiment, we obtained the title compound, N-((S)-1-((3P)-3-(4-chloro-3-(methylsulfonamido)-1-(2,2,2-trifluoroethyl)-1H- indazol-7-yl)-7-(4-(difluoromethyl)pyrimidin-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]pyrazole-1- yl)acetamide. The sample was analyzed using LC-MS method F: retention time = 11.5 min; observed ion 999.2 (M-H). 1H NMR (METAHOJI-d4, 500 MHz) Shift 9.19 (d, 1H, J=5.1 Hz), 8.98 (d, 1H, J=1.2 Hz), 8.73 (dd, 1H , J=1.8, 8.3 Hz), 8.38 (d, 1H, J=8.3 Hz), 7.76 (d, 1H, J=5.1 Hz), 7.43 (d , 1H, J=8.0 Hz), 7.37 (d, 1H, J=8.0 Hz), 6.5-7.0 (m, 5H), 4.6-4.8 (m, 4H), 4.20 (d, 1H, J=8.0 Hz), 3.3-3.4 (m, 1H), 3.2-3.3 (m, 3H), 3.02 (dd , 1H, J=9.7, 14.2 Hz), 2.4-2.5 (m, 2H), 1.34 (br d, 1H, J=6.6 Hz), 0.99 (td , 1H, J=2.1, 3.6 Hz)

Preparation of Example 105: N-((S)-1-((3P)-3-(4-chloro-3-(methylsulfonamido)-1-(2,2,2-trifluoroethyl)-1H-indazol-7-yl )-7-(5,6-dimethyl-1,2,4-triazin-3-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.

The title compound was prepared according to General Procedure Q using 3-chloro-5,6-dimethyl-1,2,4-triazine as a coupling agent. As a result of the experiment, we obtained the title compound, N-((S)-1-((3P)-3-(4-chloro-3-(methylsulfonamido)-1-(2,2,2-trifluoroethyl)-1H- indazol-7-yl)-7-(5,6-dimethyl-1,2,4-triazin-3-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. The sample was analyzed using LC-MS method F: retention time = 11.43 min; observed ion 980.1 (M+H). 1H NMR (METAHOJI-d4, 500 MHz) Shift 8.97 (d, 1H, J=1.5 Hz), 8.72 (dd, 1H, J=1.5, 8.3 Hz), 8.42 (d, 1H, J=8.6 Hz), 7.4-7.5 (m, 2H), 6.8-6.8 (m, 1H), 6.71 (br t, 1H, J= 54.8 Hz), 6.51 (dd, 2H, J=1.9, 7.9 Hz), 4.7-4.8 (m, 4H), 4.22 (dd, 1H, J=8 ,3, 16.1 Hz), 3.3-3.4 (m, 1H), 3.25 (s, 3H), 3.04 (dd, 1H, J=9.5, 14.0 Hz) , 2.81 (s, 3H), 2.75 (s, 3H), 2.4-2.5 (m, 2H), 1.3-1.4 (m, 1H), 1.01 (dt , 1H, J=1.8, 3.7 Hz)

Preparation of Example 106: N-((S)-1-((3P)-3-(4-chloro-3-(methylsulfonamido)-1-(2,2,2-trifluoroethyl)-1H-indazol-7-yl )-7-(6-methylpyridazin-3-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.

The title compound was prepared according to General Procedure Q using 3-chloro-6-methylpyridazine as a coupling agent. As a result of the experiment, we obtained the title compound, N-((S)-1-((3P)-3-(4-chloro-3-(methylsulfonamido)-1-(2,2,2-trifluoroethyl)-1H- indazol-7-yl)-7-(6-methylpyridazin-3-yl)-4-oxo-3,4-digadroquinazolin-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 . The sample was analyzed using LC-MS method F: retention time = 11.34 min; observed ion 965.2 (M+H). 1H NMR (METHANOL-d4, 500 MHz) Shift 8.62 (d, 1H, J=1.5 Hz), 8.43 (d, 1H, J=8.3 Hz), 8.35 (dd, 1H , J=1.5, 8.3 Hz), 8.30 (d, 1H, J=8.6 Hz), 7.83 (d, 1H, J=8.6 Hz), 7.44 (br d, 1H, J=7.7 Hz), 7.37 (d, 1H, J=8.0 Hz), 6.8-6.8 (m, 1H), 6.70 (t, 1H, J =54.7 Hz), 6.5-6.5 (m, 2H), 4.7-4.8 (m, 4H), 4.22 (dd, 1H, J=8.3, 16.1 Hz), 3.3-3.4 (m, 1H), 3.2-3.3 (m, 3H), 3.04 (dd, 1H, J=9.5, 14.0 Hz), 2 .82 (s, 3H), 2.4-2.5 (m, 2H), 1.3-1.4 (m, 1H), 1.0-1.0 (m, 1H)

Preparation of Example 107: N-((S)-1-((3P)-3-(4-chloro-3-(methylsulfonamido)-1-(2,2,2-trifluoroethyl)-1H-indazol-7-yl )-4-oxo-7-(pyridazin-3-yl)-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.

The title compound was prepared according to General Procedure Q using 3-chloropyridazine as the coupling agent. As a result of the experiment, we obtained the title compound, N-((S)-1-((3P)-3-(4-chloro-3-(methylsulfonamido)-1-(2,2,2-trifluoroethyl)-1H- indazol-7-yl)-4-oxo-7-(pyridazin-3-yl)-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. The sample was analyzed using LC-MS method F: retention time = 11.31 min; observed ion = 951.2 (M+H). 1H NMR (METLIK-d4, 500 MHz) Shift 9.31 (dd, 1H, J=1.5, 5.1 Hz), 8.65 (d, 1H, J=1.2 Hz), 8.4 -8.5 (m, 3H), 7.95 (dd, 1H, J=5.1, 8.6 Hz), 7.45 (d, 1H, J=7.7 Hz), 7.38 ( d, 1H, J=8.0 Hz), 6.5-6.8 (m, 4H), 4.7-4.8 (m, 4H), 4.23 (dd, 1H, J=8, 2, 16.2 Hz), 3.3-3.4 (m, 1H), 3.2-3.3 (m, 3H), 3.05 (dd, 1H, J=9.5, 14, 3 Hz), 2.4-2.5 (m, 2H), 1.3-1.4 (m, 1H), 1.01 (dt, 1H, J=1.9, 3.7 Hz)

Preparation of Example 108: H-((S)-1-((3P)-3-(4-chloro-3-(methylsulfonamido)-1-(2,2,2-trifluoroethyl)-1H-indazol-7-yl )-7-(2-isopropylpyrimidin-4-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.

The title compound was prepared according to General Procedure Q using 4-chloro-2-isopropylpyrimidine as a coupling agent. As a result of the experiment, we obtained the title compound, N-((S)-1-((3P)-3-(4-chloro-3-(methylsulfonamido)-1-(2,2,2-trifluoroethyl)-1H- indazol-7-yl)-7-(2-isopropylpyrimidin-4-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 . The sample was analyzed using LC-MS method F: retention time = 11.54 min; observed ion = 993.3 (M+H). 1H NMR (METHANOL-d4, 500 MHz) Shift 8.88 (d, 1H, J=5.4 Hz), 8.76 (d, 1H, J=0.9 Hz), 8.4-8.5 (m, 2H), 8.01 (d, 1H, J=5.4 Hz), 7.45 (br d, 1H, J=7.5 Hz), 7.39 (d, 1H, J=8 ,0 Hz), 6.5-6.8 (m, 4H), 4.7-4.8 (m, 4H), 4.22 (dd, 1H, J=8.5, 16.2 Hz) , 3.4-3.4 (m, 1H), 3.2-3.3 (m, 3H), 3.05 (dd, 1H, J=9.7,13.9 Hz), 2.4 -2.5 (m, 2H), 1.49 (d, 6H, J=6.9 Hz), 1.36 (br dd, 2H, J=1.8, 7.7 Hz), 0.9 -1.0 (m, 1H)

Preparation of Example 109: H-((S)-1-((3P)-3-(4-chloro-3-(methylsulfonamido)-1-(2,2,2-trifluoroethyl)-1H-indazol-7-yl )-4-oxo-7-(2,5,6-trimethylpyrimidin-4-yl)-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.

The title compound was prepared according to General Procedure Q using 4-chloro-2,5,6-trimethylpyrimidine as the coupling agent. As a result of the experiment, we obtained the title compound, N-((S)-1-((3P)-3-(4-chloro-3-(methylsulfonamido)-1-(2,2,2-trifluoroethyl)-1H- indazol-7-yl)-4-oxo-7-(2,5,6-trimethylpyrimidin-4-yl)-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]pyrazole-1 -yl)acetamide. The sample was analyzed using LC-MS method F: retention time = 11.39 min; observed ion 993.2 (M+H). 1H NMR (METHANOL-d4, 500 MHz) Shift 8.40 (d, 1H, J=8.0 Hz), 8.00 (d, 1H, J=1.2 Hz), 7.8-7.8 (m, 1H), 7.4-7.5 (m, 1H), 7.4-7.4 (m, 1H), 6.7-6.8 (m, 1H), 6.69 (t , 1H, J=54.8 Hz), 6.5-6.5 (m, 2H), 4.6-4.8 (m, 4H), 4.21 (dd, 1H, J=8.0 , 16.4 Hz), 3.3-3.4 (m, 1H), 3.2-3.3 (m, 3H), 3.03 (dd, 1H, J=9.4, 14.2 Hz), 2.72 (s, 3H), 2.65 (s, 3H), 2.4-2.5 (m, 2H), 2.35 (s, 3H), 1.3-1.4 (m, 1H), 1.0-1.0 (m, 1H)

Preparation of Example 110: N-((S)-1-((3P)-3-(4-chloro-3-(methylsulfonamido)-1-(2,2,2-trifluoroethyl)-1H-indazol-7-yl )-7-(6-methoxypyridazin-3-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.

The title compound was prepared according to General Procedure Q using 3-chloro-6-methoxypyridazine as the coupling agent. As a result of the experiment, we obtained the title compound, N-((S)-1-((3P)-3-(4-chloro-3-(methylsulfonamido)-1-(2,2,2-trifluoroethyl)-1H- indazol-7-yl)-7-(6-methoxypyridazin-3-yl)-4-oxo-3,4-dihydroquinazolin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-(( 3bS,4aR)-3-(dafluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide . The sample was analyzed using LC-MS method F: retention time = 11.41 min; observed ion 981.2 (M+H). 1H NMR (METAHOJI-d4, 500 MHz) Shift 8.53 (d, 1H, J=1.8 Hz), 8.41 (d, 1H, J=8.3 Hz), 8.3-8.3 (m, 2H), 7.3-7.5 (m, 3H), 6.8-6.8 (m, 1H), 6.70 (t, 1H, J=54.8 Hz), 6, 5-6.5 (m, 2H), 4.7-4.8 (m, 4H), 4.1-4.2 (m, 4H), 3.4-3.4 (m, 1H), 3.24 (s, 3H), 3.04 (dd, 1H, J=9.5, 14.3 Hz), 2.4-2.5 (m, 2H), 1.3-1.4 ( m, 1H), 1.01 (td, 1H, J=2.1, 3.6 Hz)

Preparation of Example 111: N-((S)-1-((3P)-3-(4-chloro-3-(methylsulfonamido)-1-(2,2,2-trifluoroethyl)-1H-indazol-7-yl )-7-(4-ethylpyrimidin-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.

The title compound was prepared according to General Procedure Q using 2-chloro-4-ethylpyrimidine as a coupling agent. As a result of the experiment, we obtained the title compound, N-((S)-1-((3P)-3-(4-chloro-3-(methylsulfonamido)-1-(2,2,2-trifluoroethyl)-1H- indazol-7-yl)-7-(4-ethylpyrimidin-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 . The sample was analyzed using LC-MS method F: retention time = 11.55 min; observed ion = 979.2 (M+H). 1H NMR (METHANOL-d4, 500 MHz) Shift 8.95 (d, 1H, J=1.2 Hz), 8.85 (d, 1H, J=5.1 Hz), 8.71 (dd, 1H , J=1.5, 8.3 Hz), 8.38 (d, 1H, J=8.3 Hz), 7.4-7.5 (m, 3H), 6.8-6.8 ( m, 1H), 6.71 (t, 1H, J=54.7 Hz), 6.5-6.5 (m, 2H), 4.7-4.8 (m, 4H), 4.22 (dd, 1H, J=8.5, 16.2 Hz), 3.3-3.4 (m, 1H), 3.25 (s, 3H), 3.0-3.1 (m, 3H ), 2.4-2.5 (m, 2H), 1.4-1.5 (m, 3H), 1.3-1.4 (m, 1H), 1.0-1.0 (m , 1H)

Preparation of Example 112: N-((S)-1-((3P)-3-(4-chloro-3-(methylsulfonamido)-1-(2,2,2-trifluoroethyl)-1H-indazol-7-yl )-7-(3-(methylsulfonyl)pyridin-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.

The title compound was prepared according to General Procedure Q using 2-chloro-3-(methylsulfonyl)pyridine as the coupling agent. As a result of the experiment, we obtained the title compound, N-((S)-1-((3P)-3-(4-chloro-3-(methylsulfonamido)-1-(2,2,2-trifluoroethyl)-1H- indazol-7-yl)-7-(3-(methylsulfonyl)pyridin-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]pyrazole-1- yl)acetamide. The sample was analyzed using LC-MS method F: retention time = 11.35 min; observed ion = 1028.2 (M+H). 1H NMR (METHANOL-d4, 500 MHz) Shift 8.98 (dd, 1H, J=1.6,4.9 Hz), 8.69 (d, 1H, J=7.9 Hz), 8.39 (d, 1H, J=8.2 Hz), 8.11 (d, 1H, J=1.2 Hz), 7.8-7.9 (m, 2H), 7.4-7.5 ( m, 2H), 6.79 (br t, 1H, J=2.4 Hz), 6.69 (br t, 1H, J=54.8 Hz), 6.50 (br d, 2H, J= 6.3 Hz), 4.7-4.8 (m, 3H), 4.6-4.7 (m, 1H), 4.24 (s, 1H), 3.3-3.4 (m , 1H), 3.25 (s, 3H), 3.03 (dd, 1H, J=9.5, 14.0 Hz), 2.96 (s, 3H), 2.44 (ddd, 2H, J=3.9, 7.5, 11.3 Hz), 1.37 (br d, 1H, J=7.5 Hz), 1.01 (br dd, 1H, J=1.8, 3, 6 Hz)

Preparation of Example 113: N-((S)-1-((3P)-3-(4-chloro-3-(methylsulfonamido)-1-(2,2,2-trifluoroethyl)-1H-indazol-7-yl )-7-(3-fluoro-6-methylpyridin-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.

The title compound was prepared according to General Procedure Q using 2-chloro-3-fluoro-6-methylpyridine as the coupling agent. As a result of the experiment, we obtained the title compound, N-((S)-1-((3P)-3-(4-chloro-3-(methylsulfonamido)-1-(2,2,2-trifluoroethyl)-1H- indazol-7-yl)-7-(3-fluoro-6-methylpyridin-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]pyrazole-1 -yl)acetamide. The sample was analyzed using LC-MS method F: retention time = 11.53 min; observed ion 982.2 (M+H). 1H NMR (METHANOL-d4, 500 MHz) Shift 8.43 (s, 1H), 8.38 (d, 1H, J=8.3 Hz), 8.23 (td, 1H, J=1.3, 8.5 Hz), 7.70 (dd, 1H, J=8.5, 10.9 Hz), 7.4-7.5 (m, 3H), 6.8-6.8 (m, 1H ), 6.70 (br t, 1H, J=54.7 Hz), 6.50 (d, 2H, J=6.7 Hz), 4.6-4.8 (m, 4H), 4, 22 (dd, 1H, J=8.3, 16.4 Hz), 3.3-3.4 (m, 1H), 3.2-3.3 (m, 3H), 3.04 (dd, 1H, J=9.5, 14.3 Hz), 2.67 (s, 3H), 2.45 (td, 2H, J=3.6, 7.4 Hz), 1.3-1.4 (m, 1H), 1.0-1.0 (m, 1H)

Preparation of Example 114: N-((S)-1-((3P)-3-(4-chloro-3-(methylsulfonamido)-1-(2,2,2-trifluoroethyl)-1H-indazol-7-yl )-7-(2-methylthiazol-5-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.

The title compound was prepared according to General Procedure Q using 5-bromo-2-methylthiazole as a coupling agent. As a result of the experiment, we obtained the title compound, N-((S)-1-((3P)-3-(4-chloro-3-(methylsulfonamido)-1-(2,2,2-trifluoroethyl)-1H- indazol-7-yl)-7-(2-methyltaazol-5-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 . The sample was analyzed using LC-MS method F: retention time = 11.51 min; observed ion = 970.4 (M+H). 1H NMR (METHANOL-d4, 500 MHz) Shift 8.37 (d, 1H, J=1.8 Hz), 8.33 (d, 1H, J=8.3 Hz), 8.17 (dd, 1H , J=1.8, 8.3 Hz), 7.73 (d, 1H, J=1.2 Hz), 7.44 (br d, 1H, J=7.5 Hz), 7.38 ( d, 1H, J=8.0 Hz), 6.8-6.8 (m, 1H), 6.70 (br t, 1H, J=54.7 Hz), 6.50 (d, 2H, J=6.6 Hz), 4.7-4.8 (m, 4H), 4.2-4.3 (m, 1H), 3.3-3.4 (m, 1H), 3.2 -3.3 (m, 3H), 3.03 (dd, 1H, J=9.7,14.2 Hz), 2.64 (d, 3H, J=1.2 Hz), 2.4- 2.5 (m, 2H), 1.3-1.4 (m, 1H), 1.01 (td, 1H, J=2.1, 3.6 Hz)

Preparation of Example 115: N-((S)-1-((3P)-3-(4-chloro-3-(methylsulfonamido)-1-(2,2,2-trifluoroethyl)-1H-indazol-7-yl )-7-(5-methoxypyrimidin-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.

The title compound was prepared according to General Procedure Q using 2-chloro-5-methoxypyrimidine as the coupling agent. As a result of the experiment, we obtained the title compound, N-((S)-1-((3P)-3-(4-chloro-3-(methylsulfonamido)-1-(2,2,2-trifluoroethyl)-1H- indazol-7-yl)-7-(5-methoxypyrimidin-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 . The sample was analyzed using LC-MS method F: retention time = 11.47 min; observed ion 981.2 (M+H). 1H NMR (METHANOL-d4, 500 MHz) Shift 8.83 (d, 1H, J=2.1 Hz), 8.68 (s, 2H), 8.61 (dd, 1H, J=1.8, 8.3 Hz), 8.32 (d, 1H, J=8.9 Hz), 7.42 (br d, 1H, J=7.7 Hz), 7.34 (d, 1H, J=8 ,0 Hz), 6.7-6.8 (m, 1H), 6.68 (br t, 1H, J=54.8 Hz), 6.49 (d, 2H, J=6.6 Hz) , 4.6-4.8 (m, 4H), 4.1-4.2 (m, 1H), 4.05 (s, 3H), 3.3-3.4 (m, 1H), 3 ,2-3.2 (m, 3H), 3.02 (dd, 1H, J=9.5, 14.3 Hz), 2.43 (td, 2H, J=4.0, 8.0 Hz ), 1.35 (br dd, 1H, J=1.5, 6.9 Hz), 0.99 (td, 1H, J=2.1, 3.6 Hz)

Preparation of Example 116: N-((S)-1-((3P)-3-(4-chloro-3-(methylsulfonamido)-1-(2,2,2-trifluoroethyl)-1H-indazol-7-yl )-7-(2-methoxypyrimidin-5-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.

