WO2018011160A1

WO2018011160A1 - 6,7-dihydro-4h-pyrazolo[1,5-a]pyrazine compounds for the treatment of infectious diseases

Info

Publication number: WO2018011160A1
Application number: PCT/EP2017/067315
Authority: WO
Inventors: Taishan HU; Buyu KOU; Xianfeng Lin; Haixia Liu; Zhisen ZHANG
Original assignee: F. Hoffmann-La Roche Ag; Hoffmann-La Roche Inc.
Priority date: 2016-07-14
Filing date: 2017-07-11
Publication date: 2018-01-18

Abstract

The present invention relates to compounds of the formula (I) or pharmaceutically acceptable salts, enantiomer or diastereomer thereof, wherein R¹ to R⁴ are as described above. The compounds may be useful for the treatment or prophylaxis of hepatitis B virus infection.

Description

6,7-DIHYDRO-4H-PYRAZOLO[1 ,5-A]PYRAZINE COMPOUNDS FOR THE TREATMENT OF INFECTIOUS DISEASES

The present invention relates to organic compounds useful for therapy and/or prophylaxis in a mammal, and in particular for treating hepatitis B virus infection, and their pharmaceutical activity, manufacture, pharmaceutical compositions containing them and their potential use as medicaments. FIELD OF THE INVENTION The present invention relates to compounds of the formula (I),

or pharmaceutically acceptable salt, enantiomer or diastereomer thereof, wherein R¹ to R⁴ are as described below.The compounds of this invention are useful for the treatment or prophylaxis of hepatitis B virus infection. Hepatitis B virus (HBV) infection is a major public health problem worldwide, roughly 30% of the world's population show serological evidence of current or past infection. Despite the introduction of a safe and effective prophylactic vaccine against the virus in the early 1980s, it is estimated that there are still more than 240 million chronic HBV carriers worldwide, a high percentage of whom will eventually develop liver cirrhosis or hepatocellular carcinoma (HCC) (WHO Hepatitis B. Fact Sheet N°204). In the 2010 Global Burden of Disease study (R Lozano, et al. Lancet, 380 (2012), 2095–2128), HBV infection ranked in the top health priorities in the world, and was the tenth leading cause of death (780,000 deaths per year). Recent studies have shown that progression to liver cirrhosis and HCC in patients with chronic HBV infection is significantly associated with circulating HBV DNA levels. Thus, antiviral therapy against HBV is critical to prevent the progression to cirrhosis or development of HCC. HBV is a small, enveloped virus that belongs to the Hepadnaviridae family. It contains a partly double-stranded DNA genome with approximately 3200 base pairs. HBV have a strong preference for infecting human hepatocytes. The life cycle begins when HBV attaches to the host cell membrane via its envelope proteins. The precise mechanism of viral entry has not been fully elucidated. The viral relaxed circular DNA (rcDNA) containing nucleocapsids are released into the cytoplasm and transported to the nucleus. In the nucleus, the rcDNA is repaired by both viral and cellular enzymes to form covalently closed circular DNA (cccDNA). There is evidence that each infected cell contains 1-50 cccDNA molecules as unique episomal minichromosomes. Both subgenomic RNA (sgRNA) and pregenomic RNA (pgRNA) are transcribed from the cccDNA using the cellular transcriptional machinery. After nuclear export, the pgRNA is translated into the core protein and the viral polymerase. The sgRNA is translated into the regulatory X protein and the three envelope proteins. Self-assembly of the RNA-containing viral nucleocapsid takes place via complex formation of the pgRNA with the core protein and the polymerase. Inside the nucleocapsid, the pgRNA is reverse transcribed into negative-strand DNA. rcDNA is then generated by plus-strand synthesis from the negative-strand DNA. The nucleocapsids are either re-imported to the nucleus for cccDNA amplification or enveloped and released via the endoplasmic reticulum (ER). The reverse transcriptase lacks proofreading activity; thus, mutations of the viral genome are frequent and result in the coexistence of genetically distinct viral species in infected individuals (quasispecies). Currently, seven treatments are approved for chronic hepatitis B (CHB), including two formulations of interferon (IFN) (conventional IFN and PEG-IFN) and five nucleos(t)ide analogues (NUCs: lamivudine, adefovir dipivoxil, entecavir, telbivudine, and tenofovir disoproxil). The main difference between immunomodulatory agents and NUCs is that PEG-IFN has the advantage of a finite duration of use, whereas the use of NUCs is indefinite. The major drawback of PEG-IFN is its high frequency of adverse events. Some viral genotypes do not show good responses to interferon therapy. Long-term use of NUCs, on the other hand, poses the risk of drug resistance. The ultimate goal of antiviral therapy for CHB is to prevent progression to cirrhosis or HCC via eradication of HBV or persistent viral suppression. The majority of currently treated patients fail to achieve this goal. As indicated above, nucleocapsid assembly is a critical step for HBV genome replication. As the synthesis of viral DNA takes place exclusively within the nucleocapsid, the assembly and disassembly of nucleocapsid must be precisely regulated to ensure correct packaging and release of the viral genome. Nucleocapsid assembly is an evolutionary constraint process that limits the diversity of HBV, and it is highly sensitive to even subtle molecular disturbances. Both assembly and disassembly of nucleocapsid make the process an attractive therapeutic target for the development of new antiviral therapies against various HBV genotypes and drug resistance isolates. A few capsid related anti-HBV compounds have been reported. For example, heteroaryldihydropyrimidines (HAP), including compounds named Bay 41-4109, Bay 38-7690 and Bay 39-5493 (Deres K. et al. Science 2003, 893), and phenylpropenamide derivatives such as AT-61 and AT-130 (Feld J. et al. Antiviral Research 2007, 168-177). Capsid has become a promising drug target with several molecules under clinical stage. There is still a need to develop new treatments for the prophylaxis and treatment of hepatitis B virus infection. SUMMARY OF THE INVENTION Objects of the present invention are novel compounds of formula (I), their manufacture, medicaments based on a compound in accordance with the invention and their production as well as the use of compounds of formula (I) as HBV inhibitors and for the treatment or prophylaxis of HBV infection. The compounds of formula (I) show superior anti-HBV activity. DETAILED DESCRIPTION OF THE INVENTION DEFINITIONS The term“C_1-6alkyl” denotes a monovalent linear or branched saturated hydrocarbon group of 1 to 6 carbon atoms. In particular embodiments, C1-6alkyl has 1 to 6 carbon atoms, and in more particular embodiments 1 to 4 carbon atoms. Examples of C_1-6alkyl include, but not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl and tert-butyl.

The term“halo” or“halogen” are used interchangeably herein and denote fluoro, chloro, bromo or iodo.

The term“haloC_1-6alkyl” denotes a C_1-6alkyl group wherein at least one of the hydrogen atoms of the C_1-6alkyl group has been replaced by same or different halogen atoms, particularly fluoro atoms. Examples of haloC_1-6alkyl include monofluoro-, difluoro- or trifluoro-methyl, - ethyl or -propyl, for example 3,3,3-trifluoropropyl, 2-fluoroethyl, trifluoroethyl, fluoromethyl, difluoromethyl, difluoroethyl or trifluoromethyl. The term“oxo” denotes a divalent oxygen atom =O.

The term“pyrimidinyloxy” denotes pyrimidinyl-O-.

The term“diastereomer” denotes a stereoisomer with two or more centers of chirality and whose molecules are not mirror images of one another. Diastereomers have different physical properties, e.g. melting points, boiling points, spectral properties, activities and reactivities.

The term“enantiomers” denotes two stereoisomers of a compound which are non- superimposable mirror images of one another.

The term“pharmaceutically acceptable salts” denotes salts which are not biologically or otherwise undesirable. Pharmaceutically acceptable salts include both acid and base addition salts.

The term“pharmaceutically acceptable acid addition salt” denotes those pharmaceutically acceptable salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid, phosphoric acid, and organic acids selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic, and sulfonic classes of organic acids such as formic acid, acetic acid, propionic acid, glycolic acid, gluconic acid, lactic acid, pyruvic acid, oxalic acid, malic acid, maleic acid, maloneic acid, succinic acid, fumaric acid, tartaric acid, citric acid, aspartic acid, ascorbic acid, glutamic acid, anthranilic acid, benzoic acid, cinnamic acid, mandelic acid, embonic acid, phenylacetic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and salicyclic acid.

The term“pharmaceutically acceptable base addition salt” denotes those pharmaceutically acceptable salts formed with an organic or inorganic base. Examples of acceptable inorganic bases include sodium, potassium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum salts. Salts derived from pharmaceutically acceptable organic nontoxic bases includes salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-diethylaminoethanol, trimethylamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperizine, piperidine, N-ethylpiperidine, and polyamine resins.

Compounds of the general formula (I) which contain one or several chiral centers can either be present as racemates, diastereomeric mixtures, or optically active single isomers. The racemates can be separated according to known methods into the enantiomers. Particularly, diastereomeric salts which can be separated by crystallization are formed from the racemic mixtures by reaction with an optically active acid such as e.g. D- or L-tartaric acid, mandelic acid, malic acid, lactic acid or camphorsulfonic acid.

INHIBITOR OF HBV The present invention provides (i) novel compounds having the general formula (I):

wherein

R¹ is

, wherein R⁵, R⁶ and R⁷ are independently selected from H or C_1- ₆alkyl;

R² is H;

R³ is C_1-6alkyl;

R⁴ is phenyl which is three times substituted by halogen; or pyridinyl which is once or twice substituted by substituents independently selected from halogen and haloC_1- ₆alkyl;

or pharmaceutically acceptable salt, enantiomer or diastereomer thereof;

with the proviso that R⁵, R⁶ and R⁷ are not H simultaneously, and

(6S)-3-(5,5-dimethyl-2-oxo-oxazolidin-3-yl)-6-methyl-N-(3,4,5-trifluorophenyl)-6,7- dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide;

(6S)-N-[2-(difluoromethyl)-4-pyridyl]-3-(5,5-dimethyl-2-oxo-oxazolidin-3-yl)-6-methyl- 6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide; (6S)-N-[6-(difluoromethyl)-5-fluoro-2-pyridyl]-3-(5,5-dimethyl-2-oxo-oxazolidin-3-yl)-6- methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide;

(6S)-N-(2-chloro-4-pyridyl)-3-(5,5-dimethyl-2-oxo-oxazolidin-3-yl)-6-methyl-6,7- dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide;

(6S)-3-(5,5-dimethyl-2-oxo-oxazolidin-3-yl)-6-methyl-N-[2-(trifluoromethyl)-4-pyridyl]- 6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide;

and their enantiomers or diastereomers are excluded. A further embodiment of present invention is (ii) a compound of formula (I), wherein

R¹ is

R² is H;

R³ is methyl;

R⁴ is trifluorophenyl, chloropyridinyl, difluoropyridinyl, fluorochloropyridinyl,

difluoromethylpyridinyl or trifluoromethylpyridinyl. A further embodiment of present invention is (iii) a compound of formula (I), wherein

R¹ is , wherein R⁵, R⁶ and R⁷ are C_1-6alkyl;

R² is H;

R³ is C_1-6alkyl;

R⁴ is phenyl three times substituted by halogen, or pyridinyl substituted by haloC_1-6alkyl. A further embodiment of present invention is (iv) a compound of formula (I), wherein R¹ is

R² is H;

R³ is methyl;

R⁴ is trifluorophenyl or difluoromethylpyridinyl. In another embodiment of the present invention, particular compounds of the present invention are (v) selected from:

(6S)-6-methyl-N-(3,4,5-trifluorophenyl)-3-[(4S)-4,5,5-trimethyl-2-oxo-oxazolidin-3-yl]-6,7- dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide;

(6S)-6-methyl-N-(3,4,5-trifluorophenyl)-3-[(4R)-4,5,5-trimethyl-2-oxo-oxazolidin-3-yl]-6,7- dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide;

(6S)-N-(6-chloro-5-fluoro-3-pyridyl)-6-methyl-3-[(4S)-4,5,5-trimethyl-2-oxo-oxazolidin-3-yl]- 6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide;

(6S)-N-[2-(difluoromethyl)-4-pyridyl]-6-methyl-3-[(4S)-4,5,5-trimethyl-2-oxo-oxazolidin-3-yl]- 6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide;

(6S)-N-(2-chloro-4-pyridyl)-6-methyl-3-[(4S)-4,5,5-trimethyl-2-oxo-oxazolidin-3-yl]-6,7- dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide;

(6S)-6-methyl-N-[2-(trifluoromethyl)-4-pyridyl]-3-[(4S)-4,5,5-trimethyl-2-oxo-oxazolidin-3-yl]- 6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide;

(6S)-3-[(4S)-4,5-dimethyl-2-oxo-oxazolidin-3-yl]-6-methyl-N-(3,4,5-trifluorophenyl)-6,7- dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide;

(6S)-6-methyl-3-[(4S)-4-methyl-2-oxo-oxazolidin-3-yl]-N-(3,4,5-trifluorophenyl)-6,7-dihydro- 4H-pyrazolo[1,5-a]pyrazine-5-carboxamide;

(6S)-N-[2-(difluoromethyl)-4-pyridyl]-3-[(4S,5S)-4,5-dimethyl-2-oxo-oxazolidin-3-yl]-6- methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide;

(6S)-N-[2-(difluoromethyl)-4-pyridyl]-3-[(4S,5R)-4,5-dimethyl-2-oxo-oxazolidin-3-yl]-6- methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide; (6S)-N-(2,6-difluoro-4-pyridyl)-3-[(4S,5S)-4,5-dimethyl-2-oxo-oxazolidin-3-yl]-6-methyl-6,7- dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide;

(6S)-N-(2,6-difluoro-4-pyridyl)-3-[(4S,5R)-4,5-dimethyl-2-oxo-oxazolidin-3-yl]-6-methyl-6,7- dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide;

(6S)-N-(2,6-difluoro-4-pyridyl)-6-methyl-3-[(4S)-4,5,5-trimethyl-2-oxo-oxazolidin-3-yl]-6,7- dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide; and

(6S)-N-(2,6-difluoro-4-pyridyl)-3-(5,5-dimethyl-2-oxo-oxazolidin-3-yl)-6-methyl-6,7-dihydro- 4H-pyrazolo[1,5-a]pyrazine-5-carboxamide. In another embodiment of the present invention, more particular compounds of the present invention are (vi) selected from:

(6S)-6-methyl-N-(3,4,5-trifluorophenyl)-3-[(4S)-4,5,5-trimethyl-2-oxo-oxazolidin-3-yl]-6,7- dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide; and

(6S)-N-[2-(difluoromethyl)-4-pyridyl]-6-methyl-3-[(4S)-4,5,5-trimethyl-2-oxo-oxazolidin-3-yl]- 6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide. Another embodiment of the present invention is (vii) a compound of formula (I), wherein

, wherein R⁸ is H, pyridinyl or haloC_1-6alkyl; R⁹ is H, pyridinyl or C_1- ₆alkyl;

R² is H;

R³ is C_1-6alkyl;

R⁴ is phenyl which is three times substituted by halogen;

or pharmaceutically acceptable salt, enantiomer or diastereomer thereof;

with the proviso that R⁸ and R⁹ are not H simultaneously. A further embodiment of the present invention is (viii) a compound of formula (I), wherein R¹ is , wherein R⁸ is H, pyridinyl or trifluoromethyl; R⁹ is H, pyridinyl or methyl;

R² is H;

R³ is methyl;

R⁴ is trifluorophenyl. In another embodiment of the present invention, particular compounds of the present invention are (ix) selected from:

(6S)-6-methyl-3-[(4S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl]-N-(3,4,5-trifluorophenyl)- 6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide;

(6S)-6-methyl-3-[(5S)-5-methyl-2-oxo-imidazolidin-1-yl]-N-(3,4,5-trifluorophenyl)-6,7-dihydro- 4H-pyrazolo[1,5-a]pyrazine-5-carboxamide;

(6S)-6-methyl-3-[2-oxo-4-(2-pyridyl)imidazolidin-1-yl]-N-(3,4,5-trifluorophenyl)-6,7-dihydro- 4H-pyrazolo[1,5-a]pyrazine-5-carboxamide; and

(6S)-6-methyl-3-[2-oxo-5-(2-pyridyl)imidazolidin-1-yl]-N-(3,4,5-trifluorophenyl)-6,7-dihydro- 4H-pyrazolo[1,5-a]pyrazine-5-carboxamide. Another embodiment of the present invention is (x) a compound of formula (I), wherein

R¹

s , wherein R¹⁰ is H, halogen or hydroxy; R¹¹ is H or halogen; R¹² is H, cyano, hydroxy, pyridinyl or pyrimidinyloxy; R¹³ is H, C_1-6alkyl or morpholinylcarbonyl; R¹⁴ is H, C_1-6alkyl, C_1-6alkylaminocarbonyl or (C_1- ₆alkyl)₂aminoC_1-6alkyl;

R² is H or C_1-6alkyl;

R³ is C_1-6alkyl; R⁴ is phenyl which is three times substituted by halogen; or pyridinyl which is once or twice substituted by substituents independently selected from halogen and haloC_1- ₆alkyl;

with the proviso that R¹⁰, R¹¹, R¹², R¹³ and R¹⁴ are not H simultaneously, and

(6S)-3-(4-cyano-2-oxo-pyrrolidin-1-yl)-6-methyl-N-(3,4,5-trifluorophenyl)-6,7-dihydro- 4H-pyrazolo[1,5-a]pyrazine-5-carboxamide;

