Coronavirus inhibiting compounds

Abstract

The present invention relates to compounds of formula (I) for treating and / or preventing infection or diseases caused by coronavirus. The invention is also directed to pharmaceutical compositions comprising such compounds, to processes for preparing such compounds and compositions, and to the use of such compounds and compositions for the prevention and / or treatment of coronavirus infections and / or diseases.

Description

[0001] CORONAVIRUS INHIBITING COMPOUNDS

[0002] This invention was made with Government support under Agreement HHS0100201700018C, awarded by HHS. The Government has certain rights in the invention.

[0003] FIELD OF THE INVENTION

[0004] The present invention relates to compounds of formula (I) for treating and / or preventing infection or diseases caused by coronavirus. The invention is also directed to pharmaceutical compositions comprising such compounds, to processes for preparing such compounds and compositions, and to the use of such compounds and compositions for the prevention and / or treatment of coronavirus infections and / or diseases.

[0005] BACKGROUND OF THE INVENTION

[0006] Coronaviruses are a group of related viruses that cause diseases in mammals and birds. In humans, coronaviruses cause respiratory tract infections that can be mild, like the common cold, to severe. Some respiratory tract infections caused by coronaviruses can be lethal to humans, including Severe Acute Respiratory Syndrome (SARS, caused by SARS-CoV-1), Middle East Respiratory Syndrome (MERS), and Coronavirus Disease 2019 (COVID-19 caused by SARS coronavirus-2, SARS-CoV-2). Various mutant strains of SARS-CoV-2 have been identified, including the Delta variant (B.1.617.2 variant), and the Omicron variant (BA.1 , BA.2, BA.3, BA.4 and BA 5 variants and descendent lineages).

[0007] In light of the spread of SARS-CoV-2 infection which has caused the COVID-19 pandemic, it is desirable to have compounds and methods of treatment and / or prevention of coronavirus infections and / or diseases in patients. WO-2016 / 016395 discloses 6,7-dihydropyrazolo[1 ,5-a]pyrazin-4(5H)-one derivatives as negative allosteric modulators (NAMs) of the metabotropic glutamate receptor subtype 2 ("mGluR2").

[0008] DETAILED DESCRIPTION OF THE INVENTION

[0009] The present invention relates to compounds of formula (I) including any stereochemically isomeric form thereof, wherein,

[0010] X is -(CO)-NH- or -NH-(CO)-;

[0011] R1is hydrogen; C1-6alkyl; C1-6alkyl substituted with hydroxy, amino, or mono- or di(C1 -4alkyl)amino;

[0012] C1_4alkyl-oxy-C1_4alkyl;

[0013] - L2-R5;

[0014] -L1-L2-R6or -L2-L1-R6;

[0015] -L1-R7or -L1-O-R7; or

[0016] -SO2-R8; wherein L1is C1-6alkanediyl;

[0017] L2is -(C=O)-;

[0018] R5is C1_4alkyl, C1 -4alkyloxy, C3-6cycloalkyl or Heterocycl;

[0019] R6is hydroxy, C1 -4alkyloxy, amino, mono- or di(C1 -4alkyl)amino;

[0020] R7is Het1or Heterocycl;

[0021] R8is C1-6alkyl; polyhaloC1 -4alkyl; C1 -4alkyloxyC1 -4alkyl; polyhaloC1 -4alkyloxyC1 -4alkyl; C3-6cycloalkyl; C3-6cycloalkyl substituted with one, two or three substituents each independently selected from C1 -4alkyl, C1 -4alkyloxy, polyhaloC1 -4alkyl, and halo; _6alkyl substituted with amino, mono- or di(C1 -4alkyl)amino; _6alkyl substituted with one C3_6cycloalkyl; C1-6alkyl substituted with one C3-6cycloalkyl substituted with one, two or three substituents each independently selected from C1 -4alkyl,C1 -4alkyloxy, polyhaloC1 -4alkyl, and halo; C1-6 alkyl substituted with one Het2;

[0022] Het1is pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, oxazolyl or isoxazolyl; and Het1is optionally substituted with one C1_4alkyl or C1 -4alkyloxy;

[0023] Het2is oxazolyl, or isoxazolyl;

[0024] Heterocycl is oxetanyl, azetidinyl, 2-oxopyrrolidin-3-yl or piperidinyl; and Heterocycl is optionally substituted with one C1 -4alkyl, C1 -4alkyloxy or C1 -4alkylcarbonyl;

[0025] R2is hydrogen, halo, C1 -4alkyl or C1.4alkyloxy; n is an integer 1 , 2 or 3; each R3is independently selected from hydrogen, halo, C1_4alkyl, C1 -4alkyloxy, and polyhaloC1.4alkyl; and

[0026] R4is C3-6cycloalkyl or phenyl, wherein said C3-6cycloalkyl and phenyl are substituted with one, two or three substituents each independently selected from hydrogen, halo, C1 -4alkyl, C1 -4alkyloxy, and polyhaloC1.4alkyl.

[0027] Definitions

[0028] For the purposes of the present invention, as described and claimed herein, the following terms are defined as follows :

[0029] - halo is generic to fluoro, chloro, bromo and iodo;

[0030] - C1_4alkyl defines straight and branched chain saturated hydrocarbon radicals having from 1 to 4 carbon atoms such as, for example, methyl, ethyl, propyl, butyl, 1 methylethyl, 2-methyl- propyl and the like;

[0031] - C-j.galkyl is meant to include C1_4alkyl and the higher homologues thereof having 5 or 6 carbon atoms, such as, for example, 2 methylbutyl, pentyl, hexyl and the like;

[0032] - C3-6cycloalkyl is generic to cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl;

[0033] - polyhaloC1.4alkyl is defined as polyhalosubstituted C1_4alkyl, in particular C1_4alkyl (as hereinabove defined) substituted with 2 to 6 halogen atoms such as difluoromethyl, trifluoromethyl, trifluoroethyl, and the like;

[0034] - C-j.galkanediyl defines bivalent straight or branched chain hydrocarbon radicals containing from 1 to 6 carbon atoms such as, for example, 1 ,2-ethanediyl, 1 ,3 propanediyl, 1 ,4-butane- diyl, 1 ,5 pentanediyl, 1 ,6 hexanediyl and the branched isomers thereof;

[0035] - -(CO)- or (CO) means carbonyl.

[0036] The term "compounds of the invention" as used herein, is meant to include the compounds of formula (I), and the salts and solvates thereof. As used herein, the terms "comprising" and "including" are used in their open, non-limiting sense.

[0037] As used herein, the terms "treat", "treatment" and "treating" refer to both therapeutic and prevention treatments. For example, therapeutic treatments include the reduction or amelioration of the progression, severity and / or duration of coronaviruses mediated conditions, or the amelioration of one or more symptoms (specifically, one or more discernible symptoms) of coronaviruses mediated conditions, resulting from the administration of one or more therapies (e.g., one or more therapeutic agents such as a compound or composition of the invention). In other embodiments the therapeutic treatment includes the inhibition of the progression of a coronavirus mediated condition, either physically by, e.g., stabilization of a discernible symptom, physiologically by, e.g., stabilization of a physical parameter, or both. In other embodiments the therapeutic treatment includes the reduction or stabilization of coronaviruses mediated infections. Antiviral drugs can be used in the community setting to treat people infected by coronavirus to reduce the severity of symptoms and reduce the number of days that they are sick.

[0038] As used herein, the terms "prevent", "prevention", "preventing" and “prophylactic use” refer to the reduction in the risk of acquiring or developing a given condition, or the reduction or inhibition of the recurrence or said condition in a subject who is not ill, but who has been or may be near a person with the disease.

[0039] As used herein, any chemical formula with bonds shown only as solid lines and not as solid wedged or hashed wedged bonds, or otherwise indicated as having a particular configuration (e.g. R, S) around one or more atoms, contemplates each possible stereoisomer, or mixture of two or more stereoisomers.

[0040] Hereinbefore and hereinafter, the terms "compound of formula (I)" and "intermediates of synthesis of formula (I)" are meant to include the stereoisomers thereof and the tautomeric forms thereof.

[0041] The terms "stereoisomers", "stereoisomeric forms" or "stereochemically isomeric forms" hereinbefore or hereinafter are used interchangeably.

[0042] The invention includes all stereoisomers of the compounds of the invention either as a pure stereoisomer or as a mixture of two or more stereoisomers. Enantiomers are stereoisomers that are non-superimposable mirror images of each other. A 1 :1 mixture of a pair of enantiomers is a racemate or racemic mixture. Diastereomers (or diastereoisomers) are stereoisomers that are not enantiomers, i.e. they are not related as mirror images. If a compound contains a double bond, the substituents may be in the E or the Z configuration. Substituents on bivalent cyclic (partially) saturated radicals may have either the cis- or transconfiguration; for example, if a compound contains a disubstituted cycloalkyl group, the substituents may be in the cis or trans configuration.

[0043] The term "stereoisomers" also includes any rotamers, also called conformational isomers, the compounds of formula (I) may form.

[0044] Therefore, the invention includes enantiomers, diastereomers, racemates, E isomers, Z isomers, cis isomers, trans isomers, rotamers, and mixtures thereof, whenever chemically possible.

[0045] The meaning of all those terms, i.e. enantiomers, diastereomers, racemates, E isomers, Z isomers, cis isomers, trans isomers and mixtures thereof are known to the skilled person.

[0046] The absolute configuration is specified according to the Cahn-lngold-Prelog system. The configuration at an asymmetric atom is specified by either R or S. Resolved stereoisomers whose absolute configuration is not known can be designated by (+) or (-) depending on the direction in which they rotate plane polarized light. For instance, resolved enantiomers whose absolute configuration is not known can be designated by (+) or (-) depending on the direction in which they rotate plane polarized light.

[0047] When a specific stereoisomer is identified, this means that said stereoisomer is substantially free, i.e. associated with less than 50%, preferably less than 20%, more preferably less than 10%, even more preferably less than 5%, in particular less than 2% and most preferably less than 1%, of the other stereoisomers. Thus, when a compound of formula (I) is for instance specified as (R), this means that the compound is substantially free of the (S) isomer; when a compound of formula (I) is for instance specified as E, this means that the compound is substantially free of the Z isomer; when a compound of formula (I) is for instance specified as cis, this means that the compound is substantially free of the trans isomer.

[0048] Some of the compounds according to formula (I) may also exist in their tautomeric form. Such forms in so far as they may exist, although not explicitly indicated in the above formula (I) are intended to be included within the scope of the present invention.

[0049] It follows that a single compound may exist in both stereoisomeric and tautomeric form. Atropisomers (or atropoisomers) are stereoisomers which have a particular spatial configuration, resulting from a restricted rotation about a single bond, due to large steric hindrance. All atropisomeric forms of the compounds of formula (I) are intended to be included within the scope of the present invention.

[0050] The pharmaceutically acceptable acid addition salts as mentioned hereinabove are meant to comprise the therapeutically active non-toxic acid addition salt forms that the compounds of formula (I) are able to form. These pharmaceutically acceptable acid addition salts can conveniently be obtained by treating the base form with such appropriate acid. Appropriate acids comprise, for example, inorganic acids such as hydrohalic acids, e.g. hydrochloric or hydrobromic acid, sulfuric, nitric, phosphoric and the like acids; or organic acids such as, for example, acetic, propanoic, hydroxyacetic, lactic, pyruvic, oxalic (i.e. ethanedioic), malonic, succinic (i.e. butanedioic acid), maleic, fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic, p-aminosalicylic, pamoic and the like acids.

[0051] Conversely said salt forms can be converted by treatment with an appropriate base into the free base form.

[0052] The compounds of formula (I) may exist in both unsolvated and solvated forms. The term 'solvate' is used herein to describe a molecular association comprising a compound of the invention and one or more pharmaceutically acceptable solvent molecules, e.g. water or ethanol. The term 'hydrate' is used when said solvent is water.

[0053] For the avoidance of doubt, compounds of formula (I) may contain the stated atoms in any of their natural or non-natural isotopic forms. In this respect, embodiments of the invention that may be mentioned include those in which (a) the compound of formula (I) is not isotopically enriched or labelled with respect to any atoms of the compound; and (b) the compound of formula (I) is isotopically enriched or labelled with respect to one or more atoms of the compound. Compounds of formula (I) that are isotopically enriched or labelled (with respect to one or more atoms of the compound) with one or more stable isotopes include, for example, compounds of formula (I) that are isotopically enriched or labelled with one or more atoms such as deuterium,13C,14C,14N,15O or the like.

[0054] Whenever the term “substituted” is used in the present invention, it is meant, unless otherwise is indicated or is clear from the context, to indicate that one or more hydrogens, preferably from 1 to 3 hydrogens, more preferably from 1 to 2 hydrogens, more preferably 1 hydrogen, on the atom or radical indicated in the expression using “substituted” are replaced with a selection from the indicated group, provided that the normal valency is not exceeded, and that the substitution results in a chemically stable compound, i.e. a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into a therapeutic agent.

[0055] If substituents are described as “independently” having more than one variable, each instance of a substituent is selected independent of the other(s) from the list of variables available. Each substituent therefore may be identical to or different from the other substituent(s).

[0056] If substituents are described as “independently selected” from a group, each instance of a substituent is selected independent of the other(s). Each substituent therefore may be identical to or different from the other substituent(s).

[0057] A first group of compounds are compounds of formula (l-a) that are compounds of formula (I)

[0058] A second group of compounds of formula (l-b) that are compounds of formula (I) wherein X In an embodiment, a compound of formula (I) or a compound of formula (l-a) or a compound of formula (l-b) wherein R2is C1 -4alkyloxy, optionally R2is methoxy.

[0059] In an embodiment, a compound of formula (I) or a compound of formula (l-a) or a compound of formula (l-b) wherein R3is hydrogen.

[0060] In an embodiment, a compound of formula (I) or a compound of formula (l-a) or a compound of formula (l-b) wherein R1is - L2-R5wherein L2is -(C=O)- and R5is C1_4alkyl.

[0061] In an embodiment, a compound of formula (I) or a compound of formula (l-a) or a compound of formula (l-b) wherein R1is - SO2-R8wherein R8is -(C=O)- and R8is C1-6alkyl.

[0062] In an embodiment, a compound of formula (I) or a compound of formula (l-a) or a compound of formula (l-b) wherein R4is phenyl, or phenyl substituted with one, two or three substituents each independently selected from hydrogen, halo, C1_4alkyl, C1 -4alkyloxy, and polyhaloC1.4alkyl.

[0063] In an embodiment, a compound of formula (l-a), including any stereochemically isomeric form thereof, wherein R1is - L2-R5; wherein L2is -(C=O)-;

[0064] R5is C1_4alkyl, C1 -4alkyloxy, C3-6cycloalkyl or Heterocycl;

[0065] Heterocycl is oxetanyl, azetidinyl, 2-oxopyrrolidin-3-yl or piperidinyl; and Heterocycl is optionally substituted with one C1_4alkyl, C1 -4alkyloxy or C1 -4alkylcarbonyl;

[0066] R2is C1 -4alkyloxy; n is an integer 1 ;

[0067] R3is hydrogen; and

[0068] R4is phenyl substituted with one, two or three substituents each independently selected from hydrogen, halo, C-|_4alkyl, C1 -4alkyloxy, and polyhaloC1 -4alkyl.

[0069] In an embodiment, a compound of formula (l-a), including any stereochemically isomeric form thereof, wherein

[0070] R1is -L1-L2-R6or -L2-L1-R6; wherein

[0071] R6is hydroxy, C1 -4alkyloxy, amino, mono- or di(C1 -4alkyl)amino; R2is C1 -4alkyloxy; n is an integer 1 ;

[0072] R3is hydrogen; and

[0073] R4is phenyl substituted with one, two or three substituents each independently selected from hydrogen, halo, C1 -4alkyl, C1 -4alkyloxy, and polyhaloC1 -4alkyl.

[0074] In an embodiment, a compound of formula (l-a), including any stereochemically isomeric form thereof, wherein

[0075] R1is -L1-R7or -L1-O-R7; wherein L1is C1-6alkanediyl;

[0076] R7is Het1or Heterocycl;

[0077] Het1is pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, oxazolyl or isoxazolyl; and Het1is optionally substituted with one C1_4alkyl or C1 -4alkyloxy;

[0078] Heterocycl is oxetanyl, azetidinyl, 2-oxopyrrolidin-3-yl or piperidinyl; and Heterocycl is optionally substituted with one C1_4alkyl, C1 -4alkyloxy or C1 -4alkylcarbonyl;

[0079] R2is C1 -4alkyloxy; n is an integer 1 ;

[0080] R3is hydrogen; and

[0081] R4is phenyl substituted with one, two or three substituents each independently selected from hydrogen, halo, C-|_4alkyl, C1 -4alkyloxy, and polyhaloC1 -4alkyl.

[0082] In an embodiment, a compound of formula (l-a), including any stereochemically isomeric form thereof, wherein R1is -SO2-R8; wherein R8is C1-6alkyl; polyhaloC1 -4alkyl; C1 -4alkyloxyC1 -4alkyl; polyhaloC1 -4alkyloxyC1 -4alkyl; C3-6cycloalkyl; C3-6cycloalkyl substituted with one, two or three substituents each independently selected from alkyl, C1 -4C1 -4alkyloxy, polyhaloC1 -4alkyl, and halo; C1-6alkyl substituted with amino, mono- or di(C1 -4alkyl)amino; C1-6alkyl substituted with one C3-6cycloalkyl; C1-6alkyl substituted with one C3-6cycloalkyl substituted with one, two or three substituents each independently selected from C1_4alkyl, C1 -4alkyloxy, polyhaloC1_4alkyl, and halo; C1-6alkyl substituted with one Het2;

[0083] Het2is oxazolyl, or isoxazolyl;

[0084] R2is C1 -4alkyloxy; n is an integer 1 ;

[0085] R3is hydrogen; and R4is phenyl substituted with one, two or three substituents each independently selected from hydrogen, halo, C1 -4alkyl, C1 -4alkyloxy, and polyhaloC1 -4alkyl.

[0086] In an embodiment, a compound of formula (l-a), including any stereochemically isomeric form thereof, wherein

[0087] R1is hydrogen; substituted with hydroxy, amino, or mono- or di(C1 -4alkyl)amino; or oxy-C1_4alkyl; y; n is an integer 1 ;

[0088] R3is hydrogen; and

[0089] R4is phenyl substituted with one, two or three substituents each independently selected from hydrogen, halo, C-|_4alkyl, C1 -4alkyloxy, and polyhaloC1 -4alkyl.

[0090] Representative compounds are listed below :

[0091]

[0092] In an embodiment, a compound having the following structure :

[0093]

[0094] As mentioned herein, the present invention relates to compounds of formula (I) including any stereochemically isomeric form thereof, wherein, X is -(CO)-NH- or -NH-(CO)-;

[0095] R1is hydrogen; C1-6alkyl; C1-6alkyl substituted with hydroxy, amino, or mono- or di(C1 -4alkyl)amino; C1 -4alkyl-oxy-C^alkyl;

[0096] - L2-R5;

[0097] -L1-L2-R6or -L2-L1-R6;

[0098] -L1-R7or -L1-O-R7; or

[0099] -SO2-R8; wherein L1is C1-6alkanediyl;

[0100] L2is -(C=O)-;

[0101] R8is C1 -4alkyl, C^alkyloxy, C3-6cycloalkyl or Heterocycl;

[0102] R® is hydroxy, C1 -4alkyloxy, amino, mono- or di(C1 -4alkyl)amino;

[0103] R7is Het"' or Heterocycl;

[0104] R8 is C1-6alkyl; polyhaloC1 -4alkyl; C^alkyloxyC1 -4alkyl; polyhaloC1 -4alkyloxyC1 -4alkyl; C3-6cycloalkyl; C3-6cycloalkyl substituted with one, two or three substituents each independently selected from C1 -4alkyl, C1 -4alkyloxy, polyhaloC1 -4alkyl, and halo; C1-6alkyl substituted with amino, mono- or di(C1 -4alkyl)amino; C1-6alkyl substituted with one C3-6cycloalkyl; C1-6alkyl substituted with one C3-6cycloalkyl substituted with one, two or three substituents each independently selected from C1 -4alkyl, C1 -4alkyloxy, polyhaloC1 -4alkyl, and halo; C1-6alkyl substituted with one Het2;

[0105] Het1is pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, oxazolyl or isoxazolyl; and Het1is optionally substituted with one C1 -4alkyl or C1 -4alkyloxy;

[0106] Het2is oxazolyl, or isoxazolyl;

[0107] Heterocycl is oxetanyl, azetidinyl, 2-oxopyrrolidin-3-yl or piperidinyl; and Heterocycl is optionally substituted with one C1 -4alkyl, C1 -4alkyloxy or C1 -4alkylcarbonyl;

[0108] R2is hydrogen, halo, C1 -4alkyl or C1 -4alkyloxy; n is an integer 1 , 2 or 3; each RS is independently selected from hydrogen, halo, C1 -4alkyl, C1 -4alkyloxy, and polyhaloC1 -4alkyl; and

[0109] R^ is C3-6cycloalkyl or phenyl, wherein said C3-6cycloalkyl and phenyl are substituted with one, two or three substituents each independently selected from hydrogen, halo, C1 -4alkyl, C1 -4alkyloxy, and polyhaloC1 -4alkyl, and there is now presented further embodiments of this invention, for instance, in alternative or cumulative embodiments: R1represents a moiety represented in the examples, and hence may be a more diverse range of groups than those presented above, and for instance in an embodiment may also contain a cyclic, bridged cyclic or spiro-cyclic moiety (and for the avoidance of doubt the specific R1moieties, may be combined with the other alternative embodiments described herein, for instance below);

[0110] R2represents Ci-4alkyloxy, for instance in an embodiment, represents -OCi-2alkyl;

[0111] R3represents hydrogen, halo (e.g. chloro), -OCi-4alkyl (where the alkyl is optionally substituted by one or more fluoro atoms), -C(O)OCi-4alkyl or Cs-ecycloalkyl; n represents 1 ; and / or

[0112] R4represents fluoro, phenyl (optionally substituted as defined above, and / or by one or more, e.g. one, fluoro atoms) or Cs-ecycloalkyl, optionally substituted as defined above, and wherein such cycloalkyl group may further contain an alkylene bridge, for instance an additional -CH2- linker (so forming a bridged cycloalkyl group).

[0113] In an embodiment:

[0114] R1represents -C(O)Ci-2alkyl, and in an embodiment, represents -C(O)CH3;

[0115] R2represents -OCi-2alkyl, and in an embodiment, represents -OCH3; n represents 1 ;

[0116] R3represents hydrogen; and / or (in an embodiment, these are taken cumulatively, hence “and”) R4represents Cs-ecycloalkyl and, in an embodiment, represents C4-scycloalkyl (for instance, cyclobutyl).

[0117] The synthesis of compounds of formula (I) can be performed as outlined in the Schemes 1 to 5 that can be found in the experimental part below.

[0118] Other synthetic pathways for preparing compounds of formula (I) have been described in the experimental section as general methods of preparation and specific working examples.

[0119] The starting materials and some of the intermediates are known compounds and are commercially available or may be prepared according to conventional reaction procedures generally known in the art.

[0120] The compounds of formula (I) as prepared in the hereinabove described processes may be synthesized in the form of racemic mixtures of enantiomers which can be separated from one another following art-known resolution procedures. Those compounds of formula (I) that are obtained in racemic form may be converted into the corresponding diastereomeric salt forms by reaction with a suitable chiral acid. Said diastereomeric salt forms are subsequently separated, for example, by selective or fractional crystallization and the enantiomers are liberated therefrom by alkali. An alternative manner of separating the enantiomeric forms of the compounds of formula (I) involves liquid chromatography using a chiral stationary phase. Said pure stereochemically isomeric forms may also be derived from the corresponding pure stereochemically isomeric forms of the appropriate starting materials, provided that the reaction occurs stereospecifically. Preferably if a specific stereoisomer is desired, said compound will be synthesized by stereospecific methods of preparation. These methods will advantageously employ enantiomerically pure starting materials.

[0121] A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier.

[0122] A pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier wherein the composition is in the form of an intravenous, subcutaneous, inhaled or oral dosage form.

[0123] A pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, further comprising an additional therapeutic agent.

[0124] The additional therapeutic agent comprises one or more of dexamethasone, azithromycin and remdesivir.

[0125] A method of treating COVID-19 in a subject, the method comprising administering a pharmaceutical composition comprising a compound of formula (I).

[0126] A method of treating and / or preventing infection or diseases caused by coronavirus comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0127] Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the treatment and / or prevention of infection or diseases caused by coronavirus, in particular for the treatment and / or prevention of COVID-19.

[0128] Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the preparation of a medicament that is useful for the treatment and / or prevention of infection or diseases caused by coronavirus, in particular for the treatment and / or prevention of COVID-19. A compound of formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of a compound formula (I), for use as a medicament.

[0129] A compound of formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of a compound of formula (I), for use in treating and / or preventing infection or diseases caused by coronavirus, in particular COVID-19.

[0130] The present invention also provides a method of targeting SARS-CoV-2 infection as a means of treating one or more symptoms caused by SARS-CoV-2-related viral infections.

[0131] An aspect of the invention is to treat and / or prevent SARS-CoV-2 infection or diseases by administering an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt. The SARS-CoV-2 infection or diseases result from infection by one or more strains or variants of SARS-CoV-2, including, but not limited to, the strains or variants provided below. _

[0132] The term "subject" as used herein, refers to an animal, preferably a mammal, most preferably a human, who is or has been the object of treatment, observation or experiment.

[0133] The term "therapeutically effective amount" as used herein, means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes alleviation of the symptoms of the disease or disorder being treated. The term “agent” refers to a drug substance having pharmacological activity — an effect of the agent on an individual. The terms “agent,” “active ingredient”, “drug substance,” and “compound” are used interchangeably herein.

[0134] The term “coronavirus” includes naturally occurring (e.g. wild-type) coronavirus; naturally occurring coronavirus variants; and coronavirus variants generated in the laboratory, including variants generated by selection, variants generated by chemical modification, and genetically modified variants (e.g., coronavirus modified in a laboratory by recombinant DNA methods). In an embodiment, a subject can be tested for a viral infection within a few days after symptoms begin, or after treatment according to the present disclosure, by collecting nasal secretions (nasal or nasopharyngeal (NP) swabs), throat (oropharyngeal) swab, blood, or other body fluid samples and testing the sample for detection of viral antigens or RNA in blood and other body fluids using, for example, an antigen-capture enzyme-linked immunosorbent assay (ELISA), using an IgM ELISA (to determine whether the subject has IgM antibodies), using an IgG ELISA (to determine whether the subject has IgG antibodies), using polymerase chain reaction (PCR), or by virus isolation. In an embodiment, the coronavirus is selected from the group consisting of Middle East respiratory syndrome (MERS), severe acute respiratory syndrome (SARS) and SARS-CoV-2.

[0135] The terms “co-administer,” “coadministration,” or “in combination” are used to describe the administration of a compound of the present invention in combination with at least one other antiviral active agent. The timing of the coadministration is best determined by the medical specialist treating the patient. It is sometimes desired that the agents be administered at the same time. Alternatively, the drugs selected for combination therapy may be administered at different times to the patient. Of course, when more than one viral or other infection or other condition is present, the present compounds may be combined with other agents to treat that other infection or condition as required.

[0136] As related to the present invention, the term “treatment”, “treating”, and the like, is defined as prior to prophylactic administration of the compounds in the methods described herein, prior to viral infection, or inhibiting viral activity after infection has occurred. In an embodiment, the term “treating” is meant to administer one or more compounds of the present invention to measurably inhibit the replication of a virus in vitro or in vivo, to measurably decrease the load of a virus in a cell in vitro or in vivo, or to reduce at least one symptom associated with having a CoV- mediated disease in a patient. Desirably, the inhibition in replication or the decrease in viral load is at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 97%, 98%, 99%, as determined using a suitable assay. Assays that monitor replication of viruses include, but are not limited to, cytopathic viral assays, reportervirus and reporter-cell assays, viral replicon assays, and gene-targeted viral assays. Viral load testing can be carried out using nucleic acid amplification based tests (NATs or NAATs) and non-nucleic acid-based tests on blood plasma samples to determine the quantity of virus in a given volume including viral RNA levels in plasma and tissue and total viral DNA. Alternatively, in certain embodiments, treatment is observed by a trained physician as an appreciable or substantial relief of symptoms in a patient with a SARS-CoV-2-mediated disease. Typically, a decrease in viral replication is accomplished by reducing the rate of RNA polymerization, RNA translation, protein processing or modification, or by reducing the activity of a molecule involved in any step of viral replication (e.g., proteins or coded by the genome of the virus or host important for viral replication). In an embodiment, the term “treat” refers to the ability of a compound or compounds of the present invention to inhibit or suppress replication of a virus, such as an RNA virus. In an embodiment, the term “treat” refers to the ability of a compound or compounds of the present invention to inhibit the cytopathic effect during a RNA virus infection.

[0137] In some embodiments, an “effective amount” or “immune-stimulatory amount” of a compound of the invention is an amount which, when administered to a subject, is sufficient to engender a detectable immune response. In other embodiments, a “protective effective amount” of an immunogenic composition is an amount which, when administered to a subject, is sufficient to confer protective immunity upon the subject. In other embodiments, a “therapeutic effect amount” of a compound is an amount which, when administered to a subject, is sufficient to treat a viral infection, such as increase viral clearance.

[0138] A dose of the pharmaceutical composition may contain at least a therapeutically effective amount of a coronavirus, in particular, SARS-CoV-2-inhibiting agent and preferably is made up of one or more pharmaceutical dosage units. The selected dose may be administered to a mammal, for example, a human patient, in need of treatment related coronavirus activity, by any known or suitable method of administering the dose, including topically, for example, as topical gel, spray, ointment or cream; orally; rectally, for example, as a suppository; parenterally by injection; intravenously; or continuously by intravaginal, intranasal, intrabronchial, intraaural, or intraocular infusion. The term patient means animals, including mammals and particularly humans.

[0139] Administration of the compounds of the invention and their pharmaceutically acceptable prodrugs, salts, active metabolites, and solvates may be performed according to any of the accepted modes of administration available to those skilled in the art. Illustrative examples of suitable modes of administration include oral, nasal, pulmonary, parenteral, topical, intravenous, injected, transdermal, and rectal. Oral, intravenous, subcutaneous and nasal deliveries are preferred.

[0140] A compound of the invention may be administered as a pharmaceutical composition in any suitable pharmaceutical form. Suitable pharmaceutical forms include solid, semisolid, liquid, or lyophilized formulations, such as tablets, powders, capsules, suppositories, suspensions, liposomes, and aerosols. The compounds of the invention may be prepared as a solution using any of a variety of methodologies.

[0141] The compounds and methods of the present invention may be utilized to treat a subject in need thereof. In certain embodiments, the subject is a mammal such as a human, or a non-human mammal. When administered to an animal, such as a human, the compound is preferably administered as a pharmaceutical composition comprising, for example, at least one compound of the invention with a substance or collection of substances capable of being combined with the at least one compound of the invention.

[0142] The term “pharmaceutically-acceptable carrier materials” as used herein means a substance or collection of substances capable of being combined with an agent that is suitable for use in contact with the tissues of mammals for purposes of a therapeutic treatment in the mammals under anticipated exposure conditions. Pharmaceutically-acceptable carrier materials are well known in the art and include, for example, inert solid, semi-solid or liquid filler, diluent, encapsulating material. Pharmaceutically-acceptable carrier materials must, of course, be of sufficiently high purity and sufficiently low toxicity to render them suitable for administration to the human or lower animal being treated. The pharmaceutical composition can be in unit dosage form such as tablet, capsule (including sprinkle capsule and gelatin capsule), granule, powder, syrup, suppository, injection or the like.

[0143] Acceptable methods of preparing suitable pharmaceutical forms of the pharmaceutical compositions are known or may be routinely determined by those skilled in the art. For example, pharmaceutical preparations may be prepared following conventional techniques of the pharmaceutical chemist involving steps such as mixing, granulating, and compressing when necessary for tablet forms, or mixing, filling and dissolving the ingredients as appropriate, to give the desired products for intravenous, oral, parenteral, topical, intravaginal, intranasal, intrabronchial, intraocular, intraaural, and / or rectal administration.

[0144] By “more effective” is meant that a treatment exhibits greater efficacy, or is less toxic, safer, more convenient, or less expensive than another treatment with which it is being compared. Efficacy may be measured by a skilled practitioner using any standard method that is appropriate for a given indication.

[0145] Examples of greater clinical benefits could include a larger reduction in COVID-19 symptoms, a faster time to alleviation of symptoms, reduced lung pathology, a larger reduction in the amount of SARS-CoV-2 coronavirus in the patient (viral load), and decreased mortality.

[0146] As used herein, the term “a suitable period of time” refers to the period of time starting when a patient begins treatment for a diagnosis of coronavirus infection using a method of the present disclosure, throughout the treatment, and up until when the patient stops treatment due to either a reduction in symptoms associated with the coronavirus infection or due to a laboratory diagnosis indicating that the viral infection is under control. In an embodiment, a suitable period of time is one (1) week. In an embodiment, a suitable period of time is between one (1) week and two (2) weeks. In an embodiment, a suitable period of time is two (2) weeks. In an embodiment, a suitable period of time is between two (2) weeks and three (3) weeks. In an embodiment, a suitable period of time is three (3) weeks. In an embodiment, a suitable period of time is between three (3) weeks and four (4) weeks. In an embodiment, a suitable period of time is four (4) weeks. In an embodiment, a suitable period of time is between four (4) weeks and five (5) weeks. In an embodiment, a suitable period of time is five (5) weeks. In an embodiment, a suitable period of time is between five (5) weeks and six (6) weeks. In an embodiment, a suitable period of time is six (6) weeks. In an embodiment, a suitable period of time is between six (6) weeks and seven (7) weeks. In an embodiment, a suitable period of time is seven (7) weeks. In an embodiment, a suitable period of time is between seven (7) weeks and eight (8) weeks. In an embodiment, a suitable period of time is eight (8) weeks.

[0147] The compounds of the present invention can be prepared according to the methods set forth below.

[0148] Experimental Part Examples

[0149] The following illustrate the synthesis of various compounds of the present invention. Additional compounds within the scope of this invention may be prepared using the methods illustrated in these Examples, either alone or in combination with techniques generally known in the art. All starting materials in these preparations and Examples are either commercially available or can be prepared by methods known in the art or as described herein.

[0150] Reactions were performed in air or, when oxygen- or moisture-sensitive reagents or intermediates were employed, under an inert atmosphere (nitrogen or argon). When appropriate, reaction apparatuses were dried under dynamic vacuum using a heat gun and anhydrous solvents (Sure-Seal™ products from Aldrich Chemical Company, Milwaukee, Wisconsin or DriSolv™ products from EMO Chemicals, Gibbstown, NJ) were employed. In some cases, commercial solvents were passed through columns packed with 4A molecular sieves, until the following QC standards for water were attained: a) <100 ppm for dichloromethane, toluene, N,N-dimethylformamide, and tetrahydrofuran; b) <180 ppm for methanol, ethanol, 1,4-dioxane, and diisopropylamine. For very sensitive reactions, solvents were further treated with metallic sodium, calcium hydride, or molecular sieves, and distilled just prior to use.

[0151] Other commercial solvents and reagents were used without further purification. For syntheses referencing procedures in other Examples or Methods, reaction conditions (reaction time and temperature) may vary. Products were generally dried under vacuum before being carried on to further reactions or submitted for biological testing.

[0152] Unless otherwise noted, chemical reactions were performed at room temperature (about 23 degrees Celsius).

[0153] Unless noted otherwise, all reactants were obtained commercially and used without further purification, or were prepared using methods known in the literature.

[0154] The terms "concentrated", "evaporated", and "concentrated in vacuo" refer to the removal of solvent at reduced pressure on a rotary evaporator with a bath temperature less than 60°C. The abbreviation "min" and "h" stand for "minutes" and "hours" respectively.

[0155] The term "TLC" refers to thin-layer chromatography, "room temperature or ambient temperature" means a temperature between 18 to 25°C, "GCMS" refers to gas chromatography-mass spectrometry, "LCMS" refers to liquid chromatography-mass spectrometry, "UPLC" refers to ultra-performance liquid chromatography and "HPLC" refers to high-performance liquid chromatography, "SFC" refers to supercritical fluid chromatography.

[0156] Microwave assisted reactions were performed in a single-mode reactor: InitiatorTM Sixty EXP microwave reactor (Biotage AB), or in a multimode reactor: MicroSYNTH Labstation (Milestone, Inc.).

[0157] Thin layer chromatography (TLC) was carried out on silica gel 60 F254 plates (Merck) using reagent grade solvents. Open column chromatography was performed on silica gel, particle size 60 A, mesh = 230-400 (Merck) using standard techniques. Automated flash column chromatography was performed using ready-to-connect cartridges from different vendors, on irregular silica gel, (normal phase disposable flash columns) on different flash systems. Nuclear Magnetic Resonance (NMR): For a number of compounds, 1H NMR spectra were recorded either on a Bruker Avance III, on a Bruker DPX-400 or on a Bruker AV-500 spectrometer with standard pulse sequences, operating at 400 MHz and 500 MHz, respectively. Chemical shifts (d) are reported in parts per million (ppm) downfield from tetramethylsilane (TMS), which was used as internal standard.

[0158] Other abbreviations used herein include: br = broad; °C = degrees Celsius; s = singlet; d = doublet; dd = doublet of doublets; ddd = doublet of doublet of doublets; t = triplet; q = quadruplet; DMSO = dimethylsulfoxide; g = gram; Hz = hertz; L = liter; M = molar; m = multiplet; mg = milligram; MHz = megahertz; ml = milliliter, pL = microliter, mmol = millimole.

[0159] Melting points values are peak values and are obtained with experimental uncertainties that are commonly associated with this analytical method.

[0160] Abbreviations : LCMS

[0161] General procedure

[0162] The High Performance Liquid Chromatography (HPLC) measurement was performed using a LC pump, a diode-array (DAD) or a UV detector and a column as specified in the respective methods. If necessary, additional detectors were included (see table of methods below).

[0163] Flow from the column was brought to the Mass Spectrometer (MS) which was configured with an atmospheric pressure ion source. It is within the knowledge of the skilled person to set the tune parameters (e.g. scanning range, dwell time...) in order to obtain ions allowing the identification of the compound’s nominal monoisotopic molecular weight (MW) and / or exact mass monoisotopic molecular weight. Data acquisition was performed with appropriate software.

[0164] Compounds are described by their experimental retention times (Rt) and ions. If not specified differently in the table of data, the reported molecular ion corresponds to the [M+H]+ (protonated molecule). For molecules with multiple isotopic patterns (Br, Cl), the reported value is the one obtained for the lowest isotope mass. All results were obtained with experimental uncertainties that are commonly associated with the method used.

[0165] Photochemistry reactions were performed using a Penn Photoreactor®.

[0166] The names of the compounds of the present invention were generated according to the nomenclature rules agreed upon by the International Union of Pure and Applied Chemistry (IUPAC) generated by ChemDraw Ultra 20.1. In case of tautomeric forms, the name of the depicted tautomeric form of the structure was generated. However it should be clear that the other non-depicted tautomeric form is also included within the scope of the present invention.

[0167] The compounds according to the invention can generally be prepared by a succession of steps, each of which is known to the skilled person. In particular, the compounds can be prepared according to the following synthesis methods.

[0168] The compounds of formula (I) may be synthesized in the form of racemic mixtures of enantiomers which can be separated from one another following art-known resolution procedures. The racemic compounds of formula (I) may be converted into the corresponding diastereomeric salt forms by reaction with a suitable chiral acid. Said diastereomeric salt forms are subsequently separated, for example, by selective or fractional crystallization and the enantiomers are liberated therefrom by alkali. An alternative manner of separating the enantiomeric forms of the compounds of formula (I) involves liquid chromatography using a chiral stationary phase or chiral supercritical fluid chromatography (SFC). Said pure stereochemically isomeric forms may also be derived from the corresponding pure stereochemically isomeric forms of the appropriate starting materials, provided that the reaction occurs stereospecifically.

[0169] The absolute configuration of compounds of the invention reported herein was determined by analysis of the racemic mixture by supercritical fluid chromatography (SFC) followed by SFC comparison of the separate enantiomer(s) which were obtained by asymmetric synthesis, followed by vibrational circular dichroism (VCD) analysis of the particular enantiomer(s).

[0170] General Synthesis Schemes :

[0171] Compounds of formula (I) of the present invention may be prepared as described in the general synthesis schemes and Examples which follow hereinafter, selecting and substituting suitable reagents and conditions, as would be well within the skill of persons versed in the art. Additionally, the preparation of any starting materials used in the schemes and synthesis examples which follow hereinafter is well within the skill of persons versed in the art.

[0172] Experimental Part.

[0173] Synthesis of compounds of Formula (l-a) wherein X is -NH-(CO)- (Reverse Amides) Compounds of formula (l-a) wherein X is -NH-(CO)- may be prepared as described in Scheme (1), below.

[0174] Preparation of Intermediate Compounds

[0175] Intermediate 1 : 1 -Bromo-4-(difluoro(4-fluorophenyl)methyl)benzene.

[0176] Step A: 2-(4-Bromophenyl)-2-(4-fluorophenyl)-1,3-dithiane.

[0177] (4-Bromophenyl)(4-fluorophenyl) methanone (5.00 g, 17.9 mmol), a stir bar, propane-1, 3-dithiol (2.16 mL, 21.5 mmol), 4-methylbenzenesulfonic acid (1.54 g, 8.96 mmol) and toluene (50.0 mL) were added to a 250 mL three-necked round-bottomed flask fitted with a reflux condenser, and the brown mixture stirred for 48 h at 110°C, then the solution turns yellow. The reaction progress was monitored by TLC. The reaction mixture was poured into H2O (40 mL), extracted with EtOAc (50 mL x 3). The combined extracts were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuum to give a brown oil. The oil was then subjected to silica gel chromatography (0-20% ethyl acetate / Pet ether) to give 2-(4- bromophenyl)-2-phenyl-1 ,3-dithiane as a white solid (6.00 g, 91% yield).1H NMR (400 MHz, CDCI3)_δ: 7.67 - 7.5Q (m, 4H), 7.52 - 7.46 (m, 2H), 7.06 - 6.99 (m, 2H), 2.80 - 2.75 (m, 4H), 2.04 - 1.99 (m, 2H). Mass spectrum (ESI, m / z): Calcd. for CieHi4BrFS2 368.0; found [M+H] 379.3

[0178] Step B: 1-Bromo-4-(difluoro(4-fluorophenyl)methyl)benzene Selectfluor™ (1.92 g, 5.42 mmol), a stir bar and PPHF (5.0 mL, 70% purity) were added to a 50 mL polyethylene bottle and cooled to 0 °C, 2-(4-bromophenyl)-2-(4-fluorophenyl)-1 ,3-dithiane (1.00 g, 2.71 mmol) in DCM (20.0 mL) was added dropwise to the reaction solution, the reaction vessel was removed from the ice bath and stirred at r.t. for 1 h to give a light yellow solution. The reaction progress was monitored by TLC. The reaction mixture was added H2O (50 mL), extracted with DCM (40 mL x 2). The combined extracts were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuum to give as a yellow oil. The oil was then subjected to silica gel chromatography (0-10% EtOAc / pet ether) to give 1-bromo-4- (difluoro(4-fluorophenyl)methyl)benzene as a colorless oil (700.0 mg, 86% yield).1H NMR (400 MHz, CDCI3) δ: 7.57 (d, J = 8.4 Hz, 2H), 7.47 (dd, J = 5.2, 8.4 Hz, 2H), 7.37 (d, J = 8.4 Hz, 2H), 7.11 (t, J = 8.4 Hz, 2H).

[0179] Intermediate 2: 1 -Bromo-4-((4-chlorophenyl)difluoromethyl)benzene.

[0180] Step A: 2-(4-Bromophenyl)-2-(4-chlorophenyl)-1 ,3-dithiane (4-Bromophenyl)(4-chlorophenyl)methanone (2.00 g, 6.77 mmol), a stir bar, TsOH (233.1 mg, 1.353 mmol) and toluene (20.0 mL) were added to an oven-dried and nitrogen-purged 50 mL round-bottomed flask fitted with a reflux condenser, which was subsequently evacuated and refilled with nitrogen (x3), and the resulting mixture treated with propane-1 , 3-dithiol (1.4 mL, 14 mmol, 1.078 g / mL). Then the reaction vessel placed in an oil bath that had been pre-heated to 120°C, and the mixture stirred overnight. The reaction mixture were poured into brine (20 mL), extracted with EtOAc (20 mL x 3). The combined extracts were dried over anhydrous Na2SC>4, filtered and concentrated in vacuum to give a brown oil. The oil was then subjected to silica gel chromatography (0-10% EtOAc / pet ether) to give the 2-(4-bromophenyl)-2-(4- chlorophenyl)-1 ,3-dithiane as a white solid (2.3 g, 88%).1H NMR (400 MHz, DMSO-d6) δ:: 7.64 - 7.59 (m, 2H), 7.59 - 7.54 (m, 2H), 7.53 - 7.46 (m, 4H), 2.78 - 2.73 (m, 4H), 1.94 - 1.86 (m, 2H). Step B: 1-Bromo-4-((4-chlorophenyl)difluoromethyl)benzene 2-(4-Bromophenyl)-2-(4-chlorophenyl)-1 ,3-dithiane (2.30 g, 5.96 mmol), a stir bar, and DCM (10 mL) were added to an oven-dried and nitrogen-puerged 50 mL round-bottomed flask, then the mixture cooled to 0°C and treated with DAST (1.7 mL, 1.22 g / mL, 12.8 mmol), the resulting mixture stirred at r.t. for 12 h. The reaction mixture poured into NaHCO3 (15 mL) at 0°C and extracted with DCM (15 mL x 3). The combined extracts were washed with brine (10 ml ), dried over anhydrous Na2SO4, filtered, and concentrated to dryness in vacuo to give a brown oil. The oil was subjected to silica gel chromatography (0-5% EtOAc / pet ether) to give the 1-bromo-4- ((4 chlorophenyl)difluoromethyl)benzene (1.19 g, 63%).1H NMR (400 MHz, DMSO-d6) δ:: 7.72 (d, J = 8.4 Hz, 2H), 7.60 - 7.53 (m, 4H), 7.48 (d, J = 8.4 Hz, 2H).

[0181] Step A: (4-Bromophenyl)(4-fluoro-3-methoxyphenyl)methanone 4-Bromo-1-fluoro-2-methoxybenzene (8.82 g, 43.0 mmol), a stir bar, and THF (70.0 mL) were added to a 250 mL three-necked bottomed flask, which was subsequently evacuated and refilled with nitrogen (x3) and cooled to -70°C in an EtOH / dry ice bath, and the resulting mixture treated with n-BuLi (17.2 mL, 43.0 mmol, 2.5 M) dropwise over 15 min, the mixture changed to be a yellow suspension and stirred at -70°C for 0.5 h, then which charged with the solution of 4-bromo- / V-methoxy- / \ / -methylbenzamide (7.00 g, 28.7 mmol) in THF (20.0 mL), and the mixture stirred at -70°C for 3 h. The reaction progress was monitored by TLC. The reaction mixture was quenched with sat. NH4CI (30 mL) and was extracted with EtOAc (30 mL x 3). The combined extracts were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuum to give a yellow oil. The oil was then subjected to silica gel chromatography (0-30% EtOAc / pet ether) to give (4-bromophenyl)(4-fluoro-3- methoxyphenyl)methanone as a white solid (8.2 g, 73%).1H NMR (400 MHz, DMSO-d6) δ: 7.80 - 7.75 (m, 2H), 7.72 - 7.64 (m, 2H), 7.51 (dd, J = 1.6, 8.4 Hz, 1 H), 7.39 (dd, J = 8.4, 11.2 Hz, 1 H), 7.31 (dt, J = 2.0, 4.0 Hz, 1 H), 3.90 (s, 3H). Step B: 2-(4-Bromophenyl)-2-(4-fluoro-3-methoxyphenyl)-1 ,3-dithiane (4-Bromophenyl)(4-fluoro-3-methoxyphenyl)methanone (6.00 g, 19.4 mmol), a stir bar, DCM (60.0 mL) were added to 250 mL round-bottomed flask, which was subsequently cooled to 0°C in the water / ice bath, and the resulting mixture treated with Et2O BF3 (6.0 mL, 49 mmol) dropwise over 10 min, The mixture was stirred at r.t. for 2 min before treated with propane-1, 3- dithiol (3.9 mL, 39 mmol) and the yellow homogeneous mixture stirred at r.t. for 12 h. The reaction progress was monitored by TLC. The reaction mixture was quenched by sat. NaHCO3 (30 mL) dropwise, extracted with DCM (30 mL x 3). The combined extracts were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuum to give a yellow oil. The oil was then subjected to silica gel chromatography (0-50% DCM / pet ether) to give 2-(4-bromophenyl)-2-(4-fluoro-3-methoxyphenyl)-1 ,3-dithiane as a white solid (7.20 g, 67%).1H NMR (400 MHz, DMSO-d6) δ:: 7.60 (d, J = 8.8 Hz, 2H), 7.49 (d, J = 8.8 Hz, 2H), 7.44 (dd, J = 1.6, 8.0 Hz, 1H), 7.24 (dd, J = 8.8, 11.2 Hz, 1 H), 7.05 (d, J = 1.2 Hz, 1 H), 3.79 (s, 3H), 2.80 - 2.75 (m, 4H), 1.95 - 1.88 (m, 2H) Mass spectrum (ESI, m / z): calcd. for Ci?Hi6BrFOS2 398.0; found [M+H]+, 399.0.

[0182] Step C: 4-((4-Bromophenyl)difluoromethyl)-1-fluoro-2-methoxybenzene PPHF (34.2 mL) and a stir bar were added to a 250 mL round-bottomed flask and cooled to 0°C, then pyridine (5.7 mL), Selectfluor™ (10.11 g, 28.55 mmol) was added, the mixture stirred at 0°C for 1 min and 2-(4-bromophenyl)-2-(4-fluoro-3-methoxyphenyl)-1,3-dithiane (5.70 g, 14.3 mmol) in DCM (142 mL) was added to the contents dropwise, the reaction vessel was removed from the ice bath and stirred at r.t for 30 min to give a yellow suspension mixture. The reaction progress was monitored by TLC. The reaction mixture was diluted with DCM (20 mL), quenched with sat NaHCC>3 (30 mL) and extracted with DCM (20 mL*3). The combined extracts were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuum to give a yellow oil. The oil was subjected to silica gel chromatography (0-5% EtOAc / pet ether) to give 4-((4-bromophenyl)difluoromethyl)-1-fluoro-2-methoxybenzene as a colorless oil (3.50 g, 55%).1H NMR (400 MHz, DMSO-d6) δ:: 7.71 (d, J = 8.4 Hz, 2H), 7.51 (d, J = 8. Hz, 2H), 7.39 - 7.27 (m, 2H), 7.09 - 7.00 (m, 1H), 3.88 (s, 3H).

[0183] Intermediate 4: 4-((4-Bromophenyl)difluoromethyl)-1 -chloro-2-methoxybenzene. Step A: (4-Bromophenyl)(4-chloro-3-methoxyphenyl)methanone. 4-Bromo-1-chloro-2-methoxybenzene (8.17 g, 36.9 mmol, co-evaporated with toluene), a stir bar and THF (40.0 mL) were added to a 250 mL three necked flask, which was subsequently evacuated and refilled with nitrogen (x3) and cooled to -70°C in an EtOH / dry ice bath, and the resulting mixture treated with n-BuLi (14.7 mL, 36.9 mmol, 2.5 M) dropwise over 15 min. The mixture changed to be a yellow suspension and stirred at -70°C for 0.5 h, then the mixture charged with the solution of 4-bromo- / V-methoxy- / \ / -methylbenzamide (6.00 g, 24.6 mmol, removed water with toluene) in THF (10 mL), and stirred at -70°C for 2 h. The reaction progress was monitored by TLC. The reaction mixture was quenched with saturated NH4CI (80 mL) and extracted with EtOAc (80 mL x 3). The combined extracts were washed with brine (80 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuum to give a yellow oil. The oil was then subjected to silica gel chromatography (0-20% EtOAc / pet ether) to give (4-bromo- phenyl)(4-chloro-3-methoxyphenyl)methanone (5.5 g, 52%) as a white solid.1H NMR (400 MHz, CDCI3) δ: 7.66 (d, J = 2.0 Hz, 3H), 7.47 (d, J = 8.0 Hz, 1 H), 7.43 (d, J = 2.0 Hz, 1 H), 7.25 - 7.24 (m, 1 H), 3.97 (s, 3H). Mass spectrum (ESI, m / z): calcd. for Ci4HwBrCIO2 324.0; found [M+H]+, 325.0.

[0184] Step B: 2-(4-Bromophenyl)-2-(4-chloro-3-methoxyphenyl)-1 ,3-dithiane (4-bromophenyl)(4-chloro-3-methoxyphenyl)methanone (800.0 mg, 2.460 mmol), a stir bar, CH2CI2 (15.0 mL) were added to 100 mL round-bottomed flack, which was subsequently cooled to 0°C in the water / ice bath, and the resulting mixture treated with BF3'OEt2 (758 μL, 6.14 mmol) dropwise over 10 min, The mixture was stirred at r.t. for 2 min before treated with propane-1 , 3-dithiol (493 μL, 4.91 mmol) then stirred for 12 h. The reaction progress was monitored by TLC. The reaction mixture was quenched by adding into saturated NaHCO3 (20 mL) dropwise, then extracted with EtOAc (30 mL x 2). The combined extracts were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuum to give a yellow oil. The oil was then subjected to silica gel chromatography (0-5% EtOAc / pet ether) to give 2-(4-bromophenyl)-2-(4-chloro-3-methoxyphenyl)-1 ,3-dithiane (700 mg, 67%) as a white solid.1H NMR (400 MHz, CDCI3) δ: 7.60 - 7.52 (m, 2H), 7.51 - 7.44 (m, 3H), 7.34 (d, J = 8.0 Hz, 1 H), 7.22 - 7.15 (m, 1 H), 3.89 (s, 3H), 2.83 - 2.79 (m, 4H), 2.03 (br s, 2H). Mass spectrum (ESI, m / z): calcd. for Ci7Hi6BrCIOS2414.0; found [M+H]+, 414.8. Step C: 4-((4-Bromophenyl)difluoromethyl)-1-chloro-2-methoxybenzene 2-(4-bromophenyl)-2-(4-chloro-3-methoxyphenyl)-1 ,3-dithiane (700.0 mg, 1.680 mmol), a stir bar and DCM (10.0 mL) were added to a 50 mL round-bottomed flack, which was subsequently cooled to 0°C in the water / ice bath, and the resulting mixture treated with DAST (0.44 mL, 3.4 mmol) dropwise over 2 min, and the mixture stirred at r.t. for overnight. The reaction progress was monitored by TLC. The reaction mixture was quenched by adding into saturated NaHCO3 (30 mL) dropwise, then extracted with EtOAc (20 mL x 2). The combined extracts were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuum to give a brown oil. The oil was then subjected to silica gel chromatography (0~2% EtOAc / pet ether) to give 4-((4-bromophenyl)difluoromethyl)-1-chloro-2-methoxybenzene as a white oil (500 mg, 85%).1H NMR (400 MHz, CDCI3)_δ: 7.57 (d, J = 8.4 Hz, 2H), 7.44 - 7.34 (m, 3H), 7.07 (d, J = 1.6 Hz, 1 H), 6.97 - 6.96 (m, 1 H), 3.92 (s, 3H).