The title compound was prepared according to General Procedure Q using 5-bromo-2-methoxypyrimidine as a coupling agent. As a result of the experiment, we obtained the title compound, N-((S)-1-((3P)-3-(4-chloro-3-(methylsulfonamido)-1-(2,2,2-trifluoroethyl)-1H- indazol-7-yl)-7-(2-methoxypyrimidin-5-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 . The sample was analyzed using LC-MS method F: retention time = 11.39 min; observed ion = 981.3 (M+H). 1H NMR (METHANOL-d4, 500 MHz) Shift 9.05 (s, 2H), 8.36 (d, 1H, J=8.3 Hz), 8.14 (d, 1H, J=1.8 Hz ), 7.97 (dd, 1H, J=1.8, 8.3 Hz), 7.42 (d, 1H, J=8.0 Hz), 7.32 (d, 1H, J=8, 0 Hz), 6.5-6.8 (m, 2H), 6.48 (dd, 2H, J=1.9, 7.9 Hz), 4.7-4.8 (m, 4H), 4.19 (s, 1H), 4.12 (s, 3H), 3.3-3.4 (m, 1H), 3.23 (s, 3H), 3.01 (dd, 1H, J= 9.5, 14.0 Hz), 2.42 (dt, 2H, J=4.0, 7.4 Hz), 1.35 (br d, 1H, J=7.2 Hz), 0.99 (br dd, 1H, J=2.1, 3.6 Hz)

Preparation of Example 117: N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7-(6-( difluoromethyl)pyridin-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.

The title compound was prepared according to General Procedure D using 2-bromo-6-(difluoromethyl)pyridine as the coupling agent. As a result of the experiment, we obtained the title compound, N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7 -(6-(difluoromethyl)pyridin-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. The sample was analyzed using LC-MS method F: retention time = 11.42 min; observed ion = 930.1 (M-H). 1H NMR (METHANOL-d4, 500 MHz) Shift 9.2-9.2 (m, 1H), 8.88 (d, 1H, J=1.5 Hz), 8.47 (s, 1H), 8 .45 (d, 1H, J=8.0 Hz), 8.24 (d, 1H, J=1.5 Hz), 8.04 (dd, 1H, J=1.8, 8.0 Hz) , 7.33 (d, 1H, J=8.0 Hz), 7.23 (d, 1H, J=7.7 Hz), 7.09 (t, 1H, J=55.3 Hz), 6 ,6-6.8 (m, 4H), 4.8-4.9 (m, 1H), 4.54 (d, 2H, J=3.0 Hz), 3.64 (s, 3H), 3.51 (dd, 1H, J=5.1, 14.0 Hz), 3.26 (s, 3H), 3.13 (dd, 1H, J=9.4, 14.2 Hz), 2 .43 (dt, 2H, J=3.7, 7.5 Hz), 1.3-1.4 (m, 1H), 1.01 (br dd, 1H, J=1.8, 3.6 Hz)

Preparation of Example 118: N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7-(2-( hydroxymethyl)-6-methylpyrimidin-4-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.

The title compound was prepared according to General Procedure D using (4-chloro-6-methylpyrimidin-2-yl)methanol as the coupling agent. As a result of the experiment, we obtained the title compound, N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7 -(2-(hydroxymethyl)-6-methylpyrimidin-4-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. The sample was analyzed using LC-MS method F: retention time = 11.31 min; observed ion 9273 (M+H). 1H NMR (METHANOL-d4, 500 MHz) Shift 8.75 (d, 1H, J=0.9 Hz), 8.4-8.5 (m, 2H), 7.99 (s, 1H), 7 .31 (d, 1H, J=7.7 Hz), 7.22 (d, 1H, J=7.7 Hz), 6.8-6.8 (m, 1H), 6.71 (brt, 1H, J=54.7 Hz), 6.65 (dd, 2H, J=2.2, 8.2 Hz), 4.9-4.9 (m, 1H), 4.8-4.9 (m, 2H), 4.53 (s, 2H), 3.64 (s, 3H), 3.4-3.5 (m, 1H), 3.25 (s, 3H), 3.13 ( dd, 1H, J=8.9, 14.0 Hz), 2.70 (s, 3H), 2.4-2.5 (m, 2H), 1.36 (br d, 1H, J=5 .7 Hz), 1.01 (br dd, 1H, J=1.9, 3.4 Hz)

Preparation of Example 119: N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7-(5-fluoro -2,6-dimethylpyrimidin-4-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.

The title compound was prepared according to General Procedure D using 4-chloro-5-fluoro-2,6-dimethylpyrimidine as a coupling agent. As a result of the experiment, we obtained the title compound, N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7 -(5-fluoro-2,6-dimethylpyrimidin-4-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. The sample was analyzed using LC-MS method F: retention time = 11.49 min; observed ion = 929.2 (M+H). 1H NMR (METHANOL-d4, 500 MHz) Shift 8.57 (s, 1H), 8.44 (d, 1H, J=8.3 Hz), 8.32 (td, 1H, J=1.3, 8.5 Hz), 7.32 (d, 1H, J=7.7 Hz), 7.25 (d, 1H, J=7.7 Hz), 6.79 (br t, 1H, J=2 ,4 Hz), 6.70 (br t, 1H, J=54.7 Hz), 6.63 (dd, 2H, J=2.1, 8.0 Hz), 4.8-4.9 ( m, 1H), 4.54 (d, 2H, J=5.1 Hz), 3.64 (s, 3H), 3.50 (dd, 1H, J=5.1, 14.0 Hz), 3.26 (s, 3H), 3.13 (dd, 1H, J=9.2, 14.0 Hz), 2.77 (d, 3H, J=0.9 Hz), 2.64 (d , 3H, J=2.7 Hz), 2.44 (br dd, 2H, J=3.9, 7.5 Hz), 1.3-1.4 (m, 1H), 1.01 (brdd , 1H, 1=2,1,3,6 Hz)

Preparation of Example 120: N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7-(3-( difluoromethyl)phenyl)-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.

The title compound was prepared according to General Procedure D using 1-bromo-3-(difluoromethyl)benzene as a coupling agent. As a result of the experiment, we obtained the title compound, N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7 -(3-(difluoromethyl)phenyl)-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. The sample was analyzed using LC-MS method F: retention time = 11.55 min; observed ion = 929 (M-H). 1H NMR (METAHOJI-d4, 500 MHz) Shift 8.40 (d, 1H, J=8.1 Hz), 8.17 (d, 1H, J=1.5 Hz), 8.0-8.0 (m, 3H), 7.7-7.7 (m, 2H), 7.32 (d, 1H, J=7.7 Hz), 7.23 (d, 1H, J=8.0 Hz) , 6.94 (t, 1H, J=56.0 Hz), 6.80 (brt, 1H, J=2.4 Hz), 6.70 (brt, 1H, J=54.8 Hz), 6.64 (dd, 2H, J=2.4, 8.0 Hz), 4.8-4.9 (m, 1H), 4.55 (d, 2H, J=4.5 Hz), 3 .64 (s, 3H), 3.50 (dd, 1H, J=4.9, 14.2 Hz), 3.26 (s, 3H), 3.13 (dd, 1H, J=9.2 , 14.3 Hz), 2.43 (dt, 2H, J=4.2, 7.6 Hz), 1.36 (br d, 1H, J=7.5 Hz), 1.01 (br dd , 1H,;=1,9,3,4 Hz)

Preparation of Example 121: N-((S)-1-((3P)-3-(4-chloro-1-(2,2-difluoroethyl)-3-(methylsulfonamido)-1H-indazol-7-yl)- 7-(2-methylpyrimidin-4-yl)-4-oxo-3,4-dihydroquinazolin-2-yl)-2-(3,5-difluorophenyl)ztyl)-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.

The title compound was prepared according to General Procedure I using 4-chloro-2-methylpyrimidine as a coupling agent. As a result of the experiment, we obtained the title compound, N-((S)-1-((3P)-3-(4-chloro-1-(2,2-difluoroethyl)-3-(methylsulfonamido)-1H-indazol- 7-yl)-7-(2-methylpyrimidin-4-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. The sample was analyzed using LC-MS method F: retention time = 11.38 min; observed ion 947.2 (M+H). 1H NMR (METHANOL-d4, 500 MHz) 5 8.83 (d, 1H, J=5.4 Hz), 8.67 (s, 1H), 8.4-8.4 (m, 2H), 7 .99 (d, 1H, J=5.4 Hz), 7.3-7.4 (m, 1H), 7.28 (d, 1H, J=7.7 Hz), 6.5-6, 8 (m, 4H), 6.02 (br d, 1H, J=8.3 Hz), 6.02 (br t, 1H, J=55.3 Hz), 4.75 (dd, 1H, J =4.8, 9.2 Hz), 4.6-4.6 (m, 2H), 3.2-3.3 (m, 3H), 3.07 (dd, 1H, J=9.4 , 14.2 Hz), 2.83 (s, 3H), 2.4-2.5 (m, 2H), 1.1-1.2 (m, 3H), 0.99 (td, 1H, J=2.1, 3.6 Hz)

Preparation of Example 122: N-((S)-1-((3P)-3-(4-chloro-1-(2,2-difluoroethyl)-3-(methylsulfonamido)-1H-indazol-7-yl)- 7-(3-fluoro-6-methylpyridin-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.

The title compound was prepared according to General Procedure I using 2-chloro-3-fluoro-6-methylpyridine as a coupling agent. As a result of the experiment, we obtained the title compound, N-((S)-1-((3P)-3-(4-chloro-1-(2,2-difluoroethyl)-3-(methylsulfonamido)-1H-indazol- 7-yl)-7-(3-fluoro-6-methylpyridin-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. The sample was analyzed using LC-MS method F: retention time = 11.52 min; observed ion 964.2 (M+H). 1H NMR (METHANOL-d14, 500 MHz) Shift 8.42 (t, 1H, J=1.3 Hz), 8.37 (d, 1H, J=8.3 Hz), 8.20 (td, 1H , J=1.3, 8.5 Hz), 7.68 (dd, 1H, J=8.5, 10.9 Hz), 7.41 (dd, 1H, J=3.6, 8.6 Hz), 7.37 (d, 1H, J=7.7 Hz), 7.27 (d, 1H, J=7.7 Hz), 6.5-6.8 (m, 4H), 6, 02 (br d, 1H, J=8.3 Hz), 6.02 (br t, 1H, J=55.3 Hz), 4.7-4.8 (m, 1H), 4.5-4 .7 (m, 2H), 4.35 (br d, 1H, J=4.2 Hz), 3.8-4.0 (m, 1H), 3.4-3.4 (m, 1H) , 3.24 (s, 3H), 3.07 (dd, 1H, J=9.4, 14.2 Hz), 2.64 (s, 3H), 2.4-2.5 (m, 2H ), 1.3-1.4 (m, 1H), 1.0-1.0 (m, 1H)

Preparation of Example 123: N-((S)-1-((3P)-3-(4-chloro-1-(2,2-difluoroethyl)-3-(methylsulfonamido)-1H-indazol-7-yl)- 7-(2-methylthiazol-5-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.

The title compound was prepared according to General Procedure I using 5-bromo-2-methylthiazole as a coupling agent. As a result of the experiment, we obtained the title compound, N-((S)-1-((3P)-3-(4-chloro-1-(2,2-difluoroethyl)-3-(methylsulfonamido)-1H-indazol- 7-yl)-7-(2-methylthiazol-5-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. The sample was analyzed using LC-MS method F: retention time = 11.5 min; observed ion 952.1 (M+H). 1H NMR (METHANOL-d4, 500 MHz) Shift 8.35 (d, 1H, J=1.8 Hz), 8.33 (d, 1H, J=8.6 Hz), 8.15 (dd, 1H , J=1.8, 8.3 Hz), 7.71 (s, 1H), 7.36 (d, 1H, J=8.0 Hz), 7.27 (d, 1H, J=8, 0 Hz), 6.5-6.8 (m, 4H), 6.01 (br d, 1H, J=8.0 Hz), 6.01 (t, 1H, J=55.3 Hz), 4.73 (dd, 1H, J=4.8, 9.2 Hz), 4.5-4.7 (m, 2H), 4.3-4.4 (m, 1H), 3.93 ( br dd, 1H, J=4.0, 15.3 Hz), 3.4-3.4 (m, 1H), 3.24 (s, 3H), 3.06 (dd, 1H, J=9 ,4, 14.2 Hz), 2.61 (d, 3H, J=1.2 Hz), 2.4-2.5 (m, 2H), 1.3-1.4 (m, 1H) , 1.0-1.0 (m, 1H)

Preparation of Example 124: N-((S)-1-((3P)-3-(4-chloro-1-(2,2-difluoroethyl)-3-(methylsulfonamido)-1H-indazol-7-yl)- 7-(5-methoxypyrimidin-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.

The title compound was prepared according to General Procedure I using 2-chloro-5-methoxypyrimidine as a coupling agent. As a result of the experiment, we obtained the title compound, N-((S)-1-((3P)-3-(4-chloro-1-(2,2-difluoroethyl)-3-(methylsulfonamido)-1H-indazol- 7-yl)-7-(5-methoxypyrimidin-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. The sample was analyzed using LC-MS method F: retention time = 11.46 min; observed ion 963.2 (M+H). 1H NMR (METAHOJI-d4, 500 MHz) Shift 8.83 (s, 1H), 8.68 (s, 2H), 8.61 (dd, 1H, J=1.8, 8.3 Hz), 8 .34 (d, 1H, J=8.2 Hz), 7.36 (d, 1H, J=8.0 Hz), 7.26 (d, 1H, J=7.7 Hz), 6.7 -6.8 (m, 1H), 6.67 (br t, 1H, J=51.1 Hz), 6.5-6.6 (m, 2H), 6.02 (br d, 1H, J =8.3 Hz), 6.02 (t, 1H, J=55.4 Hz), 4.9-4.9 (m, 1H), 4.8-4.8 (m, 1H), 4 .75 (dd, 1H, J=4.8, 9.2 Hz), 4.61 (q, 2H, J=16.4 Hz), 4.35 (br d, 1H, J=4.5 Hz ), 4.05 (s, 3H), 3.94 (br d, 1H, J=11.3 Hz), 3.42 (dd, 1H, J=4.9, 14.5 Hz), 3, 07 (dd, 1H, J=9.4, 14.2 Hz), 2.4-2.5 (m, 2H), 1.3-1.4 (m, 1H), 1.0-1, 0 (m, 1H)

Preparation of Example 125: N-((S)-1-((3P)-3-(4-chloro-1-(2,2-difluoroethyl)-3-(methylsulfonamido)-1H-indazol-7-yl)- 7-(2-methoxypyrimidin-5-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.

The title compound was prepared according to General Procedure I using 5-bromo-2-methoxypyrimidine as a coupling agent. As a result of the experiment, we obtained the title compound, N-((S)-1-((3P)-3-(4-chloro-1-(2,2-difluoroethyl)-3-(methylsulfonamido)-1H-indazol- 7-yl)-7-(2-methoxypyrimidin-5-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. The sample was analyzed using LC-MS method F: retention time = 11.38 min; observed ion = 963.3 (M+H). 1H NMR (METHANOL-d4, 500 MHz) Shift 9.05 (s, 2H), 8.38 (d, 1H, J=7.7 Hz), 8.16 (d, 1H, J=1.8 Hz ), 7.97 (dd, 1H, J=1.8, 8.3 Hz), 7.3-7.4 (m, 1H), 7.24 (d, 1H, J=8.0 Hz) , 6.5-6.8 (m, 4H), 6.02 (br d, 1H, J=8.3 Hz), 6.02 (t, 1H, J=55.3 Hz), 4.74 (dd, 1H, J=4.8, 9.2 Hz), 4.6-4.6 (m, 2H), 4.35 (br d, 1H, J=4.2 Hz), 4.12 (s, 3H), 3.92 (br d, 1H, J=11.3 Hz), 3.4-3.4 (m, 1H), 3.24 (s, 3H), 3.06 (dd , 1H, J=9.4, 14.2 Hz), 2.4-2.5 (m, 2H), 1.3-1.4 (m, 1H), 0.9-1.0 (m , 1H)

Preparation of Example 126: N-((S)-1-((3P)-3-(4-chloro-1-(2,2-difluoroethyl)-3-(methylsulfonamido)-1H-indazol-7-yl)- 7-(4-ethyl-6-methylpyrimidin-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.

The title compound was prepared according to General Procedure I using 2-chloro-4-ethyl-6-methylpyrimidine as a coupling agent. As a result of the experiment, we obtained the title compound, N-((S)-1-((3P)-3-(4-chloro-1-(2,2-difluoroethyl)-3-(methylsulfonamido)-1H-indazol- 7-yl)-7-(4-ethyl-6-methylpyrimidin-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. The sample was analyzed using LC-MS method F: retention time = 11.61 min; observed ion = 975.2 (M+H). 1H NMR (METHANOL-d4, 500 MHz) Shift 8.92 (d, 1H, J=1.5 Hz), 8.67 (dd, 1H, J=1.5, 8.3 Hz), 8.36 (d, 1H, J=8.3 Hz), 7.36 (d, 1H, J=7.7 Hz), 7.27 (s, 1H), 7.27 (d, 2H, J=6, 4 Hz), 6.7-6.8 (m, 1H), 6.68 (br t, 1H, J=54.7 Hz), 6.56 (dd, 2H, J=2.2, 8, 2 Hz), 6.02 (br d, 1H, J=8.3 Hz), 6.02 (t, 1H, J=55.4 Hz), 4.76 (dd, 1H, J=4.9 , 9.4 Hz), 4.6-4.7 (m, 2H), 4.3-4.4 (m, 1H), 3.95 (br s, 1H), 3.4-3.5 (m, 1H), 3.24 (s, 3H), 3.07 (dd, 1H, J=9.2, 14.0 Hz), 2.90 (q, 2H, J=7.7 Hz) , 2.63 (s, 3H), 2.41 (td, 1H, J=4.5, 8.6 Hz), 1.41 (t, 3H, J=7.6 Hz), 1.34 ( br dd, 1H, J=1.5, 6.9 Hz), 1.0-1.0 (m, 1H)

Preparation of Example 127: N-((S)-1-(7-(3-(tert-butylsulfonyl)phenyl)-(3P)-3-(4-chloro-1-(2,2-difluoroethyl)-3- (methylsulfonamido)-1H-indazol-7-yl)-4-oxo-3,4-dihydroquinazolin-2-yl)-2-(3,5-difluorophenyl)ztyl)-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.