(6S)-3-[(4R)-4-cyano-2-oxo-pyrrolidin-1-yl]-6-methyl-N-(3,4,5-trifluorophenyl)-6,7- dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide;

(6S)-3-[(4S)-4-cyano-2-oxo-pyrrolidin-1-yl]-6-methyl-N-(3,4,5-trifluorophenyl)-6,7- dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide;

(6S)-N-(2-chloro-4-pyridyl)-6-methyl-3-[2-oxo-4-(trifluoromethyl)pyrrolidin-1-yl]-6,7- dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide;

(6S)-3-[(3R)-3-hydroxy-2-oxo-pyrrolidin-1-yl]-6-methyl-N-(3,4,5-trifluorophenyl)-6,7- dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide;

(6S)-6-methyl-3-[2-oxo-4-(3-pyridyl)pyrrolidin-1-yl]-N-(3,4,5-trifluorophenyl)-6,7- dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide;

(6S)-6-methyl-3-[2-oxo-4-(2-pyridyl)pyrrolidin-1-yl]-N-(3,4,5-trifluorophenyl)-6,7- dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide;

(6S)-6-methyl-3-[2-oxo-4-(4-pyridyl)pyrrolidin-1-yl]-N-(3,4,5-trifluorophenyl)-6,7- dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide;

(6S)-3-(4-cyano-2-oxo-pyrrolidin-1-yl)-N-[2-(difluoromethyl)-4-pyridyl]-6-methyl-6,7- dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide;

(6S)-3-[(4R)-4-hydroxy-2-oxo-pyrrolidin-1-yl]-6-methyl-N-(3,4,5-trifluorophenyl)-6,7- dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide;

(6S)-3-[(4S)-4-hydroxy-2-oxo-pyrrolidin-1-yl]-6-methyl-N-(3,4,5-trifluorophenyl)-6,7- dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide;

(6S)-6-methyl-3-[(4S)-2-oxo-4-pyrimidin-2-yloxy-pyrrolidin-1-yl]-N-(3,4,5- trifluorophenyl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide;

(6S)-6-methyl-3-[4-(morpholine-4-carbonyl)-2-oxo-pyrrolidin-1-yl]-N-(3,4,5- trifluorophenyl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide;

(6S)-6-methyl-3-[(4R)-2-oxo-4-pyrimidin-2-yloxy-pyrrolidin-1-yl]-N-(3,4,5- trifluorophenyl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide; (6S)-3-[(3R,4R)-3,4-dihydroxy-2-oxo-pyrrolidin-1-yl]-6-methyl-N-(3,4,5-trifluorophenyl)- 6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide;

(6S)-3-(3-cyano-2-methyl-5-oxo-pyrrolidin-1-yl)-6-methyl-N-(3,4,5-trifluorophenyl)-6,7- dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide;

(6S)-3-[(3S,4R)-3,4-dihydroxy-2-oxo-pyrrolidin-1-yl]-6-methyl-N-(3,4,5-trifluorophenyl)- 6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide;

(6S)-3-[(3S,4R)-3-hydroxy-2-oxo-4-pyrimidin-2-yloxy-pyrrolidin-1-yl]-6-methyl-N- (3,4,5-trifluorophenyl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide;

(6S)-3-[(2R,3R,4S)-4-hydroxy-2-methyl-5-oxo-3-pyrimidin-2-yloxy-pyrrolidin-1-yl]-6- methyl-N-(3,4,5-trifluorophenyl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide; and their enantiomers or diastereomers are excluded. A further embodiment of the present invention is (xi) a compound of formula (I), wherein

R¹ is

, wherein R¹⁰ is H, fluoro or hydroxy; R¹¹ is H or fluoro; R¹² is H, cyano, hydroxy, pyridinyl or pyrimidinyloxy; R¹³ is H, methyl or

morpholinylcarbonyl; R¹⁴ is H, methyl, methylaminocarbonyl or

dimethylaminomethyl;

R² is H or methyl;

R³ is methyl;

R⁴ is trifluorophenyl, difluoropyridinyl or difluoromethylpyridinyl. A further embodiment of the present invention is (xii) a compound of formula (I), wherein

R¹ is

, wherein R¹⁰ is H; R¹¹ is H; R¹² is cyano, hydroxy or

pyrimidinyloxy; R¹³ is H; R¹⁴ is H or C_1-6alkyl;

R² is H or C_1-6alkyl;

R³ is C_1-6alkyl; R⁴ is phenyl which is three times substituted by halogen; or pyridinyl which is once or twice substituted by substituents independently selected from halogen and haloC_1- ₆alkyl. A further embodiment of the present invention is (xiii) a compound of formula (I), wherein

;

R² is H or methyl;

R³ is methyl;

R⁴ is trifluorophenyl, difluoropyridinyl or difluoromethylpyridinyl. In another embodiment of the present invention, particular compounds of the present invention are (xiv) selected from:

(6S)-3-[3-hydroxy-2-oxo-4-(2-pyridyl)pyrrolidin-1-yl]-6-methyl-N-(3,4,5-trifluorophenyl)-6,7- dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide;

(6S)-3-[(2S,3S)-3-hydroxy-2-methyl-5-oxo-pyrrolidin-1-yl]-6-methyl-N-(3,4,5-trifluorophenyl)- 6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide;

(6S)-6-methyl-3-[(2S,3S)-2-methyl-3-(morpholine-4-carbonyl)-5-oxo-pyrrolidin-1-yl]-N-(3,4,5- trifluorophenyl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide;

(6S)-6-methyl-3-[(2S,3R)-2-methyl-3-(morpholine-4-carbonyl)-5-oxo-pyrrolidin-1-yl]-N-(3,4,5- trifluorophenyl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide;

(6S)-3-(3,4-trans-4-cyano-3-hydroxy-2-oxo-pyrrolidin-1-yl)-6-methyl-N-(3,4,5-trifluorophenyl)- 6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide;

(6S)-3-(3,4-cis-4-cyano-3-hydroxy-2-oxo-pyrrolidin-1-yl)-6-methyl-N-(3,4,5-trifluorophenyl)- 6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide;

(6S)-3-[(2S,3S)-3-cyano-2-methyl-5-oxo-pyrrolidin-1-yl]-N-[2-(difluoromethyl)-4-pyridyl]-6- methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide; (6S)-3-(3,3-difluoro-2-oxo-pyrrolidin-1-yl)-6-methyl-N-(3,4,5-trifluorophenyl)-6,7-dihydro-4H- pyrazolo[1,5-a]pyrazine-5-carboxamide;

(6S)-3-[(2S,3S,4R)-3-cyano-4-hydroxy-2-methyl-5-oxo-pyrrolidin-1-yl]-6-methyl-N-(3,4,5- trifluorophenyl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide;

(6S)-3-[(2S,3S)-3-cyano-2-methyl-5-oxo-pyrrolidin-1-yl]-N-(2,6-difluoro-4-pyridyl)-6-methyl- 6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide;

(6S)-3-[(5S)-3-hydroxy-5-methyl-2-oxo-pyrrolidin-1-yl]-6-methyl-N-(3,4,5-trifluorophenyl)-6,7- dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide;

(6S)-6-methyl-3-[(2S)-2-(methylcarbamoyl)-5-oxo-pyrrolidin-1-yl]-N-(3,4,5-trifluorophenyl)- 6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide;

(6S)-6-methyl-3-[(2S,3S)-2-methyl-5-oxo-3-pyrimidin-2-yloxy-pyrrolidin-1-yl]-N-(3,4,5- trifluorophenyl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide;

(6S)-3-(4-cyano-2-oxo-pyrrolidin-1-yl)-N-(2,6-difluoro-4-pyridyl)-6-methyl-6,7-dihydro-4H- pyrazolo[1,5-a]pyrazine-5-carboxamide;

(6S)-N-(2,6-difluoro-4-pyridyl)-6-methyl-3-[(2S,3S)-2-methyl-5-oxo-3-pyrimidin-2-yloxy- pyrrolidin-1-yl]-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide;

(6S)-N-[2-(difluoromethyl)-4-pyridyl]-6-methyl-3-[(2S,3S)-2-methyl-5-oxo-3-pyrimidin-2- yloxy-pyrrolidin-1-yl]-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide;

(6S)-3-(4-cyano-4-methyl-2-oxo-pyrrolidin-1-yl)-N-(2,6-difluoro-4-pyridyl)-6-methyl-6,7- dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide;

(6S)-3-(4-cyano-4-methyl-2-oxo-pyrrolidin-1-yl)-N-[2-(difluoromethyl)-4-pyridyl]-6-methyl- 6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide;

(6S,7S)-3-(4-cyano-2-oxo-pyrrolidin-1-yl)-6,7-dimethyl-N-(3,4,5-trifluorophenyl)-6,7-dihydro- 4H-pyrazolo[1,5-a]pyrazine-5-carboxamide;

(6S,7S)-3-(4-cyano-2-oxo-pyrrolidin-1-yl)-N-(2,6-difluoro-4-pyridyl)-6,7-dimethyl-6,7-dihydro- 4H-pyrazolo[1,5-a]pyrazine-5-carboxamide;

(6S,7R)-3-(4-cyano-2-oxo-pyrrolidin-1-yl)-N-(2,6-difluoro-4-pyridyl)-6,7-dimethyl-6,7-dihydro- 4H-pyrazolo[1,5-a]pyrazine-5-carboxamide;

(6S)-3-[2-[(dimethylamino)methyl]-5-oxo-pyrrolidin-1-yl]-6-methyl-N-(3,4,5-trifluorophenyl)- 6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide; and

(6S,7R)-3-(4-cyano-2-oxo-pyrrolidin-1-yl)-6,7-dimethyl-N-(3,4,5-trifluorophenyl)-6,7-dihydro- 4H-pyrazolo[1,5-a]pyrazine-5-carboxamide. In another embodiment of the present invention, particular compounds of the present invention are (xv) selected from:

(6S)-3-[(2S,3S)-3-cyano-2-methyl-5-oxo-pyrrolidin-1-yl]-N-[2-(difluoromethyl)-4-pyridyl]-6- methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide;

(6S,7S)-3-(4-cyano-2-oxo-pyrrolidin-1-yl)-6,7-dimethyl-N-(3,4,5-trifluorophenyl)-6,7-dihydro- 4H-pyrazolo[1,5-a]pyrazine-5-carboxamide; and

(6S,7R)-3-(4-cyano-2-oxo-pyrrolidin-1-yl)-6,7-dimethyl-N-(3,4,5-trifluorophenyl)-6,7-dihydro- 4H-pyrazolo[1,5-a]pyrazine-5-carboxamide. Another embodiment of the present invention is (xvi) a compound of formula (I), wherein R¹ is oxoazaspiro[2.4]heptanyl;

oxobenzimidazolyl;

oxodiazabicyclo[3.1.1]heptanyl;

oxodiazabicyclo[3.2.1]octanyl substituted by C_1-6alkylcarbonyl, C_1-6alkylsulfonyl or C_1-6alkyl;

oxodiazabicyclo[3.3.1]nonanyl unsubstituted or substituted by C_1-6alkylcarbonyl; oxodiazaspiro[3.4]octanyl substituted by C_1-6alkoxycarbonyl;

oxohexahydrobenzimidazolyl;

oxohexahydrocyclopenta[d]imidazolyl unsubstituted or substituted by hydroxy; oxooxaazabicyclo[3.2.1]octanyl;

oxooxaazaspiro[2.4]heptanyl unsubstituted or substituted by C_1-6alkyl; oxooxadiazabicyclo[3.3.1]nonanyl substituted by C_1-6alkylcarbonyl;

oxooxazinanyl which is twice substituted by C_1-6alkyl and cyano;

oxopyridinyl;

oxotetrahydrocyclopenta[d]oxazolyl; oxotetrahydrofuro[3,4-d]imidazolyl; or

oxotetrahydrofuro[3,4-d]oxazolyl;

R² is H;

R³ is C_1-6alkyl;

with the proviso that

(6S)-6-methyl-3-(6-oxo-5-azaspiro[2.4]heptan-5-yl)-N-(3,4,5-trifluorophenyl)-6,7- dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide;

Methyl 6-[(6S)-6-methyl-5-[(3,4,5-trifluorophenyl)carbamoyl]-6,7-dihydro-4H- pyrazolo[1,5-a]pyrazin-3-yl]-7-oxo-2,6-diazaspiro[3.4]octane-2-carboxylate;

Ethyl 6-[(6S)-6-methyl-5-[(3,4,5-trifluorophenyl)carbamoyl]-6,7-dihydro-4H- pyrazolo[1,5-a]pyrazin-3-yl]-7-oxo-2,6-diazaspiro[3.4]octane-2-carboxylate;

(6S)-6-methyl-3-(5-oxo-4-oxa-6-azaspiro[2.4]heptan-6-yl)-N-(3,4,5-trifluorophenyl)-6,7- dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide;

and their enantiomers or diastereomers are excluded. A further embodiment of the present invention is (xvii) a compound of formula (I), wherein

R¹ is 5-oxo-4-azaspiro[2.4]heptan-4-yl; 2-oxo-3H-benzimidazol-1-yl; 6-acetyl-4-oxo-3,6- diazabicyclo[3.1.1]heptan-3-yl; 8-acetyl-4-oxo-3,8-diazabicyclo[3.2.1]octan-3-yl; 8- ethylsulfonyl-4-oxo-3,8-diazabicyclo[3.2.1]octan-3-yl; 8-methyl-4-oxo-3,8- diazabicyclo[3.2.1]octan-3-yl; 4-oxo-3,7-diazabicyclo[3.3.1]nonan-3-yl; 7-acetyl-4- oxo-3,7-diazabicyclo[3.3.1]nonan-3-yl; 2-tert-butylcarbonyl-7-oxo-2,6- diazaspiro[3.4]octanyl; 2-oxo-3a,4,5,6,7,7a-hexahydro-3H-benzimidazol-1-yl; 2-oxo- 1,3a,4,5,6,6a-hexahydrocyclopenta[d]imidazol-3-yl; 5-hydroxy-2-oxo-1,3a,4,5,6,6a- hexahydrocyclopenta[d]imidazol-3-yl; 4-oxo-8-oxa-3-azabicyclo[3.2.1]octan-3-yl; 5- oxo-4-oxa-6-azaspiro[2.4]heptan-6-yl; 7-methyl-5-oxo-4-oxa-6-azaspiro[2.4]heptan- 6-yl; 9-acetyl-6-oxo-3-oxa-7,9-diazabicyclo[3.3.1]nonan-7-yl;

cyano(methyl)oxooxazinanyl; oxopyridinyl, 2-oxo-4,5,6,6a-tetrahydro-3aH- cyclopenta[d]oxazol-3-yl; 2-oxo-3a,4,6,6a-tetrahydro-1H-furo[3,4-d]imidazol-3-yl or 2-oxo-3a,4,6,6a-tetrahydrofuro[3,4-d]oxazol-3-yl; R² is H;

R³ is methyl;

R⁴ is trifluorophenyl, chloropyridinyl, difluoropyridinyl, difluoromethylpyridinyl or

trifluoromethylpyridinyl. A further embodiment of the present invention is (xviii) a compound of formula (I), wherein

R¹ is oxooxaazaspiro[2.4]heptanyl substituted by C_1-6alkyl;

R² is H;

R³ is C_1-6alkyl;

R⁴ is pyridinyl which is once or twice substituted by substituents independently selected from halogen and haloC_1-6alkyl. A further embodiment of the present invention is (xix) a compound of formula (I), wherein R¹ is 7-methyl-5-oxo-4-oxa-6-azaspiro[2.4]heptan-6-yl;

R² is H;

R³ is methyl;

R⁴ is difluoropyridinyl or difluoromethylpyridinyl. In another embodiment of the present invention, particular compounds of the present invention are (xx) selected from:

(6S)-N-(2-chloro-4-pyridyl)-6-methyl-3-(5-oxo-4-oxa-6-azaspiro[2.4]heptan-6-yl)-6,7-dihydro- 4H-pyrazolo[1,5-a]pyrazine-5-carboxamide;

(6S)-N-(2,6-difluoro-4-pyridyl)-6-methyl-3-(5-oxo-4-oxa-6-azaspiro[2.4]heptan-6-yl)-6,7- dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide;

(6S)-N-[2-(difluoromethyl)-4-pyridyl]-6-methyl-3-(5-oxo-4-oxa-6-azaspiro[2.4]heptan-6-yl)- 6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide;

(6S)-6-methyl-3-(5-oxo-4-oxa-6-azaspiro[2.4]heptan-6-yl)-N-[2-(trifluoromethyl)-4-pyridyl]- 6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide;

(6S)-N-(2,6-difluoro-4-pyridyl)-6-methyl-3-[(7S)-7-methyl-5-oxo-4-oxa-6-azaspiro[2.4]heptan- 6-yl]-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide;