[0185] Intermediate 5: N-((5aS,8aS)-7-acetyl-4-oxo-5,5a,6,7,8,8a-hexahvdro-4H-pyrazolori ,5- alpyrrolor3,4-e]pyrazin-3-yl)-3-cvano-4-methoxybenzamide.

[0186] Step A: (5aS,8aS)-7-acetyl-3-iodo-5,5a,6,7,8,8a-hexahvdro-4 / 7-pyrazolon ,5-alpyrrolof3,4- elpyrazin-4-one (5aS,8aS)-3-lodo-5,5a,6,7,8,8a-hexahydro-4 / 7-pyrazolo[1 ,5-a]pyrrolo[3,4-e]pyrazin-4-one (10.00 g, 29.36 mmol), a stir bar and CH3CN (100.0 mL) were added to a 250 mL three-necked round-bottomed flask, then treated with TEA (12.2 mL, 0.728 g / mL, 88.1 mmol) and stirred for 30 min before treating with AC2O (3.3 mL, 1.08 g / mL, 35 mmol). The resulting mixture stirred for 2 h, which formed a white suspension mixture. The reaction progress was monitored by LCMS. The reaction mixture was poured into H2O (60 mL), aged 60 min, then let settles before filtration. The filter cake was washed with H2O (30 mL x 2), collected and concentrated in vacuo to give (5aS,8aS)-7-acetyl-3-iodo-5,5a,6,7,8,8a-hexahydro-4 / 7-pyrazolo[1 ,5-a]pyrrolo[3,4- e]pyrazin-4-one as an off-white solid (9.17 g, 89%).1H NMR (400 MHz, DMSO-d6) δ:: 8.92 (d, J = 19.2 Hz, 1 H), 7.74 (d, J = 2.0 Hz, 1 H), 4.61 - 4.45 (m, 1 H), 4.26 - 3.97 (m, 2H), 3.91 - 3.66 (m, 2H), 3.50 - 3.12 (m, 1 H), 2.00 (d, J = 7.2 Hz, 3H). Mass spectrum (ESI, m / z): Calcd. for C1OH11 I N4O2, 346.0, found [M+H]+, 346.9. Step B: N-((5aS,8aS)-7-Acetyl-4-oxo-5,5a,6,7,8,8a-hexahvdro-4H-pyrazolon ,5-alpyrrolof3,4- elpyrazin-3-yl)-3-cyano-4-methoxybenzamide (5aS,8aS)-7-Acetyl-3-iodo-5,5a,6,7,8,8a-hexahydro-4 / 7-pyrazolo[1 ,5-a]pyrrolo[3,4-e]pyrazin-4- one (5.44 g, 15.7 mmol), a stir bar, 3-cyano-4-methoxybenzamide (Intermediate 5, 6.92 g, 39.3 mmol), CS2CO3 (20.5 g, 62.9 mmol) and dioxane (170 mL) were added to an oven-dried and nitrogen-purged 500 mL three-necked flask fitted with a reflux condenser, which was subsequently evacuated and refilled with N2 (x3), then stirred for 5 min before treating with tBubrettphos (380.9 mg, 0.7860 mmol) and tBubrettphos Pd G3 (1.34 g, 1.57 mmol), which was subsequently evacuated and refilled with N2 (x3), and the resulting mixture stirred at 100 °C for 18 h as a brown homogenous mixture. The reaction progress was monitored by LCMS. The reaction mixture was cooled to r.t., added water (150 mL), the brown suspension mixture stirred at r.t. for 1 h, then let to settle 1 h, filtered and the filter cake was added acetone (200 mL) and the brown suspension mixture stirred at 75 °C for 1 h, then let settle 1 h, filtered and the filter cake was concentrated in vacuum to give the (5aS,8aS)-3-iodo-7-(4-methoxybenzyl)- 5,5a,6,7,8,8a-hexahydro-4 / 7-pyrazolo[1 ,5-a]pyrrolo[3,4-e]pyrazin-4-one as an off-white solid (3.53 g, 56%).1H NMR (400 MHz, DMSO-d6) δ:: 8.27 (s, 1 H), 8.21 (d, J = 8.8 Hz, 1 H), 8.15 (d, J = 6.0 Hz, 1 H), 7.39 - 7.33 (m, 1 H), 4.44 - 4.32 (m, 1 H), 4.32 - 4.23 (m, 1 H), 4.21 - 4.04 (m, 1 H), 3.99 (s, 3H), 3.93 - 3.81 (m, 2H), 3.73 - 3.13 (m, 1 H), 2.01 (d, J = 8.8 Hz, 3H). Mass spectrum (m / z): Calcd. for CigHisNeCL, 394.1 ; found [M+H]+, 395.0.

[0187] Intermediate 6: N-((5aS,8aR)-7-acetyl-4-oxo-5,5a,6,7,8,8a-hexahvdro-4H-pyrazolori ,5- alpyrrolor3,4-e]pyrazin-3-yl)-3-cvano-4-methoxybenzamide.

[0188] Step A: (5aS,8a / ?)-7-Acetyl-3-iodo-5,5a,6,7,8,8a-hexahvdro-4 / 7-pyrazolon ,5-alpyrrolof3,4- elpyrazin-4-one.

[0189] (5aS,8a / ?)-7-Acetyl-3-iodo-5, 5a, 6,7,8, 8a-hexahydro-4 / 7-pyrazolo[1 ,5-a]pyrrolo[3,4-e]pyrazin-4- one (2.90 g, 7.69 mmol), a stir bar and CH3CN (30.0 mL) were added to a 100 mL round- bottomed flask, then TEA (3.21 mL, 0.728 g / mL, 23.1 mmol) was added and the brown suspension mixture stirred at r.t. for 30 min. which treated with AC2O (800 μL, 1.08 g / mL, 8.46 mmol). The resulting mixture stirred at r.t. for 2 h, which formed a brown suspension mixture. The reaction progress was monitored by LCMS. The reaction mixture quenched with sat. NaHCOs (30 mL), then extracted with dichloromethane (30 mL x 8). The combined extracts were washed with brine (200 mL), dried over anhydrous Na2SO4, filtered and the filtrate concentrated in vacuum to give a yellow oil. The oil was subjected to silica gel chromatography (0-20% MeOH / dichloromethane) to give the (5aS,8aR)-7-acetyl-3-iodo-5,5a,6,7,8,8a- hexahydro-4 / 7-pyrazolo[1 ,5-a]pyrrolo[3,4-e]pyrazin-4-one (2.6 g, 93% yield) as an off-white solid.1H NMR (400 MHz, DMSO-d6) δ: 8.63 - 8.46 (m, 1 H), 7.78 (d, J = 2.4 Hz, 1 H), 5.15 - 4.93 (m, 1 H), 4.51 - 4.42 (m, 1 H), 4.18 - 3.95 (m, 2H), 3.89 - 3.62 (m, 2H), 1.91 (d, J = 14.0 Hz, 3H). Mass spectrum (ESI, m / z): calcd. for C10H11IN4O2 346.0; found [M+H]+, 346.9.

[0190] Step B: / V-((5aS,8a / ?)-7-acetyl-4-oxo-5,5a,6,7,8,8a-hexahydro-4 / - / -pyrazolon ,5-alpyrrolof3,4- elpyrazin-3-yl)-3-cyano-4-methoxybenzamide.

[0191] (5aS,8a / ?)-7-acetyl-3-iodo-5, 5a, 6,7,8, 8a-hexahydro-4 / 7-pyrazolo[1 ,5-a]pyrrolo[3,4-e]pyrazin-4- one (3.60 g, 10.4 mmol), a stir bar, 3-cyano-4-methoxybenzamide (Intermediate 10, 3.67 g, 20.8 mmol), CS2CO3 (13.56 g, 41.60 mmol), and 1 ,4-dioxane (110 mL) were added to an oven-dried and nitrogen-purged 500 mL three-necked flask fitted with a reflux condenser, which was subsequently evacuated and refilled with N2 (x3), then stirred for 5 min before treated with tBubrettphos (252.1 mg, 0.5200 mmol) and tBubrettphos Pd G3 (888.7 mg, 1.040 mmol), which was subsequently evacuated and refilled with N2 (x3), and the resulting mixture stirred at 100 °C for 16 h as a yellow suspension. The reaction mixture was diluted with DCM (100 mL), and stirred at r.t. for 0.5 h, filtered and the filtrate was concentrated in vacuum to give a yellow solid, the solid was added DCM: MeOH / (10:1 , 50 mL), and the brown suspension mixture stirred at r.t. for 0.5 h, filtered and the filtrate was concentrated in vacuum to give a yellow solid. The solid was subjected to silica gel chromatography (0-10% MeOH / DCM) to give the / \ / -((5aS,8a / ?)-7- acetyl-4-oxo-5, 5a, 6,7,8, 8a- hexa hydro-4 / 7-pyrazolo[1 , 5-a]pyrrolo[3, 4-e]pyrazin-3-yl)-3-cyano-4- methoxybenzamide (2.96 g, 53% purity, 35%) as a brown solid.1H NMR (400 MHz, DMSO-d6) δ: 8.25 - 8.19 (m, 1 H), 8.18 - 8.11 (m, 2H), 7.42 (d, J = 8.4 Hz, 1 H), 5.06 - 4.89 (m, 1 H), 4.58 - 4.44 (m, 1 H), 4.19 - 4.05 (m, 1 H), 3.99 (s, 3H), 3.96 - 3.89 (m, 1 H), 3.80 - 3.73 (m, 2H), 3.34 - 3.12 (m, 1 H), 1.92 (d, J = 14.4 Hz, 3H). Mass spectrum (m / z): Calcd. for C19H18N6O4 394.1 m / z, found [M+H]+, 395.0.

[0192] Intermediate 6: 3-Cvano-N-((5aS,8aS)-5-(4-(difluoro(4-fluorophenyl)methyl)phenyl)-4-oxo- 5,5a,6,7,8,8a-hexahvdro-4H-pyrazolori,5-a]pyrrolor3,4-elpyrazin-3-yl)-4- methoxybenzamide as HCI salt.

[0193]

[0194] Step A: (5aS,8aS)-3-lodo-7-(4-methoxybenzyl)-5,5a,6,7,8,8a-hexahydro-4 / - / -pyrazolon,5- alpyrrolo[3,4-elpyrazin-4-one.

[0195] (5aS,8aS)-3-lodo-5,5a,6,7,8,8a-hexahydro-4 / 7-pyrazolo[1,5-a]pyrrolo[3,4-e]pyrazin-4-one (10.00 g, HCI salt, 29.36 mmol), 4-methoxybenzaldehyde (10.7 mL, 88.1 mmol), a stir bar, and anhydrous MeOH (180 mL) were added to an oven-dried and nitrogen-purged 500 mL three- neck round-bottom flask fitted with a reflux condenser to afford a white suspension. The flask was then charged with acetic acid (3.4 mL, 59 mmol) and placed in a pre-heated oil bath (50 °C) and the mixture stirred for 5 min. The flask was then charged with sodium cyanotrihydroborate (5.54 g, 88.1 mmol) and subjected to 3 cycles of vacuum and recharging of nitrogen, and the mixture stirred at 50 °C for 16 h to give a white suspension. The reaction progress was monitored by LC-MS. The mixture was cooled to rt and filtered, and the filter cake was rinsed with MeOH (15 mL x 2), concentrated to dryness in vacuo to give (5aS,8aS)-3-iodo-7-(4- methoxybenzyl)-5,5a,6,7,8,8a-hexahydro-4 / 7-pyrazolo[1 ,5-a]pyrrolo[3,4-e]pyrazin-4-one as a white solid (9.14 g, 73%). The filtrate was concentrated to dryness in vacuo to give a white solid, which was taken up to H2O (20 mL) and extracted with EtOAc (20 mL x 3). The combined extracts were washed with brine (10 mL x 2), dried over anhydrous Na2SO4, filtered and concentrated to dryness in vacuo to give a white solid, which was subjected to silica-gel chromatography (30-100% EtOAc / pet ether) to give (5aS,8aS)-3-iodo-7-(4-methoxybenzyl)- 5,5a,6,7,8,8a-hexahydro-4 / 7-pyrazolo[1,5-a]pyrrolo[3,4-e]pyrazin-4-one as a white solid (1.27 g, 10% ).1H NMR (400 MHz, DMSO-d6) δ:: 8.76 (s, 1 H), 7.66 (s, 1 H), 7.25 (d, J = 8.4 Hz, 2H), 6.89 (d, J = 8.4 Hz, 2H), 4.47 - 4.37 (m, 1 H), 4.01 - 3.91 (m, 1H), 3.85 - 3.76 (m, 2H), 3.74 (s, 3H), 3.38 - 3.34 (m, 1 H), 3.05 - 2.95 (m, 2H), 2.75 (t, J = 9.6 Hz, 1 H). Mass spectrum (ESI, m / z): Calcd. for C16H17IN4O2 424.0 m / z, found [M+H]+, 424.7.

[0196] Step B: 3-Cyano-4-methoxy- / \ / -((5aS,8aS)-7-(4-methoxybenzyl)-4-oxo-5,5a,6,7,8,8a-hexahvdro- 4 / 7-pyrazolon,5-alpyrrolof3,4-elpyrazin-3-yl)benzamide.

[0197] (5aS,8aS)-3-lodo-7-(4-methoxybenzyl)-5,5a,6,7,8,8a-hexahydro-4 / 7-pyrazolo[1,5-a]pyrrolo[3,4- e]pyrazin-4-one (2.00 g, 4.67 mmol, co-evaporated with toluene), 3-cyano-4-methoxybenzamide (Intermediate 5, 904.7 mg, 5.135 mmol, co-evaporated with toluene), a stir bar, and anhydrous dioxane (46.7 mL) were added to an oven-dried and nitrogen-purged 100 mL round-bottom flask fitted with a reflux condenser. The flask was subjected to 3 cycles of vacuum and recharging of nitrogen, then treated with dicesium carbonate (2.97 g, 14.0 mmol), and ‘Bubrettphos Pd G3 (199.5 mg, 233.4 pmol) and then subjected to 3 cycles of vacuum and recharging of nitrogen again. Placed the flask in a pre-heated oil bath (115 °C) and the mixture stirred for 16 h to afford a yellow suspension. The reaction progress was monitored by LC-MS. The reaction mixture was cooled to rt and poured in H2O (500 mL) to give a brown suspension, which was filtered and the filter cake was collected and concentrated to dryness in vacuo to give an brown solid, which was subjected to silica-gel chromatography (50-100% EtOAc / pet ether) and subsequently re-chromatographed (10% Methanol / Dichloromethane) to give two eluents. First eluting: 3-cyano-4-methoxy- / V-((5aS,8aS)-7-(4-methoxybenzyl)-4-oxo-5,5a,6,7,8,8a- hexahydro-4 / 7-pyrazolo[1,5-a]pyrrolo[3,4-e]pyrazin-3-yl)benzamide as a yellow solid (348.0 mg, 92% purity, 15%). Second eluting: 3-cyano-4-methoxy- / V-((5aS,8aS)-7-(4-methoxybenzyl)-4- oxo-5,5a,6,7,8,8a-hexahydro-4 / 7-pyrazolo[1 ,5-a]pyrrolo[3,4-e]pyrazin-3-yl)benzamide as a yellow solid (975.0 mg, >97% purity, 43%).1H NMR (400 MHz, DMSO-d6) δ:: 9.85 (s, 1H), 8.89 (s, 1H), 8.24 (d, J = 2.0 Hz, 1 H), 8.19 - 8.13 (m, 1 H), 8.06 (s, 1 H), 7.43 (d, J = 8.8 Hz, 1 H), 7.26 (d, J = 8.4 Hz, 2H), 6.90 (d, J = 8.4 Hz, 2H), 4.44 - 4.33 (m, 1 H), 4.08 - 3.98 (m, 4H), 3.88 - 3.77 (m, 2H), 3.74 (s, 3H), 3.41 - 3.36 (m, 1 H), 3.10 - 3.00 (m, 2H), 2.84 - 2.76 (m, 1 H). Mass spectrum (ESI, m / z): Calcd. for C25H24N6O4472.2 m / z, found [M+H]+, 473.2.

[0198] Step C: 3-Cyano- / V-((5aS,8aS)-5-(4-(difluoro(4-fluorophenyl)methyl)phenyl)-7-(4- methoxybenzyl)-4-oxo-5, 5a, 6,7,8, 8a-hexahvdro-4 / 7-pyrazolon,5-alpyrrolof3,4-elpyrazin-3-yl)-4- methoxybenzamide.

[0199] 3-Cyano-4-methoxy- / V-((5aS,8aS)-7-(4-methoxybenzyl)-4-oxo-5,5a,6,7,8,8a-hexahydro-4 / 7- pyrazolo[1,5-a]pyrrolo[3,4-e]pyrazin-3-yl)benzamide (1.00 g, 1.91 mmol), 1-bromo-4-(difluoro(4- fluorophenyl)methyl)benzene (Intermediate 1, 860.8 mg, 2.859 mmol), a stir bar, and anhydrous DMF (16.5 mL) were added to an oven-dried and nitrogen-purged 100 mL round-bottomed flask fitted with a reflux condenser. The flask was then subjected to 3 cycles of vacuum and recharging with nitrogen, and charged with Potassium carbonate (790.2 mg, 5.718 mmol), copper(l) iodide (435.6 mg, 2.287 pmol) and N, N'-dimethylethane-1,2-diamine (0.25 mL, 2.3 mmol) in sequence and then subjected to 3 cycles of vacuum and recharging with nitrogen again. Put the flask in a pre-heated oil bath (100 °C) and the mixture stirred for 16 h to give a black suspension. The reaction progress was monitored by LC-MS. The mixture was cooled to r.t. before poured into H2O (40 mL), and extracted with EtOAc (30 mL x 3). The combined extracts were washed with brine (20 mL x 3), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a yellow oil. The oil was subjected to silica gel chromatography (45-80% EtOAc / Pet ether) to give 3-cyano- / V-((5aS,8aS)-5-(4-(difluoro(4- fluorophenyl)methyl)phenyl)-7-(4-methoxybenzyl)-4-oxo-5, 5a, 6,7,8, 8a-hexahydro-4 / 7- pyrazolo[1,5-a]pyrrolo[3,4-e]pyrazin-3-yl)-4-methoxybenzamide as a yellow semi-solid (940.6 mg, 62%).1H NMR (400 MHz, CDCI3) 5: 9.65 (s, 1H), 8.42 (s, 1H), 8.13 (d, J = 2.4 Hz, 1 H),

[0200] 8.10 - 8.06 (m, 1 H), 7.59 (d, J = 8.4 Hz, 2H), 7.55 - 7.49 (m, 2H), 7.32 (d, J = 8.4 Hz, 2H), 7.21 (d, J = 8.4 Hz, 2H), 7.13 (t, J = 8.4 Hz, 2H), 7.00 (d, J = 8.8 Hz, 1 H), 6.87 (d, J = 8.4 Hz, 2H), 4.70 - 4.55 (m, 2H), 3.99 (s, 3H), 3.93 - 3.85 (m, 1 H), 3.84 - 3.78 (m, 4H), 3.68 (d, J = 8.8 Hz, 1 H), 3.46 - 3.36 (m, 1H), 3.13 - 3.03 (m, 1H), 2.88 - 2.81 (m, 1 H). Mass spectrum (ESI, m / z): Calcd. for C38H31F3N6O4692.2 m / z, found [M+H]+, 693.3.

[0201] Step D: 3-Cyano- / V-((5aS,8aS)-5-(4-(difluoro(4-fluorophenyl)methyl)phenyl)-4-oxo- 5,5a,6,7,8,8a-hexahydro-4 / - / -pyrazolon,5-alpyrrolof3,4-elpyrazin-3-yl)-4-methoxybenzamide. 3-Cyano- / V-((5aS,8aS)-5-(4-(difluoro(4-fluorophenyl)methyl)phenyl)-7-(4-methoxybenzyl)-4-oxo- 5,5a,6,7,8,8a-hexahydro-4 / 7-pyrazolo[1,5-a]pyrrolo[3,4-e]pyrazin-3-yl)-4-methoxybenzamide (935.0 mg, 1.175 mmol), a stir bar, and DCE (8.0 mL) were added to an oven-dried and nitrogen-purged 40 mL glass vial to afford a yellow solution. The vial was charged with carbonochloridic acid 1 -chloro-ethyl ester (0.25 mL, 2.4 mmol) and the mixture stirred at 30 °C for 2 h to give a yellow solution, then treated with anhydrous MeOH (2.0 mL). The temperature was then increased to 60 °C and stirring continued for 1 h to afford a yellow suspension. The reaction progress was monitored by LC-MS. The mixture was cooled to rt and concentrated to dryness in vacuo to give a yellow solid. The solid was subjected to silica gel chromatography (0- 10% Methanol / Dichloromethane) to give 3-cyano- / V-((5aS,8aS)-5-(4-(difluoro(4- fluorophenyl)methyl)phenyl)-4-oxo-5,5a,6,7,8,8a-hexahydro-4 / 7-pyrazolo[1,5-a]pyrrolo[3,4- e]pyrazin-3-yl)-4-methoxybenzamide as a pale yellow solid (HCI salt, 580.8 mg, 77%).1H NMR (400 MHz, DMSO-d6) 6 10.09 - 9.94 (m, 2H), 9.87 (s, 1H), 8.25 - 8.20 (m, 2H), 8.18 - 8.13 (m, 1 H), 7.68 (d, J = 8.4 Hz, 2H), 7.66 - 7.60 (m, 2H), 7.53 (d, J = 8.4 Hz, 2H), 7.42 - 7.33 (m, 3H),

[0202] 5.11 - 4.95 (m, 2H), 4.16 - 4.06 (m, 1H), 3.99 (s, 3H), 3.63 (t, J = 10.4 Hz, 1H), 3.52 - 3.43 (m, 1 H), 3.16 - 3.09 (m, 1H). Mass spectrum (ESI, m / z): Calcd. for C30H23F3N6O3 572.2 m / z, found [M+H]+, 573.1.

[0203] Intermediate 7: 3-Cvano-N-((5aS,8aR)-5-(4-(difluoro(4-fluorophenyl)methyl)phenyl)-4-oxo- 5,5a,6,7,8,8a-hexahvdro-4H-pyrazolori,5-a]pyrrolor3,4-elpyrazin-3-yl)-4- methoxybenzamide as HCI salt.

[0204]

[0205] Step A: (5aS,8aF?)-tert-Butyl 3-(3-cvano-4-methoxybenzamido)-4-oxo-5a,6,8,8a-tetrahydro-4 / 7- pyrazolon ,5-alpyrrolo[3,4-elpyrazine-7(5 / - / )-carboxylate. tert-Butyl (5aS,8aF?)-3-iodo-4-oxo-4,5,5a,6,8,8a-hexahydro-7 / 7-pyrazolo[1 ,5-a]pyrrolo[3,4- e]pyrazine-7-carboxylate (5.00 g, 12.4 mmol), 3-cyano-4-methoxybenzamide (Intermediate 5, 3.27 g, 18.6 mmol), CS2CO3 (16.12 g, 49.48 mmol), a stir bar, and anhydrous dioxane (250 mL) were added to an oven-dried and nitrogen-purged 500 mL three round-bottomed flask fitted with a reflux condenser, which was subsequently evacuated and refilled with N2 (x3). The mixture was stirred for 5 min before treated with t-Bubrettphos (299.8 mg, 618.5 pmol) and t- Bubrettphos Pd G3 (1.06 g, 1.24 mmol), which was subsequently evacuated and refilled with N2 (x3). Put the flask in a 100 °C oil bath and the mixture was stirred for 16 h to give a yellow suspension. The reaction progress was monitored by TLC and LCMS. The reaction mixture was added H2O (200 mL), then extracted with ethyl acetate (80 mL x 3). The combined extracts were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuum to give a brown solid. The brown solid was subjected to silica gel chromatography (10-70% EtOAc / DCM) to give (5aS,8aR)-tert-butyl 3-(3-cyano-4-methoxybenzamido)-4-oxo- 5a,6,8,8a-tetrahydro-4H-pyrazolo[1 ,5-a]pyrrolo[3,4-e]pyrazine-7(5H)-carboxylate as a yellow solid (11 .3 g, 57% purity, 57%). Mass spectrum (ESI, m / z): calcd. for C22H24N6O5 452.2; found [M+H]+, 452.9.

[0206] Step B: (5aS,8aF?)-tert-Butyl 3-(3-cvano-4-methoxybenzamido)-5-(4-(difluoro(4- fluorophenyl)methyl)phenyl)-4-oxo-5a,6,8,8a-tetrahvdro-4 / 7-pyrazolon ,5-alpyrrolof3,4- elpyrazine-7(5 / - / )-carboxylate.

[0207] The title compound was prepared in a manner analogous to Intermediate 6, Step C, reacting 3-cyano-4-methoxy- / V-((5aS,8a / ?)-7-(methylsulfonyl)-4-oxo-5, 5a, 6,7,8, 8a-hexahydro-4 / 7- pyrazolo[1 ,5-a]pyrrolo[3,4-e]pyrazin-3-yl)benzamide (1.85 g, 2.45 mmol, 60% purity), a stir bar, 1-bromo-4-(difluoro(4-fluorophenyl)methyl)benzene (Intermediate 1 , 1.48 g, 4.91 mmol), / V.A / 2- dimethylethane-1 ,2-diamine (0.32 mL, 0.819 g / mL, 2.9 mmol), K2CO3 (1.02 g, 7.36 mmol) in DMF (20.0 mL), and Cui (560.7 mg, 2.944 mmol). Mass spectrum (m / z): Calcd. for C35H31 F3N6O5 672.2 m / z, found [M+H]+, 673.3. Step C: 3-Cyano- / V-((5aS,8a / ?)-5-(4-(difluoro(4-fluorophenyl)methyl)phenyl)-4-oxo- 5,5a,6,7,8,8a-hexahydro-4 / 7-pyrazolon ,5-alpyrrolo[3,4-elpyrazin-3-yl)-4-methoxybenzamide as HCI salt. tert-Butyl (5aS,8a / ?)-3-(3-cyano-4-methoxybenzamido)-5-(4-(difluoro(4-fluorophenyl)methyl)- phenyl)-4-oxo-4,5,5a,6,8,8a-hexahydro-7 / 7-pyrazolo[1 ,5-a]pyrrolo[3,4-e]pyrazine-7-carboxylate (2.40 g, 3.57 mmol), a stir bar, 2 M HCI / dioxane (50.0 mL) were added to a 100 mL round- bottomed flask. The white suspension mixture stirred at r.t. for 6 h. The reaction progress was monitored by LCMS. The reaction mixture was concentrated in vacuum to give the 3-cyano- / V- ((5aS,8a / ?)-5-(4-(difluoro(4-fluorophenyl)methyl)phenyl)-4-oxo-5, 5a, 6,7,8, 8a-hexahydro-4 / 7- pyrazolo[1 ,5-a]pyrrolo[3,4-e]pyrazin-3-yl)-4-methoxybenzamide (2.30 g, 93% purity, 98%) as an off-white solid.1H NMR (400 MHz, DMSO-d6) δ:: 9.92 (s, 1 H), 8.32 (s, 1 H), 8.22 (d, J = 2.0 Hz, 1 H), 8.19 - 8.13 (m, 1 H), 7.72 - 7.60 (m, 6H), 7.44 - 7.34 (m, 3H), 5.38 - 5.33 (m, 1 H), 5.14 - 5.06 (m, 1 H), 4.20 (d, J = 12.8 Hz, 1 H), 4.00 (s, 3H), 3.84 - 3.76 (m, 2H), 3.57 (s, 2H). Mass spectrum (m / z): Calcd. for C30H23F3N6O3 572.2 m / z, found 573.3 [M+H]+

[0208] Intermediate 8: N-((5aS,8aR)-5-(3-chloro-4-(trifluoromethyl)phenyl)-4-oxo-5,5a,6,7,8,8a- hexahvdro-4H-pyrazolori,5-alpyrrolor3,4-e]pyrazin-3-yl)-3-cvano-4-methoxybenzamide as HCI salt

[0209] Step A: (5aS,8aR)-tert-Butyl 5-(3-chloro-4-(trifluoromethyl)phenyl)-3-((3-cyano-4- methoxyphenyl)carbamoyl)-4-oxo-5a,6,8,8a-tetrahydro-4 / - / -pyrazolon ,5-alpyrrolof3,4- elpyrazine-7(5 / - / )-carboxylate.

[0210] The title compound was prepared in a manner analogous to Intermediate 6, Step C, reacting tert-butyl (5aS,8aR)-3-((3-cyano-4-methoxyphenyl)carbamoyl)-4-oxo-4,5,5a,6,8,8a-hexahydro- 7 / 7-pyrazolo[1 ,5-a]pyrrolo[3,4-e]pyrazine-7-carboxylate (Intermediate 7, product from Step A, 1.00 g, 1.26 mmol), 4-bromo-2-chloro-1-(trifluoromethyl)benzene (653.7 mg, 2.520 mmol), copper(l) iodide (287.9 mg, 1.512 mmol), DMEDA (0.16 mL, 1.5 mmol, 0.819 g / mL), K2CO3 (522.3 mg, 3.779 mmol), a stir bar, and DMF (6.0 mL). Mass spectrum (ESI, m / z): calcd. for C29H26CIF3N6O5 630.2; found [M+H]+, 631.1. Step B: (5aS,8aF?)-5-(3-Chloro-4-(trifluoromethyl)phenyl)- / \ / -(3-cyano-4-methoxyphenyl)-4-oxo- 5,5a,6,7,8,8a-hexahydro-4 / 7-pyrazolon,5-alpyrrolo[3,4-elpyrazine-3-carboxamide as HCI salt. tert-Butyl (5aS,8aR)-5-(3-chloro-4-(trifluoromethyl)phenyl)-3-(3-cyano-4-methoxybenzamido)-4- oxo-4,5,5a,6,8,8a-hexahydro-7 / 7-pyrazolo[1 ,5-a]pyrrolo[3,4-e]pyrazine-7-carboxylate (1.60 g, 2.54 mmol), a stir bar and 2 N HCI / dioxane (35.0 mL) were added to a 100 mL round-bottomed flask, the mixture was stired at r.t. for 6 h as a yellow suspension. The reaction progress was monitored by LCMS. The reaction mixture was concentrated in vacuum to afford the title compound as a yellow solid (1.39 g, 87% purity, HCI salt).1H NMR (400 MHz, DMSO-d6) δ: 9.93 (s, 1H), 9.80 (s, 2H), 8.33 (s, 1 H), 8.25 (d, J= 1.6 Hz, 1H), 8.18 (dd, J = 1.6, 8.8 Hz, 1 H), 8.04 (d, J = 8.4 Hz, 1 H), 7.98 (s, 1H), 7.74 (d, J = 8.4 Hz, 1H), 7.43 (d, J = 9.2 Hz, 1 H), 5.37 (s,

[0211] 1 H), 5.28 - 5.18 (m, 1H), 4.18 (d, J = 13.2 Hz, 1 H), 4.02 - 3.98 (m, 3H), 3.88 - 3.77 (m, 2H), 3.31

[0212] - 3.26 (m, 1 H)._Mass spectrum (ESI, m / z): calcd. for C24H18CIF3N6O3 530.1; found [M+H]+, 531.0. Table 1 : A

[0213] General Scheme for the synthesis of compounds described in Table 1 and 2 Scheme 1

[0214] Example 1 : 3-Cvano-N-((5aS,8aS)-5-(4-(difluoro(phenyl)methyl)phenyl)-4-oxo-

[0215] 5,5a,6,7,8,8a-hexahvdro-4H-pyrazolori,5-a]pyrrolor3,4-elpyrazin-3-yl)-4- methoxybenzamide hydrochloride.

[0216] Step A: tert-Butyl (3S,4S)-3-((tert-butoxycarbonyl)amino)-4-hydroxypyrrolidine-1-carboxylate tert-Butyl (3S,4S)-3-amino-4-hydroxypyrrolidine-1-carboxylate (5.00 g, 24.7 mmol), a stir bar, and anhydrous 1,4-dioxane (100 mL) were added to a 500 mL three-necked round-bottomed flask fitted with thermometer. The resulting mixture was cooled to 0°C and treated with NaOH (1.48 g, 37.1 mmol) and BOC2O (8.09 g, 37.1 mmol), stirred at r.t. for 12 h. The reaction was monitored by TLC. The reaction mixture was poured into H2O (150 mL) and extracted with EtOAc (100 mL x 3). The combined extracts were washed with brine (50 mL x 2), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a light yellow oil. The oil was subjected to silica gel chromatography (0-50% EtOAc / ChLCh) to give (3S,4S)-tert-butyl 3-((tert- butoxycarbonyl)amino)-4-hydroxypyrrolidine-1 -carboxylate as a white foamed solid (7.0 g, 94%).1H NMR (400 MHz, DMSO-d6) d : 7.09 (s, 1 H), 5.21 (d, J = 4.0 Hz, 1 H), 3.93 (s, 1 H), 3.68 (s, 1H), 3.49 - 3.35 (m, 2H), 3.12 - 3.01 (m, 2H), 1.38 (d, J = 2.4 Hz, 18H)

[0217] Step B: tert-Butyl (3R,4S)-3-(benzoyloxy)-4-((tertbutoxycarbonyl)amino)pyrrolidine-1- carboxylate tert-Butyl (3S,4S)-3-((tert-butoxycarbonyl)amino)-4-hydroxypyrrolidine-1-carboxylate (1.00 g, 3.31 mmol), benzoic acid (889 mg, 7.276 mmol), PPha (1.74 g, 6.61 mmol), a stir bar and anhydrous THF (25 mL) were added to a 100 mL round-bottomed flask. The resuting mixture was cooled to 0°C before treated with DIAD (1.3 mL, 6.6 mmol), after that, warmed to r.t. and stirred at r.t. for 16 h. The reaction was monitored by TLC and LC-MS. The reaction mixture was turned from colourless to yellow after the addition of DIAD. The reaction mixture was concentrated in vacuo to give a yellow oil. The oil was subjected to silica gel chromatography (0-17% EtOAc / Petroleum ether) to give tert-butyl (3R,4S)-3-(benzoyloxy)-4-((tert- butoxycarbonyl)amino)pyrrolidine-1 -carboxylate as a white foamed solid (1.1 g, 70%). Mass spectrum (ESI, m / z): calcd. for C21H30N2O6, 406.2; found [M+Na]+, 429.0.

[0218] Step C: tert-Butyl (3S,4R)-3-((tert-butoxycarbonyl)amino)-4-hydroxypyrrolidine-1 -carboxylate tert-Butyl (3R,4S)-3-(benzoyloxy)-4-((tert-butoxycarbonyl)amino)pyrrolidine-1 -carboxylate (1.10 g, 2.71 mmol), LiOH H2O (454 mg, 10.8 mmol), a stir bar, anhydrous THF (6.0 mL), H2O (3.0 mL) and anhydrous MeOH (6.0 mL) were added to a 50 mL round-bottomed flask. The resultant mixture was stirred at r.t. for 3 h. The reaction was monitored by TLC. The reaction mixture was poured into H2O (10 mL) and extracted with EtOAc (10 mL x 2). The combined extracts were dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a colourless oil. The oil was subjected to silica-gel chromatography (0-50% EtOAc / Petroleum ether) to give tert-butyl (3S,4R)-3-((tert-butoxycarbonyl)amino)-4-hydroxypyrrolidine-1- carboxylate as a colourless oil (600 mg, 73% ).1H NMR (400 MHz, DMSO-d6) d : 6.53 - 6.52 (m, 1 H), 5.19 - 5.09 (m, 1H), 4.09 - 3.98 (m, 1H), 3.94 - 3.82 (m, 1 H), 3.47 - 3.36 (m, 2H), 3.19 (d, J = 11.6 Hz, 1H), 3.03 (t, J = 9.6 Hz, 1H), 1.39 (s, 18H).

[0219] Step D: Ethyl 1-((3S,4S)-1-(tert-butoxycarbonyl)-4-((tert-butoxycarbonyl)amino)pyrrolidin-3-yl)-4- iodo-1 H-pyrazole-5-carboxylate

[0220] Ethyl 4-iodo-1 / 7-pyrazole-5-carboxylate (5.28 g, 19.8 mmol), tert-butyl (3S,4R)-3-((tert- butoxycarbonyl)amino)-4-hydroxypyrrolidine-1 -carboxylate (6.00 g, 19.8 mmol), PPhs (7.81 g, 29.8 mmol), a stir bar and toluene (120 mL) were added to a 500 mL three-necked flask fitted with a reflux condenser. The solution was charged with DTBAD (6.85 g, 29.8 mml). The resulting solution was stirred at 100°C for 12 h. The reaction was monitored by TLC and LC-MS. The reaction mixture was concentrated in vacuo to give a yellow oil. The oil was subjected to silica gel chromatography (0-40% EtOAc / pet ether) followed by HPLC (Xtimate C18, 10 pm, 150 mm x 40 mm, 50% to 88% CH3CN and H2O (with 0.05% of 28% aq. NH3.H2O) to give ethyl 1- ((3S,4S)-1-(tert-butoxycarbonyl)-4-((tert-butoxycarbonyl)amino)pyrrolidin-3-yl)-1 / 7-pyrazole-5- carboxylate as white solid (3.5 g, 30%).1H NMR (400 MHz, DMSO-d6) d : 7.80 (s, 1H), 7.35 (s, 1 H), 5.48 (t, J = 6.8 Hz, 1 H), 4.43 - 4.26 (m, 3H), 3.83 - 3.82 (m, 1 H), 3.74 - 3.63 (m, 1 H), 3.52 (d, J = 16.0 Hz, 1H), 3.23 - 3.09 (m, 1 H), 1.39 (d, J = 6.4 Hz, 9H), 1.37 - 1.28 (m, 12H)

[0221] Step E: Ethyl 1-((3S,4S)-4-aminopyrrolidin-3-yl)-4-iodo-1 H-pyrazole-5-carboxylate Ethyl 1-((3S,4S)-1-(tert-butoxycarbonyl)-4-((tert-butoxycarbonyl)amino)pyrrolidin-3-yl)-1 / 7- pyrazole-5-carboxylate (3.50 g, 6.36 mmol), a stir bar and 4 N HCI / dioxane (30.0 mL) were added to 250 mL three-necked flack, the mixture was stirred at r.t. for 1 h. The solution was concentrated under pressure to give ethyl 1-((3S,4S)-4-aminopyrrolidin-3-yl)-4-iodo-1 H- pyrazole-5-carboxylate HCI salt as a white solid (3 g, crude). Mass spectrum (ESI, m / z): calcd. for C10H15IN4O2, 350.0; found [M+H]+, 350.7. Step F: (5aS,8aS)-3-lodo-5, 5a, 6,7,8, 8a-hexahvdro-4H-pyrazolon ,5-alpyrrolo[3,4-elpyrazin-4- one

[0222] Ethyl 1-((3S,4S)-4-aminopyrrolidin-3-yl)-1 H-pyrazole-5-carboxylate (HCI salt, 3.00 g, 7.76 mmol), H2O (20.0 mL), a stir bar, Na3CO3(1.23 g, 11.6 mmol) were added to 100 round- bottomed flask fitted with a reflux condenser, the mixture was stirred at 50°C for 12 h. The reaction was monitored by LC-MS. The mixture was adjusted pH = 7 with 1 N HCI. The mixture was concentrated under pressure to give (5aS,8aS)-3-iodo-5,5a,6,7,8,8a-hexahydro-4 / 7- pyrazolo[1 ,5-a]pyrrolo[3,4-e]pyrazin-4-one as a light yellow solid (700 mg, 24%) and crude product (4 g). The crude product was then subjected to HPLC (Xtimate C18, 10 pm, 150 mm x 40 mm; 1-30% CH3CN and H2O (with 0.225% HCOOH)) to give (5aS,8aS)-3-iodo-5,5a,6,7,8,8a- hexahydro-4 / 7-pyrazolo[1 ,5-a]pyrrolo[3,4-e]pyrazin-4-one as a light yellow solid (600 mg, 23%). Mass spectrum (ESI, m / z): calcd. for C8H9IN4O, 304.0; found [M+H]+, 304.6.1H NMR (400 MHz, DMSO-d6) d : 8.80 (s, 1 H), 7.68 (s, 1 H), 4.30 (d, J = 7.6 Hz, 1 H), 3.95 - 3.79 (m, 2H), 3.47 (s, 1 H), 3.15 (d, J = 9.2 Hz, 1 H), 3.09 - 2.99 (m, 1 H), 2.85 (d, J = 9.6 Hz, 1 H).

[0223] Step G: (5aS,8aS)-3-lodo-7-(4-methoxybenzyl)-5,5a,6,7,8,8a-hexahydro-4H-pyrazolon ,5- alpyrrolof3,4-elpyrazin-4-one (5aS,8aS)-3-lodo-5,5a,6,7,8,8a-hexahydro-4 / 7-pyrazolo[1 ,5-a]pyrrolo[3,4-e]pyrazin-4-one (20.00 g, 58.73 mmol), 4-methoxybenzaldehyde (21.4 mL, 176 mmol, 1.12 g / mL), AcOH (6.7 mL, 117 mmol, 1.05 g / mL), a stir bar, and anhydrous MeOH (200 mL) were added to a 500 mL three-necked flask. The yellow mixture was stirred at r.t. for 5 min before treated with NaBH3CN (11.07 g, 176.2 mmol) and stirred 40°C for 12 h, which formed a light brown suspension. The reaction was monitored by TLC and LC-MS. The reaction mixture was filtered and the filter cake were washed with MeOH (40 mL x 2), collected and concentrated in vacuo to give a white solid. The filtrate concentrated in vacuum to move MeOH, then poured into H2O (80 mL), and adjusted pH = 8~9 with sat. NaHCO3solution, and extracted with EtOAc (80 mL x 3). The combined extracts were washed with brine (60 mL) and concentrated in vacuum to give a white solid. The solid was then subjected to silica gel chromatography (0-100% EtOAc / pet ether) to give the (5aS,8aS)-3-iodo-7-(4-methoxybenzyl)-5,5a,6,7,8,8a-hexahydro-4 / 7-pyrazolo[1 ,5- a]pyrrolo[3,4-e]pyrazin-4-one as a white solid (22.0 g, 87%).1H NMR (400 MHz, DMSO-d6) δ: 8.94 - 8.60 (m, 1 H), 7.66 (s, 1 H), 7.24 (d, J = 8.4 Hz, 2H), 6.89 (d, J = 8.4 Hz, 2H), 4.42 (dt, J = 7.2, 10.4 Hz, 1 H), 3.95 (dt, J = 7.2, 10.8 Hz, 1 H), 3.87 - 3.75 (m, 2H), 3.74 (s, 3H), 3.07 - 2.91 (m, 2H), 2.80 - 2.67 (m, 1 H). Mass spectrum (ESI, m / z): calcd. for C16H17IN4O2, 424.0; found [M+H]+, 424.8. Step H: Tert-butyl (5aS,8aS)-3-iodo-7-(4-methoxybenzyl)-4-oxo-6,7,8,8a-tetrahydro-4 / 7- pyrazolon ,5-alpyrrolo[3,4-elpyrazine-5(5a / - / )-carboxylate.

[0224] (5aS,8aS)-3-lodo-7-(4-methoxybenzyl)-5,5a,6,7,8,8a-hexahydro-4H-pyrazolo[1 ,5-a]pyrrolo[3,4- e]pyrazin-4-one (10.50 g, 24.75 mmol), a stir bar, BOC2O (10.80 g, 49.50 mmol), DMAP (605.0 mg, 4.950 mmol), TEA (5.2 mL, 37 mmol) and toluene (160 mL) were added to 500 mL threenecked flask fitted with a reflux condenser, the mixture was stirred at 100°C for 3 h. The reaction mixture was turned from white to brown. The reaction was monitored by TLC. The brown mixture was diluted with H2O (200 mL), extracted with EtOAc (100 mL x 3), the combined extracts were washed with brine (200 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuum to give a brown oil. The oil was then subjected to silica gel chromatography (10-50% EtOAc / pet ether) to give (5aS,8aS)-3-iodo-7-(4-methoxybenzyl)- 5,5a,6,7,8,8a-hexahydro-4H-pyrazolo[1 ,5-a]pyrrolo[3,4-e]pyrazin-4-one as a yellow solid (11.2 g, 85.5%). Mass spectrum (ESI, m / z): calcd. for C21H25IN4O4, 524.1 ; found [M+H]+, 525.1.

[0225] Step I: tert-Butyl (5aS,8aS)-3-((tert-butoxycarbonyl)amino)-7-(4-methoxybenzyl)-4-oxo-6,7,8,8a- tetrahvdro-4 / 7-pyrazolon ,5-alpyrrolof3,4-elpyrazine-5(5a / - / )-carboxylate. tert-Butyl (5aS,8aS)-3-iodo-7-(4-methoxybenzyl)-4-oxo-6,7,8,8a-tetrahydro-4H-pyrazolo[1 ,5- a]pyrrolo[3,4-e]pyrazine-5(5aH)-carboxylate (11.2 g, 21.4 mmol), a stir bar, toluene (160 mL), tert-butyl carbamate (5.00 g, 42.7 mmol), CS2CO3 (13.9 g, 42.7 mmol), Xphos (2.72 g, 6.41 mmol) and Pd2(dba)s (1.96 g, 2.14 mmol) were added to an oven-dried and nitrogen-purged 250 mL three-necked flask fitted with a reflux condenser and a thermometer, which was subsequently evacuated and refilled with nitrogen (x3), and the reaction vessel placed in an oil bath that had been pre-heated to 95°C, and the mixture stirred at 95°C for 12 h . The reaction was monitored by TLC and LC-MS. The reaction mixture was filtered and the filtrate was concentrated in vacuum to give a dark brown oil. The dark brown oil was diluted with H2O (100 mL), extracted with EtOAc (100 mL x 3). The combined extracts were washed with brine (200 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuum to give a brown oil. The oil was then subjected to silica gel chromatography (10-50% EtOAc / pet ether) to give tert-butyl (5aS,8aS)-3-((tert-butoxycarbonyl)amino)-7-(4-methoxybenzyl)-4-oxo-6,7,8,8a-tetrahydro-4H- pyrazolo[1 ,5-a]pyrrolo[3,4-e]pyrazine-5(5aH)-carboxylate as a yellow solid (8.1 g, 73.7%). Mass spectrum (ESI, m / z): calcd. for C26H35N5O6 513.3 found [M+H]+, 514.3.

[0226] Step J: (5aS,8aS)-3-Amino-7-(4-methoxybenzyl)-5,5a,6,7,8,8a-hexahvdro-4 / 7-pyrazolon ,5- alpyrrolof3,4-elpyrazin-4-one. tert-Butyl (5aS,8aS)-3-((tert-butoxycarbonyl)amino)-7-(4-methoxybenzyl)-4-oxo-6,7,8,8a- tetrahydro-4H-pyrazolo[1 ,5-a]pyrrolo[3,4-e]pyrazine-5(5aH)-carboxylate (8.1 g, 15.8 mmol), a stir bar, and HCI / 1 ,4-dioxane(71.2 mL, 4 M) were added to a 250 mL round-bottomed flask. The reaction was stirred at r.t. for 12 h. The reaction was monitored by TLC and LC-MS. The reaction solution was concentrated in vacuum to give a yellow solid. The solid was dissolved in EtOAc (60 mL) and quenched with Na2COs (100 mL), extracted with EtOAc (50 mL x 3). The combined extracts were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuum to give a yellow solid (4.5 g, 91%).1H NMR (400 MHz, DMSO-d6)_δ: 8.21 (s, 1 H), 7.25 (d, J = 8.8 Hz, 2H), 7.01 (s, 1 H), 6.89 (d, J = 8.8 Hz, 2H), 4.83 (s, 2H), 4.13 - 4.01 (m, 1 H), 3.91 - 3.76 (m, 3H), 3.74 (s, 3H), 3.31 - 3.27 (m, 1 H), 3.02 - 2.94 (m, 2H), 2.74 - 2.69 (m, 1 H). Mass spectrum (ESI, m / z): Calcd. for C16H19N5O2 313.2; found [M+H]+, 314.2.

[0227] 4 / 7-pyrazolo[1 ,5-a]pyrrolo[3,4-e]pyrazin-3-yl)benzamide.

[0228] 3-Cyano-4-methoxybenzoic acid (2.99 g, 16.9 mmol), a stir bar, HATLI (6.94 g, 18.3 mmol), DIEA (9.3 mL, 0.782 g / mL, 56 mmol) and DMF (80.0 mL) were added to a 250 mL round- bottomed flask and stirred at 25°C for 0.5 h, The solution turns black, then the resulting mixture treated with (5aS,8aS)-3-amino-7-(4-methoxybenzyl)-5,5a,6,7,8,8a-hexahydro-4 / 7-pyrazolo[1 ,5- a]pyrrolo[3,4-e]pyrazin-4-one (4.40 g, 14.0 mmol) and the reaction mixture was stirred at 25°C for 12 h. some yellow precipitate separated out. The reaction was stirred at r.t. for 12 h. The reaction was monitored by LC-MS. H2O (50 mL) was added to the solution and more yellow precipitate separated out. The reaction mixture was filtered and the filter cake was washed with H2O (80 mL). The solid was concentrated in vacuum to give 3-cyano-4-methoxy- / V-((5aS,8aS)- 7-(4-methoxybenzyl)-4-oxo-5, 5a, 6,7,8, 8a-hexahydro-4 / 7-pyrazolo[1 ,5-a]pyrrolo[3,4-e]pyrazin-3- yl)benzamide as a yellow solid (5.66 g, 81%).1H NMR (400 MHz, DMSO-d6) δ:: 9.84 (s, 1 H), 8.90 (s, 1 H), 8.23 (d, J = 2.0 Hz, 1 H), 8.15 (dd, J = 2.0, 8.8 Hz, 1 H), 8.05 (s, 1 H), 7.43 (d, J = 9.2 Hz, 1 H), 7.26 (d, J = 8.4 Hz, 2H), 6.90 (d, J = 8.4 Hz, 2H), 4.44 - 4.32 (m, 1 H), 4.09 - 3.94 (m, 4H), 3.89 - 3.77 (m, 2H), 3.74 (s, 3H), 3.38 (br t, J = 8.0 Hz, 1 H), 3.13 - 2.98 (m, 2H), 2.79 (br t, J = 9.6 Hz, 1 H). Mass spectrum (ESI, m / z): Calcd. for C25H24N6O4, 472.2; found [M+H]+, 473.0. i-7-(4-methoxybenzyl)-4-oxo-

[0229] 5,5a,6,7,8,8a-hexahydro-4 / 7-pyrazolo[1 ,5-a]pyrrolo[3,4-e]pyrazin-3-yl)-4-methoxybenzamide. 3-Cyano-4-methoxy- / V-((5aS,8aS)-7-(4-methoxybenzyl)-4-oxo-5,5a,6,7,8,8a-hexahydro-4 / 7- pyrazolo[1 ,5-a]pyrrolo[3,4-e]pyrazin-3-yl)benzamide (12.5 g, 26.5 mmol), a stir bar, 1-bromo-4- (difluoro(phenyl)methyl)benzene (11.2 g, 31.7 mmol), A / V / ^-dimethylethane-l ^-diamine (3.42 mL, 31.7 mmol, 0.819 g / mL), K2CO3 (11.0 g, 79.4 mmol) and Cui (6.05 g, 31.7 mmol) in DMF (125 mL) were added to an oven-dried 500 mL round-bottomed flask with a reflux condenser. The resulting mixture was sparged with N2 for 3 times. The resulting mixture was heated to 100°C for 12 h. The reaction was monitored by TLC and LC-MS. The reaction mixture was filtered and concentrated in vacuo to give a black oil. The black oil diluted with water (300 mL), extracted with EtOAc (300 mL x 2). The combined extracts were washed with water (200 mL x 4), brine (200 mL), dried over anhydrous Na2SC>4, filtered and concentrated in vacuo to give a brown oil. The oil was subjected to silica gel chromatography (38-43% EtOAc / DCM) to give the 3-cyano- / V-((5aS,8aS)-5-(4-(difluoro(phenyl)methyl)phenyl)-7-(4-methoxybenzyl)-4-oxo- 5,5a,6,7,8,8a-hexahydro-4 / 7-pyrazolo[1,5-a]pyrrolo[3,4-e]pyrazin-3-yl)-4-methoxybenzamide as a light brown foam (12.0 g, 64%).1H NMR (400 MHz, DMSO-d6) δ:: 9.84 (s, 1 H), 8.21 (d, J = 2.4 Hz, 1H), 8.18 - 8.10 (m, 2H), 7.66 - 7.44 (m, 9H), 7.38 (d, J = 9.2 Hz, 1 H), 7.21 (d, J = 8.8 Hz, 2H), 6.86 (d, J = 8.8 Hz, 2H), 4.92 - 4.74 (m, 2H), 4.04 - 3.93 (m, 3H), 3.86 - 3.74 (m, 2H), 3.72 (s, 3H), 3.51 - 3.44 (m, 1 H), 3.25 - 3.13 (m, 1 H), 2.96 - 2.90 (m, 1 H), 2.67 (br t, J = 8.8 Hz, 1 H). Mass spectrum (ESI, m / z): Calcd. for C38H32F2N6O4, 674.3; found [M+H]+, 675.2. i-4-oxo-5, 5a, 6,7,8,8a- hexahydro-4 / 7-pyrazolo[1,5-a]pyrrolo[3,4-e]pyrazin-3-yl)-4-methoxybenzamide.

[0230] 3-Cyano- / V-((5aS,8aS)-5-(4-(difluoro(phenyl)methyl)phenyl)-7-(4-methoxybenzyl)-4-oxo- 5,5a,6,7,8,8a-hexahydro-4 / 7-pyrazolo[1,5-a]pyrrolo[3,4-e]pyrazin-3-yl)-4-methoxybenzamide (5.5 g, 8.15 mmol), a stir bar and DCE (35 mL) were added to a 100 mL round-bottomed flask fitted with a reflux condenser. The mixture was charged with 1 -chloroethyl carbonochloridate (2.33 g, 16.3 mmol) and stirred at r.t. for 2 h, then treated with anhydrous MeOH (15 mL). The solution was stirred at 60°C for 1 h, some white precipitate separated out. The reaction was monitored by LC-MS. The reaction mixture was cooled to r.t. and filtered, the filter cake was rinsed with DCM (30 mL x 3) and collected 3-cyano- / V-((5aS,8aS)-5-(4 (difluoro(phenyl)methyl)phenyl)-4-oxo-5,5a,6,7,8,8a-hexahydro-4 / 7-pyrazolo[1,5-a]pyrrolo[3,4- e]pyrazin-3-yl)-4-methoxybenzamide as a white solid and the filtrate was concentrated in vacuo to give 3-cyano- / V-((5aS,8aS)-5-(4-(difluoro(phenyl)methyl)phenyl)-4-oxo-5,5a,6,7,8,8a- hexahydro-4 / 7-pyrazolo[1,5-a]pyrrolo[3,4-e]pyrazin-3-yl)-4-methoxybenzamide as a white solid, total (4.8 g, 98%).1H NMR (400 MHz, DMSO-d6) δ:: 9.98 - 9.84 (m, 3H), 8.26 - 8.20 (m, 2H), 8.16 (dd, J = 2.0, 9.2 Hz, 1H), 7.68 (d, J = 8.4 Hz, 2H), 7.61 - 7.49 (m, 7H), 7.39 (d, J = 9.2 Hz, 1 H), 5.09 - 4.93 (m, 2H), 4.10 (br dd, J = 6.8, 10.8 Hz, 1 H), 3.99 (s, 3H), 3.63 (br t, J = 10.8 Hz, 1 H), 3.47 (br dd, J = 6.0, 10.8 Hz, 1H), 3.19 - 3.08 (m, 1 H). Mass spectrum (ESI, m / z): Calcd. For C30H24F2N6O3, 554.2; found [M+ H]+, 555.3. Example 2: N-((5aS,8aS)-7-Acetyl-5-(4-(difluoro(phenyl)methyl)phenyl)-4-oxo- 5,5a,6,7,8,8a-hexahvdro-4H-pyrazolori,5-a]pyrrolor3,4-elpyrazin-3-yl)-3-cvano-4- methoxybenzamide.