The title compound was prepared according to General Procedure I using 1-bromo-3-(tert-butylsulfonyl)benzene as a coupling agent. The experiment resulted in the title compound, N-((S)-1-(7-(3-(tert-butylsulfonyl)phenyl)-(3P)-3-(4-chloro-1-(2,2- difluoroethyl)-3-(methylsulfonamido)-1H-indazol-7-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. The sample was analyzed using LC-MS method F: retention time = 11.49 min; observed ion = 1051.3 (M+H). 1H NMR (METHANOL-d4, 500 MHz) Shift 8.40 (d, 1H, J=8.3 Hz), 8.27 (t, 1H, J=1.6 Hz), 8.22 (d, 1H , J=7.6 Hz), 8.14 (d, 1H, J=1.8 Hz), 8.0-8.0 (m, 2H), 7.86 (t, 1H, J=7, 5 Hz), 7.37 (d, 1H, J=7.8 Hz), 7.29 (d, 1H, J=8.0 Hz), 6.5-6.8 (m, 4H), 6 .02 (br d, 1H, J=8.3 Hz), 6.02 (br t, 1H, J=55.4 Hz), 4.6-4.7 (m, 2H), 4.6- 4.6 (m, 1H), 4.3-4.4 (m, 1H), 3.9-4.0 (m, 1H), 3.4-3.4 (m, 1H), 3. 2-3.3 (m, 3H), 3.06 (dd, 1H, J=9.5, 14.0 Hz), 2.4-2.5 (m, 2H), 1.40 (s, 9H), 1.3-1.4 (m, 1H), 0.9-1.0 (m, 1H)

Preparation of Example 128: N-((S)-1-((3P)-3-(4-chloro-1-(2,2-difluoroethyl)-3-(methyl sulfonamido)-1H-indazol-7-yl) -4-oxo-7-(4-(trifluoromethyl)pyrimidin-2-yl)-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.

The title compound was prepared according to General Procedure I using 2-chloro-4-(trifluoromethyl)pyrimidine as a coupling agent. As a result of the experiment, we obtained the title compound, N-((S)-1-((3P)-3-(4-chloro-1-(2,2-difluoroethyl)-3-(methylsulfonamido)-1H-indazol- 7-yl)-4-oxo-7-(4-(trifluoromethyl)pyrimidin-2-yl)-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 The sample was analyzed using LC-MS method F: retention time = 11.54 min; observed ion = 999.3 (M-H). 1H NMR (METHANOL-d4, 500 MHz) Shift 9.29 (d, 1H, J=5.1 Hz), 9.00 (s, 1H), 8.74 (dd, 1H, J=1.5, 8, 3 Hz), 8.42 (d, 1H, J=8.2 Hz), 7.90 (d, 1H, J=5.1 Hz), 7.38 (d, 1H, J=8.0 Hz ), 7.30 (d, 1H, J=8.0 Hz), 6.5-6.8 (m, 4H), 6.02 (br d, 1H, J=8.3 Hz), 6, 02 (t, 1H, J=55.4 Hz), 4.75 (dd, 1H, J=4.8, 9.5 Hz), 4.6-4.7 (m, 2H), 4.3-4 .4 (m, 1H), 3.95 (br dd, 1H, J=4.2, 15.2 Hz), 3.4-3.4 (m, 1H), 3.24 (s, 3H) , 3.08 (dd, 1H, J=9.5,14.0 Hz), 2.4-2.5 (m, 2H), 1.3-1.4 (m, 1H), 0.99 (tdd, 1H, J=2.2, 3.8, 5.6 Hz)

Preparation of Example 129: N-((S)-1-((3P)-3-(4-chloro-1-(2,2-difluoroethyl)-3-(methylsulfonamido)-1H-indazol-7-yl)- 7-(6-methoxypyridazin-3-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.

The title compound was prepared according to General Procedure I using 3-chloro-6-methoxypyridazine as a coupling agent. As a result of the experiment, we obtained the title compound, N-((S)-1-((3P)-3-(4-chloro-1-(2,2-difluoroethyl)-3-(methylsulfonamido)-1H-indazol- 7-yl)-7-(6-methoxypyridazin-3-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. The sample was analyzed using LC-MS method F: retention time = 11.4 min; observed ion 963.4 (M+H). 1H NMR (METHANOL-d4, 500 MHz) Shift 8.52 (d, 1H, J=1.2 Hz), 8.40 (d, 1H, J=8.3 Hz), 8.28 (s, 1H ), 8.3-8.3 (m, 1H), 7.3-7.4 (m, 2H), 7.26 (d, 1H, J=7.7 Hz), 6.7-6, 8 (m, 1H), 6.66 (s, 1H), 6.5-6.6 (m, 2H), 6.02 (br d, 1H, J=8.3 Hz), 6.02 ( t, 1H, J=55.3 Hz), 4.76 (dd, 1H, J=4.9, 9.4 Hz), 4.6-4.7 (m, 2H), 4.3-4 .4 (m, 1H), 4.21 (s, 3H), 3.94 (br s, 1H), 3.4-3.4 (m, 1H), 3.2-3.3 (m, 3H), 3.07 (dd, 1H, J=9.2, 14.0 Hz), 2.4-2.4 (m, 2H), 1.3-1.4 (m, 1H), 0 .98 (dt, 1H, J=1.9, 3.7 Hz)

Preparation of Example 130: M-((S)-1-(7-(2-(tert-butylsulfonyl)phenyl)-(3P)-3-(4-chloro-1-(2,2-difluoroethyl)-3- (methylsulfonamido)-1H-indazol-7-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.

The title compound was prepared according to General Procedure I using 1-bromo-2-(tert-butylsulfonyl)benzene as a coupling agent. The experiment resulted in the title compound, N-((S)-1-(7-(2-(tert-butylsulfonyl)phenyl)-(3P)-3-(4-chloro-1-(2,2- difluoroethyl)-3-(methylsulfonamido)-1H-indazol-7-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. The sample was analyzed using LC-MS method F: retention time = 11.49 min; observed ion = 1051.2 (M+H). 1H NMR (METHANOL-d4, 500 MHz) Shift 8.23 (d, 1H, J=8.6 Hz), 8.16 (dd, 1H, J=1.3, 8.2 Hz), 7.8 -7.9 (m, 2H), 7.76 (t, 1H, J=7.7 Hz), 7.64 (dd, 1H, J=1.6, 8.2 Hz), 7.53 ( dd, 1H, J=1.2, 7.5 Hz), 7.36 (d, 1H, J=7.6 Hz), 7.2-7.3 (m, 1H), 6.5-6 .8 (m, 4H), 6.04 (t, 1H, J=55.3 Hz), 4.75 (br s, 1H), 4.5-4.6 (m, 2H), 4.3 -4.4 (m, 1H), 3.9-4.0 (m, 1H), 3.4-3.4 (m, 1H), 3.24 (s, 3H), 3.04 (dd , 1H, J=8.9, 14.0 Hz), 2.4-2.5 (m, 2H), 1.3-1.4 (m, 1H), 1.17 (s, 9H), 1.0-1.0 (m, 1H)

Preparation of Example 131: N-((S)-1-((3P)-3-(4-chloro-1-(2,2-difluoroethyl)-3-(methylsulfonamido)-1H-indazol-7-yl)- 7-(2,6-dimethylpyrimidin-4-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.

The title compound was prepared according to General Procedure I using 4-chloro-2,6-dimethylpyrimidine as a coupling agent. As a result of the experiment, we obtained the title compound, N-((S)-1-((3P)-3-(4-chloro-1-(2,2-difluoroethyl)-3-(methylsulfonamido)-1H-indazol- 7-yl)-7-(2,6-dimethylpyrimidin-4-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 . The sample was analyzed using LC-MS method F: retention time = 11.41 min; observed ion = 961.4 (M+H). 1H NMR (METAHOJI-d4, 500 MHz) Shift 8.64 (s, 1H), 8.3-8.4 (m, 2H), 7.89 (s, 1H), 7.3-7.4 ( m, 1H), 7.27 (d, 1H, J=8.0 Hz), 6.5-6.8 (m, 4H), 6.01 (br t, 1H, J=55.3 Hz) , 4.75 (dd, 1H, J=5.1, 9.2 Hz), 4.5-4.7 (m, 2H), 4.3-4.4 (m, 1H), 3.9 -4.0 (m, 1H), 3.4-3.4 (m, 1H), 3.2-3.3 (m, 3H), 3.07 (dd, 1H, J=9.5, 14.0 Hz), 2.79 (s, 3H), 2.63 (s, 3H), 2.4-2.5 (m, 2H), 1.2-1.4 (m, 1H), 0.9-1.0 (m, 1H)

Preparation of Example 132: N-((S)-1-((3P)-3-(4-chloro-1-(2,2-dafluoroethyl)-3-(methylsulfonamido)-1H-indazol-7-yl)- 7-(4-(difluoromethyl)pyrimidin-2-yl)-4-oxo-3,4-dihydroquinazolin-2-yl)-2-(3,5-dafluorophenyl)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.

The title compound was prepared according to General Procedure I using 2-chloro-4-(difluoromethyl)pyrimidine as a coupling agent. As a result of the experiment, we obtained the title compound, N-((S)-1-((3P)-3-(4-chloro-1-(2,2-difluoroethyl)-3-(methylsulfonamido)-1H-indazol- 7-yl)-7-(4-(difluoromethyl)pyrimidin-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 The sample was analyzed using LC-MS method F: retention time = 11.49 min; observed ion = 983.2 (M+H). 1H NMR (METHANOL-d4, 500 MHz) Shift 9.19 (d, 1H, J=5.1 Hz), 8.99 (s, 1H), 8.7-8.7 (m, 1H), 8 .40 (d, 1H, J=8.3 Hz), 7.76 (d, 1H, J=5.1 Hz), 7.37 (d, 1H, J=8.0 Hz), 7.29 (d, 1H, J=8.0 Hz), 6.5-7.0 (m, 5H), 6.02 (t, 1H, J=55.4 Hz), 4.76 (dd, 1H, J=4.8, 9.2 Hz), 4.6-4.7 (m, 2H), 4.3-4.4 (m, 1H), 3.95 (br dd, 1H, J=4 ,0, 15.1 Hz), 3.4-3.5 (m, 1H), 3.24 (s, 3H), 3.08 (dd, 1H, J=9.2, 14.0 Hz) , 2.4-2.5 (m, 2H), 1.3-1.4 (m, 1H), 1.0-1.0 (m, 1H)

Preparation of Example 133: N-((S)-1-((3P)-3-(4-chloro-1-(2,2-difluoroethyl)-3-(methylsulfonamido)-1H-indazol-7-yl)- 7-(5,6-dimethyl-1,2,4-triazin-3-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]pyrazole-1- yl)acetamide.

The title compound was prepared according to General Procedure I using 3-chloro-5,6-dimethyl-1,2,4-triazine as a coupling agent. As a result of the experiment, we obtained the title compound, N-((S)-1-((3P)-3-(4-chloro-1-(2,2-difluoroethyl)-3-(methylsulfonamido)-1H-indazol- 7-yl)-7-(5,6-dimethyl-1,2,4-triazin-3-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. The sample was analyzed using LC-MS method F: retention time = 11.42 min; observed ion = 960.2 (M-H). 1H NMR (METHANOL-d4, 500 MHz) Shift 8.95 (d, 1H, J=1.2 Hz), 8.70 (dd, 1H, J=1.5, 8.3 Hz), 8.41 (d, 1H, J=8.3 Hz), 7.37 (d, 1H, J=8.0 Hz), 7.29 (d, 1H, J=8.0 Hz), 6.6-6 .8 (m, 4H), 6.02 (br t, 1H, J=55.4 Hz), 4.76 (dd, 1H, J=4.8, 9.5 Hz), 4.6-4 .6 (m, 2H), 4.3-4.4 (m, 1H), 3.9-4.0 (m, 1H), 3.4-3.4 (m, 1H), 3.2 -3.2 (m, 3H), 3.07 (dd, 1H, J=9.4, 14.2 Hz), 2.78 (s, 3H), 2.73 (s, 3H), 2, 4-2.5 (m, 2H), 1.3-1.4 (m, 1H), 1.0-1.0 (m, 1H)

Preparation of Example 134: N-((S)-1-((3P)-3-(4-chloro-1-(2,2-difluoroethyl)-3-(methylsulfonamido)-1H-indazol-7-yl)- 7-(6-methylpyridazin-3-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.

The title compound was prepared according to General Procedure I using 3-chloro-6-methylpyridazine as a coupling agent. As a result of the experiment, we obtained the title compound, N-((S)-1-((3P)-3-(4-chloro-1-(2,2-difluoroethyl)-3-(methylsulfonamido)-1H-indazol- 7-yl)-7-(6-methylgo!ridazin-3-yl)-4-oxo-3,4-digadroquinazolin-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 . The sample was analyzed using LC-MS method F: retention time = 11.33 min; observed ion = 947.2 (M+H). 1H NMR (METHANOL-d4, 500 MHz) Shift 8.60 (d, 1H, J=1.5 Hz), 8.42 (d, 1H, J=8.2 Hz), 8.33 (dd, 1H , J=1.8, 8.3 Hz), 8.28 (d, 1H, J=8.9 Hz), 7.80 (d, 1H, J=8.9 Hz), 7.36 (d , 1H, J=8.0 Hz), 7.27 (d, 1H, J=8.0 Hz), 6.55 (s, 4H), 6.02 (brt, 1H, J=55.4 Hz ), 4.76 (dd, 1H, J=4.8, 9.2 Hz), 4.6-4.6 (m, 2H), 4.3-4.4 (m, 1H), 3, 9-4.0 (m, 1H), 3.4-3.4 (m, 1H), 3.23 (s, 3H), 3.07 (dd, 1H, J=9.5, 14.0 Hz), 2.80 (s, 3H), 2.4-2.4 (m, 2H), 1.3-1.4 (m, 1H), 0.98 (tdd, 1H, J=2, 1, 3.9, 5.6 Hz)

Preparation of Example 135: N-((S)-1-((3P)-3-(4-chloro-1-(2,2-difluoroethyl)-3-(methylsulfonamido)-1H-indazol-7-yl)- 4-oxo-7-(pyridazin-3-yl)-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.

The title compound was prepared according to General Procedure I using 3-chloropyridazine as a coupling agent. As a result of the experiment, we obtained the title compound, N-((S)-1-((3P)-3-(4-chloro-1-(2,2-difluoroethyl)-3-(methylsulfonamido)-1H-indazol- 7-yl)-4-oxo-7-(pyridazin-3-yl)-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. The sample was analyzed using LC-MS method F: retention time = 11.3 min; observed ion = 933.2 (M+H). 1H NMR (METHANOL-d4, 500 MHz) Shift 9.28 (dd, 1H, J=1.6, 4.9 Hz), 8.63 (d, 1H, J=1.8 Hz), 8.3 -8.5 (m, 3H), 7.92 (dd, 1H, J=5.1, 8.6 Hz), 7.37 (d, 1H, J=8.0 Hz), 7.28 ( d, 1H, J=7.7 Hz), 6.5-6.8 (m, 4H), 6.03 (br t, 1H, J=55.4 Hz), 4.76 (dd, 1H, J=4.9, 9.4 Hz), 4.6-4.7 (m, 2H), 4.38 (br dd, 1H, J=4.3, 15.1 Hz), 3.9- 4.0 (m, 1H), 3.4-3.5 (m, 1H), 3.2-3.3 (m, 3H), 3.08 (dd, 1H, J=9.4, 14 ,2 Hz), 2.4-2.4 (m, 2H), 1.3-1.4 (m, 1H), 0.98 (dt, 1H, J=1.9, 3.7 Hz)

Preparation of Example 136: N-((S)-1-((3P)-3-(4-chloro-1-(2,2-difluoroethyl)-3-(methylsulfonamido)-1H-indazol-7-yl)- 7-(3-(methylsulfonyl)pyridin-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.

The title compound was prepared according to General Procedure I using 2-chloro-3-(methylsulfonyl)pyridine as a coupling agent. As a result of the experiment, we obtained the title compound, N-((S)-1-((3P)-3-(4-chloro-1-(2,2-difluoroethyl)-3-(methylsulfonamido)-1H-indazol- 7-yl)-7-(3-(methylsulfonyl)pyridin-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 The sample was analyzed using LC-MS method F: retention time = 11.34 min; observed ion 1010.1 (M+H). 1H NMR (METHANOL-d4, 500 MHz) 8 8.95 (dd, 1H, J=1.6, 4.9 Hz), 8.66 (dd, 1H, J=1.5, 8.0 Hz) , 8.38 (d, 1H, J=7.9 Hz), 8.1-8.1 (m, 1H), 7.8-7.8 (m, 2H), 7.3-7.4 (m, 1H), 7.30 (d, 1H, J=7.7 Hz), 6.7-6.8 (m, 1H), 6.66 (br t, 1H, J=53.9 Hz ), 6.5-6.6 (m, 2H), 6.03 (s, 1H), 6.04 (br t, 1H, J=55.3 Hz), 4.5-4.6 (m , 2H), 4.3-4.5 (m, 1H), 3.9-4.0 (m, 1H), 3.4-3.4 (m, 1H), 3.24 (s, 3H ), 3.06 (dd, 1H, J=9.2, 14.0 Hz), 2.94 (s, 3H), 2.41 (ddd, 2H, J=4.0, 7.6, 11 .3 Hz), 1.3-1.4 (m, 1H), 1.0-1.0 (m, 1H)

Preparation of Example 137: N-((S)-1-((3P)-3-(4-chloro-1-(2,2-difluoroethyl)-3-(methylsulfonamido)-1H-indazol-7-yl)- 7-(4,6-dimethylpyridin-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.

The title compound was prepared according to General Procedure I using 2-bromo-4,6-dimethylpyridine as a coupling agent. As a result of the experiment, we obtained the title compound, N-((S)-1-((3P)-3-(4-chloro-1-(2,2-difluoroethyl)-3-(methylsulfonamido)-1H-indazol- 7-yl)-7-(4,6-dimethylpyridin-2-yl)-4-oxo-3,4-dihydroquinazolin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-(( 3bS,4aR)-3-(difluoromethyl)-5,5-dafluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide . The sample was analyzed using LC-MS method F: retention time = 11.46 min; observed ion 960.2 (M+H). 1H NMR (METHANOL-d4, 500 MHz) Shift 8.43 (d, 1H, J=1.2 Hz), 8.35 (d, 1H, J=7.7 Hz), 8.20 (dd, 1H , J=1.5, 8.3 Hz), 7.69 (s, 1H), 7.35 (d, 1H, J=7.7 Hz), 7.24 (d, 1H, J=8, 0 Hz), 7.22 (s, 1H), 6.5-6.8 (m, 4H), 6.02 (t, 1H, J=55.4 Hz), 4.75 (dd, 1H, J=4.8, 9.2 Hz), 4.6-4.7 (m, 2H), 4.3-4.4 (m, 1H), 3.9-4.0 (m, 1H) , 3.4-3.4 (m, 1H), 3.24 (s, 3H), 3.06 (dd, 1H, J=9.2, 14.0 Hz), 2.62 (s, 3H ), 2.4-2.5 (m, 5H), 1.3-1.4 (m, 1H), 0.9-1.0 (m, 1H)

Preparation of Example 138: N-((S)-1-((3P)-3-(4-chloro-1-(2,2-difluoroethyl)-3-(methylsulfonamido)-1H-indazol-7-yl)- 4-oxo-7-(6-(trifluoromethyl)pyridin-2-yl)-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.

