WO2024008909A1

WO2024008909A1 - Inhibitors of coronavirus

Info

Publication number: WO2024008909A1
Application number: PCT/EP2023/068815
Authority: WO
Inventors: Michiel Luc Maria Van Gool; José Enrique GÓMEZ PULIDO; Ellen VAN DAMME; Christophe Francis Robert Nestor Buyck; Matthieu Dominique Jouffroy; Brahmananda GHOSH; Sergio Alvar ALONSO DE DIEGO; Koen Boudewijn A TEMMERMAN; Marnix Van Loock
Original assignee: Janssen Pharmaceutica Nv
Priority date: 2022-07-08
Filing date: 2023-07-07
Publication date: 2024-01-11

Abstract

The present invention relates to novel compounds of Formula (I) (cyanophenyl/cyanopyridinyl- 4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine amide compounds) 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 infection.

Description

INHIBITORS OF CORONAVIRUS This invention was made with Government support under Agreement HHSO100201700018C, awarded by HHS. The Government has certain rights in the invention. FIELD OF THE INVENTION 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. BACKGROUND OF THE INVENTION 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). 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"). WO-2022/010948 relates to compounds that bind to fatty acid-binding protein 4 (FABP4) and inhibit viral replication (e.g. SARS-CoV2). SUMMARY OF INVENTION The present invention provides compounds for the treatment and/or prevention of infections or diseases caused by coronavirus, in particular, SARs-CoV-2 viral infection or disease. The compounds of the present invention can be used for treating and/or preventing coronavirus infection, comprising administering to a human or animal infected with a coronavirus, an effective amount of the compound. The compound inhibits coronavirus binding to a host cell of the human or animal or disrupts replication of the coronavirus. In some cases, the coronavirus is SARS-CoV-2 virus. The present invention is directed to compounds of Formula (I) (cyanophenyl/cyano-pyridinyl-4- oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine amide compounds)

and stereoisomeric forms thereof, wherein W is C or N X is -C(O)NH- or -NHC(O)-; R2 is H or CH₃; R3 is H or CH₃; Ra is selected from the group consisting of H, OH, C_1-4alkyl, halo, N₃, ethyne, -O-C_1-4alkyl, -O-C_1-4alkyl-OH, -O-C_1-4alkyl-CN, -O-C_1-4alkyl-ethyne, -O-C_1-4alkyl-O-C_1-4alkyl, -O-C_1-4alkyl-NH₂, -O-C_1-4alkyl-NH(CH₃), -C_1-4alkyl-NH(C_1-4alkyl)_, -C_1-4alkyl-N(C_1-4alkyl)_2, C_1-4alkyl -O-C_1-4alkyl, -O-C_3-7cycloalkyl, -O-C_1-4alkyl -O-C_3-7cycloalkyl, -C1-4alkyl-C3-7heterocycloalkyl -C1-4alkyl-O-C3-7heterocycloalkyl, -O-C3-7heterocycloalkyl, halo-C1-4alkyl (mono, di, tri), SO2NH2, SO2-C1-4alkyl and triazole; n is 0 or 1; A is phenyl or heteroaryl selected from pyridinyl, pyridazinyl, pyrimidinyl or pyrazinyl; L is selected from the group consisting of C1-4alkyl, CF2, -C(O)- and CHF; m is 0 or 1; Rb is selected from the group consisting of -CH2F, -CHF₂, -CF3, -C1-4alkylCF3, -O-C1-4alkylCF3, -O-C1-4alkylCF3, -C1-4alkyl-O-CF3, CF2CH3, -NH-C1-4alkylCF3, -C1-4alkyl-NH-C1-4alkyl-CF3, C3-7cycloalkyl, C3-7cycloalkyl-CF3, C3-7heterocycloalkyl, phenyl, 3-pyridyl, triazole, thiophene, isothiazole, isoxazole, pyridinyl, pyridazinyl, pyrimidinyl, -^C _1-4 ^{alkyl, -O-C} _1-4 ^{alkyl, -NH-C} _1-4 ^{alkyl, -NH-C} _3-7 ^cycloalkyl, each optionally substituted with one or more substituents each independently selected from the group consisting of, halo, OH, NH2, SF5, alkyne (C2), C=C=C, CF3, CO2H, C1-4alkylOH, C1-4alkyl-O-C1-4alkyl, C1-4alkylNH2, C1-4alkylNHC1-4alkyl, C1-4alkylNH(C1-4alkyl)2, C1-4alkylNHC(O)-C1-4alkyl, (C1-4alkyl)2NC(O)-C1-4alkyl, C1-4alkyl-OH, C1-4alkyl-O-C1-4alkyl, C3-7cycloalkyl, C3-7heterocycloalkyl, C1-4alkyl-C3-7heterocycloalkyl, C1-4alkyl-C3-7heteroaromatic, C1-4alkyl-pyrrolidin-2-one, C1-4alkyl, C1-4alkyloxy, CF3O and each variable can be optionally substituted with one, two or three substituents each individually selected from halo, NH2, CN, C1-4alkyl, C1-4alkyl-NH-C1-4alkyl, C(O)C1-4alkyl, C(O)OC1-4alkyl, C3-7cycloalkyl, CF₃, CF₃O and C_1-4alkyloxy; and the pharmaceutically acceptable salts and the solvates thereof. The present invention also relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (I) and at least one pharmaceutically acceptable carrier or excipient. Additionally, the invention relates to a compound of Formula (I) for use as a medicament, and to a compound of Formula (I) for use in the treatment and/or in the prevention of coronavirus infections and/or diseases. The invention also relates to the use of a compound of Formula (I) in combination with an additional pharmaceutical agent for use in the treatment and/or prevention of coronavirus infection and/or diseases. Furthermore, the invention relates to a process for preparing a pharmaceutical composition according to the invention, characterized in that at least one pharmaceutically acceptable carrier is mixed with a therapeutically effective amount of a compound of Formula (I). The details of one or more embodiments are set forth in the description below. Other features, objects, and advantages will be apparent from the description and drawings, and from the claims. DETAILED DESCRIPTION OF THE INVENTION The present invention provides compounds of Formula (I) for the treatment and/or prevention of coronavirus infection and/or diseases. The present invention provides pharmaceutical compositions comprising compounds of the invention, compounds of formula (I), and stereoisomeric forms thereof. A compound of formula (I)

and stereoisomeric forms thereof, wherein W is C or N X is -C(O)NH- or -NHC(O)-; R2 is H or CH₃; R3 is H or CH₃; Ra is selected from the group consisting of H, OH, C_1-4alkyl, halo, N₃, ethyne, -O-C_1-4alkyl, -O-C_1-4alkyl-OH, -O-C_1-4alkyl-CN, -O-C_1-4alkyl-ethyne, -O-C1-4alkyl-O-C1-4alkyl, -O-C1-4alkyl-NH2, -O-C1-4alkyl-NH(CH3), -C1-4alkyl-NH(C1-4alkyl), -C1-4alkyl-N(C1-4alkyl)2, C1-4alkyl -O-C1-4alkyl, -O-C3-7cycloalkyl, -O-C1-4alkyl -O-C3-7cycloalkyl, -C1-4alkyl-C3-7heterocycloalkyl -C1-4alkyl-O-C3-7heterocycloalkyl, -O-C3-7heterocycloalkyl, halo-C1-4alkyl (mono, di, tri), SO2NH2, SO2-C1-4alkyl and triazole; n is 0 or 1; A is phenyl or heteroaryl selected from pyridinyl, pyridazinyl, pyrimidinyl or pyrazinyl; L is selected from the group consisting of C1-4alkyl, CF2, -C(O)- and CHF; m is 0 or 1; Rb is selected from the group consisting of -CH2F, -CHF₂, -CF3, -C1-4alkylCF3, -O-C1-4alkylCF3, -O-C1-4alkylCF3, -C1-4alkyl-O-CF3, CF2CH3, -NH-C1-4alkylCF3, -C1-4alkyl-NH-C1-4alkyl-CF3, C3-7cycloalkyl, C3-7cycloalkyl-CF3, C3-7heterocycloalkyl, phenyl, 3-pyridyl, triazole, thiophene, isothiazole, isoxazole, pyridinyl, pyridazinyl, pyrimidinyl, -^C _1-4 ^{alkyl, -O-C} _1-4 ^{alkyl, -NH-C} _1-4 ^{alkyl, -NH-C} _3-7 ^cycloalkyl, each optionally substituted with one or more substituents each independently selected from the group consisting of, halo, OH, NH2, SF5, alkyne (C2), C=C=C, CF3, CO2H, C1-4alkylOH, C1-4alkyl-O-C1-4alkyl, C1-4alkylNH2, C1-4alkylNHC1-4alkyl, C1-4alkylNH(C1-4alkyl)2, C1-4alkylNHC(O)-C1-4alkyl, (C1-4alkyl)2NC(O)-C1-4alkyl, C1-4alkyl-OH, C1-4alkyl-O-C1-4alkyl, C3-7cycloalkyl, C3-7heterocycloalkyl, C1-4alkyl-C3-7heterocycloalkyl, C1-4alkyl-C3-7heteroaromatic, C1-4alkyl-pyrrolidin-2-one, C1-4alkyl, C1-4alkyloxy, CF3O and each variable can be optionally substituted with one, two or three substituents each individually selected from halo, NH2, CN, C1-4alkyl, C1-4alkyl-NH-C1-4alkyl, C(O)C1-4alkyl, C(O)OC1-4alkyl, C3-7cycloalkyl, CF₃, CF₃O and C_1-4alkyloxy; and the pharmaceutically acceptable salts and the solvates thereof. In an embodiment, a compound of Formula I, wherein W is C; or pharmaceutically acceptable salts and the solvates thereof. In an embodiment, a compound of Formula I, wherein W is N; or pharmaceutically acceptable salts and the solvates thereof. In an embodiment, a compound of Formula I, wherein X is -C(O)NH-; or pharmaceutically acceptable salts and the solvates thereof. In an embodiment, a compound of Formula I, wherein X is -NHC(O)-; or pharmaceutically acceptable salts and the solvates thereof. In an embodiment, a compound of Formula I, wherein W is C and X is -C(O)NH-; or pharmaceutically acceptable salts and the solvates thereof. In an embodiment, a compound of Formula I, wherein W is N and X is -C(O)NH-; or pharmaceutically acceptable salts and the solvates thereof. In an embodiment, a compound of Formula I, wherein W is C and X is -NHC(O)-; or pharmaceutically acceptable salts and the solvates thereof. In an embodiment, a compound of Formula I, wherein W is N and X is -NHC(O)-; or pharmaceutically acceptable salts and the solvates thereof. In an embodiment, a compound of Formula I, wherein A is phenyl; or pharmaceutically acceptable salts and the solvates thereof. In an embodiment, a compound of Formula I, wherein A is pyridinyl; or pharmaceutically acceptable salts and the solvates thereof. In an embodiment, a compound of Formula I, wherein W is C and A is phenyl; or pharmaceutically acceptable salts and the solvates thereof. In an embodiment, a compound of Formula I, wherein W is N and A is phenyl; or pharmaceutically acceptable salts and the solvates thereof. In an embodiment, a compound of Formula I, wherein W is C and A is pyridinyl; or pharmaceutically acceptable salts and the solvates thereof. In an embodiment, a compound of Formula I, wherein W is N and A is pyridinyl; or pharmaceutically acceptable salts and the solvates thereof. In an embodiment, a compound of Formula I, wherein X is -C(O)NH- and A is phenyl; or pharmaceutically acceptable salts and the solvates thereof. In an embodiment, a compound of Formula I, wherein X is -NHC(O)- and A is phenyl; or pharmaceutically acceptable salts and the solvates thereof. In an embodiment, a compound of Formula I, wherein X is -C(O)NH- and A is pyridinyl; or pharmaceutically acceptable salts and the solvates thereof. In an embodiment, a compound of Formula I, wherein X is -NHC(O)- and A is pyridinyl; or pharmaceutically acceptable salts and the solvates thereof. In an embodiment, a compound of Formula I, wherein W is C, X is -C(O)NH- and A is phenyl; or pharmaceutically acceptable salts and the solvates thereof. In an embodiment, a compound of Formula I, wherein W is N, X is -C(O)NH- and A is phenyl; or pharmaceutically acceptable salts and the solvates thereof. In an embodiment, a compound of Formula I, wherein W is C, X is -NHC(O)- and A is phenyl; or pharmaceutically acceptable salts and the solvates thereof. In an embodiment, a compound of Formula I, wherein W is N, X is -NHC(O)- and A is phenyl; or pharmaceutically acceptable salts and the solvates thereof. In an embodiment, a compound of Formula I, wherein W is C, X is -C(O)NH- and A is pyridinyl; or pharmaceutically acceptable salts and the solvates thereof. In an embodiment, a compound of Formula I, wherein W is N, X is -C(O)NH- and A is pyridinyl; or pharmaceutically acceptable salts and the solvates thereof. In an embodiment, a compound of Formula I, wherein W is C, X is -NHC(O)- and A is pyridinyl; or pharmaceutically acceptable salts and the solvates thereof. In an embodiment, a compound of Formula I, wherein W is N, X is -NHC(O)- and A is pyridinyl; or pharmaceutically acceptable salts and the solvates thereof. In an embodiment, a compound of Formula I, wherein m is 0; or pharmaceutically acceptable salts and the solvates thereof. In an embodiment, a compound of Formula I, wherein W is C and m is 0; or pharmaceutically acceptable salts and the solvates thereof. In an embodiment, a compound of Formula I, wherein W is N and m is 0; or pharmaceutically acceptable salts and the solvates thereof. In an embodiment, a compound of Formula I, wherein W is C, X is -C(O)NH- and m is 0; or pharmaceutically acceptable salts and the solvates thereof. In an embodiment, a compound of Formula I, wherein W is N, X is -C(O)NH- and m is 0; or pharmaceutically acceptable salts and the solvates thereof. In an embodiment, a compound of Formula I, wherein W is C, X is -NHC(O)- and m is 0; or pharmaceutically acceptable salts and the solvates thereof. In an embodiment, a compound of Formula I, wherein W is N; X is -NHC(O)- and m is 0; or pharmaceutically acceptable salts and the solvates thereof. In an embodiment, a compound of Formula I, wherein m is 1; or pharmaceutically acceptable salts and the solvates thereof. In an embodiment, a compound of Formula I, wherein W is C and m is 1; or pharmaceutically acceptable salts and the solvates thereof. In an embodiment, a compound of Formula I, wherein W is N and m is 1; or pharmaceutically acceptable salts and the solvates thereof. In an embodiment, a compound of Formula I, wherein W is C, X is -C(O)NH- and m is 1; or pharmaceutically acceptable salts and the solvates thereof. In an embodiment, a compound of Formula I, wherein W is N, X is -C(O)NH- and m is 1; or pharmaceutically acceptable salts and the solvates thereof. In an embodiment, a compound of Formula I, wherein W is C, X is -NHC(O)- and m is 1; or pharmaceutically acceptable salts and the solvates thereof. In an embodiment, a compound of Formula I, wherein W is N; X is -NHC(O)- and m is 1; or pharmaceutically acceptable salts and the solvates thereof. In an embodiment, a compound of Formula I, wherein m is 1 and L is C1-4alkyl or CF2; or pharmaceutically acceptable salts and the solvates thereof. In an embodiment, a compound of Formula I, wherein W is C, m is 1 and L is C1-4alkyl or CF2; or pharmaceutically acceptable salts and the solvates thereof. In an embodiment, a compound of Formula I, wherein W is N, m is 1 and L is C1-4alkyl or CF2; or pharmaceutically acceptable salts and the solvates thereof. In an embodiment, a compound of Formula I, wherein W is C, X is -C(O)NH- and m is 1; or pharmaceutically acceptable salts and the solvates thereof. In an embodiment, a compound of Formula I, wherein W is N, X is -C(O)NH- and m is 1; or pharmaceutically acceptable salts and the solvates thereof. In an embodiment, a compound of Formula I, wherein W is C, X is -NHC(O)- and m is 1; or pharmaceutically acceptable salts and the solvates thereof. In an embodiment, a compound of Formula I, wherein W is N; X is -NHC(O)- and m is 1; or pharmaceutically acceptable salts and the solvates thereof. In an embodiment, a compound of Formula I, wherein m is 1 and L is C_1-4alkyl; or pharmaceutically acceptable salts and the solvates thereof. In an embodiment, a compound of Formula I, wherein m is 1 and L is CF₂; or pharmaceutically acceptable salts and the solvates thereof. In an embodiment, a compound of Formula I, wherein X is -C(O)NH, m is 1 and L is C1-4alkyl or CF₂; or pharmaceutically acceptable salts and the solvates thereof. In an embodiment, a compound of Formula I, wherein X is -C(O)NH, m is 1 and L is C1-4alkyl; or pharmaceutically acceptable salts and the solvates thereof. In an embodiment, a compound of Formula I, wherein X is -C(O)NH, m is 1 and L is CF2; or pharmaceutically acceptable salts and the solvates thereof In an embodiment, a compound of Formula I, wherein X is -NHC(O)-, m is 1 and L is C_1-4alkyl or CF2; or pharmaceutically acceptable salts and the solvates thereof. In an embodiment, a compound of Formula I, wherein X is -NHC(O)-, m is 1 and L is C_1-4alkyl; or pharmaceutically acceptable salts and the solvates thereof. In an embodiment, a compound of Formula I, wherein X is -NHC(O)-, m is 1 and L is CF2; or pharmaceutically acceptable salts and the solvates thereof. In an embodiment the present invention also provides compounds of formula (I),

and stereoisomeric forms thereof, wherein W is C or N X is -C(O)NH- (amide) or -NHC(O)- (inverse amide); R2 is H or CH3; R3 is H or CH3; Ra is selected from the group consisting of H, OH, C1-4alkyl, halo, N3, ethyne, -O-C1-4alkyl, -O-C1-4alkyl-OH, -O-C1-4alkyl-CN, -O-C1-4alkyl-ethyne, -O-C1-4alkyl-O-C1-4alkyl, -O-C1-4alkyl-NH2, -O-C1-4alkyl-NH(CH3), -C1-4alkyl-NH(C1-4alkyl), -C1-4alkyl-N(C1-4alkyl)2, C1-4alkyl -O- C1-4alkyl, -O-C3-7cycloalkyl, -O-C1-4alkyl -O-C3-7cycloalkyl, -C1-4alkyl-C3-7 heterocycloalkyl, -C1-4alkyl-O-C3-7 heterocycloalkyl, -O-C3-7 heterocycloalkyl, halo-C1-4alkyl (mono, di, tri), SO2NH2, SO2-C1-4alkyl and triazole; n is 0 to 1; A is phenyl or heteroaryl selected from pyridinyl, pyridazinyl, pyrimidinyl and pyrazinyl; L is selected from the group consisting of C1-4alkyl, CF2 and -C(O)-; m is 0-1; Rb is selected from the group consisting of -CH2F, -CF3, -C1-4alkylCF3, -O-C1-4alkylCF3, -O-C1-4alkylCF3, -C1-4alkyl-O-CF3, CF2CH3, -NH-C1-4alkylCF3, -C1-4alkyl-NH-C1-4alkyl-CF3, C3-7cycloalkyl, C3-7cycloalkyl-CF3, C3-7heterocycloalkyl, phenyl, 3-pyridyl, triazole, thiophene, isothiazole, and isoxazole, each optionally substituted with one or more substituents each independently selected from the group consisting of, halo, OH, NH2, SF5, alkyne (C2), C=C=C, CF3, CO2H, C1-4alkylOH, C1-4alkyl-O-C1-4alkyl, C1-4alkylNH2, C1-4alkylNHC1-4alkyl, C1-4alkylNH(C1-4alkyl)2, C1-4alkylNHC(O)-C1-4alkyl, (C1-4alkyl)2NC(O)-C1-4alkyl, C1-4alkyl-OH, C1-4alkyl-O-C1-4alkyl, C3-7cycloalkyl, C3-7 heterocycloalkyl, C1-4alkyl-C3-7 heterocycloalkyl, C1-4alkyl- C3-7heteroaromatic or C1-4alkyl-pyrrolidin-2-one) and each variable can be optionally substituted with halo, NH2, CN, C1-4alkyl, C1-4alkyl-NH-C1-4alkyl, C(O)C1-4alkyl C(O)OC1-4alkyl and C3-7cycloalkyl; and the pharmaceutically acceptable salts and the solvates thereof. 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. 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. A pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof, further comprising an additional therapeutic agent. The additional therapeutic agent comprises one or more of dexamethasone, azithromycin and remdesivir. A method of treating COVID-19 in a subject, the method comprising administering a pharmaceutical composition comprising a compound of Formula (I). 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. 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. 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. 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. 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. 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.

Depicted in Tables 1 to 5 are some examples of Formula (I) compounds: Table 1: Amide

CMPD # (Compoun d #) 168 169 170 171

(S)-N-(3-cyanophenyl)-6-methyl-4-oxo-5-(2- (4,4,4-trifluorobutyl)pyrimidin-5-yl)-4,5,6,7- 172 tetrahydropyrazolo[1,5-a]pyrazine-3- carboxamide (S)-N-(3-cyanophenyl)-6-methyl-4-oxo-5-(5- (4,4,4-trifluorobutyl)pyrazin-2-yl)-4,5,6,7- 173 tetrahydropyrazolo[1,5-a]pyrazine-3- carboxamide

Table 2: Amide

Table 3: Inverse amide

Table 4: Inverse amide

Table 5 with structure of compounds 270 to 407 :

and the pharmaceutically acceptable salts and solvates of such compounds. The stereochemical configuration for some compounds has been designated as *R or *S when the absolute stereochemistry is undetermined (even if the bonds are drawn stereospecifically) although the compound itself has been isolated as a single stereoisomer and is enantiomerically pure. This means that the absolute stereoconfiguration of the stereocentre indicated by * is undetermined (even if the bonds are drawn stereospecifically) although the compound is enantiomerically pure at the indicated centre. Each of the embodiments described above can be combined with any other embodiment described herein not inconsistent with the embodiment with which it is combined. Furthermore, each of the embodiments described herein envisions within its scope pharmaceutically acceptable salts of the compounds described herein. Definitions For the purposes of the present invention, as described and claimed herein, the following terms are defined as follows: As used herein, the terms "comprising" and "including" are used in their open, non-limiting sense. 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. As used herein, the terms "prevent", "prevention" and "preventing" 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. The term “C1-4alkyl” as used herein alone or as part of another group, defines a saturated, straight or branched, hydrocarbon radical having, unless otherwise stated, from 1 to 4 carbon atoms, such as methyl, ethyl, 1-propyl, 1-methylethyl, butyl, 1-methyl-propyl, 2-methyl-1- propyl, 1,1-dimethylethyl and the like. The notation “-C1-4alkyl-OH” as used herein alone or as part of another group, refers to C1-4alkyl as defined before, substituted with one OH group at any available carbon atom. The term “halogen” or “halo” as used herein alone or as part of another group, refers to fluoro (F), chloro (Cl), bromo (Br) or iodo (I), with fluoro (F) or chloro (Cl) being preferred. The term “monohalo-C1-4alkyl, polyhalo-C1-4alkyl” as used herein alone or as part of another group, refers to C1-4alkyl as defined before, substituted with 1, 2, 3 or where possible with more halo atoms as defined before. The term “C3-7cycloalkyl” as used herein refers to a saturated, cyclic hydrocarbon radical having from 3 to 7 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. The term “C_3-7heterocycloalkyl” as used herein refers to a C3-7cycloalkyl group wherein one CH2 is replaced with a heteroatom selected from O, N or S, such as for instance tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, pyrrolidinyl, piperidinyl, and piperazidinyl. The term “C_3-7heteroaromatic” as used herein refers to a monocyclic aromatic 3- to 7- membered ring ring wherein one heteroatom selected from O, N or S is present such as e.g. pyrrolyl, furanyl, thiophenyl pyridinyl, pyranyl, and thiopyranyl. The term “triazole” as used herein refers to 1,2,3-triazole and 1,2,4-triazole. The term “ethyne” and “alkyne (C₂)” as used herein refers to the substituent “-C≡C-“. 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. 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). 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). As used herein, the term "composition" is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combinations of the specified ingredients in the specified amounts. It will be appreciated that some of the compounds of Formula (I) and their pharmaceutically acceptable addition salts and solvates thereof may contain one or more centres of chirality and exist as stereoisomeric forms. 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, 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. Hereinbefore and hereinafter, the term “compound of Formula (I)” is meant to include the stereoisomers thereof and the tautomeric forms thereof. The terms “stereoisomers”, “stereoisomeric forms” or “stereochemically isomeric forms” hereinbefore or hereinafter are used interchangeably. Stereoisomers of Formula I include cis and trans isomers, optical isomers such as R and S enantiomers, diastereomers, geometric isomers, rotational isomers, conformational isomers, and tautomers of the compounds of the invention, including compounds exhibiting more than one type of isomerism; and mixtures thereof (such as racemates and diastereomeric pairs). 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 trans- configuration; for example, if a compound contains a disubstituted cycloalkyl group, the substituents may be in the cis or trans configuration. Therefore, the invention includes enantiomers, diastereomers, racemates, E isomers, Z isomers, cis isomers, trans isomers and mixtures thereof, whenever chemically possible. 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. The absolute configuration is specified according to the Cahn-Ingold-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. 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 isomers. 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. 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 are intended to be included within the scope of the present invention. It follows that a single compound may exist in both stereisomeric and tautomeric forms. The compounds of Formula I may exhibit the phenomenon of tautomerism; such tautomers are also regarded as compounds of the invention. All such tautomeric forms, and mixtures thereof, are included within the scope of compounds of Formula I. Tautomers exist as mixtures of a tautomeric set in solution. In solid form, usually one tautomer predominates. Even though one tautomer may be described, the present invention includes all tautomers of the compounds of Formula I and salts thereof. With respect to the compounds of the invention used in the methods of the invention, if the compounds also exist as tautomeric forms then this invention relates to those tautomers and the use of all such tautomers and mixtures thereof. For therapeutic use, salts of the compounds of Formula (I) are those wherein the counterion is pharmaceutically acceptable. However, salts of acids and bases which are non-pharmaceutically acceptable may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound. All salts, whether pharmaceutically acceptable or not, are included within the ambit of the present invention. The phrase "pharmaceutically acceptable salts(s)", as used herein, unless otherwise indicated, includes salts of acidic or basic groups which may be present in the compounds described herein. The compounds used in the methods of the invention that are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids. The acids that may be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds are those that form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, such as the acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium edetate, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edislyate, estolate, esylate, ethylsuccinate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, iodide, isethionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylsulfate, mucate, napsylate, nitrate, oleate, oxalate, pamoate (embonate), palmitate, pantothenate, phosphate/diphosphate, polygalacturonate, salicylate, stearate, subacetate, succinate, tannate, tartrate, teoclate, tosylate, triethiodode, and valerate salts. The pharmaceutically acceptable acid and base addition salts as mentioned hereinabove or hereinafter are meant to comprise the therapeutically active non-toxic acid and base addition salt forms which the compounds of Formula (I) are able to form. The 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. Conversely said salt forms can be converted by treatment with an appropriate base into the free base form. The compounds of Formula (I) containing an acidic proton may also be converted into their non- toxic metal or amine addition salt forms by treatment with appropriate organic and inorganic bases. Appropriate base salt forms comprise, for example, the ammonium salts, the alkali and earth alkaline metal salts, e.g. the lithium, sodium, potassium, magnesium, calcium salts and the like, salts with organic bases, e.g. primary, secondary and tertiary aliphatic and aromatic amines such as methylamine, ethylamine, propylamine, isopropylamine, the four butylamine isomers, dimethylamine, diethylamine, diethanolamine, dipropylamine, diisopropylamine, di-n-butylamine, pyrrolidine, piperidine, morpholine, trimethylamine, triethylamine, tripropylamine, quinuclidine, pyridine, quinoline and isoquinoline; the benzathine, N-methyl-D-glucamine, hydrabamine salts, and salts with amino acids such as, for example, arginine, lysine and the like. Conversely the salt form can be converted by treatment with acid into the free acid form. The term solvate comprises the solvent addition forms as well as the salts thereof, which the compounds of Formula (I) are able to form. Examples of such solvent addition forms are e.g. hydrates, alcoholates and the like. In the framework of this application, an element, in particular when mentioned in relation to a compound according to Formula (I), comprises all isotopes and isotopic mixtures of this element, either naturally occurring or synthetically produced, either with natural abundance or in an isotopically enriched form, for example 2H. Radiolabelled compounds of Formula (I) may comprise a radioactive isotope selected from the group consisting of 2H, 3H, 11C, 13C, 14C, 18F, 122I, 123I, 125I, 131I, 75Br, 76Br, 77Br, 82Br, 36Cl, 15N, 17O, and 18O,. Preferably, the radioactive isotope is selected from the group consisting of 3H, 11C and 18F. 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. 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. 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. 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. 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, reporter- virus 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. The compounds of the present invention can be prepared according to the methods set forth below. The schemes provided below further illustrate and exemplify the compounds of the present invention and methods of preparing such compounds. It is to be understood that the scope of the present invention is not limited in any way by the scope of the following examples and preparations. In the following examples, molecules with a single chiral center may exist as a single enantiomer or a racemic mixture. Those molecules with two or more chiral centers may exist as a single enantiomer, a racemic or otherwise mixture of two enantiomers, or as various mixtures of diastereomers. Such enantiomers, racemates, and diastereomers may be obtained and / or separated by methods known to those skilled in the art. It will be appreciated by one skilled in the art that certain synthetic manipulations may epimerize or racemize a stereocenter, and synthetic conditions may be selected to either promote or discourage such epimerization or racemization. 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. 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. EXAMPLES 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. 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 4Å 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. 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. Unless otherwise noted, chemical reactions were performed at room temperature (about 23 degrees Celsius). Unless noted otherwise, all reactants were obtained commercially and used without further purification, or were prepared using methods known in the literature. 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. 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. Hereinafter, the term “AcOH” means acetic acid, “aq.” means aqueous, “RT” or “rt” means room temperature, “h” means hours, “min” means minutes, “BOC” or “Boc” means tert- butyloxycarbonyl, “calcd.” means calculated, “CO” means carbon monoxide, “CHCl3” means chloroform, “CDCl3” means deuterochloroform, “DIPEA” or “DIEA” means N,N- diisopropylethylamine, “DIPE” means diisopropylether, “DMSO” means dimethylsulfoxide, “DAST” means diethylaminosulfur trifluoride, “DMF” means dimethylformamide, “DCM” means dichloromethane, “DMAP” means 4-dimethylaminopiridine, “DPPA” means diphenyl phosphoryl azide, “dppf” means 1,1'-bis(diphenylphosphino)ferrocene, “EtOAc” or “EA” means ethyl acetate, “EtOH” means ethanol, “ESI” means electrospray ionization, “FA” means formic acid, “Et3N” or “TEA” means triethylamine, “HATU” means O-(7-azabenzotriazol-1-yl)- N,N,N’,N’-tetramethyluronium hexafluorophosphate (1-[bis(dimethylamino)methylene]-1H- 1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate), “I.D.” means internal diameters, “i-PrOH” means isopropanol, (Ir[dF(CF3)ppy]2(dtbpy))PF6 means [4,4′-bis(1,1-dimethylethyl)- 2,2′-bipyridine-N1,N1′]bis[3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridinyl-N]phenyl- C]Iridium(III) hexafluorophosphate, “LiHMDS” means lithium bis(trimethylsilyl)amide, “Prep.” means preparative, “MeCN”, “ACN” or “CH3CN” means acetonitrile, “MeOH” means methanol, “MeOTf” means methyl trifluoromethane-sulfonate, ‘sat.’ means saturated, ‘SFC’ means supercritical fluid chromatography, “LC-MS” means liquid chromatography/mass spectrometry, “HPLC” means high-performance liquid chromatography, “RP” means reversed phase, “[M+H]+” means the protonated mass of the free base of the compound, [M-H]- means deprotonated mass of the free base of the compound, [M-tBu+2H]+ means protonated mass of the free base of the compound with loss of tert-butyl, [M-COOtBu+2H]+ means protonated mass of the free base of the compound with loss of tert-butyloxycarbonyl, “PdCl2(dppf)” or “Pd(dppf)Cl ” 2 means [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), Pd(OAc)2 means palladium(II) acetate, Pd(PPh3)4 means tetrakis(triphenylphosphine)-palladium(0), “PPh3” means triphenylphosphine, “quant.” means quantitative, “Red-Al®” means sodium bis(2- methoxyethoxy)aluminiumhydride, “sat.” means saturated, “sol.” means solution, “THF” means tetrahydrofuran, “TBAF” means tetrabutyl ammonium fluoride, “tBu” means tert-butyl, “t-BuOH” means tert-butyl alcohol, “NMR” means Nuclear Magnetic Resonance, (4,4'-dtbbpy)NiCl2 means [4,4′-bis(1,1-dimethylethyl)-2,2′-bipyridine] nickel (II) dichloride, “DBAD” means di-tert-butyl azodicarboxylate, “PE” means petroleum ether, “MTBE” means tert-butyl methyl ether, “NaHCO3” means sodium bicarbonate, “CuI” means copper(I) iodide, "K2CO3" means potassium carbonate, “NaOH” means sodium hydroxide, “Na2SO4” means sodium sulfate, “MgSO4” means magnesium sulfate, “NH4Cl” means ammonium chloride. 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.). 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 Å, 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 ( ^ ^ are reported in parts per million (ppm) downfield from tetramethylsilane (TMS), which was used as internal standard. The stereochemical configuration for the compounds has been designated “R” or “S”; for some compounds, the stereochemical configuration has been designated as “*R” or “*S” when the absolute stereochemistry is undetermined although the compound itself has been isolated as a single stereoisomer and is enantiomerically pure. 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, µL = microliter, mmol = millimole. Melting points values are peak values, and are obtained with experimental uncertainties that are commonly associated with this analytical method. LCMS General procedure 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). 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. 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. Photochemistry reactions were performed using a Penn Photoreactor®. 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. 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. 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. 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). General Synthesis Schemes : 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. Synthesis of compounds of Formula (I) wherein X is -C(O)NH (Amide) Compounds of formula (I) wherein X is -C(O)NH- and W, (Ra) 2 3 b n, R , R , A, Lm and R are as hereinbefore defined may be prepared as described in Scheme (1), below.

Scheme 1 Accordingly, a commercially available pyrazole of formula (II), wherein Rg is C_1-4alkyl is reacted with an appropriate alcohol of formula (III), wherein R2 and R3 are as hereinbefore defined and PG is a protecting group, for example Boc, by a Mitsunobu type reaction in the presence of a suitable triarylphosphine, such as triphenylphosphine, and a suitable dialkyl azodicarboxylate reagent, such as di-tert-butyl in a suitable inert solvent, such as THF, under suitable reaction conditions, such as at a convenient temperature, typically ranging from 0ºC to rt, for a period of time to ensure the completion of the reaction to yield the corresponding compound of formula (IV). The compound of formula (V) can be prepared from a compound of formula (IV) by removal of the protecting group, for example a Boc group, in the presence of acidic media, such as hydrochloric acid, in an inert solvent such as 1,4-dioxane, acetonitrile and the like, under suitable reaction conditions, such as at a convenient temperature, in particular rt, for a period of time to ensure the completion of the reaction followed by treatment with a base such as NaHCO₃, under suitable reaction conditions, such as at a convenient temperature, typically at rt , for a period of time to ensure the completion of the reaction. The compound of formula (V), can be subjected to a palladium-catalyzed carbonylation reaction to afford ester of formula (VII), wherein Rg is C1-4alkyl, under a carbon monoxide atmosphere and in the presence of a suitable catalyst, such as palladium(II) acetate and a suitable ligand, such as, 1,1'-bis(diphenylphosphino)ferrocene and an appropriate base, such as, triethylamine, in a mixture of an inert suitable solvent and an alcohol of formula (VI), such as 1,4-dioxane and ethanol, at a temperature of about 90°C, for a period of time to ensure the completion of the reaction. The compound of formula (VII) is reacted with an appropriate aryl halide of formula (VIII), wherein A, Lm and Rb are as hereinbefore defined and halo is typically bromo, a known compound (e.g. commercially available) or a compound prepared by known method, by a copper-mediated Ullmann reaction, in the presence of a catalyst and a ligand, such as, copper(I) iodide and N,N'-dimethylethylenediamine, a base, such as potassium carbonate and a suitably mixture of solvents, such as, toluene and dimethylformamide, at a temperature in the range of from about rt to 100ºC, for a period of time to ensure the completion of the reaction and yielding the corresponding compound of formula (IX). The compound of formula (IX) is reacted with a suitably substituted amine of formula (X), wherein W and (Ra)n are as hereinbefore defined to afford an amide of formula (Ia), in the presence of an organosilicon compound, such as, LiHMDS or an organometallic compound, such as, isopropylmagnesium chloride lithium chloride, in a suitably inert solvent, such as tetrahydrofuran at a temperature in the range of from about -10ºC to 100ºC, for a period of time to ensure the completion of the reaction. An amine of formula (X) can be a known compound (e.g. commercially available) or a compound prepared by known method. Alternatively, compounds of formula (I) wherein X is -C(O)NH- and W, (Ra) 2 3 n, R , R , A, Lm and Rb are as hereinbefore defined may be prepared as described in Scheme (2), below.

Scheme 2 Accordingly, an ester of formula (IX), wherein Rg is C1-4alkyl, can be hydrolysed to the corresponding acid of formula (XI) in the presence of an aqueous solution of a base, such as, NaOH, KOH and the like, in a suitably solvent such as EtOH, MeOH and the like, at a convenient temperature, typically at rt, for a period of time to ensure the completion of the reaction. The acid compound of formula (XI) is then reacted with a suitably substituted amine of formula (X), wherein W and (Ra)n are as hereinbefore defined to afford an amide of formula (Ia), through the corresponding acyl chloride obtained in the presence of phosphorus (V) oxychloride and a base, such as pyridine, in a suitable inert solvent, such as DCM or the like, at a temperature in the range of from about -10ºC to rt, for a period of time to ensure the completion of the reaction. Alternatively, a compound of formula (Ia) can be prepared by an amide coupling reaction between the acid compound of formula (XI) with a suitably substituted amine of formula (X), by activation of the carboxylic acid in the presence of HATU, propylphosphonic anhydride or the like, a suitable base, such as DIPEA, Et₃N or the like, in a suitable inert solvent, such as, DMF, DCM or the like; at a temperature in the range of from about rt to 40ºC, for a period of time to ensure the completion of the reaction. An amine of formula (X) can be a known compound (e.g. commercially available) or a compound prepared by known method. Alternatively, compounds of formula (I) wherein X is -C(O)NH- and W, (Ra)n, R2, R3, A, Lm and Rb are as hereinbefore defined may be prepared as described in Scheme (3), below.

Scheme 3 Accordingly, a compound of formula (V), can be subjected to a palladium-catalyzed aminocarbonylation reaction to afford amide of formula (XII), under a carbon monoxide atmosphere and in the presence of a suitably substituted amine of formula (X), a suitable catalyst, such as palladium(II) acetate and a suitable ligand, such as, 1,1'-bis(diphenylphosphino)ferrocene and an appropriate base, such as, triethylamine, in an inert suitable, such as 1,4-dioxane, at a temperature of about 90°C, for a period of time to ensure the completion of the reaction. An amine of formula (X) can be a known compound (e.g. commercially available) or a compound prepared by known method. The compound of formula (XII) is reacted with an appropriate aryl or heteroaryl halide of formula (VIII), wherein A, Lm and Rb are as hereinbefore defined and halo is typically bromo, a known compound (e.g. commercially available) or a compound prepared by known method, by a copper-mediated Ullmann reaction, in the presence of a catalyst and a ligand, such as, copper(I) iodide and N,N'-dimethylethylenediamine, a base, such as potassium carbonate and a suitably mixture of solvents, such as, toluene and dimethylformamide, at a temperature in the range of from about rt to 100ºC, for a period of time to ensure the completion of the reaction and yielding the corresponding compound of formula (Ia). Alternatively, compounds of formula (I) wherein X is -C(O)NH-, m is 0, A is phenyl and W, (Ra)_n, R2, R3 and Rb are as hereinbefore defined may be prepared as described in Scheme (4), below.

Scheme 4 Accordingly, a compound of formula (VII), wherein Rg is C1-4alkyl, by a copper-mediated Ullmann reaction, is reacted with an appropriate aryl halide, such as 1,4-dibromobenzene, in the presence of a catalyst and a ligand, such as, copper(I) iodide and N,N'-dimethylethylenediamine, a base, such as potassium carbonate and a suitably mixture of solvents, such as, toluene and dimethylformamide, at a temperature in the range of from about rt to 100ºC, for a period of time to ensure the completion of the reaction to afford the corresponding bromoarylester compound of formula (XIII). The compound of formula (XIII) is reacted with a suitably substituted amine of formula (X), wherein W and (Ra)n are as hereinbefore defined to afford an amide of formula (XIV), in the presence of an organometallic compound, such as, isopropylmagnesium chloride lithium chloride, in a suitably inert solvent, such as tetrahydrofuran at a temperature in the range of from about rt to 70ºC, for a period of time to ensure the completion of the reaction. An amine of formula (X) can be a known compound (e.g. commercially available) or a compound prepared by known method. The compound of formula (XIV) is reacted with a boronic acid or boronic ester of formula (XV), wherein Rb is as hereinbefore defined, by a palladium-mediated Suzuki reaction, in the presence of a catalyst, such as [1,1'-bis(diphenylphosphino)ferrocene]-dichloropalladium(II), an appropriate base, such as sodium carbonate, in a suitably solvent, such as 1,4-dioxane, water or a mixture thereof, at a temperature in the range of about 70ºC, for a period of time to ensure the completion of the reaction to provide a compound of formula (Ib). A boronic acid or boronic ester of formula (XV) can be a known compound (e.g. commercially available) or a compound prepared by known method. Alternatively, compounds of formula (I) wherein X is -C(O)NH-, A is phenyl, L_m is -CH₂- and W, (Ra)n, R2, R3 and Rb are as hereinbefore defined may be prepared as described in Scheme (5), below.

Scheme 5 Accordingly, a compound of formula (XIV) can be subjected to a photochemistry reaction with an appropriate halide compound of formula (XVI), wherein Rb is as hereinbefore defined, to afford a compound of formula (Ic) using a Penn Photoreactor® in the presence of a catalytic system, such as the combination of (Ir[dF(CF3)ppy]2(dtbpy))PF6, (4,4'-dtbbpy)NiCl2 and hydroxy- bis(trimethylsilyl)silyl)-trimethylsilane or the like, a base, such as sodium carbonate, in a suitably solvent, such as acetonitrile; typically at a wavelength of 450 nm, for a period of time to ensure the completion of the reaction. A halide compound of formula (XVI) can be a known compound (e.g. commercially available) or a compound prepared by known method. Alternatively, compounds of formula (I) wherein X is -C(O)NH-, A is phenyl, L_m is -CH₂- and W, (Ra)n, R2, R3 and Rb are as hereinbefore defined may be prepared as described in Scheme (6), below.

Scheme 6 Accordingly, a compound of formula (XIV) is borylated employing palladium catalyzed borylation conditions known to those skilled in the art, for example, using a borylation reagent such as 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi-1,3,2-dioxaborolane (bis(pinacolato)diboron), and the like; a base such as potassium acetate; a palladium catalyst such as 1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II), and the like; in a suitable solvent such as 1,4-dioxane; typically at a temperature of 80°C; for a period of time to ensure the completion of the reaction, to provide a compound of formula (XVII). The compound of formula (XVII) is fluorinated by reaction with potassium hydrogen fluoride to afford the organotrifluoroborate salt of formula (XVIII), in a suitable solvent, such as methanol, and the like; at a convenient temperature, typically at rt, for a period of time to ensure the completion of the reaction. The organotrifluoroborate salt of formula (XVIII), is subjected to a palladium-catalyzed cross- coupling reaction with an appropriate aryl or heteroaryl halide of formula (XVI), wherein Rb is as hereinbefore defined, in the presence of a suitable catalyst, such as mesylate[(di(1- adamantyl)-n-butylphosphine)-2-(2'-amino-1,1'-biphenyl)]palladium(II), bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex and the like; a suitable base, such as cesium carbonate or the like, in an appropriate mixture of solvents, such as THF and water, and the like; at a temperature ranging from rt to 100°C, for a period of time to ensure the completion of the reaction, to provide compounds of formula (Ic). Alternatively, compounds of formula (I) wherein X is -C(O)NH-, A is phenyl, L is b m -CH2-, R is phenyl substituted with C_1-4alkylNH₂, (C_1-4alkyl)₂-N-C_1-4alkyl or C_1-4alkyl-NH-C_1-4alkyl, and W, (Ra)_n, R2, R3 are as hereinbefore defined may be prepared as described in Scheme (7), below.

Scheme 7 Accordingly, a compound of formula (XII) is reacted with an appropriate aryl halide of formula (XIX), wherein p is 1 or 2, and halo is typically bromo, a known compound (e.g. commercially available) or a compound prepared by known method, by a copper-mediated Ullmann reaction, in the presence of a catalyst and a ligand, such as, copper(I) iodide and N,N'- dimethylethylenediamine, a base, such as potassium carbonate and a suitably mixture of solvents, such as, toluene and dimethylformamide, at a temperature in the range of from about rt to 100ºC, for a period of time to ensure the completion of the reaction and yielding the corresponding compound of formula (Id-1). The compound of formula (Id-1), is reacted with an aldehyde of formula (XX), wherein both Rh are C_1-4alkyl, by a reductive amination in the presence of a reducing agent, such as sodium cyanoborohydride, or the like, in a suitable inert solvent, such as, MeOH or the like; at a convenient temperature, typically rt, for a period of time to ensure the completion of the reaction to afford the compound of formula (Id-2). An aldehyde of formula (XX) can be a known compound (e.g. commercially available) or a compound prepared by known method. The compound of formula (Id-2), wherein one Rh is H and the other is methyl, can be prepared by methylation reaction of a compound of formula (Id-1) with methyl trifluoromethanesulfonate (MeOTf) in an appropriate solvent, such as, 1,1,1,3,3,3-hexafluoropropan-2-ol or the like; at a convenient temperature, typically rt, for a period of time to ensure the completion of the reaction. Alternatively, compounds of formula (I) wherein X is -C(O)NH-, A is phenyl, L b m is -CH2-, R is phenyl substituted with C alkylC(O)-NH-C a 2 3 1-4 1-4alkyl, and W, (R )n, R , R are as hereinbefore defined may be prepared as described in Scheme (8), below.

Scheme 8 Accordingly, a compound of formula (Id-1), wherein p is 1 or 2, is reacted with an acyl chloride of formula (XXI), wherein Ri is C1-4alkyl, in the presence of a base, such as Et3N, or the like, in a suitable inert solvent, such as, DCM or the like; at a convenient temperature, typically rt, for a period of time to ensure the completion of the reaction to afford the compound of formula (Id-3). An acyl chloride of formula (XXI) can be a known compound (e.g. commercially available) or a compound prepared by known method. Alternatively, compounds of formula (I) wherein X is -C(O)NH-, W is C, n is 1, Ra is OH, -O- C1-4alkyl, -O-C1-4alkyl-OH, -O-C1-4alkyl-CN, -O-C1-4alkyl-ethyne, -O-C1-4alkyl-O-C1-4alkyl, -O- C1-4alkyl-NH2, -O-C1-4alkyl-NH(CH3) and R2, R3, A, Lm and Rb are as hereinbefore defined may be prepared as described in Scheme (9), below.

Scheme 9 Accordingly, a compound of formula (Ie-1) can be prepared by an amide coupling reaction between the acid compound of formula (XI) with 5-amino-2-hydroxybenzonitrile by activation of the carboxylic acid in the presence of HATU, a suitable base, such as DIPEA, in a suitable inert solvent, such as, DMF; at a convenient temperature, typically rt, for a period of time to ensure the completion of the reaction. The compound of formula (Ie-1) can be reacted with a haloalkyl of formula (XXII), wherein halo is bromo and Rj is C_1-4alkyl, C_1-4alkyl-OH, C_1-4alkyl-CN, C_1-4alkyl-ethyne, C_1-4alkyl-O-C_1-4alkyl, C1-4alkyl-NH2, C1-4alkyl-NH(CH3), in the presence of a base, such as Cs2CO3, or the like, in a suitable inert solvent, such as, DMF or the like; at a convenient temperature, typically at 100ºC, for a period of time to ensure the completion of the reaction to afford the compound of formula (Ie-2). A haloalkyl of formula (XXII) can be a known compound (e.g. commercially available) or a compound prepared by known method. Alternatively, a compound of formula (Ie-2) can be prepared by a Mitsunobu type reaction by treatment of a compound of formula (Ie-1) with an alcohol of formula (XXIII) wherein R is as hereinbefore defined, in the presence of a suitable triarylphosphine, such as triphenylphosphine, and a suitable dialkyl azodicarboxylate reagent, such as di-iso-propyl in a suitable inert solvent, such as THF, under suitable reaction conditions, such as at a convenient temperature, typically ranging from 50ºC, for a period of time to ensure the completion of the reaction. An alcohol of formula (XXIII) can be a known compound (e.g. commercially available) or a compound prepared by known method. Synthesis of compounds of Formula (I) wherein X is -NHC(O)- (Reverse Amide) Alternatively, compounds of formula (I) wherein X is -NHC(O)- and W, (Ra)_n, R2, R3, A, L_m and Rb are as hereinbefore defined may be prepared as described in Scheme (10), below.

Scheme 10 Accordingly, a compound of formula (XI) can be subjected to a Curtius rearrangement in a one pot procedure, by transformation of the carboxylic acid group into a Boc-protected amino group, in the presence of diphenyl phosphoryl azide (DPPA) and tert-butanol (t-BuOH), and a base such as triethylamine; at a temperature ranging from rt to 80°C, for a period of time to ensure the completion of the reaction, to provide the Boc-protected amine of formula (XXIV). The amine of formula (XXV) can be prepared from a compound of formula (XXIV) by removal of the Boc-protecting group, in the presence of acidic media, such as hydrochloric acid, in an inert solvent such as 1,4-dioxane and the like, under suitable reaction conditions, such as at a convenient temperature, typically rt, for a period of time to ensure the completion of the reaction. The amine of formula (XXV) is reacted with a carboxylic acid of formula (XXVI), wherein W and (Ra)_n are as hereinbefore defined, by an amide coupling reaction using HATU or the like, for the activation of the carboxylic acid and a suitable base, such as DIPEA, or the like, in a suitable inert solvent, such as, DCM or the like; at a convenient temperature, typically rt, for a period of time to ensure the completion of the reaction to afford the compound of formula (If). A carboxylic acid of formula (XXVI) can be a known compound (e.g. commercially available) or a compound prepared by known method. Alternatively, compounds of formula (I) wherein X is -NHC(O)- and W, (Ra) 2 3 n, R , R , A, Lm and Rb are as hereinbefore defined may be prepared as described in Scheme (11), below.

Scheme 11 Accordingly, a compound of formula (V) can be protected, for example with Boc in a suitable base such as triethylamine or the like, with a suitable additive such as dimethylaminopyridine or the like, in a suitable solvent such as THF or the like, at a suitable temperature, for example room temperature. The halogen in a compound of formula (XXVII) can be reacted with a suitable amine such as tert-butyl carbamate in presence of a catalyst and a ligand such as Tris(dibenzylideneacetone)dipalladium (Pd2(dba)3) or the like and dicyclohexyl[2′,4′,6′- tris(propan-2-yl)[1,1′-biphenyl]-2-yl]phosphane (Xphos) or the like and a suitable base such as cesium carbonate or the like in a suitable solvent such as toluene or the like under suitable reaction conditions such as nitrogen atmosphere at a convenient temperature, typically 100ºC. The amine of formula (XXIX) can be prepared from a compound of formula (XXVIII) by removal of the Boc-protecting groups, for example step wise treating a compound of formula (XXVIII) with a solvent such as 1,1,1,3,3,3-hexafluoropropan-2-ol (HFIP) or the like, at a convenient temperature, typically 100ºC, for a period of time to ensure the completion of the reaction. Subsequent treatment of the compound in the presence of acidic media, such as hydrochloric acid, in an inert solvent such as 1,4-dioxane and the like, under suitable reaction conditions, such as at a convenient temperature, typically rt, for a period of time to ensure the completion of the reaction. The amine of formula (XXIX) is reacted with a carboxylic acid of formula (XXVI), wherein W and (Ra)n are as hereinbefore defined, by an amide coupling reaction using HATU or the like, for the activation of the carboxylic acid and a suitable base, such as DIPEA, or the like, in a suitable inert solvent, such as, DCM or the like; at a convenient temperature, typically rt, for a period of time to ensure the completion of the reaction to afford the compound of formula (If). A carboxylic acid of formula (XXVI) can be a known compound (e.g. commercially available) or a compound prepared by known method. The compound of formula (XXX) is reacted with an appropriate aryl or heteroaryl halide of formula (VIII), wherein A, Lm and Rb are as hereinbefore defined and halo is typically bromo, a known compound (e.g. commercially available) or a compound prepared by known method, by a copper-mediated Ullmann reaction, in the presence of a catalyst and a ligand, such as, copper(I) iodide and N,N'-dimethylethylenediamine, a base, such as potassium carbonate and a suitably mixture of solvents, such as, toluene and dimethylformamide, at a temperature in the range of from about rt to 100ºC, for a period of time to ensure the completion of the reaction and yielding the corresponding compound of formula (If). Preparation of Intermediate Compounds Intermediate 1: (S)-5-(4-(difluoro(phenyl)methyl)phenyl)-6-methyl-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxylic acid.

Step A: ethyl (S)-1-(2-((tert-butoxycarbonyl)amino)propyl)-4-iodo-1H-pyrazole-5-carboxylate. A solution of ethyl 4-iodo-1H-pyrazole-5-carboxylate (42.0 g, 157.9 mmol), tert-butyl (S)-(1- hydroxypropan-2-yl)carbamate (55.3 g, 315.7 mmol), Ph₃P (74.5 g, 284.2 mmol) and DBAD (65.4 g, 284.2 mmol) in THF (800 mL) was stirred at rt and under nitrogen for 16 h. The mixture was concentrated under reduced pressure. Then, MTBE (600 mL) was added and the mixture was stirred at rt for 1 h. Then, the mixture was filtered to remove Ph₃PO and concentrated under reduced pressure. The residue was purified by silica gel chromatography (20%-25%, EtOAc/PE) to afford ethyl (S)-1-(2-((tert-butoxycarbonyl)amino)propyl)-4-iodo-1H-pyrazole-5-carboxylate (117.6 g, quant.) as a colorless oily solid.1H NMR (400 MHz, CDCl₃) δ: 7.58 (s, 1H), 6.25 (br s, 2H), 4.81 (br d, J = 6.8 Hz, 1H), 4.62 - 4.56 (m, 2H), 4.19 - 4.08 (m, 1H), 1.35 (s, 12H), 1.13 (d, J = 6.8 Hz, 3H). Mass spectrum (ESI, m/z): calcd. for C + 14H22IN3O4, 423.1; found [M+H] , 424.0. Step B: ethyl (S)-1-(2-aminopropyl)-4-iodo-1H-pyrazole-5-carboxylate hydrochloride. HCl/dioxane (570 mL, 2.28 mol, 4 M) was added to a stirred mixture of ethyl (S)-1-(2-((tert- butoxycarbonyl)amino)propyl)-4-iodo-1H-pyrazole-5-carboxylate (117.4 g, 277.4 mmol) in CH₃CN (570 mL). The mixture was stirred at rt for 16 h. Then, the mixture was filtered and the filtered cake was washed with EtOAc and MTBE. The residue was dried under vacuum to afford ethyl (S)-1-(2-aminopropyl)-4-iodo-1H-pyrazole-5-carboxylate hydrochloride (69.1 g, 76% yield) as a white solid. Mass spectrum (ESI, m/z): calcd. for C₉H₁₄IN₃O₂, 323.0; found [M+H]+, 324.1. Step C: (S)-3-iodo-6-methyl-6,7-dihydropyrazolo a]pyrazin-4(5H)-one.

NaHCO₃ (72.5 g, 863.5 mmol) was added to a stirred mixture of ethyl (S)-1-(2-aminopropyl)-4- iodo-1H-pyrazole-5-carboxylate hydrochloride (69 g, 191.9 mmol) in H2O (2 L). The mixture was stirred at rt 16 h. The reaction mixture was filtered under vacuum. The filtered cake was washed with H₂O and PE. The residue was dried under reduced pressure to afford (S)-3-iodo-6- methyl-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (30.6 g, 56% yield) as a white solid. Part of this product (10.5 g, 37.9 mmol) was dissolved in H2O (250 mL) and the mixture was stirred at rt 16 h. The reaction mixture was filtered under vacuum. The filtered cake was washed with H₂O and PE. The residue was dried under reduced pressure to afford (S)-3-iodo-6-methyl-6,7- dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (10.1 g) as a white solid, that was used in the next Step D.1H NMR (400 MHz, DMSO-d₆) δ: 8.32 (s, 1H), 7.67 (s, 1H), 4.43 (dd, J = 3.6, 11.6 Hz, 1H), 4.05 - 3.92 (m, 2H), 1.20 (d, J = 6.4 Hz, 3H). Mass spectrum (ESI, m/z): calcd. for C H IN O, 277.0; found + 7 8 3 [M+H] , 278.0. Step D: ethyl (S)-6-methyl-4-oxo- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxylate.

TEA (7.2 mL, 51.7 mmol) was added to a mixture of (S)-3-iodo-6-methyl-6,7- dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (4.5 g, 16.2 mmol), palladium(II) acetate (72 mg, 0.3 mmol) and DPPF (360 mg, 0.65 mmol) in EtOH (65 mL) and dioxane (25 mL). The mixture was stirred under CO (8 atm) at 90ºC for 16 h. The reaction mixture was concentrated under reduced pressure. The crude product was purified by silica gel chromatography (0%-10%, DCM/MeOH). The desired fractions were combined and concentrated in vacuo. Then, the product was dissolved in DCM and the organic layer was washed with HCl. The organic layer was dried over MgSO4, filtered and evaporated in vacuo to afford ethyl (S)-6-methyl-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxylate (3.7 g, 97% yield) as a brown solid.1H NMR (400 MHz, DMSO-d6) δ: 8.43 (s, 1H), 7.89 (s, 1H), 4.43 (dd, J = 12.5, 3.7 Hz, 1H), 4.20 (q, J = 7.1 Hz, 2H), 4.08 – 3.93 (m, 2H), 1.25 (t, J = 7.1 Hz, 3H), 1.21 (d, J = 6.3 Hz, 3H). Mass spectrum (ESI, m/z): calcd. for C₁₀H₁₃N₃O₃, 223.1; found [M+H]+, 224.1. Step E: ethyl (S)-5-(4-(difluoro(phenyl)methyl)phenyl)-6-methyl-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxylate CuI (0.94 g, 4.9 mmol) was added to a solution of ethyl (S)-6-methyl-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxylate (1.0 g, 4.5 mmol), 1-bromo-4- (difluoro(phenyl)methyl)benzene (2.0 g, 7.2 mmol), N,N'-dimethylethylenediamine (530 µL, 4.9 mmol) and K₂CO₃ (1.86 g, 13.4 mmol) in toluene (35 mL) and DMF (9 mL). The solution was stirred at 100ºC for 16 h. The solution was diluted with EtOAc, washed with sat. aq. NaHCO₃ and brine. The organic layers were combined, dried over MgSO4, filtered and concentrated in vacuo. The residue purified by silica gel chromatography (0%-90% heptane/EtOAc). The desired fractions were combined and concentrated in vacuo to afford ethyl (S)-5-(4- (difluoro(phenyl)methyl)phenyl)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3- carboxylate (1.34 g, 69% yield) as a yellowish solid.1H NMR (300 MHz, DMSO-d6) δ: 8.00 (s, 1H), 7.67 – 7.50 (m, 9H), 4.82 (dd, J = 13.1, 4.0 Hz, 1H), 4.51 – 4.36 (m, 2H), 4.27 – 4.15 (m, 2H), 1.24 (t, J = 7.1 Hz, 3H), 1.19 (d, J = 6.5 Hz, 3H). Mass spectrum (ESI, m/z): calcd. for C H F N O , + 23 21 2 3 3 425.2; found [M+H] , 426.1. Step F: (S)-5-(4-(difluoro(phenyl)methyl)phenyl)-6-methyl-4-oxo-4,5,6,7- tetrahydropyrazolo a]pyrazine-3-carboxylic acid

NaOH (2.3 mL, 4.6 mmol, 2M) was added to a solution of ethyl (S)-5-(4- (difluoro(phenyl)methyl)phenyl)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3- carboxylate (1.3 g, 3 mmol) in EtOH (12 mL). The mixture was stirred at rt for 1 h. The pH was adjusted to pH = 2 with aq. HCl 6M. The aqueous phase was extracted with CHCl3/i-PrOH (3:1) and the organic phase was dried over MgSO4, filtered and concentrated in vacuo to yield (S)-5- (4-(difluoro(phenyl)methyl)phenyl)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine- 3-carboxylic acid (1.18 g, 99% yield) as a white brownish solid.1H NMR (300 MHz, DMSO-d₆) δ: 8.15 (s, 1H), 7.70 (d, J = 8.6 Hz, 2H), 7.66 – 7.50 (m, 7H), 4.88 (dd, J = 13.2, 4.6 Hz, 1H), 4.65 – 4.55 (m, 1H), 4.50 (dd, J = 13.2, 4.2 Hz, 1H), 1.21 (d, J = 6.6 Hz, 3H). Mass spectrum (ESI, m/z): calcd. for C + 21H17F2N3O3, 397.1; found [M+H] , 398.1. Intermediate 2: ethyl 5-(4-(difluoro(phenyl)methyl)phenyl)-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxylate.

Step A: ethyl 4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxylate. The title compound was prepared in a manner analogous to Intermediate 1, Step D, reacting 3- iodo-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (15 g, 57.0 mmol).1H NMR (300 MHz, DMSO-d₆) δ: 8.37 (s, 1H), 7.89 (s, 1H), 4.33 (dd, J = 6.8, 5.3 Hz, 2H), 4.20 (q, J = 7.1 Hz, 2H), 3.65 – 3.54 (m, 2H), 1.25 (t, J = 7.1 Hz, 3H). Mass spectrum (ESI, m/z): calcd. for C₉H₁₁N₃O₃, 209.1; found [M+H]+, 210.1. Step B: ethyl 5-(4-(difluoro(phenyl)methyl)phenyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrazine-3-carboxylate The title compound was prepared in a manner analogous to Intermediate 1, Step E, reacting ethyl 4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxylate (3 g, 14.3 mmol) and 1-bromo-4- (difluoro(phenyl)methyl)benzene (5.1 g, 18.2 mmol).1H NMR (300 MHz, DMSO-d₆) δ: 1.13 - 1.20 (m, 3H) 4.09 - 4.17 (m, 2H) 4.17 - 4.21 (m, 2H) 4.47 - 4.53 (m, 2H) 7.45 - 7.54 (m, 9H) 7.90 - 7.92 (m, 1H). Mass spectrum (ESI, m/z): calcd. for C₂₂H₁₉F₂N₃O₃, 411.1; found [M+H]+, 412.2. Intermediate 3: 5-(4-(difluoro(phenyl)methyl)phenyl)-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxylic acid.

The title compound was prepared in a manner analogous to Intermediate 1, Step F, reacting ethyl 5-(4-(difluoro(phenyl)methyl)phenyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3- carboxylate (Intermediate 2, 660 mg, 1.6 mmol) and NaOH (1.15 mL, 2.3 mmol, 2M).1H NMR (400 MHz, DMSO-d6) δ: 8.13 (s, 1H), 7.66 – 7.38 (m, 9H), 4.79 – 4.61 (m, 2H), 4.36 – 4.32 (m, 2H). Mass spectrum (ESI, m/z): calcd. for C20H15F2N3O3, 383.1; found [M+H]+, 384.1. Intermediate 4: ethyl (S)-5-(4-benzylphenyl)-6-methyl-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxylate.

The title compound was prepared in a manner analogous to Intermediate 1, Step E, reacting ethyl (S)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxylate (Intermediate 1, product from Step D, 776 mg, 3.5 mmol) and 1-benzyl-4-bromobenzene (1.72 g, 7.0 mmol).1H NMR (400 MHz, DMSO-d₆) δ: 7.98 (s, 1H), 7.34 - 7.25 (m, 9H), 4.79 (dd, J = 4.0, 13.2 Hz, 1H), 4.41 - 4.32 (m, 2H), 4.25 - 4.15 (m, 2H), 3.98 (s, 2H), 1.24 (t, J = 7.2 Hz, 3H), 1.15 (d, J = 6.4 Hz, 4H). Mass spectrum (ESI, m/z): calcd. for C + 23H23N3O3, 389.2; found [M+H] , 390.2. Intermediate 5: ethyl 5-(4-benzylphenyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine- 3-carboxylate.

The title compound was prepared in a manner analogous to Intermediate 1, Step E, reacting ethyl 4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxylate (Intermediate 2, product from Step A, 200 mg, 0.96 mmol) and 1-benzyl-4-bromobenzene (473 mg, 1.91 mmol).1H NMR (400 MHz, CDCl3) δ: 7.96 (s, 1H), 7.27 (s, 9H), 4.55 - 4.49 (m, 2H), 4.34 (q, J = 7.2 Hz, 2H), 4.20 - 4.14 (m, 2H), 3.99 (s, 2H), 1.35 (t, J = 7.2 Hz, 3H). Mass spectrum (ESI, m/z): calcd. for C H N O , 375.2; + 22 21 3 3 found [M+H] , 376.0. Intermediate 6: (S)-N-(3-cyanophenyl)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrazine-3-carboxamide.

A mixture of (S)-3-iodo-6-methyl-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (Intermediate 1, product from Step C, 20.0 g, 72.2 mmol), 3-aminobenzonitrile (25.6 g, 216.6 mmol), TEA (30.1 mL, 217 mol), palladium(II) acetate (405 mg, 1.8 mmol) and DPPF (1.60 g, 2.89 mmol) in 1,4- dioxane (500 mL) was stirred at 90°C under CO atmosphere (1.2 atm) for 16 h. The mixture was treated with HCl (500 mL, 1M) and water. The suspension was filtered and the solid was washed with HCl (500 mL, 0.5M), water (250 mL), methanol (250 mL), EtOAc (250 mL) and MTBE (500 mL) to afford (S)-N-(3-cyanophenyl)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrazine-3-carboxamide (20.5 g, 95% yield) as a white solid.1H NMR (400 MHz, DMSO-d6) δ: 12.86 (s, 1H), 9.26 (s, 1H), 8.19 (s, 1H), 8.12 (s, 1H), 7.76 (br d, J = 7.6 Hz, 1H), 7.63 - 7.49 (m, 2H), 4.55 (br d, J = 8.8 Hz, 1H), 4.21 - 4.05 (m, 2H), 1.28 (d, J = 6.0 Hz, 3H). Mass spectrum (ESI, m/z): calcd. for C + 15H13N5O2, 295.1; found [M+H] , 296.1. Intermediate 7: (S)-N-(3-cyano-4-methoxyphenyl)-6-methyl-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

The title compound was prepared in a manner analogous to Intermediate 6, reacting (S)-3-iodo- 6-methyl-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (Intermediate 1, product from Step C, 10.0 g, 36.1 mmol) and 5-amino-2-methoxybenzonitrile (16.0 g, 108.3 mmol).1H NMR (400 MHz, DMSO-d6) δ: 12.63 (s, 1H), 9.22 (s, 1H), 8.16 - 8.02 (m, 2H), 7.73 (dd, J = 2.4, 9.2 Hz, 1H), 7.28 (d, J = 9.6 Hz, 1H), 4.54 (br d, J = 8.8 Hz, 1H), 4.27 - 4.04 (m, 2H), 3.90 (s, 3H), 1.27 (br d, J = 5.6 Hz, 3H). Mass spectrum (ESI, m/z): calcd. for C H N O , 3 + 16 15 5 3 25.1; found [M+H] , 325.8. Intermediate 8 4-(3-((3-cyanophenyl)carbamoyl)-6-methyl-4-oxo-6,7-

dihydropyrazolo[1,5-a]pyrazin-5 -yl)phenyl)trifluoroborate potassium salt.

Step A: ethyl (S)-5-(4-bromophenyl)-6-methyl-4-oxo- tetrahydropyrazolo[1,5-a]pyrazine-

3-carboxylate. The title compound was prepared in a manner analogous to Intermediate 1, Step E, reacting ethyl (S)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxylate (Intermediate 1, product from Step D, 1.5 g, 6.7 mmol) and 1,4-dibromobenzene (3.2 g, 13.4 mmol).1H NMR (400 MHz, DMSO-d6) δ: 7.99 (s, 1H), 7.67 (d, J = 8.4 Hz, 2H), 7.38 (d, J = 8.8 Hz, 2H), 4.87 - 4.75 (m, 1H), 4.48 - 4.34 (m, 2H), 4.28 - 4.14 (m, 2H), 1.24 (t, J = 7.2 Hz, 3H), 1.17 (d, J = 6.4 Hz, 3H). Mass spectrum (ESI, m/z): calcd. for C₁₆H₁₆BrN₃O₃, 377.0; found [M+H]+, 378.1. Step B: Intermediate 8A: (S)-5-(4-bromophenyl)-N-(3-cyanophenyl)-6-methyl-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide. Isopropylmagnesium lithium chloride (21.6 mL, 28.1 mmol, 1.3 M) was added to a stirred solution of 3-aminobenzonitrile (1.8 g, 15.2 mmol) in THF (47.5 mL) under nitrogen. The mixture was stirred at rt for 1 h. Then, ethyl (S)-5-(4-bromophenyl)-6-methyl-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxylate (3.8 g, 10.0 mmol) and THF (47.5 mL) were added. The mixture was stirred at 70°C for 2 h. The reaction mixture was quenched by aq. NaHCO3 and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na₂SO₄, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (42-63%, EtOAc/PE) and the resulting product was suspended in water (40 mL). The mixture was freeze dried to afford (S)-5-(4-bromophenyl)-N-(3-cyanophenyl)-6- methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide (Intermediate 8A, 3.7 g, 79% yield) as a yellow solid.1H NMR (400 MHz, DMSO-d₆) δ: 12.41 (s, 1H), 8.21 (s, 1H), 8.17 (s, 1H), 7.77 - 7.68 (m, 3H), 7.57 - 7.45 (m, 4H), 4.94 - 4.86 (m, 1H), 4.54 - 4.44 (m, 2H), 1.20 (d, J = 6.4 Hz, 3H). Mass spectrum (ESI, m/z): calcd. for C₂₁H₁₆BrN₅O₂, 449.0; found [M+H]+, 450.1. Step C: (S)-N-(3-cyanophenyl)-6-methyl-4-oxo-5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide. (S)-5-(4-bromophenyl)-N-(3-cyanophenyl)-6-methyl-4-oxo-4,5,6,7-tetrahydro-pyrazolo[1,5- a]pyrazine-3-carboxamide (Intermediate 8A, 2.5 g, 5.6 mmol), bis(pinacolato)diboron (2.1 g, 8.3 mmol), [1,1'-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) (406.2 mg, 0.56 mmol) and potassium acetate (1.1 g, 11.1 mmol) were charged in one portion into an EasyMax® reactor, followed by 1,4-dioxane (15 mL). The resulting mixture was stirred at 80°C for 16 h. Then, the reaction mixture was cooled down and water and EtOAc were added. The organic phase was extracted and the aqueous phase back extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered and concentrated in vacuo to afford (S)-N-(3- cyanophenyl)-6-methyl-4-oxo-5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)- 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide (2 g, 81.5% pure, 59% yield) as a white solid. Mass spectrum (ESI, m/z): calcd. for C₂₇H₂₈BN₅O₄, 497.2; found [M+H]+, 498.2. Step D: (S)-(4-(3-((3-cyanophenyl)carbamoyl)-6-methyl-4-oxo-6,7-dihydropyrazolo[1,5- a]pyrazin-5(4H)-yl)phenyl)trifluoroborate potassium salt. Potassium hydrogen fluoride (1.38 g, 17.7 mmol) was added to a stirred solution of (S)-N-(3- cyanophenyl)-6-methyl-4-oxo-5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)- 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide (2 g, 3.3 mmol) in MeOH (14 mL) and the mixture was stirred at rt for 30 min. Then, the mixture was concentrated in vacuo. The residue was redissolved in 50% aq. MeOH (12 mL) and the mixture was concentrated in vacuo. The solid residue was triturated with MTBE, the liquid phase was decanted, and the residual inorganic salts were washed with additional MTBE. The combined washings were collected and concentrated in vacuo to afford (S)-(4-(3-((3-cyanophenyl)carbamoyl)-6-methyl-4-oxo-6,7- dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl)phenyl)trifluoroborate potassium salt (1.3 g, 77% yield).1H NMR (400 MHz, DMSO-d₆) δ: 12.71 (s, 1H) 8.26 - 8.30 (m, 1H) 8.19 (s, 1H) 7.64 (dt, J = 6.6, 2.3 Hz, 1H) 7.50 - 7.53 (m, 2H) 7.45 (d, J = 8.1 Hz, 2H) 7.18 (d, J = 7.6 Hz, 2H) 4.89 (dd, J = 13.4, 4.6 Hz, 1H) 4.46 - 4.53 (m, 1H) 4.36 - 4.44 (m, 1H) 3.92 (s, 3H). Mass spectrum (ESI, m/z): calcd. for C₂₁H₁₆BF₃N₅O₂, 438.1; found [M]-, 438.1. Intermediate 9: N-(3-cyanophenyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3- carboxamide.

Step A: tert-butyl 3-iodo-4-oxo-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate. A solution of 3-iodo-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (7.0 g, 26.6 mmol), DMAP (325 mg, 2.7 mmol), TEA (7.4 mL, 53 mmol) and di-tert-butyl dicarbonate (8.7 g, 39.9 mmol) in THF (100 mL) was stirred at 45°C under nitrogen for 16 h. The mixture was concentrated in vacuo. The residue was purified by silica gel chromatography (35-45%, EtOAc/PE) to afford tert-butyl 3-iodo-4-oxo-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate (9.2 g, 96% yield), as a white solid.1H NMR (400 MHz, CDCl₃) δ: 7.62 (s, 1H), 4.45 - 4.41 (m, 2H), 4.25 - 4.21 (m, 2H), 1.58 (s, 9H). Mass spectrum (ESI, m/z): calcd. for C11H14IN3O3, 363.0; found [M- tBu+2H]+, 308.0. Step B: tert-butyl 3-((3-cyanophenyl)carbamoyl)-4-oxo-6,7-dihydropyrazolo[1,5-a]pyrazine- 5(4H)-carboxylate. The title compound was prepared in a manner analogous to Intermediate 6, reacting tert-butyl 3- iodo-4-oxo-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate (4.6 g, 12.7 mmol) and 3- aminobenzonitrile (6.0 g, 50.7 mmol).1H NMR (400 MHz, CDCl3) δ: 11.86 (s, 1H), 8.30 (s, 1H), 8.16 (t, J=1.6 Hz, 1H), 7.94 (td, J=1.6, 8.1 Hz, 1H), 7.47 - 7.37 (m, 2H), 4.53 (dd, J=4.8, 7.0 Hz, 2H), 4.34 - 4.28 (m, 2H), 1.63 (s, 9H). Mass spectrum (ESI, m/z): calcd. for C19H19N5O4, 381.1; found [M-COOtBu+2H]+, 282.2. Step C: N-(3-cyanophenyl)-4-oxo- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

The title compound was prepared in a manner analogous to Intermediate 1, Step B, reacting tert- butyl 3-((3-cyanophenyl)carbamoyl)-4-oxo-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)- carboxylate (3.3 g, 8.7 mmol) and HCl/dioxane (20 mL, 80 mmol, 4M).1H NMR (400 MHz, DMSO-d6) δ: 12.87 (s, 1H), 9.22 (br s, 1H), 8.20 - 8.18 (m, 1H), 8.12 (s, 1H), 7.77 (td, J = 2.0, 7.5 Hz, 1H), 7.61 - 7.53 (m, 2H), 4.45 (dd, J = 5.6, 6.9 Hz, 2H), 3.76 - 3.69 (m, 2H). Mass spectrum (ESI, m/z): calcd. for C + 14H11N5O2, 281.1; found [M+H] , 282.2. Intermediate 10: 5-(4-bromophenyl)-N-(3-cyanophenyl)-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

Step A: ethyl 5-(4-bromophenyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3- carboxylate. Copper(II) acetate (32.8 g, 180.5 mmol) was added to a solution of ethyl 4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxylate (20.4 g, 90.2 mmol), (4-bromophenyl)boronic acid (36.2 g, 180.5 mmol), TEA (50.2 mL, 361 mmol) and molecular sieves 4 Å (2 g) in DCM (240 mL). The mixture was stirred at rt for 16 h under O₂ atmosphere. The reaction was quenched with a diluted solution of 25% ammonia hydrate (110 mL) in water (440 mL). The aqueous phase was back extracted with DCM. The organic layers were dried with Na2SO4 and concentrated in vacuo. The residue was purified by silica gel chromatography (45-60%, DCM/EtOAc) to afford ethyl 5-(4-bromophenyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrazine-3-carboxylate (14.7 g, 86.9% pure, 39% yield) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ: 7.97 (s, 1H), 7.65 (d, J = 8.8 Hz, 2H), 7.40 (d, J = 8.4 Hz, 2H), 4.57 (t, J = 6.4 Hz, 2H), 4.28 - 4.15 (m, 4H), 1.24 (t, J = 7.2 Hz, 3H). Mass spectrum (ESI, m/z): calcd. for C H BrN O , 364.2; fou + 15 14 3 3 nd [M+H] , 365.6. Step B: 5-(4-bromophenyl)-N-(3-cyanophenyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrazine-3-carboxamide. A solution of 3-aminobenzonitrile (2.4 g, 20.6 mmol) in THF (15 mL) was stirred for 5 min and then, isopropylmagnesium chloride lithium chloride complex solution (16.9 mL, 22.0 mmol, 1.3 M) was added over 3 min. The mixture was stirred at rt for 1 h. Then, a solution of ethyl 5-(4- bromophenyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxylate (5 g, 13.7 mmol) in THF (10 mL) was added and the mixture was stirred at 70°C for 30 min. After reaction completion, the mixture was cooled down to rt and subsequently treated with sat. aq. NH4Cl and diluted with EtOAc. The organic layer was separated, dried and concentrated in vacuo. The crude mixture was purified by silica gel chromatography (0-50%, heptane/EtOAc) to afford 5-(4- bromophenyl)-N-(3-cyanophenyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3- carboxamide (4.6 g, 71% yield) as a pink solid.1H NMR (400 MHz, DMSO-d₆) δ: 12.36 - 12.48 (m, 1H) 8.12 - 8.22 (m, 2H) 7.65 - 7.79 (m, 3H) 7.52 - 7.56 (m, 2H) 7.49 (d, J = 8.8 Hz, 2H) 4.62 - 4.73 (m, 2H) 4.22 - 4.36 (m, 2H). Mass spectrum (ESI, m/z): calcd. for C20H14BrN5O2, 435.0; found [M-H]-, 434.0. Intermediate 11: 3-amino-5-(4-benzylphenyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4 -one

hydrochloride.

Step A: 5-(4-benzylphenyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxylic acid. The title compound was prepared in a manner analogous to Intermediate 1, Step F, reacting ethyl 5-(4-benzylphenyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxylate (Intermediate 5, 7.5 g, 20.0 mmol) and NaOH (10.49 mL, 20.98 mmol, 2M), using MeOH (39 mL) as solvent instead of EtOH. Mass spectrum (ESI, m/z): calcd. for C20H17N3O3, 347.1; found [M+H]+, 347.8. Step B: tert-butyl (5-(4-benzylphenyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3- yl)carbamate. A solution of 5-(4-benzylphenyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxylic acid (7.1 g, 20.4 mmol), TEA (8.8 mL, 40.9 mmol) and DPPA (5.7 mL, 40.9 mmol) in t-BuOH (100 mL) was stirred under nitrogen for 16 h. Then, the mixture was stirred at 80°C under nitrogen for 16 h. The reaction mixture was then poured into water and extracted with EtOAc. The combined extracts were washed with sat. aq. NaHCO3 and brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (48% EtOAc/PE) to afford tert-butyl (5-(4-benzylphenyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrazin-3-yl)carbamate (7.9 g, 77.5% pure, quant.) as a white solid.1H NMR (400 MHz, CDCl3) δ: 8.08 - 8.01 (m, 1H), 7.32 - 7.26 (m, 4H), 7.26 - 7.17 (m, 5H), 4.45 (t, J = 5.9 Hz, 2H), 4.17 - 4.13 (m, 2H), 4.01 (s, 2H), 1.49 (s, 9H). Mass spectrum (ESI, m/z): calcd. for C₂₄H₂₆N₄O₃, 418.2; found [M-tBu+2H]+, 363.1. Step C: 3-amino-5-(4-benzylphenyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one hydrochloride. A solution of tert-butyl (5-(4-benzylphenyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3- yl)carbamate (13.0 g, 31.1 mmol) in HCl/dioxane (195 mL, 780 mmol, 4M) was stirred at rt for 16 h. The mixture was filtered, and the filtered cake was washed with EA and PE under vacuum and concentrated in vacuo. The solid was dissolved in a solution of 10% EtOAc/PE and stirred for 1.5 h. Then, the mixture was filtered, and the filtered cake was washed with EA and PE under vacuum. The residue was freeze dried to afford 3-amino-5-(4-benzylphenyl)-6,7- dihydropyrazolo[1,5-a]pyrazin-4(5H)-one hydrochloride (8.1 g, 72% yield) as a brown solid.1H NMR (400 MHz, DMSO-d6) δ: 7.42 (s, 1H), 7.35 - 7.17 (m, 9H), 4.43 (br t, J = 6.0 Hz, 2H), 4.18 - 4.12 (m, 2H), 3.96 (s, 2H). Mass spectrum (ESI, m/z): calcd. for C₁₉H₁₈N₄O, 318.1; found [M+H]+, 319.2. Intermediate 12: (S)-3-amino-5-(4-(difluoro(phenyl)methyl)phenyl)-6-methyl-6,7- dihydropyrazolo[1,5-a]pyrazin-4(5H)-one.

Step A: tert-butyl (S)-(5-(4-(difluoro(phenyl)methyl)phenyl)-6-methyl-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazin-3-yl)carbamate. A mixture of (S)-5-(4-(difluoro(phenyl)methyl)phenyl)-6-methyl-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxylic acid (Intermediate 1, 620 mg, 1.6 mmol), TEA (550 µL, 3.1 mmol) and DPPA (670 µL, 3.1 mmol) in tert-butanol anhydrous (6.2 mL) was stirred under nitrogen at 80ºC for 16 h. The reaction progress was monitored by LC-MS. Sat. aq. NaHCO3 was added dropwise to the mixture and the aqueous phase was extracted with EtOAc. The organic layers were joined, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (0-100% heptane/EtOAc) to afford tert-butyl (S)-(5-(4-(difluoro(phenyl)methyl)phenyl)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrazin-3-yl)carbamate (551 mg, 70% yield) as a yellowish solid.1H NMR (300 MHz, DMSO- d₆) δ: 7.99 (brs, 1H), 7.83 (brs, 1H), 7.65 – 7.51 (m, 9H), 4.66 (dd, J = 13.1, 4.3 Hz, 1H), 4.53 – 4.43 (m, 1H), 4.31 (dd, J = 13.0, 3.1 Hz, 1H), 1.46 (s, 9H), 1.18 (d, J = 6.8 Hz, 3H). Mass spectrum (ESI, m/z): calcd. for C₂₅H₂₆F₂N₄O₃, 468.2; found [M+H]+, 469.1. Step B: (S)-3-amino-5-(4-(difluoro(phenyl)methyl)phenyl)-6-methyl-6,7-dihydropyrazolo[1,5- a]pyrazin-4(5H)-one. HCl in dioxane (2.7 mL, 4 M, 10.9 mmol) was added to a solution of tert-butyl (S)-(5-(4- (difluoro(phenyl)methyl)phenyl)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3- yl)carbamate (551 mg, 1.1 mmol) in DCM (6 mL) and the mixture was stirred at rt for 16 h. Then, Na₂CO₃ was added until pH = 7 and the reaction mixture was filtered and rinsed with DCM. The residue was purified by silica gel chromatography (0-100% DCM/[DCM/MeOH/NH3, 9:1:0.05]) to afford (S)-3-amino-5-(4- (difluoro(phenyl)methyl)phenyl)-6-methyl-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (327 mg, 80% yield) as a dark yellow solid.1H NMR (300 MHz, DMSO-d₆) δ: 7.61 – 7.49 (m, 9H), 7.07 (s, 1H), 4.86 (brs, 2H), 4.48 (dd, J = 12.6, 4.2 Hz, 1H), 4.43 – 4.35 (m, 1H), 4.15 (dd, J = 12.7, 2.9 Hz, 1H), 1.19 (d, J = 6.5 Hz, 3H). Mass spectrum (ESI, m/z): calcd. for C20H18F2N4O, 368.1; found [M+H]+, 369.1. Intermediate 13: (S)-3-cyano-4-methoxy-N-(6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrazin-3-yl)benzamide.

Step A: tert-butyl (S)-3-iodo-6-methyl-4-oxo-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)- carboxylate. (S)-3-Iodo-6-methyl-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (Intermediate 1, product from Step C, 10 g, 36 mmol), a stir bar, DMAP (0.441 g, 3.61 mmol), TEA (10 mL, 72 mmol) and THF (100 mL) was added to a 250 mL round-bottomed flask. The resulting mixture treated with Boc2O (11.8 g, 54.1 mmol) in one portion. The resulting solution was stirred at rt for 12 h. The reaction mixture was concentrated to dryness in vacuo to give yellow oil. The oil was then subjected to silica gel chromatography (0-50% EtOAc/PE) to give (S)-tert-butyl 3-iodo-6- methyl-4-oxo-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate as a white solid (13.5 g, 98% yield).1H NMR (400 MHz, DMSO-d₆) δ: 7.77 (s, 1H), 4.79 - 4.69 (m, 1H), 4.60 (dd, J = 4.4, 13.6 Hz, 1H), 4.34 (dd, J = 1.2, 13.6 Hz, 1H), 1.50 (s, 9H), 1.18 - 1.17 (m, 1H), 1.17 (d, J = 6.8 Hz, 2H). Mass spectrum (ESI, m/z): calcd. for C H IN O , 377.2; fo + 12 16 3 3 und [M-56+H] , 321.9. Step B: tert-butyl (S)-3-((tert-butoxycarbonyl)amino)-6-methyl-4-oxo-6,7-dihydropyrazolo[1,5- a]pyrazine-5(4H)-carboxylate. (S)-tert-Butyl 3-iodo-6-methyl-4-oxo-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate (7.0 g, 19 mmol), a stir bar, toluene (70 mL), tert-butyl carbamate (4.35 g, 37.2 mmol), Cs2CO3 (12 g, 37 mmol), Xphos (2.65 g, 5.57 mmol) and Pd2(dba)3 (1.67 g, 1.86 mmol) were added to an oven-dried and nitrogen-purged 250 mL three-necked flask fitted with a reflux condenser, the reaction vessel placed in an oil bath that had been pre-heated to 100 °C. The reaction solution was stirred for 15 h. The reaction mixture was filtered and the filtrate was poured into H2O (40 mL) and extracted with EtOAc (50 mL*3). The combined organic phase washed with brine (120 mL), dried with anhydrous Na2SO4, filtered and concentrated in vacuum to give a brown oil. The brown oil was subjected to silica gel chromatography (0-30% EtOAc/PE) to give the (S)- tert-butyl 3-((tert-butoxycarbonyl)amino)-6-methyl-4-oxo-6,7-dihydropyrazolo[1,5-a]pyrazine- 5(4H)-carboxylate as brown oil (3.2 g, 36% yield).1H NMR (400 MHz, DMSO-d₆) δ: 8.08 (s, 1H), 7.83 (br s, 1H), 4.79 - 4.66 (m, 1H), 4.49 (dd, J = 4.0, 13.4 Hz, 1H), 4.25 (dd, J = 1.1, 12.4 Hz, 1H), 1.50 (s, 9H), 1.47 (s, 9H), 1.21 - 1.18 (m, 3H). Mass spectrum (ESI, m/z): calcd. for C + 17H26N4O5, 366.2; found [M+H] , 367.1. Step C: (S)-3-amino-6-methyl-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one. (S)-tert-Butyl 3-((tert-butoxycarbonyl)amino)-6-methyl-4-oxo-6,7-dihydropyrazolo[1,5- a]pyrazine-5(4H)-carboxylate (28 g, 76 mmol), a stir bar, 1,1,1,3,3,3-hexafluoropropan-2-ol (150 mL) were added to a 250 mL round-bottomed flask fitted with a reflux condenser. The solution was stirred at 100 °C for 48 h. The reaction vessel was allowed gradually to cool to rt and concentrated to dryness under reduced pressure to give a red viscous oil (20 g). The oil and a stir bar were added to a 500 mL round-bottomed flask then treated with HCl (100 mL, 4 M in dioxane) and the solution was stirred at rt for 4 h to give a white suspension. The suspension was concentrated to dryness in vacuo to give a red oil. The oil was then subjected to silica gel chromatography (0-20% MeOH/DCM (added 0.1% NH3•H2O)) to give (S)-3-amino-6-methyl- 6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one as a brown solid (9.1 g, 96% yield). Mass spectrum (ESI, m/z): calcd. for C₇H₁₀N₄O, 166.1; found [M+H]+.167.1 Step D: (S)-3-cyano-4-methoxy-N-(6-methyl-4-oxo- tetrahydropyrazolo[1,5-a]pyrazin-3-

yl)benzamide. (S)-3-Amino-6-methyl-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (4.58 g, 22.6 mmol), a stir bar, 3-cyano-4-methoxybenzoic acid (4.81 g, 27.1 mmol), DIEA (11.2 mL, 67.8 mmol), HATU (12.9 g, 33.9 mmol) and DMF (100 mL) were added to an oven-dried and nitrogen-purged 250 mL round bottomed flask and the mixture was stirred overnight at rt to give a brown suspension. The reaction mixture was filtered and the filter cake was washed with MeOH (10 mL*4) to afford (S)-3-cyano-4-methoxy-N-(6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3- yl)benzamide as an off-white solid (10.58 g, 99% yield).1H NMR (400MHz, DMSO-d₆) δ: 9.78 (s, 1H), 8.44 (s, 1H), 8.24 (d, J = 2.0 Hz, 1H), 8.17 (dd, J = 2.0, 8.8 Hz, 1H), 8.02 (s, 1H), 7.43 (d, J = 9.2 Hz, 1H), 4.43 - 4.37 (m, 1H), 4.01 (s, 3H), 4.00 - 3.94 (m, 2H), 1.25 (d, J = 6.0 Hz, 3H). Mass spectrum (ESI, m/z): calcd. for C + 16H15N5O3, 325.1; found [M+H] , 325.9. Intermediate 14: (S)-5-(4-(1,1-difluoroethyl)phenyl)-6-methyl-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxylic acid.

Step A: ethyl (S)-5-(4-(1,1-difluoroethyl)phenyl)-6-methyl-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxylate. The title compound was prepared in a manner analogous to Intermediate 1, Step E, reacting ethyl (S)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxylate (Intermediate 1, product from Step D, 1.0 g, 4.5 mmol) and 1-bromo-4-(1,1-difluoroethyl)benzene (445.6 mg, 2.02 mmol). Mass spectrum (ESI, m/z): calcd. for C + 18H19F2N3O3, 363.1; found [M+H] , 364.0. Step B: (S)-5-(4-(1,1-difluoroethyl)phenyl)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrazine-3-carboxylic acid. The title compound was prepared in a manner analogous to Intermediate 1, Step F, reacting (S)- ethyl 5-(4-(1,1-difluoroethyl)phenyl)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine- 3-carboxylate (320 mg, 0.881 mmol) and NaOH (0.57 mL, 1.2 mmol, 2 M in water).1H NMR (400 MHz, DMSO-d6) δ: 13.94 (s, 1H), 8.25 - 8.09 (m, 1H), 7.80 - 7.53 (m, 4H), 4.89 (dd, J = 4.4, 13.4 Hz, 1H), 4.68 - 4.43 (m, 2H), 3.34 (s, 9H), 2.02 (t, J = 18.8 Hz, 3H), 1.22 (d, J = 6.4 Hz, 3H). Mass spectrum (ESI, m/z): calcd. for C₁₆H₁₅F₂N₃O₃, 335.1; found [M+H]+, 335.8. Intermediate 15: (R)-N-(3-cyano-4-methoxyphenyl)-7-methyl-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

Step A: ethyl (R)-1-(1-((tert-butoxycarbonyl)amino)propan-2-yl)-4-iodo-1H-pyrazole-5- carboxylate. The title compound was prepared in a manner analogous to Intermediate 1, Step A, reacting (S)- tert-butyl (2-hydroxypropyl)carbamate (26.3 g, 150 mmol) and ethyl 4-iodo-1H-pyrazole-5- carboxylate (20 g, 75 mmol). Mass spectrum (ESI, m/z): calcd. for C14H22IN3O4423.2; found [M-100+H]+, 323.9. Step B: ethyl (R)-1-(1-aminopropan-2-yl)-4-iodo-1H-pyrazole-5-carboxylate as HCl salt. The title compound was prepared in a manner analogous to Intermediate 1, Step B, reacting ethyl (R)-1-(1-((tert-butoxycarbonyl)amino)propan-2-yl)-4-iodo-1H-pyrazole-5-carboxylate (16 g, 37.8 mmol) and 4 N HCl/dioxane (40 mL).1H NMR (400 MHz, DMSO-d6) δ: 8.23 (br s, 2H), 7.82 (s, 1H), 5.51 - 5.43 (m, 1H), 4.35 (dd, J = 1.6, 7.2 Hz, 2H), 3.45 - 3.32 (m, 1H), 3.23 - 3.14 (m, 1H), 2.07 (s, 1H), 1.40 - 1.33 (m, 6H). Step C: (R)-3-iodo-7-methyl-6,7-dihydropyrazolo a]pyrazin-4(5H)-one.

The title compound was prepared in a manner analogous to Intermediate 1, Step C, reacting (R)- ethyl 1-(1-aminopropan-2-yl)-4-iodo-1H-pyrazole-5-carboxylate (7.10 g, 22.0 mmol), H2O (100 mL), and NaHCO3 (5.54 g, 65.9 mmol).1H NMR 400 MHz, DMSO-d6) δ: 8.24 (s, 1H), 7.67 (s, 1H), 4.57 - 4.46 (m, 1H), 3.65 (td, J = 4.0, 13.2 Hz, 1H), 3.34 - 3.28 (m, 1H), 1.42 (d, J = 6.4 Hz, 3H). Mass spectrum (ESI, m/z): calcd. for C₇H₈IN₃O 277.0; found [M+H]+, 278.0. Step D: (R)-N-(3-cyano-4-methoxyphenyl)-7-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrazine-3-carboxamide. The title compound was prepared in a manner analogous to Intermediate 6, reacting (R)-3-iodo- 7-methyl-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one(800 mg, 2.89 mmol) and 5-amino-2- methoxybenzonitrile (856 mg, 5.78 mmol). Mass spectrum (ESI, m/z): calcd. for C₁₆H₁₅N₅O₃ 325.1; found [M+H]+, 326.1. Intermediate 16: (R)-3-cyano-4-methoxy-N-(7-methyl-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazin-3-yl)benzamide.

Step A: tert-butyl (R)-3-iodo-7-methyl-4-oxo-6,7-dihydropyrazolo a]pyrazine-5(4H)-

carboxylate. The title compound was prepared in a manner analogous to Intermediate 13, Step A, reacting (R)-3-iodo-7-methyl-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (Intermediate 15, product from Step C, 1 g, 3.61 mmol) and Boc2O (1.18 g, 5.41 mmol). Mass spectrum (ESI, m/z): calcd. for C₁₂H₁₆IN₃O₃377.0; found [M-56+H]+, 322.0. Step B: tert-butyl (R)-3-((tert-butoxycarbonyl)amino)-7-methyl-4-oxo-6,7-dihydropyrazolo[1,5- a]pyrazine-5(4H)-carboxylate. The title compound was prepared in a manner analogous to Intermediate 13, Step B, reacting tert-butyl (R)-3-iodo-7-methyl-4-oxo-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate (580 mg, 1.54 mmol) and tert-butyl carbamate (360 mg, 3.08 mmol).1H NMR (400 MHz, CDCl₃) δ: 8.08 (br s, 1H), 8.04 (br s, 1H), 4.52 - 4.43 (m, 1H), 4.29 (dd, J=3.8, 13.6 Hz, 1H), 3.82 (dd, J=8.1, 13.7 Hz, 1H), 1.63 - 1.59 (m, 12H), 1.51 (s, 9H). Mass spectrum (ESI, m/z): calcd. for C H N O 366.2; f + 17 26 4 5 ound [M+H] , 367.2. Step C: (R)-3-amino-7-methyl-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one. tert- Butyl (R)-3-((tert-butoxycarbonyl)amino)-7-methyl-4-oxo-6,7-dihydropyrazolo[1,5- a]pyrazine-5(4H)-carboxylate (160 mg, 0.437 mmol), 4 N HCl/dioxane and a stir bar were added to a 50 mL round-bottomed flask. The resulting solution was stirred at rt for 2 hours to give a yellow oil. The mixture was concentrated to dryness under reduced pressure to give (R)-3- amino-7-methyl-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one as a white solid (90 mg, 86% yield). Step D: (R)-3-cyano-4-methoxy-N-(7-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3- yl)benzamide. The title compound was prepared in a manner analogous to Intermediate 13, Step D, reacting (R)-3-amino-7-methyl-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (90 mg, 0.376 mmol), 3- cyano-4-methoxybenzoic acid (80.0 mg, 0.452 mmol), and HATU (172 mg, 0.452 mmol). Mass spectrum (ESI, m/z): calcd. for C16H15N5O3325.1; found [M+H]+, 326.1. Intermediate 17: (S)-5-(4-(difluoro methyl)phenyl)-7-methyl-4-oxo-4,5,6,7-

tetrahydropyrazolo[1,5-a]pyrazine-3-carboxylic acid.

Step A: ethyl (ethyl (S)-7-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3- carboxylate. XantPhos (628 mg, 1.09 mmol) and Pd(OAc)2 (124 mg, 0.55 mmol) were added to a suspension of (S)-3-iodo-7-methyl-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (3 g, 10.83 mmol), tungsten hexacarbonyl (6.4 g, 18.19 mmol) and Et₃N (4.48 mL, 32.14 mmol) in EtOH (65 mL) under nitrogen, and the mixture was heated at 80ºC for 48 h. Water was added to the mixture and it was extracted with EtOAc. The organic layers were joined and dried over MgSO4 anh., filtered and concentrated in vacuo. The residue purified by silica gel chromatography (0%-90% heptane/EtOAc). The desired fractions were combined and concentrated in vacuo to afford ethyl (S)-7-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxylate (1.268 g, 39% yield) as a brown solid.1H NMR (300 MHz, DMSO-d6) δ: 8.31 - 8.44 (m, 1H), 7.91 (s, 1H), 4.49 - 4.61 (m, 1H), 4.21 (q, J=7.16Hz, 2H), 3.62 - 3.73 (m, 1H), 3.36 - 3.41 (m, 1H), 1.46 (d, J=6.42 Hz, 3H), 1.26 (t, J=7.04 Hz, 3H).Mass spectrum (ESI, m/z): calcd. for C₁₀H₁₃N₃O₃, 223.1; found [M+Na]+, 246.1. Step B: ethyl (S)-5-(4-(difluoro(phenyl)methyl)phenyl)-7-methyl-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxylate CuI (72 mg, 0.378 mmol) was added to a solution of ethyl (S)-7-methyl-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxylate (370 mg, 1.66 mmol), 1-bromo-4- (difluoro(phenyl)methyl)benzene (510 mg, 1.80 mmol), (R,R)-(-)-N,N'-Dimethyl-1,2- cyclohexanediamine (72 mg, 0.506 mmol) and K₂CO₃ (468 mg, 3.39 mmol) 1,4-dioxane (5mL). The solution was stirred at 110ºC for 16 h. The solution was diluted with EtOAc, washed with sat. aq. NaHCO₃ and brine. The organic layers were combined, dried over MgSO₄, filtered and concentrated in vacuo. The residue purified by silica gel chromatography (0%-90% heptane/EtOAc). The desired fractions were combined and concentrated in vacuo to afford ethyl (S)-5-(4-(difluoro(phenyl)methyl)phenyl)-7-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrazine-3-carboxylate (538 mg, 63% yield) as a yellowish solid.1H NMR (300 MHz, DMSO- d₆) δ: 7.98 (s, 1H), 7.61 – 7.50 (m, 9H), 4.79 (dd, J = 10.7, 7.1 Hz, 1H), 4.33 (dd, J = 13.1, 4.1 Hz, 1H), 4.21 (q, J = 7.1Hz, 2H), 4.05 (dd, J = 13.0, 7.5 Hz, 1H), 1.54 (d, J = 6.5 Hz, 3H), 1.27 – 1.19 (m, 3H).Mass spectrum (ESI, m/z): calcd. for C₂₃H₂₁F₂N₃O₃, 425.2; found [M+H]+, 426.1. Step C: (S)-5-(4-(difluoro(phenyl)methyl)phenyl)-7-methyl-4-oxo-4,5,6,7- tetrahydropyrazolo a]pyrazine-3-carboxylic acid

LiOH (4.4 mL, 8.8 mmol, 2M) was added to a solution of ethyl (S)-5-(4- (difluoro(phenyl)methyl)phenyl)-7-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3- carboxylate (260 mg, 0.58 mmol) in EtOH (20 mL). The mixture was stirred at rt for 15 min. The mixture was concentrated in vacuo to yield (S)-5-(4-(difluoro(phenyl)methyl)phenyl)-7- methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxylic acid (212 mg, 85% yield) as a yellowish oil.1H NMR (300 MHz, DMSO-d6) δ: 8.15 (s, 1H), 7.58 – 7.49 (m, 9H), 4.96 – 4.84 (m, 1H), 4.40 (dd, J = 13.0, 4.5 Hz, 1H), 4.16 (dd, J = 12.9, 8.3 Hz, 1H), 1.58 (d, J = 6.5 Hz, 3H). Mass spectrum (ESI, m/z): calcd. for C₂₁H₁₇F₂N₃O₃, 397.1; found [M+H]+, 398.0. Intermediate 18: (S)-7-methyl-4-oxo-5-(4-(trifluoromethoxy)phenyl)-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxylic acid

Step A: ethyl (S)-7-methyl-4-oxo-5-(4-(trifluoromethoxy)phenyl)-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxylate The title compound was prepared in a manner analogous to Intermediate 17, Step B, reacting ethyl (S)-7-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxylate (736 mg, 2.21 mmol) and 1-bromo-4-(trifluoromethoxy)benzene (0.357 mL, 2.40 mmol).1H NMR (300 MHz, DMSO-d6) δ: 1.24 (t, J=7.10 Hz, 3H) 1.55 (d, J=6.54 Hz, 3H) 4.04 (dd, J=1.00 Hz, 1H) 4.21 (q, J=7.16 Hz, 2H) 4.31 (dd, J=1.00 Hz, 1H) 4.75 - 4.85 (m, 1H) 7.43 - 7.49 (m, 2H) 7.54 - 7.57 (m, 1H) 7.57 - 7.59 (m, 1H) 7.98 (s, 1H). Mass spectrum (ESI, m/z): calcd. for C17H16F3N3O4, 383.1; found [M+H]+, 384.2. Step B: (S)-7-methyl-4-oxo-5-(4-(trifluoromethoxy)phenyl)-4,5,6,7-tetrahydro-pyrazolo[1,5- a]pyrazine-3-carboxylic acid HCl aqueous solution (9.2 mL, 18.4 mmol, 2M) was added to a solution of (S)-7-methyl-4-oxo- 5-(4-(trifluoromethoxy)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxylate (560 mg, 1.23 mmol) in EtOH (56 mL). The mixture was stirred at 60ºC for 16 hr. The mixture was extracted with DCM and the organic phase was dried over MgSO4, filtered and concentrated in vacuo to yield (S)-7-methyl-4-oxo-5-(4-(trifluoromethoxy)phenyl)-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxylic acid (539 mg, 74% yield) as a yellow solid.1H NMR (300 MHz, DMSO-d6) δ: 1.59 (d, J=6.54 Hz, 3H) 4.18 (dd, J=1.00 Hz, 1H) 4.38 (dd, J=12.96, 4.57 Hz, 1H) 4.91 (m, J=7.96, 6.48, 4.69 Hz, 1H) 7.50 - 7.55 (m, 2H) 7.62 - 7.68 (m, 2H) 8.16 (s, 1H). Mass spectrum (ESI, m/z): calcd. for C + 15H12F3N3O4, 355.1; found [M+H] , 355.9. Intermediate 19: (S)-3-amino-7-methyl-5-(4-(trifluoromethoxy)phenyl)-6,7- dihydropyrazolo[1,5-a]pyrazin-4(5H)-one hydrochloride.

Step A: tert-butyl (S)-(7-methyl-4-oxo-5-(4-(trifluoromethoxy)phenyl)-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazin-3-yl)carbamate. A mixture of (S)-7-methyl-4-oxo-5-(4-(trifluoromethoxy)phenyl)-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxylic acid (Intermediate 18, 140 mg, 0.236 mmol), DPPA (113 µL, 0.524 mmol), TEA (906 µL, 6.5 mmol), 1,4-dioxane (9 mL) and tert-butanol anhydrous (2.8 mL) was stirred under nitrogen at 110ºC for 16 h. The reaction progress was monitored by LC-MS. The mixture was cooled to room temperature, then diluted with ethylacetate and washed with water. The organic layer was dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (0-60% heptane/EtOAc) to afford tert-butyl (S)-(7-methyl-4-oxo-5-(4-(trifluoromethoxy)phenyl)-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazin-3-yl)carbamate (20 mg, 19% yield).1H NMR (300 MHz, DMSO-d6) δ: 1.46 (s, 9H) 1.52 (d, J=6.42 Hz, 3H) 4.01 (dd, J=12.84, 8.27 Hz, 1H) 4.24 (dd, J=12.78, 4.26 Hz, 1H) 4.67 (m, J=7.99, 6.51, 4.26 Hz, 1H) 7.42 - 7.50 (m, 2H) 7.53 - 7.62 (m, 2H) 7.84 (br s, 1H) 8.04 (br s, 1H). Mass spectrum (ESI, m/z): calcd. for C₁₉H₂₁F₃N₄O₄, 426.2; found [M+H]+, 427.2. Step B: (S)-3-amino-7-methyl-5-(4-(trifluoromethoxy)phenyl)-6,7-dihydropyrazolo[1,5- a]pyrazin-4(5H)-one hydrochloride. HCl in dioxane (0.48 mL, 4 M, 1.9 mmol) was added to a solution of tert-butyl (S)-(7-methyl-4- oxo-5-(4-(trifluoromethoxy)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)carbamate (54 mg, 0.127 mmol) in DCM (1 mL) and the mixture was stirred at rt for 16 h. The mixture was concentrated to dry in vacuo to afford (S)-3-amino-7-methyl-5-(4-(trifluoromethoxy)phenyl)- 6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one hydrochloride (50 mg, 94% yield) as a white solid. 1H NMR (300 MHz, DMSO-d₆) δ: 1.48 (d, J=6.42 Hz, 3H) 3.97 (dd, J=12.72, 8.15 Hz, 2H) 4.20 (dd, J=12.72, 4.20 Hz, 2H) 4.55 - 4.66 (m, 1H) 7.34 (s, 1H) 7.41 - 7.46 (m, 2H) 7.51 - 7.55 (m, 2H). Mass spectrum (ESI, m/z): calcd. for C₁₄H₁₃F₃N₄O₂, 326.1; found [M+H]+, 327.0. Intermediate 20: -3-amino-6,7-dimethyl-5-(4-(trifluoromethyl)phenyl)-6,7-

dihydropyrazolo[1,5-a]pyrazin-4(5H)-one.