(6S)-N-[2-(difluoromethyl)-4-pyridyl]-6-methyl-3-[(7S)-7-methyl-5-oxo-4-oxa-6- azaspiro[2.4]heptan-6-yl]-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide; (6S)-3-[(3ar,7ar)-2-oxo-3a,4,5,6,7,7a-hexahydro-3H-benzimidazol-1-yl]-6-methyl-N-(3,4,5- trifluorophenyl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide;

(6S)-3-[(3ar,6as)-2-oxo-4,5,6,6a-tetrahydro-3ah-cyclopenta[d]oxazol-3-yl]-6-methyl-N-(3,4,5- trifluorophenyl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide;

(6S)-6-methyl-3-(2-oxo-1,3a,4,5,6,6a-hexahydrocyclopenta[d]imidazol-3-yl)-N-(3,4,5- trifluorophenyl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide;

(6S)-3-[(3as,6ar)-2-oxo-4,5,6,6a-tetrahydro-3ah-cyclopenta[d]oxazol-3-yl]-6-methyl-N-(3,4,5- trifluorophenyl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide;

(6S)-6-methyl-3-(2-oxo-3a,4,6,6a-tetrahydrofuro[3,4-d]oxazol-3-yl)-N-(3,4,5-trifluorophenyl)- 6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide;

(6S)-6-methyl-3-(2-oxo-3a,4,6,6a-tetrahydro-1H-furo[3,4-d]imidazol-3-yl)-N-(3,4,5- trifluorophenyl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide;

(6S)-3-(5-hydroxy-2-oxo-1,3a,4,5,6,6a-hexahydrocyclopenta[d]imidazol-3-yl)-6-methyl-N- (3,4,5-trifluorophenyl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide;

(6S)-6-methyl-3-(5-oxo-4-azaspiro[2.4]heptan-4-yl)-N-(3,4,5-trifluorophenyl)-6,7-dihydro-4H- pyrazolo[1,5-a]pyrazine-5-carboxamide;

Tert-butyl 6-[(6S)-5-[[2-(difluoromethyl)-4-pyridyl]carbamoyl]-6-methyl-6,7-dihydro-4H- pyrazolo[1,5-a]pyrazin-3-yl]-7-oxo-2,6-diazaspiro[3.4]octane-2-carboxylate;

Tert-butyl 6-[(6S)-5-[(2,6-difluoro-4-pyridyl)carbamoyl]-6-methyl-6,7-dihydro-4H- pyrazolo[1,5-a]pyrazin-3-yl]-7-oxo-2,6-diazaspiro[3.4]octane-2-carboxylate;

(6S)-6-methyl-3-(4-oxo-8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-N-(3,4,5-trifluorophenyl)-6,7- dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide;

(6S)-3-(8-acetyl-4-oxo-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-methyl-N-(3,4,5-trifluorophenyl)- 6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide;

(6S)-3-(8-ethylsulfonyl-4-oxo-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-methyl-N-(3,4,5- trifluorophenyl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide;

(6S)-6-methyl-3-(8-methyl-4-oxo-3,8-diazabicyclo[3.2.1]octan-3-yl)-N-(3,4,5-trifluorophenyl)- 6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide;

(6S)-6-methyl-3-(4-oxo-3,7-diazabicyclo[3.3.1]nonan-3-yl)-N-(3,4,5-trifluorophenyl)-6,7- dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide;

(6S)-6-methyl-3-(4-oxo-3,7-diazabicyclo[3.3.1]nonan-3-yl)-N-(3,4,5-trifluorophenyl)-6,7- dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide; (6S)-3-(7-acetyl-4-oxo-3,7-diazabicyclo[3.3.1]nonan-3-yl)-6-methyl-N-(3,4,5-trifluorophenyl)- 6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide;

(6R)-3-(7-acetyl-4-oxo-3,7-diazabicyclo[3.3.1]nonan-3-yl)-6-methyl-N-(3,4,5-trifluorophenyl)- 6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide;

(6S)-3-(6-acetyl-4-oxo-3,6-diazabicyclo[3.1.1]heptan-3-yl)-6-methyl-N-(3,4,5-trifluorophenyl)- 6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide;

(6S)-3-(9-acetyl-6-oxo-3-oxa-7,9-diazabicyclo[3.3.1]nonan-7-yl)-6-methyl-N-(3,4,5- trifluorophenyl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide;

(6S)-3-(5-cyano-5-methyl-2-oxo-1,3-oxazinan-3-yl)-6-methyl-N-(3,4,5-trifluorophenyl)-6,7- dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide;

(6S)-6-methyl-3-(2-oxo-3H-benzimidazol-1-yl)-N-(3,4,5-trifluorophenyl)-6,7-dihydro-4H- pyrazolo[1,5-a]pyrazine-5-carboxamide; and

(6S)-6-methyl-3-(2-oxo-1-pyridyl)-N-(3,4,5-trifluorophenyl)-6,7-dihydro-4H-pyrazolo[1,5- a]pyrazine-5-carboxamide. In another embodiment of the present invention, more particular compounds of the present invention are (xxi) selected from:

(6S)-N-(2,6-difluoro-4-pyridyl)-6-methyl-3-[(7S)-7-methyl-5-oxo-4-oxa-6-azaspiro[2.4]heptan- 6-yl]-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide; and

(6S)-N-[2-(difluoromethyl)-4-pyridyl]-6-methyl-3-[(7S)-7-methyl-5-oxo-4-oxa-6- azaspiro[2.4]heptan-6-yl]-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide. SYNTHESIS The compounds of the present invention can be prepared by any conventional means. Suitable processes for synthesizing these compounds as well as their starting materials are provided in the schemes below and in the examples. All substituents, in particular, R¹ to R⁴ are as defined above unless otherwise indicated. Furthermore, and unless explicitly otherwise stated, all reactions, reaction conditions, abbreviations and symbols have the meanings well known to a person of ordinary skill in organic chemistry.

Scheme 1:

Compound of formula IV (ring A) is

or any one selected from unsubstituted or substituted ring of oxoazaspiro[2.4]heptane, oxobenzimidazole, oxodiazabicyclo[3.1.1]heptane, oxodiazabicyclo[3.2.1]octane,

oxodiazabicyclo[3.3.1]nonane, oxodiazaspiro[3.4]octane, oxohexahydrobenzimidazole, oxohexahydrocyclopenta[d]imidazole, oxooxaazabicyclo[3.2.1]octane,

oxooxaazaspiro[2.4]heptane, oxooxadiazabicyclo[3.3.1]nonane, oxooxazinane, oxopyridine, oxotetrahydrocyclopenta[d]oxazole, oxotetrahydrofuro[3,4-d]imidazole and

oxotetrahydrofuro[3,4-d]oxazole. X is Br or I. As depicted in Scheme 1, the synthesis of compounds of the present invention could be started from bicyclic compound of formula (II), which was treated with halogenating agents, such as N-iodosuccinimide or N-bromosuccinimide, to give compound of formula (III).

Coupling reaction between compound of formula (III) and compound of formula (IV) in the presence of copper catalyst, such as CuI, afforded compound of formula (V). The following Boc- deprotection in an acidic condition such as HCl/EtOAc or TFA/DCM and urea formation with amine R⁴NH₂ in the presence of a phosgene equivalent, such as triphosgene and

carbonyldiimidazole, could afford final compound of formula (I). In the aforementioned urea formation reaction, a suitable isocyanate or phenyl carbamate was also applied (Padiya, K. J. et al. Org Lett. 2012, 14, 2814 and references cited therein). This invention also relates to a process for the preparation of a compound of formula (I) comprising the reaction of: (a) the reaction of a compound of formula (IV),

with an acid followed by urea formation with amine R⁴NH₂ in the presence of a phosgene equivalent;

wherein R¹ to R⁴ are defined above;

In step (a), the acid can be, for example, HCl in EtOAc and TFA in DCM; phosgene equivalent can be, for example, triphosgene and carbonyldiimidazole.

A compound of formula (I) when manufactured according to the above process is also an object of the invention. PHARMACEUTICAL COMPOSITIONS AND ADMINISTRATION Another embodiment provides pharmaceutical compositions or medicaments containing the compounds of the invention and a therapeutically inert carrier, diluent or excipient, as well as methods of using the compounds of the invention to prepare such compositions and medicaments. In one example, compounds of formula (I) may be formulated by mixing at ambient temperature at the appropriate pH, and at the desired degree of purity, with physiologically acceptable carriers, i.e., carriers that are non-toxic to recipients at the dosages and concentrations employed into a galenical administration form. The pH of the formulation depends mainly on the particular use and the concentration of compound, but preferably ranges anywhere from about 3 to about 8. In one example, a compound of formula (I) is formulated in an acetate buffer, at pH 5. In another embodiment, the compounds of formula (I) are sterile. The compound may be stored, for example, as a solid or amorphous composition, as a lyophilized formulation or as an aqueous solution. Compositions are formulated, dosed, and administered in a fashion consistent with good medical practice. Factors for consideration in this context include the particular disorder being treated, the particular mammal being treated, the clinical condition of the individual patient, the cause of the disorder, the site of delivery of the agent, the method of administration, the scheduling of administration, and other factors known to medical practitioners. The“effective amount” of the compound to be administered will be governed by such considerations, and is the minimum amount necessary to the suppression of serum HBV DNA levels, or HBeAg seroconversion to HBeAb, or HBsAg loss, or normalization of alanine aminotransferase levels and improvement in liver histology. For example, such amount may be below the amount that is toxic to normal cells, or the mammal as a whole. In one example, the pharmaceutically effective amount of the compound of the invention administered parenterally per dose will be in the range of about 0.01 to 100 mg/kg, alternatively about 0.1 to 20 mg/kg of patient body weight per day, with the typical initial range of compound used being 0.3 to 15 mg/kg/day. In another embodiment, oral unit dosage forms, such as tablets and capsules, contain from about 0.1 to about 1000 mg of the compound of the invention. The compounds of the invention may be administered by any suitable means, including oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, subcutaneous, intraperitoneal, intrapulmonary, intradermal, intrathecal and epidural and intranasal, and, if desired for local treatment, intralesional administration. Parenteral infusions include intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration. The compounds of the present invention may be administered in any convenient administrative form, e.g., tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, etc. Such compositions may contain components conventional in pharmaceutical preparations, e.g., diluents, carriers, pH modifiers, sweeteners, bulking agents, and further active agents. A typical formulation is prepared by mixing a compound of the present invention and a carrier or excipient. Suitable carriers and excipients are well known to those skilled in the art and are described in detail in, e.g., Ansel, Howard C., et al., Ansel’s Pharmaceutical Dosage Forms and Drug Delivery Systems. Philadelphia: Lippincott, Williams & Wilkins, 2004;

Gennaro, Alfonso R., et al. Remington: The Science and Practice of Pharmacy. Philadelphia: Lippincott, Williams & Wilkins, 2000; and Rowe, Raymond C. Handbook of Pharmaceutical Excipients. Chicago, Pharmaceutical Press, 2005. The formulations may also include one or more buffers, stabilizing agents, surfactants, wetting agents, lubricating agents, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming agents, flavoring agents, diluents and other known additives to provide an elegant presentation of the drug (i.e., a compound of the present invention or pharmaceutical composition thereof) or aid in the manufacturing of the pharmaceutical product (i.e., medicament). An example of a suitable oral dosage form is a tablet containing about 0.1 mg to 1000 mg of the compound of the invention compounded with about 30 mg to 90 mg anhydrous lactose, about 5 mg to 40 mg sodium croscarmellose, about 5 mg to 30 mg polyvinylpyrrolidone (PVP) K30, and about 1 mg to 10 mg magnesium stearate. The powdered ingredients are first mixed together and then mixed with a solution of the PVP. The resulting composition can be dried, granulated, mixed with the magnesium stearate and compressed to tablet form using

conventional equipment. An example of an aerosol formulation can be prepared by dissolving the compound, for example 5 mg to 400 mg, of the invention in a suitable buffer solution, e.g. a phosphate buffer, adding a tonicifier, e.g. a salt such sodium chloride, if desired. The solution may be filtered, e.g., using a 0.2 micron filter, to remove impurities and contaminants. An embodiment, therefore, includes a pharmaceutical composition comprising a compound of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof. In a further embodiment includes a pharmaceutical composition comprising a compound of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier or excipient. INDICATIONS AND METHODS OF TREATMENT The compounds of the invention can inhibit HBV’s DNA synthesis and reduce HBV DNA levels. Accordingly, the compounds of the invention are useful for the treatment or prophylaxis of HBV infection. The invention relates to the use of a compound of formula (I) for the treatment or prophylaxis of HBV infection. The use of a compound of formula (I) for the preparation of medicaments useful in the treatment or prophylaxis diseases that are related to HBV infection is an object of the invention. The invention relates in particular to the use of a compound of formula (I) for the preparation of a medicament for the treatment or prophylaxis of HBV infection. Another embodiment includes a method for the treatment or prophylaxis of HBV infection which method comprises administering an effective amount of a compound of formula (I), a stereoisomer, tautomer, prodrug or pharmaceutically acceptable salt thereof. EXAMPLES The invention will be more fully understood by reference to the following examples. They should not, however, be construed as limiting the scope of the invention. Abbreviations used herein are as follows: DCE: 1,2-dichloroethylene

DIAD: diisopropyl azodicarboxylate

DIPEA: N,N-diisopropylethylamine

DMAc: N,N-dimethylacetamide

DMAP: 4-dimethylaminopyridine

EA or EtOAc: ethyl acetate

EC₅₀: half maximal effective concentration

HATU: 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5- b]pyridinium 3-oxid hexafluorophosphate

HPLC: high performance liquid chromatography

IPA: isopropanol

LCMS liquid chromatography–mass spectrometry

mCPBA: meta-chloroperoxybenzoic acid

min(s): minute(s)

MS: mass spectrometry

MsCl: methanesulfonyl chloride

NCS: N-chlorosuccinimide

NIS: N-iodosuccinimide

PE: petroleum ether

prep-HPLC: preparative high performance liquid chromatography

prep-TLC: preparative thin layer chromatography psi: pounds per square inch

SFC: supercritical fluid chromatography

TEA: trimethylamine

TBSCl: tert-butyldimethylsilyl chloride

t- BuXPhos: 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl

TMG: 1,1,3,3-tetramethylguanidine

Pd₂(dba)₃: Tris(dibenzylideneacetone)dipalladium(0)

pgRNA: pre-genomic RNA

qPCR: quantitative polymerase chain reaction

v/v volume ratio

General Experimental Conditions Intermediates and final compounds were purified by flash chromatography using one of the following instruments: i) Biotage SP1 system and the Quad 12/25 Cartridge module. ii) ISCO combi-flash chromatography instrument. Silica gel brand and pore size: i) KP-SIL 60 Å, particle size: 40-60 µm; ii) CAS registry NO: Silica Gel: 63231-67-4, particle size: 47-60 micron silica gel; iii) ZCX from Qingdao Haiyang Chemical Co., Ltd, pore: 200-300 or 300-400. Intermediates and final compounds were purified by preparative HPLC on reversed phase column using XBridge^TM Prep-C18 (5 µm, OBDTM 30 × 100 mm) column or SunFire^TM Prep- C18 (5 µm, OBD^TM 30 × 100 mm) column. Waters AutoP purification System (Column:

XBridge^TM Prep-C18, 30 × 100 mm, Sample Manager 2767, Pump 2525, Detector: Micromass ZQ and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water). LC/MS spectra of compounds were obtained using a LC/MS (Waters^TM Alliance 2795- Micromass ZQ), LC/MS conditions were as follows (running time 6 mins): Acidic condition: A: 0.1% formic acid in H₂O; B: 0.1% formic acid in acetonitrile; Basic condition: A: 0.1% NH₃·H₂O in H₂O; B: acetonitrile; Neutral condition: A: H₂O; B: acetonitrile. Mass spectra (MS): generally only ions which indicate the parent mass are reported, and unless otherwise stated the mass ion quoted is the positive mass ion (MH)⁺. NMR Spectra were obtained using Bruker Avance 400 MHz. The microwave assisted reactions were carried out in a Biotage Initiator Sixty microwave synthesizer. All reactions involving air-sensitive reagents were performed under an argon atmosphere. Reagents were used as received from commercial suppliers without further purification unless otherwise noted. The following examples are intended to illustrate the meaning of the present invention but should by no means represent a limitation within the meaning of the present invention: PREPARATIVE EXAMPLES The invention will be more fully understood by reference to the following examples. They should not, however, be construed as limiting the scope of the invention.

Intermediate I-1

tert-Butyl (6S)-3-iodo-6-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate

Intermediate I-1was prepared according to the following scheme:

Step 1: preparation of tert-butyl N-[(1S)-2-hydroxy-1-methyl-ethyl]-N-(1H-pyrazol-5- ylmethyl)carbamate (compound I-1b) To a solution of 1H-pyrazole-5-carbaldehyde (compound I-1a, 54.0 g, 562.5 mmol) in MeOH (300 mL) was added (2S)-2-aminopropan-1-ol (41.2 g, 675 mmol) and the reaction mixture was stirred at 25 ^oC for 1 hour. NaBH₄ (25.9 g, 675.0 mmol) was added at 0 ^oC and the reaction mixture was stirred for another hour followed by the addition of H₂O (300 mL) and Boc2O (147.1 g, 675.0 mmol). The resulting mixture was stirred at room temperature for 12 hours, and extracted with EtOAc (600 mL). The organic layer was dried over Na₂SO₄, filtered and concentrated. The residue was purified by column chromatography (eluting with 0%~5% MeOH in DCM) to afford compound I-1b (80 g) as a colorless oil. LCMS (M+H⁺): 334.