The title compound was prepared according to General Procedure I using 2-chloro-6-(trifluoromethyl)pyridine as a coupling agent. As a result of the experiment, we obtained the title compound, N-((S)-1-((3P)-3-(4-chloro-1-(2,2-difluoroethyl)-3-(methylsulfonamido)-1H-indazol- 7-yl)-4-oxo-7-(6-(trifluoromethyl)pyridin-2-yl)-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 The sample was analyzed using LC-MS method F: retention time = 11.56 min; observed ion 100.3 (M+H). 1H NMR (METHANOL-d4, 500 MHz) Shift 8.7-8.7 (m, 1H), 8.3-8.4 (m, 3H), 8.22 (t, 1H, J=7.9 Hz), 7.88 (d, 1H, J=7.7 Hz), 7.37 (d, 1H, J=7.7 Hz), 7.28 (d, 1H, J=7.7 Hz) , 6.5-6.8 (m, 4H), 6.02 (br d, 1H, J=8.3 Hz), 6.02 (br t, 1H, J=55.3 Hz), 4, 75 (dd, 1H, J=4.8, 9.2 Hz), 4.6-4.6 (m, 2H), 4.3-4.4 (m, 1H), 3.9-4, 0 (m, 1H), 3.4-3.4 (m, 1H), 3.2-3.3 (m, 3H), 3.08 (dd, 1H, J=9.4, 14.2 Hz), 2.3-2.5 (m, 2H), 1.2-1.4 (m, 1H), 0.9-1.0 (m, 1H)

Preparation of Example 139: 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-(6-ethyl-2-methylpyrimidin-4-yl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)acetamide

Synthesis scheme:

To a solution of N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7-(6-ethyl-2 -methylpyrimidin-4-yl)-4-oxo-3,4-dihydroquinazolin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(dafluoromethyl)- 5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide (“Example 62”, 50 mg, 0.054 mmol ) in 1,4-dioxane (2 ml) and water (0.400 ml), potassium orthophosphate (34.4 mg, 0.162 mmol) was added with stirring and the resulting reaction mixture was degassed under argon for 10 min. 2,4,6-Trimethyl-1,3,5,2,4,6-trioxatriborinane (271 mg, 1.081 mmol) was then added to the reaction mixture, followed by RuPhos Pd G3 (4.52 mg, 5.40 µmol) at 27°C. The reaction mixture was heated to 100°C and stirred for 16 hours. The progress of the reaction was monitored by TLC (SiO ₂ , 50% EtOAc/Pet., Rf=0.4, UV active). Once complete, the reaction mixture was diluted with EtOAc (50 ml) and filtered through a short pad of celite. The celite layer was extracted with EtOAc (5×20 ml). The combined filtrate was washed with water (2×10 ml), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure, resulting in a crude residue as a pale yellow semi-solid (90 mg), which was purified using Rev. HPLC using the following conditions: Mobile phase A=10 mM ammonium bicarbonate (aq); mobile phase B = acetonitrile; column = X-Select-C ₁₈ (150x25 mm, 10 µm); flow = 25 ml/min; Gradient (time (minutes)/%V)=0/57, 15/57, 15.1/98, 20/98, 20.1/57, 23/57; Sample solution (dissolved in) = acetonitrile:water:THF; Temperature = ambient. Fractions containing the product were collected, frozen and then lyophilized to give 2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cycloprop[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-(6-ethyl-2-methylpyrimidin-4-yl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)acetamide in as a white solid. 1H-NMR (400 MHz, CD ₃ OD) δ = 8.62 (d, J=1.3 Hz, 1H), 8.42-8.34 (m, 2H), 7.86 (s, 1H) , 7.11 (d, J=7.4 Hz, 1H), 7.02 (d, J=7.0 Hz, 1H), 6.82-6.51 (m, 4H), 4.81 ( dd, J=9.3, 4.4 Hz, 1H), 4.65-4.54 (m, 2H), 3.56 (s, 3H), 3.49-3.42 (m, 1H) , 3.16 (s, 3H), 3.06-2.99 (m, 1H), 2.90 (q, J=7.6 Hz, 2H), 2.86 (s, 3H), 2, 79 (s, 3H), 2.46-2.37 (m, 2H), 1.39 (t, J=7.6 Hz, 2H), 1.36-1.31 (m, 1H), 1 .02-0.98 (m, 1H). Method B LC-MS: retention time = 2.73 min; observed ion = 905.55 (M+H).

Preparation of Example 140: 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-(5-fluoro-2-methylpyrimidin-4-yl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)acetamide

Synthesis scheme:

To a solution of N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7-(5-fluoro-2 -methylpyrimidin-4-yl)-4-oxo-3,4-digadroquinazolin-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 64”, 20 mg, 0.022 mmol ) in 1,4-dioxane (1 ml) and water (0.200 ml), potassium orthophosphate (13.92 mg, 0.066 mmol) was added with stirring and the resulting reaction mixture was degassed under argon for 5 min. 2,4,6-Trimethyl-1,3,5,2,4,6-trioxatriborinane (54.9 mg, 0.437 mmol) was then added to the reaction mixture, followed by RuPhos-Pd-G3 (1.828 mg, 2.185 µmol) at 27°C. The reaction mixture was heated to 90°C and stirred for 16 hours. The progress of the reaction was monitored by TLC (SiO ₂ , 80% EtOAc/Pet., Rf=0.4, UV active). Once complete, the reaction mixture was diluted with EtOAc (50 ml) and filtered through a short pad of celite. The celite layer was extracted with EtOAc (5×20 ml). The combined filtrate was washed with water (2×20 ml), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to leave a crude residue as a light yellow semi-solid (45 mg). This product was purified by silica gel chromatography (4 g column), eluting with 0-60% EtOAc/pet. Fractions containing the product were collected and concentrated under reduced pressure to give 2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cycloprop[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-(5-fluoro-2-methylpyrimidin-4-yl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)acetamide in the form off-white solid. ^1H NMR (400 MHz, CD ₃ OD) δ = 8.78 (d, J=3.5 Hz, 1H), 8.59 (s, 1H), 8.43 (d, J=8.3 Hz , 1H), 8.34 (d, J=7.4 Hz, 1H), 7.16 (d, J=7.5 Hz, 1H), 7.08 (d, J=7.4 Hz, 1H ), 6.79-6.50 (m, 4H), 4.83-4.79 (m, 1H), 4.64-4.53 (m, 2H), 3.61 (s, 3H), 3.58-3.42 (m, 1H), 3.20 (s, 3H), 3.06-3.00 (m, 1H), 3.86 (s, 3H), 3.81 (s, 3H), 2.43-2.37 (m, 2H), 1.36-1.33 (m, 1H), 1.00-0.96 (m, 1H). Method D LC-MS: retention time = 5.09 min; observed ion = 895.46 (M+H).

Preparation of Example 141: 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-((3P)-3-(1,4-dimethyl-3-(methylsulfonamido)-1H-indazole -7-yl)-4-oxo-7-(pyridazin-3-yl)-3,4-dihydroquinazolin-2-yl)ethyl)acetamide

Synthesis scheme:

To a solution of N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-4-oxo-7-(pyridazine -3-yl)-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 49”, 45 mg, 0.051 mmol) in 1,4- Potassium orthophosphate (32.4 mg, 0.153 mmol) was added to dioxane (2 mL) and water (0.400 mL) with stirring and the resulting reaction mixture was degassed under argon for 5 min. 2,4,6-Trimethyl-1,3,5,2,4,6-trioxatriborinane (256 mg, 1.019 mmol) was then added to the reaction mixture, followed by RuPhos-Pd-G3 (8.52 mg, 10.19 µmol) at 27°C. The reaction mixture was heated to 90°C and stirred for 16 hours. The completeness of the reaction was monitored by TLC (SiO ₂ , 50% EtOAc/Pet, Rf=0.3, UV active). Once complete, the reaction mixture was diluted with EtOAc (50 ml) and filtered through a short pad of celite. The celite layer was extracted with EtOAc (5×20 ml). The combined filtrate was washed with water (2×20 ml), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to leave a crude residue as a pale yellow semi-solid (95 mg). This product was purified by preparative HPLC using the following conditions: Mobile phase A=10 mM ammonium bicarbonate (aq); mobile phase B = acetonitrile; column = X-Select-C ₁₈ (250x19 mm, 5 µm); flow = 25 ml/min; Gradient (time (minutes)/%V)=0/50, 14/50, 14.1/98, 22/98, 22.1/50, 25/50; Sample solution (dissolved in) = acetonitrile:water:THF; Temperature = ambient. Fractions containing the product were collected and frozen and then lyophilized to give 2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cycloprop[3 ,4]cyclopenta[1,2-c]pyrazol-1-yl)-N-((S)-2-(3,5-difluorophenyl)-1-((3P)-3-(1,4-dimethyl -3-(methylsulfonamido)-1H-indazol-7-yl)-4-oxo-7-(pyridazin-3-yl)-3,4-dihydroquinazolin-2-yl)ethyl)acetamide as an off-white solid . ^1H NMR (400 MHz, CD ₃ OD) δ = 9.27 (dd, J=4.8, 1.3 Hz, 1H), 8.60 (d, J=1.8 Hz, 1H), 8 .45 (d, J=8.3 Hz, 1H), 8.40 (d, J=1.3 Hz, 1H), 8.38-8.33 (m, 1H), 7.92 (dd, J=8.6, 5.1 Hz, 1H), 7.11 (d, J=7.5 Hz, 1H), 7.03 (d, J=7.0 Hz, 1H), 6.79- 6.52 (m, 4H), 4.83-1.81 (m, 1H), 4.64-4.53 (m, 2H), 3.58 (s, 3H), 3.45 (dd, J=13.8, 4.6 Hz, 1H), 3.17 (s, 3H), 3.07-3.01 (m, 1H), 2.86 (s, 3H), 2.44-2 .38 (m, 2H), 1.37-1.31 (m, 1H), 1.00-0.97 (m, 1H). Method B LC-MS: retention time = 2.42 min; observed ion = 863.42 (M+H).

Preparation of Example 142: N-((S)-1-(7-(2-(tert-butylsulfonyl)phenyl)-(3P)-3-(3-(cyclopropanesulfonamido)-1-(2,2-difluoroethyl)- 4-methyl-1H-indazol-7-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

Synthesis scheme:

To a solution of N-((S)-1-(7-(2-(tert-butylsulfonyl)phenyl)-(3R)-3-(4-chloro-3-(cyclopropanesulfonamido)-1-(2,2-difluoroethyl )-1H-indazol-7-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 143”, 40 mg , 0.037 mmol) in 1,4-dioxane (2 ml) and water (0.4 ml), potassium orthophosphate (23.64 mg, 0.111 mmol) was added with stirring and the resulting reaction mixture was degassed under argon for 5 min. 2,4,6-Trimethyl-1,3,5,2,4,6-trioxatriborinane (186 mg, 0.742 mmol) was then added to the reaction mixture, followed by RuPhos-Pd-G3 (6.21 mg, 7.42 µmol) at 27°C. The reaction mixture was heated to 90°C and stirred for 18 hours. The progress of the reaction was monitored by TLC (SiO ₂ , 50% EtOAc/Pet, Rf=0.4, UV active). Once complete, the reaction mixture was diluted with EtOAc (50 ml) and filtered through a short pad of celite. The celite layer was extracted with EtOAc (5×20 ml). The combined filtrate was washed with water (2×10 ml), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to leave a crude residue as a pale yellow semi-solid (110 mg). This product was purified by preparative HPLC using the following conditions: Mobile phase A=10 mM ammonium bicarbonate (water); mobile phase B=acetonitrile; column = X-Select CSH C ₁₈ (250x19 mm, 5 µm); flow = 25 ml/min; Gradient (time (minutes)/%V) = 0/65, 2/65, 10/35, 20/35; Sample solution (dissolved in) = acetonitrile:THF; Temperature = ambient. Fractions containing the product were pooled, frozen and then lyophilized to give N-((S)-1-(7-(2-(tert-butylsulfonyl)phenyl)-(3P)-3-(3-(cyclopropanesulfonamido)- 1-(2,2-difluoroethyl)-4-methyl-1H-indazol-7-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]pyrazole-1 -yl)acetamide as an off-white solid. ¹ H NMR (400 MHz, CD ₃ OD) δ = 8.23 (d, J=8.3 Hz, 1H), 8.16 (dd, J=7.9, 1.4 Hz, 1H), 7 .87-7.83 (m, 2H), 7.77-7.73 (m, 1H), 7.63 (dd, J=8.1, 1.6 Hz, 1H), 7.53 (dd , J=7.7, 1.1 Hz, 1H), 7.21-7.18 (m, 1H), 7.12-7.09 (m, 1H), 6.78-6.51 (m , 2H), 6.43 (d, J=6.6 Hz, 2H), 6.15-5.85 (m, 1H), 4.74-4.58 (m, 3H), 4.35- 4.31 (m, 1H), 3.94-3.91 (m, 1H), 3.37-3.32 (m, 1H), 2.99-2.93 (m, 1H), 2, 90 (s, 3H), 2.89-2.83 (m, 1H), 2.44-2.38 (m, 2H), 1.36-1.31 (m, 1H), 1.18 ( s, 9H), 1.08-1.02 (m, 2H), 1.01-0.96 (m, 3H). LC-MS Method A: retention time = 6.50 min; observed ion = 1057.2 (M+H).

Preparation of Example 143: N-((S)-1-((7-(2-(tert-butylsulfonyl)phenyl)-(3P)-3-(4-chloro-3-(cyclopropanesulfonamido)-1-(2, 2-difluoroethyl)-1H-indazol-7-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

To a solution of N-((S)-1-((3P)-3-(4-chloro-3-(cyclopropanesulfonamido)-1-(2,2-difluoroethyl)-1H-indazol-7-yl)-4- oxo-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-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 (250 mg, 0.129 mmol), 1-bromo-2-(tert-butylsulfonyl)benzene (54.2 mg, 0.194 mmol) in THF (4 ml) and water (4 ml) with stirring at 26 °C in an atmosphere of N ₂ , potassium hydrogen phosphate (67.4 mg, 0.387 mmol) was added. The mixture was degassed by bubbling N ₂ gas for 10 minutes, and then dichloro[9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene]palladium(II) (4.88 mg, 6. 45 µmol). The mixture was stirred for 5 hours at 60°C. The progress of the reaction was monitored by TLC (SiO ₂ , 80% EtOAc/Pet, Rf = 0.3). After completion of the reaction, the reaction mixture was diluted with water (20 ml) and extracted with ethyl acetate (2×35 ml). The combined organic compounds were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to obtain the crude product. This product was purified by preparative HPLC using the following conditions: Mobile phase A = 0.1% formic acid in water; mobile phase B = acetonitrile; column = Synergy Polar (250x21 mm, 4.7 µm); flow = 18 ml/min; Gradient (time (minutes)/%V) = 0/15, 2/15, 10/50; Sample solution (dissolved in) = acetonitrile:water:THF; Temperature = ambient. Fractions containing pure product were pooled, frozen and then lyophilized to give N-((s)-1-((7-(2-(tert-butylsulfonyl)phenyl)-(3P)-3-(4-chloro- 3-(cyclopropanesulfonamido)-1-(2,2-difluoroethyl)-1H-indazol-7-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]pyrazole -1-yl)acetamide as an off-white solid ^1H NMR (400 MHz, DMSO- _d6 ) δ = 9.98 (br s, 1H), 9.24 (br s, 1H), 8, 15 (d, J=8.1 Hz, 1H), 8.08 (dd, J=8.1, 1.2 Hz, 1H), 7.89-7.73 (m, 4H), 7.61 -7.46 (m, 3H), 7.04-6.75 (m, 2H), 6.61-6.56 (m, 2H), 6.23-5.96 (m, 1H), 4 .71-4.55 (m, 2H), 4.46-4.40 (m, 1H), 4.28-4.19 (m, 1H), 3.92-3.86 (m, 1H) , 3.41-3.34 (m, 1H), 2.98-2.92 (m, 1H), 2.88-2.82 (m, 1H), 2.46-2.40 (m, 2H), 1.35-1.29 (m, 1H), 1.12 (s, 9H), 0.97-0.82 (m, 5H) LC-MS Method A: retention time = 6.77 min; observed ion = 1077.00 (M+H).

Preparation of Example 144: N-((S)-1-((3P)-3-(4-chloro-3-(cyclopropanesulfonamido)-1-(2,2-difluoroethyl)-1H-indazol-7-yl)- 7-(2-(N-methylmethylsulfonamido)phenyl)-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

To a solution of N-((S)-1-((3P)-3-(4-chloro-3-(cyclopropanesulfonamido)-1-(2,2-difluoroethal)-1H-indazol-7-yl)-4- oxo-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-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 (250 mg, 0.213 mmol) and N-(2-bromophenyl)-N-methylmethanesulfonamide (89 mg, 0.320 mmol) in THF (4 ml) and water (4 ml) with stirring at 26°C in Potassium hydrogen phosphate (112 mg, 0.640 mmol) was added under _N2 atmosphere. The mixture was degassed by bubbling N ₂ for 10 minutes. Dichloro[9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene]palladium(II) (8.07 mg, 10.67 μmol) was then added to the reaction mixture, and the mixture was stirred for 5 h at 60°C . The progress of the reaction was monitored by TLC (SiO ₂ , 80% EtOAc/Pet, Rf=0.3). After completion of the reaction, the reaction mixture was diluted with water (20 ml) and extracted with ethyl acetate (2×35 ml). The combined organic compounds were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to obtain the crude product. This product was purified by preparative HPLC using the following conditions: Mobile phase A = 10 mM ammonium bicarbonate (aq); mobile phase B = acetonitrile; column = X-Select C ₁₈ (250x19 mm, 5 µm); flow = 16 ml/min; Gradient (time (minutes)/%V) = 0/40, 2/40, 10/50; Sample solution (dissolved in) = acetonitrile:THF:MeOH; Temperature = ambient. Fractions containing pure product were pooled, frozen and then lyophilized to give N-((S)-1-((3P)-3-(4-chloro-3-(cyclopropanesulfonamido)-1-(2,2-difluoroethyl )-1H-indazol-7-yl)-7-(2-(N-methylmethylsulfonamido)phenyl)-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 as an off-white solid. ^1H NMR (400 MHz, DMSO-d6) δ = 9.98 (br s, 1H), 9.19 (d, J=8.8 Hz, 1H), 8.22 (d, J=8.3 Hz, 1H), 7.85-7.81 (m, 2H), 7.72-7.61 (m, 2H), 7.61-7.54 (m, 4H), 7.06-7, 76 (m, 2H), 6.58 (d, J=6.4 Hz, 2H), 6.07 (t, J=55.4 Hz, 1H), 4.72 (d, J=16.7 Hz, 1H), 4.60 (d, J=16.6 Hz, 1H), 4.48-4.43 (m, 1H), 4.17-4.13 (m, 1H), 3.86 -3.82 (m, 1H), 3.41-3.35 (m, 1H), 3.16 (s, 3H), 3.01-2.81 (m, 5H), 2.46-2 .39 (m, 2H), 1.36-1.31 (m, 1H), 0.92-0.94 (m, 4H), 0.86-0.82 (m, 1H). Method B LC-MS: retention time = 2.69 min; observed ion = 1064.30 (M+H).