[0231] 3-Cyano-N-((5aS,8aS)-5-(4-(difluoro(phenyl)methyl)phenyl)-4-oxo-5, 5a, 6,7,8, 8a- hexa hydro-4 H- pyrazolo[1 ,5-a]pyrrolo[3,4-e]pyrazin-3-yl)-4-methoxybenzamide (Example 1 , product from Step M, 6.00 g, 10.8 mmol), a stir bar, AC2O (1.23 mL, 1.08 g / mL, 13.0 mmol), TEA (2.26 mL, 0.728 g / mL, 16.2 mmol) and DCE (120 mL) were added to a 250 mL round-bottomed flask, and the resulting mixture was stirred at r.t. for 12 h, which formed the white suspension. The reaction was monitored by LC-MS. The two batches were combined, and diluted with DCM (250 mL) and washed with H2O (150 mL x 3). Then the combined extracts were washed with brine (150 mL), dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure to give a light yellow oil. The oil was subjected to silica gel chromatography (3~5% MeOH / DCM) to give the / V-((5aS,8aS)-7-acetyl-5-(4-(difluoro(phenyl)methyl)phenyl)-4-oxo-5,5a,6,7,8,8a- hexahydro-4 / 7-pyrazolo[1 ,5-a]pyrrolo[3,4-e]pyrazin-3-yl)-3-cyano-4-methoxybenzamide as a white solid (6.72 g, 74%).1H NMR (400 MHz, DMSO-d6) δ:: 9.87 (br s, 1 H), 8.23 (t, J = 2.4 Hz, 1 H), 8.20 (s, 1 H), 8.16 (dd, J = 2.0, 8.8 Hz, 1 H), 7.65 (d, J = 8.4 Hz, 2H), 7.61 - 7.46 (m, 7H), 7.39 (d, J = 9.2 Hz, 1 H), 5.06 - 4.84 (m, 2H), 4.52 - 4.24 (m, 1 H), 3.99 (s, 3H), 3.93 - 3.82 (m, 1 H), 3.80 - 3.50 (m, 1 H), 3.40 - 2.96 (m, 1 H), 2.05 - 1.90 (m, 3H). Mass spectrum (ESI, m / z): Calcd. for C32H26F2N6O4596.2; found [M+H]+, 597.3.

[0232] Example 3: 3-Cvano-N-((5aS,8aS)-5-(4-(difluoro(phenyl)methyl)phenyl)-7-(methylsulfonyl)- 4-oxo-5,5a,6,7,8,8a-hexahvdro-4H-pyrazolori,5-alpyrrolor3,4-e]pyrazin-3-yl)-4-

[0233] 3-Cyano- / V-((5aS,8aS)-5-(4-(difluoro(phenyl)methyl)phenyl)-4-oxo-5,5a,6,7,8,8a-hexahydro-4 / 7- pyrazolo[1 ,5-a]pyrrolo[3,4-e]pyrazin-3-yl)-4-methoxybenzamide (Example 1 , product from Step M, 150.0 mg, 270.5μmol), a stir bar, MS2O (94.2 μL, 541 μmol), DIPEA (0.13 mL, 0.81 mmol) and CH2CI2 (3.0 mL) were added to 10 mL round-bottomed flask. The mixture was stirred at r.t. for 12 h and lots of precipitate formed. The reaction was monitored by TLC. The precipitate was isolated via vacuum filtration and then washed with DCM (25 mL x 3) to give 3-cyano- / V- ((5aS,8aS)-5-(4-(difluoro(phenyl)methyl)phenyl)-7-(methylsulfonyl)-4-oxo-5,5a,6,7,8,8a- hexahydro-4 / 7-pyrazolo[1 ,5-a]pyrrolo[3,4-e]pyrazin-3-yl)-4-methoxybenzamide as a white solid (84.2 mg, 49%).1H NMR (400 MHz, DMSO-d6) d : 9.88 (s, 1 H), 8.23 (d, J = 2.0 Hz, 1 H), 8.20 (s, 1 H), 8.16 (m, 1 H), 7.67 - 7.63 (m, 2H), 7.62 - 7.50 (m, 7H), 7.39 (d, J = 8.8 Hz, 1 H), 4.96 (s, 2H), 4.26 - 4.20 (m, 1 H), 3.99 (s, 3H), 3.75 (t, J = 9.2 Hz, 1 H), 3.64 - 3.59 (m, 1 H), 3.25 - 3.20 (m, 1 H), 3.10 (s, 3H). Mass spectrum (ESI, m / z): calcd. for C31H26F2N6O5S, 632.2; found [M+H]+, 633.2.

[0234] Example 4: 3-Cvano-N-((5aS,8aS)-5-(4-(difluoro(phenyl)methyl)phenyl)-7-glvcyl-4-oxo- 5,5a,6,7,8,8a-hexahvdro-4H-pyrazolori,5-a]pyrrolor3,4-elpyrazin-3-yl)-4- Step A: tert-Butyl (2-((5aS,8aS)-3-(3-cvano-4-methoxybenzamido)-5-(4- (difluoro(phenyl)methyl)phenyl)-4-oxo-4,5,5a,6,8,8a-hexahydro-7H-pyrazolon ,5-alpyrrolo[3,4- elpyrazin-7-yl)-2-oxoethyl)carbamate

[0235] 3-Cyano- / V-((5aS,8aS)-5-(4-(difluoro(phenyl)methyl)phenyl)-4-oxo-5,5a,6,7,8,8a-hexahydro-4 / 7- pyrazolo[1 ,5-a]pyrrolo[3,4-e]pyrazin-3-yl)-4-methoxybenzamide (Example 1 , product from Step M, 120.0 mg, 0.2160 mmol), (tert-butoxycarbonyl)glycine (45.5 mg, 0.260 mmol), HATLI (107.0 mg, 0.281 mmol), DIPEA (0.11 mL, 0.65 mmol, 0.742 g / mL) and DMF (2.5 mL) were added to a 10 mL round-bottomed flask. The reaction mixture stirred at r.t. for 12 h and then turn yellow. The reaction was monitored by TLC and LC-MS. The mixture was then diluted with DCM (10 mL), washed with H2O (10 mL) and brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated to dryness in vacuo to give yellow oil. The oil was subjected to silica-gel chromatography (0-10% MeOH / DCM) to give tert-butyl (2-((5aS,8aS)-3-(3-cyano-4- methoxybenzamido)-5-(4-(difluoro(phenyl)methyl)phenyl)-4-oxo-4,5,5a,6,8,8a-hexahydro-7 / 7- pyrazolo[1 ,5-a]pyrrolo[3,4-e]pyrazin-7-yl)-2-oxoethyl)carbamate as a yellow oil (160 mg, 98% ). Mass spectrum (ESI, m / z): calcd. for C37H35F2N7O6, 711.3; found [M-56+H]+, 656.2.

[0236] Step B: 3-Cvano- / V-((5aS,8aS)-5-(4-(difluoro(phenyl)methyl)phenyl)-7-glvcyl-4-oxo- 5,5a,6,7,8,8a-hexahvdro-4 / 7-pyrazolon ,5-alpyrrolof3,4-elpyrazin-3-yl)-4-methoxybenzamide tert-Butyl (2-((5aS,8aS)-3-(3-cyano-4-methoxybenzamido)-5-(4-(difluoro(phenyl)methyl)phenyl)-

[0237] 4-oxo-4,5,5a,6,8,8a-hexahydro-7 / 7-pyrazolo[1 ,5-a]pyrrolo[3,4-e]pyrazin-7-yl)-2- oxoethyl)carbamate (184.0 mg, 0.2590 mmol), a stir bar, and 4 N HCI / dioxane (5.0 mL) were added to 10 mL round-bottomed flask. The reaction mixture stirred at r.t. for 12 h. The reaction was monitored by LC-MS. The reaction mixture was treated with sat. NaHCC>3 (10 mL), then extracted with EtOAc (10 mL x 3). The combined organic extracts were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and the filtrate concentrated to dryness in vacuo to give yellow oil. The oil was subjected to silica-gel chromatography (0-10% MeOH / DCM) to give 3-cyano- / V-((5aS,8aS)-5-(4-(difluoro(phenyl)methyl)phenyl)-7-glycyl-4-oxo-5,5a,6,7,8,8a- hexahydro-4 / 7-pyrazolo[1 ,5-a]pyrrolo[3,4-e]pyrazin-3-yl)-4-methoxybenzamide as a white solid (84.9 mg, 52%).1H NMR (400 MHz, DMSO-d6) δ:: 9.87 (s, 1 H), 8.23 - 8.22 (m, 1 H), 8.20 - 8.19 (m, 1 H), 8.16 - 8.15 (m, 1 H), 7.68 - 7.62 (m, 2H), 7.61 - 7.50 (m, 7H), 7.39 (d, J = 8.8 Hz, 1 H), 5.03 - 4.81 (m, 2H), 4.45 - 4.28 (m, 1 H), 3.99 (s, 3H), 3.89 - 3.56 (m, 2H), 3.47 - 3.37 (m, 1 H), 3.30 (s, 1 H), 3.20 - 3.00 (m, 1 H). Mass spectrum (ESI, m / z): calcd. for C32H27F2N7O4, 611.2; found [M+H]+, 612.3. Example 5: 3-Cyano-N-((5aS,8aS)-5-(4-(difluoro(phenyl)methyl)phenyl)-7-(2- methoxyethyl)-4-oxo-5,5a,6,7,8,8a-hexahvdro-4H-pyrazolori,5-a]pyrrolor3,4-elpyrazin-3- vD-4-methoxybenzamide.

[0238] 3-Cyano- / V-((5aS,8aS)-5-(4-(difluoro(phenyl)methyl)phenyl)-4-oxo-5,5a,6,7,8,8a-hexahydro-4 / 7- pyrazolo[1,5-a]pyrrolo[3,4-e]pyrazin-3-yl)-4-methoxybenzamide (Example 1 , product from Step M, 100.0 mg, 0.1800 mmol), 1-bromo-2-methoxyethane (20.3 μL, 0.216 mmol), DIPEA (62.8 pL, 0.361 mmol) and DMF (2.0 mL) were added to a 10 mL round-bottomed flask. The yellow mixture was stirred at 80°C for 12 h. The reaction was monitored by TLC. The yellow mixture was diluted with H2O (5 mL), extrated with EtOAc (5 mL x 3). The combined extracts were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuum to give a yellow oil. The oil was then subjected to silica gel chromatography (0-10% MeOH / DCM) followed by prep-HPLC (Xtimate C18, 10 pm, 150 mm x 40 mm; 7 min gradient (35-65% ACN / H2O (with 0.225% HCOOH) at 25 mL / min) to give 3-cyano- / V-((5aS,8aS)-5-(4- (difluoro(phenyl)methyl)phenyl)-7-(2-methoxyethyl)-4-oxo-5, 5a, 6,7,8, 8a-hexahydro-4 / 7- pyrazolo[1,5-a]pyrrolo[3,4-e]pyrazin-3-yl)-4-methoxybenzamide as a white solid (40.0 mg, 30%).1H NMR (400 MHz, DMSO-d6) d : 9.85 (s, 1 H), 8.21 (d, J = 2.4 Hz, 1 H), 8.17 - 8.09 (m, 2H), 7.62 (d, J = 8.4 Hz, 2H), 7.56 (d, J = 3.2 Hz, 2H), 7.55 - 7.51 (m, 4H), 7.50 (s, 1 H), 7.39 (d, J = 9.2 Hz, 1 H), 4.81 (d, J = 2.4 Hz, 2H), 3.98 (s, 3H), 3.62 - 3.50 (m, 1 H), 3.37 (d, J = 5.6 Hz, 2H), 3.26 (d, J = 5.2 Hz, 1 H), 3.22 (s, 3H), 3.05 - 2.95 (m, 1H), 2.93 - 2.79 (m, 2H), 2.74 - 2.65 (m, 1 H). Mass spectrum (ESI, m / z): calcd. for C33H30F2N6O4, 612.2; found [M+H]+, 613.3.

[0239] 3-Cyano- / V-((5aS,8aS)-5-(4-(difluoro(phenyl)methyl)phenyl)-4-oxo-5,5a,6,7,8,8a-hexahydro-4 / 7- pyrazolo[1 ,5-a]pyrrolo[3,4-e]pyrazin-3-yl)-4-methoxybenzamide (Example 1 , product from Step M, 100.0 mg, 0.1800 mmol), / V-(tert-butoxycarbonyl)- / V-methylglycine (40.9 mg, 0.216 mmol), HATLI (89.1 mg, 0.234 mmol), DI PEA (94 μL, 0.54 mmol) and DMF (2.5 mL) were added to a 8 mL vial. The reaction mixture stirred at r.t. for 12 h and then turn yellow. The reaction was monitored by LC-MS and TLC. The reaction mixture was then poured over H2O (20 mL), extracted with DCM (10 mL x 3). The combined extracts were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and the filtrate concentrated to dryness in vacuo to give yellow oil. The oil was subjected to silica gel chromatography (0-10% MeOH / DCM) to give tert-butyl (2- ((5aS,8aS)-3-(3-cyano-4-methoxybenzamido)-5-(4-(difluoro(phenyl)methyl)phenyl)-4-oxo- 4,5,5a,6,8,8a-hexahydro-7 / 7-pyrazolo[1 ,5-a]pyrrolo[3,4-e]pyrazin-7-yl)-2- oxoethyl)(methyl)carbamate as a white solid (126 mg, 76%). Mass spectrum (ESI, m / z): calcd. for C38H37F2N7O6, 725.2; found [M-100+H]+, 626.2.

[0240] Step B: 3-Cyano- / V-((5aS,8aS)-5-(4-(difluoro(phenyl)methyl)phenyl)-7-(methylglycyl)-4-oxo- 5,5a,6,7,8,8a-hexahydro-4 / 7-pyrazolo[1 ,5-a]pyrrolo[3,4-e]pyrazin-3-yl)-4-methoxybenzamide tert-Butyl (2-((5aS,8aS)-3-(3-cyano-4-methoxybenzamido)-5-(4 (difluoro(phenyl)methyl)phenyl)- 4-oxo-4,5,5a,6,8,8a-hexahydro-7 / 7-pyrazolo[1 ,5-a]pyrrolo[3,4-e]pyrazin-7-yl)-2- oxoethyl)(methyl)carbamate (148.0 mg, 0.2040 mmol) and 4 N HCI / dioxane (4 mL) were added to 10 mL round-bottomed flask. The reaction mixture stirred at r.t. for 12 h. The reaction was monitored by LC-MS. The reaction mixture was adjusted pH= 8 with sat. NaHCO3 and then extracted with EtOAc (10 mL x 3). The combined extracts were washed with brine (10 mL), dried over anhydrous Na2SC>4, filtered, and the filtrate concentrated to dryness in vacuo to give yellow solid. The solid was subjected to prep-HPLC (Boston Prime C18, 10 pm, 150 mm x 30 mm; 7 min gradient (50% to 80% ACN / H2O (with NH3 H2O+NH4HCO3)) to give 3-cyano- / V- ((5aS,8aS)-5-(4-(difluoro(phenyl)methyl)phenyl)-7-(methylglycyl)-4-oxo-5,5a,6,7,8,8a- hexahydro-4 / 7-pyrazolo[1 ,5-a7pyrrolo[3,4-e]pyrazin-3-yl)-4-methoxybenzamide as a white solid (30.0 mg, 24%).1H NMR (400 MHz, DMSO-d6) δ:: 9.87 (d, J = 6.2 Hz, 1 H), 8.23 (t, J = 2.0 Hz, 1 H), 8.20 (s, 1 H), 8.16 (td, J = 1.6, 9.2 Hz, 1 H), 7.65 (d, J = 8.2 Hz, 2H), 7.61 - 7.56 (m, 2H), 7.56 - 7.51 (m, 5H), 7.39 (d, J = 8.8 Hz, 1 H), 5.05 - 4.82 (m, 2H), 4.50 - 4.28 (m, 1 H), 3.99 (s, 3H), 3.93 - 3.72 (m, 2H), 3.66 - 3.38 (m, 2H), 3.28 - 2.97 (m, 2H), 2.26 (d, J = 16.4 Hz, 3H). Mass spectrum (ESI, m / z): calcd. for C33H29F2N7O4, 625.2 m / z, found [M+H]+, 626.3. ,6,7,8,8a-hexahvdro-4H-i 5-alpvrrolof3,4-

[0241] 3-Cyano- / V-((5aS,8aS)-5-(4-(difluoro(phenyl)methyl)phenyl)-4-oxo-5,5a,6,7,8,8a-hexahydro-4 / 7- pyrazolo[1 ,5-a]pyrrolo[3,4-e]pyrazin-3-yl)-4-methoxybenzamide (Example 1 , product from Step M, 80.0 mg, 0.144 mmol), a stir bar, 2-bromo- / V-methylacetamide(26.3 mg, 0.173 mmol), K2CO3 (39.9 mg, 0.289 mmol) and DMF (1.5 mL) were added to a 10 mL round-bottomed flask, and the resulting mixture was stirred at 50°C for 3 h. The reaction was monitored by LC-MS. The reaction solution was then subjected to prep-HPLC (Boston Prime C18, 10 pm, 150 mm x 30 mm; 7 min gradient (52-82% (v / v) ACN / H2O (with NH3 H2O + NH4HCO3) ) to give 3-cyano- / V- ((5aS,8aS)-5-(4-(difluoro(phenyl)methyl)phenyl)-7-(2-(methylamino)-2-oxoethyl)-4-oxo- 5,5a,6,7,8,8a-hexahydro-4 / 7-pyrazolo[1 ,5-a]pyrrolo[3,4-e]pyrazin-3-yl)-4-methoxybenzamide as a white solid (70.2 mg, 77.4%).1H NMR (400 MHz, CD3CN) 5: 9.65 (s, 1 H), 8.27 (s, 1 H), 8.13 (d, J = 2.4 Hz, 1 H), 8.05 (dd, J = 2.4, 8.8 Hz, 1 H), 7.68 - 7.39 (m, 9H), 7.21 (d, J = 8.8 Hz, 1 H), 6.96 (br d, J = 3.2 Hz, 1 H), 4.80 - 4.69 (m, 2H), 3.97 (s, 3H), 3.61 (dd, J = 6.8, 8.4 Hz, 1 H), 3.45 - 3.38 (m, 1 H), 3.31 (d, J = 4.8 Hz, 2H), 3.05 - 2.98 (m, 1 H), 2.93 - 2.85 (m, 1 H), 2.67 (d, J = 4.8 Hz, 3H). Mass spectrum (ESI, m / z): calcd. for C33H29F2N7O4, 625.2; found [M+H]+, 626.3. Example 8: 3-Cyano-N-((5aS,8aS)-5-(4-(difluoro(phenyl)methyl)phenyl)-7-(2- methoxyacetyl)-4-oxo-5, 5a, 6,7,8, 8a-hexahvdro-4H-pyrazolori,5-a]pyrrolor3,4-elpyrazin-3- yl)-4-methoxybenzamide

[0242] The title compound was prepared in a manner analogous to Example 4, Step A above, reacting 3-cyano- / V-((5aS,8aS)-5-(4-(difluoro(phenyl)methyl)phenyl)-7-(2-methoxyacetyl)-4-oxo- 5,5a,6,7,8,8a-hexahydro-4 / 7-pyrazolo[1 ,5-a]pyrrolo[3,4-e]pyrazin-3-yl)-4-methoxybenzamide (Example 1 , product from Step M, 100.0 mg, 180.3μmol), 2-methoxyacetic acid (19.4 mg, 0.216 mmol), HATU (89.1 mg, 0.234 mmol), DIPEA (69.9 mg, 0.541 mmol) and DMF (3.0 mL).1H NMR (400 MHz, DMSO-d6) δ: 9.87 (d, J = 6.0 Hz, 1 H), 8.26 - 8.18 (m, 2H), 8.16 (dd, J = 2.0, 9.2 Hz, 1 H), 7.65 (d, J = 8.4 Hz, 2H), 7.61 - 7.50 (m, 7H), 7.39 (d, J = 9.2 Hz, 1 H), 4.92 (tt, J = 10.8, 18.4 Hz, 2H), 4.48 - 4.27 (m, 1 H), 4.19 - 3.72 (m, 7H), 3.61 - 3.05 (m, 1 H), 3.32 - 3.22 (m, 3H). Mass spectrum (ESI, m / z): Calcd. for C33H28F2N6O5, 626.2; found [M+H]+, 627.3.

[0243] Example 9: 3-Cyano-N-((5aS,8aS)-5-(4-(difluoro(phenyl)methyl)phenyl)-7-(2- hydroxyethyl)-4-oxo-5, 5a, 6,7,8, 8a-hexahvdro-4H-pyrazolori,5-a]pyrrolor3,4-elpyrazin-3- vD-4-methoxybenzamide.

[0244] 3-Cyano- / V-((5aS,8aS)-5-(4-(difluoro(phenyl)methyl)phenyl)-4-oxo-5, 5a, 6,7,8, 8a-hexahydro-4 / 7- pyrazolo[1 ,5-a]pyrrolo[3,4-e]pyrazin-3-yl)-4-methoxybenzamide (Example 1 , product from Step M, 80.0 mg, 0.144 mmol), a stir bar, 2-bromoethan-1-ol (13 μL, 0.19 mmol), DIPEA (50 μL, 0.29 mmol), and DMF (1.0 mL) were added to a 10 mL round-bottomed flask. The resulting mixture was stirred at 80°C for 12 h. The reaction solution was black. The reaction was monitored by LC-MS and TLC. The reaction mixture was then poured over H2O (20 mL), extracted with EtOAc (10 mL x 3). The combined extracts were washed with brine (10 mL x 3), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a white solid. The solid was subjected to silica-gel chromatography (0-10% MeOH / DCM) to give 3-cyano- / V-((5aS,8aS)-5-(4- (difluoro(phenyl)methyl)phenyl)-7-(2-hydroxyethyl)-4-oxo-5, 5a, 6,7,8, 8a-hexahydro-4 / 7- pyrazolo[1 ,5-a]pyrrolo[3,4-e]pyrazin-3-yl)-4-methoxybenzamide as a white solid (29.6 mg, 34%).1H NMR (400 MHz, CD3CN) 5: 9.64 (s, 1 H), 8.26 (s, 1 H), 8.12 (d, J = 2.4 Hz, 1 H), 8.04 (dd, J = 2.0, 8.8 Hz, 1 H), 7.65 - 7.54 (m, 7H), 7.42 (d, J = 8.4 Hz, 2H), 7.20 (d, J = 8.8 Hz, 1 H), 4.80 - 4.53 (m, 2H), 3.97 (s, 3H), 3.70 - 3.26 (m, 4H), 3.11 - 2.69 (m, 4H). Mass spectrum (ESI, m / z): calcd. for C32H28F2N6O4 598.2; found [M+ H]+, 599.3.

[0245] Example 10: 3-Cvano-N-((5aS,8aS)-5-(4-(difluoro(phenyl)methyl)phenyl)-7-(2-hydroxy- acetyl)-4-oxo-5,5a,6,7,8,8a-hexahvdro-4H-pyrazolori,5-a]pyrrolor3,4-elpyrazin-3-yl)-4-

[0246] 3-Cyano-N-((5aS,8aS)-5-(4-(difluoro(phenyl)methyl)phenyl)-4-oxo-5, 5a, 6,7,8, 8a- hexa hydro-4 H- pyrazolo[1 ,5-a]pyrrolo[3,4-e]pyrazin-3-yl)-4-methoxybenzamide (Example 1 , product from Step M, 95.0 mg, 0.161 mmol), a stir bar, 2-hydroxyacetic acid (14.7 mg, 0.193 mmol), DIEA (80 pL, 0.48 mmol), HATU (79.5 mg, 0.209 mmol) and DMF (1.5 mL) were added to a 10 mL oven- dried and nitrogen-purged round-bottomed flask, and the reaction vessel placed on heating plate that had been pre-heated to 25°C, and the mixture stirred for 4 h. The reaction mixture was poured into H2O (10 mL) and extracted with EtOAc (8 mL x 3). The combined extracts were washed with water (10 mL x 4) and brine (10 mLx 2), dried over anhydrous Na2SO4, filtered and concentrated in vacuum to give a brown oil. The oil was then subjected to silica gel chromatography (0~5% MeOH / DCM) followed by prep-HPLC (Boston Green ODS, 5 pm, 150 mm x 30 mm; 7 min gradient (50% to 80% CH3CN and H2O with (0.05%FA)) to give 3-cyano-N- ((5aS,8aS)-5-(4-(difluoro(phenyl)methyl)phenyl)-7-(2-hydroxyacetyl)-4-oxo-5,5a,6,7,8,8a- hexahydro-4H-pyrazolo[1 ,5-a]pyrrolo[3,4-e]pyrazin-3-yl)-4-methoxybenzamide as a white solid (67.8 mg, 53%).1H NMR (400 MHz, DMSO-d6) δ: 9.87 (d, J = 5.6 Hz, 1 H), 8.24 - 8.18 (m, 2H), 8.18 - 8.13 (m, 1 H), 7.65 (dd, J = 3.2, 8.4 Hz, 2H), 7.61 - 7.51 (m, 7H), 7.39 (d, J = 8.8 Hz, 1 H), 5.01 - 4.82 (m, 3H), 4.44 - 4.27 (m, 1 H), 4.20 - 3.74 (m, 7H), 3.65 - 3.03 (m, 1 H). Mass spectrum (ESI, m / z): calcd. for C32H26F2N6O5, 612.2 m / z, found [M+H]+, 613.3.

[0247] The title compound was prepared in a manner analogous to Example 4, Step A above, reacting 3-cyano-N-((5aS,8aS)-5-(4-(difluoro(phenyl)methyl)phenyl)-4-oxo-5, 5a, 6,7,8, 8a- hexa hydro-4 H- pyrazolo[1 ,5-a]pyrrolo[3,4-e]pyrazin-3-yl)-4-methoxybenzamide (Example 1 , product from Step M, 70.0 mg, 0.13 mmol), dimethylglycine (15.6 mg, 0.151 mmol), HATLI (62.4 mg, 0.164 mmol), DIPEA (66 μL, 0.38 mmol), and DMF (1.5 mL).1H NMR (400 MHz, DMSO-cfe )_δ: 9.90 - 9.85 (m, 1 H), 8.23 (d, J = 2.0 Hz, 1 H), 8.19 (s, 1 H), 8.16 (dd, J = 2.0, 8.8 Hz, 1 H), 7.68 - 7.62 (m, 2H), 7.59 - 7.51 (m, 7H), 7.39 (d, J = 8.8 Hz, 1 H), 5.01 - 4.82 (m, 2H), 4.61 - 4.24 (m, 1 H), 3.99 (s, 3H), 3.92 (t, J = 9.6 Hz, 1 H), 3.79 - 3.54 (m, 1 H), 3.22 - 2.96 (m, 3H), 2.23 - 2.12 (m, 6H). Mass spectrum (ESI, m / z): calcd. for C34H31F2N7O4, 639.2; found [M+H]+, 640.3.

[0248] Example 12: N-((5aS,8aS)-7-(2-Amino-2-oxoethyl)-5-(4-(difluoro(phenyl)methyl)phenyl)-4- oxo-5,5a,6,7,8,8a-hexahydro-4H-pyrazolori,5-alpyrrolor3,4-elpyrazin-3-yl)-3-cyano-4- The title compound was prepared in a manner analogous to Example 5, reacting 3-cyano- / V- ((5aS,8aS)-5-(4-(difluoro(phenyl)methyl)phenyl)-4-oxo-5,5a,6,7,8,8a-hexahydro-4 / 7- pyrazolo[1 ,5-a]pyrrolo[3,4-e]pyrazin-3-yl)-4-methoxybenzamide (Example 1 , product from Step M, 100.0 mg, 0.1804 mmol), 2-bromoacetamide (29.9 mg, 0.216 mmol), DIPEA (94.2 μL, 0.54 mmol) and DMF (1 .5 mL).1H NMR (400 MHz, DMSO-d6) δ:: 9.86 (s, 1 H), 8.22 (d, J = 2.2 Hz, 1 H), 8.18 - 8.11 (m, 2H), 7.62 (d, J = 8.4 Hz, 2H), 7.58 - 7.47 (m, 7H), 7.39 (d, J = 9.2 Hz, 1 H), 7.27 (s, 1 H), 7.04 (s, 1 H), 4.93 - 4.80 (m, 2H), 3.99 (s, 3H), 3.56 (dd, J = 6.8, 8.0 Hz, 1 H), 3.40 - 3.35 (m, 1 H), 3.32 - 3.23 (m, 2H), 3.03 - 2.97 (m, 1 H), 2.87 - 2.79 (m, 1 H). Mass spectrum (ESI, m / z): calcd. for C32H27F2N7O4, 611.2; found [M+H]+, 612.3.

[0249] Example 13: 3-Cyano-N-((5aS,8aS)-5-(4-(difluoro(phenyl)methyl)phenyl)-7-(2-(dimethyl- amino)-2-oxoethyl)-4-oxo-5, 5a, 6,7,8, 8a-hexahvdro-4H-pyrazolori,5-a]pyrrolor3,4-el- pyrazin-3-yl)-4-methoxybenzamide.

[0250] The title compound was prepared in a manner analogous to Example 7, reacting 3-cyano- / V- ((5aS,8aS)-5-(4-(difluoro(phenyl)methyl)phenyl)-4-oxo-5,5a,6,7,8,8a-hexahydro-4 / 7- pyrazolo[1 ,5-a]pyrrolo[3,4-e]pyrazin-3-yl)-4-methoxybenzamide (Example 1 , product from Step M, 70.0 mg, 0.126 mmol), K2CO3 (52.3 mg, 0.379 mmol), 2-bromo- / V, / V-dimethylacetamide (25.1 mg, 0.151 mmol), and DMF (2.0 mL).1H NMR (400 MHz, DMSO-d6) δ:: 9.86 (s, 1 H), 8.22 (d, J = 2.4 Hz, 1 H), 8.17 - 8.13 (m, 2H), 7.62 (d, J = 8.4 Hz, 2H), 7.59 - 7.48 (m, 7H), 7.39 (d, J = 9.2 Hz, 1 H), 4.95 - 4.89 (m, 2H), 3.99 (s, 3H), 3.67 - 3.53 (m, 3H), 3.39 (t, J = 8.8 Hz, 1 H), 3.00 - 2.94 (m, 1 H), 2.89 - 2.77 (m, 6H). Mass spectrum (ESI, m / z): calcd. for C34H31F2N7O4 639.2; found [M+H]+, 640.3. i-4-oxo-

[0251] (5aS,8aS)-3-lodo-5,5a,6,7,8,8a-hexahydro-4 / 7-pyrazolo[1 ,5-a]pyrrolo[3,4-e]pyrazin-4-one (10.00 g, 29.36 mmol), a stir bar and CH3CN (100.0 mL) were added to a 250 mL three-necked round-bottomed flask, then treated with TEA (12.2 mL, 0.728 g / mL, 88.1 mmol) and stirred for 30 min before treating with AC2O (3.3 mL, 1.08 g / mL, 35 mmol). The resulting mixture stirred for 2 h, which formed a white suspension mixture. The reaction progress was monitored by LCMS. The reaction mixture was poured into H2O (60 mL), aged 60 min, then let settles before filtration. The filter cake was rinsed with H2O (30 mL x 2) before collected and concentrated in vacuo to give (5aS,8aS)-7-acetyl-3-iodo-5,5a,6,7,8,8a-hexahydro-4 / 7-pyrazolo[1 ,5-a]pyrrolo[3,4- e]pyrazin-4-one as an off-white solid (9.17 g, 89%).1H NMR (400 MHz, DMSO-d6) δ:: 8.92 (d, J = 19.2 Hz, 1 H), 7.74 (d, J = 2.0 Hz, 1 H), 4.61 - 4.45 (m, 1 H), 4.26 - 3.97 (m, 2H), 3.91 - 3.66 (m, 2H), 3.50 - 3.12 (m, 1 H), 2.00 (d, J = 7.2 Hz, 3H). Mass spectrum (ESI, m / z): Calcd. for C1OH11 I N4O2, 346.0, found [M+H]+, 346.9.

[0252] B: N-((5aS,8aS)-7-Acetyl-4-oxo-5,5a,6,7,8,8a-hexahydro-4H-pyrazolo[1 ,5-a]pyrrolo[3,4- e]pyrazin-3-yl)-3-cyano-4-methoxybenzamide (5aS,8aS)-7-Acetyl-3-iodo-5,5a,6,7,8,8a-hexahydro-4 / 7-pyrazolo[1 ,5-a]pyrrolo[3,4-e]pyrazin-4- one (5.44 g, 15.7 mmol), a stir bar, 3-cyano-4-methoxybenzamide (Intermediate 5, 6.92 g, 39.3 mmol), CS2CO3 (20.5 g, 62.9 mmol) and dioxane (170 mL) were added to an oven-dried and nitrogen-purged 500 mL three-necked flask fitted with a reflux condenser, which was subsequently evacuated and refilled with N2 (x3), then stirred for 5 min before treating with tBubrettphos (380.9 mg, 0.7860 mmol) and tBubrettphos Pd G3 (1.34 g, 1.57 mmol), which was subsequently evacuated and refilled with N2 (x3), and the resulting mixture stirred at 100°C for 18 h as a brown homogenous mixture. The reaction progress was monitored by LCMS. The reaction mixture was cooled to r.t., added water (150 mL), the brown suspension mixture stirred at r.t. for 1 h, then let to settle 1 h, filtered and the filter cake was added acetone (200 mL) and the brown suspension mixture stirred at 75°C for 1 h, then let settle 1 h, filtered and the filter cake was concentrated in vacuum to give the (5aS,8aS)-3-iodo-7-(4-methoxybenzyl)- 5,5a,6,7,8,8a-hexahydro-4 / 7-pyrazolo[1,5-a]pyrrolo[3,4-e]pyrazin-4-one as an off-white solid (3.53 g, 56%).1H NMR (400 MHz, DMSO-d6) δ:: 8.27 (s, 1 H), 8.21 (d, J = 8.8 Hz, 1 H), 8.15 (d, J = 6.0 Hz, 1 H), 7.39 - 7.33 (m, 1 H), 4.44 - 4.32 (m, 1H), 4.32 - 4.23 (m, 1H), 4.21 - 4.04 (m, 1H), 3.99 (s, 3H), 3.93 - 3.81 (m, 2H), 3.73 - 3.13 (m, 1 H), 2.01 (d, J = 8.8 Hz, 3H). Mass spectrum (m / z): Calcd. for Ci9Hi8N6O4, 394.1 ; found [M+H]+, 395.0.

[0253] Step C: N-((5aS,8aS)-7-Acetyl-5-(4-(difluoro(4-fluorophenyl)methyl)phenyl)-4-oxo-5,5a,6,7,8,8a- hexahydro-4H-pyrazolon,5-alpyrrolof3,4-elpyrazin-3-yl)-3-cyano-4-methoxybenzamide.

[0254] / \ / -((5aS,8aS)-7-acetyl-4-oxo-5,5a,6,7,8,8a-hexahydro-4 / 7-pyrazolo[1,5-a]pyrrolo[3,4-e]pyrazin- 3-yl)-3-cyano-4-methoxybenzamide (500.0 mg, 1.268 mmol), a stir bar, 1-bromo-4-(difluoro(4- fluorophenyl)methyl)benzene (Intermediate 1, 763.5 mg, 2.536 mmol), DMEDA (0.17 mL, 1.5 mmol), K2CO3 (350.4 mg, 2.536 mmol), DMF (5.0 mL) and toluene (5.0 mL), Cui (289.7 mg, 1.521 mmol) were added to 50 mL round-bottomed flask fitted with a reflux condenser with nitrogen for 3 times, the resulting mixture stirred for 12 h at 100°C to give a blue solution. The reaction progress was monitored by TLC. The mixture filtered and the filtrate was poured into H2O (40 mL), extracted with EtOAc (50 mL x 3). The combined extracts were washed with brine (50 mL x 3), dried over anhydrous Na2SO4, filtered and concentrated in vacuum to give a blue solid. The solid was then subjected to silica gel chromatography (0-10% Methanol / DCM) to give / V-((5aS,8aS)-7-acetyl-5-(4-(difluoro(4-fluorophenyl)methyl)phenyl)-4-oxo-5,5a,6,7,8,8a- hexahydro-4 / 7-pyrazolo[1 ,5-a]pyrrolo[3,4-e]pyrazin-3-yl)-3-cyano-4-methoxybenzamide as a white solid (461.0 mg, 59%).1H NMR (400 MHz, CDCI3) δ: 9.75 - 9.54 (m, 1 H), 8.50 (s, 1 H), 8.21 - 8.04 (m, 2H), 7.71 - 7.58 (m, 2H), 7.54 (dd, J = 5.2, 8.0 Hz, 2H), 7.40 - 7.31 (m, 2H), 7.15 (t, J = 8.4 Hz, 2H), 7.01 (d, J = 8.8 Hz, 1 H), 4.76 - 4.60 (m, 2H), 4.57 (s, 1 H), 4.13 - 4.03 (m, 1 H), 4.00 (s, 3H), 3.99 - 3.74 (m, 1H), 3.51 - 3.16 (m, 1H), 2.22 - 1.99 (m, 3H). Mass spectrum (ESI, m / z): Calcd. For C32H25F3N6CU, 614.2; found [M+H]+, 615.1.

[0255] Example 15: 3-Cvano-N-((5aS,8aS)-5-(4-(difluoro(4-fluorophenyl)methyl)phenyl)-7- (methylsulfonyl)-4-oxo-5, 5a, 6,7,8, 8a-hexahvdro-4H-pyrazolori,5-a]pyrrolor3,4-elpyrazin-3- yl)-4-methoxybenzamide.

[0256] Step A: 3-Cyano-N-((5aS,8aS)-5-(4-(difluoro(4-fluorophenyl)methyl)phenyl)-7-(4-methoxy- benzyl)-4-oxo-5,5a,6,7,8,8a-hexahydro-4H-pyrazolon ,5-alpyrrolo[3,4-elpyrazin-3-yl)-4- methoxybenzamide.

[0257] 3-Cyano-4-methoxy- / V-((5aS,8aS)-7-(4-methoxybenzyl)-4-oxo-5,5a,6,7,8,8a-hexahydro-4 / 7- pyrazolo[1 ,5-a]pyrrolo[3,4-e]pyrazin-3-yl)benzamide (Example 1 , product from step L, 660.0 mg, 1.397 mmol), a stir bar, 1-bromo-4-(difluoro(4-fluorophenyl)methyl)benzene (Intermediate 1 , 631.9 mg, 2.095 mmol), Cui (319.2 mg, 1.676 mmol), DMEDA (147.8 mg, 1.676 mmol), K2CO3(386.1 mg, 2.794 mmol) in DMF (3.0 mL) and toluene (3.0 mL) were added to a 50 mL oven- dried round-bottomed flask. The reaction mixture was sparged with N2, Then the mixture was heated to 100°C for 16 h, finally the reaction mixture was became a black suspension. The reaction progress was monitored by LC-MS. The reaction mixture was diluted with water (20 mL), extracted with EtOAc (25 mL x 3). The combined extracts were washed with brine (10 mL x 3), dried over anhydrous Na2SC>4, filtered and concentrated in vacuo to give a yellow oil. The oil was subjected to silica gel chromatography (5-80% EtOAc / pet ether) to give 3-cyano- / V- ((5aS,8aS)-5-(4-(difluoro(4-fluorophenyl)methyl)phenyl)-7-(4-methoxybenzyl)-4-oxo- 5,5a,6,7,8,8a-hexahydro-4 / 7-pyrazolo[1 ,5-a]pyrrolo[3,4-e]pyrazin-3-yl)-4-methoxybenzamide the as a yellow oil (630 mg, 63%). Mass spectrum (ESI, m / z): Calcd. for C38H31F3N6O4, 692.2; found [M+H]+, 693.3.

[0258] Step B: 3-Cyano-N-((5aS,8aS)-5-(4-(difluoro(4-fluorophenyl)methyl)phenyl)-4-oxo- 5,5a,6,7,8,8a-hexahydro-4H-pyrazolon ,5-alpyrrolof3,4-elpyrazin-3-yl)-4-methoxybenzamide 3-Cyano- / V-((5aS,8aS)-5-(4-(difluoro(4-fluorophenyl)methyl)phenyl)-7-(4-methoxybenzyl)-4-oxo- 5,5a,6,7,8,8a-hexahydro-4 / 7-pyrazolo[1 ,5-a]pyrrolo[3,4-e]pyrazin-3-yl)-4 methoxybenzamide (630.0 mg, 0.9094 mmol), a stir bar, 1-chloroethyl carbonochloridate (0.29 mL, 2.7 mmol) in DCE (6.0 mL) were added to a 50 mL oven-dried round-bottomed flask. The reaction mixture was sparged with N2. Then the mixture was heated to 60°C for 3 h, which formed yellow solution. The solution was concentrated in vacuum to give a yellow solid. Then MeOH (10.0 mL) was added and the mixture was stirred for 2 h at 60°C, finally the reaction mixture became a yellow suspension. The reaction progress was monitored by LC-MS. The suspension was filtered and the filter cake was concentrated in vacuum to give 3-cyano- / V-((5aS,8aS)-5-(4- (difluoro(4-fluorophenyl)methyl)phenyl)-4-oxo-5,5a,6,7,8,8a-hexahydro-4 / 7-pyrazolo[1 ,5- a]pyrrolo[3,4-e]pyrazin-3-yl)-4-methoxybenzamide as a white soid (400 mg, 75%). Mass spectrum (ESI, m / z): Calcd. for C30H23F3N6O3, 572.2; found [M+H]+, 573.2.

[0259] Step C: 3-Cyano-N-((5aS,8aS)-5-(4-(difluoro(4-fluorophenyl)methyl)phenyl)-7-(methylsulfonyl)- 4-OXO-5, 5a, 6,7,8, 8a-hexahvdro-4H-pyrazolon ,5-alpyrrolof3,4-elpyrazin-3-yl)-4-methoxy- benzamide

[0260] The title compound was prepared in a manner analogous to Example 3, reacting 3-cyano- / V- ((5aS,8aS)-5-(4-(difluoro(4-fluorophenyl)methyl)phenyl)-4-oxo-5,5a,6,7,8,8a-hexahydro-4 / 7- pyrazolo[1 ,5-a]pyrrolo[3,4-e]pyrazin-3-yl)-4-methoxybenzamide (400.0 mg, 0.6990 mmol), a stir bar, TEA (0.29 mL, 2.1 mmol), Ms2O (365.1 mg, 2.096 mmol), and DCE (5.0 mL)1H NMR (400 MHz, DMSO-d6) δ:: 9.88 (s, 1 H), 8.27 - 8.11 (m, 3H), 7.69 - 7.53 (m, 6H), 7.44 - 7.31 (m, 3H), 5.07 - 4.85 (m, 2H), 4.23 (dd, J = 6.4, 8.4 Hz, 1 H), 3.99 (s, 3H), 3.75 (t, J = 9.2 Hz, 1 H), 3.61 (dd, J = 6.4, 8.0 Hz, 1 H), 3.23 (t, J = 9.6 Hz, 1 H), 3.10 (s, 3H). Mass spectrum (ESI, m / z): Calcd. for C31H25F3N6O5S, 650.2; found [M+H]+, 651.2.

[0261] Example 16: N-((5aS,8aS)-7-acetyl-5-(4-((4-chlorophenyl)difluoromethyl)phenyl)-4-oxo- 5,5a,6,7,8,8a-hexahvdro-4H-pyrazolori,5-alpyrrolor3,4-e]pyrazin-3-yl)-3-cvano-4-methoxy-

[0262] / V-((5aS,8aS)-7-Acetyl-4-oxo-5,5a,6,7,8,8a-hexahydro-4 / - / -pyrazolo[1 ,5-a]pyrrolo[3,4-e]pyrazin- 3-yl)-3-cyano-4-methoxybenzamide (Example 14, product from Step B, 400.0 mg, 1.014 mmol), a stir bar, 1-bromo-4-((4-chlorophenyl)difluoromethyl)benzene (Intermediate 2, 644.2 mg, 2.028 mmol), A / V / ^-dimethylethane-l ^-diamine (0.13 mL, 1.2 mmol, 0.819 g / mL), K2CO3 (420.5 mg, 3.043 mmol), DMF (2.0 mL) and toluene (2.0 mL) were added to an oven-dried 10 mL round- bottomed flask with a reflux condenser. Then Cui (231.8 mg, 1.217 mmol) was added. The resulting mixture was fitted with N2 for 3 times. The resulting brown suspension mixture stirred at 100°C for 24 h. The reaction progress was monitored by LCMS. The reaction mixture cooled to r.t. and diluted with water (8 mL), extracted with EtOAc (8 mL x 6). The combine extracts were washed with water (40 mL x 3), brine (40 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a brown oil. The oil was subjected to silica gel chromatography (0-5% MeOH / DCM) followed by prep-HPLC (Phenomenex C18, 5pm, 80 mm x 30 mm; 55% to 85% CH3CN and H2O (containing 0.05% NH3 H2O + 10 mM NH4HCO3) to give / V-((5aS,8aS)-7- acetyl-5-(4-((4-chlorophenyl)difluoromethyl)phenyl)-4-oxo-5, 5a, 6,7,8, 8a-hexahydro-4 / 7- pyrazolo[1 ,5-a]pyrrolo[3,4-e]pyrazin-3-yl)-3-cyano-4-methoxybenzamide as a white solid (263.6 mg, 52% ) and give the N-((5aS,8aS)-7-acetyl-5-(4-((4-chlorophenyl)difluoromethyl)phenyl)-4- oxo-5, 5a, 6,7,8, 8a-hexahydro-4H-pyrazolo[1 ,5-a]pyrrolo[3,4-e]pyrazin-3-yl)-3-cyano-4- hydroxybenzamide (55 mg, 61% purity) as a brown solid.1H NMR (400 MHz, DMSO-d6) δ: 9.87 (d, J = 6.4 Hz, 1 H), 8.31 - 8.09 (m, 3H), 7.72 - 7.48 (m, 8H), 7.39 (d, J = 8.8 Hz, 1 H), 5.02 - 4.83 (m, 2H), 4.47 - 4.26 (m, 1 H), 3.99 (s, 3H), 3.94 - 3.83 (m, 1 H), 3.79 - 3.51 (m, 1 H), 3.41 - 2.98 (m, 1 H), 2.04 -1.92 (m, 3H). Mass spectrum (ESI, m / z): Calcd. for C32H25CIF2N6O4, 630.2; found 631.2 [M+H]+.

[0263] Example 17: N-((5aS,8aS)-7-acetyl-5-(4-((4-chlorophenyl)difluoromethyl)phenyl)-4-oxo- 5,5a,6,7,8,8a-hexahvdro-4H-pyrazolori,5-alpyrrolor3,4-e]pyrazin-3-yl)-3-cvano-4-hvdroxy- benzamide.

[0264] The N-((5aS,8aS)-7-Acetyl-5-(4-((4-chlorophenyl)difluoromethyl)phenyl)-4-oxo-5,5a,6,7,8,8a- hexahydro-4H-pyrazolo[1 ,5-a]pyrrolo[3,4-e]pyrazin-3-yl)-3-cyano-4-hydroxybenzamide (from Example 16, 55 mg, 61 % purity) was purified by prep-HPLC (Welch Xtimate C18, 5 pm, 150 mm x 25 mm; (25% to 55% CH3CN and H2O (containing 0.05% NH3 H2O + 10 mM NH4HCO3) to give / \ / -((5aS,8aS)- 7-acetyl-5-(4-((4-chlorophenyl)difluoromethyl)phenyl)-4-oxo-5,5a,6,7,8,8a- hexahydro-4 / 7-pyrazolo[1 ,5-a]pyrrolo[3,4-e]pyrazin-3-yl)-3-cyano-4-hydroxybenzamide as a white solid. (7.1 mg, 18%).1H NMR (400 MHz, DMSO-d6) δ:: 9.71 (d, J = 5.6 Hz, 1 H), 8.20 (s, 1 H), 8.05 (s, 1 H), 7.89 (d, J = 8.8 Hz, 1 H), 7.68 - 7.59 (m, 6H), 7.58 - 7.51 (m, 2H), 7.05 - 6.95 (m, 1 H), 5.03 - 4.81 (m, 2H), 4.48 - 4.25 (m, 1 H), 3.94 - 3.83 (m, 1 H), 3.78 - 3.70 (m, 1 H), 3.55 - 2.95 (m, 1 H), 2.03 - 1.91 (m, 3H). Mass spectrum (ESI, m / z): Calcd. for C31H23CIF2N6O4, 616.1 ; found [M+H]+, 617.2. a- hexahydro-4 / 7-pyrazolo[1 ,5-a]pyrrolo[3,4-e]pyrazin-3-yl)-3-cyano-4-methoxybenzamide. / V-((5aS,8aS)-7-acetyl-4-oxo-5,5a,6,7,8,8a-hexahydro-4 / 7-pyrazolo[1 ,5-a]pyrrolo[3,4-e]pyrazin- 3-yl)-3-cyano-4-methoxybenzamide (Example 14, product from Step B, 250.0 mg, 0.6340 mmol), a stir bar, 1-bromo-4-(difluoro(phenyl)methyl)benzene (269.2 mg, 0.9510 mmol), N',N"- dimethylethane-1 ,2-diamine (82 μL, 0.76 mmol), K2CO3 (2.63 g, 1.90 mmol) and Cui (145 mg, 0.761 mmol) in DMF (2.5 mL) were added to a 50 mL round-bottomed flask. The resulting mixture was sparged with N2 for 3 times. The resulting mixture was heated to 100°C for 12 h, finally the reaction mixture became a black suspension. The reaction progress was monitored by TLC and LC-MS. The light brown mixture was diluted with H2O (10 mL), extracted with EtOAc (10 mL x 3). The combined extracts were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuum to give a brown oil. The oil was then subjected to silica gel chromatography (75-100% EA / DCM) to give the / \ / -((5aS,8aS)-7-acetyl-5- (4-(difluoro(phenyl)methyl)phenyl)-4-oxo-5,5a,6,7,8,8a-hexahydro-4 / 7-pyrazolo[1 ,5- a]pyrrolo[3,4-e]pyrazin-3-yl)-3-cyano-4-methoxybenzamide as a light yellow foam (170 mg, 43%). Mass spectrum (ESI, m / z): Calcd. for C32H26F2N6O4, 596.2; found [M+H]+, 597.2. i-4-oxo-5, 5a, 6,7,8,8a- hexahydro-4 / 7-pyrazolo[1 ,5-a]pyrrolo[3,4-e]pyrazin-3-yl)-3-cyano-4-hydroxybenzamide.

[0265] / V-((5aS,8aS)-7-Acetyl-5-(4-(difluoro(phenyl)methyl)phenyl)-4-oxo-5,5a,6,7,8,8a-hexahydro-4 / - / - pyrazolo[1 ,5-a]pyrrolo[3,4-e]pyrazin-3-yl)-3-cyano-4-methoxybenzamide (150.0 mg, 0.2514 mmol), LiCI (42.6 mg, 1.01 mmol), a stir bar, and anhydrous DMF (3.0 mL) were added to a 10 mL microwave tube. The tube was sealed and put the tube in a microwave reactor and the mixture was stirred at 150°C for 2 h via microwave. A colorless solution was formed. The reaction progress was monitored by LC-MS. The reaction mixture was cooled to r.t., quenched with aq. HCI (1 M, 0.2 mL) and poured into H2O (10 mL). Some white solid separated out, then filtered. The filter cake was collected and subjected to silica gel chromatography (0-5% MeOH / DCM) followed by prep-HPLC (Boston Prime C18, 5 pm, 150 mm x 40 mm; 7 min gradient (31% to 61% CH3CN and H2O (containing 0.05% NH3 + 10 mM NH4HCO3)) to give / V- ((5aS,8aS)-7-acetyl-5-(4-(difluoro(phenyl)methyl)phenyl)-4-oxo-5,5a,6,7,8,8a-hexahydro-4 / 7- pyrazolo[1 ,5-a]pyrrolo[3,4-e]pyrazin-3-yl)-3-cyano-4-hydroxybenzamide as a white solid (68.8 mg, 69%).1H NMR (400 MHz, DMSO-d6) δ:: 9.73 (br d, J = 6.4 Hz, 1 H), 8.20 (s, 1 H), 8.08 (t, J = 2.0 Hz, 1 H), 7.94 - 7.88 (m, 1 H), 7.65 (br d, J = 8.4 Hz, 2H), 7.61 - 7.50 (m, 7H), 7.04 (d, J = 8.8 Hz, 1 H), 5.01 - 4.82 (m, 2H), 4.47 - 4.25 (m, 1 H), 3.94 - 3.84 (m, 1 H), 3.77 - 3.68 (m, 1 H), 3.61 - 3.47 (m, 0.5H), 3.03 - 2.94 (m, 0.5H), 2.06 - 1.88 (m, 3H). Mass spectrum (ESI, m / z): Calcd. for C31H24F2N6O4, 582.2; found [M+H]+, 583.2.

[0266] Example 19: N-((5aS,8aS)-5-(4-((4-Chlorophenyl)difluoromethyl)phenyl)-7- (methylsulfonyl)-4-oxo-5, 5a, 6,7,8, 8a-hexahvdro-4H-pyrazolori,5-a]pyrrolor3,4-elpyrazin-3- yl)-3-cvano-4-methoxybenzamide.

[0267] Step A: / V-((5aS,8aS)-5-(4-((4-Chlorophenyl)difluoromethyl)phenyl)-7-(4-methoxybenzyl)-4-oxo- 5,5a,6,7,8,8a-hexahydro-4 / - / -pyrazolon ,5-alpyrrolo[3,4-elpyrazin-3-yl)-3-cyano-4- methoxybenzamide.

[0268] 3-Cyano-4-methoxy- / V-((5aS,8aS)-7-(4-Methoxybenzyl)-4-oxo-5,5a,6,7,8,8a-hexahydro-4 / 7- pyrazolo[1 ,5-a]pyrrolo[3,4-e]pyrazin-3-yl)benzamide (Example 1 , product from Step L, 700.0 mg, 1.481 mmol), a stir bar, 1-bromo-4-((4-chlorophenyl)difluoromethyl)benzene (Intermediate 5, 705.7 mg, 2.222 mmol), A / V / ^-dimethylethane-l ^-diamine (0.19 mL, 1.78 mmol, 0.819 g / mL), K2CO3 (409.5 mg, 2.96 mmol), DMF (3.5 mL) and toluene (3.5 mL) were added to an oven-dried and and nitrogen-purged 50 mL round-bottomed flask. Then Cui (338.6 mg, 1.778 mmol) was added. The resulting brown suspension mixture stirred at 100°C for 6 h. The reaction progress was monitored by LCMS. The reaction mixture cooled to r.t. , quenched with water (10 mL), extracted with EtOAc (10 mL x 3). The combined extracts were washed with water (20 mL x 3), brine (20 mL), dried over anhydrous Na2SC>4, filtered and concentrated in vacuo to give a brown oil. The oil was subjected to sillica gel chromatography (0-10% MeOH / DCM) to give the / \ / -((5aS,8aS)-5-(4-((4-chlorophenyl)difluoromethyl)phenyl)-7-(4- methoxybenzyl)-4-oxo-5, 5a, 6,7,8, 8a-hexahydro-4H-pyrazolo[1,5-a]pyrrolo[3,4-e]pyrazin-3-yl)-3- cyano-4 methoxybenzamide as an off-white solid (910 mg, 80%). Mass spectrum (ESI, m / z): Calcd. for C38H31CIF2N6O4, 708.2, found [M+ H]+, 709.3.