Step 2: preparation of [(2S)-2-[tert-butoxycarbonyl(1H-pyrazol-5- ylmethyl)amino]propyl] methanesulfonate (compound I-1c)

To a mixture of tert-butyl N-[(1S)-2-hydroxy-1-methyl-ethyl]-N-(1H-pyrazol-5- ylmethyl)carbamate (compound I-1b, 80.0 g, 117.2 mmol) and Et₃N (100.5 g, 995.6 mmol) in DCM (800 mL) was added MsCl (57.3 g, 497.8 mmol) slowly at 0 ^oC. The resulting mixture was stirred at room temperature for 2 hours, then washed with water (500 mL), brine (500 mL), and dried over Na₂SO₄. The organic layer was concentrated to afford compound I-1c (100 g, crude), which was used directly in next step.

Step 3: preparation of tert-butyl (6S)-6-methyl-6,7-dihydro-4H-pyrazolo[1,5- a]pyrazine-5-carboxylate (compound I-1d)

To a solution of [(2S)-2-[tert-butoxycarbonyl(1H-pyrazol-5-ylmethyl)amino]propyl] methanesulfonate (compound I-1c, 100.0 g, 313.4 mmol) in DMF (1000 mL) was added NaH (15.0 g, 376.2 mmol) in portions at 0 ^oC. The reaction mixture was then stirred at room

temperature for 12 hours, poured into water (2000 mL) and extracted with EtOAc (1000 mL) twice. The organic layers were combined and concentrated. The residue was purified by column chromatography (eluting with 10%~80% EtOAc in petroleum ether) to afford compound I-1d (18.0 g) as a colorless oil. LCMS (M+H⁺): 238.

Step 4: preparation of tert-butyl (6S)-3-iodo-6-methyl-6,7-dihydro-4H-pyrazolo[1,5- a]pyrazine-5-carboxylate (compound I-1):To a solution of tert-butyl 6-methyl-6,7-dihydro- 4H-pyrazolo[1,5-a]pyrazine-5-carboxylate (compound 53c, 3.3 g, 14.8 mmol) in CH₃CN (40 mL) was added NIS (5.0 g, 22.1 mmol) slowly. The reaction mixture was stirred at room temperature for 16 hours and then extracted with EtOAc (50 mL), washed with brine (50 mL). The organic layer was dried over Na₂SO₄ and concentrated, and the residue was purified by column

chromatography (eluting with 10%~80% EtOAc in petroleum ether) to afford compound I-1 (4.8 g) as a white solid. Intermediate I-1-1

(6S)-3-iodo-6-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine

A mixture of tert-butyl (6S)-3-iodo-6-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5- carboxylate (compound I-1, 2.0 g, 5.5 mmol) in HCl/EA (4 N, 50 mL) was stirred for 1 hour at room temperature, and then concentrated under reduced pressure. The residue was dissolved in DCM (100 mL), and basified with K₂CO₃. The solid was filtered off and organic layer was evaporated to give Intermediate I-1-1 (1.3 g). LCMS (M+H⁺): 264. Intermediate I-2

tert-Butyl (6S,7S)-3-iodo-6,7-dimethyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5- carboxylate

Intermediate I-2 was prepared according to the following scheme:

Step 1: Preparation of (4R,5R)-4,5-dimethyl-1,3,2-dioxathiolane 2,2-dioxide

(compound I-2b)

A solution of SOCl₂ (7.26 g, 4.45 mL, 61 mmol) in DCM (50 mL) was added dropwise to a stirred mixture of (2R,3R)-butane-2,3-diol (5 g, 55.5 mmol), imidazole (18.9 g, 277 mmol) and triethylamine (19.6 g, 27.1 mL, 194 mmol) in DCM (200 mL) at 0 ^oC, and the reaction mixture was stirred for 1 hour at 0 ^oC. The reaction mixture was quenched with H₂O and extracted twice with DCM. The combined organic layer was washed with H₂O, dried over MgSO₄, filtered and concentrated to give a residue. To a stirred solution of the crude residue in acetonitrile (200 mL) at 0 ^oC were added sodium periodate (17.8 g, 83.2 mmol), water (150 mL) and rhodium (III) chloride (1.16 g, 5.55 mmol) sequentially and the reaction mixture was stirred at 0 ^oC for 3 hours. The two layers were separated and the aqueous layer was extracted three times with EtOAc. The combined organic layer was washed with saturated aqueous NaHCO₃ and brine, and then dried over MgSO₄, filtered and concentrated to give compound I-2b as a colorless oil (8 g).

Step 2: Preparation of (2R,3S)-3-(4-bromo-1H-pyrazol-1-yl)butan-2-ol (compound I- 2c)

A mixture of (4R,5R)-4,5-dimethyl-1,3,2-dioxathiolane 2,2-dioxide (compound I-2b, 8 g, 52.6 mmol), 4-bromo-1H-pyrazole (11.6 g, 78.9 mmol) and Cs₂CO₃ (34.3 g, 105 mmol) in DMF (50 mL) was stirred at room temperature for 16 hours. The reaction mixture was filtered and concentrated. The resulting residue was taken up in 400 mL of THF/50% aq. H₂SO₄ (v/v 1/2), and stirred vigorously for 48 hours. The reaction mixture was then carefully basified with 10 M aqueous NaOH solution, and the layers were separated. The aqueous layer was extracted twice with DCM, and the combined organic layer was washed with brine, dried over MgSO4, filtered and concentrated to give compound I-2c as a colorless oil (8 g). LCMS (M+H⁺): 219.

Step 3: Preparation of 2-((2S,3S)-3-(4-bromo-1H-pyrazol-1-yl)butan-2-yl)isoindoline- 1,3-dione (compound I-2d)

To a mixture of (2R,3S)-3-(4-bromo-1H-pyrazol-1-yl)butan-2-ol (compound I-2c, 8 g, 36.5 mmol), isoindoline-1,3-dione (5.91 g, 40.2 mmol) and triphenylphosphine (12.5 g, 47.5 mmol) in THF (75 mL) was added DIAD (11.1 g, 54.8 mmol) dropwise at room temperature. Then the reaction mixture was stirred at room temperature for 2 hours, and concentrated in vacuo. The crude product was purified by flash chromatography (silica gel, 0% to 50% EtOAc in hexanes) to give compound I-2d as a white solid (5 g). LCMS (M+H⁺): 348.

Step 4: Preparation of (2S,3S)-3-(4-bromo-1H-pyrazol-1-yl)butan-2-amine

(compound I-2e)

A mixture of 2-((2S,3S)-3-(4-bromo-1H-pyrazol-1-yl)butan-2-yl)isoindoline-1,3-dione (compound I-2d, 5 g, 14.4 mmol) and Hydrazine hydrate (7.19 g, 144 mmol) in MeOH (50 mL) was stirred at 80 °C for 15 hours. The reaction mixture was concentrated in vacuo. The residue was dissolved in DCM, the solid was filtered off and the filtrate was concentrated to give compound I-2e as a slight yellow oil (3 g). LCMS (M+H⁺): 218.

Step 5: Preparation of (2S,3S)-N-benzyl-3-(4-bromo-1H-pyrazol-1-yl)butan-2-amine (compound I-2f)

A mixture of (2S,3S)-3-(4-bromo-1H-pyrazol-1-yl)butan-2-amine (compound I-2e, 3 g, 13.8 mmol) and benzaldehyde (1.61 g, 15.1 mmol) in MeOH (50 mL) was stirred for 2 hours at room temperature. Then sodium borohydride (624 mg, 16.5 mmol) was added slowly at 0 ^oC in 30 mins and the reaction mixture was stirred at room temperature for another 30 mins. The reaction mixture was poured into 100 mL of H₂O and extracted with EtOAc (100 mL) twice. The combined organic layer was dried over Na₂SO₄ and then concentrated in vacuo. The crude product was purified by flash chromatography (silica gel, 0% to 50% EtOAc in hexanes) to give compound I-2f as light yellow oil (4 g). LCMS (M+H⁺): 308.

Step 6: Preparation of (6S,7S)-5-benzyl-3-bromo-6,7-dimethyl-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine (compound I-2g) To a stirred solution of (2S,3S)-N-benzyl-3-(4-bromo-1H-pyrazol-1-yl)butan-2-amine (compound I-2f, 4 g, 13 mmol) in acetonitrile (50 mL) was added paraformaldehyde (1.95 g, 64.9 mmol) and 2,2,2-trifluoroacetic acid (296 mg, 2.6 mmol), and the reaction mixture was stirred at 70 ^oC for 6 hours. The reaction mixture was concentrated and the residue was then taken up in EtOAc, and washed with NaHCO3 aq. solution and brine. The organic layer was concentrated and the residue was purified on a silica gel column (heptane: EtOAc 1:0 to 9:1) to give compound I-2g as a colorless oil (2.3 g). LCMS (M+H⁺): 320.

Step 7: Preparation of tert-butyl (6S,7S)-6,7-dimethyl-6,7-dihydro-4H-pyrazolo[1,5- a]pyrazine-5-carboxylate (compound I-2h)

A mixture of (6S,7S)-5-benzyl-3-bromo-6,7-dimethyl-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrazine (compound I-2g, 1.5 g, 4.68 mmol), di-tert-butyl dicarbonate (2.18 mL, 9.37 mmol) and Pd(OH)₂/C (329 mg) in MeOH (50 mL) was heated to 50 °C and stirred for 15 h under hydrogen. Then the solid was filtered off and the filtrate was concentrated. The residue was dissolved in THF/MeOH (v/v 5:1, 50 ml), di-tert-butyl dicarbonate (2.18 ml, 9.37 mmol) and Na₂CO₃ (496 mg, 4.68 mmol) were added. The reaction mixture was stirred at room temperature for 16 hours and then filtered through celite, the filtrate was concentrated and the crude material was purified by flash chromatography (silica gel, 10% to 50% EtOAc in hexanes, EtOAc contain 10% MeOH). LCMS (M+H⁺): 252.

Step 8: Preparation of tert-butyl (6S,7S)-3-iodo-6,7-dimethyl-6,7-dihydro-4H- pyrazolo[1,5-a]pyrazine-5-carboxylate (compound I-2)

To a solution of (6S,7S)-tert-butyl 6,7-dimethyl-6,7-dihydropyrazolo[1,5-a]pyrazine- 5(4H)-carboxylate (compound I-2, 1.2 g, 4.77 mmol) in MeCN (20 mL) was added NIS (1.61 g, 7.16 mmol) and then stirred at room temperature for 16 hours. The reaction mixture was quenched with aq. NaHSO₃, extracted with EtOAc, dried and concentrated, The crude material was purified by flash chromatography (silica gel, 0% to 50% EtOAc in hexanes) to give compound I-2 as colorless oil, 1.2 g. LCMS (M+H⁺): 378. Intermediate I-3

tert-Butyl (6S,7R)-3-iodo-6,7-dimethyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5- carboxylate

Intermediate I-3 was prepared according to the following scheme:

Step 1: preparation of (S)-tert-butyl (1-oxopropan-2-yl)carbamate (compound I-3b) To a solution of (S)-tert-butyl (1-hydroxypropan-2-yl)carbamate (compound I-3a, 8.76 g, 50 mmol) in DCM (200 mL) was added Dess-Martin periodinane (31.8 g, 75 mmol) slowly. After stirred at room temperature for 2 hours, the reaction mixture was filtered through silica gel. The filtrate was concentrated in vacuo to give compound I-3b as a colorless oil (10 g).

Step 2: preparation of tert-butyl N-[(1S)-2-hydroxy-1-methyl-propyl]carbamate (compound I-3c)

To a solution of (S)-tert-butyl (1-oxopropan-2-yl)carbamate (compound I-3b, 8.66 g, 50 mmol) in THF (100 mL) at -78 ^oC was added methylmagnesium bromide (150 mL, 150 mmol) slowly. The reaction mixture was stirred at -78 ^oC for 2 hours and then quenched with water. The reaction mixture was poured into 200 mL of brine and extracted with EtOAc (100 mL) twice. The combined organic layer was dried and concentrated in vacuo to give crude compound I-3c as a colorless oil (9 g). LCMS (M+H⁺): 190

Step 3: preparation of tert-butyl (3S)-3-(benzylamino)butan-2-ol (compound I-3d) A mixture of tert-butyl ((2S)-3-hydroxybutan-2-yl)carbamate (compound I-3c, 8 g, 25.4 mmol) and trifluoroacetic acid (28.9 g, 19.5 mL, 254 mmol) in DCM (40 mL) was stirred at room temperature for 1 hour. The reaction mixture was concentrated in vacuo and the residue was dissolved in DCM (100 mL), to which benzaldehyde (2.69 g, 25.4 mmol) and sodium triacetoxyborohydride (10.8 g, 50.7 mmol) were added. The reaction mixture was stirred at room temperature for 16 hours, then poured into 250 mL saturated aqueous NaHCO₃ and extracted with EtOAc (200 mL) twice. The combined organic phase was dried over Na₂SO₄ and

concentrated in vacuo. The crude product was purified by flash chromatography (silica gel, 20% to 80% EtOAc in hexanes) to give compound I-3d as a light yellow oil (2 g). LCMS (M+H⁺): 180.

Step 4: preparation of (5S)-3-benzyl-4,5-dimethyl-1,2,3-oxathiazolidine 2,2-dioxide (compound I-3e)

A solution of SOCl₂ (1.46 g, 896 µL, 12.3 mmol) in DCM (10 mL) was added dropwise to a stirred mixture of (3S)-3-(benzylamino)butan-2-ol (compound I-3d, 2 g, 11.2 mmol), imidazole (3.8 g, 55.8 mmol) and triethylamine (3.95 g, 39 mmol) in DCM (50 mL) at 0 ^oC, and the reaction mixture was allowed to stirred at 0 ^oC for 1 hour. The reaction mixture was quenched with H₂O and extracted twice with DCM. The combined organic layer was washed with H₂O, dried over MgSO₄, filtered and concentrated. To a stirred solution of the crude residue in acetonitrile (100 mL) at 0 ^oC were added sodium periodate (3.82 g, 17.9 mmol), water (75 mL) and rhodium (III) chloride (233 mg, 1.12 mmol) sequentially and the reaction mixture was stirred at 0 ^oC for 3 hours. The two layers were separated and the aqueous layer was extracted three times with EtOAc. The combined organic layer was washed with saturated aqueous

NaHCO₃ and brine, the organic layer was dried over MgSO₄, filtered and concentrated to give compound I-3e as a colorless oil (3 g), LCMS (M+H⁺): 242.

Step 5: preparation of (2S)-N-benzyl-3-(4-bromo-1H-pyrazol-1-yl)butan-2-amine (compound I-3f)

A mixture of (5S)-3-benzyl-4,5-dimethyl-1,2,3-oxathiazolidine 2,2-dioxide (compound I- 3e, 3 g, 10.6 mmol), 4-bromo-1H-pyrazole (3.11 g, 21.1 mmol) and Cs₂CO₃ (6.89 g, 21.1 mmol) in DMF (50 mL) was stirred at room temperature for 16 hours. The reaction mixture was filtered and concentrated. The residue was dissolved in DCM and 20% aq. H₂SO₄ (150 mL, v/v 1:1) and stirred vigorously for 12 hours. The reaction mixture was then carefully basified with 10 M aqueous NaOH solution, the layers were separated. The aqueous layer was extracted twice with DCM, and the combined organic layer was washed with brine, dried over MgSO₄, filtered and concentrated. The crude product was purified by flash chromatography (silica gel, 20% to 60% EtOAc in hexanes) to give compound I-3f as a colorless oil (1 g). LCMS (M+H⁺): 308

Preparation of tert-butyl (6S,7R)-3-iodo-6,7-dimethyl-6,7-dihydro-4H-pyrazolo[1,5- a]pyrazine-5-carboxylate (Intermediate I-3)

The compound I-3 was prepared in analogy to compound I-2 by using (2S)-N-benzyl-3- (4-bromo-1H-pyrazol-1-yl)butan-2-amine (compound I-3f) instead of (2S,3S)-N-benzyl-3-(4- bromo-1H-pyrazol-1-yl)butan-2-amine (compound I-2f). Intermediate I-3 was obtained as colorless oil (550 mg). LCMS (M+H⁺): 378. Intermediate I-4

Phenyl N-(3,4,5-trifluorophenyl)carbamate

Intermediate I-4 was prepared according to the following scheme:

^I-4

To a solution of 3,4,5-trifluoroaniline (1.47 g, 10 mmol) in DCM (30 mL) was added DIPEA (2.06 mL, 12 mmol), followed by adding phenyl chloroformate (1.38 mL, 11 mmol) dropwise at 0 ^oC. After addition the reaction mixture was warmed to room temperature and stirred overnight. The reaction mixture was diluted with DCM, washed with water. The organic phase was seperated, dried over Na₂SO₄ and concentrated. The residue was purified by column to give Intermediate I-4 as a white solid, 1.87 g. LCMS (M+H⁺): 268. Intermediate I-5

Phenyl N-(2-chloro-4-pyridyl)carbamate

Intermediae I-5 was prepared in analogy to Intermediate I-4 by using 2-chloropyridin-4- amine instead of 3,4,5-trifluoroaniline. Intermediae I-5 was obtained as a white solid. LCMS (M+H⁺): 249. Intermediate I-6

Phenyl N-(2-trifluoromethyl-4-pyridyl)carbamate

Intermediate I-6 was prepared in analogy to Intermediate I-4 by using 2- (trifluoromethyl)pyridin-4-amine instead of 3,4,5-trifluoroaniline. Intermediae I-6 was obtained as a white solid. LCMS (M+H⁺): 283. Intermediate I-7

Phenyl N-(6-chloro-5-fluoro-3-pyridyl)carbamate

Intermediate I-7 was prepared in analogy to Intermediate I-4 by using 6-chloro-5-fluoro- pyridin-3-amine instead of 3,4,5-trifluoroaniline. Intermediae I-7 was obtained as a white solid. LCMS (M+H⁺): 267.