Step A: benzyl dibenzyl-L-alaninate. Benzyl bromide (160 mL, 1347.1 mmol) was added to a suspension of L-Alanine (20 g, 224.5 mmol) and K2CO3 (186.2 g, 1347.2 mmol) in EtOH (600 mL) and water (120 mL), and the mixture was stirred at 85ºC for 16h. Water was added to the mixture and it was extracted with EtOAc (x3). The organic layers were joined and dried over MgSO4 anh., filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (0-60% heptane/EtOAc) to afford benzyl dibenzyl-L-alaninate (80 g, 56% pure, 55% yield) as a colourless oil.1H NMR (300 MHz, DMSO-d6) δ: 1.27 (d, J=7.16 Hz, 3H) 3.47 - 3.51 (m, 1H) 3.53 - 3.77 (m, 4H) 5.09 - 5.25 (m, 2H) 7.18 - 7.44 (m, 15H). Mass spectrum (ESI, m/z): calcd. for C₂₄H₂₅NO₂, 359.2; found [M+H]+, 360.1. Step B: (S)-2-(dibenzylamino)propan-1-ol. LiAlH4 (6.3 g, 167 mmol) was added portionwise to a solution of benzyl dibenzyl-L-alaninate (40 g, 111.3 mmol) and diethylether (300 mL) at 0ºC under nitrogen. The mixture was stirred for 30 min at 0ºC. Then, NaHCO3 (aq) was added dropwised at 0ºC to the reaction mixture and the mixture was filtered over a pad of celite. The organic solvents were evaporated in vacuo and the residue was extracted with DCM (x3). The organic layers were combined, dried over MgSO₄ anh. and filtered. The solvent was evaporated in vacuo and the residue was purified by silica gel chromatography (0-30% heptane/EtOAc) to afford (S)-2-(dibenzylamino)propan-1-ol (19.1 g, 67% yield) as a colorless oil.1H NMR (400 MHz, DMSO-d₆) δ: 1.00 (d, J=6.77 Hz, 3H) 2.71 (q, J=6.48 Hz, 1H) 3.34 - 3.38 (m, 1H) 3.50 (d, J=14.02 Hz, 2H) 3.53 - 3.59 (m, 1H) 3.66 (d, J=14.02 Hz, 2H) 4.31 (dd, J=6.20, 4.29 Hz, 1H) 7.20 (t, J=1.00 Hz, 2H) 7.29 (t, J=7.49 Hz, 4H) 7.36 (d, J=1.00 Hz, 4H). Mass spectrum (ESI, m/z): calcd. for C H NO, 255.2; fo + 17 21 und [M+H] , 256.0. Step C: (S)-2-(dibenzylamino)propanal. Oxalyl chloride (6.7 mL, 78.5 mmol) was added dropwise during 15 min. to a stirred solution of DMSO (10.9 mL, 153.3 mmol) in DCM (150 mL) at -78ºC, then the mixture was stirred for 5 min. A solution of (S)-2-(dibenzylamino)propan-1-ol (10 g, 38.8 mmol) in DCM (10 mL) was added and the reaction mixture was stirred at -78ºC for 1 h. Triethylamine (32.2 mL, 232.1 mmol) was added. The reaction mixture was warmed at rt and the solution was stirred for 1 h. The reaction mixture was diluted with dichloromethane (100 mL) and washed with water (x4). The organic layer was dried over MgSO4 anh., filtered and concentrated in vacuo to yield (S)-2- (dibenzylamino)-propanal (8.6 g, 87% yield) as a yellowish oil.1H NMR (300 MHz, DMSO-d₆) δ: 1.12 (d, J=1.00 Hz, 3H) 3.24 - 3.30 (m, 1H) 3.56 - 3.69 (m, 4H) 7.25 (t, J=1.00 Hz, 2H) 7.33 (t, J=1.00 Hz, 4H) 7.41 (d, J=1.00 Hz, 4H) 9.63 (s, 1H). Mass spectrum (ESI, m/z): calcd. for C H NO, 253. + 17 19 2; found [M+H] , 254.2. Step D: (2R,3S)-3-(dibenzylamino)butan-2-ol and (2S,3S)-3-(dibenzylamino)butan-2-ol A previously cooled solution of (S)-2-(dibenzylamino)propanal (8.6 g, 34 mmol) in diethylether (30 mL) was added dropwise to a methylmagnesium iodide solution in diethyeter (28.2 mL, 85 mmol, 3M), under nitrogen at 0ºC. The mixture was stirred for 2 h at 0ºC under nitrogen. Ammonium chloride sat. solution was added dropwise to the mixture keeping the temperature below 10ºC, and the mixture was extracted with diethyl ether (x3). The combined organic layers were separated, dried over MgSO₄, filtered and the solvent was reduced in vacuo. The residue was purified by silica gel chromatography (0-20% heptane/EtOAc) to afford (2R,3S)-3- (dibenzylamino)butan-2-ol (5.31 g, 57% yield) as a white solid.1H NMR (300 MHz, DMSO-d6) δ: 1.03 (d, J=1.00 Hz, 3H) 1.09 (d, J=1.00 Hz, 3H) 2.24 - 2.35 (m, 1H) 3.39 (s, 2H) 3.65 (br d, J=13.83 Hz, 3H) 4.33 (d, J=1.00 Hz, 1H) 7.16 - 7.24 (m, 2H) 7.27 - 7.38 (m, 8H). Mass spectrum (ESI, m/z): calcd. for C + 18H23NO, 269.2; found [M+H] , 270.2. And (2S,3S)-3-(dibenzylamino)butan-2-ol (686 mg, 7% yield) as a yellowish solid.1H NMR (300 MHz, DMSO-d₆) δ: 0.98 (dd, J=1.00 Hz, 6H) 2.36 (q, J=1.00 Hz, 1H) 3.34 (br s, 2H) 3.59 (q, J=1.00 Hz, 1H) 3.79 (d, J=1.00 Hz, 2H) 4.18 (d, J=1.60 Hz, 1H) 7.19 - 7.25 (m, 2H) 7.28 - 7.36 (m, 8H). Mass spectrum (ESI, m/z): calcd. for C + 18H23NO, 269.2; found [M+H] , 270.2. Step E: ethyl 1-((2S,3S)-3-(dibenzylamino)butan-2-yl)-1H-pyrazole-5-carboxylate DIAD [2446-83-5] (1.2 mL, 6.2 mmol) was added at 0ºC to a stirred solution of ethyl 3- pyrazolecarboxylate (472 mg, 3.4 mmol), (2R,3S)-3-(dibenzylamino)butan-2-ol (1 g, 3.7 mmol) and triphenylphosfine (1.6 g, 6.1 mmol) in THF anhydrous (50 mL). The reaction mixture was stirred at room temperature for 16 h. Water was added and the mixture was extracted with EtOAc (x3). The combined organic layer was driedover MgSO₄ anh., filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (0-80% heptane/EtOAc) to afford ethyl 1-((2S,3S)-3-(dibenzylamino)butan-2-yl)-1H-pyrazole-5-carboxylate (825 mg, 50% yield) as a white solid.1H NMR (300 MHz, DMSO-d₆) δ: 0.53 (d, J=6.67 Hz, 3H) 1.27 (t, J=1.00 Hz, 3H) 1.45 (d, J=6.54 Hz, 3H) 2.95 - 3.08 (m, 1H) 3.38 (s, 2H) 3.71 - 3.78 (m, 2H) 4.28 (q, J=7.16 Hz, 2H) 5.48 (dd, J=9.94, 6.60 Hz, 1H) 6.80 - 6.82 (m, 1H) 7.23 - 7.30 (m, 2H) 7.32 - 7.41 (m, 7H) 7.53 (d, J=1.98 Hz, 1H) Mass spectrum (ESI, m/z): calcd. for C₂₄H₂₉N₃O₂, 391.2; found [M+H]+, 392.3. Step F: (6S,7S)-6,7-dimethyl-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one Palladium on carbon (640 mg, 0.6 mmol, 10%) was added to a solution of ethyl 1-((2S,3S)-3- (dibenzylamino)butan-2-yl)-1H-pyrazole-5-carboxylate (825 mg, 1.7 mmol) in methanol (15 mL) at rt under nitrogen atmosphere. Then, the reaction mixture was stirred for 16h at rt under hydrogen atmosphere. The reaction mixture was filtered through a pad of celite, washed with DCM and concentrated in vacuo. The residue was purified by silica gel chromatography (0-70% heptane/EtOAc) to afford (6S,7S)-6,7-dimethyl-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (278 mg, 99% yield) as a colorless oil.1H NMR (300 MHz, DMSO-d6) δ: 1.13 (d, J=1.00 Hz, 3H) 1.24 (d, J=6.67 Hz, 3H) 4.03 (m, J=7.04 Hz, 1H) 4.45 - 4.56 (m, 1H) 6.70 (d, J=1.00 Hz, 1H) 7.56 (d, J=1.00 Hz, 1H) 8.11 (s, 1H). Mass spectrum (ESI, m/z): calcd. for C8H11N3O, 165.1; found [M+H]+, 166.2. Step G: (6S,7S)-6,7-dimethyl-5-(4-(trifluoromethyl)phenyl)-6,7-dihydropyrazolo[1,5-a]pyrazin- 4(5H)-one. CuI (180 mg, 0.95 mmol) was added to a solution of (6S,7S)-6,7-dimethyl-6,7- dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (269 mg, 1.63 mmol), 4-bromobenzotrifluoride (440 μL, 3.11 mmol), N,N'-dimethylethylenediamine (170 μL, 1.58 mmol) and K2CO3 (628 mg, 4.54 mmol) in toluene (13 mL) and DMF (3.3 mL) in a sealed reactor under nitrogen. The solution was stirred at 100ºC for 16 h. The mixture was diluted with water and extracted with EtOAc. The organic layer was separated, dried (MgSO4), filtered and the solvents evaporated in vacuo. The residue was purified by silica gel chromatography (0-20% heptane/EtOAc) to afford (6S,7S)-6,7- dimethyl-5-(4-(trifluoromethyl)phenyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (330 mg, 66% yield) as a white solid.1H NMR (300 MHz, DMSO-d6) δ: 7.84 (d, J = 8.5 Hz, 2H), 7.70 (d, J = 8.3 Hz, 2H), 7.65 (d, J = 2.0 Hz, 1H), 6.90 (d, J = 2.0 Hz, 1H), 4.97 (qd, J = 6.7, 4.0 Hz, 1H), 4.45 (qd, J = 6.7, 4.0 Hz, 1H), 1.55 (d, J = 6.7 Hz, 3H), 1.04 (d, J = 6.7 Hz, 3H). Mass spectrum (ESI, m/z): calcd. for C + 15H14F3N3O, 309.1; found [M+Na] , 332.1. Step H: (6S,7S)-3-iodo-6,7-dimethyl-5-(4-(trifluoromethyl)phenyl)-6,7-dihydropyrazolo[1,5- a]pyrazin-4(5H)-one. Iodine (180 mg, 0.71 mmol) was added to a solution of (6S,7S)-6,7-dimethyl-5-(4- (trifluoromethyl)phenyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (300 mg, 0.97 mmol) and ammonium cerium (IV) nitrate (375 mg, 0.68 mmol) in CH₃CN (5 mL). The mixture was stirred at 70ºC for 1 h. The reaction mixture was diluted with EtOAC and washed with sat. Na2S2O3 aqueous solution. The organic layer was washed with brine, dried over MgSO4 (anh.), filtered and concentrated in vacuo to afford (6S,7S)-3-iodo-6,7-dimethyl-5-(4- (trifluoromethyl)phenyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (510 mg, 100% yield) as a yellowish solid.1H NMR (400 MHz, DMSO-d6) δ: 7.84 (d, J = 8.4 Hz, 2H), 7.78 (s, 1H), 7.69 (d, J = 8.3 Hz, 2H), 5.00 (qd, J = 6.7, 4.0 Hz, 1H), 4.46 (qd, J = 6.7, 4.0 Hz, 1H), 1.51 (d, J = 6.7 Hz, 3H), 1.04 (d, J = 6.7 Hz, 3H). Mass spectrum (ESI, m/z): calcd. for C15H13F3IN3O, 435.1; found [M+Na]+, 458.0. Step I: tert-butyl ((6S,7S)-6,7-dimethyl-4-oxo-5-(4-(trifluoromethyl)phenyl)-4,5,6,7- tetrahydropyrazolo a]pyrazin-3-yl)carbamate.

Copper (I) iodide (29 mg, 0.15 mmol) was added to a stirred suspension of (6S,7S)-3-iodo-6,7- dimethyl-5-(4-(trifluoromethyl)phenyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (450 mg, 1.03 mmol), tert-butyl carbamate (206 mg, 1.76 mmol), (±)-trans-1,2-diaminocyclohexane (18 uL, 0.15 mmol) and K3PO4 (615 mg, 2.90 mmol) in 1,4-dioxane (5 mL) at rt under nitrogen. The mixture was stirred at 120ºC for 16 h. Water was added and the mixture wasextracted with EtOAc (x3). The organic layers were combined, dried over MgSO₄ anh., filtered and the solvent reduced in vacuo. The residue was purified by silica gel chromatography (0-100% heptane/EtOAc) to afford tert-butyl ((6S,7S)-6,7-dimethyl-4-oxo-5-(4-(trifluoromethyl)phenyl)- 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)carbamate (266 mg, 41% yield) as a yellow solid. 1H NMR (300 MHz, DMSO-d6) δ: 1.02 - 1.09 (m, 3H) 1.47 (s, 9H) 1.50 - 1.55 (m, 3H) 4.41 - 4.51 (m, 1H) 4.84 - 4.94 (m, 1H) 6.11 (br s, 1H) 7.66 - 7.76 (m, 2H) 7.82 - 7.88 (m, 2H) 8.02 (br s, 1H). Mass spectrum (ESI, m/z): calcd. for C₂₀H₂₃F₃N₄O, 424.2; found [M+H]+, 425.3. Step J: (6S,7S)-3-amino-6,7-dimethyl-5-(4-(trifluoromethyl)phenyl)-6,7-dihydro-pyrazolo[1,5- a]pyrazin-4(5H)-one. HCl in dioxane (2.3 mL, 4 M, 9.4 mmol) was added to a solution of tert-butyl ((6S,7S)-6,7- dimethyl-4-oxo-5-(4-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3- yl)carbamate (266 mg, 0.627 mmol) in DCM (3mL) and the mixture was stirred at rt for 72 h. Then, Na₂CO₃ was added until pH = 7 and the reaction mixture was filtered and rinsed with DCM. The residue was purified by silica gel chromatography (0-100% heptane/EtOAc) to afford (6S,7S)-3-amino-6,7-dimethyl-5-(4-(trifluoromethyl)phenyl)-6,7-dihydropyrazolo[1,5-a]pyrazin- 4(5H)-one (63 mg, 28% yield) as a yellow solid.1H NMR (300 MHz, DMSO-d₆) δ: 1.07 (d, J=6.54 Hz, 3H) 1.47 (d, J=6.67 Hz, 3H) 4.31 - 4.41 (m, 1H) 4.62 - 4.74 (m, 1H) 4.91 (s, 2H) 7.09 (s, 1H) 7.67 (m, J=8.39 Hz, 2H) 7.75 - 7.82 (m, 2H). Mass spectrum (ESI, m/z): calcd. for C₁₅H₁₅F₃N₄O, 324.1; found [M+H]+, 325.2. Intermediate 21: -3-amino-5-(4-(difluoro(phenyl)methyl)phenyl)-6,7-dimethyl-6,7-

dihydropyrazolo[1,5-a]pyrazin-4(5H)-one.

Step A: (6S,7S)-5-(4-(difluoro(phenyl)methyl)phenyl)-6,7-dimethyl-6,7-dihydropyrazolo[1,5- a]pyrazin-4(5H)-one The title compound was prepared in a manner analogous to Intermediate 20, Step G, reacting (6S,7S)-6,7-dimethyl-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (275 mg, 1.66 mmol) and 1- bromo-4-(difluoro(phenyl)methyl)benzene (899 mg, 3.17 mmol).1H NMR (300 MHz, DMSO- d₆) δ: 1.02 (d, J=6.67 Hz, 3H) 1.54 (d, J=6.79 Hz, 3H) 4.46 (s, 1H) 4.89 - 5.01 (m, 1H) 6.88 (d, J=1.98 Hz, 1H) 7.50 - 7.67 (m, 10H). Mass spectrum (ESI, m/z): calcd. for C₂₁H₁₉F₂N₃O, 367.1; found [M+H]+, 368.1. Step B: (6S,7S)-5-(4-(difluoro(phenyl)methyl)phenyl)-3-iodo-6,7-dimethyl-6,7- dihydropyrazolo a]pyrazin-4(5H)-one

The title compound was prepared in a manner analogous to Intermediate 20, Step H, reacting (6S,7S)-5-(4-(difluoro(phenyl)methyl)phenyl)-6,7-dimethyl-6,7-dihydropyrazolo[1,5-a]pyrazin- 4(5H)-one (570 mg, 1.55 mmol).1H NMR (300 MHz, DMSO-d6) δ: 7.83 (d, J = 8.6 Hz, 2H), 7.80 – 7.74 (m, 3H), 7.68 – 7.55 (m, 5H), 5.01 (dd, J = 6.7, 3.8 Hz, 1H), 4.49 (dd, J = 6.7, 3.9 Hz, 1H), 1.53 (d, J = 6.7 Hz, 3H), 1.08 (d, J = 6.7 Hz, 3H). Mass spectrum (ESI, m/z): calcd. for C H F IN O, 493.1; foun + 21 18 2 3 d [M+Na] , 516.0. Step C: tert-butyl ((6S,7S)-5-(4-(difluoro(phenyl)methyl)phenyl)-6,7-dimethyl-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazin-3-yl)carbamate The title compound was prepared in a manner analogous to Intermediate 20, Step I, reacting (6S,7S)-5-(4-(difluoro(phenyl)methyl)phenyl)-3-iodo-6,7-dimethyl-6,7-dihydropyrazolo[1,5- a]pyrazin-4(5H)-one (72 mg, 0.146 mmol).1H NMR (300 MHz, DMSO-d6) δ: 1.04 (d, J=6.67 Hz, 3H) 1.46 (s, 9H) 1.51 (d, J=6.67 Hz, 3H) 4.34 - 4.45 (m, 1H) 4.87 (m, 1H) 7.51 -7.63 (m, 9H) 7.83 (br s, 1H) 8.01 (br s, 1H). Mass spectrum (ESI, m/z): calcd. for C₂₆H₂₈F₂N₄O₃, 482.2; found [M+Na]+, 505.0. Step D: (6S,7S)-3-amino-5-(4-(difluoro(phenyl)methyl)phenyl)-6,7-dimethyl-6,7- dihydropyrazolo[1,5-a]pyrazin-4(5H)-one The title compound was prepared in a manner analogous to Intermediate 11, Step C, reacting tert-butyl ((6S,7S)-5-(4-(difluoro(phenyl)methyl)phenyl)-6,7-dimethyl-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazin-3-yl)carbamate (40 mg, 0.083 mmol).1H NMR (300 MHz, DMSO-d₆) δ: 1.05 (d, J=6.42 Hz, 3H) 1.47 (d, J=6.54 Hz, 3H) 4.26 - 4.35 (m, 1H) 4.62 - 4.78 (m, 1H) 7.17 (br s, 1H) 7.56 (m, J=8.15, 4.81 Hz, 9H). Mass spectrum (ESI, m/z): calcd. for C₂₁H₂₀F₂N₄O, 382.2; found [M+NH]+, 383.0. Intermediate 22: -3-amino-5-(4-(difluoro(phenyl)methyl)phenyl)-6,7-dimethyl-6,7-

dihydropyrazolo[1,5-a]pyrazin-4(5H)-one.

Step A: benzyl dibenzyl-D-alaninate. The title compound was prepared in a manner analogous to Intermediate 20, Step A, reacting D- alanine (5.0, 56.1 mmol).1H NMR (300 MHz, DMSO-d₆) δ: 1.28 (d, J=7.04 Hz, 3H) 3.46 - 3.52 (m, 1H) 3.53 - 3.61 (m, 2H) 3.69 - 3.78 (m, 2H) 5.10 - 5.25 (m, 2H) 7.27 - 7.34 (m, 10H) 7.37 - 7.45 (m, 5H).Mass spectrum (ESI, m/z): calcd. for C H NO , 359.2; f + 24 25 2 ound [M+H] , 360.1. Step B: (R)-2-(dibenzylamino)propan-1-ol. The title compound was prepared in a manner analogous to Intermediate 20, Step B, reacting benzyl dibenzyl-D-alaninate (78.4 g, 218.1 mmol).1H NMR (300 MHz, DMSO-d₆) δ: 1.01 (d, J=6.67 Hz, 3H) 2.72 (sxt, J=6.62 Hz, 1H) 3.51 (s, 2H) 3.59 - 3.70 (m, 2H) 4.33 (dd, J=6.30, 4.32 Hz, 1H) 7.20 - 7.25 (m, 2H) 7.31 - 7.33 (m, 4H) 7.35 - 7.40 (m, 4H). Mass spectrum (ESI, m/z): calcd. for C₁₇H₂₁NO, 255.2; found [M+H]+, 256.1. Step C: (R)-2-(dibenzylamino)propanal. The title compound was prepared in a manner analogous to Intermediate 20, Step C, reacting (R)-2-(dibenzylamino)propan-1-ol (10.0, 39.2 mmol).1H NMR (300 MHz, DMSO-d₆) δ: 1.10 - 1.13 (m, 3H) 3.08 (m, J=2.59 Hz, 1H) 3.60 - 3.65 (m, 4H) 7.21 - 7.28 (m, 2H) 7.30 - 7.36 (m, 4H) 7.40 (s, 4H) 9.63 (s, 1H) Mass spectrum (ESI, m/z): calcd. for C17H19NO, 253.2; found [M+H]+, 254.2. Step D: (2S,3R)-3-(dibenzylamino)butan-2-ol and (2R,3R)-3-(dibenzylamino)butan-2-ol A previously cooled solution of (R)-2-(dibenzylamino)propanal (5.0 g, 19.7 mmol) in diethylether (15 mL) was added dropwise to a mixture of methylmagnesium iodide solution in diethyeter (16.4 mL, 49.3 mmol, 3M) and diethylether (7.5 mL), under nitrogen at 0ºC. The mixture was stirred for 2 h at 0ºC under nitrogen. Ammonium chloride sat. solution was added dropwise to the mixture keeping the temperature below 10ºC, and the mixture was extracted with diethyl ether (x3). The combined organic layers were separated, dried over MgSO₄, filtered and the solvent was reduced in vacuo. The residue was purified by silica gel chromatography (0-20% heptane/EtOAc) to afford (2S,3R)-3-(dibenzylamino)butan-2-ol (3.5 g, 57% yield) as a white solid.1H NMR (300 MHz, DMSO-d₆) δ: 7.38 – 7.27 (m, 8H), 7.25 – 7.17 (m, 2H), 4.34 (d, J = 5.7 Hz, 1H), 3.72 – 3.60 (m, 3H), 3.43 – 3.34 (m, 2H), 2.30 (p, J = 6.6 Hz, 1H), 1.09 (d, J = 6.2 Hz, 3H), 1.04 (d, J = 6.6 Hz, 3H).Mass spectrum (ESI, m/z): calcd. for C18H23NO, 269.2; found [M+H]+, 270.2. And (2R,3R)-3-(dibenzylamino)butan-2-ol (250 mg, 4% yield) as a yellowish oil.1H NMR (300 MHz, DMSO-d₆) δ: 7.36 – 7.27 (m, 8H), 7.22 (m, 2H), 4.19 (s, 1H), 3.79 (d, J = 13.7 Hz, 2H), 3.60 (p, J = 6.4 Hz, 1H), 3.42 –3.31 (m, 4H), 2.37 (p, J = 6.8 Hz, 1H), 0.99 (d, J = 1.9 Hz, 3H), 0.97 (d, J = 1.2 Hz, 3H).Mass spectrum (ESI, m/z): calcd. for C + 18H23NO, 269.2; found [M+H] , 270.2. Step E: ethyl 1-((2R,3R)-3-(dibenzylamino)butan-2-yl)-1H-pyrazole-5-carboxylate The title compound was prepared in a manner analogous to Intermediate 20, Step E, reacting (2S,3R)-3-(dibenzylamino)butan-2-ol (3.88 g, 14.4 mmol).1H NMR (300 MHz, DMSO-d₆) δ:7.53 (d, J = 1.9 Hz, 1H), 7.38 (t, J = 6.4 Hz, 8H), 7.28 (dd, J = 6.0, 2.5 Hz, 2H), 6.81 (d, J = 2.0 Hz, 1H), 5.55 – 5.41 (m, 1H), 4.26 (dd, J = 8.3, 5.8 Hz, 2H), 3.75 (d, J = 13.8 Hz, 2H), 3.40 (s, 2H), 3.02 (dq, J = 13.1, 6.5 Hz, 1H), 1.45 (d, J = 6.5 Hz, 3H), 1.26 (d, J = 7.0 Hz, 3H), 0.52 (d, J = 6.6 Hz, 3H). Mass spectrum (ESI, m/z): calcd. for C₂₄H₂₉N₃O₂, 391.2; found [M+H]+, 392.2. Step F: (6R,7R)-6,7-dimethyl-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one The title compound was prepared in a manner analogous to Intermediate 20, Step F, reacting ethyl 1-((2R,3R)-3-(dibenzylamino)butan-2-yl)-1H-pyrazole-5-carboxylate (4.61 g, 9.42 mmol). 1H NMR (300 MHz, DMSO-d6) δ: 8.12 (s, 1H), 7.55 (d, J = 2.0 Hz, 1H), 6.70 (d, J = 2.0 Hz, 1H), 4.51 (qd, J = 6.7, 4.4 Hz, 1H), 4.08 – 3.94 (m, 1H), 1.24 (d, J = 6.7 Hz, 3H), 1.13 (d, J = 6.8 Hz, 3H). Mass spectrum (ESI, m/z): calcd. for C₈H₁₁N₃O, 165.1; found [M+Na]+, 188.1. Step G: (6R,7R)-5-(4-(difluoro(phenyl)methyl)phenyl)-6,7-dimethyl-6,7-dihydropyrazolo[1,5- a]pyrazin-4(5H)-one The title compound was prepared in a manner analogous to Intermediate 20, Step G, reacting (6R,7R)-6,7-dimethyl-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one, (550 mg, 3.33 mmol) and 1-bromo-4-(difluoro(phenyl)methyl)benzene (1.79 g, 6.35 mmol).1H NMR (400 MHz, DMSO- d₆) δ: 1.01 (d, J=6.77 Hz, 3H) 1.54 (d, J=6.77 Hz, 3H) 4.38 (m, J=6.63, 6.63, 6.63, 4.05 Hz, 1H) 4.95 (m, J=6.66, 6.66, 6.66, 4.05 Hz, 1H) 6.87 (d, J=2.00 Hz, 1H) 7.51 - 7.54 (m, 3H) 7.55 - 7.59 (m, 4H) 7.61 (s, 1H) 7.62 - 7.64 (m, 2H)Mass spectrum (ESI, m/z): calcd. for C21H19F2N3O, 367.1; found [M+H]+, 368.1. Step H: (6R,7R)-5-(4-(difluoro(phenyl)methyl)phenyl)-3-iodo-6,7-dimethyl-6,7-dihydro- pyrazolo[1,5-a]pyrazin-4(5H)-one The title compound was prepared in a manner analogous to Intermediate 20, Step H, reacting (6R,7R)-5-(4-(difluoro(phenyl)methyl)phenyl)-6,7-dimethyl-6,7-dihydropyrazolo[1,5-a]pyrazin- 4(5H)-one (500 mg, 1.36 mmol).1H NMR (400 MHz, DMSO-d6) δ: 1.02 (d, J=6.77 Hz, 3H) 1.50 (d, J=6.68 Hz, 3H) 4.39 (m, 1H) 4.98 (m, 1H) 7.51 - 7.54 (m, 3H) 7.54 -7.59 (m, 4H) 7.60 - 7.64 (m, 2H) 7.76 (s, 1H) Mass spectrum (ESI, m/z): calcd. for C21H18F2IN3O, 493.1; found [M+H]+, 493.9. Step I: tert-butyl ((6R,7R)-5-(4-(difluoro(phenyl)methyl)phenyl)-6,7-dimethyl-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazin-3-yl)carbamate The title compound was prepared in a manner analogous to Intermediate 20, Step I, reacting (6R,7R)-5-(4-(difluoro(phenyl)methyl)phenyl)-3-iodo-6,7-dimethyl-6,7-dihydropyrazolo[1,5- a]pyrazin-4(5H)-one (326 mg, 0.661 mmol).1H NMR (300 MHz, DMSO-d6) δ: 1.04 (d, J=6.68 Hz, 3H) 1.36 (s, 9H) 1.51 (d, J=4.29 Hz, 3H) 4.34 -4.43 (m, 1H) 4.82 - 4.91 (m, 1H) 7.51 - 7.54 (m, 3H) 7.55 - 7.59 (m, 4H) 7.61 (s, 2H) 7.76 (s, 1H) 8.00 (br s, 1H). Mass spectrum (ESI, m/z): calcd. for C₂₆H₂₈F₂N₄O₃, 482.2; found [M+H]+, 483.2. Step J: (6R,7R)-3-amino-5-(4-(difluoro(phenyl)methyl)phenyl)-6,7-dimethyl-6,7- dihydropyrazolo[1,5-a]pyrazin-4(5H)-one The title compound was prepared in a manner analogous to Intermediate 20, Step J, reacting tert- butyl ((6R,7R)-5-(4-(difluoro(phenyl)methyl)phenyl)-6,7-dimethyl-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazin-3-yl)carbamate (253 mg, 0.283 mmol).1H NMR (300 MHz, DMSO-d₆) δ: 1.05 (d, J=6.67 Hz, 3H) 1.46 (d, J=6.67 Hz, 3H) 4.29 (m, 1H) 4.59 - 4.71 (m, 1H) 4.85 (s, 2H) 7.08 (s, 1H) 7.50 - 7.63 (m, 9H). Mass spectrum (ESI, m/z): calcd. for C21H20F2N4O, 382.2; found [M+H]+, 383.0. Intermediate 23: (S)-3-amino-5-(4-(difluoro(phenyl)methyl)phenyl)-7-methyl-6,7- dihydropyrazolo[1,5-a]pyrazin-4(5H)-one hydrochloride.

Step A: tert-butyl (S)-(5-(4-(difluoro(phenyl)methyl)phenyl)-7-methyl-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazin-3-yl)carbamate The title compound was prepared in a manner analogous to Intermediate 19, Step A, reacting (S)-5-(4-(difluoro(phenyl)methyl)phenyl)-7-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrazine-3-carboxylic acid (Intermediate 17, 383 mg, 0.472 mmol).1H NMR (300 MHz, DMSO-d₆) δ: 1.47 (s, 9H) 1.49 - 1.54 (m, 3H) 4.00 - 4.07 (m, 1H) 4.22 - 4.30 (m, 1H) 4.61 - 4.74 (m, 1H) 7.32 - 7.33 (m, 3H) 7.52 - 7.56 (m, 4H) 7.56 - 7.60 (m, 3H) 7.97 - 8.24 (m, 1H). Mass spectrum (ESI, m/z): calcd. for C + 25H26F2N4O3, 468.2; found [M+Na] , 491.0. Step B: (S)-3-amino-5-(4-(difluoro(phenyl)methyl)phenyl)-7-methyl-6,7-dihydropyrazolo[1,5- a]pyrazin-4(5H)-one hydrochloride The title compound was prepared in a manner analogous to Intermediate 19, Step B, reacting tert-butyl (S)-(5-(4-(difluoro(phenyl)methyl)phenyl)-7-methyl-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazin-3-yl)carbamate (42 mg, 0.09 mmol).1H NMR (300 MHz, DMSO-d6) δ: 1.45 (d, J=6.30 Hz, 3H) 3.89 - 3.98 (m, 1H) 4.14 - 4.22 (m, 1H) 4.46 - 4.56 (m, 1H) 7.12 (s, 1H) 7.51 -7.56 (m, 9H). Mass spectrum (ESI, m/z): calcd. for C₂₀H₁₈F₂N₄O, 368.1; found [M+H]+, 369.2. Intermediate 24: 1-bromo-4-((4-chlorophenyl)difluoromethyl)benzene.

Step A: 2-(4-bromophenyl)-2-(4-chlorophenyl)-1,3-dithiane 1,3-Propanedithiol (194 μL, 1.9 mmol) was added to a stirred solution of boron trifluoride etherate (2.5 mL, 20 mmol) in glacial acetic acid (11 mL). Then, (4-bromophenyl)(4- chlorophenyl)methanone (400 mg, 0.9 mmol) was added and the mixture was stirred for 16 h at room temperature. An aq. sat. sol. of NaHCO3 was added until pH was 7. The mixture was extracted with EtOAc (x3), the combined organic extracts were dried over anh. MgSO4, filtered and concentrated in vacuo to yield 2-(4-bromophenyl)-2-(4-chlorophenyl)-1,3-dithiane (640 mg, 99% yield) as a yellowish solid.1H NMR (300 MHz, DMSO-d₆) δ: 1.86 - 1.95 (m, 2H) 2.73 - 2.78 (m, 4H) 7.45 - 7.53 (m, 4H) 7.54 - 7.64 (m, 4H). Mass spectrum (ESI, m/z): calcd. for C H BrClS + 16 14 2, 383.9; found [M+H] , 384.8. Step B: 1-bromo-4-((4-chlorophenyl)difluoromethyl)benzene. The title compound was prepared in a manner analogous to Example 100, Step B, reacting 2-(4- bromophenyl)-2-(4-chlorophenyl)-1,3-dithiane (400 mg, 1.037 mmol).1H NMR (300 MHz, DMSO-d6) δ: 7.45 - 7.50 (m, 2H) 7.51 - 7.60 (m, 4H) 7.68 - 7.74 (m, 2H). Mass spectrum (ESI, m/z): calcd. for C H BrClF , 315 + 13 8 2 .9; found [M+H] , 316.9. Intermediate 25: 3-((4-bromophenyl)difluoromethyl)-5-methoxypyridine.

Step A: (4-bromophenyl)(5-methoxypyridin-3-yl)methanol Isopropylmagnesium chloride lithium chloride complex solution in THF (2.755 mL, 3.58 mmol, 1.3 M) was added dropwise to a stirred solution of 1-bromo-4-iodobenzene (928 mg, 3.28 mmol) in THF (5 mL), at -78ºC under nitrogen. The mixture was stirred at -78ºC for 1 h. Then, 5- methoxpyridine-3-carbaldehyde (500 mg, 3.65 mmol) was added at -78ºC and the mixture was stirred from -78ºC to room temperature for 16 h. Water was added and the mixture was extracted with EtOAc. The combined organic layer washed with brine, dried over MgSO₄ and concentrated in vacuo to afford (4-bromophenyl)(5-methoxypyridin-3-yl)methanol (1.12 g, 74% yield) as a yellow oil. Mass spectrum (ESI, m/z): calcd. for C + 13H12BrNO2, 293.0; found [M+H] , 294.0. Step B: (4-bromophenyl)(5-methoxypyridin-3-yl)methanone Dess-Martin periodinane (1.449 g, 3.42 mmol) was added to a stirred solution of (4- bromophenyl)(5-methoxypyridin-3-yl)methanol (1.12 g, 2.44 mmol) in DCM (7.5 mL) at room temperature. The mixture wasstirred at room temperature for 2 h. Then, water and EtOAc was added. The mixture was extracted with EtOAc (x3). The organic phase was dried over MgSO4 anh., filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (0%-50%, EtOAc/hept) to afford (4-bromophenyl)(5-methoxypyridin-3-yl)methanone (606 mg, 84% yield) as a white solid.1H NMR (300 MHz, DMSO-d6) δ: 3.90 (s, 3H) 7.61 - 7.66 (m, 1H) 7.71 - 7.76 (m, 2H) 7.77 - 7.84 (m, 2H) 8.44 (d, J=1.60 Hz, 1H) 8.56 (d, J=2.84 Hz, 1H). Mass spectrum (ESI, m/z): calcd. for C + 13H10BrNO2, 291.0; found [M+H] , 291.9. Step C: 3-(2-(4-bromophenyl)-1,3-dithian-2-yl)-5-methoxypyridine The title compound was prepared in a manner analogous to Intermediate 24, Step A, reacting (4- bromophenyl)(5-methoxypyridin-3-yl)methanone (250 mg, 0.599 mmol). Mass spectrum (ESI, m/z): calcd. for C H BrNOS , 381 + 16 16 2 .0; found [M+H] , 381.9. Step D: 3-((4-bromophenyl)difluoromethyl)-5-methoxypyridine. Pyridine hydrofluoride (17.959 mL, 199.33 mmol) and a solution of 3-(2-(4-bromophenyl)-1,3- dithian-2-yl)-5-methoxypyridine (1 g, 0.58 mmol) in DCM (5 mL) were added sequentialy to a solution of N-iodosuccinimide (3.753 g, 16.68 mmol) in DCM (20 mL) at -30ºC under nitrogen. The mixture was stirred at -30ºC for 30 min and then allowed to warm to room temperature. The mixture was stirred at room temperature for 16 h. The mixture was diluted with DCM and washed with Na2S2O3 saturated aqueous solution. The organic phase was dried over MgSO₄ anh., filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (0%-50%, EtOAc/hept) to afford 3-((4-bromophenyl)difluoromethyl)-5-methoxypyridine (121 mg, 56% yield) as a brown solid.1H NMR (300 MHz, DMSO-d6) δ: 3.88 (s, 3H) 7.52 - 7.54 (m, 1H) 7.56 (d, J=8.64 Hz, 2H) 7.73 (d, J=8.64 Hz, 2H) 8.32 - 8.35 (m, 1H) 8.44 (d, J=2.72 Hz, 1H). Mass spectrum (ESI, m/z): calcd. for C₁₃H₁₀BrF₂NO, 313.0; found [M+H]+, 313.9. Intermediate 26: 3-cyano-N-((6R*,7S*)-6,7-dimethyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrazin-3-yl)-4-methoxybenzamide.

Step A: rac-(2S,3S)-3-(dibenzylamino)butan-2-ol and rac-(2R,3S)-3-(dibenzylamino)butan-2-ol TiCl4 (4.605 mL, 42 mmol) was dropwise added via syringe to a 500 mL round bottom flask containing diethylether anhydrous (127 mL) at -40ºC. Then, methylmagnesium iodide solution (14 mL, 42 mmol, 3 M), which has been precooled to -20ºC, was added to the mixture. After complete addition, the mixture was stirred for 2 h at -40ºC. Then cooled to -78ºC A previously cooled solution of (R)-2-(dibenzylamino)propanal (Intermediate 22, product from Step C, 4.23 g, 17 mmol) in diethylether (300 mL) was added dropwise. The resulting mixture was stirred at - 78ºC for 16 h. The reaction mixture was then treated with a NaHCO₃ sat. solution dropwise. The organic layer was separated and the aqueous layer was extracted with DCM (30 mL x 3). The organic extracts were combined, dried over anhydrous MgSO4, filtered and concentrated to dryness in vacuo to give a yellowish oil. The crude product was subjected to silica gel chromatography (80 g silica gel; 0-20% EtOAc/Heptane) to afford rac-(2S,3S)-3- (dibenzylamino)butan-2-ol (449 mg, 9% yield) as a yellowish oil.1H NMR (300 MHz, DMSO- d6) δ: 0.98 (m, 6H) 2.29 - 2.43 (m, 1H) 3.37 (d, J=13.70 Hz, 2H) 3.55 - 3.65 (m, 1H) 3.79 (d, J=13.70 Hz, 2H) 4.18 (d, J=1.60 Hz, 1H) 7.19 - 7.26 (m, 2H) 7.30 - 7.35 (m, 8H). Mass spectrum (ESI, m/z): calcd. for C₁₈H₂₃NO, 269.2; found [M+H]+, 270.0 and rac-(2R,3S)-3- (dibenzylamino)butan-2-ol (405 mg, 8% yield) as a white solid.1H NMR (300 MHz, DMSO-d6) δ: 1.01 - 1.06 (m, 3H) 1.09 (d, J=6.17 Hz, 3H) 2.20 - 2.39 (m, 1H) 3.37 (d, J=13.83 Hz, 2H) 3.59 - 3.71 (m, 3H) 4.35 (d, J=5.80 Hz, 1H) 7.18 - 7.26 (m, 2H) 7.28 - 7.39 (m, 8H). Mass spectrum (ESI, m/z): calcd. for C H NO, 269.2; found [M+H]+ 18 23 , 270.0. Step B: rac-ethyl 1-((2R,3S)-3-(dibenzylamino)butan-2-yl)-1H-pyrazole-5-carboxylate The title compound was prepared in a manner analogous to Intermediate 20, Step E, reacting rac- (2S,3S)-3-(dibenzylamino)butan-2-ol (0.449 g, 1.667 mmol).1H NMR (300 MHz, DMSO-d6) δ: 1.11 (m, J=6.94, 3.63, 3.63 Hz, 6H) 1.32 (d, J=6.79 Hz, 3H) 3.07 - 3.21 (m, 1H) 3.25 - 3.31 (m, 2H) 3.62 (d, J=14.32 Hz, 2H) 3.78 - 3.90 (m, 1H) 3.91 - 4.04 (m, 1H) 5.53 - 5.67 (m, 1H) 6.94 (m, J=4.26, 2.04 Hz, 5H) 7.13 - 7.21 (m, 6H) 7.49 (d, J=1.85 Hz, 1H). Mass spectrum (ESI, m/z): calcd. for C H N O , 391.2; found [ + 24 29 3 2 M+H] , 391.9. Step C: (6S*,7R*)-6,7-dimethyl-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one and (6R*,7S*)- 6,7-dimethyl-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one The title compounds were prepared in a manner analogous to Intermediate 20, Step F, reacting rac-ethyl 1-((2R,3S)-3-(dibenzylamino)butan-2-yl)-1H-pyrazole-5-carboxylate (0.345 g, 0.864 mmol). The resulting racemic mixture was then separated by SFC (Phenomenex Lux Cellulose-4 column, 5 µm, 250 x 30 mm; 30% (v/v) iPrOH (containing 0.1% of DEA)/CO2) and then freeze- dried to afford (6S*,7R*)-6,7-dimethyl-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one.1H NMR (300 MHz, DMSO-d6) δ: 1.21 (d, J=6.54 Hz, 3H) 1.46 (d, J=6.42 Hz, 3H) 3.61 (td, J=6.64, 2.28 Hz, 1H) 4.19 (t, J=6.60 Hz, 1H) 6.72 (d, J=1.85 Hz, 1H) 7.57 (d, J=1.85 Hz, 1H) 8.21 (br s, 1H). Mass spectrum (ESI, m/z): calcd. for C₈H₁₁N₃O, 165.1; found [M+H]+, 166.1 and (6R*,7S*)- 6,7-dimethyl-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one.1H NMR (300 MHz, DMSO-d6) δ: 1.21 (d, J=6.54 Hz, 3H) 1.46 (d, J=6.54 Hz, 3H) 3.61 (td, J=6.60, 2.35 Hz, 1H) 4.14 - 4.24 (m, 1H) 6.72 (d, J=1.98 Hz, 1H) 7.57 (d, J=1.98 Hz, 1H) 8.21 (br s, 1H). Mass spectrum (ESI, m/z): calcd. for C H N O, + 8 11 3 165.1; found [M+H] , 166.1. Step D: (6R*,7S*)-3-iodo-6,7-dimethyl-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one The title compound was prepared in a manner analogous to Intermediate 20, Step H, reacting (6R*,7S*)-6,7-dimethyl-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (319 mg, 1.93 mmol).1H NMR (300 MHz, DMSO-d₆) δ: 1.13 (d, J=6.54 Hz, 3H) 1.38 (d, J=6.42 Hz, 3H) 3.54 (m, 1H) 4.11 - 4.21 (m, 1H) 7.55 - 7.69 (m, 1H) 8.22 (s, 1H). Mass spectrum (ESI, m/z): calcd. for C H IN O, 291 + 8 10 3 .0; found [M+H] , 292.1. Step E: 3-cyano-N-((6R*,7S*)-6,7-dimethyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3- yl)-4-methoxybenzamide The title compound was prepared in a manner analogous to Intermediate 13, Step B, reacting (6R*,7S*)-3-iodo-6,7-dimethyl-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (549 mg, 1.886 mmol).1H NMR (300 MHz, DMSO-d₆) δ: 1.19 (br d, J=6.54 Hz, 3H) 1.42 (d, J=6.54 Hz, 3H) 3.61 (m, 1H) 3.94 (s, 3H) 4.10 - 4.17 (m, 1H) 7.37 (d, J=8.89 Hz, 1H) 7.88 (s, 1H) 8.00 (s, 1H) 8.18 (d, J=2.22 Hz, 1H) 8.32 - 8.39 (m, 1H) 9.75 (s, 1H). Mass spectrum (ESI, m/z): calcd. for C₁₇H₁₇N₅O₃, 339.1; found [M+H]+, 340.3. Intermediate 27: 3-cyano-N-((6S*,7R*)-6,7-dimethyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrazin-3-yl)-4-methoxybenzamide.

Step A: (6S*,7R*)-3-iodo-6,7-dimethyl-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one The title compound was prepared in a manner analogous to Intermediate 20, Step H, reacting (6S*,7R*)-6,7-dimethyl-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (345 mg, 2.09 mmol).1H NMR (300 MHz, DMSO-d6) δ: 1.19 (d, J=1.00 Hz, 3H) 1.44 (d, J=6.42 Hz, 3H) 3.57 - 3.64 (m, 1H) 4.22 (q, J=1.00 Hz, 1H) 7.68 (s, 1H) 8.28 (s, 1H). Mass spectrum (ESI, m/z): calcd. for C₈H₁₀IN₃O, 291.0; found [M+H]+, 292.0. Step B: 3-cyano-N-((6S*,7R*)-6,7-dimethyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3- yl)-4-methoxybenzamide. The title compound was prepared in a manner analogous to Intermediate 13, Step B, reacting (6S*,7R*)-3-iodo-6,7-dimethyl-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (606 mg, 2.04 mmol).1H NMR (300 MHz, DMSO-d₆) δ: 1.25 (d, J=1.00 Hz, 3H) 1.48 (d, J=1.00 Hz, 3H) 3.61 (td, J=6.57, 2.41 Hz, 1H) 4.01 (s, 3H) 4.17 - 4.22 (m, 1H) 7.42 - 7.46 (m, 1H) 7.98 - 8.02 (m, 1H) 8.05 - 8.08 (m, 1H) 8.24 (d, J=2.10 Hz, 1H) 8.40 - 8.43 (m, 1H) 9.80 - 9.83 (m, 1H). Mass spectrum (ESI, m/z): calcd. for C₁₇H₁₇N₅O₃, 339.1; found [M+H]+, 340.1. Intermediate 28: (S)-3-amino-5-(4-(4-methoxybenzoyl)phenyl)-6-methyl-6,7- dihydropyrazolo[1,5-a]pyrazin-4(5H)-one.

Step A: (4-bromophenyl)(4-methoxyphenyl)methanone Iodomethane (325 μL, 5.22 mmol) was added to a stirred mixture of 4-(4-bromobenzoyl)phenol (500 mg, 1.71 mmol) and K₂CO₃ (948 mg, 6.86 mmol) in DMF (20 mL) under N₂ atmosphere at rt. The reaction mixture was stirred at rt for 16 h. The reaction mixture was diluted with brine and extracted with EtOAc (x2). The organic layer was dried over MgSO4 (anh.), filtered and the solvents were evaporated in vacuo. The residue was purified by silica gel chromatography (42- 63%, EtOAc/hept) to afford (4-bromophenyl)(4-methoxyphenyl)methanone (340 mg, 68% yield) as a white solid.1H NMR (300 MHz, DMSO-d6) δ: 7.80 – 7.71 (m, 4H), 7.66 – 7.59 (m, 2H), 7.14 – 7.05 (m, 2H), 3.87 (s, 3H). Mass spectrum (ESI, m/z): calcd. for C₁₄H₁₁BrO₂, 290.0; found [M+H]+, 291.0. Step B: ethyl (S)-5-(4-(4-methoxybenzoyl)phenyl)-6-methyl-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxylate The title compound was prepared in a manner analogous to Intermediate 1, Step E, reacting ethyl (S)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxylate (Intermediate 1, product from Step D, 408 mg, 1.825 mmol) and (4-bromophenyl)(4-methoxyphenyl)methanone (600 mg, 2.06 mmol).1H NMR (300 MHz, DMSO-d₆) δ: 8.01 (s, 1H), 7.79 (d, J = 8.5 Hz, 4H), 7.61 (d, J = 8.5 Hz, 2H), 7.16 – 7.08 (m, 2H), 4.85 (dd, J = 13.4, 4.3 Hz, 1H), 4.60 – 4.50 (m, 1H), 4.44 (dd, J = 13.4, 3.2 Hz, 1H), 4.29 – 4.17 (m, 2H), 3.88 (s, 3H), 1.31 – 1.22 (m, 6H). Mass spectrum (ESI, m/z): calcd. for C₂₄H₂₃N₃O₅, 433.2; found [M+Na]+, 456.1. Step C: (S)-5-(4-(4-methoxybenzoyl)phenyl)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrazine-3-carboxylic acid The title compound was prepared in a manner analogous to Intermediate 1, Step F, reacting ethyl (S)-5-(4-(4-methoxybenzoyl)phenyl)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine- 3-carboxylate (470 mg, 1.03 mmol).1H NMR (300 MHz, DMSO-d6) δ: 8.16 (s, 1H), 7.82 (dd, J = 11.3, 8.7 Hz, 4H), 7.68 (d, J = 8.5 Hz, 2H), 7.12 (d, J = 8.9 Hz, 2H), 4.91 (dd, J = 13.3, 4.7 Hz, 1H), 4.66 (dd, J = 11.1, 4.4 Hz, 1H), 4.53 (dd, J = 13.3, 4.2 Hz, 1H), 3.88 (s, 3H), 1.27 (d, J = 6.6 Hz, 3H). Mass spectrum (ESI, m/z): calcd. for C H N O , 405.1; fo + 22 19 3 5 und [M+H] , 406.2. Step D: (tert-butyl (S)-(5-(4-(4-methoxybenzoyl)phenyl)-6-methyl-4-oxo-4,5,6,7- tetrahydropyrazolo a]pyrazin-3-yl)carbamate

The title compound was prepared in a manner analogous to Intermediate 12, Step A, reacting (S)-5-(4-(4-methoxybenzoyl)phenyl)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine- 3-carboxylic acid (460 mg, 0.908 mmol).1H NMR (300 MHz, DMSO-d₆) δ: 8.03 (s, 1H), 7.78 (d, J = 8.3 Hz, 4H), 7.62 (d, J = 8.5 Hz, 2H), 7.12 (d, J = 8.9 Hz, 2H), 4.69 (dd, J = 13.1, 4.4 Hz, 1H), 4.57 (s, 1H), 4.39 – 4.30 (m, 1H), 3.87 (s, 3H), 1.47 (s, 9H), 1.25 (d, J = 6.5 Hz, 3H). Mass spectrum (ESI, m/z): calcd. for C + 26H28N4O5, 476.2; found [M+Na] , 499.2. Step E: (S)-3-amino-5-(4-(4-methoxybenzoyl)phenyl)-6-methyl-6,7-dihydropyrazolo[1,5- a]pyrazin-4(5H)-one. The title compound was prepared in a manner analogous to Intermediate 19, Step B, reacting (tert-butyl (S)-(5-(4-(4-methoxybenzoyl)phenyl)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrazin-3-yl)carbamate (210 mg, 0.388 mmol).1H NMR (400 MHz, DMSO-d₆) δ: 1.24 - 1.27 (m, 3H) 2.70 - 2.73 (m, 1H) 2.87 - 2.90 (m, 1H) 3.87 (s, 3H) 4.26 - 4.35 (m, 1H) 4.48 - 4.60 (m, 1H) 4.62 - 4.70 (m, 1H) 7.09 - 7.13 (m, 2H) 7.39 - 7.41 (m, 1H) 7.58 - 7.63 (m, 2H) 7.75 - 7.81 (m, 4H). Mass spectrum (ESI, m/z): calcd. for C₂₁H₂₀N₄O₃, 376.2; found [M+H]+, 377.2. Intermediate 29: 4-((4-bromophenyl)difluoromethyl)-2-methoxypyridine.

Step A: (4-bromophenyl)(2-methoxypyridin-4-yl)methanol The title compound was prepared in a manner analogous to Intermediate 25, Step A, reacting 2- methoxyisonicotinaldehyde (700 mg, 5.10 mmol). Mass spectrum (ESI, m/z): calcd. for C H BrNO , 2 + 13 12 2 93.0; found [M+H] , 294.0. Step B: (4-bromophenyl)(2-methoxypyridin-4-yl)methanone The title compound was prepared in a manner analogous to Intermediate 25, Step B, reacting (4- bromophenyl)(2-methoxypyridin-4-yl)methanol (769 mg, 2.61 mmol).1H NMR (400 MHz, DMSO-d₆) δ: 8.44 (dd, J = 5.2, 0.6 Hz, 1H), 7.86 (d, J = 8.6 Hz, 2H), 7.78 (d, J = 8.7 Hz, 2H), 7.25 (dd, J = 5.2, 1.4 Hz, 1H), 7.14 –6.99 (m, 1H), 3.98 (s, 3H). Mass spectrum (ESI, m/z): calcd. for C H BrNO , 2 + 13 10 2 91.0; found [M+H] , 292.0. Step C: 4-(2-(4-bromophenyl)-1,3-dithian-2-yl)-2-methoxypyridine The title compound was prepared in a manner analogous to Intermediate 241-bromo-4-((4- chlorophenyl)difluoromethyl)benzene, Step A, reacting (4-bromophenyl)(2-methoxypyridin-4- yl)methanone (1.1 g, 3.765 mmol).1H NMR (300 MHz, DMSO-d₆) δ: 8.21 (d, J = 5.5 Hz, 1H), 7.63 – 7.56 (m, 2H), 7.48 – 7.41 (m, 2H), 7.19 (dd, J = 5.5, 1.7 Hz, 1H), 6.96 (d, J = 1.2 Hz, 1H), 3.87 (s, 3H), 2.85 – 2.68 (m, 4H), 1.98 – 1.80 (m, 2H). Mass spectrum (ESI, m/z): calcd. for C H Br + 16 16 NOS2, 381.0; found [M+H] , 382.0. Step D: 4-((4-bromophenyl)difluoromethyl)-2-methoxypyridine. The title compound was prepared in a manner analogous to Intermediate 25, Step D, 4-(2-(4- bromophenyl)-1,3-dithian-2-yl)-2-methoxypyridine (490 mg, 0.961 mmol).1H NMR (300 MHz, DMSO-d₆) δ: 8.30 (d, J = 5.3 Hz, 1H), 7.72 (d, J = 8.7 Hz, 2H), 7.53 (d, J = 8.7 Hz, 2H), 7.12 (dd, J = 5.4, 1.4 Hz, 1H), 6.99 (d, J = 0.6 Hz, 1H), 3.88 (s, 3H). Mass spectrum (ESI, m/z): calcd. for C₁₃H₁₀BrF₂NO, 313.0; found [M+H]+, 314.0. Intermediate 30: (S)-7-methyl-4-oxo-5-(4-(trifluoromethyl)phenyl)-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxylic acid

Step A: ethyl (S)-7-methyl-4-oxo-5-(4-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrazine-3-carboxylate Tris(dibenzylideneacetone)dipalladium (167 mg, 0.2 mmol) was added to a stirred mixture of (Intermediate 17, product from Step A, 370 mg, 1.7 mmol), 4- bromobenzotrifluoride (255 μL, 1.8 mmol), Xantphos (208 mg, 0.4 mmol), and cesium carbonate (1.6 g, 4.9 mmol) in 1,4-dioxane (5 mL) which was previously degassed with nitrogen for 5 min. and the mixture was stirred at 95ºC for 16 hours. Water was added and the product was extracted with EtOAc (x3). The organic layers were combined, dried over MgSO4 anh., filtered and concentrated in vacuo. The residue purified by silica gel chromatography (0%-100% heptane/EtOAc) to afford (S)-7-methyl-4-oxo-5-(4-(trifluoromethyl)phenyl)-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxylate (350 mg, 55% yield) as a yellowish solid.1H NMR (300 MHz, DMSO-d6) δ: 1.24 (t, J=7.10 Hz, 3H) 1.55 (d, J=6.54 Hz, 3H) 4.10 (dd, J=13.09, 7.53 Hz, 1H) 4.22 (q, J=7.04 Hz, 2H) 4.37 (dd, J=13.09, 4.07 Hz, 1H) 4.78 - 4.86 (m, 1H) 7.67 (d, J=1.00 Hz, 2H) 7.84 (d, J=1.00 Hz, 2H) 8.00 (s, 1H). Mass spectrum (ESI, m/z): calcd. for C17H16F3N3O3, 367.1; found [M+H]+, 368.1. Step B: (S)-7-methyl-4-oxo-5-(4-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrazine-3-carboxylic acid The title compound was prepared in a manner analogous to Intermediate 18, Step B, reacting ethyl (S)-7-methyl-4-oxo-5-(4-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrazine-3-carboxylate (324 mg, 0.838 mmol).1H NMR (300 MHz, DMSO-d₆) δ: 1.59 (d, J=6.54 Hz, 3H) 4.23 (dd, J=1.00 Hz, 1H) 4.43 (dd, J=1.00 Hz, 1H) 4.92 (m, J=8.12, 6.51, 4.38 Hz, 1H) 7.74 (d, J=8.39 Hz, 2H) 7.90 (d, J=8.52 Hz, 2H) 8.16 (s, 1H). Mass spectrum (ESI, m/z): calcd. for C₁₅H₁₂F₃N₃O₃, 339.1; found [M+H]+, 339.7. Intermediate 31: (S)-3-amino-5-(4-(6-methoxynicotinoyl)phenyl)-6-methyl-6,7- dihydropyrazolo[1,5-a]pyrazin-4(5H)-one

Step A: (4-bromophenyl)(6-methoxypyridin-3-yl)methanone The title compound was prepared in a manner analogous to Intermediate 25, Step A, reacting 6- methoxynicotinaldehyde (1.57 g, 11.45 mmol).1H NMR (300 MHz, DMSO-d₆) δ: 8.55 (d, J = 2.0 Hz, 1H), 8.08 (dd, J = 8.7, 2.5 Hz, 1H), 7.82 – 7.75 (m, 2H), 7.73 – 7.66 (m, 2H), 6.99 (d, J = 8.7 Hz, 1H), 3.96 (s, 3H). Mass spectrum (ESI, m/z): calcd. for C13H10BrNO2, 291.0; found [M+H]+, 292.1. Step B: ethyl (S)-5-(4-(6-methoxynicotinoyl)phenyl)-6-methyl-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxylate The title compound was prepared in a manner analogous to Intermediate 1, Step E, reacting ethyl (S)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxylate (Intermediate 1, product from Step D, 550 mg, 2.464 mmol) and (4-bromophenyl)(6-methoxypyridin-3- yl)methanone (809 mg, 2.769 mmol).1H NMR (300 MHz, DMSO-d6) δ: 8.60 (d, J = 2.4 Hz, 1H), 8.12 (dd, J = 8.7, 2.5 Hz, 1H), 8.01 (s, 1H), 7.86 (d, J = 8.6 Hz, 2H), 7.63 (d, J = 8.5 Hz, 2H), 7.01 (d, J = 8.7 Hz, 1H), 4.85 (dd, J = 13.5, 4.3 Hz, 1H), 4.62 – 4.50 (m, J = 6.7, 4.1 Hz, 1H), 4.44 (dd, J = 13.4, 3.2 Hz, 1H), 4.28 – 4.16 (m, 2H), 3.97 (s, 3H), 1.29 – 1.22 (m, 6H). Mass spectrum (ESI, m/z): calcd. for C₂₃H₂₂N₄O₅, 434.2; found [M+Na]+, 456.9. Step C: (S)-5-(4-(6-methoxynicotinoyl)phenyl)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrazine-3-carboxylic acid The title compound was prepared in a manner analogous to Intermediate 18, Step B, reacting ethyl (S)-5-(4-(6-methoxynicotinoyl)phenyl)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrazine-3-carboxylate (645 mg, 1.485 mmol).1H NMR (300 MHz, DMSO-d6) δ: 8.62 (d, J = 2.4 Hz, 1H), 8.19 – 8.10 (m, 2H), 7.91 (d, J = 8.5 Hz, 2H), 7.71 (d, J = 8.5 Hz, 2H), 7.02 (d, J = 8.7 Hz, 1H), 4.92 (dd, J = 13.3, 4.6 Hz, 1H), 4.72 – 4.62 (m, 1H), 4.54 (dd, J = 13.4, 4.2 Hz, 1H), 3.98 (s, 3H), 1.27 (d, J = 6.6 Hz, 3H). Mass spectrum (ESI, m/z): calcd. for C21H18N4O5, 406.1; found [M+Na]+, 429.1. Step D: tert-butyl (S)-(5-(4-(6-methoxynicotinoyl)phenyl)-6-methyl-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazin-3-yl)carbamate The title compound was prepared in a manner analogous to Intermediate 12, Step A, reacting (S)-5-(4-(6-methoxynicotinoyl)phenyl)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrazine-3-carboxylic acid (430 mg, 1.058 mmol).1H NMR (300 MHz, DMSO-d6) δ: 8.59 (d, J = 2.1 Hz, 1H), 8.11 (dd, J = 8.7, 2.4 Hz, 1H), 8.03 (s, 1H), 7.85 (d, J = 8.5 Hz, 3H), 7.65 (d, J = 8.5 Hz, 2H), 7.01 (d, J = 8.7 Hz, 1H), 4.69 (dd, J = 13.1, 4.1 Hz, 1H), 4.58 (s, 1H), 4.34 (dd, J = 13.1, 2.9 Hz, 1H), 3.98 (s, 3H), 1.47 (s, 9H), 1.25 (d, J = 6.6 Hz, 3H).Mass spectrum (ESI, m/z): calcd. for C H N O , 4 + 25 27 5 5 77.2; found [M+H] , 478.2. Step E: (S)-3-amino-5-(4-(6-methoxynicotinoyl)phenyl)-6-methyl-6,7-dihydropyrazolo[1,5- a]pyrazin-4(5H)-one HCl in dioxane) (2 mL, 8 mmol, 4M) was added to a solution of tert-butyl (S)-(5-(4-(6- methoxynicotinoyl)phenyl)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3- yl)carbamate (283.6 mg, 0.52 mmol) in THF (3mL) and water (3mL) and the mixture was stirred at rt for 4h. Then, the solvents were reduced in vacuo to afford (S)-3-amino-5-(4-(6- methoxynicotinoyl)phenyl)-6-methyl-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (283mg, 77% yield) as a yellow solid. Mass spectrum (ESI, m/z): calcd. for C20H19N5O3, 377.1; found [M+H]+, 378.1. Intermediate 32: (S)-3-amino-5-(4-(3-methoxybenzoyl)phenyl)-6-methyl-6,7- dihydropyrazolo[1,5-a]pyrazin-4(5H)-one

Step A: ethyl (S)-5-(4-(3-methoxybenzoyl)phenyl)-6-methyl-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxylate The title compound was prepared in a manner analogous to Intermediate 1, Step E, reacting ethyl (S)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxylate (Intermediate 1, product from Step D, 710 mg, 3.181 mmol) and 4-Bromo-3'-methoxybenzophenone (1.0 g, 3.33 mmol).1H NMR (300 MHz, DMSO-d6) δ: 8.01 (s, 1H), 7.85 (d, J = 8.5 Hz, 2H), 7.63 (d, J = 8.6 Hz, 2H), 7.55 – 7.43 (m, 1H), 7.33 – 7.23 (m, 3H), 4.85 (dd, J = 13.4, 4.3 Hz, 1H), 4.61 – 4.50 (m, 1H), 4.44 (dd, J = 13.4, 3.1 Hz, 1H), 4.30 – 4.15 (m, 2H), 3.83 (s, 3H), 1.26 (t, J = 7.2 Hz, 6H). Mass spectrum (ESI, m/z): calcd. for C₂₄H₂₃N₃O₅, 433.2; found [M+Na]+, 456.2. Step B: (S)-5-(4-(3-methoxybenzoyl)phenyl)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrazine-3-carboxylic acid The title compound was prepared in a manner analogous to Intermediate 18, Step B, reacting ethyl (S)-5-(4-(3-methoxybenzoyl)phenyl)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrazine-3-carboxylate (962 mg, 2.22 mmol).1H NMR (300 MHz, DMSO-d₆) δ: 8.16 (s, 1H), 7.88 (dd, J = 7.8, 5.9 Hz, 2H), 7.69 (d, J = 8.6 Hz, 2H), 7.56 – 7.46 (m, 1H), 7.35 – 7.25 (m, 3H), 4.91 (dd, J = 13.3, 4.7 Hz, 1H), 4.74 – 4.62 (m, 1H), 4.53 (dd, J = 13.4, 4.2 Hz, 1H), 3.84 (s, 3H), 1.27 (d, J = 6.6 Hz, 3H). Mass spectrum (ESI, m/z): calcd. for C₂₂H₁₉N₃O₅, 405.1; found [M+Na]+, 427.9. Step C: tert-butyl (S)-(5-(4-(3-methoxybenzoyl)phenyl)-6-methyl-4-oxo-4,5,6,7- tetrahydropyrazolo a]pyrazin-3-yl)carbamate

The title compound was prepared in a manner analogous to Intermediate 12, Step A, reacting (S)-5-(4-(3-methoxybenzoyl)phenyl)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine- 3-carboxylic acid (855 mg, 2.11 mmol).1H NMR (300 MHz, DMSO-d₆) δ: 8.03 (s, 1H), 7.84 (d, J = 8.6 Hz, 3H), 7.64 (d, J = 8.6 Hz, 2H), 7.54 – 7.45 (m, 1H), 7.32 – 7.21 (m, 3H), 4.68 (dd, J = 13.0, 4.3 Hz, 1H), 4.62 – 4.52 (m, 1H), 4.34 (dd, J = 13.0, 2.9 Hz, 1H), 3.83 (s, 3H), 1.47 (s, 9H), 1.25 (d, J = 6.6 Hz, 3H). Mass spectrum (ESI, m/z): calcd. for C₂₆H₂₈N₄O₅, 476.2; found [M+Na]+, 498.9. Step D: (S)-3-amino-5-(4-(3-methoxybenzoyl)phenyl)-6-methyl-6,7-dihydropyrazolo[1,5- a]pyrazin-4(5H)-one. The title compound was prepared in a manner analogous to Intermediate 19, Step B, reacting tert-butyl (S)-(5-(4-(3-methoxybenzoyl)phenyl)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrazin-3-yl)carbamate (785 mg, 1.65 mmol).1H NMR (300 MHz, DMSO-d6) δ: 7.89 – 7.81 (m, 2H), 7.67 – 7.60 (m, 3H), 7.54 – 7.46 (m, 1H), 7.32 – 7.24 (m, 3H), 4.74 (dd, J = 13.1, 4.3 Hz, 1H), 4.64 – 4.54 (m, 1H), 4.37 (dd, J = 13.1, 3.0 Hz, 1H), 3.83 (s, 3H), 1.26 (d, J = 6.6 Hz, 3H). Mass spectrum (ESI, m/z): calcd. for C21H20N4O3, 376.2; found [M+H]+, 377.2. Intermediate 33: 1-((4-bromophenyl)difluoromethyl)-2-methoxybenzene.

Step A: 2-(4-bromophenyl)-2-(2-methoxyphenyl)-1,3-dithiane The title compound was prepared in a manner analogous to Intermediate 24, Step A, reacting 4- Bromo-2'-methoxybenzophenone (333 mg, 1.109 mmol).1H NMR (300 MHz, CDCl3) δ: 8.04 (dd, J = 7.8, 1.6 Hz, 1H), 7.46 – 7.33 (m, 4H), 7.31 (dd, J = 7.8, 1.4 Hz, 1H), 7.04 (td, J = 7.6, 1.1 Hz, 1H), 6.86 (d, J = 8.1 Hz, 1H), 3.47 (s, 3H), 2.98 – 2.75 (m, 4H), 2.66 (dt, J = 11.9, 7.0 Hz, 2H). Mass spectrum (ESI, m/z): calcd. for C + 17H17BrOS2, 380.0; found [M+H] , 381.0. Step B: 1-((4-bromophenyl)difluoromethyl)-2-methoxybenzene. The title compound was prepared in a manner analogous to Example 100, Step B, reacting 2-(4- bromophenyl)-2-(2-methoxyphenyl)-1,3-dithiane (134 mg, 0.351 mmol).1H NMR (300 MHz, CDCl₃) δ: 7.68 (dd, J = 7.7, 1.5 Hz, 1H), 7.50 (d, J = 8.7 Hz, 2H), 7.46 – 7.40 (m, 1H), 7.36 (d, J = 8.7 Hz, 2H), 7.05 (t, J = 7.6 Hz, 1H), 6.91 (d, J = 8.3 Hz, 1H), 3.65 (s, 3H). Intermediate 34: 2-((4-bromophenyl)difluoromethyl)-5-methoxypyridine.

Step A: (4-bromophenyl)(5-methoxypyridin-2-yl)methanol The title compound was prepared in a manner analogous to Intermediate 25, Step A, reacting 5- methoxypicolinaldehyde (1.0 g, 7.07 mmol).1H NMR (300 MHz, DMSO-d₆) δ: 8.15 (d, J = 2.7 Hz, 1H), 7.49 – 7.43 (m, 3H), 7.39 – 7.28 (m, 3H), 6.11 (d, J = 4.4 Hz, 1H), 5.66 (d, J =4.3 Hz, 1H), 3.78 (s, J = 5.4 Hz, 3H).Mass spectrum (ESI, m/z): calcd. for C13H12BrNO2, 293.0; found [M+H]+, 294.0. Step B: (4-bromophenyl)(5-methoxypyridin-2-yl)methanone The title compound was prepared in a manner analogous to Intermediate 25, Step B, reacting (4- bromophenyl)(5-methoxypyridin-2-yl)methanol (2.24 g, 7.61 mmol).1H NMR (300 MHz, DMSO-d6) δ: 8.40 (d, J = 2.7 Hz, 1H), 8.09 (d, J = 8.8 Hz, 1H), 7.97 – 7.88 (m, 2H), 7.78 – 7.71 (m, 2H), 7.62 (dd, J = 8.8, 2.9 Hz, 1H), 3.94 (s, 3H). Mass spectrum (ESI, m/z): calcd. for C H BrNO + 13 10 2, 291.0; found [M+H] , 292.0. Step C: 2-(2-(4-bromophenyl)-1,3-dithian-2-yl)-5-methoxypyridine The title compound was prepared in a manner analogous to Intermediate 241-bromo-4-((4- chlorophenyl)difluoromethyl)benzene, Step A, reacting (4-bromophenyl)(5-methoxypyridin-2- yl)methanone (1.1 g, 3.765 mmol). Mass spectrum (ESI, m/z): calcd. for C16H16BrNOS2, 381.0; found [M+H]+, 381.8. Step D: 2-((4-bromophenyl)difluoromethyl)-5-methoxypyridine. The title compound was prepared in a manner analogous to Example 100, Step B, reacting 2-(2- (4-bromophenyl)-1,3-dithian-2-yl)-5-methoxypyridine (280 mg, 0.732 mmol).1H NMR (400 MHz, DMSO-d6) δ: 8.32 (d, J = 2.8 Hz, 1H), 7.78 (d, J = 8.7 Hz, 1H), 7.69 (d, J = 8.6 Hz, 2H), 7.54 (dd, J = 8.7, 2.9 Hz, 1H), 7.48 (d, J = 8.6 Hz, 2H), 3.87 (s, 3H). Mass spectrum (ESI, m/z): calcd. for C₁₃H₁₀BrF₂NO, 313.0; found [M+H]+, 313.9. Intermediate 35: 3-((4-bromophenyl)difluoromethyl)-2-methoxypyridine.

Step A: (4-bromophenyl)(2-methoxypyridin-3-yl)methanol n-Butyllithium in hexanes (3 mL, 7.5 mmol, 2.5 M) was added to a stirred solution of 3-bromo- 2-methoxypyridine (900 μL, 7.44 mmol) in THF (13 mL) at -78ºC under nitrogen. The mixture was stirred for 1 h while the temperature was allowed to reach - 40ºC.4-Bromobenzaldehyde (1.5 g, 8.11 mmol) in THF (13 mL) was added at -78ºC under nitrogen. The reaction mixture was stirred for 2 h while the temperature was allowed to reach room temperature. The reaction mixture was diluted with brine and extracted with EtOAc. The organic layer was separated, dried over MgSO4 and concentrated in vacuo to afford (4-bromophenyl)(2-methoxypyridin-3- yl)methanol (2.16 g, 99% yield) as an orange oil.1H NMR (300 MHz, DMSO-d₆) δ: 8.05 (dd, J = 5.0, 1.9 Hz, 1H), 7.83 (dd, J = 7.5, 1.5 Hz, 1H), 7.51 – 7.44 (m, 2H), 7.31 – 7.25 (m, 2H), 7.01 (dd, J = 7.3, 5.0 Hz, 1H), 5.96 (d, J = 4.4 Hz, 1H), 5.81 (d, J = 4.3 Hz, 1H), 3.83 (s, 3H). Mass spectrum (ESI, m/z): calcd. for C₁₃H₁₂BrNO₂, 293.0; found [M+H]+, 294.0. Step B: (4-bromophenyl)(2-methoxypyridin-3-yl)methanone The title compound was prepared in a manner analogous to Intermediate 25, Step B, reacting (4- bromophenyl)(2-methoxypyridin-3-yl)methanol (2.16 g, 7.34 mmol).1H NMR (300 MHz, DMSO-d6) δ: 8.40 (dd, J = 5.0, 1.9 Hz, 1H), 7.86 (dd, J = 7.3, 1.9 Hz, 1H), 7.78 – 7.72 (m, 2H), 7.68 – 7.61 (m, 2H), 7.18 (dd, J = 7.3, 5.0 Hz, 1H), 3.79 (s, 3H). Mass spectrum (ESI, m/z): calcd. for C₁₃H₁₀BrNO₂, 291.0; found [M+H]+, 292.0. Step C: 3-((4-bromophenyl)difluoromethyl)-2-methoxypyridine. Diethylaminosulfur trifluoride (7.2 mL, 54.5 mmol) was added in 4 portions during 5 h to a solution of (4-bromophenyl)(2-methoxypyridin-3-yl)methanone (770 mg, 2.64 mmol) in DCM (5 mL) at room temperature. The solution was stirred for 1 h at room temperature, then was quenched with water at 0ºC and extracted with DCM. The combined organic layer was dried over MgSO₄ anh., filtered and concentrated in vacuo. The residue purified by silica gel chromatography (0%-100% heptane/EtOAc) to afford 3-((4-bromophenyl)difluoromethyl)-2- methoxypyridine (60 mg, 7% yield) as a yellowish solid.1H NMR (300 MHz, DMSO-d6) δ: 8.33 (d, J = 4.1 Hz, 1H), 8.04 (dd, J = 7.5, 1.8 Hz, 1H), 7.68 (d, J = 8.6 Hz, 2H), 7.43 (d, J = 8.6 Hz, 2H), 7.17 (dd, J = 7.5, 5.0 Hz, 1H), 3.76 (s, 3H). Mass spectrum (ESI, m/z): calcd. for C H Br + 13 10 F2NO, 313.0; found [M+H] , 313.8. Intermediate 36: (S)-3-cyano-4-methoxy-N-(7-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrazin-3-yl)benzamide.

Step A: tert-butyl (S)-3-iodo-7-methyl-4-oxo-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)- carboxylate Di-tert-butyl dicarbonate (0.77 mL, 3.38 mmol) was added to a stirred solution of (S)-3-iodo-7- methyl-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (500 mg, 1.71 mmol), triethylamine (0.49 mL, 3.5 mmol) and DMAP (32 mg, 0.26 mmol) in dry dichlorometane (10 mL) under N₂ atmosphere. The resulting mixture was stirred at room temperature for 16 h. The mixture was quenched by addition of NaHCO3 sat. aq. solution ands extracted with DCM (x3). The organic layers were joined and dried over MgSO₄ anh., filtered and concentrated in vacuo. The residue purified by silica gel chromatography (0%-100% heptane/EtOAc) to afford tert-butyl (S)-3-iodo- 7-methyl-4-oxo-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate (640 mg, 99% yield) as a white solid.1H NMR (300 MHz, DMSO-d₆) δ: 1.46 (d, J=6.54 Hz, 3H) 1.51 (s, 9H) 3.87 (dd, J=13.46, 8.15 Hz, 1H) 4.20 - 4.33 (m, 1H) 4.58 - 4.72 (m, 1H) 7.77 (s, 1H). Mass spectrum (ESI, m/z): calcd. for C H IN O , 377.0; fou + 12 16 3 3 nd [M+Na] , 399.9. Step B: tert-butyl (S)-3-(3-cyano-4-methoxybenzamido)-7-methyl-4-oxo-6,7- dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate The title compound was prepared in a manner analogous to Intermediate 30, Step A, reacting tert-butyl (S)-3-iodo-7-methyl-4-oxo-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate (200 mg, 0.53 mmol) and 3-cyano-4-methoxybenzamide (Intermediate 13, product from Step A, 103 mg, 0.585 mmol. Mass spectrum (ESI, m/z): calcd. for C + 21H23N5O5, 425.2; found [M+H] , 426.1. Step C: (S)-3-cyano-4-methoxy-N-(7-methyl-4-oxo- tetrahydropyrazolo[1,5-a]pyrazin-3-

yl)benzamide HCl solution in 1,4-dioxane (376 uL, 1.50 mmol, 4N) was added to a solution of tert-butyl (S)-3- (3-cyano-4-methoxybenzamido)-7-methyl-4-oxo-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)- carboxylate (64 mg, 0.15 mmol) in DCM dry (5 mL) and the mixture was stirred at rt for 20 h. Then, HCl solution in 1,4-dioxane (376 uL, 1.50 mmol, 4N) (190 uL, 0.75 mmol, 4N.) was added and the mixture was stirred for 20 h and the mixure was heated to 35ºC. The mixture was evaporated in vacuo. The residue was purified by silica gel chromatography (0-10% MeOH/DCM) to afford (S)-3-cyano-4-methoxy-N-(7-methyl-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazin-3-yl)benzamide (48 mg, 98% yield) as a yellowish solid.1H NMR (300 MHz, DMSO-d6) δ: 1.19 - 1.34 (m, 3H) 1.47 (d, J=6.42 Hz, 3H) 3.37 - 3.45 (m, 1H) 3.71 (dt, J=13.15, 3.98 Hz, 1H) 4.42 - 4.57 (m, 1H) 7.45 (d, J=9.01 Hz, 1H) 8.07 (s, 1H) 8.17 (dd, J=8.89, 2.35 Hz, 1H) 8.24 (d, J=2.22 Hz, 1H) 8.39 (br s, 1H) 9.81 - 9.88 (m, 1H). Mass spectrum (ESI, m/z): calcd. for C H IN O , 325.1; fou + 16 15 5 3 nd [M+H] , 326.2. Intermediate 37: (S)-3-amino-5-(4-(4-chloro-3-methoxybenzoyl)phenyl)-6-methyl-6,7- dihydropyrazolo[1,5-a]pyrazin-4(5H)-one

Step A: (4-bromophenyl)(4-chloro-3-methoxyphenyl)methanol The title compound was prepared in a manner analogous to Intermediate 25, Step A, reacting 4- Chloro-3-methoxybenzaldehyde (1.5 g, 8.8 mmol).1H NMR (300 MHz, DMSO-d6) δ: 7.54 – 7.45 (m, 2H), 7.38 – 7.29 (m, 3H), 7.19 (d, J = 1.7 Hz, 1H), 6.90 (dd, J = 8.2, 1.7 Hz, 1H), 6.09 (d, J = 4.1 Hz, 1H), 5.70 (d, J = 4.1 Hz, 1H), 3.83 (s, 3H). Mass spectrum (ESI, m/z): calcd. for C H 2BrClO2, + 14 1 326.0; found [M+Na] , 348.9. Step B: (4-bromophenyl)(4-chloro-3-methoxyphenyl)methanone The title compound was prepared in a manner analogous to Intermediate 25, Step B, reacting (4- bromophenyl)(4-chloro-3-methoxyphenyl)methanol (1.59 g, 4.85 mmol).1H NMR (300 MHz, DMSO-d6) δ: 7.82 – 7.75 (m, 2H), 7.74 – 7.67 (m, 2H), 7.62 (d, J = 8.1 Hz, 1H), 7.44 (d, J = 1.8 Hz, 1H), 7.27 (dd, J = 8.1, 1.9 Hz, 1H), 3.92 (s, 3H). Step C: ethyl -5-(4-(4-chloro-3-methoxybenzoyl)phenyl)-6-methyl-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxylate The title compound was prepared in a manner analogous to Intermediate 1, Step E, reacting ethyl (S)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxylate (Intermediate 1, product from Step D, 1.03 g, 4.61 mmol) and (4-bromophenyl)(4-chloro-3- methoxyphenyl)methanone (1.69 g, 5.19 mmol).1H NMR (300 MHz, DMSO-d₆) δ: 8.01 (s, 1H), 7.87 (d, J = 8.6 Hz, 2H), 7.69 – 7.60 (m, 3H), 7.49 (d, J = 1.8 Hz, 1H), 7.35 – 7.27 (m, 1H), 4.85 (dd, J = 13.4, 4.3 Hz, 1H), 4.62 – 4.50 (m, 1H), 4.44 (dd, J = 13.4, 3.1 Hz, 1H), 4.29 – 4.16 (m, 2H), 3.94 (s, 3H), 1.26 (t, J = 7.2 Hz, 5H). Mass spectrum (ESI, m/z): calcd. for C₂₄H₂₂ClN₃O₅, 467.1; found [M+H]+, 468.2. Step D: (S)-5-(4-(4-chloro-3-methoxybenzoyl)phenyl)-6-methyl-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxylic acid The title compound was prepared in a manner analogous to Intermediate 18, Step B, reacting ethyl (S)-5-(4-(4-chloro-3-methoxybenzoyl)phenyl)-6-methyl-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxylate (2.07 g, 3.98 mmol).1H NMR (300 MHz, DMSO-d6) δ: 8.16 (s, 1H), 7.92 (d, J = 8.5 Hz, 2H), 7.70 (d, J = 8.5 Hz, 2H), 7.64 (d, J = 8.1 Hz, 1H), 7.51 (d, J = 1.8 Hz, 1H), 7.31 (dd, J = 8.1, 1.8 Hz, 1H), 4.91 (dd, J = 13.3, 4.6 Hz, 1H), 4.73 – 4.61 (m, J = 6.6 Hz, 1H), 4.53 (dd, J = 13.4, 4.2 Hz, 1H), 3.95 (s, 3H), 1.26 (d, J = 6.6 Hz, 3H). Mass spectrum (ESI, m/z): calcd. for C₂₂H₁₈ClN₃O₅, 439.1; found [M+H]+, 440.1. Step E: tert-butyl (S)-(5-(4-(4-chloro-3-methoxybenzoyl)phenyl)-6-methyl-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazin-3-yl)carbamate The title compound was prepared in a manner analogous to Intermediate 12, Step A, reacting (S)-5-(4-(4-chloro-3-methoxybenzoyl)phenyl)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrazine-3-carboxylic acid (672 mg, 1.53 mmol).1H NMR (400 MHz, DMSO-d₆) δ: 8.03 (s, 1H), 7.87 (d, J = 8.6 Hz, 3H), 7.64 (dd, J = 8.4, 3.0 Hz, 3H), 7.48 (d, J = 1.8 Hz, 1H), 7.29 (dd, J = 8.1, 1.8 Hz, 1H), 4.68 (dd, J = 13.1, 4.3 Hz, 1H), 4.63 – 4.54 (m, J = 3.8 Hz, 1H), 4.34 (dd, J = 13.0, 2.9 Hz, 1H), 3.94 (s, 3H), 1.47 (s, 9H), 1.25 (d, J = 6.6 Hz, 3H). Mass spectrum (ESI, m/z): calcd. for C₂₆H₂₇ClN₄O₅, 510.2; found [M+H]+, 511.2. Step F: (S)-3-amino-5-(4-(4-chloro-3-methoxybenzoyl)phenyl)-6-methyl-6,7- dihydropyrazolo a]pyrazin-4(5H)-one

The title compound was prepared in a manner analogous to Intermediate 19, Step B, reacting tert-butyl (S)-(5-(4-(4-chloro-3-methoxybenzoyl)phenyl)-6-methyl-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazin-3-yl)carbamate (410 mg, 0.706 mmol).1H NMR (400 MHz, DMSO-d₆) δ: 7.90 – 7.83 (m, 2H), 7.66 – 7.60 (m, 3H), 7.48 (d, J = 1.7 Hz, 1H), 7.38 (s, 1H), 7.30 (dd, J = 8.1, 1.9 Hz, 1H), 4.64 (dd, J = 13.0, 4.2 Hz, 1H), 4.60 – 4.52 (m, 1H), 4.30 (dd, J = 13.0, 2.8 Hz, 1H), 3.94 (s, 3H), 1.26 (d, J = 6.5 Hz, 3H). Mass spectrum (ESI, m/z): calcd. for C₂₁H₁₉ClN₄O₃, 410.1; found [M+H]+, 411.1. Intermediate 38: 2-((4-bromophenyl)difluoromethyl)-6-methoxypyridine.

Step A: 3-(2-(4-bromophenyl)-1,3-dithian-2-yl)-5-methoxypyridine The title compound was prepared in a manner analogous to Intermediate 24, Step A, reacting (4- bromophenyl)(6-methoxypyridin-2-yl)methanone (330 mg, 1.02 mmol).1H NMR (300 MHz, DMSO-d₆) δ: 1.82 - 2.05 (m, 2H) 2.64 - 2.77 (m, 2H) 2.78 - 2.88 (m, 2H) 3.81 (s, 3H) 6.71 (d, J=8.15 Hz, 1H) 7.09 (d, J=7.41 Hz, 1H) 7.54 - 7.62 (m, 2H) 7.65 - 7.72 (m, 2H) 7.72 - 7.77 (m, 1H). Mass spectrum (ESI, m/z): calcd. for C + 16H16BrNOS2, 381.0; found [M+H] , 381.8. Step B: 2-((4-bromophenyl)difluoromethyl)-6-methoxypyridine The title compound was prepared in a manner analogous to Intermediate 25, Step D, reacting 3- (2-(4-bromophenyl)-1,3-dithian-2-yl)-5-methoxypyridine (375 mg, 0.794 mmol).1H NMR (300 MHz, DMSO-d₆) δ: 3.78 (s, 3H) 6.95 (d, J=8.39 Hz, 1H) 7.38 (d, J=7.28 Hz, 1H) 7.55 (d, J=8.64 Hz, 2H) 7.71 (d, J=8.64 Hz, 2H) 7.87 (d, J=7.78 Hz, 1H). Mass spectrum (ESI, m/z): calcd. for C H BrF NO, 31 + 13 10 2 3.0; found [M+H] , 313.8. Intermediate 39: (6R,7R)-3-amino-6,7-dimethyl-5-(4-(trifluoromethyl)phenyl)-6,7- dihydropyrazolo[1,5-a]pyrazin-4(5H)-one.

Step A: (6R,7R)-6,7-dimethyl-5-(4-(trifluoromethyl)phenyl)-6,7-dihydropyrazolo[1,5-a]pyrazin- 4(5H)-one The title compound was prepared in a manner analogous to Intermediate 20, Step G, reacting (6R,7R)-6,7-dimethyl-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (566 mg, 3.42 mmol) and 1-bromobenzotrifluroide (0.930 mL, 6.58 mmol).1H NMR (400 MHz, DMSO-d6) δ7.84 (d, J = 8.4 Hz, 2H), 7.70 (d, J = 8.3 Hz, 2H), 7.65 (d, J = 2.0 Hz, 1H), 6.90 (d, J = 2.0 Hz, 1H), 4.97 (qd, J = 6.7, 4.0 Hz, 1H), 4.45 (qd, J = 6.7, 4.0 Hz, 1H), 1.55 (d, J = 6.7 Hz, 3H), 1.04 (d, J = 6.7 Hz, 3H). Mass spectrum (ESI, m/z): calcd. for C + 15H14F3N3O, 309.1; found [M+Na] , 332.0. Step B: (6R,7R)-3-iodo-6,7-dimethyl-5-(4-(trifluoromethyl)phenyl)-6,7-dihydropyrazolo[1,5- a]pyrazin-4(5H)-one The title compound was prepared in a manner analogous to Intermediate 20, Step H, reacting (6R,7R)-6,7-dimethyl-5-(4-(trifluoromethyl)phenyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)- one (500 mg, 1.1.62 mmol).1H NMR (400 MHz, DMSO-d6) δ: 7.84 (d, J = 8.4 Hz, 2H), 7.78 (s, 1H), 7.69 (d, J = 8.3 Hz, 2H), 5.00 (qd, J = 6.7, 4.0 Hz, 1H), 4.46 (qd, J = 6.7, 4.0 Hz, 1H), 1.51 (d, J = 6.7 Hz, 3H), 1.04 (d, J = 6.7 Hz, 3H). Mass spectrum (ESI, m/z): calcd. for C H F IN O, 435.0; found + 15 13 3 3 [M+Na] , 457.9. Step C: tert-butyl ((6R,7R)-6,7-dimethyl-4-oxo-5-(4-(trifluoromethyl)phenyl)-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazin-3-yl)carbamate The title compound was prepared in a manner analogous to Intermediate 20, Step I, reacting (6R,7R)-3-iodo-6,7-dimethyl-5-(4-(trifluoromethyl)phenyl)-6,7-dihydropyrazolo[1,5-a]pyrazin- 4(5H)-one (733 mg, 1.68 mmol).1H NMR (400 MHz, DMSO-d₆) δ8.02 (s, 1H), 7.84 (d, J = 8.5 Hz, 3H), 7.70 (t, J = 7.4 Hz, 2H), 4.89 (qd, J = 6.6, 4.1 Hz, 1H), 4.50 – 4.42 (m, 1H), 1.53 (d, J = 6.7 Hz, 3H), 1.47 (s, 9H), 1.06 (t, J = 5.1 Hz, 3H). Mass spectrum (ESI, m/z): calcd. for C₂₀H₂₃F₃N₄O, 424.2; found [M+Na]+, 447.0. Step D: (6R,7R)-3-amino-6,7-dimethyl-5-(4-(trifluoromethyl)phenyl)-6,7-dihydropyrazolo[1,5- a]pyrazin-4(5H)-one. The title compound was prepared in a manner analogous to Intermediate 20, Step J, reacting tert- butyl ((6R,7R)-6,7-dimethyl-4-oxo-5-(4-(trifluoromethyl)phenyl)-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazin-3-yl)carbamate (524 mg, 1.235 mmol).1H NMR (400 MHz, DMSO-d₆) δ: 7.79 (d, J = 8.5 Hz, 2H), 7.67 (d, J = 8.3 Hz, 2H), 7.09 (s, 1H), 4.91 (s, 2H), 4.68 (qd, J = 6.7, 3.9 Hz, 1H), 4.36 (qd, J = 6.6, 3.8 Hz, 1H), 1.47 (d, J = 6.7 Hz, 3H), 1.06 (t, J = 7.4 Hz, 3H). Mass spectrum (ESI, m/z): calcd. for C + 15H15F3N4O, 324.1; found [M+H] , 325.0. Intermediate 40: (S)-2-(4-(3-((3-cyanophenyl)carbamoyl)-6-methyl-4-oxo-6,7- dihydropyrazolo[1,5-a]pyrazin-5 -yl)phenyl)-2,2-difluoroacetic acid

(S)-N-(3-cyanophenyl)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3- carboxamide (Intermediate 6, 3.7 g, 13 mmol), 2-(4-bromophenyl)-2,2-difluoroacetic acid (3.8 g, 15 mmol), copper(I) iodide (1.4 g, 7.6 mmol), N, N'-dimethylethylenediamine (815 µL, 7.6 mmol), potassium carbonate (7.0 g, 50 mmol), a stir bar, DMF (40 mL) and toluene (40 mL) were added to an oven-dried and nitrogen-purged 250 mL round bottomed flask fitted with a reflux condenser, the reslutant mixture was stirred for 16 h at 120 °C. The reaction progress was monitored by LC-MS. The reaction mixture was treated with HCl (1N, 100 mL) and extracted with EtOAc (60 mL x 3). The combined extracts washed with brine (80 mL), dried over anhydrous Na2SO4, filtered, and concentrated to dryness in vacuo to give the light yellow oil, which was subjected to silica gel chromatography (0-100% EtOAc/pet ether) to give (S)-2-(4-(3- ((3-cyanophenyl)carbamoyl)-6-methyl-4-oxo-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)- yl)phenyl)-2,2-difluoroacetic acid (4 g, 68% yield) as a light yellow solid.1H NMR (400 MHz, DMSO- d6): δ: 12.37 (s, 1H), 8.25 - 8.18 (m, 2H), 7.80 - 7.68 (m, 5H), 7.57 - 7.50 (m, 2H), 4.98 - 4.89 (m, 1H), 4.61 - 4.49 (m, 2H), 1.23 (d, J = 6.4 Hz, 3H). Mass spectrum (ESI, m/z): calcd. for C₂₃H₁₇F₂N₅O₄465.1; found [M+H]+, 465.9. Intermediate 41: 1-bromo-4-((1s,3s)-3-(trifluoromethoxy)cyclobutyl)benzene

Step A: (1s,3s)-3-(4-bromophenyl)cyclobutan-1-ol. 3-(4-Bromophenyl)cyclobutanone (2.0 g, 8.9 mmol), THF (50 mL) and a stir bar was added to a nitrogen-purged 100 mL round-bottomed flask which was cooled to -70 °C (EtOH/dry ice), and the resulting mixture treated with Lithium tri-sec-butylhydroborate (13 mL, 13 mmol, 1 M in THF), dropwise over 10 min. The solution was stirred at -70 °C for 2 h. Then the solution was quenched with sat. NH₄Cl (100 mL), extracted with DCM (100 mL x 2), and the combined extracts washed with brine (80 mL), dried over anhydrous Na2SO4, filtered, and concentrated to dryness in vacuo to give colorless oil. The oil was then subjected to silica gel chromatography (0 - 15% EtOAc/PE) to give (1s,3s)-3-(4-bromophenyl)cyclobutan-1-ol (2.0 g, 99% yield) as colorless oil.1H NMR (400 MHz, CDCl3) δ: 7.49 - 7.37 (m, 2H), 7.15 - 7.07 (m, 2H), 4.36 - 4.24 (m, 1H), 2.98 - 2.87 (m, 1H), 2.82 - 2.73 (m, 2H), 2.03 - 1.93 (m, 2H) Step B: 1-bromo-4-((1s,3s)-3-(trifluoromethoxy)cyclobutyl)benzene. (1s,3s)-3-(4-Bromophenyl)cyclobutanol (1.0 g, 4.4 mmol), oxo((trifluoromethyl)sulfonyl)silver (2.3 g, 8.8 mmol), Selectfluor (2.34 g, 6.61 mmol), potassium fluoride (767 mg, 13.2 mmol), 2- fluoropyridine (855 mg, 8.81 mmol), trimethyl(trifluoromethyl)silane (1.25 g, 8.81 mmol), EtOAc (10 mL) and a stir bar were added to a 50 mL round-bottomed flask, and the resulting mixture was stirred for 12 h at 25 °C in dark. The solution was became brown. The solution was filtered and concentrated to dryness in vacuo to give a nearly black viscous oil. The oil was then subjected to silica gel chromatography (0 - 10% EtOAc/PE) to give 1-bromo-4-((1s,3s)-3- (trifluoromethoxy)cyclobutyl)benzene (480 mg, 37% yield) as colorless oil.1H NMR (400 MHz, CDCl₃) δ: 7.48 - 7.43 (m, 2H), 7.09 (s, 1H), 4.69 - 4.60 (m, 1H), 3.09 - 3.00 (m, 1H), 2.86 - 2.74 (m, 2H), 2.37 - 2.26 (m, 2H) Intermediate 42: 1-bromo-4-((1r,3r)-3-(trifluoromethoxy)cyclobutyl)benzene

Step A: (1r,3r)-3-(4-bromophenyl)cyclobutyl benzoate. (1s,3s)-3-(4-Bromophenyl)cyclobutanol (Intermediate 41, product from step A, 0.95 g, 4.2 mmol), a stir bar, benzoic acid (1.12 g, 9.2 mmol), triphenylphosphane (2.2 g, 8.4 mmol) and THF (10 mL) were added to an oven-dried and nitrogen-purged 50 mL round bottomed flask and the resulting mixture treated with Diisopropyl azodicarboxylate (1.69 g, 8.4 mmol), portion-wise over 2 min. The reslutant mixture was stirred overnight at rt. The reaction mixture was poured into H₂O (20 mL) and extracted with EtOAc (20 mL x 2). The combined extracts washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated to dryness in vacuo to give a light yellow oil. The oil was subjected to silica gel chromatography (0-40% EtOAc/PE) to give (1r,3r)-3-(4-bromophenyl)cyclobutyl benzoate (1.25 g, 90% yield) as a white solid.1H NMR (400 MHz, CDCl3) δ: 8.10 (d, J = 7.6 Hz, 2H), 7.63 - 7.56 (m, 1H), 7.53 - 7.41 (m, 4H), 7.17 (d, J = 8.4 Hz, 2H), 5.51 - 5.34 (m, 1H), 3.81 - 3.65 (m, 1H), 2.80 - 2.58 (m, 4H). Step B: (1r,3r)-3-(4-bromophenyl)cyclobutan-1-ol. (1r,3r)-3-(4-Bromophenyl)cyclobutyl benzoate (1.25 g, 3.8 mmol), a stir bar, LiOH (0.36 g, 15.1 mmol), H2O (2 mL), MeOH (4 mL) and THF (4 mL) were added to an oven-dried and nitrogen- purged 50 mL round bottomed flask. The mixture was stirred at rt for 2 h. The reaction mixture was poured into H2O (20 mL) and extracted with DCM (20 mL x 2). The combined extracts washed with brine (30 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness in vacuo to give a light yellow oil. The oil was subjected to silica gel chromatography (0-25% EtOAc/PE) to give (1r,3r)-3-(4-bromophenyl)cyclobutan-1-ol (0.74 g, 86% yield) as colorless oil.1H NMR (400 MHz, CDCl₃) δ: 7.43 (d, J = 8.4 Hz, 2H), 7.11 (d, J = 8.4 Hz, 2H), 4.59 - 4.48 (m, 1H), 3.65 - 3.54 (m, 1H), 2.53 - 2.37 (m, 4H) Step C: 1-bromo-4-((1r,3r)-3-(trifluoromethoxy)cyclobutyl)benzene. The title compound was prepared in a manner analogous to Intermediate 41, Step B, reacting (1r,3r)-3-(4-bromophenyl)cyclobutanol (0.72 g, 3.2 mmol), silver(I) trifluoromethanesulfonate (1.63 g, 6.34 mmol), Selectfluor (1.69 g, 4.76 mmol), potassium fluoride (0.55 g, 9.5 mmol), 2- fluoropyridine (0.62 g, 6.34 mmol), and trimethyl(trifluoromethyl)silane (0.9 g, 6.34 mmol).1H NMR (400 MHz, CDCl₃) δ: 7.46 (d, J = 8.4 Hz, 2H), 7.11 (d, J = 8.4 Hz, 2H), 4.85 (quin, J = 6.4 Hz, 1H), 3.73 - 3.58 (m, 1H), 2.80 - 2.68 (m, 2H), 2.60 - 2.48 (m, 2H). Intermediate 43: 4-oxo-5-(4-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrazine-3-carboxylic acid.

Step A: ethyl 4-oxo-5-(4-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3- carboxylate. The title compound was prepared in a manner analogous to Intermediate 1, Step E, reacting ethyl 4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxylate (Intermediate 2, product from Step A, (1.77 g, 8.46 mmol) and 1-bromo-4-(trifluoromethyl)benzene (3.807 g, 16.92 mmol).1H NMR (400 MHz, CDCl3) δ: 7.99 (br s, 1H), 7.68 (d, J = 8.6 Hz, 2H), 7.51 (d, J = 8.4 Hz, 2H), 4.58 (br t, J = 5.5 Hz, 2H), 4.34 (q, J = 7.1 Hz, 2H), 4.25 (br t, J = 5.2 Hz, 2H), 1.35 (t, J = 7.2 Hz, 3H). Mass spectrum (ESI, m/z): calcd. for C₁₆H₁₄F₃N₃O₃353.3; found [M+H]+, 353.8. Step B: 4-oxo-5-(4-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3- carboxylic acid. The title compound was prepared in a manner analogous to Intermediate 1, Step F, reacting ethyl 4-oxo-5-(4-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxylate (2.2 g, 6.227 mmol) and NaOH (3.425 mL, 6.850 mmol, 2 M in water).1H NMR (400 MHz, CDCl₃) δ: 13.38 (br s, 1H), 8.19 (s, 1H), 7.78 (d, J = 8.4 Hz, 2H), 7.55 (d, J = 8.4 Hz, 2H), 4.75 - 4.64 (m, 2H), 4.44 - 4.31 (m, 2H). Mass spectrum (ESI, m/z): calcd. for C₁₄H₁₀F₃N₃O₃325.2; found [M+H]+, 326.1. Intermediate 44: (S)-3-cyano-N-(6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin- 3-yl)benzamide.

The title compound was prepared in a manner analogous to Intermediate 13, Step D, reacting (S)-3-amino-6-methyl-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (Intermediate 13, product from Step C, 2.5 g, 15.0 mmol) and 3-cyanobenzoic acid (2.88 g, 19.6 mmol).1H NMR (400 MHz, DMSO-d₆) δ: 9.91 (s, 1H), 8.45 (s, 1H), 8.31 (s, 1H), 8.17 (br d, J = 8.0 Hz, 1H), 8.12 - 8.01 (m, 2H), 7.78 (t, J = 8.0 Hz, 1H), 4.41 (br d, J = 8.8 Hz, 1H), 4.07 - 3.93 (m, 2H), 1.25 (br d, J = 5.6 Hz, 3H). Mass spectrum (ESI, m/z): calcd. for C₁₅H₁₃N₅O₂, 295.1; found [M+H]+, 296.1. Intermediate 45: (S)-N-(3-cyano-4-hydroxyphenyl)-5-(4-(difluoro(phenyl)methyl)phenyl)-6- methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

The title compound was prepared in a manner analogous to Intermediate 13, Step D, reacting (S)-5-(4-(difluoro(phenyl)methyl)phenyl)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrazine-3-carboxylic acid (Intermediate 1, 2.24 g, 5.64 mmol), 5-amino-2- hydroxybenzonitrile (907 mg, 6.76 mmol), and HATU (3.22 g, 8.45 mmol).1H NMR (400 MHz, DMSO-d6) δ: 12.06 (s, 1H), 10.94 (br s, 1H), 8.17 (s, 1H), 7.98 (d, J = 2.8 Hz, 1H), 7.75 - 7.68 (m, 2H), 7.68 - 7.58 (m, 4H), 7.57 - 7.51 (m, 3H), 7.48 - 7.45 (m, 1H), 6.98 (d, J = 9.0 Hz, 1H), 4.96 - 4.85 (m, 1H), 4.57 - 4.46 (m, 2H), 1.21 (d, J = 6.0 Hz, 3H). Mass spectrum (ESI, m/z): calcd. for C + 28H21F2N5O3513.2; found [M+H] , 514.2. Intermediate 46: (S)-6-methyl-4-oxo-5-(4-(trifluoromethoxy)phenyl)-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxylic acid.

Step A: ethyl (S)-6-methyl-4-oxo-5-(4-(trifluoromethoxy)phenyl)-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxylate. The title compound was prepared in a manner analogous to Intermediate 1, Step E, reacting (S)- ethyl 6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxylate (Intermediate 1, product from Step D , 300 mg, 1.34 mmol) and 1-bromo-4-(trifluoromethoxy)benzene (389 mg, 1.61 mmol).1H NMR (400 MHz, CDCl3) δ: 8.01 (s, 1H), 7.42 - 7.37 (m, 2H), 7.30 (d, J = 8.4 Hz, 2H), 4.73 - 4.68 (m, 1H), 4.43 - 4.29 (m, 4H), 1.40 - 1.33 (m, 6H). Mass spectrum (ESI, m/z): calcd. for C₁₇H₁₆F₃N₃O₄383.1; found [M+H]+, 383.9. Step B: (S)-6-methyl-4-oxo-5-(4-(trifluoromethoxy)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrazine-3-carboxylic acid. The title compound was prepared in a manner analogous to Intermediate 1, Step F, reacting (S)- ethyl 6-methyl-4-oxo-5-(4-(trifluoromethoxy)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine- 3-carboxylate (207 mg, 500 μmol), NaOH (375 μL, 750 μmol, 2 M in H₂O).1H NMR (400 MHz, CDCl₃) δ: 13.54 (s, 1H), 8.24 (s, 1H), 7.43 - 7.37 (m, 4H), 4.81 - 4.77 (m, 1H), 4.53 - 4.41 (m, 2H), 1.43 (d, J = 6.8 Hz, 3H). Mass spectrum (ESI, m/z): calcd. for C15H12F3N3O4355.1; found [M+H]+, 355.7. Intermediate 47: (S)-5-(4-benzylphenyl)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrazine-3-carboxylic acid.

The title compound was prepared in a manner analogous to Intermediate 1, Step F, reacting ethyl (S)-5-(4-benzylphenyl)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxylate (Intermediate 4, 470 mg, 1.21 mmol) and NaOH (0.784 mL, 1.57 mmol, 2 M).1H NMR (400 MHz, CDCl₃) δ: 13.80 (s, 1H), 8.25 (s, 1H), 7.40 - 7.33 (m, 4H), 7.29 (br d, J = 6.0 Hz, 4H), 7.24 (s, 1H), 4.78 (dd, J = 4.6, 13.4 Hz, 1H), 4.51 - 4.40 (m, 2H), 4.07 (s, 2H), 1.43 (d, J = 6.4 Hz, 3H). Mass spectrum (ESI, m/z): calcd. for C₂₁H₁₉N₃O₃361.1; found [M+H]+, 362.1. Intermediate 48: (R)-5-(4-benzylphenyl)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrazine-3-carboxylic acid.

Step A: ethyl (R)-1-(2-((tert-butoxycarbonyl)amino)propyl)-4-iodo-1H-pyrazole-5-carboxylate. The title compound was prepared in a manner analogous to Intermediate 1, Step A, reacting ethyl 4-iodo-1H-pyrazole-5-carboxylate (5 g, 19 mmol) and (R)-tert-butyl (1-hydroxypropan-2- yl)carbamate (6.6 g, 38 mmol). Mass spectrum (ESI, m/z): calcd. for C14H22IN3O4, 423.1; found [M+H]+, 424.0. Step B: ethyl (R)-1-(2-aminopropyl)-4-iodo-1H-pyrazole-5-carboxylate hydrochloride. The title compound was prepared in a manner analogous to Intermediate 1, Step B, reacting (R)- ethyl 1-(2-((tert-butoxycarbonyl)amino)propyl)-4-iodo-1H-pyrazole-5-carboxylate (12 g, 28.4 mmol) and HCl/dioxane (27.4 mL, 110 mmol, 4 M). Step C: (R)-3-iodo-6-methyl-6,7-dihydropyrazolo a]pyrazin-4(5H)-one.

The title compound was prepared in a manner analogous to Intermediate 1, Step C, reacting (R)- ethyl 1-(2-aminopropyl)-4-iodo-1H-pyrazole-5-carboxylate (12 g, 37 mmol) and sat. aq. NaHCO3 (150 mL).1H NMR (400 MHz, DMSO-d6) ^ ^ ^8.32 (s, 1H), 7.66 (s, 1H), 4.43 (dd, J = 3.6, 12.0 Hz, 1H), 4.05 - 3.91 (m, 2H), 1.19 (d, J = 6.0 Hz, 3H). Mass spectrum (ESI, m/z): calcd. for C H IN O, 277.0 + 7 8 3 ; found [M+H] , 277.9. Step D: ethyl (R)-6-methyl-4-oxo- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxylate.

The title compound was prepared in a manner analogous to Intermediate 1, Step D, reacting (R)- 3-iodo-6-methyl-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (2 g, 7.2 mmol).1H NMR (400 MHz, DMSO-d₆) ^ 8.44 (s, 1H), 7.90 (s, 1H), 4.43 (dd, J = 3.6, 12.4 Hz, 1H), 4.20 (q, J = 7.2 Hz, 2H), 4.07 - 3.95 (m, 2H), 1.25 (t, J = 7.0 Hz, 3H), 1.21 (d, J = 6.4 Hz, 3H). Mass spectrum (ESI, m/z): calcd. for C₁₀H₁₃N₃O₃, 223.1; found [M+H]+, 224.0. Step E: ethyl (R)-5-(4-benzylphenyl)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine- 3-carboxylate. The title compound was prepared in a manner analogous to Intermediate 1, Step E, reacting (R)- ethyl 6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxylate (500 mg, 2.24 mmol) and 1-benzyl-4-bromobenzene (1.1 g, 4.5 mmol).1H NMR (400 MHz, DMSO-d6) ^ ^ 7.97 (s, 1H), 7.34 - 7.30 (m, 5H), 7.30 - 7.25 (m, 4H), 7.23 - 7.18 (m, 1H), 4.79 (d, J = 9.6 Hz, 1H), 4.41 - 4.34 (m, 2H), 4.23 - 4.17 (m, 2H), 3.98 (s, 2H), 1.24 (t, J = 7.2 Hz, 3H), 1.15 (d, J = 6.4 Hz, 3H). Mass spectrum (ESI, m/z): calcd. for C + 23H23N3O3389.2; found [M+H] , 390.1. Step F: (R)-5-(4-benzylphenyl)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3- carboxylic acid. The title compound was prepared in a manner analogous to Intermediate 1, Step F, reacting (R)- ethyl 5-(4-benzylphenyl)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3- carboxylate (300 mg, 0.8 mmol) and NaOH (0.58 mL, 1.2 mmol, 2 M).1H NMR (400 MHz, DMSO-d₆) ^ ^ ^14.07 (s, 1H), 8.13 (s, 1H), 7.38 (s, 4H), 7.34 - 7.27 (m, 5H), 4.92 - 4.78 (m, 1H), 4.56 - 4.44 (m, 2H), 4.00 (s, 2H), 1.19 (d, J = 6.4 Hz, 3H). Mass spectrum (ESI, m/z): calcd. for C₂₁H₁₉N₃O₃361.1; found [M+H]+, 362.1. Intermediate 49: (S)-6-methyl-4-oxo-5-(4-(trifluoromethyl)phenyl)-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxylic acid.

Step A: ethyl (S)-6-methyl-4-oxo-5-(4-(trifluoromethoxy)phenyl)-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxylate. The title compound was prepared in a manner analogous to Intermediate 1, Step E, reacting (S)- ethyl 6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxylate (Intermediate 1, product from Step D, 5.00 g, 22.4 mmol) and 1-bromo-4-(trifluoromethyl)benzene (10.1 g, 44.8mmol).1H NMR (400 MHz, CDCl₃) ^ ^ ^ 8.08 (s, 1H), 7.71 (d, J = 8.4 Hz, 2H), 7.50 (d, J = 8.4 Hz, 2H), 4.74 (dd, J = 4.4, 13.2 Hz, 1H), 4.57 (br s, 1H), 4.44 - 4.32 (m, 3H), 1.40 - 1.33 (m, 6H). Mass spectrum (ESI, m/z): calcd. for C₁₇H₁₆F₃N₃O₃367.1; found [M+H]+, 367.8. Step B: (S)-6-methyl-4-oxo-5-(4-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrazine-3-carboxylic acid. The title compound was prepared in a manner analogous to Intermediate 1, Step F, reacting (S)- ethyl 6-methyl-4-oxo-5-(4-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine- 3-carboxylate (2.00 g, 5.45 mmol) and NaOH (3.00 mL, 5.99 mmol, 2 M). Mass spectrum (ESI, m/z): calcd. for C₁₅H₁₂F₃N₃O₃339.1; found [M+H]+, 340.1. Intermediate 50: 1-(((benzyloxy)methoxy)methyl)-3-(4-bromobenzyl)bicyclo[1.1.1]pentane.