[0269] Step B: / V-((5aS,8aS)-5-(4-((4-Chlorophenyl)difluoromethyl)phenyl)-4-oxo-5,5a,6,7,8,8a- hexahydro-4 / - / -pyrazolon,5-alpyrrolof3,4-elpyrazin-3-yl)-3-cyano-4-methoxybenzamide / V-((5aS,8aS)-5-(4-((4-Chlorophenyl)difluoromethyl)phenyl)-7-(4-methoxybenzyl)-4-oxo- 5,5a,6,7,8,8a-hexahydro-4 / 7-pyrazolo[1,5-a]pyrrolo[3,4-e]pyrazin-3-yl)-3-cyano-4- methoxybenzamide (910.0 mg, 1.283 mmol), a stir bar and DCE (10.0 mL) were added to an oven-dried and nitrogen-purged 50 mL round-bottomed flask fitted with a reflux condenser, then treated with 1-chloroethyl carbonochloridate (0.28 mL, 2.6 mmol, 1.325 g / mL), and the resulting mixture stirred for 1.5 h at r.t.. Then the reaction was added MeOH (5 mL), and the reaction vessel placed in an oil bath that had been pre-heated to 60°C. The resulting mixture stirred for 1.5 h, which formed an off-white suspension mixture. The reaction progress was monitored by LCMS. The reaction mixture was filtered, the filter cake was washed with DCM (3 mL x 3) and concentrated in vacuum to give the / V-((5aS,8aS)-5-(4-((4-chlorophenyl)difluoromethyl)phenyl)- 4-oxo-5, 5a, 6,7,8, 8a-hexahydro-4 / 7-pyrazolo[1,5-a]pyrrolo[3,4-e]pyrazin-3-yl)-3-cyano-4- methoxybenzamide as a white solid (590 mg, 71%). Mass spectrum (ESI, m / z): Calcd. for C30H23CIF2N6O3, 588.1 ; found [M+H]+, 589.1.

[0270] Step C: N-((5aS,8aS)-5-(4-((4-Chlorophenyl)difluoromethyl)phenyl)-7-(methylsulfonyl)-4-oxo- 5,5a,6,7,8,8a-hexahydro-4H-pyrazolon,5-alpyrrolof3,4-elpyrazin-3-yl)-3-cyano-4- methoxybenzamide / \ / -((5aS,8aS)-5-(4-((4-Chlorophenyl)difluoromethyl)phenyl)-4-oxo-5,5a,6,7,8,8a-hexahydro-4 / 7- pyrazolo[1,5-a]pyrrolo[3,4-e]pyrazin-3-yl)-3-cyano-4-methoxybenzamide (570 mg, 0.968 mmol), a stir bar, DCE (6.0 mL), TEA (0.40 mL, 2.9 mmoL, 0.728 g / mL) and MS2O (505.7 mg, 2.903 mmol) were added to an oven-dried 50 mL round-bottomed flask. The resulting mixture was fitted with N2 for 3 times, the resulting yellow mixture was stirred at 25°C for 12 h, and the reaction mixture turned to off-white suspension mixture. Then MS2O (505.7 mg, 2.903 mmol) and TEA (0.40 mL, 2.90 mmol, 0.728 g / mL,) was added, fitted with N2 for 3 times, and the off- white suspension mixture stirred at r.t. for 0.5 h. The reaction progress was monitored by LCMS. The reaction mixture was filtered and the filter cake was stirred with DCM (3 mL) for 1 h, filtered and the filter cake washed with DCM (3 mL x 3), the filter cake was concentrated in vacuum to give the / V-((5aS,8aS)-5-(4-((4-chlorophenyl)difluoromethyl)phenyl)-7-(methylsulfonyl)-4-oxo- 5,5a,6,7,8,8a-hexahydro-4 / 7-pyrazolo[1,5-a]pyrrolo[3,4-e]pyrazin-3-yl)-3-cyano-4- methoxybenzamide (421.6 mg, 64%).1H NMR (400 MHz, DMSO-d6) δ: 9.88 (s, 1 H), 8.27 - 8.11 (m, 3H), 7.67 - 7.55 (m, 8H), 7.39 (d, J = 8.8 Hz, 1 H), 5.01 - 4.92 (m, 2H), 4.28 - 4.19 (m, 1 H), 3.99 (s, 3H), 3.79 - 3.71 (m, 1 H), 3.65 - 3.56 (m, 1 H), 3.26 - 3.19 (m, 1 H), 3.10 (s, 3H). Mass spectrum (ESI, m / z): Calcd. for C31H25CIF2N6O5S, 666.1 ; found [M+H]+, 667.2.

[0271] Example 20: N-((5aS,8aS)-7-Acetyl-5-(4-(difluoro(4-fluoro-3- methoxyphenyl)methyl)phenyl)-4-oxo-5,5a,6,7,8,8a-hexahvdro-4H-pyrazolori,5- alpyrrolor3,4-e]pyrazin-3-yl)-3-cvano-4-methoxybenzamide.

[0272] / \ / -((5aS,8aS)-7-Acetyl-4-oxo-5,5a,6,7,8,8a-hexahydro-4 / 7-pyrazolo[1 ,5-a]pyrrolo[3,4-e]pyrazin-

[0273] 3-yl)-3-cyano-4-methoxybenzamide (Example 14, product from Step B, 400.0 mg, 1.014 mmol),

[0274] 4-((4-bromophenyl)difluoromethyl)-1-fluoro-2-methoxybenzene (Intermediate 3, 503.8 mg, 1.521 mmol), copper(l) iodide (231.8 mg, 1.217 mmol), DMEDA (131 μL, 1.22 mmol), K2CO3 (420.5 mg, 3.043 mmol), a stir bar, DMF (2.00 mL), and toluene (2.00 mL) were added to a 40 mL round-bottomed flask. The mixture was then stirred at 100°C for 16 h. The light blue suspension turned green during the progress. The reaction progress was monitored by TLC and LC-MS.

[0275] The mixture was concentrated to dryness to give a green solid. The solid was subjected to silica gel chromatography (0-100% EtOAc / pet ether) followed by prep-HPLC (Xtimate C18, 10 pm 150 mm x 40 mm, 60% - 90% CH3CN and H2O with (0.05%FA) at 25 mL / min) to give N- ((5aS,8aS)-7-acetyl-5-(4-(difluoro(4-fluoro-3-methoxyphenyl)methyl)phenyl)-4-oxo- 5,5a,6,7,8,8a-hexahydro-4H-pyrazolo[1 ,5-a]pyrrolo[3,4-e]pyrazin-3-yl)-3-cyano-4 methoxybenzamide as a white solid (166.7 mg, 25%).1H NMR (400 MHz, DMSO-d6) δ: 9.86 (br d, J = 6.0 Hz, 1 H), 8.22 (t, J = 2.4 Hz, 1 H), 8.19 (s, 1 H), 8.15 (td, J = 2.0, 9.2 Hz, 1 H), 7.71 - 7.65 (m, 2H), 7.57 - 7.51 (m, 2H), 7.41 - 7.33 (m, 3H), 7.11 - 7.09 (m, 1 H), 5.02 - 4.86 (m, 2H), 4.50 - 4.23 (m, 1 H), 3.99 (s, 3H), 3.90 (s, 3H), 3.90 - 3.84 (m, 1 H), 3.77 - 3.52 (m, 1 H), 3.41 - 3.36 (m, 0.5H), 2.98 (t, J = 10.4 Hz, 0.5H), 2.05 - 1.90 (m, 3H). Mass spectrum (ESI, m / z): calcd. for C33H27F3N6O5 644.2; found [M+ H]+, 645.2. Example 21 : 3-Cyano-N-((5aS,8aS)-5-(4-(difluoro(4-fluoro-3- methoxyphenyl)methyl)phenyl)-7-(methylsulfonyl)-4-oxo-5, 5a, 6,7,8, 8a-hexahydro-4H- Pyrazolori,5-alpyrrolor3,4-e]pyrazin-3-yl)-4-methoxybenzamide.

[0276] Step A: 3-Cyano- / V-((5aS,8aS)-5-(4-(difluoro(4-fluoro-3-methoxyphenyl)methyl)phenyl)-7-(4- methoxybenzyl)-4-oxo-5,5a,6,7,8,8a-hexahydro-4 / - / -pyrazolon ,5-alpyrrolo[3,4-elpyrazin-3-yl)-4- methoxybenzamide

[0277] The title compound was prepared in a manner analogous to Example 19, Step A above, reacting 3-cyano-4-methoxy-N-((5aS,8aS)-7-(4-methoxybenzyl)-4-oxo-5, 5a, 6,7,8, 8a-hexahydro- 4H-pyrazolo[1 ,5-a]pyrrolo[3,4-e]pyrazin-3-yl)benzamide (Example 1 , product from Step L, 550.0 mg, 1.164 mmol), 4-((4-bromophenyl)difluoromethyl)-1-fluoro-2-methoxybenzene (Intermediate 3, 578.2 mg, 1.746 mmol), copper(l) iodide (266.0 mg, 1.397 mmol), DMEDA (150 μL, 1.40 mmol), K2CO3(321 .8 mg, 2.328 mmol), a stir bar, DMF (2.70 mL), toluene (2.7 mL).1H NMR (400 MHz, DMSO-d6) δ:: 9.84 (s, 1 H), 8.20 (d, J = 2.0 Hz, 1 H), 8.17 - 8.10 (m, 2H), 7.62 (d, J = 8.4 Hz, 2H), 7.49 (d, J = 8.4 Hz, 2H), 7.40 - 7.32 (m, 3H), 7.21 (d, J = 8.4 Hz, 2H), 7.10 - 7.04 (m, 1 H), 6.86 (d, J = 8.4 Hz, 2H), 4.89 - 4.80 (m, 2H), 3.98 (s, 3H), 3.88 (s, 3H), 3.72 (s, 3H), 3.48 (br d, J = 2.0 Hz, 1 H), 3.20 (s, 1 H), 2.92 (br d, J = 6.4 Hz, 1 H), 2.89 (s, 1 H), 2.73 (s, 1 H), 2.66 (s, 1 H). Mass spectrum (ESI, m / z): calcd. for C39H33F3N6O5, 722.2; found [M+H]+, 723.2.

[0278] Step B: 3-cyano- / V-((5aS,8aS)-5-(4-(Difluoro(4-fluoro-3-methoxyphenyl)methyl)phenyl)-4-oxo- 5,5a,6,7,8,8a-hexahydro-4 / - / -pyrazolon ,5-alpyrrolof3,4-elpyrazin-3-yl)-4-methoxybenzamide The title compound was prepared in a manner analogous to Example 19, Step B above, reacting / V-((5aS,8aS)-5-(4-((4-chlorophenyl)difluoromethyl)phenyl)-7-(4-methoxybenzyl)-4-oxo- 5,5a,6,7,8,8a-hexahydro-4 / 7-pyrazolo[1 ,5-a]pyrrolo[3,4-e]pyrazin-3-yl)-3-cyano-4- methoxybenzamide (910.0 mg, 1.283 mmol), a stir bar, DCE (10.0 mL), 1-chloroethyl carbonochloridate (0.28 mL, 2.6 mmol, 1.325 g / mL), and MeOH (5 mL).1H NMR (400 MHz, DMSO-d6) δ: 10.06 (br s, 1H), 9.87 (s, 1 H), 8.22 (s, 2H), 8.15 (dd, J = 2.0, 8.8 Hz, 1 H), 7.70 (d, J = 8.4 Hz, 2H), 7.53 (d, J = 8.4 Hz, 2H), 7.41 - 7.34 (m, 3H), 7.10 - 7.05 (m, 1 H), 5.06 - 4.95 (m, 2H), 4.10 (br dd, J = 6.4, 10.4 Hz, 1 H), 3.99 (s, 3H), 3.90 (s, 3H), 3.63 (br t, J = 10.4 Hz, 1 H), 3.46 (brdd, J = 6.0, 10.4 Hz, 1H), 3.15 (brd, J= 11.2 Hz, 1H). Mass spectrum (ESI, m / z): calcd. for C31H25F3N6O4, 602.2; found [M+H]+, 603.2.

[0279] Step C: 3-Cyano- / V-((5aS,8aS)-5-(4-(difluoro(4-fluoro-3-methoxyphenyl)methyl)phenyl)-7- (methylsulfonyl)-4-oxo-5, 5a, 6,7,8, 8a-hexahydro-4 / 7-pyrazolon,5-alpyrrolof3,4-elpyrazin-3-yl)-4- methoxybenzamide

[0280] The title compound was prepared in a manner analogous to Example 19, Step C above, reacting 3-cyano- / V-((5aS,8aS)-5-(4-(difluoro(4-fluoro-3-methoxyphenyl)methyl)phenyl)-4-oxo- 5,5a,6,7,8,8a-hexahydro-4 / 7-pyrazolo[1,5-a]pyrrolo[3,4-e]pyrazin-3-yl)-4-methoxybenzamide (362.0 mg, 0.6010 mmol), a stir bar, DCE (3.6 mL), TEA (0.25 mL, 1.8 mmoL, 0.728 g / mL) and Ms2O (157.0 mg, 0.9010 mmol).1H NMR (400 MHz, DMSO-d6) δ:: 9.87 (brs, 1H), 8.22 (d, J = 2.0 Hz, 1H), 8.20 (s, 1H), 8.16 (brd, J= 8.8 Hz, 1H), 7.67 (brd, J= 8.4 Hz, 2H), 7.57 (brd, J = 8.4 Hz, 2H), 7.41 - 7.34 (m, 3H), 7.12 - 7.06 (m, 1H), 4.97 (br s, 2H), 4.27 - 4.19 (m, 1H), 3.99 (s, 3H), 3.90 (s, 3H), 3.78-3.73 (m, 1H), 3.63-3.57 (m, 1H), 3.25-3.20 (m, 1H), 3.10 (s, 3H) Mass spectrum (ESI, m / z): calcd. for C33H27F3N6O5, 680.2; found [M+H]+, 681.1.

[0281] Example 22: N-((5aS,8aS)-7-Acetyl-5-(4-((4-chloro-3-methoxyphenyl)difluoromethyl)- phenyl)-4-oxo-5, 5a, 6,7,8, 8a-hexahvdro-4H-pyrazolori,5-a]pyrrolor3,4-elpyrazin-3-yl)-3- cyano-4-methoxybenzamide.

[0282] The title compound was prepared in a manner analogous to Example 20, reacting / \ / -((5aS,8aS)-7-acetyl-4-oxo-5,5a,6,7,8,8a-hexahydro-4 / 7-pyrazolo[1,5-a]pyrrolo[3,4-e]pyrazin- 3-yl)-3-cyano-4-methoxybenzamide (Example 14, product from Step B, 500.0 mg, 1.268 mmol), a stir bar, 4-((4-bromophenyl)difluoromethyl)-1-chloro-2-methoxybenzene (Intermediate 4, 661.0 mg, 1.902 mmol), Cui (289.7 mg, 1.521 mmol), K2CO3 (525.7 mg, 3.803 mmol), DMF (10 mL), DMEAD (0.16 mL, 1.5 mmol, 0.819 g / mL).1H NMR (400 MHz, DMSO-d6) δ:: 9.86 (s, 1H), 8.22 (t, J= 2.0 Hz, 1H), 8.19 (s, 1H), 8.15 (td, J= 2.0, 9.2 Hz, 1H), 7.72-7.64 (m, 2H), 7.61 -7.50 (m, 3H), 7.39 (d, J= 9.2 Hz, 1H), 7.34 (s, 1H), 7.16-7.06 (m, 1H), 5.05-4.80 (m, 2H), 4.51 - 4.24 (m, 1H), 3.99 (s, 3H), 3.95 - 3.83 (m, 4H), 3.79 - 3.50 (m, 1H), 3.41 - 3.37 (m, 0.5H), 2.98 (t, J = 10.4 Hz, 0.5H), 2.07 - 1.88 (m, 3H). Mass spectrum (ESI, m / z): Calcd. for C33H27F2CIN6O5, 660.2; found [M+H]+, 661.2.

[0283] Example 23: N-((5aS,8aS)-5-(4-((4-Chloro-3-methoxyphenyl)difluoromethyl)phenyl)-7- (methylsulfonyl)-4-oxo-5, 5a, 6,7,8, 8a-hexahvdro-4H-pyrazolori,5-a]pyrrolor3,4-elpyrazin-3- yl)-3-cvano-4-methoxybenzamide.

[0284] Step A: / V-((5aS,8aS)-5-(4-((4-Chloro-3-methoxyphenyl)difluoromethyl)phenyl)-7-(4- methoxybenzyl)-4-oxo-5, 5a, 6,7,8, 8a-hexahvdro-4 / 7-pyrazolon ,5-alpyrrolof3,4-elpyrazin-3-yl)-3- cyano-4-methoxybenzamide.

[0285] The title compound was prepared in a manner analogous to Example 19, Step A above, reacting 3-cyano-4-methoxy- / V-((5aS,8aS)-7-(4-methoxybenzyl)-4-oxo-5,5a,6,7,8,8a-hexahydro- 4 / 7-pyrazolo[1 ,5-a]pyrrolo[3,4-e]pyrazin-3-yl)benzamide (Example 1 , product from Step L, 375.0 mg, 793.7μmol), 4-((4-bromophenyl)difluoromethyl)-1-chloro-2-methoxybenzene (Intermediate 4, 331.0 mg, 952.4μmol), A / V / ^-dimethylethane-l ^-diamine (102.5 μL, 952.3 pmol, 0.819 g / mL), K2CO3 (219.4 mg, 1.587 mmol), Cui (181.4 mg, 952.3μmol), DMF (4.0 mL) and toluene (4.0 mL). Mass spectrum (ESI, m / z): calcd. for C39H33CIF2N6O5, 738.2; found [M+H]+, 739.3.

[0286] Step B: / V-((5aS,8aS)-5-(4-((4-Chloro-3-methoxyphenyl)difluoromethyl)phenyl)-4-oxo- 5,5a,6,7,8,8a-hexahydro-4 / - / -pyrazolon ,5-alpyrrolof3,4-elpyrazin-3-yl)-3-cyano-4- methoxybenzamide.

[0287] The title compound was prepared in a manner analogous to Example 19, Step B above, reacting / V-((5aS,8aS)-5-(4-((4-chloro-3-methoxyphenyl)difluoromethyl)phenyl)-7-(4- methoxybenzyl)-4-oxo-5, 5a, 6,7,8, 8a-hexahydro-4 / 7-pyrazolo[1 ,5-a]pyrrolo[3,4-e]pyrazin-3-yl)-3- cyano-4-methoxybenzamide (655.0 mg, 886.1μmol), DCE (8.0 mL), 1-chloroethyl carbonochloridate (0.19 mL, 1.77 mmol, 1.325 g / mL), and MeOH (40.0 mL). Mass spectrum (ESI, m / z): calcd. for C31H25CIF2N6O4, 618.2; found [M+H]+, 619.2. Step C: / V-((5aS,8aS)-5-(4-((4-Chloro-3-methoxyphenyl)difluoromethyl)phenyl)-7- (methylsulfonyl)-4-oxo-5, 5a, 6,7,8, 8a-hexahvdro-4 / 7-pyrazolon ,5-alpyrrolof3,4-elpyrazin-3-yl)-3- cyano-4-methoxybenzamide.

[0288] The title compound was prepared in a manner analogous to Example 19, Step C above, reacting / V-((5aS,8aS)-5-(4-((4-chloro-3-methoxyphenyl)difluoromethyl)phenyl)-4-oxo- 5,5a,6,7,8,8a-hexahydro-4 / 7-pyrazolo[1 ,5-a]pyrrolo[3,4-e]pyrazin-3-yl)-3-cyano-4- methoxybenzamide (425.0 mg, 686.6μmol), DCE (5.0 mL), TEA (0.29 mL, 2.1 mmoL, 0.728 g / mL) and Ms2O (239.2 mg, 1.373 mmol).1H NMR (400 MHz, DMSO-d6) δ:: 9.88 (s, 1 H), 8.27 - 8.10 (m, 3H), 7.68 (d, J = 8.4 Hz, 2H), 7.57 (t, J = 6.8 Hz, 3H), 7.39 (d, J = 8.8 Hz, 1 H), 7.33 (d, J = 1.6 Hz, 1 H), 7.10 (dd, J = 1.6, 8.4 Hz, 1 H), 5.04 - 4.90 (m, 2H), 4.25 - 4.21 (m, 1 H), 3.99 (s, 3H), 3.93 (s, 3H), 3.80 - 3.71 (m, 1 H), 3.67 - 3.55 (m, 1 H), 3.22 (br s, 1 H), 3.09 (s, 3H). Mass spectrum (ESI, m / z): calcd. for C32H27CIF2N6O6S, 696.1 ; found [M + H]+, 697.2.

[0289] Example 24: N-((5aS,8aS)-7-((2-Aminoethyl)sulfonyl)-5-(4-(difluoro(phenyl)methyl)- phenyl)-4-oxo-5, 5a, 6,7,8, 8a-hexahvdro-4H-pyrazolori,5-a]pyrrolor3,4-elpyrazin-3-yl)-3- cyano-4-methoxybenzamide.

[0290] Step A: Benzyl (2-(((5aS,8aS)-3-(3-cyano-4-methoxybenzamido)-5-(4-(difluoro(phenyl)- methyl)phenyl)-4-oxo-4,5,5a,6,8,8a-hexahydro-7 / - / -pyrazolon ,5-alpyrrolof3,4-elpyrazin-7- yl)sulfonyl)ethyl)carbamate 3-Cyano- / V-((5aS,8aS)-5-(4-(difluoro(phenyl)methyl)phenyl)-4-oxo-5,5a,6,7,8,8a-hexahydro-4 / 7- pyrazolo[1 ,5-a]pyrrolo[3,4-e]pyrazin-3-yl)-4-methoxybenzamide (Example 1 , product from Step M, 117.0 mg, 0.1980 mmol), a stir bar, benzyl (2-(chlorosulfonyl)ethyl)carbamate (66.0 mg, 0.238 mmol), TEA (83 μL, 0.59 mmol, 0.728 g / mL) and DCE (2.0 mL) were added to a 10 mL round-bottomed flask, and the white suspension mixture stirred at r.t. for 12 h. The reaction progress was monitored by LCMS. The reaction mixture was diluted with DCM (3 mL) and treated with water (3 mL), then extrcted with DCM (5 mL x 3), the combined extracts were washed with brine (15 mL), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated in vacuum to give a colorless oil. The oil was subjected to silica gel chromatography (0-10% MeOH / DCM) to give the benzyl (2-(((5aS,8aS)-3-(3-cyano-4- methoxybenzamido)-5-(4-(difluoro(phenyl)methyl)phenyl)-4-oxo-4,5,5a,6,8,8a-hexahydro-7 / 7- pyrazolo[1 ,5-a]pyrrolo[3,4-e]pyrazin-7-yl)sulfonyl)ethyl)carbamate as an off-white solid (120 mg, 74%). Mass spectrum (ESI, m / z): Calcd. for C40H35F2N7O7S, 795.2; found [M+H]+, 796.3.

[0291] Step B: N-((5aS,8aS)-7-((2-Aminoethyl)sulfonyl)-5-(4-(difluoro(phenyl)methyl)phenyl)-4-oxo- 5,5a,6,7,8,8a-hexahydro-4H-pyrazolon ,5-alpyrrolof3,4-elpyrazin-3-yl)-3-cyano-4- methoxybenzamide

[0292] Benzyl (2-(((5aS,8aS)-3-(3-cyano-4-methoxybenzamido)-5-(4-(difluoro(phenyl)methyl)phenyl)-4- oxo-4,5,5a,6,8,8a-hexahydro-7 / 7-pyrazolo[1 ,5-a]pyrrolo[3,4-e]pyrazin-7-yl)sulfonyl)ethyl) carbamate (150.0 mg, 0.1880 mmol), a stir bar and DCM (2.0 mL) were added to a 10 mL round-bottomed flask, then TMSI (80 μL, 0.57 mmol, 1.406 g / mL) was added under 0°C for 2 h. The reaction progress was monitored by LCMS. The reaction mixture was concentrated to dryness under reduced pressure to give a solid. The solid was then subjected to prep-HPLC (Welch Xtimate C18, 5 pm, 150 mm x 30 mm, 55% to 85% CH3CN and H2O (containing 0.05% NH3 H2O + 10 mM NH4HCO3) to give / V-((5aS,8aS)-7-((2- aminoethyl)sulfonyl)-5-(4- (difluoro(phenyl)methyl)phenyl)-4-oxo- 5,5a,6,7,8,8a-hexahydro-4 / 7-pyrazolo[1 ,5-a]pyrrolo[3,4- e]pyrazin- 3-yl)-3-cyano-4-methoxybenzamide as a white solid (55.2 mg, 65%).

[0293] 1H NMR (400 MHz, DMSO-d6) δ:: 9.87 (s, 1 H), 8.24 - 8.18 (m, 2H), 8.17 - 8.13 (m, 1 H), 7.64 (d, J = 8.4 Hz, 2H), 7.61 - 7.50 (m, 7H), 7.39 (d, J = 9.1 Hz, 1 H), 5.04 - 4.94 (m, 2H), 4.28 - 4.19 (m, 1 H), 3.98 (s, 3H), 3.81 - 3.74 (m, 1 H), 3.68 - 3.62 (m, 1 H), 3.28 - 3.20 (m, 3H), 2.96 - 2.90 (m, 2H). Mass spectrum (ESI, m / z): Calcd. for C32H29F2N7O5S, 661.2, found [M+H]+, 662.2.

[0294] Example 25: 3-Cyano-N-((5aS,8aS)-5-(4-(difluoro(phenyl)methyl)phenyl)-7-((2- (dimethylamino)ethyl)sulfonyl)-4-oxo-5,5a,6,7,8,8a-hexahvdro-4H-pyrazolori,5- a]pyrrolor3,4-elpyrazin-3-yl)-4-methoxybenzamide. / V-((5aS,8aS)-7-((2-Aminoethyl)sulfonyl)-5-(4-(difluoro(phenyl)methyl)phenyl)-4-oxo- 5,5a,6,7,8,8a-hexahydro-4 / 7-pyrazolo[1,5-a]pyrrolo[3,4-e]pyrazin-3-yl)-3-cyano-4- methoxybenzamide (Example 1 , product from Step M, 20.0 mg, 0.0300 mmol), a stir bar, DMF (0.3 mL), K2CO3 (8.4 mg, 0.060 mmol) and Mel (2 μL, 0.03 mmol, 2.28 g / mL) were added to a 10 mL round-bottomed flask. The colorless homogenous mixture stirred at r.t. for 2 h. The reaction progress was monitored by LCMS. The reaction mixture was concentrated in vacuum to give an off-white solid, the solid was then subjected to prep-HPLC (Welch Xtimate C18, 5 pm, 150 mm x 30 mm 35% to 65% CH3CN and H2O (containing 0.05% NH3 H2O + 10 mM NH4HCO3) to give 3-cyano- / V-((5aS,8aS)-5-(4-(difluoro(phenyl)methyl)phenyl)-7-((2- (dimethylamino)ethyl)sulfonyl)-4-oxo-5,5a,6,7,8,8a-hexahydro-4 / 7-pyrazolo[1,5-a]pyrrolo[3,4- e]pyrazin-3-yl)-4-methoxybenzamide as a white solid (3.4 mg, 15%).1H NMR (400 MHz, DMSO-d6) δ:: 9.87 (s, 1H), 8.27 - 8.12 (m, 4H), 7.65 (d, J = 8.4 Hz, 2H), 7.59 - 7.51 (m, 6H), 7.39 (d, J = 9.2 Hz, 1H), 4.99 - 4.90 (m, 2H), 4.28 - 4.23 (m, 1H), 3.99 (s, 3H), 3.82 - 3.71 (m, 2H), 3.69 - 3.59 (m, 3H), 2.62 - 2.54 (m, 2H), 2.14 (s, 6H). Mass spectrum (ESI, m / z): Calcd. for C34H33F2N7O5S, 689.2; found [M+H]+, 690.2.

[0295] Example 26: 3-Cyano-N-((5aS,8aS)-5-(4-(difluoro(phenyl)methyl)phenyl)-7-((2- a]pyrrolor3,4-elpyrazin-3-yl)-4-methoxybenzamide.

[0296] The title compound was prepared in a manner analogous to Example 24, Step A above, reacting 3-cyano- / V-((5aS,8aS)-5-(4-(difluoro(phenyl)methyl)phenyl)-4-oxo-5,5a,6,7,8,8a- hexahydro-4 / 7-pyrazolo[1 ,5-a]pyrrolo[3,4-e]pyrazin-3-yl)-4-methoxybenzamide (Example 1 , product from Step M, 150.0 mg, 253.8 μmol), benzyl (2-(chlorosulfonyl)ethyl)(methyl)carbamate (185.0 mg, 634.1 μmol), TEA (0.14 mL, 1.0 mmol, 0.728 g / mL), and DCE (2.0 mL). Mass spectrum (ESI, m / z): Calcd. for C41H37F2N7O7S, 809.2; found [M+H]+, 810.3.

[0297] Step B: 3-Cyano-N-((5aS,8aS)-5-(4-(difluoro(phenyl)methyl)phenyl)-7-((2-(methylamino)ethyl)- sulfonyl)-4-oxo-5, 5a, 6,7,8, 8a-hexahydro-4H-pyrazolon,5-alpyrrolof3,4-elpyrazin-3-yl)-4- methoxybenzamide.

[0298] The title compound was prepared in a manner analogous to Example 24, Step B above, reacting benzyl (2-(((5aS,8aS)-3-(3-cyano-4-methoxybenzamido)-5-(4- (difluoro(phenyl)methyl)phenyl)-4-oxo-4,5,5a,6,8,8a-hexahydro-7 / 7-pyrazolo[1,5-a]pyrrolo[3,4- e]pyrazin-7-yl)sulfonyl)ethyl)(methyl)carbamate (150.0 mg, 185.2 μmol), DCM (8.0 mL), and TMSI (79 μL, 56 pmol, 1.41 g / mL).1H NMR (400 MHz, DMSO-d6) δ: 9.88 (s, 1 H), 8.25 - 8.18 (m, 2H), 8.18 - 8.13 (m, 1H), 7.66 (d, J = 8.4 Hz, 2H), 7.61 - 7.49 (m, 7H), 7.43 - 7.35 (m, 1 H), 5.02 (br s, 2H), 4.33 - 4.23 (m, 1 H), 3.99 (s, 3H), 3.80 (br t, J = 9.2 Hz, 1 H), 3.70 - 3.63 (m, 1 H), 3.54 (br t, J = 7.2 Hz, 3H), 3.11 (br t, J = 6.8 Hz, 2H), 2.46 (s, 3H). Mass spectrum (ESI, m / z): Calcd. for C33H31F2N7O5S, 675.2; found [M+H]+, 676.3.

[0299] Example 27: Methyl 4-((5aS,8aS)-3-(3-cvano-4-methoxybenzamido)-5-(4-(difluoro(4- fluorophenyl)methyl)phenyl)-4-oxo-4,5,5a,6,8,8a-hexahvdro-7H-pyrazolori,5- a]pyrrolor3,4-elpyrazin-7-yl)-3,3-dimethylbutanoate.

[0300] Step A: Methyl 3,3-dimethyl-4-oxobutanoate

[0301] Methyl 3,3-dimethylpent-4-enoate (2.00 g, 14.1 mmol), a stir bar, and anhydrous DCM (20.0 mL) were added to a 100 mL three-necked round-bottomed flask, the resuting mixture was sparged with N2 for 3 times. Ozone was passed through a solution at a temperature of -65°C or lower for 0.6 h. Then N2 was bubbled into the reaction mixture until it became colorless. PPhs (4.43 g, 16.9 mmol) was added in one portion and the reaction was warmed to r.t. The resulting mixture was stired at r.t. for 2 h, finally the reaction mixture w became a yellow solution. The reaction progress was monitored by TLC. The reaction mixture was diluted with DCM (20 mL), washed with water (2 x 50 mL), and brine (50 mL), dried over anhydrous Na2SC>4, filtered and concentrated in vacuum to give methyl 3,3-dimethyl-4-oxobutanoate (2.70 g, crude) as a colorless oil.1H NMR (400 MHz, CDCI3)_δ: 9.51 (s, 1 H), 3.60 (s, 3H), 2.50 (s, 2H), 1.10 (s, 6H)

[0302] Step B: 3-Cyano- / V-((5aS,8aS)-5-(4-(difluoro(4-fluorophenyl)methyl)phenyl)-7-(4- methoxybenzyl)-4-oxo-5, 5a, 6,7,8, 8a-hexahvdro-4 / 7-pyrazolon ,5-alpyrrolof3,4-elpyrazin-3-yl)-4- methoxybenzamide. 3-Cyano-4-methoxy- / V-((5aS,8aS)-7-(4-methoxybenzyl)-4-oxo-5,5a,6,7,8,8a-hexahydro-4 / 7- pyrazolo[1 ,5-a]pyrrolo[3,4-e]pyrazin-3-yl)benzamide (Example 1 , product from Step L, 500.0 mg, 1.058 mmol), a stir bar, 1-bromo-4-(difluoro(4-fluorophenyl)methyl)benzene (intermediate 1 , 477.9 mg, 1.587 mmol), A / V / ^-dimethylethane-l ^-diamine (111.9 mg, 1.270 mmol), K2CO3 (445.2 mg, 3.175 mmol) and Cui (243.1 mg, 1.270 mmol) in DMF (5.0 mL) were added to an oven-dried 50 mL round-bottomed flask. The resulting mixture was sparged with N2 for 3 times. The resulting mixture was heated to 100°C for 12 h, finally the reaction mixture became a black suspension. The reaction progress was monitored by TLC and LCMS. This mixture was filtered with celite. The filtrate was concentrated to give crude. The reaction mixture was diluted with EtOAc (30 mL), washed with brine (30 mL x 2). The combined extracts were dried over Na2SO4 and filtered and concentrated under reduced pressure to give a yellow oil. The oil was then subjected to silica gel chromatography (0-70% EtOAc / pet ether) to give 3-cyano- / V-((5aS,8aS)- 5-(4-(difluoro(4-fluorophenyl)methyl)phenyl)-7-(4-methoxybenzyl)-4-oxo-5,5a,6,7,8,8a- hexahydro-4 / 7-pyrazolo[1 ,5-a]pyrrolo[3,4-e]pyrazin-3-yl)-4-methoxybenzamide as a white solid (376 mg, 49%).1H NMR (400 MHz, CDCI3) δ: 9.69 - 9.60 (m, 1 H), 8.42 (s, 1 H), 8.13 (d, J = 2.0 Hz, 1 H), 8.08 (dd, J = 2.4, 8.8 Hz, 1 H), 7.63 - 7.56 (m, 2H), 7.52 (dd, J = 5.2, 8.8 Hz, 2H), 7.32 (d, J = 8.4 Hz, 2H), 7.24 - 7.17 (m, 2H), 7.16 - 7.08 (m, 2H), 7.02 - 6.96 (m, 1 H), 6.87 (d, J = 8.4 Hz, 2H), 4.67 - 4.58 (m, 2H), 3.99 (s, 3H), 3.92 - 3.78 (m, 5H), 3.70 - 3.66 (m, 1 H), 3.41 (s, 1 H), 3.14 - 3.05 (m, 1 H), 2.88 (br s, 1 H). Mass spectrum (ESI, m / z): Calcd. for C38H31F3N6O4, 692.2; found [M+H]+, 693.4.

[0303] Step C: 3-Cyano- / V-((5aS,8aS)-5-(4-(difluoro(4-fluorophenyl)methyl)phenyl)-4-oxo- 5,5a,6,7,8,8a-hexahydro-4 / - / -pyrazolon ,5-alpyrrolof3,4-elpyrazin-3-yl)-4-methoxybenzamide, chloride salt.

[0304] 3-Cyano- / V-((5aS,8aS)-5-(4-(difluoro(4-fluorophenyl)methyl)phenyl)-7-(4-methoxybenzyl)-4-oxo- 5,5a,6,7,8,8a-hexahydro-4 / 7-pyrazolo[1 ,5-a]pyrrolo[3,4-e]pyrazin-3-yl)-4-methoxybenzamide (370.0 mg, 534.2μmol), a stir bar and DCE (7.0 mL) were added to a 50 mL round-bottomed flask fitted with a reflux condenser. The mixture was charged with 1 -chloroethyl carbonochloridate (190.9 mg, 1.335 mmol) and stirred at r.t. for 1 h, then treated with anhydrous MeOH (7.0 mL). The reaction solution was stirred at 60°C for 3 h, some white precipitate separated out. The reaction progress was monitored by TLC and LCMS. The reaction mixture was concentrated under reduced pressure to give a yellow oil. The oil was then subjected to silica gel chromatography (0-8% MeOH / DCM) to give 3-cyano- / V-((5aS,8aS)-5-(4-(difluoro(4- fluorophenyl)methyl)phenyl)-4-oxo-5,5a,6,7,8,8a-hexahydro-4 / 7-pyrazolo[1 ,5-a]pyrrolo[3,4- e]pyrazin-3-yl)-4-methoxybenzamide, chloride salt as a white solid (280 mg, 81%).1H NMR (400 MHz, DMSO-d6) δ: 10.23 - 10.02 (m, 2H), 9.90 - 9.84 (m, 1 H), 8.25 - 8.19 (m, 2H), 8.16 (br d, J = 8.8 Hz, 1 H), 7.72 - 7.59 (m, 4H), 7.53 (br d, J = 8.0 Hz, 2H), 7.44 - 7.31 (m, 3H), 5.02 (br s, 2H), 4.17 - 4.07 (m, 1 H), 3.99 (s, 3H), 3.69 - 3.55 (m, 1 H), 3.49 - 3.43 (m, 1 H), 3.15 - 3.07 (m, 1 H). Mass spectrum (ESI, m / z): Calcd. For C3oH23F3Ne03,572.2; found [M+H]+, 573.3.

[0305] Step D: Methyl 4-((5aS,8aS)-3-(3-cyano-4-methoxybenzamido)-5-(4-(difluoro(4- fluorophenyl)methyl)phenyl)-4-oxo-4,5,5a,6,8,8a-hexahydro-7H-pyrazolon ,5-alpyrrolof3,4- elpyrazin-7-yl)-3,3-dimethylbutanoate 3-Cyano- / V-((5aS,8aS)-5-(4-(difluoro(4-fluorophenyl)methyl)phenyl)-4-oxo-5,5a,6,7,8,8a- hexahydro-4 / 7-pyrazolo[1 ,5-a]pyrrolo[3,4-e]pyrazin-3-yl)-4-methoxybenzamide (150.0 mg, 0.26 mmol), methyl 3,3-dimethyl-4-oxobutanoate (56.6 mg, 0.393 mmol), AcOH (15.7 mg, 0.262 mmol), a stir bar, and anhydrous DCE (4.0 mL) were added to a 50 mL single-necked round- bottomed flask. The mixture was stirred at rt for 5 min before treated with NaBH(OAc)3 (83.2 mg, 0.393 mmol) and stirred at r.t. for 16 h. The suspension became clear after a while, and a yellow solution was formed. The reaction progress was monitored by LC-MS. The reaction mixture was quenched with aq. NH4CI (10 mL), extracted with EtOAc (15 mL x 2), and the combined extracts were washed with sat. NaHCO3 (10 mL) and brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure to give a yellow oil. The oil was subjected to silica gel chromatography (0-80% EtOAc / pet ether) to give methyl 4-((5aS,8aS)-3-(3-cyano-4-methoxybenzamido)-5-(4-(difluoro(4- fluorophenyl)methyl)phenyl)-4-oxo-4,5,5a,6,8,8a-hexahydro-7 / 7-pyrazolo[1 ,5-a]pyrrolo[3,4- e]pyrazin-7-yl)-3,3-dimethylbutanoate as a white solid (123.0 mg, 63%).1H NMR (400 MHz, CDCI3)_δ: 9.66 (s, 1 H), 8.44 (s, 1 H), 8.14 (d, J = 2.0 Hz, 1 H), 8.11 - 8.07 (m, 1 H), 7.61 (d, J = 8.4 Hz, 2H), 7.54 (dd, J = 5.2, 8.8 Hz, 2H), 7.34 (d, J = 8.0 Hz, 2H), 7.14 (t, J = 8.8 Hz, 2H), 7.01 (d, J = 8.8 Hz, 1 H), 4.60 (s, 2H), 4.00 (s, 3H), 3.72 - 3.56 (m, 5H), 3.14 - 2.95 (m, 2H), 2.77 - 2.62 (m, 2H), 2.33 - 2.18 (m, 2H), 0.97 (d, J = 6.8 Hz, 6H). Mass spectrum (ESI, m / z): Calcd for C37H35F3N6O5, 700.2; found [M+H]+, 701.3. Example 28: 4-((5aS,8aS)-3-(3-Cvano-4-methoxybenzamido)-5-(4-(difluoro(4- fluorophenyl)methyl)phenyl)-4-oxo-4,5,5a,6,8,8a-hexahvdro-7H-pyrazolori,5- a]pyrrolor3,4-elpyrazin-7-yl)-3,3-dimethylbutanoic acid.

[0306] Methyl 4-((5aS,8aS)-3-(3-cyano-4-methoxybenzamido)-5-(4-(difluoro(4-fluorophenyl)methyl)- phenyl)-4-oxo-4,5,5a,6,8,8a-hexahydro-7 / 7-pyrazolo[1,5-a]pyrrolo[3,4-e]pyrazin-7-yl)-3,3- dimethylbutanoate (Example 27, product from Step D, 150.0 mg, 0.2140 mmol), a stir bar, MeaSnOH (387.1 mg, 2.141 mmol) and DCE (2.0 mL) were added to an oven-dried 10 mL round-bottomed flask. The resuting mixture was sparged with N2 for 3 times. The resulting mixture was stired at 100°C for 16 h, finally the reaction mixture became a yellow solution. The reaction progress was monitored by LC-MS. The reaction mixture was added aq. HCI (1 M) to adjust pH <7, then extracted with EtOAc (30 mL x 5). The combined extracts were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuum to give a yellow solid. The solid was then subjected to silica gel chromatography (0-80% EtOAc / pet ether) to give 4-((5aS,8aS)-3-(3-cyano-4-methoxybenzamido)-5-(4-(difluoro(4- fluorophenyl)methyl)phenyl)-4-oxo-4,5,5a,6,8,8a-hexahydro-7 / 7-pyrazolo[1,5-a]pyrrolo[3,4- e]pyrazin-7-yl)-3,3-dimethylbutanoic acid as a white solid (50.4 mg, 33%).1H NMR (400 MHz, CDCI3) δ: 9.61 (s, 1 H), 8.47 (s, 1 H), 8.17 - 8.03 (m, 2H), 7.64 (d, J = 8.8 Hz, 2H), 7.53 (dd, J = 4.8, 8.8 Hz, 2H), 7.35 (d, J = 8.4 Hz, 2H), 7.14 (t, J = 8.4 Hz, 2H), 7.01 (d, J = 8.8 Hz, 1 H), 4.73 - 4.55 (m, 2H), 4.00 (s, 3H), 3.94 - 3.50 (m, 2H), 3.39 - 2.91 (m, 2H), 2.86 (s, 1 H), 2.47 (s, 1 H), 1.32 (d, J = 19.2 Hz, 1H), 1.27 - 1.21 (m, 1 H), 1.11 (s, 3H), 1.02 (s, 3H). Mass spectrum (ESI, m / z): Calcd for C36H33F3N6O5, 686.2; found [M+ H]+, 687.2. Example 29: 3-((5aS,8aS)-3-(3-Cvano-4-methoxybenzamido)-5-(4-(difluoro(4- fluorophenyl)methyl)phenyl)-4-oxo-4,5,5a,6,8,8a-hexahvdro-7H-pyrazolori,5- a]pyrrolor3,4-elpyrazin-7-yl)propanoic acid.

[0307] Step A: Methyl 3-((5aS,8aS)-3-(3-cyano-4-methoxybenzamido)-5-(4-(difluoro(4- fluorophenyl)methyl)phenyl)-4-oxo-4,5,5a,6,8,8a-hexahydro-7 / 7-pyrazolon,5-alpyrrolo[3,4- elpyrazin-7-yl)propanoate.

[0308] The title compound was prepared in a manner analogous to Example 7, above, reacting 3-cyano- / V-((5aS,8aS)-5-(4-(difluoro(4-fluorophenyl)methyl)phenyl)-4-oxo-5,5a,6,7,8,8a- hexahydro-4 / 7-pyrazolo[1 ,5-a]pyrrolo[3,4-e]pyrazin-3-yl)-4-methoxybenzamide (Example 27, product from Step C, 257.0 mg, 448.9 μmol), a stir bar, methyl 3-bromopropanoate (224.9 mg, 1.347μmol), K2CO3 (124.0 mg, 884.3 pmol) in DMF (10.0 mL). Mass spectrum (ESI, m / z): calcd. for C34H29F3NeO5,658.2; found [M+H]+, 659.3.

[0309] Step B: 3-((5aS,8aS)-3-(3-Cyano-4-methoxybenzamido)-5-(4-(difluoro(4- fluorophenyl)methyl)phenyl)-4-oxo-4,5,5a,6,8,8a-hexahydro-7 / - / -pyrazolon,5-alpyrrolof3,4- elpyrazin-7-yl)propanoic acid..

[0310] The title compound was prepared in a manner analogous to Example 28, above, reacting Methyl 3-((5aS,8aS)-3-(3-cyano-4-methoxybenzamido)-5-(4-(difluoro(4-fluorophenyl)methyl)- phenyl)-4-oxo-4,5,5a,6,8,8a-hexahydro-7 / 7-pyrazolo[1,5-a]pyrrolo[3,4-e]pyrazin-7-yl)propanoate (175.0 mg, 265.7 μmol), a stir bar, trimethylstannanol (480.5 mg, 2.657 mmol) and DCE (12.0 mL).1H NMR (400 MHz, DMSO-d6) δ:: 9.85 (s, 1H), 8.21 (d, J = 2.0 Hz, 1 H), 8.18 - 8.11 (m, 2H),

[0311] 7.67 - 7.58 (m, 4H), 7.55 - 7.48 (m, 2H), 7.42 - 7.32 (m, 3H), 4.88 - 4.74 (m, 2H), 3.99 (s, 3H), 3.58 - 3.48 (m, 1 H), 3.26 - 3.17 (m, 1H), 2.98 (br d, J = 6.4 Hz, 1H), 2.92 (br t, J = 6.8 Hz, 2H),

[0312] 2.68 (br t, J = 8.8 Hz, 1H), 2.36 (br t, J = 7.2 Hz, 2H). Mass spectrum (ESI, m / z): Calcd. for C33H27F3N6O5, 644.2; found [M+H]+, 645.3. Example 30: Ethyl (5aS,8aS)-3-(3-cvano-4-methoxybenzamido)-5-(4-(difluoro(4- fluorophenyl)methyl)phenyl)-4-oxo-4,5,5a,6,8,8a-hexahvdro-7H-pyrazolori,5- a]pyrrolor3,4-elpyrazine-7-carboxylate.

[0313] 3-Cyano- / V-((5aS,8aS)-5-(4-(difluoro(4-fluorophenyl)methyl)phenyl)-4-oxo-5,5a,6,7,8,8a- hexahydro-4 / 7-pyrazolo[1 ,5-a]pyrrolo[3,4-e]pyrazin-3-yl)-4-methoxybenzamide, chloride salt (Example 27, product from Step C, 280.0 mg, 459.8 μmol), a stir bar, DCE (5.0 mL) and TEA (139.6 mg, 1.379 mmoL) were added to an oven-dried 10 mL round-bottomed flask, then ethyl carbonochloridate (500.0 mg, 4.607 mmol) was added under 0°C. The resulting mixture was fitted with N2 for 3 times, the resulting yellow homogenous mixture stirred at 25°C for 2 h. The reaction progress was monitored by TLC and LCMS. The reaction mixture quenched with water (20 mL), and extracted with DCM (20 mL x 3). The combined extracts were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated in vacuum to give an off-white solid. The solid was subjected to silica gel chromatography (0-1% MeOH / DCM) to give ethyl (5aS,8aS)-3-(3-cyano-4-methoxybenzamido)-5-(4-(difluoro(4- fluorophenyl)methyl)phenyl)-4-oxo-4,5,5a,6,8,8a-hexahydro-7 / 7-pyrazolo[1,5-a]pyrrolo[3,4- e]pyrazine-7-carboxylate as a white solid (178.5 mg, 57%).1H NMR (400 MHz, DMSO-d6) δ: 9.85 (s, 1 H), 8.25 - 8.09 (m, 3H), 7.70 - 7.58 (m, 4H), 7.58 - 7.50 (m, 2H), 7.43 - 7.31 (m, 3H), 5.03 - 4.77 (m, 2H), 4.30 - 4.17 (m, 1 H), 4.12 - 4.01 (m, 2H), 3.99 (s, 3H), 3.77 - 3.58 (m, 2H), 3.21 - 3.06 (m, 1 H), 1.26 - 1.09 (m, 3H). Mass spectrum (ESI, m / z): Calcd. For C33H27F3N6O5, 644.2; found [M+H]+, 645.3.

[0314]

[0315] 3-Cyano- / V-((5aS,8aS)-5-(4-(difluoro(phenyl)methyl)phenyl)-4-oxo-5,5a,6,7,8,8a-hexahydro-4 / 7- pyrazolo[1,5-a]pyrrolo[3,4-e]pyrazin-3-yl)-4-methoxybenzamide (Example 1 , product from Step M, 90.0 mg, 152 μmol), a stir bar, DCE (1.5 mL) and TEA (64 μL, 0.46 mmoL, 0.728 g / mL) were added to an oven-dried 10 mL round-bottomed flask, then ethyl carbonochloridate (10.0 mg, 92.1 pmol) was added under 0°C. The resulting mixture was fitted with N2 for 3 times, the resulting yellow homogenous mixture stirred at 25°C for 0.5 h. And the homogenous mixture turned to white suspension mixture. The suspension mixture stirred at r.t. for 2 h. The reaction progress was monitored by LCMS. The reaction mixture was filtered and the filtrate was quenched with water (5 mL), the filter cake was subjected to silica gel chromatography (100% dichloromethane) to give the ethyl (5aS,8aS)-3-(3-cyano-4-methoxybenzamido)-5-(4- (difluoro(phenyl)methyl)phenyl)-4-oxo-4,5,5a,6,8,8a-hexahydro-7 / 7-pyrazolo[1,5-a]pyrrolo[3,4- e]pyrazine-7-carboxylate as a white solid (44.3 mg, 45%).1H NMR (400 MHz, DMSO-d6) δ: 9.86 (s, 1H), 8.22 (s, 1 H), 8.20 - 8.12 (m, 2H), 7.65 (d, J = 6.8 Hz, 2H), 7.61 - 7.51 (m, 7H), 7.39 (d, J = 8.8 Hz, 1 H), 5.00 - 4.88 (m, 2H), 4.26 - 4.18 (m, 1H), 4.11 - 4.01 (m, 2H), 3.99 (s, 3H), 3.74 - 3.63 (m, 2H), 3.21 - 3.07 (m, 1H), 1.24 - 1.13 (m, 3H). Mass spectrum (m / z): Calcd. for C33H28F2N6O5, 626.2; found [M+H]+, 627.2.

[0316]

[0317] 3-Cyano- / V-((5aS,8aS)-5-(4-(difluoro(phenyl)methyl)phenyl)-4-oxo-5,5a,6,7,8,8a-hexahydro-4 / 7- pyrazolo[1 ,5-a]pyrrolo[3,4-e]pyrazin-3-yl)-4-methoxybenzamide (Example 1 , product from Step M, 45.0 mg, 0.081 mmol), a stir bar, 2-methylpropane-1 -sulfonyl chloride (48.2 mg, 0.308 mmol), TEA (70 μL, 0.50 mmol, 0.728 g / mL) and DMF (2.0 mL) were added to a 2 mL vial. The mixture was stirred at r.t. for 1 h. The reaction progress was monitored by LCMS. The reaction mixture was quenched with NaHCO3 (0.5 mL), diluted with DMSO (2 mL) and filtered. The crude product was subjected to Reverse Phase HPLC (Stationary phase: C18 XBridge 30 x 100 mm 10 pm. Mobile phase: NH4HCO3 0.25% solution in Water and CH3CN) to give 3-cyano-N- ((5aS,8aS)-5-(4-(difluoro(phenyl)methyl)phenyl)-7-(isobutylsulfonyl)-4-oxo-5,5a,6,7,8,8a- hexahydro-4H-pyrazolo[1 ,5-a]pyrrolo[3,4-e]pyrazin-3-yl)-4-methoxybenzamide (16.9 mg, 31%).1H NMR (500 MHz, DMSO-d6) δ:: 9.87 (s, 1 H), 8.23 (d, J = 2.3 Hz, 1 H), 8.19 (s, 1 H), 8.16 (dd, J = 8.9, 2.3 Hz, 1 H), 7.65 (s, 1 H), 7.64 (s, 1 H), 7.56 - 7.61 (m, 3H), 7.50 - 7.55 (m, 4H), 7.39 (d, J = 9.0 Hz, 1 H), 4.91 - 5.03 (m, 2H) 4.18 - 4.28 (m, 1 H), 3.99 (s, 3 H), 3.74 (br t, J = 9.3 Hz, 1 H), 3.55 - 3.65 (m, 1 H), 3.20 - 3.26 (m, 1 H), 3.17 (d, J = 6.6 Hz, 2 H), 2.11 (dt, J = 13.4, 6.7 Hz, 1 H), 1.02 (d, J = 6.8 Hz, 3H), 1.02 (d, J = 6.6 Hz, 3H). Mass spectrum (ESI, m / z): Calcd. for C34H32F2N6O5S, 674.2; found [M+H]+, 675.4. Example 33 : 3-cyano-N-((5aS,8aS)-5-(4-(difluoro(phenyl)methyl)phenyl)-7-((2,2- difluorocvclopropyl)sulfonyl)-4-oxo-5,5a,6,7,8,8a-hexahvdro-4H-pyrazolori,5- a]pyrrolor3,4-elpyrazin-3-yl)-4-methoxybenzamide

[0318] The title compound was prepared in a manner analogous to Example 32, reacting 3-Cyano- / V- ((5aS,8aS)-5-(4-(difluoro(phenyl)methyl)phenyl)-4-oxo-5,5a,6,7,8,8a-hexahydro-4 / 7- pyrazolo[1 ,5-a]pyrrolo[3,4-e]pyrazin-3-yl)-4-methoxybenzamide (Example 1 , product from Step M, 45.0 mg, 0.081 mmol) and 2,2-difluorocyclopropane-1-sulfonyl chloride (54.3 mg, 0.308 mmol) to give 3-cyano-N-((5aS,8aS)-5-(4-(difluoro(phenyl)methyl)phenyl)-7-((2,2- difluorocyclopropyl)sulfonyl)-4-oxo-5,5a,6,7,8,8a-hexahydro-4H-pyrazolo[1 ,5-a]pyrrolo[3,4- e]pyrazin-3-yl)-4-methoxybenzamide (14.9 mg, 27%).1H NMR (500 MHz, DMSO-d6) δ: 9.88 (s, 1 H), 8.23 (d, J = 2.3 Hz, 1 H), 8.20 (s, 1 H), 8.16 (dd, J = 9.0, 2.3 Hz, 1 H), 7.65 (d, J = 8.5 Hz, 2 H), 7.55 - 7.61 (m, 3H), 7.54 (q, J = 3.6 Hz, 4H), 7.39 (d, J = 9.0 Hz, 1 H), 4.97 - 5.08 (m, 2H), 4.24 - 4.32 (m, 1 H), 4.12 - 4.24 (m, 1 H), 3.99 (s, 3H), 3.77 - 3.86 (m, 1 H), 3.64 - 3.77 (m, 1 H), 3.27 - 3.31 (m, 1 H), 2.21 - 2.41 (m, 2H). Mass spectrum (ESI, m / z): Calcd. For C33H26F4N6O5S, 694.2; found [M+H]+, 695.4.