Preparation of Example 145: N-((S)-1-((3P)-3-(3-(cyclopropanesulfonamido)-1-(2,2-difluoroethyl)-4-methyl-1H-indazol-7-yl)- 7-(2-(N-methylsulfonamido)phenyl)-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

Synthesis scheme:

To a solution of N-((S)-1-((3P)-3-(4-chloro-3-(cyclopropanesulfonamido)-1-(2,2-difluoroethyl)-1H-indazol-7-yl)-7- (2-(N-methylmethylsulfonamido)phenyl)-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 144”, 40 mg , 0.038 mmol) in 1,4-dioxane (2 ml) and water (0.400 ml), potassium orthophosphate (23.93 mg, 0.113 mmol) was added with stirring at 26°C under N ₂ atmosphere. The mixture was degassed by bubbling _N2 for 10 minutes, then 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (189 mg, 0.752 mmol) was added to the mixture, followed by RuPhos-Pd -G3 (3.14 mg, 3.76 µmol). The mixture was stirred for 16 hours at 75°C. The progress of the reaction was monitored by TLC (SiO ₂ , 50% EtOAc/Pet, Rf=0.4). After completion of the reaction, the reaction mixture was diluted with ethyl acetate (40 ml) and filtered through a pad of celite. The celite layer was extracted with ethyl acetate (5 X 20 ml). The combined filtrate was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to obtain the crude product. This product was purified by preparative HPLC using the following conditions: Mobile phase A = 10 mM ammonium bicarbonate (water); mobile phase B = acetonitrile; column = X-Select CSH C ₁₈ (150x19 mm, 5 µm); flow = 19 ml/min; Gradient (time (minutes)/%V) = 0/50, 2/50, 10/60; Sample solution (dissolved in) = water:acetonitrile:THF; Temperature = ambient. Fractions containing pure product were pooled, frozen and then lyophilized to give N-((S)-1-((3P)-3-(3-(cyclopropanesulfonamido)-1-(2,2-dafluoroethyl)-4- methyl-1H-ivdazol-7-yl)-7-(2-(N-methylmethylsulfonamido)phenyl)-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 as an off-white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 9.96-9.86 (m, 1H), 9.30-9.24 (m, 1H), 8.29-8.21 (m, 1H), 7.83-7.77 (m, 1H), 7.76-7.62 (m, 3H), 7.59-7.44 (m, 3H), 7.23-7.14 ( m, 1H), 7.06-6.88 (m, 2H), 6.55-6.45 (m, 2H), 6.27-5.92 (m, 1H), 4.77-4, 60 (m, 2H), 4.44-4.38 (m, 1H), 4.30-4.19 (m, 1H), 3.98-3.88 (m, 1H), 3.45- 3.37 (m, 1H), 3.21-3.08 (m, 3H), 3.04-2.82 (m, 5H), 2.80-2.58 (m, 3H), 2, 45-2.29 (m, 2H), 1.40-1.32 (m, 1H), 1.08-0.89 (m, 4H), 0.84-0.76 (m, 1H). LC-MS Method A: retention time = 6.24 min; observed ion = 1044.10 (M+H).

Preparation of 1-bromo-3-(tert-butylsulfonyl)benzene:

To a solution of (3-bromophenyl)(tert-butyl)sulfane (10 g, 24.47 mmol) in DCM (100 ml) mCPBA (20 g, 116 mmol) was added portionwise with stirring at 0° C. under nitrogen atmosphere. The reaction mixture was left to warm to 28°C and then stirred for 24 hours. The progress of the reaction was monitored by TLC (SiO ₂ , 20% EtOAc/Pet., Rf=0.3, UV active). Once complete, the reaction mixture was diluted with water (100 ml) and extracted with DCM (3×300 ml). The combined organic layers were washed with saturated sodium thiosulfate (2×200 ml), saturated NaHCO ₃ (2×200 ml), then brine (500 ml), and then dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure, in resulting in the crude compound being obtained as an off-white solid. This product was purified by silica gel chromatography, eluting with 0-5% EtOAc/Pet. Fractions containing the product were collected and concentrated under reduced pressure to give 1-bromo-3-(tert-butylsulfonyl)benzene (5 g, 15%) as an off-white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.02-7.99 (m, 1H), 7.93-7.91 (m, 1H), 7.86-7.83 (m, 1H), 7.64 (t, J=8.1 Hz, 1H), 1.25 (s, 9H).

Preparation of 2-(3-(tert-butylsulfonyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane:

To a solution of 1-bromo-3-(tert-butylsulfonyl)benzene (500 mg, 1.752 mmol) and bis(pinacol)diborane (667 mg, 2.63 mmol) in DMF (5 ml) was added potassium acetate (860 mg) with stirring , 8.76 mmol). The reaction mixture was degassed by bubbling nitrogen for 10 minutes, then PdCl ₂ (dppf)-CH ₂ Cl ₂ adduct (229 mg, 0.280 mmol) was added to the reaction mixture. The mixture was stirred at 80°C for 16 hours. The progress of the reaction was monitored by TLC (SiO ₂ , 30% EtOAc/Pet, Rf=0.5, UV active). Once complete, the reaction mixture was filtered through a small pad of celite. The celite layer was extracted with EtOAc (2×10 ml). The combined filtrate was washed with water (20 ml), brine (10 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to obtain 2-(3-(tert-butylsulfonyl)phenyl)-4, 4,5,5-tetramethyl-1,3,2-dioxaborolane (250 mg, 16%) as a brown liquid. This product was directly used in the next step without further purification.

Preparation of Example 146: N-((S)-1-(7-(3-(tert-butylsulfonyl)phenyl)-(3P)-3-(4-chloro-3-(cyclopropanesulfonamido)-1-(2,2 -difluoroethyl)-1H-indazol-7-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

To a solution of N-((S)-1-((3P)-7-bromo-3-(4-chloro-3-(cyclopropanesulfonamido)-1-(2,2-difluoroethyl)-1H-indazol-7-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 (50 mg, 0.051 mmol) in THF (5 ml) and water (0 .5 ml) at 27°C, degassed by bubbling nitrogen for 10 minutes, 2-(3-(tert-butylsulfonyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane was added (65.7 mg, 0.077 mmol) and potassium hydrogen phosphate (44.4 mg, 0.255 mmol). Dichloro[9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene]palladium(11) (2.93 mg, 3.06 μmol) was added to the reaction mixture, and the mixture was then stirred at 70°C for 3 h The completeness of the reaction was monitored by TLC (SiCh, 50% EtOAc/Pet., Rf=0.3, UV active). Once complete, the reaction mixture was filtered through a pad of celite. The celite layer was extracted with EtOAc (30 ml). The combined filtrate was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the crude product as a brown solid, which was purified by preparative HPLC using the following conditions: Mobile phase A = 10 mM ammonium bicarbonate (aq) .); mobile phase B = acetonitrile; column = Kromosil-phenyl C ₁₈ (150×25 mm, 10 µm); flow = 25 ml/min; Gradient (time (minutes)/%V) = 0/60, 15/60, 15.1/98, 18/98, 18.1/60, 20/60; Sample solution (dissolved in) = water:acetonitrile:THF; Temperature = ambient. Fractions containing the product were collected, frozen and lyophilized to give N-((S)-1-(7-(3-(tert-butylsulfonyl)phenyl)-(3P)-3-(4-chloro-3-(cyclopropanesulfonamido )-1-(2,2-difluoroethyl)-1H-indazol-7-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 as an off-white solid. ¹ H NMR (400 MHz, DMSO-d6) δ = 9.97 (br s, 1H), 1.19 (d, J=7.2 Hz, 1H), 8.34-8.29 (m, 2H ), 8.18 (br s, 1H), 8.07-8.02 (m, 2H), 7.99-7.95 (m, 1H), 7.92-7.88 (m, 1H) , 7.74 (br s, 1H), 7.49 (br s, 1H), 7.06-6.76 (m, 2H), 6.61 (d, J=6.6 Hz, 2H), 6.11 (t, J=54.8 Hz, 1H), 4.74 (d, J=16.6 Hz, 1H), 4.62 (d, J=16.5 Hz, 1H), 4, 46-4.40 (m, 1H), 4.26-4.19 (m, 1H), 3.94-3.88 (m, 1H), 3.41-3.35 (m, 1H), 3.03-2.97 (m, 1H), 2.99-2.83 (m, 1H), 2.46-2.41 (m, 2H), 1.34 (s, 10H), 1. 24 (br s, 1H), 0.97-0.82 (m, 4H). Method B LC-MS: retention time = 2.83 min; observed ion = 1077.3 (M+H).

Preparation of N-methyl-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanesulfonamide:

To a solution of N-(4-bromophenyl)-N-methylmethanesulfonamide (1.5 g, 5.45 mmol) in 1,4-dioxane (5 ml) was added bis(pinacol)diborane (2.077 g, 8.18 mmol) with stirring ) and potassium acetate (0.535 g, 5.45 mmol). The reaction mixture was degassed by bubbling nitrogen for 10 min. PdCl ₂ (dppf)-CH ₂ Cl ₂ adduct (0.712 g, 0.872 mmol) was added to the reaction mixture, and then the mixture was stirred at 90°C for 16 hours. The reaction progress was monitored by TLC (SiO ₂ , 30% EtOAc/ Pet, Rf=0.5, UV active). Once complete, the reaction mixture was filtered through a small pad of celite. The celite layer was extracted with EtOAc (2×10 ml). The combined filtrate was washed with water (20 ml), brine (10 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to obtain the crude compound as a brown liquid. This product was purified by silica gel chromatography, eluting with 0-10% EtOAc/Pet. Fractions containing the product were combined and concentrated under reduced pressure to give N-methyl-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl) methanesulfonamide (200 mg, 9% yield) as an off-white solid. ¹ H NMR (400 MHz, DMSO-d6) δ = 7.69 (d, J=8.8 Hz, 2H), 7.42 (d, J=8.9 Hz, 2H), 3.23 (s , 3H), 2.92 (s, 3H), 1.31 (s, 12H).

Preparation of N-methyl-N-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanesulfonamide:

To a solution of N-(3-bromophenyl)-N-methylmethanesulfonamide (1 g, 3.45 mmol) in 1,4-dioxane (10 ml) was added bis(pinacol)diborane (1.315 g, 5.18 mmol) with stirring and potassium acetate (0.678 g, 6.91 mmol). The reaction mixture was degassed by bubbling nitrogen gas for 10 min. PdCl ₂ (dppf)-CH ₂ Cl ₂ adduct (0.423 g, 0.518 mmol) was added to the reaction mixture, and then the mixture was stirred at 90°C for 16 hours. The reaction progress was monitored by TLC (SiO ₂ , 30% EtOAc/ Pet., Rf=0.5, UV active). Once complete, the reaction mixture was filtered through a small pad of celite. The celite layer was extracted with EtOAc (2×100 ml). The combined filtrate was washed with water (20 ml), brine (30 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to obtain the crude compound as a brown liquid. This product was purified by silica gel chromatography, eluting with 0-10% EtOAc/Pet. Fractions containing the product were collected and concentrated under reduced pressure to give N-methyl-N-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl) methanesulfonamide (250 mg, 13% yield) as a brown solid. ¹ H-NMR (400 MHz, CDCl ₃ ) δ = 7.76-7.69 (m, 2H), 7.54-7.48 (m, 1H), 7.40-7.37 (m, 1H ), 3.35 (s, 3H), 2.83 (s, 3H), 1.35 (s, 12H).

Preparation of Example 147: N-((S)-1-((3P)-3-(4-chloro-3-(cyclopropanesulfonamido)-1-(2,2-difluoroethyl)-1H-indazol-7-yl)- 7-(4-(N-methylmethylsulfonamido)phenyl)-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

To a solution of N-((S)-1-((3P)-7-bromo-3-(4-chloro-3-(cyclopropanesulfonamido)-1-(2,2-difluoroethyl)-1H-indazol-7-yl )-4-oxo-3,4-dihydroquinazolin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(dafluoromethyl)-5,5-dafluoro- 3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]rshrazol-1-yl)acetamide (50 mg, 0.051 mmol) in THF (4 ml) and water (0 .5 ml), degassed by bubbling with nitrogen for 10 minutes, N-methyl-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane- 2-yl)methanesulfonamide (28.3 mg, 0.077 mmol) and potassium orthophosphate (108 mg, 0.510 mmol).Dichloro[9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene]palladium(II) was added to the reaction mixture ) (2.93 mg, 3.06 μmol), and the mixture was then stirred at 70°C for 3 hours. The completeness of the reaction was monitored by TLC (SiO ₂ , 50% EtOAc/Pet., Rf = 0.3, UV-active. Once complete, the reaction mixture was filtered through a small pad of celite. The celite layer was extracted with EtOAc (30 ml). The combined filtrate was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure, resulting in the crude compound as a solid a brown substance, which was purified using Rev. HPLC using the following conditions: Mobile phase A=10 mM ammonium bicarbonate (aq); mobile phase B = acetonitrile; column = YMC Triart C ₁₈ (150x25 mm, 10 µm); flow = 25 ml/min; Gradient (time (minutes)/%V) = 0/50, 2/50, 10/70; Sample solution (dissolved in) = water:acetonitrile:THF; Temperature = ambient. Fractions containing product were combined and concentrated under reduced pressure. The remaining solution (aq) was frozen and then lyophilized to give N-((S)-1-((3P)-3-(4-chloro-3-(cyclopropanesulfonamido)-1-(2,2-difluoroethyl)-1H -indazol-7-yl)-7-(4-(N-methylsulfonamido)phenyl)-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 as an off-white solid. ^1H NMR (400 MHz, DMSO-d6) δ = 10.1-9.95 (br s, 1H), 9.18 (d, J=7.2 Hz, 1H), 8.28 (d, J =8.3 Hz, 1H), 8.04-7.99 (m, 2H), 7.92 (d, J=8.8 Hz, 2H), 7.70 (br s, 1H), 7, 61 (d, J=8.6 Hz, 1H), 7.46-7.36 (m, 2H), 7.06-6.76 (m, 2H), 6.61 (d, J=7, 1 Hz, 2H), 6.10 (t, J=55.7 Hz, 1H), 4.72 (d, J=16.6 Hz, 1H), 4.60 (d, J=16.6 Hz , 1H), 4.48-4.42 (m, 1H), 4.20 (br s, 1H), 3.91 (br s, 1H), 3.38 (d, J=12.1 Hz, 1H), 3.33 (s, 3H), 3.03 (s, 3H), 3.01-2.96 (m, 1H), 2.87-2.81 (m, 1H), 2.47 -2.40 (m, 2H), 1.36-1.30 (m, 1H), 0.93 (br s, 5H). LC-MS Method A: retention time = 6.51 min; observed ion = 1064.1 (M+H).

Preparation of Example 148: N-((S)-1-((3P)-3-(4-chloro-3-(cyclopropanesulfonamido)-1-(2,2-dafluoroethyl)-1H-indazol-7-yl)- 7-(3-(N-methylmethylsulfonamido)phenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)-2-(3,5-dafluorophenyl)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

To a solution of N-((S)-1-((3P)-7-bromo-3-(4-chloro-3-(cyclopropanesulfonamido)-1-(2,2-difluoroethyl)-1H-indazol-7-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 (50 mg, 0.051 mmol) in THF (4 ml) and water (0 .5 ml), degassed by bubbling with nitrogen for 10 minutes, N-methyl-N-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane- 2-yl)methanesulfonamide (42.6 mg, 0.077 mmol) and potassium orthophosphate (108 mg, 0.510 mmol).Dichloro[9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene]palladium(II) was added to the reaction mixture ) (2.93 mg, 3.06 µmol), and the reaction mixture was then stirred at 70°C for 3 hours. The completeness of the reaction was monitored by TLC (SiO ₂ , 50% EtOAc/Pet, Rf=0.3, UV-active. Once complete, the reaction mixture was filtered through a small pad of celite. The celite layer was extracted with EtOAc (30 ml). The combined filtrate was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure, resulting in the crude compound as a solid a brown substance, which was purified using Rev. HPLC using the following conditions: Mobile phase A=10 mM ammonium bicarbonate (aq); mobile phase B = acetonitrile; column = YMC Triart C ₈ (150x25 mm, 10 µm); flow = 25 ml/min; Gradient (time (minutes)/%V) = 0/60, 15/60, 15.1/98, 18/98, 18.1/60, 20/60; Sample solution (dissolved in) = water:acetonitrile:THF; Temperature = ambient. Fractions containing the product were pooled, frozen and then lyophilized to give N-((S)-1-((3P)-3-(4-chloro-3-(cyclopropanesulfonamido)-1-(2,2-difluoroethyl) -1H-indazol-7-yl)-7-(3-(N-methylsulfonamido)phenyl)-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]pyrazole-1 -yl)acetamide as an off-white solid. ¹ H NMR (400 MHz, MeOH-d ₄ ) δ = 8.35 (d, J=8.3 Hz, 1H), 8.11 (d, J=1.8 Hz, 1H), 7.95 ( dd, J=8.3, 1.8 Hz, 1H), 7.89 (t, J=1.6 Hz, 1H), 7.79-7.76 (m, 1H), 7.64-7 .56 (m, 2H), 7.38-7.35 (m, 1H), 7.24 (d, J=7.9 Hz, 1H), 6.81-6.52 (m, 4H), 6.18-5.86 (m, 1H), 4.76-4.71 (m, 1H), 4.69-1.56 (m, 2H), 4.42-1.31 (m, 1H ), 3.97-3.87 (m, 1H), 3.42 (s, 3H), 3.41-3.37 (m, 1H), 3.05 (dd, J=14.0, 9 ,2 Hz, 1H), 2.95 (s, 3H), 2.89 (tt, J=8.1, 4.9 Hz, 1H), 2.45-2.37 (m, 2H), 1 .37-1.28 (m, 1H), 1.13-1.03 (m, 2H), 1.01-0.89 (m, 3H). Method D LC-MS: retention time = 5.28 min; observed ion = 1064.09 (M+H).

Preparation of 2-amino-4-(4-(trifluoromethyl)pyrimidin-2-yl)benzoic acid:

Step 1: Preparation of methyl 2-nitro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate

Bis(pinacol)diborane (615 g, 2423 mmol) was added to a solution of methyl 4-bromo-2-nitrobenzoate (600 g, 2307 mmol) in 1,4-dioxane (6000 ml) with stirring at 26°C under N2. and potassium acetate (679 g, 6922 mmol). The reaction mixture was degassed by bubbling N ₂ through the mixture for 10 minutes. PdCl ₂ (dppf) (84 g, 115 mmol) was added to the reaction mixture, and then the mixture was stirred at 80° C. for 3 hours. The progress of the reaction was monitored by TLC (SiO ₂ , 20% EtOAc/Pet, Rf=0.4). After completion, the reaction mixture was concentrated under reduced pressure. The resulting residue was dissolved in EtOAc (6000 ml) and then diluted with water (2400 ml). The mixture was stirred and then filtered through a pad of celite to remove solids. The celite layer was extracted with EtOAc (2400 ml). The combined filtrate was separated, and the organic layer was separated, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to obtain the crude product. This product 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 by filtration, washed with Et ₂ O (2 x 900 ml) and set aside (480 g was isolated). The combined filtrate was concentrated under a stream of N ₂ gas to half the original volume, after which the solution was cooled to below ambient temperature, whereby an off-white solid precipitated. The precipitate was collected by filtration, washed with Et ₂ O (2×600 ml) and set aside (90 g were isolated). The combined filtrate was concentrated under a stream of N ₂ gas to half the original volume, after which the solution was cooled to below ambient temperature, whereby an off-white solid precipitated. The precipitate was filtered, washed with Et ₂ O (2 x 600 ml), and this material (30 g of isolated material) was combined with the previously isolated solids to give the product, methyl-2-nitro-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate as an off-white solid, 600 g (83% yield). ^1H NMR (400 MHz, DMSO-d6) δ = 8.20-8.14 (m, 1H), 8.10-8.05 (m, 1H), 7.87 (d, J=7.5 Hz, 1H), 3.86 (s, 3H), 1.33 (s, 12H). Purity according to GC-MS = 97.5%.