Step A: methyl 3-(hydroxymethyl)bicyclo[1.1.1]pentane-1-carboxylate. Borane dimethyl sulfide (2M in THF) (45.0 mL, 90.0 mmol) was added dropwise to a solution of Bicyclo[1.1.1]pentane-1,3-dicarboxylic acid, 1-methyl ester (10.00 g, 58.180 mmol) in THF anhydrous (70 mL) at 0 ºC and the mixture was stirred at 40 ºC for 21 hours. The mixture was cooled to room temperature and HCl (1N in water) was added at 0ºC until end of bubbling. The pH was adjusted to 7 with NaHCO₃ saturated aqueous solution, and the aqueous layer was extracted with ethyl acetate, dried (MgSO₄), filtered and concentrated to yield methyl 3- (hydroxymethyl)bicyclo[1.1.1]pentane-1-carboxylate (7.51 g, 74% yield) as a colourless oil.. Mass spectrum (ESI, m/z): calcd. for C + 8H12O3, 156.1; found [M+H] , 157.2. Step B: methyl 3-(((benzyloxy)methoxy)methyl)bicyclo[1.1.1]pentane-1-carboxylate. To a solution of methyl 3-(hydroxymethyl)bicyclo[1.1.1]pentane-1-carboxylate (7.51 g, 48.086 mmol) in THF (70 mL) (previously degassed with nitrogen), DIPEA (25.13 mL, 144.274 mmol), tetrabutylammonium iodide (1.71 g, 4.812 mmol) and benzyl chloromethyl eter (60% w/w, 16.7 mL, 72.299 mmol) were added into the reaction vessel sequentially. The resulting mixture was stirred for 72 hours at room temperature protected from light. The reaction mixture was diluted with ethyl acetate and was washed with NaHCO₃ saturated aqueous solution (100 mL), dried with MgSO4 (anhydrous), filtered and concentrated in vacuo to dryness. The crude was purified by flash column chromatography (0%-75% heptane/EtOAc) The desired fractions were collected and concentrated in vacuo to yield methyl 3- (((benzyloxy)methoxy)methyl)bicyclo[1.1.1]pentane-1-carboxylate (6.5 g, 47% yield) as a colorless oil. Mass spectrum (ESI, m/z): calcd. for C₁₆H₂₀O₄, 276.1; found [M+H]+, 277.2. Step C: (3-(((benzyloxy)methoxy)methyl)bicyclo[1.1.1]pentan-1-yl)methanol. To a suspension of LiAlH4 (1.786 g, 47.046 mmol) in anhydrous THF (20 mL), a solution of methyl 3-(((benzyloxy)methoxy)methyl)bicyclo[1.1.1]pentane-1-carboxylate (6.5 g, 23.523 mmol) in anhydrous THF (20 mL) was slowly added at 0 ºC under N2 atmosphere. The resulting mixture was allowed to warm up until room temperature and stirred for 18 hours. The crude was quenched with water, some drops of NaOH 1M and water at 0 ºC. Et2O was added and the solution was filtered off over a pad of celite. The mother liquors were collected, and the organics phase was and extracted with Et2O and washed with water. The organics were collected, dried over anhydrous MgSO4, filtered, and evaporated in vacuo to yield (3- (((benzyloxy)methoxy)methyl)bicyclo[1.1.1]pentan-1-yl)methanol (5.06 g, 81% yield) as a colorless oil.1H NMR (300 MHz, CDCl3) δ: 7.37 – 7.28 (m, 5H), 4.76 (s, 2H), 4.60 (s, 2H), 3.60 (s, 2H), 1.68 (s, 6H), 1.36 (t, J = 5.9 Hz, 1H). Step D: (E)-N'-((3-(((benzyloxy)methoxy)methyl)bicyclo[1.1.1]pentan-1-yl)methylene)-4- methylbenzenesulfonohydrazide. Oxalyl chloride (0.83 mL, 9.678 mmol) was added to DCM (15 mL) under nitrogen atmosphere and the resulting mixture was cooled down to -78 ºC. Then, DMSO (1.2 mL, 16.894 mmol) was added dropwise carefully and the mixture was stirred for 15 min at this temperature. After that, a solution of (3-(((benzyloxy)methoxy)methyl)bicyclo[1.1.1]pentan-1-yl)methanol (2 g, 8.054 mmol) in DCM (15 mL) was added to the reaction mixture and it was stirred for 30 min. at -78 ºC. TEA (3.4 mL, 24.394 mmol) was added dropwise into the reaction vessel and it was stirred for 15 min. Then, the reaction mixture was warmed up to room temperature. The product was diluted with ether (25 mL) and the mixture was washed once with saturated aq. NaHCO3 (10 mL). The organics layer was collected, dried over anh. MgSO4, filtered and concentrated in vacuo to dryness. The residue obtained was dissolved in MeOH (10 mL) and added to a stirred solution of tosylhydrazine (1.5 g, 8.054 mmol) in MeOH (10 mL) at 60 ºC. The resulting mixture was stirred for 30 min at 60 ºC. The solvents were removed under high vacuum. The crude was purified by flash column chromatography (0%-70% heptane/EtOAc). The desired fractions were collected and concentrated in vacuo to yield (E)-N'-((3- (((benzyloxy)methoxy)methyl)bicyclo[1.1.1]pentan-1-yl)methylene)-4- methylbenzenesulfonohydrazide (1.46 g, 41% yield) as a yellowish sticky oil.1H NMR (300 MHz, CDCl3) δ: 7.82 – 7.78 (m, 2H), 7.34 (dd, J = 8.5, 3.0 Hz, 5H), 7.32 – 7.28 (m, 2H), 7.11 (s, 1H), 4.74 (s, 2H), 4.59 (d, J = 5.7 Hz, 2H), 3.57 (s, 2H), 2.43 (s, 3H), 1.84 (d, J = 5.9 Hz, 6H). Mass spectrum (ESI, m/z): calcd. for C₂₂H₂₆N₂O₄S, 414.2; found [M+H]+, 415.2. Step E: 1-(((benzyloxy)methoxy)methyl)-3-(4-bromobenzyl)bicyclo[1.1.1]pentane. 4-Bromophenyl) boronic acid (1.37 g, 6.822 mmol) and potassium carbonate (1.4 g, 10.130 mmol) were added to solution of (E)-N'-((3-(((benzyloxy)methoxy)methyl)bicyclo[1.1.1]pentan- 1-yl)methylene)-4-methylbenzenesulfonohydrazide (1.395 g, 3.365 mmol) in dioxane (25 mL). The reaction vessel was evacuated and backfilled with nitrogen. The resulting mixture was heated at 110 °C for 2 hours. The mixture was cooled down to room temperature and diluted with ether, then washed three times with brine. The combined organic layers were dried over MgSO4, filtered and evaporated in vacuo. The crude was purified by flash column chromatography (0%-70% heptane/EtOAc). The desired fractions were collected and concentrated in vacuo to yield 1-(((benzyloxy)methoxy)methyl)-3-(4- bromobenzyl)bicyclo[1.1.1]pentane (0.411 g, 30% yield) as a colourless sticky oil.1H NMR (300 MHz, CDCl₃) δ: 7.42 – 7.37 (m, 2H), 7.36 – 7.28 (m, 5H), 7.00 – 6.93 (m, 2H), 4.72 (s, 2H), 4.56 (s, 2H), 3.54 (d, J = 3.9 Hz, 2H), 2.73 (s, 2H), 1.54 (s, 6H). Intermediate 51: tert-butyl(4-(4-iodobenzyl)phenoxy)dimethylsilane

Step A: (4-iodophenyl)(4-methoxyphenyl)methanone. Aluminum chloride (550 mg, 4.12 mmol) was added portionwise to a solution of 4-Iodobenzoyl chloride (1.00 g, 3.75 mmol) in nitrobenzene (7 mL) at 0 ºC, while keeping the reaction temperature below 10 ºC. The mixture was stirred at 0 ºC for 10 min, and anisole (0.400 mL, 3.68 mmol) was added dropwise to maintain temperature below 10 ºC. The reaction was stirred while warmed to rt over 16 h. Then, the reaction was poured into ice water and extracted with DCM (x3). The organic phase was washed with NaHCO₃ (x2), dried over MgSO₄ anh., and the solvent was removed in vacuo. The residue was triturated with DIPE to yield (4-iodophenyl)(4- methoxyphenyl)methanone (754 mg, 60% yield) as a pink-white solid.1H NMR (400 MHz, CDCl₃) δ: 7.84 (d, J = 8.3 Hz, 2H), 7.80 (d, J = 8.8 Hz, 2H), 7.48 (d, J = 8.4 Hz, 2H), 6.96 (d, J = 8.8 Hz, 2H), 3.89 (s, 3H). Mass spectrum (ESI, m/z): calcd. for C₁₄H₁₁IO₂, 338.0; found [M+H]+, 338.9. Step B: 1-iodo-4-(4-methoxybenzyl)benzene. Triethylsilane (0.756 mL, 4.73 mmol) was added dropwise to a solution of (4-iodophenyl)(4- methoxyphenyl)methanone (700 mg , 2.07 mmol) in TFA (3 mL) at 0ºC and under N2. The reaction mixture was stirred for 16h rt. The mixture was diluted in EtOAc and washed NaHCO₃ saturated aqueous solution (x2) and HCl 6N (x2). The organic layers were combined and dried over MgSO4 (anh.), filtered and evaporated in vacuo to yield 1-iodo-4-(4- methoxybenzyl)benzene (1.05 g , 97% yield) as a crude.1H NMR (300 MHz, DMSO-d₆) δ: 3.71 (s, 3H) 3.82 (s, 2H) 6.80 - 6.87 (m, 2H) 6.99 - 7.05 (m, 2H) 7.09 - 7.15 (m, 2H) 7.58 - 7.65 (m, 2H). Step C: 4-(4-iodobenzyl)phenol. Boron tribromide(4.00 mL, 4.02 mmol) was added dropwise to a solution of 1-iodo-4-(4- methoxybenzyl)benzene (1.05 g , 2.01 mmol) in DCM (40 mL) at -78ºC and under N2. The mixture was allowed to warm and stirred for 16h at rt. The mixture was quenched with ice water and extracted with DCM.The organic layer was washed with NaHCO3 saturated aqueous solution (x2) and brine (x2), then dried over MgSO4 (anh.), filtered and evaporated in vacuo. The crude was purified by flash column chromatography (0%-50% heptane/EtOAc). The desired fractions were collected and concentrated in vacuo to yield 4-(4-iodobenzyl)phenol (396 mg, 60% yield) as a yellowish solid.1H NMR (300 MHz, DMSO-d6) δ: 3.76 (s, 2H) 6.62 - 6.71 (m, 2H) 6.96 - 6.99 (m, 2H) 6.99 - 7.03 (m, 2H) 7.57 - 7.66 (m, 2H) 9.20 (s, 1H). Step D: tert-butyl(4-(4-iodobenzyl)phenoxy)dimethylsilane. Tert-Butyldimethylsilyl chloride (113 mg, 0.727 mmol) was added at 0ºC to a stirred solution of 4-(4-iodobenzyl)phenol (150 mg, 0.484 mmol) and imidazole (66 mg, 0.969 mmol) in THF anhydrous (7 mL). The reaction mixture was stirred at room temperature for 48 h. The solution was diluted with EtOAc and washed with NaHCO3 and brine (x3). The organic layers were combined, dried over MgSO₄, filtered and concentrated. The crude was purified by flash column chromatography (0%-30% heptane/EtOAc). The desired fractions were collected and concentrated in vacuo to yield tert-butyl(4-(4-iodobenzyl)phenoxy)dimethylsilane (160 mg , 76% yield) as a colourless oil.1H NMR (300 MHz, DMSO-d₆) δ: -0.02 - 0.02 (m, 6H) 0.76 - 0.79 (m, 9H) 3.63 - 3.68 (m, 2H) 6.56 - 6.63 (m, 2H) 6.83 -6.95 (m, 4H) 7.44 - 7.50 (m, 2H). Intermediate 52: 3-amino-5-(4-(trifluoromethyl)phenyl)-6,7-dihydropyrazolo[1,5- a]pyrazin-4(5H)-one

Step A: tert-butyl (4-oxo-5-(4-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrazin-3-yl)carbamate The title compound was prepared in a manner analogous to Intermediate 12, Step A, with 4-oxo- 5-(4-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxylic acid (Intermediate 43, 500 mg, 1.54 mmol), resulting in tert-butyl (4-oxo-5-(4- (trifluoromethyl)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)carbamate (400 mg, 66% yield).1H NMR (400MHz, CDCl3) δ: 8.10 (br s, 1H), 7.95 (br s, 1H), 7.71 (d, J = 8.4 Hz, 2H), 7.49 (d, J = 8.4 Hz, 2H), 4.52 - 4.47 (m, 2H), 4.25 - 4.19 (m, 2H), 1.50 (s, 9H) Step B: 3-amino-5-(4-(trifluoromethyl)phenyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one The title compound was prepared in a manner analogous to Intermediate 12, Step B, with tert- butyl (4-oxo-5-(4-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3- yl)carbamate (140 mg, 0.35 mmol), resulting in 3-amino-5-(4-(trifluoromethyl)phenyl)-6,7- dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (100 mg, 96% yield).1H NMR (400MHz, DMSO-d6) δ: 8.09 (s, 1H), 7.81 (d, J=8.4 Hz, 2H), 7.68 (d, J=8.4 Hz, 2H), 4.50 - 4.45 (m, 2H), 4.30 - 4.24 (m, 2H) Intermediate 53: (S)-4-bromo-3-cyano-N-(5-(4-(difluoro(phenyl)methyl)phenyl)-6-methyl- 4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)benzamide

The title compound was prepared in a manner analogous to Intermediate 13, Step D, reacting (S)-3-amino-5-(4-(difluoro(phenyl)methyl)phenyl)-6-methyl-6,7-dihydropyrazolo[1,5-a]pyrazin- 4(5H)-one (Intermediate 12, 1.50 g, 3.71 mmol), 4-bromo-3-cyanobenzoic acid (1.26 g, 5.56 mmol), and HATU (2.11 g, 5.56 mmol) yielding (S)-4-bromo-3-cyano-N-(5-(4- (difluoro(phenyl)methyl)phenyl)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3- yl)benzamide (1.44 g, 64% yield).1H NMR (400MHz, CDCl₃) δ: 9.74 (s, 1H), 8.42 (s, 1H), 8.22 (d, J = 2.0 Hz, 1H), 7.93 (dd, J = 2.4, 8.8 Hz, 1H), 7.77 (d, J = 8.4 Hz, 1H), 7.65 (d, J = 8.4 Hz, 2H), 7.57 - 7.51 (m, 2H), 7.47 - 7.38 (m, 5H), 4.71 - 4.62 (m, 1H), 4.47 - 4.33 (m, 2H), 1.41 (d, J = 6.4 Hz, 3H). Mass spectrum (ESI, m/z): calcd. for C₂₈H₂₀BrF₂N₅O₂, 575.1; found [M+H]+, 576.1. Intermediate 54: (S)-N-(3-cyanophenyl)-5-(4-formylphenyl)-6-methyl-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide

Step A: (S)-N-(3-cyanophenyl)-5-(4-(hydroxymethyl)phenyl)-6-methyl-4-oxo-

tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide (S)-N-(3-cyanophenyl)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3- carboxamide (Intermediate 6, 500 mg, 1.69 mmol), (4-bromophenyl)methanol (380.0 mg, 2.03 mmol), CuI (193.5 mg, 1.02 mmol), N1,N2-dimethylethane-1,2-diamine (109.3 µl, 1.02 mmol), K2CO3 (702.0 mg, 5.08 mmol), a stir bar, DMF (10 ml) were added to an oven-dried and nitrogen-purged 50 mL round bottomed flask fitted with a reflux condenser, the reslutant mixture was stirred overnight at 100 °C. The reaction mixture diluted with water (50 mL), extracted with EtOAc (3 x 60 mL). The combined organics were washed with brine (50 mL), dried over anhydrous Na₂S0₄, filtered and concentrated in vacuo to give vacuo a nearly yellow viscous oil, which was subjected to sillica-gel chromatography (eluent:0-50% Ethyl acetate/Methylene chloride) to give (S)-N-(3-cyanophenyl)-5-(4-(hydroxymethyl)phenyl)-6-methyl-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide (500 mg, 62% yield).1H NMR (400 MHz, DMSO-d6) δ: 12.55 (s, 1H), 8.32 - 7.92 (m, 2H), 7.70 (br d, J = 3.3 Hz, 1H), 7.56 - 7.40 (m, 5H), 5.41 - 5.19 (m, 1H), 5.00 - 4.83 (m, 1H), 4.72 - 4.13 (m, 4H), 1.21 (br d, J = 6.3 Hz, 3H). Mass spectrum (ESI, m/z): calcd. for C₂₂H₁₉N₅O₃, 401.1; found [M+H]+, 401.9. Step B: (S)-N-(3-cyanophenyl)-5-(4-formylphenyl)-6-methyl-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide (S)-N-(3-cyanophenyl)-5-(4-(hydroxymethyl)phenyl)-6-methyl-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide (500 mg, 1.25 mmol), a stir bar, CH3CN (10 mL) was added to an oven-dried and nitrogen-purged 50 mL round-bottomed flask fitted with a reflux condenser, the solution was treated with IBX (697.6 mg, 2.49 mmol).The resulting solution was stirred at 60 °C for 1 h. The mixture was filtered and the filtrate was concentrated to dryness in vacuo to give (S)-N-(3-cyanophenyl)-5-(4-formylphenyl)-6-methyl-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide (450 mg, 76% yield).1H NMR (400 MHz, DMSO-d6) δ: 12.33 (s, 1H), 10.07 (s, 1H), 8.24 - 7.55 (m, 9H), 4.93 (dd, J = 4.5, 13.3 Hz, 1H), 4.65 - 4.46 (m, 2H), 1.25 (br d, J = 6.5 Hz, 3H). Mass spectrum (ESI, m/z): calcd. for C₂₂H₁₇N₅O₃, 399.1; found [M+H]+, 399.9. Intermediate 55: (S)-3-amino-6-methyl-5-(4-(trifluoromethyl)phenyl)-6,7- dihydropyrazolo[1,5-a]pyrazin-4(5H)-one

Step A: tert-butyl (S)-(6-methyl-4-oxo-5-(4-(trifluoromethyl)phenyl)-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazin-3-yl)carbamate The title compound was prepared in a manner analogous to Intermediate 12, Step A, reacting (S)-6-methyl-4-oxo-5-(4-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyrazine-3- carboxylic acid (intermediate 49, 5.8 g, 17.1 mmol) yielding tert-butyl (S)-(6-methyl-4-oxo-5- (4-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)carbamate (5.7 g, 79% yield).1H NMR (400 MHz, CDCl3) δ: 8.12 (s, 1H), 7.95 (s, 1H), 7.75 - 7.72 (m, 2H), 7.50 - 7.47 (m, 2H), 4.63 - 4.58 (m, 1H), 4.45 - 4.27 (m, 2H), 1.50 (s, 9H), 1.39 - 1,37 (m, 3H). Step B: (S)-3-amino-6-methyl-5-(4-(trifluoromethyl)phenyl)-6,7-dihydropyrazolo[1,5-a]pyrazin- 4(5H)-one The title compound was prepared in a manner analogous to Intermediate 12, Step B, reacting tert-butyl (S)-(6-methyl-4-oxo-5-(4-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrazin-3-yl)carbamate (5.7 g, 13.9 mmol) yielding (S)-3-amino-6-methyl-5-(4- (trifluoromethyl)phenyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (4.6 g, 96% yield).1H NMR (400 MHz, DMSO-d₆) δ: 7.87 - 7.84 (m, 2H), 7.69 - 7.55 (m, 2H), 7.54 (s, 1H), 4.74 - 4.69 (m, 1H), 4.58 - 4.53 (m, 1H), 4.37 - 4.32 (m, 1H), 3.56 (s, 2H), 1.23 - 1.20 (m, 3H). Mass spectrum (ESI, m/z): Calcd. for C H F N O, 31 + 14 13 3 4 0.1, found [M+H] , 310.7. Preparation Of Final Compounds Example 1: 5-(4-benzylphenyl)-N-(3-cyanophenyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrazine-3-carboxamide.

Isopropylmagnesium chloride lithium chloride (5.79 mL, 7.53 mmol, 1.3 M) was added to a stirred suspension of 3-aminobenzonitrile (477 mg, 4.03 mmol) in THF (15 ml) under nitrogen. The reaction mixture was stirred at rt for 1 h. The resulting mixture was added to a stirred solution of ethyl 5-(4-benzylphenyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3- carboxylate (Intermediate 5, 2.00 g, 2.69 mmol) in THF (5 ml) and the resulting reaction mixture was stirred at 70°C for 1 h. The reaction progress was monitored by TLC. Upon completion of the reaction, the mixture was cooled down to rt, diluted with sat. aq. NaHCO₃ and extracted with DCM. The organic layer was separated, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by SFC (Phenomenex column, 3 µm, 80 x 40 mm; 55-85% (v/v) EtOH (containing 0.1% of 25% aq. NH₃)/CO₂) and then freeze-dried to afford 5- (4-benzylphenyl)-N-(3-cyanophenyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3- carboxamide as a white solid (751.3 mg, 62% yield).1H-NMR (400 MHz, DMSO-d6) δ: 12.53 (s, 1H), 8.18 (s, 2H), 7.73 - 7.67 (m, 1H), 7.55 - 7.48 (m, 2H), 7.45 - 7.39 (m, 2H), 7.39 - 7.34 (m, 2H), 7.33 - 7.27 (m, 4H), 7.24 - 7.17 (m, 1H), 4.67 - 4.63 (m, 2H), 4.26 - 4.22 (m, 2H), 3.99 (s, 2H). Mass spectrum (ESI, m/z): Calcd. for C H N O , 447.2, foun + 27 21 5 2 d [M+H] , 448.2. Example 2: N-(3-cyanophenyl)-5-(4-(difluoro(phenyl)methyl)phenyl)-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide

TEA (2.6 mL, 18.8 mmol) was added to a stirred mixture of 5-(4- (difluoro(phenyl)methyl)phenyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxylic acid (Intermediate 3, 2.0 g, 5.2 mmol) and 3-aminobenzonitrile (853 mg, 7.2 mmol) in dry DMF (100 mL) at rt under nitrogen. The mixture was stirred for 5 min. Then, propylphosphonic anhydride (solution 50% in DMF) (6 mL, 10.1 mmol) was added and the mixture was stirred at rt for 16 h. Then, more propylphosphonic anhydride (solution 50% in DMF) (1.6 mL, 2.7 mmol) was added and the mixture was stirred at 40ºC for 16 h. The reaction progress was monitored by LC-MS. The mixture was diluted with sat. aq. NaHCO₃ and extracted with EtOAc. The organic layer was separated, dried over MgSO4, filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography (0%-100% heptane/EtOAc) to afford impure product, that was then purified by reverse phase chromatography with the following conditions: column, Brand Phenomenex Type Gemini; I.D. (mm) 100 x 30; particle size 30 µm (C18) 110A; mobile phase, (30%-73%, 0.1% FA/CH3CN). The desired fractions were combined and the mixture was neutralized to pH=7. The mixture was extracted with DCM. The organic layer was dried over MgSO4, filtered and the solvent removed in vacuo to afford N-(3-cyanophenyl)-5-(4- (difluoro(phenyl)methyl)phenyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3- carboxamide (910 mg, 36% yield) as a white solid.1H NMR (400 MHz, DMSO-d₆) δ: 12.39 (s, 1H), 8.20 (s, 2H), 7.74 – 7.62 (m, 5H), 7.63 – 7.57 (m, 2H), 7.57 – 7.49 (m, 5H), 4.71 – 4.60 (m, 2H), 4.35 – 4.27 (m, 2H). Mass spectrum (ESI, m/z): calcd. for C27H19F2N5O2, 483.2; found [M+H]+, 484.0. Example 3: (R)-N-(3-cyanophenyl)-5-(4-(difluoro(phenyl)methyl)phenyl)-6-methyl-4-oxo- 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

Step A: ethyl (R)-1-(2-((tert-butoxycarbonyl)amino)propyl)-4-iodo-1H-pyrazole-5-carboxylate. The title compound was prepared in a manner analogous to Intermediate 1, Step A, reacting ethyl 1H-pyrazole-5-carboxylate (10 g, 37.59 mmol) and tert-butyl (R)-(1-hydroxypropan-2- yl)carbamate (13.17 g, 75.18 mmol). Step B: ethyl (R)-1-(2-aminopropyl)-4-iodo-1H-pyrazole-5-carboxylate. The title compound was prepared in a manner analogous to Intermediate 1, Step B, reacting ethyl (R)-1-(2-((tert-butoxycarbonyl)amino)propyl)-4-iodo-1H-pyrazole-5-carboxylate (13 g, 30.71 mmol) and HCl in 1,4-dioxane (29.72 mL, 118.9 mmol, 4 M). Step C: (R)-3-iodo-6-methyl-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one. The title compound was prepared in a manner analogous to Intermediate 1, Step C, reacting ethyl (R)-1-(2-aminopropyl)-4-iodo-1H-pyrazole-5-carboxylate (22 g, 68.08 mmol) and NaHCO3 (80 g, 952.27 mmol). Step D: tert-butyl (R)-3-iodo-6-methyl-4-oxo-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)- carboxylate. To a solution of (R)-3-iodo-6-methyl-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (2.7 g, 9.8 mmol) in THF (10 mL) was added DMAP (119 mg, 0.98 mmol), Et3N (1.98 g, 19.5 mmol) and di-tert-butyl dicarbonate (3.2 g, 15 mmol) under nitrogen. The resulting mixture was stirred at 50°C for 3 h. The reaction was monitored by TLC. Upon completion of the reaction, the mixture was cooled down to rt, diluted with H2O and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced. The residue was purified by silica gel chromatography (5-50% EtOAc/PE) to afford tert-butyl (R)-3- iodo-6-methyl-4-oxo-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate as a white solid (3.38 g, 92% yield).1H-NMR (400 MHz, CDCl3) δ: 7.63 (s, 1H), 4.93 - 4.80 (m, 1H), 4.51 (dd, J = 4.4, 13.2 Hz, 1H), 4.28 (dd, J = 1.2, 13.6 Hz, 1H), 1.58 (s, 9H), 1.32 (d, J = 6.8 Hz, 3H). Step E: tert-butyl (R)-3-((3-cyanophenyl)carbamoyl)-6-methyl-4-oxo-6,7-dihydropyrazolo[1,5- a]pyrazine-5(4H)-carboxylate. To a solution of tert-butyl (R)-3-iodo-6-methyl-4-oxo-6,7-dihydropyrazolo[1,5-a]pyrazine- 5(4H)-carboxylate (1 g, 2.7 mmol) in 1,4-dioxane (40 mL) in a reactor, was added Pd(OAc)2 (12 mg, 0.05 mmol), dppf (59 mg, 0.1 mmol), 3-aminobenzonitrile (940 mg, 8 mmol) and triethylamine (1.1 mL, 8 mmol). The mixture was stirred under CO atmosphere (1.2 MPa) at 90ºC for 12 h. Then, the reaction mixture was filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (0-50% EtOAc/PE) to afford tert- butyl (R)-3-((3-cyanophenyl)carbamoyl)-6-methyl-4-oxo-6,7-dihydropyrazolo[1,5-a]pyrazine- 5(4H)-carboxylate as a yellow oil (656 mg, 63% yield). Step F: (R)-N-(3-cyanophenyl)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3- carboxamide. A solution of tert-butyl (R)-3-((3-cyanophenyl)carbamoyl)-6-methyl-4-oxo-6,7- dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate (656 mg, 1.7 mmol), in HCl in 1,4-dioxane (12 mL, 50 mmol, 4 M) was stirred at rt for 3 h. The reaction was monitored by TLC. Upon completion of the reaction, the mixture was filtered, washed with EtOAc and and concentrated under reduced pressure to afford (R)-N-(3-cyanophenyl)-6-methyl-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide as a white solid (440 mg, 90% yield) that was used in next step without further purification.1H-NMR (400 MHz, DMSO-d6) δ: 12.88 (s, 1H), 9.29 (s, 1H), 8.20 (br d, J = 11.2 Hz, 1H), 8.16 - 8.09 (m, 1H), 7.78 (br s, 1H), 7.63 - 7.54 (m, 2H), 4.64 - 4.46 (m, 1H), 4.22 - 4.11 (m, 2H), 1.30 (br s, 3H). Mass spectrum (ESI, m/z): Calcd. for C15H13N5O2, 295.1, found [M+H]+, 296. Step G: (R)-N-(3-cyanophenyl)-5-(4-(difluoro(phenyl)methyl)phenyl)-6-methyl-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide. 1-Bromo-4-(difluoro(phenyl)methyl)benzene (278 mg, 1 mmol), N1,N2-dimethylethane-1,2- diamine (26 mg, 0.3 mmol), K₂CO₃ (204 mg, 1.5 mmol) and CuI (56 mg, 0.3 mmol) were added to a stirred solution of (R)-N-(3-cyanophenyl)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrazine-3-carboxamide (145 mg, 0.5 mmol) in DMF (0.6 mL, dried with 3Å molecular sieves) and toluene (6 mL, dried with 3Å molecular sieves), in an oven-dried and nitrogen- purged flask. The mixture was stirred at 100°C for 12 h. The reaction was monitored by LC-MS. The cooled mixture was filtered and washed with EtOAc. The filtrate was diluted with H2O and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (50-100% EtOAc/PE) to afford (R)-N-(3-cyanophenyl)-5-(4- (difluoro(phenyl)methyl)phenyl)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3- carboxamide, that was freeze-dried to afford a light yellow solid (177.3 mg, 71% yield).1H- NMR (400 MHz, DMSO-d6) δ: 12.36 (s, 1H), 8.21 - 8.17 (m, 2H), 7.73 - 7.69 (m, 3H), 7.67 - 7.60 (m, 4H), 7.55 - 7.50 (m, 5H), 4.95 - 4.87 (m, 1H), 4.56 - 4.48 (m, 2H), 1.21 (d, J = 6.4 Hz, 3H). Mass spectrum (ESI, m/z): Calcd. for C₂₈H₂₁F₂N₅O₂, 497.2, found [M+H]+, 498.3. Example 4: (S)-5-(4-benzylphenyl)-N-(3-cyanophenyl)-6-methyl-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

1-Benzyl-4-bromobenzene (167.4 mg, 0.68 mmol), N1,N2-dimethylethane-1,2-diamine (18 mg, 0.2 mmol), K₂CO₃ (187 mg, 1.4 mmol) and CuI (38.7 mg, 0.2 mmol) were added to a stirred solution of (S)-N-(3-cyanophenyl)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3- carboxamide (Intermediate 6, 100 mg, 0.34 mmol) in DMF (0.5 mL, dried with 3Å molecular sieves) and toluene (5 mL, dried with 3Å molecular sieves) under nitrogen. The mixture was stirred at 100°C for 12 h. The reaction was monitored by LC-MS. The cooled mixture was filtered and washed with EtOAc. The filtrate was diluted with water and extracted with additional EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (50%-100% EtOAc/PE) to afford impure product (126.6 mg) that was then purified by Prep-HPLC with the following conditions: column, Welch Xtimate C18, 150 mm, 25 mm x 5 µm; mobile phase, 65% to 95% (v/v) CH₃CN and water with 0.225% FA. This resulted in (S)-5-(4-benzylphenyl)-N-(3-cyanophenyl)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrazine-3-carboxamide, that was freeze-dried to afford a white solid (80.7 mg, 51% yield). 1H- NMR (400 MHz, DMSO-d₆) δ: 12.50 (s, 1H), 8.22 - 8.14 (m, 2H), 7.74 - 7.66 (m, 1H), 7.56 - 7.48 (m, 2H), 7.43 - 7.36 (m, 4H), 7.36 - 7.28 (m, 4H), 7.25 - 7.18 (m, 1H), 4.88 (dd, J = 4.4, 13.2 Hz, 1H), 4.52 - 4.38 (m, 2H), 4.00 (s, 2H), 1.19 (d, J = 6.4 Hz, 3H). Mass spectrum (ESI, m/z): Calcd. for C₂₈H₂₃N₅O₂, 461.2, found [M+H]+, 462.2. Example 5: (S)-N-(3-cyanophenyl)-5-(4-(difluoro(phenyl)methyl)phenyl)-6-methyl-4-oxo- 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

1-Bromo-4-(difluoro(phenyl)methyl)benzene (182 mg, 0.64 mmol), N1,N2-dimethylethane-1,2- diamine (17 mg, 0.19 mmol), K₂CO₃ (133 mg, 1 mmol) and CuI (36.8 mg, 0.2 mmol) were added to a stirred solution of (S)-N-(3-cyanophenyl)-6-methyl-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide (Intermediate 6, 95 mg, 0.3 mmol) in DMF (0.5 mL, dried with 3Å molecular sieves) and toluene (5 mL, dried with 3Å molecular sieves) under nitrogen. The mixture was stirred at 100°C for 12 h. The reaction was monitored by LC- MS. The cooled mixture was filtered and washed with EtOAc. The filtrate was diluted with water and extracted with additional EtOAc. The combined organic layers were washed with brine, dried over Na₂SO₄, filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (50-100% EtOAc/PE) to afford (S)-N-(3- cyanophenyl)-5-(4-(difluoro(phenyl)methyl)phenyl)-6-methyl-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide, that was freeze-dried to afford a light yellow solid (61 mg, 37% yield).1H-NMR (400 MHz, DMSO-d6) δ: 12.35 (s, 1H), 8.20 - 8.15 (m, 2H), 7.73 - 7.67 (m, 3H), 7.66 - 7.58 (m, 4H), 7.56 - 7.48 (m, 5H), 4.93 - 4.85 (m, 1H), 4.54 - 4.47 (m, 2H), 1.21 (d, J = 6.4 Hz, 3H). Mass spectrum (ESI, m/z): Calcd. for C₂₈H₂₁F₂N₅O₂, 497.2, found [M+H]+, 498.2. Example 6: 5-(4-benzoylphenyl)-N-(3-cyanophenyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrazine-3-carboxamide.

Step A: ethyl 5-(4-benzoylphenyl)-4-oxo- tetrahydropyrazolo[1,5-a]pyrazine-3-

carboxylate The title compound was prepared in a manner analogous to Example 4, reacting ethyl 4-oxo- 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxylate (Intermediate 2, product from Step A, 500 mg, 2.1 mmol) and 4-bromobenzophenone (740 mg, 2.83 mmol).1H NMR (300 MHz, DMSO-d₆) δ: 1.25 (t, J = 7.1 Hz, 3H) 4.22 (q, J = 7.2 Hz, 2H) 4.33 (m, J = 6.7, 4.8 Hz, 2H) 4.56 - 4.64 (m, 2H) 7.60 (m, J = 7.7 Hz, 2H) 7.62 - 7.66 (m, 2H) 7.66 - 7.72 (m, 1H) 7.73 - 7.79 (m, 2H) 7.80 - 7.87 (m, 2H) 7.99 (s, 1H). Mass spectrum (ESI, m/z): calcd. for C₂₂H₁₉N₃O₄, 389.1; found [M+H]+, 390.2. Step B: 5-(4-benzoylphenyl)-N-(3-cyanophenyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrazine-3-carboxamide Lithium bis(trimethylsilyl)amide solution in THF 1M (0.39 mL, 0.39 mmol) was added to a mixture of 3-aminobenzonitrile (37 mg, 0.3 mmol) in dry THF (2 mL) at 0°C and under nitrogen. The mixture was stirred at 0°C for 30 min. Then, the mixture was cooled to -10°C and a solution of ethyl 5-(4-benzoylphenyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3- carboxylate (100 mg, 0.26 mmol) in dry THF (1 mL) was added to the reaction. The mixture was stirred at 0°C for 1 h and then, at rt for 16 h more. The reaction progress was monitored by LC- MS. A sat. aq. solution of NaHCO₃ was added to the mixture and it was extracted with DCM. The organic layer was dried over MgSO₄, filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography (0-100% heptane/EtOAc). The desired fractions were joined and concentrated in vacuo. The solid was triturated with DIPE, filtered and dried in vacuo to afford 5-(4-benzoylphenyl)-N-(3-cyanophenyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrazine-3-carboxamide (17 mg, 14% yield) as a yellowish solid.1H NMR (400 MHz, DMSO- d6) δ: 12.37 (s, 1H), 8.21 (s, 1H), 8.19 (s, 1H), 7.89 (d, J = 8.5 Hz, 2H), 7.82 – 7.68 (m, 6H), 7.63 – 7.54 (m, 4H), 4.75 – 4.67 (m, 2H), 4.42 – 4.34 (m, 2H). Mass spectrum (ESI, m/z): calcd. for C₂₇H₁₉N₅O₃, 461.2; found [M+H]+, 462.1. Example 7: N-(3-cyano-4-methylphenyl)-5-(4-(difluoro(phenyl)methyl)phenyl)-4-oxo- 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

The title compound was prepared in a manner analogous to Example 1, reacting ethyl 5-(4- (difluoro(phenyl)methyl)phenyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxylate (Intermediate 2, 80 mg, 0.2 mmol) and 5-amino-2-methylbenzonitrile (40 mg, 0.3 mmol).1H NMR (400 MHz, DMSO-d6) δ: 2.42 (s, 3H), 4.28 - 4.34 (m, 2H), 4.64 - 4.70 (m, 2H), 7.41 (d, J = 1.0 Hz, 1H), 7.52 - 7.55 (m, 3H), 7.57 - 7.61 (m, 3H), 7.63 - 7.66 (m, 2H), 7.67 - 7.70 (m, 2H), 8.13 (d, J = 1.0 Hz, 1H), 8.18 (s, 1H), 12.30 (s, 1H). Mass spectrum (ESI, m/z): calcd. for C H F N O , 497.2; fo + 28 21 2 5 2 und [M+H] , 498.1. Example 8: N-(3-cyano-4-methoxyphenyl)-5-(4-(difluoro(phenyl)methyl)phenyl)-4-oxo- 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

Isopropyl magnesium chloride lithium chloride complex solution 1.3 M (275 µL, 0.36 mmol) was added to a stirred solution of 5-amino-2-methoxybenzonitrile (45 mg, 0.30 mmol) in dry THF (1 mL) under nitrogen. The mixture was stirred at rt for 1 h. A solution of 5-(4- (difluoro(phenyl)methyl)phenyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxylate (Intermediate 2, 80 mg, 0.19 mmol) in dry THF (1 mL) was added to the mixture and the reaction was stirred at 70ºC for 1 h under nitrogen. The reaction progress was monitored by LC- MS. Sat. aq. NaHCO₃ was added to the mixture and the aqueous phase was extracted with DCM. The organic layers were joined, dried over MgSO4, filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography (0-100% EtOAc/ heptane). The desired fractions were joined and concentrated in vacuo. The solid was triturated with DIPE, filtered and dried in vacuo to afford N-(3-cyano-4-methoxyphenyl)-5-(4-(difluoro(phenyl)methyl)phenyl)-4- oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide (10.4 mg, 10% yield) as a yellowish solid.1H NMR (400 MHz, DMSO-d₆) δ: 12.17 (s, 1H), 8.16 (s, 1H), 8.04 (d, J = 2.7 Hz, 1H), 7.73 – 7.62 (m, 5H), 7.62 – 7.57 (m, 2H), 7.56 – 7.50 (m, 3H), 7.22 (d, J = 9.2 Hz, 1H), 4.73 – 4.60 (m, 2H), 4.36 – 4.25 (m, 2H), 3.88 (s, 3H). Mass spectrum (ESI, m/z): calcd. for C28H21F2N5O3, 513.2; found [M+H]+, 514.1. Example 9: 5-(4-(2-(aminomethyl)benzyl)phenyl)-N-(3-cyanophenyl)-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

Step A: 2-(4-bromobenzyl)benzonitrile. A mixture of 2-cyanobenzylzinc bromide (5 mL, 0.5 M in THF, 2.5 mmol), 1-bromo-4- iodobenzene (707 mg, 2.50 mmol) and Pd(PPh₃)₄ (29 mg, 0.025 mmol) in THF (10 mL) under nitrogen was stirred at 65°C for 18 h. The reaction was monitored by TLC. The mixture was diluted with sat. aq NH4Cl and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na₂SO₄, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography (0-10% EtOAc/PE) to afford 2-(4- bromobenzyl)benzonitrile as colourless oil (300 mg, 44% yield). Step B: tert-butyl (2-(4-bromobenzyl)benzyl)carbamate. To a solution of 2-(4-bromobenzyl)benzonitrile (300 mg, 1.10 mmol), di-tert-butyl dicarbonate (0.51 mL, 2.21 mmol) and nickel chloride hexahydrate (15.7 mg, 0.066 mmol) in MeOH (6 mL) at 0ºC was added portionwise NaBH4 (250 mg, 6.61 mmol) over 10 min. The mixture was stirred at rt for 2 h. The reaction was monitored by TLC. The mixture was diluted with sat. aq NH4Cl and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na₂SO₄, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography (0-10% EtOAc/PE) to afford tert-butyl (2-(4-bromobenzyl)benzyl)carbamate as a white solid (310 mg, 75% yield).1H-NMR (400 MHz, CDCl3) δ: 7.42 - 7.35 (m, 2H), 7.31 - 7.27 (m, 1H), 7.26 - 7.22 (m, 2H), 7.15 - 7.10 (m, 1H), 6.99 (d, J = 8.0 Hz, 2H), 4.53 (br s, 1H), 4.26 (br d, J = 5.2 Hz, 2H), 3.99 (s, 2H), 1.42 (s, 9H). Step C: tert-butyl (2-(4-(3-((3-cyanophenyl)carbamoyl)-4-oxo-6,7-dihydropyrazolo[1,5- a]pyrazin-5(4H)-yl)benzyl)benzyl)carbamate. The title compound was prepared in a manner analogous to Example 4, reacting N-(3- cyanophenyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide (Intermediate 9, 148 mg, 0.47 mmol) and tert-butyl (2-(4-bromobenzyl)benzyl)carbamate (210 mg, 0.56 mmol). Step D: 5-(4-(2-(aminomethyl)benzyl)phenyl)-N-(3-cyanophenyl)-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide. Tert-butyl 2-(4-(3-((3-cyanophenyl)carbamoyl)-4-oxo-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)- yl)benzyl)benzylcarbamate (210 mg, 0.36 mmol) in HCl in 1,4-dioxane (6 mL, 25 mmol, 4 M) was stirred at rt for 18 h. The reaction was monitored by LC-MS. Upon completion of the reaction, the mixture was concentrated under reduced. The crude product was purified by silica gel chromatography (0-12% MeOH/DCM (with 1% NH₃·H₂O)) to afford 5-(4-(2- (aminomethyl)benzyl)phenyl)-N-(3-cyanophenyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrazine-3-carboxamide as a white solid (150 mg, 86% yield).1H-NMR (400 MHz, DMSO-d6) δ: 12.54 (s, 1H), 8.18 (s, 2H), 7.75 - 7.66 (m, 1H), 7.56 - 7.52 (m, 2H), 7.45 - 7.39 (m, 3H), 7.32 - 7.16 (m, 5H), 4.68 - 4.62 (m, 2H), 4.28 - 4.22 (m, 2H), 4.07 (s, 2H), 3.73 (s, 2H). Mass spectrum (ESI, m/z): Calcd. for C + 28H24N6O2, 476.2, found [M+H] , 477.2. Example 10: N-(3-cyanophenyl)-5-(4-(2-((dimethylamino)methyl)benzyl)phenyl)-4-oxo- 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

To a solution of 5-(4-(2-(aminomethyl)benzyl)phenyl)-N-(3-cyanophenyl)-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide (Example 9, 70 mg, 0.15 mmol) in MeOH (2 mL) was added formaldehyde (109 µL, 1.47 mmol) and sodium cyanoborohydride (9.2 mg, 0.15 mmol). The mixture was stirred at rt for 18 h. The reaction was monitored by LC-MS. Upon completion of the reaction, the mixture was concentrated under reduced pressure. The crude product was purified by silica gel chromatography (0-10% MeOH/DCM) to afford N-(3- cyanophenyl)-5-(4-(2-((dimethylamino)methyl)benzyl)phenyl)-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide as a white solid (37.4 mg, 50% yield).1H- NMR (400 MHz, DMSO-d6) δ: 12.54 (s, 1H), 8.20 - 8.15 (m, 2H), 7.74 - 7.68 (m, 1H), 7.56 - 7.50 (m, 2H), 7.41 (d, J = 8.4 Hz, 2H), 7.31 - 7.17 (m, 6H), 4.69 - 4.62 (m, 2H), 4.28 - 4.22 (m, 2H), 4.15 (s, 2H), 3.37 (br s, 2H), 2.16 (br s, 6H). Mass spectrum (ESI, m/z): Calcd. for C H N O , 504.2 + 30 28 6 2 , found [M+H] , 505.3. Example 11: N-(3-cyanophenyl)-4-oxo-5-(4-(2-(propionamidomethyl)benzyl)-phenyl)- 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

To a solution of 5-(4-(2-(aminomethyl)benzyl)phenyl)-N-(3-cyanophenyl)-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide (Example 9, 40 mg, 0.08 mmol) in DCM (1 mL) was added Et3N (23.3 µL, 0.17 mmol) and propionyl chloride (8.8 µL, 0.10 mmol). The mixture was stirred at rt for 18 h. The reaction was monitored by LC-MS. Upon completion of the reaction, the mixture was concentrated under reduced pressure. The crude product was purified by silica gel chromatography (0-10% MeOH/DCM) to afford N-(3-cyanophenyl)-4-oxo- 5-(4-(2-(propionamidomethyl)-benzyl)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3- carboxamide as a white solid (31.3 mg, 68% yield).1H-NMR (400 MHz, DMSO-d₆) δ: 12.53 (s, 1H), 8.22 - 8.13 (m, 3H), 7.74 - 7.68 (m, 1H), 7.57 - 7.50 (m, 2H), 7.42 (d, J = 8.4 Hz, 2H), 7.32 - 7.19 (m, 6H), 4.70 - 4.60 (m, 2H), 4.32 - 4.21 (m, 4H), 4.06 (s, 2H), 2.13 (q, J = 7.6 Hz, 2H), 1.01 (t, J = 7.6 Hz, 3H). Mass spectrum (ESI, m/z): Calcd. for C₃₁H₂₈N₆O₃, 532.2, found [M+H]+, 533.2. Example 12: N-(3-cyanophenyl)-5-(4-(2-((methylamino)methyl)benzyl)phenyl)-4-oxo- 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

To a solution of 5-(4-(2-(aminomethyl)benzyl)phenyl)-N-(3-cyanophenyl)-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide (Example 9, 100 mg, 0.19 mmol) in 1,1,1,3,3,3-hexafluoropropan-2-ol (2 mL) was added methyl trifluoromethanesulfonate (33.1 µL, 0.29 mmol). The mixture was stirred at rt for 18 h. The reaction was monitored by LC-MS. Upon completion of the reaction, the mixture was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions: column, Boston Prime C18, 5 µm, 150 x 30 mm; mobile phase, 50-80% (v/v) CH₃CN/water (containing 0.05% NH₃·H₂O + 10 mM NH₄HCO₃) and then freeze dried to afford N-(3-cyanophenyl)-5-(4-(2- ((methylamino)methyl)benzyl)-phenyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3- carboxamide as a white solid (50.4 mg, 52% yield).1H-NMR (400 MHz, DMSO-d6) δ: 12.54 (s, 1H), 8.21 - 8.14 (m, 2H), 7.75 - 7.67 (m, 1H), 7.57 - 7.50 (m, 2H), 7.41 (d, J=8.4 Hz, 2H), 7.37 - 7.33 (m, 1H), 7.28 (d, J=8.4 Hz, 2H), 7.24 - 7.16 (m, 3H), 4.69 - 4.61 (m, 2H), 4.29 - 4.22 (m, 2H), 4.11 (s, 2H), 3.63 (s, 2H), 2.29 (s, 3H). Mass spectrum (ESI, m/z): Calcd. for C29H26N6O2, 490.2, found [M+H]+, 491.2. Example 13: 5-(4-(4-(aminomethyl)benzyl)phenyl)-N-(3-cyanophenyl)-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide hydrochloride.

Step A: 4-(4-bromobenzyl)benzonitrile. The title compound was prepared in a manner analogous to Example 9, Step A, reacting 4- cyanobenzylzinc bromide (5 mL, 2.5 mmol, 0.5 M in THF) and 1-bromo-4-iodobenzene (1.73 g, 6.12 mmol). Step B: tert-butyl (4-(4-bromobenzyl)benzyl)carbamate. The title compound was prepared in a manner analogous to Example 9, Step B, reacting 4-(4- bromobenzyl)benzonitrile (100 mg, 0.37 mmol), di-tert-butyl dicarbonate (160 mg, 0.73 mmol), NaBH4 (80 mg, 2.11 mmol) and nickel chloride hexahydrate (5.2 mg, 0.022 mmol). Step C: tert-butyl (4-(4-(3-((3-cyanophenyl)carbamoyl)-4-oxo-6,7-dihydropyrazolo[1,5- a]pyrazin-5(4H)-yl)benzyl)benzyl)carbamate. The title compound was prepared in a manner analogous to Example 4, reacting N-(3- cyanophenyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide (Intermediate 9, 75 mg, 0.27 mmol) and tert-butyl (4-(4-bromobenzyl)benzyl)carbamate (100 mg, 0.27 mmol). Step D: 5-(4-(4-(aminomethyl)benzyl)phenyl)-N-(3-cyanophenyl)-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide hydrochloride. The title compound was prepared in a manner analogous to Example 9, Step D, reacting tert- butyl (4-(4-(3-((3-cyanophenyl)carbamoyl)-4-oxo-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)- yl)benzyl)benzyl)carbamate (50 mg, 0.087 mmol) and HCl in 1,4-dioxane (2 mL, 8 mmol, 4 M). 1H-NMR (400 MHz, DMSO-d6) δ: 12.48 (s, 1H), 8.17 (s, 1H), 8.10 (m, 1H), 7.75 - 7.70 (m, 1H), 7.56 - 7.51 (m, 2H), 7.43 - 7.34 (m, 8H), 4.67 - 4.61 (m, 2H), 4.25 - 4.19 (m, 2H), 3.99 (d, J = 8.8 Hz, 4H). Mass spectrum (ESI, m/z): Calcd. for C₂₈H₂₄N₆O₂, 476.2, found [M+H]+, 477.2. Example 14: (rac)- 5-(4'-(1-aminoethyl)-[1,1'-biphenyl]-4-yl)-N-(3-cyanophenyl)-4-oxo- 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

5-(4-Bromophenyl)-N-(3-cyanophenyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3- carboxamide (Intermediate 10, 45 mg, 0.1 mmol), PdCl₂(dppf) (7.0 mg, 0.01 mmol) and 1-[4- (tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethan-1-amine hydrochloride (32.7 mg, 0.12 mmol) were dissolved in 1,4-dioxane (1 mL) and aqueous Na₂CO₃ (0.5 mL, 0.1 g/mL, 0.47 mmol). Then, the reaction was heated to 70ºC for 1 h. After the reaction was completed, water was added, and the crude product was extracted with EtOAc. The combined organic extracts were concentrated in vacuo. Then, the crude product was redissolved in DMSO, MeOH and aqueous ammonium bicarbonate (4 mL, 2:1.5:0.5 ratio). SiliaMetS ® Triamine scavenger (20 mg) was added and the mixture was stirred for 1 h. The crude mixture was filtered and purified by Prep- HPLC (Conditions: stationary phase: C18 XBridge 30 x 100 mm 5 µm. Mobile phase: NH₄HCO₃ 0.25% solution in water and CH₃CN), to afford (rac)- 5-(4'-(1-aminoethyl)-[1,1'- biphenyl]-4-yl)-N-(3-cyanophenyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3- carboxamide (14 mg, 31% yield) as a solid after freeze drying.1H-NMR (500 MHz, DMSO-d6) δ: 12.54 (s, 1H) 8.21 (s, 1H) 8.19 (d, J = 1.1 Hz, 1H) 7.77 - 7.81 (m, 2H) 7.74 (ddd, J = 5.7, 3.7, 2.2 Hz, 1H) 7.63 - 7.69 (m, 2H) 7.57 - 7.62 (m, 2H) 7.53 - 7.56 (m, 2H) 7.48 (d, J = 8.1 Hz, 2H) 4.70 (dd, J = 7.0, 5.2 Hz, 2H) 4.27 - 4.39 (m, 2H) 4.04 (q, J = 6.6 Hz, 1H) 1.28 (d, J = 6.6 Hz, 3H). Mass spectrum (ESI, m/z): calcd. for C₂₈H₂₄N₆O₂, 476.2; found [M+H]+, 477.4. Example 15: (rac)- N-(3-cyanophenyl)-5-(4'-(1-hydroxyethyl)-[1,1'-biphenyl]-4-yl)-4-oxo- 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

The title compound was prepared in a manner analogous to Example 14, reacting 5-(4- bromophenyl)-N-(3-cyanophenyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3- carboxamide (Intermediate 10, 45 mg, 0.1 mmol) and 4-(1-hydroxyethyl)phenylboronic acid (19.1 mg, 0.12 mmol).1H NMR (500 MHz, DMSO-d6) δ: 12.54 (s, 1H) 8.21 (s, 1H) 8.19 (d, J=0.9 Hz, 1H) 7.79 (d, J=8.5 Hz, 2H) 7.72 - 7.77 (m, 1H) 7.67 (d, J = 8.2 Hz, 2H) 7.59 - 7.62 (m, 2H) 7.53 - 7.56 (m, 2H) 7.46 (d, J = 8.1 Hz, 2H) 5.20 (d, J = 4.3 Hz, 1H) 4.78 (dd, J = 6.3, 4.4 Hz, 1H) 4.70 (t, J = 6.1 Hz, 2H) 4.29 - 4.37 (m, 2H) 1.34 - 1.39 (m, 3H). Mass spectrum (ESI, m/z): calcd. for C₂₈H₂₃N₅O₃, 477.2; found [M+H]+, 478.3. Example 16: N-(3-cyanophenyl)-5-(4'-(methoxymethyl)-[1,1'-biphenyl]-4-yl)-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

The title compound was prepared in a manner analogous to Example 14, reacting 5-(4- bromophenyl)-N-(3-cyanophenyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3- carboxamide (Intermediate 10, 45 mg, 0.1 mmol) and 4-(methoxymethyl)phenylboronic acid (19.1 mg, 0.12 mmol).1H NMR (500 MHz, DMSO-d₆) δ: 12.54 (s, 1H) 8.21 (s, 1H) 8.19 (d, J = 1.1 Hz, 1H) 7.79 - 7.85 (m, 2H) 7.74 - 7.77 (m, 1H) 7.70 - 7.74 (m, 2H) 7.59 - 7.63 (m, 2H) 7.53 - 7.57 (m, 2H) 7.44 (d, J=8.2 Hz, 2H) 4.64 - 4.75 (m, 2H) 4.45 - 4.50 (m, 2H) 4.28 - 4.37 (m, 2H) 3.33 (s, 3H). Mass spectrum (ESI, m/z): calcd. for C + 28H23N5O3, 477.2; found [M+H] , 478.3. Example 17: 5-(3'-amino-4'-(hydroxymethyl)-[1,1'-biphenyl]-4-yl)-N-(3-cyanophenyl)-4- oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

The title compound was prepared in a manner analogous to Example 14, reacting 5-(4- bromophenyl)-N-(3-cyanophenyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3- carboxamide (Intermediate 10, 45 mg, 0.1 mmol) and [2-amino-4-(tetramethyl-1,3,2- dioxaborolan-2-yl)phenyl]methanol (28.7 mg, 0.12 mmol).1H NMR (500 MHz, DMSO-d6) δ: 12.55 (s, 1H) 8.11 - 8.26 (m, 2H) 7.74 (ddd, J = 5.8, 3.6, 2.2 Hz, 1H) 7.66 - 7.71 (m, 2H) 7.53 - 7.61 (m, 4H) 7.17 (d, J = 7.8 Hz, 1H) 6.96 (d, J = 1.7 Hz, 1H) 6.87 (dd, J = 7.7, 1.8 Hz, 1H) 5.00 - 5.09 (m, 3H) 4.66 - 4.77 (m, 2H) 4.43 (d, J = 5.3 Hz, 2H) 4.28 - 4.35 (m, 2H). Mass spectrum (ESI, m/z): calcd. for C₂₇H₂₂N₆O₃, 478.2; found [M+H]+, 479.3. Example 18: N-(3-cyanophenyl)-5-(4'-((dimethylamino)methyl)-[1,1'-biphenyl]-4-yl)-4-oxo- 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

The title compound was prepared in a manner analogous to Example 14, reacting 5-(4- bromophenyl)-N-(3-cyanophenyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3- carboxamide (Intermediate 10, 45 mg, 0.1 mmol) and 4-[(N,N- dimethylamino)methyl]benzeneboronic acid pinacol ester hydrochloride (34.3 mg, 0.12 mmol). 1H NMR (500 MHz, DMSO-d₆) δ: 12.54 (s, 1H) 8.21 (s, 1H) 8.18 (d, J = 0.9 Hz, 1H) 7.80 (d, J = 8.5 Hz, 2H) 7.74 (ddd, J = 5.6, 3.7, 2.1 Hz, 1H) 7.68 (d, J = 8.2 Hz, 2H) 7.60 (d, J = 8.5 Hz, 2H) 7.53 - 7.57 (m, 2H) 7.41 (d, J = 8.1 Hz, 2H) 4.65 - 4.76 (m, 2H) 4.25 - 4.40 (m, 2H) 3.44 (s, 2H) 2.18 (s, 6H). Mass spectrum (ESI, m/z): calcd. for C₂₉H₂₆N₆O₂, 490.2; found [M+H]+, 491.3. Example 19: N-(3-cyanophenyl)-5-(4'-(2-hydroxypropan-2-yl)-[1,1'-biphenyl]-4-yl)-4-oxo- 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

The title compound was prepared in a manner analogous to Example 14, reacting 5-(4- bromophenyl)-N-(3-cyanophenyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3- carboxamide (Intermediate 10, 45 mg, 0.1 mmol) and 2-(4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)phenyl)propan-2-ol (30.2 mg, 0.12 mmol).1H NMR (500 MHz, DMSO-d6) δ: 12.54 (s, 1H) 8.21 (s, 1H) 8.19 (s, 1H) 7.79 (d, J = 8.4 Hz, 2H) 7.74 (br s, 1H) 7.63 - 7.67 (m, 2H) 7.59 (t, J = 8.1 Hz, 4H) 7.52 - 7.56 (m, 2H) 5.06 (s, 1H) 4.64 - 4.74 (m, 2H) 4.33 (t, J = 6.1 Hz, 2H) 1.47 (s, 6H). Mass spectrum (ESI, m/z): calcd. for C₂₉H₂₅N₅O₃, 491.2; found [M+H]+, 492.3. Example 20: N-(3-cyanophenyl)-5-(4'-(1-hydroxycyclobutyl)-[1,1'-biphenyl]-4-yl)-4-oxo- 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

The title compound was prepared in a manner analogous to Example 14, reacting 5-(4- bromophenyl)-N-(3-cyanophenyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3- carboxamide (Intermediate 10, 45 mg, 0.1 mmol) and [4-(1-hydroxycyclobutyl)phenyl]boronic acid (22.1 mg, 0.12 mmol).1H NMR (500 MHz, DMSO-d6) ^ ^ 12.54 (s, 1H) 8.21 (s, 1H) 8.19 (s, 1H) 7.81 (d, J = 8.5 Hz, 2H) 7.72 - 7.77 (m, 1H) 7.70 (d, J = 8.2 Hz, 2H) 7.58 - 7.63 (m, 4H) 7.52 - 7.57 (m, 2H) 5.54 (s, 1H) 4.70 (br t, J = 6.1 Hz, 2H) 4.33 (br t, J = 6.1 Hz, 2H) 2.38 - 2.47 (m, 2H) 2.26 - 2.35 (m, 2H) 1.94 (ddq, J = 15.3, 10.0, 4.9, 4.9, 4.9 Hz, 1H) 1.62 - 1.75 (m, 1H). Mass spectrum (ESI, m/z): calcd. for C₃₀H₂₅N₅O₃, 503.2; found [M+H]+, 504.3. Example 21: N-(3-cyanophenyl)-5-(4'-(ethoxymethyl)-3'-fluoro-[1,1'-biphenyl]-4-yl)-4-oxo- 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

5-(4-Bromophenyl)-N-(3-cyanophenyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3- carboxamide (Intermediate 10, 45 mg, 0.1 mmol), PdCl2(dppf) (7.0 mg, 0.01 mmol) and 2-[4- (ethoxymethyl)-3-fluorophenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (32.3 mg, 0.12 mmol) were dissolved in 1,4-dioxane (1 mL) and aqueous Na₂CO₃ (0.5 mL, 0.1 g/mL, 0.47 mmol). Then, the reaction was heated to 70ºC for 1 h. After the reaction was completed, water was added, and the crude product was extracted with EtOAc. The combined organic extracts were concentrated in vacuo. Then, the crude product was redissolved in DMSO, MeOH and aqueous ammonium bicarbonate (4 mL, 2:1.5:0.5 ratio). SiliaMetS ® Triamine scavenger (20 mg) was added and the mixture was stirred for 1 h. The crude mixture was then filtered and purified by Prep-HPLC (Conditions: stationary phase: C18 XBridge 30 x 100 mm 5 µm. Mobile phase: NH4HCO3 0.25% solution in water and CH3CN), to afford N-(3-cyanophenyl)-5-(4'- (ethoxymethyl)-3'-fluoro-[1,1'-biphenyl]-4-yl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine- 3-carboxamide (27.6 mg, 57% yield) as a solid after freeze-drying.1H NMR (500 MHz, DMSO- d₆) δ: 12.52 (s, 1H) 8.21 (s, 1H) 8.18 (s, 1H) 7.86 (d, J = 8.5 Hz, 2H) 7.74 (td, J = 4.7, 2.2 Hz, 1H) 7.62 (d, J = 8.5 Hz, 2H) 7.58 (s, 2H) 7.50 - 7.56 (m, 3H) 4.70 (br d, J = 6.6 Hz, 2H) 4.55 (s, 2H) 4.33 (t, J = 6.1 Hz, 2H) 3.54 (q, J = 7.0 Hz, 2H) 1.17 (t, J = 7.0 Hz, 3H). Mass spectrum (ESI, m/z): calcd. for C₂₉H₂₄FN₅O₃, 509.2; found [M+H]+, 510.3. Example 22: 5-(4'-(1-aminocyclopentyl)-[1,1'-biphenyl]-4-yl)-N-(3-cyanophenyl)-4-oxo- 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

The title compound was prepared in a manner analogous to Example 14, reacting 5-(4- bromophenyl)-N-(3-cyanophenyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3- carboxamide (Intermediate 10, 45 mg, 0.1 mmol) and 1-[4-(tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl]cyclopentan-1-amine (37.3 mg, 0.12 mmol).1H NMR (500 MHz, DMSO-d6) δ: 12.54 (s, 1H) 8.21 (s, 1H) 8.18 (d, J=1.1 Hz, 1H) 7.77 - 7.81 (m, 2H) 7.74 (ddd, J = 5.7, 3.7, 2.2 Hz, 1H) 7.64 - 7.67 (m, 2H) 7.58 - 7.62 (m, 4H) 7.52 - 7.56 (m, 2H) 4.66 - 4.78 (m, 2H) 4.26 - 4.38 (m, 2H) 1.86 - 1.94 (m, 4H) 1.77 - 1.84 (m, 2H) 1.69 - 1.76 (m, 2H). Mass spectrum (ESI, m/z): calcd. for C₃₁H₂₈N₆O₂, 516.2; found [M+H]+, 517.4.

biphenyl]-4-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide

The title compound was prepared in a manner analogous to Example 14, reacting 5-(4- bromophenyl)-N-(3-cyanophenyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3- carboxamide (Intermediate 10, 45 mg, 0.1 mmol) and 4,4,5,5-tetramethyl-2-[4-(oxan-2- yl)phenyl]-1,3,2-dioxaborolane (33.2 mg, 0.12 mmol).1H NMR (500 MHz, DMSO-d₆) δ: 12.48 - 12.62 (m, 1H) 8.21 (s, 1H) 8.19 (s, 1H) 7.80 (d, J=8.5 Hz, 2H) 7.74 (dt, J = 5.7, 2.8 Hz, 1H) 7.68 (d, J=8.1 Hz, 2H) 7.60 (br d, J = 8.4 Hz, 2H) 7.54 - 7.57 (m, 2H) 7.44 (d, J = 8.1 Hz, 2H) 4.70 (br t, J = 6.0 Hz, 2H) 4.37 (br d, J = 10.5 Hz, 1H) 4.33 (br t, J=6.0 Hz, 2H) 4.05 (br d, J = 10.7 Hz, 1H) 3.51 - 3.61 (m, 1H) 1.80 - 1.93 (m, 2H) 1.62 - 1.74 (m, 1H) 1.54 - 1.61 (m, 2H) 1.42 - 1.52 (m, 1H). Mass spectrum (ESI, m/z): calcd. for C + 31H27N5O3, 517.2; found [M+H] , 518.3. Example 24: N-(3-cyanophenyl)-4-oxo-5-(4'-(piperidin-1-ylmethyl)-[1,1'-biphenyl]-4-yl)- 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

The title compound was prepared in a manner analogous to Example 14, reacting 5-(4- bromophenyl)-N-(3-cyanophenyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3- carboxamide (Intermediate 10, 45 mg, 0.1 mmol) and 1-[4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)benzyl]piperidine (34.7 mg, 0.12 mmol). 1H NMR (500 MHz, DMSO-d₆) δ: 12.54 (s, 1H) 8.21 (s, 1H) 8.19 (d, J = 1.2 Hz, 1H) 7.78 - 7.82 (m, 2H) 7.74 (ddd, J = 5.6, 3.7, 2.2 Hz, 1H) 7.67 (d, J = 8.2 Hz, 2H) 7.58 - 7.63 (m, 2H) 7.53 - 7.56 (m, 2H) 7.40 (d, J = 8.2 Hz, 2H) 4.70 (dd, J = 7.0, 5.3 Hz, 2H) 4.28 - 4.37 (m, 2H) 3.47 (s, 2H) 2.36 (dt, J = 3.5, 1.8 Hz, 4H) 1.47 - 1.55 (m, 4H) 1.40 (br d, J = 4.6 Hz, 2H). Mass spectrum (ESI, m/z): calcd. for C₃₂H₃₀N₆O₂, 530.2; found [M+H]+, 531.4. Example 25: N-(3-cyanophenyl)-5-(4'-(morpholinomethyl)-[1,1'-biphenyl]-4-yl)-4-oxo- 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide

The title compound was prepared in a manner analogous to Example 14, reacting 5-(4- bromophenyl)-N-(3-cyanophenyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3- carboxamide (Intermediate 10, 45 mg, 0.1 mmol) and 4-[4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)benzyl]morpholine (34.9 mg, 0.12 mmol).1H NMR (500 MHz, DMSO-d6) ^ ^ ^12.54 (s, 1H) 8.21 (s, 1H) 8.17 - 8.19 (m, 1H) 7.78 - 7.82 (m, 2H) 7.72 - 7.76 (m, 1H) 7.69 (d, J = 8.2 Hz, 2H) 7.58 - 7.62 (m, 2H) 7.53 - 7.56 (m, 2H) 7.43 (d, J = 8.2 Hz, 2H) 4.68 - 4.73 (m, 2H) 4.31 - 4.36 (m, 2H) 3.59 (t, J = 4.6 Hz, 4H) 3.52 (s, 2H) 2.37 - 2.42 (m, 4H). Mass spectrum (ESI, m/z): calcd. for C₃₁H₂₈N₆O₃, 532.2; found [M+H]+, 533.2. Example 26: 5-(4'-(aminomethyl)-[1,1'-biphenyl]-4-yl)-N-(3-cyanophenyl)-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

The title compound was prepared in a manner analogous to Example 14, reacting 5-(4- bromophenyl)-N-(3-cyanophenyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3- carboxamide (Intermediate 10, 45 mg, 0.1 mmol) and 4-aminomethylphenylboronic acid hydrochloride (21.6 mg, 0.115 mmol).1H NMR (400 MHz, DMSO-d6) δ: 12.55 (s, 1H) 8.20 - 8.22 (m, 1H) 8.19 (d, J = 0.9 Hz, 1H) 7.80 (d, J = 8.6 Hz, 2H) 7.72 - 7.77 (m, 1H) 7.67 (d, J = 8.1 Hz, 2H) 7.60 (d, J = 8.6 Hz, 2H) 7.55 (d, J = 5.1 Hz, 2H) 7.46 (d, J = 8.3 Hz, 2H) 4.71 (t, J = 6.1 Hz, 2H) 4.33 (s, 2H) 3.77 (s, 2H). Mass spectrum (ESI, m/z): calcd. for C₃₂H₃₀N₆O₂, 462.2; found [M+H]+, 463.2. Example 27: N-(3-cyanophenyl)-5-(4-(2-((N-methylpropionamido)methyl)-benzyl)phenyl)- 4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide

The title compound was prepared in a manner analogous to Example 11, reacting N-(3- cyanophenyl)-5-(4-(2-((methylamino)methyl)benzyl)phenyl)-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide (Example 12, 20 mg, 0.041 mmol) and propionyl chloride (4.27 µL, 0.049 mmol).1H-NMR (400 MHz, DMSO-d6) δ: 12.39 (s, 1H), 8.16 (s, 1H), 8.13 - 8.09 (m, 1H), 7.74 (br d, J = 8.0 Hz, 1H), 7.56 - 7.47 (m, 2H), 7.43 (br d, J = 8.0 Hz, 2H), 7.31 - 7.06 (m, 6H), 4.69 - 4.63 (m, 2H), 4.57 (s, 2H), 4.28 - 4.22 (m, 2H), 4.07 (s, 2H), 2.81 (s, 3H), 2.31 - 2.16 (m, 2H), 1.06 - 0.90 (m, 3H). Mass spectrum (ESI, m/z): Calcd. for C H N O , 546.2, found [M+ + 32 30 6 3 H] , 547.3. Example 28: N-(3-cyanophenyl)-5-(4-(4-((dimethylamino)methyl)benzyl)phenyl)-4-oxo- 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

The title compound was prepared in a manner analogous to Example 10, reacting 5-(4-(4- (aminomethyl)benzyl)phenyl)-N-(3-cyanophenyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrazine-3-carboxamide (Example 13, 50 mg, 0.1 mmol) and formaldehyde (95.5 mg, 1.05 mmol).1H-NMR (400 MHz, DMSO-d6) δ: 12.54 (s, 1H), 8.20 - 8.16 (m, 2H), 7.74 - 7.68 (m, 1H), 7.56 - 7.50 (m, 2H), 7.45 - 7.39 (m, 2H), 7.39 - 7.34 (m, 2H), 7.26 - 7.20 (m, 4H), 4.65 (t, J = 6.0 Hz, 2H), 4.24 (t, J = 6.0 Hz, 2H), 3.97 (s, 2H), 3.36 (s, 2H), 2.14 (s, 6H). Mass spectrum (ESI, m/z): Calcd. for C H N O , 504.2, found [M + 30 28 6 2 +H] , 505.3.

The title compound was prepared in a manner analogous to Example 4, reacting N-(3- cyanophenyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide (Intermediate 9, 135 mg, 0.48 mmol) and (3-(4-bromobenzyl)phenyl)methanol (200 mg, 0.72 mmol).1H-NMR (400 MHz, DMSO-d6) δ: 12.52 (s, 1H), 8.18 (s, 2H), 7.71 - 7.70 (m, 1H), 7.56 - 7.51 (m, 2H), 7.44 - 7.40 (m, 2H), 7.39 - 7.34 (m, 2H), 7.28 - 7.23 (m, 2H), 7.19 - 7.14 (m, 2H), 5.16 (t, J = 5.6 Hz, 1H), 4.67 - 4.62 (m, 2H), 4.47 (d, J = 4.8 Hz, 2H), 4.27 - 4.22 (m, 2H), 3.98 (s, 2H). Mass spectrum (ESI, m/z): Calcd. for C₂₈H₂₃N₅O₃, 477.2, found [M+H]+, 478.2. Example 30: N-(3-cyanophenyl)-5-(4-(3-(methoxymethyl)benzyl)phenyl)-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

Step A: 1-(4-bromobenzyl)-3-(methoxymethyl)benzene. NaH (190 mg, 4.76 mmol, 60%) was added to a solution of (3-(4-bromobenzyl)phenyl)methanol (440 mg, 1.59 mmol) in DMF (5 mL) at 0°C. The mixture was stirred at 0°C for 30 min and then, iodomethane (296 µL, 4.76 mmol) was added dropwise. The resulting mixture was stirred at rt for 2 h. The reaction was monitored by TLC. The mixture was poured into sat. aq NH4Cl and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na₂SO₄, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography (0-20% EtOAc/PE) to afford 1-(4-bromobenzyl)-3-(methoxymethyl)benzene as yellow oil (350 mg, 76% yield).1H-NMR (400 MHz, DMSO-d6) δ: 7.47 (d, J = 8.0 Hz, 2H), 7.27 (d, J = 6.4 Hz, 2H), 7.23 (d, J = 5.6 Hz, 1H), 7.18 (d, J = 8.4 Hz, 3H), 4.35 (s, 2H), 3.92 (d, J = 6.8 Hz, 2H), 3.26 (s, 3H). Step B: N-(3-cyanophenyl)-5-(4-(3-(methoxymethyl)benzyl)phenyl)-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide. The title compound was prepared in a manner analogous to Example 4, reacting N-(3- cyanophenyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide (Intermediate 9, 225.4 mg, 0.8 mmol) and 1-(4-bromobenzyl)-3-(methoxymethyl)benzene (350 mg, 1.2 mmol). 1H-NMR (400 MHz, Methanol-d4) δ: 8.17 (s, 2H), 7.77 (d, J = 7.6 Hz, 1H), 7.46 - 7.35 (m, 6H), 7.31 - 7.23 (m, 2H), 7.22 - 7.17 (m, 2H), 4.66 - 4.61 (m, 2H), 4.43 (s, 2H), 4.25 (t, J = 6.0 Hz, 2H), 4.04 (s, 2H), 3.36 (s, 3H). Mass spectrum (ESI, m/z): Calcd. for C29H25N5O3, 491.2, found [M+H]+, 492.2. Example 31: 5-(4-(3-(aminomethyl)benzyl)phenyl)-N-(3-cyanophenyl)-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

Step A: 3-(4-bromobenzyl)benzonitrile. The title compound was prepared in a manner analogous to Example 9, Step A, reacting 3- cyanobenzylzinc bromide (10 mL, 5 mmol, 0.5 M in THF) and 1-bromo-4-iodobenzene (1.41 g, 5 mmol). Step B: tert-butyl (3-(4-bromobenzyl)benzyl)carbamate. The title compound was prepared in a manner analogous to Example 9, Step B, reacting 3-(4- bromobenzyl)benzonitrile (700 mg, 2.57 mmol), di-tert-butyl dicarbonate (1.18 ml, 5.14 mmol), NaBH4 (584 mg, 14.43 mmol) and nickel chloride hexahydrate (37 mg, 0.15 mmol). Step C: tert-butyl (3-(4-(3-((3-cyanophenyl)carbamoyl)-4-oxo-6,7-dihydropyrazolo[1,5- a]pyrazin-5(4H)-yl)benzyl)benzyl)carbamate. The title compound was prepared in a manner analogous to Example 4, reacting N-(3- cyanophenyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide (Intermediate 9, 507 mg, 1.59 mmol) and tert-butyl (3-(4-bromobenzyl)benzyl)carbamate (720 mg, 1.91 mmol). Step D: 5-(4-(3-(aminomethyl)benzyl)phenyl)-N-(3-cyanophenyl)-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide. The title compound was prepared in a manner analogous to Example 9, Step D, reacting tert- butyl (3-(4-(3-((3-cyanophenyl)carbamoyl)-4-oxo-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)- yl)benzyl)benzyl)carbamate (900 mg, 1.56 mmol) and HCl in 1,4-dioxane (12 mL, 48 mmol, 4 M).1H-NMR (400 MHz, DMSO-d6) δ: 12.53 (s, 1H), 8.20 - 8.14 (m, 2H), 7.74 - 7.66 (m, 1H), 7.55 - 7.49 (m, 2H), 7.44 - 7.34 (m, 4H), 7.28 - 7.21 (m, 2H), 7.19 - 7.10 (m, 2H), 4.65 (m, 2H), 4.28 - 4.20 (m, 2H), 3.96 (s, 2H), 3.69 (s, 2H). Mass spectrum (ESI, m/z): Calcd. for C₂₈H₂₄N₆O₂, 476.2, found [M+H]+, 477.2. Example 32: N-(3-cyanophenyl)-4-oxo-5-(4-(3-(propionamidomethyl)benzyl)-phenyl)- 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

The title compound was prepared in a manner analogous to Example 11, reacting 5-(4-(3- (aminomethyl)benzyl)phenyl)-N-(3-cyanophenyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrazine-3-carboxamide (Example 31, 40 mg, 0.084 mmol) and propionyl chloride (8.8 µL, 0.1 mmol).1H-NMR (400 MHz, DMSO-d₆) δ: 12.53 (s, 1H), 8.24 (br t, J = 5.2 Hz, 1H), 8.20 - 8.16 (m, 2H), 7.74 - 7.67 (m, 1H), 7.56 - 7.50 (m, 2H), 7.44 - 7.33 (m, 4H), 7.29 - 7.24 (m, 1H), 7.19 - 7.15 (m, 2H), 7.09 (d, J = 7.6 Hz, 1H), 4.69 - 4.62 (m, 2H), 4.28 - 4.21 (m, 4H), 3.97 (s, 2H), 2.13 (q, J = 7.6 Hz, 2H), 1.02 (t, J=7.6 Hz, 3H). Mass spectrum (ESI, m/z): Calcd. for C H N O , 532.2, found [M+H]+ 31 28 6 3 , 533.3. Example 33: N-(3-cyanophenyl)-5-(4-(4-(hydroxymethyl)benzyl)phenyl)-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

Step A: (4-(4-bromobenzyl)phenyl)methanol. A mixture of 1-bromo-4-(bromomethyl)benzene (6.41 g, 25.7 mmol), (4- (hydroxymethyl)phenyl)boronic acid (3 g, 19.7 mmol), Na₂CO₃ (4.18 g, 39.5 mmol) and Pd(PPh₃)₄ (1.14 g, 0.99 mmol) in toluene (40 mL), EtOH (30 mL) and water (20 mL) under nitrogen was stirred at 100°C for 12 h. The reaction was monitored by TLC. Upon completion of reaction, the mixture was concentrated in vacuo. The crude product was purified by silica gel chromatography (0-20% EtOAc/PE) to afford (4-(4-bromobenzyl)phenyl)methanol as yellow oil (1.47 g, 19% yield).1H-NMR (400 MHz, Methanol-d₄) δ: 7.41 (d, J = 8.0 Hz, 2H), 7.27 (s, 2H), 7.22 - 7.15 (m, 2H), 7.06 (d, J = 8.0 Hz, 2H), 4.67 (br s, 2H), 4.02 - 3.91 (m, 2H). Step B: N-(3-cyanophenyl)-5-(4-(4-(hydroxymethyl)benzyl)phenyl)-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide. The title compound was prepared in a manner analogous to Example 4, reacting N-(3- cyanophenyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide (Intermediate 9, 100 mg, 0.36 mmol) and (4-(4-bromobenzyl)phenyl)methanol (148 mg, 0.53 mmol).1H-NMR (400 MHz, DMSO-d₆) δ: 12.54 (s, 1H), 8.18 (s, 2H), 7.73 - 7.68 (m, 1H), 7.57 - 7.51 (m, 2H), 7.45 - 7.38 (m, 2H), 7.38 - 7.32 (m, 2H), 7.25 (s, 4H), 5.17 - 5.06 (m, 1H), 4.65 (t, J = 6.8 Hz, 2H), 4.49 - 4.42 (m, 2H), 4.24 (t, J = 6.4 Hz, 2H), 3.97 (s, 2H). Mass spectrum (ESI, m/z): Calcd. for C H N O , 477.2, found [M+H + 28 23 5 3 ] , 478.2. Example 34: N-(3-cyanophenyl)-5-(4-(4-(methoxymethyl)benzyl)phenyl)-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

Step A: 1-bromo-4-(4-(methoxymethyl)benzyl)benzene. The title compound was prepared in a manner analogous to Example 30, Step A, reacting (4-(4- bromobenzyl)phenyl)methanol (Example 36, product from Step A, 500 mg, 1.8 mmol) and iodomethane (0.337 mL, 5.41 mmol). Step B: N-(3-cyanophenyl)-5-(4-(4-(methoxymethyl)benzyl)phenyl)-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide. The title compound was prepared in a manner analogous to Example 4, reacting N-(3- cyanophenyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide (Intermediate 9, 100 mg, 0.36 mmol) and 1-bromo-4-(4-(methoxymethyl)benzyl)benzene (155 mg, 0.53 mmol). 1H-NMR (400 MHz, DMSO-d6) δ: 12.54 (s, 1H), 8.18 (s, 2H), 7.70 (td, J = 2.4, 6.8 Hz, 1H), 7.57 - 7.49 (m, 2H), 7.44 - 7.39 (m, 2H), 7.39 - 7.33 (m, 2H), 7.30 - 7.23 (m, 4H), 4.68 - 4.62 (m, 2H), 4.36 (s, 2H), 4.28 - 4.21 (m, 2H), 3.98 (s, 2H), 3.27 (s, 3H). Mass spectrum (ESI, m/z): Calcd. for C29H25N5O3, 491.2, found [M+H]+, 492.0.

biphenyl]-4-yl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

The title compound was prepared in a manner analogous to Example 14, reacting 5-(4- bromophenyl)-N-(3-cyanophenyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3- carboxamide (Intermediate 10, 45 mg, 0.1 mmol) and 2-methyl-1-{[4-(tetramethyl-1,3,2- dioxaborolan-2-yl)phenyl]methyl}pyrrolidine (34.7 mg, 0.12 mmol).1H NMR (500 MHz, DMSO-d6) δ: 12.54 (s, 1H) 8.21 (s, 1H) 8.19 (d, J = 1.1 Hz, 1H) 7.78 - 7.82 (m, 2H) 7.72 - 7.76 (m, 1H) 7.67 (d, J = 8.1 Hz, 2H) 7.58 - 7.62 (m, 2H) 7.53 - 7.57 (m, 2H) 7.41 (d, J = 8.2 Hz, 2H) 4.67 - 4.76 (m, 2H) 4.28 - 4.39 (m, 2H) 4.02 (d, J = 13.3 Hz, 1H) 3.17 (d, J = 13.3 Hz, 1H) 2.82 (ddd, J = 9.0, 7.3, 3.5 Hz, 1H) 2.38 - 2.45 (m, 1H) 2.08 (q, J = 8.7 Hz, 1H) 1.89 - 1.98 (m, 1H) 1.57 - 1.67 (m, 2H) 1.36 (dddd, J = 12.2, 10.1, 8.5, 6.6 Hz, 1H) 1.12 (d, J = 6.0 Hz, 3H). Mass spectrum (ESI, m/z): calcd. for C + 32H30N6O2, 530.2; found [M+H] , 531.4. Example 36: N-(3-cyanophenyl)-5-(3'-fluoro-4'-(methoxymethyl)-[1,1'-biphenyl]-4-yl)-4- oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

The title compound was prepared in a manner analogous to Example 14, reacting 5-(4- bromophenyl)-N-(3-cyanophenyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3- carboxamide (Intermediate 10, 45 mg, 0.1 mmol) and 2-[3-fluoro-4-(methoxymethyl)phenyl]- 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (30.6 mg, 0.12 mmol).1H NMR (500 MHz, DMSO-d₆) δ: 12.52 (s, 1H) 8.21 (s, 1H) 8.18 (d, J = 1.1 Hz, 1H) 7.84 - 7.88 (m, 2H) 7.74 (br dd, J = 3.7, 1.5 Hz, 1H) 7.58 - 7.65 (m, 4H) 7.50 - 7.56 (m, 3H) 4.70 (dd, J = 7.0, 5.3 Hz, 2H) 4.51 (s, 2H) 4.26 - 4.37 (m, 2H) 3.34 (s, 3H). Mass spectrum (ESI, m/z): calcd. for C28H22FN5O3, 495.2; found [M+H]+, 496.3. Example 37: N-(3-cyanophenyl)-5-(4-(3-((dimethylamino)methyl)benzyl)phenyl)-4-oxo- 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

The title compound was prepared in a manner analogous to Example 10, reacting 5-(4-(3- (aminomethyl)benzyl)phenyl)-N-(3-cyanophenyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrazine-3-carboxamide (Example 31, 100 mg, 0.21 mmol) and formaldehyde (156 µL, 2.1 mmol).1H-NMR (400 MHz, DMSO-d₆) δ: 12.53 (s, 1H), 8.20 - 8.13 (m, 2H), 7.74 - 7.67 (m, 1H), 7.56 - 7.49 (m, 2H), 7.44 - 7.40 (m, 2H), 7.38 - 7.33 (m, 2H), 7.31 - 7.23 (m, 2H), 7.22 - 7.12 (m, 2H), 4.68 - 4.59 (m, 2H), 4.28 - 4.20 (m, 2H), 3.99 (s, 2H), 3.44 (br s, 2H), 2.18 (s, 6H). Mass spectrum (ESI, m/z): Calcd. for C₃₀H₂₈N₆O₂, 504.2, found [M+H]+, 505.3. Example 38: N-(3-cyanophenyl)-5-(4-(3-((methylamino)methyl)benzyl)phenyl)-4-oxo- 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

The title compound was prepared in a manner analogous to Example 12, reacting 5-(4-(3- (aminomethyl)benzyl)phenyl)-N-(3-cyanophenyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrazine-3-carboxamide (Example 31, 200 mg, 0.42 mmol) and methyl trifluoromethanesulfonate (71.25 µL, 0.63 mmol).1H-NMR (400 MHz, DMSO-d6) δ: 12.54 (s, 1H), 8.21 - 8.14 (m, 2H), 7.74 - 7.67 (m, 1H), 7.55 - 7.49 (m, 2H), 7.45 - 7.39 (m, 2H), 7.39 - 7.34 (m, 2H), 7.28 - 7.21 (m, 2H), 7.17 - 7.11 (m, 2H), 4.65 (m, 2H), 4.29 - 4.21 (m, 2H), 3.97 (s, 2H), 3.60 (s, 2H), 2.25 (s, 3H). Mass spectrum (ESI, m/z): Calcd. for C29H26N6O2, 490.2, found [M+H]+, 491.2. Example 39: N-(3-cyanophenyl)-5-(4-(3-((N-methylpropionamido)methyl)-benzyl)phenyl)- 4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

The title compound was prepared in a manner analogous to Example 11, reacting N-(3- cyanophenyl)-5-(4-(3-((methylamino)methyl)benzyl)phenyl)-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide (Example 38, 60 mg, 0.12 mmol) and propionyl chloride (12.82 µL, 0.15 mmol).1H-NMR (400 MHz, DMSO-d6) δ: 12.37 (s, 1H), 8.17 - 8.11 (m, 2H), 7.74 (td, J = 1.6, 7.6 Hz, 1H), 7.55 - 7.47 (m, 2H), 7.46 - 7.40 (m, 2H), 7.38 - 7.32 (m, 2H), 7.32 - 7.15 (m, 2H), 7.13 (s, 1H), 7.05 (d, J = 7.6 Hz, 1H), 4.69 - 4.63 (m, 2H), 4.52 (br s, 2H), 4.30 - 4.21 (m, 2H), 4.01 (s, 2H), 2.88 (br s, 3H), 2.41 - 2.29 (m, 2H), 1.11 - 0.94 (m, 3H). Mass spectrum (ESI, m/z): Calcd. for C₃₂H₃₀N₆O₃, 546.2, found [M+H]+, 547.3. Example 40: N-(3-cyanophenyl)-5-(4-((3,3-difluorocyclobutyl)methyl)phenyl)-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

CH3CN (0.75 mL) was added to a mixture of 5-(4-bromophenyl)-N-(3-cyanophenyl)-4-oxo- 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide (Intermediate 10, 34.1 mg, 0.07 mmol), 3-(bromomethyl)-1,1-difluorocyclobutane (26.9 mg, 0.15 mmol), Na₂CO₃ (23.1 mg, 0.22 mmol), (4,4'-dtbbpy)NiCl2 (2.9 mg, 0.007 mmol) and (Ir[dF(CF3)ppy]2(dtbpy))PF6 (1.6 mg, 0.002 mmol). Then, (hydroxy-bis(trimethylsilyl)silyl)-trimethylsilane (22.4 µL, 0.073 mmol) was added. The reaction was irradiated in a Penn Photoreactor® (wavelength: 450 nm; LED intensity: 100%; fan speed: ~6000 rpm; stir: ~1000 rpm) for 1 h. After the reaction was completed, water was added. The crude product was extracted with EtOAc and the organic phase was concentrated in vacuo. The crude product was then redissolved in a mixture of DMSO, MeOH and aqueous ammonium bicarbonate (4 mL, 2:1.5:0.5 ratio). The resulting solution was filtered and purified by Prep-HPLC (Conditions: stationary phase: C18 XBridge 30 x 100 mm 10 µm. Mobile phase: NH₄HCO₃0.25% solution in water and CH₃CN). The desired fractions were collected and concentrated in vacuo to afford N-(3-cyanophenyl)-5-(4-((3,3- difluorocyclobutyl)methyl)phenyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3- carboxamide (5.0 mg, 15% yield) as a white solid after freeze-drying.1H NMR (500 MHz, DMSO-d6) ^ ^ 12.53 (s, 1H) 8.19 (s, 1H) 8.15 - 8.18 (m, 1H) 7.70 - 7.74 (m, 1H) 7.53 - 7.56 (m, 2H) 7.41 - 7.45 (m, 2H) 7.33 - 7.38 (m, 2H) 4.64 - 4.69 (m, 2H) 4.23 - 4.28 (m, 2H) 2.84 (d, J = 7.5 Hz, 2H) 2.60 - 2.71 (m, 2H) 2.40 - 2.49 (m, 2H) 2.27 - 2.39 (m, 1H). Mass spectrum (ESI, m/z): Calcd. for C + 25H21F2N5O2, 461.2, found [M+H] , 462.3. Example 41: N-(3-cyanophenyl)-5-(4-(cyclopentylmethyl)phenyl)-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

The title compound was prepared in a manner analogous to Example 40, reacting 5-(4- bromophenyl)-N-(3-cyanophenyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3- carboxamide (Intermediate 10, 34.1 mg, 0.07 mmol) and (bromomethyl)cyclopentane (23.7 mg, 0.15 mmol).1H NMR (500 MHz, DMSO-d₆) δ: 12.55 (s, 1H) 8.19 (s, 2H) 7.69 - 7.74 (m, 1H) 7.51 - 7.57 (m, 2H) 7.38 - 7.45 (m, 2H) 7.32 (d, J = 8.4 Hz, 2H) 4.66 (dd, J = 6.9, 5.3 Hz, 2H) 4.17 - 4.31 (m, 2H) 2.63 - 2.65 (m, 2H) 2.05 - 2.18 (m, 1H) 1.56 - 1.72 (m, 4H) 1.45 - 1.53 (m, 2H) 1.16 - 1.29 (m, 2H). Mass spectrum (ESI, m/z): Calcd. for C₂₆H₂₅N₅O₂, 439.2, found [M+H]+, 440.3. Example 42: (rac)- N-(3-cyanophenyl)-5-(4-((1-methyl-5-oxopyrrolidin-3- yl)methyl)phenyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

The title compound was prepared in a manner analogous to Example 40, reacting 5-(4- bromophenyl)-N-(3-cyanophenyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3- carboxamide (Intermediate 10, 34.1 mg, 0.07 mmol) and 4-(bromomethyl)-1-methyl-2- pyrrolidinone (27.9 mg, 0.15 mmol).1H NMR (500 MHz, DMSO-d6) δ: 12.53 (s, 1H) 8.19 (s, 1H) 8.18 (d, J = 1.1 Hz, 1H) 7.72 (td, J = 4.7, 2.2 Hz, 1H) 7.53 - 7.56 (m, 2H) 7.42 - 7.46 (m, 2H) 7.34 - 7.39 (m, 2H) 4.67 (dd, J = 7.0, 5.3 Hz, 2H) 4.21 - 4.36 (m, 2H) 3.38 (dd, J = 9.6, 7.8 Hz, 1H) 3.08 (dd, J = 9.6, 6.0 Hz, 1H) 2.74 - 2.78 (m, 2H) 2.70 (s, 3H) 2.65 - 2.69 (m, 1H) 2.29 - 2.35 (m, 1H) 2.04 (dd, J = 16.5, 7.0 Hz, 1H). Mass spectrum (ESI, m/z): Calcd. for C₂₆H₂₄N₆O₃, 468.2, found [M+H]+, 469.3. Example 43: N-(3-cyanophenyl)-4-oxo-5-(4-phenethylphenyl)-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

The title compound was prepared in a manner analogous to Example 40, reacting 5-(4- bromophenyl)-N-(3-cyanophenyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3- carboxamide (Intermediate 10, 34.1 mg, 0.07 mmol) and (2-bromoethyl)benzene (26.9 mg, 0.15 mmol).1H NMR (500 MHz, DMSO-d6) δ: 12.57 (s, 1H) 8.19 (s, 1H) 8.17 (d, J=0.9 Hz, 1H) 7.70 - 7.77 (m, 1H) 7.52 - 7.56 (m, 2H) 7.36 - 7.44 (m, 4H) 7.26 - 7.32 (m, 4H) 7.15 - 7.23 (m, 1H) 4.58 - 4.73 (m, 2H) 4.14 - 4.32 (m, 2H) 2.93 (s, 4H). Mass spectrum (ESI, m/z): Calcd. for C H N O , 461.2, f + 28 23 5 2 ound [M+H] , 462.3. Example 44: N-(3-cyanophenyl)-4-oxo-5-(4-(3,3,3-trifluoropropyl)phenyl)-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

CH3CN (0.75 mL) was added to a mixture of 5-(4-bromophenyl)-N-(3-cyanophenyl)-4-oxo- 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide (Intermediate 10, 34.1 mg, 0.07 mmol), 3-bromo-1,1,1-trifluoropropane (25.7 mg, 0.15 mmol), Na₂CO₃ (23.1 mg, 0.22 mmol), (4,4'-dtbbpy)NiCl2 (2.9 mg, 0.007 mmol) and (Ir[dF(CF3)ppy]2(dtbpy))PF6 (1.6 mg, 0.001 mmol). Then, (hydroxy-bis(trimethylsilyl)silyl)-trimethylsilane (22.4 µL, 0.073 mmol) was added. The reaction was irradiated in a Penn Photoreactor® (wavelength: 450 nm; LED intensity: 100%; fan speed: ~6000 rpm; stir: ~1000 rpm) for 1 h. After the reaction was completed, water was added. The crude product was extracted with EtOAc and the organic phase was concentrated in vacuo. The crude product was then redissolved in a mixture of DMSO, MeOH and aqueous ammonium bicarbonate (4 mL, 2:1.5:0.5 ratio). The resulting solution was filtered and purified by Prep-HPLC (Conditions: stationary phase: C18 XBridge 30 x 100 mm 10 µm. Mobile phase: NH4HCO30.25% solution in water and CH3CN). The desired fractions were collected and concentrated in vacuo to afford N-(3-cyanophenyl)-4-oxo-5-(4-(3,3,3- trifluoropropyl)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide (11.2 mg, 34% yield) as a white solid after freeze-drying.1H NMR (500 MHz, DMSO-d6) δ: 12.54 (s, 1H) 8.19 (s, 1H) 8.15 - 8.17 (m, 1H) 7.73 (dd, J = 4.7, 2.1 Hz, 1H) 7.53 - 7.58 (m, 2H) 7.45 (d, J = 1.8 Hz, 4H) 4.67 (dd, J = 7.1, 5.3 Hz, 2H) 4.26 (dd, J = 6.9, 5.4 Hz, 2H) 2.82 - 2.93 (m, 2H) 2.63 - 2.70 (m, 2H). Mass spectrum (ESI, m/z): Calcd. for C₂₃H₁₈F₃N₅O₂, 453.2, found [M+H]+, 454.3. Example 45: N-(3-cyanophenyl)-4-oxo-5-(4-(4,4,4-trifluorobutyl)phenyl)-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

CH₃CN (0.75 mL) was added to a mixture of 5-(4-bromophenyl)-N-(3-cyanophenyl)-4-oxo- 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide (Intermediate 10, 34.1 mg, 0.07 mmol), 4,4,4-trifluorobutyl bromide (27.8 mg, 0.15 mmol), Na2CO3 (23.1 mg, 0.22 mmol), (4,4'- dtbbpy)NiCl2 (2.9 mg, 0.007 mmol) and (Ir[dF(CF3)ppy]2(dtbpy))PF6 (1.6 mg, 0.001 mmol). Then, (hydroxy-bis(trimethylsilyl)silyl)-trimethylsilane (22.4 µL, 0.07 mmol) was added. The reaction was irradiated in a Penn Photoreactor® (wavelength: 450 nm; LED intensity: 100%; fan speed: ~6000 rpm; stir: ~1000 rpm) for 1 h. After the reaction was completed, was added. The crude product was extracted with EtOAc and the organic phase was concentrated in vacuo. The crude product was then redissolved in a mixture of DMSO, MeOH and aqueous ammonium bicarbonate (4 mL, 2:1.5:0.5 ratio). The resulting solution was filtered and purified by Prep- HPLC (Conditions: stationary phase: C18 XBridge 30 x 100 mm 10 µm. Mobile phase: NH₄HCO₃ 0.25% solution in water and CH₃CN). The desired fractions were collected and concentrated in vacuo to afford N-(3-cyanophenyl)-4-oxo-5-(4-(4,4,4-trifluorobutyl)phenyl)- 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide (4.0 mg, 12% yield) as a white solid after freeze-drying.1H NMR (500 MHz, DMSO-d₆) δ: 12.55 (s, 1H) 8.19 (s, 1H) 8.18 (d, J = 1.1 Hz, 1H) 7.69 - 7.74 (m, 1H) 7.53 - 7.56 (m, 2H) 7.42 - 7.46 (m, 2H) 7.35 - 7.39 (m, 2H) 4.67 (dd, J = 6.9, 5.3 Hz, 2H) 4.22 - 4.31 (m, 2H) 2.72 (t, J = 7.8 Hz, 2H) 2.23 - 2.34 (m, 2H) 1.83 (quin, J = 7.9 Hz, 2H). Mass spectrum (ESI, m/z): Calcd. for C₂₄H₂₀F₃N₅O₂, 467.2, found [M+H]+, 468.3. Example 46: N-(3-cyanophenyl)-5-(4-(4-((methylamino)methyl)benzyl)phenyl)-4-oxo- 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

The title compound was prepared in a manner analogous to Example 12, reacting 5-(4-(4- (aminomethyl)benzyl)phenyl)-N-(3-cyanophenyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrazine-3-carboxamide (Example 13, 300 mg, 0.58 mmol) and methyl trifluoromethanesulfonate (99.3 µL, 0.88 mmol).1H-NMR (400 MHz, DMSO-d6) δ: 12.54 (s, 1H), 8.18 (s, 2H), 7.75 - 7.66 (m, 1H), 7.58 - 7.49 (m, 2H), 7.45 - 7.31 (m, 4H), 7.28 - 7.20 (m, 4H), 4.65 (m, 2H), 4.24 (m, 2H), 3.96 (s, 1H), 4.01 - 3.90 (m, 1H), 3.58 (s, 2H), 2.24 (s, 3H). Mass spectrum (ESI, m/z): Calcd. for C + 29H26N6O2, 490.2, found [M+H] , 491.2. Example 47: N-(3-cyanophenyl)-5-(4-(4-((N-methylpropionamido)methyl)-benzyl)phenyl)- 4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

The title compound was prepared in a manner analogous to Example 11, reacting N-(3- cyanophenyl)-5-(4-(4-((methylamino)methyl)benzyl)phenyl)-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide (Example 46, 30 mg, 0.057 mmol) and propionyl chloride (6 µL, 0.068 mmol).1H-NMR (400 MHz, DMSO-d₆) δ: 12.36 (s, 1H), 8.14 (m, 2H), 7.74 (d, J = 7.6 Hz, 1H), 7.57 - 7.47 (m, 2H), 7.45 - 7.32 (m, 4H), 7.25 (br s, 2H), 7.16 (m, 2H), 4.66 (t, J = 5.6 Hz, 2H), 4.49 (s, 2H), 4.25 (t, J = 6.0 Hz, 2H), 3.99 (s, 2H), 2.88 (s, 3H), 2.42 - 2.30 (m, 2H), 1.03 (t, J = 7.2 Hz, 3H). Mass spectrum (ESI, m/z): Calcd. for C₃₂H₃₀N₆O₃, 546.2, found [M+H]+, 547.3. Example 48: N-(3-cyanophenyl)-5-(4-(3-(2-hydroxyethyl)benzyl)phenyl)-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

Step A: 2-(3-(4-bromobenzyl)phenyl)ethan-1-ol. The title compound was prepared in a manner analogous to Example 33, Step A, reacting 1- bromo-4-(bromomethyl)benzene (979 mg, 3.92 mmol) and (3-(2-hydroxyethyl)phenyl)boronic acid (500 mg, 3.01 mmol). Step B: N-(3-cyanophenyl)-5-(4-(3-(2-hydroxyethyl)benzyl)phenyl)-4-oxo-

tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide. The title compound was prepared in a manner analogous to Example 4, reacting N-(3- cyanophenyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide (Intermediate 9, 160 mg, 0.57 mmol) and 2-(3-(4-bromobenzyl)phenyl)ethan-1-ol (199 mg, 0.68 mmol).1H- NMR (400 MHz, DMSO-d6) δ: 12.54 (s, 1H), 8.18 (s, 2H), 7.73 - 7.66 (m, 1H), 7.55 - 7.50 (m, 2H), 7.45 - 7.33 (m, 4H), 7.24 - 7.18 (m, 1H), 7.16 (s, 1H), 7.08 (dd, J = 7.6, 16.4 Hz, 2H), 4.70 - 4.59 (m, 3H), 4.25 (br t, J = 6.0 Hz, 2H), 3.95 (s, 2H), 3.65 - 3.55 (m, 2H), 2.70 (t, J=7.2 Hz, 2H). Mass spectrum (ESI, m/z): Calcd. for C₂₉H₂₅N₅O₃, 491.2, found [M+H]+, 492.2. Example 49: N-(3-cyanophenyl)-5-(4-(3-(2-methoxyethyl)benzyl)phenyl)-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

Step A: 1-(4-bromobenzyl)-3-(2-methoxyethyl)benzene. The title compound was prepared in a manner analogous to Example 30, Step A, reacting 2-(3- (4-bromobenzyl)phenyl)ethan-1-ol (Example 48, product from Step A, 190 mg, 0.65 mmol) and iodomethane (278 mg, 1.96 mmol). Step B: N-(3-cyanophenyl)-5-(4-(4-(methoxymethyl)benzyl)phenyl)-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide. The title compound was prepared in a manner analogous to Example 4, reacting N-(3- cyanophenyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide (Intermediate 9, 82.2 mg, 0.29 mmol) and 1-(4-bromobenzyl)-3-(2-methoxyethyl)benzene (107 mg, 0.35 mmol). 1H-NMR (400 MHz, DMSO-d6) δ: 12.54 (s, 1H), 8.18 (s, 2H), 7.73 - 7.70 (m, 1H), 7.56 - 7.50 (m, 2H), 7.45 - 7.34 (m, 4H), 7.26 - 7.16 (m, 2H), 7.10 (dd, J = 7.6, 14.8 Hz, 2H), 4.65 (br t, J = 5.6 Hz, 2H), 4.25 (br t, J = 6.4 Hz, 2H), 3.96 (s, 2H), 3.53 (t, J = 6.8 Hz, 2H), 3.23 (s, 3H), 2.78 (t, J = 6.8 Hz, 2H). Mass spectrum (ESI, m/z): Calcd. for C + 30H27N5O3, 505.2, found [M+H] , 506.2. Example 50: N-(3-cyanophenyl)-5-(4-(2-(hydroxymethyl)benzyl)phenyl)-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide

Step A: methyl 2-(4-bromobenzyl)benzoate. To a solution of N'-(4-bromobenzylidene)-4-methylbenzenesulfonohydrazide (286 mg, 0.81 mmol) in MeOH (5 mL) under nitrogen, was added K2CO3 (224 mg, 1.62 mmol), Pd(OAc)2 (6.1 mg, 0.027 mmol), dppf (22 mg, 0.04 mmol) and 2-bromobenzaldehyde (100 mg, 0.54 mmol). The mixture was stirred at 100°C for 3 h. The reaction was monitored by TLC. The mixture was filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography (0-1% EtOAc/PE) to afford methyl 2-(4-bromobenzyl)benzoate as a yellow oil (200 mg, 61% yield).1H-NMR (400 MHz, CDCl₃) δ: 7.91 (m, 1H), 7.76 - 7.69 (m, 1H), 7.48 - 7.41 (m, 2H), 7.39 - 7.35 (m, 2H), 7.30 (m, 1H), 7.23 - 7.18 (m, 1H), 7.02 (m, 2H), 4.33 (s, 2H), 3.82 (s, 3H). Step B: (2-(4-bromobenzyl)phenyl)methanol. To a solution of methyl 2-(4-bromobenzyl)benzoate (200 mg, 0.65 mmol) in THF (8 mL), at 0ºC and under nitrogen, was added Red-Al® (0.37 mL, 1.31 mmol, 3.5 M of toluene solution) diluted with THF (2 mL). The mixture was stirred at rt for 12 h. The reaction was monitored by TLC. Upon completion of the reaction, the mixture was diluted with sat. aq. NH₄Cl and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography (1:0 to 1:2 EtOAc/PE) to afford (2-(4-bromobenzyl)phenyl)methanol as colourless oil (105 mg, 58% yield).1H-NMR (400 MHz, CDCl₃) δ: 7.31 - 7.29 (m, 2H), 7.18 - 7.16 (m, 2H), 7.10 - 7.06 (m, 1H), 7.06 - 7.02 (m, 2H), 6.91 (d, J=8.5 Hz, 2H), 4.52 (s, 2H), 3.93 (s, 2H). Step C: N-(3-cyanophenyl)-5-(4-(2-(hydroxymethyl)benzyl)phenyl)-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide. The title compound was prepared in a manner analogous to Example 4, reacting N-(3- cyanophenyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide (Intermediate 9, 80.2 mg, 0.25 mmol) and (2-(4-bromobenzyl)phenyl)methanol (105 mg, 0.38 mmol).1H-NMR (400 MHz, DMSO-d6) δ: 12.53 (s, 1H), 8.18 (s, 2H), 7.71 (m, 1H), 7.56 - 7.52 (m, 2H), 7.45 - 7.39 (m, 3H), 7.28 (d, J = 8.0 Hz, 2H), 7.25 - 7.22 (m, 2H), 7.21 - 7.17 (m, 1H), 5.17 (t, J = 5.2 Hz, 1H), 4.65 (m, 2H), 4.53 (m, 2H), 4.25 (m, 2H), 4.04 (s, 2H). Mass spectrum (ESI, m/z): Calcd. for C + 28H23N5O3, 477.2, found [M+H] , 478.2. Example 51: N-(3-cyanophenyl)-5-(4-(2-(methoxymethyl)benzyl)phenyl)-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

Step A: 1-(4-bromobenzyl)-2-(methoxymethyl)benzene. NaH (173 mg, 4.33 mmol, 60%) was added to a solution of (2-(4-bromobenzyl)phenyl)methanol (Example 50, product from Step B, 400 mg, 1.44 mmol) in DMF (4 mL) at 0°C. The mixture was stirred at 0°C for 30 min and then, methyl trifluoromethanesulfonate (0.18 mL, 1.73 mmol) was added. The resulting mixture was stirred at rt for 2 h. The reaction was monitored by TLC. The mixture was quenched with aq NH₄Cl and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography (0-30% EtOAc/PE) to afford 1-(4- bromobenzyl)-2-(methoxymethyl)benzene as colourless oil (403 mg, 96% yield). Step B: N-(3-cyanophenyl)-5-(4-(2-(methoxymethyl)benzyl)phenyl)-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide. The title compound was prepared in a manner analogous to Example 4, reacting N-(3- cyanophenyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide (Intermediate 9, 145.5 mg, 0.46 mmol) and 1-(4-bromobenzyl)-2-(methoxymethyl)benzene (200 mg, 0.69 mmol). 1H-NMR (400 MHz, DMSO-d6) δ: 12.53 (s, 1H), 8.20 - 8.15 (m, 2H), 7.74 - 7.67 (m, 1H), 7.57 - 7.51 (m, 2H), 7.42 (d, J = 8.2 Hz, 2H), 7.36 (m, 1H), 7.32 - 7.19 (m, 5H), 4.66 (m, 2H), 4.45 (s, 2H), 4.25 (m, 2H), 4.06 (s, 2H), 3.31 (s, 3H). Mass spectrum (ESI, m/z): Calcd. for C29H25N5O3, 491.2, found [M+H]+, 492.2. Example 52: N-(3-cyanophenyl)-5-(4-(4-(2-hydroxyethyl)benzyl)phenyl)-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

Step A: 2-(4-(4-bromobenzyl)phenyl)ethan-1-ol. The title compound was prepared in a manner analogous to Example 33, Step A, reacting 1- bromo-4-(bromomethyl)benzene (941 mg, 3.77 mmol) and (4-(2-hydroxyethyl)phenyl)boronic acid (500 mg, 3.01 mmol). Step B: N-(3-cyanophenyl)-5-(4-(4-(2-hydroxyethyl)benzyl)phenyl)-4-oxo-

tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide. The title compound was prepared in a manner analogous to Example 4, reacting N-(3- cyanophenyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide (Intermediate 9, 129 mg, 0.46 mmol) and 2-(4-(4-bromobenzyl)phenyl)ethan-1-ol (200 mg, 0.69 mmol).1H- NMR (400 MHz, DMSO-d₆) δ: 12.53 (s, 1H), 8.21 - 8.15 (m, 2H), 7.73 - 7.67 (m, 1H), 7.56 - 7.50 (m, 2H), 7.44 - 7.33 (m, 4H), 7.23 - 7.12 (m, 4H), 4.69 - 4.57 (m, 3H), 4.24 (t, J = 6.0 Hz, 2H), 3.94 (s, 2H), 3.62 - 3.52 (m, 2H), 2.68 (t, J = 6.8 Hz, 2H). Mass spectrum (ESI, m/z): Calcd. for C₂₉H₂₅N₅O₃, 491.2, found [M+H]+, 492.1. Example 53: N-(3-cyanophenyl)-5-(4-(4-(2-methoxyethyl)benzyl)phenyl)-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

Step A: 1-bromo-4-(4-(2-methoxyethyl)benzyl)benzene. The title compound was prepared in a manner analogous to Example 30, Step A, reacting 2-(4- (4-bromobenzyl)phenyl)ethan-1-ol (Example 52, product from Step A, 300 mg, 1.03 mmol) and iodomethane (92.11 µL, 3.09 mmol). Step B: N-(3-cyanophenyl)-5-(4-(4-(2-methoxyethyl)benzyl)phenyl)-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide. The title compound was prepared in a manner analogous to Example 4, reacting N-(3- cyanophenyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide (Intermediate 9, 123 mg, 0.44 mmol) and 1-bromo-4-(4-(methoxymethyl)benzyl)benzene (200 mg, 0.66 mmol). 1H-NMR (400 MHz, DMSO-d6) δ: 12.55 (s, 1H), 8.18 (s, 2H), 7.74 - 7.69 (m, 1H), 7.56 - 7.49 (m, 2H), 7.44 - 7.33 (m, 4H), 7.19 (q, J = 7.6 Hz, 4H), 4.65 (t, J = 6 Hz, 2H), 4.25 (t, J = 6.4 Hz, 2H), 3.95 (s, 2H), 3.51 (t, J = 7.2 Hz, 2H), 3.23 (s, 3H), 2.76 (t, J = 6.8 Hz, 2H). Mass spectrum (ESI, m/z): Calcd. for C₃₀H₂₇N₅O₃, 505.2, found [M+H]+, 506.1. Example 54: 5-(4-(4-(2-aminoethyl)benzyl)phenyl)-N-(3-cyanophenyl)-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

Step A: tert-butyl (4-(4-bromobenzyl)phenethyl)carbamate. Di-tert-butyl dicarbonate (496 mg, 2.27 mmol) was added to a mixture of 2-(4-(4- bromobenzyl)phenyl)ethan-1-amine (440 mg, 1.52 mmol) in NaOH (10 mL, 2M in water). The pH value was ~8 to 9. The mixture was stirred at rt for 12 h. The reaction was monitored by TLC and LC-MS. The mixture was extracted with EtOAc several times. The combined organic layers were washed brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (20% EtOAc/PE) to afford tert-butyl (4-(4-bromobenzyl)phenethyl)carbamate as a white solid (430 mg, 62% yield). Mass spectrum (ESI, m/z): Calcd. for C t + 20H24BrNO2, 390.3, found [M-COOBu+2H] , 291.9. Step B: tert-butyl (4-(4-(3-((3-cyanophenyl)carbamoyl)-4-oxo-6,7-dihydropyrazolo[1,5- a]pyrazin-5(4H)-yl)benzyl)phenethyl)carbamate. The title compound was prepared in a manner analogous to Example 4, reacting N-(3- cyanophenyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide (Intermediate 9, 242 mg, 0.86 mmol) and tert-butyl (4-(4-bromobenzyl)phenethyl)carbamate (280 mg, 0.72 mmol). Step C: 5-(4-(4-(2-aminoethyl)benzyl)phenyl)-N-(3-cyanophenyl)-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide. The title compound was prepared in a manner analogous to Example 9, Step D, reacting tert- butyl (4-(4-(3-((3-cyanophenyl)carbamoyl)-4-oxo-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)- yl)benzyl)phenethyl)carbamate (440 mg, 0.74 mmol) and HCl in 1,4-dioxane (8 mL, 4 M).1H- NMR (400 MHz, DMSO-d6) δ: 12.52 (s, 1H), 8.19 (s, 1H), 8.17 - 8.13 (m, 1H),8.00 (br s, 2H), 7.76 - 7.69 (m, 1H), 7.57 - 7.52 (m, 2H), 7.45 - 7.36 (m, 4H), 7.31 -7.26 (m, 2H), 7.24 - 7.18 (m, 2H), 4.66 (t, J=6.2 Hz, 2H), 4.25 (t, J=6.2 Hz, 2H),3.97 (s, 2H), 3.05 - 2.98 (m, 2H), 2.90 - 2.81 (m, 2H). Mass spectrum (ESI, m/z): Calcd. for C₂₉H₂₆N₆O₂, 490.2, found [M+H]+, 491.2. Example 55: (S)-N-(4-bromo-3-cyanophenyl)-5-(4-(difluoro(phenyl)methyl)phenyl)-6- methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

HATU (3.32 g, 8.72 mmol) was added to a mixture of (S)-5-(4-(difluoro(phenyl)methyl)phenyl)- 6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxylic acid (Intermediate 1, 2.31 g, 5.81 mmol), 5-amino-2-bromobenzonitrile (1.37 g, 6.98 mmol) and DIPEA (3.04 mL, 17.44 mmol) in DMF (23 mL) under nitrogen. The mixture was stirred at 25ºC for 12 h. The reaction was monitored by LC-MS. The mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine and dried over Na₂SO₄, filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography (62-70% EtOAc/PE) to afford (S)-N-(4-bromo-3-cyanophenyl)-5-(4-(difluoro(phenyl)methyl)phenyl)-6- methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide, that was freeze-dried to afford a white solid (2.53 g, 76% yield).1H-NMR (400 MHz, DMSO-d6) δ: 12.44 (s, 1H), 8.27 (d, J = 2.4 Hz, 1H), 8.21 (s, 1H), 7.78 (d, J = 8.8 Hz, 1H), 7.74 - 7.69 (m, 2H), 7.67 - 7.59 (m, 5H), 7.57 - 7.51 (m, 3H), 4.96 - 4.87 (m, 1H), 4.58 - 4.46 (m, 2H), 1.21 (d, J = 6.0 Hz, 3H). Mass spectrum (ESI, m/z): Calcd. for C₂₈H₂₀BrF₂N₅O₂, 575.1, found [M+H]+, 576.1. Example 56: (S)-N-(3-cyano-4-hydroxyphenyl)-5-(4-(difluoro(phenyl)methyl)-phenyl)-6- methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

HATU (3.93 g, 10.34 mmol) was added to a mixture of (S)-5-(4- (difluoro(phenyl)methyl)phenyl)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3- carboxylic acid (Intermediate 1, 2.74 g, 6.9 mmol), DIPEA (3.6 mL, 20.69 mmol) and 5-amino- 2-hydroxybenzonitrile (1.11 g, 8.27 mmol) in DMF (27 mL) under nitrogen. The mixture was stirred at 25ºC for 12 h. The reaction was monitored by LC-MS. The mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine and dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography (78-81% EtOAc/PE) to afford (S)-N-(3-cyano-4-hydroxyphenyl)-5-(4- (difluoro(phenyl)methyl)phenyl)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3- carboxamide, that was freeze-dried to afford a white solid (3.15 g, 89% yield).1H-NMR (400 MHz, DMSO-d6) δ: 12.06 (s, 1H), 10.94 (br s, 1H), 8.17 (s, 1H), 7.98 (d, J = 2.8 Hz, 1H), 7.75 - 7.68 (m, 2H), 7.68 - 7.58 (m, 4H), 7.57 - 7.51 (m, 3H), 7.48 - 7.45 (m, 1H), 6.98 (d, J = 9.0 Hz, 1H), 4.96 - 4.85 (m, 1H), 4.57 - 4.46 (m, 2H), 1.21 (d, J = 6.0 Hz, 3H). Mass spectrum (ESI, m/z): Calcd. for C H F N O , 513.2, fo + 28 21 2 5 3 und [M+H] , 514.2. Example 57: (S)-N-(3-cyanophenyl)-6-methyl-4-oxo-5-(4-(pyridin-3-ylmethyl)phenyl)- 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

A solution of THF and water (1 mL, 9:1) was added to a mixture of 3-(bromomethyl)pyridine hydrobromide (15.9 mg, 0.063 mmol), (S)-(4-(3-((3-cyanophenyl)carbamoyl)-6-methyl-4-oxo- 6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl)phenyl)trifluoroborate potassium salt (Intermediate 8, 20 mg, 0.04 mmol), mesylate[(di(1-adamantyl)-N-butylphosphine)-2-(2'-amino-1,1'- biphenyl)]palladium(II) (1.5 mg, 0.002 mmol) and Cs2CO3 (81.9 mg, 0.25 mmol). The mixture was stirred at 100°C for 2 h. Once the reaction was completed, EtOAc and water were added, and the organic phase extracted and concentrated in vacuo. Then, the crude product was redissolved in DMSO/MeOH/NaHCO3 (2,1.5,0.5 mL) and purified by Prep-HPLC (Conditions: stationary phase: C18 XBridge 30 x 100 mm 10 µm. Mobile phase: NH4HCO30.25% solution in water and CH₃CN), to afford (S)-N-(3-cyanophenyl)-6-methyl-4-oxo-5-(4-(pyridin-3- ylmethyl)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide (6.7 mg, 32% yield) as a brown oil.1H NMR (400 MHz, CDCl3-d) δ: 12.27 (s, 1H) 8.49 - 8.57 (m, 2H) 8.32 (s, 1H) 8.09 (t, J = 1.6 Hz, 1H) 7.95 (dt, J = 7.9, 1.8 Hz, 1H) 7.52 - 7.58 (m, 1H) 7.32 - 7.41 (m, 4H) 7.27 - 7.31 (m, 3H) 4.77 (dd, J = 13.5, 4.7 Hz, 1H) 4.46 (dd, J = 13.4, 3.5 Hz, 1H) 4.30 - 4.39 (m, 1H) 4.07 (s, 2H) 1.38 (d, J = 6.7 Hz, 3H). Mass spectrum (ESI, m/z): Calcd. for C28H21F2N5O3, 462.2, found [M+H]+, 463.1. Example 58: (S)-N-(3-cyano-4-ethoxyphenyl)-5-(4-(difluoro(phenyl)methyl)-phenyl)-6- methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

To a solution of (S)-N-(3-cyano-4-hydroxyphenyl)-5-(4-(difluoro(phenyl)methyl)phenyl)-6- methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide (Example 56, 200 mg, 0.38 mmol) in DMF (3 mL) was added bromoethane (84.9 mg, 0.78 mmol) and Cs₂CO₃ (381 mg, 1.16 mmol). The mixture was stirred at 100°C for 16 h. The reaction was monitored by LC- MS. Upon completion of the reaction, the mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed brine, dried over Na₂SO₄, filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (70-72% EtOAc/PE) to afford (S)-N-(3-cyano-4-ethoxyphenyl)-5-(4- (difluoro(phenyl)methyl)phenyl)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3- carboxamide, that was freeze dried to afford a white solid (107.8 mg, 50% yield).1H-NMR (400 MHz, DMSO-d6) δ: 12.14 (s, 1H), 8.18 (s, 1H), 8.03 (d, J = 2.4 Hz, 1H), 7.74 - 7.59 (m, 7H), 7.58 - 7.51 (m, 3H), 7.21 (d, J = 9.6 Hz, 1H), 4.96 - 4.86 (m, 1H), 4.58 - 4.47 (m, 2H), 4.15 (q, J = 6.8 Hz, 2H), 1.35 (t, J = 6.8 Hz, 3H), 1.21 (br d, J = 6.4 Hz, 3H). Mass spectrum (ESI, m/z): Calcd. for C H F N O , 54 + 30 25 2 5 3 1.2, found [M+H] , 542.2. Example 59: (S)-N-(3-cyano-4-(2-hydroxyethoxy)phenyl)-5-(4-(difluoro(phenyl)- methyl)phenyl)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

The title compound was prepared in a manner analogous to Example 58, reacting (S)-N-(3- cyano-4-hydroxyphenyl)-5-(4-(difluoro(phenyl)methyl)phenyl)-6-methyl-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide (Example 56, 100 mg, 0.19 mmol) and 2- bromoethanol (48.7 mg, 0.39 mmol).1H-NMR (400 MHz, DMSO-d₆) δ: 12.16 (s, 1H), 8.19 (s, 1H), 8.04 (d, J = 2.4 Hz, 1H), 7.74 - 7.69 (m, 2H), 7.69 - 7.59 (m, 5H), 7.58 - 7.51 (m, 3H), 7.24 (d, J = 9.2 Hz, 1H), 4.97 - 4.87 (m, 2H), 4.60 - 4.46 (m, 2H), 4.12 (t, J = 4.8 Hz, 2H), 3.73 (q, J = 4.8 Hz, 2H), 1.22 (br d, J = 6.4 Hz, 3H). Mass spectrum (ESI, m/z): Calcd. for C30H25F2N5O4, 557.2, found [M+H]+, 558.2. Example 60: (S)-N-(3-cyano-4-(2-methoxyethoxy)phenyl)-5-(4-(difluoro(phenyl)- methyl)phenyl)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide

To a solution of (S)-N-(3-cyano-4-hydroxyphenyl)-5-(4-(difluoro(phenyl)methyl)phenyl)-6- methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide (Example 56, 100 mg, 0.19 mmol) in DMF (1.5 mL) was added 1-bromo-2-methoxyethane (54.1 mg, 0.39 mmol) and Cs2CO3 (190 mg, 0.58 mmol). The mixture was stirred at 100°C for 16 h. The reaction was monitored by LC-MS. Upon completion of the reaction, the mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed brine, dried over Na₂SO₄, filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (68-72% EtOAc/PE) to afford (S)-N-(3-cyano-4-(2-methoxyethoxy)phenyl)-5- (4-(difluoro(phenyl)methyl)phenyl)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine- 3-carboxamide, that was freeze-dried to afford a white solid (58.6 mg, 51% yield).1H-NMR (400 MHz, CDCl3) δ: 12.02 (s, 1H), 8.32 (s, 1H), 7.98 - 7.86 (m, 2H), 7.69 (d, J = 8.4 Hz, 2H), 7.60 - 7.53 (m, 2H), 7.52 - 7.45 (m, 3H), 7.43 (d, J = 8.4 Hz, 2H), 6.93 (d, J = 8.5 Hz, 1H), 4.80 (dd, J = 4.8, 13.6 Hz, 1H), 4.48 (dd, J = 3.2, 13.6 Hz, 1H), 4.44 - 4.35 (m, 1H), 4.24 - 4.17 (m, 2H), 3.84 - 3.76 (m, 2H), 3.48 (s, 3H), 1.40 (d, J = 6.4 Hz, 3H). Mass spectrum (ESI, m/z): Calcd. for C₃₁H₂₇F₂N₅O₄, 571.2, found [M+H]+, 572.2. Example 61: N-(3-cyanophenyl)-5-(4-(4-(2-(dimethylamino)ethyl)benzyl)phenyl)-4-oxo- 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

To a solution of 5-(4-(4-(2-aminoethyl)benzyl)phenyl)-N-(3-cyanophenyl)-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide (Example 54, 45 mg, 0.085 mmol) in MeOH (1 mL) was added DIPEA (33 mg, 0.26 mmol), formaldehyde (69 mg, 0.85 mmol, 37%) and sodium cyanoborohydride (5 mg, 0.085 mmol). The mixture was stirred at rt for 18 h. The reaction was monitored by LC-MS. Upon completion of the reaction, the mixture was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions: column, Welch Xtimate C18, 150 mm, 30 mm x 5 µm; mobile phase, 20% to 50% (v/v) CH₃CN and water with 0.2% FA. This resulted in N-(3-cyanophenyl)-5-(4-(4-(2- (dimethylamino)ethyl)-benzyl)phenyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3- carboxamide, that was freeze dried to afford a white solid (13.4 mg, 98% yield).1H-NMR (400 MHz, DMSO-d6) δ: 12.54 (s, 1H), 8.19 - 8.16 (m, 2H), 7.74 - 7.69 (m,1H), 7.55 - 7.51 (m, 2H), 7.43 - 7.33 (m, 4H), 7.22 - 7.12 (m, 4H), 4.65 (m, 2H), 4.25 (m, 2H), 3.94 (s, 2H), 2.70 - 2.64 (m, 2H), 2.45 - 2.41 (m, 2H), 2.18 (s, 6H). Mass spectrum (ESI, m/z): Calcd. for C31H30N6O2, 518.2, found [M+H]+, 519.3. Example 62: N-(3-cyanophenyl)-4-oxo-5-(4-(4-(2-propionamidoethyl)benzyl)-phenyl)- 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

To a solution of 5-(4-(4-(2-aminoethyl)benzyl)phenyl)-N-(3-cyanophenyl)-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide (Example 54, 40 mg, 0.071 mmol) in DCM (3 mL), was added DIPEA (46 mg, 0.36 mmol) and propionyl chloride (10 mg, 0.11 mmol). The mixture was stirred at rt for 3 h. The reaction was monitored by LC-MS. Upon completion of the reaction, the mixture was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions: column, Welch Xtimate C18, 150 mm, 30 mm x 5 µm; mobile phase, 40% to 70% (v/v) CH3CN and water with 0.2% FA. This resulted in N-(3- cyanophenyl)-4-oxo-5-(4-(4-(2-propionamidoethyl)benzyl)phenyl)-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide, that was freeze dried to afford a white solid (21.6 mg, 55% yield).1H-NMR (400 MHz, DMSO-d6) δ: 12.54 (s, 1H), 8.19 (s, 2H), 7.82 (m, 1H), 7.71 (tm, 1H), 7.56 - 7.52 (m, 2H), 7.45 - 7.35 (m, 4H), 7.24 - 7.20 (m, 2H), 7.17 - 7.12 (m, 2H), 4.69 - 4.63 (m, 2H), 4.28 - 4.23 (m, 2H), 3.96 (s, 2H), 3.26 - 3.20 (m, 2H), 2.69- 2.66 (m, 2H), 2.09 - 2.00 (m, 2H), 0.97 (t, J=7.6 Hz, 3H).). Mass spectrum (ESI, m/z): Calcd. for C H N O , 546.2, fou + 32 30 6 3 nd [M+H] , 547.2.