[0319] Example 34: 3-cvano-N-((5aS,8aS)-5-(4-(difluoro(phenyl)methyl)phenyl)-7-(ethylsulfonyl)-

[0320] 4-oxo-5,5a,6,7,8,8a-hexahydro-4H-i 5-alpyrrolor3,4-elpyrazin-3-yl)-4- The title compound was prepared in a manner analogous to Example 32, reacting 3-Cyano- / V- ((5aS,8aS)-5-(4-(difluoro(phenyl)methyl)phenyl)-4-oxo-5,5a,6,7,8,8a-hexahydro-4 / 7- pyrazolo[1,5-a]pyrrolo[3,4-e]pyrazin-3-yl)-4-methoxybenzamide (Example 1 , product from Step M, 45.0 mg, 0.081 mmol) and ethanesulfonyl chloride (38.8 mg, 0.302 mmol) to give 3-cyano-N- ((5aS,8aS)-5-(4-(difluoro(phenyl)methyl)phenyl)-7-(ethylsulfonyl)-4-oxo-5,5a,6,7,8,8a- hexahydro-4H-pyrazolo[1,5-a]pyrrolo[3,4-e]pyrazin-3-yl)-4-methoxybenzamide (3.2 mg, 6%).1H NMR (500 MHz, DMSO-d6) δ:: 9.87 (s, 1 H), 8.23 (d, J = 2.3 Hz, 1H), 8.19 (s, 1H), 8.16 (dd, J = 9.0, 2.3 Hz, 1H), 7.64 (d, J = 8.5 Hz, 2H), 7.50 - 7.60 (m, 7H), 7.39 (d, J = 9.1 Hz, 1 H), 4.94 - 5.06 (m, 2H), 4.23 (br dd, J = 8.4, 6.7 Hz, 1 H), 3.99 (s, 3H), 3.75 (br t, J = 9.2 Hz, 1 H), 3.62 (br dd, J = 8.0, 6.6 Hz, 1H), 3.25 - 3.30 (m, 2H), 3.18 - 3.25 (m, 1H), 1.21 (t, J = 7.4 Hz, 3H). Mass spectrum (ESI, m / z): Calcd. For C32H28F2N6O5S, 646.2; found [M+H]+, 647.4.

[0321] Example 35: 3-cyano-N-((5aS,8aS)-5-(4-(difluoro(phenyl)methyl)phenyl)-7-((1- methoxypropan-2-yl)sulfonyl)-4-oxo-5,5a,6,7,8,8a-hexahvdro-4H-pyrazolori,5- a]pyrrolor3,4-elpyrazin-3-yl)-4-methoxybenzamide.

[0322] The title compound was prepared in a manner analogous to Example 32 reacting 3-Cyano- / V- ((5aS,8aS)-5-(4-(difluoro(phenyl)methyl)phenyl)-4-oxo-5,5a,6,7,8,8a-hexahydro-4 / 7- pyrazolo[1,5-a]pyrrolo[3,4-e]pyrazin-3-yl)-4-methoxybenzamide (Example 1 , product from Step M, 45.0 mg, 0.081 mmol) and 1 -methoxypropane-2-sulfonyl chloride (53.0 mg, 0.310 mmol) to give 3-cyano-N-((5aS,8aS)-5-(4-(difluoro(phenyl)methyl)phenyl)-7-((1-methoxypropan-2- yl)sulfonyl)-4-oxo-5, 5a, 6,7,8, 8a-hexahydro-4H-pyrazolo[1,5-a]pyrrolo[3,4-e]pyrazin-3-yl)-4- methoxybenzamide (6.7 mg, 12%).1H NMR (500 MHz, DMSO-d6) δ:: 9.86 (s, 1H), 8.22 (d, J = 2.1 Hz, 1 H), 8.19 (s, 1 H), 8.15 (dd, J = 8.9, 2.3 Hz, 1 H), 7.65 (br d, J = 7.0 Hz, 2H), 7.56 - 7.61 (m, 2H), 7.50 - 7.56 (m, 5H), 7.39 (d, J = 9.0 Hz, 1 H), 4.92 - 5.03 (m, 2H), 4.17 - 4.29 (m, 1 H), 3.99 (s, 3H), 3.70 - 3.82 (m, 2H), 3.55 - 3.65 (m, 2H), 3.45 (ddd, J = 10.4, 5.0, 1.4 Hz, 1 H), 3.17 - 3.28 (m, 4H), 1.20 - 1.27 (m, 3H). Mass spectrum (ESI, m / z): Calcd. For C34H32F2N6O6S, 690.2; found [M+H]+, 691.4. Example 36: 3-cvano-N-((5aS,8aS)-5-(4-(difluoro(phenyl)methyl)phenyl)-7-((isoxazol-3- ylmethyl)sulfonyl)-4-oxo-5, 5a, 6,7,8, 8a-hexahvdro-4H-pyrazolori,5-a]pyrrolor3,4-elpyrazin- 3-yl)-4-methoxybenzamide.

[0323] The title compound was prepared in a manner analogous to Example 32, reacting 3-cyano- / V- ((5aS,8aS)-5-(4-(difluoro(phenyl)methyl)phenyl)-4-oxo-5,5a,6,7,8,8a-hexahydro-4 / 7- pyrazolo[1 ,5-a]pyrrolo[3,4-e]pyrazin-3-yl)-4-methoxybenzamide (Example 1 , product from Step M, 45.0 mg, 0.081 mmol) and isoxazol-3-ylmethanesulfonyl chloride (55.1 mg, 0.303 mmol) to give 3-cyano-N-((5aS,8aS)-5-(4-(difluoro(phenyl)methyl)phenyl)-7-((isoxazol-3- ylmethyl)sulfonyl)-4-oxo-5, 5a, 6,7,8, 8a-hexahydro-4H-pyrazolo[1,5-a]pyrrolo[3,4-e]pyrazin-3-yl)- 4-methoxybenzamide (9.7 mg, 16%).1H NMR (500 MHz, DMSO-d6) δ:: 9.87 (s, 1 H), 8.69 - 9.02 (m, 1 H), 8.23 (s, 1 H), 8.18 - 8.21 (m, 1 H), 8.16 (dt, J = 8.8, 1.0 Hz, 1 H), 7.61 - 7.69 (m, 2H), 7.50 - 7.60 (m, 7H), 7.39 (d, J = 9.0 Hz, 1 H), 6.48 - 6.71 (m, 1 H), 4.96 - 5.05 (m, 2H), 4.18 - 4.28 (m, 1 H), 3.99 (s, 3H), 3.72 - 3.83 (m, 2H), 3.57 - 3.66 (m, 1 H), 3.09 (q, J = 7.2 Hz, 2H). Mass spectrum (ESI, m / z): Calcd. For C34H27F2N7O6S, 699.2; found [M+H]+, 700.4.

[0324] Example 37: 3-cyano-N-((5aS,8aS)-5-(4-(difluoro(phenyl)methyl)phenyl)-7-((1- methylcvclopropyl)sulfonyl)-4-oxo-5,5a,6,7,8,8a-hexahvdro-4H-pyrazolori,5-a]pyrrolor3,4- e]pyrazin-3-yl)-4-methoxybenzamide.

[0325] The title compound was prepared in a manner analogous to Example 32, reacting 3-Cyano- / V- ((5aS,8aS)-5-(4-(difluoro(phenyl)methyl)phenyl)-4-oxo-5,5a,6,7,8,8a-hexahydro-4 / 7- pyrazolo[1 ,5-a]pyrrolo[3,4-e]pyrazin-3-yl)-4-methoxybenzamide (Example 1 , product from Step M, 45.0 mg, 0.081 mmol) and 1-methylcyclopropane-1 -sulfonyl chloride (47.6 mg, 0.308 mmol) to give 3-cyano-N-((5aS,8aS)-5-(4-(difluoro(phenyl)methyl)phenyl)-7-((1- methylcyclopropyl)sulfonyl)-4-oxo-5,5a,6,7,8,8a-hexahydro-4H-pyrazolo[1 ,5-a]pyrrolo[3,4- e]pyrazin-3-yl)-4-methoxybenzamide (30.4 mg, 55%).1H NMR (500 MHz, DMSO-d6) δ: 9.87 (s, 1 H), 8.23 (d, J = 2.1 Hz, 1 H), 8.20 (s, 1 H), 8.16 (dd, J = 8.9, 2.2 Hz, 1 H), 7.65 (d, J = 8.5 Hz, 2H), 7.49 - 7.61 (m, 7H), 7.39 (d, J = 9.0 Hz, 1 H), 5.02 - 5.14 (m, 2H), 4.22 (br t, J = 7.4 Hz, 1 H), 3.99 (s, 3H), 3.70 - 3.81 (m, 1 H), 3.63 (br t, J = 7.1 Hz, 1 H), 3.21 - 3.28 (m, 1 H), 1.45 (s, 3H), 1.16 - 1.21 (m, 2H), 0.84 - 0.90 (m, 2H). Mass spectrum (ESI, m / z): Calcd. For C34H30F2N6O5S, 672.2; found [M+H]+, 673.4.

[0326] Example 38: 3-cvano-N-((5aS,8aS)-5-(4-(difluoro(phenyl)methyl)phenyl)-7-((2-(isoxazol-4- i-4-oxo-5,5a,6,7,8,8a-l -4H-i

[0327] 3-yl)-4-methoxybenzamide.

[0328] The title compound was prepared in a manner analogous to Example 32, reacting 3-Cyano- / V- ((5aS,8aS)-5-(4-(difluoro(phenyl)methyl)phenyl)-4-oxo-5,5a,6,7,8,8a-hexahydro-4 / 7- pyrazolo[1 ,5-a]pyrrolo[3,4-e]pyrazin-3-yl)-4-methoxybenzamide (Example 1 , product from Step M, 45.0 mg, 0.081 mmol) and 2-(isoxazol-4-yl)ethane-1-sulfonyl chloride (59.2 mg, 0.303 mmol) to give 3-cyano-N-((5aS,8aS)-5-(4-(difluoro(phenyl)methyl)phenyl)-7-((2-(isoxazol-4- yl)ethyl)sulfonyl)-4-oxo-5, 5a, 6,7,8, 8a-hexahydro-4H-pyrazolo[1 , 5-a]pyrrolo[3, 4-e]pyrazin-3-yl)-4- methoxybenzamide (11.3 mg, 19%).1H NMR (500 MHz, DMSO-d6) δ:: 9.87 (s, 1 H), 8.58 (s, 1 H), 8.53 (s, 1 H), 8.23 (d, J = 2.1 Hz, 1 H), 8.20 (s, 1 H), 8.16 (dd, J = 8.9, 2.2 Hz, 1 H), 7.65 (d, J = 8.5 Hz, 2H), 7.51 - 7.61 (m, 7H), 7.39 (d, J = 9.1 Hz, 1 H), 4.92 - 5.04 (m, 2H), 4.19 - 4.32 (m, 1 H), 3.99 (s, 3H), 3.78 (br t, J = 9.1 Hz, 1 H), 3.55 - 3.61 (m, 2H), 3.20 - 3.33 (m, 1 H), 3.09 (q, J = 7.3 Hz, 1 H), 2.80 - 2.91 (m, 2 H). Mass spectrum (ESI, m / z): Calcd. For C35H29F2N7O6S, 713.2; found [M+H]+, 714.4. Example 39: 3-cyano-N-((5aS,8aS)-5-(4-(difluoro(phenyl)methyl)phenyl)-7- (isopropylsulfonyl)-4-oxo-5,5a,6,7,8,8a-hexahvdro-4H-pyrazolori,5-a]pyrrolor3,4- e]pyrazin-3-yl)-4-methoxybenzamide.

[0329] The title compound was prepared in a manner analogous to Example 32, , reacting 3-Cyano- / V- ((5aS,8aS)-5-(4-(difluoro(phenyl)methyl)phenyl)-4-oxo-5,5a,6,7,8,8a-hexahydro-4 / 7- pyrazolo[1 ,5-a]pyrrolo[3,4-e]pyrazin-3-yl)-4-methoxybenzamide (Example 1 , product from Step M, 45.0 mg, 0.081 mmol) and propane-2-sulfonyl chloride (42.8 mg, 0.300 mmol) to give 3- cyano-N-((5aS,8aS)-5-(4-(difluoro(phenyl)methyl)phenyl)-7-(isopropylsulfonyl)-4-oxo- 5,5a,6,7,8,8a-hexahydro-4H-pyrazolo[1 ,5-a]pyrrolo[3,4-e]pyrazin-3-yl)-4-methoxybenzamide (27.7 mg, 51 %).1H NMR (500 MHz, DMSO-d6) δ:: 9.86 (s, 1 H), 8.23 (d, J = 2.3 Hz, 1 H), 8.19 (s, 1 H), 8.16 (dd, J = 8.9, 2.2 Hz, 1 H), 7.65 (d, J = 8.5 Hz, 2H), 7.50 - 7.61 (m, 7H), 7.39 (d, J = 9.0 Hz, 1 H), 4.98 - 5.13 (m, 2H), 4.24 (br t, J = 7.4 Hz, 1 H), 3.99 (s, 3H), 3.72 - 3.81 (m, 1 H), 3.59 - 3.65 (m, 1 H), 3.50 - 3.59 (m, 1 H), 3.23 (br s, 1 H), 1.05 (d, J = 6.9 Hz, 6H). Mass spectrum (ESI, m / z): Calcd. For C33H30F2N6O5S, 660.2; found [M+H]+, 661.4. difluoroethyl)sulfonyl)-4-oxo-5,5a,6,7,8,8a-hexahvdro-4H-pyrazolori,5-a]pyrrolor3,4-

[0330] :in-3-yl)-4-i

[0331] The title compound was prepared in a manner analogous to Example 32, reacting 3-Cyano- / V- ((5aS,8aS)-5-(4-(difluoro(phenyl)methyl)phenyl)-4-oxo-5,5a,6,7,8,8a-hexahydro-4 / 7- pyrazolo[1 ,5-a]pyrrolo[3,4-e]pyrazin-3-yl)-4-methoxybenzamide (Example 1 , product from Step M, 45.0 mg, 0.081 mmol) and 1 ,1-difluoroethane-1 -sulfonyl chloride (50.0 mg, 0.300 mmol) to give 3-cyano-N-((5aS,8aS)-5-(4-(difluoro(phenyl)methyl)phenyl)-7-((1 ,1-difluoroethyl)sulfonyl)-4- oxo-5, 5a, 6,7,8, 8a-hexahydro-4H-pyrazolo[1 , 5-a]pyrrolo[3, 4-e]pyrazin-3-yl)-4- methoxybenzamide (22.9 mg, 42%).1H NMR (500 MHz, DMSO-d6) δ:: 9.87 (s, 1 H), 8.23 (d, J = 2.3 Hz, 1 H), 8.20 (s, 1 H), 8.16 (dd, J = 8.9, 2.3 Hz, 1 H), 7.66 (d, J = 8.4 Hz, 2H), 7.50 - 7.60 (m, 7H), 7.39 (d, J = 9.0 Hz, 1 H), 5.09 - 5.21 (m, 2H), 4.34 (br t, J = 7.5 Hz, 1 H), 3.99 (s, 3H), 3.92 (br t, J = 9.0 Hz, 1 H), 3.71 (br t, J = 7.0 Hz, 1 H), 3.40 (br t, J = 9.1 Hz, 1 H), 1.98 - 2.11 (m, 3H). Mass spectrum (ESI, m / z): Calcd. For C32H26F4N6O5S, 682.2; found [M+H]+, 681.3.

[0332] Example 41 : 3-cvano-N-((5aS,8aS)-5-(4-(difluoro(phenyl)methyl)phenyl)-4-oxo-7-((2,2,2- trifluoroethyl)sulfonyl)-5, 5a, 6,7,8, 8a-hexahvdro-4H-pyrazolori,5-a]pyrrolor3,4-elpyrazin-3- vD-4-methoxybenzamide.

[0333] The title compound was prepared in a manner analogous to Example 32, reacting 3-Cyano- / V- ((5aS,8aS)-5-(4-(difluoro(phenyl)methyl)phenyl)-4-oxo-5,5a,6,7,8,8a-hexahydro-4 / 7- pyrazolo[1 ,5-a]pyrrolo[3,4-e]pyrazin-3-yl)-4-methoxybenzamide (Example 1 , product from Step M, 45.0 mg, 0.081 mmol) and 2,2,2-trifluoroethane-1-sulfonyl chloride (55.5 mg, 0.304 mmol) to give 3-cyano-N-((5aS,8aS)-5-(4-(difluoro(phenyl)methyl)phenyl)-4-oxo-7-((2,2,2- trifluoroethyl)sulfonyl)-5, 5a, 6,7,8, 8a-hexahydro-4H-pyrazolo[1,5-a]pyrrolo[3,4-e]pyrazin-3-yl)-4- methoxybenzamide (7.0 mg, 12%).1H NMR (500 MHz, DMSO-d6) δ:: 9.87 (s, 1 H), 8.23 (d, J = 2.3 Hz, 1 H), 8.20 (s, 1 H), 8.16 (dd, J=8.9, 2.3 Hz, 1 H), 7.65 (d, J=8.5 Hz, 2H), 7.49 - 7.61 (m, 7H), 7.39 (d, J=9.0 Hz, 1 H), 4.92 - 5.03 (m, 2H), 4.76 (q, J=10.1 Hz, 2H), 4.33 (br dd, J=8.4, 6.9 Hz, 1 H), 3.99 (s, 3H), 3.81 - 3.91 (m, 1 H), 3.72 (br dd, J=8.0, 6.6 Hz, 1 H), 3.05 - 3.13 (m, 1 H). Mass spectrum (ESI, m / z): Calcd. For C32H25F5N6O5S, 700.2; found [M+H]+, 701.4. Example 42: 3-cyano-N-((5aS,8aS)-5-(4-(difluoro(phenyl)methyl)phenyl)-7-((2-(2,2- difluoroethoxy)ethyl)sulfonyl)-4-oxo-5,5a,6,7,8,8a-hexahvdro-4H-pyrazolori,5- alpyrrolor3,4-e]pyrazin-3-yl)-4-methoxybenzamide.

[0334] The title compound was prepared in a manner analogous to Example 32,, reacting 3-Cyano- / V- ((5aS,8aS)-5-(4-(difluoro(phenyl)methyl)phenyl)-4-oxo-5,5a,6,7,8,8a-hexahydro-4 / 7- pyrazolo[1 ,5-a]pyrrolo[3,4-e]pyrazin-3-yl)-4-methoxybenzamide (Example 1 , product from Step M, 45.0 mg, 0.081 mmol) and 2-(2,2-difluoroethoxy)ethane-1-sulfonyl chloride (64.0 mg, 0.310 mmol) to give 3-cyano-N-((5aS,8aS)-5-(4-(difluoro(phenyl)methyl)phenyl)-7-((2-(2,2- difluoroethoxy)ethyl)sulfonyl)-4-oxo-5,5a,6,7,8,8a-hexahydro-4H-pyrazolo[1 ,5-a]pyrrolo[3,4- e]pyrazin-3-yl)-4-methoxybenzamide (14.4 mg, 24%).1H NMR (500 MHz, DMSO-d6) δ: 9.87 (s, 1 H), 8.23 (d, J=2.3 Hz, 1 H), 8.19 (s, 1 H), 8.16 (dd, J=9.0, 2.3 Hz, 1 H), 7.64 (d, J=8.5 Hz, 2H), 7.50 - 7.61 (m, 7 H) 7.39 (d, J=9.0 Hz, 1 H) 5.95 - 6.31 (m, 1 H) 4.88 - 5.01 (m, 2 H) 4.26 (dd, J=8.5, 7.0 Hz, 1 H) 3.99 (s, 3 H) 3.81 - 3.91 (m, 2 H) 3.69 - 3.80 (m, 3 H) 3.56 - 3.67 (m, 3 H) 3.24 (br t, J=9.1 Hz, 1 H). Mass spectrum (ESI, m / z): Calcd. For C34H30F4N6O6S, 726.2; found [M+H]+, 727.4.

[0335] Example 43 : rac-3-cyano-N-((5aR,8aR)-5-(4-(difluoro(phenyl)methyl)phenyl)-7-((3- methyloxetan-3-yl)methyl)-4-oxo-5,5a,6,7,8,8a-hexahvdro-4H-pyrazolori,5-a]pyrrolor3,4- e]pyrazin-3-yl)-4-methoxybenzamide.

[0336] A stock solution of 3-Cyano-N-((5aS,8aS)-5-(4-(difluoro(phenyl)methyl)phenyl)-4-oxo- 5,5a,6,7,8,8a-hexahydro-4H-pyrazolo[1 ,5-a]pyrrolo[3,4-e]pyrazin-3-yl)-4-methoxybenzamide hydrochloride (Example 1 , 50 mg, 0.09 mmol), in DMSO (1.5 mL) was added to a vial with 3- (bromomethyl)-3-methyloxetane CAS 78385-26-9 (30 mg, 0.18 mmol), followed by DIPEA (78 μL, 0.75 g / mL, 0.45 mmol). The reactions were stirred at 80°C for 18h. Then, the crude mixtures were diluted with 1 mL of DMSO, 1 mL of MeOH, filtered and submitted to RP HPLC. The crude products were purified by RP. (Stationary phase: C18 XBridge 30 x 100 mm 5 pm, Mobile phase: Gradient from 70% NH4HCO3 0.25% solution in Water, 30% CH3CN to 35% NH4HCO3 0.25% solution in Water, 65% CH3CN), yielding rac-3-cyano-N-((5aR,8aR)-5-(4- (difluoro(phenyl)methyl)phenyl)-7-((3-methyloxetan-3-yl)methyl)-4-oxo-5, 5a, 6,7,8, 8a-hexahydro- 4H-pyrazolo[1 ,5-a]pyrrolo[3,4-e]pyrazin-3-yl)-4-methoxybenzamide (31.8 mg, 55%).1H NMR (500 MHz, DMSO-d6) δ:: d ppm 9.68 (s, 1 H) 8.08 - 8.20 (m, 3 H) 7.58 - 7.64 (m, 2 H) 7.47 - 7.58 (m, 6 H) 7.37 (d, J=8.9 Hz, 1 H) 4.73 - 4.85 (m, 2 H) 4.32 - 4.39 (m, 2 H) 4.17 (dd, J=5.5, 4.1 Hz, 2 H) 4.01 (s, 3 H) 3.52 - 3.61 (m, 1 H) 3.34 - 3.43 (m, 1 H) 3.00 - 3.07 (m, 1 H) 2.97 (br s, 2 H) 2.82 - 2.90 (m, 2 H) 1.25 - 1.30 (m, 3 H). Mass spectrum (ESI, m / z): Calcd. for C35H32F2N6O4, 638.25, found [M+H]+, 639.4.

[0337] Example 241 : 3-Cvano-N-((5aS,8aS)-5-(4-(difluoro(4-fluorophenyl)methyl)phenyl)-7-(2- methoxyethyl)-4-oxo-5, 5a, 6,7,8, 8a-hexahvdro-4H-pyrazolori,5-a]pyrrolor3,4-elpyrazin-3- vD-4-methoxybenzamide.

[0338]

[0339] The title compound was prepared in a manner analogous to Example 217, Step B herein, reacting 3-cyano- / V-((5aS,8aS)-5-(4-(difluoro(4-fluorophenyl)methyl)phenyl)-4-oxo- 5,5a,6,7,8,8a-hexahydro-4 / 7-pyrazolo[1 ,5-a]pyrrolo[3,4-e]pyrazin-3-yl)-4-methoxybenzamide as HCI salt (Intermediate 6, 150.0 mg, 0.2460 mmol), a stir bar, 1-bromo-2-methoxyethane (85.6 mg, 0.616 mmol), DIEA (0.16 mL, 0.74 mmol, 0.782 g / mL), and DMF (3.0 mL).1H NMR (400 MHz, DMSO-d6) δ:: 9.84 (s, 1 H), 8.21 (d, J = 2.0 Hz, 1 H), 8.17 - 8.11 (m, 2H), 7.67 - 7.59 (m, 4H), 7.51 (d, J = 8.4 Hz, 2H), 7.42 - 7.33 (m, 3H), 4.87 - 4.74 (m, 2H), 3.99 (s, 3H), 3.60 - 3.52 (m, 1 H), 3.38 (t, J = 6.0 Hz, 2H), 3.29 - 3.25 (m, 1 H), 3.22 (s, 3H), 3.04 - 2.97 (m, 1 H), 2.85 (t, J = 5.6 Hz, 2H), 2.76 - 2.66 (m, 1 H). Mass spectrum (ESI, m / z): Calcd.for C33H29F3N6O4 630.2 m / z, found [M+H]+, 631.3.

[0340] Example 242: 3-Cvano-N-((5aS,8aS)-5-(4-(difluoro(4-fluorophenyl)methyl)phenyl)-7-(2- hvdroxyethyl)-4-oxo-5, 5a, 6,7,8, 8a-hexahvdro-4H-pyrazolori,5-a]pyrrolor3,4-elpyrazin-3- vD-4-methoxybenzamide.

[0341] The title compound was prepared in a manner analogous to Example 217, Step B herein, reacting 3-cyano- / V-((5aS,8aS)-5-(4-(difluoro(4-fluorophenyl)methyl)phenyl)-4-oxo- 5,5a,6,7,8,8a-hexahydro-4 / 7-pyrazolo[1 ,5-a]pyrrolo[3,4-e]pyrazin-3-yl)-4-methoxybenzamide as HCI salt (Intermediate 6, 140.0 mg, 229.9μmol), / V-ethyl- / V-isopropylpropan-2-amine (0.16 mL, 0.92 mmol), a stir bar, anhydrous DMF (2.0 mL), and 2-bromoethan-1-ol (33 μL, 0.46 mmol).1H NMR (400 MHz, CDCI3)_δ: 9.65 (s, 1 H), 8.45 (s, 1 H), 8.14 (d, J = 2.0 Hz, 1 H), 8.11 - 8.06 (m, 1 H), 7.62 (d, J = 8.4 Hz, 2H), 7.56 - 7.50 (m, 2H), 7.35 (d, J = 8.4 Hz, 2H), 7.14 (t, J = 8.8 Hz, 2H), 7.01 (d, J = 8.8 Hz, 1 H), 4.74 - 4.62 (m, 2H), 4.00 (s, 3H), 3.80 - 3.71 (m, 1 H), 3.71 - 3.61 (m, 2H), 3.58 - 3.49 (m, 1 H), 3.21 - 3.12 (m, 1 H), 3.04 - 2.89 (m, 3H). Mass spectrum (ESI, m / z): Calcd. for C32H27F3N6O4 616.2 m / z, found [M+H]+, 617.3.

[0342] Example 243: 3-Cvano-N-((5aS,8aS)-5-(4-(difluoro(4-fluorophenyl)methyl)phenyl)-7-(2- hvdroxyacetyl)-4-oxo-5, 5a, 6,7,8, 8a-hexahvdro-4H-pyrazolori,5-a]pyrrolor3,4-elpyrazin-3- vD-4-methoxybenzamide.

[0343] The title compound was prepared in a manner analogous to Example 210, reacting 3-cyano- / V-((5aS,8aS)-5-(4-(difluoro(4-fluorophenyl)methyl)phenyl)-4-oxo-5,5a,6,7,8,8a- hexahydro-4 / 7-pyrazolo[1 ,5-a]pyrrolo[3,4-e]pyrazin-3-yl)-4-methoxybenzamide as HCI salt (Intermediate 6, 117.0 mg, 0.192 mmol), 2-hydroxyacetic acid (21.9 mg, 0.288 mmol), a stir bar, HATU (94.5 mg, 0.250 mmol), DIPEA (100 μL, 0.742 g / mL, 0.576 mmol), and DMF (2.0 mL).1H NMR (400 MHz, DMSO-d6) δ:: 9.86 (d, J = 5.2 Hz, 1 H), 8.23 - 8.14 (m, 3H), 7.68 - 7.62 (m, 4H), 7.58 - 7.51 (m, 2H), 7.42 - 7.34 (m, 3H), 5.00 - 4.82 (m, 3H), 4.43 - 4.29 (m, 1 H), 4.19 - 3.91 (m, 5H), 3.88 - 3.75 (m, 2H), 3.06 (t, J = 10.4 Hz, 1 H). Mass spectrum (ESI, m / z): Calcd. for C32H25F3N6O5 630.2 m / z, found [M+H]+, 631.2. -3-

[0344]

[0345] The title compound was prepared in a manner analogous to Example 210, reacting 3-cyano- / V-((5aS,8aS)-5-(4-(difluoro(4-fluorophenyl)methyl)phenyl)-4-oxo-5,5a,6,7,8,8a- hexahydro-4 / 7-pyrazolo[1,5-a]pyrrolo[3,4-e]pyrazin-3-yl)-4-methoxybenzamide as HCI salt (Intermediate 6, 130.0 mg, 0.202 mmol), 2-methoxyacetic acid (23.6 mg, 0.262 mmol), a stir bar, HATU (173.2 mg, 0.3020 mmol), DIPEA (0.11 ml, 0.742 g / ml, 0.61 mmol), and DCM (5.0 mL).1H NMR (400 MHz, DMSO-d6) δ:: 9.86 (d, J = 6.0 Hz, 1 H), 8.29 - 8.11 (m, 3H), 7.68 - 7.61 (m, 4H), 7.58 - 7.50 (m, 2H), 7.43 - 7.31 (m, 3H), 5.02 - 4.83 (m, 2H), 4.46 - 4.27 (m, 1 H), 4.16 - 4.00 (m, 2H), 3.99 (s, 3H), 3.90 - 3.56 (m, 2H), 3.32 - 3.01 (m, 4H). Mass spectrum (ESI, m / z): Calcd for C33H27F3N6O5644.2 m / z, found [M+H]+, 645.3.

[0346] Example 245: N-((5aS,8aS)-7-acetyl-5-(3-methoxy-4-(trifluoromethyl)phenyl)-4-oxo- 5,5a,6,7,8,8a-hexahvdro-4H-pyrazolori,5-alpyrrolor3,4-e]pyrazin-3-yl)-3-cvano-4- methoxybenzamide.

[0347] The title compound was prepared in a manner analogous to Example 201, Step L herein, reacting / V-((5aS,8aS)-7-acetyl-4-oxo-5,5a,6,7,8,8a-hexahydro-4 / 7-pyrazolo[1,5-a]pyrrolo[3,4-e]pyrazin- 3-yl)-3-cyano-4-methoxybenzamide (Intermediate 9, 50.0 mg, 0.127 mmol), a stir bar, 4-bromo- 2-methoxy-1-(trifluoromethyl)benzene (48.5 mg, 0.190 mmol), K2CO3 (53.3 mg, 0.380 mmol), Cui (29.1 mg, 0.152 mmol), DMEDA (17 μL, 0.15 mmol), DMF (1.0 mL), and toluene (1.0 mL).1H NMR (400 MHz, DMSO-d6) δ:: 9.88 (d, J = 3.6 Hz, 1 H), 8.31 - 8.09 (m, 3H), 7.73 (dd, J = 3.2, 8.4 Hz, 1 H), 7.45 - 7.31 (m, 2H), 7.14 (d, J = 8.8 Hz, 1 H), 5.06 - 4.80 (m, 2H), 4.52 - 4.26 (m, 1 H), 4.04 - 3.97 (m, 3H), 3.90 (d, J = 9.6 Hz, 4H), 3.81 - 3.73 (m, 0.5H), 3.60 - 3.36 (m, 1 H), 3.02 (t, J = 10.4 Hz, 0.5H), 2.07 - 1.92 (m, 3H). Mass spectrum (ESI, m / z): Calcd. for C27H23F3N6O5 568.2 m / z, found [M+H]+, 569.0.

[0348] Example 246: N-((5aS,8aS)-7-acetyl-5-(3-ethyl-4-(trifluoromethyl)phenyl)-4-oxo- 5,5a,6,7,8,8a-hexahvdro-4H-pyrazolori,5-a]pyrrolor3,4-elpyrazin-3-yl)-3-cvano-4- methoxybenzamide.

[0349] The title compound was prepared in a manner analogous to Example 201 , Step L herein, reacting / V-((5aS,8aS)-7-acetyl-4-oxo-5,5a,6,7,8,8a-hexahydro-4 / 7-pyrazolo[1 ,5-a]pyrrolo[3,4-e]pyrazin- 3-yl)-3-cyano-4-methoxybenzamide (Intermediate 9, 80.0 mg, 0.203 mmol), a stir bar, 4-bromo-

[0350] 2-ethyl-1-(trifluoromethyl)benzene (77.0 mg, 0.304 mmol), K2CO3 (56.1 mg, 0.406 mmol), DMF (2.0 mL), Toluene (2.0 mL), Cui (46.4 mg, 0.243 mmol), and DMEDA (27 μL, 0.803 g / mL, 0.24 mmol).1H NMR (400 MHz, DMSO-d6) δ:: 9.96 - 9.77 (m, 1 H), 8.24 (s, 1 H), 8.22 - 8.13 (m, 2H), 7.78 (dd, J = 3.6, 8.4 Hz, 1 H), 7.57 (s, 1 H), 7.46 - 7.38 (m, 2H), 5.03 - 4.87 (m, 2H), 4.48 - 4.27 (m, 1 H), 3.99 (s, 3H), 3.92 (t, J = 9.6 Hz, 1 H), 3.77 (dd, J = 7.2, 9.6 Hz, 0.5H), 3.56 (t, J = 10.4 Hz, 0.5H), 2.98 (t, J = 9.6 Hz, 1 H), 2.85 - 2.78 (m, 2H), 2.05 - 1.92 (m, 3H), 1.23 (q, J = 6.8 Hz, 3H). Mass spectrum (ESI, m / z): Calcd for C28H25F3N6O4 566.2 m / z, found [M+H]+, 567.0.

[0351] Example 247: N-((5aS,8aS)-7-acetyl-4-oxo-5-(3-(trifluoromethoxy)-4- (trifluoromethyl)phenyl)-5, 5a, 6,7,8, 8a-hexahvdro-4H-pyrazolori,5-a]pyrrolor3,4-elpyrazin-

[0352] 3-yl)-3-cvano-4-methoxybenzamide.

[0353]

[0354] The title compound was prepared in a manner analogous to Example 201, Step L herein, reacting / \ / -((5aS,8aS)-7-acetyl-4-oxo-5,5a,6,7,8,8a-hexahydro-4 / 7-pyrazolo[1,5-a]pyrrolo[3,4-e]pyrazin- 3-yl)-3-cyano-4-methoxybenzamide (Intermediate 9, 80.0 mg, 0.203 mmol), a stir bar, 4-bromo- 2-(trifluoromethoxy)-1-(trifluoromethyl)benzene (94.0 mg, 0.304 mmol), K2CO3 (56.1 mg, 0.406 mmol), DMF (1.0 mL), Toluene (1.0 mL), Cui (46.4 mg, 0.243 mmol), and DMEDA (27 μL, 0.803 g / mL, 0.80 mmol).1H NMR (400 MHz, DMSO-d6) δ:: 9.87 (s, 1 H), 8.32 - 8.10 (m, 3H), 8.05 (dd, J = 3.6, 8.4 Hz, 1 H), 7.79 (s, 1 H), 7.68 (d, J = 8.4 Hz, 1 H), 7.40 (d, J = 9.2 Hz, 1 H), 5.06 - 4.87 (m, 2H), 4.49 - 4.28 (m, 1H), 3.99 (s, 3H), 3.96 - 3.88 (m, 1H), 3.83 (dd, J = 6.8, 10.4 Hz, 0.5H), 3.55 (t, J = 10.4 Hz, 0.5H), 3.41 (s, 0.5H), 3.00 (t, J = 10.4 Hz, 0.5H), 2.08 - 1.90 (m, 3H). Mass spectrum (ESI, m / z): Calcd for C27H20F6N6O5622.1 m / z, found [M+H]+, 623.0.

[0355] Example 248: N-((5aS,8aS)-7-acetyl-5-(3-chloro-4-(trifluoromethyl)phenyl)-4-oxo- 5,5a,6,7,8,8a-hexahvdro-4H-pyrazolori,5-alpyrrolor3,4-e]pyrazin-3-yl)-3-cvano-4- methoxybenzamide.

[0356] The title compound was prepared in a manner analogous to Example 201, Step L herein, reacting / V-((5aS,8aS)-7-acetyl-4-oxo-5,5a,6,7,8,8a-hexahydro-4 / 7-pyrazolo[1,5-a]pyrrolo[3,4-e]pyrazin- 3-yl)-3-cyano-4-methoxybenzamide (Intermediate 9, 50.0 mg, 0.116 mmol), 4-bromo-2-chloro-1- (trifluoromethyl)benzene (60.2 mg, 0.232 mmol), copper(l) iodide (26.7 mg, 0.139 mmol), DMEDA (15 μL, 0.14 mmol, 0.819 g / mL), K2CO3 (48.8 mg, 0.348 mmol), a stir bar, DMF (3.0 mL), and toluene (3.0 mL).1H NMR (400 MHz, DMSO-d6) δ:: 9.87 (d, J = 4.4 Hz, 1 H), 8.27 - 8.14 (m, 3H), 8.00 (dd, J = 2.0, 8.4 Hz, 1 H), 7.87 (s, 1 H), 7.62 (dd, J = 1.2, 8.4 Hz, 1 H), 7.40 (d, J = 9.2 Hz, 1 H), 5.02 - 4.84 (m, 2H), 4.50 - 4.28 (m, 1 H), 4.02 - 3.83 (m, 5H), 3.55 (t, J = 10.4 Hz, 0.5H), 3.02 (t, J = 10.4 Hz, 0.5H), 2.06 - 1.93 (m, 3H). Mass spectrum (ESI, m / z): Calcd for C26H20CIF3N6O4 572.1 m / z, found [M+ H]+, 573.0.

[0357] Example 249: N-((5aS,8aS)-7-acetyl-5-(3-cvclopropyl-4-(trifluoromethyl)phenyl)-4-oxo- 5,5a,6,7,8,8a-hexahvdro-4H-pyrazolori,5-alpyrrolor3,4-e]pyrazin-3-yl)-3-cvano-4- methoxybenzamide.

[0358] Step A: 3-Cyclopropyl-4-(trifluoromethyl)aniline.

[0359] 3-Bromo-4-(trifluoromethyl)aniline (1.00 g, 4.17 mmol), a stir bar, dioxane (10.0 mL) and H2O (2.0 mL) were added to an oven-dried 100 mL round-bottomed flask, and the resulting mixture treated with K2CO3 (1.75 g, 12.5 mmol), cyclopropylboronic acid (429.5 mg, 5.000 mmol) and Pd(dppf)Ch (304.9 mg, 0.417 mmol) in sequence. The mixture was degassed and purged with N2 three times. Then the resulting mixture was stirred at 80 °C for 16 h, finally the reaction mixture was become a yellow suspension. The reaction progress was monitored by TLC. The reaction mixture was added H2O (30 mL), then extracted with ethyl acetate (40 mL x 3), washed with brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated to dryness in vaco to give a yellow oil. The oil was then subjected to silica gel chromatography (0-20% Ethyl acetate / Petroleum ether) to give 3-cyclopropyl-4-(trifluoromethyl)aniline as a yellow oil. (753.0 mg, 64%).1H NMR (400 MHz, CDCI3) δ: 7.37 (d, J = 8.4 Hz, 1 H), 6.47 (dd, J = 2.0, 8.4 Hz, 1 H), 6.27 (d, J = 2.0 Hz, 1 H), 3.84 (s, 2H), 2.20 - 2.07 (m, 1 H), 1.04 - 0.89 (m, 2H), 0.82 - 0.63 (m, 2H). Mass spectrum (ESI, m / z): Calcd for CioHwFsN 201.1 m / z, found [M+H]+, 202.3.

[0360] Step B: 4-Bromo-2-cvclopropyl-1-(trifluoromethyl)benzene. 3-Cyclopropyl-4-(trifluoromethyl)aniline (200.0 mg, 0.9940 mmol), a stir bar, CuBr (359.0 mg, 2.485 mmol), CH3CN (10.0 mL) and H2O (1.0 mL) were added to a 50 mL round-bottomed flask to afford a heterogeneous mixture. The flask was then cooled to 0 °C (ice bath) and charged with TSOH H2O (756.4 mg, 3.976 mmol) at 0 °C and stirred for 1 h, then added NaNCh (104.4 mg, 1.491 mmol) in H2O (1.0 mL) dropwise at 0 °C and stirred for 1 h to give a blue suspension. The reaction progress was monitored by TLC. The reaction mixture was added H2O (30 mL), extracted with EtOAc (30 mL x2). The combined extracts were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure to give a yellow oil. The oil was then subjected to silica gel chromatography (0~0% EtOAc / pet ether) to give 4-bromo-2-cyclopropyl-1-(trifluoromethyl)benzene as a colorless oil (113.0 mg, 43%).1H NMR (400 MHz, CDCI3)_δ: 7.49 - 7.43 (m, 1 H), 7.40 - 7.35 (m, 1 H), 7.16 (s, 1 H), 2.23 - 2.12 (m, 1 H), 1.11 - 1.02 (m, 2H), 0.82 - 0.74 (m, 2H).

[0361] Step C: / V-((5aS,8aS)-7-acetyl-5-(3-cyclopropyl-4-(trifluoromethyl)phenyl)-4-oxo-5,5a,6,7,8,8a- hexahydro-4 / 7-pyrazolo[1 ,5-a]pyrrolo[3,4-e]pyrazin-3-yl)-3-cyano-4-methoxybenzamideas.

[0362] The title compound was prepared in a manner analogous to Example 201 , Step L herein, reacting / V-((5aS,8aS)-7-acetyl-4-oxo-5,5a,6,7,8,8a-hexahydro-4 / 7-pyrazolo[1 ,5-a]pyrrolo[3,4-e]pyrazin- 3-yl)-3-cyano-4-methoxybenzamide (Intermediate 9, 100.0 mg, 0.2540 mmol), a stir bar, 4- bromo-2-cyclopropyl-1-(trifluoromethyl)benzene (80.7 mg, 0.304 mmol), DMEDA (26.8 mg, 0.304 mmol), K2CO3(105.1 mg, 0.7610 mmol), DMF (2.0 mL), toluene (2.0 mL), and Cui (57.9 mg, 0.304 mmol).1H NMR (400 MHz, DMSO-d6) δ:: 9.86 (d, J = 5.2 Hz, 1 H), 8.25 - 8.22 (m, 1 H), 8.20 (s, 1 H), 8.18 - 8.14 (m, 1 H), 7.78 (d, J = 8.4 Hz, 1 H), 7.43 - 7.36 (m, 2H), 7.19 (s, 1 H), 5.03 - 4.82 (m, 2H), 4.50 - 4.26 (m, 1 H), 3.99 (s, 3H), 3.92 - 3.76 (m, 1 H), 3.68 (dd, J = 6.4, 10.4 Hz, 0.5H), 3.54 (t, J = 10.4 Hz, 0.5H), 3.38 - 3.35 (m, 0.5H), 2.95 (t, J = 10.4 Hz, 0.5H), 2.23 - 2.11 (m, 1 H), 2.06 - 1.90 (m, 3H), 1.13 - 1.03 (m, 2H), 0.88 - 0.78 (m, 2H). Mass spectrum (ESI, m / z): Calcd for C29H25F3N6O4 578.2 m / z, found [M+H]+, 579.0.

[0363] The following compounds were synthesized by the method described for Example 43

[0364]

[0365] Preparation of Final Compounds

[0366] Example 201 : 3-Cvano-4-methoxy-N-((5aS,8aS)-7-methyl-4-oxo-5-(4-

[0367] (trifluoromethyl)phenyl)-5, 5a, 6,7,8, 8a-hexahvdro-4H-pyrazolori,5-a]pyrrolor3,4-elpyrazin- 3-yl)benzamide.

[0368]

[0369] Step A: tert-Butyl (3S,4S)-3-((tert-butoxycarbonyl)amino)-4-hydroxypyrrolidine-1-carboxylate tert-Butyl (3S,4S)-3-amino-4-hydroxypyrrolidine-1-carboxylate (5.00 g, 24.7 mmol), a stir bar, and anhydrous 1,4-dioxane (100 mL) were added to a 500 mL three-necked round-bottomed flask fitted with thermometer. The resulting mixture was cooled to 0 °C and treated with NaOH (1.48 g, 37.1 mmol) and BOC2O (8.09 g, 37.1 mmol), stirred at r.t. for 12 h. The reaction was monitored by TLC. The reaction mixture was poured into H2O (150 mL) and extracted with EtOAc (100 mL x 3). The combined extracts were washed with brine (50 mL x 2), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a light yellow oil. The oil was subjected to silica gel chromatography (0-50% EtOAc / ChLCh) to give (3S,4S)-tert-butyl 3-((tert- butoxycarbonyl)amino)-4-hydroxypyrrolidine-1 -carboxylate as a white foamed solid (7.0 g, 94%).1H NMR (400 MHz, DMSO-d6) □ □ 7.09 (s, 1 H), 5.21 (d, J = 4.0 Hz, 1 H), 3.93 (s, 1 H), 3.68 (s, 1 H), 3.49 - 3.35 (m, 2H), 3.12 - 3.01 (m, 2H), 1.38 (d, J = 2.4 Hz, 18H).

[0370] Step B: tert-Butyl (3R,4S)-3-(benzoyloxy)-4-((tertbutoxycarbonyl)amino)pyrrolidine-1- carboxylate tert-Butyl (3S,4S)-3-((tert-butoxycarbonyl)amino)-4-hydroxypyrrolidine-1-carboxylate (1.00 g, 3.31 mmol), benzoic acid (889 mg, 7.276 mmol), PPha (1.74 g, 6.61 mmol), a stir bar and anhydrous THF (25 mL) were added to a 100 mL round-bottomed flask. The resuting mixture was cooled to 0 °C before treated with DIAD (1.3 mL, 6.6 mmol), after that, warmed to r.t. and stirred at r.t. for 16 h. The reaction was monitored by TLC and LC-MS. The reaction mixture was turned from colourless to yellow after the addition of DIAD. The reaction mixture was concentrated in vacuo to give a yellow oil. The oil was subjected to silica gel chromatography (0-17% EtOAc / Petroleum ether) to give tert-butyl (3R,4S)-3-(benzoyloxy)-4-((tert- butoxycarbonyl)amino)pyrrolidine-1 -carboxylate as a white foamed solid (1.1 g, 70%). Mass spectrum (ESI, m / z): calcd. for C21H30N2O6, 406.2; found [M+Na]+, 429.0.

[0371] Step C: tert-Butyl (3S,4R)-3-((tert-butoxycarbonyl)amino)-4-hvdroxypyrrolidine-1 -carboxylate tert-Butyl (3R,4S)-3-(benzoyloxy)-4-((tert-butoxycarbonyl)amino)pyrrolidine-1 -carboxylate (1.10 g, 2.71 mmol), LiOH H2O (454 mg, 10.8 mmol), a stir bar, anhydrous THF (6.0 mL), H2O (3.0 mL) and anhydrous MeOH (6.0 mL) were added to a 50 mL round-bottomed flask. The resultant mixture was stirred at r.t. for 3 h. The reaction was monitored by TLC. The reaction mixture was poured into H2O (10 mL) and extracted with EtOAc (10 mL x 2). The combined extracts were dried over anhydrous Na2SC>4, filtered and concentrated in vacuo to give a colourless oil. The oil was subjected to silica-gel chromatography (0-50% EtOAc / Petroleum ether) to give tert-butyl (3S,4R)-3-((tert-butoxycarbonyl)amino)-4-hydroxypyrrolidine-1- carboxylate as a colourless oil (600 mg, 73% ).1H NMR (400 MHz, DMSO-d6) □ □ 6.53 - 6.52 (m, 1 H), 5.19 - 5.09 (m, 1 H), 4.09 - 3.98 (m, 1 H), 3.94 - 3.82 (m, 1 H), 3.47 - 3.36 (m, 2H), 3.19 (d, J = 11.6 Hz, 1 H), 3.03 (t, J = 9.6 Hz, 1 H), 1.39 (s, 18H).

[0372] Step D: Ethyl 1-((3S,4S)-1-(tert-butoxycarbonyl)-4-((tert-butoxycarbonyl)amino)pyrrolidin-3-yl)-4- iodo-1 H-pyrazole-5-carboxylate Ethyl 4-iodo-1 / 7-pyrazole-5-carboxylate (5.28 g, 19.8 mmol), tert-butyl (3S,4R)-3-((tert-butoxycarbonyl)amino)-4-hydroxypyrrolidine-1 -carboxylate (6.00 g, 19.8 mmol), PPha (7.81 g, 29.8 mmol), a stir bar and toluene (120 mL) were added to a 500 mL three-necked flask fitted with a reflux condenser. The solution was charged with DTBAD (6.85 g, 29.8 mml). The resulting solution was stirred at 100 °C for 12 h. The reaction was monitored by TLC and LC-MS. The reaction mixture was concentrated in vacuo to give a yellow oil. The oil was subjected to silica gel chromatography (0-40% EtOAc / pet ether) followed by HPLC (Xtimate C18, 10 pm, 150 mm x 40 mm, 50% to 88% CH3CN and H2O (with 0.05% of 28% aq. NH3.H2O) to give ethyl 1-((3S,4S)-1-(tert-butoxycarbonyl)-4-((tert- butoxycarbonyl)amino)pyrrolidin-3-yl)-1 / 7-pyrazole-5-carboxylate as a white solid (3.5 g, 30%).1H NMR (400 MHz, DMSO-d6) □ □ 7.80 (s, 1 H), 7.35 (s, 1 H), 5.48 (t, J = 6.8 Hz, 1 H), 4.43 - 4.26 (m, 3H), 3.83 - 3.82 (m, 1 H), 3.74 - 3.63 (m, 1 H), 3.52 (d, J = 16.0 Hz, 1 H), 3.23 - 3.09 (m, 1 H), 1.39 (d, J = 6.4 Hz, 9H), 1.37 - 1.28 (m, 12H).

[0373] Step E: Ethyl 1-((3S,4S)-4-aminopyrrolidin-3-yl)-4-iodo-1 H-pyrazole-5-carboxylate

[0374] Ethyl 1-((3S,4S)-1-(tert-butoxycarbonyl)-4-((tert-butoxycarbonyl)amino)pyrrolidin-3-yl)-1 / 7- pyrazole-5-carboxylate (3.50 g, 6.36 mmol), a stir bar and 4 N HCI / dioxane (30.0 mL) were added to 250 mL three-necked flack, the mixture was stirred at r.t. for 1 h. The solution was concentrated under pressure to give ethyl 1-((3S,4S)-4-aminopyrrolidin-3-yl)-4-iodo-1 H- pyrazole-5-carboxylate HCI salt as a white solid (3 g, crude). Mass spectrum (ESI, m / z): calcd. for C10H15IN4O2, 350.0; found [M+H]+, 350.7.

[0375] Step F: (5aS,8aS)-3-lodo-5, 5a, 6,7,8, 8a-hexahydro-4H-pyrazolon ,5-alpyrrolof3,4-elpyrazin-4- one.

[0376] Ethyl 1-((3S,4S)-4-aminopyrrolidin-3-yl)-1 H-pyrazole-5-carboxylate (HCI salt, 3.00 g, 7.76 mmol), H2O (20.0 mL), a stir bar, Na2COs (1 .23 g, 11 .6 mmol) were added to 100 mL round- bottomed flask fitted with a reflux condenser, the mixture was stirred at 50 °C for 12 h. The reaction was monitored by LC-MS. The mixture was adjusted pH = 7 with 1 N HCI. The mixture was concentrated under pressure to give (5aS,8aS)-3-iodo-5,5a,6,7,8,8a-hexahydro-4 / 7- pyrazolo[1 ,5-a]pyrrolo[3,4-e]pyrazin-4-one as a light yellow solid (700 mg, 24%) and crude product (4 g). The crude product was then subjected to HPLC (Xtimate C18, 10 pm, 150 mm x 40 mm; 1-30% CH3CN and H2O (with 0.225% HCOOH)) to give (5aS,8aS)-3-iodo-5,5a,6,7,8,8a- hexahydro-4 / 7-pyrazolo[1 ,5-a]pyrrolo[3,4-e]pyrazin-4-one as a light yellow solid (600 mg, 23%). Mass spectrum (ESI, m / z): calcd. for C8H9IN4O, 304.0; found [M+H]+, 304.6.1H NMR (400 MHz, DMSO-d6) > > 8.80 (s, 1 H), 7.68 (s, 1 H), 4.30 (d, J = 7.6 Hz, 1 H), 3.95 - 3.79 (m, 2H), 3.47 (s, 1 H), 3.15 (d, J = 9.2 Hz, 1 H), 3.09 - 2.99 (m, 1 H), 2.85 (d, J = 9.6 Hz, 1 H).

[0377] ,5-

[0378] (5aS,8aS)-3-lodo-5,5a,6,7,8,8a-hexahydro-4 / 7-pyrazolo[1 ,5-a]pyrrolo[3,4-e]pyrazin-4-one (20.00 g, 58.73 mmol), 4-methoxybenzaldehyde (21.4 mL, 176 mmol, 1.12 g / mL), AcOH (6.7 mL, 117 mmol, 1.05 g / mL), a stir bar, and anhydrous MeOH (200 mL) were added to a 500 mL three-necked flask. The yellow mixture was stirred at r.t. for 5 min before treated with NaBhhCN (11.07 g, 176.2 mmol) and stirred at 40 °C for 12 h, which formed a light brown suspension. The reaction was monitored by TLC and LC-MS. The reaction mixture was filtered and the filter cake were washed with MeOH (40 mL x 2), collected and concentrated in vacuo to give a white solid. The filtrate concentrated in vacuum to move MeOH, then poured into H2O (80 mL), and adjusted pH to 8~9 with sat. NaHCOs, and extracted with EtOAc (80 mL x 3). The combined extracts were washed with brine (60 mL) and concentrated in vacuum to give a white solid. The solid was then subjected to silica gel chromatography (0-100% EtOAc / pet ether) to give the (5aS,8aS)-3-iodo-7-(4-methoxybenzyl)-5,5a,6,7,8,8a-hexahydro-4 / 7-pyrazolo[1 ,5-a]pyrrolo[3,4- e]pyrazin-4-one as a white solid (22.0 g, 87%).1H NMR (400 MHz, DMSO-d6) δ:: 8.94 - 8.60 (m, 1 H), 7.66 (s, 1 H), 7.24 (d, J = 8.4 Hz, 2H), 6.89 (d, J = 8.4 Hz, 2H), 4.42 (dt, J = 7.2, 10.4 Hz, 1 H), 3.95 (dt, J = 7.2, 10.8 Hz, 1 H), 3.87 - 3.75 (m, 2H), 3.74 (s, 3H), 3.07 - 2.91 (m, 2H), 2.80 - 2.67 (m, 1 H). Mass spectrum (ESI, m / z): calcd. for C16H17IN4O2, 424.0; found [M+H]+, 424.8. Step H: Tert-butyl (5aS,8aS)-3-iodo-7-(4-methoxybenzyl)-4-oxo-6,7,8,8a-tetrahydro-4 / 7-

[0379] (5aS,8aS)-3-lodo-7-(4-methoxybenzyl)-5,5a,6,7,8,8a-hexahydro-4H-pyrazolo[1 ,5-a]pyrrolo[3,4- e]pyrazin-4-one (10.50 g, 24.75 mmol), a stir bar, BOC2O (10.80 g, 49.50 mmol), DMAP (605.0 mg, 4.950 mmol), TEA (5.2 mL, 37 mmol) and toluene (160 mL) were added to 500 mL threenecked flask fitted with a reflux condenser, the mixture was stirred at 100 °C for 3 h. The reaction mixture was turned from white to brown. The reaction was monitored by TLC. The brown mixture was diluted with H2O (200 mL), extracted with EtOAc (100 mL x 3), the combined extracts were washed with brine (200 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuum to give a brown oil. The oil was then subjected to silica gel chromatography (10-50% EtOAc / pet ether) to give (5aS,8aS)-3-iodo-7-(4-methoxybenzyl)- 5,5a,6,7,8,8a-hexahydro-4H-pyrazolo[1 ,5-a]pyrrolo[3,4-e]pyrazin-4-one as a yellow solid (11.2 g, 85.5%). Mass spectrum (ESI, m / z): calcd. for C2iH2slN4O4, 524.1 ; found [M+H]+, 525.1.