Step 2: Preparation of methyl 2-nitro-4-(4-(trifluoromethyl)pyrimidin-2-yl)benzoate

To a solution of methyl 2-nitro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (600 g, 1954 mmol) and 2-chloro-4-(trifluoromethyl )pyrimidine (357 ml, 2931 mmol) in tetrahydrofuran (THF) (5214 ml) at 26°C under N ₂ , a solution of potassium orthophosphate (1244 g, 5861 mmol) in water (1307 ml) was slowly added. The reaction mixture was degassed by bubbling N ₂ through the mixture for 10 minutes. Dichloro[9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene]palladium(11) (73.8 g, 98 mmol) was added to the mixture, after which the mixture was stirred under a nitrogen atmosphere at 60°C for 16 hours . The progress of the reaction was monitored by TLC (SiO ₂ , 20% EtOAc/Pet, Rf=0.3). Once complete, the reaction mixture was concentrated under reduced pressure and the resulting residue was diluted with ethyl acetate (5000 ml) and then washed with water (2×2000 ml). The organic layer was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness. The residue was mixed with diethyl ether (634 ml) and the solids were filtered, washed with Et ₂ O (634 ml), and then dried under vacuum to give an off-white solid (420 g was isolated), which was set aside. The combined filtrate (red) was concentrated under a stream of N ₂ gas to half the original volume, and an off-white solid precipitated.

The solids were collected by filtration, washed with diethyl ether (2×634 ml), and the isolated product (80 g) was combined with the previously isolated solids. The mixed material was dried under vacuum to give methyl 2-nitro-4-(4-(trifluoromethyl)pyrimidin-2-yl)benzoate as an off-white solid, 500 g (75% yield). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 9.39 (d, J=5.0 Hz, 1H), 8.91 (d, J=1.4 Hz, 1H), 8.82- 8.78 (m, 1H), 8.14 (d, J=5.1 Hz, 1H), 8.08 (d, J=8.1 Hz, 1H), 3.91 (s, 3H). Purity according to LC-MS = 95.71%.

Step 3: Preparation of methyl 2-amino-4-(4-(trifluoromethyl)pyrimidin-2-yl)benzoate

Fe powder ( 853 g, 15.3 mol) and NH ₄ Cl (817 g, 15.3 mol). The reaction mixture was stirred at 70°C for 16 hours. The progress of the reaction was monitored by TLC (SiO ₄ , 20% EtOAc/Pet Rf: 0.4). Once complete, the reaction mixture was filtered while still hot through a pad of celite and the filtrate was concentrated under reduced pressure. The resulting residue was diluted with water (2500 ml) and then extracted with EtOAC (2×5000 ml). The combined organic solutions were washed with brine (3000 ml) and then dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to obtain methyl 2-amino-4-(4-(trifluoromethyl)pyrimidine-2- yl)benzoate as a yellow solid, 330 g (69% yield). ¹ H NMR (400 MHz, DMSO-d6) δ = 9.30-9.28 (m, 1H), 8.00 (d, J=5.0 Hz, 1H), 7.93 (d, J= 1.5 Hz, 1H), 7.88 (d, J=8.5 Hz, 1H), 7.55 (dd, 7=1.7, 8.5 Hz, 1H), 6.93 (s, 2H), 3.84 (s, 3H). Purity according to LC-MS = 95.51%.

Step 4: Preparation of 2-amino-4-(4-(trifluoromethyl)pyrimidin-2-yl)benzoic acid

To a solution of methyl 2-amino-4-(4-(trifluoromethyl)pyrimidin-2-yl)benzoate (320 g, 1077 mmol) in methanol (1600 ml) and THF (1600 ml) at 20°C was added dropwise . 5M sodium hydroxide (646 ml, 3230 mmol). The reaction mixture was stirred at 60°C for 16 hours. The progress of the reaction was monitored by TLC (SiO ₂ , 80% EtOAc/Pet. Rf: 0.3). Once complete, the reaction mixture was concentrated under reduced pressure to remove volatile organic compounds, and the resulting residue was then acidified to pH~4 by adding an aqueous solution of 1 N. HCl. The solids were filtered and washed with water (5000 ml). The solids were dried under vacuum and then further dried in an oven at 50°C for 24 hours, resulting in 2-amino-4-(4-(trifluoromethyl)pyrimidin-2-yl)benzoic acid as a yellow solid colors, 288 g (yield 91%). ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ = 9.31-9.26 (m, 1H), 7.99 (d, J=5.0 Hz, 1H), 7.90-7, 85 (m, 2H), 7.53 (dd, J=1.7, 8.4 Hz, 1H). Purity according to LC-MS = 96.71%.

Alternative preparation of Example 3: N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-4-oxo-7 -(4-(trifluoromethyl)pyrimidin-2-yl)-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.

Synthesis scheme:

Step 1: Preparation of tert-butyl-(S)-(1-(3-(4-chloro-3-(H-(4-methoxybenzyl)methyl-sulfonamido)-1-methyl-1H-indazol-7-yl) -4-oxo-7-(4-(trifluoromethyl)pyrimidin-2-yl)-3,4-dihydroquinazolin-2-yl)-2-(3,5-difluorophenyl)ethyl)carbamate

To a solution of (S)-2-((tert-butoxycarbonyl)amino)-3-(3,5-difluorophenyl)propanoic acid (76 g, 253 mmol) and 2-amino-4-(4-(trifluoromethyl)pyrimidine- 2-yl)benzoic acid (79 g, 279 mmol) in acetonitrile (2560 ml), pyridine (49.2 ml, 608 mmol) was added with stirring and the resulting mixture was then cooled to -5°C and stirred at this temperature for 10 min. T3P (50% in EtOAc, 754 mL, 1266 mmol) was slowly added to the mixture at -5°C. The reaction mixture was stirred at -5°C for 2 hours, then N-(7-amino-4-chloro-1-methyl-1H-indazol-3-yl)-N-(4-methoxybenzyl)methanesulfonamide ( 100 g, 253 mmol) per dose. The mixture was slowly heated to 25°C and stirred for 18 hours. The progress of the reaction was monitored by TLC (SiCh, 40% EtOAc/Pet. Rf=0.2). Once complete, the reaction mixture was concentrated under reduced pressure to remove acetonitrile and pyridine. The resulting residue was diluted with EtOAc (2500 ml) and washed with aq. 2M sodium hydroxide solution (~4000 ml) and then saline solution (4000 ml). The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to obtain the crude product. This material was purified by silica gel chromatography, eluting with 30-40% EtOAc/pet. ether. Fractions containing the desired product were collected and concentrated under reduced pressure to obtain 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-difluorophenyl )ethyl)carbamate (215 g, 87% yield, yellow solid) as a mixture of homochiral atropisomers (diastereomers). Purity according to LC-MS = 94.91%.

Step 2: Preparation of (S)-N-((6P)-7-(2-(1-amino-2-(3,5-difluorophenyl)ethyl)-4-oxo-7-(4-(trifluoromethyl)pyrimidine -2-yl)quinazolin-3(4H)-yl)-4-chloro-1-methyl-1H-indazol-3-yl)methanesulfonamide

To a solution of tert-butyl-(S)-(1-(3-(4-chloro-3-(N-(4-methoxybenzyl)methyl-sulfonamido)-1-methyl-1H-indazol-7-yl)-4 -oxo-7-(4-(trifluoromethyl)pyrimidin-2-yl)-3,4-dihydroquinazolin-2-yl)-2-(3,5-difluorophenyl)ethyl)carbamate (425 g, 459 mmol) in TFA (1415 ml, 18.4 mol), trifluoromethanesulfonic acid (122 ml, 1378 mmol) was slowly added with stirring at 27°C. The solution was stirred under nitrogen atmosphere for 2 hours. The progress of the reaction was monitored by TLC (SiO ₂ , 50% EtOAc/Pet. Rf = 0.2). Once completed, volatiles were removed under a gentle stream of nitrogen gas. The resulting residue was dissolved in EtOAc (3000 ml). The organic solution was washed with 2M sodium hydroxide solution (4000 ml, sufficient to achieve aqueous phase pH >7) and then with brine (4000 ml). The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to obtain crude (S)-N-(7-(2-(1-amino-2-(3,5-difluorophenyl)ethyl)- 4-oxo-7-(4-(trifluoromethyl)pyrimidin-2-yl)quinazolin-3(4H)-yl)-4-chloro-1-methyl-1H-indazol-3-yl)methanesulfonamide (425 g, yield 97%, yellow solid) as a mixture of homochiral atropisomers (diastereomers). The above procedure was repeated and both products were combined (total 825 g), mixed and then purified by silica gel chromatography eluting with 5-10% MeOH in DCM. Fractions containing the desired product were combined and then concentrated under reduced pressure to obtain a yellow solid, 580 g, a mixture of atropisomers (diastereomers). A portion of this material (490 g) was mixed with methanol (5000 ml, 10 vol.) and then filtered to remove remaining solids. The filtrate was concentrated under reduced pressure, resulting in 255 g of product with an atropisomer ratio of ~85:15 in favor of the target atropisomer. This product was dissolved in methanol:acetonitrile (10:90, approx. 1.5 L). The resulting solution was subjected to pre-supercritical fluid chromatography according to the following method: Column = (R,R) Welk-01, 30×250 mm, 5 µm; Eluent = CO ₂ :methanol (1:1); Flow = 100.0 g/min; Back pressure = 100.0 bar; Detection = 254 nm (UV); Stacking time = 14.0 min; Sample amount per injection (Load per injection) = 1000 mg. These two peaks were collected separately, and the main peak (eluted by the second one) was concentrated under reduced pressure to give (S)-N-((6P)-7-(2-(1-amino-2-(3,5 -difluorophenyl)ethyl)-4-oxo-7-(4-(trifluoromethyl)pyrimidin-2-yl)quinazolin-3(4H)-yl)-4-chloro-1-methyl-1H-indazol-3-yl) methanesulfonamide as a yellow solid, 199. This product was contaminated with 0.5% of the other atropoisomer (first eluted peak), so a portion of the material (173 g) was repurified by prep-SFC according to the method described above. Fractions corresponding to the main peak were combined and concentrated under reduced pressure to give (S)-N-((6P)-7-(2-(1-amino-2-(3,5-difluorophenyl)ethyl)-4-oxo -7-(4-(trifluoromethyl)pyrimidin-2-yl)quinazolin-3(4H)-yl)-4-chloro-1-methyl-1H-indazol-3-yl)methanesulfonamide as yellow solid, 160 g The product is a single stereoisomer. ^1H NMR (300 MHz, DMSO-d6) δ = 9.42 (d, J=5.1 Hz, 1H), 8.81 (d, J=1.5 Hz, 1H), 8.59 (dd , J=8.9, 2.9 Hz, 1H), 8.39 (d, J=8.4 Hz, 1H), 8.13 (d, J=5.1 Hz, 1H), 7.40 -7.34 (m, 2H), 7.01 (tt, J=9.5, 2.2 Hz, 1H), 6.81-6.72 (m, 2H), 3.71 (s, 3H ), 3.62-3.57 (m, 1H), 3.38-3.34 (m, 1H), 3.23 (s, 3H), 2.92-2.85 (m, 1H). Purity according to LC-MS = 95.86%.

Step 3: Preparation of N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-4-oxo-7- (4-(trifluoromethyl)pyrimidin-2-yl)-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

To a solution of (S)-N-((6P)-7-(2-(1-amino-2-(3,5-difluorophenyl)ethyl)-4-oxo-7-(4-(trifluoromethyl)pyrimidine-2 -yl)quinazolin-3(4H)-4-chloro-1-methyl-1H-indazol-3-yl)methanesulfonamide (40 g, 56.7 mmol) in DMF (280 ml) with stirring at 27°C in atmosphere N ₂ was added 2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c] pyrazol-1-yl)acetic acid (17.99 g, 68.1 mmol) followed by EDC.HCl (13.05 g, 68.1 mmol), HOBt hydrate (10.43 g, 68.1 mmol) and N-methylmorpholine (24.95 ml, 227 mmol).The reaction mixture was stirred for 16 hours at 27° C. The progress of the reaction was monitored by TLC (SiO ₂ , 50% EtOAc/Pet. Rf = 0.5). When complete, the reaction mixture was diluted with ice water (2000 ml), and the precipitated solid was isolated by filtration, washed with ice water (2000 ml) and dried under reduced pressure to obtain crude N-((S)-1-((3P)-3-( 4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-4-oxo-7-(4-(trifluoromethyl)pyrimidin-2-yl)-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 as an off-white solid, 60 g (98% yield). Purity according to LC-MS = 88.31%. The above procedure was repeated three more times, resulting in a total of 233 g of crude product. This crude material was purified in two equal portions by silica gel chromatography, eluting with 40% ESA in petroleum ether. The purified product thus obtained was combined and heated in isopropanol (1650 ml) at 95°C for 2 hours and then slowly cooled to 27°C over 16 hours to accelerate crystallization. The resulting solids were collected by filtration, washed with isopropanol (1200 ml), and then dried under vacuum. Trace amounts of remaining isopropanol were removed by grinding the compound with a mortar and pestle and storing the resulting fine solids in an oven at 52°C for 1-2 hours; this process of grinding and heating was repeated 4 more times until the residual isopropanol was completely removed to obtain N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazole -7-yl)-4-oxo-7-(4-(trifluoromethyl)pyrimidosh-2-yl)-3,4-digadroquinazolin-2-yl)-2-(((3bS,4aR)-3-(difluoromethyl )-5,5-difluoro-3b,4,4a,5-tetrahadro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide as an off-white solid, 132 .2 g (80% yield) ^1H NMR (acetone-d6) δ: 9.40 (d, J=4.8 Hz, 1H), 8.88 (d, J=1.5 Hz, 1H) , 8.69 (dd, J=8.3, 1.5 Hz, 1H), 8.58 (br s, 1H), 8.41 (d, J=8.3 Hz, 1H), 8.14 (br d, J=8.6 Hz, 1H), 8.02 (d, J=5.1 Hz, 1H), 7.52 (d, J=7.7 Hz, 1H), 7.38 ( d, J=7.7 Hz, 1H), 6.86 (tt, J=9.3, 2.2 Hz, 1H), 6.73 (br d, J=6.3 Hz, 2H), 6 .77 (br t, J=54.7 Hz, 1H), 4.93 (td, J=8.9, 4.8 Hz, 1H), 4.65-4.77 (m, 2H), 3 .69 (s, 3H), 3.56 (dd, J=14.3, 4.5 Hz, 1H), 3.27 (s, 3H), 3.15 (dd, J=14.0, 9 .2 Hz, 1H), 2.41-2.53(m, 2H), l.37-1.43 (m, 1H), 0.95-1.00 (m, 1H). Method A LC- MS: retention time = 6.59 min; observed ion = 951.0 (M+H), purity = 99.78%.

Preparation of 2-amino-4-(4-(difluoromethyl)pyrimidin-2-yl)benzoic acid:

Synthesis scheme:

Step 1: Preparation of methyl 2-amino-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate

Mixture of methyl 2-amino-4-bromobenzoate (10 g, 43.5 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2''-bi( 1,3,2-dioxaborolane) (11.04 g, 43.5 mmol), PdCl ₂ (dppf) (1.590 g, 2.173 mmol) and potassium acetate (12.80 g, 130 mmol) in 1,4-dioxane (100 ml) under argon was heated at 97°C for 2 hours. The mixture was cooled to room temperature and then diluted with DCM. The organic layer was washed with water, then brine, dried over MgSO ₄ , filtered and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel chromatography (330 g column, 5-30% EtOAc:Hex) to give the product, methyl-2-amino-4-(4,4,5,5-tetramethyl-1,3 ,2-dioxaborolan-2-yl)benzoate (9.2 g, 76%), as a yellow solid. ¹ H NMR (500 MHz, CDCl ₃ ) δ ppm 7.86 (d, J=8.05 Hz, 1H), 7.14 (s, 1H), 7.06 (dd, J=7.90, 1.04 Hz, 1H), 5.67 (br s, 2H), 3.89 (s, 3H), 1.37 (s, 12H).

Step 2: Preparation of methyl 2-amino-4-(4-(difluoromethyl)pyrimidin-2-yl)benzoate

Combine methyl 2-amino-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (14.8 g, 53.4 mmol), 2- chloro-4-(difluoromethyl)pyrimidine (8.79 g, 53.4 mmol), PdCl ₂ (xanthos) (2.019 g, 2.67 mmol) and potassium carbonate (22.14 g, 160 mmol). The flask was sealed with a rubber membrane and 1,4-dioxane (200 ml) and water (50.0 ml) were added to the flask. Then the flask was filled with argon (vacuuming, then filling with argon 3 times). The mixture was stirred at 60°C for 3.5 hours. The mixture was cooled to room temperature and volatile organic compounds were removed under reduced pressure to obtain an aqueous mixture. The suspension was taken into EtOAc (300 ml) and then further diluted with water (400 ml). The mixture was stirred and then filtered through a pad of celite to remove insoluble material. The organic layer was then separated and washed with brine, dried over MgSO ₄ , filtered and concentrated under reduced pressure. This residue was taken up in a minimal amount of EtOAc (100 ml) and then mixed with celite and concentrated under reduced pressure to obtain a free-flowing powder. This powder was divided into three equal parts, and each part was subjected to reverse phase chromatography (415 g RediSep Gold C18 column), eluting (95:5 water:MeCN + 0.1% formic acid): (95:5 MeCN:water + 0.1% formic acid) 25:75→0:100. Fractions containing the desired product were combined and partially concentrated under reduced pressure to obtain an aqueous mixture. The suspension was combined with EtOAc, and the aqueous layer was made alkaline to a slightly alkaline pH (pH 8) by adding aq. 5 n. NaOH. The mixture was stirred and then the organic layer was separated and washed with brine, dried over MgSO ₄ and concentrated under reduced pressure to give the product, methyl 2-amino-4-(4-(difluoromethyl)pyrimidin-2-yl)benzoate (10.2 g, 68%), as a dark yellow solid. ¹ H NMR (500 MHz, CDCl ₃ ) δ ppm 9.02 (br d, J=4.77 Hz, 1H), 8.01 (d, J=8.34 Hz, 1H), 7.86 (s, 1H), 7.76 (br d, J =8.35 Hz, 1H), 7.55 (br d, 7 = 4.77 Hz, 1H), 6.52-6.78 (m, 1H), 5.88 (br s, 2H), 3 .94 (s, 3H). LC-MS Method G: retention time = 2.66 min; observed ion = 321.1 (M+MeCN).