Intermediate I-8

Phenyl N-[2-(difluoromethyl)-4-pyridyl]carbamate

Intermediate I-8 was prepared according to the following scheme:

To a mixture of 4-bromo-2-(difluoromethyl)pyridine (compound I-8a, 416 mg, 2.0 mmol), diphenylmethanimine (725 mg, 4.0 mmol) in toluene (15 mL) were added Pd₂(dba)₃ (92 mg, 0.1 mmol), t-BuXPhos (85 mg, 0.2 mmol) and NaOt-Bu (577 mg, 6 mmol). The reaction mixture was flushed with nitrogen and heated to 100 ^oC for 2 hours under nitrogen. The reaction mixture was cooled down, diluted with EtOAc (30 mL), and washed with water. The organic layer was separated and concentrated to give crude compound I-8b (617 mg). LCMS (M+H⁺): 309.

Compound I-8b (617 mg, 2.0 mmol) was dissolved in THF (10 mL) and hydrochloride acid (2 mL, 12 M). The reaction mixture was stirred at room temperature for 2 hours, and then concentrated. The residue was dissolved in DCM (5.0 mL), to which was added DIPEA (1.0 mL, 5.8 mmol) followed by phenyl carbonochloridate (251 μL, 2.0 mmol) at 0 ^oC. The resulting mixture was stirred at room temperature for 2 hours, poured into water (20 mL), and extracted with EtOAc (20 mL) twice. The combined organic layer was concentrated, the residue was purified by column chromatography (eluting with 0%~20% EtOAc in petroleum ether) to afford compound I-8 (264 mg), as white solid. LCMS (M+H⁺): 265. Intermediate I-9

Phenyl N-(2,6-difluoro-4-pyridyl)carbamate

To a solution of 2,6-difluoropyridin-4-amine (550 mg, 4.23 mmol) and pyridine (1.71 ml, 21.1 mmol) in THF (15 mL) was added phenyl carbonochloridate (993 mg, 6.34 mmol) slowly at room temperature, then the mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with EtOAc, washed with H₂O (20 mL), 1 M HCl (20 mL) and sat NaHCO₃ (2 x 25 mL). The organic layers were dried over Na2SO4 and concentrated in vacuo. Intermediate I-9 was obtained as a white solid. LCMS (M+H⁺): 251. Example 1

(6S)-6-methyl-N-(3,4,5-trifluorophenyl)-3-[(4S)-4,5,5-trimethyl-2-oxo-oxazolidin-3-yl]-6,7- dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide

The title compound was prepared according to the following scheme:

Step 1: preparation of methyl (2S)-2-aminopropanoate (compound 1b)

To the mixture of (2S)-2-aminopropanoic acid (compound 1a, 20.0 g, 224.5 mmol) in MeOH (300.0 mL) was added SOCl₂ (20.0 mL) at room temperature, then the mixture was stirred at 60 ^oC for 3 hours and then concentrated to give compound 1b (23.0 g, crude) which was used in next step directly.

Step 2: preparation of methyl (2S)-2-(tert-butoxycarbonylamino)propanoate

(compound 1c) To a mixture of methyl (2S)-2-aminopropanoate (compound 1b, 23.0 g, 223 mmol) in dioxane (200 mL) was added Boc₂O (48.7 g, 223.1 mmol) and NaHCO₃ aq. solution (200 mL) at room temperature, then the mixture was stirred at room temperature for 16 hours. The reaction mixture was filtered, the filtrate was extracted with EtOAc twice (200 mL), the combined organic layer was dried over Na2SO4, filtered and concentrated to give compound 1c (45.0 g) as colorless oil which was used in next step directly. ¹H NMR (400MHz, CHLOROFORM-d) ppm 5.06 (br. s., 1H), 4.42 - 4.24 (m, 1H), 3.76 (s, 3H), 1.46 (s, 9H), 1.39 (d, J=7.2 Hz, 4H).

Step 3: preparation of methyl tert-butyl N-[(1S)-2-hydroxy-1,2-dimethyl- propyl]carbamate (compound 1d)

To a mixture of methyl (2S)-2-(tert-butoxycarbonylamino)propanoate (compound 1c, 30.0 g, 147.6 mmol) in THF (500.0 mL) was added MeMgBr (147.6 mL, 443.0 mmol) at 0 ^oC, then the mixture was stirred at room temperature for 6 hours. The mixture was quenched with sat. aqueous NH₄Cl solution and extracted with EtOAc (200 mL) three times, the combined organic layer was dried over Na₂SO₄, filtered and concentrated to give the crude product, which was purified by chromatograph (PE/EtOAc=3/1) to give compound 1d (11.0 g) as colorless oil . ¹H NMR (400MHz, CHLOROFORM-d) ppm 4.70 (br. s., 1H), 3.60 (br. s., 1H), 1.45 (s, 9H), 1.23 (s, 3H), 1.18 (s, 3H), 1.14 (d, J=6.8 Hz, 3H).

Step 4: preparation of (4S)-4,5,5-trimethyloxazolidin-2-one (compound 1e)

To a solution of methyl tert-butyl N-[(1S)-2-hydroxy-1,2-dimethyl-propyl]carbamate (compound 1d, 5.0 g, 24.6 mmol) in toluene (5 mL) was added NaH (2.0 g, 49.2 mmol) at 0 ^oC, then the mixture was stirred at room temperature for 16 hours. The mixture was quenched with sat. aqueous NH₄Cl solution (10 mL) and extracted with EtOAc (20 mL) twice. The organic layer was separated and concentrated. The residue was dissolved in THF (50 mL) and stirred for 1 hour. Then the mixture was filtered, and the filtrate was concentrated to give compound 1e (1.5 g) as colorless oil which was used in next step directly. LCMS (M+H⁺): 130.1

Step 5: preparation of tert-butyl (6S)-6-methyl-3-[(4S)-4,5,5-trimethyl-2-oxo- oxazolidin-3-yl]-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate (compound 1f)

A mixture of (4S)-4,5,5-trimethyloxazolidin-2-one (compound 1e, 1.5 g, 11.6 mmol), tert- butyl (6S)-3-iodo-6-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate (compound I-1, 4.2 g, 11.6 mmol), (1R,2R)-N1,N2-dimethylcyclohexane-1,2-diamine (156.4 mg, 1.1 mmol), CuI (208.8 mg, 1.1 mmol) and K₃PO₄ (4.9 g, 23.2 mmol) in dioxane (30.0 mL) was degassed and refilled with N₂, and stirred at 100 ^oC under N₂ for 16 hours. The mixture was filtered, the filtrate was concentrated and the crude product was purified by prep-HPLC to give compound 1f (1.2 g) as a colorless solid. LCMS (M+H⁺): 365.2, ¹H NMR (400MHz, CHLOROFORM-d) ppm 7.48 (s, 1H), 4.98 (d, J=17.4 Hz, 1H), 4.83 (br. s., 1H), 4.27 - 4.16 (m, 2H), 4.14 - 4.06 (m, 1H), 3.81 - 3.71 (m, 1H), 1.50 (s, 3H),1.41 (s, 9H), 1.40 (s, 3H), 1.18 (t, J=7.1 Hz, 6H).

Step 6: preparation of (4S)-4,5,5-trimethyl-3-[(6S)-6-methyl-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazin-3-yl]oxazolidin-2-one (compound 1g)

A solution of tert-butyl (6S)-6-methyl-3-[(4S)-4,5,5-trimethyl-2-oxo-oxazolidin-3-yl]-6,7- dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate (compound 1f, 45.0 mg, 0.12 mmol) in HCl in EtOAc (4 N, 5.0 mL) was stirred at room temperature for 1 hour, then the mixture was concentrated to give crude compound 1g (40.0 mg, crude) as a colorless oil.

Step 7: preparation of (6S)-6-methyl-N-(3,4,5-trifluorophenyl)-3-[(4S)-4,5,5-trimethyl- 2-oxo-oxazolidin-3-yl]-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide (Example 1) To a mixture of (4S)-4,5,5-trimethyl-3-[(6S)-6-methyl-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrazin-3-yl]oxazolidin-2-one (compound 1g, 40.0 mg, 0.13 mmol) and TEA (40.5 mg, 0.40 mmol) in DMF (5.0 mL) was added phenyl N-(3,4,5-trifluorophenyl)carbamate (Intermediate I- 4, 35.5 mg, 0.13 mmol). The mixture was stirred at room temperature for 2 hours. Then the mixture was purified by prep-HPLC to give Example 1 (41.2 mg) as a colorless oil. LCMS (M+H⁺): 438.2, ¹H NMR (400MHz, CHLOROFORM-d) ppm 7.79 (s, 1H), 7.39 (s, 1H), 7.25 - 7.13 (m, 2H), 5.18 - 4.96 (m, 2H), 4.37 - 4.16 (m, 2H), 4.07 - 3.92 (m, 2H), 1.60 (s, 3H), 1.44 (s, 3H), 1.34 (d, J=7.0 Hz, 3H), 1.21 (d, J=6.5 Hz, 3H). Example 2

(6S)-6-methyl-N-(3,4,5-trifluorophenyl)-3-[(4R)-4,5,5-trimethyl-2-oxo-oxazolidin-3-yl]-6,7- dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide

The Example 2 was prepared in analogy to Example 1 by using (2R)-2-aminopropanoic acid instead of (2S)-2-aminopropanoic acid (compound 1a). Example 2 (37 mg) was obtained as a colorless oil. LCMS (M+H⁺): 438.2, ¹H NMR (400MHz, CHLOROFORM-d) ppm 7.52 (s, 1H), 7.41 (s, 1H), 7.23 - 7.13 (m, 2H), 5.12– 5.02 (m, 1H), 4.79 (d, J=16.4 Hz, 1H), 4.53 (d, J=16.4 Hz, 1H), 4.29 - 4.25 (m, 1H), 4.08 (d, J=13.2 Hz, 1H), 3.88-3.85 (m, 1H), 1.58 (s, 3H), 1.44 (s, 3H), 1.32 (d, J=6.8 Hz, 3H), 1.27 (d, J=6.4 Hz, 3H). Example 3

(6S)-N-(6-chloro-5-fluoro-3-pyridyl)-6-methyl-3-[(4S)-4,5,5-trimethyl-2-oxo-oxazolidin-3- yl]-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide

The Example 3 was prepared in analogy to Example 1 by using phenyl N-(6-chloro-5- fluoro-3-pyridyl)carbamate (Intermediate I-7) instead of phenyl N-(3,4,5- trifluorophenyl)carbamate (Intermediate I-4). Example 3 (30 mg) was obtained as a white solid. LCMS (M+H⁺): 437.1, ¹H NMR (400MHz, METHANOL-d4) δ ppm 8.30 (d, J=2.2 Hz, 1H), 8.03 (dd, J=2.3, 10.6 Hz, 1H), 7.61 (s, 1H), 5.14 - 4.95 (m, 2H), 4.46 (d, J=16.8 Hz, 1H), 4.34 (dd, J=4.3, 12.8 Hz, 1H), 4.19 (dd, J=1.1, 12.8 Hz, 1H), 4.03 (q, J=6.6 Hz, 1H), 1.58 (s, 3H), 1.44 (s, 3H), 1.24 (d, J=6.8 Hz, 3H), 1.21 (d, J=6.6 Hz, 3H). Example 4

(6S)-N-[2-(difluoromethyl)-4-pyridyl]-6-methyl-3-[(4S)-4,5,5-trimethyl-2-oxo-oxazolidin-3- yl]-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide

The Example 4 was prepared in analogy to Example 1 by using phenyl N-[2- (difluoromethyl)-4-pyridyl]carbamate (Intermediate I-8) instead of phenyl N-(3,4,5- trifluorophenyl)carbamate (Intermediate I-4). Example 4 (25 mg) was obtained as a white solid. LCMS (M+H⁺): 435.2, ¹H NMR (400MHz, METHANOL-d₄) δ ppm 8.43 (d, J=5.7 Hz, 1H), 7.88 (s, 1H), 7.68 (dd, J=2.0, 5.7 Hz, 1H), 7.61 (s, 1H), 6.67 (t, J=56.0 Hz, 1H), 5.17 - 4.97 (m, 2H), 4.47 (d, J=16.8 Hz, 1H), 4.35 (dd, J=4.3, 12.8 Hz, 1H), 4.20 (d, J=12.2 Hz, 1H), 4.03 (q, J=6.6 Hz, 1H), 1.58 (s, 3H), 1.45 (s, 3H), 1.25 (d, J=6.8 Hz, 3H), 1.21 (d, J=6.6 Hz, 3H). Example 5

(6S)-N-(2-chloro-4-pyridyl)-6-methyl-3-[(4S)-4,5,5-trimethyl-2-oxo-oxazolidin-3-yl]-6,7- dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide

The Example 5 was prepared in analogy to Example 1 by using phenyl N-(2-chloro-4- pyridyl)carbamate (Intermediates I-5) instead of phenyl N-(3,4,5-trifluorophenyl)carbamate (Intermediate I-4). Example 5 (15 mg) was obtained as a white solid. LCMS (M+H⁺): 419.2, ¹H NMR (400MHz, METHANOL-d₄) δ ppm 8.16 (d, J=5.9 Hz, 1H), 7.70 (d, J=1.8 Hz, 1H), 7.61 (s, 1H), 7.49 (dd, J=1.9, 5.8 Hz, 1H), 5.08 (d, J=16.8 Hz, 1H), 5.03 - 4.97 (m, 1H), 4.46 (d, J=16.9 Hz, 1H), 4.34 (dd, J=4.4, 13.0 Hz, 1H), 4.19 (d, J=12.1 Hz, 1H), 4.03 (q, J=6.6 Hz, 1H), 1.58 (s, 3H), 1.45 (s, 3H), 1.25 (d, J=6.8 Hz, 3H), 1.21 (d, J=6.6 Hz, 3H). Example 6

(6S)-6-methyl-N-[2-(trifluoromethyl)-4-pyridyl]-3-[(4S)-4,5,5-trimethyl-2-oxo-oxazolidin-3- yl]-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide

The Example 6 was prepared in analogy to Example 1 by using phenyl N-(2- trifluoromethyl-4-pyridyl)carbamate (Intermediate I-6) instead of phenyl N-(3,4,5- trifluorophenyl)carbamate (Intermediate I-4). Example 6 (15 mg) was obtained as a white solid. LCMS (M+H⁺): 453.2, ¹H NMR (400MHz, METHANOL-d₄) δ ppm 8.49 (d, J=5.6 Hz, 1H), 8.03 (d, J=2.0 Hz, 1H), 7.76 (dd, J=2.0, 5.7 Hz, 1H), 7.61 (s, 1H), 5.11 (d, J=16.9 Hz, 1H), 5.06 - 4.99 (m, 1H), 4.48 (d, J=16.8 Hz, 1H), 4.35 (dd, J=4.3, 12.8 Hz, 1H), 4.20 (dd, J=1.1, 12.8 Hz, 1H), 4.03 (q, J=6.5 Hz, 1H), 1.59 (s, 3H), 1.45 (s, 3H), 1.26 (d, J=6.8 Hz, 3H), 1.21 (d, J=6.5 Hz, 3H). Example 7

(6S)-3-[(4S)-4,5-dimethyl-2-oxo-oxazolidin-3-yl]-6-methyl-N-(3,4,5-trifluorophenyl)-6,7- dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide

The title compound was prepared according to the following scheme:

Preparation of (6S)-3-[(4S)-4,5-dimethyl-2-oxo-oxazolidin-3-yl]-6-methyl-N-(3,4,5- trifluorophenyl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide (Example 7) The title compound was prepared in analogy to Example 1 by using tert-butyl N-[(1S)-2- hydroxy-1-methyl-propyl]carbamate (compound I-3c) instead of methyl tert-butyl N-[(1S)-2- hydroxy-1,2-dimethyl-propyl]carbamate (compound 1d). Final separation by SFC (Column: Chiralpak AD-3100×4.6 mm I.D., 3um; Mobile phase: ethanol (0.05% DEA) in CO₂ from 5% to 40%; Wavelength: 220nm) gave Example 7 as two separated isomers, Example 7-1 and

Example 7-2.