[0380] Step I: tert-Butyl (5aS,8aS)-3-((tert-butoxycarbonyl)amino)-7-(4-methoxybenzyl)-4-oxo-6,7,8,8a- tetrahydro-4 / 7-pyrazolo[1 ,5-a]pyrrolo[3,4-e]pyrazine-5(5a / - / )-carboxylate. tert-Butyl (5aS,8aS)-3-iodo-7-(4-methoxybenzyl)-4-oxo-6,7,8,8a-tetrahydro-4H-pyrazolo[1 ,5- a]pyrrolo[3,4-e]pyrazine-5(5aH)-carboxylate (11.2 g, 21.4 mmol), a stir bar, toluene (160 mL), tert-butyl carbamate (5.00 g, 42.7 mmol), CS2CO3 (13.9 g, 42.7 mmol), Xphos (2.72 g, 6.41 mmol) and Pd2(dba)s (1.96 g, 2.14 mmol) were added to an oven-dried and nitrogen-purged 250 mL three-necked flask fitted with a reflux condenser and a thermometer, which was subsequently evacuated and refilled with nitrogen (x3), and the reaction vessel placed in an oil bath that had been pre-heated to 95 °C, and the mixture stirred at 95 °C for 12 h . The reaction was monitored by TLC and LC-MS. The reaction mixture was filtered and the filtrate was concentrated in vacuum to give a dark brown oil. The dark brown oil was diluted with H2O (100 mL), extracted with EtOAc (100 mL x 3). The combined extracts were washed with brine (200 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuum to give a brown oil. The oil was then subjected to silica gel chromatography (10-50% EtOAc / pet ether) to give tert-butyl (5aS,8aS)-3-((tert-butoxycarbonyl)amino)-7-(4-methoxybenzyl)-4-oxo-6,7,8,8a-tetrahydro-4H- pyrazolo[1 ,5-a]pyrrolo[3,4-e]pyrazine-5(5aH)-carboxylate as a yellow solid (8.1 g, 73.7%). Mass spectrum (ESI, m / z): calcd. for C26H35N5O6 513.3 found [M+H]+, 514.3.

[0381] Step J: (5aS,8aS)-3-Amino-7-(4-methoxybenzyl)-5,5a,6,7,8,8a-hexahydro-4 / - / -pyrazolon ,5- alpyrrolof3,4-elpyrazin-4-one. tert-Butyl (5aS,8aS)-3-((tert-butoxycarbonyl)amino)-7-(4-methoxybenzyl)-4-oxo-6,7,8,8a- tetrahydro-4H-pyrazolo[1 ,5-a]pyrrolo[3,4-e]pyrazine-5(5aH)-carboxylate (8.1 g, 15.8 mmol), a stir bar, and HCI / 1 ,4-dioxane(71.2 mL, 4 M) were added to a 250 mL round-bottomed flask. The reaction was stirred at r.t. for 12 h. The reaction was monitored by TLC and LC-MS. The reaction solution was concentrated in vacuum to give a yellow solid. The solid was dissolved in EtOAc (60 mL) and quenched with Na2COs (100 mL), extracted with EtOAc (50 mL x 3). The combined extracts were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuum to give a yellow solid (4.5 g, 91%).1H NMR (400 MHz, DMSO-d6)_δ: 8.21 (s, 1 H), 7.25 (d, J = 8.8 Hz, 2H), 7.01 (s, 1 H), 6.89 (d, J = 8.8 Hz, 2H), 4.83 (s, 2H), 4.13 - 4.01 (m, 1 H), 3.91 - 3.76 (m, 3H), 3.74 (s, 3H), 3.31 - 3.27 (m, 1 H), 3.02 - 2.94 (m, 2H), 2.74 - 2.69 (m, 1 H). Mass spectrum (ESI, m / z): Calcd. for C16H19N5O2 313.2; found [M+H]+, 314.2. Step K: 3-Cyano-4-methoxy- / \ / -((5aS,8aS)-7-(4-methoxybenzyl)-4-oxo-5,5a,6,7,8,8a-hexahydro- 4 / 7-pyrazolon ,5-alpyrrolof3,4-elpyrazin-3-yl)benzamide.

[0382] 3-Cyano-4-methoxybenzoic acid (2.99 g, 16.9 mmol), a stir bar, HATU (6.94 g, 18.3 mmol), DIEA (9.3 mL, 0.782 g / mL, 56 mmol) and DMF (80.0 mL) were added to a 250 mL round- bottomed flask and stirred at 25 °C for 0.5 h. The solution turns black, then the resulting mixture treated with (5aS,8aS)-3-amino-7-(4-methoxybenzyl)-5,5a,6,7,8,8a-hexahydro-4 / 7-pyrazolo[1 ,5- a]pyrrolo[3,4-e]pyrazin-4-one (4.40 g, 14.0 mmol) and the reaction mixture was stirred at 25 °C for 12 h. some yellow precipitate separated out. The reaction was stirred at r.t. for 12 h. The reaction was monitored by LC-MS. H2O (50 mL) was added to the solution and more yellow precipitate separated out. The reaction mixture was filtered and the filter cake was washed with H2O (80 mL). The solid was concentrated in vacuum to give 3-cyano-4-methoxy- / V-((5aS,8aS)- 7-(4-methoxybenzyl)-4-oxo-5,5a,6,7,8,8a-hexahydro-4 / 7-pyrazolo[1 ,5-a]pyrrolo[3,4-e]pyrazin-3- yl)benzamide as a yellow solid (5.66 g, 81%).1H NMR (400 MHz, DMSO-d6) δ: 9.84 (s, 1 H), 8.90 (s, 1 H), 8.23 (d, J = 2.0 Hz, 1 H), 8.15 (dd, J = 2.0, 8.8 Hz, 1 H), 8.05 (s, 1 H), 7.43 (d, J = 9.2 Hz, 1 H), 7.26 (d, J = 8.4 Hz, 2H), 6.90 (d, J = 8.4 Hz, 2H), 4.44 - 4.32 (m, 1 H), 4.09 - 3.94 (m, 4H), 3.89 - 3.77 (m, 2H), 3.74 (s, 3H), 3.38 (br t, J = 8.0 Hz, 1 H), 3.13 - 2.98 (m, 2H), 2.79 (br t, J = 9.6 Hz, 1 H). Mass spectrum (ESI, m / z): Calcd. for C25H24N6O4, 472.2; found [M+H]+, 473.0.

[0383] Step L: 3-Cyano-4- methoxy- / \ / -((5aS,8aS)-7-(4-methoxybenzyl)-4-oxo-5-(4- (trifluoromethyl)phenyl)-5, 5a, 6,7,8, 8a-hexahydro-4 / 7pyrazolon ,5-alpyrrolof3,4-elpyrazin-3- yDbenzamide.

[0384] 3-Cyano-4-methoxy-N-((5aS,8aS)-7-(4-methoxybenzyl)-4-oxo-5, 5a, 6,7,8, 8a-hexahydro-4H- pyrazolo[1 ,5-a]pyrrolo[3,4-e]pyrazin-3-yl)benzamide (250.0 mg, 0.529 mmol), a stir bar, 1- bromo-4-(trifluoromethyl)benzene (111 μL, 0.794 mmol), DMEDA (34.9 μL, 0.317 mmol), K2CO3 (219 mg, 1.59 mmol), DMF (3 mL), Cui (60.5 mg, 0.317 mmol) were added to 50 mL round- bottomed flask fitted with a reflux condenser, and the resulting mixture stirred for 12 h at 100 °C to give a blue solution. The reaction was monitored by TLC. The reaction mixture was cooled to r.t. and poured into H2O (5 mL), extracted with EtOAc (10 mL x 3). The combined extracts were washed with brine (10 mL x 2), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a yellow oil. The oil was then subjected to silica gel chromatography (0-50% Ethyl acetate / Petroleum ether) to give 3-cyano-4-methoxy-N-((5aS,8aS)-7-(4-methoxybenzyl)-4-oxo- 5-(4-(trifluoromethyl)phenyl)-5, 5a, 6,7,8, 8a-hexahydro-4H-pyrazolo[1 ,5-a]pyrrolo[3,4-e]pyrazin-3- yl)benzamide (200 mg, 51% yield) as a light yellow oil.1H NMR (400 MHz, DMSO-d6)D D 9.85 (s, 1 H), 8.22 (d, J = 2.0 Hz, 1 H), 8.19 - 8.12 (m, 2H), 7.82 (d, J = 8.4 Hz, 2H), 7.61 (d, J = 8.0 Hz, 2H), 7.39 (d, J = 9.2 Hz, 1 H), 7.22 (d, J = 8.4 Hz, 2H), 6.87 (d, J = 8.4 Hz, 2H), 4.95 - 4.81 (m, 2H), 3.99 (s, 3H), 3.87 - 3.76 (m, 2H), 3.72 (s, 3H), 3.54 - 3.48 (m, 1 H), 3.23 - 3.18 (m, 1 H), 3.00 - 2.93 (m, 1 H), 2.69 - 2.64 (m, 1 H). Mass spectrum (ESI, m / z): Calcd. for C32H27F3N6O4, 616.2; found [M+H]+, 617.2.

[0385] Step M: 3-Cyano-4-methoxy-N-((5aS,8aS)-4-oxo-5-(4-(trifluoromethyl)phenyl)-5,5a,6,7,8,8a- hexahydro-4H-pyrazolon ,5-alpyrrolof3,4-elpyrazin-3-yl)benzamide.

[0386] 3-Cyano-4-methoxy-N-((5aS,8aS)-7-(4-methoxybenzyl)-4-oxo-5-(4-(trifluoromethyl)phenyl)- 5,5a,6,7,8,8a-hexahydro-4H-pyrazolo[1 ,5-a]pyrrolo[3,4-e]pyrazin-3-yl)benzamide (200 mg, 0.32 mmol), a stir bar, and DCE (2 mL) were added to a 8 mL glass vial. The mixture was charged with carbonochloridic acid 1 -chloro-ethyl ester (70.0 μL, 0.65 mmol) and stirred at r.t. for 2 h, then treated with anhydrous MeOH (1 mL). Then the solution stirred at 60 °C for 1 h, some white precipitate separated out. The reaction was monitored by TLC. The reaction mixture was cooled to rt and filtered, the filter cake was washed with DCM (25 mL x 3) and dried in vacuo to give 3-cyano-4-methoxy-N-((5aS,8aS)-4-oxo-5-(4-(trifluoromethyl)phenyl)-5,5a,6,7,8,8a- hexahydro-4H-pyrazolo[1 ,5-a]pyrrolo[3,4-e]pyrazin-3-yl)benzamide as a white solid (87.7 mg, 54.5%).1H NMR (400 MHz, DMSO-d6) > 9.89 (s, 1 H), 8.22 (d, J = 5.6 Hz, 2H), 8.16 (d, J = 8.4 Hz, 1 H), 7.90 (d, J = 8.0 Hz, 2H), 7.64 (d, J = 7.6 Hz, 2H), 7.40 (d, J = 8.8 Hz, 1 H), 5.04 (s, 2H), 4.08 (s, 1 H), 3.99 (s, 3H), 3.67 - 3.58 (m, 2H), 3.16 - 3.09 (m, 1 H). Mass spectrum (ESI, m / z): Calcd. For C24H19F3N6O3, 496.1 ; found [M+H]+, 497.1.

[0387] Step N: 3-cyano-4-methoxy-N-((5aS,8aS)-7-methyl-4-oxo-5-(4-(trifluoromethyl)phenyl)- 5,5a,6,7,8,8a-hexahydro-4H-pyrazolon ,5-alpyrrolof3,4-elpyrazin-3-yl)benzamide. 3-cyano-4-methoxy- / V-((5aS,8aS)-4-oxo-5-(4-(trifluoromethyl)phenyl)-5,5a,6,7,8,8a-hexahydro- 4 / 7-pyrazolo[1 ,5-a]pyrrolo[3,4-e]pyrazin-3-yl)benzamide (35.0 mg, 70.5μmol), HCHO (37%, 10.5 μL, 106μmol), AcOH (3.3 μL, 58 μmol), NaBHsCN (6.6 mg, 106μmol), a stir bar, and anhydrous MeOH (1 mL) were added to a 8 mL glass vial. The mixture was stirred at r.t. for 4 h. The white suspension was turned to clear after 2 h. The reaction mixture was concentrated in vacuo to give a colourless oil. The oil was then subjected to silica gel chromatography (0-6% Methanol / Dichloromethane) to give 3-cyano-4-methoxy- / V-((5aS,8aS)-7-methyl-4-oxo-5-(4- (trifluoromethyl)phenyl)-5, 5a, 6,7,8, 8a-hexahydro-4 / 7-pyrazolo[1 ,5-a]pyrrolo[3,4-e]pyrazin-3- yl)benzamide as a white solid (10 mg, 21%).1H NMR (400 MHz, DMSO-d6) □ □ 9.87 (s, 1 H), 8.23 (d, J = 2.4 Hz, 1 H), 8.19 - 8.13 (m, 2H), 7.85 (d, J = 8.4 Hz, 2H), 7.63 (d, J = 8.4 Hz, 2H), 7.40 (d, J = 8.8 Hz, 1 H), 4.88 - 4.87 (m, 2H), 4.00 (s, 3H), 3.47 - 3.46 (m, 1 H), 3.24 - 3.19 (m, 1 H), 2.99 - 2.92 (m, 1 H), 2.65 - 2.64 (m, 1 H), 2.46 (s, 3H). Mass spectrum (ESI, m / z): Calcd. for C25H21F3N6O3, 510.2; found [M+H]+, 511.2.

[0388] Example 202: 3-Cvano-4-methoxy-N-((5aS,8aS)-7-(methylsulfonyl)-4-oxo-5-(4- (trifluoromethyl)phenyl)-5, 5a, 6,7,8, 8a-hexahvdro-4H-pyrazolori,5-a]pyrrolor3,4-elpyrazin- 3-yl)benzamide.

[0389] 3-Cyano-N-((5aS,8aS)-5-(4-(difluoro(phenyl)methyl)phenyl)-4-oxo-5, 5a, 6,7,8, 8a- hexa hydro-4 H- pyrazolo[1 ,5-a]pyrrolo[3,4-e]pyrazin-3-yl)-4-methoxybenzamide (Example 201 , product from Step M, 2.20 g, 4.43 mmol), anhydrous DCE (20.0 mL), a stir bar, TEA (1.85 mL, 13.3 mmol), and MS2O (1.16 g, 6.65 mmol) were added to a 50 mL round-bottomed flask. The mixture was stirred at r.t. for 2 h, the suspension became clear after nearly 1 h. Then the mixture became a white suspension. The reaction was monitored by LC-MS. The reaction mixture was cooled to r.t. and concentrated in vacuo to give a white solid. The white solid was dissolved in EtOAc (500 mL), washed with H2O (300 mL), sat.NaHCO3 (300 mL) and brine (300 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuum to give 3-cyano-4-methoxy-N- ((5aS,8aS)-7-(methylsulfonyl)-4-oxo-5-(4-(trifluoromethyl)phenyl)-5, 5a, 6,7,8, 8a- hexa hydro-4 H- pyrazolo[1 ,5-a]pyrrolo[3,4-e]pyrazin-3-yl)benzamide as white solid (1765.6 mg, 87%).1H NMR (400 MHz, DMSO-d6)n nn 09.90 (br s, 1 H), 8.24 (d, J = 2.4 Hz, 1 H), 8.21 (s, 1 H), 8.17 (dd, J = 2.4, 8.8 Hz, 1 H), 7.87 (d, J = 8.4 Hz, 2H), 7.68 (d, J = 8.4 Hz, 2H), 7.40 (d, J = 9.2 Hz, 1 H), 5.07 - 4.91 (m, 2H), 4.24 (br dd, J = 6.8, 8.8 Hz, 1 H), 3.99 (s, 3H), 3.82 - 3.72 (m, 1 H), 3.65 (br t, J = 7.2 Hz, 1 H), 3.27 - 3.18 (m, 1 H), 3.10 (s, 3H). Mass spectrum (ESI, m / z): Calcd. for C25H21F3N6O5S 574.1. m / z, found [M+H]+, 575.1.

[0390] Example 203: 3-vano-4-methoxy-N-((5aS,8aS)-7-(methylsulfonyl)-4-oxo-5-(4- (trifluoromethyl)phenyl)-5, 5a, 6,7,8, 8a-hexahvdro-4H-pyrazolori,5-a]pyrrolor3,4-elpyrazin- 3-yl)benzamide.

[0391] Step A: N-(tert-butyldimethylsilyl)methanesulfonamide.

[0392] Methanesulfonamide (1.00 g, 10.5 mmol), a stir bar, DCM (10.0 mL) and TEA (2.2 mL, 16 mmol) were charged to a 50 mL round-bottom flask and cooled to 0 °C with ice / water bath. The mixture was treated with TBSCI (2.38 g, 15.8 mmol) in DCM (5.0 mL) dropwise at 0 °C. Then the ice / water bath was removed and the mixture was stirred at r.t. for 12 h. The suspension gradually turned to a clear solution and then a white suspension during the progress. The reaction was monitored by TLC. The mixture was concentrated to dryness, re-dissolved with water (10 mL) and extracted with EtOAc (10 mL x 3). The combined extracts were washed with brine (5 mL x 3), dried over anhydrous Na2SO4 and concentrated to dryness under reduced pressure to give N-(tert-butyldimethylsilyl)methanesulfonamide as a white solid (2.04 g, 93%).1H NMR (400 MHz, DMSO-d6) δ: 7.06 (s, 1 H), 2.90 (s, 3H), 0.89 (s, 9H), 0.17 - 0.15 (m, 6H). Step B: N-((5aS,8aS)-7-(N-(tert-butyldimethylsilyl)-S-methylsulfonimidoyl)-4-oxo-5-(4- (trifluoromethyl)phenyl)-5,5a,6,7,8,8a-hexahydro-4H-pyrazolon ,5-alpyrrolof3,4-elpyrazin-3-yl)- 3-cyano-4-methoxybenzamide.

[0393] Triphenylphosphine dichloride (1.01 g, 3.02 mmol) and a stir bar were charged to an oven-dried 100 mL three-neck round-bottom flask, which was then evacuated and back-filled with nitrogen for 3 times. Then DCM (12.0 mL) and TEA (0.14 mL, 1.0 mmol) were added to the flask and the mixture was stirred at 20 ° for 10 min. Then the mixture was cooled to 0 °C with ice / water bath and treated with / V-(tert-butyldimethylsilyl)methanesulfonamide (632.6 mg, 3.022 mmol) in DCM (9.0 mL) dropwise at 0 °C. The mixture was stirred at 0 °C for 20 min. The colorless solution gradually turned to orange solution during the progress. Then 3-cyano-4-methoxy- / V- ((5aS,8aS)-4-oxo-5-(4-(trifluoromethyl)phenyl)-5,5a,6,7,8,8a-hexahydro-4 / 7-pyrazolo[1 ,5- a]pyrrolo[3,4-e]pyrazin-3-yl)benzamide (300.0 mg, 0.6040 mmol) in DCM (9.0 mL) was added to the above orange solution to form a yellow solution. The final mixture was stirred at 0° C for 30 mins and then the ice / water bath was removed, the mixture was allowed to warmed to room temperature and stirred for 12 h. The reaction was monitored by LC-MS. The mixture was concentrated to dryness and subjected to silica gel chromatography (0-25% EtOAc / DCM) to give / V-((5aS,8aS)-7-( / V-(tert-butyldimethylsilyl)-S-methylsulfonimidoyl)-4-oxo-5-(4- (trifluoromethyl)phenyl)-5, 5a, 6,7,8, 8a-hexahydro-4H-pyrazolo[1 ,5-a]pyrrolo[3,4-e]pyrazin-3-yl)- 3-cyano-4-methoxybenzamide as a white solid (381.6 mg, 90%).1H NMR (400 MHz, CDCh) 5: 9.60 (s, 1 H), 8.47 (d, J = 2.0 Hz, 1 H), 8.13 (d, J = 2.0 Hz, 1 H), 8.07 (dd, J = 2.4, 8.8 Hz, 1 H), 7.78 (d, J = 8.4 Hz, 2H), 7.43 (dd, J = 4.4, 8.0 Hz, 2H), 7.00 (d, J = 8.8 Hz, 1 H), 4.73 - 4.56 (m, 2H), 4.39 - 4.26 (m, 1 H), 3.99 (s, 3H), 3.87 - 3.70 (m, 2H), 3.28 - 3.11 (m, 1 H), 2.90 (d, J = 6.8 Hz, 3H), 0.88 (d, J = 5.2 Hz, 9H), 0.12 - 0.07 (m, 6H). Mass spectrum (ESI, m / z): Calcd. for C3iH36F3N7O4SSi, 687.2; m / z found [M+H]+, 688.4.

[0394] Step C: 3-Cyano-4-methoxy-N-((5aS,8aS)-7-(S-methylsulfonimidoyl)-4-oxo-5-(4- (trifluoromethyl)phenyl)-5,5a,6,7,8,8a-hexahydro-4H-pyrazolon ,5-alpyrrolof3,4-elpyrazin-3- vDbenzamide.

[0395] / V-((5aS,8aS)-7-( / V-(tert-Butyldimethylsilyl)-S-methylsulfonimidoyl)-4-oxo-5-(4- (trifluoromethyl)phenyl)-5, 5a, 6,7,8, 8a-hexahydro-4 / 7-pyrazolo[1 , 5-a]pyrrolo[3, 4-e]pyrazin-3-yl)- 3-cyano-4-methoxybenzamide (400.0 mg, 0.5820 mmol), a stir bar, MeOH (2.0 mL) and 4 M HCI / dioxane (2.0 mL) were charged into a 10 mL round-bottom flask at 20 °C. The mixture was stirred at 20 °C for 2 h. The reaction mixture was a clear solution. The mixture was concentrated to dryness to give an off-white solid. The solid was subjected to HPLC (Gilson, Welch Xtimate C18 5 pm, 150 x 30 mm; 42-72% ACN / H2O (with 0.05% of 25% aq. NH3and 10 mM NH4HCO3)) to give 3-cyano-4-methoxy- / V-((5aS,8aS)-7-(S-methylsulfonimidoyl)-4-oxo-5-(4-(trifluoromethyl)- phenyl)-5,5a,6,7,8,8a-hexahydro-4 / 7-pyrazolo[1 ,5-a]pyrrolo[3,4-e]pyrazin-3-yl)benzamide as a white solid (253.5 mg, 74%).1H NMR (400 MHz, DMSO-d6) δ:: 9.89 (s, 1 H), 8.24 (d, J = 2.4 Hz, 1 H), 8.20 (s, 1 H), 8.17 (dd, J = 2.4, 8.8 Hz, 1 H), 7.88 (br d, J = 7.2 Hz, 2H), 7.68 (dd, J = 2.4, 8.4 Hz, 2H), 7.40 (d, J = 8.8 Hz, 1 H), 5.03 - 4.88 (m, 2H), 4.24 - 4.10 (m, 1 H), 3.99 (s, 3H), 3.93 (s, 1 H), 3.73 - 3.61 (m, 1 H), 3.61 - 3.54 (m, 1 H), 3.11 (q, J = 9.6 Hz, 1 H), 2.95 (s, 3H). Mass spectrum (ESI, m / z): Calcd. for C25H22F3N7O4S, 573.1 ; m / z found, [M+H]+574.2. Example 204: Methyl 5-((5aS,8aS)-3-(3-cyano-4-methoxybenzamido)-7-(methylsulfonyl)-4- oxo-6, 7,8, 8a-tetrahvdro-4H-pyrazolori,5-a]pyrrolor3,4-elpyrazin-5(5aH)-yl)-2- (trifluoromethyl)benzoate.

[0396] Step A: 1 -Chloroethyl (5aS,8aS)-3-(3-cyano-4-methoxybenzamido)-4-oxo-4,5,5a,6,8,8a- hexahydro-7H-pyrazolon,5-alpyrrolo[3,4-elpyrazine-7-carboxylate.

[0397] 3-Cyano-4-methoxy- / V-((5aS,8aS)-7-(4-methoxybenzyl)-4-oxo-5,5a,6,7,8,8a-hexahydro-4 / 7- pyrazolo[1,5-a]pyrrolo[3,4-e]pyrazin-3-yl)benzamide (Example 201 , product from Step K, 3.00 g, 6.34 mmol), a stir bar, DIPEA (0.55 mL, 3.2 mmol) and CH3CN (60 mL) were added to a 250 mL three-necked round-bottomed flask fitted with a thermometer and a reflux condenser. The mixture was charged with 1-chloroethyl carbonochloridate (1.37 mL, 12.7 mmol) before put the flask in 80 °C oil bath and the mixture stirred for 16 h. The mixture is a buff suspension in the whole process. The reaction progress was monitored by LC-MS. The reaction mixture was cooled to r.t. , and concentrated in vacuo to give 1-chloroethyl (5aS,8aS)-3-(3-cyano-4- methoxybenzamido)-4-oxo-4,5,5a,6,8,8a-hexahydro-7 / 7-pyrazolo[1,5-a]pyrrolo[3,4-e]pyrazine-7- carboxylate as a brown solid (4.00 g, crude). Mass spectrum (ESI, m / z): Calcd. for C20H19CIN6O5458.1 m / z, found, [M+H]+, 459.1.

[0398] Step B: 3-Cyano-4-methoxy- / \ / -((5aS,8aS)-4-oxo-5,5a,6,7,8,8a-hexahvdro-4 / 7-pyrazolon,5- alpyrrolof3,4-elpyrazin-3-yl)benzamide.

[0399] 1 -Chloroethyl (5aS,8aS)-3-(3-cyano-4-methoxybenzamido)-4-oxo-4,5,5a,6,8,8a-hexahydro-7 / 7- pyrazolo[1,5-a]pyrrolo[3,4-e]pyrazine-7-carboxylate (3.00 g, crude), a stir bar, and anhydrous MeOH (60.0 mL) were added to a 250 mL round-bottomed flask fitted with a reflux condenser. Then put the flask in 80 °C oil bath and the suspension stirred for 6 h. The mixture is a buff suspension in the whole process. The reaction progress was monitored by LC-MS. The reaction mixture was cooled to r.t. and filtered, the filter cake was washed with DCM (20 mL x 3) and collected to give 3-cyano-4-methoxy- / V-((5aS,8aS)-4-oxo-5,5a,6,7,8,8a-hexahydro-4 / 7- pyrazolo[1,5-a]pyrrolo[3,4-e]pyrazin-3-yl)benzamide as a solid (2.30 g, 95%). Mass spectrum (ESI, m / z): Calcd. for C17H16N6O3 352.1 m / z, found, [M+H]+, 353.1.

[0400] Step C: 3-Cyano-4-methoxy- / \ / -((5aS,8aS)-7-(methylsulfonyl)-4-oxo-5,5a,6,7,8,8a-hexahydro- 4 / 7-pyrazolon,5-alpyrrolof3,4-elpyrazin-3-yl)benzamide. 3-Cyano-4-methoxy- / V-((5aS,8aS)-4-oxo-5,5a,6,7,8,8a-hexahydro-4 / 7-pyrazolo[1 ,5- a]pyrrolo[3,4-e]pyrazin-3-yl)benzamide (800.0 mg, 2.27 mmol), a stir bar and Pyridine (30.0 mL) were added to a 100 mL three-necked flask fitted with a reflux condenser, then treated with MS2O (1.98 g, 11.4 mmol). The resulting mixture stirred for 12 h at 100 °C, which formed a black suspension. The reaction progress was monitored by LC-MS. The black mixture was concentrated in vacuo to give an black solid, then was poured into MeOH (50 mL) and filtered, the filter cake was washed with MeOH (20 mL x 3) and collected to give 3-cyano-4-methoxy- / V- ((5aS,8aS)-7-(methylsulfonyl)-4-oxo-5,5a,6,7,8,8a-hexahydro-4 / 7-pyrazolo[1 ,5-a]pyrrolo[3,4- e]pyrazin-3-yl)benzamide as a dark gray solid (580 mg, 87% purity, 52%).1H NMR (400 MHz, DMSO-d6) δ:: 9.88 (s, 1 H), 9.04 (s, 1 H), 8.85 (d, J = 4.8 Hz, 1 H), 8.26 (d, J = 2.4 Hz, 1 H), 8.12 (s, 1 H), 7.44 (d, J = 9.2 Hz, 1 H), 4.60 - 4.49 (m, 1 H), 4.22 - 4.05 (m, 1 H), 4.05 - 4.05 (m, 1 H), 4.01 (s, 3H), 3.76 - 3.71 (m, 1 H), 3.63 (d, J = 9.6 Hz, 1 H), 3.08 (s, 3H), 2.31 (s, 1 H). Mass spectrum (ESI, m / z): Calcd. for CisHisNeOsS 430.1 m / z, found, [M+H]+, 431.1.

[0401] Step D: Methyl 5-((5aS,8aS)-3-(3-cyano-4-methoxybenzamido)-7-(methylsulfonyl)-4-oxo- 6,7,8,8a-tetrahydro-4 / - / -pyrazolon ,5-alpyrrolof3,4-elpyrazin-5(5a / - / )-yl)-2- (trifluoromethyl)benzoate.

[0402] The title compound was prepared in a manner analogous to Example 201 , Step L above, reacting 3-cyano-4-methoxy- / V-((5aS,8aS)-7-(methylsulfonyl)-4-oxo-5,5a,6,7,8,8a-hexahydro- 4 / 7-pyrazolo[1 ,5-a]pyrrolo[3,4-e]pyrazin-3-yl)benzamide (100.0 mg, 0.2323 mmol), a stir bar, methyl 5-bromo-2-(trifluoromethyl)benzoate (98.6 mg, 0.348 mmol), / VV / ^-dimethylethane-l ^- diamine (30 μL, 0.28 mmol, 0.819 g / mL), K2CO3 (96.3 mg, 0.697 mmol), Cui (53.1 mg, 0.28 mmol), and DMF (2.5 mL).1H NMR (400 MHz, DMSO-d6) δ:: 9.89 (s, 1 H), 8.25 (d, J = 2.0 Hz, 1 H), 8.23 - 8.12 (m, 2H), 8.02 (d, J = 8.4 Hz, 1 H), 7.94 (s, 1 H), 7.86 (br d, J = 8.8 Hz, 1 H), 7.40 (d, J = 9.2 Hz, 1 H), 5.07 - 4.91 (m, 2H), 4.28 - 4.24 (m, 1 H), 3.99 (s, 3H), 3.89 (s, 3H), 3.82 - 3.66 (m, 2H), 3.27 - 3.20 (m, 1 H), 3.10 (s, 3H). Mass spectrum (ESI, m / z): calcd. for C27H23F3N6O7S, 632.1 m / z, found, [M + H]+, 633.2.

[0403] Table 2 Example 53: N-((5aS,8aS)-7-Acetyl-5-(4-(cvclobutyldifluoromethyl)phenyl)-4-oxo- 5,5a,6,7,8,8a-hexahvdro-4H-pyrazolori,5-a]pyrrolor3,4-elpyrazin-3-yl)-3-cvano-4- methoxybenzamide.

[0404] / V-((5aS,8aS)-7-Acetyl-4-oxo-5,5a,6,7,8,8a-hexahydro-4 / 7-pyrazolo[1 ,5-a]pyrrolo[3,4-e]pyrazin- 3-yl)-3-cyano-4-methoxybenzamide (Example 14, product from Step B, 100.0 mg, 0.2540 mmol), K2CO3 (70.0 mg, 0.507 mmol), 1-bromo-4-(cyclobutyldifluoromethyl)benzene (79.4 mg, 0.304 mmol), DMEDA (26.8 mg, 0.304 mmol), Cui (57.9 mg, 0.304 mmol), DMF (10.0 mL) and a stir bar were added to an oven-dried and nitrogen-purged 50 mL round-bottomed flask fitted with a reflux condenser, which was subsequently evacuated and refilled with nitrogen (x3), and stirred until homogeneous. The reaction vessel placed in an oil bath that had been pre-heated to 100°C, and the mixture stirred for 12 h to give a green suspension. The reaction progress was monitored by TLC and LC-MS. The reaction mixture was then concentrated to dryness in vacuo, taken up in EtOAc (30 mL), washed with water (30 mL), sat. NaHCO3 (30 mL) and brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated to dryness in vacuo to give a green oil. The oil was then subjected to silica gel chromatography (30-100% EtOAc / pet ether) to give / V-((5aS,8aS)-7-acetyl-5-(4-(cyclobutyldifluoromethyl)phenyl)-4-oxo-5,5a,6,7,8,8a- hexahydro-4H-pyrazolo[1 ,5-a]pyrrolo[3,4-e]pyrazin-3-yl)-3-cyano-4-methoxybenzamide as a white solid (51.2 mg, 35%).

[0405] 1H NMR (400 MHz, CDCI3)_δ: 9.64 (s, 1 H), 8.49 (s, 1 H), 8.17 - 8.05 (m, 2H), 7.64 - 7.55 (m, 2H), 7.37 - 7.28 (m, 2H), 7.04 - 6.97 (m, 1 H), 4.74 - 4.54 (m, 2H), 4.47 (dd, J = 7.2, 9.6 Hz, 1 H), 4.08 - 3.97 (m, 4.5H), 3.83 - 3.72 (m, 0.5H), 3.23 (t, J = 11.2 Hz, 1 H), 3.05 - 2.91 (m, 1 H), 2.31 - 2.20 (m, 2H), 2.14 (s, 2H), 2.08 - 1.85 (m, 5H). Mass spectrum (ESI, m / z): calcd. for C30H28F2N6O4, 574.2; found [M+H]+, 575.3. Example 54: N-((5aS,8aS)-7-Acetyl-5-(4-(cvclopropyldifluoromethyl)phenyl)-4-oxo- 5,5a,6,7,8,8a-hexahvdro-4H-pyrazolori,5-alpyrrolor3,4-e]pyrazin-3-yl)-3-cvano-4- methoxybenzamide.

[0406] Step A: 1-Bromo-4-(cyclopropyldifluoromethyl)benzene. (4-Bromophenyl)(cyclopropyl)methanone (400.0 mg, 1.777 mmol), a stir bar, and 2,2-difluoro- 1 ,3-dimethylimidazolidine (1.60 g, 11.8 mmol) were added to an oven-dried and nitrogen-purged 4 mL microwave vial, which was subsequently capped and heated at 120°C via microwave irradiation for 6 h. The reaction progress was monitored by TLC. The reaction mixture was then treated with sat. NaHCO3 (30 mL), dropwise over 2 min at 0°C, extracted with EtOAc (30 mL x 2), and the combined extracts were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated to dryness in vacuo to give a yellow oil. The oil was then subjected to silica gel chromatography (100% pet ether) to give 1-bromo-4 (cyclopropyldifluoromethyl)- benzene as colorless oil (350 mg, 80%).1H NMR (400 MHz, CDCI3)_δ: 7.5Q (d, J = 8.4 Hz, 2H), 7.42 (d, J = 8.8 Hz, 2H), 1.54 - 1.42 (m, 1 H), 0.79 - 0.73 (m, 2H), 0.73 - 0.64 (m, 2H)

[0407] Step B: N-((5aS,8aS)-7-Acetyl-5-(4-(cyclopropyldifluoromethyl)phenyl)-4-oxo-5,5a,6,7,8,8a- hexahydro-4H-pyrazolon,5-alpyrrolof3,4-elpyrazin-3-yl)-3-cyano-4-methoxybenzamide.

[0408] N-((5aS,8aS)-7-Acetyl-4-oxo-5, 5a, 6,7,8, 8a-hexahydro-4H-pyrazolo[1,5-a]pyrrolo[3,4-e]pyrazin- 3-yl)-3-cyano-4-methoxybenzamide (Example 14, product from Step B, 150.0 mg, 0.380 mmol), a stir bar, 1-bromo-4-(cyclopropyldifluoromethyl)benzene (112.8 mg, 0.456 mmol), K2CO3 (105.1 mg, 0.761 mmol), DMF (1.5 mL), toluene (1.5 mL), Cui (86.9 mg, 0.456 mmol), and DMEDA (40.2 mg, 0.456 mmol) were added to an oven-dried and nitrogen-purged 10 mL round- bottomed flask fitted with a reflux condenser, and the resulting mixture stirred for 12 h at 100°C. The reaction progress was monitored by TLC. The reaction vessel was removed from the heating mantle and allowed to gradually cool to r.t. The reaction mixture was diluted with EtOAc (80 mL), washed with H2O (40 mL) and brine (40 mL), dried over anhydrous Na2SO4, filtered, and concentrated to dryness in vacuo to give a brown oil. The oil was then subjected to silica gel chromatography (0-5% DCM / MeOH) followed by prep-HPLC (55-Boston Prime C18, 5 pm, 150 mm x 30 mm; 7 min gradient ( 53-83% ACN / H2O (0.05% of 30% aq NH3+ 10 mM NH4HCO3)) at 25 mL / min to give the N-((5aS,8aS)-7-acetyl-5-(4-(cyclopropyldifluoromethyl)- phenyl)-4-oxo-5, 5a, 6,7,8, 8a-hexahydro-4H-pyrazolo[1, 5-a]pyrrolo[3, 4-e]pyrazin-3-yl)-3-cyano-4- methoxybenzamide as a white solid (85.3 mg, 40% yield).1H NMR (400 MHz, DMSO-d6) d : 9.88 (s, 1H), 8.23 (t, J = 2.0 Hz, 1 H), 8.20 (s, 1H), 8.18 - 8.13 (m, 1 H), 7.68 (d, J = 8.4 Hz, 2H),

[0409] 7.57 - 7.49 (m, 2H), 7.39 (d, J = 9.2 Hz, 1 H), 5.06 - 4.80 (m, 2H), 4.45 (dd, J = 7.6, 8.8 Hz, 0.5 H), 4.30 (dd, J = 7.2, 10.4 Hz, 0.5 H), 3.99 (s, 3H), 3.95 - 3.83 (m, 1H), 3.73 (dd, J = 7.2, 10.4 Hz, 0.5 H), 3.60 - 3.50 (m, 0.5 H), 3.42 - 3.38 (m, 0.5 H), 2.99 (t, J = 10.4 Hz, 0.5 H), 2.08 - 1.87 (m, 3H), 1.84 - 1.67 (m, 1H), 0.77 - 0.64 (m, 4H). Mass spectrum (ESI, m / z): calcd. for C29H26F2N6O4, 560.2; found [M+H]+, 561.2.

[0410] Table 3

[0411] General Scheme for the synthesis of compounds described in Table 3 and 4

[0412] 5 Scheme 2

[0413] Example 55: 3-Cvano-N-((5aS,8aR)-5-(4-(difluoro(phenyl)methyl)phenyl)-4-oxo- 5,5a,6,7,8,8a-hexahvdro-4H-pyrazolori,5-alpyrrolor3,4-e]pyrazin-3-yl)-4-

[0414] Step A: ethyl 1-((3R,4S)-1-(tert-butoxycarbonyl)-4-((tert-butoxycarbonyl)amino)pyrrolidin-3-yl)-4- iodo-1 H-pyrazole-5-carboxylate

[0415] A mixture of compound 2 (10 g, 33.1 mmol, 1.4 eq), compound 2A (6.28 g, 23.6 mmol, 1 eq) CMBP (7.98 g, 33.1 mmol, 1.4 eq) and Tol. (100 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 60°C for 12 hrs under N2 atmosphere. LC-MS showed reactant 1 was consumed completely and one main peak with desired m / z. Combined the 20 batches. The reaction mixture was quenched by addition sat., aq., Na2COs (300 mL), and then extracted with EtOAc (200 mL * 3). The combined organic layers were washed with brine (500 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a crude ethyl 1-((3R,4S)-1-(tert-butoxycarbonyl)-4-((tert-butoxycarbonyl)amino)pyrrolidin-3-yl)-4- iodo-1 H-pyrazole-5-carboxylate and was purified by column chromatography yield ethyl 1- ((3R,4S)-1-(tert-butoxycarbonyl)-4-((tert-butoxycarbonyl)amino)pyrrolidin-3-yl)-4-iodo-1 H- pyrazole-5-carboxylate (92.1 g, 150.6 mmol, 31.8% yield, 90% purity) as a yellow solid. LCMS: MS (ESI) m / z = 438.9 [M+H-56-56]+ 1HNMR: 400 MHz, chloroform-d 5 = 7.63 (s, 1 H), 5.98 - 5.82 (m, 1 H), 4.87 - 4.56 (m, 2H), 4.46 - 4.36 (m, 2H), 3.90 - 3.71 (m, 3H), 3.55 - 3.46 (m, 1H), 1.45 (s, 12H), 1.42 (s, 9H) ppm.

[0416] Step B: tert-butyl (5aS,8aR)-3-iodo-4-oxo-4,5,5a,6,8,8a-hexahvdro-7H-pyrazolon,5- alpyrrolof3,4-elpyrazine-7-carboxylate

[0417] A mixture of ethyl 1-((3R,4S)-1-(tert-butoxycarbonyl)-4-((tert-butoxycarbonyl)amino)pyrrolidin-3- yl)-4-iodo-1 H-pyrazole-5-carboxylate (80.0 g, 145 mmol, 1 eq), HCI / dioxane (4 M, 363 mL, 10 eq) and dioxane (300 mL) at 0°C, was degassed and purged with N2 for 3 times, and then the mixture was stirred at 20°C for 1 hr under N2 atmosphere. LC-MS showed reactant was consumed completely and one main peak with desired ms was detected. To the mixture was added H2O (400 mL) then extracted by EtOAc (200 mL*2). The aqueous of compound 4 (crude, HCI) was used to next step without further purification. LCMS (ESI) m / z = 351 [M+H]+To a solution of ethyl 1-((3R,4S)-4-aminopyrrolidin-3-yl)-4-iodo-1 H-pyrazole-5-carboxylate (174 mmol, 1 eq) in H2O (600 mL) was added K2CO3 (96.3 g, 697 mmol, 4 eq). The mixture was stirred at 25°C for 1 hr. LCMS showed compound 4 was consumed completely and one main peak with desired MS was detected. Then drip BOC2O (114 g, 523 mmol, 120 mL, 3 eq) to the reaction. Then the mixture was stirred at 40°C for 3 hrs under N2 atmosphere. LC-MS showed reactant was consumed completely. The reaction mixture was extracted with EtOAc (100 mL * 3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiC>2, Petroleum ether / Ethyl acetate=10 / 1 to 0 / 1). (PE: EA = 0:1 reactant Rf= 0.1, product Rf = 0.7 UV = 254). tert-butyl (5aS,8aR)-3-iodo-4-oxo-4,5,5a,6,8,8a- hexahydro-7H-pyrazolo[1,5-a]pyrrolo[3,4-e]pyrazine-7-carboxylate (40.1 g, 96.2 mmol, 55.2% yield, 97.0% purity) was obtained as a white solid. LCMS: Product: RT = 1.266 min, MS (ESI) m / z = 348.7 [M+H-56]+HNMR: 400 MHz, DMSO-cfe 6 = 8.51 (br d, J = 3.3 Hz, 1 H), 7.78 (s, 1 H), 4.99 (br d, J = 4.6 Hz, 1 H), 4.49 - 4.40 (m, 1 H), 3.97 - 3.85 (m, 1 H), 3.82 - 3.58(m, 2H), 3.14 - 3.00 (m, 1 H), 1.37 (br s, 9H) ppm.

[0418] Step C (5aS,8aR)-3-iodo-5, 5a, 6,7,8, 8a-hexahvdro-4 / 7-pyrazolon,5-alpyrrolof3,4-elpyrazin-4- one tert-Butyl (5aS,8aR)-3-iodo-4-oxo-4,5,5a,6,8,8a-hexahydro-7 / 7-pyrazolo[1,5-a]pyrrolo[3,4- e]pyrazine-7-carboxylate (7.84 g, 19.4 mmol), a stir bar, and HCI / 1 , 4-dioxane (80.0 mL, 2 M) were added to a 250 mL round-bottom flask. The mixture stirred for 3 h at r.t. , which formed off- white suspension. The reaction progress was monitored by TLC and LC-MS. The mixture was concentrated in vacuum to give the (5aS,8aR)-3-iodo-5,5a,6,7,8,8a-hexahydro-4 / 7-pyrazolo[1,5- a]pyrrolo[3,4-e]pyrazin-4-one (6.53 g, 99%) as a white solid. Mass spectrum (ESI, m / z): Calcd. for C8H9IN4O, 304.1; found [M+H]+, 305.0.

[0419] Step D: (5aS,8aR)-3-lodo-7-(4-methoxybenzyl)-5,5a,6,7,8,8a-hexahydro-4 / - / -pyrazolon,5- alpyrrolof3,4-elpyrazin-4-one.

[0420] (5aS,8aR)-3-lodo-5,5a,6,7,8,8a-hexahydro-4 / 7-pyrazolo[1,5-a]pyrrolo[3,4-e]pyrazin-4-one HCI salt (6.53 g, 19.2 mmol), 4-methoxybenzaldehyde (6.99 mL, 57.5 mmol, 1.12 g / mL), AcOH (2.2 mL, 38 mmol, 1.05 g / mL), a stir bar, and anhydrous MeOH (140 mL) were added to a 500 mL three-necked flask. The light yellow mixture was stirred at r.t. for 5 min before treated with NaBHsCN (3.62 g, 57.5 mmol) and stirred at 50°C for 12 h, which formed a light yellow suspension. The reaction progress was monitored by TLC and LC-MS. The reaction mixture was filtered and the filter cake was washed with MeOH (20 mL x 2). The filtrate concentrated in vacuum to move MeOH, then the mixture was basified with sat. NaHCOs (100 mL), extracted with EtOAc (100 mL x 2). The combined extracts were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the a brown solid. The solid was then subjected to silica gel chromatography (87-100% EtOAc / Pet ether) to give the (5aS,8aR)- 3-iodo-7-(4-methoxybenzyl)-5,5a,6,7,8,8a-hexahydro-4 / 7-pyrazolo[1 ,5-a]pyrrolo[3,4-e]pyrazin-4- one as a white foam (7.70 g, 95%).1H NMR (400 MHz, DMSO-d6) δ:: 8.37 (d, J = 2.8 Hz, 1 H), 7.72 (s, 1 H), 7.13 (d, J = 8.8 Hz, 2H), 6.85 (d, J = 8.8 Hz, 2H), 5.01 - 4.87 (m, 1 H), 4.34 - 4.21 (m, 1 H), 3.72 (s, 3H), 3.57 - 3.44 (m, 2H), 3.07 - 2.92 (m, 2H), 2.76 (dd, J = 6.8, 9.6 Hz, 1 H), 2.58 (dd, J = 4.8, 9.6 Hz, 1 H). Mass spectrum (ESI, m / z): Calcd. for C16H17IN4O2, 424.0; found [M+H]+, 425.1.

[0421] E: tert- i-3-iodo-7-(4- i-4-oxo-6, 7 , 8 , 8a-tetrahyd ro-4 / 7- pyrazolo[1 ,5-a]pyrrolo[3,4-e]pyrazine-5(5a / - / )-carboxylate.

[0422] (5aS,8aR)-3-lodo-7-(4-methoxybenzyl)-5,5a,6,7,8,8a-hexahydro-4 / 7-pyrazolo[1 ,5-a]pyrrolo[3,4- e]pyrazin-4-one (7.70 g, 18.1 mmol), BOC2O (7.92 g, 36.3 mmol), DMAP (443.0 mg, 3.630 mmol), TEA (3.80 mL, 27.2 mmol, 0.726 g / mL), a stir bar and toluene (120 mL) were added to 250 mL three-necked flask fitted with a reflux condenser, the mixture was stirred at 100°C for 3 h and give a light brown solution. The reaction progress was monitored by TLC and LC-MS. The light brown mixture was diluted with H2O (120 mL), extracted with EtOAc (120 mL x 2), the combined extracts were washed with brine (120 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuum to give a brown oil. The oil was then subjected to silica gel chromatography (25-30% EtOAc / Pet ether) to give the tert-butyl (5aS,8aR)-3-iodo-7-(4- methoxybenzyl)-4-oxo-6,7,8,8a-tetrahydro-4 / 7-pyrazolo[1 ,5-a]pyrrolo[3,4-e]pyrazine-5(5a / - / )- carboxylate as a light yellow oil. (9.00 g, 94%)1H NMR (400 MHz, CDCI3) d : 7.71 (s, 1 H), 7.11 (d, J = 8.4 Hz, 2H), 6.83 (d, J = 8.4 Hz, 2H), 5.01 (q, J = 7.2 Hz, 1 H), 4.86 - 4.81 (m, 1 H), 3.80 (s, 3H), 3.63 - 3.57 (m, 2H), 3.56 - 3.49 (m, 1 H), 3.29 - 3.16 (m, 2H), 2.67 - 2.63 (m, 1 H), 1.57 (s, 9H). Mass spectrum (ESI, m / z): Calcd. for C21H25IN4O4 524.1 ; found [M+H]+, 525.1.

[0423] F: tert- i-3-((tert-butoxycarbonyl)amino)-7-(4-methoxybenzyl)-4-oxo-

[0424] 6,7,8,8a-tetrahydro-4 / 7-pyrazolo[1 ,5-a]pyrrolo[3,4-e]pyrazine-5(5a / - / )-carboxylate.

[0425] (5aS,8aR)-tert-Butyl 3-iodo-7-(4-methoxybenzyl)-4-oxo-6,7,8,8a-tetrahydro-4H-pyrazolo[1 ,5- a]pyrrolo[3,4-e]pyrazine-5(5aH)-carboxylate (8.90 g, 17.0 mmol), tert-butyl carbamate (9.94 g, 84.9 mmol), Xphos (2.43 g, 5.09 mmol), CS2CO3 (11.1 g, 33.9 mmol), a stir bar, and toluene (150 mL) were added to a 250 mL round-bottomed flask fitted with a thermometer and a reflux condenser. The resulting mixture was evaporated and backfilled with N2 for 3 times before charged with Pd2(dba)s (1.55 g, 1.70 mmol), then evaporated and backfilled with N2 for 3 times, and then heated to 90°C for 16 h. The suspension became yellow from brown after a while. The reaction progress was monitored by TLC and LC-MS. The reaction mixture was cooled to r.t. and diluted with H2O (150 mL) and EtOAc (150 mL), then extracted with EtOAc (150 mL x 3). The combined extracts were washed with brine (150 mL x 4), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a yellow solid. The solid was subjected to silica gel chromatography (0-60% EtOAc / pet ether to 0-10% MeOH / DCM) to give two products. First eluting: (5aS,8aR)-tert-butyl 3-((tert-butoxycarbonyl)amino)-7-(4-methoxybenzyl)-4-oxo- 6,7,8,8a-tetrahydro-4H-pyrazolo[1,5-a]pyrrolo[3,4-e]pyrazine-5(5aH)-carboxylate as an lightyellow solid (10 g, crude).1H NMR (400 MHz, DMSO-d6) d : 8.49 (d, J = 2.8 Hz, 1 H), 8.05 (br s, 1 H), 7.83 (br s, 1H), 7.14 (d, J = 8.4 Hz, 2H), 6.86 (d, J = 8.8 Hz, 2H), 4.89 - 4.81 (m, 1 H), 4.34 - 4.26 (m, 1 H), 3.72 (s, 3H), 3.52 (s, 2H), 3.01 (d, J = 4.8 Hz, 2H), 2.81 - 2.77 (m, 1 H), 2.58 - 2.55 (m, 1 H), 1.47 (s, 9H). Mass spectrum (ESI, m / z): Calcd. for C26H35N5O6 513.3; found [M+H]+, 514.3. Second eluting: tert-butyl ((5aS,8aR)-7-(4-methoxybenzyl)-4-oxo-5,5a,6,7,8,8a- hexahydro-4H-pyrazolo[1,5-a]pyrrolo[3,4-e]pyrazin-3-yl)carbamate as an yellow foamed solid (1.1 g, 16%). Mass spectrum (ESI, m / z): Calcd. for C21H27N5O4, 413.2; found [M+H]+, 414.2.

[0426] Step G: (5aS,8aR)-3-Amino-7-(4-methoxybenzyl)-5,5a,6,7,8,8a-hexahydro-4 / 7-pyrazolon,5- alpyrrolof3,4-elpyrazin-4-one. tert-Butyl (5aS,8aR)-3-((tert-butoxycarbonyl)amino)-7-(4-methoxybenzyl)-4-oxo-6,7,8,8a- tetrahydro-4H-pyrazolo[1,5-a]pyrrolo[3,4-e]pyrazine-5(5aH)-carboxylate (9.00 g, 17.5 mmol) and tert-butyl ((5aR,8aS)-7-(4-methoxybenzyl)-4-oxo-5,5a,6,7,8,8a-hexahydro-4H-pyrazolo[1,5- a]pyrrolo[3,4-e]pyrazin-3-yl)carbamate (800.0 mg, 1.935 mmol), a stir bar, and 4 N HCI / dioxane (100 mL) were added to a 250 mL round-bottomed flask, and the resulting mixture stirred for 2 h at r.t. The reaction progress was monitored by TLC and LC-MS. The mixture was quenched with aq. NaHCO3 to pH at 8, then extracted with EtOAc (200 mL x 2). The combined extracts were washed with brine (200 mL x 2), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a light-brown oil (2.98 g, 46%). Mass spectrum (ESI, m / z): Calcd. for C16H19N5O2 313.2; found [M+H]+, 314.2.

[0427] Step H: 3-Cyano-4-methoxy- / \ / -((5aS,8aR)-7-(4-methoxybenzyl)-4-oxo-5,5a,6,7,8,8a-hexahydro- 4 / 7-pyrazolon,5-alpyrrolof3,4-elpyrazin-3-yl)benzamide.