Step 3: Preparation of 2-amino-4-(4-(difluoromethyl)pyrimidin-2-yl)benzoic acid

To a solution of methyl 2-amino-4-(4-(difluoromethyl)pyrimidin-2-yl)benzoate (12 g, 43.0 mmol) in methanol (50 ml) and THF (50.0 ml) was added an aqueous solution of 5 n. sodium hydroxide (25.8 ml, 129 mmol), and the resulting mixture was then stirred at 60°C for 1 hour, after which LC-MS analysis showed that the reaction was complete. The mixture was cooled to room temperature, and then an aqueous 1M HCl solution (129 mL, 129 mmol) was added to the mixture. EtOAc (250 ml) and water (150 ml) were added to the thick yellow suspension, after which the yellow suspension was partially dissolved; the organic layer was cloudy, while the aqueous layer appeared homogeneous. The organic layer was washed with saline; it remained cloudy. The organic layer was separated and heated until the cloudy mixture became a clear yellow solution. The solution was dried over MgSO ₄ , filtered and concentrated under reduced pressure to give the product, 2-amino-4-(4-(difluoromethyl)pyrimidin-2-yl)benzoic acid (11.3 g, 99%) as yellow solid. ¹ H NMR (500 MHz, CD ₃ OD) δ ppm 9.06 (d, J=5.07 Hz, 1H), 7.96 (d, J=8.35 Hz, 1H), 7.93 (d, J=1.19 Hz, 1H), 7. 67 (dd, J=8.49, 1.64 Hz, 1H), 7.64 (d, J=5.07 Hz, 1H), 6.66-6.91 (m, 1H). LC-MS Method G: retention time = 2.14 min; observed ion = 307.0 (M+MeCN).

Alternative preparation of 2-amino-4-(4-(difluoromethyl)pyrimidin-2-yl)benzoic acid:

Synthesis scheme:

Preparation of methyl 4-bromo-2-nitrobenzoate:

This compound was prepared in an amount of 200 g according to the procedure described in WO 2005037796 and J. Am. Chem. Soc, 2018, 140(33), 10553-10561.

Step 1: Preparation of methyl 4-cyano-2-nitrobenzoate

Copper cyanide (234 g, 2615 mmol) was added to a solution of methyl 4-bromo-2-nitrobenzoate (340 g, 1307 mmol) in DMF (3000 ml) under a nitrogen atmosphere with stirring at 27°C. The reaction mixture was then stirred at 150°C for 5 hours. The progress of the reaction was monitored by TLC (SiO ₂ , 20% EtOAc/Pet, Rf=0.6, UV active). Once complete, the reaction mixture was left to cool to 27°C.

The reaction mixture was poured into EtOAc (5000 ml) and the resulting mixture was washed with water. 5% ethylenediamine (5000 ml) to remove copper salts. The organic solution was then washed with ice water (3×3000 ml) and then with ice-cold brine (3000 ml). The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give methyl 4-cyano-2-nitrobenzoate as a brown solid, 280 g (83%). The resulting product was directly used in the next step without further purification. ^1H NMR (400 MHz, CDCl ₃ ) δ = 8.37 (d, J=1.6 Hz, 1H), 7.97 (dd, 7=7.9, 1.6 Hz, 1H), 7, 87 (d, J=7.9 Hz, 1H), 3.97 (s, 3H). Note: The workup was further optimized to avoid the need for filtration: The reaction mixture was poured into EtOAc (5000 ml) and the resulting mixture was washed with water. 5% ethylenediamine (5000 ml) to remove copper salts. The organic solution was then washed with ice water (3×3000 ml) and then with ice-cold brine (3000 ml). The rest of the process is the same as described above.

Step 2: Preparation of methyl 4-carbamidoyl-2-nitrobenzoate hydrochloride

To a solution of methyl 4-cyano-2-nitrobenzoate (280 g, 1358 mmol) in MeOH (4000 ml) was added sodium methoxide (44.0 g, 815 mmol) with stirring under a nitrogen atmosphere, and the reaction mixture was then stirred at 27° C for 16 hours. Ammonium chloride (72.6 g, 1358 mmol) was added to the reaction mixture and the reaction mixture was then stirred at 27°C for 18 hours. The reaction progress was monitored by TLC (SiO ₂ , 80% EtOAc/ Pet., Rf=0.1, UV active). Once complete, the reaction mixture was filtered and the filter residue was extracted with 10% MeOH in DCM (3×1000 ml). The combined filtrate was concentrated under reduced pressure to obtain the crude product as a viscous solid. This product was triturated with EtOAc (1000 ml) to obtain methyl 4-carbamidoyl-2-nitrobenzoate hydrochloride as a yellow solid, 250 g (56%). The resulting product was directly used in the next step without further purification. ^1H NMR (400 MHz, DMSO-d6) δ = 9.01 (br s, 3H), 8.50 (d, J=1.6 Hz, 1H), 8.23 (dd, J=7.9 , 1.6 Hz, 1H), 8.08 (d, J=7.9 Hz, 1H), 3.91 (s, 3H). Purity according to LC-MS = 79%.

Preparation of (E)-4-ethoxy-1,1-difluorobut-3-en-2-one:

To a solution of 2,2-difluoroacetic anhydride (179 ml, 1436 mmol) in DCM (1250 ml) with stirring at 0°C, a mixture of pyridine (128 ml, 1580 mmol) and ethoxyethene (165 ml, 1724 mmol). The reaction mixture was allowed to warm to 27°C and then stirred for 12 hours. The reaction mixture was quenched by adding ice water (1000 ml). The organic layer was separated and washed with aqueous saturated NaHCO ₃ solution (1000 ml), then with brine (1000 ml), dried over Na ₂ SO ₄ and filtered. The filtrate was carefully concentrated under reduced pressure (pressure ≥ 100 mbar; bath temperature ≤ 25°C), resulting in (E)-4-ethoxy-1,1-difluorobut-3-en-2-one as a brown liquid, 180 g (80%). The crude compound was directly used in the next step without further purification. ^1H NMR (400 MHz, CDCl ₃ ) δ = 7.84 (d, J=12.4 Hz, 1H), 5.89-5.63 (m, 2H), 4.06 (q, J=7 ,0 Hz, 2H), 1.39 (t, 7=7.0 Hz, 3H). Purity according to GC-MS = 95%.

Step 3: Preparation of methyl 4-(4-(difluoromethyl)pyrimidin-2-yl)-2-nitrobenzoate

To a solution of methyl 4-carbamidoyl-2-nitrobenzoate (200 g, 708 mmol) in EtOH (2000 ml) in a 5 L autoclave flask under nitrogen atmosphere, (E)-4-ethoxy-1 was added with stirring at 27°C. 1-difluorobut-3-en-2-one (159 g, 1062 mmol) followed by triethylamine (296 ml, 2124 mmol). The reaction mixture was stirred at 80°C for 16 hours. The progress of the reaction was monitored by TLC (SiO ₂ , 20% EtOAc/Pet., Rf=0.5, UV-active). The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give methyl 4-(4-(difluoromethyl)pyrimidin-2-yl)-2-nitrobenzoate as a brown liquid, 220 g (58%). The resulting product was directly used in the next step without further purification. ^1H NMR (400 MHz, CDCl ₃ ) δ = 9.07-9.00 (m, 1H), 8.80 (dd, J=7.9, 1.6 Hz, 1H), 7.88 (d , J=7.9 Hz, 1H), 7.78-7.56 (m, 1H), 7.62 (d, J=4.8 Hz, 1H), 6.65 (t, J=54, 8 Hz, 1H), 3.96 (s, 3H). Purity according to HPLC: 58%.

Step 4: Preparation of methyl 2-amino-4-(4-(difluoromethyl)pyrimidin-2-yl)benzoate

Ammonium chloride was added to a solution of methyl 4-(4-(difluoromethyl)pyrimidin-2-yl)-2-nitrobenzoate (220 g, 711 mmol) in EUN (2150 ml) and water (215 ml) with stirring at 27°C (190 g, 3557 mmol), followed by iron (199 g, 3557 mmol). The reaction mixture was stirred at 80°C for 16 hours. The progress of the reaction was monitored by TLC (SiO ₂ , 20% EtOAc/Pet., Rf=0.4, UV active). Once complete, the reaction mixture was filtered while still hot through a pad of celite, and then the celite pad was extracted with EtOAC (4×500 ml). The combined filtrate was concentrated under reduced pressure to give methyl 2-amino-4-(4-(difluoromethyl)pyrimidin-2-yl)benzoate as a yellow solid, 230 g (64%). The resulting product was directly used in the next step without further purification. ¹ H-NMR (400 MHz, CDCl ₃ ) δ = 8.99 (d, J=4.8 Hz, 1H), 7.98 (d, J=8.3 Hz, 1H), 7.83 (s , 1H), 7.73 (d, J=8.4 Hz, 1H), 7.52 (d, J=4.8 Hz, 1H), 6.61 (t, J=54.8 Hz, 1H ), 3.91 (s, 3H). Purity according to LC-MS = 56%.

Step 5: Preparation of 2-amino-4-(4-(difluoromethyl)pyrimidin-2-yl)benzoic acid

To a solution of methyl 2-amino-4-(4-(difluoromethyl)pyrimidin-2-yl)benzoate (230 g, 461 mmol) in THF (2300 ml), MeOH (575 ml) and water (192 ml) with stirring LiOH (66.3 g, 2767 mmol) was added at 27°C. The reaction mixture was stirred at 50°C for 16 hours. The progress of the reaction was monitored by TLC (SiO ₂ , 40% EtOAc/Pet., Rf = 0.1, UV active). After completion, the reaction mixture was allowed to cool to 27°C and then concentrated under reduced pressure. The crude residue was dissolved in water (1000 ml) and washed with EtOAc (2×250 ml). The aqueous layer was acidified with water. 1 n. HCl to pH ~6. The precipitated solid was collected by filtration and washed with water (500 ml), then n-pentane (500 ml), and then dried to give 2-amino-4-(4-(difluoromethyl)pyrimidin-2-yl)benzoic acid in yellow solid, 80 g (63%). ^1H NMR (400 MHz, DMSO-d6) δ = 9.15 (d, J=4.8 Hz, 1H), 7.87-7.84 (m, 2H), 7.74 (d, J= 4.8 Hz, 1H), 7.53 (d, J=8.4 Hz, 1H), 7.06 (t, 7=54.2 Hz, 1H). Purity according to LC-MS = 96%.

Alternative preparation of Example 56: N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7-(4- (difluoromethyl)pyrimidin-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

Synthesis scheme:

Step 1: Preparation of tert-butyl-(S)-(1-(3-(4-chloro-3-(N-(4-methoxybenzyl)methyl-sulfonamido)-1-methyl-1H-indazol-7-yl) -7-(4-(difluoromethyl)pyrimidin-2-yl)-4-oxo-3,4-dihydroquinazolin-2-yl)-2-(3,5-difluorophenyl)ethyl)carbamate

To a solution of (S)-2-((tert-butoxycarbonyl)amino)-3-(3,5-dafluorophenyl)propanoic acid (76 g, 253 mmol) and 2-amino-4-(4-(difluoromethyl)pyrimidine- 2-yl)benzoic acid (73.9 g, 279 mmol) in acetonitrile (2.1 L), pyridine (0.049 L, 608 mmol) was added with stirring and the reaction mixture was cooled to -5°C and stirred at this temperature in for 10 minutes. T3P (50% in EtOAc) (0.754 L, 1266 mmol) was then slowly added to the reaction mixture at -5°C. The mixture was stirred at -5°C for 20 minutes, then left to warm to 27°C and then stirred for 2 hours. N-(7-amino-4-chloro-1-methyl-1H- indazol-3-yl)-N-(4-methoxybenzyl)methanesulfonamide (100 g, 253 mmol) in one dose at 27°C, and the mixture was then stirred for 18 hours. The reaction progress was monitored by TLC (SiO ₂ , 40 % EtOAc/Pet., Rf=0.4, UV active). The reaction mixture was concentrated under reduced pressure to remove acetonitrile and then diluted with EtOAc (1000 ml) and washed with water (2000 ml). The organic layer was separated and washed with saturated aqueous Na ₂ CO ₃ (3×500 ml) and then with brine (500 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure, resulting in the crude product in in the form of a brown viscous liquid, which was purified using silica gel column chromatography, eluting with 30-40% EtOAc/Pet. Fractions containing the desired product were collected and concentrated under reduced pressure to obtain tert-butyl-(S)-(1-(3-(4-chloro-3-(N-(4-methoxybenzyl)methylsulfonamido)-1 -methyl-1H-indazol-7-yl)-7-(4-(difluoromethyl)-pyrimidin-2-yl)-4-oxo-3,4-dihydroquinazolin-2-yl)-2-(3,5- difluorophenyl)ethyl)carbamate (180 g, 78%, yellow solid) as a mixture of homochiral atropoisomers (diastereomers).

Step 2: Preparation of (S)-N-((6P)-7-(2-(1-amino-2-(3,5-dafluorophenyl)ethyl)-7-(4-(difluoromethyl)pyrimidine-2 -yl)-4-oxoquinazolin-3(4H)-yl)-4-chloro-1-methyl-1H-indazol-3-yl)methanesulfonamide

To a solution of tert-butyl-(S)-(1-(3-(4-chloro-3-(N-(4-methoxybenzyl)methyl-sulfonamido)-1-methyl-1H-indazol-7-yl)-7 -(4-(difluoromethyl)pyrimidin-2-yl)-4-oxo-3,4-dihydroquinazolin-2-yl)-2-(3,5-difluorophenyl)ethyl)carbamate (110 g, 121 mmol) in DCM (500 ml) with stirring at 27°C under N ₂ atmosphere, TFA (374 ml, 4849 mmol) was added and the solution was stirred for 10 minutes. Trifluoromethanesulfonic acid (32.3 mL, 364 mmol) was added to this solution, and the solution was stirred for 1 hour at 27°C. The progress of the reaction was monitored by TLC (SiO ₂ , 50% EtOAc/Pet., Rf=0.2). Volatiles were removed under a gentle stream of nitrogen gas. The resulting residue was dissolved in EtOAc (1500 ml) and then washed with 1M water. NaOH (2×750 ml) followed by brine (750 ml), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the crude product as an off-white solid. This product was purified by silica gel chromatography, eluting with 80-98% EtOAc/Pet. Fractions containing the desired product were collected and concentrated under reduced pressure to give (S)-N-(7-(2-(1-amino-2-(3,5-difluorophenyl)ethyl)-7-(4 -(difluoromethyl)pyrimidin-2-yl)-4-oxoquinazolin-3(4H)-yl)-4-chloro-1-methyl-1H-indazol-3-yl)methanesulfonamide as a yellow solid, 65 g ( 74%). The product is a mixture of homochiral atropoisomers (diastereomers). The above procedure was repeated four more times to obtain a total of 310 g of (S)-N-(7-(2-(1-amino-2-(3,5-difluorophenyl)ethyl)-7-(4-(difluoromethyl) pyrimidin-2-yl)-4-oxoquinazolin-3(4H)-yl)-4-chloro-1-methyl-1H-indazol-3-yl)methanesulfonamide, which was dissolved in DCM:MeCN (30:70, 3055 ml ), and then subjected to pre-supercritical fluid chromatography (SFC) as follows: Column = (R,R) Welk-01.30×250 mm, 5 µm; Eluent = CO ₂ :methanol (1:1); Flow = 90.0 g/min; Back pressure = 120.0 bar; Detection = 254 nm (UV); Stacking time = 16.0 min; Sample amount per injection = 800 mg. The separation produced two peaks. The main peak (eluted second) was collected and concentrated under reduced pressure to give (S)-N-((6P)-7-(2-(1-amino-2-(3,5-difluorophenyl)ethyl)- 7-(4-(difluoromethyl)pyrimidin-2-yl)-4-oxoquinazolin-3(4H)-yl)-4-chloro-1 -methyl-1H-indazol-3-yl)methanesulfonamide as a yellow solid , 170 g (51%). The product is a single stereoisomer. ^1H NMR (400 MHz, CDCl ₃ ) δ = 9.16-9.07 (m, 1H), 9.01-8.95 (m, 1H), 8.71-8.62 (m, 1H) , 8.46-8.37 (m, 1H), 7.68-7.61 (m, 1H), 7.11 (d, J=7.8 Hz, 1H), 6.86-6.55 (m, 2H), 6.54-6.45 (m, 3H), 3.79-3.74 (m, 3H), 3.71-3.63 (m, 1H), 3.44-3 .33 (m, 4H), 2.94-2.83 (m, 1H). Purity according to LC-MS = 94%.

Step 3: Preparation of N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7-(4-( difluoromethyl)pyrimidin-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

To a solution of (S)-N-((6P)-7-(2-(1-amino-2-(3,5-difluorophenyl)ethyl)-7-(4-(difluoromethyl)pyrimidin-2-yl)- 4-oxoquinazolin-3(4H)-yl)-4-chloro-1-methyl-1H-indazol-3-yl)methanesulfonamide (50 g, 61.9 mmol), 2-((3bS,4aR)-3- (difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetic acid (16.34 g, 61.9 mmol) and 1-hydroxybenzotriazole hydrate (“HOBt hydrate”, 3.79 g, 24.74 mmol) in DMF (500 ml) at 27°C was added N-methylmorpholine (13.60 ml, 124 mmol) and N-(3-dimethyl)-damethylpropyl)-N''-ethylcarbodiimide hydrochloride (21.34 g, 111 mmol). The reaction mixture was stirred at 27°C for 16 hours. The progress of the reaction was monitored by TLC (SiO ₂ , 50% EtOAc/Pet., Rf=0.5, UV active). The reaction mixture was diluted with ice water (7 L) and then stirred for 30 minutes. The precipitated solid was collected by filtration and then dried under vacuum to give the crude compound as an off-white solid, 75 g. Purity by LC-MS = 60%. The above procedure was repeated three more times to obtain a total of 185 g of crude N-(S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7- yl)-7-(4-(difluoromethyl)pyrimidin-2-yl)-4-oxo-3,4-dihydroquinazolin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3b8 ,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide, which was mixed and then purified by chromatography on silica gel, eluting with 30-40% EtOAc/Pet. Fractions containing the target product were collected and concentrated under reduced pressure to obtain the target product as an off-white solid (100 g, LC-MS purity: 97%). This material was suspended in isopropanol (1000 ml, 10 vol), heated at 70°C for 30 minutes, after which it cooled slowly to 27°C over 16 hours to obtain a crystalline product. The resulting solid was collected by filtration and then dried under vacuum to give N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl )-7-(4-(difluoromethyl)pyrimidin-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 in the form off-white solid, 80 g (79%). 1H NMR (acetone-d ₆ ) δ: 9.27 (d, J=5.1 Hz, 1H), 8.89 (d, J=1.8 Hz, 1H), 8.69 (dd, J= 8.3, 1.8 Hz, 1H), 8.57 (br s, 1H), 8.39 (d, J=8.3 Hz, 1H), 8.12 (d, J=8.9 Hz , 1H), 7.84 (d, J=5.1 Hz, 1H), 7.51 (d, J=7.7 Hz, 1H), 7.37 (d, J=8.0 Hz, 1H ), 7.03 (t, J=54.4 Hz, 1H), 6.86 (tt, J=9.2, 2.4 Hz, 1H), 6.70-6.76 (m, 2H) , 6.78 (t, J=54.7 Hz, 1H), 4.93 (td, J=9.0, 4.6 Hz, 1H), 4.65-4.76 (m, 2H), 3.69 (s, 3H), 3.56 (dd, J=14.2,4.6 Hz, 1H), 3.27 (s, 3H), 3.15 (dd, J=14.3, 9.2 Hz, 1H), 2.42-2.53 (m, 2H), 1.37-1.44 (m, 1H), 0.95-1.00 (m, 1H). Method B LC-MS: retention time = 2.73 min; observed ion = 933.09 (M+H); purity = 99%.