Example 63: (S)-N-(4-(2-aminoethoxy)-3-cyanophenyl)-5-(4-(difluoro(phenyl)- methyl)phenyl)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

Step A: tert-butyl (S)-(2-(2-cyano-4-(5-(4-(difluoro(phenyl)methyl)phenyl)-6-methyl-4-oxo- 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamido)phenoxy)ethyl)carbamate. The title compound was prepared in a manner analogous to Example 58, reacting (S)-N-(3- cyano-4-hydroxyphenyl)-5-(4-(difluoro(phenyl)methyl)phenyl)-6-methyl-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide (Example 56, 100 mg, 0.19 mmol) and tert- butyl (2-bromoethyl)carbamate (65.5 mg, 0.29 mmol). Step B: (S)-N-(4-(2-aminoethoxy)-3-cyanophenyl)-5-(4-(difluoro(phenyl)methyl)-phenyl)-6- methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide. The title compound was prepared in a manner analogous to Example 9, Step D, reacting, tert- butyl (S)-(2-(2-cyano-4-(5-(4-(difluoro(phenyl)methyl)phenyl)-6-methyl-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamido)phenoxy)ethyl)carbamate (75 mg, 0.11 mmol) and and HCl in 1,4-dioxane (1 mL, 4 mmol, 4 M).1H-NMR (400 MHz, DMSO-d6) δ: 12.15 (s, 1H), 8.19 - 8.17 (m, 1H), 8.04 (d, J = 2.8 Hz, 1H), 7.73 - 7.63 (m, 5H), 7.63 - 7.59 (m, 2H), 7.57 - 7.52 (m, 3H), 7.22 (d, J = 9.2 Hz, 1H), 4.86 (s, 1H), 4.57 - 4.46 (m, 2H), 4.04 (t, J = 6 Hz, 2H), 2.92 - 2.86 (m, 2H), 1.21 (d, J = 6.8 Hz, 3H).). Mass spectrum (ESI, m/z): Calcd. for C H F N O , 556.2, fou + 30 26 2 6 3 nd [M+H] , 557.3. Example 64: (S)-N-(3-cyano-4-methoxyphenyl)-5-(4-(difluoro(phenyl)methyl)-phenyl)-6- methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide

Pyridine (0.9 mL, 11.3 mmol) and 5-amino-2-methoxybenzonitrile (373 mg, 2.5 mmol) were added to a solution of (S)-5-(4-(difluoro(phenyl)methyl)phenyl)-6-methyl-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxylic acid (Intermediate 1, 500 mg, 1.3 mmol) in DCM dry (20 mL) at -10°C. Then, phosphorus (V) oxychloride (520 µL, 5.6 mmol) was added and the resulting mixture was stirred at -10°C for 1 h. Then, the mixture was stirred at rt for 16 h. Then, more pyridine (0.9 mL, 11.3 mmol), 5-amino-2-methoxybenzonitrile (186 mg, 1.3 mmol) and phosphorus (V) oxychloride (520 µL, 5.6 mmol) were added at -10°C and the reaction was stirred at rt for 4 days. Then, the reaction was heated and stirred at 40°C for 4 h. Then, more pyridine (0.9 mL, 11.3 mmol), 5-amino-2-methoxybenzonitrile (186 mg, 1.3 mmol) and phosphorus (V) oxychloride (520 µL, 5.6 mmol) were added at -10°C and the reaction was stirred at rt for 2 days. The reaction progress was monitored by LC-MS. Then, the reaction was quenched with HCl 1M and the aqueous phase was extracted with DCM. The organic layers were combined, dried over MgSO₄, filtered and evaporated in vacuo. The crude product was purified by silica gel chromatography (0-100% heptane/EtOAc) to afford impure product (418 mg) that was then purified by reverse phase chromatography with the following conditions: column, Brand Phenomenex Type Gemini; I.D. (mm) 100 x 30; particle size 5 µm (C18) 110A; mobile phase, 41%-83% 25 mM NH₄HCO₃/CH₃CN. The desired fractions were joined and extracted with DCM. The combined organic layers were dried over MgSO4, filtered and concentrated in vacuo. The resulting solid was triturated with DIPE to afford (S)-N-(3-cyano-4- methoxyphenyl)-5-(4-(difluoro(phenyl)methyl)phenyl)-6-methyl-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide (254 mg, 38% yield) as an off-white solid.1H NMR (400 MHz, DMSO-d6, 100ºC) δ: 11.90 (s, 1H), 8.15 (s, 1H), 7.97 (d, J = 2.6 Hz, 1H), 7.72 (dd, J = 9.1, 2.7 Hz, 1H), 7.69 – 7.62 (m, 4H), 7.59 (ddd, J = 6.5, 4.7, 2.9 Hz, 2H), 7.54 (q, J = 3.3 Hz, 3H), 7.20 (d, J = 9.1 Hz, 1H), 4.89 (dd, J = 13.3, 4.5 Hz, 1H), 4.60 – 4.51 (m, 1H), 4.48 (dd, J = 13.3, 4.0 Hz, 1H), 3.91 (s, 3H), 1.27 (d, J = 6.6 Hz, 3H). Mass spectrum (ESI, m/z): calcd. for C₂₉H₂₃F₂N₅O₃, 527.2; found [M+H]+, 528.1. Example 65: N-(3-cyanophenyl)-5-(4-(4-ethynylbenzyl)phenyl)-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

Step A: 4-(4-bromobenzyl)benzaldehyde. A mixture of 1-bromo-4-(bromomethyl)benzene (1.08 g, 4.34 mmol), (4-formylphenyl)boronic acid (500 mg, 3.34 mmol), K2CO3 (1.48 g, 10.7 mmol) and Pd(PPh3)4 (116 mg, 0.100 mmol) in THF (10 mL) under nitrogen was stirred at 90°C for 18 h. The reaction was monitored by TLC. The mixture was filtered and the filtrate was concentrated in vacuum. The crude product was purified by silica gel chromatography (0-8% EtOAc/PE) to afford 4-(4- bromobenzyl)benzaldehyde as a light yellow oily solid (325 mg, 35% yield).1H-NMR (400 MHz, CDCl3) δ: 9.98 (s, 1H), 7.83 - 7.79 (m, 2H), 7.45 - 7.40 (m, 2H), 7.32 (d, J = 8.0 Hz, 2H), 7.08 - 7.03 (m, 2H), 4.01 (s, 2H). Step B: N-(3-cyanophenyl)-5-(4-(4-formylbenzyl)phenyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrazine-3-carboxamide. The title compound was prepared in a manner analogous to Example 4, reacting N-(3- cyanophenyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide (Intermediate 9, 273 mg, 0.97 mmol) and 4-(4-bromobenzyl)benzaldehyde (320 mg, 1.16 mmol). Step C: N-(3-cyanophenyl)-5-(4-(4-ethynylbenzyl)phenyl)-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide. To a solution of N-(3-cyanophenyl)-5-(4-(4-formylbenzyl)phenyl)-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide (116 mg, 0.24 mmol) in MeOH (2 mL) was added dimethyl (1-diazo-2-oxopropyl)phosphonate (94 mg, 0.49 mmol) and K₂CO₃ (101 mg, 0.73 mmol) under nitrogen. The mixture was stirred at 30ºC for 12 h. The reaction was monitored by TLC. The mixture was concentrated in vacuum. The crude product was purified by silica gel chromatography (0-10% MeOH/DCM) to afford impure product (67 mg) that was then purified by Prep-HPLC with the following conditions: column, Boston Green ODS, 150 mm, 30 mm x 5 µm; mobile phase, 55% to 85% (v/v) CH3CN and water with 0.225% FA. This resulted in N-(3-cyanophenyl)-5-(4-(4-ethynylbenzyl)phenyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrazine-3-carboxamide as a yellow solid (13 mg, 11% yield).1H-NMR (400 MHz, DMSO-d₆) δ: 12.53 (s, 1H), 8.18 (s, 2H), 7.75 - 7.67 (m, 1H), 7.55 - 7.51 (m, 2H), 7.45 - 7.41 (m, 4H), 7.39 - 7.35 (m, 2H), 7.31 (d, J = 8.0 Hz, 2H), 4.66 (t, J = 5.6 Hz, 2H), 4.25 (t, J = 6.4 Hz, 2H), 4.13 (s, 1H), 4.01 (s, 2H). Mass spectrum (ESI, m/z): Calcd. for C₂₉H₂₁N₅O₂, 471.2, found [M+H]+, 472.2. Example 66: N-(3-cyanophenyl)-5-(4-(2-(1-ethyl-1H-1,2,3-triazol-4-yl)benzyl)phenyl)-4- oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

Step A: 1-(4-bromobenzyl)-2-ethynylbenzene. To a solution of N'-(4-bromobenzylidene)-4-methylbenzenesulfonohydrazide (484 mg, 1.37 mmol) in 1,4-dioxane (9 mL) under nitrogen, was added K₂CO₃ (284 mg, 2.06 mmol) and (2- ethynylphenyl)boronic acid (300 mg, 2.06 mmol). The mixture was stirred at 110°C for 2 h. The reaction was monitored by TLC. The mixture was filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography (0-2% EtOAc/PE) to afford 1-(4- bromobenzyl)-2-ethynylbenzene as yellow oil (297 mg, 80% yield).1H-NMR (400 MHz, CDCl3) δ: 7.52 (d, J = 7.6 Hz, 1H), 7.40 (d, J = 8.8 Hz, 2H), 7.32 - 7.27 (m, 1H), 7.23 - 7.17 (m, 1H), 7.15 - 7.08 (m, 3H), 4.14 (s, 2H), 3.27 (s, 1H). Step B: 4-(2-(4-bromobenzyl)phenyl)-1-ethyl-1H-1,2,3-triazole. Bromoethane (121 mg, 1.11 mmol) was added to a stirred solution of sodium azide (120 mg, 1.85 mmol) in DMSO (3 mL) under nitrogen. The mixture was stirred at rt for 3 h. Then, 1-(4- bromobenzyl)-2-ethynylbenzene (150 mg, 0.55 mmol), sodium ascorbate (43.8 mg, 0.221 mmol), water (1 mL) and copper(II) sulfate pentahydrate (27.6 mg, 0.11 mmol) were added. The resulting mixture was stirred at 30°C for 16 h. The reaction was monitored by TLC. The pH of the mixture was adjusted to pH > 9 with sat. NaHCO₃ and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography (0-40% EtOAc/PE) to afford 4-(2- (4-bromobenzyl)phenyl)-1-ethyl-1H-1,2,3-triazole as a white solid (151 mg, 78% yield).1H- NMR (400 MHz, CD3CN) δ: 7.76 (s, 1H), 7.60 - 7.55 (m, 1H), 7.38 - 7.31 (m, 4H), 7.29 - 7.24 (m, 1H), 6.97 (d, J = 8.4 Hz, 2H), 4.39 (q, J = 7.2 Hz, 2H), 4.22 (s, 2H), 1.48 (t, J = 7.2 Hz, 3H). Mass spectrum (ESI, m/z): Calcd. for C₁₇H₁₆BrN₃, 341.2, found [M+H]+, 342.2. Step C: N-(3-cyanophenyl)-5-(4-(2-(1-ethyl-1H-1,2,3-triazol-4-yl)benzyl)phenyl)-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide. The title compound was prepared in a manner analogous to Example 4, reacting N-(3- cyanophenyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide (Intermediate 9, 89 mg, 0.32 mmol) and 4-(2-(4-bromobenzyl)phenyl)-1-ethyl-1H-1,2,3-triazole (130 mg, 0.38 mmol).1H-NMR (400 MHz, DMSO-d₆) δ: 12.53 (s, 1H), 8.36 (s, 1H), 8.17 (s, 2H), 7.75 - 7.68 (m, 1H), 7.62 - 7.58 (m, 1H), 7.55 - 7.51 (m, 2H), 7.39 - 7.29 (m, 5H), 7.19 (d, J = 8.4 Hz, 2H), 4.64 (t, J = 5.6 Hz, 2H), 4.44 (q, J = 7.6 Hz, 2H), 4.33 (s, 2H), 4.22 (t, J = 6.4 Hz, 2H), 1.48 (t, J = 7.2 Hz, 3H). Mass spectrum (ESI, m/z): Calcd. for C₃₁H₂₆N₈O₂, 542.2, found [M+H]+, 543.3. Example 67: 5-(4-(3-(2-aminoethyl)benzyl)phenyl)-N-(3-cyanophenyl)-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide hydrochloride.

Step A: tert-butyl (3-(4-bromobenzyl)phenethyl)carbamate. The title compound was prepared in a manner analogous to Example 54, Step A, reacting 2-(3- (4-bromobenzyl)phenyl)ethan-1-amine (800 mg, 2.76 mmol) and di-tert-butyl dicarbonate (902 mg, 4.14 mmol). Step B: tert-butyl (3-(4-(3-((3-cyanophenyl)carbamoyl)-4-oxo-6,7-dihydropyrazolo[1,5- a]pyrazin-5(4H)-yl)benzyl)phenethyl)carbamate. The title compound was prepared in a manner analogous to Example 4, reacting N-(3- cyanophenyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide (Intermediate 9, 108.5 mg, 0.34 mmol) and tert-butyl (3-(4-bromobenzyl)phenethyl)carbamate (160 mg, 0.41 mmol). Step C: 5-(4-(3-(2-aminoethyl)benzyl)phenyl)-N-(3-cyanophenyl)-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide hydrochloride. To a solution of tert-butyl (3-(4-(3-((3-cyanophenyl)carbamoyl)-4-oxo-6,7-dihydropyrazolo[1,5- a]pyrazin-5(4H)-yl)benzyl)phenethyl)carbamate (210 mg, 0.36 mmol) in 1,4-dioxane (3 mL) was added HCl in 1,4-dioxane (1.87 mL, 7.48 mmol, 4 M). The mixture was stirred at rt for 2 h. The reaction was monitored by TLC. The mixture was filtered and the solid was washed with additional 1,4-dioxane to afford 5-(4-(3-(2-aminoethyl)benzyl)phenyl)-N-(3-cyanophenyl)-4- oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide hydrochloride (182 mg, 97% yield).1H-NMR (400 MHz, DMSO-d₆) δ: 12.52 (s, 1H), 8.18 (s, 1H), 8.15 (s, 1H), 7.96 (br s, 3H), 7.75 - 7.69 (m, 1H), 7.56 - 7.52 (m, 2H), 7.45 - 7.35 (m, 4H), 7.31 - 7.26 (m, 1H), 7.23 - 7.17 (m, 2H), 7.12 (d, J = 7.6 Hz, 1H), 4.66 (m, 2H), 4.24 (m, 2H), 3.98 (s, 2H), 3.03 (m, 2H), 2.90 - 2.80 (m, 2H). Mass spectrum (ESI, m/z): Calcd. for C₂₉H₂₆N₆O₂, 490.2, found [M+H]+, 491.3. Example 68: N-(3-cyanophenyl)-5-(4-(2-(2-hydroxyethyl)benzyl)phenyl)-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

Step A: 1-(4-bromobenzyl)-2-vinylbenzene. The title compound was prepared in a manner analogous to Example 33, Step A, reacting 1- bromo-4-(bromomethyl)benzene (4.39 g, 17.57 mmol) and (2-vinylphenyl)boronic acid (2 g, 13.52 mmol). Step B: 2-(2-(4-bromobenzyl)phenyl)ethan-1-ol. To a solution of 1-(4-bromobenzyl)-2-vinylbenzene (1 g, 3.7 mmol) in anhydrous THF (10 mL) under nitrogen, was added borane dimethyl sulfide complex (0.11 mL, 1.1 mmol) at 0°C. Then, the mixture was stirred at rt for 2 h, and NaOH (8.5 mL, 25.6 mmol, 3M in water) and 30% (w/w) hydrogen peroxide solution (2.9 g, 25.6 mmol) were sequentially added to the mixture at 0°C. The mixture was allowed to warm to rt and stirred for 2 h. The reaction was monitored by TLC. The mixture was extracted with DCM. The organic layer was separated, dried over Na₂SO₄, filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (2/1 EtOAc/PE) to afford 2-(2-(4-bromobenzyl)phenyl)ethan-1-ol as yellow oil (450 mg, 32% yield). Step C: N-(3-cyanophenyl)-5-(4-(2-(2-hydroxyethyl)benzyl)phenyl)-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide. The title compound was prepared in a manner analogous to Example 4, reacting N-(3- cyanophenyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide (Intermediate 9, 85 mg, 0.3 mmol) and 2-(2-(4-bromobenzyl)phenyl)ethan-1-ol (80 mg, 0.27 mmol).1H-NMR (400 MHz, DMSO-d6) δ: 12.54 (s, 1H), 8.19 (s, 2H), 7.72 (m, 1H), 7.57 -7.52 (m, 2H), 7.43 (m, 2H), 7.31 - 7.17 (m, 6H), 4.73 - 4.62 (m, 3H), 4.26 (t, J=6.0Hz, 2H), 4.08 (s, 2H), 3.61 - 3.53 (m, 2H), 2.78 (t, J=7.2 Hz, 2H). Mass spectrum (ESI, m/z): Calcd. for C29H25N5O3, 491.2, found [M+H]+, 492.2. Example 69: N-(3-cyanophenyl)-5-(4-(4-(2-(methylamino)ethyl)benzyl)phenyl)-4-oxo- 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

The title compound was prepared in a manner analogous to Example 12, reacting 5-(4-(4-(2- aminoethyl)benzyl)phenyl)-N-(3-cyanophenyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrazine-3-carboxamide (Example 54, 55 mg, 0.11 mmol) and methyl trifluoromethanesulfonate (33.12 mg, 0.2 mmol).1H-NMR (400 MHz, Methanol-d4) δ: 8.55 (br s, 1H), 8.17 (s, 1H), 7.90 (m, 1H), 7.58 -7.49 (m, 2H), 7.48 - 7.39 (m, 4H), 7.27 (m, 4H), 4.97 (m, 2H), 4.52 - 4.43 (m, 2H),4.37 (s, 3H), 4.07 (s, 2H), 3.21 - 3.08 (m, 2H), 3.01 - 2.88 (m, 2H). Mass spectrum (ESI, m/z): Calcd. for C H + 30 28N6O2, 504.2, found [M+H] , 505.3. Example 70: (S)-5-(4-((2-(tert-butyl)pyrimidin-5-yl)methyl)phenyl)-N-(3-cyanophenyl)-6- methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

A solution of THF and water (1 mL, 9:1) was added to a mixture of 5-(bromomethyl)-2-(tert- butyl)pyrimidine (28.8 mg, 0.13 mmol), (S)-(4-(3-((3-cyanophenyl)carbamoyl)-6-methyl-4-oxo- 6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl)phenyl)trifluoroborate potassium salt (Intermediate 8, 30 mg, 0.06 mmol), 1,1'-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (2.6 mg, 0.003 mmol) and Cs2CO3 (122.9 mg, 0.38 mmol). The resultant mixture was stirred at 100°C for 16 h. Then, water and EtOAc were added, and the organic phase extracted and concentrated in vacuo. The residue was redissolved in DMSO/MeOH/NaHCO3 (2; 1.5; 0.5 mL), filtered and purified by Prep-HPLC (Conditions: stationary phase: C18 XBridge 30 x 100 mm 10 µm. Mobile phase: NH₄HCO₃0.25% solution in water and CH₃CN) to afford (S)-5-(4-((2-(tert-butyl)pyrimidin-5-yl)methyl)phenyl)-N-(3- cyanophenyl)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide (13.5 mg, 41% yield, 60% pure) as solid, after freeze-drying. Product contained 40% of Intermediate 8.1H NMR (500 MHz, DMSO-d₆) δ: 12.50 (s, 1H) 8.73 (s, 2H) 8.20 (s, 1H) 8.15 - 8.18 (m, 2H) 7.89 - 7.93 (m, 1H) 7.74 - 7.78 (m, 1H) 7.69 - 7.73 (m, 1H) 7.62 - 7.68 (m, 1H) 7.54 - 7.56 (m, 2H) 7.54 (br d, J=1.0 Hz, 2H) 4.93 - 5.00 (m, 1H) 4.53 - 4.60 (m, 2H) 4.44 (dt, J=6.6, 4.2 Hz, 1H) 4.02 (s, 2H) 1.34 (s, 9H). Mass spectrum (ESI, m/z): Calcd. for C₃₀H₂₉N₇O₂, 519.2, found [M+H]+, 520.3. Example 71: (S)-N-(3-cyanophenyl)-5-(4-((5,6-difluoropyridin-3-yl)methyl)phenyl)-6- methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

The title compound was prepared in a manner analogous to Example 70, reacting 5- (bromomethyl)-2,3-difluoropyridine (26.1 mg, 0.13 mmol) and (S)-(4-(3-((3- cyanophenyl)carbamoyl)-6-methyl-4-oxo-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)- yl)phenyl)trifluoroborate potassium salt (Intermediate 8, 30 mg, 0.06 mmol).1H NMR (500 MHz, DMSO-d6) ^ ^ 12.48 (s, 1H) 8.20 (s, 1H) 8.15 - 8.17 (m, 1H) 8.02 - 8.09 (m, 2H) 7.68 - 7.72 (m, 1H) 7.52 - 7.56 (m, 2H) 7.45 (s, 4H) 4.90 (dd, J = 13.3, 4.6 Hz, 1H) 4.49 (dd, J = 13.3, 3.6 Hz, 1H) 4.40 - 4.47 (m, 1H) 4.08 (s, 2H) 1.20 (d, J = 6.6 Hz, 3H). Mass spectrum (ESI, m/z): Calcd. for C₂₇H₂₀F₂N₆O₂, 498.2, found [M+H]+, 499.3. Example 72: -N-(3-cyanophenyl)-6-methyl-4-oxo-5-(4-((5-(trifluoromethyl)-thiophen-2- yl)methyl)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

A solution of THF and water (1 mL, 9:1) was added to a mixture of 2-(bromomethyl)-5- (trifluoromethyl)thiophene (30.8 mg, 0.13 mmol), (S)-(4-(3-((3-cyanophenyl)carbamoyl)-6- methyl-4-oxo-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl)phenyl)trifluoroborate potassium salt (Intermediate 8, 30 mg, 0.06 mmol), 1,1'-bis(diphenylphosphino)ferrocene- palladium(II)dichloride dichloromethane complex (2.6 mg, 0.003 mmol) and Cs2CO3 (122.9 mg, 0.38 mmol). The mixture was stirred at 100°C for 16 h. Then, water and EtOAc were added and the organic phase extracted and concentrated in vacuo. The residue was redissolved in DMSO/MeOH/NaHCO3 (2; 1.5; 0.5 mL), filtered and purified by Prep-HPLC (Conditions: stationary phase: C18 XBridge 30 x 100 mm 10 µm. Mobile phase: NH₄HCO₃0.25% solution in water and CH₃CN), to afford (S)-N-(3-cyanophenyl)-6-methyl-4-oxo-5-(4-((5- (trifluoromethyl)thiophen-2-yl)methyl)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3- carboxamide (6.0 mg, 18% yield) as solid, after freeze-drying.1H NMR (500 MHz, DMSO-d6) ^ ^ ^12.48 (s, 1H) 8.21 (s, 1H) 8.16 - 8.19 (m, 1H) 7.70 - 7.74 (m, 1H) 7.57 - 7.61 (m, 1H) 7.51 - 7.56 (m, 2H) 7.47 (d, J = 1.4 Hz, 4H) 7.08 - 7.14 (m, 1H) 4.90 (dd, J = 13.2, 4.4 Hz, 1H) 4.42 - 4.54 (m, 2H) 4.31 (s, 2H) 1.21 (d, J = 6.5 Hz, 3H). Mass spectrum (ESI, m/z): Calcd. for C + 27H20F3N5O2S, 535.1, found [M+H] , 536.2. Example 73: (S)-N-(3-cyanophenyl)-6-methyl-4-oxo-5-(4-((5-(trifluoromethyl)-isothiazol-3- yl)methyl)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

The title compound was prepared in a manner analogous to Example 72, reacting 3- (bromomethyl)-5-(trifluoromethyl)isothiazole (30.9 mg, 0.13 mmol) and (S)-(4-(3-((3- cyanophenyl)carbamoyl)-6-methyl-4-oxo-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)- yl)phenyl)trifluoroborate potassium salt (Intermediate 8, 30 mg, 0.06 mmol).1H NMR (500 MHz, DMSO-d6) δ: 12.48 (s, 1H) 8.21 (s, 1H) 8.15 - 8.19 (m, 2H) 8.05 - 8.07 (m, 1H) 7.68 - 7.74 (m, 2H) 7.53 - 7.55 (m, 3H) 7.43 - 7.46 (m, 1H) 7.18 - 7.22 (m, 1H) 5.37 (s, 1H) 4.90 (dd, J = 13.3, 4.5 Hz, 1H) 4.47 - 4.54 (m, 2H) 4.43 - 4.46 (m, 1H) 4.30 (s, 2H). Mass spectrum (ESI, m/z): Calcd. for C₂₆H₁₉F₃N₆O₂S, 536.2, found [M+H]+, 537.3. Example 74: -N-(3-cyanophenyl)-5-(4-((2-cyanothiophen-3-yl)methyl)phenyl)-6-methyl- 4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

The title compound was prepared in a manner analogous to Example 72, reacting 3- (bromomethyl)thiophene-2-carbonitrile (25.4 mg, 0.13 mmol) and (S)-(4-(3-((3- cyanophenyl)carbamoyl)-6-methyl-4-oxo-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)- yl)phenyl)trifluoroborate potassium salt (Intermediate 8, 30 mg, 0.06 mmol).1H NMR (500 MHz, DMSO-d6) δ: 12.47 (s, 1H) 8.20 (s, 1H) 8.15 - 8.19 (m, 1H) 8.02 (d, J = 5.0 Hz, 1H) 7.72 (ddd, J = 6.2, 3.2, 2.3 Hz, 1H) 7.51 - 7.56 (m, 2H) 7.44 - 7.49 (m, 2H) 7.40 - 7.43 (m, 2H) 7.27 (d, J = 5.1 Hz, 1H) 4.90 (dd, J = 13.3, 4.6 Hz, 1H) 4.40 - 4.53 (m, 2H) 4.19 (s, 2H) 1.20 (d, J = 6.6 Hz, 3H). Mass spectrum (ESI, m/z): Calcd. for C H N O S, 492.1 + 27 20 6 2 , found [M+H] , 493.2. Example 75: (S)-N-(3-cyanophenyl)-5-(4-((5-cyclopropyl-3-methylisoxazol-4- yl)methyl)phenyl)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3- carboxamide.

The title compound was prepared in a manner analogous to Example 72, reacting 4- (bromomethyl)-5-cyclopropyl-3-methyl-1,2-oxazole (27.1 mg, 0.13 mmol) and (S)-(4-(3-((3- cyanophenyl)carbamoyl)-6-methyl-4-oxo-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)- yl)phenyl)trifluoroborate potassium salt (Intermediate 8, 30 mg, 0.06 mmol).1H NMR (500 MHz, DMSO-d₆) ^ ^ 12.50 (s, 1H) 8.20 (s, 1H) 8.15 - 8.17 (m, 1H) 7.71 (ddd, J = 5.8, 3.5, 2.2 Hz, 1H) 7.54 (d, J = 0.9 Hz, 1H) 7.52 - 7.55 (m, 1H) 7.41 - 7.46 (m, 2H) 7.33 (d, J = 8.5 Hz, 2H) 4.90 (dd, J = 13.1, 4.4 Hz, 1H) 4.41 - 4.56 (m, 2H) 3.87 (s, 2H) 2.15 - 2.25 (m, 1H) 2.07 (s, 3H) 1.20 (d, J = 6.5 Hz, 3H) 0.89 - 1.09 (m, 4H). Mass spectrum (ESI, m/z): Calcd. for C29H26N6O3, 506.2, found [M+H]+, 507.3. Example 76: N-(3-cyanophenyl)-5-(4-(4-(1-ethyl-1H-1,2,3-triazol-4-yl)benzyl)phenyl)-4- oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

Step A: 1-bromo-4-(4-ethynylbenzyl)benzene. The title compound was prepared in a manner analogous to Example 66, Step A, reacting N'-(4- bromobenzylidene)-4-methylbenzenesulfonohydrazide (484 mg, 1.37 mmol) and (4- ethynylphenyl)boronic acid (300 mg, 2.06 mmol). Step B: 4-(4-(4-bromobenzyl)phenyl)-1-ethyl-1H-1,2,3-triazole. The title compound was prepared in a manner analogous to Example 66, Step B, reacting 1- bromo-4-(4-ethynylbenzyl)benzene (230 mg, 0.85 mmol) and bromoethane (185 mg, 1.7 mmol). Step C: N-(3-cyanophenyl)-5-(4-(4-(1-ethyl-1H-1,2,3-triazol-4-yl)benzyl)phenyl)-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide. The title compound was prepared in a manner analogous to Example 4, reacting N-(3- cyanophenyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide (Intermediate 9, 103 mg, 0.37 mmol) and 4-(4-(4-bromobenzyl)phenyl)-1-ethyl-1H-1,2,3-triazole (150 mg, 0.44 mmol).1H-NMR (400 MHz, DMSO-d₆) δ: 12.54 (s, 1H), 8.55 (s, 1H), 8.18 (s, 2H), 7.78 (d, J = 8.0 Hz, 2H), 7.72 - 7.67 (m, 1H), 7.55 - 7.49 (m, 2H), 7.46 - 7.35 (m, 6H), 4.65 (br t, J = 6.0 Hz, 2H), 4.41 (q, J = 7.2 Hz, 2H), 4.25 (br t, J = 6.0 Hz, 2H), 4.02 (s, 2H), 1.47 (t, J = 7.2 Hz, 3H). Mass spectrum (ESI, m/z): Calcd. for C₃₁H₂₆N₈O₂, 542.2, found [M+H]+, 543.3. Example 77: N-(3-cyanophenyl)-4-oxo-5-(4-(3-(2-propionamidoethyl)-benzyl)phenyl)- 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

The title compound was prepared in a manner analogous to Example 11, reacting 5-(4-(3-(2- aminoethyl)benzyl)phenyl)-N-(3-cyanophenyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrazine-3-carboxamide (Example 67, 40 mg, 0.076 mmol) and propionyl chloride (7.95 µL, 0.09 mmol).1H-NMR (400 MHz, DMSO-d6) δ: 12.55 (s, 1H), 8.18 (s, 2H), 7.83 (, J=5.2 Hz, 1H), 7.70 (m, 1H), 7.56 - 7.49 (m, 2H), 7.45 - 7.33 (m, 4H), 7.27 - 7.20 (m, 1H), 7.16 - 7.10 (m, 2H), 7.05 (d, J=7.6 Hz, 1H), 4.65 (t, J = 6.0 Hz, 2H), 4.24 (t, J = 6.0 Hz, 2H), 3.96 (s, 2H), 3.29 - 3.20 (m, 2H), 2.68 (t, J = 7.6 Hz, 2H), 2.08 - 1.98 (m, 2H), 0.96 (t, J =7.6 Hz, 3H). Mass spectrum (ESI, m/z): Calcd. for C H N O , 5 + 32 30 6 3 46.2, found [M+H] , 547.3. Example 78 N-(3-cyanophenyl)-5-(4-(3-(1-ethyl-1H-1,2,3-triazol-4-yl)benzyl)phenyl)-4-oxo- 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

Step A: 1-(4-bromobenzyl)-3-ethynylbenzene. The title compound was prepared in a manner analogous to Example 66, Step A, reacting N'-(4- bromobenzylidene)-4-methylbenzenesulfonohydrazide (300 mg, 0.85 mmol) and (3- ethynylphenyl)boronic acid (186 mg, 1.27 mmol). Step B: 4-(3-(4-bromobenzyl)phenyl)-1-ethyl-1H-1,2,3-triazole. The title compound was prepared in a manner analogous to Example 66, Step B, reacting 1-(4- bromobenzyl)-3-ethynylbenzene (195 mg, 0.72 mmol) and bromoethane (157 mg, 1.44 mmol). Step C: N-(3-cyanophenyl)-5-(4-(3-(1-ethyl-1H-1,2,3-triazol-4-yl)benzyl)phenyl)-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide. The title compound was prepared in a manner analogous to Example 4, reacting N-(3- cyanophenyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide (Intermediate 9, 163 mg, 0.58 mmol) and 4-(3-(4-bromobenzyl)phenyl)-1-ethyl-1H-1,2,3-triazole (165 mg, 0.48 mmol).1H-NMR (400 MHz, CDCl3) δ: 12.29 (s, 1H), 8.30 (s, 1H), 8.09 (s, 1H), 7.96 - 7.91 (m, 1H), 7.82 (s, 1H), 7.77 (s, 1H), 7.63 (d, J = 8.0 Hz, 1H), 7.41 - 7.27 (m, 7H), 7.21 (d, J = 7.6 Hz, 1H), 4.67 - 4.62 (m, 2H), 4.47 (q, J = 7.2 Hz, 2H), 4.28 - 4.22 (m, 2H), 4.09 (s, 2H), 1.63 - 1.59 (m, 3H). Mass spectrum (ESI, m/z): Calcd. for C₃₁H₂₆N₈O₂, 542.2, found [M+H]+, 543.3. Example 79: N-(3-cyanophenyl)-5-(4-(2-ethynylbenzyl)phenyl)-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

Step A: 2-(4-bromobenzyl)benzaldehyde. The title compound was prepared in a manner analogous to Example 65, Step A, reacting 1- bromo-4-(bromomethyl)benzene (1.08 g, 4.34 mmol) and (2-formylphenyl)boronic acid (500 mg, 3.33 mmol). Step B: N-(3-cyanophenyl)-5-(4-(2-formylbenzyl)phenyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrazine-3-carboxamide. The title compound was prepared in a manner analogous to Example 4, reacting N-(3- cyanophenyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide (Intermediate 9, 400 mg, 1.42 mmol) and 2-(4-bromobenzyl)benzaldehyde (587 mg, 2.13 mmol). Step C: N-(3-cyanophenyl)-5-(4-(2-ethynylbenzyl)phenyl)-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide. The title compound was prepared in a manner analogous to Example 65, Step C, reacting N-(3- cyanophenyl)-5-(4-(2-formylbenzyl)phenyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3- carboxamide (300 mg, 0.63 mmol) and dimethyl (1-diazo-2-oxopropyl)phosphonate (242 mg, 1.26 mmol).1H-NMR (400 MHz, DMSO-d₆) δ: 12.53 (s, 1H), 8.18 (s, 2H), 7.70 (m, 1H), 7.57 - 7.47 (m, 3H), 7.45 - 7.40 (m, 2H), 7.39 - 7.34 (m, 4H), 7.30 - 7.22 (m, 1H), 4.65 (t, J = 5.6 Hz, 2H), 4.44 (s, 1H), 4.24 (t, J = 6.4 Hz, 2H), 4.17 (s, 2H). Mass spectrum (ESI, m/z): Calcd. for C₂₉H₂₁N₅O₂, 471.2, found [M+H]+, 472.1. Example 80: (S)-N-(3-cyano-4-(2-(dimethylamino)ethoxy)phenyl)-5-(4- (difluoro(phenyl)methyl)phenyl)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrazine-3-carboxamide.

The title compound was prepared in a manner analogous to Example 10, reacting (S)-N-(4-(2- aminoethoxy)-3-cyanophenyl)-5-(4-(difluoro(phenyl)methyl)phenyl)-6-methyl-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide (Example 63, 100 mg, 0.18 mmol) and formaldehyde (134 µL, 1.8 mmol).1H-NMR (400 MHz, DMSO-d₆) δ: 12.15 (s, 1H), 8.19 (s, 1H), 8.03 (d, J = 2.8 Hz, 1H), 7.73 - 7.64 (m, 5H), 7.62 (br dd, J = 4.4, 5.6 Hz, 2H), 7.57 - 7.52 (m, 3H), 7.27 - 7.22 (m, 1H), 4.96 - 4.87 (m, 1H), 4.56 - 4.47 (m, 2H), 4.17 (t, J = 5.6 Hz, 2H), 2.67 - 2.63 (m, 2H), 2.23 (s, 6H), 1.22 (d, J = 6.4 Hz, 3H). Mass spectrum (ESI, m/z): Calcd. for C₃₂H₃₀F₂N₆O₃, 584.2, found [M+H]+, 585.2. Example 81: (S)-N-(3-cyano-4-(2-(methylamino)ethoxy)phenyl)-5-(4- (difluoro(phenyl)methyl)phenyl)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrazine-3-carboxamide.

To a solution of (S)-N-(4-(2-aminoethoxy)-3-cyanophenyl)-5-(4- (difluoro(phenyl)methyl)phenyl)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3- carboxamide (Example 63, 200 mg, 0.36 mmol) in 1,1,1,3,3,3-hexafluoropropan-2-ol (5 mL) was added methyl trifluoromethanesulfonate (61 µL, 0.54 mmol) and Et₃N (75 µL, 0.54 mmol). The mixture was stirred at rt for 12 h. The reaction was monitored by LC-MS. Upon completion of the reaction, the mixture was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions: column, Phenomenex C18, 3 µm, 75 x 30 mm; mobile phase, 54-84% (v/v) CH₃CN and water with 0.225% FA. This resulted in (S)-N-(3- cyano-4-(2-(methylamino)ethoxy)phenyl)-5-(4-(difluoro(phenyl)methyl)phenyl)-6-methyl-4- oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide (30.6 mg, 14% yield).1H-NMR (400 MHz, DMSO-d₆) δ: 12.15 (s, 1H), 8.18 (s, 1H), 8.03 (d, J = 2.8 Hz, 1H), 7.72 - 7.59 (m, 7H), 7.56 - 7.51 (m, 3H), 7.23 (d, J = 9.2 Hz, 1H), 4.94 - 4.87 (m, 1H), 4.55 - 4.47 (m, 2H), 4.12 (t, J = 5.6 Hz, 2H), 2.84 (t, J = 5.2 Hz, 2H), 2.34 (s, 3H), 1.21 (br d, J = 6.4 Hz, 3H). Mass spectrum (ESI, m/z): Calcd. for C₃₁H₂₈F₂N₆O₃, 570.2, found [M+H]+, 571.2. Example 82: N-(3-cyanophenyl)-5-(4-(2-(2-methoxyethyl)benzyl)phenyl)-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

Step A: 1-(4-bromobenzyl)-2-(2-methoxyethyl)benzene. The title compound was prepared in a manner analogous to Example 30, Step A, reacting 2-(2- (4-bromobenzyl)phenyl)ethan-1-ol (Example 68, product from Step B, 150 mg, 0.46 mmol) and iodomethane (195 mg, 1.37 mmol). Step B: N-(3-cyanophenyl)-5-(4-(2-(2-methoxyethyl)benzyl)phenyl)-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide. The title compound was prepared in a manner analogous to Example 4, reacting N-(3- cyanophenyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide (Intermediate 9, 110.6 mg, 0.39 mmol) and 1-(4-bromobenzyl)-2-(2-methoxyethyl)benzene (100 mg, 0.33 mmol). 1H-NMR (400 MHz, DMSO-d₆) δ: 12.55 (s, 1H), 8.20 - 8.13 (m, 2H), 7.75 - 7.68 (m,1H), 7.58 - 7.53 (m, 2H), 7.43 (m, 2H), 7.30 - 7.18 (m, 6H), 4.66 (m, 2H), 4.26 (m,2H), 4.08 (s, 2H), 3.42 (t, J = 7.2 Hz, 2H), 3.22 (s, 3H), 2.84 (t, J = 7.2 Hz, 2H). Mass spectrum (ESI, m/z): Calcd. for C₃₀H₂₇N₅O₃, 505.2, found [M+H]+, 506.2. Example 83: N-(3-cyanophenyl)-5-(4-(4-(2-(N-methylpropionamido)ethyl)benzyl)phenyl)-4- oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

Propionyl chloride (6 mg, 0.06 mmol) was added to a mixture of N-(3-cyanophenyl)-5-(4-(4-(2- (methylamino)ethyl)benzyl)phenyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3- carboxamide (Example 69, 23 mg, 0.04 mmol) and DIPEA (15 mg, 0.12 mmol) in DCM (2 mL). The mixture was stirred at 25ºC for 3 h. The reaction was monitored by LC-MS. The mixture was concentrated in vacuo and the crude product was purified by prep-HPLC with the following conditions: column, Welch Xtimate C18, 150 mm, 30 mm x 5 µm; mobile phase, 32% to 62% (v/v) CH3CN and water with 0.2% FA. The desired fractions were evaporated in vacuo to afford N-(3-cyanophenyl)-5-(4-(4-(2-(N-methylpropionamido)ethyl)benzyl)phenyl)-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide formate salt, that was freeze-dried to afford a white solid (5.5 mg, 23% yield).1H-NMR (400 MHz, Methanol-d4) δ: 9.19 (s, 1H), 8.57 (br s, 1H), 8.25 (s, 1H), 7.82 (m,1H), 7.59 - 7.49 (m, 2H), 7.43 (m, 4H), 7.25 - 7.14 (m, 4H), 4.95 (m, 2H), 4.47 (m,2H), 4.37 (s, 3H), 4.04 (s, 2H), 3.39 (t, J = 7.2 Hz, 2H), 2.78 (t, J = 7.2 Hz, 2H), 2.17(q, J = 7.6 Hz, 2H), 1.10 (t, J = 7.6 Hz, 3H). Mass spectrum (ESI, m/z): Calcd. for C33H32N6O3, 560.2, found [M+H]+, 561.3. The product sticked to the flask was recovered as additional N-(3-cyanophenyl)-5-(4-(4-(2-(N- methylpropionamido)ethyl)benzyl)phenyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3- carboxamide (6.3 mg, 27% yield).1H-NMR (400 MHz, Methanol-d4) δ: 9.18 (s, 1H), 8.24 (s, 1H), 7.90 - 7.75 (m, 1H), 7.55 -7.48 (m, 2H), 7.41 (m 4H), 7.21 - 7.15 (m, 4H), 4.96 - 4.93 (m, 2H), 4.45 (br t, J =6.0 Hz, 2H), 4.36 (s, 3H), 4.02 (s, 2H), 3.37 (t, J = 7.2 Hz, 2H), 2.77 (t, J = 7.2 Hz,2H), 2.16 (q, J = 7.6 Hz, 2H), 1.08 (t, J = 7.6 Hz, 3H). Mass spectrum (ESI, m/z): Calcd. for C + 33H32N6O3, 560.2, found [M+H] , 561.3. Example 84: N-(3-cyanophenyl)-5-(4-(3-ethynylbenzyl)phenyl)-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

Step A: 3-(4-bromobenzyl)benzaldehyde. The title compound was prepared in a manner analogous to Example 65, Step A, reacting 1- bromo-4-(bromomethyl)benzene (4.33 g, 17.34 mmol) and (3-formylphenyl)boronic acid (2 g, 13.34 mmol). Step B: N-(3-cyanophenyl)-5-(4-(3-formylbenzyl)phenyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrazine-3-carboxamide. The title compound was prepared in a manner analogous to Example 4, reacting N-(3- cyanophenyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide (Intermediate 9, 192.5 mg, 0.61 mmol) and 3-(4-bromobenzyl)benzaldehyde (200 mg, 0.73 mmol). Step C: N-(3-cyanophenyl)-5-(4-(3-ethynylbenzyl)phenyl)-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide. The title compound was prepared in a manner analogous to Example 65, Step C, reacting N-(3- cyanophenyl)-5-(4-(2-formylbenzyl)phenyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3- carboxamide (57 mg, 0.12 mmol) and dimethyl (1-diazo-2-oxopropyl)phosphonate (25.3 mg, 0.13 mmol).1H-NMR (400 MHz, DMSO-d₆) δ: 12.52 (s, 1H), 8.18 (s, 2H), 7.71 (m, 1H), 7.55 - 7.49 (m, 2H), 7.46 - 7.25 (m, 8H), 4.65 (m, 2H), 4.25 (m, 2H), 4.16 (s, 1H), 3.99 (s, 2H). Mass spectrum (ESI, m/z): Calcd. for C H N + 29 21 5O2, 471.2, found [M+H] , 472.2. Example 85: N-(3-cyanophenyl)-5-(4-(3-(2-(methylamino)ethyl)benzyl)phenyl)-4-oxo- 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

The title compound was prepared in a manner analogous to Example 81, reacting 5-(4-(3-(2- aminoethyl)benzyl)phenyl)-N-(3-cyanophenyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrazine-3-carboxamide hydrochloride (Example 67, 300 mg, 0.57 mmol) and methyl trifluoromethanesulfonate (97 µL, 0.85 mmol).1H-NMR (400 MHz, DMSO-d6) δ: 12.55 (s, 1H), 8.20 - 8.16 (m, 2H), 7.71 (m, 1H), 7.55 - 7.49 (m, 2H), 7.44 - 7.34 (m, 4H), 7.24 - 7.19 (m, 1H), 7.16 - 7.03 (m, 3H), 4.65 (m, 2H), 4.25 (m, 2H), 3.96 (s, 2H), 2.66 (s, 4H), 2.28 (s, 3H). Mass spectrum (ESI, m/z): Calcd. for C + 30H28N6O2, 504.2, found [M+H] , 505.2. Example 86: N-(3-cyanophenyl)-4-oxo-5-(4-(2-(propa-1,2-dien-1-yl)benzyl)phenyl)-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

Step A: 1-(2-(4-bromobenzyl)phenyl)-3-(trimethylsilyl)prop-2-yn-1-ol. Ethynyltrimethylsilane (468 mg, 4.76 mmol) was added to a solution of 2-(4- bromobenzyl)benzaldehyde (Example 79, product from Step A, 1 g, 3.43 mmol) in THF (30 mL) under nitrogen at 0°C. Then n-butyllithium (1.89 mL, 4.72 mmol, 2.5 M) was added and the mixture was stirred at 0ºC for 3 h. The reaction was monitored by TLC. The mixture was quenched with NH4Cl and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography (0-20% EtOAc/PE) to afford 1-(2-(4- bromobenzyl)phenyl)-3-(trimethylsilyl)prop-2-yn-1-ol as an oil (1.21 g, 89% yield).1H-NMR (400 MHz, CDCl3) δ: 7.75 - 7.69 (m, 1H), 7.41 (d, J = 8.4 Hz, 2H), 7.33 - 7.28 (m, 2H), 7.13 - 7.08 (m, 1H), 7.04 (d, J = 8.4 Hz, 2H), 5.56 (s, 1H), 4.19 - 4.14 (m, 2H), 0.19 (s, 8H). Step B: (3-(2-(4-bromobenzyl)phenyl)prop-1-yn-1-yl)trimethylsilane. Triethylsilane (486 mg, 4.18 mmol) was added to a stirred solution of 1-(2-(4- bromobenzyl)phenyl)-3-(trimethylsilyl)prop-2-yn-1-ol (1.2 g, 3.21 mmol) in DCM (32 mL) under nitrogen at 0°C. The mixture was then treated dropwise with BF3·Et2O (593 mg, 4.18 mmol) over 1 min at 0°C. The resulting mixture was stirred at 0°C for 1 h. The reaction was monitored by TLC. The mixture was diluted with sat. aq. NaHCO₃ and extracted with DCM. The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography (0-5% EtOAc/PE) to afford (3-(2-(4- bromobenzyl)phenyl)prop-1-yn-1-yl)trimethylsilane as a yellow oil (742 mg, 65% yield).1H- NMR (400 MHz, CDCl3) δ: 7.48 (d, J = 6.8 Hz, 1H), 7.42 - 7.37 (m, 2H), 7.25 - 7.20 (m, 2H), 7.10 (d, J = 6.8 Hz, 1H), 7.00 (d, J = 8.4 Hz, 2H), 4.04 - 3.98 (m, 2H), 3.50 (s, 2H), 0.17 (s, 9H). Step C: mixture of N-(3-cyanophenyl)-4-oxo-5-(4-(2-(propa-1,2-dien-1-yl)benzyl)phenyl)- 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide and N-(3-cyanophenyl)-4-oxo-5-(4-(2- (2-oxopropyl)benzyl)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide. The title compounds were prepared in a manner analogous to Example 4, reacting N-(3- cyanophenyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide (Intermediate 9, 328 mg, 1.17 mmol) and (3-(2-(4-bromobenzyl)phenyl)prop-1-yn-1-yl)trimethylsilane (500 mg, 1.4 mmol). Step D: N-(3-cyanophenyl)-4-oxo-5-(4-(2-(propa-1,2-dien-1-yl)benzyl)phenyl)-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide. The mixture of N-(3-cyanophenyl)-4-oxo-5-(4-(2-(propa-1,2-dien-1-yl)benzyl)phenyl)-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide and N-(3-cyanophenyl)-4-oxo-5-(4-(2-(2- oxopropyl)benzyl)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide (180 mg) was purified by prep-HPLC with the following conditions: column, Welch Xtimate C18, 150 mm, 30 mm x 5 µm; mobile phase, 50% to 80% (v/v) CH3CN and water with 0.225% FA. This resulted in impure title compounds N-(3-cyanophenyl)-4-oxo-5-(4-(2-(propa-1,2-dien-1- yl)benzyl)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide (45 mg) and N-(3- cyanophenyl)-4-oxo-5-(4-(2-(2-oxopropyl)benzyl)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrazine-3-carboxamide (50 mg). Impure fraction of N-(3-cyanophenyl)-4-oxo-5-(4-(2-(propa-1,2-dien-1-yl)benzyl)phenyl)- 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide (45 mg) was further purified by SFC (DAICEL CHIRALCEL OJ column, 10 µm, 250 x 30 mm; 45% (v/v) EtOH (containing 0.1% of 25% aq. NH₃)/CO₂) and then freeze-dried to afford N-(3-cyanophenyl)-4-oxo-5-(4-(2-(propa- 1,2-dien-1-yl)benzyl)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide as a white solid (8.2 mg, 17% yield).1H-NMR (400 MHz, DMSO-d₆) δ: 12.53 (s, 1H), 8.18 (s, 2H), 7.75 - 7.68 (m, 1H), 7.57 - 7.50 (m, 2H), 7.44 - 7.37 (m, 3H), 7.29 (d, J = 8.4 Hz, 3H), 7.26 - 7.19 (m, 2H), 6.59 (t, J = 6.8 Hz, 1H), 5.26 (d, J = 6.8 Hz, 2H), 4.66 - 4.63 (m, 2H), 4.28 - 4.21 (m, 2H), 4.12 (s, 2H). Mass spectrum (ESI, m/z): Calcd. for C + 30H23N5O2, 485.2, found [M+H] , 486.2. Example 87: N-(3-cyanophenyl)-4-oxo-5-(4-(2-(2-oxopropyl)benzyl)phenyl)-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

The title compound was isolated from Example 86. Impure fraction of N-(3-cyanophenyl)-4-oxo-5-(4-(2-(2-oxopropyl)benzyl)phenyl)-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide (50 mg) was further purified by SFC (DAICEL CHIRALPAK AS column, 10 µm, 250 x 30 mm; 40% (v/v) EtOH (containing 0.1% of 25% aq. NH3)/CO2) and then freeze-dried to afford N-(3-cyanophenyl)-4-oxo-5-(4-(2-(2- oxopropyl)benzyl)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide as a white solid (27.7 mg, 54% yield).1H-NMR (400 MHz, DMSO-d₆) δ: 12.55 (s, 1H), 8.18 (s, 1H), 8.17 (s, 1H), 7.71 (td, J = 2.8, 6.0 Hz, 1H), 7.57 - 7.52 (m, 2H), 7.41 (d, J = 8.4 Hz, 2H), 7.28 - 7.15 (m, 6H), 4.66 (t, J = 6.4 Hz, 2H), 4.24 (t, J = 6.8 Hz, 2H), 3.93 (s, 2H), 3.84 (s, 2H), 2.11 (s, 3H). Mass spectrum (ESI, m/z): Calcd. for C₃₀H₂₅N₅O₂, 503.2, found [M+H]+, 504.2. Example 88: N-(3-cyanophenyl)-5-(4-(3-(2-(dimethylamino)ethyl)benzyl)phenyl)-4-oxo- 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

The title compound was prepared in a manner analogous to Example 10, reacting 5-(4-(3-(2- aminoethyl)benzyl)phenyl)-N-(3-cyanophenyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrazine-3-carboxamide hydrochloride (Example 67, 140 mg, 0.25 mmol) and formaldehyde (226 mg, 2.48 mmol).1H-NMR (400 MHz, DMSO-d₆) δ: 12.54 (s, 1H), 8.21 - 8.14 (m, 2H), 7.75 - 7.69 (m, 1H), 7.56 - 7.49 (m, 2H), 7.44 - 7.35 (m, 4H), 7.26 - 7.21 (m, 1H), 7.18 (s, 1H), 7.10 (m, 2H), 4.66 (t, J = 6.0 Hz, 2H), 4.24 (t, J = 6.0 Hz, 2H), 3.96 (s, 2H), 2.78 - 2.71 (m, 2H), 2.65 (m, 1H), 2.69 - 2.59 (m, 1H), 2.32 (s, 6H). Mass spectrum (ESI, m/z): Calcd. for C₃₁H₃₀N₆O₂, 518.2, found [M+H]+, 519.3. Example 89: 5-(4-(2-(2-aminoethyl)benzyl)phenyl)-N-(3-cyanophenyl)-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

Step A: 2-(2-(4-bromobenzyl)phenyl)acetaldehyde. 2-Iodoxybenzoic acid (1.92 g, 6.87 mmol) was added to a solution of 2-(2-(4- bromobenzyl)phenyl)ethan-1-ol (Example 68, product from Step B, 1 g, 3.43 mmol) in CH3CN (18 mL). The mixture was stirred at 55°C for 4 h. The reaction was monitored by TLC. The mixture was filtered and the filtrate was concentrated in vacuo to afford 2-(2-(4- bromobenzyl)phenyl)acetaldehyde as a yellow gum (980 mg, 99% yield), that was used in next step without further purification. Step B: 2-(2-(4-bromobenzyl)phenyl)acetaldehyde oxime. To a solution of 2-(2-(4-bromobenzyl)phenyl)acetaldehyde (1000 mg, 3.46 mmol) in MeOH (15 mL) was added hydroxylamine hydrochloride (480 mg, 6.92 mmol) and pyridine (0.28 mL, 3.46 mmol). The mixture was stirred at 25°C for 2 h. The reaction was monitored by TLC. The mixture was concentrated under reduced pressure and the residue was diluted with 1M HCl sol. and extracted with DCM. The combined organic layers were washed with brine, dried over Na₂SO₄ and then concentrated in vacuo. The crude product was purified by silica gel chromatography (0-50% EtOAc/PE) to afford 2-(2-(4-bromobenzyl)phenyl)acetaldehyde oxime as a white solid (930 mg, 86% yield). Mass spectrum (ESI, m/z): Calcd. for C15H14BrNO, 304.2, found [M+H]+, 305.9. Step C: tert-butyl (2-(4-bromobenzyl)phenethyl)carbamate. To a mixture of 2-(2-(4-bromobenzyl)phenyl)acetaldehyde oxime (350 mg, 1.15 mmol) in THF (30 ml) and 2N HCl (12 mL) was added zinc (1.5 g, 23.01 mmol) under nitrogen. The resulting mixture was stirred at 80°C for 30 mins. After that, to the mixture was added di-tert-butyl dicarbonate (504 mg, 2.31 mmol) and the pH of the mixture was adjusted to 8-9 with 2N NaOH (10 mL). The resulting mixture was stirred at 25°C for 12 h. The reaction was monitored by LC- MS. Upon completion of the reaction, the mixture was extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced. The residue was purified by silica gel chromatography (5/1 EtOAc/PE) to afford tert-butyl (2-(4- bromobenzyl)phenethyl)carbamate as a white solid (350 mg, 75% yield). Mass spectrum (ESI, m/z): Calcd. for C t + 15H14BrNO, 390.3, found [M-COOBu+2H] , 291.7. Step D: tert-butyl (2-(4-(3-((3-cyanophenyl)carbamoyl)-4-oxo-6,7-dihydropyrazolo[1,5- a]pyrazin-5(4H)-yl)benzyl)phenethyl)carbamate. The title compound was prepared in a manner analogous to Example 4, reacting N-(3- cyanophenyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide (Intermediate 9, 303 mg, 1.08 mmol) and tert-butyl (2-(4-bromobenzyl)phenethyl)carbamate (350 mg, 0.9 mmol). Step E: 5-(4-(2-(2-aminoethyl)benzyl)phenyl)-N-(3-cyanophenyl)-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide. The title compound was prepared in a manner analogous to Example 9, Step D, reacting tert- butyl (2-(4-(3-((3-cyanophenyl)carbamoyl)-4-oxo-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)- yl)benzyl)phenethyl)carbamate (230 mg, 0.39 mmol) and HCl in 1,4-dioxane (8 mL, 4 M).1H- NMR (400 MHz, DMSO-d6) δ: 12.52 (s, 1H), 8.19 (s, 1H), 8.15 (br s, 1H), 8.04 (brs, 2H), 7.76 - 7.71 (m, 1H), 7.57 - 7.53 (m, 2H), 7.44 (m, 2H), 7.33 (m, 2H), 7.26 (s, 4H), 4.66 (br t, J = 6.0 Hz, 2H), 4.26 (br t, J = 6.0 Hz, 2H), 4.09 (s, 2H), 3.57 (s, 2H), 2.94 (br s, 2H). Mass spectrum (ESI, m/z): Calcd. for C + 29H26N6O2, 490.2, found [M+H] , 491.9.

Example 90: N-(3-cyanophenyl)-4-oxo-5-(4-(2-(2-propionamidoethyl)-benzyl)phenyl)- 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

The title compound was prepared in a manner analogous to Example 62, reacting 5-(4-(2-(2- aminoethyl)benzyl)phenyl)-N-(3-cyanophenyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrazine-3-carboxamide (Example 89, 30 mg, 0.053 mmol) and propionyl chloride (7.39 mg, 0.08 mmol).1H-NMR (400 MHz, Methanol-d₄) δ: 8.22 - 8.16 (m, 2H), 7.80 (m, 1H), 7.50 - 7.37 (m, 4H), 7.32 - 7.28 (m, 2H), 7.24 - 7.19 (m, 4H), 4.69 - 4.63 (m, 2H), 4.33 - 4.25 (m, 2H), 4.15 (s, 2H), 3.35 - 3.32 (m, 2H), 2.89 - 2.74 (m, 2H), 2.17 (q, J = 7.6 Hz, 2H),1.11 (t, J = 7.6 Hz, 3H). Mass spectrum (ESI, m/z): Calcd. for C + 32H30N6O3, 546.2, found [M+H] , 547.3. Example 91: N-(3-cyanophenyl)-5-(4-(2-((1-ethyl-1H-1,2,3-triazol-4- yl)methyl)benzyl)phenyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

Step A: 1-(4-bromobenzyl)-2-(prop-2-yn-1-yl)benzene. To a mixture of (3-(2-(4-bromobenzyl)phenyl)prop-1-yn-1-yl)trimethylsilane (Example 86, product from Step B, 800 mg, 2.24 mmol) and AcOH (269 mg, 4.48 mmol) in THF (10 mL) was added dropwise TBAF (4.47 mL, 4.47 mmol, 1M in THF) over 1 min. The mixture was stirred at rt for 12 h. The reaction was monitored by LC-MS. Upon completion of the reaction, the mixture was quenched with sat. NH₄Cl and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na₂SO₄, filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography (0-5% EtOAc/PE) to afford 1-(4-bromobenzyl)-2- (prop-2-yn-1-yl)benzene as a yellow solid (550 mg, 86% yield). Step B: 4-(2-(4-bromobenzyl)benzyl)-1-ethyl-1H-1,2,3-triazole. The title compound was prepared in a manner analogous to Example 66, Step B, reacting 1-(4- bromobenzyl)-2-(prop-2-yn-1-yl)benzene (200 mg, 0.7 mmol) and bromoethane (153 mg, 1.4 mmol). Step C: N-(3-cyanophenyl)-5-(4-(2-((1-ethyl-1H-1,2,3-triazol-4-yl)methyl)benzyl)phenyl)-4- oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide. The title compound was prepared in a manner analogous to Example 4, reacting N-(3- cyanophenyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide (Intermediate 9, 104 mg, 0.37 mmol) and 4-(2-(4-bromobenzyl)benzyl)-1-ethyl-1H-1,2,3-triazole (158 mg, 0.44 mmol).1H-NMR (400 MHz, DMSO-d6) δ: 12.54 (s, 1H), 8.19 (s, 2H), 7.76 - 7.67 (m, 2H), 7.57 - 7.50 (m, 2H), 7.42 (d, J = 8.4 Hz, 2H), 7.27 - 7.18 (m, 6H), 4.66 (br t, J = 6.0 Hz, 2H), 4.36 - 4.20 (m, 4H), 4.10 (s, 2H), 3.99 (s, 2H), 1.37 (t, J = 7.6 Hz, 3H). Mass spectrum (ESI, m/z): Calcd. for C H N O , 556.2, found [M+H]+ 32 28 8 2 , 557.3. Example 92: N-(3-cyanophenyl)-5-(4-(2-(2-(dimethylamino)ethyl)benzyl)phenyl)-4-oxo- 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

The title compound was prepared in a manner analogous to Example 10, reacting 5-(4-(2-(2- aminoethyl)benzyl)phenyl)-N-(3-cyanophenyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrazine-3-carboxamide (Example 89, 60 mg, 0.11 mmol) and formaldehyde (92.4 mg, 1.14 mmol).1H-NMR (400 MHz, Methanol-d4) δ: 12.56 (s, 1H), 8.22 - 8.17 (m, 1H), 8.13 (s, 1H),7.76 - 7.70 (m, 1H), 7.56 - 7.52 (m, 2H), 7.42 (m, 2H), 7.29 - 7.18 (m, 6H), 4.66 (br t, J = 6.0 Hz, 2H), 4.24 (br t, J = 6.0 Hz, 2H), 4.06 (s, 2H), 2.79 - 2.71 (m, 2H), 2.41 - 2.31 (m, 2H), 2.20 (s, 6H). Mass spectrum (ESI, m/z): Calcd. for C₃₁H₃₀N₆O₂, 518.2, found [M+H]+, 519.3. Example 93: (S)-N-(3-cyano-4-methoxyphenyl)-6-methyl-4-oxo-5-(4-(pentafluoro-l6- sulfaneyl)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

4-Bromophenylsulphur pentafluoride (174 mg, 0.61 mmol), N1,N2-dimethylethane-1,2-diamine (0.02 mL, 0.18 mmol), K2CO3 (85 mg, 0.62 mmol) and CuI (35 mg, 0.18 mmol) were added to a stirred solution of (S)-N-(3-cyano-4-methoxyphenyl)-6-methyl-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide (Intermediate 7, 100 mg, 0.31 mmol) in DMF (1 mL) and toluene (1 mL), under nitrogen. The mixture was stirred at 100°C for 18 h. The reaction was monitored by LC-MS. The cooled mixture was filtered and the filtrate was diluted with water and extracted with EtOAc. The combined organic layers were washed with water and brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (0%-95% EtOAc/PE) to afford (S)-N-(3-cyano-4- methoxyphenyl)-6-methyl-4-oxo-5-(4-(pentafluoro-l6-sulfaneyl)phenyl)-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide, that was freeze-dried to afford a white solid (49 mg, 30% yield).1H-NMR (400 MHz, CDCl3) δ: 11.89 (s, 1H), 8.32 (s, 1H), 7.97 - 7.90 (m, 4H), 7.50 (d, J = 8.8 Hz, 2H), 6.90 (d, J = 9.6 Hz, 1H), 4.81 (dd, J = 4.8, 13.6 Hz, 1H), 4.50 (dd, J = 3.2, 13.2 Hz, 1H), 4.46 - 4.39 (m, 1H), 3.90 (s, 3H), 1.42 (d, J = 6.8 Hz, 3H). Mass spectrum (ESI, m/z): Calcd. for C + 22H18F5N5O3S, 527.1, found [M+H] , 528.1.

Example 94: N-(3-cyanophenyl)-5-(4-(2-(2-(N-methylpropionamido)ethyl)benzyl)phenyl)-4- oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

Step A: N-(3-cyanophenyl)-5-(4-(2-(2-(methylamino)ethyl)benzyl)phenyl)-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide. To a solution of 5-(4-(2-(2-aminoethyl)benzyl)phenyl)-N-(3-cyanophenyl)-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide (Example 89, 300 mg, 0.61 mmol) in 1,1,1,3,3,3-hexafluoropropan-2-ol (3 mL) was added methyl trifluoromethanesulfonate (181 mg, 1.1 mmol) and DIPEA (0.21 mL, 1.22 mmol). The mixture was stirred at 50ºC for 4 h. The reaction was monitored by LC-MS. Upon completion of the reaction, the mixture was concentrated in vacuo. The crude product was purified by Prep-HPLC with the following conditions: column, Welch Xtimate C18, 5 µm, 150 x 30 mm; mobile phase, 13-43% (v/v) CH3CN and water with 0.2% FA. This resulted in N-(3-cyanophenyl)-5-(4-(2-(2- (methylamino)ethyl)benzyl)phenyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3- carboxamide that was freeze-dried to afford a white solid (95 mg, 24% yield). Mass spectrum (ESI, m/z): Calcd. for C H N + 30 28 6O2, 504.2, found [M+H] , 505.1. Step B: N-(3-cyanophenyl)-5-(4-(2-(2-(N-methylpropionamido)ethyl)benzyl)phenyl)-4-oxo- 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide. The title compound was prepared in a manner analogous to Example 62, reacting N-(3- cyanophenyl)-5-(4-(2-(2-(methylamino)ethyl)benzyl)phenyl)-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide (25 mg, 0.043 mmol) and propionyl chloride (6.01 mg, 0.065 mmol).1H-NMR (400 MHz, DMSO-d6) δ: 12.56 (m, 1H), 8.22 - 8.16 (m, 2H), 7.74 - 7.64 (m, 1H), 7.58 - 7.53 (m, 2H), 7.47 - 7.39 (m, 2H), 7.33 - 7.18 (m, 6H), 4.66 (br t, J = 6.0 Hz, 2H), 4.26 (br t, J = 6.0 Hz, 2H), 4.12 (d, J = 12.4 Hz, 2H), 3.39 (m, 1H), 3.32 -3.27 (m, 1H), 2.91 (s, 2H), 2.86 - 2.73 (m, 3H), 2.29 (q, J = 7.2 Hz, 1H), 1.99 (q, J =7.2 Hz, 1H), 1.03 - 0.80 (m, 3H). Mass spectrum (ESI, m/z): Calcd. for C₃₃H₃₂N₆O₃, 560.2, found [M+H]+, 561.3. Example 95: N-(3-cyanophenyl)-5-(4-(3-(2-(N-methylpropionamido)ethyl)-benzyl)phenyl)- 4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

The title compound was prepared in a manner analogous to Example 11, reacting N-(3- cyanophenyl)-5-(4-(3-(2-(methylamino)ethyl)benzyl)phenyl)-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide (Example 85, 23 mg, 0.046 mmol) and propionyl chloride (8 µL, 0.091 mmol).1H-NMR (400 MHz, DMSO-d₆) δ: 12.38 (s, 1H), 8.15 (s, 1H), 8.12 (s, 1H), 7.74 (m, 1H), 7.55 - 7.47 (m, 2H), 7.44 - 7.32 (m, 4H), 7.27 - 7.21 (m, 1H), 7.17 - 7.05 (m, 3H), 4.68 - 4.63 (m, 2H), 4.28 - 4.23 (m, 2H), 3.98 (s, 2H), 3.50 (t, J=7.2 Hz, 2H), 2.88 - 2.73 (m, 5H), 2.27 - 2.02 (m, 2H), 1.02 - 0.82 (m, 3H). Mass spectrum (ESI, m/z): Calcd. for C H N O , 560.2, found [M+H + 33 32 6 3 ] , 561.3. Example 96: N-(3-cyanophenyl)-5-(4-(4-((1-ethyl-1H-1,2,3-triazol-4- yl)methyl)benzyl)phenyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

Step A: 1-(4-(4-bromobenzyl)phenyl)-3-(trimethylsilyl)prop-2-yn-1-ol. The title compound was prepared in a manner analogous to Example 86, Step A, reacting 4-(4- bromobenzyl)benzaldehyde (Example 65, product from Step A, 1 g, 3.63 mmol) and ethynyltrimethylsilane (654 µL, 4.72 mmol). Step B: (3-(4-(4-bromobenzyl)phenyl)prop-1-yn-1-yl)trimethylsilane. The title compound was prepared in a manner analogous to Example 86, Step B, reacting 1-(4- (4-bromobenzyl)phenyl)-3-(trimethylsilyl)prop-2-yn-1-ol (200 mg, 0.54 mmol) and triethylsilane (111 µL, 0.7 mmol). Step C: 1-bromo-4-(4-(prop-2-yn-1-yl)benzyl)benzene. The title compound was prepared in a manner analogous to Example 91, Step A, reacting (3-(4- (4-bromobenzyl)phenyl)prop-1-yn-1-yl)trimethylsilane (130 mg, 0.36 mmol) and TBAF (0.73 mL, 0.73 mmol, 1M in THF). Step D: 4-(4-(4-bromobenzyl)benzyl)-1-ethyl-1H-1,2,3-triazole. The title compound was prepared in a manner analogous to Example 66, Step B, reacting 1- bromo-4-(4-(prop-2-yn-1-yl)benzyl)benzene (166 mg, 0.58 mmol) and bromoethane (190 mg, 1.75 mmol). Step E: N-(3-cyanophenyl)-5-(4-(4-((1-ethyl-1H-1,2,3-triazol-4-yl)methyl)benzyl)phenyl)-4- oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide. The title compound was prepared in a manner analogous to Example 4, reacting N-(3- cyanophenyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide (Intermediate 9, 50 mg, 0.18 mmol) and 4-(4-(4-bromobenzyl)benzyl)-1-ethyl-1H-1,2,3-triazole (63 mg, 0.18 mmol).1H-NMR (400 MHz, DMSO-d₆) δ: 12.53 (s, 1H), 8.18 (s, 2H), 7.84 (s, 1H), 7.72 - 7.69 (m, 1H), 7.55 - 7.49 (m, 2H), 7.43 - 7.38 (m, 2H), 7.38 - 7.33 (m, 2H), 7.24 - 7.17 (m, 4H), 4.65 (t, J = 5.6 Hz, 2H), 4.30 (q, J = 7.2 Hz, 2H), 4.24 (t, J = 6.4 Hz, 2H), 3.94 (d, J = 3.6 Hz, 4H), 1.38 (t, J = 7.2 Hz, 3H). Mass spectrum (ESI, m/z): Calcd. for C₃₂H₂₈N₈O₂, 556.2, found [M+H]+, 557.3. Example 97: (S)-N-(3-cyano-4-(((R)-1-methylpyrrolidin-3-yl)oxy)phenyl)-5-(4- (difluoro(phenyl)methyl)phenyl)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrazine-3-carboxamide.

Diisopropyl azodicarboxylate (59 mg, 0.29 mmol) was added to a mixture of (S)-N-(3-cyano-4- hydroxyphenyl)-5-(4-(difluoro(phenyl)methyl)phenyl)-6-methyl-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide (Example 56, 100 mg, 0.19 mmol), (S)-1- methylpyrrolidin-3-ol (29.5 mg, 0.29 mmol) and PPh3 (77 mg, 0.29 mmol) in toluene (2 mL) under nitrogen. The mixture was stirred at 80°C for 12 h. The reaction was monitored by TLC. The mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography (0-50% DCM/MeOH) first and then by prep- HPLC with the following conditions: column, Boston Green ODS 5 µm, 150 x 30 mm; mobile phase, 27-57% (v/v) CH₃CN and water with 0.225% FA. This resulted in (S)-N-(3-cyano-4- (((R)-1-methylpyrrolidin-3-yl)oxy)phenyl)-5-(4-(difluoro(phenyl)methyl)phenyl)-6-methyl-4- oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide as a white solid (31.6 mg, 27% yield).1H-NMR (400 MHz, DMSO-d6) δ: 12.15 (s, 1H), 8.18 (s, 1H), 8.01 (s, 1H), 7.72 - 7.68 (m, 2H), 7.68 - 7.59 (m, 5H), 7.57 - 7.51 (m, 3H), 7.15 (d, J = 9.2 Hz, 1H), 4.93 (m, 2H), 4.56 - 4.46 (m, 2H), 2.78 (m, 1H), 2.74 - 2.62 (m, 3H), 2.32 (br d, J = 3.2 Hz, 1H), 2.27 (s, 3H), 1.82 - 1.74 (m, 1H), 1.21 (br d, J = 6.4 Hz, 3H). Mass spectrum (ESI, m/z): Calcd. for C₃₃H₃₀F₂N₆O₃, 596.2, found [M+H]+, 597.2. Example 98: (S)-N-(3-cyanophenyl)-6-methyl-4-oxo-5-(4-(2-(trifluoromethoxy)- ethyl)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

1-Bromo-4-(2-(trifluoromethoxy)ethyl)benzene (109 mg, 0.41 mmol), N1,N2-dimethylethane- 1,2-diamine (22.3 µL, 0.20 mmol), K2CO3 (187 mg, 1.36 mmol) and CuI (38.7 mg, 0.2 mmol) were added to a stirred solution of (S)-N-(3-cyanophenyl)-6-methyl-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide (Intermediate 6, 100 mg, 0.34 mmol) in DMF (1 mL) and toluene (1 mL). The mixture was stirred at 100°C for 12 h. The reaction was monitored by TLC. The mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (0%-100% EtOAc/PE) to afford impure product (60 mg) that was then purified by Prep-HPLC with the following conditions: column, Boston Green ODS, 150 mm, 25 mm x 5 µm; mobile phase, 65% to 95% (v/v) CH3CN and water with 0.225% FA. This resulted in (S)-N-(3-cyanophenyl)-6- methyl-4-oxo-5-(4-(2-(trifluoromethoxy)ethyl)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrazine-3-carboxamide as a white solid (51 mg, 31% yield).1H-NMR (400 MHz, DMSO-d6) δ: 12.51 (s, 1H), 8.21 (s, 1H), 8.16 (s, 1H), 7.75 - 7.69 (m, 1H), 7.56 - 7.50 (m, 2H), 7.46 (s, 4H), 4.95 - 4.87 (m, 1H), 4.54 - 4.44 (m, 2H), 4.38 (t, J = 6.4 Hz, 2H), 3.06 (br t, J = 6.8 Hz, 2H), 1.21 (d, J = 6.4 Hz, 3H). Mass spectrum (ESI, m/z): Calcd. for C₂₄H₂₀F₃N₅O₃, 483.2, found [M+H]+, 484.2. Example 99: (S)-N-(3-cyano-4-(((S)-1-methylpyrrolidin-3-yl) phenyl)-5-(4-

(difluoro(phenyl)methyl)phenyl)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrazine-3-carboxamide.

The title compound was prepared in a manner analogous to Example 97, reacting (S)-N-(3- cyano-4-hydroxyphenyl)-5-(4-(difluoro(phenyl)methyl)phenyl)-6-methyl-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide (Example 56, 100 mg, 0.19 mmol) and (R)-1- methylpyrrolidin-3-ol (29.5 mg, 0.29 mmol).1H-NMR (400 MHz, DMSO-d6) δ: 12.15 (s, 1H), 8.18 (s, 1H), 8.02 (m, 1H), 7.72 - 7.68 (m, 2H), 7.68 - 7.59 (m, 5H), 7.54 (br d, J = 2.4 Hz, 3H), 7.15 (m, 1H), 4.99 - 4.88 (m, 2H), 4.56 - 4.47 (m, 2H), 2.82 (m, 1H), 2.78 - 2.66 (m, 3H), 2.44 - 2.39 (m, 1H), 2.30 (s, 3H), 1.85 - 1.73 (m, 1H), 1.21 (br d, J = 6.0 Hz, 3H). Mass spectrum (ESI, m/z): Calcd. for C₃₃H₃₀F₂N₆O₃, 596.2, found [M+H]+, 597.3. Example 100: (S)-N-(3-cyanophenyl)-5-(4-(difluoro(1-fluorocyclopropyl)-methyl)phenyl)-6- methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

Step A: 2-(4-bromophenyl)-2-(1-fluorocyclopropyl)-1,3-dithiane. To a mixture of (4-bromophenyl)(1-fluorocyclopropyl)methanone (8.6 g, 35.4 mmol) and p- toluenesulfonic acid (1.22 g, 7.08 mmol) in toluene (90 mL) under nitrogen was added propane- 1,3-dithiol (6.57 mL, 65.44 mmol). The mixture was stirred at 120ºC for 18 h. The reaction was monitored by LC-MS. The mixture was diluted with brine and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered and evaporated in vacuo. The crude product was purified by silica gel chromatography (0-0.2% EtOAc/PE) to afford 2-(4- bromophenyl)-2-(1-fluorocyclopropyl)-1,3-dithiane light brown oily solid (4.53 g, 38% yield). 1H-NMR (400 MHz, CDCl3) δ: 7.94 - 7.89 (m, 2H), 7.55 - 7.50 (m, 2H), 2.74 - 2.67 (m, 4H), 1.99 - 1.92 (m, 2H), 1.08 - 1.00 (m, 4H). Step B: 1-bromo-4-(difluoro(1-fluorocyclopropyl)methyl)benzene. DAST (0.85 mL, 6.5 mmol) was dropwise added over 1 min to a solution of 2-(4-bromophenyl)- 2-(1-fluorocyclopropyl)-1,3-dithiane (1.0 g, 3.0 mmol) in DCM (10 mL) under nitrogen and at 0ºC. The mixture was stirred at rt for 5 min and then stirred at 30°C for 18 h. The reaction was monitored by TLC. The mixture was cooled to 0ºC and quenched with sat. NaHCO3. The mixture was extracted with DCM, the organic layer was washed with brine, dried over Na₂SO₄, filtered and evaporated in vacuo. The crude product was purified by silica gel chromatography (PE) to afford 1-bromo-4-(difluoro(1-fluorocyclopropyl)methyl)benzene as colourless oil (240 mg, 30% yield).1H-NMR (400 MHz, CDCl3) δ: 7.60 (d, J = 8.4 Hz, 2H), 7.46 (d, J = 8.4 Hz, 2H), 1.24 - 1.14 (m, 4H). Step C: (S)-N-(3-cyanophenyl)-5-(4-(difluoro(1-fluorocyclopropyl)methyl)phenyl)-6-methyl-4- oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide. 1-bromo-4-(difluoro(1-fluorocyclopropyl)methyl)benzene (144 mg, 0.542 mmol), N1,N2- dimethylethane-1,2-diamine (22.3 µL, 0.20 mmol), K2CO3 (94 mg, 0.68 mmol) and CuI (38.7 mg, 0.2 mmol) were added to a stirred solution of (S)-N-(3-cyanophenyl)-6-methyl-4-oxo- 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide (Intermediate 6, 100 mg, 0.34 mmol) in DMF (1 mL) and toluene (1 mL) under nitrogen. The mixture was stirred at 100°C for 18 h. The reaction was monitored by LC-MS. The mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with water and brine, dried over Na₂SO₄, filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (0%-75% EtOAc/PE) and then freeze-dried to afford (S)-N-(3-cyanophenyl)-5- (4-(difluoro(1-fluorocyclopropyl)methyl)phenyl)-6-methyl-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide as a white solid (62 mg, 38% yield).1H-NMR (400 MHz, CDCl3) δ: 12.21 (s, 1H), 8.34 (s, 1H), 8.13 (s, 1H), 7.92 (br d, J = 8.0 Hz, 1H), 7.79 (d, J = 8.4 Hz, 2H), 7.47 (d, J = 8.4 Hz, 2H), 7.41 - 7.32 (m, 2H), 4.81 (dd, J = 4.8, 13.6 Hz, 1H), 4.50 (dd, J = 2.8, 13.2 Hz, 1H), 4.46 - 4.38 (m, 1H), 1.42 (d, J = 6.8 Hz, 3H), 1.30 - 1.22 (m, 4H). Mass spectrum (ESI, m/z): Calcd. for C₂₅H₂₀F₃N₅O₂, 479.2, found [M+H]+, 480.1. Example 101: N-(3-cyano-4- 2-yn-1-yloxy)phenyl)-5-(4-

(difluoro methyl)phenyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-

carboxamide

Step A: 5-amino-2-(prop-2-yn-1-yloxy)benzonitrile Propargyl bromide (57 µL, 0.45 mmol), cesium carbonate (244 mg, 0.75 mmol) and potassium iodide (2 mg, 0.012 mmol) were added to a solution of 5-amino-2-hydroxybenzonitrile (50 mg, 0.37 mmol) in acetone (1 mL). The mixture was stirred at 70°C for 16 h. The reaction progress was monitored by LC-MS. Water was added and the aqueous phase was extracted with EtOAc. The organic layer was dried over MgSO4, filtered and evaporated in vacuo. The residue was purified by silica gel chromatography (0-100% heptane/EtOAc). The desired fractions were collected and evaporated in vacuo to afford 5-amino-2-(prop-2-yn-1-yloxy)benzonitrile (27 mg, 41% yield).1H NMR (300 MHz, DMSO-d₆) δ: 3.57 - 3.61 (m, 1H) 4.78 - 4.84 (m, 2H) 5.15 (s, 2H) 6.80 (d, J = 2.7 Hz, 1H) 6.83 - 6.88 (m, 1H) 7.01 - 7.05 (m, 1H). Mass spectrum (ESI, m/z): calcd. for C₁₀H₈N₂O, 172.1; found [M+H]+, 173.1. Step B: N-(3-cyano-4-(prop-2-yn-1-yloxy)phenyl)-5-(4-(difluoro(phenyl)methyl)-phenyl)-4-oxo- 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide The title compound was prepared in a manner analogous to Example 55, reacting 5-amino-2- (prop-2-yn-1-yloxy)benzonitrile (27 mg, 0.16 mmol) and 5-(4-(difluoro(phenyl)methyl)phenyl)- 4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxylic acid (Intermediate 3, 53 mg, 0.14 mmol).1H NMR (400 MHz, DMSO-d₆) δ: 12.19 (s, 1H), 8.17 (s, 1H), 8.06 (d, J = 2.6 Hz, 1H), 7.72 (dd, J = 9.2, 2.6 Hz, 1H), 7.66 (q, J = 8.8 Hz, 4H), 7.59 (qd, J = 5.2, 4.7, 1.9 Hz, 2H), 7.54 (q, J = 3.3 Hz, 3H), 7.29 (d, J = 9.2 Hz, 1H), 4.97 (d, J = 2.3 Hz, 2H), 4.71 – 4.63 (m, 2H), 4.35 – 4.27 (m, 2H), 3.69 – 3.65 (m, 1H). Mass spectrum (ESI, m/z): calcd. for C₁₀H₈N₂O, 537.2; found [M+H]+, 538.2. Example 102: N-(3-cyanophenyl)-4-oxo-5-(4- 2-yn-1-yl)benzyl)phenyl)-4,5,6,7-

tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

Step A: N-(3-cyanophenyl)-4-oxo-5-(4-(2-(2-oxoethyl)benzyl)phenyl)-

tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide. The title compound was prepared in a manner analogous to Example 4, reacting N-(3- cyanophenyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide (Intermediate 9, 437.7 mg, 1.56 mmol) and 2-(2-(4-bromobenzyl)phenyl)acetaldehyde (Example 89, product from Step A, 450 mg, 1.56 mmol). Step B: N-(3-cyanophenyl)-4-oxo-5-(4-(2-(prop-2-yn-1-yl)benzyl)phenyl)-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide. To a mixture of N-(3-cyanophenyl)-4-oxo-5-(4-(2-(2-oxoethyl)benzyl)phenyl)-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide (240 mg, 0.49 mmol) and K2CO3 (203 mg, 1.47 mmol) in CH3CN (4 mL) and MeOH (4 mL) was added dimethyl (1-diazo-2- oxopropyl)phosphonate (188 mg, 0.98 mmol) under nitrogen. The mixture was stirred at 30ºC for 12 h. The reaction was monitored by LC-MS. The mixture was evaporated in vacuo and the crude product was purified by HPLC with the following conditions: column, Welch Xtimate C18, 150 mm, 30 mm x 5 µm; mobile phase, 61% to 91% (v/v) CH3CN and water with 0.2% FA. This resulted in N-(3-cyanophenyl)-4-oxo-5-(4-(2-(prop-2-yn-1-yl)benzyl)phenyl)-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide, that was freeze dried to afford a white solid (14.4 mg, 6% yield) and N-(3-cyanophenyl)-4-oxo-5-(4-(2-(propa-1,2-dien-1-yl)benzyl)phenyl)-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide (Example 86, 26.7 mg, 11% yield).1H-NMR (400 MHz, CDCl3) δ: 12.30 (s, 1H), 8.32 (s, 1H), 8.11 (d, J = 1.6 Hz, 1H),7.95 (m, 1H), 7.60 - 7.52 (m, 1H), 7.42 - 7.28 (m, 8H), 7.25 - 7.17 (m, 1H), 4.73 -4.62 (m, 2H), 4.32 - 4.22 (m, 2H), 4.14 (s, 2H), 3.52 (d, J = 2.4 Hz, 2H), 2.22 (t, J =2.4 Hz, 1H). Mass spectrum (ESI, m/z): calcd. for C H N O , 485.2; fo + 30 23 5 2 und [M+H] , 486.2. Example 103: N-(3-cyanophenyl)-4-oxo-5-(4-(trifluoromethyl)phenyl)-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

4-Oxo-5-(4-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxylic acid (Intermediate 43, 80 mg, 0.25 mmol), a stir bar, 3-aminobenzonitrile (34.9 mg, 0.295 mmol), DIPEA (0.129 mL, 0.738 mmol, 0.742 g/mL), HATU (140 mg, 0.369 mmol), and DMF (2 mL) were added to a 10 mL round-bottomed flask and the resulting mixture was stirred for 12 h at 25 °C under N2 atmosphere. The solution was concentrated under reduced pressure to give brown oil. The brown oil was purified by Prep-HPLC with the following conditions: column, Boston Prime C18, 150 mm, 30 mm x 5 ^m; mobile phase, 55% to 85% (v/v) CH3CN and H2O with (0.05% FA) and then freeze dried to afford N-(3-cyanophenyl)-4-oxo-5-(4- (trifluoromethyl)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide (49.9 mg, 47% yield) as a white solid.1H NMR (400 MHz, DMSO-d₆) ^ ^ 12.34 (s, 1H), 8.21 (s, 1H), 8.18 (s, 1H), 7.91 (d, J = 8.4 Hz, 2H), 7.80 - 7.70 (m, 3H), 7.57 - 7.53 (m, 2H), 4.73 - 4.66 (m, 2H), 4.39 - 4.32 (m, 2H). Mass spectrum (ESI, m/z): calcd. For C₂₁H₁₄F₃N₅O₂425.1; found [M+H]+, 426.2. Example 104: N-(3-cyanophenyl)-5-(4-(cyclobutylmethyl)phenyl)-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide

A 8-mL vial with a magnetic stirring bar was charged with intermediate 10 (30 mg, 0.064 mmol), (bromomethyl)cyclobutane (19.061 mg, 0.128 mmol), Na2CO3 (20.33 mg, 0.192 mmol), (4,4'-dtbbpy)NiCl₂ (2.545 mg, 0.00639 mmol) and (Ir[dF(CF₃)ppy]₂(dtbpy))PF6 (1.435 mg, 0.00128 mmol). CH3CN was added to the vial (750 µL) followed by variable tris(trimethylsilyl)silane (22.4 uL). Finally, the reactions were irradiated on the Penn Photoreactor® (wavelength: 450 nm; LED intensity: 100%; fan speed: ~6000 rpm; stir: ~1000 rpm). Once the reaction was completed, the crude mixture was diluted with MeOH (1 mL) and DMSO (2 mL) and MS Imidazole Resin was added (50 mg). The mixture was stirred for 1h and then filtered. The crude product was purified by Prep-HPLC. Conditions: Stationary phase: C18 XBridge 30 x 100 mm 10 µm. Mobile phase: NH₄HCO₃0.25% solution in Water and CH₃CN, to yield N-(3-cyanophenyl)-5-(4-(cyclobutylmethyl)phenyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrazine-3-carboxamide (22.2 mg, 79.1% yield) as white solid.1H NMR (400MHz, DMSO-d₆) ^ ^ ^12.64 (s, 1H), 8.59 (d, J = 5.6 Hz, 1H), 8.25 (s, 1H), 8.20 (d, J = 2.0 Hz, 1H), 7.91 (d, J = 8.8 Hz, 2H), 7.79 - 7.73 (m, 3H), 4.71 (m, 2H), 4.36 (t, J = 6.0 Hz, 2H). Mass spectrum (ESI, m/z): Calcd. for C + 20H13F3N6O2, 425.2, found [M+H] , 426.2. Examples 105-119 were prepared in a manner analogous to Example 104, with the appropriate reagent substitutions.

Example 120: N-(3-cyanophenyl)-5-(4-((3-(hydroxymethyl)bicyclo[1.1.1]pentan-1- yl)methyl)phenyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

Step A: ethyl 5-(4-((3-(((benzyloxy)methoxy)methyl)bicyclo[1.1.1]pentan-1-yl)methyl)phenyl)- 4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxylate. The title compound was prepared in a manner analogous to Intermediate 1, Step E, reacting ethyl 4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxylate (Intermediate 2, Step A, 150 mg, 0.717 mmol) and 1-(((benzyloxy)methoxy)methyl)-3-(4-bromobenzyl)bicyclo[1.1.1]pentane (Intermediate 50, 417 mg, 1.076 mmol).1H NMR (400 MHz, CDCl₃) δ: 1.28 (t, J=7.15 Hz, 3H) 1.47 - 1.52 (m, 6H) 2.72 (s, 2H) 3.47 (s, 2H) 4.08 - 4.16 (m, 2H) 4.28 (q, J=7.09 Hz, 2H) 4.45 - 4.49 (m, 2H) 4.49 (s, 2H) 4.65 (s, 2H) 7.07 (d, J=7.70 Hz, 2H) 7.21 - 7.30 (m, 7H) 7.89 (s, 1H). Mass spectrum (ESI, m/z): calcd. for C₃₀H₃₃N₃O₅, 515.2; found [M+H]+, 516.5. Step B: 5-(4-((3-(((benzyloxy)methoxy)methyl)bicyclo[1.1.1]pentan-1-yl)methyl)phenyl)-N-(3- cyanophenyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide. TMPMgCl·LiCl (0.84 M in THF) (0.29 ml, 0.24 mmol) was added to a solution of ethyl 5-(4- ((3-(((benzyloxy)methoxy)methyl)bicyclo[1.1.1]pentan-1-yl)methyl)phenyl)-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxylate (57 mg, 0.11 mmol) and 3-aminobenzonitrile (14 mg, 0.112 mmol) in THF anhydrous (3 mL) at 0ºC under nitrogen. The mixture was stirred at rt for 30 min. Then NH4Cl sat. solution was added and extracted with EtOAc. The organic layer was dried (MgSO4), filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (0%-85% heptane/EtOAc). The desired fractions were collected and concentrated in vacuo to yield 5-(4-((3- (((benzyloxy)methoxy)methyl)bicyclo[1.1.1]pentan-1-yl)methyl)phenyl)-N-(3-cyanophenyl)-4- oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide (41 mg; 57% yield) as a yellow foam.1H NMR (400 MHz, CDCl3) δ: 1.53 - 1.55 (m, 6H) 2.78 (s, 2H) 3.50 (s, 2H) 4.20 (dd, J=6.96, 5.34 Hz, 2H) 4.50 (s, 2H) 4.59 (dd, J=6.96, 5.25 Hz, 2H) 4.67 (s, 2H) 7.20 - 7.33 (m, 11H) 7.86 (dt, J=7.99, 1.78 Hz, 1H) 8.04 - 8.09 (m, 1H) 8.24 (s, 1H) 12.24 (s, 1H). Mass spectrum (ESI, m/z): calcd. for C₃₅H₃₃N₅O₄, 587.2; found [M+H]+, 588.3. Step C: N-(3-cyanophenyl)-5-(4-((3-(hydroxymethyl)bicyclo[1.1.1]pentan-1-yl)methyl)phenyl)- 4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide. 4N HCl in dioxane (2 mL, 8 mmol) was added to 5-(4-((3- (((benzyloxy)methoxy)methyl)bicyclo[1.1.1]pentan-1-yl)methyl)phenyl)-N-(3- cyanophenyl)-4- oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide (39 mg , 0.06 mmol) at 0ºC and the reaction mixture was stirred at rt for 1h. The mixture was diluted with DCM and sat NaHCO₃. The organic layer was separated, dried (MgSO₄), filtered and the solvents evaporated in vacuo. The residue was purified by silica gel chromatography (0%-2%, MeOH-DCM) to afford N-(3-cyanophenyl)-5-(4-((3-(hydroxymethyl)bicyclo[1.1.1]pentan-1-yl)methyl)phenyl)-4- oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide (14 mg; 43% yield) as a white foam.1H-NMR (400 MHz, CDCl3) δ: 1.50 - 1.53 (m, 6H) 2.79 (s, 2H) 3.52 (d, J=5.82 Hz, 2H) 4.21 (dd, J=6.96, 5.34 Hz, 2H) 4.59 (dd, J=7.06, 5.25 Hz, 2H) 7.19 - 7.20 (m, 2H) 7.21 - 7.34 (m, 4H) 7.89 (dt, J=8.03, 1.75 Hz, 1H) 8.03 (t, J=1.67 Hz, 1H) 8.24 (s, 1H) 12.24 (s, 1H). Mass spectrum (ESI, m/z): Calcd. for C + 27H25N5O3, 567.2, found [M+H] , 468.1. Example 121: methyl (S)-1-(4-(3-((3-cyanophenyl)carbamoyl)-6-methyl-4-oxo-6,7- dihydropyrazolo[1,5-a]pyrazin-5 -yl)benzyl)cyclobutane-1-carboxylate

A 2-dram vials equipped with a magnetic stirring bar were charged respectively with (S)-5-(4- bromophenyl)-N-(3-cyanophenyl)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3- carboxamide (Intermediate 8A, 34 mg, 0.073 mmol), methyl 1-(bromomethyl)cyclobutane-1- carboxylate (30 mg, 0.15 mmol), Na₂CO₃ (23 mg, 0.22 mmol), (4,4'-dtbbpy)NiCl₂ (2.9 mg, 0.0073 mmol) and (Ir[dF(CF3)ppy]2(dtbpy))PF6 (1.6 mg, 0.0015 mmol). ACN (0.75 mL) was added to the corresponding vials followed by (hydroxy-bis(trimethylsilyl)silyl)-trimethylsilane (22.4 µL, 0.859 g/mL, 0.0728 mmol). The reaction was irradiated on the Penn Photoreactor® (wavelength: 450 nm; LED intensity: 100%; fan speed: ~6000 rpm; stir: 900 rpm) for 1 hour. Water (2 mL) and DCM (2 mL) were added. The mixture was stirred at RT for 20 min and placed in a SCX separator cartridge eluting with more DCM (2 mL). The organic layer was evaporated in vacuo and sent to Prep-HPLC (conditions: Stationary phase: C18 XBridge 30 x 100 mm 10 µm. Mobile phase: NH4HCO30.25% solution in Water and CH3CN (BA-10um)) yielding methyl (S)-1-(4-(3-((3-cyanophenyl)carbamoyl)-6-methyl-4-oxo-6,7- dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl)benzyl)cyclobutane-1-carboxylate (17 mg, 47% yield) as a colorless oil. Example 122: (S)-N-(3-cyanophenyl)-6-methyl-4-oxo-5-(4-(trifluoromethyl)phenyl)-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

(S)-N-(3-cyanophenyl)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3- carboxamide (Intermediate 6, 200 mg, 0.677 mmol), 1-bromo-4-(trifluoromethyl)benzene (114 μL, 0.813 mmol), copper(I) iodide（77 mg, 0.41 mmol), N, N'-dimethylethylenediamine (43.7 μL, 0.406 mmol), potassium carbonate (374 mg, 2.71 mmol), a stir bar, DMF (2 mL) and toluene (2 mL) were added to an oven-dried and nitrogen-purged 10 mL round bottomed flask fitted with a reflux condenser, the resulting mixture was stirred overnight at 100 °C. The reaction mixture was filtered and the filter cake washed with EtOAc (40 mL), then the filtrate washed with water (10 mL), brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated to dryness in vacuo to give light yellow oil. The oil was subjected to silica gel chromatography (0-65% EtOAc/PE) to give (S)-N-(3-cyanophenyl)-6-methyl-4-oxo-5-(4-(trifluoromethyl)phenyl)- 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide (112.6 mg, 38% yield) as a white solid.1H NMR (400 MHz, DMSO-d6) δ: 12.32 (s, 1H), 8.22 (s, 1H), 8.18 (s, 1H), 7.93 (d, J = 8.4 Hz, 2H), 7.78 (d, J = 8.4 Hz, 2H), 7.74 - 7.69 (m, 1H), 7.57 - 7.51 (m, 2H), 4.93 (dd, J = 4.0, 12.8 Hz, 1H), 4.63 - 4.50 (m, 2H), 1.23 (d, J = 6.4 Hz, 3H). Mass spectrum (ESI, m/z): calcd. for C H F N O 4 + 22 16 3 5 2 39.1; found [M+H] , 440.2. Example 123: (S)-N-(3-cyanophenyl)-6-methyl-4-oxo-5-(4-(pentafluoro-

sulfaneyl)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide

The title compound was prepared in a manner analogous to Example 122, reacting (S)-N-(3- cyanophenyl)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide (Intermediate 6, 200 mg, 0.677 mmol) and 4-BromophenylsulfurPentafluoride (154 μL, 0.813 mmol).1H NMR (400 MHz, DMSO-d6) δ: 12.27 (s, 1H), 8.22 (s, 1H), 8.20 (s, 1H), 8.11 (d, J = 9.2 Hz, 2H), 7.80 (d, J = 8.4 Hz, 2H), 7.75 - 7.69 (m, 1H), 7.58 - 7.51 (m, 2H), 4.93 (dd, J = 4.4, 13.2 Hz, 1H), 4.64 - 4.50 (m, 2H), 1.24 (d, J = 6.8 Hz, 3H). Mass spectrum (ESI, m/z): calcd. for C H F N O S 497.1; found [M+H + 21 16 5 5 2 ] , 498.1. Example 124: (S)-N-(3-cyanophenyl)-6-methyl-4-oxo-5-(4-(2,2,2-trifluoroethyl)phenyl)- 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide

The title compound was prepared in a manner analogous to Example 122, reacting (S)-N-(3- cyanophenyl)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide (Intermediate 6, 200 mg, 0.677 mmol) and 1-bromo-4-(2,2,2-trifluoroethyl)benzene (194 mg, 0.813 mmol).1H NMR (400 MHz, DMSO-d₆) δ: 12.46 (s, 1H), 8.23 - 8.18 (m, 2H), 7.77 - 7.65 (m, 1H), 7.57 - 7.50 (m, 6H), 4.96 - 4.87 (m, 1H), 4.55 - 4.46 (m, 2H), 3.75 (q, J = 11.6 Hz, 2H), 1.22 (d, J = 6.4 Hz, 3H). Mass spectrum (ESI, m/z): calcd. for C23H18F3N5O2453.1; found [M+H]+, 454.2. Example 125: (S)-N-(3-cyano-4-methoxyphenyl)-5-(4-(cyclobutyldifluoromethyl)phenyl)-6- methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

Step A: N-methoxy-N-methylcyclobutanecarboxamide. Cyclobutanecarboxylic acid (1.00 g, 9.99 mmol), a stir bar, CDI (2.11g, 13.0 mmol) and DCM (20 mL) were added to a 100 mL round bottomed flask, the mixture was treated with N,O- dimethylhydroxylamine hydrochloride (1.36 g, 14.0 mmol) and TEA (1.95 mL, 14.0 mmol), and the mixture was stirred overnight at rt. The reaction mixture was washed with 1 M aq. HCl (20 mL), sat. aq. NaHCO3 (20 mL), water (20 mL) and brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuum to give light brown oil. The oil was subjected to silica gel chromatography (0~7% EtOAc/PE) to give N-methoxy-N-methylcyclobutanecarboxamide as colorless oil (1.06 g, 66% yield).1H NMR (400 MHz, CDCl3) δ: 3.64 (s, 3H), 3.47 (br d, J = 8.0 Hz, 1H), 3.16 (s, 3H), 2.38 - 2.26 (m, 2H), 2.18 - 2.07 (m, 2H), 2.04 - 1.92 (m, 1H), 1.91 - 1.79 (m, 1H). Mass spectrum (ESI, m/z): calcd. for C₇H₁₃NO₂143.1; found [M+H]+, 144.2. Step B: (4-bromophenyl)(cyclobutyl)methanone. 1-Bromo-4-iodobenzene (2.46 g, 8.70 mmol), a stir bar, and THF (10 mL) were added to an oven-dried and nitrogen-purged 100 mL three-necked flask, which was subsequently evacuated and refilled with nitrogen and cooled to -70 °C in an EtOH/Dry Ice bath, and the resulting mixture treated with n-BuLi (3.48 mL, 8.70 mmol) dropwise over 4 min, and the mixture was stirred at -70 °C for 0.5 h, then which charged with a solution of N-methoxy-N- methylcyclobutanecarboxamide (830 mg, 5.80 mmol) in THF (6 mL), and then the mixture was stirred at -70 °C for 2.5 h. The reaction mixture was quenched with sat. aq. NH4Cl (20 mL), extracted with EtOAc (20 mL x 3). The combined extracts washed with brine (40 mL), dried over anhydrous Na₂SO₄, filtered and concentrated in vacuum to give yellow oil. The oil was then subjected to silica gel chromatography (0~0.2% EtOAc/PE) to give (4-bromophenyl)- (cyclobutyl)methanone as a white solid (1.05 g, 73% yield).1H NMR (400 MHz, CDCl₃) δ: 7.68 (d, J = 8.4 Hz, 2H), 7.52 (d, J = 8.4 Hz, 2H), 3.95 - 3.82 (m, 1H), 2.40 - 2.16 (m, 4H), 2.09 - 1.93 (m, 1H), 1.91 - 1.77 (m, 1H). Mass spectrum (ESI, m/z): calcd. for C11H11BrO1238.0; found [M+H]+, 239.0 Step C: 2-(4-bromophenyl)-2-cyclobutyl-1,3-dithiane. (4-Bromophenyl)(cyclobutyl)methanone (1.05 g, 4.39 mmol), a stir bar, propane-1,3-dithiol (0.75 mL, 7.5 mmol), TsOH (151 mg, 0.878 mmol), and toluene (10 mL) were added to an oven- dried and nitrogen-purged 50 mL round-bottomed flask fitted with a reflux condenser, and the reaction vessel placed in an oil bath that had been pre-heated to 120 °C, and the mixture was stirred overnight. The reaction mixture was poured into water (30 mL), extracted with EtOAc (20 mL x 3). The combined extracts washed with brine (40 mL), dried over anhydrous Na2SO4, filtered and concentrated to dryness under reduced pressure to give light brown oil. The oil was then subjected to silica gel chromatography (0~0.5% EtOAc/PE) to give 2-(4-bromophenyl)-2- cyclobutyl-1,3-dithiane as colorless oil (1.5 g, crude). Mass spectrum (ESI, m/z): calcd. for C H BrS 328.0; fo + 14 17 2 und [M+H] , 329.0. Step D: 1-bromo-4-(cyclobutyldifluoromethyl)benzene. 2-(4-Bromophenyl)-2-cyclobutyl-1,3-dithiane (1.5 g, 4.6 mmol), a stir bar and DCM (15 mL) were added to a 100 mL three-necked flask, which was subsequently evacuated and refilled with nitrogen and subsequently cooled to 0 °C in the water/ice bath, and the resulting mixture treated with DAST (1.3 mL, 9.8 mmol) dropwise over 2 min, and the mixture was stirred at rt overnight. The reaction mixture was quenched with sat. aq. NaHCO3 (30 mL) dropwise, then extracted with EtOAc (30 mL x 2). The combined extracts washed with brine (50 mL), dried over anhydrous Na₂SO₄, filtered and concentrated in vacuum to give brown oil. The oil was then subjected to silica gel chromatography (0~0.2% EtOAc/PE) to give 1-bromo-4- (cyclobutyldifluoromethyl)benzene as colorless oil (635 mg, 53% yield).1H NMR (400 MHz, CDCl₃) δ: 7.53 (d, J = 8.4 Hz, 2H), 7.31 (d, J = 8.4 Hz, 2H), 3.01 - 2.85 (m, 1H), 2.28 - 2.09 (m, 2H), 2.05 - 1.75 (m, 4H). Step E: (S)-N-(3-cyano-4-methoxyphenyl)-5-(4-(cyclobutyldifluoromethyl)phenyl)-6-methyl-4- oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide. The title compound was prepared in a manner analogous to Example 122, reacting (S)-N-(3- cyano-4-methoxyphenyl)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3- carboxamide (Intermediate 7, 100 mg, 0.307 mmol and 1-bromo-4- (cyclobutyldifluoromethyl)benzene (161 mg, 0.615 mmol).1H NMR (400 MHz, DMSO-d₆) δ: 12.16 (s, 1H), 8.19 (s, 1H), 8.04 (d, J = 2.4 Hz, 1H), 7.70 (dd, J = 2.4, 8.8 Hz, 1H), 7.67 - 7.61 (m, 4H), 7.23 (d, J = 9.2 Hz, 1H), 4.96 - 4.87 (m, 1H), 4.55 - 4.47 (m, 2H), 3.88 (s, 3H), 3.28 - 3.16 (m, 1H), 2.20 - 2.09 (m, 2H), 2.05 - 1.88 (m, 3H), 1.86 - 1.75 (m, 1H), 1.22 (d, J = 6.4 Hz, 3H). Mass spectrum (ESI, m/z): calcd. for C₂₇H₂₅F₂N₅O₃505.2; found [M+H]+, 506.2. Example 126: (S)-N-(3-cyanophenyl)-5-(4-(cyclopropylmethyl)phenyl)-6-methyl-4-oxo- 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