[0428] 3-Cyano-4-methoxybenzoic acid (1.89 g, 10.6 mmol), (5aS,8aR)-3-amino-7-(4-methoxybenzyl)- 5,5a,6,7,8,8a-hexahydro-4H-pyrazolo[1,5-a]pyrrolo[3,4-e]pyrazin-4-one (2.90 g, 9.26 mmol), DIPEA (4.8 mL, 28 mmol), a stir bar, and anhydrous DMF (40.0 mL) were added to a 100 mL round-bottomed flask. The resulting mixture was treated with HATU (4.58 g, 12.0 mmol) and stirred at r.t. for 16 h. The reaction progress was monitored by TLC and LC-MS. The reaction mixture was poured into H2O (80 mL) and some precipitate separate out. The suspension was filtered and filter cake was rinsed with EtOAc (80 mL x 3). The precipitate was collected and concentrated in vacuo to give 3-cyano-4-methoxy-N-((5aS,8aR)-7-(4-methoxybenzyl)-4-oxo- 5,5a,6,7,8,8a-hexahydro-4H-pyrazolo[1,5-a]pyrrolo[3,4-e]pyrazin-3-yl)benzamide as an off-white solid (3.4 g, 66%).1H NMR (400 MHz, DMSO-d6) d : 9.87 (s, 1 H), 8.59 (d, J = 2.8 Hz, 1 H), 8.23 (d, J = 2.0 Hz, 1H), 8.17 - 8.15 (m, 1 H), 8.11 (s, 1 H), 7.44 (d, J= 9.2 Hz, 1 H), 7.15 (d, J = 8.8 Hz, 2H), 6.86 (d, J = 8.8 Hz, 2H), 4.96 - 4.89 (m, 1H), 4.38 - 4.32 (m, 1 H), 4.01 (s, 3H), 3.75 - 3.69 (m, 3H), 3.59 - 3.49 (m, 2H), 3.08 - 3.01 (m, 2H), 2.84 - 2.78 (m, 1 H), 2.62 - 2.57 (m, 1 H).

[0429] Mass spectrum (ESI, m / z): Calcd. for C25H24N6O4, 472.2; found [M+H]+, 473.1.

[0430] Step I: 3-Cvano- / V-((5aS,8aF?)-5-(4-(difluoro(phenyl)methyl)phenyl)-7-(4-methoxybenzyl)-4-oxo- 5,5a,6,7,8,8a-hexahydro-4 / 7-pyrazolon ,5-alpyrrolof3,4-elpyrazin-3-yl)-4-methoxybenzamide. 3-Cyano-4-methoxy-N-((5aS,8aR)-7-(4-methoxybenzyl)-4-oxo-5, 5a, 6,7,8, 8a-hexahydro-4H- pyrazolo[1 ,5-a]pyrrolo[3,4-e]pyrazin-3-yl)benzamide (6.20 g, 13.1 mmol), 1-bromo-4- (difluoro(phenyl)methyl)benzene (5.57 g, 19.7 mmol), N1,N2-dimethylethane-1 ,2-diamine (1.7 mL, 16 mmol), K2CO3 (5.44 g, 39.4 mmol), a stir bar, anhydrous DMF (120 mL) were added to a 250 mL round-bottomed flask. The flask was evaporated and backfilled with N2 for 3 times before charged with Cui (3.00 g, 15.7 mmol), then evaporated and backfilled with N2 for 3 times. The flask was then stirred at 100°C for 4 h. The reaction progress was monitored by TLC. The reaction mixture was cooled to r.t. and poured into H2O (250 mL), extracted with EtOAc (120 mL x 3). The combined extracts were washed with brine (120 mL x 3), dried over anhydrous Na2SC>4, filtered and concentrated in vacuo to give a green solid. The solid was subjected to silica-gel chromatography (50-75% EtOAc / pet ether) to give 3-cyano-N-((5aR,8aS)-5-(4- (difluoro(phenyl)methyl)phenyl)-7-(4-methoxybenzyl)-4-oxo-5, 5a, 6,7,8, 8a-hexahydro-4H- pyrazolo[1 ,5-a]pyrrolo[3,4-e]pyrazin-3-yl)-4-methoxybenzamide as an off-white solid (4.3 g, 48%).1H NMR (400 MHz, DMSO-d6) δ: 9.91 (s, 1 H), 8.21 (s, 2H), 8.15 (dd, J = 2.0, 8.8 Hz, 1 H), 7.66 - 7.59 (m, 2H), 7.59 - 7.47 (m, 7H), 7.40 (d, J = 9.2 Hz, 1 H), 7.11 (d, J = 8.4 Hz, 2H), 6.83 (d, J = 8.8 Hz, 2H), 5.16 - 5.08 (m, 1 H), 4.92 (q, J = 7.2 Hz, 1 H), 3.99 (s, 3H), 3.71 (s, 3H), 3.61 - 3.49 (m, 2H), 3.37 (br d, J = 2.0 Hz, 1 H), 3.09 (dd, J = 5.2, 10.4 Hz, 1 H), 2.99 - 2.88 (m, 1 H), 2.75 (dd, J = 6.8, 10.0 Hz, 1 H). Mass spectrum (ESI, m / z): Calcd. for C38H32F2N6O4, 674.3; found [M+H]+, 675.3.

[0431] Step J: 3-Cvano- / V-((5aS,8aF?)-5-(4-(difluoro(phenyl)methyl)phenyl)-4-oxo-5,5a,6,7,8,8a- hexahydro-4 / 7-pyrazolon ,5-alpyrrolof3,4-elpyrazin-3-yl)-4-methoxybenzamide. 3-Cyano-N-((5aS,8aR)-5-(4-(difluoro(phenyl)methyl)phenyl)-7-(4-methoxybenzyl)-4-oxo- 5,5a,6,7,8,8a-hexahydro-4H-pyrazolo[1 ,5-a]pyrrolo[3,4-e]pyrazin-3-yl)-4-methoxybenzamide (4.30 g, 6.37 mmol), a stir bar, and DCE (50.0 mL) were added to a 100 mL round-bottomed flask. The mixture was charged with carbonochloridic acid 1 -chloro-ethyl ester (1.3 mL, 13 mmol) and stirred at r.t. for 2 h, then treated with anhydrous MeOH (12.0 mL). The flask was stirred at 60°C for 1 h, some white precipitate separated out. The reaction progress was monitored by TLC. The reaction mixture was cooled to r.t. and filtered, the filter cake was washed with DCM (50 mL x 3) to give 3-cyano-N-((5aR,8aS)-5-(4- (difluoro(phenyl)methyl)phenyl)-4-oxo-5,5a,6,7,8,8a-hexahydro-4H-pyrazolo[1 ,5-a]pyrrolo[3,4- e]pyrazin-3-yl)-4-methoxybenzamide as a white solid (2.59 g, 67%).1H NMR (400 MHz, DMSO- cfe)_δ: 9.93 (s, 1 H), 9.88 (br s, 1 H), 8.31 (s, 1 H), 8.22 (d, J = 2.4 Hz, 1 H), 8.19 - 8.13 (m, 1 H), 7.71 - 7.62 (m, 4H), 7.60 - 7.50 (m, 5H), 7.41 (d, J = 8.8 Hz, 1H), 5.39 - 5.33 (m, 1H), 5.14 - 5.05 (m, 1 H), 4.18 (d, J = 12.8 Hz, 1 H), 3.99 (s, 3H), 3.86 - 3.75 (m, 2H), 3.32 - 3.24 (m, 1 H). Mass spectrum (ESI, m / z): Calcd. For C30H24F2N6O3, 554.2; found [M+H]+, 555.2.

[0432] Example 250: N-((5aS,8aS)-7-acetyl-5-(4-(bicvclori.1.1]pentan-1-yldifluoromethyl)phenyl)- 4-OXO-5, 5a, 6,7,8, 8a-hexahvdro-4H-pyrazolori,5-a]pyrrolor3,4-elpyrazin-3-yl)-3-cvano-4- methoxybenzamide.

[0433] Step A: / V-methoxy- / \ / -methylbicyclon.1.1lpentane-1 -carboxamide.

[0434] Bicyclo[1.1.1]pentane-1 -carboxylic acid (300.0 mg, 2.676 mmol), EDCI (769.4 mg, 4.013 μmol), a stir bar and DCE(6.0 mL) were added to a 50 mL round-bottomed flask. The resulting mixture was stirred at r.t. for 0.5 h as a white suspension, then which charged with HOBt (72.3 mg, 0.535μmol), DIPEA (1.5 mL, 9.4 mmol), / V.O-dimethylhydroxylamine hydrochloride (522.0 mg, 5.351 mmol). The resulting mixture was stirred at r.t. for 12 h as a white homogeneous. The reaction progress was monitored by TLC. The reaction mixture was quenched with aq. NaHCO3 (3 mL), diluted with H2O (5 mL), extracted with DCM (10 mL x 3). The combined extracts were washed with brine (10 mL x 2), dried over anhydrous Na2SO4, filtered and concentrated in vacuum to give a colorless oil. The oil was then subjected to silica gel chromatography (0-10% EtOAc / Petroleum ether) to give / V-methoxy- / V-methylbicyclo[1.1.1]pentane-1 -carboxamide as a colorless oil (233.7 mg, 56%).1H NMR (400 MHz, DMSO-d6) δ:: 3.64 (s, 3H), 3.07 (s, 3H), 2.43 (s, 1H), 2.04 (s, 6H).

[0435] Step B: Bicvclon .1.11pentan-1-yl(4-bromophenyl)methanone. 1-Bromo-4-iodobenzene (1.09 g, 3.87 mmol), a stir bar and THF (4.0 mL) were added to an oven-dried and nitrogen-purged 50 mL round bottomed flask, which was subsequently evacuated and refilled with nitrogen (x3) and cooled to -70 °C in an EtOH / Dry Ice bath, and the resulting mixture treated with n-BuLi (1.55 mL, 2.5 M, 3.87 mmol) dropwise over 1 min, the mixture stirred for 0.5 h, then which charged with the solution of / V-methoxy-ZV- methylbicyclo[1.1.1]pentane-1 -carboxamide (400.0 mg, 2.577 mmol) in THF (4.0 mL), and the mixture stirred at -70 °C for 2 h, finally the reaction mixture was yellow suspension. The reaction progress was monitored by TLC and LCMS. The resulting mixture was adjusted pH to 1-2 with 1 M HCI. The reaction mixture was diluted with water (20 mL), and extracted with EtOAc (20 mL x 3). The combined extracts were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuum to give a yellow solid. The solid was then subjected to silica gel chromatography (0-10% EtOAc / pet ether) to give bicyclo[1.1.1]pentan-1-yl(4- bromophenyl)methanone as a colorless oil (335.7 mg, 47%).1H NMR (400 MHz, CDCh) 5: 7.87 (d, J = 8.4 Hz, 2H), 7.59 (d, J = 8.4 Hz, 2H), 2.59 (s, 1 H), 2.32 (s, 6H). Mass spectrum (ESI, m / z): Calcd for Ci2HnBrO 250.0 / 252.0; found [M+H]+, 251.0 / 252.9.

[0436] Step C: 2-(Bicyclon .1.1lpentan-1-yl)-2-(4-bromophenyl)-1 ,3-dithiane. Bicyclo[1.1.1]pentan-1-yl(4-bromophenyl)methanone (330.0 mg, 1.314 mmol), a stir bar, DCM (8.0 mL) were added to 50 mL round-bottomed flask, which was subsequently cooled to 0 °C in the water / ice bath, and the resulting mixture treated with BF3'OEt2 (0.41 mL, 3.3 mmol) dropwise over 1 min, The mixture was stirred at r.t. for 2 min before treated with propane-1 , 3- dithiol (0.26 mL, 2.6 mmol) and the yellow homogeneous mixture stirred at r.t. for 12 h. The reaction progress was monitored by TLC. The reaction mixture was quenched by adding into saturated NaHCO3 (10 mL) dropwise, then extracted with DCM (10 mL x 3). The combined extracts were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuum to give a yellow oil. The oil was subjected to silica gel chromatography (0-10% EtOAc / Petroleum ether gradient) to give 2-(bicyclo[1.1.1]pentan-1-yl)-2-(4- bromophenyl)-1 ,3-dithiane as a white solid (487.3 mg, 96%).1H NMR (400 MHz, CDCI3) 5: 7.84 - 7.74 (m, 2H), 7.57 - 7.45 (m, 2H), 2.66 - 2.60 (m, 4H), 2.47 (s, 1 H), 1.93 - 1.89 (m, 2H), 1.66 (s, 6H). Mass spectrum (ESI, m / z): Calcd for Ci5Hi?BrS2 340.0 / 342.0; found [M+H]+, 341.0 / 342.9

[0437] Step D: 1-((4-Bromophenyl)difluoromethyl)bicyclon .1.1lpentane. 2-(Bicyclo[1.1.1]pentan-1-yl)-2-(4-bromophenyl)-1 ,3-dithiane (200.0 mg, 585.9μmol), DCM (4.0 mL), a stir bar, and DAST (0.23 mL, 1.22 g / mL, 1.76 mmol) were added to a 10 mL singlenecked round bottomed flask, the yellow homogeneous mixture stirred at r.t. overnight. The reaction progress was monitored by TLC. The reaction mixture was diluted with DCM (10 mL), quenched with saturated NaHCO3 (10 mL) under 0 °C and extracted with DCM (10 mL x 3), washed with brine (10 mL) and dried over anhydrous Na2SO4, filtered and concentrated in vacuum to give a yellow oil. The yellow oil was subjected to silica gel chromatography (0-5% EtOAc / Petroleum ether) to give 1-((4-bromophenyl)difluoromethyl)bicyclo[1.1.1]pentane as a colorless oil (116.3 mg, 73%).1H NMR (400 MHz, CDCI3) δ: 7.55 (d, J = 8.4 Hz, 2H), 7.28 (s, 1 H), 7.26 (s, 1 H), 2.55 (s, 1 H), 1.82 (s, 6H).

[0438] Step E: / V-((5aS,8aS)-7-acetyl-5-(4-(bicvclon .1.1lpentan-1-yldifluoromethyl)phenyl)-4-oxo- 5,5a,6,7,8,8a-hexahydro-4 / - / -pyrazolon ,5-alpyrrolof3,4-elpyrazin-3-yl)-3-cyano-4- methoxybenzamide.

[0439] The title compound was prepared in a manner analogous to Example 201 , Step L above, reacting / \ / -((5aS,8aS)-7-acetyl-4-oxo-5,5a,6,7,8,8a-hexahydro-4 / 7-pyrazolo[1 ,5-a]pyrrolo[3,4-e]pyrazin- 3-yl)-3-cyano-4-methoxybenzamide (Intermediate 9, 100.0 mg, 253.6μmol), 1-((4- bromophenyl)difluoromethyl)bicyclo[1.1.1]pentane (103.9 mg, 380.3μmol), copper(l) iodide (57.9 mg, 304μmol), DMEDA (33 μL, 0.30 mmol, 0.819 g / mL), K2CO3 (105.1 mg, 0.7610 mmol), a stir bar, DMF (5.0 mL), and toluene (1.00 mL).1H NMR (400 MHz, DMSO-d6) δ:: 9.74 - 9.48 (m, 1 H), 8.50 (s, 1 H), 8.23 - 8.01 (m, 2H), 7.62 - 7.52 (m, 2H), 7.39 - 7.30 (m, 2H), 7.07 - 6.97 (m, 1 H), 4.74 - 4.44 (m, 3H), 4.13 - 4.01 (m, 1.4H), 4.00 (s, 3H), 3.87 - 3.73 (m, 0.6H), 3.46 - 3.20 (m, 1 H), 2.66 - 2.50 (m, 1 H), 2.18 - 2.02 (m, 3H), 1.93 - 1.87 (m, 6H). Mass spectrum (ESI, m / z): Calcd for C31H28F2N6O4 586.2; found [M+H]+, 587.3.

[0440] Example 251 : N-((5aS,8aS)-7-acetyl-5-(4-(cvclohexyldifluoromethyl)phenyl)-4-oxo- 5,5a,6,7,8,8a-hexahvdro-4H-pyrazolori,5-alpyrrolor3,4-e]pyrazin-3-yl)-3-cvano-4- methoxybenzamide.

[0441] Step A: / V-methoxy-ZV-methylcyclohexanecarboxamide.

[0442] Cyclohexanecarboxylic acid (2.00 g, 15.6 mmol), a stir bar, / V.O-dimethylhydroxylamine (2.13 g, 21.8 mmol), GDI (3.29 g, 20.3 mmol), TEA (3.04 mL, 21.8 mmol, 0.728 g / mL) and anhydrous DCM (20.0 mL) were added to a nitrogen-purged 100 mL round-bottom flask, the resulting mixture stirred at r.t. for 16 h to give a solution. The reaction progress was monitored by TLC. The reaction mixture was poured into H2O (150 mL), extracted with EtOAc (150 mL x 3). The combined extracts washed with brine (150 mL), dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure to give a yellow oil. The oil was then subjected to silica gel chromatography (30-50% ethyl acetate / Petroleum ether) to give / V-methoxy-ZV- methylcyclohexanecarboxamide as a white solid (2.32 g, 87% yield).1H NMR (400 MHz, CDCI3) 5: 3.70 - 3.65 (m, 3H), 3.22 - 3.11 (m, 3H), 2.74 - 2.59 (m, 1 H), 1.84 - 1.67 (m, 5H), 1.54 - 1.40 (m, 2H), 1.36 - 1.16 (m, 3H).

[0443] Step B: (4-Bromophenyl)(cyclohexyl)methanone. 1-Bromo-4-iodobenzene (5.01 g, 17.70 mmol), a stir bar and THF (45.0 mL) were added to a 250 mL three-round-bottomed flask, which was subsequently subjected to 3 cycles of vacuum and recharging with nitrogen, then cooled to -70 °C in an ethanol / dry Ice bath and the resulting mixture treated with n-BuLi (7.1 mL, 17.7 mmol, 2.5 M in hexane) dropwise over 15 min at - 70°C and before stirring for 0.5 h at the same temperature, / V-methoxy-ZV- methylcyclohexanecarboxamide (2.02 g, 11.8 mmol) in THF (5.0 mL) was added dropwise to above solution. The yellow suspension mixture stirred for 3 h at -70 °C. The reaction progress was monitored by TLC. The mixture was quenched with sat. NH4CI (60 mL) and extracted with EtOAc (50 mL x 2). The combined extracts were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated to dryness in vacuo to give a yellow oil. The oil was then subjected to silica gel chromatography (0-20% EtOAc / pet ether) to give (4- bromophenyl)(cyclohexyl)methanone as a yellow solid (2.98 g, 95%).1H NMR (400 MHz, CDCI3) δ: 7.90 - 7.71 (m, 2H), 7.64 - 7.53 (m, 2H), 3.35 - 3.09 (m, 1 H), 2.70 - 2.37 (m, 1 H), 1.95 - 1.79 (m, 4H), 1.52 - 1.35 (m, 4H), 1.28 - 0.85 (m, 1 H) Step C: 2-(4-Bromophenyl)-2-cyclohexyl-1 ,3-dithiane.

[0444] (4-Bromophenyl)(cyclohexyl)methanone (2.98 g, 11.2 mmol), a stir bar, toluene (30.0 mL) were added to a 100 mL round bottle, propane-1 , 3-dithiol (4.83 g, 44.6 mmol), TsOH H2O (3.84 g, 22.3 mmol) were added. The mixture was stirred at 70 °C for 16 h, finally the mixture formed yellow suspension. The reaction progress was monitored by TLC. The reaction mixture was poured into H2O (50 mL), extracted with ethyl acetate (50 mL x 2). The combined extracts were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure to give a yellow oil. The oil was then subjected to silica gel chromatography (0-20% ethyl acetate / Petroleum ether) to give 2-(4-bromophenyl)-2- cyclohexyl-1 ,3-dithiane as a white solid (3.01 g, 76% yield).1H NMR (400 MHz, CDCI3) 5: 7.85 - 7.77 (m, 2H), 7.53 - 7.45 (m, 2H), 2.65 - 2.59 (m, 6H), 1.90 - 1.86 (m, 2H), 1.70 (d, J = 13.2 Hz, 2H), 1.37 - 1.31 (m, 4H), 1.22 - 1.09 (m, 3H).

[0445] Step D: 1-Bromo-4-(cyclohexyldifluoromethyl)benzene. 2-(4-Bromophenyl)-2-cyclohexyl-1 ,3-dithiane (1.50 g, 4.20 mmol), a stir bar, and anhydrous DCM (15.0 mL) were added to a 50 mL round-bottomed flask and the resulting mixture stirred until homogeneous. DAST (1.20 mL, 9.02 mmol, 1.213 g / mL) was added at O °C, and the round-bottomed flask was removed from the ice bath and stirred at r.t. for 20 h to give a yellow suspension. The reaction progress was monitored by TLC. The reaction mixture was then quenched with aq. NaHCO3 (40 mL) dropwise over the course of 2 min, and extracted with DCM (40 mL x 2). The combined extracts were washed with brine (80 mL), dried over anhydrous Na2SO4, filtered, and concentrated to dryness in vacuo to give a yellow oil. The oil was then subjected to silica gel chromatography (0-20% EtOAc / pet ether) to give 1-bromo-4- (cyclohexyldifluoromethyl)benzene as a colorless oil (754.5 mg, 62%).1H NMR (400 MHz, CDCI3) δ: 7.52 (d, J = 8.4 Hz, 2H), 7.28 - 7.09 (m, 2H), 1.79 - 1.59 (m, 5H), 1 .52 (s, 1 H), 1.20 - 1.04 (m, 5H)

[0446] Step E: / V-((5aS,8aS)-7-acetyl-5-(4-(cyclohexyldifluoromethyl)phenyl)-4-oxo-5,5a,6,7,8,8a- hexahydro-4 / - / -pyrazolon ,5-alpyrrolof3,4-elpyrazin-3-yl)-3-cyano-4-methoxybenzamide. The title compound was prepared in a manner analogous to Example 201 , Step L above, reacting / V-((5aS,8aS)-7-acetyl-4-oxo-5,5a,6,7,8,8a-hexahydro-4 / 7-pyrazolo[1,5-a]pyrrolo[3,4-e]pyrazin-

[0447] 3-yl)-3-cyano-4-methoxybenzamide (Intermediate 9, 90.0 mg, 0.228 mmol), a stir bar, 1-bromo-

[0448] 4-(cyclohexyldifluoromethyl)benzene (99.0 mg, 0.342 mmol), K2CO3 (63.1 mg, 0.456 mmol), DMF (5.0 mL), Cui (52.2 mg, 0.274 mmol), and DMEDA (30 μL, 0.803 g / mL, 0.27 mmol).

[0449] 1 H NMR (400 MHz, DMSO-d6) δ:: 9.87 (d, J = 5.6 Hz, 1 H), 8.28 - 8.12 (m, 3H), 7.58 - 7.50 (m, 4H), 7.40 (d, J = 9.2 Hz, 1 H), 5.01 - 4.84 (m, 2H), 4.51 - 4.26 (m, 1 H), 3.99 (s, 3H), 3.94 - 3.83 (m, 1 H), 3.75 (dd, J = 6.8, 10.4 Hz, 0.5H), 3.55 (t, J = 10.4 Hz, 0.5H), 3.40 - 3.34 (m, 0.5H), 3.00 (t, J = 10.4 Hz, 0.5H), 2.23 - 2.10 (m, 1H), 2.05 - 1.90 (m, 3H), 1.76 - 1.60 (m, 5H), 1.27 - 1.08 (m, 5H). Mass spectrum (ESI, m / z): Calcd for C32H32F2N6O4602.2 m / z, found [M+H]+, 603.1.

[0450] Example 252: N-((5aS,8aR)-7-acetyl-5-(4-(cvclohexyldifluoromethyl)phenyl)-4-oxo- 5,5a,6,7,8,8a-hexahvdro-4H-pyrazolori,5-a]pyrrolor3,4-elpyrazin-3-yl)-3-cvano-4- methoxybenzamide.

[0451] The title compound was prepared in a manner analogous to Example 201 , Step L above, reacting

[0452] / \ / -((5aS,8aF?)-7-acetyl-4-oxo-5, 5a, 6,7,8, 8a-hexahydro-4 / 7-pyrazolo[1,5-a]pyrrolo[3,4-e]pyrazin- 3-yl)-3-cyano-4-methoxybenzamide (Intermediate 10, 80.0 mg, 0.203 mmol), a stir bar, 1- bromo-4-(cyclohexyldifluoromethyl)benzene (88.0 mg, 0.304 mmol), K2CO3 (56.1 mg, 0.406 mmol), DMF (3.0 mL), Cui (46.4 mg, 0.243 mmol), and DMEDA (27 μL, 0.803 g / mL, 0.24 mmol).1H NMR (400 MHz, DMSO-d6) δ:: 9.92 (d, J= 3.2 Hz, 1 H), 8.28 - 8.21 (m, 2H), 8.16 (dd, J = 2.4, 8.8 Hz, 1 H), 7.66 - 7.54 (m, 4H), 7.44 - 7.38 (m, 1 H), 5.31 - 5.16 (m, 1 H), 5.11 - 4.97 (m, 1 H), 4.52 - 4.44 (m, 1H), 4.25 (t, J= 9.2 Hz, 0.5H), 4.11 - 3.96 (m, 4H), 3.71 (dd, J = 4.4, 12.8 Hz, 0.5H), 3.50 (t, J = 10.0 Hz, 0.5H), 3.26 (dd, J = 8.8, 11.6 Hz, 0.5H), 2.22 - 2.06 (m, 1 H), 1.94 (d, J = 19.2 Hz, 3H), 1.77 - 1.59 (m, 5H), 1.27 - 1.03 (m, 5H). Mass spectrum (ESI, m / z): Calcd for C32H32F2N6O4602.2 m / z, found [M+H]+, 603.1. Example 253: N-((5aS,8aS)-7-acetyl-5-(4-(bicvclor2.2.1]heptan-1-yldifluoromethyl)phenyl)- 4-OXO-5, 5a, 6,7,8, 8a-hexahvdro-4H-pyrazolori,5-a]pyrrolor3,4-elpyrazin-3-yl)-3-cvano-4- methoxybenzamide.

[0453] Step A: / V-methoxy- / V-methylbicyclo[22.11heptane-1 -carboxamide.

[0454] The title compound was prepared in a manner analogous to Example 251, Step A above, reacting bicyclo[2.2.1]heptane-1 -carboxylic acid (900.0 mg, 6.420 mmol), a stir bar, N,O- dimethylhydroxylamine (876.8 mg, 8.988 mmol), GDI (1.35 g, 8.35 mmol), TEA (1.25 mL, 8.988 mmol, 0.728 g / mL), and anhydrous DCM (10.0 mL).1H NMR (400 MHz, CDCI3) 5: 3.73 - 3.62 (m, 3H), 3.26 - 3.05 (m, 3H), 2.22 (s, 1H), 1.86 - 1.58 (m, 8H), 1.43 - 1.28 (m, 2H).

[0455] Step B: Bicyclo(2.2.11heptan-1-yl(4-bromophenyl)methanone .

[0456] The title compound was prepared in a manner analogous to Example 251, Step B above, reacting

[0457] 1-bromo-4-iodobenzene (1.16 g, 4.09 mmol), a stir bar and THF (10.0 mL) were added to a 100 mL three-round-bottomed flask, which was subsequently subjected to 3 cycles of vacuum and recharging with nitrogen, then cooled to -70 °C in an ethanol / dry Ice bath and the resulting mixture treated with n-BuLi (1.64 mL, 4.09 mmol, 2.5 M in hexane) dropwise over 15 min at -70 °C and before stirring for 0.5 h at the same temperature, / V-methoxy-ZV- methylbicyclo[2.2.1]heptane-1 -carboxamide (500.0 mg, 2.729 mmol)(dissolved in THF (5.0 mL)) was added above solution. The yellow suspension mixture stirred for 3 h at -70 °C.1H NMR (400 MHz, CDCI3)_δ: 7.66 (d, J = 8.4 Hz, 2H), 7.49 (d, J = 8.4 Hz, 2H), 2.28 (s, 1 H), 1.88 - 1.76 (m, 3H), 1.76 - 1.70 (m, 4H), 1.48 (s, 1H), 1.45 - 1.33 (m, 2H).

[0458] Step C: 2-(Bicvclof2.2.11heptan-1-yl)-2-(4-bromophenyl)-1 ,3-dithiane.

[0459] Bicyclo[2.2.1]heptan-1-yl(4-bromophenyl)methanone (618.7 mg, 2.216 mmol), a stir bar, and DCM (3.0 mL) were added to a 10 mL round bottomed flask, then propane-1 , 3-dithiol (431.7 mg, 3.989 mmol) and Et2O*BF3 (0.78 mL, 6.2 mmol) were then added to the reaction vessel. The mixture was stirred for 16 h at r.t. to give a yellow solution. The reaction progress was monitored by TLC. The suspensin was was quenched with sat. NaHCO3 (10 mL), then extracted with DCM (7 mL x 3). The combined extracts were washed with brine (6 mL), dried over anhydrous Na2SC>4, filtered and concentrated in vacuo to give a yellow oil. The oil was subjected to silica gel chromatography (0-10% EtOAc / pet ether) to give 2-(bicyclo[2.2.1]heptan-1-yl)-2-(4- bromophenyl)-1 ,3-dithiane as a yellow solid (336.4 mg, 41 %).1H NMR (400 MHz, CDCh) 5: 7.88 (d, J = 8.4 Hz, 2H), 7.49 (d, J = 8.4 Hz, 2H), 2.70 - 2.56 (m, 5H), 2.15 (s, 1 H), 1.95 - 1.86 (m, 4H), 1.53 (d, J = 6.0 Hz, 1 H), 1.47 - 1.41 (m, 2H), 1.30 - 1.23 (m, 2H), 1.21 - 1.11 (m, 2H). Step D: 1-((4-Bromophenyl)difluoromethyl)bicyclo[2.2.1]heptane.

[0460] The title compound was prepared in a manner analogous to Example 251 , Step D above, reacting 2-(4-bromophenyl)-2-cyclohexyl-1 ,3-dithiane (1.50 g, 4.20 mmol), a stir bar, and anhydrous DCM (15.0 mL), and DAST (1.20 mL, 9.02 mmol, 1.213 g / mL).1H NMR (400 MHz, CDCh)_δ: 7.53 (d, J = 8.4 Hz, 2H), 7.31 (d, J = 8.4 Hz, 2H), 2.27 (s, 1 H), 1.78 - 1 .70 (m, 2H), 1.66 - 1 .59 (m, 2H), 1 .42 (s, 2H), 1 .32 (t, J = 11.2 Hz, 2H), 1.28 - 1 .20 (m, 2H).

[0461] Step E: / V-((5aS,8aS)-7-acetyl-5-(4-(bicyclo[2.2.1]heptan-1-yldifluoromethyl)phenyl)-4-oxo- 5,5a,6,7,8,8a-hexahydro-4 / 7-pyrazolo[1 ,5-a]pyrrolo[3,4-e]pyrazin-3-yl)-3-cyano-4-

[0462] The title compound was prepared in a manner analogous to Example 201 , Step L above, reacting / \ / -((5aS,8aS)-7-acetyl-4-oxo-5,5a,6,7,8,8a-hexahydro-4 / 7-pyrazolo[1 ,5-a]pyrrolo[3,4-e]pyrazin- 3-yl)-3-cyano-4-methoxybenzamide (Intermediate 9, 80.0 mg, 0.203 mmol), a stir bar, 1-((4- bromophenyl)difluoromethyl)bicyclo[2.2.1]heptane (73.3 mg, 0.243 mmol), K2CO3 (56.1 mg, 0.406 mmol), DMF (1.0 mL), Toluene (1.0 mL), Cui (46.4 mg, 0.243 mmol), and DMEDA (27 pL, 0.803 g / mL, 0.24 mmol).1H NMR (400 MHz, DMSO-d6) δ:: 9.88 (d, J = 3.6 Hz, 1 H), 8.27 - 8.13 (m, 3H), 7.57 - 7.49 (m, 4H), 7.40 (d, J = 9.2 Hz, 1 H), 5.01 - 4.84 (m, 2H), 4.51 - 4.26 (m, 1 H), 3.99 (s, 3H), 3.94 - 3.82 (m, 1 H), 3.75 (dd, J = 6.8, 10.4 Hz, 0.5H), 3.56 (t, J = 10.4 Hz, 0.5H), 3.42 - 3.40 (m, 0.5H), 3.00 (t, J = 10.4 Hz, 0.5H), 2.26 (s, 1 H), 2.06 - 1.91 (m, 3H), 1.75 - 1.57 (m, 4H), 1.40 (s, 2H), 1.38 - 1.14 (m, 4H). Mass spectrum (ESI, m / z): Calcd for C33H32F2N6O4 614.2 m / z, found [M+H]+, 615.1.

[0463] Example 254: N-((5aS,8aS)-7-acetyl-5-(4-(bicvclor2.2.2]octan-1 -yldifluoromethyl)phenyl)-4- oxo-5, 5a, 6,7,8, 8a-hexahvdro-4H-pyrazolori,5-alpyrrolor3,4-e]pyrazin-3-yl)-3-cvano-4- methoxybenzamide.

[0464]

[0465] Step A: N-methoxy-N-methylbicvclo[2.2.21octane-1 -carboxamide. Bicyclo[2.2.2]octane-1-carboxylic acid (1.00 g, 6.485 mmol), a stir bar, N,0- dimethylhydroxylamine (759.1 mg, 7.782 mmol), DIEA (3.5 mL, 19 mmol), HOBT (1.05 g, 7.78 mmol), EDCI (1.49 g, 7.78 mmol) and DMF (20.0 mL) were added to an oven-dried 50 mL round-bottomed flask. The resulting mixture was stired at r.t for 16 h, finally the reaction mixture became a yellow solution. The reaction was monitored by TLC. The mixture reaction was diluted with H2O (30 mL), and extracted with EtOAc (30 mL x 3). The combined extracts were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuum to give a yellow oil. The oil was subjected to silica gel chromatography (0-60% EtOAc / PE) to give N-methoxy-N-methylbicyclo[2.2.2]octane-1-carboxamide as a colorless oil (1.24 g, 85%).1H NMR (400 MHz, CDCI3)_δ: 3.58 (s, 3H), 3.12 - 3.04 (m, 3H), 1.81 - 1.73 (m, 6H), 1.54 - 1.47 (m, 7H). Mass spectrum (ESI, m / z): Calcd for CnHigNCh 197.1 m / z, found [M+H]+, 198.0.

[0466] Step B: Bicyclof2.2.21octan-1-yl(4-bromophenyl)methanone.

[0467] The title compound was prepared in a manner analogous to Example 251, Step B above, reacting 1-bromo-4-iodobenzene (2.37 g, 8.36 mmol), a stir bar and THF (5.0 mL) were added to an oven-dried and nitrogen-purged 50 mL round bottomed flask, which was subsequently evacuated and refilled with nitrogen (x3) and cooled to -70 °C in an EtOH / Dry Ice bath, and the resulting mixture treated with n-BuLi (3.4 mL, 2.5 M, 8.4 mmol) dropwise over 1 min, the mixture stirred for 0.5 h, then which charged with the solution of / V-methoxy-ZV- methylbicyclo[2.2.2]octane-1 -carboxamide (1.10 g, 5.58 mmol, removed water with toluene) in THF (5.0 mL), and the mixture stirred at -70 °C for 2 h.1H NMR (400 MHz, DMSO-d6) δ:: 7.67 - 7.61 (m, 2H), 7.60 - 7.54 (m, 2H), 1.79 - 1.74 (m, 6H), 1.63 - 1.55 (m, 7H). Mass spectrum (ESI, m / z): calcd. for Ci5Hi7BrO 292.0 / 294.0; found [M+ H]+, 293.0 / 295.0.

[0468] Step C: 2-(Bicyclof2.2.21octan-1-yl)-2-(4-bromophenyl)-1,3-dithiane. Bicyclo[2.2.2]octan-1-yl(4-bromophenyl)methanone (930.0 mg, 3.172 mmol), a stir bar, DCM (10.0 mL) were added to a 50 mL round-bottomed flask, which was subsequently cooled to 0 °C in the water / ice bath, and the resulting mixture treated with BF3*OEt2 (0.98 mL, 7.9 mmol) dropwise over 1 min, The mixture was stirred at r.t. for 2 min before treated with propane-1, 3- dithiol (0.64 mL, 6.3 mmol) and the yellow homogeneous mixture stirred at r.t. for 12 h. The reaction progress was monitored by TLC and LCMS. The reaction mixture was quenched with sat. NaHCO3(20 mL) dropwise, then extracted with DCM (20 mL x 3). The combined extracts were washed with brine (20 mL), dried with anhydrous Na2SO4, filtered and concentrated in vacuum to give a yellow oil. The oil was subjected to silica gel chromatography (0-10% DCM / Petroleum ether) to give 2-(bicyclo[2.2.2]octan-1-yl)-2-(4-bromophenyl)-1 ,3-dithianeas a white solid (1.2 g, 86%).1H NMR (400 MHz, CDCI3)_δ: 7.83 (d, J = 8.8 Hz, 2H), 7.49 (d, J = 8.8 Hz, 2H), 2.69 - 2.48 (m, 6H), 1.65 (s, 6H), 1.50 - 1 .45 (m, 7H). Mass spectrum (ESI, m / z): calcd. for CisH23BrS2382.0 / 384.0; found [M+ H]+, 383.0 / 385.0.

[0469] Step D: 1-((4-Brornophenyl)difluoromethyl)bicyclof2.2.21octane.

[0470] The title compound was prepared in a manner analogous to Example 251 , Step D above, reacting

[0471] 2-(bicyclo[2.2.2]octan-1-yl)-2-(4-bromophenyl)-1 ,3-dithiane (1.20 g, 3.13 mmol), DCM (20.0 mL), a stir bar, and DAST (0.89 mL, 1.22 g / mL, 6.7 mmol).1H NMR (400 MHz, CDCI3) 5: 7.52 (d, J = 8.4 Hz, 2H), 7.23 (d, J = 8.4 Hz, 2H), 1.56 - 1.52 (m, 13H).

[0472] Step E: / V-((5aS,8aS)-7-acetyl-5-(4-(bicyclor2.2.21octan-1-yldifluoromethyl)phenyl)-4-oxo- 5,5a,6,7,8,8a-hexahydro-4 / - / -pyrazolon ,5-alpyrrolof3,4-elpyrazin-3-yl)-3-cyano-4- methoxybenzamide.

[0473] The title compound was prepared in a manner analogous to Example 201 , Step L above, reacting / \ / -((5aS,8aS)-7-acetyl-4-oxo-5,5a,6,7,8,8a-hexahydro-4 / 7-pyrazolo[1 ,5-a]pyrrolo[3,4-e]pyrazin-

[0474] 3-yl)-3-cyano-4-methoxybenzamide (Intermediate 9, 65.0 mg, 0.165 mmol), 1-((4- bromophenyl)difluoromethyl)bicyclo[2.2.2]octane (77.9 mg, 0.247 mmol), copper(l) iodide (37.7 mg, 0.198 mmol), DMEDA (21 μL, 0.20 mmol, 0.819 g / mL), K2CO3(34.2 mg, 0.247 mmol), a stir bar, toluene (0.50 mL), and DMF (0.50 mL).1H NMR (400 MHz, DMSO-d6) δ:: 9.86 (d, J = 4.4 Hz, 1 H), 8.25 - 8.19 (m, 2H), 8.17 (dd, J = 2.0, 8.8 Hz, 1 H), 7.52 - 7.44 (m, 4H), 7.40 (d, J = 9.2 Hz, 1 H), 5.04 - 4.85 (m, 2H), 4.52 - 4.24 (m, 1 H), 3.99 (s, 3H), 3.95 - 3.83 (m, 1 H), 3.79 - 3.51 (m, 1 H), 3.40 - 3.35 (m, 0.5H), 3.03 - 2.98 (m, 0.5H), 2.05 - 1 .90 (m, 3H), 1 .53 (s, 13H). Mass spectrum (ESI, m / z): calcd. for C34H34F2NeO4 628.3; found [M+H]+, 629.3.

[0475] Example 255: N-((5aS,8aS)-7-acetyl-5-(4-(cvclopentyldifluoromethyl)phenyl)-4-oxo- 5,5a,6,7,8,8a-hexahvdro-4H-pyrazolori,5-a]pyrrolor3,4-elpyrazin-3-yl)-3-cvano-4- methoxybenzamide.

[0476]

[0477] Step A: N-methoxy-N-methylbicvclo[2.2.21octane-1 -carboxamide.

[0478] The title compound was prepared in a manner analogous to Example 251, Step A above, reacting cyclopentanecarboxylic acid (1.00 g, 8.76 mmol), a stir bar, and anhydrous DCM (20.0 mL), 1,1- carbonyldiimidazole (1.85 g, 11.4 mmol), triethylamine (1.71 mL, 12.3 mmol), methoxy(methyl)amine hydrochloride (1.20 g, 12.3 mmol).1H NMR (400 MHz, CDCh) 5: 3.69 (s, 3H), 3.18 (s, 3H), 3.14 - 3.02 (m, 1H), 1.90 - 1.68 (m, 6H), 1.64 - 1.51 (m, 2H) Mass spectrum (ESI, m / z): Calcd for C8Hi5NO2157.1 m / z, found [M+H]+, 158.2.

[0479] Step B: Bicyclof2.2.21octan-1-yl(4-bromophenyl)methanone.

[0480] The title compound was prepared in a manner analogous to Example 251, Step B above, reacting 1-bromo-4-iodobenzene (2.61 g, 9.21 mmol), a stir bar, and anhydrous THF (10.0 mL) were added to an oven-dried and nitrogen-purged 100 mL three neck round-bottom flask. The flask was then subjected to 3 cycles of vacuum and recharging of nitrogen, cooled to -70 °C (dry ice / EtOH) and charged with butyllithium (3.68 mL, 9.21 mmol) dropwise via syringe at a rate such that the temperature didn't exceed -60 °C. The mixture stirred for 30 min and charged with a solution of N-methoxy-N-methylcyclopentanecarboxamide (1.00 g, 6.14 mmol) in anhydrous THF (5.0 mL) and the stirring was continued for 2 h to give a light-yellow solution.1H NMR (400 MHz, CDCI3) δ: 7.87 - 7.82 (m, 2H), 7.63 - 7.58 (m, 2H), 3.71 - 3.61 (m, 1 H), 1.96 - 1.87 (m, 4H), 1.78 - 1.63 (m, 4H). Mass spectrum (ESI, m / z): Calcd for Ci2Hi3BrO 252.0 / 254.0 m / z, found [M+H]+, 252.9 / 254.9.

[0481] Step C: 2-(4-Bromophenyl)-2-cyclopentyl-1,3-dithiane. (4-Bromophenyl)(cyclopentyl)methanone (869.0 mg, 3.433 mmol), a stir bar, and DCM (6.0 mL) were added to a 50 mL round bottomed flask, then propane-1, 3-dithiol (0.62 mL, 6.2 mmol) and Et2OBF3 (1.21 mL, 9.61 mmol) were then added to the reaction vessel the mixture was stirred for 16 h at r.t. to give a yellow solution. The reaction progress was monitored by TLC. The suspension was quenched with sat.NaHCO3 (10 mL), then extracted with DCM (7 mL x 3). The combined extracts were washed with brine (6 mL), dried over anhydrous Na2SC>4, filtered and concentrated in vacuo to give a yellow oil. The oil was subjected to silica gel chromatography (0-10% EtOAc / pet ether) to give 2-(4-bromophenyl)-2-cyclopentyl-1 ,3-dithiane as a white solid (700 mg, 59%).1H NMR (400 MHz, CDCI3) 5: 7.87 (d, J = 8.8 Hz, 2H), 7.50 (d, J = 8.8 Hz, 2H), 2.69 - 2.59 (m, 6H), 2.40 - 2.25 (m, 1 H), 1.96 - 1.88 (m, 3H), 1.55 - 1.45 (m, 5H). Step D: 1-Bromo-4-(cyclopentyldifluoromethyl)benzene

[0482] The title compound was prepared in a manner analogous to Example 251 , Step D above, reacting

[0483] 2-(4-bromophenyl)-2-cyclopentyl-1 ,3-dithiane (500.0 mg, 1.456 mmol), a stir bar, and DCM (6.0 mL), DAST (0.38 mL, 3.1 mmol).1H NMR (400 MHz, CDCI3) 5: 7.80 - 7.48 (m, 2H), 7.46 - 7.28 (m, 2H), 2.77 - 2.46 (m, 1 H), 1.88 - 1.50 (m, 8H).

[0484] Step E: / V-((5aS,8aS)-7-acetyl-5-(4-(cyclopentyldifluoromethyl)phenyl)-4-oxo-5,5a,6,7,8,8a- hexahydro-4 / - / -pyrazolori ,5-alpyrrolo(3,4-elpyrazin-3-yl)-3-cyano-4-methoxybenzamide. The title compound was prepared in a manner analogous to Example 201 , Step L above, reacting / \ / -((5aS,8aS)-7-acetyl-4-oxo-5,5a,6,7,8,8a-hexahydro-4 / 7-pyrazolo[1 ,5-a]pyrrolo[3,4-e]pyrazin-

[0485] 3-yl)-3-cyano-4-methoxybenzamide (Intermediate 9, 100.0 mg, 0.2540 mmol), a stir bar, 1- bromo-4-(cyclopentyldifluoromethyl)benzene (83.7 mg, 0.304 mmol), K2CO3 (106.7 mg, 0.7610 mmol), Cui (58.3 mg, 0.304 mmol) and DMEDA (33 μL, 0.30 mmol) in DMF (1.0 mL) and toluene (1.0 mL).1H NMR (400 MHz, DMSO-d6) δ:: 9.88 (d, J = 4.4 Hz, 1 H), 8.31 - 8.09 (m, 3H), 7.63 (d, J = 8.4 Hz, 2H), 7.55 - 7.44 (m, 2H), 7.44 - 7.35 (m, 1 H), 5.07 - 4.80 (m, 2H), 4.52 - 4.23 (m, 1 H), 3.99 (s, 3H), 3.94 - 3.81 (m, 1 H), 3.74 (dd, J = 6.8, 10.0 Hz, 0.5H), 3.55 (t, J = 10.0 Hz, 0.5H), 3.41 - 3.34 (m, 0.5H), 2.99 (t, J = 10.4 Hz, 0.5H), 2.92 - 2.76 (m, 1 H), 2.09 - 1.87 (m, 3H), 1.74 - 1.48 (m, 8H).Mass spectrum (ESI, m / z): Calcd. for C31H30F2N6O4, 588.2 m / z, found 589.1 [M+H]+.

[0486] Example 56: 3-Cvano-N-((5aS,8aR)-5-(4-(difluoro(phenyl)methyl)phenyl)-7-methyl-4-oxo- 5,5a,6,7,8,8a-hexahvdro-4H-pyrazolori,5-a]pyrrolor3,4-elpyrazin-3-yl)-4- methoxybenzamide.

[0487] 3-Cyano- / V-((5aR,8aS)-5-(4-(difluoro(phenyl)methyl)phenyl)-4-oxo-5, 5a, 6,7,8, 8a-hexahydro-4 / 7- pyrazolo[1 ,5-a]pyrrolo[3,4-e]pyrazin-3-yl)-4-methoxybenzamide (Example 55, 100.0 mg, 170.1 pmol), HCHO (37%, 28 μL, 285μmol), AcOH (9 μL, 157 μmol), NaBH3CN (17.9 mg, 285μmol), a stir bar, and anhydrous MeOH (2.0 mL) were added to a 10 mL round-bottomed flask. The mixture was stirred at r.t. for 4 h. An white suspension was formed. The reaction progress was monitored by LC-MS. The reaction mixture was quenched with aq. NaHCO3 (1 mL), diluted with H2O (10 mL), then extracted with EtOAc (15 mL x 3). The combined extracts were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give an colourless oil. The oil was subjected to silica gel chromatography (50-80% EtOAc / DCM) to give 3-cyano- / V-((5aR,8aS)-5-(4-(difluoro(phenyl)methyl)phenyl)-7-methyl-4-oxo-5,5a,6,7,8,8a- hexahydro-4 / 7-pyrazolo[1 ,5-a]pyrrolo[3,4-e]pyrazin-3-yl)-4-methoxybenzamide as a white solid (63.5 mg, 65%).1H NMR (400 MHz, CDCI3) d : 9.77 (s, 1 H), 8.53 (d, J = 2.4 Hz, 1 H), 8.15 (d, J = 2.4 Hz, 1 H), 8.12 - 8.06 (m, 1 H), 7.66 (d, J = 8.4 Hz, 2H), 7.58 - 7.51 (m, 2H), 7.49 - 7.40 (m, 5H), 7.02 (d, J = 8.8 Hz, 1 H), 5.13 - 5.03 (m, 1 H), 4.95 - 4.78 (m, 1 H), 4.00 (s, 3H), 3.84 - 3.49 (m, 2H), 3.47 - 3.17 (m, 1 H), 3.01 - 2.87 (m, 1 H), 2.52 (s, 3H). Mass spectrum (ESI, m / z): Calcd For C31H26F2N6O3, 568.2; found [M+H]+, 569.3.

[0488] Example 57: N-((5aS,8aR)-7-Acetyl-5-(4-(difluoro(phenyl)methyl)phenyl)-4-oxo- 5,5a,6,7,8,8a-hexahvdro-4H-pyrazolori,5-a]pyrrolor3,4-elpyrazin-3-yl)-3-cvano-4- methoxybenzamide.

[0489] 3-Cyano- / V-((5aS,8aR)-5-(4-(difluoro(phenyl)methyl)phenyl)-4-oxo-5, 5a, 6,7,8, 8a-hexahydro-4 / 7- pyrazolo[1 ,5-a]pyrrolo[3,4-e]pyrazin-3-yl)-4-methoxybenzamide (Example 55, 100.0 mg, 170.1 pmol), anhydrous DCE (2.0 mL), a stir bar, TEA (71 pl, 510 μmol), and AC2O (32 μL, 340 pmol) were added to a 10 mL round-bottomed flask. The mixture was stirred at r.t. for 2 h, the suspension became clear after nearly 1 h. The reaction progress was monitored by LC-MS. The reaction mixture was poured into H2O (10 mL) and extracted with EtOAc (15 mL x 3). The combined extracts were washed with brine (10 mL x 2), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give an white solid, which was subjected to silica gel chromatography (30-85% EtOAc / DCM) to give / \ / -((5aR,8aS)-7-acetyl-5-(4- (difluoro(phenyl)methyl)phenyl)-4-oxo-5,5a,6,7,8,8a-hexahydro-4 / 7-pyrazolo[1 ,5-a]pyrrolo[3,4- e]pyrazin-3-yl)-3-cyano-4-methoxybenzamide as a white solid (67.5 mg, 66%).1H NMR (400 MHz, CDCI3) d : 9.72 (s, 1 H), 8.57 - 8.51 (m, 1 H), 8.18 - 8.07 (m, 2H), 7.72 - 7.64 (m, 2H), 7.57 - 7.51 (m, 2H), 7.49 - 7.39 (m, 5H), 7.05 - 6.99 (m, 1 H), 5.11 - 5.01 (m, 1 H), 4.87 - 4.63 (m, 2H), 4.37 - 4.07 (m, 1 H), 4.00 (s, 3H), 3.99 - 3.91 (m, 1 H), 3.64 - 3.45 (m, 1 H), 2.15 - 2.00 (m, 3H). Mass spectrum (ESI, m / z): Calcd. For C32H26F2N6O4, 596.2; found [M+H]+, 597.2.

[0490] Example 58: 3-Cyano-N-((5aS,8aR)-5-(4-(difluoro(phenyl)methyl)phenyl)-7-(2- methoxyethyl)-4-oxo-5, 5a, 6,7,8, 8a-hexahvdro-4H-pyrazolori,5-a]pyrrolor3,4-elpyrazin-3- vD-4-methoxybenzamide.

[0491] The title compound was prepared in a manner analogous to Example 5, Step A above, reacting 3-cyano-N-((5aS,8aR)-5-(4-(difluoro(phenyl)methyl)phenyl)-4-oxo-5, 5a, 6,7,8, 8a- hexa hydro-4 H- pyrazolo[1 ,5-a]pyrrolo[3,4-e]pyrazin-3-yl)-4-methoxybenzamide (Example 55, 50.0 mg, 0.09 mmol), a stir bar, 1-bromo-2-methoxyethane (15.0 mg, 0.11 mmol), DIEA (30 μL, 0.782 g / mL, 0.18 mmol) and DMF (0.5 mL).1H NMR (400 MHz, DMSO-d6) δ:: 9.91 (s, 1 H), 8.23 - 8.19 (m, 2H), 8.15 (dd, J = 2.0, 8.8 Hz, 1 H), 7.69 - 7.63 (m, 2H), 7.61 - 7.50 (m, 7H), 7.40 (d, J = 9.2 Hz, 1 H), 5.08 (br t, J = 5.2 Hz, 1 H), 4.89 (q, J = 7.2 Hz, 1 H), 3.99 (s, 3H), 3.51 - 3.41 (m, 1 H), 3.20 - 3.10 (m, 4H), 3.06 - 2.96 (m, 1 H), 2.84 (dd, J = 6.8, 9.6 Hz, 1 H), 2.69 - 2.56 (m, 2H). Mass spectrum (ESI, m / z): Calcd. For C33H30F2N6O4, 612.2; found [M+H]+, 613.3.

[0492] Example 59: 3-Cyano-N-((5aS,8aR)-5-(4-(difluoro(phenyl)methyl)phenyl)-7- (methylsulfonyl)-4-oxo-5,5a,6,7,8,8a-hexahvdro-4H-pyrazolori,5-a]pyrrolor3,4-elpyrazin-3- The title compound was prepared in a manner analogous to Example 3, reacting 3-cyano- / V- ((5aS,8a / ?)-5-(4-(difluoro(phenyl)methyl)phenyl)-4-oxo-5, 5a, 6,7,8, 8a-hexahydro-4 / 7- pyrazolo[1 ,5-a]pyrrolo[3,4-e]pyrazin-3-yl)-4-methoxybenzamide (Example 55, product from Step H, 1.29 g, 2.33 mmol), DCE (26.0 mL), TEA (0.97 mL, 7.0 mmoL, 0.728 g / mL) and Ms2O (810.0 mg, 4.652 mmol).1H NMR (400 MHz, DMSO-d6) δ:: 9.92 (s, 1 H), 8.29 (s, 1 H), 8.21 (d, J = 2.0 Hz, 1 H), 8.16 (dd, J = 2.4, 9.2 Hz, 1 H), 7.71 - 7.60 (m, 4H), 7.60 - 7.47 (m, 5H), 7.46 - 7.39 (m, 1 H), 5.24 (t, J = 4.4 Hz, 1 H), 5.13 - 5.08 (m, 1 H), 4.32 (d, J = 11.6 Hz, 1 H), 4.04 - 3.97 (m, 4H), 3.83 (dd, J = 4.0, 11 .6 Hz, 1 H), 3.43 - 3.38 (m, 1 H), 2.82 (s, 3H). Mass spectrum (ESI, m / z): Calcd. for C31H26F2N6O5S, 632.2; found [M+H]+, 633.2.