Example 7-1: 8 mg, white solid, LCMS (M+H⁺): 424.2, ¹H NMR (400MHz,

CHLOROFORM-d) ppm 7.71 (s, 1H), 7.43 (s, 1H), 7.25 - 7.14 (m, 2H), 5.16 - 4.89 (m, 3H), 4.38 - 4.20 (m, 3H), 4.03 (dd, J=1.6, 12.9 Hz, 1H), 1.46 (d, J=6.7 Hz, 3H), 1.34 (d, J=6.9 Hz, 3H), 1.20 (d, J=6.7 Hz, 3H).

Example 7-2: 40 mg, white solid, LCMS (M+H⁺): 424.2, ¹H NMR (400MHz,

CHLOROFORM-d) ppm 7.76 (s, 1H), 7.41 (s, 1H), 7.23 - 7.11 (m, 2H), 5.16 - 5.08 (m, 1H), 5.04 (d, J=16.7 Hz, 1H), 4.44 - 4.35 (m, 1H), 4.31 (d, J=16.7 Hz, 1H), 4.22 (dd, J=5.1, 12.9 Hz, 1H), 4.03 (dd, J=1.6, 12.9 Hz, 1H), 3.96 - 3.86 (m, 1H), 1.59 (d, J=6.3 Hz, 3H), 1.38 - 1.26 (m, 6H) Example 9 (6S)-6-methyl-3-[(4S)-4-methyl-2-oxo-oxazolidin-3-yl]-N-(3,4,5-trifluorophenyl)-6,7- dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide

The title compound was prepared according to the following scheme:

Preparation of (4S)-4-methyloxazolidin-2-one (compound 9b)

To a mixture of (2S)-2-aminopropan-1-ol (compound 9a, 5 g, 66.57 mmol) and TEA (20.21 g, 199.71 mmol) in DCM (50 mL) at 0 ^oC was added a solution of triphosgene (7.90 g, 26.63 mmol) in DCM (20 mL) dropwise. The mixture was then stirred at room temperature for 18 hours and then concentrated and purified by silica gel column chromatography (DCM:

MeOH=20:1) to give compound 9b (1.5 g, crude) as a colorless oil. ¹H NMR: (400MHz, CDCl₃) ppm 4.52 - 4.47 (m, 1H), 4.04 - 3.98 (m, 1H), 3.96 - 3.92 (m, 1H), 1.29 (d, J=6.0 Hz, 3H).

Preparation of (6S)-6-methyl-3-[(4S)-4-methyl-2-oxo-oxazolidin-3-yl]-N-(3,4,5- trifluorophenyl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide (Example 9) The Example 9 was prepared in analogy to Example 1 by using (4S)-4-methyloxazolidin-2- one (compound 9b) instead of (4S)-4,5,5-trimethyloxazolidin-2-one (compound 1e). Example 9 (56 mg) was obtained as a white solid, LCMS^(M+H⁺): 410.1, ¹H NMR (400MHz, CDCl3) ppm 7.47 - 7.42 (m, 1H), 7.17 - 7.08 (m, 2H), 5.10 (m, J=6.2 Hz, 1H), 5.00 (d, J=16.6 Hz, 1H), 4.69 (t, J=8.5 Hz, 1H), 4.40 - 4.29 (m, 2H), 4.17 (dd, J=5.0, 12.9 Hz, 1H), 4.10 (dd, J=7.1, 8.5 Hz, 1H), 4.04 (d, J=12.9 Hz, 1H), 1.35 (d, J=6.1 Hz, 3H), 1.28 (d, J=7.0 Hz, 3H). Example 10

(6S)-6-methyl-3-[(4S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl]-N-(3,4,5- trifluorophenyl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide

The title compound was prepared according to the following scheme:

Step 1: preparation of 1,1,1-trifluoro-3-nitro-propan-2-ol (compound 10b) To a mixture of 2,2,2-trifluoroethane-1,1-diol (compound 10a, 25.0 g, 161.6 mmol) in CH₃NO₂ (29.5 g, 484.7 mmol) was added Na₂CO₃ (1.8 g, 16.2 mmol), the reaction mixture was stirred at 60^oC for 3 hours, then cooled to room temperature and stirred for 12 hours. The reaction mixture was partitioned between EtOAc (400 mL) and H₂O (200 mL). The organic phase was washed with brine (200 mL), dried over Na2SO4, and concentrated to give compound 10b (35.0 g, crude) as green-yellow liquid which was used in next step directly.

Step 2: preparation of (E)-3,3,3-trifluoro-1-nitro-prop-1-ene (compound 10c)

A mixture of 1,1,1-trifluoro-3-nitro-propan-2-ol (compound 10b, 35.0 g, crude) and P₂O₅ (22.9 g, 161.6 mmol) was stirred at 90 ^oC for 1 hour. The mixture was submitted to fractional distillation at atmospheric pressure (distilled at 83-85^oC), and compound 10c (5.2 g) was obtained as a green-yellow liquid. ¹H NMR (400MHz, CHLOROFORM-d)

ppm 7.45 - 7.34 (m, 1H), 7.04 (qd, J=6.5, 13.2 Hz, 1H).

Step 3: preparation of (4R)-4-phenyl-3-[(1S)-2,2,2-trifluoro-1- (nitromethyl)ethyl]oxazolidin-2-one (compound 10d)

A solution of (E)-3,3,3-trifluoro-1-nitro-prop-1-ene( compound 10c, 5.0 g, 35.4 mmol) in THF (80 mL) was cooled to -75 ^oC, n-BuLi (12.7 mL, 31.9 mmol) was added dropwise, the reaction mixture was stirred at the same temperature for 1 hour. Then (4R)-4-phenyloxazolidin- 2-one (4.6 g, 28.4 mmol) dissolved in THF (20 mL) was added dropwise. After being stirred for further 0.5 hour, the reaction was quenched by saturated aqueous NH4Cl solution, and the mixture was allowed to warm to room temperature slowly and stirred for 12 h, and then partitioned between EtOAc (200 mL) and H₂O (200 mL). Organic phase was washed with brine (100 mL) and concentrated to give compound 10d (12.3 g, crude) as light yellow solid. ¹H NMR (300MHz, CHLOROFORM-d) δ ppm 7.45 - 7.38 (m, 3H), 7.29 - 7.24 (m, 2H), 5.44 (dd, J=8.5, 14.3 Hz, 1H), 4.94 - 4.88 (m, 1H), 4.74 - 4.66 (m, 2H), 4.36 - 4.28 (m, 1H), 4.27 - 4.19 (m, 1H).

Step 4: preparation of (4R)-3-[(1S)-1-(aminomethyl)-2,2,2-trifluoro-ethyl]-4-phenyl- oxazolidin-2-one (compound 10e)

A mixture of (4R)-4-phenyl-3-[(1S)-2,2,2-trifluoro-1-(nitromethyl)ethyl]oxazolidin-2-one (compound 10d, 12.3 g, 40.4 mmol) and Pd(OH)₂ (2.8 g, 4.0 mmol) in MeOH (200 ml) was stirred for 12 hours under H₂ (50 psi) atmosphere at room temperature. The reaction mixture was filtered and the filtrate was concentrated to give compound 10e (11.5 g, crude) as a brown solid.

Step 5: preparation of (5S)-1-[(1R)-2-hydroxy-1-phenyl-ethyl]-5- (trifluoromethyl)imidazolidin-2-one (compound 10f) To a solution of (4R)-3-[(1S)-1-(aminomethyl)-2,2,2-trifluoro-ethyl]-4-phenyl-oxazolidin- 2-one (compound 10e, 11.5 g, 41.95 mmol) in MeOH (120 ml) was added NaOH (10.1 g, 251.74 mmol). The reaction mixture was stirred for 2 hours at 80 ^oC. After cooled to 0 ^oC, the mixture was neutralized by careful addition of aqueous solution of HCl (3M), and then extracted twice with EtOAc (500 mL). The combined organic layer was concentrated and the residue was purified by column chromatography (PE/EtOAc=1/1) to give a crude product (2.0 g). The crude product was further purified by prep-HPLC to give compound 10f (0.6 g) as a colorless oil. LCMS (M+H⁺): 275.0

Step 6: preparation of tert-butyl (6S)-3-[(4S)-3-[(1R)-2-hydroxy-1-phenyl-ethyl]-2-oxo- 4-(trifluoromethyl)imidazolidin-1-yl]-6-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5- carboxylate (compound 10g)

Compound 10g was prepared in analogy to tert-butyl (6S)-6-methyl-3-[(4S)-4,5,5- trimethyl-2-oxo-oxazolidin-3-yl]-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate (compound 1f) by using (5S)-1-[(1R)-2-hydroxy-1-phenyl-ethyl]-5- (trifluoromethyl)imidazolidin-2-one (compound 10f) instead of (4S)-4,5,5-trimethyloxazolidin- 2-one (compound 1e). Compound 10g was obtained as a brown solid (0.42 g). LCMS:^(M+H⁺): 510.1.

Step 7: preparation of tert-butyl (6S)-6-methyl-3-[(4S)-2-oxo-4- (trifluoromethyl)imidazolidin-1-yl]-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate (compound 10h)

NH₃ gas was bubbled into THF (40 mL) at -70 ^oC for 5 mins, then Na (45.1 mg, 1.96 mmol) was added slowly, and five drops of EtOH was added. After 10 minutes, tert-butyl (6S)-3-[(4S)- 3-[(1R)-2-hydroxy-1-phenyl-ethyl]-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl]-6-methyl-6,7- dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate (compound 10g, 200.0 mg, 0.39 mmol) in THF (10 mL) was added dropwise. The reaction mixture was stirred at -70 ^oC for 20 mins and then poured into saturated aqueous solution of NH₄Cl (100 mL), and extracted with EtOAc three times (100 mL). The organic layer was concentrated and the residue was purified by prep-TLC (DCM/MeOH=10/1) to give compound 10h as a brown solid, (145.0 mg). LCMS:^(M+H⁺): 390.1.

Preparation of (6S)-6-methyl-3-[(4S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl]-N- (3,4,5-trifluorophenyl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide (Example 10) The Example 10 was prepared in analogy to Example 1 by using tert-butyl (6S)-6-methyl-3- [(4S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl]-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5- carboxylate (compound 10h) instead of tert-butyl (6S)-6-methyl-3-[(4S)-4,5,5-trimethyl-2-oxo- oxazolidin-3-yl]-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate (compound 1f).

Example 10 (41 mg) was obtained as a white solid. LCMS:^(M+H⁺): 463.0, ¹H NMR (400MHz, METHANOL-d₄) δ ppm 7.61 (s, 1H), 7.35 - 7.24 (m, 2H), 5.08 (d, J=16.8 Hz, 1H), 4.99 - 4.95 (m, 1H), 4.55 - 4.44 (m, 2H), 4.29 (dd, J=4.4, 12.8 Hz, 1H), 4.23 - 4.11 (m, 2H), 3.93 (dd, J=4.3, 10.1 Hz, 1H), 1.26 (d, J=6.8 Hz, 1H). Example 11

(6S)-6-methyl-3-[(5S)-5-methyl-2-oxo-imidazolidin-1-yl]-N-(3,4,5-trifluorophenyl)-6,7- dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide

The title compound was prepared according to the following scheme:

Step 1: preparation of tert-butyl N-[(1S)-2-[(4-methoxyphenyl)methylamino]-1- methyl-ethyl]carbamate (compound 11b) To a solution of tert-butyl N-[(1S)-2-hydroxy-1-methyl-ethyl]carbamate (compound 11a, 4.0 g, 22.8 mmol) and Et₃N (6.9 g, 68.4 mmol) in DCM (150 mL) was added MsCl (3.2 g, 27.4 mmol) at 0 ^oC. The reaction was stirred at 0~10 ^oC for 2 hours and then quenched with NaHCO₃ (50 mL), washed with brine (50 mL). The organic layer was dried over Na₂SO₄ and concentrated. The residue was dissolved in CH3CN (150 mL), to which were added K2CO3 (6.3 g, 45.6 mmol) and PMBNH₂ (3.2 g, 22.8 mmol). The reaction was stirred at 50 ^oC for 16 hours. After cooled to room temperature, the mixture was filtered and the filtrate was concentrated. The residue was purified by silica gel chromatograph (PE: EtOAc= 1:3) to give compound 11b (1.7 g) as a yellow oil, LCMS (M+H)⁺ : 295.2.

Step 2: preparation of (4S)-1-[(4-methoxyphenyl)methyl]-4-methyl-imidazolidin-2-one (compound 11c)

To a solution of tert-butyl N-[(1S)-2-[(4-methoxyphenyl)methylamino]-1-methyl- ethyl]carbamate (compound 11b, 1.7 g, 5.8 mmol) in THF (50 mL) was added KOtBu (1.9 g, 17.3 mmol) at room temperature in portions. The reaction was stirred at 80 ^oC for 3 hours. After cooled to room temperature, the reaction was quenched with aqueous solution of HCl (11.5 mL, 1 M) and extracted with EtOAc twice (15 mL). The combined organic layer was dried over Na₂SO₄ and concentrated. The residue was purified by Prep-HPLC to give compound 11c (250.0 mg,) as a white solid, LCMS (M+Na)⁺ : 243.1.

Step 3: preparation of(4S)-1-[(4-methoxyphenyl)methyl]-4-methyl-3-[(6S)-6-methyl- 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl]imidazolidin-2-one (compound 11d)

A mixture of (4S)-1-[(4-methoxyphenyl)methyl]-4-methyl-imidazolidin-2-one (compound 11c, 125.0 mg, 0.57 mmol), (6S)-3-iodo-6-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine (Intermediate I-1-1, 164.2 mg, 0.62 mmol,) K₃PO₄ (242.0 mg, 1.14 mmol), CuI (28.6 mg, 0.15 mmol) and (1R,2R)-N1,N2-dimethylcyclohexane-1,2-diamine (21.3 mg, 0.15 mmol) in dioxane (5.0 mL) was stirred at 110 ^oC for 16 hours under N₂. The reaction mixture was filtered, and the filtrate was concentrated, the residue was purified by prep-HPLC to give compound 11d (10.0 mg) as a green solid, LCMS (M+H)⁺ = 356.2.

Step 4: preparation of (5S)-5-methyl-1-[(6S)-6-methyl-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrazin-3-yl]imidazolidin-2-one (compound 11e)

To a mixture of (4S)-1-[(4-methoxyphenyl)methyl]-4-methyl-3-[(6S)-6-methyl-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazin-3-yl]imidazolidin-2-one (compound 11d, 10.0 mg, 0.03 mol) in THF (1.0 mL) and MeOH (1.0 mL) was added Pd(OH)₂ (1.0 mg) and a drop of HCl aqueous solution at room temperature. The reaction mixture was stirred at 40 ^oC under 50 psi of H₂ for 24 hours. The reaction mixture was filtered, and the filtrate was concentrated to give compound 11e (8.3 mg, crude) as a yellow solid, which was used in the next step directly.

Step 5: preparation of (6S)-6-methyl-3-[(5S)-5-methyl-2-oxo-imidazolidin-1-yl]-N- (3,4,5-trifluorophenyl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide (Example 11)

To a mixture of (5S)-5-methyl-1-[(6S)-6-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin- 3-yl]imidazolidin-2-one (compound 11e, 8.3 mg, 0.04 mmol) and DIPEA (18.1 mg, 0.14 mmol) in DMF (1.0 mL) was added phenyl N-(3,4,5-trifluorophenyl)carbamate ( Intermediate I-4, 13.4 mg, 0.05 mmol). The mixture was stirred at room temperature for 2 hours, and then purified by prep-HPLC to give Example 11 (7 mg) as a colorless oil. LCMS (M+H⁺): 409.2.¹H NMR (400MHz, DMSO-d₆) δ ppm 9.14 (br. s., 1H), 7.47 - 7.42 (m, 3H), 6.73 (s, 1H), 4.94 (d, J=16.9 Hz, 1H), 4.90 - 4.82 (m, 1H), 4.27 - 4.18 (m, 2H), 4.15 - 4.08 (m, 1H), 4.04 - 3.95 (m, 1H), 3.55 (t, J=8.7 Hz, 1H), 2.98 (t, J=8.3 Hz, 1H), 1.14 (d, J=6.1 Hz, 3H), 1.09 (d, J=6.7 Hz, 3H). Example 12

(6S)-N-[2-(difluoromethyl)-4-pyridyl]-3-[(4S,5S)-4,5-dimethyl-2-oxo-oxazolidin-3-yl]-6- methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide

Preparation of tert-butyl (6S)-3-[(4S,5S)-4,5-dimethyl-2-oxo-oxazolidin-3-yl]-6-methyl-6,7- dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate (compound 12f-1) and tert-butyl (6S)-3- [(4S,5R)-4,5-dimethyl-2-oxo-oxazolidin-3-yl]-6-methyl-6,7-dihydro-4H-pyrazolo[1,5- a]pyrazine-5-carboxylate (compound 12f-2)

Step 1: preparation of tert-butyl N-[(1S)-2-[methoxy(methyl)amino]-1-methyl-2-oxo- ethyl]carbamate (compound 12b)

To a stirred solution of (2S)-2-(tert-butoxycarbonylamino)propanoic acid (compound 12a, 20.0 g, 105.7 mmol) in THF (300 mL) were added HATU (60.3 g, 158.5 mmol), TEA (26.7 g, 264.2 mmol) and N-methoxymethanamine (15.5 g, 158.5 mmol) at 0 ^oC. The reaction mixture was stirred under nitrogen atmosphere at room temperature for 15 hours, and then diluted with EA (200 mL), was washed with brine (200 mL), dried over

filtered and concentrated. The residue was purified by column chromatography (PE: EtOAc=1:1) to give compound 12b (21.0 g) as a white solid.