Step A: N-methoxy-N-methylcyclopropanecarboxamide. The title compound was prepared in a manner analogous to Example 125, Step A, reacting cyclopropanecarboxylic acid (5.00 g, 58.1 mmol) and N,O-dimethylhydroxylamine hydrochloride (7.93 g, 81.3 mmol).1H NMR (400 MHz, CDCl3) δ: 3.77 (s, 3H), 3.22 (s, 3H), 2.15 (br s, 1H), 1.04 - 0.95 (m, 2H), 0.87 - 0.75 (m, 2H). Mass spectrum (ESI, m/z): calcd. for C₆H₁₁NO₂129.1; found [M+H]+, 130.1. Step B: (4-bromophenyl)(cyclopropyl)methanone. The title compound was prepared in a manner analogous to Example 125, Step B, reacting N- methoxy-N-methylcyclopropanecarboxamide (4.60 g, 35.6 mmol) and 1-bromo-4-iodobenzene (15.1 g, 53.4 mmol).1H NMR (400 MHz, CDCl3) δ: 7.89 (d, J = 8.5 Hz, 2H), 7.63 (d, J = 8.8 Hz, 2H), 2.69 - 2.56 (m, 1H), 1.58 - 1.24 (m, 2H), 1.09 - 1.06 (m, 2H). Mass spectrum (ESI, m/z): calcd. for C₁₀H₉BrO 224.0; found [M+H]+, 225.0. Step C: (4-bromophenyl)(cyclopropyl)methanol. (4-Bromophenyl)(cyclopropyl)methanone (1 g, 4.43 mmol), a stirring bar, MeOH (15 mL) were added to a 100 mL three-necked round-bottomed flask which was subsequently evacuated and refilled with N2 before treated with sodium borohydride (660 mg, 17.4 mmol) in an ice-water bath. The reaction mixture was stirred at 25 °C for 2 hours. The mixture was quenched with sat. aq. NH₄Cl (30 mL) and extracted with EtOAc (30 mL x 3). The combined extracts washed with brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford colorless oil. The oil was then subjected to silica gel chromatography (15-18% EtOAc/PE) to afford the (4-bromophenyl)(cyclopropyl)methanol as a white solid (960 mg, 95% yield).1H NMR (400 MHz, CDCl₃) δ: 7.53 - 7.44 (m, 2H), 7.32 (d, J = 8.8 Hz, 2H), 3.99 (dd, J = 2.0, 6.0 Hz, 1H), 1.94 (d, J = 2.8 Hz, 1H), 1.22 - 1.12 (m, 1H), 0.70 - 0.53 (m, 2H), 0.52 - 0.34 (m, 2H). Step D: 1-bromo-4-(cyclopropylmethyl)benzene. (4-Bromophenyl)(cyclopropyl)methanol (3.13 g, 13.8 mmol), triethylsilane (3.30 mL, 20.7 mmol), a stir bar and DCM (31 mL) were added to a 100 mL round bottom flask. Then 2,2,2- trifluoroacetic acid (1.50 mL, 20.7 mmol) was added to the mixture and the mixture was then stirred at 25 °C for 2 h. The mixture was quenched with sat. aq. NaHCO3 (90 mL), extracted with DCM (45 mL x 2) and the combined extracts washed with brine (45 mL), dried over Na₂SO₄ and concentrated to dryness under reduced pressure to give yellow oil. The yellow oil was then subjected to silica gel chromatography (0-3% EtOAc/PE) to give 1-bromo-4- (cyclopropylmethyl)benzene as colorless oil (2.24 g, 77% yield).1H NMR (400 MHz, CDCl3) δ: 7.41 (d, J = 8.4 Hz, 2H), 7.14 (d, J = 8.0 Hz, 2H), 2.51 (d, J = 6.8 Hz, 2H), 1.02 - 0.86 (m, 1H), 0.61 - 0.49 (m, 2H), 0.20 (q, J = 4.8 Hz, 2H). Step E: (S)-N-(3-cyanophenyl)-5-(4-(cyclopropylmethyl)phenyl)-6-methyl-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide. The title compound was prepared in a manner analogous to Example 122, reacting (S)-N-(3- cyanophenyl)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide (Intermediate 6, 200 mg, 0.603 mmol) and 1-bromo-4-(cyclopropylmethyl)benzene (191 mg, 0.904 mmol).1H NMR (400 MHz, DMSO-d₆) δ: 12.55 (s, 1H), 8.24 - 8.14 (m, 2H), 7.76 - 7.68 (m, 1H), 7.58 - 7.50 (m, 2H), 7.41 (s, 4H), 4.91 (dd, J = 4.4, 13.2 Hz, 1H), 4.55 - 4.42 (m, 2H), 2.56 (d, J = 7.2 Hz, 2H), 1.21 (d, J = 6.8 Hz, 3H), 1.07 - 0.96 (m, 1H), 0.56 - 0.46 (m, 2H), 0.29 - 0.21 (m, 2H). Mass spectrum (ESI, m/z): calcd. for C₂₅H₂₃O₅N₂425.2; found [M+H]+, 426.2.

oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide

The title compound was prepared in a manner analogous to Example 122, reacting (S)-N-(3- cyanophenyl)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide (Intermediate 6, 200 mg, 0.677 mmol) and 1-bromo-4-(cyclobutyldifluoromethyl)benzene (Example 125, product from step D, 161 mg, 0.615 mmol).1H NMR (400 MHz, DMSO-d₆) δ: 12.39 (s, 1H), 8.21 (s, 1H), 8.19 (s, 1H), 7.72 - 7.69 (m, 1H), 7.68 - 7.61 (m, 4H), 7.56 - 7.51 (m, 2H), 4.96 - 4.89 (m, 1H), 4.57 - 4.48 (m, 2H), 3.32 - 3.13 (m, 1H), 2.20 - 2.09 (m, 2H), 2.05 - 1.75 (m, 4H), 1.22 (d, J = 6.4 Hz, 3H). Mass spectrum (ESI, m/z): calcd. for C₂₆H₂₃F₂N₅O₂ 475.2; found [M+H]+, 476.2. Example 128: (S)-N-(3-cyano-4-methoxyphenyl)-5-(4-(cyclopropylmethyl)phenyl)-6- methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

The title compound was prepared in a manner analogous to Example 122, reacting (S)-N-(3- cyano-4-methoxyphenyl)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3- carboxamide (Intermediate 7, 100 mg, 0.276 mmol) and 1-bromo-4-(cyclopropylmethyl)benzene (Example 126, product from Step D, 88 mg, 0.42 mmol). 1H NMR (400 MHz, DMSO-d6) δ: 12.33 (s, 1H), 8.18 (s, 1H), 8.03 (d, J = 2.4 Hz, 1H), 7.71 (dd, J = 2.4, 9.2 Hz, 1H), 7.41 (s, 4H), 7.23 (d, J = 9.2 Hz, 1H), 4.90 (dd, J = 4.4, 13.2 Hz, 1H), 4.54 - 4.39 (m, 2H), 3.88 (s, 3H), 2.56 (br d, J = 6.8 Hz, 2H), 1.21 (br d, J = 6.4 Hz, 3H), 1.05 - 0.99 (m, 1H), 0.56 - 0.46 (m, 2H), 0.25 (q, J = 5.2 Hz, 2H). Mass spectrum (ESI, m/z): calcd. for C H N O 455.2; fo + 26 25 5 3 und [M+H] , 456.2. Example 129: (S)-N-(3-cyano-4-methoxyphenyl)-6-methyl-4-oxo-5-(4- (trifluoromethyl)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

The title compound was prepared in a manner analogous to Example 122, reacting (S)-N-(3- cyano-4-methoxyphenyl)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3- carboxamide (Intermediate 7, 100 mg, 0.276 mmol) and 1-bromo-4-(trifluoromethyl)benzene (93 mg, 0.42 mmol).1H NMR (400 MHz, DMSO-d6) δ: 12.11 (s, 1H), 8.19 (s, 1H), 8.04 (d, J = 2.8 Hz, 1H), 7.93 (d, J = 8.8 Hz, 2H), 7.78 (d, J = 8.4 Hz, 2H), 7.70 (dd, J = 2.4, 9.2 Hz, 1H), 7.23 (d, J = 9.2 Hz, 1H), 4.93 (dd, J = 4.4, 13.2 Hz, 1H), 4.65 - 4.46 (m, 2H), 3.88 (s, 3H), 1.23 (d, J = 6.4 Hz, 3H). Mass spectrum (ESI, m/z): calcd. for C H F N O 469.1; f + 23 18 2 5 3 ound [M+H] , 470.2. Example 130: (S)-N-(3-cyano-4-methoxyphenyl)-6-methyl-4-oxo-5-(4-(2,2,2- trifluoroethyl)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

The title compound was prepared in a manner analogous to Example 122, reacting (S)-N-(3- cyano-4-methoxyphenyl)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3- carboxamide (Intermediate 7, 180 mg, 0.553 mmol) and 1-bromo-4-(2,2,2-trifluoroethyl)benzene (291 mg, 1.22 mmol).1H NMR (400 MHz, DMSO-d₆) δ: 12.24 (s, 1H), 8.18 (s, 1H), 8.05 (d, J = 2.4 Hz, 1H), 7.70 (dd, J = 2.4, 9.2 Hz, 1H), 7.53 (s, 4H), 7.22 (d, J = 9.2 Hz, 1H), 4.94 - 4.87 (m, 1H), 4.54 - 4.45 (m, 2H), 3.88 (s, 3H), 3.75 (q, J = 11.6 Hz, 2H), 1.21 (br d, J = 6.0 Hz, 3H). Mass spectrum (ESI, m/z): calcd. for C H F + 24 20 3N5O3483.2; found [M+H] , 484.2. Example 131: (S)-N-(3-cyanophenyl)-6-methyl-4-oxo-5-(4-((2,2,2- trifluoroethoxy)methyl)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

Step A: 1-bromo-4-((2,2,2-trifluoroethoxy)methyl)benzene. NaH (225 mg, 7.50 mmol), DMF (10 mL), and 2,2,2-trifluoroethan-1-ol (500 mg, 5.00 mmol) was added to an oven-dried and nitrogen-purged 50 mL round-bottomed flask at 0° C, and the resulting mixture was stirred for 15 minutes. Then a solution of 1-bromo-4- (bromomethyl)benzene (1.25 g, 5.00 mmol) in DMF (5 mL) added dropwise to above solution. The reaction mixture was slowly warmed to rt and stirred for 1 h. The reaction mixture was cooled to 10 °C, quenched with ice water (20 mL), extracted with EtOAc (50 mL x2). The combined extracts washed with brine (30 mL), dried over anhydrous Na2SO4 and concentrated to dryness under reduced pressure to obtain yellow oil. The oil was then subjected to silica gel chromatography (0-10% EtOAc/PE) to give 1-bromo-4-((2,2,2- trifluoroethoxy)methyl)benzeneas colorless oil (1.2 g, 89% yield).1H NMR (400 MHz, DMSO- d6) δ: 7.58 (d, J = 8.0 Hz, 2H), 7.31 (d, J = 8.4 Hz, 2H), 4.63 (s, 2H), 4.10 (q, J = 9.6 Hz, 2H). Step B: (S)-N-(3-cyanophenyl)-6-methyl-4-oxo-5-(4-((2,2,2-trifluoroethoxy)methyl)phenyl)- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

The title compound was prepared in a manner analogous to Example 122, reacting (S)-N-(3- cyanophenyl)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide (Intermediate 6, 150 mg, 0.452 mmol) and 1-bromo-4-((2,2,2-trifluoroethoxy)methyl)benzene (182 mg, 0.678 mmol).1H NMR (400 MHz, DMSO-d6) δ: 12.51 (s, 1H), 8.21 (s, 1H), 8.18 (s, 1H), 7.74 - 7.68 (m, 1H), 7.56 - 7.47 (m, 6H), 4.96 - 4.87 (m, 1H), 4.73 (s, 2H), 4.56 - 4.43 (m, 2H), 4.18 (q, J = 9.2 Hz, 2H), 1.22 (d, J = 6.4 Hz, 3H). Mass spectrum (ESI, m/z): calcd. for C₂₄H₂₀F₃N₅O₃483.2; found [M+H]+, 484.2. Example 132: (S)- (3-cyano-4-methoxyphenyl)-6-methyl-4-oxo-5-(4-((2,2,2-

trifluoroethoxy)methyl)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

The title compound was prepared in a manner analogous to Example 122, reacting (S)-N-(3- cyano-4-methoxyphenyl)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3- carboxamide (Intermediate 7, 150 mg, 0.452 mmol) and 1-bromo-4-((2,2,2- trifluoroethoxy)methyl)benzene (167 mg, 0.622 mmol).1H NMR (400 MHz, DMSO-d6) δ: 12.29 (s, 1H), 8.18 (s, 1H), 8.04 (d, J = 2.4 Hz, 1H), 7.70 (dd, J = 2.4, 9.2 Hz, 1H), 7.56 - 7.46 (m, 4H), 7.23 (d, J = 9.2 Hz, 1H), 4.95 - 4.86 (m, 1H), 4.73 (s, 2H), 4.56 - 4.42 (m, 2H), 4.18 (q, J = 9.2 Hz, 2H), 3.88 (s, 3H), 1.21 (d, J = 6.4 Hz, 3H). Mass spectrum (ESI, m/z): calcd. for C H F3N5O4513.2; + 25 22 found [M+H] , 514.2. Example 133: (S)-N-(3-cyanophenyl)-6-methyl-4-oxo-5-(4-(perfluoroethyl)phenyl)-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

Step A: 1-bromo-4-(perfluoroethyl)benzene. Copper(I) chloride (515 mg, 5.21 mmol), a stirring bar, and DMF (10 mL) were added to an oven-dried and nitrogen-purged 10 mL round bottomed flask, and the resulting mixture was treated with t-BuOK (1.2 g, 10 mmol) in one portion. The resulting mixture was stirred at rt for 1 h. Then the mixture was heated to 50 °C and treated with ethyl 2,2,3,3,3-pentafluoropropanoate (770 μL, 5.21 mmol) and stirred at 50 °C for 30 min. Then the mixture was treated with triethylamine trihydrofluoride (0.339 mL, 2.08 mmol) to give a brown suspension, then (4- bromophenyl)boronic acid (523 mg, 2.60 mmol) and toluene (10 mL) were added to the reaction mixture, then the mixture was stirred overnight at rt. The reaction mixture was quenched with aq. HCl (1 M, 20 mL) and extracted with MTBE (20 mL x 2), and the combined extracts washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated to dryness in vacuo to give light yellow oil. The oil was subjected to silica gel chromatography (PE) to give 1- bromo-4-(perfluoroethyl)benzene as colorless oil (150 mg, 21% yield).1H NMR (400 MHz, CDCl₃) δ: 7.65 (d, J = 8.4 Hz, 2H), 7.47 (d, J = 8.8 Hz, 2H). Step B: (S)-N-(3-cyanophenyl)-6-methyl-4-oxo-5-(4-(perfluoroethyl)phenyl)-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide. The title compound was prepared in a manner analogous to Example 122, reacting (S)-N-(3- cyanophenyl)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide (Intermediate 6, 81 mg, 0.27 mmol) and 1-bromo-4-(perfluoroethyl)benzene (90 mg, 0.33 mmol).1H NMR (400 MHz, DMSO-d6) δ: 12.28 (s, 1H), 8.26 - 8.15 (m, 2H), 7.89 (d, J = 8.4 Hz, 2H), 7.82 (d, J = 8.4 Hz, 2H), 7.76 - 7.67 (m, 1H), 7.58 - 7.48 (m, 2H), 4.94 (br dd, J = 4.4, 13.2 Hz, 1H), 4.65 - 4.50 (m, 2H), 1.24 (br d, J = 6.8 Hz, 3H). Mass spectrum (ESI, m/z): calcd. for C H F N O 489.1; found [M+H + 23 16 5 5 2 ] , 490.1. Example 134: (S)-N-(3-cyanophenyl)-6-methyl-4-oxo-5-(4-((2,2,2- trifluoroethyl)amino)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

Step A: 4-bromo-N-(2,2,2-trifluoroethyl)aniline. (4-Bromophenyl)boronic acid (2.0 g, 10 mmol), 2,2,2-trifluoroethanamine (782 μL, 10.0 mmol), a stir bar, triethylamine (5.5 mL, 40 mmol), and CH₃CN (15 mL) were added to an oven-dried and nitrogen-purged 50 mL round-bottomed flask, which was treated with copper(II) acetate (2.2 g, 12 mmol). The resulted mixture stirred at 80 °C for 12 h. The reaction mixture was poured into H₂O (15 mL) and extracted with EtOAc (20 mLx3). The combined extracts washed with brine (50 mL), dried over anhydrous Na₂SO₄, filtered and concentrated to dryness under reduced pressure to obtain brown oil. The brown oil was subjected to silica gel chromatography (0-20% EtOAc/PE) to give 4-bromo-N-(2,2,2-trifluoroethyl)aniline as yellow oil (250 mg, 9% yield). 1H NMR (400 MHz, DMSO-d₆) δ: 7.31 - 7.19 (m, 2H), 6.77 - 6.64 (m, 2H), 6.43 (br t, J = 6.8 Hz, 1H), 3.97 - 3.86 (m, 2H). Mass spectrum (ESI, m/z): calcd. for C8H7BrF3N 253.0; found [M+H]+, 254.0 Step B: (S)-N-(3-cyanophenyl)-6-methyl-4-oxo-5-(4-((2,2,2-trifluoroethyl)amino)phenyl)- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide

The title compound was prepared in a manner analogous to Example 122, reacting (S)-N-(3- cyanophenyl)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide (Intermediate 6, 100 mg, 0.339 mmol) and 4-bromo-N-(2,2,2-trifluoroethyl)aniline (103 mg, 0.406 mmol).1H NMR (400 MHz, DMSO-d6) δ: 12.67 (s, 1H), 8.19 (s, 2H), 7.73 - 7.67 (m, 1H), 7.56 - 7.51 (m, 2H), 7.21 (d, J = 8.8 Hz, 2H), 6.83 (d, J = 8.8 Hz, 2H), 6.51 (t, J = 6.8 Hz, 1H), 4.87 (dd, J = 4.4 Hz, 1H), 4.47 (dd, J = 3.6 Hz, 1H), 4.39 - 4.31 (m, 1H), 4.04 - 3.93 (m, 2H), 1.19 (d, J = 6.4 Hz, 3H). Mass spectrum (ESI, m/z): calcd. for C23H19F3N6O2468.2; found [M+H]+, 469.2. Example 135: (S)-N-(3-cyanophenyl)-6-methyl-4-oxo-5-(4-(2,2,2-trifluoroethoxy)phenyl)- 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

The title compound was prepared in a manner analogous to Example 122, reacting (S)-N-(3- cyanophenyl)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide (Intermediate 6, 150 mg, 0.452 mmol) and 1-bromo-4-(2,2,2-trifluoroethoxy)benzene (138 mg, 0.543 mmol).1H NMR (400 MHz, DMSO-d₆) δ: 12.55 (s, 1H), 8.21 (s, 1H), 8.16 (m, 1H), 7.74 - 7.69 (m, 1H), 7.57 - 7.52 (m, 2H), 7.50 - 7.45 (m, 2H), 7.24 - 7.17 (m, 2H), 4.93 - 4.80 (m, 3H), 4.53 - 4.39 (m, 2H), 1.20 (d, J = 6.4 Hz, 3H). Mass spectrum (ESI, m/z): calcd. for C₂₃H₁₈F₃N₅O₃469.1, found [M+H]+, 470.1. Example 136: (S)-N-(3-cyano-4-methoxyphenyl)-6-methyl-4-oxo-5-(4-(2,2,2- trifluoroethoxy)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

The title compound was prepared in a manner analogous to Example 122, reacting (S)-N-(3- cyano-4-methoxyphenyl)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3- carboxamide (Intermediate 7, 150 mg, 0.415 mmol) and 1-bromo-4-(2,2,2- trifluoroethoxy)benzene (127 mg, 0.498 mmol).1H NMR (400 MHz, DMSO-d6) δ: 12.32 (s, 1H), 8.18 (s, 1H), 8.02 (d, J = 2.8 Hz, 1H), 7.70 (dd, J = 2.4, 9.2 Hz, 1H), 7.50 - 7.44 (m, 2H), 7.25 - 7.18 (m, 3H), 4.93 - 4.80 (m, 3H), 4.52 - 4.40 (m, 2H), 3.88 (s, 3H), 1.19 (d, J = 6.4 Hz, 3H). Mass spectrum (ESI, m/z): calcd. for C + 24H20F3N5O4499.1, found [M+H] , 500.2. Example 137: (S)-N-(3-cyanophenyl)-6-methyl-4-oxo-5-(4-(((2,2,2- trifluoroethyl)amino)methyl)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3- carboxamide.

Step A: N-(4-bromobenzyl)-2,2,2-trifluoroethan-1-amine. 1-Bromo-4-(bromomethyl)benzene (1.50 g, 6.00 mmol), 2,2,2-trifluoroethanamine (1.78 g, 18.0 mmol), Cs2CO3 (2.93 g, 3.00 mmol), a stirring bar and MeCN (24 mL) were added to a 100 mL round-bottomed flask. The mixture was stirred at 40 °C for 8 hours. The reaction mixture was diluted with water (20 mL), extracted with EtOAc (10 mLx 3), and the combined extracts washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated to dryness in vacuo to give light yellow oil. The oil was then subjected to silica gel chromatography (7-9% EtOAc/PE) to give N-(4-bromobenzyl)-2,2,2-trifluoroethan-1-amine as colorless oil (1.12 g, 68% yield).1H NMR (400 MHz, DMSO-d6) δ: 7.51 (d, J = 8.4 Hz, 2H), 7.29 (d, J = 8.0 Hz, 2H), 3.75 (d, J = 6.8 Hz, 2H), 3.22 – 3.12 (m, 2H), 2.99 - 2.96 (m, 1H). Mass spectrum (ESI, m/z): calcd. for C₉H₉BrF₃N 267.0, found [M+H]+, 268.0. Step B: N-(4-bromobenzyl)-2,2,2-trifluoroethan-1-amine. The title compound was prepared in a manner analogous to Example 122, (S)-N-(3- cyanophenyl)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide (Intermediate 6, 200.0 mg, 0.68 mmol) and N-(4-bromobenzyl)-2,2,2-trifluoroethanamine (217.9 mg, 0.81 mmol).1H NMR (400 MHz, DMSO-d₆) δ: 12.54 (s, 1H), 8.24 - 8.13 (m, 2H), 7.76 - 7.69 (m, 1H), 7.57 - 7.42 (m, 6H), 4.91 (dd, J = 8.8, 13.2 Hz, 1H), 4.55 - 4.40 (m, 2H), 3.85 (d, J = 6.8 Hz, 2H), 3.31 - 3.23 (m, 2H), 3.01 (t, J = 6.8 Hz, 1H), 1.21 (d, J = 6.8 Hz, 3H). Mass spectrum (ESI, m/z): calcd. for C + 24H21F3N6O2482.2, found [M+H] , 483.1. Example 138: (S)-N-(3-cyano-4-methoxyphenyl)-6-methyl-4-oxo-5-(4- (perfluoroethyl)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

The title compound was prepared in a manner analogous to Example 122, reacting (S)-N-(3- cyano-4-methoxyphenyl)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3- carboxamide (Intermediate 7, 148 mg, 0.455 mmol) and 1-bromo-4-(perfluoroethyl)benzene (150 mg, 0.545 mmol).1H NMR (400 MHz, DMSO-d₆) δ: 12.07 (s, 1H), 8.19 (s, 1H), 8.04 (d, J = 2.4 Hz, 1H), 7.93 - 7.86 (m, 2H), 7.85 - 7.78 (m, 2H), 7.70 (dd, J = 2.4, 9.2 Hz, 1H), 7.23 (d, J = 8.8 Hz, 1H), 4.93 (dd, J = 4.8, 13.2 Hz, 1H), 4.64 - 4.48 (m, 2H), 3.88 (s, 3H), 1.24 (d, J = 6.4 Hz, 3H). Mass spectrum (ESI, m/z): calcd. for C₂₄H₁₈F₅N₅O₃519.1; found [M+H]+, 520.2. Example 139: (S)-N-(3-cyanophenyl)-6-methyl-4-oxo-5-(4-(3,3,3-trifluoropropoxy)phenyl)- 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

Step A: 1-bromo-4-(3,3,3-trifluoropropoxy)benzene. 4-Bromophenol (2.0 g, 12 mmol), 3,3,3-trifluoropropan-1-ol (1.2 mL, 14 mmol), PPh₃ (3.0 g 12 mmol), a stirring bar and THF (20 mL) were added to a 50 mL round-bottomed flask, and the resulting mixture treated with DIAD (2.3 mL, 12 mmol) over 10 mins. The reaction mixture was stirred at rt overnight. The reaction mixture was concentrated to dryness to give the yellow oil. The oil was subjected to silica gel chromatography (0-20% EtOAc/PE) to give 1-bromo-4-(3,3,3- trifluoropropoxy)benzene (1 g, 32% yield) as colorless oil.1H NMR (400 MHz, CDCl3) δ: 7.44 - 7.34 (m, 2H), 6.84 - 6.74 (m, 2H), 4.16 (t, J = 6.4 Hz, 2H), 2.69 - 2.55 (m, 2H) Step B: 1-bromo-4-(3,3,3-trifluoropropoxy)benzene. The title compound was prepared in a manner analogous to Example 122, reacting (S)-N-(3- cyanophenyl)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide (Intermediate 6, 100 mg, 0.339 mmol) and 1-bromo-4-(3,3,3-trifluoropropoxy)benzene (109 mg, 0.406 mmol).1H NMR (400 MHz, DMSO-d₆) δ: 12.58 (s, 1H), 8.22 - 8.15 (m, 2H), 7.74 - 7.68 (m, 1H), 7.56 - 7.50 (m, 2H), 7.43 (d, J = 8.8 Hz, 2H), 7.11 (d, J = 8.8 Hz, 2H), 4.90 (dd, J = 4.4, 13.2 Hz, 1H), 4.53 - 4.38 (m, 2H), 4.27 (t, J = 6.0 Hz, 2H), 2.89 - 2.76 (m, 2H), 1.20 (d, J = 6.8 Hz, 3H). Mass spectrum (ESI, m/z): calcd. for C + 24H20F3N5O3483.2; found [M+H] , 484.2. Example 140: (S)-N-(3-cyano-4-methoxyphenyl)-6-methyl-4-oxo-5-(4-(3,3,3- trifluoropropoxy)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

The title compound was prepared in a manner analogous to Example 122, reacting (S)-N-(3- cyano-4-methoxyphenyl)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3- carboxamide (Intermediate 7, 125 mg, 0.384 mmol) and 1-bromo-4-(3,3,3- trifluoropropoxy)benzene (124 mg, 0.461 mmol).1H NMR (400 MHz, DMSO-d₆) δ: 12.34 (s, 1H), 8.17 (s, 1H), 8.02 (d, J = 2.8 Hz, 1H), 7.69 (dd, J = 2.4, 9.2 Hz, 1H), 7.42 (d, J = 8.8 Hz, 2H), 7.22 (d, J = 9.2 Hz, 1H), 7.10 (d, J = 9.2 Hz, 2H), 4.88 (dd, J = 4.8, 13.2 Hz, 1H), 4.52 - 4.37 (m, 2H), 4.27 (t, J = 5.6 Hz, 2H), 3.88 (s, 3H), 2.89 - 2.76 (m, 2H), 1.19 (d, J = 6.4 Hz, 3H). Mass spectrum (ESI, m/z): calcd. for C + 25H22F3N5O4513.2; found [M+H] , 514.1. Example 141: (S)-N-(3-cyano-4-methoxyphenyl)-6-methyl-4-oxo-5-(4-(((2,2,2- trifluoroethyl)amino)methyl)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3- carboxamide.

The title compound was prepared in a manner analogous to Example 122, (S)-N-(3-cyano-4- methoxyphenyl)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide (Intermediate 7, 100 mg, 0.276 mmol) and N-(4-bromobenzyl)-2,2,2-trifluoroethanamine (111 mg, 0.42 mmol).1H NMR (400 MHz, DMSO-d6) δ: 12.32 (s, 1H), 8.18 (s, 1H), 8.02 (d, J = 2.4 Hz, 1H), 7.71 (dd, J = 2.8, 9.2 Hz, 1H), 7.53 - 7.42 (m, 4H), 7.23 (d, J = 9.6 Hz, 1H), 4.90 (dd, J = 4.4, 12.8 Hz, 1H), 4.55 - 4.41 (m, 2H), 3.88 (s, 3H), 3.85 (d, J = 6.8 Hz, 2H), 3.29 - 3.19 (m, 2H), 3.05 - 2.95 (m, 1H), 1.21 (d, J = 6.8 Hz, 3H). Mass spectrum (ESI, m/z): calcd. for C₂₅H₂₃F₃N₆O₃512.2, found [M+H]+, 513.2. Example 142: (S)-N-(3-cyano-4-methoxyphenyl)-5-(4-(difluoro(1- fluorocyclopropyl)methyl)phenyl)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrazine-3-carboxamide.

Step A: 1-fluoro-N-methoxy-N-methylcyclopropanecarboxamide. The title compound was prepared in a manner analogous to Example 125, Step A above, reacting 1-fluorocyclopropanecarboxylic acid (4.00 g, 38.4 mmol), CDI (8.1 g, 50 mmol, in batches) and N,O-dimethylhydroxylamine hydrochloride (5.25 g, 53.8 mmol).1H NMR (400 MHz, CDCl3) δ: 3.77 (s, 3H), 3.28 (s, 3H), 1.35 - 1.31 (m, 2H), 1.30 - 1.27 (m, 1H), 1.26 - 1.21 (m, 1H). Mass spectrum (ESI, m/z): calcd. for C₆H₁₀FNO₂147.1; found [M+H]+, 147.7. Step B: (4-bromophenyl)(1-fluorocyclopropyl)methanone. The title compound was prepared in a manner analogous to Example 125, Step B above, reacting 1-bromo-4-iodobenzene (10.96 g, 38.74 mmol) and 1-fluoro-N-methoxy-N- methylcyclopropanecarboxamide.1H NMR (400 MHz, CDCl3) δ: 7.89 (dd, J = 1.7, 8.6 Hz, 2H), 7.65 - 7.59 (m, 2H), 1.62 - 1.57 (m, 2H), 1.56 - 1.51 (m, 1H), 1.51 - 1.45 (m, 1H). Step C: 2-(4-bromophenyl)-2-(1-fluorocyclopropyl)-1,3-dithiane. The title compound was prepared in a manner analogous to Example 125, Step C above, reacting (4-bromophenyl)(cyclobutyl)methanone (4.30 g, 17.7 mmol) and propane-1,3-dithiol (3.0 mL, 30 mmol).1H NMR (400 MHz, CDCl3) δ: 7.94 - 7.89 (m, 2H), 7.55 - 7.50 (m, 2H), 2.74 - 2.67 (m, 4H), 1.99 - 1.92 (m, 2H), 1.08 - 1.00 (m, 4H). Mass spectrum (ESI, m/z): calcd. for C₁₃H₁₄BrFS₂332.0; found [M+H]+, 332.9. Step D: 1-bromo-4-(difluoro(1-fluorocyclopropyl)methyl)benzene. The title compound was prepared in a manner analogous to Example 125, Step D above, reacting 2-(4-bromophenyl)-2-(1-fluorocyclopropyl)-1,3-dithiane (1.0 g, 3.0 mmol) and DAST (0.85 mL, 6.5 mmol).1H NMR (400 MHz, CDCl3) δ: 7.60 (d, J = 8.4 Hz, 2H), 7.46 (d, J = 8.4 Hz, 2H), 1.24 - 1.14 (m, 4H). Step E: (S)-N-(3-cyano-4-methoxyphenyl)-5-(4-(cyclobutyldifluoromethyl)phenyl)-6-methyl-4- oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide. The title compound was prepared in a manner analogous to Example 122, reacting (S)-N-(3- cyano-4-methoxyphenyl)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3- carboxamide (Intermediate 7, 100 mg, 0.307 mmol) and 1-bromo-4-(difluoro(1- fluorocyclopropyl)methyl)benzene (147 mg, 0.553 mmol).1H NMR (400 MHz, CDCl₃) δ: 12.01 (s, 1H), 8.32 (s, 1H), 7.96 - 7.92 (m, 2H), 7.78 (d, J = 8.4 Hz, 2H), 7.47 (d, J = 8.4 Hz, 2H), 6.90 (d, J = 9.6 Hz, 1H), 4.80 (dd, J = 4.4, 13.2 Hz, 1H), 4.49 (dd, J = 3.2, 13.6 Hz, 1H), 4.46 - 4.37 (m, 1H), 3.90 (s, 3H), 1.41 (d, J = 6.8 Hz, 3H), 1.29 - 1.23 (m, 4H). Mass spectrum (ESI, m/z): calcd. for C₂₆H₂₂F₃N₅O₃509.2; found [M+H]+, 510.2. Example 143: (S)-N-(3-cyanophenyl)-6-methyl-4-oxo-5-(4-((1-(trifluoromethyl)- cyclopropyl)methyl)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

The title compound was prepared in a manner analogous to Example 122, reacting (S)-N-(3- cyanophenyl)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide (Intermediate 6, 100 mg, 0.301 mmol) and 1-bromo-4-((1- (trifluoromethyl)cyclopropyl)methyl)benzene (101 mg, 0.362 mmol).1H NMR (400 MHz, DMSO-d6) δ: 12.50 (s, 1H), 8.21 (s, 1H), 8.18 (m, 1H), 7.74 - 7.68 (m, 1H), 7.57 - 7.53 (m, 2H), 7.47 - 7.39 (m, 4H), 4.94 - 4.87 (m, 1H), 4.53 - 4.43 (m, 2H), 3.05 - 2.96 (m, 2H), 1.20 (m, 3H), 1.01 - 0.97 (m, 2H), 0.84 (m, 2H). Mass spectrum (ESI, m/z): calcd. for C₂₆H₂₂F₃N₅O₂493.2; found [M+H]+, 494.2. Example 144: (S)- (3-cyano-4-methoxyphenyl)-6-methyl-4-oxo-5-(4-((1-

(trifluoromethyl)cyclopropyl)methyl)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3- carboxamide.

The title compound was prepared in a manner analogous to Example 122, reacting (S)-N-(3- cyano-4-methoxyphenyl)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3- carboxamide (Intermediate 7, 100 mg, 0.276 mmol) and 1-bromo-4-((1- (trifluoromethyl)cyclopropyl)methyl)benzene (93 mg, 0.33 mmol).1H NMR (400 MHz, DMSO- d₆) δ: 12.28 (s, 1H), 8.18 (s, 1H), 8.04 (d, J = 2.8 Hz, 1H), 7.70 (dd, J = 2.4, 9.2 Hz, 1H), 7.46 - 7.38 (m, 4H), 7.24 (d, J = 8.8 Hz, 1H), 4.94 - 4.85 (m, 1H), 4.53 - 4.42 (m, 2H), 3.88 (s, 3H), 3.01 (s, 2H), 1.20 (m, 3H), 1.01 - 0.95 (m, 2H), 0.86 - 0.82 (m, 2H). Mass spectrum (ESI, m/z): calcd. for C₂₇H₂₄F₃N₅O₃523.2; found [M+H]+, 524.2. Example 145: (6S)-N-(3-cyanophenyl)-5-(4-((2,2-difluorocyclopropyl)methyl)phenyl)-6- methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

Step A: 1-allyl-4-bromobenzene. 1-Bromo-4-iodobenzene (5 g, 17.7 mmol), a stir bar, THF (5 mL) were added to an oven-dried and nitrogen-purged 100 mL three-neck round-bottom flask, which was subsequently cooled to - 10 °C (ice/brine) and charged with isopropylmagnesium chloride solution (3.5 mL, 7.1 mmol, 2.0 M in THF) and n-BuLi solution (5.7 mL, 14 mmol, 1.6 M in hexane) dropwise over 5 min. The reaction mixture was stirred for 4 h at -10°C. Copper (I) cyanide (79 mg, 0.88mmol) was added at once, and the reaction mixture was stirred for 5 mins at -10 °C.3-bromoprop-1-ene (4.28 g, 35.3mmol) was then added dropwise over a period of 30 min at -10 °C. It was then allowed to warm rt and stirred for 15 h. The black solutiom was qudenched with sat. aq. NH₄Cl (10 mL) and exacted with PE (30 mL, 10 mL x 3), and the combined extracts washed with sat. aq. NaHCO3 (30 mL x 3), brine (30 mL), and dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give yellow oil. The oil was then subjected to silica gel chromatography (0-5% EtOAc/PE) to give 1-allyl-4-bromobenzene as a colorless oil (3.1 g, 89% yield).1H NMR (400 MHz, CDCl3) δ: 7.44 - 7.39 (m, 2H), 7.09 - 7.05 (m, 2H), 5.93 (tdd, J = 6.7, 10.3, 16.7 Hz, 1H), 5.11 - 5.04 (m, 2H), 3.34 (d, J = 6.7 Hz, 2H). Step B: 1-bromo-4-((2,2-difluorocyclopropyl)methyl)benzene. 1-Allyl-4-bromobenzene (1.8 g, 9.13 mmol), a stir bar, 1,4-dioxane (7.5 mL), KI (3.41 g, 20.6 mmol), and 1-methoxy-2-(2-methoxyethoxy)ethane (123 mg, 0.913 mmol) were added to an oven-dried and nitrogen-purged 10 mL round-bottomed flask, and the resulting mixture was stirred for 5 min at 120 °C. At this temperature, TMSCl (1.99 g, 18.3 mmol) was added, followed by addition of methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (3.5 g, 18 mmol). The resulting solution was stirred at 120°C for 12 h. The reaction vessel was removed from the heating mantle and allowed to gradually cool to rt. The reaction mixture was then treated with water (30 mL), extracted with EtOAc (30 mL x 2), and the combined extracts washed with sat. aq. NaHCO3 (30 mL x 3) and brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated to dryness in vacuo to give yellow oil. The oil was then subjected to silica gel chromatography (0-5%, EtOAc/PE) to give 1-bromo-4-((2,2- difluorocyclopropyl)methyl)benzene as colorless oil (580 mg, 26% yield).1H NMR (400 MHz, CDCl3) δ: 7.44 (d, J = 8.4 Hz, 2H), 7.11 (d, J = 8.4 Hz, 2H), 2.83 - 2.66 (m, 2H), 1.82 - 1.67 (m, 1H), 1.53 - 1.43 (m, 1H), 1.12 - 1.02 (m, 1H) Step C: (6S)-N-(3-cyanophenyl)-5-(4-((2,2-difluorocyclopropyl)methyl)phenyl)-6-methyl-4-oxo- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

The title compound was prepared in a manner analogous to Example 122, reacting (S)-N-(3- cyanophenyl)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide (Intermediate 6, 100 mg, 0.301 mmol) and 1-bromo-4-((2,2-difluorocyclopropyl)methyl)benzene (89 mg, 0.36 mmol).1H NMR (400MHz, DMSO-d₆) δ: 12.53 (s, 1H), 8.21 (s, 1H), 8.17 (m, 1H), 7.76 - 7.69 (m, 1H), 7.57 - 7.52 (m, 2H), 7.49 - 7.41 (m, 4H), 4.91 (dd, J = 4.4, 13.2 Hz, 1H), 4.54 - 4.41 (m, 2H), 2.89 - 2.76 (m, 2H), 2.11 - 1.97 (m, 1H), 1.69 - 1.59 (m, 1H), 1.40 - 1.30 (m, 1H), 1.21 (d, J = 6.8 Hz, 3H). Mass spectrum (ESI, m/z): calcd. for C₂₅H₂₁F₂N₅O₂461.2; found [M+H]+, 462.2. Example 146: (6S)-N-(3-cyano-4-methoxyphenyl)-5-(4-((2,2-difluorocyclopropyl)- methyl)phenyl)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

The title compound was prepared in a manner analogous to Example 122, (S)-N-(3-cyano-4- methoxyphenyl)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide (Intermediate 7, 100 mg, 0.276 mmol) and 1-bromo-4-((2,2-difluorocyclopropyl)methyl)benzene (82 mg, 0.33 mmol).1H NMR (400 MHz, DMSO-d6) δ: 12.31 (s, 1H), 8.18 (s, 1H), 8.03 (d, J = 2.8 Hz, 1H), 7.71 (dd, J = 2.4, 9.2 Hz, 1H), 7.48 - 7.40 (m, 4H), 7.23 (d, J = 9.2 Hz, 1H), 4.90 (dd, J = 4.4, 13.2 Hz, 1H), 4.53 - 4.40 (m, 2H), 3.88 (s, 3H), 2.89 - 2.75 (m, 2H), 2.11 - 1.97 (m, 1H), 1.70 - 1.58 (m, 1H), 1.40 - 1.30 (m, 1H), 1.21 (d, J = 6.4 Hz, 3H). Mass spectrum (ESI, m/z): calcd. for C₂₆H₂₃F₂N₅O₃491.2; found [M+H]+, 492.2.

p ( )- -( - y - - yp yl)-6-methyl-4-oxo-5-(4-((2,2,2- trifluoroethyl)amino)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

The title compound was prepared in a manner analogous to Example 122, reacting (S)-N-(3- cyano-4-methoxyphenyl)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3- carboxamide (Intermediate 7, 150 mg, 0.461 mmol) and 4-bromo-N-(2,2,2-trifluoroethyl)aniline (141 μL, 0.553 mmol).1H NMR (400 MHz, DMSO-d₆) δ: 12.44 (s, 1H), 8.16 (s, 1H), 8.09 - 8.03 (m, 1H), 7.73 - 7.65 (m, 1H), 7.27 - 7.17 (m, 3H), 6.83 (d, J = 8.8 Hz, 2H), 6.51 (t, J = 6.8 Hz, 1H), 4.86 (dd, J = 4.4 Hz, 1H), 4.46 (dd, J = 3.6 Hz, 1H), 4.39 - 4.29 (m, 1H), 4.05 - 3.92 (m, 2H), 3.88 (s, 3H), 1.19 (d, J = 6.4 Hz, 3H). Mass spectrum (ESI, m/z): calcd. for C24H21F3N6O3 498.2, found [M+H]+, 499.1. Example 148: (S)- (3-cyano-4-methoxyphenyl)-6-methyl-4-oxo-5-(4-(2-

(trifluoromethoxy)ethyl)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

The title compound was prepared in a manner analogous to Example 122, reacting (S)-N-(3- cyano-4-methoxyphenyl)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3- carboxamide (Intermediate 7, 100 mg, 307 μmol) and 1-bromo-4-(2- (trifluoromethoxy)ethyl)benzene (82.7 mg, 307 μmol).1H NMR (400 MHz, DMSO-d₆) δ: 12.29 (s, 1H), 8.18 (s, 1H), 8.03 (d, J = 2.4 Hz, 1H), 7.72 - 7.70 (m, 1H), 7.48 - 7.43 (m, 4H), 7.23 (d, J = 9.2 Hz, 1H), 4.94 - 4.86 (m, 1H), 4.54 - 4.42 (m, 2H), 4.38 (t, J = 6.4 Hz, 2H), 3.88 (s, 3H), 3.06 (t, J =6.4 Hz, 2H), 1.20 (d, J = 6.4 Hz, 3H). Mass spectrum (ESI, m/z): calcd. for C₂₅H₂₂F₃N₅O₄513.2; found [M+H]+, 514.2

Example 149: (S)-N-(3-cyano-4-(oxetan-3-ylmethyl)phenyl)-5-(4-(difluoro(phenyl)- methyl)phenyl)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide

In an 8 mL vial, Example 55 (57.6 mg, 0.1 mmol), mesylate[(di(1-adamantyl)-n- butylphosphine)-2-(2’-amino-1,1’-biphenyl)]palladium(II) (3.72 mg, 0.05 mmol) , Cs₂CO₃ (114 mg, 0.35 mmol) and trifluoro(oxetan-3-ylmethyl)borate potassium salt (35.6 mg, 0.2 mmol) were added followed by water (0.2 mL) and dioxane (1.55 mL). The reaction was heated to 100 ºC for 6h. The solution was cooled to ambient temperature and water (1mL) and EtOAc (1mL) were added. Layers were separated and the aqueous phase was extracted with EtOAc (1mL x 2). Solvents were evaporated to dryness and crude material dissolved in DMSO (2 mL), MeOH (1.5 mL) and aq. NH₄HCO₃ (0.5 mL) and filtered before further purification. Crude material was purified by Prep-HPLC (Stationary phase: C18 Xbridge 30 x 100 mm 5 µm, Mobile phase: Gradient from 70% NH4HCO30.25% solution in Water, 30% CH3CN to 35% NH4HCO30.25% solution in Water, 65% CH₃CN), yielding (S)-N-(3-cyano-4-(oxetan-3-ylmethyl)phenyl)-5-(4- (difluoro(phenyl)methyl)phenyl)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3- carboxamide (2.3 mg, yield 4% yield) as white solid after lyophilization. 1H NMR (500 MHz, DMSO-d6) δ: 12.28 (s, 1H) 8.20 (s, 1H) 8.13 (d, J=2.3 Hz, 1H) 7.67 – 7.75 (m, 2H) 7.59 – 7.67 (m, 5H) 7.51 – 7.58 (m, 3H) 7.38 (d, J=8.5 Hz, 1H) 4.86 – 4.95 (m, 1H) 4.62 (dd, J=7.6, 6.0 Hz, 2H) 4.47 – 4.57 (m, 2H) 4.34 (t, J=6.1 Hz, 2H) 3.23 – 3.28 (m, 1H) 3.11 (d, J=7.9 Hz, 2H) 1.21 (d, J=6.6 Hz, 3H). Mass spectrum (ESI, m/z): Calcd. For C₃₂H₂₇F₂N₅O₃, 567.2, found [M+H]+, 568.3. Examples 150-153 and 166-168 were prepared in a manner analogous to Example 149, with the appropriate reagent substitutions.

Example 154: N-(3-cyanophenyl)-5-(4-((3-(difluoromethyl)bicyclo[1.1.1]pentan-1- yl)methyl)phenyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide..

Step A: ethyl 5-(4-((3-(hydroxymethyl)bicyclo[1.1.1]pentan-1-yl)methyl)phenyl)-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxylate. Pd/C 10% (150 mg, 1.4 mmol) was added to a solution of ethyl 5-(4-((3- (((benzyloxy)methoxy)methyl)bicyclo[1.1.1]pentan-1-yl)methyl)phenyl)-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxylate (Example VP101, product from Step A, 680 mg, 1.32 mmol) in ethanol absolute (8.9 mL) at 0ºC under nitrogen and the mixture was stirred under hydrogen at 30º C for 86 h. The mixture was filtered through celite, rinsed with EtOH and the solvent evaporated in vacuo. The crude was purified by flash column chromatography (0%- 75% heptane/EtOAc). The desired fractions were collected and concentrated in vacuo to yield ethyl 5-(4-((3-(hydroxy-methyl)bicyclo[1.1.1]pentan-1-yl)methyl)phenyl)-4-oxo-4,5,6,7- tetrahydropyrazolo-[1,5-a]pyrazine-3-carboxylate (398 mg, 76% yield) as a white foam.1H- NMR (400 MHz, CDCl₃) δ: 7.96 (s, 1H), 7.28 (d, J = 8.5 Hz, 2H), 7.14 (d, J = 8.3 Hz, 2H), 4.59 – 4.50 (m, 2H), 4.35 (q, J = 7.1 Hz, 2H), 4.22 – 4.17 (m, 2H), 3.56 (s, 2H), 2.79 (s, 2H), 1.53 (s, J = 5.2 Hz, 6H), 1.35 (t, J = 7.1 Hz, 3H). Mass spectrum (ESI, m/z): Calcd. For C22H25N3O4, 395.2, found [M+H]+, 396.1. Step B: ethyl 5-(4-((3-formylbicyclo[1.1.1]pentan-1-yl)methyl)phenyl)-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxylate Dess-Martin periodinane (0.64 g, 1.51 mmol) was added portionwise to a solution of ethyl 5-(4- ((3-(hydroxymethyl)bicyclo[1.1.1]pentan-1-yl)methyl)phenyl)-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxylate (398 mg, 1.01 mmol) in DCM (8.7 mL) and the reaction was stirred 2 h. Then, the mixture was quenched with saturated NaHCO₃ solution and stirring was continued until gas evolution had ceased (pH 8). The layers were separated and extracted with DCM (x3) and washed with brine (50 mL). The combined organic layers were dried over MgSO₄, filtered and concentrated in vacuo. The crude was purified by flash column chromatography (0%-50% heptane/EtOAc). The desired fractions were collected and concentrated in vacuo to yield ethyl 5-(4-((3-formylbicyclo[1.1.1]pentan-1-yl)methyl)phenyl)-4- oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxylate (125 mg, 32% yield) as a white solid.1H NMR (300 MHz, CDCl3) δ: 9.53 (s, 1H), 7.97 (s, 1H), 7.30 (d, J = 8.4 Hz, 2H), 7.14 (d, J = 8.4 Hz, 2H), 4.55 (dd, J = 6.9, 4.9 Hz, 2H), 4.35 (q, J =7.1 Hz, 2H), 4.20 (dd, J = 6.8, 4.9 Hz, 2H), 2.82 (s, 2H), 1.87 (s, 6H), 1.35 (t, J = 7.1 Hz, 3H). Mass spectrum (ESI, m/z): calcd. For C₂₂H₂₃N₃O₄, 393.2; found [M+H]+, 394.1. Step C: ethyl 5-(4-((3-(difluoromethyl)bicyclo[1.1.1]pentan-1-yl)methyl)phenyl)-4-oxo-

tetrahydropyrazolo[1,5-a]pyrazine-3-carboxylate. (Diethylamino) sulfur trifluoride (105 μL, 0.79 mmol) was added to a solution of ethyl 5-(4-((3- formylbicyclo[1.1.1]pentan-1-yl)methyl)phenyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrazine-3-carboxylate (125 mg, 0.32 mmol) in anhydrous dichloromethane (3 mL) at -10ºC under nitrogen. The mixture was stirred at rt for 2 h. Then the mixture was diluted with DCM and poured onto NaHCO3 sat. The organic layer was extracted, dried (MgSO₄), filtered and the solvents evaporated in vacuo. The crude was purified by flash column chromatography (0%-50% heptane/EtOAc). The desired fractions were collected and concentrated in vacuo to yield ethyl 5-(4-((3- (difluoromethyl)bicyclo[1.1.1]pentan-1-yl)methyl)phenyl)-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxylate (86 mg, 65% yield) as a yellow solid.1H NMR (400 MHz, CDCl₃) δ: 7.96 (d, J = 5.7 Hz, 1H), 7.29 (d, J = 8.4 Hz, 2H), 7.13 (d, J = 8.4 Hz, 2H), 5.63 (t, J = 56.7 Hz, 1H), 4.54 (dd, J = 6.8, 5.0 Hz, 2H), 4.34 (q, J = 7.1 Hz, 2H), 4.19 (dd, J = 6.7, 5.1 Hz, 2H), 2.81 (s, 2H), 1.69 (s, 6H), 1.35 (t, J = 7.1 Hz, 3H). Mass spectrum (ESI, m/z): calcd. For C₂₂H₂₃F₂N₃O3, 415.2; found [M+H]+, 416.0. Step D: N-(3-cyanophenyl)-5-(4-((3-(difluoromethyl)bicyclo[1.1.1]pentan-1-yl)methyl)phenyl)- 4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide. The title compound was prepared in a manner analogous to Example VP101, Step B above, reacting ethyl 5-(4-((3-(difluoromethyl)bicyclo[1.1.1]pentan-1-yl)methyl)phenyl)-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxylate (50 mg, 0.12 mmol) and 3-aminobenzonitrile (16 mg, 0.135 mmol).1H NMR (400 MHz, CDCl₃) δ: 12.29 (s, 1H), 8.32 (s, 1H), 8.10 (t, J = 1.6 Hz, 1H), 7.98 – 7.92 (m, 1H), 7.38 (t, J = 7.8 Hz, 1H), 7.35 –7.30 (m, 3H), 7.26 – 7.23 (m, 2H), 5.66 (t, J = 56.6 Hz, 1H), 4.66 (dd, J = 7.0, 5.3 Hz, 2H), 4.28 (dd, J = 6.9, 5.3 Hz, 2H), 2.88 (s, 2H), 1.74 (s, 6H). Mass spectrum (ESI, m/z): calcd. For C + 27H23F2N5O2, 487.2; found [M+H] , 488.1. Example 155 and 156: (S)-N-(3-cyanophenyl)-5-(4-(difluoro(tetrahydro-2H-pyran-4- yl)methyl)phenyl)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3- carboxamide and (S)-N-(3-cyanophenyl)-5-(4-(difluoro((RS)-tetrahydro-2H-pyran-3- yl)methyl)phenyl)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3- carboxamide

To (S)-2-(4-(3-((3-cyanophenyl)carbamoyl)-6-methyl-4-oxo-6,7-dihydropyrazolo[1,5-a]pyrazin- 5(4H)-yl)phenyl)-2,2-difluoroacetic acid (Intermediate 40, 100 mg, 0.17 mmol) in a vial equipped with a stir bar was added 1-methoxy-1,2-benziodoxol-3(1H)-one (290 mg, 1.04 mmol) and (Ir[dF(CF3)ppy]2(dtbpy))PF6 (3.9 mg, 0.0035 mmol). The vial was sealed and purged and the degassed DMSO (2.6 mL) was added followed by 3,6-dihydro-2H-pyran (0.077 mL0.87 mmol). The reaction was transferred to a PennHD photoreactor and 100% LED and fan power and stirred for 16h. The reaction progress was followed by LCMS. Upon completion of the reaction, EtOAc (20 mL) and half sat. NaHCO3 (20 mL) were added. The layers were separated and the and the aqueous layer extracted twice more with EtOAc (20 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered and the solvents removed under reduced pressure. The crude was purified by silica gel chromatography (0-100% EtOAc/Heptane). The desired fractions were collected and further purified by prep-HPLC with the following conditions: (Stationary phase: RP Xbridge Prep C18 OBD-10µm, 50x150mm, Mobile phase: 0.25% NH4HCO3 solution in water, CH3CN). This resulted in (S)-N-(3-cyanophenyl)-5-(4- (difluoro(tetrahydro-2H-pyran-4-yl)methyl)phenyl)-6-methyl-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide (5.4 mg, 6.1% yield).1H NMR (400 MHz, CD3CN) δ: 12.44 (br s, 1H), 8.22 (d, J = 3.4 Hz, 2H), 7.77 (ddd, J = 8.1, 2.2, 1.3 Hz, 1H), 7.71 – 7.62 (m, 2H), 7.58 (d, J = 8.6 Hz, 2H), 7.54 – 7.46 (m, 1H), 7.46 – 7.41 (m, 1H), 4.90 – 4.80 (m, 1H), 4.48 (ddd, J = 12.2, 7.6, 3.4 Hz, 2H), 4.01 – 3.89 (m, 2H), 3.44 – 3.28 (m, 2H), 2.18 – 2.12 (m, 1H), 1.50 – 1.67 (m, 4H), 1.30 (d, J = 3.8 Hz, 3H). Mass spectrum (ESI, m/z): Calcd. For C27H F N O , 505.2, foun + 25 2 5 3 d [M+H] , 506.4. Another fraction from the purification was further purified by prep-SFC with the following conditions (Stationary phase: Torus Diol 30 x 150 mm, Mobile phase: CO2, MeOH + 0.4 iPrNH2). This resulted in (S)-N-(3-cyanophenyl)-5-(4- (difluoro((RS)-tetrahydro-2H-pyran-3-yl)methyl)phenyl)-6-methyl-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide (3.1 mg, 3.6% yield) as a mixture of diasereomers.1H NMR (400 MHz, CD3CN) δ: 8.13 – 8.08 (m, 2H), 7.66 (ddd, J = 8.1, 2.2, 1.3 Hz, 1H), 7.54 (d, J = 8.6 Hz, 2H), 7.47 (d, J = 8.6 Hz, 2H), 7.42 – 7.30 (m, 2H), 4.81 – 4.66 (m, 1H), 4.41 – 4.31 (m, 2H), 3.93 – 3.84 (m, 1H), 3.81 – 3.72 (m, 1H), 3.38 – 3.23 (m, 2H), 1.75 – 1.38 (m, 5H), 1.22 – 1.15 (m, 3H). Mass spectrum (ESI, m/z): Calcd. For C₂₇H₂₅F₂N₅O₃, 505.2, found [M+H]+, 506.4. Example 157: N-(3-cyanophenyl)-5-(4-(3-((1-ethyl-1H-1,2,3-triazol-4- yl)methyl)benzyl)phenyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

Step A: 3-(4-bromobenzyl)benzaldehyde. (3-Formylphenyl)boronic acid (5.00 g, 33.4 mmol), 1-bromo-4-(bromomethyl)benzene (10.8 g, 43.4 mmol), a stir bar, THF (100 mL) and sodium carbonate (11.3 g, 106 mmol) were added to a 250 mL three-necked-flask. The solution was charged with tetrakis(triphenylphosphine) palladium(0) (1.16 g, 1.00 mmol). The resulting solution was stirred at 100 °C for 12 h. The reaction mixture was then diluted with water (200 mL), extracted with EtOAc (100 mL x3), and the combined extracts washed with sat. aq. NaHCO3 (200 mL), brine (200 mL), dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure to give yellow oil. The oil was then subjected to silica gel chromatography (13-15% EtOAc/PE) to give 3-(4- bromobenzyl)benzaldehyde as colorless oil (2.54 g, 28% yield).1H NMR (400 MHz, CDCl₃) δ: 9.99 (s, 1H), 7.75 (d, J = 6.8 Hz, 1H), 7.70 (s, 1H), 7.52 – 7.39 (m, 4H), 7.07 (d, J = 8.4 Hz, 2H), 4.02 (s, 2H). Step B: 1-(3-(4-bromobenzyl)phenyl)-3-(trimethylsilyl)prop-2-yn-1-ol. Ethynyltrimethylsilane (1.34 mL, 2.36 mmol), THF (4 mL) were added to an oven-dried and nitrogen-purged 50 mL round-bottomed flask, the solution was 286dded286286 with n-BuLi (3.78 mL, 9.45 mmol, 2.5 M THF solution) at 0 °C for 0.5 h. After that, the solution was charged with 3-(4-bromobenzyl)benzaldehyde (2.00 g, 7.27 mmol, in 6 mL THF) and stirred at 0 °C for 1.5 h. The reaction mixture was slowly quenched with sat. aq. NH₄Cl (40 mL), extracted with EtOAc (20 mL x 2). The combined extracts washed with brine (40 mL), dried over anhydrous Na2SO4, concentrated to dryness under reduced pressure to give light yellow oil. The oil was then subjected to silica gel chromatography (0-5% EtOAc/PE) to afford 1-(3-(4- bromobenzyl)phenyl)-3-(trimethylsilyl)prop-2-yn-1-ol as light yellow oil (2.58 g, 95% yield).1H NMR (400 MHz, CDCl3) δ: 7.41 (br d, J = 8.4 Hz, 3H), 7.37 – 7.29 (m, 2H), 7.14 (br d, J = 7.2 Hz, 1H), 7.07 (d, J = 8.4 Hz, 2H), 5.42 (d, J = 6.4 Hz, 1H), 3.96 (s, 2H), 2.13 (d, J = 6.0 Hz, 1H), 0.20 (s, 9H). Step C: (3-(3-(4-bromobenzyl)phenyl)prop-1-yn-1-yl)trimethylsilane. The title compound was prepared in a manner analogous to Example 126, step D above, reacting 1-(3-(4-bromobenzyl)phenyl)-3-(trimethylsilyl)prop-2-yn-1-ol (2.00 g, 5.36 mmol), triethylsilane (1.71 mL, 10.7 mmol, 0.728 g/mL) and boron trifluoride diethyl etherate (1.01 mL, 8.04 mmol, 1.125 g/mL).1H NMR (400 MHz, CDCl₃) δ: 7.46 – 7.36 (m, 2H), 7.26 – 7.13 (m, 3H), 7.11 – 7.00 (m, 3H), 3.93 (s, 2H), 3.68 – 3.56 (m, 2H), 1.06 – 0.95 (m, 2H), 0.61 (q, J = 8.0 Hz, 1H), 0.23 – 0.13 (m, 6H). Step D: 1-(4-bromobenzyl)-3-(prop-2-yn-1-yl)benzene. (3-(4-(4-Bromobenzyl)phenyl)prop-1-yn-1-yl)trimethylsilane (1.8 g, 5.04 mmol), a stir bar, AcOH (605 mg, 10.1 mmol) and THF (30 mL) were added to a 100 mL round-bottomed flask, and the resulting mixture treated with TBAF (10.1 mL, 10.1 mmol, 1M in THF), dropwise over 12 min. The resultant mixture was stirred at room-temperature for 12 hrs. The reaction mixture was quenched with sat. aq. NH₄Cl (60 mL), extracted with EtOAc (30 mL x 3). The combined extracts washed with brine (60 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness under reduced pressure to give yellow oil. The oil was then subjected to silica gel chromatography (0-2% EtOAc/PE) to give 1-(4-bromobenzyl)-3-(prop-2-yn-1-yl)benzene as yellow oil (1.2 g, 63% yield).1H NMR (400 MHz, CDCl3) δ: 7.41 (br d, J = 8.4 Hz, 2H), 7.27 – 7.14 (m, 3H), 7.10 – 6.99 (m, 3H), 3.93 (s, 2H), 3.58 (d, J = 2.4 Hz, 2H), 2.19 (t, J = 2.8 Hz, 1H). Step D: 4-(3-(4-bromobenzyl)benzyl)-1-ethyl-1H-1,2,3-triazole. Bromoethane (573 mg, 5.26 mmol), a stir bar, DMSO (6 mL), and NaN3 (380 mg, 5.85 mmol) was added to an oven-dried and nitrogen-purged 50 mL round-bottomed flask. The resulting mixture stirred for 4 h at rt. Then 1-bromo-4-(4-(prop-2-yn-1-yl)benzyl)benzene (500 mg, 1.75 mmol), sodium L-ascorbate (139 mg, 0.701 mmol), H2O (2 mL) and CuSO4.5H2O (88 mg, 0.35 mmol) were added to above solution. The resulting mixture was stirred for 20 h at 30 °C. The reaction mixture was adjusted to pH>9 with sat. aq. NaHCO₃ (40 mL), extracted with EtOAc (40 mL x 2). The combine extracts washed with brine (40 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness in vacuo to give yellow oil. The oil was then subjected to silica gel chromatography (0-50% EtOAc/PE) to give 4-(3-(4-bromobenzyl)benzyl)-1-ethyl-1H- 1,2,3-triazole as light yellow oil (350 mg, 56% yield).1H NMR (400 MHz, CDCl₃) δ: 7.40 (d, J = 8.4 Hz, 2H), 7.26 – 7.21 (m, 1H), 7.16 – 6.99 (m, 6H), 4.35 (q, J = 7.6 Hz, 2H), 4.05 (s, 2H), 3.90 (s, 2H), 1.51 (t, J = 7.2 Hz, 3H). Mass spectrum (ESI, m/z): calcd. For C18H18BrN3355.1; found [M+H]+, 355.7. Step E: N-(3-cyanophenyl)-5-(4-(3-((1-ethyl-1H-1,2,3-triazol-4-yl)methyl)benzyl)phenyl)-4- oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide. The title compound was prepared in a manner analogous to Example 122, reacting N-(3- cyanophenyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide (Intermediate 9, 100 mg, 0.356 mmol) and 4-(3-(4-bromobenzyl)benzyl)-1-ethyl-1H-1,2,3-triazole (152 mg, 0.427 mmol).1H NMR (400 MHz, DMSO-d₆) δ: 12.54 (s, 1H), 8.18 (s, 2H), 7.85 (s, 1H), 7.75 – 7.67 (m, 1H), 7.58 – 7.48 (m, 2H), 7.45 – 7.32 (m, 4H), 7.28 – 7.18 (m, 2H), 7.14 – 7.09 (m, 2H), 4.65 (t, J = 5.6 Hz, 2H), 4.31 (q, J = 7.6 Hz, 2H), 4.25 (t, J = 6.0 Hz, 2H), 3.96 (s, 4H), 1.39 (t, J = 7.2 Hz, 3H). Mass spectrum (ESI, m/z): calcd. For C₃₂H₂₈N₈O₂556.2; found [M+H]+, 557.2 Example 158: (S)-N-(4-(azetidin-3-yloxy)-3-cyanophenyl)-5-(4- (difluoro(phenyl)methyl)phenyl)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrazine-3-carboxamide.

Step A: tert-butyl (S)-3-(2-cyano-4-(5-(4-(difluoro(phenyl)methyl)phenyl)-6-methyl-4-oxo- 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamido)phenoxy)azetidine-1-carboxylate. (S)-N-(3-cyano-4-hydroxyphenyl)-5-(4-(difluoro(phenyl)methyl)phenyl)-6-methyl-4-oxo- 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide (Example 56, 300 mg, 0.584 mmol), a stir bar, tert-butyl 3-hydroxyazetidine-1-carboxylate (152 mg, 0.876 mmol), triphenylphine (230 mg, 0.876 mmol) and toluene (6 mL) were added to an oven-dried and nitrogen-purged 10 mL round-bottomed flask, and the resulting mixture treated with DIAD (177 mg, 0.876 mmol), dropwise over 2 min. The resulting mixture was stirred for 12 h at 80 °C. The reaction mixture was then diluted with H₂O (10 mL), extracted with EtOAc (10 mL x 3), and the combined extracts washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure to give yellow oil. The oil was then subjected to silica gel chromatography (0-75% EtOAc/PE) to give tert-butyl (S)-3-(2-cyano-4-(5-(4- (difluoro(phenyl)methyl)phenyl)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3- carboxamido)phenoxy)azetidine-1-carboxylate as yellow oil (500 mg, 75% yield). Mass spectrum (ESI, m/z): calcd. For C + 36H34F2N6O5668.3; found [M-56+H] , 613.2 Step B: (S)-N-(4-(289dded289289og-3-yloxy)-3-cyanophenyl)-5-(4- (difluoro(phenyl)methyl)phenyl)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3- carboxamide. (S)-tert-butyl 3-(2-cyano-4-(5-(4-(difluoro(phenyl)methyl)phenyl)-6-methyl-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamido)phenoxy)azetidine-1-carboxylate (300 mg, 0.449 mmol), HCl/dioxane (5 mL, 4 M) and a stir bar were added to the thumb bottle . The mixture was stirred at rt for 1.5 h. The mixture was concentrated to give yellow oil. The oil was purified by Prep-HPLC with the following conditions: column, Welch Xtimate C18, 150 mm, 30 mm x 5 ^m; mobile phase, 30% to 60% (v/v) MeCN/water (0.2%FA) and then freeze dried to afford (S)-N-(4-(289dded289289og-3-yloxy)-3-cyanophenyl)-5-(4- (difluoro(phenyl)methyl)phenyl)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3- carboxamide as a white solid (74.5 mg, 29% yield).1H NMR (400 MHz, CD₃OD) δ: 8.20 (s, 1H), 8.15 (d, J = 2.4 Hz, 1H), 7.78 – 7.75 (m, 1H), 7.70 (d, J = 8.8 Hz, 2H), 7.61 – 7.55 (m, 4H), 7.51 – 7.46 (m, 3H), 6.88 (d, J = 9.2 Hz, 1H), 5.26 – 5.16 (m, 1H), 4.85 (s, 1H), 4.58 – 4.47 (m, 2H), 4.42 – 4.31 (m, 2H), 4.10 – 4.05 (m, 2H), 1.33 (d, J = 6.8 Hz, 3H). Mass spectrum (ESI, m/z): calcd. For C + 31H26F2N6O3568.2; found [M+H] , 569.2 Example 159: (S)-N-(3-cyano-4-(piperidin-4-yloxy)phenyl)-5-(4- (difluoro(phenyl)methyl)phenyl)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrazine-3-carboxamide.

Step A: tert-butyl (S)-4-(2-cyano-4-(5-(4-(difluoro(phenyl)methyl)phenyl)-6-methyl-4-oxo- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamido)phenoxy)piperidine-1-carboxylate.

The title compound was prepared in a manner analogous to Example 158, step A above, reacting (S)-N-(3-cyano-4-hydroxyphenyl)-5-(4-(difluoro(phenyl)methyl)phenyl)-6-methyl-4-oxo- 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide (Example 56, 100 mg, 0.195 mmol) and tert-butyl 4-hydroxypiperidine-1-carboxylate (47 mg, 0.23 mmol). Mass spectrum (ESI, m/z): calcd. For C38H38F2N6O5696.3; found [M-56+H]+, 641.2. Step B: (S)-N-(3-cyano-4-(piperidin-4-yloxy)phenyl)-5-(4-(difluoro(phenyl)methyl)phenyl)-6- methyl-4-oxo- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

The title compound was prepared in a manner analogous to Example 158, step B above, reacting (S)-tert-butyl 4-(2-cyano-4-(5-(4-(difluoro(phenyl)methyl)phenyl)-6-methyl-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamido)phenoxy)piperidine-1-carboxylate (300 mg, 0.431 mmol) and HCl/dioxane (5 mL, 4 M).1H NMR (400 MHz, CD3OD) δ: 8.19 (s, 1H), 8.11 (d, J = 2.8 Hz, 1H), 7.80 – 7.72 (m, 1H), 7.69 (d, J = 8.4 Hz, 2H), 7.61 – 7.56 (m, 4H), 7.51 – 7.46 (m, 3H), 7.27 – 7.20 (m, 1H), 4.87 – 4.81 (m, 2H), 4.58 – 4.48 (m, 2H), 3.39 – 3.34 (m, 2H), 3.25 – 3.17 (m, 2H), 2.21 – 2.12 (m, 2H), 2.10 – 2.01 (m, 2H), 1.32 (d, J = 6.4 Hz, 3H) Mass spectrum (ESI, m/z): calcd. For C33H30F2N6O3596.2; found [M+H]+, 597.3. Example 160: (S)-N-(3-cyano-4-((1-methylazetidin-3-yl)oxy)phenyl)-5-(4- (difluoro(phenyl)methyl)phenyl)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrazine-3-carboxamide.

(S)-N-(4-(azetidin-3-yloxy)-3-cyanophenyl)-5-(4-(difluoro(phenyl)methyl)phenyl)-6-methyl-4- oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide (Example 158, 124.0 mg, 0.128 mmol), a stir bar, MeOH (2 mL), formaldehyde (177.0 mg, 2.181 mmol), and Sodium cyanoborohydride (13.7 mg, 0.218 mmol) were added to a 10 mL round-bottomed flask, and the resulting mixture was stirred at room temperature overnight. The reaction mixture was then concentrated to dryness under reduced pressure to give a white solid. The solid was subjected to silica gel 291dded291291ography (0-15% MeOH/DCM) to give (S)-N-(3-cyano-4-((1- methylazetidin-3-yl)oxy)phenyl)-5-(4-(difluoro(phenyl)methyl)phenyl)-6-methyl-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide as a white solid (20.1 mg, 15% yield).1H NMR (400 MHz, DMSO-d6) δ: 12.17 (s, 1H), 8.18 (s, 1H), 8.04 (d, J = 2.8 Hz, 1H), 7.72 – 7.68 (m, 2H), 7.67 – 7.60 (m, 5H), 7.56 – 7.52 (m, 3H), 6.99 (d, J = 9.2 Hz, 1H), 4.95 – 4.81 (m, 2H), 4.56 – 4.47 (m, 2H), 3.77 – 3.69 (m, 2H), 3.06 – 2.99 (m, 2H), 2.30 (s, 3H), 1.21 (d, J = 6.0 Hz, 3H). Mass spectrum (ESI, m/z): calcd. For C₃₂H₂₈F₂N₆O₃582.2; found [M+H]+, 583.2. Example 161: (S)-N-(3-cyano-4-((1-methylpiperidin-4-yl)oxy)phenyl)-5-(4- (difluoro methyl)phenyl)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-

a]pyrazine-3-carboxamide.

The title compound was prepared in a manner analogous to Example 160, reacting (S)-N-(3- cyano-4-(piperidin-4-yloxy)phenyl)-5-(4-(difluoro(phenyl)methyl)phenyl)-6-methyl-4-oxo- 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide (Example 159, 100 mg, 0.168 mmol) and formaldehyde (136 mg, 1.68 mmol).1H NMR (400 MHz, DMSO-d₆) δ: 12.15 (s, 1H), 8.18 (s, 1H), 8.03 – 8.00 (m, 1H), 7.73 – 7.59 (m, 7H), 7.58 – 7.52 (m, 3H), 7.27 (d, J = 9.2 Hz, 1H), 4.96 – 4.87 (m, 1H), 4.58 – 4.47 (m, 3H), 2.60 – 2.54 (m, 2H), 2.22 (s,2H), 2.17 (s, 3H), 1.95 – 1.86 (m, 2H), 1.74 – 1.62 (m, 2H), 1.21 (d, J = 6.4 Hz, 3H) Mass spectrum (ESI, m/z): calcd. For C H F N O 610.3; + 34 32 2 6 3 found [M+H] , 611.3. Example 162: (S)-N-(3-cyano-4-methoxyphenyl)-5-(4-(4-ethynylbenzoyl)phenyl)-6-methyl- 4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

Step A: (S)-5-(4-(4-bromobenzoyl)phenyl)-N-(3-cyano-4-methoxyphenyl)-6-methyl-4-oxo- 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide. The title compound was prepared in a manner analogous to Example 122, reacting (S)-N-(3- cyano-4-methoxyphenyl)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3- carboxamide (Intermediate 7, 400.0 mg, 1.23 mmol) and bis(4-bromophenyl)methanone (418.1 mg, 1.23 mmol).1H NMR (400 MHz, DMSO-d₆) δ: 8.03 (d, J = 2.1 Hz, 1H), 7.99 – 7.93 (m, 2H), 7.90 (br d, J = 8.3 Hz, 2H),7.81 (br d, J = 8.3 Hz, 2H), 7.76 – 7.70 (m, 5H), 7.24 (d, J = 9.1 Hz, 1H), 4.93 (br dd, J = 4.3, 13.2 Hz, 1H),4.64 – 4.57 (m, 1H), 4.53 (br dd, J = 3.3, 13.4 Hz, 1H), 3.88 (s, 3H), 1.26 (br d, J = 6.4 Hz, 3H). Mass spectrum (ESI, m/z): calcd. For C H BrN O 583.1; f + 29 22 5 4 ound [M+H] , 584.0. Step B: (S)-N-(3-cyano-4-methoxyphenyl)-6-methyl-4-oxo-5-(4-(4- ((trimethylsilyl)ethynyl)benzoyl)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3- carboxamide. (S)-5-(4-(4-bromobenzoyl)phenyl)-N-(3-cyano-4-methoxyphenyl)-6-methyl-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide (300 mg, 0.51 mmol), ethynyltrimethylsilane (108.8 μl, 770.1 μmol), (PPh3)2PdCl2 (36.0 mg, 51.3 μmol), CuI (9.78 mg, 51.3 μmol), TEA (149.8 μL, 1.08 mmol), a stir bar, and DMF (2 mL) were added to an oven-dried and nitrogen- purged 5 mL microwave vial, which was subsequently capped and heated at 110 °C via microwave irradiation for 3 h. The reaction mixture diluted with water (40 mL), extracted with EtOAc (40 mL x3). The combined extracts washed with brine (50 mL), dried over anhydrous Na₂SO₄, filtered and concentrated to dryness under reduced pressure to give yellow oil. The yellow oil was subjected to 292dded292-gel chromatography (0-40% EtOAc/DCM) to give (S)- N-(3-cyano-4-methoxyphenyl)-6-methyl-4-oxo-5-(4-(4- ((trimethylsilyl)ethynyl)benzoyl)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3- carboxamide as a yellow solid (194 mg, 46% yield).1H NMR (400 MHz, DMSO-d₆) δ: 8.04 (d, J = 2.6 Hz, 1H), 7.91 – 7.86 (m, 2H), 7.79 (d, J = 8.3 Hz, 2H), 7.76- 7.71 (m, 3H), 7.67 (d, J = 8.5 Hz, 2H), 7.24 (d, J = 9.2 Hz, 1H), 4.94 (dd, J = 4.4, 13.2 Hz, 1H), 4.64 – 4.58(m, 1H), 4.54 (dd, J = 3.6, 13.3 Hz, 1H), 4.08 – 3.80 (m, 4H), 1.27 (d, J = 6.7 Hz, 3H), 1.18 (t, J = 7.1 Hz, 1H),0.31 – 0.23 (m, 9H). Mass spectrum (ESI, m/z): calcd. For C₃₄H₃₁N₅O₄Si 601.2; found [M+H]+, 602.1. Step C: (S)-N-(3-cyano-4-methoxyphenyl)-5-(4-(4-ethynylbenzoyl)phenyl)-6-methyl-4-oxo- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

The title compound was prepared in a manner analogous to Example 157, Step D above, reacting (S)-N-(3-cyano-4-methoxyphenyl)-6-methyl-4-oxo-5-(4-(4- ((trimethylsilyl)ethynyl)benzoyl)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3- carboxamide (170 mg, 0.28 mmol), TBAF (0.57 mL, 0.57 mmol, 1 M in THF), and AcOH (32.3 μL, 0.57 mmol).1H NMR (400 MHz, DMSO-d6) δ: 12.13 (s, 1H), 8.19 (s, 1H), 8.03 (d, J = 2.4 Hz, 1H), 7.90 (d, J =8.4 Hz, 2H), 7.80 (d, J = 8.4 Hz, 2H), 7.75 – 7.64 (m, 5H), 7.23 (d, J = 9.2 Hz, 1H), 4.93 (dd, J = 4.4,13.2 Hz, 1H), 4.64 – 4.46 (m, 3H), 3.88 (s, 3H), 1.26 (d, J = 6.6 Hz, 3H). Mass spectrum (ESI, m/z): calcd. For C H N O 529.2; foun + 31 23 5 4 d [M+H] , 530.2. Example 163: (S)-N-(3-cyano-4-(((R)-pyrrolidin-3-yl)oxy)phenyl)-5-(4- (difluoro(phenyl)methyl)phenyl)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrazine-3-carboxamide.

Step A: tert-butyl (R)-3-(2-cyano-4-((S)-5-(4-(difluoro(phenyl)methyl)phenyl)-6-methyl-4-oxo- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamido)phenoxy)pyrrolidine-1-carboxylate.

The title compound was prepared in a manner analogous to Example 158, Step A above, reacting (S)-N-(3-cyano-4-hydroxyphenyl)-5-(4-(difluoro(phenyl)methyl)phenyl)-6-methyl-4-oxo- 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide (Example 56, 200 mg, 0.398 mmol) and (S)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate (109 mmg, 0.584 mmol). Mass spectrum (ESI, m/z): calcd. For C₃₇H₃₆F₂N₆O₅682.3; found [M-56+H]+, 627.3. Step B: (S)-N-(3-cyano-4-((®-pyrrolidin-3-yl)oxy)phenyl)-5-(4- (difluoro(phenyl)methyl)phenyl)-6-methyl-4-oxo- tetrahydropyrazolo[1,5-a]pyrazine-3-

carboxamide. The title compound was prepared in a manner analogous to Example 158, step B above, reacting ®-tert-butyl 3-(2-cyano-4-((S)-5-(4-(difluoro(phenyl)methyl)phenyl)-6-methyl-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamido)phenoxy)pyrrolidine-1-carboxylate (245 mg, 0.359 mmol) and HCl/dioxane (5 mL, 4 M).1H NMR (400 MHz, DMSO-d6) δ: 12.17 (s, 1H), 8.18 (s, 1H), 8.03 (d, J = 2.8 Hz, 1H), 7.73 – 7.59 (m, 7H), 7.57 – 7.51 (m, 3H), 7.23 (d, J = 9.2 Hz, 1H), 5.08 (br s, 1H), 4.96 – 4.87 (m, 1H), 4.57 – 4.47 (m, 2H), 3.30 (dd, J = 4.4 Hz, 2H), 3.10 – 3.01 (m, 3H), 2.17 – 2.05 (m, 1H), 1.98 – 1.88 (m, 1H), 1.21 (d, J = 6.4 Hz, 3H). Mass spectrum (ESI, m/z): calcd. For C + 32H28F2N6O3582.2; found [M+H] , 583.3. Example 164: (S)-N-(3-cyanophenyl)-6-methyl-4-oxo-5-(6-(4,4,4-trifluorobutyl)pyridin-3- yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

Step A: 5-bromo-2-(4,4,4-trifluorobutyl)pyridine. Zinc (552 mg, 8.44 mmol), a stir bar, and DMF (10 mL) in an nitrogen-purged 100 mL round- bottomed flask, and the resulting mixture treated with 1,2-Dibromoethane (55 ^L, 0.63 mmol) in a single portion. The mixture was stirred at 90 °C for 30 min under nitrogen and then allowed to warm to room temperature. Chlorotrimethylsilane (20 ^L, 0.158 mmol) was added and the mixture was stirred at room temperature for 15 min. A solution of 1,1,1-trifluoro-4-iodobutane (1507 mg, 6.33 mmol) in tetrahydrofuran (4 ml) was added dropwise and the mixture was stirred at 45 °C for 2.5 h. After standing for 1 hour and the supernatant liquid was transferred via syringe to a mixture of 2,5-dibromopyridine (0.5 g, 2.1 mmol) and bis(triphenylphosphine)palladium dichloride (30 mg, 0.042 mmol). The mixture was stirred at 55 °C for 4 h under nitrogen. The reaction mixture was then concentrated to dryness in vacuo, taken up in DCM (30 mL), washed with sat. aq. NaHCO₃ (30 mL x 3), brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure to give nearly black oil. The black oil was was then subjected to silica gel chromatography (0 to 20% EtOAc/PE) to give 5-bromo-2-(4,4,4-trifluorobutyl)pyridine as yellow oil (220 mg, 39% yield). Mass spectrum (ESI, m/z): calcd. For C H BrF N 267.0; found [M + 9 9 3 +H] , 267.8. Step B: (S)-N-(3-cyanophenyl)-6-methyl-4-oxo-5-(6-(4,4,4-trifluorobutyl)pyridin-3-yl)-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide. The title compound was prepared in a manner analogous to Example 122, reacting (S)-N-(3- cyanophenyl)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide (Intermediate 6, 110 mg, 0.373 mmol) and 5-bromo-2-(4,4,4-trifluorobutyl)pyridine (100 mg, 0.373 mmol).1H NMR (400 MHz, CDCl3) δ: 12.15 (s, 1H), 8.59 (br s, 1H), 8.34 (s, 1H), 8.10 (s,1H), 7.97 – 7.88 (m, 1H), 7.68 (m, 1H), 7.43 – 7.32 (m, 3H), 4.83 (m, 1H), 4.52 (m,1H), 4.45 – 4.34 (m, 1H), 2.98 (t, J = 7.6 Hz, 2H), 2.32 – 2.18 (m, 2H), 2.17 – 2.06 (m, 2H), 1.43 (d, J = 6.8 Hz, 3H). Mass spectrum (ESI, m/z): calcd. For C + 24H21F3N6O2482.2; found [M+H] , 483.2. Example 165: (S)-N-(3-cyanophenyl)-6-methyl-4-oxo-5-(6-(4,4,4-trifluorobutyl)pyridazin-3- yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

Step A: 3-bromo-6-(4,4,4-trifluorobutyl)pyridazine. The title compound was prepared in a manner analogous to Example 164, Step A above, reacting Zinc (2062 mg, 31.53 mmol), 1,1,1-trifluoro-4-iodobutane (5002 mg, 21.02 mmol), and 3,6- dibromopyridazine (0.5 g, 2.1 mmol). Mass spectrum (ESI, m/z): calcd. For C8H8BrF3N2268.0; found [M+H]+, 268.9. Step B: (S)-N-(3-cyanophenyl)-6-methyl-4-oxo-5-(5-(4,4,4-trifluorobutyl)pyridin-2-yl)-

tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide. The title compound was prepared in a manner analogous to Example 122, reacting (S)-N-(3- cyanophenyl)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide (Intermediate 6, 153 mg, 0.52 mmol) and 3-bromo-6-(4,4,4-trifluorobutyl)pyridazine (140 mg, 0.52 mmol).1H NMR (400 MHz, CDCl₃) δ: 12.00 (s, 1H), 8.37 (s, 1H), 8.24 (d, J = 9.2 Hz, 1H), 8.12 – 8.07 (m, 1H), 8.04 -7.99 (m, 1H), 7.53 (d, J = 9.2 Hz, 1H), 7.48 – 7.37 (m, 2H), 5.73 – 5.44 (m, 1H), 4.77 (m, 1H), 4.55 (m 1H), 3.14 (t, J = 7.2 Hz, 2H), 2.36 – 2.13 (m, 4H), 1.62 (d, J = 6.8 Hz, 3H). Mass spectrum (ESI, m/z): calcd. For C₂₃H₂₀F₃N₇O₂483.2; found [M+H]+, 484.2. Example 169: (S)-5-(4-benzoylphenyl)-N-(3-cyano-4-hydroxyphenyl)-6-methyl-4-oxo- 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

(S)-N-(3-cyano-4-hydroxyphenyl)-5-(4-(difluoro(phenyl)methyl)phenyl)-6-methyl-4-oxo- 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide (Example 56, 50 mg, 0.097 mmol), a stir bar, TFA (0.5 mL) and DCM (0.05 mL) were added to an oven-dried and nitrogen-purged 10 mL round-bottomed flask, and the mixture was stirred at rt overnight. The reaction mixture was adjusted pH = 7 with sat. aq. NaHCO3, then extracted with EtOAc (10 mLx3). The combined extracts washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated to dryness under reduced pressure to give a yellow solid. The solid was then subjected to silica gel chromatography (0~5.6% MeOH/DCM) to give the crude product. The crude product was purified by Prep-HPLC with the following conditions: column, Welch Xtimate C18, 150 mm, 30 mm x 5 ^m; mobile phase, 15% to 45% (v/v) MeCN/water (containing 0.05% NH₃·H₂O + 10 mM NH₄HCO₃) and then freeze dried to afford (S)-5-(4-benzoylphenyl)-N-(3-cyano-4- hydroxyphenyl)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide as a light yellow solid (15.4 mg, 17% yield).1H NMR (400 MHz, DMSO-d6) δ: 12.05 (s, 1H), 8.18 (s, 1H), 7.97 (s, 1H), 7.89 (d, J = 8.0 Hz, 2H), 7.80 (d, J = 7.2 Hz, 2H), 7.72 (d, J = 7.6 Hz, 3H), 7.65 – 7.56 (m, 2H), 7.49 (d, J = 8.0 Hz, 1H), 6.98 (d, J = 8.8 Hz, 1H), 4.93 (d, J = 10.0 Hz, 1H), 4.64 – 4.49 (m, 2H), 1.26 (d, J = 6.0 Hz, 3H). Mass spectrum (ESI, m/z): calcd. For C₂₈H₂₁N₅O₄ 491.2; found [M+H]+, 492.2. Example 170: (S)-N-(3-cyanophenyl)-6-methyl-4-oxo-5-(4-((trifluoromethyl)thio)phenyl)- 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

The title compound was prepared in a manner analogous to Example 122, reacting (S)-N-(3- cyanophenyl)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide (Intermediate 6, 100.0 mg, 0.34 mmol) and (4-bromophenyl)(trifluoromethyl)sulfane (130.6 mg, 0.51 mmol).1H NMR (400 MHz, DMSO-d6) δ: 12.31 (s, 1H), 8.22 (s, 1H), 8.18 (s, 1H), 7.90 (d, J = 8.4 Hz, 2H), 7.75 – 7.69 (m, 3H), 7.58 – 7.53 (m, 2H), 4.93 (dd, J = 4.4, 13.2 Hz, 1H), 4.57 (dd, J = 4.4, 6.8 Hz, 1H), 4.55 – 4.49 (m, 1H), 1.24 (d, J = 6.8 Hz, 3H). Mass spectrum (ESI, m/z): calcd. For C H F N O S 471.1; + 22 16 3 5 2 found [M+H] , 472.1. Example 171: (S)-N-(3-cyano-4-methoxyphenyl)-6-methyl-4-oxo-5-(4- (trifluoromethoxy)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

The title compound was prepared in a manner analogous to Example 122, reacting (S)-N-(3- cyano-4-methoxyphenyl)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3- carboxamide (Intermediate 7, 150.0 mg, 0.46 mmol) and 1-bromo-4-(trifluoromethoxy)benzene (166.7 mg, 0.69 mmol).1H NMR (400 MHz, DMSO-d₆) δ: 12.16 (s, 1H), 8.19 (s, 1H), 8.04 (d, J = 2.4 Hz, 1H), 7.73 – 7.64 (m, 3H), 7.55 (d, J = 8.4 Hz, 2H), 7.23 (d, J = 9.2 Hz, 1H), 4.96 – 4.87 (m, 1H), 4.55 – 4.47 (m, 2H), 3.88 (s, 3H), 1.21 (d, J = 6.4 Hz, 3H). Mass spectrum (ESI, m/z): calcd. For C₂₃H₁₈F₃N₅O₄485.1; found [M+H]+, 486.2. Example 172: (S)-N-(3-cyanophenyl)-6-methyl-4-oxo-5-(2-(4,4,4-trifluorobutyl)pyrimidin- 5-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

Step A: 5-bromo-2-(4,4,4-trifluorobutyl)pyrimidine. The title compound was prepared in a manner analogous to Example 164, Step A above, reacting Zinc (2062 mg, 31.53 mmol), 1,1,1-trifluoro-4-iodobutane (5002 mg, 21.02 mmol), and 5- bromo-2-iodopyrimidine (0.5 g, 1.755 mmol). Mass spectrum (ESI, m/z): calcd. For C8H8BrF3N2 268.0; found [M+H]+, 268.8. Step B: (S)-N-(3-cyanophenyl)-6-methyl-4-oxo-5-(2-(4,4,4-trifluorobutyl)pyrimidin-5-yl)- 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide. The title compound was prepared in a manner analogous to Example 122, reacting (S)-N-(3- cyanophenyl)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide (Intermediate 6, 220 mg, 0.743 mmol) and 5-bromo-2-(4,4,4-trifluorobutyl)pyrimidine (200 mg, 0.743 mmol).1H NMR (400 MHz, DMSO-d₆) δ: 12.16 (s, 1H), 8.97 (s, 2H), 8.23 (s, 1H), 8.18 (s, 1H), 7.78 – 7.71 (m, 1H),7.59 – 7.53 (m, 2H), 4.93 (m, 1H), 4.75 – 4.36 (m, 2H), 3.08 (t, J = 7.6 Hz, 2H), 2.44 – 2.34 (m, 2H), 2.04 (m, 2H), 1.26 (d, J = 6.4 Hz, 3H). Mass spectrum (ESI, m/z): calcd. f–r C₂₃H₂₀F₃N₇O₂483.2; found [M+H]+, 484.2. Example 173: (S)-N-(3-cyanophenyl)-6-methyl-4-oxo-5-(5-(4,4,4-trifluorobutyl)pyrazin-2- yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

Step A: 2-bromo-5-(4,4,4-trifluorobutyl)pyrazine. The title compound was prepared in a manner analogous to Example 164, Step A above, reacting Zinc (518 mg, 7.93 mmol), 1,1,1-trifluoro-4-iodobutane (1383 mg, 5.812 mmol), and 2- bromo-5-iodopyrazine (0.5 g, 1.76 mmol). Mass spectrum (ESI, m/z): calcd. For C₈H₈BrF₃N₂ 268.0; found [M+H]+, 268.7. Step B: (S)-N-(3-cyanophenyl)-6-methyl-4-oxo-5-(5-(4,4,4-trifluorobutyl)pyrazin-2-yl)-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide. The title compound was prepared in a manner analogous to Example 122, reacting (S)-N-(3- cyanophenyl)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide (Intermediate 6, 110 mg, 0.372 mmol) and 2-bromo-5-(4,4,4-trifluorobutyl)pyrazine (100 mg, 0.372 mmol).1H NMR (400 MHz, DMSO-d6) δ: 12.02 (s, 1H), 9.17 (d, J = 1.2 Hz, 1H), 8.58 (s, 1H), 8.24 (s, 2H), 7.90 – 7.80(m, 1H), 7.64 – 7.52 (m, 2H), 5.12 – 5.01 (m, 1H), 4.81 (m, 1H), 4.61 – 4.43 (m, 1H), 2.99 – 2.89 (m, 2H), 2.46 – 2.25 (m, 2H), 2.06 – 1.93 (m, 2H), 1.39 (d, J = 6.8 Hz, 3H). Mass spectrum (ESI, m/z): calcd. For C + 23H20F3N7O2483.2; found [M+H] , 484.2. Example 174 and 180: N-(3-cyanophenyl)-4-oxo-5-(4-(3-(prop-2-yn-1-yl)benzyl)phenyl)- 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide and N-(3-cyanophenyl)-4-oxo-5- (4-(3-(propa-1,2-dien-1-yl)benzyl)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3- carboxamide

Step A: 2-(3-(4-bromobenzyl)phenyl)ethan-1-ol. The title compound was prepared in a manner analogous to Example 157, Step A above, reacting (3-Formylphenyl)boronic acid (5.00 g, 33.4 mmol) and 1-bromo-4-(bromomethyl)benzene (10.8 g, 43.4 mmol).1H NMR (400 MHz, CDCl3) δ: 7.46 – 7.40 (m, 2H), 7.30 – 7.24 (m, 1H), 7.14 – 7.03 (m, 5H), 3.94(s, 2H), 3.86 (t, J = 6.6 Hz, 2H), 2.86 (t, J = 6.6 Hz, 2H). Step B: N-(3-cyanophenyl)-5-(4-(3-(2-hydroxyethyl)benzyl)phenyl)-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide. The title compound was prepared in a manner analogous to Example 122, reacting N-(3- cyanophenyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide (Intermediate 9, 464 mg, 1.65 mmol) and 2-(3-(4-bromobenzyl)phenyl)ethanol (480 mg, 1.648 mmol). Mass spectrum (ESI, m/z): calcd. For C₂₉H₂₅N₅O₃491.2; found [M+H]+, 492.0. Step C: N-(3-cyanophenyl)-4-oxo-5-(4-(3-(2-oxoethyl)benzyl)phenyl)-

tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide. N-(3-cyanophenyl)-5-(4-(3-(2-hydroxyethyl)benzyl)phenyl)-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide (380 mg, 0.773 mmol), a stir bar, IBX (433 mg, 1.55 mmol), and CH3CN (16 mL) were add to a nitrogen-purged 100 mL round-bottomed flask and the resulting solution was stirred at 55 °C for 4 hours. The mixture was filtered, the filtrate was concentrated to obtain a yellow gum. The yellow gum was subjected to silica gel chromatography (0 to 50% EtOAc/PE) to afford N-(3-cyanophenyl)-4-oxo-5-(4-(3-(2- oxoethyl)benzyl)phenyl)-4,5,6,7 tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide (390 mg, 68% yield) as a yellow gum. Mass spectrum (ESI, m/z): calcd. For C₂₉H₂₃N₅O₃489.2; found [M+H]+, 490.0. Step D: N-(3-cyanophenyl)-4-oxo-5-(4-(3-(prop-2-yn-1-yl)benzyl)phenyl)-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide and N-(3-cyanophenyl)-4-oxo-5-(4-(3-(propa- 1,2-dien-1-yl)benzyl)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide. N-(3-cyanophenyl)-4-oxo-5-(4-(3-(2-oxoethyl)benzyl)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrazine-3-carboxamide (200 mg, 0.409 mmol), a stir bar, dimethyl (1-diazo-2- oxopropyl)phosphonate (157 mg, 0.817 mmol), K2CO3 (169 mg, 1.23 mmol), CH3CN (2.5 mL) and MeOH (2.5 mL) were added to an oven-dried and nitrogen-purged 10 mL round-bottomed flask and the resulting mixture was stirred for 12 h at 15 °C. The reaction mixture was concentrated under reduced pressure to move MeOH to give brown oil. The brown oil was purified by Prep-HPLC with the following conditions: column, Welch Xtimate C18, 150 mm, 30 mm x 5 ^m; mobile phase, 61% to 91% (v/v) CH₃CN and H₂O with (0.5%FA) and then freeze dried to afford N-(3-cyanophenyl)-4-oxo-5-(4-(3-(prop-2-yn-1-yl)benzyl)phenyl)-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide as a white solid (33.1 mg, 16% yield) 1H NMR (400 MHz, CDCl₃) δ: 12.30 (s, 1H), 8.31 (s, 1H), 8.11 (s, 1H), 8.01 – 7.91 (m, 1H), 7.44 – 7.24 (m, 9H),7.12 (d, J = 7.2 Hz, 1H), 4.71 – 4.59 (m, 2H), 4.31 – 4.20 (m, 2H), 4.05 (s, 2H), 3.62 (d, J = 2.4 Hz, 2H), 2.21 (t, J = 2.4 Hz, 1H). Mass spectrum (ESI, m/z): calcd. For C₃₀H₂₃N₅O₂485.2; found [M+H]+ , 486.2.) and N-(3-cyanophenyl)-4-oxo-5-(4-(3-(propa-1,2- dien-1-yl)benzyl)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide (40 mg, 87% purity) which was further purified by Prep-TLC (PE/EA =1:1) to afford N-(3- cyanophenyl)-4-oxo-5-(4-(3-(propa-1,2-dien-1-yl)benzyl)phenyl)-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide (30.8 mg, 19% yield) as a off-white solid.1H NMR (400 MHz, CDCl3) δ: 12.30 (s, 1H), 8.32 (s, 1H), 8.11 (s, 1H), 7.95 (m, 1H), 7.41 – 7.27 (m, 7H), 7.23 -7.16 (m, 2H), 7.07 (m, 1H), 6.16 (t, J = 6.8 Hz, 1H), 5.16 (d, J = 6.8 Hz, 2H), 4.74 – 4.59 (m, 2H), 4.32 – 4.21(m, 2H), 4.03 (s, 2H). Mass spectrum (ESI, m/z): calcd. For C H N O 485.2; found [M+H + 30 23 5 2 ] , 486.2. Example 175: (S)-N-(3-cyano-4-(((S)-pyrrolidin-3-yl)oxy)phenyl)-5-(4- (difluoro(phenyl)methyl)phenyl)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrazine-3-carboxamide.

Step A: tert-butyl (S)-3-(2-cyano-4-((S)-5-(4-(difluoro(phenyl)methyl)phenyl)-6-methyl-4-oxo- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamido)phenoxy)pyrrolidine-1-carboxylate.

The title compound was prepared in a manner analogous to Example 158, step A above, reacting (S)-N-(3-cyano-4-hydroxyphenyl)-5-(4-(difluoro(phenyl)methyl)phenyl)-6-methyl-4-oxo- 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide (Example 56, 260 mg, 0.506 mmol)) and (R)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate (142 mg, 0.760 mmol). Mass spectrum (ESI, m/z): calcd. For C H F N O 682.3; f + 37 36 2 6 5 ound [M-56+H] , 627.2. Step B: (S)-N-(3-cyano-4-((®-pyrrolidin-3-yl)oxy)phenyl)-5-(4- (difluoro(phenyl)methyl)phenyl)-6-methyl-4-oxo- tetrahydropyrazolo[1,5-a]pyrazine-3-

carboxamide. The title compound was prepared in a manner analogous to Example 158, step B above, reacting (S)-tert-butyl 3-(2-cyano-4-((S)-5-(4-(difluoro(phenyl)methyl)phenyl)-6-methyl-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamido)phenoxy)pyrrolidine-1-carboxylate (289 mg, 0.423 mmol) and HCl/dioxane (5 mL, 4 M).1H NMR (400 MHz, DMSO-d6) δ: 12.18 (s, 1H), 8.18 (s, 1H), 8.05 (d, J = 2.4 Hz, 1H), 7.73 – 7.59 (m, 7H), 7.58 – 7.50 (m, 3H), 7.28 (d, J = 9.2 Hz, 1H), 5.23 (br s, 1H), 4.99 – 4.84 (m, 1H), 4.58 – 4.45 (m, 2H), 2.22 – 2.10 (m, 2H), 1.21 (d, J = 6.4 Hz, 3H). Mass spectrum (ESI, m/z): calcd. For C + 32H28F2N6O3582.2; found [M+H] , 583.2. Example 176: (S)-N-(3-cyano-4-methoxyphenyl)-6-methyl-4-oxo-5-(4- ((trifluoromethyl)thio)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

The title compound was prepared in a manner analogous to Example 122, reacting (S)-N-(3- cyano-4-methoxyphenyl)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3- carboxamide (Intermediate 7, 200 mg, 0.615 mmol) and (4- bromophenyl)(trifluoromethyl)sulfane (111 μL, 1.710 g/mL, 0.738 mmol).1H NMR (400 MHz, DMSO-d6) δ: 12.10 (s, 1H), 8.19 (s, 1H), 8.04 (d, J = 2.8 Hz, 1H), 7.89 (d, J = 8.4 Hz, 2H), 7.73 – 7.69 (m, 3H), 7.24 (d, J = 9.2 Hz, 1H), 4.92 (d, J = 4.4 Hz, 1H), 4.59 – 4.48 (m, 2H), 3.88 (s, 3H), 1.23 (d, J = 6.4 Hz, 3H). Mass spectrum (ESI, m/z): calcd. For C₂₃H₁₈F₃N₅O₃S 501.1; found [M+H]+, 502.1. Example 177: (S)-N-(3-cyanophenyl)-6-methyl-4-oxo-5-(4-(trifluoromethoxy)phenyl)- 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

The title compound was prepared in a manner analogous to Example 122, reacting (S)-N-(3- cyanophenyl)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide (Intermediate 6, 200.0 mg, 0.677 mmol) and 1-bromo-4-(trifluoromethoxy)benzene (195.9 mg, 0.813 mmol).1H NMR (400 MHz, DMSO-d6) δ: 12.37 (s, 1H), 8.22 – 8.15 (m, 2H), 7.73 – 7.65 (m, 3H), 7.58 – 7.50 (m, 4H), 4.96 – 4.88 (m, 1H), 4.57 – 4.47 (m, 2H), 1.22 (d, J = 6.4 Hz, 3H). Mass spectrum (ESI, m/z): calcd. For C + 22H16F3N5O3455.1; found [M+H] , 456.1. Example 178: N-(3-cyanophenyl)-4-oxo-5-(4-(4-(prop-2-yn-1-yl)benzyl)phenyl)-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

Step A: 2-(4-(4-bromobenzyl)phenyl)ethan-1-ol. The title compound was prepared in a manner analogous to Example 157, Step A above, reacting (4-(2-hydroxyethyl)phenyl)boronic acid (1.00 g, 6.03 mmol) and 1-bromo-4- (bromomethyl)benzene (1.96 g, 7.83 mmol).1H NMR (400 MHz, CDCl₃) δ: 7.42 (d, J = 8.4 Hz, 1H), 7.35 – 7.29 (m, 1H), 7.25 – 7.05 (m, 6H), 4.01 – 3.90 (m, 2H), 3.87 (t, J = 6.4 Hz, 2H), 2.86 (t, J = 6.4 Hz, 2H). Step B: N-(3-cyanophenyl)-5-(4-(4-(2-hydroxyethyl)benzyl)phenyl)-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide. The title compound was prepared in a manner analogous to Example 174, Step B above, reacting N-(3-cyanophenyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide (Intermediate 9, 100 mg, 0.356 mmol) and 2-(4-(4-bromobenzyl)phenyl)ethan-1-ol (135 mg, 0.462 mmol). Mass spectrum (ESI, m/z): calcd. For C₂₉H₂₅N₅O₃491.2; found [M+H]+, 492.1. Step C: N-(3-cyanophenyl)-4-oxo-5-(4-(4-(2-oxoethyl)benzyl)phenyl)-

tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide. The title compound was prepared in a manner analogous to Example 174, Step C above, reacting N-(3-cyanophenyl)-5-(4-(4-(2-hydroxyethyl)benzyl)phenyl)-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide (140 mg, 0.264 mmol), and IBX (148 mg, 0.528 mmol). Mass spectrum (ESI, m/z): calcd. For C₂₉H₂₃N₅O₃489.2; found [M+H]+, 490.0. Step D: N-(3-cyanophenyl)-4-oxo-5-(4-(4-(prop-2-yn-1-yl)benzyl)phenyl)-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide. The title compound was prepared in a manner analogous to Example 174, Step C above, reacting N-(3-cyanophenyl)-4-oxo-5-(4-(4-(2-oxoethyl)benzyl)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrazine-3-carboxamide (110 mg, 0.23 mmol) and dimethyl (1-diazo-2- oxopropyl)phosphonate (86 mg, 0.45 mmol).1H NMR (400 MHz, CDCl₃) δ: 12.30 (s, 1H), 8.32 (s, 1H), 8.10 (s, 1H), 7.96 (d, J = 8.4 Hz, 1H), 7.42 – 7.28 (m, 8H), 7.21 (d, J = 8.0 Hz, 2H), 4.66 (t, J = 6.0 Hz, 2H), 4.30 – 4.18 (m, 2H), 4.08 – 3.99 (m, 2H), 3.61 (d, J = 2.4 Hz, 2H), 2.20 (t, J = 2.8 Hz, 1H). Mass spectrum (ESI, m/z): calcd. For C₃₀H₂₃N₅O₂485.2; found [M+H]+ , 486.1. Example 179: (S)-N-(3-cyanophenyl)-6-methyl-4-oxo-5-(5-(4,4,4-trifluorobutyl)pyridin-2- yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

Step A: 2-bromo-5-(4,4,4-trifluorobutyl)pyridine. The title compound was prepared in a manner analogous to Example 164, Step A above, reacting Zinc (518 mg, 7.93 mmol), 1,1,1-trifluoro-4-iodobutane (1383 mg, 5.812 mmol), and 2- bromo-5-iodopyridine (498 mg, 1.755 mmol). Mass spectrum (ESI, m/z): calcd. For C9H9BrF3N 267.0; found [M+H]+, 267.8. Step B: (S)-N-(3-cyanophenyl)-6-methyl-4-oxo-5-(5-(4,4,4-trifluorobutyl)pyridin-2-yl)-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide. The title compound was prepared in a manner analogous to Example 122, reacting (S)-N-(3- cyanophenyl)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide (Intermediate 6, 110 mg, 0.373 mmol) and 2-bromo-5-(4,4,4-trifluorobutyl)pyridine (100 mg, 0.373 mmol).1H NMR (400 MHz, DMSO-d6) δ: 12.23 (s, 1H), 8.45 (s, 1H), 8.25 – 8.16 (m, 2H), 7.86 (s, 2H), 7.83 – 7.77 (m,1H), 7.61 – 7.51 (m, 2H), 5.06 (m, 1H), 4.80 (m, 1H), 4.52 (m, 1H), 2.74 (m, 2H), 2.39 – 2.25 (m, 2H), 1.85 (m,2H), 1.36 (br d, J = 6.4 Hz, 3H). Mass spectrum (ESI, m/z): calcd. For C H 1F N O 482.2; foun + 24 2 3 6 2 d [M+H] , 483.2. Example 180: see example 174 Example 181: (S)- (3-cyano-4-methoxyphenyl)-6-methyl-4-oxo-5-(4-(3-(prop-2-yn-1-

yloxy)benzoyl)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

Step A: (4-bromophenyl)(3-methoxyphenyl)methanone. 1-Bromo-3-methoxybenzene (5.75 g, 30.7 mmol), a stir bar, and anhydrous THF (20 mL) were 306dded to a 250 mL three necked flask, which was subsequently evacuated and refilled with nitrogen and cooled to -70 °C in an EtOH/Dry Ice bath, and the resulting mixture treated with n- BuLi (12.3 mL , 30.7 mmol) dropwise over 30 min, the mixture was stirred at -70 °C for 0.5 h, then which charged with a solution of 4-bromo-N-methoxy-N-methylbenzamide (5.00 g, 20.5 mmol) in THF (10 mL), and the mixture stirred at -70 °C for 2 h. The reaction mixture was quenched with sat. aq. NH4Cl (50 mL) and extracted with EtOAc (50 mL x 3). The combined extracts washed with brine (60 mL), dried over anhydrous Na₂SO₄, filtered and concentrated to dryness under reduced pressure to give yellow oil. The yellow oil was subjected to silica gel chromatography (0~20% EtOAc/PE) to give (4-bromophenyl(3-methoxyphenyl)methanone as a white solid (5.5 g, 92% yield).1H NMR (400 MHz, DMSO-d₆) δ: 7.80 – 7.74 (m, 2H), 7.70 – 7.65 (m, 2H), 7.51 – 7.45 (m, 1H), 7.28 – 7.23 (m, 3H), 3.81 (s, 3H). Mass spectrum (ESI, m/z): calcd. For C + 30H23N5O2 C14H11BrO2290.0; found [M+H] , 291.0. Step B: (4-bromophenyl)(3-hydroxyphenyl)methanone. (4-Bromophenyl)(4-methoxyphenyl)methanone (3.0 g, 10 mmol), aluminum trichloride (2.75 g, 20.6 mmol), a stir bar, and toluene (25 mL) were added to 50 mL single-necked round-bottom flask equipped with condenser at 0 °C under N₂. The resulting mixture was stirred at 100 °C for 2 h. The resulting mixture was quenched with 1N HCl (30 mL), extracted with EtOAc (80 mL x 3). The combined extracts was concentrated to dryness under reduced pressure to give black oil. The black oil was then subjected to silica gel chromatography (PE/EtOAc /DCM = 5/1/1) to give (4-bromophenyl)(3-hydroxyphenyl)methanone as colourless oil (1.8 g, 63% yield).1H NMR (400 MHz, CDCl3) δ: 7.72 – 7.66 (m, 2H), 7.66 – 7.61 (m, 2H), 7.40 – 7.34 (m, 1H), 7.33 – 7.28 (m, 2H), 7.13 – 7.08 (m, 1H), 5.49 (s, 1H). Step C: (S)-N-(3-cyano-4-methoxyphenyl)-5-(4-(3-hydroxybenzoyl)phenyl)-6-methyl-4-oxo- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

The title compound was prepared in a manner analogous to Example 122, reacting (S)-N-(3- cyano-4-methoxyphenyl)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3- carboxamide (Intermediate 7, 489 mg, 1.50 mmol) and (4-bromophenyl)(3- hydroxyphenyl)methanone (500 mg,1.80 mmol). Mass spectrum (ESI, m/z): calcd. For C₂₉H₂₃N₅O₅521.2; found [M+H]+, 522.0. Step D: (S)-N-(3-cyano-4-methoxyphenyl)-6-methyl-4-oxo-5-(4-(3-(prop-2-yn-1- yloxy)benzoyl)phenyl)- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

(S)-N-(3-cyano-4-methoxyphenyl)-5-(4-(3-hydroxybenzoyl)phenyl)-6-methyl-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide (140 mg, 0.268 mmol), K2CO3 (74.2 mg, 0.537mmol), a stir bar, 3-bromoprop-1-yne (79.8 mg, 0.537 mmol), and DMF (1.5 mL) were added to a thumb bottle and the reslutant mixture was stirred overnight at rt. The mixture was diluted with EtOAc (30 mL) and washed with H₂O: brine (1:1, 10 mL x 3). The combined extracts was dried over Na2SO4 and concentrated to dryness under reduced pressure to give yellow oil. The yellow oil was then subjected to silica gel chromatography (70-100% EtOAc/PE) to give (S)-N-(3-cyano-4-methoxyphenyl)-6-methyl-4-oxo-5-(4-(3-(prop-2-yn-1- yloxy)benzoyl)phenyl)-4,5,6,7 tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide as a white solid (130.1 mg, 86% yield).1H NMR (400 MHz, DMSO-d6) δ: 12.15 (s, 1H), 8.20 (s, 1H), 8.04 (d, J = 2.8 Hz, 1H), 7.91 (d, J = 8.4 Hz, 2H), 7.75 – 7.70 (m, 3H), 7.57 – 7.51 (m, 1H), 7.41 – 7.37 (m, 2H), 7.35 – 7.31 (m, 1H), 7.24 (d, J = 3.2 Hz, 1H), 5.00 – 4.86 (m, 3H), 4.65 – 4.49 (m, 2H), 3.88 (s, 3H), 3.65 (t, J = 2.4 Hz, 1H), 1.27 (d, J = 6.4 Hz, 3H). Mass spectrum (ESI, m/z): calcd. For C₃₂H₂₅N₅O₅559.2; found [M+H]+ , 560.2. Example 182: (S)-N-(3-cyanophenyl)-5-(4-(1,1-difluoroethyl)phenyl)-6-methyl-4-oxo- 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

The title compound was prepared in a manner analogous to Example 122, reacting (S)-N-(3- cyanophenyl)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide (Intermediate 6, 100 mg, 0.339 mmol) and 1-bromo-4-(1,1-difluoroethyl)benzene (150 mg, 0.677 mmol).1H NMR (400 MHz, DMSO-d6) δ: 12.42 (s, 1H), 8.22 (s, 1H), 8.19 – 8.17 (m, 1H), 7.76 – 7.69 (m, 3H), 7.67 – 7.63 (m, 2H), 7.57 – 7.51 (m, 2H), 4.97 – 4.89 (m, 1H), 4.57 – 4.49 (m, 2H), 2.09 – 1.98 (t, J = 18.8 Hz, 3H), 1.23 (d, J = 6.8 Hz, 3H). Mass spectrum (ESI, m/z): calcd. For C₂₃H₁₉F₂N₅O₂435.2; found [M+H]+, 436.2. Example 183: (S)- (3-cyano-4-methoxyphenyl)-6-methyl-4-oxo-5-(4-(4-(prop-2-yn-1-

yloxy)benzoyl)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

Step A: (4-bromophenyl)(4-hydroxyphenyl)methanone. The title compound was prepared in a manner analogous to Example 181, Step B above, reacting (4-Bromophenyl)(4-methoxyphenyl)methanone (2.00 g, 6.87 mmol) and AlCl₃ (2.29 g, 17.2 mmol).1H NMR (400 MHz, DMSO-d6) ^ ^ 10.49 (s, 1H), 7.75 (d, J = 8.4 Hz, 2H), 7.66 (d, J = 8.8 Hz, 2H), 7.60 (d, J = 8.4 Hz, 2H), 6.90 (d, J = 8.8 Hz, 2H). Mass spectrum (ESI, m/z): calcd. For C H BrO 276.0; found [M + 13 9 2 +H] , 277.0. Step B: (S)-N-(3-cyano-4-methoxyphenyl)-5-(4-(4-hydroxybenzoyl)phenyl)-6-methyl-4-oxo- 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide. The title compound was prepared in a manner analogous to Example 122, reacting (S)-N-(3- Cyano-4-methoxyphenyl)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3- carboxamide (Intermediate 7, 500 mg, 1.54 mmol) and (4-bromophenyl)(4- hydroxyphenyl)methanone (511 mg, 1.84 mmol).1H NMR (400 MHz, DMSO-d₆) ^ ^ ^ 12.21 – 12.16 (m, 1H), 10.54 – 10.45 (m, 1H), 8.25 – 8.17 (m, 1H), 8.06 (d, J = 2.4 Hz, 1H), 7.87 – 7.79 (m, 2H), 7.76 – 7.68 (m, 1H), 7.76 – 7.68 (m, 4H), 7.25 (d, J = 9.6 Hz, 1H), 6.99 – 6.91 (m, 2H), 4.99 – 4.89 (m, 1H), 4.63 – 4.52 (m, 2H), 3.95 – 3.84 (m, 3H), 1.29 – 1.25 (m, 3H). Mass spectrum (ESI, m/z): calcd. For C + 29H23N5O5521.2; found [M+H] , 522.0. Step C: (S)-N-(3-cyano-4-methoxyphenyl)-6-methyl-4-oxo-5-(4-(4-(prop-2-yn-1- yloxy)benzoyl)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide. The title compound was prepared in a manner analogous to Example 181, Step D above, reacting (S)-N-(3-Cyano-4-methoxyphenyl)-5-(4-(4-hydroxybenzoyl)phenyl)-6-methyl-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide (270 mg, 518 μmol) and 3-bromoprop-1-yne (154 mg, 80% in toluene, 1.04 mmol).1H NMR (400 MHz, DMSO-d6) ^ ^ ^ 12.17 (s, 1H), 8.20 (s, 1H), 8.05 (d, J = 2.4 Hz, 1H), 7.87 – 7.82 (m, 4H), 7.75 – 7.69 (m, 3H), 7.24 (d, J = 9.2 Hz, 1H), 7.18 (d, J = 8.8 Hz, 2H), 4.97 – 4.91 (m, 3H), 4.63 – 4.49 (m, 2H), 3.88 (s, 3H), 3.66 (t, J = 2.4 Hz, 1H), 1.27 (d, J = 6.4 Hz, 3H).. Mass spectrum (ESI, m/z): calcd. For C32H25N5O5559.2; found [M+H]+ , 560.2. Example 184: N-(3-cyanophenyl)-4-oxo-5-(4-(4-(prop-2-yn-1-yloxy)benzyl)phenyl)-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide..