[0493] Example 60: 3-Cyano-N-((5aS,8aR)-5-(4-(difluoro(phenyl)methyl)phenyl)-7-(2- hvdroxyethyl)-4-oxo-5,5a,6,7,8,8a-hexahvdro-4H-pyrazolori,5-a]pyrrolor3,4-elpyrazin-3-

[0494] 3-Cyano-N-((5aS,8aR)-5-(4-(difluoro(phenyl)methyl)phenyl)-4-oxo-5, 5a, 6,7,8, 8a- hexa hydro-4 H- pyrazolo[1 ,5-a]pyrrolo[3,4-e]pyrazin-3-yl)-4-methoxybenzamide (Example 55, 80.0 mg, 0.144 mmol), 2-bromoethan-1-ol (15 μL, 0.22 mmol), K2CO3 (19.9 mg, 0.144 mmol), KI (2.4 mg, 0.014 mmol) and DMF (1.2 mL) were added to an oven-dried and nitrogen-purged 10 mL round- bottomed flask, which was subsequently evacuated and refilled with nitrogen, and the reaction vessel placed on heating plate that had been pre-heated to 80°C, and the mixture stirred for 48 h. The mixture was poured into H2O (10 mL) and was extracted with EtOAc (15 mL x 3). The combined extracts were washed with water (10 mL x 4) and brine (20 mL x 2), dried over anhydrous Na2SO4, filtered and concentrated in vacuum to give a light brown oil. The oil was then subjected to silica gel chromatography (0-4.5% MeOH / DCM) followed by SFC (DAICEL CHIRALCEL OD, 10 pm, 250 mm x 30 mm; 45% EtOH (with 0.1 % of 25% aq NH3) / CO2) to give 3-cyano-N-((5aS,8aR)-5-(4-(difluoro(phenyl)methyl)phenyl)-7-(2-hydroxyethyl)-4-oxo- 5,5a,6,7,8,8a-hexahydro-4H-pyrazolo[1 ,5-a]pyrrolo[3,4-e]pyrazin-3-yl)-4-methoxybenzamide as a light yellow solid (51 mg, 51%).1H NMR (400 MHz, CDCI3)_δ: 9.77 (s, 1 H), 8.53 (s, 1 H), 8.16 (d, J = 2.4 Hz, 1 H), 8.10 (dd, J = 2.4, 8.8 Hz, 1 H), 7.68 (d, J = 8.4 Hz, 2H), 7.58 - 7.52 (m, 2H), 7.50-7.42 (m,5H), 7.03 (d, J=8.8Hz, 1H), 5.13 - 5.06 (m, 1H), 4.92 - 4.81 (m, 1H),4.05- 3.99 (m, 3H), 3.89 - 3.77 (m, 2H), 3.77 - 3.67 (m, 2H), 3.66 - 3.53 (m, 1H), 3.06 - 2.96 (m, 1H), 2.94 - 2.83 (m, 2H). Mass spectrum (ESI, m / z): Calcd. for C32H28F2N6O4, 598.2; found [M+H]+, 599.3.

[0495] Example 61 : 3-Cyano-N-((5aS,8aR)-5-(4-(difluoro(phenyl)methyl)phenyl)-7-(2- methoxyacetyl)-4-oxo-5, 5a, 6,7,8, 8a-hexahvdro-4H-pyrazolori,5-a]pyrrolor3,4-elpyrazin-3- vD-4-methoxybenzamide.

[0496] The title compound was prepared in a manner analogous to Example 4, Step A, reacting 3-cyano-N-((5aS,8aR)-5-(4-(difluoro(phenyl)methyl)phenyl)-4-oxo-5, 5a, 6,7,8, 8a- hexa hydro-4 H- pyrazolo[1,5-a]pyrrolo[3,4-e]pyrazin-3-yl)-4-methoxybenzamide (Example 55, , 85.0 mg, 0.144 mmol), a stir bar, 2-methoxyacetic acid (15.5 mg, 0.173 mmol), DIEA (71 μL, 0.43 mmol), HATLI (71.1 mg, 0.187 mmol) and DMF (1.2 mL).1H NMR (400 MHz, CDCI3) δ: 9.71 (s, 1H), 8.54 - 8.51 (m, 1H), 8.14 (dd, J=2.4, 8.8 Hz, 1H), 8.12-8.06 (m, 1H), 7.70-7.63 (m, 2H), 7.56-7.50 (m, 2H), 7.47 - 7.38 (m, 5H), 7.04 - 6.99 (m, 1H), 5.09 - 5.00 (m, 1H), 4.88 - 4.80 (m, 1H), 4.77 - 4.63 (m, 1H), 4.34 - 3.98 (m, 7H), 3.63 - 3.53 (m, 1H), 3.44 - 3.32 (m, 3H). Mass spectrum (ESI, m / z): Calcd. for C33H28F2N6O5, 626.2; found [M+H]+, 627.3.

[0497] Example 62: 3-Cyano-N-((5aS,8aR)-5-(4-(difluoro(phenyl)methyl)phenyl)-7-(2- hvdroxyacetyl)-4-oxo-5, 5a, 6,7,8, 8a-hexahvdro-4H-pyrazolori,5-a]pyrrolor3,4-elpyrazin-3- vD-4-methoxybenzamide.

[0498] The title compound was prepared in a manner analogous to Example 4,, reacting 3-cyano- / V- ((5aS,8a / ?)-5-(4-(difluoro(phenyl)methyl)phenyl)-4-oxo-5, 5a, 6,7,8, 8a-hexahydro-4 / 7- pyrazolo[1,5-a]pyrrolo[3,4-e]pyrazin-3-yl)-4-methoxybenzamide (Example 55, 150.0 mg, 0.2700 mmol), 2-hydroxyacetic acid (26.7 mg, 0.352 mmol), HATLI (133.7 mg, 0.3520 mmol), DIPEA (0.19 mL, 1.1 mmol, 0.724 g / mL), and DMF (2.0 mL).1H NMR (400 MHz, DMSO-d6) δ:: 9.92 (d, J = 3.2 Hz, 1 H), 8.27 - 8.20 (m, 2H), 8.15 (dd, J = 2.0, 8.8 Hz, 1H), 7.70 - 7.49 (m, 9H), 7.41 (dd, J = 2.4, 9.2 Hz, 1H), 5.30 - 5.15 (m, 1 H), 5.09 - 4.98 (m, 1 H), 4.89 - 4.72 (m, 1 H), 4.56 - 4.39 (m, 1 H), 4.19 - 3.72 (m, 7H), 3.46 - 3.39 (m, 1H). Mass spectrum (ESI, m / z): Calcd. for C32H26F2N6O5, 612.2; found [M+H]+, 613.2.

[0499] Example 63: 3-Cvano-N-((5aS,8aR)-5-(4-(difluoro(phenyl)methyl)phenyl)-7-(methylglvcyl)- 4-OXO-5, 5a, 6,7,8, 8a-hexahvdro-4H-pyrazolori,5-a]pyrrolor3,4-elpyrazin-3-yl)-4-

[0500] Step A: tert-Butyl (2-((5aS,8aR)-3-(3-cyano-4-methoxybenzamido)-5-(4- (difluoro(phenyl)methyl)phenyl)-4-oxo-4,5,5a,6,8,8a-hexahydro-7H-pyrazolon,5-alpyrrolof3,4- elpyrazin-7-yl)-2-oxoethyl)(methyl)carbamate.

[0501] The title compound was prepared in a manner analogous to Example 6, reacting 3-cyano- / V- ((5aS,8aR)-5-(4-(difluoro(phenyl)methyl)phenyl)-4-oxo-5, 5a, 6,7,8, 8a-hexahydro-4 / 7- pyrazolo[1 ,5-a]pyrrolo[3,4-e]pyrazin-3-yl)-4-methoxybenzamide (Example 55, product from Step H, 150.0 mg, 0.2700 mmol), / V-(tert-butoxycarbonyl)- / V-methylglycine (61.4 mg, 0.325 mmol), HATU (133.7 mg, 0.3520 mmol), DIEA (0.14 mL, 0.81 mmol), and DMF (2.0 mL).1H NMR (400 MHz, DMSO-d6) δ:: 9.94 - 9.91 (m, 1 H), 8.28 - 8.12 (m, 3H), 7.67 - 7.52 (m, 9H), 7.43 - 7.40 (m, 1 H), 4.00 (s, 3H), 3.31 (s, 2H), 2.89 (s, 2H), 2.75 - 2.71 (m, 4H), 2.69 (s, 3H), 1.38 - 1.20 (m, 9H). Mass spectrum (ESI, m / z): Calcd. for C38H3?F2N7O6 , 725.3; found [M-100+H]+, 626.2.

[0502] Step B: 3-Cyano-N-((5aS,8aR)-5-(4-(difluoro(phenyl)methyl)phenyl)-7-(methylglycyl)-4-oxo- 5,5a,6,7,8,8a-hexahydro-4H-pyrazolon ,5-alpyrrolof3,4-elpyrazin-3-yl)-4-methoxybenzamide. The title compound was prepared in a manner analogous to Example 6, Step B above, reacting tert-butyl (2-((5aS,8aR)-3-(3-cyano-4-methoxybenzamido)-5-(4-(difluoro(phenyl)methyl)phenyl)- 4-oxo-4,5,5a,6,8,8a-hexahydro-7 / 7-pyrazolo[1 ,5-a]pyrrolo[3,4-e]pyrazin-7-yl)-2- oxoethyl)carbamate (186 mg, 0.256 mmol), HCI / dioxane (6 mL, 24 mmol).1H NMR (400 MHz, CD3OD) 5: 8.36 (d, J = 12.8 Hz, 1 H), 8.21 - 8.12 (m, 2H), 7.73 - 7.41 (m, 9H), 7.32 (dd, J = 4.4, 8.8 Hz, 1 H), 5.28 - 5.14 (m, 1 H), 5.13 - 4.94 (m, 1 H), 4.85 - 4.63 (m, 1 H), 4.25 - 3.45 (m, 7H), 2.64 - 2.56 (m, 3H). Mass spectrum (ESI, m / z): Calcd. for C33H29F2N7O4, 625.2; found [M+H]+, 626.3.

[0503] Example 64: 3-Cyano-N-((5aS,8aR)-5-(4-(difluoro(phenyl)methyl)phenyl)-7-(2- (dimethylamino)-2-oxoethyl)-4-oxo-5,5a,6,7,8,8a-hexahvdro-4H-pyrazolori,5-a]pyrrolor3,4- e]pyrazin-3-yl)-4-methoxybenzamide.

[0504] The title compound was prepared in a manner analogous to Example 13, reacting 3-cyano- / V- ((5aS,8aR)-5-(4-(difluoro(phenyl)methyl)phenyl)-4-oxo-5, 5a, 6,7,8, 8a-hexahydro-4 / 7- pyrazolo[1 ,5-a]pyrrolo[3,4-e]pyrazin-3-yl)-4-methoxybenzamide (Example 55, product from Step H, 120 mg, 0.216 mmol), 2-bromo- / V, / V-di methylacetamide (43.1 mg, 0.26 mmol), K2CO3 (89.7 mg, 0.649 mmol) and DMF (1.0 mL).1H NMR (400 MHz, DMSO-d6) d : 9.92 (s, 1 H), 8.23 - 8.19 (m, 2H), 8.18 - 8.13 (m, 1 H), 7.68 - 7.63 (m, 2H), 7.59 - 7.51 (m, 7H), 7.40 (d, J = 8.8 Hz, 1 H), 5.11 (s, 1 H), 4.93 (d, J = 7.2 Hz, 1 H), 3.99 (s, 3H), 3.57 (d, J = 8.4 Hz, 1 H), 3.50 - 3.40 (m, 1 H), 3.31 (s, 2H), 3.15 (s, 1 H), 2.97 - 2.91 (m, 1H), 2.84 (s, 3H), 2.75 (s, 3H). Mass spectrum (ESI, m / z): Calcd. for C34H31F2N7O4, 639.2; found [M+H]+, 640.3.

[0505] Example 65: N-((5aS,8aR)-7-(2-Amino-2-oxoethyl)-5-(4-(difluoro(phenyl)methyl)phenyl)-4- oxo-5, 5a, 6,7,8, 8a-hexahvdro-4H-pyrazolori,5-alpyrrolor3,4-e]pyrazin-3-yl)-3-cvano-4- methoxybenzamide.

[0506] The title compound was prepared in a manner analogous to Example 12, reacting 3-cyano-N- ((5aS,8aR)-5-(4-(difluoro(phenyl)methyl)phenyl)-4-oxo-5, 5a, 6,7,8, 8a-hexahydro-4H- pyrazolo[1 ,5-a]pyrrolo[3,4-e]pyrazin-3-yl)-4-methoxybenzamide (Example 55,, product from Step H, 80.0 mg, 0.135 mmol), 2-bromoacetamide (22.4 mg, 0.162 mmol), DIEA (67 pL, 0.41 mmol), and DMF (1.2 mL).1H NMR (400 MHz, DMSO-d6) d : 9.92 (s, 1 H), 8.23 - 8.20 (m, 2H), 8.15 (dd, J = 2.4, 8.8 Hz, 1 H), 7.68 - 7.63 (m, 2H), 7.60 - 7.51 (m, 7H), 7.40 (d, J = 8.8 Hz, 1 H), 7.07 (d, J = 19.2 Hz, 2H), 5.14 - 5.08 (m,1 H), 4.91 (q, J = 7.2 Hz, 1 H), 3.99 (s, 3H), 3.54 - 3.48 (m, 1 H), 3.32 - 3.28 (m, 1 H), 3.17 - 3.03 (m, 3H), 2.93 - 2.87 (m, 1 H). Mass spectrum (ESI, m / z): Calcd. for C32H27F2N7O4, 611.1 ; found [M+H]+, 612.2.

[0507] Example 66: 3-Cyano-N-((5aS,8aR)-5-(4-(difluoro(phenyl)methyl)phenyl)-7- The title compound was prepared in a manner analogous to Example 11, Step A above, reacting 3-cyano- / V-((5aS,8aR)-5-(4-(difluoro(phenyl)methyl)phenyl)-4-oxo-5,5a,6,7,8,8a- hexahydro-4H-pyrazolo[1 ,5-a]pyrrolo[3,4-e]pyrazin-3-yl)-4-methoxybenzamide (Example 55, product from Step H, 80.0 mg, 144 μmol), dimethylglycine (17.9 mg, 173 μmol), DIPEA (75 pL, 433μmol), and DMF (2.0 mL).1H NMR (400 MHz, DMSO-d6) δ:: 9.92 (d, J = 1.4 Hz, 1 H), 8.26 - 8.20 (m, 2H), 8.16 -8.14 (m, 1H), 7.69 - 7.51 (m, 9H), 7.41 (d, J = 8.8 Hz, 1 H), 5.28 - 5.15 (m, 1 H), 5.09 - 4.97 (m, 1 H), 4.63 - 4.44 (m, 1 H), 4.26 - 4.04 (m, 1 H), 4.00 (s, 3H), 3.78 - 3.47 (m, 1 H), 3.14 - 2.97 (m, 2H), 2.20 (s, 3H), 2.13 (s, 3H). Mass spectrum (ESI, m / z): C34H31 F2N7O4, 639.2; found [M+H]+, 640.3.

[0508] Example 67: 3-Cyano-N-((5aS,8aR)-5-(4-(difluoro(phenyl)methyl)phenyl)-7-(2- (methylamino)-2-oxoethyl)-4-oxo-5,5a,6,7,8,8a-hexahvdro-4H-pyrazolori,5-a]pyrrolor3,4- e]pyrazin-3-yl)-4-methoxybenzamide.

[0509] The title compound was prepared in a manner analogous to Example 7 above, reacting 3- cyano- / V-((5aS,8aF?)-5-(4-(difluoro(phenyl)methyl)phenyl)-4-oxo-5, 5a, 6,7,8, 8a-hexahydro-4 / 7- pyrazolo[1,5-a]pyrrolo[3,4-e]pyrazin-3-yl)-4-methoxybenzamide (Example 55, product from Step H, 120.0 mg, 0.2160 mmol), K2CO3 (89.7 mg, 0.649 mmol), 2-bromo- / V-methylacetamide (39.5 mg, 0.260 mmol) and DMF (3.0 mL).1H NMR (400 MHz, DMSO-d6) δ:: 9.92 (s, 1 H), 8.23 - 8.20 (m, 2H), 8.15 (dd, J = 2.0, 8.8 Hz, 1H), 7.68 - 7.64 (m, 2H), 7.61 - 7.51 (m, 8H), 7.40 (d, J = 9.2 Hz, 1H), 5.12 (t, J = 4.8 Hz, 1 H), 4.91 (q, J = 7.2 Hz, 1 H), 3.99 (s, 3H), 3.52 - 3.47 (m, 1 H), 3.30 - 3.29 (m, 1 H), 3.17 - 3.05 (m, 3H), 2.88 (dd, J = 7.2, 9.2 Hz, 1 H), 2.54 (d, J = 4.4 Hz, 3H). Mass spectrum (ESI, m / z): C33H29F2N7O4, 625.2; found [M+H]+, 626.3.

[0510] The title compound was prepared in a manner analogous to Example 4, Step A, above, reacting 3-cyano- / V-((5aS,8aF?)-5-(4-(difluoro(phenyl)methyl)phenyl)-4-oxo-5, 5a, 6,7,8, 8a-hexahydro-4 / 7- pyrazolo[1 ,5-a]pyrrolo[3,4-e]pyrazin-3-yl)-4-methoxybenzamide (Example 55, product from Step H, 100.0 mg, 0.1800 mmol), (tert-butoxycarbonyl)glycine (37.9 mg, 0.216 mmol), HATLI (89.1 mg, 0.234 mmol), DIEA (94 μL, 0.54 mmol), and DMF (2.0 mL). Mass spectrum (ESI, m / z): calcd. for C37H35F2N7O6, 711.3; found [M-100+H]+, 612.1.

[0511] Step B: 3-Cyano- / V-((5aS,8aS)-5-(4-(difluoro(phenyl)methyl)phenyl)-7-glycyl-4-oxo- 5,5a,6,7,8,8a-hexahydro-4 / 7-pyrazolo[1 ,5-a]pyrrolo[3,4-e]pyrazin-3-yl)-4-methoxybenzamide The title compound was prepared in a manner analogous to Example 4, Step B, above, reacting tert-butyl (2-((5aS,8aF?)-3-(3-cyano-4-methoxybenzamido)-5-(4-(difluoro(phenyl)methyl)phenyl)- 4-oxo-4,5,5a,6,8,8a-hexahydro-7 / 7-pyrazolo[1 ,5-a]pyrrolo[3,4-e]pyrazin-7-yl)-2- oxoethyl)carbamate (220.0 mg, 0.3090 mmol) and 4 N HCI / dioxane (11.0 mL).1H NMR (400 MHz, DMSO-d6) d : 9.93 (s, 1 H), 8.27 - 8.19 (m, 2H), 8.17 - 8.14 (m, 1 H), 7.70 - 7.51 (m, 9H), 7.44 - 7.38 (m, 1 H), 5.32 - 5.17 (m, 1 H), 5.08 - 5.02 (m, 1 H), 4.60 - 4.36 (m, 2H), 4.23 - 4.18 (m, 1 H), 4.00 (s, 4H), 3.79 - 3.74 (m, 1 H), 3.48 - 3.31 (m, 3H). Mass spectrum (ESI, m / z): calcd. for C32H27F2N7O4, 611.2; found [M+H]+, 612.3. Example 69: 3-cvano-N-((5aS,8aR)-7-((cvclopropylmethyl)sulfonyl)-5-(4- (difluoro(phenyl)rnethyl)phenyl)-4-oxo-5,5a,6,7,8,8a-hexahvdro-4H-pyrazolori,5- a]pyrrolor3,4-elpyrazin-3-yl)-4-methoxybenzamide.

[0512] The title compound was prepared in a manner analogous to Example 32, reacting 3-cyano-N- ((5aR,8aS)-5-(4-(difluoro(phenyl)methyl)phenyl)-4-oxo-5, 5a, 6,7,8, 8a-hexahydro-4H- pyrazolo[1,5-a]pyrrolo[3,4-e]pyrazin-3-yl)-4-methoxybenzamide (Example 55, product from Step H, 60.0 mg, 0.10 mmol) and cyclopropylmethanesulfonyl chloride (47.2 mg, 0.305 mmol) to give 3-cyano-N-((5aS,8aR)-7-((cyclopropylmethyl)sulfonyl)-5-(4-(difluoro(phenyl)methyl)phenyl)-4- oxo-5, 5a, 6,7,8, 8a-hexahydro-4H-pyrazolo[1, 5-a]pyrrolo[3, 4-e]pyrazin-3-yl)-4- methoxybenzamide (16.0 mg, 23%).1H NMR (500 MHz, DMSO-d6) δ:: 9.92 (s, 1H), 8.27 (s, 1 H), 8.22 (d, J = 2.4 Hz, 1 H), 8.16 (dd, J = 8.9, 2.3 Hz, 1H), 7.59 - 7.70 (m, 4H), 7.50 - 7.59 (m, 5H), 7.41 (d, J = 9.0 Hz, 1 H), 5.24 (t, J = 4.7 Hz, 1 H), 5.09 (td, J = 8.7, 5.3 Hz, 1 H), 4.35 (d, J = 10.9 Hz, 1H), 4.01 - 4.07 (m, 1H), 4.00 (s, 3H), 3.88 (dd, J = 11.1 , 4.1 Hz, 1 H), 3.37 (br d, J = 2.3 Hz, 1 H), 2.95 - 3.05 (m, 2H), 0.82 - 0.98 (m, 1H), 0.51 (dd, J = 8.1, 1.9 Hz, 2H), 0.17 - 0.30 (m, 2H). Mass spectrum (ESI, m / z): Calcd. For C34H30F2N6O5S, 672.2; found [M+H]+, 673.4.

[0513] Example 70: 3-cvano-N-((5aS,8aR)-5-(4-(difluoro(phenyl)methyl)phenyl)-4-oxo-7-((3,3,3- trifluoropropyl)sulfonyl)-5, 5a, 6,7,8, 8a-hexahvdro-4H-pyrazolori,5-a]pyrrolor3,4-elpyrazin- 3-yl)-4-methoxybenzamide.

[0514] The title compound was prepared in a manner analogous to Example 32 reacting 3-cyano-N- ((5aR,8aS)-5-(4-(difluoro(phenyl)methyl)phenyl)-4-oxo-5, 5a, 6,7,8, 8a-hexahydro-4H- pyrazolo[1,5-a]pyrrolo[3,4-e]pyrazin-3-yl)-4-methoxybenzamide (Example 55, product from Step H, 60.0 mg, 0.10 mmol) and 3,3,3-trifluoropropane-1-sulfonyl chloride (60.6 mg, 0.308 mmol) to give 3-cyano-N-((5aS,8aR)-5-(4-(difluoro(phenyl)methyl)phenyl)-4-oxo-7-((3,3,3- trifluoropropyl)sulfonyl)-5,5a,6,7,8,8a-hexahydro-4H-pyrazolo[1,5-a]pyrrolo[3,4-e]pyrazin-3-yl)-4- methoxybenzamide (5.0 mg, 7%).1H NMR (500 MHz, DMSO-d6) δ:: 9.91 (s, 1H), 8.28 (s, 1 H), 8.21 (d, J = 2.4 Hz, 1 H), 8.15 (dd, J = 8.9, 2.3 Hz, 1H), 7.59 - 7.70 (m, 4H), 7.51 - 7.59 (m, 5H), 7.42 (d, J = 9.0 Hz, 1 H), 5.26 (t, J = 4.6 Hz, 1 H), 5.13 (td, J = 8.7, 5.3 Hz, 1 H), 4.37 (d, J = 10.8 Hz, 1H), 4.04 - 4.11 (m, 1H), 4.00 (s, 3H), 3.90 (dd, J = 11.2, 4.1 Hz, 1 H), 3.41 (t, J = 9.4 Hz, 1 H), 3.20 - 3.30 (m, 2H), 2.56 - 2.66 (m, 2H). Mass spectrum (ESI, m / z): Calcd. For C33H27F5N6O5S, 714.2; found [M+H]+, 715.4.

[0515]

[0516] The title compound was prepared in a manner analogous to Example 32, reacting 3-cyano-N- ((5aR,8aS)-5-(4-(difluoro(phenyl)methyl)phenyl)-4-oxo-5, 5a, 6,7,8, 8a-hexahydro-4H- pyrazolo[1 ,5-a]pyrrolo[3,4-e]pyrazin-3-yl)-4-methoxybenzamide (Example 55, product from Step H, 60.0 mg, 0.10 mmol) and 2-methylpropane-1 -sulfonyl chloride (47.6 mg, 0.304 mmol) to give 3-cyano-N-((5aS,8aR)-5-(4-(difluoro(phenyl)methyl)phenyl)-7-(isobutylsulfonyl)-4-oxo- 5,5a,6,7,8,8a-hexahydro-4H-pyrazolo[1 ,5-a]pyrrolo[3,4-e]pyrazin-3-yl)-4-methoxybenzamide (7.3 mg, 10%).1H NMR (500 MHz, DMSO-d6) δ:: 9.91 (s, 1 H), 8.28 (s, 1 H), 8.21 (d, J = 2.4 Hz, 1 H), 8.15 (dd, J = 8.9, 2.4 Hz, 1 H), 7.59 - 7.69 (m, 4H), 7.50 - 7.59 (m, 5H), 7.41 (d, J = 9.1 Hz, 1 H), 5.23 (t, J = 4.6 Hz, 1 H), 5.10 (td, J = 8.7, 5.3 Hz, 1 H), 4.32 (d, J = 10.9 Hz, 1 H), 4.00 (s, 4H), 3.79 - 3.86 (m, 1 H), 3.09 (q, J = 7.1 Hz, 1 H), 2.85 (d, J = Q.Q Hz, 2H), 1.91 - 2.05 (m, 1 H), 0.95 (dd, J=6.6, 2.8 Hz, 6H). Mass spectrum (ESI, m / z): Calcd. For C34H32F2N6O5S, 674.2; found [M+H]+, 675.4.

[0517] Example 72: 3-cvano-N-((5aS,8aR)-7-(cvclopropylsulfonyl)-5-(4- (difluoro(phenyl)rnethyl)phenyl)-4-oxo-5,5a,6,7,8,8a-hexahvdro-4H-pyrazolori,5- alpyrrolor3,4-e]pyrazin-3-yl)-4-methoxybenzamide. The title compound was prepared in a manner analogous to Example 32, reacting 3-cyano-N- ((5aR,8aS)-5-(4-(difluoro(phenyl)methyl)phenyl)-4-oxo-5, 5a, 6,7,8, 8a-hexahydro-4H- pyrazolo[1 ,5-a]pyrrolo[3,4-e]pyrazin-3-yl)-4-methoxybenzamide (Example 55, product from Step H, 60.0 mg, 0.10 mmol) and cyclopropanesulfonyl chloride (43.4 mg, 0.309 mmol) to give 3- cyano-N-((5aS,8aR)-7-(cyclopropylsulfonyl)-5-(4-(difluoro(phenyl)methyl)phenyl)-4-oxo- 5,5a,6,7,8,8a-hexahydro-4H-pyrazolo[1 ,5-a]pyrrolo[3,4-e]pyrazin-3-yl)-4-methoxybenzamide (5.2 mg, 7%).1H NMR (500 MHz, DMSO-d6) δ:: 9.92 (s, 1 H), 8.26 (s, 1 H), 8.22 (d, J = 2.3 Hz, 1 H), 8.16 (dd, J = 8.9, 2.3 Hz, 1 H), 7.60 - 7.68 (m, 4H), 7.50 - 7.59 (m, 5H), 7.41 (d, J = 9.0 Hz, 1 H), 5.25 (t, J = 4.7 Hz, 1 H), 5.12 (td, J = 8.6, 5.3 Hz, 1 H), 4.36 (d, J = 10.9 Hz, 1 H), 4.03 (dd, J = 9.9, 8.3 Hz, 1 H), 4.00 (s, 3H), 3.83 - 3.91 (m, 1 H), 3.09 (q, J = 7.3 Hz, 2H), 0.76 - 0.97 (m, 2H), 0.43 - 0.59 (m, 2H). Mass spectrum (ESI, m / z): Calcd. For C33H28F2N6O5S, 658.2; found [M+H]+, 659.4.

[0518] Example 73: 3-cyano-N-((5aS,8aR)-5-(4-(difluoro(phenyl)methyl)phenyl)-7-((2,2- difluorocvclopropyl)sulfonyl)-4-oxo-5,5a,6,7,8,8a-hexahvdro-4H-pyrazolori,5- alpyrrolor3,4-e]pyrazin-3-yl)-4-methoxybenzamide.

[0519] The title compound was prepared in a manner analogous to Example 32, reacting 3-cyano-N- ((5aR,8aS)-5-(4-(difluoro(phenyl)methyl)phenyl)-4-oxo-5, 5a, 6,7,8, 8a-hexahydro-4H- pyrazolo[1 ,5-a]pyrrolo[3,4-e]pyrazin-3-yl)-4-methoxybenzamide (Example 55, product from Step H, 60.0 mg, 0.10 mmol) and 2,2-difluorocyclopropane-1-sulfonyl chloride (53.1 mg, 0.301 mmol) to give 3-cyano-N-((5aS,8aR)-5-(4-(difluoro(phenyl)methyl)phenyl)-7-((2,2- difluorocyclopropyl)sulfonyl)-4-oxo-5,5a,6,7,8,8a-hexahydro-4H-pyrazolo[1 ,5-a]pyrrolo[3,4- e]pyrazin-3-yl)-4-methoxybenzamide (28.2 mg, 38%).1H NMR (500 MHz, DMSO-d6) δ: 9.92 (d, J = 1.3 Hz, 1 H), 8.28 (d, J = 11.1 Hz, 1 H), 8.22 (d, J = 1.6 Hz, 1 H), 8.12 - 8.19 (m, 1 H), 7.59 - 7.70 (m, 4H), 7.50 - 7.59 (m, 5H), 7.41 (d, J = 9.0 Hz, 1 H), 5.28 (q, J = 4.0 Hz, 1 H), 5.14 (dtd, J = 16.8, 8.6, 8.6, 5.3 Hz, 1 H), 4.38 (dd, J = 10.9, 3.1 Hz, 1 H), 4.04 - 4.13 (m, 1 H), 4.00 (s, 3H), 3.89 (ddd, J = 11.0, 6.4, 4.2 Hz, 1H), 3.69 - 3.83 (m, 1H), 3.41 - 3.48 (m, 1 H), 2.07 - 2.29 (m, 2H). Mass spectrum (ESI, m / z): Calcd. For C33H26F4N6O5S, 694.2; found [M+H]+, 695.4.

[0520] Example 74: 3-cvano-N-((5aS,8aR)-5-(4-(difluoro(phenyl)methyl)phenyl)-4-oxo-7-(((1- (trifluoromethyl)cvclopropyl)rnethyl)sulfonyl)-5,5a,6,7,8,8a-hexahvdro-4H-pyrazolori,5- a]pyrrolor3,4-elpyrazin-3-yl)-4-methoxybenzamide.

[0521] The title compound was prepared in a manner analogous to Example 32, reacting 3-cyano-N- ((5aR,8aS)-5-(4-(difluoro(phenyl)methyl)phenyl)-4-oxo-5, 5a, 6,7,8, 8a-hexahydro-4H- pyrazolo[1,5-a]pyrrolo[3,4-e]pyrazin-3-yl)-4-methoxybenzamide (Example 55, product from Step H, 60.0 mg, 0.10 mmol) and (1-(trifluoromethyl)cyclopropyl)methanesulfonyl chloride (68.6 mg, 0.308 mmol) to give 3-cyano-N-((5aS,8aR)-5-(4-(difluoro(phenyl)methyl)phenyl)-4-oxo-7-(((1- (trifluoromethyl)cyclopropyl)methyl)sulfonyl)-5,5a,6,7,8,8a-hexahydro-4H-pyrazolo[1,5- a]pyrrolo[3,4-e]pyrazin-3-yl)-4-methoxybenzamide (14.6 mg, 21%).1H NMR (500 MHz, DMSO- cfe)_δ: 9.91 (s, 1H), 8.28 (s, 1 H), 8.21 (d, J = 2.4 Hz, 1 H), 8.15 (dd, J = 8.9, 2.3 Hz, 1H), 7.59 - 7.69 (m, 4H), 7.50 - 7.59 (m, 5H), 7.42 (d, J = 9.0 Hz, 1 H), 5.24 (t, J = 4.6 Hz, 1 H), 5.07 (td, J = 8.7, 5.3 Hz, 1H), 4.33 (d, J = 11.0 Hz, 1H), 4.03 (dd, J = 10.1 , 8.6 Hz, 1 H), 4.00 (s, 3H), 3.86 (dd, J = 11.3, 4.1 Hz, 1 H), 3.36 - 3.42 (m, 2H), 3.09 (q, J = 7.3 Hz, 1 H), 0.97 - 1.12 (m, 4H). Mass spectrum (ESI, m / z): Calcd. For C35H29F5N6O5S, 740.2; found [M+H]+, 741.4.

[0522] Example 75: N-((5aS,8aR)-7-Acetyl-5-(4-(difluoro(4-fluorophenyl)methyl)phenyl)-4-oxo- 5,5a,6,7,8,8a-hexahvdro-4H-pyrazolori,5-alpyrrolor3,4-e]pyrazin-3-yl)-3-cvano-4- methoxybenzamide.

[0523] Step A: 3-Cvano- / V-((5aS,8aF?)-5-(4-(difluoro(4-fluorophenyl)methyl)phenyl)-7-(4- methoxybenzyl)-4-oxo-5, 5a, 6,7,8, 8a-hexahydro-4 / 7-pyrazolon ,5-alpyrrolo[3,4-elpyrazin-3-yl)-4- methoxybenzamide.

[0524] 3-Cyano-4-methoxy- / V-((5aS,8a / ?)-7-(4-methoxybenzyl)-4-oxo-5, 5a, 6,7,8, 8a-hexahydro-4 / 7- pyrazolo[1 ,5-a]pyrrolo[3,4-e]pyrazin-3-yl)benzamide (Example 55, product from Step H, 600.0 mg, 1.270 mmol), a stir bar, DMF (4.0 mL) and toluene (4.0 mL) were added to an oven-dried 50 mL round-bottomed flask, then the resulting mixture treated with 1-bromo-4-(difluoro(4- fluorophenyl)methyl)benzene (intermediate 1 , 458.8 mg, 1.524 mmol), Cui (290.2 mg, 1.524 mmol), DMEDA (134.3 mg, 1.524 mmol) and K2CO3 (351.0 mg, 2.540 mmol) and sparged with N2 for 3 times. Then the resulting mixture was stirred at 100°C for 16 h, finally the reaction mixture became a green suspension. The reaction progress was monitored by LC-MS. The reaction mixture was extracted with DCM (50 mL x 3), and dried over anhydrous Na2SO4, filtered and concentrated to dryness in vaco to give a yellow oil. The oil was subjected to silica- gel chromatography (50-65% EtOAc / pet ether) to give 3-cyano- / V-((5aS,8aR)-5-(4-(difluoro(4- fluorophenyl)methyl)phenyl)-7-(4-methoxybenzyl)-4-oxo-5, 5a, 6,7,8, 8a-hexahydro-4 / 7- pyrazolo[1 ,5-a]pyrrolo[3,4-e]pyrazin-3-yl)-4-methoxybenzamide as a yellow oil (730.0 mg, 71 %). Mass spectrum (ESI, m / z): Calcd. for C38H31F3N6O4, 692.2; found [M+H]+, 693.5.

[0525] Step B: 3-Cyano- / V-((5aS,8aF?)-5-(4-(difluoro(4-fluorophenyl)methyl)phenyl)-4-oxo- 5,5a,6,7,8,8a-hexahydro-4 / - / -pyrazolon ,5-alpyrrolof3,4-elpyrazin-3-yl)-4-methoxybenzamide.

[0526] 3-Cyano- / V-((5aS,8aF?)-5-(4-(difluoro(4-fluorophenyl)methyl)phenyl)-7-(4-methoxybenzyl)-4-oxo- 5,5a,6,7,8,8a-hexahydro-4 / 7-pyrazolo[1 ,5-a]pyrrolo[3,4-e]pyrazin-3-yl)-4-methoxybenzamide (730.0 mg, 1.050 mmol), a stir bar, 1 -chloroethyl carbonochloridate (0.34 mL, 3.2 mmol, 1.33 g / mL) in DCE (5.0 mL) were added to an oven-dried and nitrogen-purged a 50 ml round- bottomed flask, which was subsequently evacuated and refilled with nitrogen (x3), the resulting mixture stirred for 2 h at room temperature under N2, then which was added MeOH (5 mL), and the reaction vessel placed in an oil bath that had been pre-heated to 60°C, and the mixture stirred for 3 h under N2 to give a yellow solution. The reaction progress was monitored by LC- MS. The suspension was filtered and the filter cake was triturated with DCM / MeOH (1 :5) (20 mL), the suspension was filtered and filter cake was obtained to give 3-cyano- / V-((5aS,8aR)-5- (4-(difluoro(4-fluorophenyl)methyl)phenyl)-4-oxo-5,5a,6,7,8,8a-hexahydro-4 / 7-pyrazolo[1 ,5- a]pyrrolo[3,4-e]pyrazin-3-yl)-4-methoxybenzamide (510.0 mg, 80%) as white solid. Mass spectrum (ESI, m / z): Calcd. For C30H23F3N6O3, 572.2, found [M+H]+, 573.1. 6,7,8,8a-

[0527] 3-Cyano-N-((5aS,8aR)-5-(4-(difluoro(4-fluorophenyl)methyl)phenyl)-4-oxo-5,5a,6,7,8,8a- hexahydro-4H-pyrazolo[1 ,5-a]pyrrolo[3,4-e]pyrazin-3-yl)-4-methoxybenzamide (100 mg, 0.175 mmol), a stir bar, and DCE (1.0 mL) was added to an oven-dried and nitrogen-purgedd a 10 mL round-bottomed flask. Then reaction mixture was treated with AC2O (20 μL, 0.21 mmol) and TEA (49 μL, 0.35 mmol), the mixture was spared with N2 for 3 times, the mixture was stirred at 20°C for 16 h.

[0528] 3-Cyano- / V-((5aS,8aR)-5-(4-(difluoro(4-fluorophenyl)methyl)phenyl)-4-oxo-5,5a,6,7,8,8a- hexahydro-4 / 7-pyrazolo[1 ,5-a]pyrrolo[3,4-e]pyrazin-3-yl)-4-methoxybenzamide (410.0 mg, 0.7160 mmol), a stir bar, DCE (4.0 mL) were added to an oven-dried and nitrogen-purgedd a 10 mL round-bottomed flask. Then reaction mixture was treated with AC2O (65 μL, 0.69 mmol) and TEA (0.16 mL, 1.2 mmol), the mixture was spared with N2 for 3 times, the mixture was stirred at 25°C for 16 h to give a white suspension. The reaction progress was monitored by LC-MS. The combined reaction mixture was filtered and the filter cake was triturated with DCM / MeOH (1 :5) (20 mL), the suspension was filtered to give / V-((5aS,8aR)-7-acetyl-5-(4-(difluoro(4- fluorophenyl)methyl)phenyl)-4-oxo-5,5a,6,7,8,8a-hexahydro-4 / 7-pyrazolo[1 ,5-a]pyrrolo[3,4- e]pyrazin-3-yl)-3-cyano-4-methoxybenzamide as a white solid (321 mg, 57%).1H NMR (400 MHz, DMSO-d6) δ:: 9.91 (s, 1 H), 8.25 (d, J = 4.4 Hz, 1 H), 8.21 (d, J = 2.0 Hz, 1 H), 8.18 - 8.12 (m, 1 H), 7.69 - 7.59 (m, 6H), 7.45 - 7.30 (m, 3H), 5.30 - 4.97 (m, 2H), 4.52 - 4.42 (m, 1 H), 4.26 - 4.02 (m, 1 H), 4.00 (s, 3H), 3.74 - 3.45 (m, 1 H), 3.32 - 3.21 (m, 1 H), 1.99 - 1 .88 (m, 3H). Mass spectrum (ESI, m / z): Calcd. for C32H25F3N6O4, 614.2; found [M+H]+, 615.2. Example 76: 3-cvano-N-((5aS,8aR)-5-(4-(difluoro(4-fluorophenyl)methyl)phenyl)-7- (methylsulfonyl)-4-oxo-5, 5a, 6,7,8, 8a-hexahvdro-4H-pyrazolori,5-a]pyrrolor3,4-elpyrazin-3- vD-4-methoxybenzamide

[0529] 3-Cyano- / V-((5aS,8aR)-5-(4-(difluoro(4-fluorophenyl)methyl)phenyl)-4-oxo-5,5a,6,7,8,8a- hexahydro-4 / 7-pyrazolo[1,5-a]pyrrolo[3,4-e]pyrazin-3-yl)-4-methoxybenzamide (470.0 mg, 0.82 mmol), a stir bar, MS2O (428 mg, 2.460 mmol), TEA (0.31 mL, 2.46 mmol) and DCE (5.0 mL) were added to an oven-dried 50 mL round-bottomed flask. The resuting mixture was sparged with N2 for 3 times. The resulting mixture was stired at r.t. for 16 h, finally the reaction mixture became a yellow solution. The reaction progress was monitored by LC-MS. The reaction mixture was concentrated in vacuum to give a yellow oil, which was subjected to silica-gel chromatography (30-40% Ethyl acetate / Petroleum ether) to give 3-cyano-N-((5aS,8aR)-5-(4- (difluoro(4-fluorophenyl)methyl)phenyl)-7-(methylsulfonyl)-4-oxo-5, 5a, 6,7,8, 8a- hexa hydro-4 H- pyrazolo[1,5-a]pyrrolo[3,4-e]pyrazin-3-yl)-4-methoxybenzamide as a white soild. (190.7 mg, 36% yield), 1H NMR (400 MHz, DMSO-d6): d : 9.91 (s, 1H), 8.29 (s, 1 H), 8.21 (d, J = 2.4 Hz, 1 H), 8.17 - 8.13 (m, 1H), 7.68 - 7.61 (m, 6H), 7.44 - 7.34 (m, 3H), 5.23 (t, J = 4.4 Hz, 1 H), 5.14 - 5.05 (m, 1 H), 4.31 (d, J = 11.2 Hz, 1 H), 4.03 - 3.97 (m, 4H), 3.85 - 3.80 (m, 1H), 3.41 - 3.35 (m, 1 H), 2.81 (s, 3H)

[0530] Example 77 : 3-cyano-N-((5aS,8aR)-5-(4-(difluoro(phenyl)methyl)phenyl)-7-(((1- methoxycvclopropyl)rnethyl)sulfonyl)-4-oxo-5,5a,6,7,8,8a-hexahvdro-4H-pyrazolori,5- a]pyrrolor3,4-elpyrazin-3-yl)-4-methoxybenzamide

[0531] The title compound was prepared in a manner analogous to Example 32 reacting 3-cyano-N- ((5aR,8aS)-5-(4-(difluoro(phenyl)methyl)phenyl)-4-oxo-5, 5a, 6,7,8, 8a-hexahydro-4H- pyrazolo[1,5-a]pyrrolo[3,4-e]pyrazin-3-yl)-4-methoxybenzamide (Example 55, product from Step H, 60.0 mg, 0.10 mmol) and (l-methoxycyclopropyl)methanesulfonyl chloride (56.0 mg, 0.300 mmol) to give 3-cyano-N-((5aS,8aR)-5-(4-(difluoro(phenyl)methyl)phenyl)-7-(((1- methoxycyclopropyl)methyl)sulfonyl)-4-oxo-5,5a,6,7,8,8a-hexahydro-4H-pyrazolo[1,5- a]pyrrolo[3,4-e]pyrazin-3-yl)-4-methoxybenzamide (7.9 mg, 11%).1H NMR (500 MHz, DMSO- cfe)_δ: 9.92 (s, 1 H) 8.28 (s, 1 H), 8.22 (d, J = 2.3 Hz, 1 H), 8.16 (dd, J = 8.9, 2.3 Hz, 1H), 7.59 - 7.69 (m, 4H), 7.49 - 7.59 (m, 5H), 7.41 (d, J = 9.0 Hz, 1 H), 5.26 (t, J = 4.8 Hz, 1 H), 4.99 (td, J = 8.8, 5.4 Hz, 1H), 4.34 (d, J = 10.6 Hz, 1H), 4.06 (dd, J = 9.9, 8.5 Hz, 1H), 4.00 (s, 3H), 3.91 (dd, J = 11.0, 4.4 Hz, 1 H), 3.47 - 3.54 (m, 1 H), 3.36 - 3.43 (m, 1 H), 3.12 (d, J = 19.1 Hz, 3H), 3.05 - 3.10 (m, 1 H), 0.71 - 0.81 (m, 2H), 0.59 - 0.70 (m, 2H). Mass spectrum (ESI, m / z): Calcd. For C35H32F2N6O6S, 702.2; found [M+H]+, 703.4.

[0532] Example 78: N-((5aS,8aR)-7-Acetyl-5-(4-(difluoro(4-fluorophenyl)methyl)phenyl)-4-oxo- 5,5a,6,7,8,8a-hexahvdro-4H-pyrazolori,5-a]pyrrolor3,4-elpyrazin-3-yl)-3-cvano-4- )-4-

[0533] The title compound was prepared in a manner analogous to Example 20, Step B, above, reacting 3-cyano-4-methoxy- / V-((5aS,8a / ?)-7-(4-methoxybenzyl)-4-oxo-5, 5a, 6,7,8, 8a-hexahydro- 4 / 7-pyrazolo[1 ,5-a]pyrrolo[3,4-e]pyrazin-3-yl)benzamide (Example 55, product from Step H, 950.0 mg, 2.011 mmol), a stir bar, 4-((4-bromophenyl)difluoromethyl)-1-fluoro-2- methoxybenzene (Intermediate 3, 998.6 mg, 3.016 mmol), DMEDA (212.7 mg, 2.413 mmol), K2CO3 (555.8 mg, 4.021 mmol), Cui (459.5 mg, 2.413 mmol) in DMF (5.0 mL) and toluene (5.0 mL).1H NMR (400 MHz, DMSO-d6) δ:: 9.91 (s, 1 H), 8.23 - 8.11 (m, 3H), 7.71 - 7.51 (m, 4H), 7.45 - 7.31 (m, 3H), 7.18 - 7.03 (m, 3H), 6.83 (d, J = 8.8 Hz, 2H), 5.16 - 5.08 (m, 1 H), 4.92 (q, J = 7.2 Hz, 1 H), 3.99 (s, 3H), 3.89 (s, 3H), 3.71 (s, 3H), 3.62 - 3.49 (m, 2H), 3.36 (br d, J = 3.6 Hz, 1 H), 3.10 (dd, J = 5.2, 10.4 Hz, 1 H), 2.96 - 2.90 (m, 1 H), 2.80 - 2.74 (m, 1 H). Mass spectrum (ESI, m / z): Calcd for C39H33F3N6O5, 722.3; found [M+H]+, 723.2. i-4-oxo-

[0534] 5,5a,6,7,8,8a-hexahydro-4H-pyrazolo[1 ,5-. ,4-elpyrazin-3-yl)-4-

[0535] The title compound was prepared in a manner analogous to Example 20,, Step C, above, reacting 3-cyano- / V-((5aS,8aR)-5-(4-(difluoro(4-fluoro-3-methoxyphenyl)methyl)phenyl)-7-(4- methoxybenzyl)-4-oxo-5, 5a, 6,7,8, 8a-hexahydro-4 / 7-pyrazolo[1 ,5-a]pyrrolo[3,4-e]pyrazin-3-yl)-4- methoxybenzamide (1.30 g, 1.80 mmol), DCE (13.0 mL), ACE-CI (642.9 mg, 4.497 mmol), MeOH (20.0 mL).1H NMR (400 MHz, DMSO-d6) δ:: 9.92 (s, 1 H), 9.75 (br s, 1 H), 8.31 (s, 1 H), 8.21 (d, J = 2.4 Hz, 1 H), 8.15 (dd, J = 2.4, 8.8 Hz, 1 H), 7.76 - 7.60 (m, 4H), 7.45 - 7.31 (m, 3H), 7.11-7.04 (m, 1 H), 5.36 (br t, J = 4.8 Hz, 1 H), 5.17 - 5.01 (m, 1 H), 4.19 (br d, J = 12.8 Hz, 1 H), 3.99 (s, 3H), 3.90 (s, 3H), 3.85 - 3.77 (m, 2H), 3.30 - 3.24 (m, 1 H). Mass spectrum (ESI, m / z): Calcd for C31H25F3N6O4, 602.2; found [M+H]+, 603.2. i-4-oxo-

[0536] The title compound was prepared in a manner analogous to Example 320, above, reacting 3-cyano- / V-((5aS,8aR)-5-(4-(difluoro(4-fluoro-3-methoxyphenyl)methyl)phenyl)-4-oxo- 5,5a,6,7,8,8a-hexahydro-4 / 7-pyrazolo[1 ,5-a]pyrrolo[3,4-e]pyrazin-3-yl)-4-methoxybenzamide (400.0 mg, 0.6640 mmol), Ac2O (75 μL, 0.80 mmol), TEA (0.19 mL, 1.33 mmol) and DCE (4.0 mL).1H NMR (400 MHz, CDCh) 6 : 9.71 (s, 1 H), 8.63 - 8.46 (m, 1 H), 8.18 - 8.06 (m, 2H), 7.70 - 7.62 (m, 2H), 7.47 - 7.40 (m, 2H), 7.25 - 7.07 (m, 2H), 7.06 - 6.98 (m, 2H), 5.12 - 5.03 (m, 1 H), 4.87 - 4.65 (m, 2H), 4.36 - 4.08 (m, 1 H), 4.04 - 3.95 (m, 4H), 3.93 (s, 3H), 3.64 - 3.46 (m, 1 H), 2.12 - 2.02 (m, 3H). Mass spectrum (ESI, m / z): Calcd for C33H27F3N6O5, 644.2; found [M+H]+

[0537] 645.2.

[0538] Example 79: N-((5aS,8aR)-5-(4-((4-Chlorophenyl)difluoromethyl)phenyl)-7- (methylsulfonyl)-4-oxo-5, 5a, 6,7,8,...

Claims

Claims1. A compound of formula (I)including any stereochemically isomeric form thereof, wherein,X is -(CO)-NH- or -NH-(CO)-;R1 is hydrogen; C1-6alkyl; C1-6alkyl substituted with hydroxy, amino, or mono- or di(C1 -4alkyl)amino; C1 -4alkyl-oxy-C^alkyl;- L2-R5;-L1-L2-R6or -L2-L1-R6;-L1-R7or -L1-O-R7; or 8C3-6cycloalkyl or Heterocycl;R® is hydroxy, C1 -4alkyloxy, amino, mono- or di(C1 -4alkyl)amino;R7is Het"' or Heterocycl;R8 is C1-6alkyl; polyhaloC1 -4alkyl; C^alkyloxyC1 -4alkyl; polyhaloC1 -4alkyloxyC1 -4alkyl; C3-6cycloalkyl; C3-6cycloalkyl substituted with one, two or three substituents each independently selected from C1-4polyhaloC1 -4alkyl, and halo; C1-6alkyl substituted with amino, mono- or di(C1 -4alkyl)amino; C1-6alkyl substituted with one C3-6cycloalkyl; C1-6alkyl substituted with one C3-6cycloalkyl substituted with one, two or three substituents each independently selected from C1-4polyhaloC1 -4alkyl, and halo; C1-6alkyl substituted with one Het2;Het1is pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, oxazolyl or isoxazolyl; and Het"' is optionally substituted with one C1 -4alkyl or Chalky I oxy;Het^ is oxazolyl, or isoxazolyl;Heterocycl is oxetanyl, azetidinyl, 2-oxopyrrolidin-3-yl or piperidinyl; and Heterocycl is optionally substituted with one C1 -4alkyl, C1 -4alkyloxy or C1 -4alkylcarbonyl;R2 is hydrogen, halo, C1 -4alkyl or C1 -4alkyloxy; n is an integer 1 , 2 or 3; each RS is independently selected from hydrogen, halo, C1 -4alkyl, C1 -4alkyloxy, and polyhaloC1 -4alkyl; andR^ is C3-6cycloalkyl or phenyl, wherein said Cs.gcycloalkyl and phenyl are substituted with one, two or three substituents each independently selected from hydrogen, halo, C1 -4alkyl, C1 -4alkyloxy, and polyhaloC1 -4alkyl.

2. The compound as claimed in claim 1 wherein X is -NH-(CO)-3. The compound as claimed in claim 1 wherein X is -(CO)-NH-4. The compound as claimed in claim 2 whereinR1 is hydrogen;substituted with hydroxy, amino, or mono- or di(C1 -4alkyl)amino; or alCky1l--4oxy-C1 -4alkyl;R2is C1 -4alkyloxy; n is an integer 1 ;RS is hydrogen; andR^ is phenyl substituted with one, two or three substituents each independently selected from hydrogen, halo, C1-4and polyhaloC1 -4alkyl.

5. The compound as claimed in claim 2 whereinR1is - L2-R5; wherein L2is -(C=O)-;R$Cs.gcycloalkyl or Heterocycl;Heterocycl is oxetanyl, azetidinyl, 2-oxopyrrolidin-3-yl or piperidinyl; and Heterocycl is optionally substituted with one C1-4C1 -4alkylcarbonyl;R2is C1 -4alkyloxy; n is an integer 1 ;RS is hydrogen; andR^ is phenyl substituted with one, two or three substituents each independently selected from hydrogen, halo, C1-4and polyhaloC1 -4alkyl.

6. The compound as claimed in claim 2 whereinR1is -L1-L2-R6or -L2-L1-R6; whereinR® is hydroxy, C1 -4alkyloxy, amino, mono- or di(C1 -4alkyl)amino;R2is C1 -4alkyloxy; n is an integer 1 ;RS is hydrogen; andR^ is phenyl substituted with one, two or three substituents each independently selected from hydrogen, halo, C1-4and polyhaloC1 -4alkyl.

7. The compound as claimed in claim 2 whereinR1is -L1-R7or wherein LR7is Het"' or Heterocycl;Het1is pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, oxazolyl or isoxazolyl; and Het1is optionally substituted with one C1 -4alkyl or Chalky I oxy;Heterocycl is oxetanyl, azetidinyl, 2-oxopyrrolidin-3-yl or piperidinyl; and Heterocycl is optionally substituted with one C1 -4or C1 -4alkylcarbonyl;R2 is C1 -4alkyloxy; n is an integer 1 ;RS is hydrogen; andR^ is phenyl substituted with one, two or three substituents each independently selected from hydrogen, halo, C1-4and polyhaloC1 -4alkyl.

8. The compound as claimed in claim 2 whereinR1is -SO2-R8; wherein R^ is C1-6alkyl; polyhaloC1 -4alkyl; C^alkyloxyC1 -4alkyl; polyhaloC1 -4alkyloxyC1 -4alkyl; C3-6cycloalkyl; C3-6cycloalkyl substituted with one, two or three substituents each independently selected frompolyhaloC1 -4alkyl, and halo; C1-6alkyl substituted with amino, mono- or di(C1 -4alkyl)amino; C1-6alkyl substituted with one C3-6cycloalkyl; C1-6alkyl substituted with one Cg-gcycloalkyl substituted with one, two or three substituents each independently selected frompolyhaloC1 -4alkyl, and halo; C1-6alkyl substituted with one Het^;Het^ is oxazolyl, or isoxazolyl;R2 is C1 -4alkyloxy; n is an integer 1 ;RS is hydrogen; andR^ is phenyl substituted with one, two or three substituents each independently selected from hydrogen, halo, C1-4and polyhaloC1 -4alkyl.

9. The compound as claimed in claim 1 wherein the compound is10. A pharmaceutical composition comprising a therapeutically effective amount of a compound of any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier.

11. A pharmaceutical composition comprising a therapeutically effective amount of a compound of any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier further comprising an additional therapeutic agent.

12. A pharmaceutical composition of claim 11, wherein the additional therapeutic agent is selected from the group consisting of dexamethasone, azithromycin and remdesivir.

13. A compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, for use in treating coronaviral infections.

14. The compound of claim 13, wherein the coronaviral infection is caused by SARS-CoV-2.

15. A compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, for use as a medicament.

16. A method of treating coronavirus infection in a patient, the method comprising administering a pharmaceutical composition comprising a compound of any one of claims 1 to 9.

17. A method of inhibiting or preventing infection or diseases caused by coronavirus comprising administrating a therapeutically effective amount of a compound of any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof.

18. The method of claim 16 or claim 17, wherein the coronavirus is SARS-CoV-2.

19. The method of claim 16 or claim 17, wherein the infection is COVID-19.

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