Preparation of 2-amino-4-(6-(trifluoromethyl)pyridin-2-yl)benzoic acid:

Synthesis scheme:

Step 1: Preparation of methyl 4-bromo-2-nitrobenzoate

To a solution of 4-bromo-2-nitrobenzoic acid (500 g, 2032 mmol) in methanol (2000 ml) was added sulfuric acid (500 ml, 9381 mmol) at 0°C with stirring. The solution was stirred for 4 hours at 70°C . The progress of the reaction was monitored by TLC (SiO ₂ , 30% EtOAc/Pet. Rf=0.3). After completion of the reaction, the reaction mass was cooled to room temperature and then concentrated under reduced pressure to remove methanol. The resulting residue was poured into water (1000 ml) and the pH was adjusted to 9 by adding anhydrous sodium carbonate. The mixture was extracted with ethyl acetate (2 X 1000 ml). The combined organic solutions were washed with water (500 ml) and then with brine (500 ml). The organic layer was dried over anhydrous Na ₂ SO ₄ , filtered and then concentrated under reduced pressure to obtain methyl 4-bromo-2-nitrobenzoate (520 g, 94%) as an off-white solid. 1H NMR (400 MHz, CDCl ₃ ) δ = 8.04-7.99 (m, 1H), 7.85-7.78 (m, 1H), 7.66 (d, J=8.2 Hz, 1H), 3.92 (s, 3H). Purity according to LC-MS = 95.2%. The resulting product was directly used in the next step without further purification.

Step 2: Preparation of methyl 2-amino-4-bromobenzoate

To a solution of zinc powder (704 g, 10.8 mol) in water (2000 ml), a solution of methyl 4-bromo-2-nitrobenzoate (400 g, 1538 mmol) in tetrahydrofuran ( THF) (4000 ml) and then acetic acid (1057 ml, 18.5 mol). The reaction mixture was stirred at 27°C for 4 hours. The progress of the reaction was monitored by TLC (SiO ₂ , 20% EtOAc/Pet. Rf=0.4). Once complete, the reaction mixture was filtered through a pad of celite and the celite pad was extracted with EtOAc (2000 ml). The combined filtrate was concentrated under reduced pressure. The resulting residue was diluted with water (3000 ml) and extracted with EtOAc (2×4000 ml). The combined organic solutions were washed with saturated Na ₂ CO ₃ solution (2×3000 ml) and then with brine (2×2000 ml). The organic layer was dried over anhydrous Na ₂ SO ₄ , filtered and then concentrated under reduced pressure to obtain methyl 2-amino-4-bromobenzoate (350 g, 94%) as an off-white solid. 1H-NMR (400 MHz, CDCl ₃ ) δ = 7.76-7.65 (m, 1H), 6.84 (d, J=1.9 Hz, 1H), 6.78-6.72 (m , 1H), 5.91-5.63 (m, 2H), 3.86 (s, 3H). Purity according to LC-MS = 95.0%. The resulting product was directly used in the next step without further purification.

Step 3: Preparation of methyl 2-amino-4-(6-(trifluoromethyl)pyridin-2-yl)benzoate

To a solution of methyl 2-amino-4-bromobenzoate (350 g, 1521 mmol) in 1,4-dioxane (7000 ml), bis(pinacol)diborane (522 g, 2054 mmol) and potassium acetate (597 g, 6085 mmol). The reaction mixture was degassed by bubbling N ₂ through the mixture for 10 minutes. PdCl ₂ (dppf) (78 g, 106 mmol) was added to the reaction mixture. The mixture was stirred at 90°C for 4 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the mixture was cooled to room temperature. 2-chloro-6-(trifluoromethyl)pyridine (359 g, 1978 mmol), potassium orthophosphate (1130 g, 5325 mmol) and water (1190 ml) were added to the mixture. The mixture was degassed by bubbling nitrogen gas for 10 minutes. PdCl ₂ (dppf) (78 g, 106 mmol) was added to the mixture. The reaction mixture was stirred at 60°C for 16 hours. The progress of the reaction was monitored by TLC (SiO ₂ , 20% EtOAc/Pet. Rf=0.4). Once complete, the reaction mixture was filtered through celite, and said celite layer was then extracted with ethyl acetate (2000 ml). The combined filtrate was concentrated under reduced pressure to obtain the crude product (550 g) as a brown liquid. This product was purified by silica gel chromatography, eluting with 5-30% EtOAc/Pet. Fractions containing the target product were combined and concentrated under reduced pressure. The isolated product was washed with n-pentane (2200 ml) and the solids were collected by filtration and then dried under vacuum to give methyl 2-amino-4-(6-(trifluoromethyl)pyridin-2-yl)benzoate ( 380 g, 83%) in the form of an off-white solid. ^1H NMR (CHLOROFORM-d) δ: 7.99 (d, J=8.3 Hz, 1H), 7.92-7.98 (m, 2H), 7.67 (dd, J=6.9 , 1.5 Hz, 1H), 7.49 (d, J=l.5 Hz, 1H), 7.27 (dd, J=8.3, 1.8 Hz, 1H), 5.90 (br s, 2H), 3.93 (s, 3H). Purity according to LC-MS = 98.25%.

Step 4: Preparation of 2-amino-4-(6-(trifluoromethyl)pyridin-2-yl)benzoic acid:

To a solution of methyl 2-amino-4-(6-(trifluoromethyl)pyridin-2-yl)benzoate (650 g, 2194 mmol) in tetrahydrofuran (THF) (5000 ml) and water (2167 ml) with stirring at 0° Lithium hydroxide monohydrate (369 g, 8776 mmol) was added under nitrogen atmosphere. The reaction mixture was stirred at 70°C for 16 hours. The progress of the reaction was monitored by TLC (SiO ₂ , 50% EtOAc/Pet. Rf=0.4). Once complete, the reaction mixture was concentrated under reduced pressure and the resulting residue was then dissolved in water (5000 ml) and acidified to pH 4 by adding 3N. HCl (3000 ml). The resulting precipitate was collected by filtration and washed with water (4000 ml), then n-hexane (5000 ml), and then dried to give 2-amino-4-(6-(trifluoromethyl)pyridin-2-yl)benzoic acid (581 g, 93%) in the form of an off-white solid. ^1H NMR (400 MHz, DMSO-d6) δ = 8.18 (d, J=4.0 Hz, 2H), 7.92-7.88 (m, 1H), 7.84 (d, J= 8.3 Hz, 1H), 7.54 (d, J=1.7 Hz, 1H), 7.22 (d, J=8.4, 1.8 Hz, 1H). Purity according to LC-MS = 99.62%.

Alternative preparation of Example 59: N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-4-oxo-7 -(6-(trifluoromethyl)pyridin-2-yl)-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.

Synthesis scheme:

Step 1: Preparation of tert-butyl-(S)-(1-(3-(4-chloro-3-(N-(4-methoxybenzyl)methyl-sulfonamido)-1-methyl-1H-indazol-7-yl) -4-oxo-7-(6-(trifluoromethyl)pyridin-2-yl)-3,4-dihydroquinazolin-2-yl)-2-(3,5-difluorophenyl)ethyl)carbamate

To a solution of (S)-2-((tert-butoxycarbonyl)amino)-3-(3,5-difluorophenyl)propanoic acid (91 g, 301 mmol) and 2-amino-4-(6-(trifluoromethyl)pyridine- 2-yl)benzoic acid (94 g, 332 mmol) in acetonitrile (3.8 L)) pyridine (0.059 L, 724 mmol) was added with stirring under nitrogen at 27°C. The resulting mixture was cooled to -9°C for 10 minutes, then 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinan-2,4,6-trioxide (“T3R”) was added dropwise ", 50 wt% in EtOAc, 0.888 L, 1507 mmol) for 10 min. The solution was stirred for 2.1 hours at -9°C under N ₂ atmosphere. N-(7-amino-4-chloro-1-methyl-1H-indazol-3-yl)-N-(4-methoxybenzyl)methanesulfonamide (120 g, 301 mmol) was added to the solution at -9°C, after which the solution was heated to -5°C and kept at this temperature with stirring for 1 hour. The reaction mixture was then allowed to slowly warm to 27°C and then stirred at this temperature for 16 hours. The progress of the reaction was monitored by TLC (SiO ₂ , 50% EtOAc/Pet. Rf=0.5). Once complete, the reaction mixture was concentrated under reduced pressure and the resulting residue was dissolved in EtOAc (5000 ml) and then washed with 1 N. NaOH solution (2000 ml), and then saline solution (1000 ml). The organic layer was dried over Na ₂ SO ₄ , filtered and then concentrated under reduced pressure to give the crude product, which was purified by silica gel chromatography eluting with 30-35% EtOAc/Pet. Fractions containing the desired product were combined and concentrated under reduced pressure to obtain tert-butyl-(S)-(1-(3-(4-chloro-3-(N-(4-methoxybenzyl)methylsulfonamido)-1 -methyl-1H-indazol-7-yl)-4-oxo-7-(6-(trifluoromethyl)pyridin-2-yl)-3,4-dihydroquinazolin-2-yl)-2-(3,5-difluorophenyl )ethyl)carbamate (252 g, 88%, off-white solid) as a mixture of homochiral atropisomers (diastereomers).

Step 2: Preparation of (S)-N-((6P)-7-(2-(1-amino-2-(3,5-difluorophenyl)ethyl)-4-oxo-7-(6-(trifluoromethyl)pyridine -2-yl)quinazolin-3(4H)-yl)-4-chloro-1-methyl-1H-indazol-3-yl)methanesulfonamide

To a solution of tert-butyl-(S)-(1-(3-(4-chloro-3-(N-(4-methoxybenzyl)methyl-sulfonamido)-1-methyl-1H-indazol-7-yl)-4 -oxo-7-(6-(trifluoromethyl)pyridin-2-yl)-3,4-dihydroquinazolin-2-yl)-2-(3,5-difluorophenyl)ethyl)carbamate (97% purity, 252 g, 264 mmol) to TFA (815 ml, 10.6 mol) was added trifluoromethanesulfonic acid (70.4 ml, 793 mmol) with stirring at 27°C. The solution was stirred for 2 hours under nitrogen atmosphere. The progress of the reaction was monitored by TLC (SiO ₂ , 50% EtOAc/Pet. Rf=0.2). Once completed, volatiles were removed under a gentle stream of nitrogen gas. The residue was dissolved in EtOAc (5000 ml) and then washed with 1 N. NaOH solution (2000 ml), and then saline solution (1500 ml). The organic layer was dried over Na ₂ SO ₄ , filtered and then concentrated under reduced pressure to give the crude product, which was purified by silica gel chromatography eluting with 5-15% MeOH in DCM. Fractions containing the desired product were combined and concentrated under reduced pressure to obtain (S)-N-(7-(2-(1-amino-2-(3,5-difluorophenyl)ethyl)-4-oxo- 7-(6-(trifluoromethyl)pyridin-2-yl)quinazolin-3(4H)-yl)-4-chloro-1-methyl-1H-indazol-3-yl)methanesulfonamide (180 g, 95%, dirty white solid) as a mixture of homochiral atropisomers (diastereomers). The product was dissolved in methanol:acetonitrile (40:60, 3000 ml) and then purified by preparative SFC using the following method: Column = (R,R) Welk-01, 30x250 mm, 5 µm; Eluent = CO ₂ :methanol (1:1); Flow = 90.0 g/min; Back pressure = 120.0 bar; Detection = 254 nm (UV); Stacking time = 8.8 min; Sample amount per injection = 700 mg. Separation by SFC produced two peaks, which were collected separately. The main peak (eluted second) was concentrated under reduced pressure to give (S)-N-((6P)-7-(2-(1-amino-2-(3,5-difluorophenyl)ethyl)-4- Oxo-7-(6-(trifluoromethyl)pyridin-2-yl)quinazolin-3(4H)-yl)-4-chloro-1-methyl-1H-indazol-3-yl)methanesulfonamide (100 g, 54%) as an off-white solid. The product is a single stereoisomer. ^1H NMR (400 MHz, DMSO-d6) δ=8.64-8.55 (m, 2H), 8.44-8.25 (m, 3H), 8.01 (d, J=7.7 Hz, 1H), 7.42-7.31 (m, 2H), 7.07-6.95 (m, 1H), 6.76 (dd, J=2.0, 8.5 Hz, 2H) , 3.70 (s, 3H), 3.59 (dd, J=4.8, 8.2 Hz, 1H), 3.35 (br d, J=4.8 Hz, 1H), 3.17 (d, J=5.1 Hz, 3H), 2.92-2.83 (m, 1H). Purity according to LC-MS=99%.

Step 3: Preparation of N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-4-oxo-7- (6-(trifluoromethyl)pyridin-2-yl)-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:

To a solution of (S)-N-((6P)-7-(2-(1-amino-2-(3,5-difluorophenyl)ethyl)-4-oxo-7-(6-(trifluoromethyl)pyridine-2 -yl)quinazolin-3(4H)-4-chloro-1-methyl-1H-indazol-3-yl)methanesulfonamide (45 g, 63.9 mmol) in DMF (450 ml) was added with stirring at 27°C 2 -((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole-1- yl)acetic acid (20.26 g, 77 mmol) followed by the addition of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (“EDC-HCl”, 14.70 g, 77 mmol), 1-hydroxybenzotriazole hydrate ( "HOBt hydrate", 11.75 g, 77.75 mmol) and N-methylmorpholine (28.1 ml, 256 mmol). The reaction mass was stirred for 24 hours at 27 ° C. The progress of the reaction was monitored using TLC (SiO ₂ , 50% EtOAc/Pet. Rf=0.5) Once complete, the reaction mixture was diluted with ice water (1.5 L) and the resulting precipitate was collected by filtration and then dried under vacuum to give the crude product (59 g) in as an off-white solid. This crude product was mixed with another batch of crude product (61 g) obtained by repeating the procedure on the same scale. A total of 120 g of crude product was purified by silica gel chromatography, eluting with 20-40% EtOAc/Pet. Fractions containing the desired product were combined and concentrated under reduced pressure to obtain the purified product. Trace amounts of remaining EtOAc were removed by grinding the compound using a mortar and pestle and storing the resulting fine solids in an oven at 50° C. for approximately 2 hours; this grinding and heating process was repeated 4 more times until the EtOAc content was reduced to less than 4000 ppm, yielding N-((S)-1-((3P)-3-(4-chloro-1-methyl- 3-(methylsulfonamido)-1H-indazol-7-yl)-4-oxo-7-(6-(trifluoromethyl)pyridin-2-yl)-3,4-dihadroquinazolin-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 (85.7 g, 79%) as an off-white solid. ^1H NMR (acetone-d6) δ: 8.60 (t, J=1.0 Hz, 1H), 8.58 (s, 1H), 8.48 (d, J=8.0 Hz, 1H) , 8.39 (d, J=0.9 Hz, 2H), 8.32 (t, J=7.9 Hz, 1H), 8.16 (d, J=8.6 Hz, 1H), 7 .95-7.99 (m, 1H), 7.49 (d, J=7.7 Hz, 1H), 7.37 (d, J=8.0 Hz, 1H), 6.86 (tt, J=9.3, 2.3 Hz, 1H), 6.70-6.76 (m, 2H), 6.77 (t, J=54.7 Hz, 1H), 4.93 (td, J =9.0, 4.6 Hz, 1H), 4.63-4.74 (m, 2H), 3.69 (s, 3H), 3.55 (dd, J=14.2, 4.6 Hz, 1H), 3.28 (s, 3H), 3.15 (dd, J=14.2, 9.4 Hz, 1H), 2.42-2.51 (m, 2H), 1.37 -1.43 (m, 1H), 0.95-1.00 (m, 1H). Method D LC-MS: retention time = 5.57 min; observed ion = 949.98 (M+H); purity according to LC-MS = 99.4%.

Chemical names according to IUPAC nomenclature:

The IUPAC chemical names for each example are given below. Currently these names are not recognized by common programs such as ChemDraw or JChem. Therefore, the chemical names used in the Examples section above were obtained using ChemDraw with manual addition of P/M nomenclature. Chemical names can be converted to chemical structures using ChemDraw after removing the P/M nomenclature, such as "(3P)-".

Biological methods:

Cell Culture Study HIV MT-2 cells, 293T cells, and proviral DNA clone NL _4-3 were obtained through the NIH AIDS Research and Reference Reagent Program. MT-2 cells were propagated in RPMI 1640 medium supplemented with 10% heat-inactivated fetal bovine serum (FBS), 100 mg/ml penicillin G, and up to 100 units/ml streptomycin. 293T cells were propagated in DMEM (Dulbecco's modified Eagle's medium) supplemented with 10% heat-inactivated FBS, 100 mg/ml penicillin G, and 100 mg/ml streptomycin. To obtain the reference virus used in these studies, the recombinant proviral clone NL _4-3 was used, in which a region of the nef gene was replaced by the Renilla luciferase gene. Recombinant virus was generated by transfecting recombinant proviral clone NL _4-3 into 293T cells using Transit-293 Transfection Reagent from Mirus Bio LLC (Madison, WI). After 2-3 days, the supernatant was collected and the amount of virus present was titrated in MT-2 cells using luciferase enzyme activity as a marker by measuring luciferase enzyme activity. Luciferase was quantified using EnduRen Live Cell Substrate from Promega (Madison, WI). The antiviral activity of the compounds against the recombinant virus was quantified by measuring luciferase activity in MT-2 cells infected with the recombinant virus for 4-5 days in the presence of the compound in a serial dilution series.

The 50% effective concentration ( _EC50 ) was calculated using the exponential form of the median effect equation, where (Fa)=1/[1+( _ED50 /drugconc)m] (Johnson VA, Byington RT. Infectivity Assay. In Techniques in HIV Research. ed. Aldovini A, Walker BD. 71-76. New York: Stockton Press. 1990). The 50% inhibitory concentration ( _EC50 ) was calculated using the exponential form of the median effect equation, where percent inhibition = 1/[1+( _EC50 /drug concentration)m], where m is a parameter reflecting the slope of the concentration-response curve.

The cytotoxicity of the compound and the corresponding _CC50 values were determined using the same protocol as described in the antiviral properties study, with the difference that uninfected cells were used. Cytotoxicity was assessed at day 4 in uninfected MT2 cells using a colorimetric (2,3-bis[2-methoxy-4-nitro-5-sulfophenyl]-2H-tetrazolium-5-carboxyanilide internal salt)-based XTT assay (Sigma- Aldrich, St. Louis, MO).

The present invention is not limited to the above illustrative examples, and these examples should be considered in all respects as illustrative and not limiting, and reference is made to the appended claims rather than to the above examples; all changes within the meaning and degree of equivalence falling within the scope of the claims will also be within the scope of the present invention.

Claims (6)

1. A compound having the structural formula: or a pharmaceutically acceptable salt thereof. 2. A pharmaceutical composition for use in the treatment of HIV infection, containing an effective amount of a compound or a pharmaceutically acceptable salt thereof according to claim 1 and a pharmaceutically acceptable carrier, excipient or diluent. 3. The pharmaceutical composition according to claim 2, further containing an effective amount of at least one other agent selected from the group consisting of dolutegravir, lamivudine, fostemsavir and cabotegravir for use in the treatment of HIV infection. 4. Use of a compound or a pharmaceutically acceptable salt thereof according to claim 1 for use in the preparation of a medicament for the treatment of HIV infection.