Step A: 5-(4-(4-((tert-butyldimethylsilyl)oxy)benzyl)phenyl)-N-(3-cyanophenyl)-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide. The title compound was prepared in a manner analogous to Intermediate 1, Step E, reacting N- (3-cyanophenyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide (Intermediate 9, 72 mg, 0.256 mmol) and tert-butyl(4-(4-iodobenzyl)phenoxy)dimethylsilane (Intermediate 51, 120 mg, 0.283 mmol).1H NMR (400 MHz, DMSO-d₆) δ: -0.04 – 0.02 (m, 6H) 0.73 – 0.79 (m, 9H) 3.72 – 3.77 (m, 2H) 4.05 – 4.11 (m, 2H) 4.45 -4.52 (m, 2H) 6.59 – 6.65 (m, 2H) 6.94 – 7.02 (m, 2H) 7.15 – 7.22 (m, 2H) 7.22 – 7.27 (m, 2H) 7.32 – 7.40 (m, 2H) 7.50 – 7.59 (m, 1H) 7.97 – 8.03 (m, 2H) 12.35 – 12.39 (m, 1H). Step B: N-(3-cyanophenyl)-5-(4-(4-hydroxybenzyl)phenyl)-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide. Aq.2M HCl (0.48 mL, 0.96 mmol) was added to a solution of 5-(4-(4-((tert- butyldimethylsilyl)oxy)benzyl)phenyl)-N-(3-cyanophenyl)-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide (55 mg, 0.095 mmol) in MeOH (7 mL) at 0ºC. The mixture was stirred at room temperature for 16 h. Aq.2M HCl (0.2 mL, 0.4 mmol) was added and the mixture was stirred at room temperature for 1 h. The solution was diluted with EtOAc, washed with water. The organic layers were combined, dried over MgSO4 and filtered. The solvent was reduced in vacuo to give N-(3-cyanophenyl)-5-(4-(4-hydroxybenzyl)phenyl)-4- oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide (45 mg, 96% yield) as a red solid. 1H NMR (300 MHz, DMSO-d6) δ: 3.85 – 3.96 (m, 2H) 4.23 – 4.34 (m, 2H) 4.64 – 4.76 (m, 2H) 6.68 – 6.78 (m, 2H) 7.08 – 7.15 (m, 2H) 7.35 – 7.41 (m, 2H) 7.41 – 7.49 (m, 2H) 7.42 – 7.49 (m, 1H) 7.55 – 7.63 (m, 2H) 7.69 – 7.80 (m, 1H) 7.71 – 7.79 (m, 1H) 7.94 – 8.04 (m, 1H) 12.55 – 12.64 (m, 1H). Mass spectrum (ESI, m/z): calcd. For C₂₇H₂₁N₅O₃, 463.2; found [M+H]+, 464.2. Step C: N-(3-cyanophenyl)-4-oxo-5-(4-(4-(prop-2-yn-1-yloxy)benzyl)phenyl)-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide. Propargyl bromide (0.050 mL, 0.580 mmol) was added to a suspension of N-(3-cyanophenyl)-5- (4-(4-hydroxybenzyl)phenyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide (50 mg, 0.108 mmol) and potassium carbonate (20 mg, 0.145 mmol) in acetone (0.5 mL). The mixture was stirred at reflux for 16 h. The mixture was concentrated in vacuo to reduce the solvent. The residue was dissolved in water, extracted with EtOAc and washed with brine. The organic layer was dried over MgSO₄, filtered and concentrated in vacuo. The crude product was purified by flash column chromatography (0%-50% heptane/EtOAc). The desired fractions were combined and concentrated in vacuo. The resulting product was purified by reverse phase (Phenomenex Gemini C1830x100mm 5μm Column; from 59% [25mM NH₄HCO₃] – 41% [100% CH₃CN] to 17% [25mM NH₄HCO₃] – 83% [100% CH₃CN]). The desired fractions were collected and extracted with DCM (x3). The organic phase was dried over MgSO4 anh., filtered and concentrated in vacuo to yield N-(3-cyanophenyl)-4-oxo-5-(4-(4-(prop-2-yn-1- yloxy)benzyl)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide (11.6 mg, 21% yield) as a brownish solid.1H NMR (400 MHz, DMSO-d6) δ: 12.54 (s, 1H), 8.18 (d, J = 1.5 Hz, 2H), 7.73 – 7.68 (m, 1H), 7.55 – 7.51 (m, 2H), 7.43 – 7.39 (m, 2H), 7.35 (d, J = 8.5 Hz, 2H), 7.23 (d, J = 8.7 Hz, 2H), 6.96 – 6.90 (m, 2H), 4.76 (d, J = 2.4 Hz, 2H), 4.69 – 4.62 (m, 2H), 4.29 – 4.20 (m, 2H), 3.93 (s, 2H), 3.54 (t, J = 2.4 Hz, 1H). Mass spectrum (ESI, m/z): calcd. For C H N O , 501.2; found + 30 23 5 3 [M+H] , 502.0. Example 185: tert-butyl (S)-(4-(4-(3-((3-cyanophenyl)carbamoyl)-6-methyl-4-oxo-6,7- dihydropyrazolo[1,5-a]pyrazin-5 -yl)phenyl)-4,4-difluorobutyl)carbamate

The title compound was prepared in a manner analogous to Example 155, reacting (S)-2-(4-(3- ((3-cyanophenyl)carbamoyl)-6-methyl-4-oxo-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)- yl)phenyl)-2,2-difluoroacetic acid (Intermediate 40, 57.5 mg, 0.10 mmol) and tert-butyl allylcarbamate (78.6 mg, 0.50 mmol), yielding tert-butyl (S)-(4-(4-(3-((3- cyanophenyl)carbamoyl)-6-methyl-4-oxo-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl)phenyl)- 4,4-difluorobutyl)carbamate (7 mg, 12% yield).1H NMR (400 MHz, CDCl3) δ: 8.33 (s, 1H), 8.12 (t, J = 1.9 Hz, 1H), 7.92 (dt, J = 8.0, 1.8 Hz, 1H), 7.68 – 7.61 (m, 2H), 7.47 – 7.31 (m, 4H), 4.80 (dd, J = 13.4, 4.6 Hz, 1H), 4.59 (br s, 1H), 4.49 (dd, J = 13.4, 3.3 Hz, 1H), 4.41 (ddd, J = 7.6, 4.6, 3.3 Hz, 1H), 3.20 (q, J = 6.8 Hz, 2H), 2.30 – 2.13 (m, 2H), 1.77 – 1.69 (m, 2H), 1.50 – 1.38 (m, 12H). Mass spectrum (ESI, m/z): Calcd. For C₃₀H₃₂F₂N₆O₄, 578.2, found [M-H]-, 577.3. Example 186: (S)-N-(3-cyanophenyl)-5-(4-(1,1-difluoro-5-hydroxypentyl)phenyl)-6-methyl- 4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide

The title compound was prepared in a manner analogous to Example 155, reacting (S)-2-(4-(3- ((3-cyanophenyl)carbamoyl)-6-methyl-4-oxo-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)- yl)phenyl)-2,2-difluoroacetic acid (Intermediate 40, 20 mg, 0.035 mmol) and but-3-en-1-ol (0.015 mg, 0.83 g/mL, 0.0.174 mmol), yielding (S)-N-(3-cyanophenyl)-5-(4-(1,1-difluoro-5- hydroxypentyl)phenyl)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3- carboxamide (14 mg, 79% yield).1H NMR (400 MHz, CDCl₃) δ: 8.32 (s, 1H), 8.08 (t, J = 1.9 Hz, 1H), 7.94 (ddd, J = 8.1, 2.2, 1.3 Hz, 1H), 7.72 – 7.60 (m, 2H), 7.46 – 7.30 (m, 4H), 4.80 (dd, J = 13.4, 4.6 Hz, 1H), 4.48 (dd, J = 13.4, 3.4 Hz, 1H), 4.45 – 4.36 (m, 1H), 3.67 (t, J = 5.8 Hz, 2H), 2.22 (tt, J = 16.0, 7.3 Hz, 2H), 1.63 (dq, J = 6.7, 3.9 Hz, 5H), 1.40 (d, J = 6.7 Hz, 3H). Mass spectrum (ESI, m/z): Calcd. For C + 26H25F2N5O3, 493.2, found [M+H] , 494.4. Example 187: (S)-N-(3-cyanophenyl)-6-methyl-4-oxo-5-(4-(3,3,3-trifluoropropyl)phenyl)- 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

The title compound was prepared in a manner analogous to Example 122, reacting (S)-N-(3- cyanophenyl)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide (Intermediate 6, 100.0 mg, 0.34 mmol) and 1-bromo-4-(3,3,3-trifluoropropyl)benzene(128.5 mg, 0.51 mmol).1H NMR (400 MHz, DMSO-d6) δ: 12.53 (s, 1H), 8.21 (s, 1H), 8.16 (d, J = 1.2 Hz, 1H), 7.72 (m, 1H), 7.58 – 7.51 (m, 2H), 7.49 – 7.41 (m, 4H), 4.91 (dd, J = 4.4, 13.2 Hz, 1H), 4.55 – 4.40 (m, 2H), 2.95 – 2.85 (m, 2H), 2.73 – 2.60 (m, 2H), 1.20 (d, J = 6.4 Hz, 3H). Mass spectrum (ESI, m/z): calcd. For C H + 24 20F3N5O2467.2; found [M+H] , 468.2. Example 188: (S)-5-(4-(3-(2-(3-(but-3-yn-1-yl)-3H-diazirin-3-yl)ethoxy)benzyl)phenyl)-N- (3-cyano-4-methoxyphenyl)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3- carboxamide.

Step A: 3-((4-bromophenyl)(hydroxy)methyl)phenol. (4-bromophenyl)(3-hydroxyphenyl)methanone (Example 181, product from Step B, 2.40 g, 8.66 mmol), a stir bar, and anhydrous MeOH (45 mL) were added to a 100 mL round-bottomed flask. The resulting solution was charged with NaBH4 (1.59 g, 42.0 mmol) and stirred at 0 °C for 1 h. Then reaction mixture was quenched with sat. aq. NH₄Cl (50 mL), extracted with EA (80 mL x 3). The combined extractes was concentrated to dryness under reduced pressure to give yellow oil. The yellow oil was was then subjected to silica gel chromatography (0~10% EtOAc/PE) to give 3-((4-bromophenyl)(hydroxy)methyl)phenol as colourless oil (1.6 g, 66% yield).1H NMR (400 MHz, DMSO-d₆) δ: 7.80 – 7.74 (m, 2H), 7.70 – 7.65 (m, 2H), 7.51 – 7.45 (m, 1H), 7.28 – 7.23 (m, 3H), 3.81 (s, 3H). Mass spectrum (ESI, m/z): calcd. For C30H23N5O2 C14H11BrO2290.0; found [M+H]+ , 291.0. Step B: 3-(4-bromobenzyl)phenol. 3-((4-bromophenyl)(hydroxy)methyl)phenol (1.6 g, 5.7 mmol), a stir bar, triethylsilane (1.37 mL, 8.60 mmol), TFA (0.624 mL, 8.60 mmol) and anhydrous DCM (20 mL) were added to oven-dried and nitrogen-purged 100 mL round-bottomed flask. The reaulting solution was stirred at rt for 3 h. The reaction was slowly quenched with sat. aq. NaHCO3 (25 mL), and the resulting mixture was extracted with DCM (50 mL x 2). The combined extracts was dried over anhydrous Na₂SO₄, and concentrated to dryness under reduced pressure to give colorless oil. The oil was then subjected to silica gel chromatography (0-5% EtOAc/PE) to give 3-(4-bromobenzyl)phenol as colorless oil (900 mg, 60% yield).1H NMR (400 MHz, CDCl3) δ: 7.44 – 7.39 (m, 2H), 7.17 (t, J = 8.0 Hz, 1H), 7.07 (d, J= 8.4 Hz, 2H), 6.75 (d, J = 7.6 Hz, 1H), 6.69 (dd, J = 2.0, 8.0 Hz, 1H), 6.62 (d, J = 1.7 Hz, 1H), 4.36 – 4.20 (m, 1H), 3.89 (s, 2H). Step C: (S)-N-(3-cyano-4-methoxyphenyl)-5-(4-(3-hydroxybenzyl)phenyl)-6-methyl-4-oxo- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

The title compound was prepared in a manner analogous to Example 122, reacting (S)-N-(3- cyano-4-methoxyphenyl)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3- carboxamide (Intermediate 7, 618 mg, 1.90 mmol) and 3-(4-bromobenzyl)phenol (600 mg, 2.28 mmol). Mass spectrum (ESI, m/z): calcd. For C + 29H25N5O4507.2; found [M+H] , 508.1. Step D: (S)-5-(4-(3-(2-(3-(but-3-yn-1-yl)-3H-diazirin-3-yl)ethoxy)benzyl)phenyl)-N-(3-cyano-4- methoxyphenyl)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide. (S)-N-(3-cyano-4-methoxyphenyl)-5-(4-(3-hydroxybenzyl)phenyl)-6-methyl-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide (250 mg, 0.493 mmol), a stir bar, 2-(3-(but-3- yn-1-yl)-3H-diazirin-3-yl)ethanol (102 mg,0.739 mmol), PPh3 (258 mg, 0.985 mmol), and anhydrous toluene (5 mL) were added to a 40 mL round-bottomed flask, and the resulting mixture was treated with DIAD (0.195 mL,0.39 mmol). The resultant mixture was stirred at 80 °C for 12 hours. The mixture was concentrated to dryness under reduced pressure to give yellow oil. The yellow oil was purified by Prep-HPLC with the following conditions: column, Welch Xtimate C18, 150 mm, 25 mm x 5 ^m; mobile phase, 62% to 92% (v/v) CH3CN and H2O with (0.25% FA) and then freeze dried to afford (S)-5-(4-(3-(2-(3-(but-3-yn-1-yl)-3H-diazirin-3- yl)ethoxy)benzyl)phenyl)-N-(4-methoxy-3-methylphenyl)-6-methyl-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide as a white solid (67.8 mg, 21% yield).1H NMR (400 MHz, DMSO-d₆) δ: 12.29 (s, 1H), 8.17 (s, 1H), 8.03 (d, J = 2.4 Hz, 1H), 7.71 – 7.69 (m, 1H), 7.40 (s, 4H), 7.25 – 7.18 (m, 2H), 6.91 – 6.86 (m, 2H), 6.78 – 6.76 (m, 1H), 4.91 – 4.86 (m, 1H), 4.51 – 4.42 (m, 2H), 3.96 (s, 2H), 3.87 (s, 3H), 3.80 (t, J = 6.0 Hz, 2H), 2.85 – 2.80 (m, 1H), 2.05 – 2.01 (m, 2H), 1.86 (t, J = 6.0 Hz, 2H), 1.65 (t, J = 7.2 Hz, 2H), 1.20 – 1.18 (m, 3H). Mass spectrum (ESI, m/z): calcd. For C₃₆H₃₃N₇O₄627.3; found [M+H]+ , 628.3. Example 189: (S)-N-(3-cyano-4-methoxyphenyl)-5-(4-(1,1-difluoroethyl)phenyl)-6-methyl- 4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

The title compound was prepared in a manner analogous to Example 122, reacting (S)-N-(3- cyano-4-methoxyphenyl)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3- carboxamide (Intermediate 7, 100.0 mg, 0.34 mmol) and 1-bromo-4-(1,1-difluoroethyl)benzene (135.9 mg, 0.62 mmol).1H NMR (400 MHz, DMSO-d₆) δ: 12.20 (s, 1H), 8.19 (s, 1H), 8.03 (d, J = 2.4 Hz, 1H), 7.76 – 7.69 (m, 3H), 7.67 – 7.63 (m, 2H), 7.23 (d, J = 9.2 Hz, 1H), 4.98 – 4.88 (m, 1H), 4.57 – 4.46 (m, 2H), 3.88 (s, 3H), 2.03 (t, J = 19.0 Hz, 3H), 1.22 (d, J = 6.4 Hz, 3H). Mass spectrum (ESI, m/z): calcd. For C₂₄H₂₁F₂N₅O₃465.2; found [M+H]+, 466.2. Example 190: (S)-N-(3-cyano-4-methoxyphenyl)-6-methyl-4-oxo-5-(4-(3,3,3- trifluoropropyl)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

The title compound was prepared in a manner analogous to Example 122, reacting (S)-N-(3- cyano-4-methoxyphenyl)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3- carboxamide (Intermediate 7, 100.0 mg, 0.307 mmol) and 1-bromo-4-(3,3,3- trifluoropropyl)benzene (93 mg, 0.37 mmol).1H NMR (400 MHz, DMSO-d₆) δ: 12.30 (s, 1H), 8.17 (s, 1H), 8.01 (d, J = 2.8 Hz, 1H), 7.70 (dd, J = 2.8, 9.2 Hz, 1H), 7.45 (s, 4H), 7.23 (d, J = 9.2 Hz, 1H), 4.90 (dd, J = 4.4, 13.2 Hz, 1H), 4.54 – 4.41 (m, 2H), 3.88 (s, 3H), 2.93 – 2.86 (m, 2H), 2.74 – 2.60 (m, 2H), 1.20 (d, J = 6.4 Hz, 3H). Mass spectrum (ESI, m/z): calcd. For C H F N O 497.2; fou + 25 22 3 5 3 nd [M+H] , 498.2. Example 191: (S)-N-(3-cyanophenyl)-6-methyl-4-oxo-5-(4-(2-((2,2,2- trifluoroethyl)amino)ethyl)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3- carboxamide.

Step A: N-(4-bromophenethyl)-2,2,2-trifluoroethan-1-amine. 2,2,2-Trifluoroethyl trifluoromethanesulfonate (500 mg, 2.15 mmol), a stirring bar, 2-(4- bromophenyl)ethanamine (862 mg, 4.31 mmol) and xylene (10 mL) were added to an oven-dried and nitrogen-purged 50 mL round-bottomed and stirred at 130 °C for overnight. The reaction mixture was poured into H₂O (20 mL) and extracted with EtOAc (15 mL x 3). The combined extracts washed with brine (40 mL), dried over anhydrous Na2SO4, filtered and concentrated concentrated to dryness under reduced pressure to give brown oil. The oil was then subjected to silica gel chromatography (0-6% EtOAc/pet ether) to give N-(4- bromophenethyl)-2,2,2-trifluoroethan-1-amine as brown oil (480 mg, 75% yield).1H NMR (400 MHz, CDCl₃) δ: 7.42 (d, J = 8.4 Hz, 2H), 7.08 (d, J = 8.4 Hz, 2H), 3.18 (q, J = 9.2 Hz, 2H), 2.98 (t, J = 7.2 Hz, 2H), 2.81 – 2.71 (m, 2H). Mass spectrum (ESI, m/z): calcd. For C H BrF N 281.0; found [M+H + 10 11 3 ] , 282.0. Step B: (S)-N-(3-cyanophenyl)-6-methyl-4-oxo-5-(4-(2-((2,2,2- trifluoroethyl)amino)ethyl)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide. The title compound was prepared in a manner analogous to Example 122, reacting (S)-N-(3- cyanophenyl)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide (Intermediate 6, 130 mg, 0.440 mmol) and N-(4-bromophenethyl)-2,2,2-trifluoroethan-1-amine (149 mg, 0.528 mmol).1H NMR (400 MHz, DMSO-d₆) δ: 12.54 (s, 1H), 8.20 (s, 1H), 8.16 (s, 1H), 7.74 – 7.68 (m, 1H), 7.56 – 7.49 (m, 2H), 7.44 – 7.34 (m, 4H), 4.92 – 4.90 (m, 1H), 4.54 – 4.41 (m, 2H), 3.32 – 3.23 (m, 2H), 2.88 (q, J = 6.4 Hz, 2H),2.82 – 2.74 (m, 2H), 2.48 – 2.38 (m, 1H), 1.20 (d, J = 6.4 Hz, 3H) . Mass spectrum (ESI, m/z): calcd. For C25H23F3N6O2496.2; found [M+H]+, 497.2. Example 192: (S)- (3-cyano-4-methoxyphenyl)-6-methyl-4-oxo-5-(4-(2-((2,2,2-

trifluoroethyl)amino)ethyl)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3- carboxamide.

The title compound was prepared in a manner analogous to Example 122, reacting (S)-N-(3- cyano-4-methoxyphenyl)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3- carboxamide (Intermediate 7, 100 mg, 0.307 mmol) and N-(4-bromophenethyl)-2,2,2- trifluoroethan-1-amine (104 mg, 0.369 mmol).1H NMR (400 MHz, DMSO-d6) δ: 12.32 (s, 1H), 8.18 (s, 1H), 8.03 (d, J = 2.4 Hz, 1H), 7.72 – 7.71 (m, 1H), 7.43 – 7.34 (m, 4H), 7.23 (d, J = 9.2 Hz, 1H), 4.91 – 4.90 (m, 1H), 4.53 – 4.39 (m, 2H), 3.88 (s, 3H), 3.31 – 3.22 (m,H), 2.92 – 2.83 (m, 2H), 2.79 – 2.74 (m, 2H), 2.45 – 2.39 (m, 1H), 1.20 (d, J = 6.4 Hz, 3H). Mass spectrum (ESI, m/z): calcd. For C₂₆H₂₅F₃N₆O₃526.2; found [M+H]+, 527.2. Example 193: (S)-5-(4-(4-(2-(3-(but-3-yn-1-yl)-3H-diazirin-3-yl)ethoxy)benzyl)phenyl)-N- (3-cyano-4-methoxyphenyl)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3- carboxamide.

Step A: 4-((4-bromophenyl)(hydroxy)methyl)phenol. The title compound was prepared in a manner analogous to Example 188, Step A above, reacting (4-bromophenyl)(4-hydroxyphenyl)methanone (Example 183, product from Step A, 3.50 g, 12.6 mmol) and NaBH (1.91 g, 5 1 4 0.5 mmol). H NMR (400 MHz, DMSO-d6) ^ ^ ^ 9.29 (s, 1H), 7.47 (d, J = 8.4 Hz, 2H), 7.28 (d, J = 8.4 Hz, 2H), 7.11 (d, J = 8.4 Hz, 2H), 6.68 (d, J = 8.4 Hz, 2H), 5.79 (d, J = 4.0 Hz, 1H), 5.57 (d, J = 4.0 Hz, 1H). Step B: 4-(4-bromobenzyl)phenol. The title compound was prepared in a manner analogous to Example 188, Step B above, reacting 4-((4-bromophenyl)(hydroxy)methyl)phenol (3.10 g, 11.1 mmol), TFA (1.24 mL, 16.7 mmol) and Et SiH (2.65 1 3 mL, 16.7 mmol). H NMR (400 MHz, CDCl3) ^ ^ ^ 7.43 – 7.38 (m, 2H), 7.07 – 7.01 (m, 4H), 6.79 – 6.75 (m, 2H), 3.87 (s, 2H). Step C: (S)-N-(3-cyano-4-methoxyphenyl)-5-(4-(4-hydroxybenzyl)phenyl)-6-methyl-4-oxo- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

The title compound was prepared in a manner analogous to Example 122, reacting (S)-N-(3- cyano-4-methoxyphenyl)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3- carboxamide (Intermediate 7, 600 mg, 1.84 mmol) and 4-(4-bromobenzyl)phenol (776 mg, 2.95 mmol).1H NMR (400 MHz, DMSO-d₆) ^ ^ ^ 12.31 – 12.28 (m, 1H), 9.24 (s, 1H), 8.17 (s, 1H), 8.03 (d, J = 2.4 Hz, 1H), 7.71 – 7.68 (m, 1H), 7.41 – 7.32 (m, 4H), 7.21 (d, J = 9.2 Hz, 1H), 7.09 (d, J = 8.4 Hz, 2H), 6.70 (d, J = 8.4 Hz, 2H), 4.90 – 4.86 (m, 1H), 4.52 – 4.39 (m, 2H), 3.87 (s, 5H), 1.21 – 1.17 (m, 3H). Mass spectrum (ESI, m/z): calcd. For C H N O 5 + 29 25 5 4 07.2; found [M+H] , 508.0. Step D: (S)-5-(4-(4-(2-(3-(but-3-yn-1-yl)-3H-diazirin-3-yl)ethoxy)benzyl)phenyl)-N-(3-cyano-4- methoxyphenyl)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide. The title compound was prepared in a manner analogous to Example 188, Step D above, reacting (S)-N-(3-cyano-4-methoxyphenyl)-5-(4-(4-hydroxybenzyl)phenyl)-6-methyl-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide (200 mg, 332 μmol) and 2-(3-(but-3-yn-1-yl)- 3H-diazirin-3-yl)ethanol (91.9 mg, 665 μmol).1H NMR (400 MHz, CDCl₃) ^ ^ ^ 12.13 (s, 1H), 8.31 (s, 1H), 7.98 – 7.95 (m, 1H), 7.91 (d, J = 2.4 Hz, 1H), 7.36 – 7.32 (m, 2H), 7.26 – 7.24 (m, 2H), 7.16 (d, J = 8.4 Hz, 2H), 6.90 (d, J = 9.2 Hz, 1H), 6.86 (d, J = 8.4 Hz, 2H), 4.80 – 4.72 (m, 1H), 4.49 – 4.43 (m, 1H), 4.38 – 4.31 (m, 1H), 4.00 (s, 2H), 3.91 (s, 3H), 3.82 (t, J = 6.4 Hz, 2H), 2.10 – 2.06 (m, 2H), 2.01 – 1.98 (m, 1H), 1.90 (t, J = 6.4 Hz, 2H), 1.75 (t, J = 7.6 Hz, 2H), 1.38 (d, J = 6.4 Hz, 3H). Mass spectrum (ESI, m/z): calcd. For C36H33N7O4627.3; found [M+H]+ , 628.3. Example 194: (S)-N-(3-cyanophenyl)-6-methyl-4-oxo-5-(4-((3,3,3- trifluoropropoxy)methyl)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3- carboxamide.

Step A: 1-bromo-4-((3,3,3-trifluoropropoxy)methyl)benzene. The title compound was prepared in a manner analogous to Example 131, Step A above, reacting NaH (360 mg, 12.0 mmol), 3,3,3-trifluoropropan-1-ol (913 mg, 8.00 mmol), and 1-bromo-4- (bromomethyl)benzene (2.00 g, 8.00 mmol).1H NMR (400 MHz, CDCl3) δ: 7.49 (d, J = 8.4 Hz, 2H), 7.22 (d, J = 8.4 Hz, 2H), 4.49 (s, 2H), 3.69 (t, J = 6.4 Hz, 2H), 2.49 – 2.42 (m, 2H) Step B: (S)-N-(3-cyanophenyl)-6-methyl-4-oxo-5-(4-((3,3,3-trifluoropropoxy)methyl)phenyl)- 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide. The title compound was prepared in a manner analogous to Example 122, reacting (S)-N-(3- cyanophenyl)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide (Intermediate 6, 100 mg, 339 μmol) and 1-bromo-4-((3,3,3-trifluoropropoxy)methyl)benzene (115 mg, 406 μmol).1H NMR (400 MHz, DMSO-d6) ^ ^ ^ 12.53 (s, 1H), 8.29 – 8.03 (m, 2H), 7.76 – 7.67 (m, 1H), 7.59 – 7.43 (m, 6H), 4.96 – 4.87 (m, 1H), 4.61 – 4.44 (m, 4H), 3.72 (t, J = 6.1 Hz, 2H), 2.67 – 2.61 (m, 2H), 1.22 (d, J = 6.4 Hz, 3H). Mass spectrum (ESI, m/z): calcd. For C H F N5O3497.2; f + 25 22 3 ound [M+H] , 498.2. Example 195: (S)-N-(3-cyano-4-methoxyphenyl)-6-methyl-4-oxo-5-(4-((3,3,3- trifluoropropoxy)methyl)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3- carboxamide.

The title compound was prepared in a manner analogous to Example 122, reacting (S)-N-(3- cyano-4-methoxyphenyl)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3- carboxamide (Intermediate 7, 100.0 mg, 0.31 mmol) and 1-bromo-4-(1,1-difluoroethyl)benzene (130.5 mg, 0.46 mmol).1H NMR (400 MHz, DMSO-d₆) ^ ^ ^ 12.29 (s, 1H), 8.18 (s, 1H), 8.03 (d, J = 2.8 Hz, 1H), 7.70 (dd, J = 2.8, 9.2 Hz,1H), 7.50 -7.45 (m, 4H), 7.23 (d, J = 9.2 Hz, 1H), 4.95 – 4.86 (m, 1H), 4.57 (s, 2H), 4.53 – 4.45 (m, 2H), 3.88 (s, 3H), 3.71 (t, J = 6.1 Hz, 2H), 2.66 – 2.61 (m, 2H), 1.21 (d, J = 6.4 Hz, 3H). Mass spectrum (ESI, m/z): calcd. For C26H24F3N5O4527.2; found [M+H]+, 528.2. Example 197: (S)-5-(4-benzoylphenyl)-N-(3-cyanophenyl)-6-methyl-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide

The title compound was prepared in a manner analogous to Example 4, reacting (S)-N-(3- cyanophenyl)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide (Intermediate 6, 500 mg, 1.69 mmol) and 4-bromobenzophenone (531 mg, 2.03 mmol), yielding (S)-5-(4-benzoylphenyl)-N-(3-cyanophenyl)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrazine-3-carboxamide (571 mg, 71% yield).1H NMR (400 MHz, DMSO-d₆) ^ ^ ^ 8.23 (s, 1H), 8.21 – 8.16 (m, 1H), 7.94 – 7.87 (m, 2H), 7.84 – 7.67 (m, 6H), 7.65 – 7.50 (m, 4H), 4.95 (dd, J = 13.3, 4.5 Hz, 1H), 4.61 (q, J = 4.9 Hz, 1H), 4.55 (dd, J = 13.2, 3.8 Hz, 1H), 1.28 (d, J = 6.6 Hz, 3H). Mass spectrum (ESI, m/z): Calcd. For C + 28H21N5O3, 475.2, found [M+H] , 476.3. Example 198: N-(2-cyanopyridin-4-yl)-4-oxo-5-(4-(trifluoromethyl)phenyl)-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

The title compound was prepared in a manner analogous to Example 207, reacting 4-oxo-5-(4- (trifluoromethyl)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxylic acid (Intermediate 43, 200 mg, 0.615 mmol), POCl3 (69 μL, 0.74 mmol), and 4-methoxyaniline (81 mg, 0.68 mmol).1H NMR (400 MHz, DMSO-d₆) ^ ^ ^ 12.64 (s, 1H), 8.59 (d, J = 5.6 Hz, 1H), 8.25 (s, 1H), 8.20 (d, J = 2.0 Hz, 1H), 7.91 (d, J = 8.8 Hz, 2H), 7.79 – 7.73 (m, 3H), 4.71 (m, 2H), 4.36 (t, J = 6.0 Hz, 2H). Mass spectrum (ESI, m/z): calcd. For C20H13F3N6O2426.1; found [M+H]+, 427.1. Example 199: 5-(4-benzylphenyl)-N-(2-cyanopyridin-4-yl)-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

Isopropylmagnesium chloride lithium chloride (0.287 mL, 1.3 M, 0.373 mmol), a stirring bar was added to a suspension of 4-aminopicolinonitrile (23.8 mg, 0.200 mmol) in THF (3 ml) under nitrogen and the reaction mixture was stirred at room temperature for 1 h. A solution of the ethyl 5-(4-benzylphenyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxylate (Intermediate 5, 50 mg, 0.133 mmol) in THF (1 ml) was added to the above solution and the mixture was stirred at 70 °C for 1 h. Then the reaction was cooled to room temperature, quenched with sat. aq. NaHCO₃ (10 mL), extracted with DCM (10 mL x 3). The combined extract was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure to give brown oil. The brown oil was then subjected to silica gel chromatography (0-100% EtOAc/PE) to give 5-(4-benzylphenyl)-N-(2-cyanopyridin-4-yl)-4- oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide (crude). The crude product was further purified by SFC (Phenomenex column, 3 µm, 75 x 30 mm; 50-80% (v/v) EtOH (containing 0.1% of 25% aq. NH₃)/CO₂) and then freeze-dried to afford 5-(4-benzylphenyl)-N- (2-cyanopyridin-4-yl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide as a white solid (6.6 mg, 11% yield).1H NMR (400 MHz, DMSO-d6) δ: 12.86 (s, 1H), 8.56 (d, J = 5.6 Hz, 1H), 8.25 – 8.16 (m, 2H), 7.74 – 7.72 (m, 1H), 7.45 – 7.40 (m, 2H), 7.40 – 7.35 (m, 2H), 7.35 – 7.27 (m, 4H), 7.22 – 7.21(m, 1H), 4.66 (t, J = 6.0 Hz, 2H), 4.25 (t, J = 6.0 Hz, 2H), 3.99 (s, 2H). Mass spectrum (ESI, m/z): calcd. For C + 26H20N6O2448.2; found [M+H] , 449.2. Example 200: 5-(4-benzylphenyl)-N-(2-cyanopyridin-4-yl)-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

The title compound was prepared in a manner analogous to Example 207, reacting (S)-5-(4- benzylphenyl)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxylic acid (Intermediate 47, 250.0 mg, 0.692 mmol), POCl₃ (0.0970 mL, 1.04 mmol), and 4- aminopicolinonitrile (90.6 mg, 0.761 mmol).1H NMR (400 MHz, CDCl3) ^ ^ ^ 12.70 (s, 1H), 8.51 (d, J = 5.6 Hz, 1H), 8.31 (s, 1H), 8.09 (d, J = 2.0 Hz, 1H), 7.84 (dd, J = 2.0, 5.6 Hz, 1H), 7.38 – 7.32 (m, 4H), 7.27 (br s, 2H), 7.24 (s, 3H), 4.78 (dd, J = 4.8, 13.6 Hz, 1H), 4.47 (dd, J = 3.6, 13.6 Hz, 1H), 4.40 – 4.32 (m, 1H), 4.07 (s, 2H), 1.38 (d, J = 6.4 Hz, 3H). Mass spectrum (ESI, m/z): calcd. For C₂₇H₂₂N₆O₂462.2; found [M+H]+, 463.2. Example 201: N-(2-cyanopyridin-4-yl)-5-(4-(difluoro(phenyl)methyl)phenyl)-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide..

Pyridine (0.380 mL, 4.70 mmol) and 5-(4-(difluoro(phenyl)methyl)phenyl)-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxylic acid (Intermediate 3, 300 mg, 0.78 mmol) were added to a solution of 4-aminopyridine-2-carbonitrile (118 mg, 0.94 mmol) in DCM dry (7 mL) at -10 ºC. Then, phosphorus oxychloride (0.219 mL, 2.35 mmol) was added at -10 ºC. The resulting mixture was stirred at -10ºC for 1 hr, then allowed to warm and stirred at room temperature for 16 h. The reaction was quenched with an aq. Sat. sol. Of NaHCO3 and extracted with DCM (x3). The organic layers were combined, dried over MgSO₄ anh., filtered and concentrated in vacuo. The crude product was purified by flash column chromatography (0%- 2%, MeOH-DCM) to yield (234 mg, 51% yield) as a white solid.1H NMR (300 MHz, DMSO- d6) δ: 4.32 (m, 2H) 4.69 (m, 2H) 7.50 – 7.57 (m, 3H) 7.57 – 7.62 (m, 2H) 7.63 – 7.72 (m, 4H) 7.72 – 7.78 (m, 1H) 8.19 – 8.22 (m, 1H) 8.23 – 8.26 (m, 1H) 8.57 (d, J=5.68 Hz, 1H) 12.70 (s, 1H). Mass spectrum (ESI, m/z): calcd. For C₂₆H₁₈F₂N₆O₂, 484.2; found [M+H]+, 485.2. Example 202: (R)-5-(4-benzylphenyl)-N-(2-cyanopyridin-4-yl)-6-methyl-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

The title compound was prepared in a manner analogous to Example 207, reacting ®-5-(4- benzylphenyl)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxylic acid (Intermediate 48, 210 mg, 0.581 mmol), 4-aminopicolinonitrile (76.1 mg, 0.639 mmol), and POCl3 (0.081 mL, 0.87 mmol).1H NMR (400 MHz, CDCl3) ^ ^ ^ 12.70 (s, 1H), 8.51 (d, J = 6.0 Hz, 1H), 8.31 (s, 1H), 8.09 (d, J = 1.6 Hz, 1H), 7.84 (dd, J = 2.0, 5.6 Hz, 1H), 7.39 – 7.32 (m, 4H), 7.27 (br s, 2H), 7.24 (s, 3H), 4.78 (dd, J = 4.4, 13.2 Hz, 1H), 4.47 (dd, J = 3.6, 13.6 Hz, 1H), 4.40 – 4.31 (m, 1H), 4.07 (s, 2H), 1.38 (d, J = 6.4 Hz, 3H). Mass spectrum (ESI, m/z): calcd. For C₂₇H₂₂N₆O₂462.2; found [M+H]+, 463.2. Example 203: (S)-N-(2-cyanopyridin-4-yl)-5-(4-(difluoro(phenyl)methyl)phenyl)-6-methyl- 4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

The title compound was prepared in a manner analogous to Example 207, reacting (S)-5-(4- (difluoro(phenyl)methyl)phenyl)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3- carboxylic acid (Intermediate 1, 220 mg, 0.554 mmol), 4-aminopicolinonitrile (72.5 mg, 0.609 mmol) and POCl3 (0.077 mL, 0.83 mmol).1H NMR (400 MHz, CDCl3) ^ ^ ^ 12.57 (s, 1H), 8.52 (d, J = 5.6 Hz, 1H), 8.33 (s, 1H), 8.09 (d, J = 1.6 Hz, 1H), 7.82 (dd, J = 2.4, 6.0 Hz, 1H), 7.70 (d, J = 8.4 Hz, 2H), 7.59 – 7.55 (m, 2H), 7.50 – 7.46 (m, 3H), 7.41 (d, J = 8.4 Hz, 2H), 4.81 (dd, J = 4.8, 13.6 Hz, 1H), 4.50 (dd, J = 3.2, 13.6 Hz, 1H), 4.45 – 4.37 (m, 1H), 1.40 (d, J = 6.8 Hz, 3H). Mass spectrum (ESI, m/z): calcd. For C₂₇H₂₀F₂N₆O₂498.2; found [M+H]+, 499.2. Example 204: (R)-N-(2-cyanopyridin-4-yl)-5-(4-(difluoro(phenyl)methyl)phenyl)-6-methyl- 4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

The title compound was prepared in a manner analogous to Example 207, reacting ®-5-(4- (difluoro(phenyl)methyl)phenyl)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3- carboxylic acid (Intermediate 48, 195 mg, 0.491 mmol), 4-aminopicolinonitrile (64.3 mg, 0.540 mmol), and POCl3 (0.069 mL, 0.74 mmol).1H NMR (400 MHz, CDCl3) δ: 12.57 (s, 1H), 8.52 (d, J = 5.6 Hz, 1H), 8.33 (s, 1H), 8.09 (d, J = 1.6 Hz, 1H), 7.82 (dd, J = 2.0, 5.6 Hz, 1H), 7.70 (d, J = 8.4 Hz, 2H), 7.59 – 7.55 (m, 2H), 7.50 – 7.46 (m, 3H), 7.41 (d, J = 8.8 Hz, 2H), 4.81 (dd, J = 4.6, 13.6 Hz, 1H), 4.50 (dd, J = 3.2, 13.2 Hz, 1H), 4.45 – 4.37 (m, 1H), 1.40 (d, J = 6.8 Hz, 3H). Mass spectrum (ESI, m/z): calcd. For C H F N O 49 + 27 20 2 6 2 8.2; found [M+H] , 499.2. Example 206: (S)-N-(2-cyanopyridin-4-yl)-6-methyl-4-oxo-5-(4-(trifluoromethyl)phenyl)- 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

The title compound was prepared in a manner analogous to Example 207, reacting (S)-6-methyl- 4-oxo-5-(4-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxylic acid (Intermediate 49, 200 mg, 0.590 mmol), 4-aminopicolinonitrile (77.2 mg, 0.648 mmol), and POCl3 (0.082 mL, 0.88 mmol).1H NMR (400 MHz, DMSO-d6) δ: 12.63 (s, 1H), 8.58 (d, J = 5.6 Hz, 1H), 8.26 (s, 1H), 8.20 (d, J = 1.6 Hz, 1H), 7.94 (d, J = 8.4 Hz, 2H), 7.79 (d, J = 8.4 Hz, 2H), 7.74 (dd, J = 2.0, 5.6 Hz, 1H), 4.94 (dd, J = 4.4, 13.2 Hz, 1H), 4.64 – 4.51 (m, 2H), 1.24 (d, J = 6.8 Hz, 3H). Mass spectrum (ESI, m/z): calcd. For C₂₁H₁₅F₃N₆O₂440.1; found [M+H]+, 441.1. Example 207: (S)-N-(2-cyanopyridin-4-yl)-6-methyl-4-oxo-5-(4-(trifluoromethoxy)phenyl)- 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

(S)-6-methyl-4-oxo-5-(4-(trifluoromethoxy)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine- 3-carboxylic acid (Intermediate 46, 120 mg, 319 μmol), 4-aminopicolinonitrile (41.8 mg, 351 μmol), a stir bar, and Pyridine (3 mL) were added to a 8 mL sample vial. The resulting mixture was evacuated and refilled with nitrogen (x3) and cooled to 0 °C in an ice water bath, and treated with POCl₃ (44.7 μL, 479 μmol), then the mixture was stirred at rt for 5 h. The reaction mixture was quenched with sat. aq. NaHCO3 (1 mL) and poured into H2O (10 mL), extracted with EtOAc (15 mL x 3). The combined extracts were concentrated to dryness under reduced pressure to give a brown solid. The solid was then subjected to silica-gel chromatography (0 to 60% EtOAc/PE) to give (S)-N-(2-cyanopyridin-4-yl)-6-methyl-4-oxo-5-(4-(trifluoromethoxy)phenyl)-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide as a light-yellow solid (114 mg, 77% yield). 1H NMR (400 MHz, CDCl₃) ^ ^ ^ 12.57 (s, 1H), 8.53 (d, J = 5.6 Hz, 1H), 8.34 (s, 1H), 8.11 (d, J = 2.0 Hz, 1H), 7.83 – 7.81 (m, 1H), 7.44 – 7.39 (m, 4H), 4.84 – 4.78 (m, 1H), 4.53 – 4.49 (m, 1H), 4.45 – 4.38 (m, 1H), 1.42 (d, J = 6.8 Hz, 3H). Mass spectrum (ESI, m/z): calcd. For C + 21H15F3N6O3456.1; found [M+H] , 457.1. Example 208: (S)-N-(2-cyanopyridin-4-yl)-6-methyl-4-oxo-5-(4-((2,2,2- trifluoroethoxy)methyl)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

Step A: ethyl (S)-6-methyl-4-oxo-5-(4-((2,2,2-trifluoroethoxy)methyl)phenyl)-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxylate. The title compound was prepared in a manner analogous to Example 122, reacting 1-Bromo-4- ((2,2,2-trifluoroethoxy)methyl)benzene (160 mg, 0.60 mmol) and (S)-ethyl 6-methyl-4-oxo- 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxylate (Intermediate 1, product from Step D, 124 mg, 0.60 mmol). Mass spectrum (ESI, m/z): calcd. For C₁₉H₂₀F₃N₃O₄411.1; found [M+H]+, 412.0. Step B: (S)-6-methyl-4-oxo-5-(4-((2,2,2-trifluoroethoxy)methyl)phenyl)-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxylic acid. The title compound was prepared in a manner analogous to Intermediate 1, Step F, reacting (S)- ethyl 6-methyl-4-oxo-5-(4-((2,2,2-trifluoroethoxy)methyl)phenyl)-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxylate(0.1 g, 0.24 mmol) and NaOH (15 mg, 0.37 mmol). Mass spectrum (ESI, m/z): calcd. For C + 17H16F3N3O4383.1; found [M+H] , 384.0. Step C: (S)-N-(2-cyanopyridin-4-yl)-6-methyl-4-oxo-5-(4-((2,2,2- trifluoroethoxy)methyl)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide. The title compound was prepared in a manner analogous to Example 207, reacting (S)-6-methyl- 4-oxo-5-(4-((2,2,2-trifluoroethoxy)methyl)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3- carboxylic acid (70 mg, 0.183 mmol), 4-aminopicolinonitrile (26 mg, 0.22 mmol), and POCl3 (25 uL, 0.27 mmol) 1H NMR (400 MHz, DMSO-d6) δ: 12.84 (s, 1H), 8.58 (d, J = 5.6 Hz, 1H), 8.26 (s, 1H), 8.20 (d, J = 2.0 Hz, 1H), 7.73 (dd, J = 2.0, 5.6 Hz, 1H), 7.57 – 7.49 (m, 4H), 4.99 – 4.88 (m, 1H), 4.73 (s, 2H), 4.58 – 4.45 (m, 2H), 4.20 – 4.15 (m, 2H), 1.22 (br d, J = 6.4 Hz, 3H). Mass spectrum (ESI, m/z): calcd. For C + 23H19F3N6O3484.1; found [M+H] , 485.1. Example 209: N-(5-(4-benzylphenyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)- 3-cyanobenzamide.

HATU (76.05 mg, 0.20 mmol) and DIPEA (69 µL, 0.4 mmol) were added to a suspension of 3- cyanobenzoic acid (28.8 mg, 0.20 mmol) in DCM (1 mL). Then, the reaction mixture was stirred at rt for 5 min. Subsequently, 3-amino-5-(4-benzylphenyl)-6,7-dihydropyrazolo[1,5-a]pyrazin- 4(5H)-one (Intermediate 11, 25 mg, 0.08 mmol) in DCM (1 mL) was added. The reaction mixture was stirred at rt for 2 h. Once the reaction was completed, the mixture was diluted with sat. aq. Na₂CO₃ and stirred at rt for 5 min and then extracted with DCM. The organic layer was separated using a phase separator cartridge and concentrated in vacuo. Finally, the crude product was redissolved in DMSO (4 mL) and purified by Prep-HPLC (Stationary phase: C18 Xbridge, column with 100 mm length, 5 µm. Mobile phase: Gradient using NH₄HCO₃0.25% solution in water and CH₃CN) to afford N-(5-(4-benzylphenyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrazin-3-yl)-3-cyanobenzamide (7.1 mg, 20% yield).1H NMR (500 MHz, DMSO-d6) δ: 9.98 (s, 1H) 8.29 (t, J = 1.4 Hz, 1H) 8.16 (dt, J = 8.0, 1.4 Hz, 1H) 8.12 (s, 1H) 8.08 (dt, J = 7.8, 1.3 Hz, 1H) 7.76 (t, J = 7.9 Hz, 1H) 7.34 – 7.38 (m, 2H) 7.28 – 7.33 (m, 4H) 7.24 – 7.27 (m, 2H) 7.18 – 7.22 (m, 1H) 4.49 – 4.59 (m, 2H) 4.22 (dd, J = 6.7, 5.2 Hz, 2H) 3.97 (s, 2H). Mass spectrum (ESI, m/z): calcd. For C + 27H21N5O2, 447.2; found [M+H] , 448.2. Example 210: (S)-4-amino-3-cyano-N-(5-(4-(difluoro(phenyl)methyl)phenyl)-6-methyl-4- oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)benzamide.

The title compound was prepared in a manner analogous to Example 55, reacting (S)-3-amino-5- (4-(difluoro(phenyl)methyl)phenyl)-6-methyl-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (Intermediate 12, 200 mg, 0.54 mmol) and 4-amino-3-cyanobenzoic acid (120.15 mg, 0.74 mmol).1H-NMR (400 MHz, CDCl₃) δ: 9.55 (s, 1H), 8.42 (s, 1H), 8.01 (d, J = 1.6 Hz, 1H), 7.84 (dd, J = 1.6, 8.4 Hz, 1H), 7.64 (d, J = 8.4 Hz, 2H), 7.56 – 7.50 (m, 2H), 7.48 – 7.38 (m, 5H), 6.73 (d, J = 8.8 Hz, 1H), 4.82 (s, 2H), 4.64 (dd, J = 4.0, 12.8 Hz, 1H), 4.43 – 4.31 (m, 2H), 1.39 (d, J = 6.4 Hz, 3H). Mass spectrum (ESI, m/z): Calcd. For C₂₈H₂₂F₂N₆O₂, 512.2, found [M+H]+, 513.2. Example 211: (S)-3-cyano-N-(5-(4-(difluoro(phenyl)methyl)phenyl)-6-methyl-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazin-3-yl)-4-hydroxybenzamide.

The title compound was prepared in a manner analogous to Example 55, reacting (S)-3-amino-5- (4-(difluoro(phenyl)methyl)phenyl)-6-methyl-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (Intermediate 12, 4 g, 10.86 mmol) and 3-cyano-4-hydroxybenzoic acid (2.9 g, 17.78 mmol).1H- NMR (400 MHz, Methanol-d4) δ: 8.23 (s, 1H), 8.07 (d, J = 2.0 Hz, 1H), 7.94 – 7.89 (m, 1H), 7.67 – 7.61 (m, 2H), 7.59 – 7.53 (m, 4H), 7.50 – 7.45 (m, 3H), 6.96 (br d, J = 8.8 Hz, 1H), 4.69 (dd, J = 4.8, 13.2 Hz, 1H), 4.57 – 4.49 (m, 1H), 4.37 (dd, J = 3.2, 13.2 Hz, 1H), 1.32 (d, J = 6.8 Hz, 3H). Mass spectrum (ESI, m/z): Calcd. For C H F + 28 21 2N5O3, 513.2, found [M+H] , 514.2. Example 212: N-(5-(4-benzylphenyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)- 3-cyano-4-fluorobenzamide.

The title compound was prepared in a manner analogous to Example 209, reacting 3-amino-5-(4- benzylphenyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (Intermediate 11, 35 mg, 0.11 mmol) and 3-cyano-4-fluoro-benzoic acid (21.7 mg, 0.13 mmol).1H NMR (500 MHz, DMSO- d₆) δ: 9.97 (s, 1H) 8.41 (dd, J = 6.1, 2.3 Hz, 1H) 8.24 (ddd, J = 8.8, 5.2, 2.3 Hz, 1H) 8.10 (s, 1H) 7.69 (t, J = 9.0 Hz, 1H) 7.34 - 7.38 (m, 2H) 7.28 - 7.33 (m, 4H) 7.24 - 7.27 (m, 2H) 7.19 (s, 1H) 4.52 (dd, J = 6.9, 5.0 Hz, 2H) 4.22 (dd, J = 6.7, 5.2 Hz, 2H) 3.97 (s, 2H). Mass spectrum (ESI, m/z): calcd. for C₂₇H₂₀FN₅O₂, 465.2; found [M+H]+, 466.3. Example 213: N-(5-(4-benzylphenyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)- 3-cyano-4-methoxybenzamide.

HATU (76.0 mg, 0.2 mmol) and DIPEA (0.07 mL, 0.4 mmol) were added to a suspension of 3- cyano-4-methoxybenzoic acid (34.7 mg, 0.20 mmol) in DCM (1 mL). Then, the reaction mixture was stirred at rt for 5 min. Subsequently, 3-amino-5-(4-benzylphenyl)-6,7-dihydropyrazolo[1,5- a]pyrazin-4(5H)-one (Intermediate 11, 25 mg, 0.08 mmol) dissolved in DCM (1 mL) was added. The reaction mixture was stirred at rt for 2 h. Once the reaction was completed, the mixture was treated with sat. aq. Na₂CO₃ (250 µL) and stirred at rt for 5 minutes. The organic layer was separated and concentrated in vacuo. The crude product was redissolved in DMSO (4 mL) and purified by Prep-HPLC (Stationary phase: C18 XBridge, column with 100 mm length, 5 µm. Mobile phase: Gradient using NH₄HCO₃0.25% solution in Water and CH₃CN), to afford N-(5- (4-benzylphenyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)-3-cyano-4- methoxybenzamide (7.4 mg, 20% yield) after freeze-drying.1H NMR (500 MHz, DMSO-d6) δ: 9.85 (s, 1H) 8.21 (d, J = 2.3 Hz, 1H) 8.15 (dd, J = 8.9, 2.4 Hz, 1H) 8.10 (s, 1H) 7.40 (d, J = 9.0 Hz, 1H) 7.35 - 7.38 (m, 2H) 7.28 - 7.33 (m, 4H) 7.24 - 7.27 (m, 2H) 7.18 - 7.22 (m, 1H) 4.42 - 4.58 (m, 2H) 4.12 - 4.33 (m, 2H) 3.99 (s, 3H) 3.97 (s, 2H). Mass spectrum (ESI, m/z): calcd. for C H N O , 477.2; found [M + 30 27 5 3 +H] , 478.3. Example 214: 3-cyano-N-(5-(4-(difluoro(phenyl)methyl)phenyl)-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazin-3-yl)-4-methoxybenzamide

Step A: tert-butyl (5-(4-(difluoro(phenyl)methyl)phenyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrazin-3-yl)carbamate. A mixture of 5-(4-(difluoro(phenyl)methyl)phenyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrazine-3-carboxylic acid (Intermediate 3, 483 mg, 1.3 mmol), DPPA (543 µL, 2.5 mmol), TEA (446 µL, 2.5 mmol) and tert-butanol anhydrous (5 mL) was stirred under nitrogen at 80ºC for 16 h. The reaction progress was monitored by LC-MS. Sat. aq. NaHCO₃ was added dropwise to the mixture and the aqueous phase was extracted with EtOAc. The organic layers were joined, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (0-100% heptane/EtOAc) to afford tert-butyl (5-(4- (difluoro(phenyl)methyl)phenyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)carbamate (162 mg, 86% pure, 24% yield).1H NMR (400 MHz, DMSO-d6) δ: 1.46 (s, 9H) 4.20 - 4.26 (m, 2H) 4.43 - 4.49 (m, 2H) 7.50 - 7.53 (m, 3H) 7.53 - 7.57 (m, 1H) 7.57 - 7.62 (m, 2H) 7.82 (br s, 1H) 8.02 (br s, 1H). Mass spectrum (ESI, m/z): calcd. for C + 24H24F2N4O3, 454.2; found [M+H] , 455.1. Step B: 3-amino-5-(4-(difluoro(phenyl)methyl)phenyl)-6,7-dihydropyrazolo[1,5-a]pyrazin- 4(5H)-one. HCl in dioxane (1.3 mL, 4 M, 5.3 mmol) was added to a solution of tert-butyl (5-(4- (difluoro(phenyl)methyl)phenyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)carbamate (162 mg, 0.36 mmol) in DCM (14.5 mL) and the mixture was stirred at rt for 16 h. Then, the solvent was evaporated in vacuo. The residue was purified by silica gel chromatography (0-10% DCM/MeOH) to afford 3-amino-5-(4-(difluoro(phenyl)methyl)phenyl)-6,7-dihydropyrazolo[1,5- a]pyrazin-4(5H)-one (70 mg, 52% yield) as a yellowish solid.1H NMR (300 MHz, DMSO-d₆) δ: 7.59 – 7.48 (m, 10H), 7.16 (s, 2H), 4.34 (d, J = 5.8 Hz, 2H), 4.20 – 4.13 (m, 2H). Mass spectrum (ESI, m/z): calcd. for C₁₉H₁₆F₂N₄O, 354.1; found [M+H]+, 355.3. Step C: 3-cyano-N-(5-(4-(difluoro(phenyl)methyl)phenyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrazin-3-yl)-4-methoxybenzamide. Pyridine (83 µL, 1.0 mmol) and 3-cyano-4-methoxybenzoic acid (36 mg, 0.2 mmol) were added to a solution of 3-amino-5-(4-(difluoro(phenyl)methyl)phenyl)-6,7-dihydropyrazolo[1,5- a]pyrazin-4(5H)-one (60 mg, 0.17 mmol) in DCM dry (6 mL) at -10°C. Then, phosphorus (V) oxychloride (71 µL, 0.76 mmol) was added and the resulting mixture was stirred at -10°C for 1 h. Then, the mixture was stirred at rt for 18 h. The reaction progress was monitored by LC-MS. Sat. aq. NaHCO₃ was added dropwise to the mixture and it was extracted with DCM. The organic layers were combined, dried over MgSO₄, filtered and evaporated in vacuo. The crude product was purified by silica gel chromatography (0-100% heptane/EtOAc) to afford impure product that was then purified by silica gel chromatography (0-10% DCM/MeOH) to afford impure product that was then purified by reverse phase chromatography with the following conditions: column, Brand Phenomenex type Gemini; I.D. (mm) 100 x 30; particle size 5 µm (C18) 110A; mobile phase, 30%-73% 25 mM NH4HCO3/CH3CN to afford 3-cyano-N-(5-(4- (difluoro(phenyl)methyl)phenyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)-4- methoxybenzamide (29 mg, 33% yield) as a white solid.1H NMR (400 MHz, DMSO-d₆) δ: 9.85 (s, 1H), 8.22 (d, J = 2.3 Hz, 1H), 8.16 (dd, J = 8.9, 2.3 Hz, 1H), 8.11 (s, 1H), 7.65 – 7.57 (m, 4H), 7.57 – 7.50 (m, 5H), 7.41 (d, J = 9.0 Hz, 1H), 4.54 (dd, J = 6.7, 4.8 Hz, 2H), 4.29 (dd, J = 6.9, 4.8 Hz, 2H), 4.00 (s, 3H). Mass spectrum (ESI, m/z): calcd. for C28H21F2N5O3, 513.2; found [M+H]+, 514.2. Example 215: (S)-3-cyano-N-(5-(4-(difluoro(phenyl)methyl)phenyl)-6-methyl-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazin-3-yl)-4-methoxybenzamide

Pyridine (0.4 mL, 5.3 mmol) and (S)-3-amino-5-(4-(difluoro(phenyl)methyl)phenyl)-6-methyl- 6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (Intermediate 12, 323 mg, 0.9 mmol) were added to a solution of 3-cyano-4-methoxybenzoic acid (171 mg, 0.2 mmol) in DCM dry (12 mL) at - 10ºC. Then, phosphorus (V) oxychloride (250 µL, 2.6 mmol) was added and the mixture was stirred at -10ºC for 1 h. Then, the mixture was stirred at rt for 3 days. Then, more pyridine (0.2 mL, 2.6 mmol) and phosphorus (V) oxychloride (0.1 mL, 1.3 mmol) were added at -10ºC and the mixture was stirred at rt for 16 h. Then, more pyridine (0.2 mL, 2.6 mmol) and phosphorus (V) oxychloride (0.1 mL, 1.3 mmol) were added at -10ºC and the mixture was stirred at rt for 16 h. The reaction progress was monitored by LC-MS. The reaction was quenched with HCl 1M and the aqueous phase was extracted with DCM. The organic layers were joined, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (0- 100% heptane/EtOAc) to afford impure product (210 mg), that was then purified by reverse phase chromatography with the following conditions: column, Brand Phenomenex type Gemini; I.D. (mm) 100 x 30; particle size 5 µm (C18) 110A; mobile phase, 41%-83% 25mM NH4HCO3/CH3CN. The desired fractions were joined and extracted with DCM. The organic layer was dried over MgSO₄, filtered and the solvent removed in vacuo. Then, the resulting solid was triturated with DIPE to afford (S)-3-cyano-N-(5-(4-(difluoro(phenyl)methyl)phenyl)-6- methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)-4-methoxybenzamide (175 mg, 37% yield) as a white solid.1H NMR (400 MHz, DMSO-d₆) δ: 9.83 (s, 1H), 8.22 (d, J = 2.2 Hz, 1H), 8.16 (dd, J = 8.9, 2.3 Hz, 1H), 8.12 (s, 1H), 7.67 – 7.48 (m, 9H), 7.40 (d, J = 9.0 Hz, 1H), 4.74 (dd, J = 13.0, 4.3 Hz, 1H), 4.60 – 4.49 (m, 1H), 4.38 (dd, J = 13.2, 3.4 Hz, 1H), 4.00 (s, 3H), 1.24 (d, J = 6.6 Hz, 3H). Mass spectrum (ESI, m/z): calcd. for C₂₉H₂₃F₂N₅O₃, 527.2; found [M+H]+, 528.1. Example 216: N-(5-(4-benzylphenyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)- 4-chloro-3-cyanobenzamide.

The title compound was prepared in a manner analogous to Example 209, reacting 3-amino-5-(4- benzylphenyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (Intermediate 11, 25 mg, 0.078 mmol) and 4-chloro-3-cyanobenzoic acid (35.6 mg, 0.20 mmol).1H NMR (500 MHz, DMSO-d₆) δ: 10.02 (s, 1H) 8.41 (d, J=2.1 Hz, 1H) 8.15 (dd, J=8.5, 2.3 Hz, 1H) 8.10 (s, 1H) 7.92 (d, J=8.5 Hz, 1H) 7.33 - 7.38 (m, 2H) 7.28 - 7.33 (m, 4H) 7.24 - 7.27 (m, 2H) 7.17 - 7.22 (m, 1H) 4.52 (br d, J=6.4 Hz, 2H) 4.14 - 4.29 (m, 2H) 3.97 (s, 2H). Mass spectrum (ESI, m/z): calcd. for C H ClN O , 481.1 + 27 20 5 2 ; found [M+H] , 482.1. Example 217: (S)-4-(2-aminoethoxy)-3-cyano-N-(5-(4-(difluoro(phenyl)methyl)phenyl)-6- methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)benzamide.

Step A: tert-butyl (S)-(2-(2-cyano-4-((5-(4-(difluoro(phenyl)methyl)phenyl)-6-methyl-4-oxo- 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)carbamoyl)phenoxy)ethyl)carbamate. The title compound was prepared in a manner analogous to Example 97, reacting (S)-3-cyano-N- (5-(4-(difluoro(phenyl)methyl)phenyl)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrazin-3-yl)-4-hydroxybenzamide (Example 211, 50 mg, 0.097 mmol) and tert-butyl (2- hydroxyethyl)carbamate (18.84 mg, 0.12 mmol). Step B: (S)-4-(2-aminoethoxy)-3-cyano-N-(5-(4-(difluoro(phenyl)methyl)phenyl)-6-methyl-4- oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)benzamide. The title compound was prepared in a manner analogous to Example 9, Step D, reacting tert- butyl (S)-(2-(2-cyano-4-((5-(4-(difluoro(phenyl)methyl)phenyl)-6-methyl-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazin-3-yl)carbamoyl)phenoxy)ethyl)carbamate (164 mg, 0.25 mmol) and HCl in 1,4-dioxane (1 mL, 4 M).1H-NMR (400 MHz, DMSO-d₆) δ: 9.84 (s, 1H), 8.29 - 8.20 (m, 1H), 8.18 - 8.07 (m, 2H), 7.67 - 7.50 (m, 9H), 7.41 (d, J = 8.8 Hz, 1H), 4.74 (dd, J = 4.4, 13.2 Hz, 1H), 4.59 - 4.49 (m, 1H), 4.38 (dd, J = 3.6, 13.2 Hz, 1H), 4.21 (t, J = 6.0 Hz, 2H), 2.99 (t, J = 5.6 Hz, 2H), 1.24 (d, J = 6.8 Hz, 3H). Mass spectrum (ESI, m/z): Calcd. for C₃₀H₂₆F₂N₆O₃, 556.2, found [M+H]+, 557.2. Example 218: (S)-3-cyano-N-(5-(4-(difluoro(phenyl)methyl)phenyl)-6-methyl-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazin-3-yl)-4-(2-hydroxyethoxy)benzamide.

Method 1: (S)-3-cyano-N-(5-(4-(difluoro(phenyl)methyl)phenyl)-6-methyl-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazin-3-yl)-4-(2-hydroxyethoxy)benzamide. 2-Bromoethanol (0.017 mL, 0.20 mmol) was added to a mixture of (S)-3-cyano-N-(5-(4- (difluoro(phenyl)methyl)phenyl)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3- yl)-4-hydroxybenzamide (Example 211, 50 mg, 0.097 mmol) and K2CO3 (40 mg, 0.29 mmol) in DMF (0.5 mL). The mixture was stirred at 50°C for 18 h. The reaction was monitored by LC- MS. The mixture was diluted with water and extracted with DCM. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography (0-7% EtOAc/DCM) to afford impure (S)-3- cyano-N-(5-(4-(difluoro(phenyl)methyl)phenyl)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrazin-3-yl)-4-(2-hydroxyethoxy)benzamide (40 mg). Method 2: (S)-3-cyano-N-(5-(4-(difluoro(phenyl)methyl)phenyl)-6-methyl-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazin-3-yl)-4-(2-hydroxyethoxy)benzamide. Diisopropyl azodicarboxylate (0.029 mL, 0.15 mmol) was added to a mixture of (S)-3-cyano-N- (5-(4-(difluoro(phenyl)methyl)phenyl)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrazin-3-yl)-4-hydroxybenzamide (Example 211, 50 mg, 0.097 mmol), ethane-1,2-diol (0.011 mL, 0.20 mmol) and PPh3 (38.3 mg, 0.15 mmol) in THF (1 mL). The mixture was stirred at 50°C for 18 h. The reaction was monitored by LC-MS. The mixture was diluted with water and extracted with DCM. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography (0-1.5% DCM/MeOH) to afford impure (S)-3-cyano-N-(5-(4-(difluoro(phenyl)methyl)phenyl)- 6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)-4-(2-hydroxyethoxy)benzamide (60 mg). Impure fractions obtained from Method 1 and 2 were mixed and purified by Prep-HPLC with the following conditions: column, Welch Xtimate C18, 5 µm, 150 x 30 mm; mobile phase, 45-75% (v/v) CH₃CN and water with (0.05%NH₃H₂O+10mM NH₄HCO₃). This resulted in pure (S)-3- cyano-N-(5-(4-(difluoro(phenyl)methyl)phenyl)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrazin-3-yl)-4-(2-hydroxyethoxy)benzamide, that was freeze dried to afford a white solid (26.4 mg).1H-NMR (400 MHz, CDCl₃) δ: 9.65 (s, 1H), 8.42 (s, 1H), 8.16 (d, J = 2.4 Hz, 1H), 8.07 (dd, J = 2.4, 8.8 Hz, 1H), 7.65 (d, J = 8.0 Hz, 2H), 7.57 - 7.51 (m, 2H), 7.48 - 7.39 (m, 5H), 7.02 (d, J = 8.8 Hz, 1H), 4.66 (dd, J = 4.4, 13.2 Hz, 1H), 4.45 - 4.33 (m, 2H), 4.25 (t, J = 4.0 Hz, 2H), 4.05 (br s, 2H), 2.24 (br s, 1H), 1.40 (d, J = 6.4 Hz, 3H). Mass spectrum (ESI, m/z): Calcd. for C₃₀H₂₅F₂N₅O₄, 557.2, found [M+H]+, 558.2. Example 219: N-(5-(4-benzylphenyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)- 3-cyano-4-(trifluoromethyl)benzamide.

The title compound was prepared in a manner analogous to Example 209, reacting 3-amino-5-(4- benzylphenyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (Intermediate 11, 25 mg, 0.078 mmol) and 3-cyano-4-(trifluoromethyl)benzoic acid (42.2 mg, 0.20 mmol).1H NMR (500 MHz, DMSO-d6) δ: 10.16 (s, 1H) 8.57 (s, 1H) 8.30 - 8.36 (m, 1H) 8.19 (d, J=8.4 Hz, 1H) 8.12 (s, 1H) 7.34 - 7.38 (m, 2H) 7.27 - 7.33 (m, 4H) 7.23 - 7.26 (m, 2H) 7.17 - 7.22 (m, 1H) 4.53 (br d, J=1.8 Hz, 2H) 4.23 (dd, J=6.7, 5.2 Hz, 2H) 3.97 (s, 2H). Mass spectrum (ESI, m/z): calcd. for C H F3N O , 515.2; f + 28 20 5 2 ound [M+H] , 516.2. Example 220: (S)-3-cyano-N-(5-(4-(difluoro methyl)phenyl)-6-methyl-4-oxo-4,5,6,7-

tetrahydropyrazolo[1,5-a]pyrazin-3-yl)-4-(2-(methylamino)ethoxy)benzamide.

Step A: methyl 4-(2-((tert-butoxycarbonyl)(methyl)amino)ethoxy)-3-cyanobenzoate. The title compound was prepared in a manner analogous to Example 97, reacting methyl 3- cyano-4-hydroxybenzoate (100 mg, 0.56 mmol) and tert-butyl (2- hydroxyethyl)(methyl)carbamate (98.9 mg, 0.56 mmol). Step B: 4-(2-((tert-butoxycarbonyl)(methyl)amino)ethoxy)-3-cyanobenzoic acid. Lithium hydroxide monohydrate (41.4 mg, 0.99 mmol) was added to a mixture of methyl 4-(2- ((tert-butoxycarbonyl)(methyl)amino)ethoxy)-3-cyanobenzoate (220 mg, 0.66 mmol) in THF (3 mL) and water (1.5 mL). The mixture was stirred at rt for 12 h. The reaction was monitored by TLC. The pH of the mixture was adjusted to pH ~ 1 with 2M aq. HCl and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and evaporated in vacuo to afford 4-(2-((tert-butoxycarbonyl)(methyl)amino)ethoxy)-3- cyanobenzoic acid as a white solid (70 mg, 33% yield).1H-NMR (400 MHz, CDCl₃) δ: 8.33 (s, 1H), 8.27 (br d, J = 8.8 Hz, 1H), 7.07 (br d, J = 8.0 Hz, 1H), 4.37 - 4.23 (m, 2H), 3.71 (t, J = 5.2 Hz, 2H), 3.09 (s, 3H), 1.48 (s, 9H). Step C: tert-butyl (S)-(2-(2-cyano-4-((5-(4-(difluoro(phenyl)methyl)phenyl)-6-methyl-4-oxo- 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)carbamoyl)phenoxy)ethyl)(methyl)carbamate. The title compound was prepared in a manner analogous to Example 55, reacting (S)-3-amino-5- (4-(difluoro(phenyl)methyl)phenyl)-6-methyl-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (Intermediate 12, 73 mg, 0.2 mmol) and 4-(2-((tert-butoxycarbonyl)(methyl)amino)ethoxy)-3- cyanobenzoic acid (70 mg, 0.22 mmol). Step D: (S)-3-cyano-N-(5-(4-(difluoro(phenyl)methyl)phenyl)-6-methyl-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazin-3-yl)-4-(2-(methylamino)ethoxy)benzamide. To a solution of tert-butyl (S)-(2-(2-cyano-4-((5-(4-(difluoro(phenyl)methyl)phenyl)-6-methyl-4- oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)carbamoyl)phenoxy)ethyl)(methyl)carbamate (88 mg, 0.13 mmol) in CH₃CN (1 mL) was added HCl in 1,4-dioxane (1 mL, 4 M). The mixture was stirred at rt for 12 h. The reaction was monitored by LC-MS. The mixture was evaporated in vacuo and the crude product was purified by prep-HPLC with the following conditions: column, Boston Green ODS 5 µm, 150 x 30 mm; mobile phase, 25-55% (v/v) CH₃CN and water with 0.225% FA. This resulted in (S)-3-cyano-N-(5-(4-(difluoro(phenyl)methyl)phenyl)-6-methyl-4- oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)-4-(2-(methylamino)ethoxy)benzamide as a white solid (44 mg, 58% yield).1H-NMR (400 MHz, DMSO-d₆) δ: 9.83 (s, 1H), 8.26 - 8.10 (m, 3H), 7.67 - 7.61 (m, 2H), 7.61 - 7.49 (m, 7H), 7.42 (d, J = 9.2 Hz, 1H), 4.74 (dd, J = 4.0, 13.2 Hz, 1H), 4.54 (br d, J = 6.4 Hz, 1H), 4.38 (dd, J = 3.2, 13.2 Hz, 1H), 4.29 (t, J = 5.2 Hz, 2H), 2.94 (t, J=5.6 Hz, 2H), 2.38 (s, 3H), 1.24 (d, J=6.8 Hz, 3H). Mass spectrum (ESI, m/z): Calcd. for C₃₁H₂₈F₂N₆O₃, 570.2, found [M+H]+, 571.2. Example 221: (S)-3-cyano-N-(5-(4-(difluoro(phenyl)methyl)phenyl)-6-methyl-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazin-3-yl)-4-(2-methoxyethoxy)benzamide.

Method 1: (S)-3-cyano-N-(5-(4-(difluoro(phenyl)methyl)phenyl)-6-methyl-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazin-3-yl)-4-(2-methoxyethoxy)benzamide. The title compound was prepared in a manner analogous to Example 218, Method 1, reacting (S)-3-cyano-N-(5-(4-(difluoro(phenyl)methyl)phenyl)-6-methyl-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazin-3-yl)-4-hydroxybenzamide (Example 211, 50 mg, 0.097 mmol) and 1-bromo-2-methoxyethane (0.018 mL, 0.19 mmol). Method 2: (S)-3-cyano-N-(5-(4-(difluoro(phenyl)methyl)phenyl)-6-methyl-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazin-3-yl)-4-(2-methoxyethoxy)benzamide. The title compound was prepared in a manner analogous to Example 218, Method 2, reacting (S)-3-cyano-N-(5-(4-(difluoro(phenyl)methyl)phenyl)-6-methyl-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazin-3-yl)-4-hydroxybenzamide (Example 211, 100 mg, 0.19 mmol) and 2-methoxyethan-1-ol (0.031 mL, 0.39 mmol). Impure fractions obtained from Method 1 and 2 were mixed and purified by silica gel chromatography (0-18% EtOAc/DCM). This resulted in a light yellow product that was suspended in DMSO (1 mL) and MeOH (1 mL) and sonicated for 4 min. The solid was filtered and washed with additional MeOH to afford (S)-3-cyano-N-(5-(4- (difluoro(phenyl)methyl)phenyl)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3- yl)-4-(2-methoxyethoxy)benzamide as a white solid (75 mg, 28% yield).1H-NMR (400 MHz, CDCl3) δ: 9.65 (s, 1H), 8.42 (s, 1H), 8.16 (d, J = 2.4 Hz, 1H), 8.06 (dd, J = 2.0, 8.8 Hz, 1H), 7.65 (d, J = 8.0 Hz, 2H), 7.56 - 7.51 (m, 2H), 7.47 - 7.39 (m, 5H), 7.04 (d, J = 8.8 Hz, 1H), 4.65 (dd, J = 4.4, 12.8 Hz, 1H), 4.45 - 4.33 (m, 2H), 4.31 - 4.26 (m, 2H), 3.85 - 3.80 (m, 2H), 3.47 (s, 3H), 1.40 (d, J = 6.4 Hz, 3H). Mass spectrum (ESI, m/z): Calcd. for C31H27F2N5O4, 571.2, found [M+H]+, 572.2. Example 222: 3-cyano-4-methoxy-N-(4-oxo-5-(4-(trifluoromethyl)phenyl)-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazin-3-yl)benzamide

HATU (114.07 mg, 0.3 mmol) and DIPEA (0.103 mL, 0.6 mmol) were added to a suspension of 3-cyano-4-methoxybenzoic acid (39.86, 0.23 mmol) in DCM (1 mL) and the reaction mixture was stirred at room temperature for 5 min. Then intermediate 52 (44.438 mg, 0.15 mmol) was dissoved in 1 mL of DCM and added to the reaction mixture, which was stirred at room temperature for 2 h. Then, the mixture was treated with a saturated aqueous solution of Na2CO3 (2 mL) and stirred at room temperature for 5 minutes. Then, the product was extracted with DCM (2 mL). The organic layer was separated using a phase separator cartridge, and the extracted organic were evaporated in vacuo. The product was redissolved in DMSO, (4 mL) and purified by Prep-HPLC (Stationary phase: C18 XBridge 30 x 100 mm 5 µm, Mobile phase: Gradient from 70% NH₄HCO₃0.25% solution in Water, 30% CH₃CN to 35% NH₄HCO₃0.25% solution in Water, 65% CH3CN), yielding 3-cyano-4-methoxy-N-(4-oxo-5-(4- (trifluoromethyl)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)benzamide (14.9 mg, yield 21.8% yield) as white solid after lyophilization.1H NMR (500 MHz, DMSO-d₆) δ: 9.86 (s, 1H) 8.23 (d, J=2.3 Hz, 1H) 8.17 (dd, J=8.9, 2.4 Hz, 1H) 8.12 (s, 1H) 7.84 (d, J=8.5 Hz, 2H) 7.70 (d, J=8.4 Hz, 2H) 7.42 (d, J=9.0 Hz, 1H) 4.56 (dd, J=6.8, 5.0 Hz, 2H) 4.34 (dd, J=6.8, 5.0 Hz, 2H) 4.00 (s, 3H). Mass spectrum (ESI, m/z): Calcd. for C₂₂H₁₆F₃N₅O₃, 455.1, found [M+H]+, 456.2. Examples 223-224 were prepared in a manner analogous to Example 222, with the appropriate reagent substitutions.

Example 225: (S)-3-cyano-N-(5-(4-(cyclobutyldifluoromethyl)phenyl)-6-methyl-4-oxo- 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)-4-methoxybenzamide.

The title compound was prepared in a manner analogous to Example 122, reacting (S)-3-cyano- 4-methoxy-N-(6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)benzamide (Intermediate 13, 120 mg, 0.369 mmol) and 1-bromo-4-(cyclobutyldifluoromethyl)benzene (Example 125, product from step D, 241 mg, 0.922 mmol).1H NMR (400 MHz, CDCl₃) δ: 9.66 (s, 1H), 8.43 (s, 1H), 8.16 (d, J = 2.4 Hz, 1H), 8.10 (dd, J = 2.4, 8.8 Hz, 1H), 7.58 (d, J = 8.8 Hz, 2H), 7.40 (d, J = 8.4 Hz, 2H), 7.01 (d, J = 9.2 Hz, 1H), 4.65 (dd, J = 4.4, 13.2 Hz, 1H), 4.44 - 4.33 (m, 2H), 3.99 (s, 3H), 3.07 - 2.91 (m, 1H), 2.31 - 2.17 (m, 2H), 2.06 - 1.97 (m, 2H), 1.96 - 1.82 (m, 2H), 1.40 (d, J = 6.4 Hz, 3H). Mass spectrum (ESI, m/z): calcd. for C₂₇H₂₅F₂N₅O₃ 505.2; found [M+H]+, 506.2. Example 226: (S)-3-cyano-4-methoxy-N-(6-methyl-4-oxo-5-(4-(3,3,3-trifluoropropoxy)- phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)benzamide.

The title compound was prepared in a manner analogous to Example 122, reacting (S)-3-cyano- 4-methoxy-N-(6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)benzamide (Intermediate 13, 150 mg, 0.461 mmol) and 1-bromo-4-(3,3,3-trifluoropropoxy)benzene (149 mg, 0.553 mmol).1H NMR (400 MHz, DMSO-d₆) δ: 9.84 (s, 1H), 8.26 - 8.08 (m, 3H), 7.44 - 7.30 (m, 3H), 7.06 (br d, J = 8.4 Hz, 2H), 4.76 - 4.67 (m, 1H), 4.45 - 4.30 (m, 2H), 4.25 (br t, J = 5.6 Hz, 2H), 3.99 (s, 3H), 2.89 - 2.73 (m, 2H), 1.20 (br d, J = 6.0 Hz, 3H). Mass spectrum (ESI, m/z): calcd. for C H F N O 51 + 25 22 3 5 4 3.2; found [M+H] , 514.2. Example 227: (S)-3-cyano-4-methoxy-N-(6-methyl-4-oxo-5-(4-(2,2,2-trifluoroethoxy)- phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)benzamide.

The title compound was prepared in a manner analogous to Example 122, (S)-3-cyano-4- methoxy-N-(6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)benzamide (Intermediate 13, 150 mg, 0.415 mmol) and 1-bromo-4-(2,2,2-trifluoroethoxy)benzene (127 mg, 0.498 mmol),1H NMR (400 MHz, DMSO-d₆) δ: 9.84 (s, 1H), 8.22 (d, J = 2.4 Hz, 1H), 8.16 (m, 1H), 8.11 (s, 1H), 7.43 - 7.37 (m, 3H), 7.18 - 7.13 (m, 2H), 4.82 (q, J = 8.8 Hz, 2H), 4.72 (dd, J = 4.4, 13.2 Hz, 1H), 4.45 - 4.38 (m, 1H), 4.38 - 4.32 (m, 1H), 3.99 (s, 3H), 1.20 (d, J = 6.4 Hz, 3H). Mass spectrum (ESI, m/z): calcd. for C₂₄H₂₀F₃N₅O₄499.1, found [M+H]+, 500.2. Example 228: (S)-3-cyano-N-(6-methyl-4-oxo-5-(4-(2,2,2-trifluoroethoxy)phenyl)-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazin-3-yl)benzamide.

The title compound was prepared in a manner analogous to Example 122, reacting (S)-3-cyano- N-(6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)benzamide (Intermediate 44, 150 mg, 0.452 mmol) and 1-bromo-4-(2,2,2-trifluoroethoxy)benzene (138 mg, 0.543 mmol).1H NMR (400 MHz, DMSO-d₆) δ: 9.98 (s, 1H), 8.30 (s, 1H), 8.17 (br d, J = 8.0 Hz, 1H), 8.14 (s, 1H), 8.09 (d, J = 7.6 Hz, 1H), 7.77 (t, J = 8.0 Hz, 1H), 7.40 (d, J = 8.8 Hz, 2H), 7.16 (d, J = 9.2 Hz, 2H), 4.82 (q, J = 8.8 Hz, 2H), 4.74 (dd, J = 4.0, 12.8 Hz, 1H), 4.47 - 4.32 (m, 2H), 1.20 (d, J = 6.4 Hz, 3H). Mass spectrum (ESI, m/z): calcd. for C₂₃H₁₈F₃N₅O₃469.1, found [M+H]+, 470.1. Example 229: (S)-3-cyano-N-(6-methyl-4-oxo-5-(4-((2,2,2-trifluoroethoxy)methyl)phenyl)- 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)benzamide.

The title compound was prepared in a manner analogous to Example 122, reacting (S)-3-cyano- N-(6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)benzamide (Intermediate 44, 100 mg, 0.339 mmol) and 1-bromo-4-((2,2,2-trifluoroethoxy)methyl)benzene (137 mg, 0.508 mmol).1H NMR (400 MHz, DMSO-d6) δ: 9.98 (s, 1H), 8.30 (s, 1H), 8.22 - 8.12 (m, 2H), 8.09 (d, J = 8.0 Hz, 1H), 7.76 (t, J = 7.6 Hz, 1H), 7.45 (s, 4H), 4.75 (dd, J = 4.4, 12.8 Hz, 1H), 4.71 (s, 2H), 4.56 - 4.44 (m, 1H), 4.38 (dd, J = 3.6, 13.2 Hz, 1H), 4.14 (q, J = 9.6 Hz, 2H), 1.23 (d, J = 6.4 Hz, 3H). Mass spectrum (ESI, m/z): calcd. for C₂₄H₂₀F₃N₅O₃483.2; found [M+H]+, 484.2. Example 230: (S)-3-cyano-4-methoxy-N-(6-methyl-4-oxo-5-(4-((2,2,2-trifluoroethoxy)- methyl)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)benzamide.

The title compound was prepared in a manner analogous to Example 122, reacting (S)-3-cyano- 4-methoxy-N-(6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)benzamide (Intermediate 13, 100 mg, 0.307 mmol) and 1-bromo-4-((2,2,2-trifluoroethoxy)methyl)benzene (124 mg, 0.461 mmol).1H NMR (400 MHz, DMSO-d6) δ: 9.85 (s, 1H), 8.23 (d, J = 2.4 Hz, 1H), 8.16 (dd, J = 2.0, 8.8 Hz, 1H), 8.12 (s, 1H), 7.46 (s, 4H), 7.40 (d, J = 8.8 Hz, 1H), 4.77 - 4.68 (m, 3H), 4.52 - 4.43 (m, 1H), 4.37 (dd, J = 3.6, 13.2 Hz, 1H), 4.14 (q, J = 9.2 Hz, 2H), 3.99 (s, 3H), 1.23 (d, J = 6.4 Hz, 3H). Mass spectrum (ESI, m/z): calcd. for C25H22F3N5O4513.2; found [M+H]+, 514.2. Example 231: (S)-3-cyano-N-(5-(4-(cyclopropylmethyl)phenyl)-6-methyl-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazin-3-yl)-4-methoxybenzamide.

The title compound was prepared in a manner analogous to Example 122, reacting (S)-3-cyano- 4-methoxy-N-(6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)benzamide (Intermediate 13, 100 mg, 0.307 mmol) and 1-bromo-4-(cyclopropylmethyl)benzene (97 mg, 0.46 mmol).1H NMR (400 MHz, DMSO-d₆) δ: 9.85 (s, 1H), 8.22 (d, J = 2.0 Hz, 1H), 8.19 - 8.13 (m, 1H), 8.11 (s, 1H), 7.41 (d, J = 9.2 Hz, 1H), 7.38 - 7.30 (m, 4H), 4.72 (dd, J = 4.0, 12.8 Hz, 1H), 4.49 - 4.40 (m, 1H), 4.36 (dd, J = 4.0, 13.2 Hz, 1H), 3.99 (s, 3H), 2.54 (d, J = 6.8 Hz, 2H), 1.22 (d, J = 6.4 Hz, 3H), 1.05 - 0.94 (m, 1H), 0.54 - 0.44 (m, 2H), 0.26 - 0.17 (m, 2H). Mass spectrum (ESI, m/z): calcd. for C H N O 455. + 26 25 5 3 2; found [M+H] , 456.2. Example 232: (S)-N-(3-cyano-4-methoxyphenyl)-6-methyl-4-oxo-5-(4-(((2,2,2- trifluoroethyl)amino)methyl)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3- carboxamide.

The title compound was prepared in a manner analogous to Example 122, reacting (S)-N-(3- cyano-4-methoxyphenyl)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3- carboxamide (Intermediate 7, 100 mg, 0.307 mmol) and N-(4-bromobenzyl)-2,2,2- trifluoroethanamine (124 mg, 0.46 mmol).1H NMR (400 MHz, DMSO-d6) δ: 9.85 (s, 1H), 8.22 (d, J = 2.0 Hz, 1H), 8.16 (dd, J = 2.0, 8.8 Hz, 1H), 8.12 (s, 1H), 7.51 - 7.33 (m, 5H), 4.73 (dd, J = 4.4, 13.2 Hz, 1H), 4.50 - 4.41 (m, 1H), 4.36 (dd, J = 3.6, 13.2 Hz, 1H), 3.99 (s, 3H), 3.83 (br s, 2H), 3.23 (br d, J = 9.6 Hz, 2H), 2.99 (br s, 1H), 1.22 (d, J = 6.8 Hz, 3H). Mass spectrum (ESI, m/z): calcd. for C H F + 25 23 3N6O3512.2; found [M+H] , 513.2. Example 233: (S)-3-cyano-N-(5-(4-(cyclobutyldifluoromethyl)phenyl)-6-methyl-4-oxo- 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)benzamide.

The title compound was prepared in a manner analogous to Example 122, reacting (S)-3-cyano- N-(6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)benzamide (Intermediate 44, 100 mg, 0.339 mmol) and 1-bromo-4-(cyclobutyldifluoromethyl)benzene (Example 125, product from step D, 221 mg, 0.847 mmol).1H NMR (400 MHz, CDCl₃) δ: 9.77 (s, 1H), 8.45 (s, 1H), 8.23 (s, 1H), 8.11 (d, J = 8.0 Hz, 1H), 7.81 (d, J = 7.6 Hz, 1H), 7.61 - 7.55 (m, 3H), 7.40 (d, J = 8.0 Hz, 2H), 4.66 (dd, J = 4.0, 12.8 Hz, 1H), 4.45 - 4.34 (m, 2H), 3.08 - 2.90 (m, 1H), 2.31 - 2.18 (m, 2H), 2.07 - 1.80 (m, 4H), 1.40 (d, J = 6.4 Hz, 3H). Mass spectrum (ESI, m/z): calcd. for C H F N O 475.2; found [M + 26 23 2 5 2 +H] , 476.2. Example 234: (S)-3-cyano-4-methoxy- (6-methyl-4-oxo-5-(4-((2,2,2-

trifluoroethyl)amino)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)benzamide.

The title compound was prepared in a manner analogous to Example 122, reacting (S)-3-cyano- 4-methoxy-N-(6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)benzamide (Intermediate 13, 100 mg, 0.307 mmol) and 4-bromo-N-(2,2,2-trifluoroethyl)aniline (94 mg, 0.37 mmol).1H NMR (400 MHz, DMSO-d6) δ: 9.85 (s, 1H), 8.22 (d, J = 2.0 Hz, 1H), 8.15 (dd, J = 2.4 Hz, 1H), 8.10 (s, 1H), 7.41 (d, J = 9.2 Hz, 1H), 7.14 (d, J = 8.8 Hz, 2H), 6.79 (d, J = 8.8 Hz, 2H), 6.43 (t, J = 6.8 Hz, 1H), 4.72 - 4.65 (m, 1H), 4.36 - 4.28 (m, 2H), 4.02 - 3.91 (m, 5H), 1.19 (d, J = 6.4 Hz, 3H). Mass spectrum (ESI, m/z): calcd. for C H + 24 21F3N6O3498.2, found [M+H] , 499.2. Example 235: (S)-3-cyano-N-(6-methyl-4-oxo-5-(4-(perfluoroethyl)phenyl)-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazin-3-yl)benzamide.

The title compound was prepared in a manner analogous to Example 122, reacting (S)-3-cyano- N-(6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)benzamide (Intermediate 44, 120 mg, 0.406 mmol) and 1-bromo-4-(perfluoroethyl)benzene (134 mg, 0.488 mmol).1H NMR (400 MHz, DMSO-d₆) δ: 9.98 (s, 1H), 8.31 (s, 1H), 8.21 - 8.12 (m, 2H), 8.09 (d, J = 7.6 Hz, 1H), 7.85 - 7.80 (m, 2H), 7.79 - 7.71 (m, 3H), 4.81 - 4.73 (m, 1H), 4.67 - 4.59 (m, 1H), 4.44 - 4.37 (m, 1H), 1.27 (d, J = 6.4 Hz, 3H). Mass spectrum (ESI, m/z): calcd. for C23H16F5N5O2489.1; found [M+H]+, 490.1. Example 236: (S)-3-cyano-N-(5-(4-(cyclopropylmethyl)phenyl)-6-methyl-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazin-3-yl)benzamide.

The title compound was prepared in a manner analogous to Example 122, reacting (S)-3-cyano- N-(6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)benzamide (Intermediate 44, 100 mg, 0.339 mmol) and 1-bromo-4-(cyclopropylmethyl)benzene (Example 126, product from Step D, 107 mg, 0.508 mmol).1H NMR (400 MHz, CDCl₃) δ: 9.86 (s, 1H), 8.45 (s, 1H), 8.25 (s, 1H), 8.13 (d, J = 8.0 Hz, 1H), 7.81 (d, J = 7.6 Hz, 1H), 7.57 (t, J = 8.0 Hz, 1H), 7.41 (d, J = 8.0 Hz, 2H), 7.27 - 7.23 (m, 2H), 4.70 - 4.62 (m, 1H), 4.42 - 4.32 (m, 2H), 2.61 (d, J = 6.8 Hz, 2H), 1.41 (d, J = 6.4 Hz, 3H), 1.07 - 0.96 (m, 1H), 0.62 - 0.52 (m, 2H), 0.25 (q, J = 5.2 Hz, 2H). Mass spectrum (ESI, m/z): calcd. for C₂₅H₂₃N₅O₂425.2; found [M+H]+, 426.2. Example 237: (S)-3-cyano-N-(6-methyl-4-oxo-5-(4-(((2,2,2-trifluoroethyl)amino)methyl)- phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)benzamide.

The title compound was prepared in a manner analogous to Example 122, reacting (S)-3-cyano- N-(6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)benzamide (Intermediate 44, 100 mg, 0.339 mmol) and N-(4-bromobenzyl)-2,2,2-trifluoroethanamine (Example 137, product from Step A, 136 mg, 0.508 mmol).1H NMR (400 MHz, DMSO-d₆) δ: 9.98 (s, 1H), 8.30 (s, 1H), 8.21 - 8.12 (m, 2H), 8.09 (d, J = 7.6 Hz, 1H), 7.76 (t, J = 7.6 Hz, 1H), 7.47 - 7.34 (m, 4H), 4.74 (dd, J = 4.0, 12.8 Hz, 1H), 4.50 - 4.42 (m, 1H), 4.37 (dd, J = 3.6, 12.8 Hz, 1H), 3.82 (d, J = 6.8 Hz, 2H), 3.28 - 3.16 (m, 2H), 3.04 - 2.92 (m, 1H), 1.22 (d, J = 6.4 Hz, 3H). Mass spectrum (ESI, m/z): calcd. for C + 24H21F3N6O2482.2; found [M+H] , 483.2. Example 238: (S)-3-cyano-N-(6-methyl-4-oxo-5-(4-(trifluoromethyl)phenyl)-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazin-3-yl)benzamide.

The title compound was prepared in a manner analogous to Example 122, reacting (S)-3-cyano- N-(6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)benzamide (Intermediate 44, 200 mg, 0.68 mmol) and 1-bromo-4-(trifluoromethyl)benzene (113 μL, 0.813 mmol).1H NMR (400 MHz, DMSO-d6) δ: 9.99 (s, 1H), 8.31 (s, 1H), 8.21 - 8.13 (m, 2H), 8.11 - 8.07 (m, 1H), 7.87 (m, 2H), 7.80 - 7.70 (m, 3H), 4.77 (m, 1H), 4.61 (m, 1H), 4.41 (m, 1H), 1.26 (m, 3H), 1.23 - 1.22 (m, 1H). Mass spectrum (ESI, m/z): calcd. for C₂₂H₁₆F₃N₅O₂439.1; found [M+H]+, 440.1. Example 239: -3-cyano-4-methoxy-N-(6-methyl-4-oxo-5-(4-(pentafluoro-l6-

sulfaneyl)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)benzamide.

The title compound was prepared in a manner analogous to Example 122, reacting (S)-3-cyano- 4-methoxy-N-(6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)benzamide (Intermediate 13, 120 mg, 0.369 mmol) and (4-bromophenyl)pentafluoro-l6-sulfane (157 mg, 0.553 mmol).1H NMR (400 MHz, DMSO-d₆) ^ ^ 9.83 (s, 1H), 8.23 (s, 1H), 8.19 - 8.10 (m, 2H), 8.03 (d, J = 8.8 Hz, 2H), 7.73 (br d, J = 8.4 Hz, 2H), 7.40 (d, J = 8.8 Hz, 1H), 4.75 (dd, J = 4.4, 13.2 Hz, 1H), 4.67 - 4.58 (m, 1H),4.40 (m, 1H), 3.99 (s, 3H), 1.26 (d, J = 6.4 Hz, 3H). Mass spectrum (ESI, m/z): calcd. for C₂₂H₁₈F₅N₅O₃S 527.1, found [M+H]+, 528.2. Example 240: (S)-3-cyano-N-(6-methyl-4-oxo-5-(4-((2,2,2-trifluoroethyl)amino)phenyl)- 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)benzamide.

The title compound was prepared in a manner analogous to Example 122, reacting (S)-3-cyano- N-(6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)benzamide (Intermediate 44, 200 mg, 0.677 mmol) and 4-bromo-N-(2,2,2-trifluoroethyl)aniline (206 mg, 0.813 mmol).1H NMR (400 MHz, DMSO-d6) δ: 9.98 (s, 1H), 8.29 (s, 1H), 8.19 - 8.06 (m, 3H), 7.76 (t, J = 7.6 Hz, 1H), 7.14 (d, J = 9.2 Hz, 2H), 6.79 (d, J = 8.8 Hz, 2H), 6.43 (t, J = 6.8 Hz, 1H), 4.73 - 4.66 (m, 1H), 4.37 - 4.29 (m, 2H), 4.01 - 3.91 (m, 2H), 1.19 (d, J = 6.4 Hz, 3H). Mass spectrum (ESI, m/z): calcd. for C₂₃H₁₉F₃N₆O₂468.2, found [M+H]+, 469.1. Example 241: (S)-3-cyano-N-(6-methyl-4-oxo-5-(4-(3,3,3-trifluoropropoxy)phenyl)-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazin-3-yl)benzamide.

The title compound was prepared in a manner analogous to Example 122, reacting (S)-3-cyano- N-(6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)benzamide (Intermediate 44, 120 mg, 0.406 mmol) and 1-bromo-4-(3,3,3-trifluoropropoxy)benzene (131 mg, 0.488 mmol).1H NMR (400 MHz, DMSO-d₆) δ: 9.97 (s, 1H), 8.29 (s, 1H), 8.20 - 8.03 (m, 3H), 7.75 (m, 1H), 7.35 (d, J = 8.4 Hz, 2H), 7.06 (d, J = 8.4 Hz, 2H), 4.72 (d, J = 9.2 Hz, 1H), 4.43 - 4.31 (m, 2H), 4.25 (t, J = 5.6 Hz, 2H), 2.89 - 2.74 (m, 2H), 1.20 (d, J = 5.6 Hz, 3H). Mass spectrum (ESI, m/z): calcd. for C₂₄H₂₀F₃N₅O₃483.2, found [M+H]+, 484.2. Example 242: (S)-3-cyano-N-(6-methyl-4-oxo-5-(4-(2-(trifluoromethoxy)ethyl)phenyl)- 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)benzamide.

The title compound was prepared in a manner analogous to Example 122, reacting (S)-3-cyano- N-(6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)benzamide (Intermediate 44, 100 mg, 0.339 mmol) and 1-bromo-4-(2-(trifluoromethoxy)ethyl)benzene (109 mg, 0.406 mmol).1H NMR (400 MHz, DMSO-d₆) δ: 9.97 (s, 1H), 8.29 (s, 1H), 8.19 - 8.12 (m, 2H), 8.08 (d, J = 7.5 Hz, 1H), 7.75 (t, J = 7.6 Hz, 1H), 7.39 (s, 4H), 4.73 (dd, J = 4.4 Hz, 1H), 4.50 - 4.42 (m, 1H), 4.40 - 4.31 (m, 3H), 3.03 (t, J = 6.4 Hz, 2H), 1.22 (d, J = 6.4 Hz, 3H). Mass spectrum (ESI, m/z): calcd. for C₂₄H₂₀F₃N₅O₃483.2, found [M+H]+, 484.2. Example 243: (S)-3-cyano-N-(5-(4-(difluoro(1-fluorocyclopropyl)methyl)phenyl)-6-methyl- 4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)benzamide.

The title compound was prepared in a manner analogous to Example 122, reacting (S)-3-cyano- N-(6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)benzamide (Intermediate 44, 100 mg, 0.339 mmol) and 1-bromo-4-(difluoro(1-fluorocyclopropyl)methyl)benzene (144 mg, 0.542 mmol).1H NMR (400 MHz, CDCl₃) δ: 9.77 (s, 1H), 8.46 (s, 1H), 8.25 (s, 1H), 8.12 (br d, J = 8.0 Hz, 1H), 7.82 (d, J = 7.6 Hz, 1H), 7.74 (d, J = 8.4 Hz, 2H), 7.58 (t, J = 7.6Hz, 1H), 7.47 (d, J = 8.4 Hz, 2H), 4.68 (dd, J = 4.0, 12.8 Hz, 1H), 4.48 - 4.35 (m, 2H), 1.43 (d, J = 6.8 Hz, 3H), 1.27 - 1.19 (m, 4H). Mass spectrum (ESI, m/z): calcd. for C₂₅H₂₀F₃N₅O₂479.2; found [M+H]+, 480.1. Example 244: (S)-3-cyano-N-(6-methyl-4-oxo-5-(4-(2,2,2-trifluoroethyl)phenyl)-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazin-3-yl)benzamide.

The title compound was prepared in a manner analogous to Example 122, reacting (S)-3-cyano- N-(6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)benzamide (Intermediate 44, 150 mg, 0.508 mmol) and 1-bromo-4-(2,2,2-trifluoroethyl)benzene (146 mg, 0.610 mmol).1H NMR (400 MHz, DMSO-d6) δ: 9.98 (s, 1H), 8.30 (s, 1H), 8.20 - 8.05 (m, 3H), 7.80 - 7.73 (m, J = 8.0, 8.0 Hz, 1H), 7.47 (s, 4H), 4.78 - 4.71 (m, 1H), 4.55 - 4.46 (m, 1H), 4.42 - 4.35 (m, 1H), 3.71 (q, J = 11.6 Hz, 2H), 1.23 (br d, J = 6.4 Hz, 3H). Mass spectrum (ESI, m/z): calcd. for C H F N O 453.1; fou + 23 18 3 5 2 nd [M+H] , 454.2. Example 245: (S)-3-cyano-4-methoxy-N-(6-methyl-4-oxo-5-(4-(perfluoroethyl)phenyl)- 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)benzamide.

The title compound was prepared in a manner analogous to Example 122, reacting (S)-3-cyano- 4-methoxy-N-(6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)benzamide (Intermediate 13, 150 mg, 0.461 mmol) and 1-bromo-4-(perfluoroethyl)benzene (152 mg, 0.553 mmol).1H NMR (400 MHz, DMSO-d₆) δ: 9.84 (s, 1H), 8.26 - 8.11 (m, 3H), 7.85 - 7.72 (m, 4H), 7.41 (d, J = 8.8 Hz, 1H), 4.80 - 4.72 (m, 1H), 4.67 - 4.58 (m, 1H), 4.44 - 4.36 (m, 1H), 3.99 (s, 3H), 1.27 (d, J = 6.8 Hz, 3H). Mass spectrum (ESI, m/z): calcd. for C₂₄H₁₈F₅N₅O₃519.1; found [M+H]+, 520.2. Example 246: (S)-3-cyano-N-(6-methyl-4-oxo-5-(4-(pentafluoro-l6-sulfaneyl)phenyl)- 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)benzamide.

The title compound was prepared in a manner analogous to Example 122, reacting (S)-3-cyano- N-(6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)benzamide (Intermediate 44, 150 mg, 0.508 mmol) and 4-bromophenylsulfurPentafluoride (158 mg, 0.559 mmol).1H NMR (400 MHz, DMSO-d₆) δ: 9.99 (s, 1H), 8.31 (s, 1H), 8.21 - 8.00 (m, 5H), 7.80 - 7.69 (m, 3H), 4.81 - 4.73 (m, 1H), 4.68 - 4.59 (m, 1H), 4.45 - 4.38 (m, 1H), 1.27 (d, J = 6.4 Hz, 3H). Mass spectrum (ESI, m/z): calcd. for C + 21H16F5N5O2S 497.1; found [M+H] , 498.1. Example 247: 3-cyano-N- 2,2-difluorocyclopropyl)methyl)phenyl)-6-methyl-4-

oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)benzamide.

The title compound was prepared in a manner analogous to Example 122, reacting (S)-3-cyano- N-(6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)benzamide (Intermediate 44, 100 mg, 0.301 mmol) and 1-bromo-4-((2,2-difluorocyclopropyl)methyl)benzene (89 mg, 0.36 mmol).1H NMR (400 MHz, DMSO-d₆) δ: 9.98 (s, 1H), 8.29 (s, 1H), 8.20 - 8.05 (m, 3H), 7.76 (t, J = 8.0 Hz, 1H), 7.38 (s, 4H), 4.74 (dd, J = 4.4, 12.8 Hz, 1H), 4.50 - 4.42 (m, 1H), 4.37 (dd, J = 3.6, 13.2 Hz, 1H), 2.86 - 2.72 (m, 2H), 2.05 - 1.93 (m, 1H), 1.66 - 1.57 (m, 1H), 1.38 - 1.27 (m, 1H), 1.22 (d, J = 6.8 Hz, 3H). Mass spectrum (ESI, m/z): calcd. for C₂₅H₂₁F₂N₅O₂461.2; found [M+H]+, 462.2. Example 248: (S)-3-cyano-4-methoxy-N-(6-methyl-4-oxo-5-(4-(2,2,2-trifluoroethyl)phenyl)- 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)benzamide.

The title compound was prepared in a manner analogous to Example 122, reacting (S)-3-cyano- 4-methoxy-N-(6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)benzamide (Intermediate 13, 200.0 mg, 0.62 mmol) and 1-bromo-4-(2,2,2-trifluoroethyl)benzene (176.3 mg, 0.74 mmol).1H NMR (400 MHz, DMSO-d6) δ: 9.85 (s, 1H), 8.23 (d, J = 2.4 Hz, 1H), 8.18 - 8.14 (m, 1H), 8.12 (s, 1H), 7.47(s, 4H), 7.40 (d, J = 9.2 Hz, 1H), 4.75 - 4.70 (m, 1H), 4.53 - 4.45 (m, 1H), 4.40 - 4.34 (m, 1H), 3.99 (s, 3H),3.71 (q, J = 11.6 Hz, 2H), 1.23 (d, J = 6.4 Hz, 3H). Mass spectrum (ESI, m/z): calcd. for C + 24H20F3N5O3483.2; found [M+H] , 484.2. Example 249: 3-cyano-N- 2,2-difluorocyclopropyl)methyl)phenyl)-6-methyl-4-

oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)-4-methoxybenzamide.

The title compound was prepared in a manner analogous to Example 122, reacting (S)-3-cyano- 4-methoxy-N-(6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)benzamide (Intermediate 13, 100.0 mg, 0.31 mmol) and 1-bromo-4-((2,2- difluorocyclopropyl)methyl)benzene (91.1 mg, 0.37 mmol).1H NMR (400 MHz, DMSO-d6) δ: 9.86 (s, 1H), 8.23 (d, J = 2.4 Hz, 1H), 8.16 (dd, J = 2.3, 8.9 Hz,1H), 8.12 (s, 1H), 7.44 - 7.36 (m, 5H), 4.73 (dd, J = 4.4, 12.9 Hz, 1H), 4.49 - 4.41 (m, 1H), 4.37 (dd,J = 3.6, 13.1 Hz, 1H), 4.00 (s, 3H), 2.86 - 2.75 (m, 2H), 2.09 - 1.94 (m, 1H), 1.68 - 1.56 (m, 1H), 1.38- 1.28 (m, 1H), 1.23 (d, J = 6.8 Hz, 3H). Mass spectrum (ESI, m/z): calcd. for C₂₆H₂₃F₂N₅O₃491.2; found [M+H]+, 492.2. Example 250: (S)-3-cyano-4-methoxy-N-(6-methyl-4-oxo-5-(4-(trifluoromethyl)phenyl)- 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)benzamide.

The title compound was prepared in a manner analogous to Example 122, reacting (S)-3-cyano- 4-methoxy-N-(6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)benzamide (Intermediate 13, 100 mg, 0.31 mmol) and 1-bromo-4-(3,3,3-trifluoropropoxy)benzene (103.7 mg, 0.46 mmol).1H NMR (400 MHz, DMSO-d6) δ: 9.85 (s, 1H), 8.24 (d, J = 2.0 Hz, 1H), 8.17 (dd, J = 2.4, 8.8 Hz, 1H), 8.13 (s, 1H), 7.87 (d, J = 8.4 Hz, 2H), 7.72 (d, J = 8.4 Hz, 2H), 7.41 (d, J = 8.8 Hz, 1H), 4.76 (dd, J = 4.4, 13.2 Hz, 1H), 4.64 - 4.55 (m, 1H), 4.40 (dd, J = 3.6, 13.2 Hz, 1H), 4.00 (s, 3H), 1.26 (d, J = 6.8 Hz, 3H). Mass spectrum (ESI, m/z): calcd. for C23H18F3N5O3 469.1; found [M+H]+, 470.2. Example 251: (S)-3-cyano-N-(5-(4-(difluoro(1-fluorocyclopropyl)methyl)phenyl)-6-methyl- 4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)-4-methoxybenzamide.

The title compound was prepared in a manner analogous to Example 122, reacting (S)-3-cyano- 4-methoxy-N-(6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)benzamide (Intermediate 13, 150 mg, 0.461 mmol) and 1-bromo-4-(difluoro(1- fluorocyclopropyl)methyl)benzene (244 mg, 0.922 mmol).1H NMR (400 MHz, CDCl₃) δ: 9.67 (s, 1H), 8.43 (s, 1H), 8.17 (d, J = 2.4 Hz, 1H), 8.10 (dd, J = 2.0, 8.8 Hz, 1H), 7.74 (d, J = 8.4 Hz, 2H), 7.47 (d, J = 8.0 Hz, 2H), 7.01 (d, J = 8.8 Hz, 1H), 4.67 (dd, J = 4.4, 13.2 Hz, 1H), 4.48 - 4.41 (m, 1H), 4.40 - 4.34 (m, 1H), 3.99 (s, 3H), 1.42 (d, J = 6.4 Hz, 3H), 1.27 - 1.19 (m, 4H). Mass spectrum (ESI, m/z): calcd. for C H F N O + 26 22 3 5 3509.2; found [M+H] , 510.2. Example 252: (S)-3-cyano-N-(5-(4-(difluoro(phenyl)methyl)phenyl)-6-methyl-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazin-3-yl)-4-(oxetan-3-ylmethyl)benzamide

In an 8 mL vial, 1 mL of a Dioxane solution containing intermediate 53 (57.64 mg 0.1 mmol), 0.2 mL of a water solution containing Cs₂CO₃, (114.02 mg, 0.35 mmol), and 0.5 mL of a Dioxane solution containing Catacxium Pd G4 (3.7 mg, 0.005 mmol) were added in a 2-dram vial containing trifluoro(oxetan-3-ylmethyl)borate potassium salt (35.6 mg, 0.2 mmol). The vial was sealed and heated at 100 °C for 12 hours. The reaction was then cooled to room temperature and DCM (2 mL) and water (2 mL) were added. The reactions were stirred for 1 h and the organic layer was extracted. Then, all the organic layer was treated with Silicycle DMT (50 mg) filtered, and concentrated to residue. Then, the residue was redissolved in DMSO filtered and the product was purified by Prep-HPLC. Conditions: Stationary phase: C18 XBridge 30 x 100 mm 10 µm. Mobile phase: NH₄HCO₃0.25% solution in Water and CH₃CN to afford (S)-3-cyano-N- (5-(4-(difluoro(phenyl)methyl)phenyl)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrazin-3-yl)-4-(oxetan-3-ylmethyl)benzamide (3.2 mg, 6% yield) as solid, after lyophilization.1H NMR (500 MHz, DMSO-d₆) δ: 9.90 (s, 1H) 8.25 (d, J=1.8 Hz, 1H) 8.11 (s, 1H) 8.06 (dd, J=8.1, 1.8 Hz, 1H) 7.48 - 7.67 (m, 10H) 4.73 (dd, J=13.1, 4.4 Hz, 1H) 4.64 (dd, J=7.6, 6.0 Hz, 2H) 4.48 - 4.58 (m, 1H) 4.32 - 4.43 (m, 3H) 3.31 - 3.40 (m, 1H) 3.23 (d, J=7.9 Hz, 2H) 1.23 (d, J=6.6 Hz, 3H). Mass spectrum (ESI, m/z): Calcd. for C₃₂H₂₇F₂N₅O₃, 567.2, found [M+H]+, 568.3. Examples 253-257 and 259-260 were prepared in a manner analogous to Example 252, with the appropriate reagent substitutions.