Step 2: preparation of tert-butyl N-[(1S)-1-methyl-2-oxo-propyl]carbamate

(compound 12c)

To a solution of tert-butyl N-[(1S)-2-[methoxy(methyl)amino]-1-methyl-2-oxo- ethyl]carbamate (compound 12b, 16.0 g, 68.88 mmol) in THF (200 ml) was added dropwise MeMgBr (48.2 ml, 144.65 mmol) at 0 ^oC. The reaction mixture was stirred at room temperature under N₂ for 18 hours. The reaction mixture was cautiously quenched by adding NH₄Cl aqueous solution (200 mL) and extracted with EtOAc three times (200 mL), the organic layer was washed with brine (200.0 mL), dried over Na₂SO₄, filtered and concentrated. The residue was purified by column chromatography (PE: EtOAc=5:1) to give compound 12c (8.9 g) as a white solid.

Step 3: preparation of tert-butyl N-[(1S)-2-hydroxy-1-methyl-propyl]carbamate (compound 12d)

To a solution of tert-butyl N-[(1S)-1-methyl-2-oxo-propyl]carbamate (compound 12c, 2.0 g, 10.7 mmol) in THF (20 mL) and MeOH (5 mL) was added NaBH₄ (444.5 mg, 11.7 mmol) in one portion at 0 ^oC. The reaction mixture was stirred at 0 ^oC for 2 hours. The reaction was quenched with saturated aqueous NH₄Cl (10 mL) and extracted with EtOAc 3 times (10 mL). The combined organic layer was dried over Na₂SO₄ and concentrated to give compound 12d

(2.25 g, crude) as a color less oil.

Step 4: preparation of (4R)-4,5-dimethyloxazolidin-2-one (compound 12e)

To a solution of tert-butyl N-[(1S)-2-hydroxy-1-methyl-propyl]carbamate (1.25 g, 6.6 mmol) in toluene (40.0 mL) was added NaH (660.5 mg, 16.5 mmol) at 0 ^oC. The reaction mixture was stirred at room temperature for 16 hours, and then quenched with saturated aqueous NH₄Cl solution (20 mL) and extracted with EtOAc three times (20 mL). The combined organic layer was dried over Na₂SO₄ and concentrated to give compound 12e (800.0 mg, crude) as a yellow oil, which was used in the next step directly.

Step 4: Preparation of tert-butyl (6S)-3-[(4S,5S)-4,5-dimethyl-2-oxo-oxazolidin-3-yl]-6- methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate (compound 12f-1) and tert- butyl (6S)-3-[(4S,5R)-4,5-dimethyl-2-oxo-oxazolidin-3-yl]-6-methyl-6,7-dihydro-4H- pyrazolo[1,5-a]pyrazine-5-carboxylate (compound 12f-2)

An oven-dried resealable Schlenk tube was charged with (1R,2R)-N1,N2- dimethylcyclohexane-1,2-diamine (187.8 mg, 1.32 mmol), K₃PO₄ (2.8 g, 13.2 mmol), CuI (251.4 mg, 1.32 mmol), (4R)-4,5-dimethyloxazolidin-2-one (800.0 mg, 6.6 mmol), tert-butyl (6S)-6- methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate (compound I-1d, 2.4 g, 6.6 mmol) and dioxane (25 mL) under N₂. The mixture was stirred at 110 ^oC for 16 hours. After cooled to room temperature, the reaction mixture was filtered, and the filtrate was concentrated. The residue was purified by silica gel chromatograph (PE: EtOAc= 1:1) and then Prep-HPLC to give tert-butyl (6S)-3-[(4S)-4,5-dimethyl-2-oxo-oxazolidin-3-yl]-6-methyl-6,7-dihydro-4H- pyrazolo[1,5-a]pyrazine-5-carboxylate as a yellow oil (1.3 g), which was submitted to chiral SFC (Column: Chiralpak AD-3100×4.6 mm I.D., 3um; Mobile phase: ethanol (0.05% DEA) in CO₂ from 5% to 40%; Wavelength: 220 nm) to give compound 12f-1 (Peak 1) and compound 12f-2 (Peak 2) as white solids.

Compound 12f-1 (326 mg, Peak 1), LCMS (M+Na)⁺: 373.2, ¹H NMR (400MHz, DMSO-d₆) δ ppm 7.56 - 7.50 (m, 1H), 4.80 (d, J=17.2 Hz, 1H), 4.72 - 4.61 (m, 1H), 4.32 (quin, J=6.4 Hz, 1H), 4.22 - 4.15 (m, 1H), 4.15 - 4.03 (m, 2H), 3.80 (quin, J=6.4 Hz, 1H), 1.44 (s, 9H), 1.41 (d, J=6.1 Hz, 3H), 1.14 (d, J=6.1 Hz, 3H), 1.03 (d, J=6.8 Hz, 3H) Compound 12f-2 (592 mg, Peak 2), LCMS (M+Na)⁺: 373.2, ¹H NMR (400MHz, DMSO-d₆) δ ppm 7.54 (s, 1H), 4.91 - 4.76 (m, 2H), 4.66 (br. s., 1H), 4.29 - 3.98 (m, 4H), 1.43 (s, 9H), 1.29 (d, J=6.5 Hz, 3H), 1.03 (d, J=6.6 Hz, 6H), 1.01 (d, J=6.6 Hz, 3H). Preparation of (6S)-N-[2-(difluoromethyl)-4-pyridyl]-3-[(4S,5S)-4,5-dimethyl-2-oxo- oxazolidin-3-yl]-6-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide

(Example 12)

The Example 12 was prepared in analogy to Example 1 by using tert-butyl (6S)-3-[(4S,5S)- 4,5-dimethyl-2-oxo-oxazolidin-3-yl]-6-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5- carboxylate (compound 12f-1) instead of tert-butyl (6S)-6-methyl-3-[(4S)-4,5,5-trimethyl-2-oxo- oxazolidin-3-yl]-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate (compound 1f) and phenyl N-[2-(difluoromethyl)-4-pyridyl]carbamate (Intermediate I-8) instead of phenyl N-(3,4,5- trifluorophenyl)carbamate (Intermediate I-4). Example 12 (30 mg) was obtained as white solid. LCMS:^(M+H⁺): 421.2, ¹H NMR (400MHz, METHANOL-d₄) δ ppm 8.31 (d, J=5.7 Hz, 1H), 7.77 (d, J=2.1 Hz, 1H), 7.56 (dd, J=2.1, 5.7 Hz, 1H), 7.48 (s, 1H), 6.55 (t, J=56 Hz, 1H), 5.05 - 4.84 (m, 2H), 4.40 - 4.18 (m, 3H), 4.08 (dd, J=1.3, 12.8 Hz, 1H), 3.82 - 3.69 (m, 1H), 1.42 (d, J=6.2 Hz, 3H), 1.18 (d, J=6.1 Hz, 3H), 1.13 (d, J=6.8 Hz, 3H). Example 13

(6S)-N-[2-(difluoromethyl)-4-pyridyl]-3-[(4S,5R)-4,5-dimethyl-2-oxo-oxazolidin-3-yl]-6- methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide

The Example 13 was prepared in analogy to Example 1 by using tert-butyl (6S)-3- [(4S,5R)-4,5-dimethyl-2-oxo-oxazolidin-3-yl]-6-methyl-6,7-dihydro-4H-pyrazolo[1,5- a]pyrazine-5-carboxylate (compound 12f-2) instead of tert-butyl (6S)-6-methyl-3-[(4S)-4,5,5- trimethyl-2-oxo-oxazolidin-3-yl]-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate

(compound 1f) and phenyl N-[2-(difluoromethyl)-4-pyridyl]carbamate (Intermediate I-8) instead of phenyl N-(3,4,5-trifluorophenyl)carbamate (Intermediate I-4). Example 13 (22 mg) was obtained as white solid. LCMS:^(M+H⁺): 421.2, ¹H NMR (400MHz, METHANOL-d₄) δ ppm 8.31 (d, J=5.7 Hz, 1H), 7.77 (d, J=2.2 Hz, 1H), 7.57 (dd, J=2.1, 5.7 Hz, 1H), 7.49 (s, 1H), 6.55 (t, J=56 Hz, 1H), 5.03 - 4.80 (m, 3H), 4.35 (d, J=16.8 Hz, 1H), 4.27 - 4.14 (m, 2H), 4.08 (dd, J=1.3, 12.8 Hz, 1H), 1.32 (d, J=6.6 Hz, 3H), 1.13 (d, J=7.0 Hz, 3H), 1.08 (d, J=6.6 Hz, 3H). Example 16

(6S)-N-(2,6-difluoro-4-pyridyl)-3-[(4S,5S)-4,5-dimethyl-2-oxo-oxazolidin-3-yl]-6-methyl- 6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide

The Example 16 was prepared in analogy to Example 1 by using tert-butyl (6S)-3-[(4S,5S)- 4,5-dimethyl-2-oxo-oxazolidin-3-yl]-6-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5- carboxylate (compound 12f-1) instead of tert-butyl (6S)-6-methyl-3-[(4S)-4,5,5-trimethyl-2-oxo- oxazolidin-3-yl]-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate (compound 1f) and phenyl N-(2,6-difluoro-4-pyridyl)carbamate (Intermediate I-9) instead of phenyl N-(3,4,5- trifluorophenyl)carbamate (Intermediate I-4). Example 16 (22 mg) was obtained as white solid. LCMS:^(M+H⁺): 407.2, ¹H NMR (400MHz, METHANOL-d4) δ ppm 7.60 (s, 1H), 7.12 (s, 2H), 5.08 (d, J=16.9 Hz, 1H), 5.03 - 4.96 (m, 1H), 4.51 - 4.29 (m, 3H), 4.24 - 4.15 (m, 1H), 3.98 - 3.82 (m, 1H), 1.54 (d, J=6.2 Hz, 3H), 1.30 (d, J=6.1 Hz, 3H), 1.25 (d, J=6.8 Hz, 3H) Example 17

(6S)-N-(2,6-difluoro-4-pyridyl)-3-[(4S,5R)-4,5-dimethyl-2-oxo-oxazolidin-3-yl]-6-methyl- 6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide

The Example 17 was prepared in analogy to Example 1 by using tert-butyl (6S)-3- [(4S,5R)-4,5-dimethyl-2-oxo-oxazolidin-3-yl]-6-methyl-6,7-dihydro-4H-pyrazolo[1,5- a]pyrazine-5-carboxylate (compound 12f-2) instead of tert-butyl (6S)-6-methyl-3-[(4S)-4,5,5- trimethyl-2-oxo-oxazolidin-3-yl]-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate (compound 1f) and phenyl N-(2,6-difluoro-4-pyridyl)carbamate (Intermediate I-9) instead of phenyl N-(3,4,5-trifluorophenyl)carbamate (Intermediate I-4). Example 17 (28 mg) was obtained as white solid. LCMS:^(M+H⁺): 407.2, ¹H NMR (400MHz, METHANOL-d₄) δ ppm 7.61 (s, 1H), 7.12 (s, 2H), 5.09 (d, J=16.8 Hz, 1H), 5.05 - 4.93 (m, 2H), 4.45 (d, J=16.9 Hz, 1H), 4.39 - 4.28 (m, 2H), 4.19 (dd, J=1.3, 12.8 Hz, 1H), 1.44 (d, J=6.6 Hz, 3H), 1.25 (d, J=6.8 Hz, 3H), 1.20 (d, J=6.6 Hz, 3H). Example 18

(6S)-N-(2,6-difluoro-4-pyridyl)-6-methyl-3-[(4S)-4,5,5-trimethyl-2-oxo-oxazolidin-3-yl]-6,7- dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide

The Example 18 was prepared in analogy to Example 1 by using phenyl N-(2,6-difluoro-4- pyridyl)carbamate (Intermediate I-9) instead of phenyl N-(3,4,5-trifluorophenyl)carbamate (Intermediate I-4). Example 18 (34 mg) was obtained as a white solid. LCMS (M+H⁺): 421.2, ¹H NMR (400MHz, METHANOL-d₄) δ ppm 7.61 (s, 1H), 7.11 (s, 2H), 5.08 (d, J=16.9 Hz, 1H), 5.04 - 4.96 (m, 1H), 4.46 (d, J=16.9 Hz, 1H), 4.34 (dd, J=4.3, 12.8 Hz, 1H), 4.19 (dd, J=1.2, 12.8 Hz, 1H), 4.03 (q, J=6.6 Hz, 1H), 1.58 (s, 3H), 1.44 (s, 3H), 1.25 (d, J=6.8 Hz, 3H), 1.21 (d, J=6.5 Hz, 3H). Example 19

(6S)-N-(2,6-difluoro-4-pyridyl)-3-(5,5-dimethyl-2-oxo-oxazolidin-3-yl)-6-methyl-6,7- dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide

The title compound was prepared according to the following scheme:

Preparation of 5,5-dimethyloxazolidin-2-one (compound 19b)

To a mixture of 1-amino-2-methyl-propan-2-ol (40.0 g, 448.9 mmol) and TEA (136.3 g, 1.35 mmol) in DCM (500.0 mL) was added a solution of triphosgene (53.1 g, 179.6 mmol) in DCM (100.0 mmol) at 0 ^oC during 1 hour, then the mixture was warmed to room temperature and stirred for 1 hour. The mixture was concentrated and the residue was purified by

chromatograph (DCM/MeOH=10/1) to give compound 19b (38.3 g) as a yellow solid. ¹H NMR (400MHz, DMSO-d₆) ppm 7.55 - 7.23 (m, 1H), 3.20 (d, J=0.6 Hz, 2H), 1.34 (s, 6H).

Preparation of (6S)-N-(2,6-difluoro-4-pyridyl)-3-(5,5-dimethyl-2-oxo-oxazolidin-3-yl)- 6-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide (Example 19)

The Example 19 was prepared in analogy to Example 1 by using 5,5-dimethyloxazolidin- 2-one (compound 19b) instead of (4S)-4,5,5-trimethyloxazolidin-2-one (compound 1e) and phenyl N-(2,6-difluoro-4-pyridyl)carbamate (Intermediate I-9) instead of phenyl N-(3,4,5- trifluorophenyl)carbamate (Intermediate I-4). Example 19 (44 mg) was obtained as a white solid. LCMS (M+H⁺): 407.2, ¹H NMR (400MHz, METHANOL-d₄) δ ppm 7.64 (s, 1H), 7.10 (s, 2H), 5.12 (d, J=16.9 Hz, 1H), 5.05 - 4.94 (m, 1H), 4.58 (d, J=16.9 Hz, 1H), 4.31 (dd, J=4.4, 12.7 Hz, 1H), 4.17 (dd, J=1.0, 12.8 Hz, 1H), 3.89 - 3.75 (m, 2H), 1.58 (s, 6H), 1.28 (d, J=6.8 Hz, 3H). Example 20

(6S)-N-(2-chloro-4-pyridyl)-6-methyl-3-(5-oxo-4-oxa-6-azaspiro[2.4]heptan-6-yl)-6,7- dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide

The title compound was prepared according to the following scheme:

Preparation of 4-oxa-6-azaspiro[2.4]heptan-5-one (compound 20b)

The compound 20b was prepared in analogy to 5,5-dimethyloxazolidin-2-one (compound 19b) by using 1-(aminomethyl)cyclopropanol instead of 1-amino-2-methyl-propan-2- ol(compound 19a) and The compound 20b (330.0 mg) was obtained as a white solid. ¹H NMR (400MHz, Chloroform-d) δ ppm 6.09 - 5.69 (m, 1H), 3.70 (s, 2H), 1.29 - 1.21 (m, 2H), 0.78 - 0.70 (m, 2H), 0.78 - 0.70 (m, 1H).