Example 258: (S)-3-cyano-N-(5-(4-(difluoro methyl)phenyl)-6-methyl-4-oxo-4,5,6,7-

tetrahydropyrazolo[1,5-a]pyrazin-3-yl)-4-(2-(dimethylamino)-ethoxy)benzamide.

Step A: tert-butyl (S)-(2-(2-cyano-4-((5-(4-(difluoro(phenyl)methyl)phenyl)-6-methyl-4-oxo- 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)carbamoyl)phenoxy)ethyl)carbamate. The title compound was prepared in a manner analogous to Example 158, Step A above, reacting (S)-3-cyano-N-(5-(4-(difluoro(phenyl)methyl)phenyl)-6-methyl-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazin-3-yl)-4-hydroxybenzamide (Example 56, 340 mg, 0.662 mmol), DIAD (268 mg, 1.32 mmol), and tert-butyl (2-hydroxyethyl)carbamate (128 mg, 0.800 mmol). Mass spectrum (ESI, m/z): calcd. for C₃₅H₃₄F₂N₆O₅, 656.3; found [M-56+H]+, 601.2. Step B: (S)-4-(2-aminoethoxy)-3-cyano-N-(5-(4-(difluoro(phenyl)methyl)phenyl)-6-methyl-4- oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)benzamide. The title compound was prepared in a manner analogous to Example 158, Step B above, reacting (S)-tert-butyl (2-(2-cyano-4-((5-(4-(difluoro(phenyl)methyl)phenyl)-6-methyl-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazin-3-yl)carbamoyl)phenoxy)ethyl)carbamate (164 mg, 0.25 mmol) and HCl (1 mL, 4 M in dioxane).1H NMR (400 MHz, DMSO-d6) ^ ^ 9.84 (s, 1H), 8.29 - 8.20 (m, 1H), 8.18 - 8.07 (m, 2H), 7.67 - 7.50 (m, 9H), 7.41 (d, J = 8.8 Hz, 1H), 4.74 (dd, J = 4.4, 13.2 Hz, 1H), 4.59 - 4.49 (m, 1H), 4.38 (dd, J = 3.6, 13.2 Hz, 1H), 4.21 (t, J = 6.0 Hz, 2H), 2.99 (t, J = 5.6 Hz, 2H), 1.24 (d, J = 6.8 Hz, 3H). Mass spectrum (ESI, m/z): calcd. for C₃₀H₂₆F₂N₆O₃, 556.2; found [M+H]+, 557.2. Step C: (S)-3-cyano-N-(5-(4-(difluoro(phenyl)methyl)phenyl)-6-methyl-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazin-3-yl)-4-(2-(dimethylamino)ethoxy)benzamide. The title compound was prepared in a manner analogous to Example 158, Step C above, reacting (S)-4-(2-aminoethoxy)-3-cyano-N-(5-(4-(difluoro(phenyl)methyl)phenyl)-6-methyl-4-oxo- 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)benzamide (160 mg, 0.287 mmol), formaldehyde (262 mg, 2.88 mmol, 33%), and sodium cyanotrihydroborate (18 mg, 0.29 mmol).1H NMR (400 MHz, DMSO-d6) ^ ^ 9.83 (s, 1H), 8.21 (d, J = 2.4 Hz, 1H), 8.15 - 8.10 (m, 2H), 7.68 - 7.50 (m, 9H), 7.42 (d, J = 8.8 Hz, 1H), 4.73 (dd, J = 4.0, 12.8 Hz, 1H), 4.58 - 4.49 (m, 1H), 4.37 (dd, J = 3.2, 12.8 Hz, 1H), 4.30 (t, J = 5.2 Hz, 2H), 2.69 (t, J = 5.6 Hz, 2H), 2.24 (s, 6H), 1.23 (d, J = 6.4 Hz, 3H). Mass spectrum (ESI, m/z): calcd. for C₃₂H₃₀F₂N₆O₃, 584.2; found [M+H]+, 585.3. Example 261: (S)-3-cyano-N-(6-methyl-4-oxo-5-(4-((1-(trifluoromethyl)cyclopropyl)- methyl)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)benzamide.

The title compound was prepared in a manner analogous to Example 122, reacting (S)-3-cyano- N-(6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)benzamide (Intermediate 44, 100 mg, 0.339 mmol) and 1-bromo-4-((1-(trifluoromethyl)cyclopropyl)methyl)benzene (104 mg, 0.37 mmol).1H NMR (400 MHz, DMSO-d6) δ: 9.98 (s, 1H), 8.31 (s, 1H), 8.17 (d, J = 8.0 Hz, 1H), 8.14 (s, 1H), 8.09 (d, J = 8.0 Hz, 1H), 7.76 (t, J = 8.0 Hz, 1H), 7.40 - 7.33 (m, 4H), 4.73 (dd, J = 4.4, 13.2 Hz, 1H), 4.50 - 4.43 (m, 1H), 4.36 (dd, J = 4.0, 13.2 Hz, 1H), 2.99 (s, 2H), 1.22 (d, J = 6.8 Hz, 3H), 0.98 - 0.94 (m, 2H), 0.82 - 0.77 (m, 2H). Mass spectrum (ESI, m/z): calcd. for C H F N O 493.2; + 26 22 3 5 2 found [M+H] , 494.2. Example 262: (S)-3-cyano-4-methoxy-N-(6-methyl-4-oxo-5-(4-(trifluoromethoxy)phenyl)- 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)benzamide.

The title compound was prepared in a manner analogous to Example 122, reacting (S)-3-cyano- 4-methoxy-N-(6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)benzamide (Intermediate 13, 200 mg, 0.62 mmol) and 1-bromo-4-(trifluoromethoxy)benzene (100.5 μL, 0.68 mmol).1H NMR (400 MHz, DMSO-d₆) δ: 9.83 (s, 1H), 8.23 (d, J = 2.0 Hz, 1H), 8.16 (dd, J = 2.4, 9.2 Hz,1H), 8.12 (s, 1H), 7.61 - 7.57 (m, 2H), 7.52 - 7.47 (m, 2H), 7.43 - 7.38 (m, 1H), 4.77 - 4.70 (m, 1H), 4.56 - 4.47 (m, 1H), 4.37 (dd, J = 4.0, 13.2 Hz, 1H), 3.99 (s, 3H), 1.23 (d, J = 6.4 Hz, 3H). Mass spectrum (ESI, m/z): calcd. for C + 23H18F3N5O4485.1; found [M+H] , 486.2. Example 263: (S)-3-cyano-N-(5-(4-(difluoro(phenyl)methyl)phenyl)-6-methyl-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazin-3-yl)-4-(methylamino)benzamide.

Step A: Methyl 3-cyano-4-(methylamino) benzoate. Methyl 3-cyano-4-fluorobenzoate (700 mg, 3.91 mmol), CH₃NH₂·HCl (791.5 mg, 11.7 mmol), K₂CO₃ (1.62 g, 11.7 mmol) and DMF (10 ml) were added to 50 ml round-bottomed flask, the resultant mixture was stirred at rt for 12 h. The reaction mixture was added water (60 mL), extracted with EtOAc (60 mL x 3). The combined extracts was washed with brine (60 mL), dried over anhydrous Na₂SO₄, filtered and concentrated to dryness under reduced pressure to give methyl 3-cyano-4-(methylamino) benzoate as a white solid (700 mg, 92% yelid).1H NMR (400 MHz, DMSO-d6) δ: 8.00 - 7.90 (m, 2H), 7.04 (br d, J = 4.6 Hz, 1H), 6.77 (d, J = 8.9 Hz, 1H),3.78 (s, 3H), 2.84 (d, J = 4.8 Hz, 3H). Mass spectrum (ESI, m/z): calcd. for C10H10N2O2 190.1; found [M+H]+, 190.7. Step B: 3-cyano-4-(methylamino)benzoic acid. Methyl 3-cyano-4-(methylamino)benzoate (200 mg, 1.05 mmol), THF (1 mL), MeOH (1 mL) and water (20 μL), LiOH (103.2 mg, 4.31 mmol) were added to 10 mL round-bottomed flask, and the reaction mixture was then stirred for 12 h at 40 °C. The reaction mixture was adjusted to pH=6 with aq. HCl (1M), then concentrated to dryness under reduced pressure to give a white solid. The solid was subjected to sillica-gel chromatography (0-10% MeOH/DCM) to give 3- cyano-4-(methylamino)benzoic acid as a white solid (240 mg, crude).1H NMR (400 MHz, DMSO-d6) δ: 7.97 - 7.89 (m, 2H), 6.90 (br d, J = 4.6 Hz, 1H), 6.74 (d, J = 8.8 Hz, 1H), 4.16 (br s, 1H), 2.82 (d, J = 4.8 Hz, 3H). Step C: (S)-3-cyano-N-(5-(4-(difluoro(phenyl)methyl)phenyl)-6-methyl-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazin-3-yl)-4-(methylamino)benzamide. The title compound was prepared in a manner analogous to Example 103, reacting (S)-3-amino- 5-(4-(difluoro(phenyl)methyl)phenyl)-6-methyl-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (Intermediate 12, 200 mg, 0.54 mmol), 3-cyano-4-(methylamino)benzoic acid (143.5 mg, 0.81 mmol), and HATU (309.7 mg, 0.81 mmol).1H NMR (400 MHz, DMSO-d₆) δ: 9.63 (s, 1H), 8.12 (s, 1H), 7.97 (d, J = 2.0 Hz, 1H), 7.92 - 7.87 (m, 1H), 7.68- 7.51 (m, 9H),6.97 - 6.96 (m, 1H), 6.81 (d, J = 8.8 Hz, 1H), 4.72 (dd, J = 4.4, 12.8 Hz, 1H), 4.58 - 4.50 (m, 1H), 4.37 (dd, J = 3.2, 13.2 Hz, 1H), 2.83 (d, J = 4.8 Hz, 3H), 1.24 (d, J = 6.8Hz, 3H). Mass spectrum (ESI, m/z): calcd. for C H F N O 526 + 29 24 2 6 2 .2; found [M+H] , 527.2. Example 264: (S)-3-cyano-N-(5-(4-(difluoro(phenyl)methyl)phenyl)-6-methyl-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazin-3-yl)-4-((2-methoxyethyl)amino)benzamide.

Step A：methyl 3-cyano-4-((2-methoxyethyl) amino) benzoate. Methyl 3-cyano-4-fluorobenzoate(500 mg, 2.79 mmol), 2-methoxyethanamine(628.9 mg, 8.37 mmol), K2CO3 (1.16 g, 8.37 mmol) and DMF (10 ml) were added to 50 mL round-bottomed flask. The resultant mixture was stirred at rt for 12 h. The reaction mixture diluted with water (60 mL), extracted with EtOAc (60 mL x 3). The combined extracts washed with brine (60 mL), dried over anhydrous Na2SO4, filtered and concentrated to dryness under reduced pressure to give methyl 3-cyano-4-((2-methoxyethyl) amino) benzoate as a pink solid (700 mg, crude).1H NMR (400 MHz, DMSO-d₆) δ: 7.98 - 7.89 (m, 2H), 6.90 (d, J = 9.3 Hz, 1H), 6.84 - 6.78 (m, 1H), 3.78 (s, 3H), 3.54 - 3.41 (m, 4H), 3.27 (s, 3H). Mass spectrum (ESI, m/z): calcd. for C + 12H14N2O3234.1; found [M+H] , 234.8. Step B: 3-cyano-4-((2-methoxyethyl) amino) benzoic acid. The title compound was prepared in a manner analogous to Example 263, Step B above, reacting methyl 3-cyano-4-((2-methoxyethyl)amino)benzoate (400 mg, 1.71 mmol), THF (1 mL), MeOH (1 mL), water (71 μL), and LiOH (167.7 mg, 7.0 mmol).1H NMR (400 MHz, DMSO-d₆) δ: 7.95 (d, J = 2.0 Hz, 1H), 7.89 (dd, J = 1.8, 9.0 Hz, 1H), 6.89 (d, J = 9.0 Hz, 1H), 6.72 (br t, J = 5.6 Hz, 1H), 3.54 - 3.46 (m, 2H), 3.45 - 3.39 (m, 2H), 3.33 (br s, 1H), 3.28 - 3.25 (m, 3H). Mass spectrum (ESI, m/z): calcd. for C₁₁H₁₂N₂O₃220.1; found [M+H]+, 220.7. Step C: (S)-3-cyano-N-(5-(4-(difluoro(phenyl)methyl)phenyl)-6-methyl-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazin-3-yl)-4-((2-methoxyethyl)amino)benzamide. The title compound was prepared in a manner analogous to Example 103, reacting 3-cyano-4- ((2-methoxyethyl) amino) benzoic acid (257 mg, 1.17 mmol), HATU (332.8 mg, 0.88 mmol), and (S)-3-amino-5-(4-(difluoro(phenyl)methyl)phenyl)-6-methyl-6,7-dihydropyrazolo[1,5- a]pyrazin-4(5H)-one (Intermediate 12, 214.9 mg, 583.5 μmol).1H NMR (400 MHz, DMSO-d₆) δ: 9.63 (s, 1H), 8.12 (s, 1H), 7.86 (dd, J = 2.0, 8.8 Hz, 1H), 7.67 - 7.63 (m, 2H), 7.61 - 7.56 (m, 4H), 7.55 - 7.50 (m, 3H), 6.95 (d, J = 9.2 Hz, 1H), 6.74 (s, 1H), 4.72 (dd, J = 4.4, 12.8 Hz, 1H), 4.57 - 4.51 (m, 1H), 4.37 (dd, J = 3.2, 13.2 Hz, 1H), 3.53 - 3.40 (m, 5H), 3.27 (s, 3H), 1.24 (d, J = 6.4 Hz, 3H). Mass spectrum (ESI, m/z): calcd. for C₃₁H₂₈F₂N₆O₃570.2; found [M+H]+, 571.2. Example 265: (S)-3-cyano-4-methoxy-N-(6-methyl-4-oxo-5-(4- ((trifluoromethyl)thio)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)benzamide.

The title compound was prepared in a manner analogous to Example 122, reacting (S)-3-cyano- 4-methoxy-N-(6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)benzamide (Intermediate 13, 200 mg, 0.615 mmol) and (4-bromophenyl)(trifluoromeaulfane (111 μL, 1.710 g/mL, 0.738 mmol).1H NMR (400 MHz, DMSO-d₆) δ: 9.85 (s, 1H), 8.24 (d, J = 2.0 Hz, 1H), 8.17 (d, J = 2.0 Hz, 1H), 8.12 (s, 1H), 7.83 (d, J = 8.4 Hz, 2H), 7.66 (d, J = 8.8 Hz, 2H), 7.41 (d, J = 8.8 Hz, 1H), 4.75 (d, J = 4.4 Hz, 1H), 4.64 - 4.55 (m, 1H), 4.39 (d, J = 3.2 Hz, 1H), 4.00 (s, 3H), 1.26 (d, J = 6.4 Hz, 3H). Mass spectrum (ESI, m/z): calcd. for C₂₃H₁₈F₃N₅O₃S 501.1; found [M+H]+, 502.1. Example 266: (S)-3-cyano-4-methoxy-N-(6-methyl-4-oxo-5-(4-(2- (trifluoromethoxy)ethyl)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)benzamide.

Step A: 1-bromo-4-(2-(trifluoromethoxy)ethyl)benzene. AgOTf (1.8 g, 7.0 mmol), Selectfluor (1.85 g, 5.22 mmol), a stirr bar, KF (0.61 g, 10.4 mmol), and (4-bromophenyl)methanol (0.7 g, 3.5 mmol) were added to an oven-dried and nitrogen- purged 50 mL round-bottomed flask. Then ethyl acetate (20 mL), 2-fluoropyridine (0.68 g, 6.97 mmol) and CF3TMS (0.99 g, 6.98 mmol) were added successively under N2 atmosphere. The reaction mixture was stirred at room temperature for 12 h. The reaction mixture was then filtered, and treated with sat. aq. NaHCO3 (40 mL), extracted with DCM (40 mL x 2), and the combined extracts washed with brine (40 mL), dried over anhydrous Na2SO4, filtered, and concentrated to dryness in vacuo to give yellow oil. The oil was then subjected to silica gel chromatography (0-5% EtOAc/PE) to give 1-bromo-4-(2-(trifluoromethoxy)ethyl)benzene as colorless oil (405 mg, 43% yield).1H NMR (400 MHz, CDCl3) δ: 7.49 - 7.42 (m, 2H), 7.10 (d, J = 8.0 Hz, 2H), 4.13 (t, J = 7.2 Hz, 2H), 2.95 (t, J = 6.8 Hz, 2H) Step B: (S)-3-cyano-4-methoxy-N-(6-methyl-4-oxo-5-(4-(2-(trifluoromethoxy)ethyl)phenyl)- tetrahydropyrazolo[1,5-a]pyrazin-3-yl)benzamide.

The title compound was prepared in a manner analogous to Example 122, reacting (S)-3-cyano- 4-methoxy-N-(6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)benzamide (Intermediate 13, 150 mg, 0.415 mmol) and 1-bromo-4-(2,2,2-trifluoroethoxy)benzene (127 mg, 0.498 mmol).1H NMR (400 MHz, DMSO-d₆) δ: 9.85 (s, 1H), 8.23 (d, J = 2.4 Hz, 1H), 8.16 (dd, J = 2.4, 8.8 Hz, 1H), 8.11 (s, 1H), 7.43 - 7.36 (m, 5H), 4.72 (dd, J = 4.4, 12.8 Hz, 1H), 4.50 - 4.41 (m, 1H), 4.39 - 4.31 (m, 3H), 3.99 (s, 3H), 3.03 (t, J = 6.4 Hz, 2H), 1.22 (d, J = 6.8 Hz, 3H). Mass spectrum (ESI, m/z): calcd. for C₂₅H₂₂F₃N₅O₄513.2; found [M+H]+, 514.2. Example 267: (S)-3-cyano-4-methoxy- (6-methyl-4-oxo-5-(4-(2-((2,2,2-

trifluoroethyl)amino)ethyl)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3- yl)benzamide.

The title compound was prepared in a manner analogous to Example 122, reacting (S)-3-cyano- 4-methoxy-N-(6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)benzamide (Intermediate 13, 100 mg, 0.307 mmol) and N-(4-bromophenethyl)-2,2,2-trifluoroethan-1-amine (104 mg, 0.369 mmol).1H NMR (400 MHz, DMSO-d6) δ: 9.85 (s, 1H), 8.22 (d, J = 2.4 Hz, 1H), 8.17 - 8.16 (m, 1H), 8.11 (s, 1H), 7.41 (d, J = 8.8 Hz, 1H), 7.37 - 7.29 (m, 4H), 4.73 - 4.72 (m, 1H), 4.49 - 4.39 (m, 1H), 4.37 - 4.36 (m, 1H), 3.99 (s, 3H), 3.31 - 3.21 (m, 2H), 2.90 - 2.82 (m, 2H), 2.78 - 2.71 (m, 2H), 2.43 - 2.35 (m, 1H), 1.21 (d, J = 6.8 Hz, 3H). Mass spectrum (ESI, m/z): calcd. for C H F N O 526.2; found [M + 26 25 3 6 3 +H] , 527.3. Example 268: (S)-3-cyano-N-(5-(4-(1,1-difluoroethyl)phenyl)-6-methyl-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazin-3-yl)-4-methoxybenzamide.

The title compound was prepared in a manner analogous to Example 122, reacting (S)-3-cyano- 4-methoxy-N-(6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)benzamide (Intermediate 13, 300 mg, 0.922 mmol) and 1-bromo-4-(1,1-difluoroethyl)benzene (306 mg, 1.38 mmol).1H NMR (400 MHz, DMSO-d6) δ: 9.85 (s, 1H), 8.23 (d, J = 2.0 Hz, 1H), 8.16 (dd, J = 2.4, 9.2 Hz, 1H), 8.12 (s, 1H), 7.68 (d, J = 8.4 Hz, 2H), 7.58 (d, J = 8.4 Hz, 2H), 7.41 (d, J = 9.2 Hz, 1H), 4.75 (dd, J = 4.4, 13.2 Hz, 1H), 4.58 - 4.49 (m, 1H), 4.38 (dd, J = 3.2, 12.8 Hz, 1H), 3.99 (s, 3H), 2.01 (t, J = 18.8 Hz, 3H), 1.24 (d, J = 6.4 Hz, 3H). Mass spectrum (ESI, m/z): calcd. for C + 24H21F2N5O3465.2; found [M+H] , 466.2.

The title compound was prepared in a manner analogous to Example 209, reacting 3-amino-5-(4- benzylphenyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (Intermediate 11, 35 mg, 0.11 mmol) and 2-cyanoisonicotinic acid (19.5 mg, 0.13 mmol).1H NMR (500 MHz, DMSO-d₆) δ: 10.18 (s, 1H) 8.82 - 9.02 (m, 1H) 8.39 (d, J=0.8 Hz, 1H) 8.11 (s, 1H) 8.09 (dd, J=5.0, 1.7 Hz, 1H) 7.34 - 7.39 (m, 2H) 7.28 - 7.33 (m, 4H) 7.23 - 7.27 (m, 2H) 7.17 - 7.23 (m, 1H) 4.47 - 4.59 (m, 2H) 4.15 - 4.31 (m, 2H) 3.97 (s, 2H). Mass spectrum (ESI, m/z): calcd. for C₂₆H₂₀N₆O₂ 448.2; found [M+H]+, 449.3. Example 270: (S)-N-(3-cyano-4-methoxyphenyl)-7-methyl-4-oxo-5-(4- (trifluoromethoxy)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

The title compound was prepared in a manner analogous to Example 271, reacting (S)-7-methyl- 4-oxo-5-(4-(trifluoromethoxy)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxylic acid (Intermediate 18, 55 mg, 0.155 mmol) and 5-amino-2-methoxybenzonitrile (119 mg, 0.313 mmol).1H NMR (400 MHz, DMSO-d6) δ: 12.21 (s, 1H), 8.20 (s, 1H), 8.04 (d, J = 2.6 Hz, 1H), 7.71 (dd, J = 9.1, 2.7 Hz, 1H), 7.69 – 7.63 (m, 2H), 7.54 (d, J =8.4 Hz, 2H), 7.24 (d, J = 9.2 Hz, 1H), 4.95 – 4.86 (m, 1H), 4.37 (dd, J = 12.9, 4.3 Hz, 1H), 4.09 (dd, J = 13.0, 7.8 Hz, 1H), 3.88 (s, 3H), 1.60 (d, J= 6.5 Hz, 3H). Mass spectrum (ESI, m/z): calcd. for C23H18F3N5O4, 485.1; found [M+H]+, 486.1. Example 271: (S)-N-(3-cyano-4-methoxyphenyl)-5-(4-(difluoro methyl)phenyl)-7-

methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

HATU (132 mg, 0.347 mmol) was added to a mixture of (S)-5-(4- (difluoro(phenyl)methyl)phenyl)-7-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3- carboxylic acid (Intermediate 17, 92 mg, 0.232 mmol), 5-amino-2-methoxybenzonitrile (45mg, 0.304 mmol) and DIPEA (0.162 mL, 0.930 mmol) in DMF (5 mL) under nitrogen. The mixture was stirred at 25ºC for 16 h. The reaction was monitored by LC-MS. The mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine and dried over MgSO₄, filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography (62-70% EtOAc/Hept) to afford impure product, that was then purified by reverse phase chromatography with the following conditions: column, Brand Phenomenex Type Gemini; I.D. (mm) 100 x 30; particle size 30 µm (C18) 110A; mobile phase, (53%-17%, 25mM NH₄CO₃/CH₃CN). The mixture was extracted with DCM. The organic layer was dried over MgSO4, filtered and the solvent removed in vacuo to afford (S)-N-(3-cyano-4-methoxyphenyl)- 5-(4-(difluoro(phenyl)methyl)phenyl)-7-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrazine-3-carboxamide, as a yellow solid (28.5m g, 23% yield).1H-NMR (400 MHz, DMSO- d6) δ: 12.44 (s, 1H), 8.27 (d, J = 2.4 Hz, 1H), 8.21 (s, 1H), 7.78 (d, J = 8.8 Hz, 1H), 7.74 - 7.69 (m, 2H), 7.67 - 7.59 (m, 5H), 7.57 - 7.51 (m, 3H), 4.96 - 4.87 (m, 1H), 4.58 - 4.46 (m, 2H), 1.21 (d, J = 6.0 Hz, 3H). Mass spectrum (ESI, m/z): Calcd. for C₂₉H₂₃F₂N₅O₃, 527.2, found [M+H]+, 528.1. Example 272: (S)-N-(3-cyano-4-methoxyphenyl)-7-methyl-4-oxo-5-(4-(trifluoromethyl)- phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

The title compound was prepared in a manner analogous to Example 271, reacting (S)-7-methyl- 4-oxo-5-(4-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxylic acid (Intermediate 30, 130 mg, 0.383 mmol) and 5-amino-2-methoxybenzonitrile (57 mg, 0.385 mmol).1H NMR (400 MHz, DMSO-d₆) δ: 12.13 (s, 1H), 8.20 (s, 1H), 8.03 (d, J = 2.6 Hz, 1H), 7.91 (d, J = 8.5 Hz, 2H), 7.76 (d, J = 8.4 Hz, 2H), 7.72 (dd, J = 9.1, 2.7 Hz, 1H), 7.23 (d, J = 9.2 Hz, 1H), 4.99 – 4.87 (m, 1H), 4.42 (dd, J = 12.9, 4.3 Hz, 1H), 4.14 (dd, J = 12.9, 7.8 Hz, 1H), 3.88 (s, 3H), 1.61 (d, J = 6.5 Hz, 3H). Mass spectrum (ESI, m/z): calcd. for C₂₃H₁₈F₃N₅O₃, 469.1; found [M+H]+, 470.0. Example 273: (R)-N-(3-cyano-4-methoxyphenyl)-5-(4-(difluoro(phenyl)methyl)phenyl)-7- methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

The title compound was prepared in a manner analogous to Example 337, Step C, reacting (R)- N-(3-cyano-4-methoxyphenyl)-7-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3- carboxamide (Intermediate 15, 50 mg, 0.15 mmol) and 1-bromo-4- (difluoro(phenyl)methyl)benzene (65.3 mg, 0.231 mmol).1H NMR (400 MHz, CDCl3) δ: 12.03 (s, 1H), 8.31 (s, 1H), 7.94 (dd, J = 2.4, 9.2 Hz, 1H), 7.91 - 7.88 (m, 1H),7.67 (d, J = 8.4 Hz, 2H), 7.58 - 7.52 (m, 2H), 7.49 - 7.42 (m, 5H), 6.90 (d, J = 8.8 Hz, 1H), 4.86 - 4.78 (m, 1H),4.30 (dd, J = 4.0, 12.8 Hz, 1H), 4.04 - 3.95 (m, 1H), 3.90 (s, 3H), 1.75 (d, J = 6.4 Hz, 3H). Mass spectrum (ESI, m/z): calcd. for C₂₉H₂₃F₂N₅O₃527.2, found [M+H]+, 528.2.

The title compound was prepared in a manner analogous to Example 337, Step C, reacting (S)-N- (3-Cyano-4-methoxyphenyl)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3- carboxamide (Intermediate 7, 80 mg, 0.25 mmol), 1-bromo-4-((1R,2R)-2- (trifluoromethyl)cyclopropyl)benzene (78 mg, 0.30 mmol).1H NMR (400 MHz, CDCl3) δ: 12.05 (s, 1H), 8.26 (s, 1H), 7.95 - 7.84 (m, 2H), 7.24 (s, 1H), 6.86 (d, J = 8.8 Hz, 1H), 4.78 - 4.73 (m, 1H), 4.46 - 4.42 (m, 1H), 4.37 - 4.28 (m, 1H), 3.87 (s, 3H), 2.45 - 2.37 (m, 1H), 1.92 - 1.81 (m, 1H), 1.47 - 1.40 (m, 1H), 1.35 (d, J = 6.8 Hz, 3H), 1.26 - 1.19 (m, 1H). Mass spectrum (ESI, m/z): calcd. For C H F N O 509.2, found [M+H + 26 22 3 5 3 ] , 510.2. Example 275: (S)-N-(3-cyano-4-methoxyphenyl)-5-(4-(3-ethynylbenzoyl)phenyl)-6-methyl- 4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

1-Bromo-3-iodobenzene (10.0 g, 35.3 mmol), triisopropylsilylacetylene (7.09 g, 38.9 mmol), CuI (168 mg, 884 μmol), PdCl₂(PPh₃)₂ (1.24 g, 1.77 mmol), TEA (150 mL) and a stir bar were added to a 250 mL three-necked round-bottomed flask equipped with a reflux condenser. The mixture was heated to 40°C stirred for 17 h. The mixture was diluted in PE and filtered through a pad of Celite®. The filtrate was evaporated to give light-yellow oil. The oil was subjected to silica-gel chromatography (100% PE) to give ((3-bromophenyl)ethynyl)triisopropylsilane (11.5 g, 96% yield) as colorless oil.1H NMR (400 MHz, CDCl₃) δ: 7.62 (t, J = 1.6 Hz, 1H), 7.47 - 7.39 (m, 2H), 7.21 - 7.15 (m, 1H), 1.14 (s, 21H). Step B: (4-bromophenyl)(3-((triisopropylsilyl)ethynyl)phenyl)methanone. ((3-Bromophenyl)ethynyl)triisopropylsilane (11.7 g, 34.6 mmol), a stir bar, and anhydrous THF (120 mL) were added to a 500 mL three-necked round-bottomed flask. The resulting mixture was cooled to -70°C before charged with n-BuLi (2.5 M in hexanes, 16.0 mL, 40.0 mmol) dropwise for 30 min while maintained the temperature below -70°C, and stirred for another 30 min, then treated with a solution of 4-bromo-N-methoxy-N-methylbenzamide (6.50 g, 26.6 mmol) and anhydrous THF (30 mL) dropwise over 15 min. The final mixture was stirred for 2 h. The reaction mixture was quenched with sat. NH₄Cl (50 mL), diluted with H₂O (50 mL), and extracted with EtOAc (150 mL*2). The combined extracts dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give yellow oil. The oil was subjected to silica-gel chromatography (100% PE) to give (4-bromophenyl)(3-((triisopropylsilyl)ethynyl)phenyl)methanone (6.7 g, 56% yield) as light yellow oil.1H NMR (400 MHz, CDCl3) δ: 7.86 (t, J = 1.2 Hz, 1H), 7.72 - 7.63 (m, 6H), 7.47 - 7.41 (m, 1H), 1.15 - 1.13 (m, 21H). Mass spectrum (ESI, m/z): calcd. for C₂₄H₂₉BrOSi, 440.1; found [M+H]+, 440.9. Step C: (S)-ethyl 6-methyl-4-oxo-5-(4-(3-((triisopropylsilyl)ethynyl)benzoyl)phenyl)-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxylate. The title compound was prepared in a manner analogous to Example 337, Step C, reacting (S)- ethyl 6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxylate (Intermediate 1, product from Step D, 2.20 g, 9.86 mmol) and (4-bromophenyl)(3- ((triisopropylsilyl)ethynyl)phenyl)methanone (6.70 g, 14.8 mmol).1H NMR (400 MHz, DMSO- d6) δ: 8.02 (s, 1H), 7.85 (d, J = 8.4 Hz, 2H), 7.79 - 7.73 (m, 3H), 7.67 - 7.57 (m, 3H), 4.89 - 4.81 (m, 1H), 4.61 - 4.53 (m, 1H), 4.46 - 4.42 (m, 1H), 4.28 - 4.18 (m, 2H), 1.28 - 1.22 (m, 6H), 1.13 - 1.08 (m, 21H). Mass spectrum (ESI, m/z): calcd. for C₃₄H₄₁N₃O₄Si, 583.3, found [M+H]+, 584.1. Step D: (S)-6-methyl-4-oxo-5-(4-(3-((triisopropylsilyl)ethynyl)benzoyl)phenyl)-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxylic acid. LiOH (1.29 mL, 1.29 mmol, 1 M in H2O), a stir bar, (S)-ethyl 6-methyl-4-oxo-5-(4-(3- ((triisopropylsilyl)ethynyl)benzoyl)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3- carboxylate (500 mg, 0.856 mmol), THF (20 mL) were added to 50 mL round-bottomed flask. The resulting mixture stirred at rt for 12 h. The reaction was adjusted with 1 N HCl to pH = 3~4, then added H2O (30 mL), extracted with EtOAc (30 mL x 2). The combined organic layer washed with saturated brine (40 mL), dried over Na₂SO₄, filtered and concentrated to give yellow oil. The oil was then subjected to silica gel chromatography (0-70% EtOAc/PE) to give (S)-6-methyl-4-oxo-5-(4-(3-((triisopropylsilyl)ethynyl)benzoyl)phenyl)-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxylic acid as a white solid (250 mg, 53% yield).1H NMR (400 MHz, DMSO-d6) δ: 13.87 (s, 1H), 8.16 (s, 1H), 7.89 (d, J = 8.8 Hz, 2H), 7.80 - 7.74 (m, 3H), 7.71 (d, J = 8.4 Hz, 2H), 7.63 - 7.57 (m, 1H), 4.91 (dd, J = 4.8, 13.6 Hz, 1H), 4.72 - 4.62 (m, 1H), 4.53 (dd, J = 4.4, 13.6 Hz, 1H), 1.25 (d, J = 6.8, 1H), 1.13 - 1.08 (m, 21H). Mass spectrum (ESI, m/z): calcd. for C₃₂H₃₇N₃O₄Si, 555.3, found [M+H]+, 556.1. Step E: (S)-N-(3-cyano-4-methoxyphenyl)-6-methyl-4-oxo-5-(4-(3-((triisopropylsilyl)- ethynyl)benzoyl)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide. (S)-6-Methyl-4-oxo-5-(4-(3-((triisopropylsilyl)ethynyl)benzoyl)phenyl)-4,5,6,7-tetrahydro- pyrazolo[1,5-a]pyrazine-3-carboxylic acid (250 mg, 0.450 mmol), a stir bar, 5-amino-2- methoxybenzonitrile (100 mg, 0.675 mmol), DIPEA (174 mg, 1.35 mmol), and DMF (5 mL) were added to a 10 mL round-bottomed flask, and the resulting mixture treated with HATU (257 mg, 0.675 mmol) in one portion. The resultant mixture was stirred at rt for 12 hours. The reaction mixture was quenched with H₂O (30 mL), and extracted with ethyl acetate (30 mL x 2). The combined organic extracts washed brine (20 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness under reduced pressure to give the yellow oil. The oil was then subjected to silica gel chromatography (0-70% EtOAc/PE) to give (S)-N-(3-cyano-4- methoxyphenyl)-6-methyl-4-oxo-5-(4-(3-((triisopropylsilyl)ethynyl)benzoyl)phenyl)-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide as a yellow solid (281 mg, 90% yield).1H NMR (400 MHz, DMSO-d6) δ: 12.13 (s, 1H), 8.20 (s, 1H), 8.02 (d, J = 2.8 Hz, 1H), 7.90 (d, J = 8.4 Hz, 2H), 7.81 - 7.76 (m, 3H), 7.76 - 7.71 (m, 3H), 7.64 - 7.57 (m, 1H), 7.23 (d, J = 9.2 Hz, 1H), 4.94 (dd, J = 4.4, 13.2 Hz, 1H), 4.67 - 4.48 (m, 2H), 3.88 (s, 3H), 1.26 (d, J = 6.8 Hz, 3H), 1.15 - 1.06 (m, 21H). Mass spectrum (ESI, m/z): calcd. for C₄₀H₄₃N₅O₄Si, 685.3; found [M+H]+, 686.3. Step F: (S)-N-(3-cyano-4-methoxyphenyl)-5-(4-(3-ethynylbenzoyl)phenyl)-6-methyl-4-oxo- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

(S)-N-(3-Cyano-4-methoxyphenyl)-6-methyl-4-oxo-5-(4-(3- ((triisopropylsilyl)ethynyl)benzoyl)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3- carboxamide (281 mg, 0.410 mmol), a stir bar, and THF (4 mL) were added to a 10 mL round- bottomed flask, and the resulting mixture treated with TBAF (0.819 mL, 0.819 mmol, 1 M in THF) dropwise over 1 min. The resultant mixture was stirred at rt for 0.5 hours. The reaction mixture was quenched with sat. aq. NH₄Cl (20 mL), and extracted with ethyl acetate (20 mLx2). The combined organic extracts washed sat. aq. NH4Cl (20 mL), brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure to give yellow oil. The oil was then subjected to silica gel chromatography (0-70% EtOAc/PE) to give (S)-N-(3- cyano-4-methoxyphenyl)-5-(4-(3-ethynylbenzoyl)phenyl)-6-methyl-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide a white solid (126.6 mg, 57% yield).1H NMR (400 MHz, DMSO-d6) δ: 12.14 (s, 1H), 8.20 (s, 1H), 8.04 (d, J = 2.4 Hz, 1H), 7.93 - 7.88 (m, 2H), 7.84 - 7.78 (m, 3H), 7.76 - 7.71 (m, 3H), 7.65 - 7.58 (m, 1H), 7.24 (d, J = 9.2 Hz, 1H), 4.94 (dd, J = 4.8, 13.2 Hz, 1H), 4.66 - 4.57 (m, 1H), 4.53 (dd, J = 3.6, 13.2 Hz, 1H), 4.36 (s, 1H), 3.88 (s, 3H), 1.27 (d, J = 6.4 Hz, 3H). Mass spectrum (ESI, m/z): calcd. for C31H23N5O4, 529.2; found [M+H]+, 530.2. Example 276: (S)- (3-cyano-4-methoxyphenyl)-6-methyl-4-oxo-5-(4-(2-(2,2,2-

trifluoroethoxy)ethyl)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

The title compound was prepared in a manner analogous to Example 337, Step C, reacting (S)-N- (3-cyano-4-methoxyphenyl)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3- carboxamide (Intermediate 7, 150 mg, 0.461 mmol) and 1-bromo-4-(2-(2,2,2- trifluoroethoxy)ethyl)benzene (144 mg, 0.507 mmol).1H NMR (400 MHz, CDCl3) δ: 12.12 (s, 1H), 8.31 (s, 1H), 7.99 - 7.96 (m, 1H), 7.90 (d, J = 2.4 Hz, 1H), 7.41 (d, J = 8.4 Hz, 2H), 7.29 (d, J = 8.4 Hz, 2H), 6.90 (d, J = 9.2 Hz, 1H), 4.80 - 4.76 (m, 1H), 4.49 - 4.45 (m, 1H), 4.40 - 4.33 (m, 1H), 3.93 - 3.89 (m, 5H), 3.88 - 3.83 (m, 2H), 3.03 - 3.00 (m, 2H), 1.39 (d, J = 6.4 Hz, 3H). Mass spectrum (ESI, m/z): calcd. for C + 26H24F3N5O4527.2; found [M+H] , 528.2. Example 277: (S)-N-(3-cyano-4-methoxyphenyl)-6-methyl-4-oxo-5-(4-(2-(trifluoro- methoxy)ethoxy)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

The title compound was prepared in a manner analogous to Example 337, Step C, reacting (S)-N- (3-Cyano-4-methoxyphenyl)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3- carboxamide (Intermediate 7, 100 mg, 0.307 mmol), 1-bromo-4-(2- (trifluoromethoxy)ethoxy)benzene (96 mg, 0.34 mmol) and 1-bromo-4-(2- (trifluoromethoxy)ethoxy)benzene (145 mg, 0.507 mmol).1H NMR (400 MHz, CDCl₃) δ: 12.14 (s, 1H), 8.31 (s, 1H), 7.98 - 7.95 (m, 1H), 7.91 (d, J =2.4 Hz, 1H), 7.30 - 7.27 (m, 2H), 7.09 - 7.05 (m, 2H), 6.90 (d, J = 8.8 Hz, 1H), 4.79 - 4.75 (m, 1H), 4.48 - 4.44 (m, 1H), 4.37 - 4.31 (m, 3H), 4.30 - 4.25 (m, 2H), 3.91 (s, 3H), 1.38 (d, J = 6.8 Hz, 3H). Mass spectrum (ESI, m/z): calcd. for C H F N O 529.2, fo + 25 22 3 5 5 und [M+H] , 530.2. Example 278: (S)-N-(3-cyano-4-methoxyphenyl)-6-methyl-4-oxo-5-(4-(1,1,2,2- tetrafluoroethyl)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

Step A: 1-(4-Bromophenyl)-2,2-difluoroethan-1-one. 1,4-Dibromobenzene (2.00 g, 8.48 mmol), a stir bar, and anhydrous THF (40 mL) were added to a 100 mL three necked round-bottomed flask, then n-BuLi (4.07 mL, 10.2 mmol) at -72 °C was added dropwise over 10 min. The resulting mixture was stirred at -72 °C for 0.5 h and then ethyl 2,2-difluoroacetate (1.69 mL, 17.0 mmol) was added dropwise into above solution. The resulting mixture was stirred at -72 °C for 1 h. The reaction mixture was quenched with sat. aq. NH4Cl (20 mL) below 0 °C, extracted with EtOAc (20 mL x 3). The combined organic extracts washed with brine (30 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% EtOAc/PE) to afford the 1-(4-bromophenyl)-2,2-difluoroethanone as colorless oil (1.5 g, 75% yield).1H NMR (400 MHz, CDCl3) δ: 7.87 (d, J = 8.8 Hz, 2H), 7.65 - 7.58 (m, 2H), 6.39 - 6.01 (m, 1H). Step B: 1-bromo-4-(1,1,2,2-tetrafluoroethyl)benzene. The title compound was prepared in a manner analogous to Example 337, Step B, reacting 1-(4- Bromophenyl)-2,2-difluoroethanone (1.50 g, 6.38 mmol), DCM (20 mL), and DAST (1.86 mL, 14.0 mmol) 1H NMR (400 MHz, CDCl₃) δ: 7.64 (br d, J = 8.0 Hz, 2H), 7.59 - 7.37 (m, 2H), 6.25 - 5.70 (m, 1H), Step C: (S)-N-(3-cyano-4-methoxyphenyl)-6-methyl-4-oxo-5-(4-(1,1,2,2-tetrafluoroethyl)- phenyl)- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

The title compound was prepared in a manner analogous to Example 337, Step B, reacting (S)-N- (3-Cyano-4-methoxyphenyl)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3- carboxamide (Intermediate 7, 169 mg, 0.519 mmol) and 1-bromo-4-(1,1,2,2- tetrafluoroethyl)benzene (200 mg, 0.778 mmol).1H NMR (400 MHz, DMSO-d6) δ: 12.13 (s, 1H), 8.19 (s, 1H), 8.04 (d, J = 2.4 Hz, 1H), 7.82 - 7.73 (m, 4H), 7.73 - 7.69 (m, 1H), 7.23 (d, J = 9.2 Hz, 1H), 7.01 - 6.71 (m, 1H), 4.96 - 4.89 (m, 1H), 4.61 - 4.49 (m, 2H), 3.88 (s, 3H), 1.23 (d, J = 6.8 Hz, 3H). Mass spectrum (ESI, m/z): calcd. for C H F N O 501.1; + 24 19 4 5 3 found [M+H] , 502.1. Example 279: (S)-N-(3-cyano-4-methoxyphenyl)-5-(4-(3,3-difluorocyclobutyl)phenyl)-6- methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

Step A: 1-bromo-4-(3,3-difluorocyclobutyl)benzene. The title compound was prepared in a manner analogous to Example 337, Step B, reacting 3-(4- Bromophenyl)cyclobutanone (900 mg, 4.00 mmol), DCM (50 mL), DAST (1.3 mL, 10 mmol). 1H NMR (400 MHz, CDCl3) δ: 7.49 - 7.44 (m, 2H), 7.16 - 7.06 (m, 2H), 3.340 - 3.31 (m, 1H), 3.11 - 2.96 (m, 2H), 2.71 - 2.55 (m, 2H) Step B: (S)-N-(3-cyano-4-methoxyphenyl)-5-(4-(3,3-difluorocyclobutyl)phenyl)-6-methyl-4- oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide. The title compound was prepared in a manner analogous to Example 337, Step C, reacting (S)- N-(3-cyano-4-methoxyphenyl)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3- carboxamide (Intermediate 7, 200 mg, 0.615 mmol) and 1-bromo-4-(3,3- difluorocyclobutyl)benzene (167 mg, 0.676 mmol).1H NMR (400 MHz, CDCl₃) δ: 12.10 (s, 1H), 8.31 (s, 1H), 7.98 - 7.95 (m, 1H), 7.89 (d, J = 2.4 Hz, 1H), 7.45 - 7.40 (m, 2H), 7.36 - 7.31 (m, 2H), 6.90 (d, J = 9.2 Hz, 1H), 4.81 - 4.77 (m, 1H), 4.50 - 4.45 (m, 1H), 4.42 - 4.30 (m, 1H), 3.90 (s, 3H), 3.52 - 3.43 (m, 1H), 3.13 - 3.02 (m, 2H), 2.84 - 2.64 (m, 2H), 1.39 (d, J = 6.8 Hz, 3H). Mass spectrum (ESI, m/z): calcd. for C + 26H23F2N5O3491.2; found [M+H] , 492.2. Example 280: (S)-N-(3-cyano-4-methoxyphenyl)-6-methyl-4-oxo-5-(4-((1s,3s)-3-(trifluoro- methoxy)cyclobutyl)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

The title compound was prepared in a manner analogous to Example 337, Step C, reacting (S)- N-(3-cyano-4-methoxyphenyl)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3- carboxamide (Intermediate 7, 120 mg, 0.406 mmol) and 1-bromo-4-((1s,3s)-3- (trifluoromethoxy)cyclobutyl)benzene (Intermediate 41, 120 mg, 0.406 mmol).1H NMR (400 MHz, CDCl3) δ: 12.11 (s, 1H), 8.31 (s, 1H), 7.97 - 7.94 (m, 1H), 7.90 (d, J = 2.8 Hz, 1H), 7.43 - 7.38 (m, 2H), 7.34 - 7.29 (m, 2H), 6.90 (d, J = 9.2 Hz, 1H), 4.81 - 4.76 (m, 1H), 4.74 - 4.66 (m, 1H), 4.49 - 4.45 (m, 1H), 4.40 - 4.33 (m, 1H), 3.90 (s, 3H), 3.24 - 3.11 (m, 1H), 2.94 - 2.83 (m, 2H), 2.45 - 2.34 (m, 2H), 1.39 (d, J = 6.4 Hz, 3H). Mass spectrum (ESI, m/z): calcd. for C H F N O 539.2, found [M+H]+ 27 24 3 5 4 , 540.2. Example 281: (S)-N-(3-cyanophenyl)-7-methyl-4-oxo-5-(4-(trifluoromethyl)phenyl)-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

The title compound was prepared in a manner analogous to Example 271, reacting (S)-7-methyl- 4-oxo-5-(4-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxylic acid (Intermediate 30, 130 mg, 0.383 mmol) and 3-aminobenzonitrile (81 mg, 0.686 mmol).1H NMR (400 MHz, DMSO-d6) δ: 12.36 (s, 1H), 8.23 (s, 1H), 8.18 (d, J = 1.0 Hz, 1H), 7.91 (d, J = 8.5 Hz, 2H), 7.80 – 7.70 (m, 3H), 7.57 –7.53 (m, 2H), 4.99 – 4.88 (m, 1H), 4.43 (dd, J = 12.9, 4.4 Hz, 1H), 4.15 (dd, J = 12.9, 7.8 Hz, 1H), 1.61 (d, J = 6.5 Hz, 3H). Mass spectrum (ESI, m/z): calcd. for C₂₂H₁₆F₃N₅O₂, 439.1; found [M+H]+, 440.1. Example 282: (S)-N-(3-cyanophenyl)-7-methyl-4-oxo-5-(4-(trifluoromethoxy)phenyl)- 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

The title compound was prepared in a manner analogous to Example 271, reacting (S)-7-methyl- 4-oxo-5-(4-(trifluoromethoxy)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxylic acid (Intermediate 18, 55 mg, 0.155 mmol) and 3-aminobenzonitrile (33 mg, 0.279 mmol).1H NMR (400 MHz, DMSO-d6) δ: 12.43 (s, 1H), 8.23 (s, 1H), 8.19 (s, 1H), 7.76 – 7.70 (m, 1H), 7.70 – 7.63 (m, 2H), 7.54 (dd, J = 5.4, 3.5 Hz, 4H), 4.98 – 4.86 (m, 1H), 4.38 (dd, J = 13.0, 4.4 Hz, 1H), 4.10 (dd, J = 13.0, 7.8 Hz, 1H), 1.60 (d, J = 6.5 Hz, 3H). Mass spectrum (ESI, m/z): calcd. for C H F N O , 45 + 22 16 3 5 3 5.1; found [M+H] , 456.1. Example 283: (S)-N-(3-cyanophenyl)-5-(4-(difluoro(phenyl)methyl)phenyl)-7-methyl-4-oxo- 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

The title compound was prepared in a manner analogous to Example 271, reacting (S)-5-(4- (difluoro(phenyl)methyl)phenyl)-7-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3- carboxylic acid (Intermediate 17, 92 mg, 0.232 mmol) and 3-aminobenzonitrile (36 mg, 0.305 mmol).1H NMR (400 MHz, DMSO-d₆) δ: 12.41 (s, 1H), 8.20 (d, J = 11.6 Hz, 2H), 7.73 – 7.62 (m, 5H), 7.59 (dt, J = 7.7, 3.9 Hz, 2H), 7.56 – 7.51 (m, 5H), 4.91 (dd, J = 11.3, 7.3 Hz, 1H), 4.39 (dd, J = 13.0, 4.4 Hz, 1H), 4.11 (dd, J = 13.0, 7.7 Hz, 1H), 1.59 (d, J = 6.5 Hz, 3H). Mass spectrum (ESI, m/z): calcd. for C + 28H21F2N5O2, 497.2; found [M+H] , 498.2. Example 284: (S)-N-(3-cyanophenyl)-5-(4-(difluoromethyl)phenyl)-6-methyl-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

To a 8 mL vial, 1-bromo-4-(difluoromethyl)benzene (55.31 mg, 0.27 mmol), intermediate 6 (50 mg, 0.17 mmol), (1R,2R)-N,N'-dimethyl-1,2-cyclohexanediamine (9.50 mg, 0.07 mmol), Copper(I) iodide (12.72 mg, 0.07 mmol) and K₂CO₃ (46.15 mg, 0.33 mmol) were added. Then, a 1:1 mixture of DMF and Toluene (1.0 mL) was added to the reaction vial. The reaction was kept stirring at 100 ºC for 18 hours. Then, AcOEt (2 mL) and NH3 solution (2 mL, 32% wt in water) were added and the phases were separated and analyzed by LCMS. The aqueous phase was back extracted with 2x2 mL of AcOEt. Organic phases were combined and concentrated. Resin MS Imidazole (4 eq.) was added to the vial and the crude mixture was suspended in DMSO (2 mL), MeOH (2 mL), and stirred for 1 hour. The crude mixture was filtered and purified by Prep-HPLC (Conditions: Stationary phase: C18 XBridge 30 x 100 mm 5 µm. Mobile phase: NH₄HCO₃ 0.25% solution in Water and CH3CN), to afford (S)-N-(3-cyanophenyl)-5-(4-(difluoromethyl)- phenyl)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide (49.7 mg, 71% yield) as a solid after lyophilization.1H NMR (500 MHz, DMSO-d₆) δ: 12.40 (s, 1H) 8.22 (s, 1H) 8.15 - 8.20 (m, 1H) 7.73 - 7.78 (m, 2H) 7.70 - 7.73 (m, 1H) 7.64 - 7.70 (m, 2H) 7.50 - 7.58 (m, 2H) 7.12 (t, J=55.8 Hz, 1H) 4.87 - 4.96 (m, 1H) 4.46 - 4.62 (m, 2H) 1.23 (d, J=6.5 Hz, 3H). Mass spectrum (ESI, m/z): Calcd. for C₂₂H₁₇F₂N₅O₂, 449.1, found [M+H]+, 450.3. Example 285: (S)-N-(3-cyanophenyl)-6-methyl-4-oxo-5-(4-((1R,2R)-2- (trifluoromethyl)cyclopropyl)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3- carboxamide.

Step A: 2-hydroxy-3-isobutoxybenzaldehyde. NaH (2.9 g, 60%, 72 mmol), a stir bar and DMSO (50 mL) were added to a 250 mL round bottomed flask, the mixture was stirred at 0 °C (brine/ice) and treated with the solution of 2,3- dihydroxybenzaldehyde (5 g, 36 mmol) and DMSO (15 mL) and over 5 min. The mixture was stirred at rt for 3 h. Then isobutyl bromide (5.0 g, 36 mmol) was added to the mixture at 0 °C (brine/ice) and the mixture was stirred at rt overnight. The reaction progress was monitored by TLC and LC-MS. The reaction mixture was treated with aq. HCl (1 M) to adjust pH = 5, then extracted with MTBE (50 mL x 3), the combined extracts washed with brine (75 mL), dried over anhydrous MgSO₄, filtered, and concentrated to dryness in vacuo to give a nearly black viscous oil. The oil was subjected to silica gel chromatography (0-50% DCM/PE) to give 2-hydroxy-3- isobutoxybenzaldehyde (2.5 g, 36% yield) as yellow oil.1H NMR (400 MHz, CDCl3) δ: 10.99 (s, 1H), 9.92 (s, 1H), 7.17 (dd, J = 1.6, 8.0 Hz, 1H), 7.11 (d, J = 8.0 Hz, 1H), 6.96 - 6.91 (m, 1H), 3.80 (d, J = 6.4 Hz, 2H), 2.21 - 2.13 (m, 1H), 1.05 (d, J = 6.8 Hz, 6H). Mass spectrum (ESI, m/z): calcd. for C H O 194.1; found [ + 11 14 3 M+H] , 194.7. Step B: 2,3-dichloro-6-hydroxy-5-isobutoxybenzaldehyde. 2-Hydroxy-3-isobutoxybenzaldehyde (2.5 g, 13 mmol), a stir bar, NCS (3.6 g, 27 mmol) and AcOH (50 mL) were added to a 100 mL round bottomed flask, the mixture was stirred at 80 °C overnight. The reaction progress was monitored by TLC and LC-MS. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (20 mL x 3), the combined extracts washed with brine (35 mL), dried over anhydrous Na2SO4, filtered, and concentrated to dryness in vacuo to give yellow oil. The oil was subjected to silica gel chromatography (0-50% DCM/PE) to give 2,3-dichloro-6-hydroxy-5-isobutoxybenzaldehyde (2.8 g, 83% yield) as a yellow solid.1H NMR (400 MHz, CDCl3) δ: 12.28 (s, 1H), 10.39 (s, 1H), 7.09 (s, 1H), 3.76 (d, J = 6.4 Hz, 2H), 2.23 - 2.12 (m, 1H), 1.05 (d, J = 6.8 Hz, 6H). Step C: Cobalt, [[2,2′-[(1S,2S)-1,2-cyclohexanediylbis[(nitrilo-κN)methylidyne]]-bis[3,4- dichloro-6-(2-methylpropoxy)phenolato-κO]](2-)]-, (SP-4-2)- (ACI) 2,3-Dichloro-6-hydroxy-5-isobutoxybenzaldehyde (3.0 g, 11 mmol), (1S,2S)-cyclohexane-1,2- diamine (651 mg, 5.70 mmol), a stir bar and EtOH (114 mL) were added to a 250 mL round bottomed flask, the mixture was stirred at rt for 8 h, then cobalt(II) acetate (1.11 g, 6.27 mmol) was added to above solution to give brown suspension, the suspension was stirred for 16 h at 80 °C. The reaction was filtered to give a brown solid, the solid was washed with EtOH until the filtrate became colorless, then the solid was dry over to give Cobalt, [[2,2′-[(1S,2S)-1,2- cyclohexanediylbis[(nitrilo-κN)methylidyne]]bis[3,4-dichloro-6-(2-methylpropoxy)phenolato- κO]](2-)]-, (SP-4-2)- (ACI) (2.5 g, 66% yield) as a brown solid. Step D: 1-bromo-4-((1R,2R)-2-(trifluoromethyl)cyclopropyl)benzene. 2,2,2-Trifluoroethanamine hydrochloride (2.2 g, 16 mmol), triphenylarsine (335 mg, 1.09 mmol), sodium acetate (90 mg, 1.1 mmol), Cobalt, [[2,2′-[(1S,2S)-1,2- cyclohexanediylbis[(nitrilo-κN)methylidyne]]bis[3,4-dichloro-6-(2-methylpropoxy)phenolato- κO]](2-)]-, (SP-4-2)- (ACI) (362 mg, 546 mmol), a stir bar and 20% NaCl solution (30 mL, in water) were added a 100 mL round-bottomed flask, which was subsequently cooled to -15 °C with a low temperature thermostat. Then the con.H2SO4 (55 mg, 0.55 mmol) was added to the solution, followed by adding 1-bromo-4-vinylbenzene (1.0 g, 5.5 mmol). The NaNO₂ (1.1 g, 16 mmol) was added to the solution and then the mixture was stirred at -15 °C under N2 for 12 h. The reaction progress was monitored by TLC. Then the solution was added water (100 mL), extracted with DCM (90 mL x 2), and the combined extracts washed with brine (300 mL), dried over anhydrous Na2SO4, filtered, and concentrated to dryness in vacuo to give yellow oil. The oil was purified by Prep-TLC (PE) to give 1-bromo-4-((1R,2R)-2- (trifluoromethyl)cyclopropyl)benzene (280 mg, 19% yield) as yellow oil.1H NMR (400 MHz, CDCl₃) δ: 7.47 - 7.39 (m, 2H), 7.07 - 6.97 (m, 2H), 2.37 - 2.28 (m, 1H), 1.84 - 1.72 (m, 1H), 1.45 - 1.35 (m, 1H), 1.19 - 1.11 (m, 1H). Step E: (S)-N-(3-cyanophenyl)-6-methyl-4-oxo-5-(4-((1R,2R)-2-(trifluoromethyl)- cyclopropyl)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide. The title compound was prepared in a manner analogous to Example 337, Step C, reacting (S)-N- (3-Cyanophenyl)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide (Intermediate 6, 80 mg, 0.27 mmol) and 1-bromo-4-((1R,2R)-2-(trifluoromethyl)cyclopropyl)- benzene (86 mg, 0.33 mmol).1H NMR (400 MHz, CDCl₃) δ: 12.25 (s, 1H), 8.28 (s, 1H), 8.05 (s, 1H), 7.91 (d, J = 7.6 Hz, 1H), 7.38 - 7.29 (m, 2H), 7.27 (s, 4H), 4.78 - 4.73 (m, 1H), 4.46 - 4.42 (m, 1H), 4.37 - 4.28 (m, 1H), 2.45 - 2.37 (m, 1H), 1.92 - 1.82 (m, 1H), 1.49 - 1.40 (m, 1H), 1.35 (d, J = 6.8 Hz, 3H), 1.28 - 1.20 (m, 1H). Mass spectrum (ESI, m/z): calcd. for C₂₅H₂₀F₃N₅O₂ 479.2, found [M+H]+, 480.2. Example 287: (S)-N-(3-cyanophenyl)-5-(4-(difluoro(4-(trifluoromethyl)pyridin-2- yl)methyl)phenyl)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3- carboxamide

The title compound was prepared in a manner analogous to Example 300, reacting (S)-2-(4-(3- ((3-cyanophenyl)carbamoyl)-6-methyl-4-oxo-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)- yl)phenyl)-2,2-difluoroacetic acid (Intermediate 40, 100 mg, 0.19 mmol) and 4- (trifluoromethyl)pyridine (108 µL, 0.93 mmol).1H NMR (400 MHz, CDCl3) δ: 12.16 (s, 1H), 8.88 (d, J = 5.0 Hz, 1H), 8.32 (s, 1H), 8.09 (t, J = 1.8 Hz, 1H), 8.04 (dt, J = 1.6, 0.8 Hz, 1H), 7.95 – 7.85 (m, 1H), 7.85 – 7.77 (m, 2H), 7.63 (dt, J = 5.0, 1.1 Hz, 1H), 7.50 – 7.43 (m, 2H), 7.37 (t, J = 7.8 Hz, 1H), 7.37 – 7.30 (m, 1H), 4.79 (dd, J = 13.5, 4.6 Hz, 1H), 4.53 – 4.35 (m, 2H), 1.40 (d, J = 6.6 Hz, 3H). Mass spectrum (ESI, m/z): Calcd. for C + 28H19F5N6O2, 566.1, found [M+H] , 567.3. Examples 288-298 were prepared in a manner analogous to Example 284, with the appropriate reagent substitutions.

Example 299: (S)-N-(3-cyanophenyl)-6-methyl-4-oxo-5-(4-(2-(2,2,2- trifluoroethoxy)ethyl)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

Step A: 2-(4-bromophenyl)oxirane. 4-Bromobenzaldehyde (5.0 g, 27 mmol), a stir bar, trimethylsulfonium iodide (8.8 g, 43 mmol) and DMSO (40 mL) were added to an oven-dried and nitrogen-purged 250 mL round-bottomed flask at 25 °C. A solution of tBuOK (4.5 g, 41 mmol) and DMSO (40 mL) was added to above solution. The reaction mixture was stirred overnight at rt. The reaction progress was monitored by TLC. The reaction solution was quenched with water (80 mL), extracted with DCM (3 * 150 mL), the combined organic layers were dried over Na2SO4, filtered and and concentrated to dryness in vacuo to give yellow oil. The oil was then subjected to silica gel chromatography (0 - 10% EtOAc/PE) to give 2-(4-bromophenyl)oxirane (4.0 g, 74% yield) as colourless oil.1H NMR (400 MHz, CDCl3) δ: 7.52 - 7.43 (m, 2H), 7.19 - 7.12 (m, 2H), 3.83 (dd, J = 2.4, 4.0 Hz, 1H), 3.17 - 3.14 (m, 1H), 2.77 - 2.75 (m, 1H) Step B: 1-(4-bromophenyl)-2-(2,2,2-trifluoroethoxy)ethan-1-ol. 2-(4-Bromophenyl)oxirane (4.0 g, 20 mmol), 2,2,2-trifluoroethanol (10.0 g, 100 mmol), DMF (30 mL), tBuONa (483 mg, 5.02 mmol) and a stir bar were added an oven-dried and nitrogen- purged 100 mL round-bottomed flask fitted with a reflux condenser, and the resulting mixture was stirred for 12 h at 90 °C. The reaction progress was monitored by TLC. The solution was then concentrated to dryness in vacuo, taken up in DCM (200 mL), washed with water (100 mL x 3) and brine (100 mL), dried over anhydrous MgSO₄, filtered, and concentrated to dryness in vacuo to give yellow oil. The oil was subjected to silica gel chromatography (0-50% EtOAc/PE) to give 1-(4-bromophenyl)-2-(2,2,2-trifluoroethoxy)ethan-1-ol (4.0 g, 66% yield) as yellow oil. 1H NMR (400 MHz, CDCl₃) δ: 7.55 - 7.47 (m, 2H), 7.27 (s, 2H), 4.92 - 4.89 (m, 1H), 3.99 - 3.87 (m, 2H), 3.80 - 3.76 (m, 1H), 3.64 - 3.58 (m, 1H). Step C: 1-bromo-4-(2-(2,2,2-trifluoroethoxy)ethyl)benzene. The title compound was prepared in a manner analogous to Example 13, Step C, reacting 1-(4- bromophenyl)-2-(2,2,2-trifluoroethoxy)ethanol (2.0 g, 6.7 mmol), trifluoroborane ethoxyethane (0.95 g, 6.7 mmol) and triethylsilane (1.6 g, 13 mmol).1H NMR (400 MHz, CDCl₃) δ: 7.48 - 7.39 (m, 2H), 7.11 (d, J = 8.4 Hz, 2H), 3.84 - 3.77 (m, 4H), 2.88 (t, J = 6.8 Hz, 2H). Step D: (S)-N-(3-cyanophenyl)-6-methyl-4-oxo-5-(4-(2-(2,2,2-trifluoroethoxy)ethyl)phenyl)- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

The title compound was prepared in a manner analogous to Example 337, Step C, reacting (S)- N-(3-cyanophenyl)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide (Intermediate 6, 150 mg, 0.508 mmol) and 1-bromo-4-(2-(2,2,2-trifluoroethoxy)ethyl)benzene (158 mg, 0.559 mmol).1H NMR (400 MHz, CDCl3) δ: 12.33 (s, 1H), 8.32 (s, 1H), 8.09 (s, 1H), 7.95 (d, J = 8.0 Hz, 1H), 7.44 - 7.36 (m, 3H), 7.35 - 7.32 (m, 1H), 7.29 (d, J = 8.4 Hz, 2H), 4.81 - 4.76 (m, 1H), 4.49 - 4.45 (m, 1H), 4.40 - 4.33 (m, 1H), 3.92 - 3.82 (m, 4H), 3.02 (t, J = 6.8 Hz, 2H), 1.39 (d, J = 6.8 Hz, 3H). Mass spectrum (ESI, m/z): calcd. for C25H22F3N5O3497.2; found [M+H]+, 498.2. Example 300 and 301: (S)-N-(3-cyanophenyl)-5-(4-(difluoro(pyrimidin-2- yl)methyl)phenyl)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3- carboxamide and (S)-N-(3-cyanophenyl)-5-(4-(difluoro(pyrimidin-4-yl)methyl)phenyl)-6- methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide

A mixture of (S)-2-(4-(3-((3-cyanophenyl)carbamoyl)-6-methyl-4-oxo-6,7-dihydropyrazolo[1,5- a]pyrazin-5(4H)-yl)phenyl)-2,2-difluoroacetic acid (Intermediate 40, 100 mg, 0.19 mmol), potassium persulfate (100 mg, 0.37 mmol) and a stir bar in CH3CN (1.2 mL) and water (1.2 mL) was degassed and pyrimidine (0.073 mL, 0.93 mmol), TFA (0.071 mL, 0.93 mmol) and silver nitrate (6.3 mg, 0.037 mmol) were added. The mixture was stirred at 60ºC for 16h. The reaction was monitored by LC-MS. Upon completion of the reaction, DCM (10 mL) and half sat. NaHCO3 (10 mL) were added. The layers were separated, and the aqueous layer extracted with DCM. The combined organic layers were washed with brine, dried over MgSO4, filtered and the solvents removed under reduced pressure. The crude was filtered through a 4 µm filter eluting with CH3CN and purified by prep-HPLC (Stationary phase: RP XBridge Prep C18 OBD- 5µm,50 x 250mm, Mobile phase: 0.25% NH₄HCO₃ solution in water, CH₃CN) to afford (S)-N- (3-cyanophenyl)-5-(4-(difluoro(pyrimidin-2-yl)methyl)phenyl)-6-methyl-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide (2.7 mg, 2.9% yield).1H NMR (400 MHz, CDCl₃) δ: 12.16 (s, 1H), 8.89 (d, J = 4.9 Hz, 2H), 8.33 (s, 1H), 8.07 (t, J = 1.8 Hz, 1H), 7.96 – 7.88 (m, 3H), 7.48 – 7.30 (m, 5H), 4.79 (dd, J = 13.5, 4.6 Hz, 1H), 4.52 – 4.36 (m, 2H), 1.39 (d, J = 6.7 Hz, 3H) and (S)-N-(3-cyanophenyl)-5-(4-(difluoro(pyrimidin-4-yl)methyl)phenyl)-6- methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide (8.0 mg, 8.6% yield) 1H NMR (400 MHz, CDCl₃) δ: 12.15 (s, 1H), 9.32 (d, J = 1.4 Hz, 1H), 8.97 (d, J = 5.2 Hz, 1H), 8.32 (s, 1H), 8.09 (t, J = 1.8 Hz, 1H), 7.90 (ddd, J = 8.0, 2.2, 1.5 Hz, 1H), 7.86 – 7.77 (m, 3H), 7.50 – 7.43 (m, 2H), 7.38 (t, J = 7.8 Hz, 1H), 7.33 (dt, J = 7.6, 1.5 Hz, 1H), 4.79 (dd, J = 13.5, 4.6 Hz, 1H), 4.53 – 4.35 (m, 2H), 1.40 (d, J = 6.7 Hz, 3H). Mass spectrum (ESI, m/z): Calcd. for C₂₆H₁₉F₂N₇O₂, 499.2, found [M+H]+, 500.3. Example 302: (S)-N-(3-cyanophenyl)-6-methyl-4-oxo-5-(4-((((S)-1,1,1-trifluorobutan-2- yl)amino)methyl)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide

(S)-N-(3-Cyanophenyl)-5-(4-formylphenyl)-6-methyl-4-oxo-4,5,6,7-tetrahydro-pyrazolo[1,5- a]pyrazine-3-carboxamide (Intermediate 54, 43.59 mg, 0.1 mmol) was added to a solution of (S)- 1,1,1-trifluorobutan-2-amine (38.13 mg, 0.3 mmol) and DIPEA (68.93 µL, 0.4 mmol) in MeOH (0.5 mL). After stirring for 15 minutes at room temperature sodium triacetoxyborohydride (0.3 mmol) suspended in ethanol (1 mL) was added. The reaction mixture was stirred for 12 hours at 50ºC. Aqueous ammonium chloride (0.2 mL) and water (1.8 mL) were added, followed by aqueous ammonium bicarbonate (0.5 mL). The crude mixture was filtered and purified by Prep- HPLC (Conditions: Stationary phase: C18 XBridge 30 x 100 mm 5 µm. Mobile phase: NH4HCO3 0.25% solution in Water and CH3CN), to afford (S)-N-(3-cyanophenyl)-6-methyl-4- oxo-5-(4-((((S)-1,1,1-trifluorobutan-2-yl)amino)methyl)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrazine-3-carboxamide (6.3 mg, 12.3% yield) as a solid after lyophilization.1H NMR (500 MHz, DMSO-d6) δ: 12.55 (d, J=2.1 Hz, 1H) 8.18 - 8.22 (m, 1H) 8.14 - 8.15 (m, 1H) 7.63 - 7.75 (m, 1H) 7.53 - 7.56 (m, 2H) 7.48 - 7.52 (m, 2H) 7.43 - 7.46 (m, 2H) 4.88 - 4.95 (m, 1H) 4.43 - 4.57 (m, 2H) 3.85 - 3.96 (m, 2H) 3.05 - 3.10 (m, 1H) 2.64 - 2.72 (m, 1H) 1.59 - 1.78 (m, 1H) 1.41 - 1.54 (m, 1H) 1.18 - 1.25 (m, 3H) 0.97 - 1.00 (m, 2H) 0.78 - 0.90 (m, 1H). Mass spectrum (ESI, m/z): Calcd. for C H FNO, 4 + 26 25 3 6 2 70.1, found [M+H], 471.3. Examples 303-320, 322-334 and 355-356 were prepared in a manner analogous to Example 302, with the appropriate reagent substitutions.

Example 335: (S)-N-(3-cyanophenyl)-6-methyl-4-oxo-5-(4-(2-(trifluoromethoxy)ethoxy)- phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

Step A: 1-bromo-4-(2-(trifluoromethoxy)ethoxy)benzene. The title compound was prepared in a manner analogous to Example 4, Step B, reacting 2-(4- Bromophenoxy)ethanol (2.5 g, 12 mmol), oxo((trifluoromethyl)sulfonyl)silver (5.9 g, 23 mmol), Selectfluor (6.1 g, 17 mmol), potassium fluoride (2.0 g, 35 mmol), 2-fluoropyridine (2.2 g, 23 mmol) and trimethyl(trifluoromethyl)silane (3.3 g, 23 mmol).1H NMR (400 MHz, CDCl3) δ: 7.42 - 7.37 (m, 2H), 6.84 - 6.78 (m, 2H), 4.31 - 4.29 (m, 2H), 4.21 - 4.16 (m, 2H) Step B: (S)-N-(3-cyanophenyl)-6-methyl-4-oxo-5-(4-(2-(trifluoromethoxy)ethoxy)phenyl)- 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide. The title compound was prepared in a manner analogous to Example 337, Step C, reacting (S)- N-(3-cyanophenyl)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide (Intermediate 6, 150 mg, 0.508 mmol) and 1-bromo-4-(2-(trifluoromethoxy)ethoxy)benzene (159 mg, 0.559 mmol).1H NMR (400 MHz, CDCl3) δ: 12.34 (s, 1H), 8.33 (s, 1H), 8.10 - 8.09 (m, 1H), 7.97 - 7.94 (m, 1H), 7.41 - 7.27 (m, 4H), 7.11 - 7.04 (m, 2H), 4.80 - 4.76 (m, 1H), 4.49 - 4.45 (m, 1H), 4.37 - 4.33 (m, 3H), 4.31 - 4.25 (m, 2H), 1.39 (d, J = 6.8 Hz, 3H). Mass spectrum (ESI, m/z): calcd. for C₂₄H₂₀F₃N₅O₄499.1, found [M+H]+, 500.1. Example 336: (S)-N-(3-cyanophenyl)-5-(6-(difluoro(phenyl)methyl)pyridin-3-yl)-6-methyl- 4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

Step A: (5-bromopyridin-2-yl)(phenyl)methanone. 5-Bromo-2-iodopyridine (5.00 g, 17.6 mmol), a stir bar, and THF (40 mL) were added to an oven-dried and nitrogen-purged 100 mL three-round-bottomed flask, which was subsequently cooled to 0 °C in an ice/water bath and the resulting mixture treated with isopropylmagnesium chloride (2 M in THF, 13.2 mL, 26.4 mmol) dropwise over 15 min at 0 °C and stirring for 40 mines at the same temperature, N-methoxy-N-methylbenzamide (4.364 g, 26.42 mmol) in THF (10 mL) was added above solution. The resulting mixture was stirred at 20 °C for 1 h to give a brown suspension. The reaction progress was monitored by TLC. The mixture was quenched with sat. aq. NH₄Cl (100 mL) and extracted with EtOAc (80 mL ×2). The combined organic extracts washed with brine (100 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- 10% EtOAc/PE) to give (5-bromopyridin-2-yl)(phenyl)methanone as a yellow solid (2.8 g, 52% yield).1H NMR (400 MHz, CDCl3) δ: 8.78 (d, J = 2.0 Hz, 1H), 8.09 - 8.01 (m, 3H), 7.99 - 7.93 (m, 1H), 7.65 - 7.57 (m, 1H), 7.52 - 7.47 (m, 2H). Mass spectrum (ESI, m/z): Calcd. for C₁₂H₈BrNO 261.0, found [M+H]+, 262.0. Step B: 5-bromo-2-(difluoro(phenyl)methyl)pyridine. (5-Bromopyridin-2-yl)(phenyl)methanone (500 mg, 1.91 mmol), a stir bar, dichloromethane (2 mL) were added to a 50 mL round-bottomed flask, and charged with DAST (7.56 mL, 57.2 mmol). The resulting mixture stirred for 16 h at 50 °C to give a yellow solution. The reaction progress was monitored by TLC. The reaction mixture was poured over ice/water (50 mL), extracted with dichloromethane (50 mL ×2), and the combined extracts washed with sat. NaHCO3 (50 mL ×2), and brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure to give a yellow viscous oil. The oil was then subjected to silica gel chromatography (0-8% EtOAc/PE) to give 5-bromo-2- (difluoro(phenyl)methyl)pyridine as a yellow solid (470 mg, 80% yield).1H NMR (400 MHz, CDCl3) δ: 8.70 (d, J = 2.0 Hz, 1H), 7.94 (dd, J = 2.4, 8.4 Hz, 1H), 7.64 (d, J = 8.4 Hz, 1H), 7.59 - 7.55 (m, 2H), 7.45 - 7.40 (m, 3H).19F NMR (376 MHz, CDCl₃) δ: -94.95 (s, 2F). Mass spectrum (ESI, m/z): calcd. for C H BrF N 283.0, found [M+H + 12 8 2 ] , 284.1. Step C: (S)-N-(3-cyanophenyl)-5-(6-(difluoro(phenyl)methyl)pyridin-3-yl)-6-methyl-4-oxo- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

The title compound was prepared in a manner analogous to Example 337, Step C, reacting (S)-N- (3-Cyanophenyl)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide (Intermediate 6, 120 mg, 0.406 mmol) and 5-bromo-2-(difluoro(phenyl)methyl)pyridine (139 mg, 0.488 mmol).1H NMR (400 MHz, CDCl₃) ^ ^ 11.95 (s, 1H), 8.61 (s, 1H), 8.28 (s, 1H), 8.05 (s, 1H), 7.90 - 7.85 (m, 1H), 7.83 - 7.79 (m, 2H), 7.62 - 7.57 (m, 2H), 7.44 - 7.38 (m, 3H), 7.35 - 7.27 (m, 2H), 4.76 (dd, J = 4.0, 13.6 Hz, 1H), 4.45 (dd, J = 2.8, 13.2 Hz, 1H), 4.35 (br s, 1H), 1.36 (d, J = 6.8 Hz, 3H).19F NMR (377 MHz, CDCl₃) δ: -94.88 (s, 2F). Mass spectrum (ESI, m/z): calcd. for C H F N O 4 + 27 20 2 6 2 98.2, found [M+H] , 499.2. Example 337: (S)-N-(3-cyanophenyl)-5-(5-(difluoro(phenyl)methyl)pyridin-2-yl)-6-methyl- 4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

Step A: (6-Bromopyridin-3-yl)(phenyl)methanone. 2,5-Dibromopyridine (2.000 g, 8.443 mmol), a stir bar, and Et2O (16 mL) were added to an oven-dried and nitrogen-purged 100 mL three-round-bottomed flask, which was subsequently cooled to -70 °C (dry ice/EtOH) and the resulting mixture was treated with n-BuLi (4.1 mL, 2.5 M in hexane, 10 mmol) dropwise over 10 min at -70 °C under N2 and before stirring for 30 mines at the same temperature, N,N-dimethylbenzamide (1.889 g, 12.66 mmol) in Et2O (4 mL) was added above solution. The resulting mixture was stirred at -70 °C for 2 h under N₂ and turned to red. The reaction progress was monitored by TLC. The mixture was quenched with sat. aq. NH4Cl (60 mL) and extracted with EtOAc (50 mL ×2). The combined organic extracts washed with brine (50 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness in vacuo to give yellow oil. The oil was then subjected to silica gel chromatography (0-8% EtOAc/PE) to give (6-bromopyridin-3-yl)(phenyl)methanone as yellow oil (1 g, 32% yield).1H NMR (400 MHz, CDCl₃) δ: 8.73 (d, J = 2.4 Hz, 1H), 7.97 (dd, J = 2.4, 8.4 Hz, 1H), 7.82 - 7.76 (m, 2H), 7.67 - 7.62 (m, 2H), 7.55 - 7.50 (m, 2H). Mass spectrum (ESI, m/z): calcd. for C12H8BrNO 261.0; found [M+H]+, 262.1. Step B: 2-bromo-5-(difluoro(phenyl)methyl)pyridine. ⁽6-Bromopyridin-3-yl)(phenyl)methanone (300 mg, 1.15 mmol), a stir bar, DAST (4.537 mL, 34.34 mmol) were added to a 50 mL round-bottomed flask. The resulting mixture was stirred for 16 h at 50 °C to give a yellow solution. The reaction progress was monitored by TLC. The reaction mixture was then poured over ice/water (50 mL), extracted with dichloromethane (60 mL ×2), and the combined extracts washed with sat. NaHCO3 (50 mL ×2) and 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 (0-8% EtOAc/PE) to give 2-bromo-5-(difluoro(phenyl)methyl)pyridine as a yellow solid (120 mg, 34% yield).1H NMR (400 MHz, CDCl3) δ: 8.51 (d, J = 1.6 Hz, 1H), 7.65 (dd, J = 2.4, 8.4 Hz, 1H), 7.55 (d, J = 8.4 Hz, 1H), 7.51 - 7.42 (m, 5H).19F NMR (377MHz, CDCl₃) δ: -89.60 (s, 2F). Mass spectrum (ESI, m/z): calcd. for C₁₂H₈BrF₂N 283.0 m/z, found 284.0 [M+H]+. Step C: (S)-N-(3-cyanophenyl)-5-(5-(difluoro(phenyl)methyl)pyridin-2-yl)-6-methyl-4-oxo- 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide. 2-Bromo-5-(difluoro(phenyl)methyl)pyridine (120 mg, 0.422 mmol), a stir bar, and (S)-N-(3- cyanophenyl)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide (Intermediate 6, 104 mg, 0.352 mmol), copper(I) iodide (40 mg, 0.21 mmol), N₁,N₂- dimethylethane-1,2-diamine (19 mg, 0.21 mmol), K₂CO₃ (146 mg, 1.06 mmol), DMF (2 mL), toluene (2 mL) were added to an oven-dried and nitrogen-purged 50 mL round-bottomed flask, and the resulting mixture stirred for 12 h at 100ºC to give a black suspension. The reaction progress was monitored by LC-MS. The reaction mixture was then treated with H2O (30 mL), extracted with EtOAc (30 mL ×2), and the combined extracts washed with brine (45 mL), dried over anhydrous Na2SO4, filtered, and concentrated to dryness in vacuo to give colorless oil, which was subjected to silica gel chromatography (0-50% EtOAc/PE) to give (S)-N-(3- cyanophenyl)-5-(5-(difluoro(phenyl)methyl)pyridin-2-yl)-6-methyl-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide (91.8 mg, 52% yield) as a white solid.1H NMR (400 MHz, DMSO-d₆) δ: 12.83 (s, 1H), 8.58 (d, J = 5.6 Hz, 1H), 8.25 (s, 1H), 8.19 (d, J = 1.6 Hz, 1H), 7.74 (dd, J = 2.4, 5.6 Hz,1H), 7.46 (s, 4H), 4.92 (dd, J = 4.4, 13.2 Hz, 1H), 4.5 -4.43 (m, 2H), 4.38 (t, J = 6.8 Hz, 2H), 3.07 (t, J = 6.8 Hz, 2H), 1.21 (d, J = 6.8 Hz, 3H). 19F NMR (377 MHz, DMSO-d₆) δ: -88.62 (s, 2F). Mass spectrum (ESI, m/z): calcd. for C₂₇H₂₀F₂N₆O₂498.2; found [M+H]+, 499.2. Example 338: (S)-N-(3-cyanophenyl)-5-(4-(3-methoxybenzoyl)phenyl)-6-methyl-4-oxo- 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

CuI (7.4 mg, 0.04 mmol) was added to a solution of (S)-N-(3-cyanophenyl)-6-methyl-4-oxo- 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide (Intermediate 6, 200 mg, 0.7 mmol) and 4-bromo-3'-methoxybenzophenone (237 mg, 0.8 mmol). Then, tert-amyl alcohol (5 mL) was added and the reaction mixture was bubbled with N2 for 1 minute. Trans-N,N'- dimethylcyclohexane-1,2-diamine (119 μL, 0.7 mmol) was added and the solution was stirred for 5 minutes under nitrogen atmosphere. Then, K2CO3 (193 mg, 1.4 mmol) was added and the reaction was stirred at 102ºC for 16 h. Water was added and the product was extracted with EtOAc (x3). The organic layers were combined, dried over MgSO4 anh. and filtered. The solvent was reduced in vacuo and The crude product was purified by silica gel chromatography (0-10% MeOH/DCM, the product fractions were concentrated in vacuo and the residue triturated with DIPE and filtrated in vacuo to afford (S)-N-(3-cyanophenyl)-5-(4-(3- methoxybenzoyl)phenyl)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3- carboxamide as a white solid (162 mg, 46% yield).1H-NMR (400 MHz, DMSO-d6) δ: 12.36 (s, 1H), 8.23 (s, 1H), 8.19 (d, J = 1.1 Hz, 1H), 7.94 – 7.88 (m, 2H), 7.77 – 7.70 (m, 3H), 7.55 (dd, J = 5.1, 3.5 Hz, 2H), 7.51 (d, J = 7.8 Hz, 1H), 7.35 – 7.27 (m, 3H), 4.95 (dd, J = 13.3, 4.5 Hz, 1H), 4.66 – 4.58 (m, 1H), 4.54 (dd, J = 13.3, 3.8 Hz, 1H), 3.84 (s, 3H), 1.27 (d, J = 6.6 Hz, 3H). Mass spectrum (ESI, m/z): Calcd. for C + 29H23N5O4, 505.2, found [M+H] , 506.0. Example 339: (S)-N-(3-cyanophenyl)-5-(5-(difluoro(phenyl)methyl)pyrimidin-2-yl)-6- methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

Step A: (2-chloropyrimidin-5-yl)(phenyl)methanol. 5-Bromo-2-chloropyrimidine (1.00 g, 5.17 mmol), a stir bar, and THF (25 mL) were added to an oven-dried and nitrogen-purged 100 mL round-bottomed flask, which was subsequently cooled to -30 °C (dry ice/EtOH) and charged with iPrMgCl (3.9 mL, 7.8 mmol, 2 M in THF) dropwise over 1 min at -30 °C. The resulting mixture was stirred for 1 h at -30°C. Then benzaldehyde (713 mg, 6.72 mmol) was added dropwise over 1 min. and the resulting mixture stirred for 2 h at - 30°C. The reaction mixture was then treated with sat. NH₄Cl (50 mL), extracted with EtOAc (50 mL x 2), and the combined extracts washed with brine (50 mL), dried over anhydrous MgSO₄, filtered, and concentrated to dryness in vacuo to give yellow oil. The oil was then subjected to silica gel chromatography (0-30% EtOAc/PE) to give the (2-chloropyrimidin-5- yl)(phenyl)methanol a yellow solid (440 mg, 28% yield).1H NMR (400 MHz, CDCl₃) δ: 8.61 (s, 2H), 7.46 - 7.32 (m, 5H), 5.89 (s, 1H). Mass spectrum (ESI, m/z): calcd. for C11H9ClN2O, 220.0; found [M+H]+, 221.1. Step B: (2-chloropyrimidin-5-yl)(phenyl)methanone. (2-Chloropyrimidin-5-yl)(phenyl)methanol (400 mg, 1.81 mmol), a stir bar, DCM (10 mL), and Dess-Martin periodinane (1.54 g, 3.63 mmol) were added to a 50 mL round-bottomed flask under N2. The resulting reaction mixture was stirred at rt for 2 h. The mixture was diluted with DCM (20 mL), then poured it into sat. aq. NaHCO3 (15 mL) and sat. Na2SO3 (15 mL), and extracted with DCM (20 mLx2). The combined organic extracts washed with brine (40 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 (0~5% EtOAc/PE) to give (2-chloropyrimidin-5-yl)(phenyl)methanone (330 mg, 83% yield) as a white solid.1H NMR (400 MHz, CDCl₃) δ: 9.01 (s, 2H), 7.85 - 7.79 (m, 2H), 7.75 - 7.67 (m, 1H), 7.62 - 7.53 (m, 2H). Mass spectrum (ESI, m/z): calcd. for C + 11H7ClN2O, 218.0; found [M+H] , 218.8. Step C: 2-chloro-5-(difluoro(phenyl)methyl)pyrimidine. The title compound was prepared in a manner analogous to Example 337, Step B, reacting (5- chloropyrazin-2-yl)(phenyl)methanone (230 mg, 1.05 mmnol) and DAST (4 mL).1H NMR (400 MHz, CDCl₃) δ: 8.74 (s, 2H), 7.51 (s, 5H). Mass spectrum (ESI, m/z): calcd. for C₁₁H₇ClF₂N₂, 240.0; found [M+H]+, 240.7. Step D: (S)-N-(3-cyanophenyl)-5-(5-(difluoro(phenyl)methyl)pyrimidin-2-yl)-6-methyl-4-oxo- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

(S)-N-(3-Cyanophenyl)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3- carboxamide (Intermediate 6, 190 mg, 0.643 mmol), 2-chloro-5- (difluoro(phenyl)methyl)pyrimidine (186 mg, 0.772 mmol), Cs₂CO₃ (314 mg, 0.965 mmol), XANTPHOS (37 mg, 0.064 mmol), Pd2(dba)3 (29 mg, 32 mmol) and dioxane (5 mL) were added to an oven-dried and nitrogen-purged 10 mL round-bottomed flask with a reflux condenser, and the resulting mixture stirred for 16 h at 100 °C.The reaction mixture was then poured into H₂O (30 mL), extracted with EtOAc (30 mL x 2), and the combined extracts washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure to give brown oil. The oil was then subjected to silica gel chromatography (0~80% EtOAc/PE) to give the (S)-N-(3-cyanophenyl)-5-(5-(difluoro(phenyl)methyl)pyrimidin-2-yl)-6-methyl-4- oxo-4,5,6,7 tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide (160.4 mg, 50% yield) as a light yellow solid.1H NMR (400 MHz, DMSO-d₆) δ: 11.96 (s, 1H), 9.19 (s, 2H), 8.24 (s, 1H), 8.17 (d, J = 1.2 Hz, 1H), 7.81 - 7.74 (m, 1H), 7.72 - 7.67 (m, 2H), 7.61 - 7.54 (m, 5H), 5.03 - 5.00 (m, 1H), 4.82 (dd, J = 4.4, 14.0 Hz, 1H), 4.56 (dd, J =1.6, 13.6 Hz, 1H), 1.47 (d, J = 6.8 Hz, 3H). Mass spectrum (ESI, m/z): calcd. for C₂₆H₁₉F₂N₇O₂, 499.2; found [M+H]+, 500.2. Example 340: (S)-N-(3-cyanophenyl)-5-(4-(2-methoxybenzoyl)phenyl)-6-methyl-4-oxo- 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

The title compound was prepared in a manner analogous to Example 338, (S)-N-(3- cyanophenyl)-5-(4-(3-methoxybenzoyl)phenyl)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrazine-3-carboxamide reacting (S)-N-(3-cyanophenyl)-6-methyl-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide (Intermediate 6, 200 mg, 0.677 mmol) and (4- bromophenyl)(2-methoxyphenyl)methanone (237 mg, 0.814 mmol).1H NMR (400 MHz, DMSO-d6) δ: 12.34 (s, 1H), 8.22 (s, 1H), 8.18 (d, J = 1.0 Hz, 1H), 7.88 – 7.81 (m, 2H), 7.74 – 7.70 (m, 1H), 7.68 (d, J = 8.6 Hz, 2H), 7.54 (dd, J = 3.6, 2.2 Hz, 2H), 7.37 (dd, J = 7.5, 1.7 Hz, 1H), 7.33 – 7.29 (m, 1H), 7.22 (d, J = 8.3 Hz, 1H), 7.12 (t, J = 7.4 Hz, 1H), 4.92 (dd, J = 13.2, 4.3 Hz, 1H), 4.63 – 4.55 (m, 1H), 4.55 – 4.48 (m, 1H), 3.73 (s, 3H), 1.25 (d, J = 6.6 Hz, 3H). Mass spectrum (ESI, m/z): calcd. for C + 29H23N5O4, 505.2; found [M+H] , 506.1. Example 341: -N-(3-cyanophenyl)-5-(4-(difluoro(6-methylpyridazin-3-

yl)methyl)phenyl)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3- carboxamide

(S)-2-(4-(3-((3-cyanophenyl)carbamoyl)-6-methyl-4-oxo-6,7-dihydropyrazolo[1,5-a]pyrazin- 5(4H)-yl)phenyl)-2,2-difluoroacetic acid (Intermediate 40, 80 mg, 0.16 mmol), 3- methylpyridazine (61.52 mg, 0.65 mmol), silver nitrate (5.55 mg, 0.033 mmol) and potassium persulfate (88.35 mg, 0.33 mmol) were mixed in an 8 mL vial. Then water (1 mL) and CH₃CN (1 mL) were added, followed by TFA (62.53 µL, 1.49 g/mL, 0.82 mmol). The reaction was heated at 60 ºC for 12 hours. Then solvents were evaporated in vacuo and the crude products re-disolved in DMSO/MeOH/NH₄CO₃ (2/1.5/0.5 mL) and then purified by Prep-HPLC (Stationary phase: C18 XBridge 30 x 100 mm 5 µm, Mobile phase: Gradient from 70% NH₄HCO₃0.25% solution in Water, 30% CH₃CN to 35% NH₄HCO₃0.25% solution in Water, 65% CH₃CN), yielding (S)- N-(3-cyanophenyl)-5-(4-(difluoro(6-methylpyridazin-3-yl)methyl)phenyl)-6-methyl-4-oxo- 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide (6 mg, 7% yield) as white solid after lyophilization.1H NMR (500 MHz, DMSO-d₆) δ: 1.15 - 1.22 (m, 3H) 2.54 (s, 3H) 4.03 (q, J=7.13 Hz, 1H) 4.49 - 4.56 (m, 2H) 4.92 (dd, J=13.20, 4.31 Hz, 1H) 7.53 - 7.55 (m, 2H) 7.71 (s, 3H) 7.81 (d, J=8.63 Hz, 1H) 7.93 - 7.95 (m, 1H) 8.18 (dt, J=8.25, 1.25 Hz, 1H) 8.21 - 8.22 (m, 1H) 9.37 - 9.43 (m, 1H) 12.32 (d, J=7.25 Hz, 1H). Mass spectrum (ESI, m/z): Calcd. for C₂₇H₂₁F₂N₇O₂513.1, found [M+H]+, 514.3. Example 342: (S)-N-(3-cyanophenyl)-5-(5-(difluoro(phenyl)methyl)pyrazin-2-yl)-6-methyl- 4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

Step A: (5-bromopyrazin-2-yl)(phenyl)methanone. The title compound was prepared in a manner analogous to Example 9, Step A, reacting 5- bromopyrazine-2-carbonitrile (1.0 g, 5.4 mmol) and phenylmagnesium bromide (1.8 mL, 5.4 mmol, 3 M in diethyl ether).1H NMR (400 MHz, CDCl3) δ: 9.03 (d, J = 1.6 Hz, 1H), 8.78 (d, J = 1.2 Hz, 1H), 8.09 - 8.04 (m, 2H), 7.69 - 7.62 (m, 1H), 7.57 - 7.49 (m, 2H) Step B: 5-bromo-2-(difluoro(phenyl)methyl)pyrimidine. The title compound was prepared in a manner analogous to Example 9, Step B, reacting (5- Bromopyrazin-2-yl)(phenyl)methanone (680 mg, 2.59 mmol) and DAST (5.0 mL).1H NMR (400 MHz, CDCl₃) δ: 8.78 (d, J = 1.2 Hz, 1H), 8.70 (d, J = 1.2 Hz, 1H), 7.61 - 7.56 (m, 2H), 7.49 - 7.44 (m, 3H) Step C: (S)-N-(3-cyanophenyl)-5-(5-(difluoro(phenyl)methyl)pyrazin-2-yl)-6-methyl-4-oxo- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

The title compound was prepared in a manner analogous to Example 337, Step C, reacting (S)- N-(3-cyanophenyl)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide (Intermediate 6, 300 mg, 1.02 mmol) and 2-bromo-5-(difluoro(phenyl)methyl)pyrazine (319 mg, 1.12 mmol).1H NMR (400 MHz, DMSO-d6) δ: 11.80 (s, 1H), 9.34 (s, 1H), 9.11 (d, J = 1.2 Hz, 1H), 8.24 (s, 2H), 7.87 - 7.81 (m, 1H), 7.67 - 7.62 (m, 2H), 7.58 - 7.53 (m, 5H), 5.25 - 5.12 (m, 1H), 4.81 - 4.76 (m, 1H), 4.58 (d, J = 13.6 Hz, 1H), 1.43 (d, J = 6.8 Hz, 3H). Mass spectrum (ESI, m/z): calcd. for C26H19F2N7O2499.2; found [M+H]+, 500.2. Example 343: (S)-N-(3-cyanophenyl)-5-(2-(difluoro methyl)pyrimidin-5-yl)-6-

methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

Step A: (5-bromopyrimidin-2-yl)(phenyl)methanone. 5-Bromopyrimidine-2-carbonitrile (0.50 g, 2.7 mmol), THF (10 mL) and a stir bar was added to a 10 mL round bottomed flask which was subsequently cooled to 0 °C in an ice/water bath, and the resulting mixture treated with phenylmagnesium bromide (0.9 mL, 2.7 mmol, 3 M in diethyl ether) dropwise over 10 min. Then the mixture was stirred at 25 °C for 3 h. The reaction progress was monitored by TLC. The reaction solution was quenched with aq. HCl (1 M, ~5 mL) at 25 °C and the solution was stirred for 20 min at 25 °C. Then the solution was diluted with EA (100 mL), washed with brine (50 mL), the extracts was dried over anhydrous MgSO4, filtered, and concentrated to dryness under reduced pressure to give nearly black viscous oil. The oil was then subjected to silica gel chromatography (0-5% EtOAc/PE) to give (5-bromopyrimidin-2- yl)(phenyl)methanone (580 mg, 81% yield) as a white solid.1H NMR (400 MHz, CDCl3) δ: 9.01 (s, 2H), 8.06 - 8.01 (m, 2H), 7.69 - 7.62 (m, 1H), 7.56 - 7.48 (m, 2H) Step B: 5-bromo-2-(difluoro(phenyl)methyl)pyrimidine. The title compound was prepared in a manner analogous to Example 337, Step B, reacting (6- bromopyridin-3-yl)(phenyl)methanone (300 mg, 1.15 mmol).1H NMR (400 MHz, CDCl3) δ: 8.89 (s, 2H), 7.69 - 7.67 (m, 2H), 7.48 - 7.41 (m, 3H) Step C: (S)-N-(3-cyanophenyl)-5-(2-(difluoro(phenyl)methyl)pyrimidin-5-yl)-6-methyl-4-oxo- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

The title compound was prepared in a manner analogous to Example 337, Step C, reacting (S)- N-(3-cyanophenyl)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide (Intermediate 6, 150 mg, 0.508 mmol) and 5-bromo-2-(difluoro(phenyl)methyl)pyrimidine (159 mg, 0.559 mmol).1H NMR (400 MHz, CDCl3) δ: 11.84 (s, 1H), 8.94 (s, 2H), 8.37 (s, 1H), 8.17 (d, J = 1.6 Hz, 1H), 7.83 - 7.80 (m, 1H), 7.79 - 7.76 (m, 2H), 7.52 - 7.49 (m, 3H), 7.43 - 7.38 (m, 1H), 7.38 - 7.36 (m, 1H), 4.88 - 4.84 (m, 1H), 4.58 - 4.54 (m, 1H), 4.49 - 4.42 (m, 1H), 1.47 (d, J = 6.8 Hz, 3H). Mass spectrum (ESI, m/z): calcd. for C H F N O 499. + 26 19 2 7 2 2; found [M+H] , 500.2. Example 344: (S)-N-(3-cyanophenyl)-5-(4-(4-methoxybenzoyl)phenyl)-6-methyl-4-oxo- 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

The title compound was prepared in a manner analogous to Example 338, (S)-N-(3- cyanophenyl)-5-(4-(3-methoxybenzoyl)phenyl)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrazine-3-carboxamide, reacting (S)-N-(3-cyanophenyl)-6-methyl-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide (Intermediate 6, 150 mg, 0.508 mmol) and (4- bromophenyl)(4-methoxyphenyl)methanone (Intermediate 28, product from Step A, 178 mg, 0.611 mmol).1H NMR (400 MHz, DMSO-d₆) δ: 12.38 (s, 1H), 8.23 (s, 1H), 8.19 (s, 1H), 7.88 – 7.80 (m, 4H), 7.73 (ddd, J = 13.3, 7.3, 5.3 Hz, 3H), 7.58 – 7.53 (m, 2H), 7.16 – 7.11 (m, 2H), 4.95 (dd, J = 13.2, 4.4 Hz, 1H), 4.65 – 4.57 (m, 1H), 4.54 (dd, J = 13.2, 3.8 Hz, 1H), 3.88 (s, 3H), 1.27 (d, J = 6.6 Hz, 3H). Mass spectrum (ESI, m/z): calcd. for C₂₉H₂₃N₅O₄, 505.2; found [M+H]+, 506.1. Example 345: (S)-N-(3-cyanophenyl)-5-(4-(2-hydroxybenzoyl)phenyl)-6-methyl-4-oxo- 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

The title compound was prepared in a manner analogous to Example 346: (S)-N-(3- cyanophenyl)-5-(4-(3-hydroxybenzoyl)phenyl)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrazine-3-carboxamide, reacting (S)-N-(3-cyanophenyl)-5-(4-(2-methoxybenzoyl)phenyl)-6- methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide (Example 340, 113 mg, 0.224 mmol).1H NMR (400 MHz, DMSO-d₆) δ: 12.36 (s, 1H), 10.50 (s, 1H), 8.25 – 8.14 (m, 2H), 7.89 – 7.82 (m, 2H), 7.74 (ddd, J = 5.6, 3.7, 2.2 Hz, 1H), 7.71 – 7.65 (m, 2H), 7.55 (dt, J = 2.7, 2.1 Hz, 2H), 7.50 – 7.43 (m, 1H), 7.40 (dd, J = 7.7, 1.6 Hz, 1H), 7.03 – 6.91 (m, 2H), 4.93 (dd, J = 13.1, 4.3 Hz, 1H), 4.63 – 4.47 (m, 2H), 1.25 (d, J = 6.5 Hz, 3H). Mass spectrum (ESI, m/z): calcd. for C₂₈H₂₁N₅O₄, 491.2; found [M+H]+, 492.1. Example 346: (S)-N-(3-cyanophenyl)-5-(4-(3-hydroxybenzoyl)phenyl)-6-methyl-4-oxo- 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

Boron tribromide (35 μL, 0.36 mmol), was added to a solution of (S)-N-(3-cyanophenyl)-5-(4- (3-methoxybenzoyl)phenyl)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3- carboxamide (Example 338, 128 mg, 0.24 mmol) in dry DCM (5 mL) at -78ºC under nitrogen, and the mixture was stirred at RT for 16h. The mixture was cooled in an ice bath and quenched by slow addition of MeOH (1mL). The solvent was concentrated in vacuo. The crude product was purified by silica gel chromatography (0-100% EtOAc/Hept) to afford impure product, that was then purified by reverse phase chromatography with the following conditions: column, Brand Phenomenex Type Gemini; I.D. (mm) 100 x 21.2; particle size 5 µm (C18) ; mobile phase, (28-64%, 0.1% HCOOH/CH3CN). The mixture was neutralized to pH=7 with NaHCO3 sat. aq. Solution, then extracted with DCM. The organic layer was dried over MgSO₄, filtered and the solvent removed in vacuo, and the residue triturated with DIPE to afford ((S)-N-(3- cyanophenyl)-5-(4-(3-hydroxybenzoyl)phenyl)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrazine-3-carboxamide (36 mg, 30% yield) as a white solid.1H-NMR (400 MHz, DMSO-d₆) δ: 12.36 (s, 1H), 9.88 (s, 1H), 8.23 (s, 1H), 8.19 (s, 1H), 7.88 (d, J = 8.5 Hz, 2H), 7.73 (t, J = 8.9 Hz, 3H), 7.55 (d, J = 5.1 Hz, 2H), 7.40 (t, J = 7.8 Hz, 1H), 7.22 – 7.16 (m, 2H), 7.12 – 7.06 (m, 1H), 4.95 (dd, J = 13.3, 4.4 Hz, 1H), 4.66 – 4.58 (m, 1H), 4.54 (dd, J = 13.1, 3.8 Hz, 1H), 1.27 (d, J = 6.6 Hz, 3H). Mass spectrum (ESI, m/z): Calcd. for C₂₈H₂₁N₅O₄, 491.2, found [M+H]+, 492.0. Example 347: (S)-N-(3-cyanophenyl)-5-(4-(4-hydroxybenzoyl)phenyl)-6-methyl-4-oxo- 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

The title compound was prepared in a manner analogous to Example 346: (S)-N-(3- cyanophenyl)-5-(4-(3-hydroxybenzoyl)phenyl)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrazine-3-carboxamide, reacting (S)-N-(3-cyanophenyl)-5-(4-(4-methoxybenzoyl)phenyl)-6- methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide (Example 344, 123 mg, 0.243 mmol).1H NMR (400 MHz, DMSO-d6) δ: 12.39 (s, 1H), 10.51 (s, 1H), 8.25 – 8.17 (m, 2H), 7.82 (d, J = 8.4 Hz, 2H), 7.72 (ddd, J = 16.0, 9.4, 5.3 Hz, 5H), 7.57 – 7.53 (m, 2H), 6.92 (d, J = 8.6 Hz, 2H), 4.95 (dd, J = 13.2, 4.3 Hz, 1H), 4.65 – 4.49 (m, 2H), 1.27 (d, J = 6.5 Hz, 3H). Mass spectrum (ESI, m/z): calcd. for C H N + 28 21 5O4, 491.2; found [M+H] , 492.1. Example 348: (S)-N-(3-cyanophenyl)-6-methyl-4-oxo-5-(5-(4,4,4-trifluorobutyl)pyrimidin- 2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

Step A: iodotriphenyl(3,3,3-trifluoropropyl)phosphorene. 1,1,1-Trifluoro-3-iodopropane (5.00 g, 22.3 mmol), a stir bar, PPh₃ (6.441 g, 24.56 mmol), and toluene (50 mL) were added to an oven-dried and nitrogen-purged 100 mL round-bottomed flask fitted with a reflux condenser, and the resulting mixture stirred for 12 h at 120 °C. The reaction mixture was cooled to 0 °C and stirred for 30 min, filtered, and the filter cake was concentrated to dryness in vacuo to give iodotriphenyl(3,3,3-trifluoropropyl)phosphorene (3 g, 28% yield) as a white solid.1H NMR (400 MHz, DMSO-d6) δ: 8.01 - 7.72 (m, 15H), 4.02 - 3.92 (m, 2H), 2.75 - 2.57 (m, 2H). Step B: 2-chloro-5-(4,4,4-trifluorobut-1-en-1-yl)pyrimidine. Iodotriphenyl(3,3,3-trifluoropropyl)phosphorene (5.000 g, 10.28 mmol), a stir bar, and THF (40 mL) were added to an oven-dried and nitrogen-purged 100 mL round-bottomed flask, which was subsequently cooled to 0 °C (ice/water) and the resulting mixture treated with n-butyl lithium (4.1 mL, 2.5 M in n-hexane, 10.28 mmol) dropwise over 10 min, and stirred at 20 °C for 30 min, then the resulting reaction was cooled to 0 °C (ice/water) and added 2-chloropyrimidine-5- carbaldehyde (0.733 g, 5.14 mmol) in THF (10 mL) and stirred at 20 °C for 30 min to give a yellow solution. The reaction mixture was quenched with sat. NH4Cl (60 mL) dropwise over 20 min, extracted with EtOAc (60 mL ×3), and the combined extracts washed with brine (50 mL ×3), dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness in vacuo to give a yellow oil. The oil was subjected to silica gel chromatography (0-20%, EtOAc/PE) to give 2- chloro-5-(4,4,4-trifluorobut-1-en-1-yl)pyrimidine (380 mg, 32% yield) as yellow oil.1H NMR (400 MHz, CDCl3) δ: 8.54 (s, 2H), 6.66 (d, J = 11.6 Hz, 1H), 6.02 (dt, J = 11.6, 7.6 Hz, 1H), 2.91 - 3.17 (m, 2H).19F NMR (377 MHz, CDCl3) δ: -66.17 (s, 3F). Mass spectrum (ESI, m/z): calcd. for C H ClF N + 8 6 3 2222.0; found [M+H] , 223.1. Step C: 2-chloro-5-(4,4,4-trifluorobutyl)pyrimidine. 2-Chloro-5-(4,4,4-trifluorobut-1-en-1-yl)pyrimidine (380 mg, 1.71 mmol), a stir bar, EtOH (3 mL), Pd/C (150 mg, 10% Pd, 50% water, 0.141 mmol) were added to 10 mL round-bottomed flask and the mixture stirred at room temperature under H2 balloon (15 Psi) for 2 h. The suspension was filtered through a pad of Celite® and washed with EtOH (20 mL). The filtrate was concentrated to dryness in vacuo to give 2-chloro-5-(4,4,4-trifluorobutyl)pyrimidine (340 mg, 89% yield) as yellow oil.1H NMR (400 MHz, CDCl₃) δ: 8.49 (s, 2H), 2.65 - 2.82 (m, 2H), 2.10 - 2.22 (m, 2H), 1.83 - 2.04 (m, 2H). Step D: (S)-N-(3-cyanophenyl)-6-methyl-4-oxo-5-(5-(4,4,4-trifluorobutyl)pyrimidin-2-yl)- 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide. (S)-N-(3-Cyanophenyl)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3- carboxamide (Intermediate 6, 110 mg, 0.373 mmol), 2-chloro-5- (difluoro(phenyl)methyl)pyrimidine (100 mg, 0.447 mmol), Cs₂CO₃ (182 mg, 0.559 mmol), Xantphos (32 mg, 0.056 mmol), Pd2(dba)3 (17 mg, 0.019 mmol) and dioxane (3 mL) were stirred at 100 °C for 1.5 hours to give a yellow suspension. The reaction mixture was then poured into H2O (30 mL), extracted with EtOAc (30 mL ×2), and the combined extracts washed with brine (30 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness under reduced pressure to give brown oil. The crude product was purified by Prep-HPLC with the following conditions: column, Welch Xtimate C18, 150 mm, 30 mm x 5 ^m; mobile phase, 32% to 72% CH3CN and H2O (containing 0.05% NH3·H2O + 10 mM NH4HCO3) and then freeze dried to afford (S)-N-(3-cyanophenyl)-6-methyl-4-oxo-5-(5-(4,4,4-trifluorobutyl)pyrimidin-2-yl)-4,5,6,7 tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide (44 mg, 16% yield) as a white solid.1H NMR (400 MHz, CDCl3) δ: 12.09 (s, 1H), 8.69 (s, 2H), 8.34 (s, 1H), 8.10 (s, 1H), 8.01 (br d, J = 8.0 Hz, 1H), 7.44 - 7.32 (m, 2H), 5.03 - 4.93 (m, 1H), 4.76 (dd, J = 4.4, 13.6 Hz, 1H), 4.47 (dd, J = 2.0, 13.6 Hz, 1H), 2.80 (br t, J = 8.0 Hz, 2H), 2.31 - 2.15 (m, 2H), 2.00 (q, J = 8.0 Hz, 2H), 1.58 (d, J = 6.4 Hz, 3H).19F NMR (377 MHz, CDCl₃) δ: 65.92 (s, 3F). Mass spectrum (ESI, m/z): calcd. for C H F N O 483.2; found [M + 23 20 3 7 2 +H] , 484.2. Example 349: (S)-N-(3-cyanophenyl)-6-methyl-4-oxo-5-(4-((1s,3s)-3- (trifluoromethoxy)cyclobutyl)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3- carboxamide.

The title compound was prepared in a manner analogous to Example 337, Step C, reacting (S)- N-(3-cyanophenyl)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide (Intermediate 6, 120 mg, 0.406 mmol) and 1-bromo-4-((1s,3s)-3- (trifluoromethoxy)cyclobutyl)benzene (Intermediate 41, 132 mg, 0.447 mmol).1H NMR (400 MHz, CDCl₃) δ: 12.31 (s, 1H), 8.33 (s, 1H), 8.09 (s, 1H), 7.97 - 7.95 (m, 1H), 7.43 - 7.36 (m, 3H), 7.35 - 7.30 (m, 3H), 4.82 - 4.77 (m, 1H), 4.74 - 4.67 (m, 1H), 4.50 - 4.46 (m, 1H), 4.40 - 4.33 (m, 1H), 3.23 - 3.12 (m, 1H), 2.94 - 2.84 (m, 2H), 2.46 - 2.35 (m, 2H), 1.39 (d, J = 6.8 Hz, 3H). Mass spectrum (ESI, m/z): calcd. for C26H22F3N5O3509.2; found [M+H]+, 510.2. Examples 350-354 were prepared in a manner analogous to Example 341, with the appropriate reagent substitutions.

Example 357: 5-(4-(3-(2-aminoethyl)benzyl)phenyl)-N-(3-cyanophenyl)-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

Step A: 2-(3-(4-bromobenzyl)phenyl)ethanol. 1-Bromo-4-(bromomethyl)benzene (2.94 g, 11.7 mmol), (3-(2-hydroxyethyl)phenyl)boronic acid (1.5 g, 9.0 mmol), a stir bar, Na₂CO₃ (1.9 g, 18 mmol), tetrakis(triphenylphosphine) palladium(0) (522 mg, 0.45 mmol), toluene (20 mL), ethanol (15 mL) and water (10 mL) were added to an oven-dried and nitrogen-purged 100 mL round-bottomed flask and then stirred while heating at 100 °C for 12 hour under N₂. The reaction vessel was cool to rt, then filtered, and concentrated to give yellow oil. The oil was then subjected to silica gel chromatography (20% EtOAc/PE) to give the 2-(3-(4 bromobenzyl)phenyl)ethanol (900 mg, 19% yield) as yellow oil.1H NMR (400 MHz, CDCl3) ^ ^ 7.59 - 7.54 (m, 2H), 7.45 - 7.38 (m, 2H), 7.25 - 7.18 (m, 4H), 4.08 (s, 2H), 4.01 (t, J = 6.8 Hz, 2H), 3.00 (t, J = 6.8 Hz, 2H) Step B: 2-(3-(4-bromobenzyl)phenyl)acetaldehyde. 2-(3-(4-Bromobenzyl)phenyl)ethanol (900 mg, 3.09 mmol), CH3CN (9 mL) was added to a 50 mL round-bottomed flask, the solution was treated with IBX (1.7 g, 6.2 mmol). The resulting solution was stirred at 55 °C for 3 h. The solution was cooled to 0°C, then filtered through a pad of Celite® and washed with ethyl acetate (30 mL). The filtrate was concentrated to dryness under reduced pressure to afford the 2-(3-(4-bromobenzyl)phenyl)acetaldehyde (900 mg, crude) as yellow oil, which was used into the next step without further purification. Step C: (E)-2-(3-(4-bromobenzyl)phenyl)acetaldehyde oxime. 3-(3-(4-Bromobenzyl)phenyl)propanal (900 mg, 3.11 mmol), a stir bar, MeOH (9 mL), Py (0.252 mL, 3.11 mmol) was added to a round-bottomed flask. The solution was charged with hydroxylamine hydrochloride (433 mg, 6.23 mmol).The resulting solution was stirred at rt for 1 h. The yellow solution was consumed under pressure to give a yellow oil. The oil was subjected to silica gel chromatography (20%, EtOAc/PE) to give (E)-2-(3-(4- bromobenzyl)phenyl)acetaldehyde oxime (800 mg, 38% yield). Mass spectrum (ESI, m/z): calcd. for C H B + 15 14 rNO 303.0; found [M+H] , 304.0. Step D: 2-(3-(4-bromobenzyl)phenyl)ethanamine. (E)-2-(3-(4-Bromobenzyl)phenyl)acetaldehyde oxime (800 mg, 2.63 mmol), THF (80 ml), a stir bar and 2 N HCl (29 mL) were add to a 250 mL round-bottomed flask. The resulting mixture was treated with Zn (1.38 g, 21.1 mmol) at 25 °C. The resultant mixture was stirred at 80 °C for 30 mines under N2. The reaction was monitored by TLC. The reaction mixture was no work-up and used directly to the next step. Step E: tert-butyl (3-(4-bromobenzyl)phenethyl)carbamate. 2-(3-(4-Bromobenzyl)phenyl)ethanamine (80 mL in THF solution), a stir bar were added to a 250 mL round-bottomed flask, the solution was treated with NaOH (2 M, 39 mL), the pH value was ~8 to 9. After that the solution was charged with Boc2O (902 mg, 4.14 mmol). The resulting solution was stirred at rt for 12 h. The reaction was monitored by TLC and LC-MS. The reaction mixture was extracted with DCM (30 mL x 2), and the combined extracts washed with sat. NaHCO₃ (30 mL x 3) and brine (30 mL), dried over anhydrous MgSO₄, filtered, and concentrated to dryness in vacuo to give nearly black viscous oil. The oil was then subjected to silica gel chromatography (0-30% EtOAc/PE) to give tert-butyl (3-(4- bromobenzyl)phenethyl)carbamate as colorless oil (750 mg, crude). The crude product was purified by Prep-HPLC with the following conditions: column, Boston Prime C18, 150 mm, 30 mm x 5 ^m; mobile phase, 75% to 100% (v/v) CH3CN/water (containing 0.05% NH3·H2O + 10 mM NH4HCO3) and then freeze dried to afford tert-butyl (3-(4- bromobenzyl)phenethyl)carbamate as colorless oil (210 mg, 20% yield). Mass spectrum (ESI, m/z): calcd. for C₂₀H₂₄BrNO₂389.1; found [M-56+H]+, 334.1 Step F: tert-butyl (3-(4-(3-((3-cyanophenyl)carbamoyl)-4-oxo-6,7-dihydropyrazolo[1,5- a]pyrazin-5(4H)yl)benzyl)phenethyl)carbamate. The title compound was prepared in a manner analogous to Example 337, Step C, reacting N-(3- cyanophenyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide (Intermediate 9, 109 mg, 0.342 mmol) and tert-butyl (3-(4-bromobenzyl)phenethyl)carbamate (160 mg, 0.410 mmol).1H NMR (400MHz, CDCl₃) δ: 12.29 (s, 1H), 8.31 (s, 1H), 8.10 (s, 1H), 8.04 (s, 1H), 7.94 (td, J = 1.6, 8.0 Hz, 1H), 7.40 - 7.27 (m, 6H), 7.11 - 7.05 (m, 3H), 4.67 - 4.62 (m, 2H), 4.60 - 4.51 (m, 1H), 4.02 (s, 2H), 3.36 (q, J = 6.4 Hz, 2H), 2.78 (t, J = 7.2 Hz, 2H), 1.44 (s, 9H). Mass spectrum (ESI, m/z): calcd. for C34H34N6O4590.3; found [M+H]+, 591.3. Step G: 5-(4-(3-(2-aminoethyl)benzyl)phenyl)-N-(3-cyanophenyl)-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide. tert-Butyl 4-(4-(3-((3-cyanophenyl)carbamoyl)-4-oxo-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)- yl)benzyl)benzylcarbamate (210 mg, 0.356 mmol), a stir bar, HCl (1.87 mL, 4 M in 1,4-dioxane) and 1,4-dioxane (3 mL) were added to a 10 mL round bottomed flask. The resulting solution was stirred at rt for 2 h to give a white suspension. The white suspension was filtrated and washed with 1,4-dioxane (5 mL x 3) and concentrated under pressure to give 5-(4-(3-(2- aminoethyl)benzyl)phenyl)-N-(3-cyanophenyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrazine-3-carboxamide as white solid (182 mg, 97% yield).1H NMR (400 MHz, DMSO-d6) δ: 12.52 (s, 1H), 8.18 (s, 1H), 8.15 (s, 1H), 7.96 (br s, 3H), 7.75 - 7.69 (m, 1H), 7.56 - 7.52 (m, 2H), 7.45 - 7.35 (m, 4H), 7.31 - 7.26 (m, 1H), 7.23 - 7.17 (m, 2H), 7.12 (d, J = 7.6 Hz, 1H), 4.66 (m, 2H), 4.24 (m, 2H), 3.98 (s, 2H), 3.03 (m, 2H), 2.90 - 2.80 (m, 2H). Mass spectrum (ESI, m/z): calcd. for C₂₉H₂₆N₆O₂490.2, found [M+H]+, 491.3. Example 358: N-(3-cyanophenyl)-5-(4-(4-(2-(N-methylpropionamido)ethyl)benzyl)phenyl)- 4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

5-(4-(4-(2-Aminoethyl)benzyl)phenyl)-N-(3-cyanophenyl)-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide (23 mg, 0.04 mmol), DIPEA (15 mg, 0.12 mmol), a stir bar, propionyl chloride (6 mg, 0.06 mmol), and DCM (2 mL) were added to a 10 mL round-bottomed flask. The mixture was stirred for 3 hours at 25 °C. The reaction mixture was concentrated to dryness in vacuo to give a yellow solid. The crude product was purified by Prep-HPLC with the following conditions: column, Welch Xtimate C18, 150 mm, 30 mm x 5 ^m; mobile phase, 32% to 62% (v/v) CH3CN and water with 0.2% FA and then freeze dried to afford N-(3-cyanophenyl)-5-(4-(4-(2-(N-methylpropionamido)ethyl)benzyl)phenyl)-4-oxo- 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide as a white solid (11.8 mg, 50% yield). 1H NMR (400 MHz, CD₃OD) δ: 9.19 (s, 1H), 8.57 (br s, 1H), 8.25 (s, 1H), 7.82 (m,1H), 7.59 - 7.49 (m, 2H), 7.43 (m, 4H), 7.25 - 7.14 (m, 4H), 4.95 (m, 2H), 4.47 (m,2H), 4.37 (s, 3H), 4.04 (s, 2H), 3.39 (t, J = 7.2 Hz, 2H), 2.78 (t, J = 7.2 Hz, 2H), 2.17(q, J = 7.6 Hz, 2H), 1.10 (t, J = 7.6 Hz, 3H). Mass spectrum (ESI, m/z): calcd. for C + 33H32N6O3560.3; found [M+H] , 561.3. Example 359: (S)-N-(2-cyanopyridin-4-yl)-5-(4-(1,1-difluoroethyl)phenyl)-6-methyl-4-oxo- 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

The title compound was prepared in a manner analogous to Example 337, Step C, reacting (S)-5- (4-(1,1-difluoroethyl)phenyl)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3- carboxylic acid (Intermediate 14, 260 mg, 0775 mmol) and 4-aminopicolinonitrile (102 mg, 0.853 mmol).1H NMR (400MHz, DMSO-d6) δ: 12.73 (s, 1H), 8.58 (d, J = 5.6 Hz, 1H), 8.26 (s,1H), 8.19 (d, J = 2.0 Hz, 1H), 7.78 - 7.71 (m, 3H), 7.69 - 7.62 (m, 2H), 5.03 - 4.85 (m, 1H), 4.61 - 4.46 (m, 2H), 2.04 (t, J = 18.8 Hz, 3H), 1.23 (d, J = 6.4 Hz, 3H). Mass spectrum (ESI, m/z): calcd. for C H F N O 4 + 22 18 2 6 2 36.1; found [M+H] , 437.1. Example 360: (S)-N-(2-cyanopyridin-4-yl)-6-methyl-4-oxo-5-(4-(2- (trifluoromethoxy)ethyl)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

Step A: ethyl (S)-6-methyl-4-oxo-5-(4-(2-(trifluoromethoxy)ethyl)phenyl)-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxylate. The title compound was prepared in a manner analogous to Example 337, Step C, reacting (S)- ethyl 6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxylate (Intermediate 1, product from Step D, 400 mg, 1.79 mmol) and 1-bromo-4-(2-(trifluoromethoxy)ethyl)benzene (579 mg, 2.15 mmol).1H NMR (400 MHz, DMSO-d₆) ^ ^ 7.99 (s, 1H), 7.37 (q, J = 8.4 Hz, 4H), 4.80 (s, 1H), 4.43 - 4.31 (m, 4H), 4.25 - 4.16 (m, 2H), 3.03 (t, J = 6.4 Hz, 2H), 1.25 (t, J = 7.1 Hz, 3H), 1.17 (d, J = 6.4 Hz, 3H). Mass spectrum (ESI, m/z): calcd. for C₁₉H₂₀F₃N₃O₄411.1; found [M+H]+, 411.9. Step B: (S)-6-methyl-4-oxo-5-(4-(2-(trifluoromethoxy)ethyl)phenyl)-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxylic acid. The title compound was prepared in a manner analogous to Intermediate 1, Step F, reacting (S)- ethyl 6-methyl-4-oxo-5-(4-(2-(trifluoromethoxy)ethyl)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrazine-3-carboxylate(380 mg, 0.924 mmol), EtOH (25 mL) and NaOH (0.924 mL, 2M in water).1H NMR (400 MHz, DMSO-d₆) ^ ^ 14.08 (br s, 1H), 8.15 (s, 1H), 7.44 (s, 4H), 4.91 - 4.84 (m, 1H), 4.57 - 4.47 (m, 2H), 4.36 (t, J = 6.4 Hz, 2H), 3.05 (t, J = 6.4 Hz, 2H), 1.21 (d, J = 6.4 Hz, 3H). Mass spectrum (ESI, m/z): calcd. for C₁₇H₁₆F₃N₃O₄383.1; found [M+H]+, 383.9. Step C: (S)-N-(2-cyanopyridin-4-yl)-6-methyl-4-oxo-5-(4-(2-(trifluoromethoxy)ethyl)phenyl)- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

(S)-6-Methyl-4-oxo-5-(4-(2-(trifluoromethoxy)ethyl)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrazine-3-carboxylic acid (200 mg, 0.522 mmol), a stir bar, 4-aminopicolinonitrile (93.2 mg, 0.783 mmol) and Pyridine (5 mL) were added to a 10 mL round-bottomed flask, and the resulting mixture treated with POCl₃ (97 μL, 1.0 mmol) in one portion. Then the mixture stirred at rt for 3 h to give a light brown solution. The reaction mixture was then poured into sat. aq. NaHCO3 (30 mL), extracted with EtOAc (20 mL x 2), and the combined extracts washed with brine (30 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness under reduced pressure to give a brown oil. The oil was then subjected to silica gel chromatography (0~70% EtOAc/PE) to give the (S)-N-(2-cyanopyridin-4-yl)-6-methyl-4-oxo-5-(4-(2- (trifluoromethoxy)ethyl)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide (147.3 mg, 57% yield) as a white solid.1H NMR (400 MHz, DMSO-d6) ^: 12.83 (s, 1H), 8.58 (d, J = 5.6 Hz, 1H), 8.25 (s, 1H), 8.19 (d, J = 1.6 Hz, 1H), 7.74 (dd, J = 2.4, 5.6 Hz, 1H), 7.46 (s, 4H), 4.92 (dd, J = 4.4, 13.2 Hz, 1H), 4.55 - 4.43 (m, 2H), 4.38 (t, J = 6.8 Hz, 2H), 3.07 (t, J = 6.8 Hz, 2H), 1.21 (d, J = 6.8 Hz, 3H). Mass spectrum (ESI, m/z): calcd. for C23H19F3N6O3484.1; found [M+H]+, 485.1. Example 361: 3-cyano-4-methoxy-N-((S)-6-methyl-4-oxo-5-(4-((1R,2R)-2- (trifluoromethyl)cyclopropyl)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3- yl)benzamide.

The title compound was prepared in a manner analogous to Example 337, Step C, reacting (S)-3- cyano-4-methoxy-N-(6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)benzamide (Intermediate 13, 3.0 g, 9.2 mmol) and 1-bromo-4-((1R,2R)-2- (trifluoromethyl)cyclopropyl)benzene (2.69 g, 10.1 mmol).1H NMR (400 MHz, DMSO-d₆) δ: 9.83 (s, 1H), 8.21 (s, 1H), 8.18 - 8.13 (m, 1H), 8.11 (s, 1H), 7.44 - 7.29 (m, 5H), 4.72 (dd, J = 4.4, 12.8 Hz, 1H), 4.48 - 4.40 (m, 1H), 4.36 (dd, J = 3.6, 12.8 Hz, 1H), 3.99 (s, 3H), 2.48 - 2.44 (m, 1H), 2.36 - 2.28 (m, 1H), 1.43 - 1.36 (m, 1H), 1.35 - 1.28 (m, 1H), 1.21 (d, J = 6.4 Hz, 3H). Mass spectrum (ESI, m/z): Calcd. for C₂₆H₂₂F₃N₅O₃509.2, found [M+H]+, 510.2. Example 362: (S)-3-cyano-4-methoxy-N-(6-methyl-4-oxo-5-(4-(3,3,3-trifluoropropyl)- phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)benzamide.

The title compound was prepared in a manner analogous to Example 337, Step C, reacting (S)-3- cyano-4-methoxy-N-(6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)benzamide (Intermediate 13, 100 mg, 0.31 mmol) and 1-bromo-4-(3,3,3-trifluoropropyl)benzene (93.3 mg, 0.369 mmol).1H NMR (400 MHz, DMSO-d6) δ: 9.84 (s, 1H), 8.22 (d, J = 2.4 Hz, 1H), 8.16 (dd, J = 2.4, 9.2 Hz, 1H), 8.11 (s, 1H), 7.43 - 7.35 (m, 5H), 4.72 (dd, J = 4.4, 13.2 Hz, 1H), 4.49 - 4.41 (m, 1H), 4.36 (dd, J = 3.6, 13.2 Hz, 1H), 3.99 (s, 3H), 2.91 - 2.82 (m, 2H), 2.69 - 2.58 (m, 2H), 1.21 (d, J = 6.4 Hz, 3H). Mass spectrum (ESI, m/z): calcd. for C25H22F3N5O3497.2; found [M+H]+, 498.2. Example 363: (S)-3-cyano-4-methoxy-N-(6-methyl-4-oxo-5-(4-((3,3,3-trifluoropropoxy)- methyl)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)benzamide.

The title compound was prepared in a manner analogous to Example 337, Step C, reacting (S)-3- cyano-4-methoxy-N-(6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)benzamide (Intermediate 13, 100 mg, 0.31 mmol) and 1-bromo-4-((3,3,3-trifluoropropoxy)methyl)benzene (130.5 mg,0.46 mmol).1H NMR (400 MHz, DMSO-d6) δ: 9.84 (s, 1H), 8.22 (d, J = 2.0 Hz, 1H), 8.16 (dd, J = 2.0, 8.8 Hz, 1H), 8.12 (s, 1H), 7.46 - 7.38 (m, 5H), 4.73 (dd, J = 4.4, 13.2 Hz, 1H), 4.55 (s, 2H), 4.50 - 4.44 (m, 1H), 4.36 (dd, J = 4.0, 13.2 Hz, 1H), 3.99 (s, 3H), 3.68 (t, J = 6.0 Hz, 2H), 2.67 - 2.56 (m, 2H), 1.22 (d, J = 6.8 Hz, 3H). Mass spectrum (ESI, m/z): calcd. for C H F N O 527.2; found [M+H]+ 26 24 3 5 4 , 528.2. Example 364: (S)-3-cyano-4-methoxy-N-(6-methyl-4-oxo-5-(4-(2-(2,2,2-trifluoroethoxy)- ethyl)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)benzamide.

The title compound was prepared in a manner analogous to Example 337, Step C, reacting (S)-3- cyano-4-methoxy-N-(6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)benzamide (Intermediate 13, 150 mg, 0.461 mmol) and 1-bromo-4-(2-(2,2,2-trifluoroethoxy)ethyl)benzene (144 mg, 0.507 mmol).1H NMR (400 MHz, CDCl₃) δ: 9.62 (s, 1H), 8.32 (s, 1H), 8.07 (d, J = 2.0 Hz, 1H), 8.02 - 7.99 (m, 1H), 7.27 (d, J = 8.4 Hz, 2H), 7.21 - 7.16 (m, 2H), 6.91 (d, J = 8.8 Hz, 1H), 4.60 - 4.49 (m, 1H), 4.31 - 4.21 (m, 2H), 3.90 (s, 3H), 3.80 - 3.71 (m, 4H), 2.89 (t, J = 6.8 Hz, 2H), 1.30 (d, J = 6.4 Hz, 3H). Mass spectrum (ESI, m/z): Calcd. for C26H24F3N5O4527.2; found [M+H]+, 528.2. Example 365: (S)-3-cyano-4-methoxy-N-(6-methyl-4-oxo-5-(4-((1-(trifluoromethyl)- cyclopropyl)methyl)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)benzamide.

Step A: N-methoxy-N-methyl-1-(trifluoromethyl)cyclopropane-1-carboxamide. 1-(Trifluoromethyl)cyclopropanecarboxylic acid (9.0 g, 58 mmol), a stir bar, CDI (12 g, 76 mmol) and DCM (100 mL) were added to a 250 mL round bottomed flask, the mixture was treated with N,O-dimethylhydroxylamine hydrochloride (8.0 g, 82 mmol) and TEA (11 mL, 82 mmol), the reaction mixture was stirred overnight at rt. The reaction progress was monitored by TLC. The reaction mixture was quenched with 3 M HCl (60 mL), extracted with DCM (30 mL x 2), the combined extracts washed with brine (40 mL), dried over anhydrous Na2SO4, filtered, and concentrated to dryness in vacuo to give colorless oil. The oil was subjected to silica gel chromatography (0-15% EtOAc/PE) to give N-methoxy-N-methyl-1- (trifluoromethyl)cyclopropane-1-carboxamide (11 g, 78% yield) as colorless oil.1H NMR (400 MHz, CDCl₃) δ: 3.71 (d, J = 1.2 Hz, 3H), 3.26 (s, 3H), 1.30 - 1.18 (m, 4H) Step B: (4-bromophenyl)(1-(trifluoromethyl)cyclopropyl)methanone. 1-Bromo-4-iodobenzene (6.4 g, 32 mmol), a stir bar and THF (50 mL) were added to an oven- dried and nitrogen-purged 250 mL round bottomed flask, which was subsequently cooled to -70 °C (dry ice/EtOH), the resulting mixture treated with n-BuLi (15 mL, 2.5 M), dropwise over 10 min. The mixture was stirred at -70 °C for 1 h, then a solution of N-methoxy-N-methyl-1- (trifluoromethyl)cyclopropanecarboxamide (11 g, 39 mmol) and THF (50 mL) was added to the above solution. The mixture was stirred at -70 °C for 1 h. The reaction progress was monitored by TLC. The reaction mixture was diluted with water (50 mL), extracted with EtOAc (50 mL x 2), the combined extracts washed with brine (30 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness in vacuo to give the light yellow oil. The oil was then subjected to silica gel chromatography (0-5% EtOAc/PE) to give (4-bromophenyl)(1- (trifluoromethyl)cyclopropyl)methanone (3.1 g, 33% yield) as a yellow solid.1H NMR (400MHz, CDCl₃) δ: 7.71 (d, J = 8.5 Hz, 2H), 7.57 - 7.47 (m, 2H), 1.41 - 1.30 (m, 4H) Step C: 1-bromo-4-((1-(trifluoromethyl)cyclopropyl)methyl)benzene. (4-Bromophenyl)(1-(trifluoromethyl)cyclopropyl)methanone (500 mg, 1.71 mmol), a stir bar, triethylsilane (652 μL, 4.09 mmol), and DCE (15 mL) were added to an oven-dried and nitrogen- purged 50 mL round bottomed flask, which was subsequently cooled to 0 °C (ice/water), and the resulting mixture treated with boron trifluoride diethyl etherate (259 μL, 2.05 mmol), dropwise over 5 min. The mixture was stirred at 50 °C for 3 h. The reaction mixture was treated with sat. aq. NaHCO₃ (5 mL), extracted with DCM (10 mL x 2), the combine combined extracts washed with brine (25 mL), dried over anhydrous Na2SO4, filtered, and concentrated to dryness in vacuo to give colorless oil. The oil was subject to silica gel chromatography (0-10% MTBE/PE) to give 1-bromo-4-((1-(trifluoromethyl)cyclopropyl)methyl)benzene (210 mg, 44% yield) as colorless oil.1H NMR (400 MHz, CDCl3) δ: 7.42 (d, J = 8.4 Hz, 2H), 7.04 (d, J=8.4 Hz, 2H), 2.95 (s, 2H), 0.97 - 0.92 (m, 2H), 0.51 (s, 2H) Step D: (S)-3-cyano-4-methoxy-N-(6-methyl-4-oxo-5-(4-((1-(trifluoromethyl)cyclopropyl)- methyl)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)benzamide. The title compound was prepared in a manner analogous to Example 337, Step C, reacting (S)-3- Cyano-4-methoxy-N-(6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)benzamide (Intermediate 13, 150 mg, 0.461 mmol) and 1-bromo-4-((1- (trifluoromethyl)cyclopropyl)methyl)benzene (142 mg, 0.507 mmol).1H NMR (400 MHz, CDCl₃) δ: 9.70 (s, 1H), 8.43 (s, 1H), 8.17 (d, J = 2.4 Hz, 1H), 8.13 - 8.10 (m, 1H), 7.35 - 7.27 (m, 4H), 7.01 (d, J = 8.8 Hz, 1H), 4.69 - 4.60 (m, 1H), 4.42 - 4.31 (m, 2H), 4.00 (s, 3H), 3.05 (s, 2H), 1.40 (d, J = 6.4 Hz, 3H), 1.03 - 0.98 (m, 2H), 0.65 - 0.58 (m, 2H). Mass spectrum (ESI, m/z): calcd. for C₂₇H₂₄F₃N₅O₃523.2; found [M+H]+ , 524.2. Example 366: (S)-3-cyano-4-methoxy-N-(6-methyl-4-oxo-5-(4-(2-(trifluoromethoxy)- ethoxy)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)benzamide.

The title compound was prepared in a manner analogous to Example 337, Step C, reacting (S)-3- Cyano-4-methoxy-N-(6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)benzamide (Intermediate 13, 150 mg, 0.461 mmol) and 1-bromo-4-(2-(trifluoromethoxy)ethoxy)benzene (145 mg, 0.507 mmol).1H NMR (400MHz, CDCl3) δ: 9.72 (s, 1H), 8.42 (s, 1H), 8.17 (d, J = 2.4 Hz, 1H), 8.12 - 8.09 (m, 1H), 7.28 - 7.27 (m, 1H), 7.27 - 7.26 (m, 1H), 7.07 - 6.97 (m, 3H), 4.67 - 4.61 (m, 1H), 4.37 - 4.31 (m, 4H), 4.27 - 4.23 (m, 2H), 4.00 (s, 3H), 1.38 (d, J = 6.4 Hz, 3H). Mass spectrum (ESI, m/z): calcd. for C + 25H22F3N5O5529.2, found [M+H] , 530.2. Example 367: (S)-3-cyano-4-methoxy-N-(6-methyl-4-oxo-5-(4-(1,1,2,2-tetrafluoroethyl)- phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)benzamide.

The title compound was prepared in a manner analogous to Example 337, Step C, reacting (S)-3- cyano-4-methoxy-N-(6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)benzamide (Intermediate 13, 169 mg, 0.519 mmol) and 1-bromo-4-(1,1,2,2-tetrafluoroethyl)benzene (200 mg, 0.778 mmol).1H NMR (400 MHz, DMSO-d₆) δ: 9.85 (s, 1H), 8.24 (d, J = 2.0 Hz, 1H), 8.19 - 8.15 (m, 1H), 8.13 (s, 1H), 7.79 - 7.62 (m, 4H), 7.41 (d, J = 9.2 Hz, 1H), 6.99 - 6.66 (m, 1H), 4.81 - 4.70 (m, 1H), 4.62 - 4.54 (m, 1H), 4.42 - 4.36 (m, 1H), 4.00 (s, 3H), 1.26 (d, J = 6.8 Hz, 3H). Mass spectrum (ESI, m/z): calcd. for C₂₄H₁₉F₄N₅O₃501.1; found [M+H]+, 502.1. Example 368: (S)-3-cyano-4-methoxy-N-(7-methyl-4-oxo-5-(4-(trifluoromethyl)phenyl)- 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)benzamide.

The title compound was prepared in a manner analogous to Intermediate 17, Step B, reacting (S)- 3-cyano-4-methoxy-N-(7-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3- yl)benzamide (Intermediate 36, 30 mg, 0.092 mmol) and 4-bromobenzotrifluoride (0.014 mL, 0.10 mmol).1H NMR (300 MHz, DMSO-d₆) δ: 9.88 (s, 1H), 8.23 (d, J = 2.3 Hz, 1H), 8.17 (dd, J = 8.4, 2.8 Hz, 2H), 7.85 (d, J = 8.6 Hz, 2H), 7.71 (d, J = 8.4 Hz, 2H), 7.42 (d, J = 9.0 Hz, 1H), 4.82 – 4.72 (m, 1H), 4.36 (dd, J = 12.8, 4.2 Hz, 1H), 4.14 (dd, J = 12.8, 8.2 Hz, 1H), 4.00 (s, 3H), 1.57 (d, J = 6.5 Hz, 3H). Mass spectrum (ESI, m/z): calcd. for C23H18F3N5O3, 469.1; found [M+H]+, 470.1. Example 369: (S)-3-cyano-N-(5-(4-(3,3-difluorocyclobutyl)phenyl)-6-methyl-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazin-3-yl)-4-methoxybenzamide.

The title compound was prepared in a manner analogous to Example 337, Step C, reacting (S)-3- cyano-4-methoxy-N-(6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)benzamide (Intermediate 13, 200 mg, 0.615 mmol) and 1-bromo-4-(3,3-difluorocyclobutyl)benzene (167 mg, 0.676 mmol).1H NMR (400 MHz, CDCl₃) δ: 9.70 (s, 1H), 8.41 (s, 1H), 8.15 (d, J = 2.4 Hz, 1H), 8.11 - 8.08 (m, 1H), 7.41 - 7.36 (m, 2H), 7.34 - 7.30 (m, 2H), 7.00 (d, J = 8.8 Hz, 1H), 4.70 - 4.59 (m, 1H), 4.43 - 4.32 (m, 2H), 3.99 (s, 3H), 3.47 - 3.42 (m, 1H), 3.11 - 2.97 (m, 2H), 2.78 - 2.62 (m, 2H), 1.39 (d, J = 6.4 Hz, 3H) Mass spectrum (ESI, m/z): calcd. for C26H23F2N5O3491.2; found [M+H]+, 492.2. Example 370: 3-cyano-4-methoxy-N-((S)-6-methyl-4-oxo-5-(4-((1s,3s)-3-(trifluoromethoxy)- cyclobutyl)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)benzamide.

The title compound was prepared in a manner analogous to Example 337, Step C, reacting (S)-3- cyano-4-methoxy-N-(6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)benzamide (Intermediate 13, 150 mg, 0.461 mmol) and 1-bromo-4-((1s,3s)-3- (trifluoromethoxy)cyclobutyl)benzene (Intermediate 41, 150 mg, 0.507 mmol).1H NMR (400 MHz, DMSO-d6) δ: 9.84 (s, 1H), 8.22 (s, 1H), 8.17 - 8.15 (m, 1H), 8.11 (s, 1H), 7.42 - 7.37 (m, 5H), 4.89 - 4.82 (m, 1H), 4.75 - 4.70 (m, 1H), 4.48 - 4.41 (m, 1H), 4.38 - 4.31 (m, 1H), 3.99 (s, 3H), 3.23 - 3.09 (m, 1H), 2.86 - 2.76 (m, 2H), 2.32 - 2.24 (m, 2H), 1.21 (d, J = 6.4 Hz, 3H). Mass spectrum (ESI, m/z): calcd. for C H F N O 53 + 27 24 3 5 4 9.2; found [M+H] , 540.2. Example 371: 3-cyano-4-methoxy-N-((S)-6-methyl-4-oxo-5-(4-((1S,2S)-2- (trifluoromethyl)cyclopropyl)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3- yl)benzamide.

Step A: Cobalt, [[2,2′-[(1R,2R)-1,2-cyclohexanediylbis[(nitrilo-κN)methylidyne]]bis[3,4- dichloro-6-(2-methylpropoxy)phenolato-κO]](2-)]-, (SP-4-2)- (ACI) The title compound was prepared in a manner analogous to Example 18, Step C, reacting 2,3- dichloro-6-hydroxy-5-isobutoxybenzaldehyde (Example 18, product from step B, 2.8 g, 11 mmol) and (1R,2R)-cyclohexane-1,2-diamine (608 mg, 5.32 mmol). Step B: 1-bromo-4-((1S,2S)-2-(trifluoromethyl)cyclopropyl)benzene. The title compound was prepared in a manner analogous to Example 18, Step D, reacting Cobalt, [[2,2′-[(1R,2R)-1,2-cyclohexanediylbis[(nitrilo-κN)methylidyne]]bis[3,4-dichloro-6-(2- methylpropoxy)phenolato-κO]](2-)]-, (SP-4-2)- (ACI) (1.08 g, 1.64 mmol), triphenylarsine (1.00 g, 3.28 mmol), NaOAc (269 mg, 3.28 mmol) and trifluoroethylamine hydrochloride (6.66 g, 49.2 mmol).1H NMR (400 MHz, CDCl₃) δ: 7.42 (d, J = 8.4 Hz, 2H), 7.00 (d, J = 8.4 Hz, 2H), 2.36 - 2.28 (m, 1H), 1.83 - 1.72 (m, 1H), 1.42 - 1.35 (m, 1H), 1.18 - 1.11 (m, 1H). Step C: 3-cyano-4-methoxy-N-((S)-6-methyl-4-oxo-5-(4-((1S,2S)-2- (trifluoromethyl)cyclopropyl)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)benzamide. The title compound was prepared in a manner analogous to Example 337, Step C, reacting (S)-3- cyano-4-methoxy-N-(6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)benzamide (Intermediate 13, 118 mg, 0.362 mmol) and 1-bromo-4-((1S,2S)-2- (trifluoromethyl)cyclopropyl)benzene (144 mg, 0.543 mmol).1H NMR (400 MHz, DMSO-d6) δ: 9.84 (s, 1H), 8.22 (d, J = 2.0 Hz, 1H), 8.15 (dd, J = 2.4, 8.8 Hz, 1H), 8.11 (s, 1H), 7.41 (d, J = 8.8 Hz, 1H), 7.38 - 7.30 (m, 4H), 4.72 (dd, J = 4.4, 13.2 Hz, 1H), 4.48 - 4.40 (m, 1H), 4.36 (dd, J = 4.0, 13.2 Hz, 1H), 4.00 (m, 3H), 2.47 - 2.44 (m, 1H), 2.35 - 2.31 (m, 1H), 1.40 (m, 1H), 1.34 - 1.27 (m, 1H), 1.21 (d, J = 6.4 Hz, 3H). Mass spectrum (ESI, m/z): calcd. for C26H22F3N5O3 509.2; found [M+H]+, 510.2. Example 372: 3-cyano-4-methoxy- ((S)-6-methyl-4-oxo-5-(4-((1r,3r)-3- (trifluoromethoxy)cyclobutyl)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3- yl)benzamide.

The title compound was prepared in a manner analogous to Example 337, Step C, reacting (S)-3- cyano-4-methoxy-N-(6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)benzamide (Intermediate 13, 165 mg, 0.51 mmol) and 1-bromo-4-((1r,3r)-3- (trifluoromethoxy)cyclobutyl)benzene (Intermediate 42, 180 mg, 0.61 mmol).1H NMR (400 MHz, CDCl3) δ: 9.71 (s, 1H), 8.43 (s, 1H), 8.17 (d, J = 2.4 Hz, 1H), 8.11 (dd, J = 2.4, 8.8 Hz, 1H), 7.41 - 7.35 (m, 2H), 7.34 - 7.29 (m, 2H), 7.01 (d, J = 8.8 Hz, 1H), 4.89 (m, 1H), 4.70 - 4.61 (m, 1H), 4.42 - 4.32 (m, 2H), 4.00 (s, 3H), 3.82 - 3.70 (m, 1H), 2.83 - 2.72 (m, 2H), 2.66 - 2.56 (m, 2H), 1.41 (d, J = 6.4 Hz, 3H). Mass spectrum (ESI, m/z): calcd. for C27H24F3N5O4539.2; found [M+H]+, 540.2. Example 373 and 374: 3-cyano-4-methoxy-N-((S)-6-methyl-4-oxo-5-(4-((1s,3s)-3- (trifluoromethyl)cyclobutyl)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3- yl)benzamide and 3-cyano-4-methoxy-N-((S)-6-methyl-4-oxo-5-(4-((1r,3r)-3- (trifluoromethyl)cyclobutyl)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3- yl)benzamide

Step A: 3-(4-bromophenyl)-1-(trifluoromethyl)cyclobutan-1-ol. 3-(4-Bromophenyl)cyclobutanone (2 g, 8.88 mmol), a stir bar, TMSCF₃ (1.96 mL, 0.89 mmol) and anhydrous THF (15 mL) were added to a 50 mL single-necked round-bottomed flask. The resulting mixture was cooled to 0 °C before treated with TBAF (1 M in THF, 0.89 mL, 0.89 mmol) and then warmed to rt for 16 h. The reaction mixture was cooled to 0 °C before acified by 6 M HCl to pH = 1 while the solution turned yellow and further stirred at rt for 2 h. The reaction mixture was poured into H2O (10 mL) and extracted with EtOAc (20 mL x 2). The combined extracts was dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo to give a light- brown solid. The solid was then subjected to silica-gel chromatography (0-10% EtOAc/PE) to give 3-(4-bromophenyl)-1-(trifluoromethyl)cyclobutanol as a light-yellow solid (2.04 g, 77.8% yield).1H NMR (400 MHz, CDCl3) δ: 7.50 - 7.43 (m, 2H), 7.19 - 7.10 (m, 2H), 3.29 (quin, J = 9.2 Hz, 1H), 3.03 - 2.93 (m, 2H), 2.38 - 2.26 (m, 2H). Step B: (S)-3-cyano-N-(5-(4-(3-hydroxy-3-(trifluoromethyl)cyclobutyl)phenyl)-6-methyl-4-oxo- 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)-4-methoxybenzamide. The title compound was prepared in a manner analogous to Example 337, Step C, reacting (S)-3- cyano-4-methoxy-N-(6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)benzamide (Intermediate 13, 500 mg, 1.54 mmol)and 3-(4-bromophenyl)-1-(trifluoromethyl)cyclobutanol (544.3 mg, 1.84 mmol).1H NMR (400 MHz, CDCl₃) δ: 9.69 (s, 1H), 8.42 (s, 1H), 8.16 (d, J = 2.4 Hz, 1H), 8.11 (dd, J = 2.4, 8.8 Hz, 1H), 7.44 - 7.37 (m, 2H), 7.33 - 7.28 (m, 2H), 7.01 (d, J = 8.8 Hz, 1H), 4.70 - 4.59 (m, 1H), 4.43 - 4.30 (m, 2H), 3.99 (s, 3H), 3.36 (t, J = 9.2 Hz, 1H), 3.06 - 2.94 (m, 2H), 2.37 (br dd, J = 10.0, 11.2 Hz, 2H), 1.40 (d, J = 6.4 Hz, 3H). Mass spectrum (ESI, m/z): calcd. for C + 27H24F3N5O4539.2; found [M+H] , 540.3. Step C: (S)-O-(3-(4-(3-(3-cyano-4-methoxybenzamido)-6-methyl-4-oxo-6,7- dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl)phenyl)-1-(trifluoromethyl)cyclobutyl) O-phenyl carbonothioate. (S)-3-Cyano-N-(5-(4-(3-hydroxy-3-(trifluoromethyl)cyclobutyl)phenyl)-6-methyl-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazin-3-yl)-4-methoxybenzamide (200 mg, 0.37 mmol), sodium bis(trimethylsilyl)amide (1.11 mL, 1.11 mmol) and anhydrous THF (5 mL) were added to a 10 mL single-necked round-bottomed flask, then the solution was stirred at -78 °C for 1 h. The resulting mixture was treated with O-phenyl carbonochloridothioate (320.0 mg, 1.85 mmol) and then stirred at rt for 2 h. The reaction was quenched with sat. NaHCO₃ (15 mL). The reaction mixture was poured into H₂O (10 mL) and extracted with EtOAc (10 mL*3). The combined extracts was dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a light- brown solid. The solid was subjected to silica-gel chromatography (0-100% EtOAc/PE) to give (S)-O-(3-(4-(3-(3-cyano-4-methoxybenzamido)-6-methyl-4-oxo-6,7-dihydropyrazolo[1,5- a]pyrazin-5(4H)-yl)phenyl)-1-(trifluoromethyl)cyclobutyl) O-phenyl carbonothioate as a yellow solid (130 mg, 52% yield).1H NMR (400 MHz, CDCl3) δ: 9.71 (s, 1H), 8.43 (s, 1H), 8.17 (d, J = 2.4 Hz, 1H), 8.11 (dd, J = 2.4, 8.8 Hz, 1H), 7.50 - 7.40 (m, 4H), 7.38 - 7.31 (m, 3H), 7.14 - 7.09 (m, 2H), 7.01 (d, J = 8.8 Hz, 1H), 4.72 - 4.59 (m, 1H), 4.44 - 4.32 (m, 2H), 4.00 (s, 3H), 3.59 - 3.47 (m, 1H), 3.33 - 3.23 (m, 2H), 3.15 - 3.02 (m, 2H), 1.41 (d, J = 6.4 Hz, 3H). Mass spectrum (ESI, m/z): calcd. for C₃₄H₂₈F₃N₅O₅S 675.2, found [M+H]+, 676.2. Step D: (S)-3-cyano-4-methoxy-N-(6-methyl-4-oxo-5-(4-(3-(trifluoromethyl)cyclobutyl)phenyl)- tetrahydropyrazolo[1,5-a]pyrazin-3-yl)benzamide.

(S)-O-(3-(4-(3-(3-Cyano-4-methoxybenzamido)-6-methyl-4-oxo-6,7-dihydropyrazolo[1,5- a]pyrazin-5(4H)-yl)phenyl)-1-(trifluoromethyl)cyclobutyl) O-phenyl carbonothioate (990 mg, 1.47 mmol), AIBN (240.6 mg, 1.47 mmol), Tri-n-butyltin hydride (1.28 g, 1.2 mL, 4.4 mmol), a stir bar and toluene (10 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 reslutant mixture was stirred at 110 °C for 4 h. After cooled to rt, the solution was poured into 1 M KF (50 mL) at 25 °C and stirred for 1 h, extacted with EtOAc (3* 20 mL), and the combined extracts washed with brine (50 mL), dried over anhydrous MgSO₄, filtered, and concentrated to dryness under reduced pressure to give yellow oil. The oil was subjected to silica gel chromatography (0~100% EtOAc/PE) to give (S)-3-cyano-4-methoxy-N- (6-methyl-4-oxo-5-(4-(3-(trifluoromethyl)cyclobutyl)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrazin-3-yl)benzamide as a yellow solid (650 mg, 68.6% yield).1H NMR (400 MHz, CDCl₃) δ: 9.72 (s, 1H), 8.43 (s, 1H), 8.19 - 8.15 (m, 1H), 8.11 (td, J = 2.4, 8.8 Hz, 1H), 7.40 - 7.34 (m, 2H), 7.33 - 7.28 (m, 2H), 7.00 (d, J = 8.8 Hz, 1H), 4.69 - 4.61 (m, 1H), 4.43 - 4.32 (m, 2H), 4.00 (s, 3H), 3.85 - 3.47 (m, 1H), 3.07 - 2.92 (m, 1H), 2.73 - 2.54 (m, 2H), 2.51 - 2.29 (m, 2H), 1.40 (d, J = 6.4 Hz, 3H). Mass spectrum (ESI, m/z): calcd. for C₂₇H₂₄F₃N₅O₃523.2; found [M+H]+, 524.2. Step D: 3-cyano-4-methoxy-N-((S)-6-methyl-4-oxo-5-(4-((1s,3s)-3- (trifluoromethyl)cyclobutyl)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)benzamide and 3-cyano-4-methoxy-N-((S)-6-methyl-4-oxo-5-(4-((1r,3r)-3- (trifluoromethyl)cyclobutyl)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)benzamide. The (S)-3-cyano-4-methoxy-N-(6-methyl-4-oxo-5-(4-(3-(trifluoromethyl)cyclobutyl)phenyl)- 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)benzamide (500 mg, 0.955 mmol) was purified by SFC (DAICEL CHIRALPAK IG column, 10 ^m, 250 *30 mm,); 50% (v/v) EtOH (containing 0.1% of 25% aq. NH3)/CO2) and then freeze-dried to afford (3-cyano-4-methoxy-N-((S)-6- methyl-4-oxo-5-(4-((1s,3s)-3-(trifluoromethyl)cyclobutyl)phenyl)-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazin-3-yl)benzamide (240.4 mg, 47% yield) as a white solid (1H NMR (400 MHz, CDCl3) δ: 9.71 (s, 1H), 8.42 (s, 1H), 8.17 (d, J = 2.4 Hz, 1H), 8.10 (dd, J = 2.4, 8.8 Hz, 1H), 7.39 - 7.33 (m, 2H), 7.32 - 7.28 (m, 2H), 7.00 (d, J = 8.8 Hz, 1H), 4.70 - 4.60 (m, 1H), 4.43 - 4.31 (m, 2H), 4.00 (s, 3H), 3.53 - 3.50 (m, 1H), 3.06 - 2.91 (m, 1H), 2.65 - 2.52 (m, 2H), 2.41 - 2.28 (m, 2H), 1.40 (d, J = 6.8 Hz, 3H). Mass spectrum (ESI, m/z): calcd. for C27H24F3N5O3523.2; found [M+H]+, 524.2.) and (3-cyano-4-methoxy-N-((S)-6-methyl-4-oxo-5- (4-((1r,3r)-3-(trifluoromethyl)cyclobutyl)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3- yl)benzamide (113.5 mg, 22% yield) as a white solid.1H NMR (400 MHz, CDCl3) δ: 9.71 (s, 1H), 8.42 (s, 1H), 8.16 (d, J = 2.4 Hz, 1H), 8.11 (dd, J = 2.4, 8.8 Hz, 1H), 7.40 - 7.34 (m, 2H), 7.34 - 7.28 (m, 2H), 7.00 (d, J = 8.8 Hz, 1H), 4.70 - 4.60 (m, 1H), 4.45 - 4.29 (m, 2H), 4.00 (s, 3H), 3.80 - 3.79 (m, 1H), 3.06 - 2.90 (m, 1H), 2.67 - 2.65 (m, 2H), 2.55 - 2.39 (m, 2H), 1.40 (d, J = 6.4 Hz, 3H). Mass spectrum (ESI, m/z): calcd. for C + 27H24F3N5O3523.2; found [M+H] , 524.2. Example 375: (S)-3-cyano-4-methoxy-N-(7-methyl-4-oxo-5-(4-(trifluoromethoxy)phenyl)- 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)benzamide.

The title compound was prepared in a manner analogous to Example 55, reacting 3-Cyano-4- methoxybenzoic acid (26 mg, 0.15 mmol) and (S)-3-amino-7-methyl-5-(4- (trifluoromethoxy)phenyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one hydrochloride (Intermediate 19, 50 mg, 0.138 mmol).1H NMR (400 MHz, DMSO-d₆) δ: 9.87 (s, 1H), 8.22 (d, J = 2.3 Hz, 1H), 8.16 (dd, J = 8.5, 2.6 Hz, 2H), 7.64 – 7.56 (m, 2H), 7.48 (d, J = 8.5 Hz, 2H), 7.41 (d, J = 9.0 Hz, 1H), 4.83 – 4.69 (m, 1H), 4.31 (dd, J = 12.8, 4.2 Hz, 1H), 4.08 (dd, J = 12.9, 8.2 Hz, 1H), 4.00 (s, 3H), 1.56 (d, J = 6.5 Hz, 3H). Mass spectrum (ESI, m/z): calcd. for C H F + 23 18 3N5O4, 485.1; found [M+H] , 486.1. Example 376: -N-(3-cyanophenyl)-5-(4-(difluoro(6-methylpyridazin-3-

To a 1-mL vial charged with 3-cyano-4-ethylbenzoic acid (26.3 mg, 0.15 mmol), was added a stock solution of (S)-3-amino-6-methyl-5-(4-(trifluoromethyl)phenyl)-6,7-dihydropyrazolo[1,5- a]pyrazin-4(5H)-one (intermediate 55) in DMF (0.3 mL). Subsequently, a stock solution of HATU in DMF (0.3 mL) was added followed by DIPEA (75.94 µL, 0.75 g/mL, 0.44 mmol). The reactions were shaked at room temperature for 1 h. Then, the crude mixtures were diluted with 1 mL of DMSO, filtered and purified by Prep-HPLC (Stationary phase: C18 XBridge 30 x 100 mm 5 µm, Mobile phase: Gradient from 70% NH4HCO30.25% solution in Water, 30% CH3CN to 35% NH₄HCO₃0.25% solution in Water, 65% CH₃CN), yielding (S)-N-(3-cyanophenyl)-5-(4- (difluoro(6-methylpyridazin-3-yl)methyl)phenyl)-6-methyl-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide as a white solid after lyophilization.1H NMR (500 MHz, DMSO-d6) δ: 1.26 (d, J=7.75 Hz, 6H) 2.88 (q, J=7.50 Hz, 2H) 4.40 (dd, J=13.13, 3.50 Hz, 1H) 4.56 - 4.66 (m, 1H) 4.77 (dd, J=13.13, 4.38 Hz, 1H) 7.68 (d, J=8.25 Hz, 1H) 7.72 (d, J=8.38 Hz, 2H) 7.87 (d, J=8.38 Hz, 2H) 8.10 (dd, J=8.13, 1.63 Hz, 1H) 8.14 (s, 1H) 8.26 (d, J=1.50 Hz, 1H) 9.93 (s, 1H). Mass spectrum (ESI, m/z): Calcd. for C24H20F3N5O2, 513.1, found [M+H]+, 514.3. Example 377 was prepared in a manner analogous to Example 376, with the appropriate reagent substitutions.

Example 378: 3-cyano-N-((6S,7S)-6,7-dimethyl-4-oxo-5-(4-(trifluoromethyl)phenyl)-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazin-3-yl)-4-methoxybenzamide.

The title compound was prepared in a manner analogous to Example 55, reacting 3-Cyano-4- methoxybenzoic acid (24 mg, 0.135 mmol) and (6S,7S)-3-amino-6,7-dimethyl-5-(4- (trifluoromethyl)phenyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (Intermediate 20, 40 mg, 0.123 mmol).1H NMR (400 MHz, DMSO-d₆) δ: 9.86 (s, 1H), 8.24 (d, J = 2.3 Hz, 1H), 8.17 (dd, J = 8.9, 2.3 Hz, 1H), 8.14 (s, 1H), 7.86 (d, J = 8.5 Hz, 2H), 7.75 (d, J = 8.4 Hz, 2H), 7.42 (d, J = 9.0 Hz, 1H), 5.02 – 4.92 (m, 1H), 4.58 – 4.47 (m, 1H), 4.00 (s, 3H), 1.56 (d, J = 6.7 Hz, 3H), 1.12 (d, J = 6.7 Hz, 3H).Mass spectrum (ESI, m/z): calcd. for C₂₄H₂₀F₃N₅O₃, 483.1; found [M+H]+, 484.1. Example 379: (S)-3-cyano-4-methoxy-N-(5-(4-(6-methoxynicotinoyl)phenyl)-6-methyl-4- oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)benzamide.

Iodomethane (20 μL, 0.32 mmol) was added to a solution of silver (I) carbonate (70 mg, 0.25 mmol) and (S)-3-cyano-N-(5-(4-(6-hydroxynicotinoyl)phenyl)-6-methyl-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazin-3-yl)-4-methoxybenzamide (100 mg, 0.21 mmol) in dry dioxane (1 mL) under N2 at room temperature. The mixture was stirred and irradiated in microwave at 150ºC for 30 min. Then a new load of iodomethane (10 μL, 0.16 mmol) was added at room temperature. The mixture was stirred and irradiated in microwave at 150ºC for 10 min. The crude was filtered off through celite. The solvents were evaporated in vacuo. The residue purified by silica gel chromatography (0%-100% heptane/EtOAc). The desired fractions were combined and concentrated in vacuo to afford (S)-3-cyano-4-methoxy-N-(5-(4-(6- methoxynicotinoyl)phenyl)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3- yl)benzamide (30 mg, 28% yield) as a white solid.1H NMR (300 MHz, CDCl3) δ: 9.65 (s, 1H), 8.66 (d, J = 1.9 Hz, 1H), 8.43 (s, 1H), 8.16 (d, J = 2.2 Hz, 1H), 8.14 – 8.06 (m, 2H), 7.91 (d, J = 8.6 Hz, 2H), 7.52 (d, J = 8.6 Hz, 2H), 7.03 (d, J = 8.9 Hz, 1H), 6.86 (dd, J = 8.7, 0.5 Hz, 1H), 4.68 (dd, J = 13.0, 4.3 Hz, 1H), 4.54 – 4.44 (m, 1H), 4.38 (dd, J = 13.0, 3.4 Hz, 1H), 4.03 (s, 3H), 3.99 (s, 3H), 1.44 (d, J = 6.6 Hz, 3H). Mass spectrum (ESI, m/z): calcd. for C29H24N6O5, 536.2; found [M+Na]+, 559.2. Example 380: (S)-3-cyano-4-methoxy-N-(5-(4-(4-methoxybenzoyl)phenyl)-6-methyl-4-oxo- 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)benzamide.

The title compound was prepared in a manner analogous to Example 55, reacting 3-Cyano-4- methoxybenzoic acid (121 mg, 0.684 mmol) and (S)-3-amino-5-(4-(4-methoxybenzoyl)phenyl)- 6-methyl-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (Intermediate 28, 189 mg, 0.458 mmol). 1H NMR (400 MHz, DMSO-d₆) δ: 1.30 (d, J=6.58 Hz, 3H) 3.88 (s, 3H) 4.00 (s, 3H) 4.36 - 4.47 (m, 1H) 4.58 - 4.67 (m, 1H) 4.77 (dd, J=13.11, 4.34 Hz, 1H) 7.09 - 7.16 (m, 2H) 7.42 (d, J=8.96 Hz, 1H) 7.66 (d, J=8.58 Hz, 2H) 7.76 - 7.84 (m, 4H) 8.14 (s, 1H) 8.16 - 8.21 (m, 1H) 8.25 (d, J=2.29 Hz, 1H) 9.87 (s, 1H). Mass spectrum (ESI, m/z): calcd. for C30H25N5O5, 535.2; found [M+Na]+, 558.2. Example 381: (S)-3-cyano-N-(5-(4-(6-hydroxynicotinoyl)phenyl)-6-methyl-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazin-3-yl)-4-methoxybenzamide.

The title compound was prepared in a manner analogous to Example 55, reacting 3-cyano-4- methoxybenzoic acid (169 mg, 0.954 mmol) and (S)-3-amino-5-(4-(6- methoxynicotinoyl)phenyl)-6-methyl-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (Intermediate 31, 270 mg, 0.458 mmol). Mass spectrum (ESI, m/z): calcd. for C28H26N6O5, 522.2; found [M+Na]+, 545.2. Example 382: (S)-N-(5-(4-(4-chloro-3-methoxybenzoyl)phenyl)-6-methyl-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazin-3-yl)-3-cyano-4-methoxybenzamide.

The title compound was prepared in a manner analogous to Example 55, reacting 3-Cyano-4- methoxybenzoic acid (183 mg, 1.03 mmol) and (S)-3-amino-5-(4-(4-chloro-3- methoxybenzoyl)phenyl)-6-methyl-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (Intermediate 37, 387 mg, 0.693 mmol).1H NMR (400 MHz, DMSO-d6) δ: 1.30 (d, J=6.68 Hz, 3H) 3.94 (s, 3H) 4.00 (s, 3H) 4.41 (dd, J=13.11, 3.19 Hz, 1H) 4.59 - 4.69 (m, 1H) 4.72 - 4.81 (m, 1H) 7.25 - 7.35 (m, 1H) 7.39 - 7.45 (m, 1H) 7.49 (d, J=1.81 Hz, 1H) 7.62 - 7.71 (m, 3H) 7.89 (d, J=8.68 Hz, 2H) 8.14 (s, 1H) 8.18 (dd, J=8.92, 2.34 Hz, 1H) 8.25 (d, J=2.29 Hz, 1H) 9.76 - 10.05 (m, 1H). Mass spectrum (ESI, m/z): calcd. for C₃₀H₂₄ClN₅O₅, 569.2; found [M+Na]+, 592.1. Example 383: 3-cyano-N-((6R,7R)-5-(4-(difluoro(phenyl)methyl)phenyl)-6,7-dimethyl-4- oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)-4-methoxybenzamide.

The title compound was prepared in a manner analogous to Example 55, reacting 3-Cyano-4- methoxybenzoic acid (45 mg, 0.254 mmol) and (6R,7R)-3-amino-5-(4- (difluoro(phenyl)methyl)phenyl)-6,7-dimethyl-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (Intermediate 22, 87 mg, 0.228 mmol).1H NMR (400 MHz, DMSO-d₆) δ: 9.85 (s, 1H), 8.22 (d, J = 2.3 Hz, 1H), 8.16 (dd, J = 8.9, 2.3 Hz, 1H), 8.13 (s, 1H), 7.67 – 7.60 (m, 4H), 7.55 (dtd, J = 6.6, 4.0, 2.2 Hz, 5H), 7.41 (d, J = 9.0 Hz, 1H), 4.99 – 4.89 (m, 1H), 4.51 – 4.39 (m, 1H), 4.00 (s, 3H), 1.55 (d, J = 6.7 Hz, 3H), 1.10 (d, J = 6.7 Hz, 3H). Mass spectrum (ESI, m/z): calcd. for C₃₀H₂₅F₂N₅O₃, 541.2; found [M+Na]+, 564.2. Example 384: 3-cyano-N-((6R,7R)-6,7-dimethyl-4-oxo-5-(4-(trifluoromethyl)phenyl)- 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)-4-methoxybenzamide.

The title compound was prepared in a manner analogous to Example 55, reacting 3-Cyano-4- methoxybenzoic acid (60 mg, 0.618 mmol) and 6R,7R)-3-amino-6,7-dimethyl-5-(4- (trifluoromethyl)phenyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (Intermediate 39, 100 mg, 0.308 mmol).1H NMR (400 MHz, DMSO-d6) δ: 9.86 (s, 1H), 8.24 (d, J = 2.3 Hz, 1H), 8.17 (dd, J = 8.9, 2.3 Hz, 1H), 8.14 (s, 1H), 7.87 (d, J = 8.5 Hz, 2H), 7.75 (d, J = 8.4 Hz, 2H), 7.42 (d, J = 9.0 Hz, 1H), 5.01 – 4.92 (m, 1H), 4.57 – 4.49 (m, 1H), 4.00 (s, 3H), 1.56 (d, J = 6.7 Hz, 3H), 1.12 (d, J = 6.7 Hz, 3H). Mass spectrum (ESI, m/z): calcd. for C24H20F3N5O3, 483.1; found [M+Na]+, 506.1. Example 385: (S)-3-cyano-N-(5-(4-(difluoro(4-methoxyphenyl)methyl)phenyl)-6-methyl-4- oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)-4-methoxybenzamide.

Step A: (S)-3-cyano-4-methoxy-N-(5-(4-(2-(4-methoxyphenyl)-1,3-dithian-2-yl)phenyl)-6- methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)benzamide. The title compound was prepared in a manner analogous to Intermediate 24, Step A, reacting (S)-3-cyano-4-methoxy-N-(5-(4-(4-methoxybenzoyl)phenyl)-6-methyl-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazin-3-yl)benzamide (Example 380, 111 mg, 0.458 mmol). Mass spectrum (ESI, m/z): calcd. for C H N O S , 625. + 33 31 5 4 2 2; found [M+Na] , 647.6. Step B: (S)-3-cyano-N-(5-(4-(difluoro(4-methoxyphenyl)methyl)phenyl)-6-methyl-4-oxo- 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)-4-methoxybenzamide. The title compound was prepared in a manner analogous to Example 100, Step B, reacting (S)-3- cyano-4-methoxy-N-(5-(4-(2-(4-methoxyphenyl)-1,3-dithian-2-yl)phenyl)-6-methyl-4-oxo- 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)benzamide (50 mg, 0.071 mmol).1H NMR (300 MHz, DMSO-d6) δ: 9.83 (s, 1H), 8.23 (d, J = 2.3 Hz, 1H), 8.16 (dd, J = 8.9, 2.3 Hz, 1H), 8.12 (s, 1H), 7.60 (q, J = 8.9 Hz, 4H), 7.46 (d, J = 8.9 Hz, 2H), 7.40 (d, J = 9.0 Hz, 1H), 7.05 (d, J = 8.8 Hz, 2H), 4.74 (dd, J = 13.1, 4.4 Hz, 1H), 4.53 (dd, J = 6.8, 4.0 Hz, 1H), 4.38 (dd, J = 13.1, 3.5 Hz, 1H), 4.00 (s, 3H), 3.80 (s, 3H), 1.25 (s, J = 6.6 Hz, 3H). Mass spectrum (ESI, m/z): calcd. for C₃₀H₂₅F₂N₅O₄, 557.2; found [M+Na]+, 580.2. Example 386: (R)-3-cyano-N-(5-(4-(difluoro(phenyl)methyl)phenyl)-7-methyl-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazin-3-yl)-4-methoxybenzamide.

The title compound was prepared in a manner analogous to Example 337, Step C, reacting (R)-3- cyano-4-methoxy-N-(7-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)benzamide (Intermediate 16, 120 mg, 0.369 mmol) and 1-bromo-4-(difluoro(phenyl)methyl)benzene (209 mg, 0.738 mmol).1H NMR (400 MHz, DMSO-d₆) δ: 9.88 (s, 1H), 8.23 - 8.20 (m, 1H), 8.17 - 8.12 (m, 2H), 7.63-7.51 (m, 9H), 7.42 - 7.39 (m, 1H), 4.78 - 4.70 (m, 1H), 4.35 - 4.28 (m, 1H), 4.13 - 4.06 (m, 1H), 3.99 (s, 3H), 1.57 - 1.52 (m, 3H). Mass spectrum (ESI, m/z): calcd. for C H + 29 23F2N5O3527.2; found [M+H] , 528.2. Example 387: (S)-3-cyano-N-(5-(4-(difluoro(phenyl)methyl)phenyl)-7-methyl-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazin-3-yl)-4-methoxybenzamide.

The title compound was prepared in a manner analogous to Example 55, reacting 3-Cyano-4- methoxybenzoic acid (30 mg, 0.169 mmol) and (S)-3-amino-5-(4- (difluoro(phenyl)methyl)phenyl)-7-methyl-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one hydrochloride (Intermediate 23, 30 mg, 0.074 mmol).1H NMR (400 MHz, DMSO-d6) δ: 9.88 (s, 1H), 8.21 (d, J = 2.3 Hz, 1H), 8.15 (dd, J = 8.6, 2.6 Hz, 2H), 7.64 – 7.51 (m, 9H), 7.41 (d, J = 9.0 Hz, 1H), 4.80 – 4.70 (m, 1H), 4.32 (dd, J = 12.8, 4.2 Hz, 1H), 4.10 (dd, J = 12.9, 8.1 Hz, 1H), 4.00 (s, 3H), 1.55 (d, J = 6.5 Hz, 3H). Mass spectrum (ESI, m/z): calcd. for C30H25F2N5O3, 527.2; found [M+Na]+, 550.2. Example 388: (S)-N-(5-(4-((4-chloro-3-methoxyphenyl)difluoromethyl)phenyl)-6-methyl-4- oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)-3-cyano-4-methoxybenzamide.

Step A: (S)-N-(5-(4-(2-(4-chloro-3-methoxyphenyl)-1,3-dithian-2-yl)phenyl)-6-methyl-4-oxo- tetrahydropyrazolo[1,5-a]pyrazin-3-yl)-3-cyano-4-methoxybenzamide.

The title compound was prepared in a manner analogous to Intermediate 24, Step A, reacting (S)-N-(5-(4-(4-chloro-3-methoxybenzoyl)phenyl)-6-methyl-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazin-3-yl)-3-cyano-4-methoxybenzamide (Example 382, 70 mg, 0.111 mmol).1H NMR (400 MHz, DMSO-d₆) δ: 1.24 (d, J=6.42 Hz, 3H) 1.91 - 2.02 (m, 2H) 2.82 (br t, J=5.43 Hz, 4H) 3.84 (s, 3H) 3.98 - 4.02 (m, 3H) 4.29 - 4.42 (m, 1H) 4.43 - 4.54 (m, 1H) 4.64 - 4.80 (m, 1H) 7.21 - 7.32 (m, 1H) 7.35 - 7.61 (m, 7H) 8.06 - 8.28 (m, 3H) 9.82 - 9.89 (m, 1H). Mass spectrum (ESI, m/z): calcd. for C₃₃H₃₀ClN₅O₄S₂, 659.1; found [M+Na]+, 681.7. Step B: (S)-N-(5-(4-((4-chloro-3-methoxyphenyl)difluoromethyl)phenyl)-6-methyl-4-oxo- tetrahydropyrazolo[1,5-a]pyrazin-3-yl)-3-cyano-4-methoxybenzamide.

The title compound was prepared in a manner analogous to Example 100, Step B, reacting (S)- N-(5-(4-(2-(4-chloro-3-methoxyphenyl)-1,3-dithian-2-yl)phenyl)-6-methyl-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazin-3-yl)-3-cyano-4-methoxybenzamide (70 mg, 0.106 mmol).1H NMR (400 MHz, DMSO-d₆) δ: 9.84 (s, 1H), 8.23 (d, J = 2.3 Hz, 1H), 8.17 (dd, J = 8.9, 2.3 Hz, 1H), 8.12 (s, 1H), 7.69 (d, J = 8.7 Hz, 2H), 7.59 (dd, J = 8.3, 5.6 Hz, 3H), 7.41 (d, J = 9.0 Hz, 1H), 7.34 (d, J = 1.9 Hz, 1H), 7.10 (dd, J = 8.2, 2.0 Hz, 1H), 4.75 (dd, J =13.1, 4.4 Hz, 1H), 4.60 – 4.51 (m, 1H), 4.39 (dd, J = 13.1, 3.4 Hz, 1H), 4.00 (s, 3H), 3.94 (s, 3H), 1.25 (d, J = 6.6 Hz, 3H). Mass spectrum (ESI, m/z): calcd. for C + 30H24ClF2N5O4, 591.1; found [M+Na] , 614.1. Example 389: 3-cyano-N-((6S,7S)-5-(4-(difluoro(phenyl)methyl)phenyl)-6,7-dimethyl-4- oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)-4-methoxybenzamide.

The title compound was prepared in a manner analogous to Example 55, reacting 3-Cyano-4- methoxybenzoic acid (34 mg, 0.192 mmol) and (6S,7S)-3-amino-5-(4- (difluoro(phenyl)methyl)phenyl)-6,7-dimethyl-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (Intermediate 21, 35 mg, 0.084 mmol).1H NMR (400 MHz, DMSO-d₆) δ: 9.85 (s, 1H), 8.22 (d, J = 2.3 Hz, 1H), 8.16 (dd, J = 8.9, 2.3 Hz, 1H), 8.13 (s, 1H), 7.66 – 7.60 (m, 4H),7.58 – 7.51 (m, 5H), 7.41 (d, J = 9.0 Hz, 1H), 4.99 – 4.91 (m, 1H), 4.50 – 4.42 (m, 1H), 4.00 (s, 3H), 1.55 (d, J = 6.7 Hz, 3H), 1.10 (d, J = 6.7 Hz, 3H).Mass spectrum (ESI, m/z): calcd. for C₃₀H₂₅F₂N₅O₃, 541.2; found [M+H]+, 542.2. Example 390: (S)-3-cyano-N-(5-(4-(difluoro(3-methoxyphenyl)methyl)phenyl)-6-methyl-4- oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)-4-methoxybenzamide.

Step A: (S)-3-cyano-4-methoxy-N-(5-(4-(3-methoxybenzoyl)phenyl)-6-methyl-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazin-3-yl)benzamide. The title compound was prepared in a manner analogous to Example 55, reacting 3-Cyano-4- methoxybenzoic acid (200 mg, 1.106 mmol) and (S)-3-amino-5-(4-(3-methoxybenzoyl)phenyl)- 6-methyl-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (Intermediate 32, 400 mg, 0.823 mmol). 1H NMR (400 MHz, DMSO-d₆) δ: 9.86 (s, 1H), 8.24 (d, J = 2.3 Hz, 1H), 8.18 (dd, J = 8.9, 2.3 Hz, 1H), 8.13 (s, 1H), 7.88 – 7.83 (m, 2H), 7.69 – 7.65 (m, 2H), 7.53 – 7.47 (m, 1H), 7.41 (d, J = 9.0 Hz, 1H), 7.33 – 7.25 (m, 3H), 4.76 (dd, J = 13.1, 4.3 Hz, 1H), 4.66 – 4.58 (m, 1H), 4.40 (dd, J = 13.1, 3.2 Hz, 1H), 4.00 (s, 3H), 3.83 (s, 3H), 1.30 (d, J = 6.6 Hz, 3H). Mass spectrum (ESI, m/z): calcd. for C + 30H25N5O5, 535.2; found [M+Na] , 558.2 Step B: (S)-3-cyano-4-methoxy-N-(5-(4-(2-(3-methoxyphenyl)-1,3-dithian-2-yl)phenyl)-6- methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)benzamide The title compound was prepared in a manner analogous to Intermediate 24, Step A, reacting (S)-3-cyano-4-methoxy-N-(5-(4-(3-methoxybenzoyl)phenyl)-6-methyl-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazin-3-yl)benzamide (345 mg, 0.0.644 mmol).1H NMR (400 MHz, DMSO-d6) δ: 9.83 (s, 1H), 8.22 (d, J = 2.2 Hz, 1H), 8.16 (dd, J = 8.9, 2.3 Hz, 1H), 8.11 (s, 1H), 7.63 (d, J = 8.6 Hz, 2H), 7.46 (d, J = 8.7 Hz, 2H), 7.43 – 7.33 (m, 2H), 7.27 – 7.17 (m, 2H), 6.93 (dd, J = 8.1, 1.8 Hz, 1H), 4.71 (dd, J = 13.1, 4.3 Hz, 1H), 4.49 (dd, J = 6.8, 3.9 Hz, 1H), 4.36 (dd, J = 13.0, 3.3 Hz, 1H), 3.99 (s, 3H), 3.74 (s, 3H), 2.84 – 2.74 (m, 4H), 2.02 – 1.84 (m, 2H), 1.25 (d, J = 6.6 Hz, 3H). Mass spectrum (ESI, m/z): calcd. for C + 33H31N5O4S2, 625.2; found [M+H] , 626.2 Step C: (S)-3-cyano-N-(5-(4-(difluoro(3-methoxyphenyl)methyl)phenyl)-6-methyl-4-oxo- tetrahydropyrazolo[1,5-a]pyrazin-3-yl)-4-methoxybenzamide.

The title compound was prepared in a manner analogous to Example 100, Step B, reacting (S)-3- cyano-4-methoxy-N-(5-(4-(2-(3-methoxyphenyl)-1,3-dithian-2-yl)phenyl)-6-methyl-4-oxo- 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)benzamide (100 mg, 0.16 mmol).1H NMR (400 MHz, DMSO-d₆) δ: 9.83 (s, 1H), 8.22 (d, J = 2.2 Hz, 1H), 8.16 (dd, J = 8.9, 2.3 Hz, 1H), 8.12 (s, 1H), 7.65 (d, J = 8.6 Hz, 2H), 7.58 (d, J = 8.5 Hz, 2H), 7.48 – 7.42 (m, 1H), 7.40 (d, J = 9.0 Hz, 1H), 7.17 – 7.04 (m, 3H), 4.74 (dd, J = 13.1, 4.3 Hz, 1H), 4.60 – 4.49 (m, 1H), 4.38 (dd, J = 13.1, 3.5 Hz, 1H), 3.99 (s, 3H), 3.80 (s, 3H), 1.24 (d, J = 6.6 Hz, 3H). Mass spectrum (ESI, m/z): calcd. for C H F N O , 55 + 30 25 2 5 4 7.2; found [M+H] , 558.2. Example 391: (S)-N-(5-(4-(4-chloro-3-methoxybenzyl)phenyl)-6-methyl-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazin-3-yl)-3-cyano-4-methoxybenzamide.

The title compound was prepared in a manner analogous to Example 399, Step A, reacting (S)- N-(5-(4-(4-chloro-3-methoxybenzoyl)phenyl)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrazin-3-yl)-3-cyano-4-methoxybenzamide (Example 382, 70 mg, 0.123 mmol).1H NMR (400 MHz, DMSO-d6) δ: 1.18 - 1.23 (m, 3H) 3.85 (s, 3H) 3.96 - 4.01 (m, 5H) 4.29 - 4.38 (m, 1H) 4.39 - 4.48 (m, 1H) 4.66 - 4.76 (m, 1H) 6.73 - 6.88 (m, 1H) 7.13 (d, J=1.53 Hz, 1H) 7.31 - 7.43 (m, 6H) 8.11 (s, 1H) 8.15 (dd, J=8.92, 2.24 Hz, 1H) 8.21 (d, J=2.10 Hz, 1H) 9.69 - 9.95 (m, 1H). Mass spectrum (ESI, m/z): calcd. for C₃₀H₂₆ClN₅O₄, 555.2; found [M+H]+, 556.2. Example 392: (S)-3-cyano-N-(5-(4-(difluoro(6-methoxypyridin-3-yl)methyl)phenyl)-6- methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)-4-methoxybenzamide.

Step A: (S)-3-cyano-4-methoxy-N-(5-(4-(2-(6-methoxypyridin-3-yl)-1,3-dithian-2-yl)phenyl)-6- methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)benzamide. The title compound was prepared in a manner analogous to Intermediate 24, Step A, reacting (S)-3-cyano-4-methoxy-N-(5-(4-(6-methoxynicotinoyl)phenyl)-6-methyl-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazin-3-yl)benzamide (30 mg, 0.056 mmol).1H NMR (300 MHz, CDCl₃) δ: 9.68 (s, 1H), 8.43 (s, 1H), 8.38 – 8.32 (m, 1H), 8.17 (d, J = 2.3 Hz, 1H), 8.11 (dd, J = 8.8, 2.3 Hz, 1H), 8.03 (dd, J = 8.8, 2.7 Hz, 1H), 7.81 (d, J = 8.7 Hz, 2H), 7.34 (d, J = 8.7 Hz, 2H), 7.02 (d, J = 8.9 Hz, 1H), 6.77 (d, J = 8.9 Hz, 1H), 4.70 – 4.59 (m, 1H), 4.43 – 4.29 (m, 2H), 3.99 (s, 3H), 3.96 (s, 3H), 2.89 – 2.77 (m, 4H), 1.42 (d, J = 6.6 Hz, 3H), 0.92 – 0.73 (m, 2H). Mass spectrum (ESI, m/z): calcd. for C₃₂H₃₀N₆O₄S₂, 626.2; found [M+H]+, 627.2. Step B: (S)-3-cyano-N-(5-(4-(difluoro(6-methoxypyridin-3-yl)methyl)phenyl)-6-methyl-4-oxo- 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)-4-methoxybenzamide. The title compound was prepared in a manner analogous to Example 100, Step B, reacting (S)-3- cyano-4-methoxy-N-(5-(4-(2-(6-methoxypyridin-3-yl)-1,3-dithian-2-yl)phenyl)-6-methyl-4-oxo- 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)benzamide (25 mg, 0.04 mmol).1H NMR (400 MHz, DMSO-d₆) δ: 9.83 (s, 1H), 8.37 (d, J = 1.8 Hz, 1H), 8.23 (d, J = 2.2 Hz, 1H), 8.16 (dd, J = 8.9, 2.3 Hz, 1H), 8.12 (s, 1H), 7.87 (dd, J = 8.7, 2.5 Hz, 1H), 7.67 (d, J = 8.6 Hz, 2H), 7.61 (d, J = 8.6 Hz, 2H), 7.41 (d, J = 9.0 Hz, 1H), 6.96 (d, J = 8.7 Hz, 1H), 4.74 (dd, J = 13.1, 4.4 Hz, 1H), 4.60 – 4.50 (m, 1H), 4.38 (dd, J = 13.1, 3.5 Hz, 1H), 4.00 (s, 3H), 3.90 (s, 3H), 1.24 (d, J = 6.6 Hz, 3H). Mass spectrum (ESI, m/z): calcd. for C + 29H24F2N6O4, 558.2; found [M+H] , 559.2. Example 393: (S)-3-cyano-N-(5-(4-(difluoro(2-methoxypyridin-4-yl)methyl)phenyl)-6- methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)-4-methoxybenzamide.

The title compound was prepared in a manner analogous to Example 395: (S)-N-(5-(4-((4- chlorophenyl)difluoromethyl)phenyl)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin- 3-yl)-3-cyano-4-methoxybenzamide, reacting (S)-3-cyano-4-methoxy-N-(6-methyl-4-oxo- 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)benzamide (Intermediate 13, 60 mg, 0.184 mmol) and 4-((4-bromophenyl)difluoromethyl)-2-methoxypyridine (Intermediate 29, 90 mg, 0.287 mmol).1H NMR (400 MHz, DMSO-d6) δ: 9.83 (s, 1H), 8.33 (d, J = 5.3 Hz, 1H), 8.22 (d, J = 2.3 Hz, 1H), 8.16 (dd, J = 8.9, 2.3 Hz, 1H), 8.12 (s, 1H), 7.70 (d, J = 8.7 Hz, 2H), 7.62-7.59 (m, 2H), 7.40 (d, J = 9.0 Hz, 1H), 7.18 (dd, J = 5.4, 1.5 Hz, 1H), 7.02 (s, 1H), 4.74 (dd, J = 13.1, 4.4 Hz, 1H), 4.59-4.50 (m, 1H), 4.40-4.34 (m, 1H), 3.99 (s, 3H), 3.89 (s, 3H), 1.23 (d, J = 6.6 Hz, 3H). Mass spectrum (ESI, m/z): calcd. for C₂₉H₂₄F₂N₆O₄, 558.2; found [M+H]+, 559.2. Example 394: (S)-3-cyano-N-(5-(4-(difluoro(2-methoxyphenyl)methyl)phenyl)-6-methyl-4- oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)-4-methoxybenzamide.

The title compound was prepared in a manner analogous to Example 395: (S)-N-(5-(4-((4- chlorophenyl)difluoromethyl)phenyl)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin- 3-yl)-3-cyano-4-methoxybenzamide reacting (S)-3-cyano-4-methoxy-N-(6-methyl-4-oxo- 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)benzamide (Intermediate 13, 47 mg, 0.144 mmol) and 1-((4-bromophenyl)difluoromethyl)-2-methoxybenzene (Intermediate 33, 45 mg, 0.144 mmol).1H NMR (400 MHz, DMSO-d6) δ: 9.83 (s, 1H), 8.23 (s, 1H), 8.16 (d, J = 8.9 Hz, 1H), 8.11 (s, 1H), 7.65 (d, J = 7.5 Hz, 1H), 7.58 – 7.50 (m, 5H), 7.40 (d, J = 9.0 Hz, 1H), 7.17 – 7.07 (m, 2H), 4.73 (dd, J = 13.0, 3.9 Hz, 1H), 4.53 (d, J = 2.7 Hz, 1H), 4.37 (d, J = 13.0 Hz, 1H), 3.99 (s, 3H), 3.67 (s, 3H), 1.24 (d, J = 6.4 Hz, 3H). Mass spectrum (ESI, m/z): calcd. for C₃₀H₂₅F₂N₅O₄, 557.2; found [M+H]+, 558.1. Example 395: (S)-N-(5-(4-((4-chlorophenyl)difluoromethyl)phenyl)-6-methyl-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazin-3-yl)-3-cyano-4-methoxybenzamide.

CuI (49 mg, 0.26 mmol) was added to a solution of (S)-3-cyano-4-methoxy-N-(6-methyl-4-oxo- 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)benzamide (Intermediate 13, 70 mg, 0.22 mmol), 1-bromo-4-((4-chlorophenyl)difluoromethyl)benzene (Intermediate 24, 82 mg, 0.24 mmol), N,N'-dimethylethylenediamine (56 μL, 0.52 mmol) and K2CO3 (90 mg, 0.65 mmol) in DMF (0.4 mL) and toluene (1.7 mL). The solution was stirred at 110ºC for 16 h. Water was added, and the mixture was extracted with EtOAc. and washed with water. The organic phase was dried over MgSO4 and evaporated. The crude product was purified by silica gel chromatography (0-100% heptane/EtOAc) to afford impure product that was then purified by reverse phase chromatography with the following conditions: column, Brand Phenomenex Type Gemini; I.D. (mm) 100 x 30; particle size 5 µm (C18) 110A; mobile phase, 41%-83% 25 mM NH4HCO3/CH3CN. The desired fractions were joined and extracted with DCM. The combined organic layers were dried over MgSO₄, filtered and concentrated in vacuo to afford (S)-N-(5-(4- ((4-chlorophenyl)difluoromethyl)phenyl)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrazin-3-yl)-3-cyano-4-methoxybenzamide (10 mg, 8% yield) as a white solid.1H NMR (400 MHz, DMSO-d₆, 100ºC) δ: 9.83 (s, 1H), 8.22 (d, J = 2.3 Hz, 1H), 8.16 (dd, J = 8.9, 2.3 Hz, 1H), 8.12 (s, 1H), 7.65 (d, J = 8.8 Hz, 2H), 7.59 (d, J = 6.8 Hz, 6H), 7.40 (d, J = 9.0 Hz, 1H), 4.74 (dd, J = 13.1, 4.4 Hz, 1H), 4.59 – 4.48 (m, 1H), 4.38 (dd, J = 13.1, 3.5 Hz, 1H), 4.00 (s, 3H), 1.24 (d, J = 6.6 Hz, 3H). Mass spectrum (ESI, m/z): calcd. for C H + 29 22ClF2N5O3, 561.1; found [M+H] , 562.1. Example 396: (S)-3-cyano-N-(5-(4-(difluoro(5-methoxypyridin-2-yl)methyl)phenyl)-6- methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)-4-methoxybenzamide.

The title compound was prepared in a manner analogous to Example 395: (S)-N-(5-(4-((4- chlorophenyl)difluoromethyl)phenyl)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin- 3-yl)-3-cyano-4-methoxybenzamide, reacting (S)-3-cyano-4-methoxy-N-(6-methyl-4-oxo- 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)benzamide (Intermediate 13, 83 mg, 0.255 mmol) and 2-((4-bromophenyl)difluoromethyl)-5-methoxypyridine (Intermediate 34, 80 mg, 0.255 mmol).1H NMR (400 MHz, DMSO-d₆) δ: 9.83 (s, 1H), 8.35 (d, J = 2.0 Hz, 1H), 8.22 (s, 1H), 8.16 (d, J = 8.7 Hz, 1H), 8.12 (s, 1H), 7.80 (d, J = 8.7 Hz, 1H), 7.64 (d, J = 8.3 Hz, 2H), 7.56 (d, J = 8.3 Hz, 3H), 7.40 (d, J = 8.9 Hz, 1H), 4.74 (dd, J = 12.9, 3.9 Hz, 1H), 4.53 (d, J = 2.6 Hz, 1H), 4.38 (dd, J = 13.0, 2.7 Hz, 1H), 3.99 (s, 3H), 3.88 (s, 3H), 1.24 (d, J = 6.4 Hz, 3H). Mass spectrum (ESI, m/z): calcd. for C₂₉H₂₄F₂N₆O₄, 558.2; found [M+H]+, 559.2. Example 398: (S)-3-cyano-N-(5-(4-(difluoro(5-methoxypyridin-3-yl)methyl)phenyl)-6- methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)-4-methoxybenzamide.

The title compound was prepared in a manner analogous to Example 395: (S)-N-(5-(4-((4- chlorophenyl)difluoromethyl)phenyl)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin- 3-yl)-3-cyano-4-methoxybenzamide, reacting (S)-3-cyano-4-methoxy-N-(6-methyl-4-oxo- 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)benzamide (Intermediate 13, 96 mg, 0.295 mmol) and 3-((4-bromophenyl)difluoromethyl)-5-methoxypyridine (Intermediate 25, 120 mg, 0.321 mmol).1H NMR (400 MHz, DMSO-d₆) δ: 9.83 (s, 1H), 8.46 (d, J = 2.7 Hz, 1H), 8.37 (d, J = 1.6 Hz, 1H), 8.22 (d, J = 2.3 Hz, 1H), 8.16 (dd, J = 8.9, 2.3 Hz, 1H), 8.12 (s, 1H), 7.72 (d, J = 8.7 Hz, 2H), 7.63 – 7.56 (m, 3H), 7.40 (d, J = 9.0 Hz, 1H), 4.74 (dd, J = 13.1, 4.4 Hz, 1H), 4.60– 4.51 (m, 1H), 4.38 (dd, J = 13.1, 3.5 Hz, 1H), 3.99 (s, 3H), 3.90 (s, 3H), 1.24 (d, J = 6.6 Hz, 3H). Mass spectrum (ESI, m/z): calcd. for C + 29H24F2N6O4, 558.2; found [M+H] , 559.1. Example 399: (S)-5-(4-(4-chlorobenzyl)phenyl)-N-(3-cyano-4-methoxyphenyl)-6-methyl-4- oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

Step A: 1-bromo-4-(4-chlorobenzyl)benzene. A solution of triflic acid (150 μL, 1.7 mmol) and triethylsilane (1.7 mL, 10.5 mmol) in dry DCM (3 mL) was added to a stirred solution of (4-bromophenyl)(4-chlorophenyl)methanone (500 mg, 1.7 mmol) in 15 mL of dry DCM. The mixture was stirred at rt for 3 days. NaHCO3 saturated aqueous solution was added carefuly and the mixture was extracted with EtOAc. The organic phase was washed with water and dried over MgSO4. The residue was purified by silica gel chromatography (0-100% heptane/EtOAc) to afford 1-bromo-4-(4-chlorobenzyl)benzene (450 mg, 93% yield) as a white solid.1H NMR (300 MHz, DMSO-d6) δ: 3.92 (s, 2H) 7.15 - 7.21 (m, 2H) 7.22 - 7.27 (m, 2H) 7.29 - 7.39 (m, 2H) 7.44 - 7.51 (m, 2H). Step B: (S)-5-(4-(4-chlorobenzyl)phenyl)-N-(3-cyano-4-methoxyphenyl)-6-methyl-4-oxo- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide.

The title compound was prepared in a manner analogous to Intermediate 1, Step E, reacting (S)- N-(3-cyano-4-methoxyphenyl)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3- carboxamide (Intermediate 7, 130 mg, 0.193 mmol) and 1-bromo-4-(4-chlorobenzyl)benzene (108 mg, 0.385 mmol).1H NMR (400 MHz, DMSO-d₆) δ: 9.83 (s, 1H), 8.21 (d, J = 2.3 Hz, 1H), 8.15 (dd, J = 8.9, 2.3 Hz, 1H), 8.11 (s, 1H), 7.36 (tdd, J = 22.5, 16.0, 8.7 Hz, 9H), 4.71 (dd, J = 13.0, 4.4 Hz, 1H), 4.48 – 4.38 (m, 1H), 4.35 (dd, J = 13.0, 3.7 Hz, 1H), 3.99 (d, J = 2.2 Hz, 5H), 1.21 (d, J = 6.6 Hz, 3H).Mass spectrum (ESI, m/z): calcd. for C₂₉H₂₄ClN₅O₃, 525.2; found [M+H]+, 526.1. Example 400: (S)-3-cyano-N-(5-(4-(difluoro(6-methoxypyridin-2-yl)methyl)phenyl)-6- methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)-4-methoxybenzamide.

The title compound was prepared in a manner analogous to Example 395: (S)-N-(5-(4-((4- chlorophenyl)difluoromethyl)phenyl)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin- 3-yl)-3-cyano-4-methoxybenzamide, reacting (S)-3-cyano-4-methoxy-N-(6-methyl-4-oxo- 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)benzamide (Intermediate 13, 98 mg, 0.302 mmol) and 2-((4-bromophenyl)difluoromethyl)-6-methoxypyridine (Intermediate 38, 95 mg, 0.302 mmol).1H NMR (400 MHz, DMSO-d₆) δ: 1.24 (br d, J=6.39 Hz, 3H) 3.80 - 3.83 (m, 3H) 3.97 - 4.01 (m, 3H) 4.37 (dd, J=13.21, 3.67 Hz, 1H) 4.49 - 4.58 (m, 1H) 4.73 (dd, J=13.07, 4.39 Hz, 1H) 6.91 - 6.99 (m, 1H) 7.39 (d, J=2.86 Hz, 1H) 7.41 (s, 1H) 7.58 (d, J=8.58 Hz, 2H) 7.71 (d, J=8.58 Hz, 2H) 7.90 (t, J=7.87 Hz, 1H) 8.11 (s, 1H) 8.16 (dd, J=8.87, 2.29 Hz, 1H) 8.22 (d, J=2.29 Hz, 1H) 9.81 - 9.86 (m, 1H). Mass spectrum (ESI, m/z): calcd. for C₂₉H₂₄F₂N₆O₄, 558.2; found [M+H]+, 559.2.

y y y y y y methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)-4-methoxybenzamide.

The title compound was prepared in a manner analogous to Example 395: (S)-N-(5-(4-((4- chlorophenyl)difluoromethyl)phenyl)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin- 3-yl)-3-cyano-4-methoxybenzamide, reacting (S)-3-cyano-4-methoxy-N-(6-methyl-4-oxo- 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)benzamide (Intermediate 13, 63 mg, 0.194 mmol) and 3-((4-bromophenyl)difluoromethyl)-2-methoxypyridine (Intermediate 35, 60 mg, 0.191 mmol).1H NMR (400 MHz, DMSO-d₆) δ: 9.83 (s, 1H), 8.35 (dd, J = 5.0, 1.5 Hz, 1H), 8.23 (d, J = 2.3 Hz, 1H), 8.16 (dd, J = 8.9, 2.3 Hz, 1H), 8.12 (s, 1H), 8.06 (dd, J = 7.5, 1.7 Hz, 1H), 7.62 – 7.53 (m, 4H), 7.40 (d, J = 9.0 Hz, 1H), 7.19 (dd, J = 7.5, 5.0 Hz, 1H), 4.73 (dd, J = 13.1, 4.4 Hz, 1H), 4.59 – 4.50 (m, 1H), 4.37 (dd, J = 13.1, 3.5 Hz, 1H), 3.99 (s, 3H), 3.80 (s, 3H), 1.24 (d, J = 6.6 Hz, 3H). Mass spectrum (ESI, m/z): calcd. for C + 29H24F2N6O4, 558.2; found [M+H] , 559.2. Example 402: 3-cyano-N-( -5-(4-(difluoro(phenyl)methyl)phenyl)-6,7-dimethyl-4-

oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)-4-methoxybenzamide.

The title compound was prepared in a manner analogous to Example 395: (S)-N-(5-(4-((4- chlorophenyl)difluoromethyl)phenyl)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin- 3-yl)-3-cyano-4-methoxybenzamide, reacting 3-cyano-N-((6R*,7S*)-6,7-dimethyl-4-oxo- 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)-4-methoxybenzamide (Intermediate 26, 50 mg, 0.148 mmol) and 1-bromo-4-(difluoro(phenyl)methyl)benzene (45 mg, 0.159 mmol).1H NMR (400 MHz, DMSO-d6) δ: 9.83 (s, 1H), 8.22 (d, J = 2.3 Hz, 1H), 8.16 (dd, J = 8.9, 2.3 Hz, 1H), 8.13 (s, 1H), 7.65 (d, J = 8.7 Hz, 2H), 7.58 (d, J = 8.9 Hz, 4H), 7.53 (q, J = 3.6 Hz, 3H), 7.41 (d, J = 9.0 Hz, 1H), 4.69 – 4.58 (m, 1H), 4.32 – 4.21 (m, 1H), 4.00 (s, 3H), 1.52 (d, J = 6.6 Hz, 3H), 1.30 (d, J = 6.6 Hz, 3H). Mass spectrum (ESI, m/z): calcd. for C₃₀H₂₅F₂N₅O₃, 541.2; found [M+H]+, 542.2. Example 403: 3-cyano-N-( -5-(4-(difluoro(phenyl)methyl)phenyl)-6,7-dimethyl-4-

oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)-4-methoxybenzamide.

The title compound was prepared in a manner analogous to Example 395: (S)-N-(5-(4-((4- chlorophenyl)difluoromethyl)phenyl)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin- 3-yl)-3-cyano-4-methoxybenzamide, reacting 3-cyano-N-((6S*,7R*)-6,7-dimethyl-4-oxo- 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)-4-methoxybenzamide (Intermediate 27, 50 mg, 0.147 mmol) and 1-bromo-4-(difluoro(phenyl)methyl)benzene (45 mg, 0.158 mmol).1H NMR (400 MHz, DMSO-d₆) δ: 9.84 (s, 1H), 8.23 (d, J = 2.2 Hz, 1H), 8.16 (dd, J = 8.9, 2.3 Hz, 1H), 8.13 (s, 1H), 7.65 (d, J = 8.6 Hz, 2H), 7.57 (t, J = 6.7 Hz, 4H), 7.53 (q, J = 3.5 Hz, 3H), 7.41 (d, J = 9.0 Hz, 1H), 4.69 – 4.58 (m, 1H), 4.32 – 4.23 (m, 1H), 4.00 (s, 3H), 1.52 (d, J = 6.6 Hz, 3H), 1.30 (d, J = 6.6 Hz, 3H). Mass spectrum (ESI, m/z): calcd. for C30H25F2N5O3, 541.2; found [M+H]+, 542.2. Example 404: 3-cyano-N-( -6,7-dimethyl-4-oxo-5-(4-(trifluoromethyl)phenyl)-

4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)-4-methoxybenzamide.

The title compound was prepared in a manner analogous to Example 395: (S)-N-(5-(4-((4- chlorophenyl)difluoromethyl)phenyl)-6-methyl-4-oxo-4,5,6,7-tetrahydro-pyrazolo[1,5- a]pyrazin-3-yl)-3-cyano-4-methoxybenzamide, reacting 3-cyano-N-((6S*,7R*)-6,7-dimethyl-4- oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)-4-methoxybenzamide (Intermediate 27, 50 mg, 0.147 mmol) and 4-bromobenzo-trifluoride (0.041 mL, 0.295 mmol).1H NMR (400 MHz, DMSO-d6) δ: 9.86 (s, 1H), 8.24 (d, J = 2.3 Hz, 1H), 8.18 (dd, J = 8.9, 2.3 Hz, 1H), 8.14 (s, 1H), 7.87 (d, J = 8.5 Hz, 2H), 7.71 (d, J = 8.4 Hz, 2H), 7.42 (d, J = 9.0 Hz, 1H), 4.71 – 4.61 (m, 1H), 4.39 – 4.29 (m, 1H), 4.00 (s, 3H), 1.53 (d, J = 6.6 Hz, 3H), 1.32 (d, J = 6.7 Hz, 3H). Mass spectrum (ESI, m/z): calcd. for C + 24H20F3N5O3, 483.1; found [M+H] , 484.1.

Example 405: 3-cyano-N-( -6,7-dimethyl-4-oxo-5-(4-(trifluoromethyl)phenyl)-

4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)-4-methoxybenzamide.

The title compound was prepared in a manner analogous to Example 395: (S)-N-(5-(4-((4- chlorophenyl)difluoromethyl)phenyl)-6-methyl-4-oxo-4,5,6,7-tetrahydro-pyrazolo[1,5- a]pyrazin-3-yl)-3-cyano-4-methoxybenzamide, reacting 3-cyano-N-((6R*,7S*)-6,7-dimethyl-4- oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)-4-methoxybenzamide (Intermediate 26, 45 mg, 0.133 mmol) and 4-bromobenzo-trifluoride (0.02 mL, 0.143 mmol).1H NMR (400 MHz, DMSO-d6) δ: 9.67 (s, 1H), 8.45 (s, 1H), 8.18 (d, J = 2.3 Hz, 1H), 8.11 (dd, J = 8.9, 2.3 Hz, 1H), 7.79 (d, J = 8.4 Hz, 2H), 7.53 (d, J = 8.3 Hz, 2H), 7.04 (d, J = 8.9 Hz, 1H), 4.62 – 4.54 (m, 1H), 4.13 – 4.05 (m, 1H), 4.01 (s, 3H), 1.67 (d, J = 6.7 Hz, 3H), 1.46 (d, J = 6.7 Hz, 3H). Mass spectrum (ESI, m/z): calcd. for C H F N + 24 20 3 5O3, 483.1; found [M+H] , 484.1. Example 406: (S)-3-cyano-N-(5-(4-((2-(dimethylamino)pyridin-4-yl)difluoromethyl)- phenyl)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)-4-methoxy- benzamide.

Step A: (2-(dimethylamino)pyridin-4-yl)(4-iodophenyl)methanone. The title compound was prepared in a manner analogous to Example 28, Step A, reacting 4- bromo-N,N-dimethylpyridin-2-amine (1.24 g, 6.18 mmol) and 4-iodo-N-methoxy-N- methylbenzamide (1.5 g, 5.2 mmol).1H NMR (400 MHz, CDCl₃) δ: 8.28 (d, J = 5.2 Hz, 1H), 7.89 - 7.82 (m, 2H), 7.56 (d, J = 8.4 Hz, 2H), 6.74 (s, 1H), 6.70 (dd, J = 1.2, 5.2 Hz, 1H), 3.13 (s, 6H). Mass spectrum (ESI, m/z): calcd. for C₁₄H₁₃IN₂O 352.0; found [M+H]+, 352.9. Step B: 4-(difluoro(4-iodophenyl)methyl)-N,N-dimethylpyridin-2-amine. The title compound was prepared in a manner analogous to Example 337, Step B, reacting (2- (dimethylamino)pyridin-4-yl)(4-iodophenyl)methanone (500 mg, 0.994 mmol), DCM (5 mL) and DAST (1.3 mL, 9.9 mmol).1H NMR (400 MHz, CDCl3) δ: 8.19 (d, J = 5.2 Hz, 1H), 7.76 (d, J = 8.4 Hz, 2H), 7.23 (d, J = 8.8 Hz, 2H), 6.61 (s, 1H), 6.55 (dd, J = 1.2, 5.2 Hz, 1H), 3.11 (s, 6H). Mass spectrum (ESI, m/z): calcd. for C₁₄H₁₃F₂IN₂374.0; found [M+H]+ , 375.0. Step C: (S)-3-cyano-N-(5-(4-((2-(dimethylamino)pyridin-4-yl)difluoromethyl)phenyl)-6-methyl- 4-oxo- tetrahydropyrazolo[1,5-a]pyrazin-3-yl)-4-methoxybenzamide.

The title compound was prepared in a manner analogous to Example 337, Step C, reacting (S)-3- cyano-4-methoxy-N-(6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)benzamide (Intermediate 13, 100 mg, 0.307 mmol) and 4-(difluoro(4-iodophenyl)methyl)- N,N - dimethylpyridin-2-amine (138 mg, 0.369 mmol).1H NMR (400 MHz, DMSO-d₆) δ: 9.83 (s, 1H), 8.26 - 8.08 (m, 4H), 7.72 - 7.65 (m, 2H), 7.59 (d, J = 8.4 Hz,2H), 7.40 (d, J = 9.2 Hz, 1H), 6.76 (s, 1H), 6.67 (d, J = 5.2 Hz, 1H), 4.73 (dd, J = 4.4, 13.2 Hz, 1H), 4.58 - 4.49 (m, 1H), 4.37 (dd, J = 3.2, 13.2 Hz, 1H), 3.99 (s, 3H), 3.06 (s, 6H), 1.23 (d, J = 6.4 Hz, 3H). Mass spectrum (ESI, m/z): calcd. for C₃₀H₂₇F₂N₇O₃571.2, found [M+H]+, 572.3. Example 407 and 397: (S)-3-cyano-N-(5-(4-(difluoro(2-(methylamino)pyridin-4- yl)methyl)phenyl)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)-4- methoxybenzamide and (S)-3-cyano-N-(5-(4-(difluoro(2-(methylamino)pyridin-4- yl)methyl)phenyl)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)-4- hydroxybenzamide

Step A: 4-iodo-N-methoxy-N-methylbenzamide. 4-Iodobenzoic acid (5.00 g, 20.2 mol), PPh3 (7.93 g, 30.2 mmol), a stir bar and DCM (180 mL) were added to 500 mL round-bottomed flask, which was subsequently evacuated and refilled with nitrogen (x3), and placed in ice/water bath, the mixture was added NBS (5.38 g, 30.2 mmol) in batches and stirred at 0 °C for 15 min. The mixture was brought to rt, then which was added N, O-dimethylhydroxylamine hydrochloride (2.95 g, 30.2 mmol) and Et3N (5.62 mL, 40.3 mmol). The solution was stirred overnight at rt. The reaction progress was monitored by LC-MS. The reaction mixture was quenched with saturated NaHCO3 (150 mL) and extracted with DCM (100 mL x 3). The combined extracts washed with brine (200 mL), dried with anhydrous Na2SO4, filtered and concentrated in vacuum to give brown oil. The oil was then subjected to silica gel chromatography (0~30% EtOAc/PE) to give 4-iodo-N-methoxy-N-methylbenzamide as brown oil (5.048 g, 85% yield).1H NMR (400 MHz, CDCl3) δ: 7.78 - 7.73 (m, 2H), 7.45 - 7.40 (m, 2H), 3.53 (s, 3H), 3.35 (s, 3H). Mass spectrum (ESI, m/z): calcd. for C9H10INO2291.0; found [M+H]+, 292.0. Step B: tert-butyl (4-(4-iodobenzoyl)pyridin-2-yl)carbamate. tert-Butyl (4-bromopyridin-2-yl)carbamate (5.00 g, 18.3 mmol), a stir bar and THF (50 mL) were added to an oven-dried and nitrogen-purged 250 mL three-necked flask fitted with a thermometer, 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 MeLi (13.7 mL g, 22.0 mmol) dropwise over 15 min, the mixture stirred for 0.5 h, then treated with n-BuLi (11.7 mL g, 29.3 mmol) dropwise over 15 min, the mixture stirred for 40 min. Then a solution of 4-iodo-N- methoxy-N-methylbenzamide (7.99 g, 27.5 mmol) in THF (50 mL) was added above solution. The mixture was stirred at -70 °C for 2.5 h, then gradually warmed to rt and stirred overnight at rt. The reaction progress was monitored by LC-MS. The reaction mixture was quenched with saturated NH₄Cl (60 mL) and was extracted with EtOAc (100 mL*3). The combined extracts washed with brine (200 mL) and concentrated in vacuum to give a light brown solid. The solid was then subjected to silica gel chromatography (0~20% EtOAc/PE) to give tert-butyl (4-(4- iodobenzoyl)pyridin-2-yl)carbamate as a light yellow solid (1.26 g, 14% yield).1H NMR (400 MHz, CDCl₃) δ: 8.39 (d, J = 5.2 Hz, 1H), 8.22 (s, 1H), 7.88 (d, J = 8.4 Hz, 2H), 7.56 (d, J = 8.4 Hz, 2H), 7.21 (dd, J = 1.2, 5.2 Hz, 1H), 1.52 (s, 9H). Mass spectrum (ESI, m/z): calcd. for C 7H17IN2O3424.0; f + 1 ound [M+H] , 425.1. Step C: tert-butyl (4-(4-iodobenzoyl)pyridin-2-yl)(methyl)carbamate. tert-Butyl (4-(4-iodobenzoyl)pyridin-2-yl)carbamate (1.26 g, 2.97 mmol), a stir bar, and THF (40 mL) were added to an oven-dried and nitrogen-purged 100 mL three-necked flask fitted with a thermometer and a reflux condenser, which was subsequently evacuated and refilled with nitrogen (x3), and the reaction vessel placed in a 0 °C (ice/water) bath before treated with NaH (178 mg, 4.46 mmol). The reaction mixture was stirred for 30 min, the mixture turned into a yellow suspension, then which was treated with MeI (0.29 mL, 4.5 mmol) dropwise over 1 min. Then the mixture was stirred at 40 °C for overnight. The reaction progress was monitored by LC- MS. The reaction mixture was quenched with sat. NH₄Cl solution (30 mL), extracted with EtOAc (20 mL x 3). The combined extracts washed with brine (40 mL), dried over anhydrous Na₂SO₄, filtered and concentrated in vacuum to give brown oil. The oil was then subjected to silica gel chromatography (0~7% EtOAc/PE) to give tert-butyl (4-(4-iodobenzoyl)pyridin-2- yl)(methyl)carbamate as light brown oil (988 mg, 71% yield). Mass spectrum (ESI, m/z): calcd. for C H19IN2O3438.0, fo + 18 und [M+H] , 438.8. Step D: tert-butyl (4-(difluoro(4-iodophenyl)methyl)pyridin-2-yl)(methyl)carbamate. The title compound was prepared in a manner analogous to Example 337, Step B, reacting tert- butyl (4-(4-iodobenzoyl)pyridin-2-yl)(methyl)carbamate (1.41 g, 3.22 mmol) and DAST (22 mL).1H NMR (400 MHz, CDCl₃) δ: 8.42 (d, J = 5.2 Hz, 1H), 7.85 (s, 1H), 7.77 (d, J = 8.4 Hz, 2H), 7.24 (d, J = 8.4 Hz, 2H), 7.05 (d, J = 4.8 Hz, 1H), 3.41 (s, 3H), 1.49 (s, 9H). Mass spectrum (ESI, m/z): calcd. for C H F IN O 46 + 18 19 2 2 2 0.1; found [M+H] , 461.0. Step E: tert-butyl (S)-(4-((4-(3-(3-cyano-4-methoxybenzamido)-6-methyl-4-oxo-6,7- dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl)phenyl)difluoromethyl)pyridin-2-yl)(methyl)carbamate and tert-butyl (S)-(4-((4-(3-(3-cyano-4-hydroxybenzamido)-6-methyl-4-oxo-6,7- dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl)phenyl)difluoromethyl)pyridin-2-yl)(methyl)carbamate. The title compound was prepared in a manner analogous to Example 337, Step C, reacting (S)-3- cyano-4-methoxy-N-(6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)benzamide (Intermediate 13,150 mg, 0.461 mmol) and tert-butyl (4-(difluoro(4-iodophenyl)methyl)pyridin- 2-yl)(methyl)carbamate (255 mg, 0.553 mmol). Step F: (S)-3-cyano-N-(5-(4-(difluoro(2-(methylamino)pyridin-4-yl)methyl)phenyl)-6-methyl-4- oxo- tetrahydropyrazolo[1,5-a]pyrazin-3-yl)-4-methoxybenzamide and (S)-3-cyano-N-(5-

(4-(difluoro(2-(methylamino)pyridin-4-yl)methyl)phenyl)-6-methyl-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazin-3-yl)-4-hydroxybenzamide. tert-Butyl (S)-(4-((4-(3-(3-cyano-4-methoxybenzamido)-6-methyl-4-oxo-6,7- dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl)phenyl)difluoromethyl)pyridin-2-yl)(methyl)carbamate and tert-butyl (S)-(4-((4-(3-(3-cyano-4-hydroxybenzamido)-6-methyl-4-oxo-6,7- dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl)phenyl)difluoromethyl)pyridin-2-yl)(methyl)carbamate (180 mg, mixture), a stir bar, HCl/dioxane (3 mL, 4 M) and CH₃CN (0.5 mL) were added to an oven-dried and nitrogen-purged 10 mL round-bottomed flask, and the mixture was stirred at rt for 8 h. The reaction mixture was concentrated in vacuum to give brown oil. The crude product was purified by Prep-HPLC with the following conditions: column, Welch Xtimate C18, 150 mm, 30 mm x 5 ^m; mobile phase, 26% to 56% (v/v) CH3CN and H2O with (0.05%FA) and then freeze dried to afford (S)-3-cyano-N-(5-(4-(difluoro(2-(methylamino)pyridin-4- yl)methyl)phenyl)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)-4- methoxybenzamide (54 mg, 29% yield) as a white solid.1H NMR (400 MHz, DMSO-d6) δ: 9.84 (s, 1H), 8.23 (d, J = 2.4 Hz, 1H), 8.16 (dd, J = 2.4, 9.2 Hz, 1H), 8.12 (s, 1H), 8.09 (d, J = 5.6 Hz, 1H), 7.65 - 7.57 (m, 4H), 7.40 (d, J = 9.2 Hz, 1H), 6.88 - 6.83 (m, 1H), 6.61 - 6.56 (m, 2H), 4.74 (dd, J = 4.4, 13.2 Hz, 1H), 4.58 - 4.49 (m,1H), 4.38 (dd, J = 3.6, 13.2 Hz, 1H), 3.99 (s, 3H), 2.78 (d, J = 4.8 Hz, 3H), 1.24 (d, J = 6.8 Hz, 3H). Mass spectrum (ESI, m/z): calcd. for C₂₉H₂₅F₂N₇O₃ 557.2, found [M+H]+ , 558.3.) and (S)-3-cyano-N-(5-(4-(difluoro(2-(methylamino)pyridin-4- yl)methyl)phenyl)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)-4- hydroxybenzamide (41.3 mg, 23% yield) as a light yellow solid.1H NMR (400 MHz, DMSO-d6) δ: 11.98 (s, 1H), 9.75 (s, 1H), 8.14 - 8.08 (m, 3H), 7.98 (dd, J = 2.0, 8.8 Hz, 1H), 7.66 - 7.57 (m, 4H), 7.14 (d, J = 9.2 Hz, 1H), 6.89 - 6.82 (m,1H), 6.62 - 6.56 (m, 2H), 4.73 (dd, J = 4.4, 13.2 Hz, 1H), 4.58 - 4.49 (m, 1H), 4.37 (dd, J = 3.6, 13.2 Hz, 1H), 2.78 (d, J = 4.8 Hz, 3H), 1.23 (d, J = 6.4 Hz, 3H). Mass spectrum (ESI, m/z): calcd. for C₂₈H₂₃F₂N₇O₃543.2; found [M+H]+ , 544.2.). Pharmacological Examples Experimental methods Antiviral activity in immortal cell lines Compounds were tested for their ability to inhibit SARS-CoV-2 in A549-hACE2 cells. SARS‑CoV‑2-Belgium (strain BetaCov/Belgium/GHB-03021/2020) was recovered from a nasopharyngeal swab taken from a patient returning from Wuhan, China. SARS-CoV-2 Belgium stocks were passaged six times in VeroE6-eGFP cells prior to storage (-80°C). The high content imaging protocol for the SARS-CoV-2 antiviral assay in VeroE6-eGFP cells is described in Chui et al. J Med Virol. (2022) Feb 28 (doi: 10.1002/jmv.27683). A549-hACE2 cells were obtained from Invivogen and propagated as instructed by the manufacturer. To obtain antiviral activity data, A549-hACE2 cells were infected with SARS- CoV-2 at an MOI of 0.1 in the presence of compounds. Twenty-four hours post infection, the cells are fixed, permeabilized and antibody stained for viral spike protein, next to nuclear and whole cell staining. After imaging of the plates on a high-throughput confocal imaging device, the two latter stains are utilized for cell segmentation of subsequent images. The number of infected cells was scored based on intracellular anti-spike staining. The percentage of spike- positive cells is plotted across compound-containing wells in a dose-response manner to obtain a final AC50. Table 6: Pharmacological Data for Compounds of the Invention (Examples 1-407) Co. No. : compound number EC50 (µM) : SARS-CoV-2 A549-hACE antiviral assay EC50 (µM) CC50 (µM) : SARS-CoV-2 A549-hACE toxicity counterscreen CC50 (µM) A comma is used as the decimal separator in the table below.

All patents and publications described hereinabove are hereby incorporated by reference in their entirety. While the invention has been described in terms of various preferred embodiments and specific examples, the invention should be understood as not being limited by the foregoing detailed description, but as being defined by the appended claims and their equivalents.

Claims

CLAIMS 1. A compound of Formula (I)

and stereoisomeric forms thereof, wherein W is C or N X is -C(O)NH- or -NHC(O)-; R2 is H or CH3; R3 is H or CH3; Ra is selected from the group consisting of H, OH, C1-4alkyl, halo, N3, ethyne, -O-C1-4alkyl, -O-C1-4alkyl-OH, -O-C1-4alkyl-CN, -O-C1-4alkyl-ethyne, -O-C1-4alkyl-O-C1-4alkyl, -O-C1-4alkyl-NH2, -O-C1-4alkyl-NH(CH3), -C1-4alkyl-NH(C1-4alkyl), -C1-4alkyl-N(C1-4alkyl)2, C1-4alkyl-O-C1-4alkyl, -O-C3-7cycloalkyl, -O-C1-4alkyl -O-C3-7cycloalkyl, -C1-4alkyl-C3-7heterocycloalkyl -C1-4alkyl-O-C3-7heterocycloalkyl, -O-C3-7heterocycloalkyl, halo-C1-4alkyl (mono, di, tri), SO2NH2, SO2-C1-4alkyl and triazole; n is 0 or 1; A is phenyl or heteroaryl selected from pyridinyl, pyridazinyl, pyrimidinyl or pyrazinyl; L is selected from the group consisting of C1-4alkyl, CF2, -C(O)- and CHF; m is 0 or 1; Rb is selected from the group consisting of -CH2F, -CHF₂, -CF3, -C1-4alkylCF3, -O-C1-4alkylCF3, -O-C1-4alkylCF3, -C1-4alkyl-O-CF3, CF2CH3, -NH-C1-4alkylCF3, -C1-4alkyl-NH-C1-4alkyl-CF3, C3-7cycloalkyl, C3-7cycloalkyl-CF3, C3-7heterocycloalkyl, phenyl, 3-pyridyl, triazole, thiophene, isothiazole, isoxazole, pyridinyl, pyridazinyl, pyrimidinyl, -^C _1-4 ^{alkyl, -O-C} _1-4 ^{alkyl, -NH-C} _1-4 ^{alkyl, -NH-C} _3-7 ^cycloalkyl, each optionally substituted with one or more substituents each independently selected from the group consisting of, halo, OH, NH2, SF5, alkyne (C2), C=C=C, CF3, CO2H, C1-4alkylOH, C1-4alkyl-O-C1-4alkyl, C1-4alkylNH2, C1-4alkylNHC1-4alkyl, C1-4alkylNH(C1-4alkyl)2, C1-4alkylNHC(O)-C1-4alkyl, (C1-4alkyl)2NC(O)-C1-4alkyl, C1-4alkyl-OH, C1-4alkyl-O-C1-4alkyl, C3-7cycloalkyl, C3-7heterocycloalkyl, C1-4alkyl-C3-7heterocycloalkyl, C1-4alkyl-C3-7heteroaromatic, C1-4alkyl-pyrrolidin-2-one, C1-4alkyl, C1-4alkyloxy, CF3O and each variable can be optionally substituted with one, two or three substituents each individually selected from halo, NH2, CN, C1-4alkyl, C1-4alkyl-NH-C1-4alkyl, C(O)C1-4alkyl, C(O)OC1-4alkyl, C3-7cycloalkyl, CF₃, CF₃O and C_1-4alkyloxy; and the pharmaceutically acceptable salts and the solvates thereof.

2. The compound according to claim 1, W is C; or pharmaceutically acceptable salts and the solvates thereof.

3. The compound according to claim 1, W is N; or pharmaceutically acceptable salts and the solvates thereof.

4. The compound according to claim 1, wherein W is C and X is -C(O)NH; or pharmaceutically acceptable salts and the solvates thereof.

5. The compound according to claim 1, wherein W is C and X is -NHC(O)-; or pharmaceutically acceptable salts and the solvates thereof.

6. The compound according to claim 1, wherein A is phenyl.

7. The compound according to claim 1, wherein W is C, and A is phenyl; or pharmaceutically acceptable salts and the solvates thereof.

8. The compound according to claim 1, wherein W is C, and A is pyridinyl; or pharmaceutically acceptable salts and the solvates thereof.

9. The compound according to any one of claims 1 to 8, wherein m is 1 and L is C_1-4alkyl or CF₂; or pharmaceutically acceptable salts and the solvates thereof.

10. 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.