Preparation of (6S)-N-(2-chloro-4-pyridyl)-6-methyl-3-(5-oxo-4-oxa-6-azaspiro[2.4]heptan- 6-yl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide (Example 20)

The Example 20 was prepared in analogy to Example 1 by using 4-oxa-6- azaspiro[2.4]heptan-5-one (compound 20b) instead of (4S)-4,5,5-trimethyloxazolidin-2-one (compound 1e) and phenyl N-(2-chloro-4-pyridyl)carbamate (Intermediate I-5) instead of phenyl N-(3,4,5-trifluorophenyl)carbamate (Intermediate I-4). Example 20 (15 mg) was obtained as a white solid. LCMS (M+H⁺): 403.1, ¹H NMR (400MHz, METHANOL-d₄) δ ppm 8.15 (d, J=5.9 Hz, 1H), 7.73 - 7.66 (m, 2H), 7.48 (dd, J=2.0, 5.8 Hz, 1H), 5.15 (d, J=17.0 Hz, 1H), 5.06 - 4.98 (m, 1H), 4.61 (d, J=17.0 Hz, 1H), 4.32 (dd, J=4.5, 12.8 Hz, 1H), 4.23 - 4.07 (m, 3H), 1.34 - 1.23 (m, 5H), 1.00 - 0.87 (m, 2H). Example 21

(6S)-N-(2,6-difluoro-4-pyridyl)-6-methyl-3-(5-oxo-4-oxa-6-azaspiro[2.4]heptan-6-yl)-6,7- dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide

The Example 21 was prepared in analogy to Example 1 by using 4-oxa-6- azaspiro[2.4]heptan-5-one (compound 20b) instead of (4S)-4,5,5-trimethyloxazolidin-2-one (compound 1e) and phenyl N-(2,6-difluoro-4-pyridyl)carbamate (Intermediate I-9) instead of phenyl N-(3,4,5-trifluorophenyl)carbamate (Intermediate I-4). Example 21(34 mg) was obtained as a white solid. LCMS (M+H⁺): 405.1, ¹H NMR (400MHz, METHANOL-d₄) δ ppm 7.68 (s, 1H), 7.12 (s, 2H), 5.15 (d, J=16.9 Hz, 1H), 5.06 - 4.96 (m, 1H), 4.60 (d, J=16.9 Hz, 1H), 4.32 (dd, J=4.4, 12.8 Hz, 1H), 4.23 - 4.07 (m, 3H), 1.36 - 1.20 (m, 5H), 0.96 - 0.88 (m, 2H). Example 22

(6S)-N-[2-(difluoromethyl)-4-pyridyl]-6-methyl-3-(5-oxo-4-oxa-6-azaspiro[2.4]heptan-6-yl)- 6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide

The Example 22 was prepared in analogy to Example 1 by using 4-oxa-6- azaspiro[2.4]heptan-5-one (compound 20b) instead of (4S)-4,5,5-trimethyloxazolidin-2-one (compound 1e) and phenyl N-[2-(difluoromethyl)-4-pyridyl]carbamate (Intermediate I-8) instead of phenyl N-(3,4,5-trifluorophenyl)carbamate (Intermediate I-4). Example 22 (40 mg) was obtained as a white solid. LCMS (M+H⁺): 419.2, ¹H NMR (400MHz, METHANOL-d₄) δ ppm 8.43 (d, J=5.7 Hz, 1H), 7.89 (d, J=2.1 Hz, 1H), 7.73 - 7.63 (m, 2H), 6.88 - 6.42 (m, 1H), 5.17 (d, J=16.9 Hz, 1H), 5.05-5.02 (m, 1H), 4.61 (d, J=16.9 Hz, 1H), 4.33 (dd, J=4.4, 12.7 Hz, 1H), 4.26 - 4.07 (m, 3H), 1.41 - 1.17 (m, 5H), 1.01 - 0.83 (m, 2H). Example 23

(6S)-6-methyl-3-(5-oxo-4-oxa-6-azaspiro[2.4]heptan-6-yl)-N-[2-(trifluoromethyl)-4- pyridyl]-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide

The Example 23 was prepared in analogy to Example 1 by using 4-oxa-6- azaspiro[2.4]heptan-5-one (compound 20b) instead of (4S)-4,5,5-trimethyloxazolidin-2-one (compound 1e) and phenyl N-(2-trifluoromethyl-4-pyridyl)carbamate (Intermediate I-6) instead of phenyl N-(3,4,5-trifluorophenyl)carbamate (Intermediate I-4). Example 22 (40 mg) was obtained as white solid. LCMS (M+H⁺): 437.1, ¹H NMR (400MHz, METHANOL-d₄) δ = 8.49 (d, J=5.6 Hz, 1H), 8.04 (d, J=2.1 Hz, 1H), 7.76 (dd, J=2.1, 5.6 Hz, 1H), 7.68 (s, 1H), 5.17 (d, J=16.9 Hz, 1H), 5.07 - 5.00 (m, 1H), 4.62 (d, J=16.9 Hz, 1H), 4.33 (dd, J=4.5, 12.8 Hz, 1H), 4.24 - 4.06 (m, 3H), 1.35 - 1.20 (m, 5H), 0.97 - 0.88 (m, 2H). Example 24

(6S)-N-(2,6-difluoro-4-pyridyl)-6-methyl-3-[(7S)-7-methyl-5-oxo-4-oxa-6- azaspiro[2.4]heptan-6-yl]-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide

The title compound was prepared according to the following scheme:

Preparation of tert-butyl N-[(1S)-1-(1-hydroxycyclopropyl)ethyl]carbamate (compound 24a)

To a solution of methyl (2S)-2-(tert-butoxycarbonylamino)propanoate (compound 1c, 2.0 g, 9.84 mmol) and Titanium(IV) isopropoxide (559.38 mg, 1.97 mmol) in THF (30 mL) was added ethylmagnesium bromide (9.84 mL, 29.52 mmol) dropwise over 1 hour at 0 ^oC. The mixture was stirred at room temperature for 17 hours, and then quenched with HCl (1.0 N, 20 mL). Water (50 mL) was added, and the mixture was extracted with EtOAc (50 mL). The organic phase was concentrated, and the residue was purified by column chromatography (PE:EtOAc=3:1) to afford compound 24a (350 mg) as yellow oil. LCMS: (M+H⁺): 202.1.

Preparation of (7S)-7-methyl-4-oxa-6-azaspiro[2.4]heptan-5-one (compound 24b)

To a solution of tert-butyl N-[(1S)-1-(1-hydroxycyclopropyl)ethyl]carbamate (compound 24a, 350.0 mg, 1.74 mmol) in toluene (15 mL) was added sodium hydride (84 mg, 3.48 mmol), and the mixture was stirred at 80 ^oC for 2 hours. After cooled to room temperature, the mixture was quenched with ammonium chloride solution (20 mL) and extracted with EtOAc three times (20 mL). The combine organic phase was concentrated to afford compound 24b (400 mg) as yellow oil. LCMS: (M+H⁺): 128.1.

Preparation of (6S)-N-(2,6-difluoro-4-pyridyl)-6-methyl-3-[(7S)-7-methyl-5-oxo-4-oxa-6- azaspiro[2.4]heptan-6-yl]-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide

(Example 24)

The Example 24 was prepared in analogy to Example 1 by using (7S)-7-methyl-4-oxa-6- azaspiro[2.4]heptan-5-one (compound 24b) instead of (4S)-4,5,5-trimethyloxazolidin-2-one (compound 1e) and phenyl N-(2,6-difluoro-4-pyridyl)carbamate (Intermediate I-9) instead of phenyl N-(3,4,5-trifluorophenyl)carbamate (Intermediate I-4). Example 24 (15 mg) was obtained as a white solid. LCMS (M+H⁺): 419.2, ¹H NMR (400MHz, METHANOL-d₄) δ ppm 7.53 (s, 1H), 7.00 (s, 2H), 5.00 (d, J=16.9 Hz, 1H), 4.94 - 4.86 (m, 1H), 4.37 (d, J=16.9 Hz, 1H), 4.28 - 4.18 (m, 2H), 4.12 - 4.05 (m, 1H), 1.30 - 1.05 (m, 7H), 1.01 - 0.90 (m, 2H), 0.84 - 0.72 (m, 1H). Example 25

(6S)-N-[2-(difluoromethyl)-4-pyridyl]-6-methyl-3-[(7S)-7-methyl-5-oxo-4-oxa-6- azaspiro[2.4]heptan-6-yl]-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide

The Example 25 was prepared in analogy to Example 1 by using (7S)-7-methyl-4-oxa-6- azaspiro[2.4]heptan-5-one (compound 24b) instead of (4S)-4,5,5-trimethyloxazolidin-2-one (compound 1e) and phenyl N-[2-(difluoromethyl)-4-pyridyl]carbamate (Intermediate I-8) instead of phenyl N-(3,4,5-trifluorophenyl)carbamate (Intermediate I-4). Example 25 (20 mg) was obtained as a white solid. LCMS (M+H⁺): 433.2, ¹H NMR (400MHz, METHANOL-d₄) δ ppm 8.31 (d, J=5.7 Hz, 1H), 7.78 (d, J=2.1 Hz, 1H), 7.63 - 7.47 (m, 2H), 6.55 (d, J=56 Hz, 1H),, 5.01 (d, J=16.9 Hz, 1H), 4.96 - 4.87 (m, 1H), 4.39 (d, J=16.8 Hz, 1H), 4.29 - 4.19 (m, 2H), 4.09 (dd, J=1.2, 12.8 Hz, 1H), 1.21 - 1.08 (m, 7H), 1.02 - 0.92 (m, 2H), 0.84 - 0.72 (m, 1H). Example 26

(6S)-3-[(3aR,7aR)-2-oxo-3a,4,5,6,7,7a-hexahydro-3H-benzimidazol-1-yl]-6-methyl-N-(3,4,5- trifluorophenyl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide

The title compound was prepared according to the following scheme:

Step 1: preparation of (3aR,7aR)-1,3,3a,4,5,6,7,7a-octahydrobenzimidazol-2-one (compound 26b)

The mixture of diphenyl carbonate (7.5 g, 35.0 mmol) and (1R,2R)-cyclohexane-1,2- diamine (4.0 g, 35.0 mmol) in 2-propanol (40 mL) was refluxed overnight. The solvent was removed and the residue was purified by column chromatography (eluting with 50% EtOAc in petroleum ether) to afford compound 26b (2.4 g). LCMS (M+H⁺): 127.

Step 2: preparation of tert-butyl (6S)-3-[(3aR,7aR)-2-oxo-3a,4,5,6,7,7a-hexahydro- 3H-benzimidazol-1-yl]-6-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate (compound 26c)

An oven-dried re-sealable Schlenk tube was charged with (S)-tert-butyl 3-iodo-6-methyl- 6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate (Intermediate I-1, 400 mg, 1.1 mmol), K3PO4 (468 mg, 2.2 mmol), CuI (83.9 mg, 0.44 mmol), and (1R,2R)-N1,N2- dimethylcyclohexane-1,2-diamine (62.7 mg, 0.44 mmol), evacuated and backfilled with argon. Methyl (3aR,7aR)-hexahydro-1H-benzo[d]imidazol-2(3H)-one (compound 26b, 201 mg, 1.43 mmol) in DMSO (5 ml) were added under nitrogen. The mixture was stirred at 110 ^oC for 2 hours under microwave, quenched with sat. aqueous solution of NH₄Cl and diluted with EtOAc. The organic layer was separated and washed with sat. NH₄Cl and brine, dried over Na₂SO₄ and concentrated. The residue was purified by silica gel chromatograph to afford the product compound 26c (260 mg). LCMS (M+H⁺): 376.

Step 3: preparation of (3aR,7aR)-3-[(6S)-6-methyl-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrazin-3-yl]-3a,4,5,6,7,7a-hexahydro-1H-benzimidazol-2-one 2,2,2-trifluoroacetic acid (compound 26d) The mixture of tert-butyl (6S)-3-[(3aR,7aR)-2-oxo-3a,4,5,6,7,7a-hexahydro-3H- benzimidazol-1-yl]-6-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate (compound 26c, 260 mg, 692 µmol), 2,2,2-trifluoroacetic acid (2.0 mL) in DCM (5.0 mL) was stirred at room temperature for 30 minutes. The reaction mixture was concentrated to afford crude compound 26d (283 mg). LCMS (M+H⁺): 276.

Step 4: (6S)-3-[(3aR,7aR)-2-oxo-3a,4,5,6,7,7a-hexahydro-3H-benzimidazol-1-yl]-6- methyl-N-(3,4,5-trifluorophenyl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide (Example 26)

The crude compound 26d (100 mg, 0.25 mmol) was dissolved in DCM (3 ml), to which were added DIPEA (0.5 mL), and phenyl (3,4,5-trifluorophenyl)carbamate (intermediate I-4, 80.0 mg, 0.30 mol). The reaction mixture was stirred at 50^oC for 1 hour. The reaction mixture was cooled down, washed with ice-water, extracted with DCM twice. The combined organic phase was concentrated. The residue was purified by prepare-HPLC to afford Example 26 (39 mg). LCMS (M+H⁺): 449; ¹H NMR (400MHz, METHANOL-d₄) δ = 7.38 (s, 1H), 7.17 (dd, J=6.4, 10.3 Hz, 2H), 4.87 - 4.79 (m, 2H), 4.41 (d, J=16.8 Hz, 1H), 4.20 - 4.13 (m, 1H), 4.06 - 4.00 (m, 1H), 3.25 (br d, J=3.1 Hz, 1H), 3.15 (br d, J=10.9 Hz, 1H), 2.02 - 1.72 (m, 4H), 1.45 - 1.29 (m, 4H), 1.17 (d, J=7.0 Hz, 3H). Example 27

(6S)-3-[(3aR,6aS)-2-oxo-4,5,6,6a-tetrahydro-3aH-cyclopenta[d]oxazol-3-yl]-6-methyl-N- (3,4,5-trifluorophenyl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide

The title compound was prepared according to the following scheme:

Step 1: preparation of (3aR,6aS)-3,3a,4,5,6,6a-hexahydrocyclopenta[d]oxazol-2-one (compound 27b)

A mixture of (1S,2R)-2-aminocyclopentanol hydrochloride (compound 27a, 500 mg, 3.63 mmol) and potassium hydroxide (1.83 g, 32.7 mmol) in water (25 mL) was stirred at 0 ^oC for 2 hours, then THF (50 mL) and triphosgene (2.16 g, 7.27 mmol) was added slowly, the reaction mixture was stirred at 0 ^oC for 2 hours. The reaction mixture was poured into 20 mL H₂O and extracted with EtOAc twice (50 mL). The combined organic layer was washed with sat. aqueous sloution of NaHCO3 (50 mL) and brine (50 mL), dried over Na2SO4 and concentrated in vacuo. The residue was washed with n-heptane to give compound 27b (260 mg) as a white solid. LCMS (M+H⁺): 128.1.

Step 2: preparation of tert-butyl (6S)-3-[(3S,6aS)-2-oxo-4,5,6,6a-tetrahydro-3aH- cyclopenta[d]oxazol-3-yl]-6-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate (compound 27c)

To a 10 mL microwave vial was added (3aR,6aS)-3,3a,4,5,6,6a- hexahydrocyclopenta[d]oxazol-2-one (compound 27b, 52.5 mg, 0.41 mmol), (S)-tert-butyl 3- iodo-6-methyl-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate (Intermediate I-1, 100 mg, 0.27 mmol), potassium phosphate (117 mg, 0.55 mmol), (1R,2R)-N1,N2-dimethylcyclohexane- 1,2-diamine (15.7 mg, 0.11 mmol) and copper (I) iodide (10.5 mg, 0.055 mmol) and DMSO (5 mL), the vial was capped and heated in the microwave at 105 ºC for 2 hours. The reaction mixture was poured into EtOAc (50 mL) and washed with water and brine. The organic layer was dried over Na₂SO₄ and concentrated in vacuo to give compound 27c (100 mg) as a light brown oil. LCMS (M+H⁺): 363.4.

Step 3: preparation of (6S)-3-[(3aR,6aS)-2-oxo-4,5,6,6a-tetrahydro-3aH- cyclopenta[d]oxazol-3-yl]-6-methyl-N-(3,4,5-trifluorophenyl)-6,7-dihydro-4H-pyrazolo[1,5- a]pyrazine-5-carboxamide (Example 27)

A mixture of tert-butyl (6S)-3-[(3S,6aS)-2-oxo-4,5,6,6a-tetrahydro-3aH- cyclopenta[d]oxazol-3-yl]-6-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate (compound 27c, 80 mg, 221 µmol) in DCM/TFA(2 mL, 1:1) was stirred at room temperature for 30 mins. The reaction mixture was concentrated and the residue was disolved in DMF (2 mL), then N-ethyl-N-isopropylpropan-2-amine (143 mg, 1.1 mmol), phenyl (3,4,5- trifluorophenyl)carbamate (Intermediate I-4, 70.8 mg, 265 µmol) were added. The reaction mixture was stirred at 70 ^oC for 1 hour, then purified by prep-HPLC to give Example 27 (65 mg) as a white solid, LCMS (M+H⁺): 436.2. ¹H NMR (400MHz, METHANOL-d4) δ ppm 7.53 (s, 1H), 7.19-7.13 (m, 2H), 5.07 (dd, J=5.3, 7.1 Hz, 1H), 4.87 - 4.78 (m, 2H), 4.61 - 4.54 (m, 1H), 4.42 (d, J=16.9 Hz, 1H), 4.20 (dd, J=4.5, 12.8 Hz, 1H), 4.05 (dd, J=0.9, 12.7 Hz, 1H), 2.05 - 1.94 (m, 1H), 1.80 - 1.64 (m, 4H), 1.60 - 1.47 (m, 1H), 1.16 (d, J=7.0 Hz, 3H). Example 28

(6S)-6-methyl-3-(2-oxo-1,3a,4,5,6,6a-hexahydrocyclopenta[d]imidazol-3-yl)-N-(3,4,5- trifluorophenyl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide

The title compound was prepared according to the following scheme:

Preparation of tert-butyl 2-oxo-1,3a,4,5,6,6a-hexahydrocyclopenta[d]imidazole-3- carboxylate (compound 28b)

A mixture of cis 2-((tert-butoxycarbonyl)amino)cyclopentanecarboxylic acid (compound 28a, 500 mg, 2.18 mmol) and 4-methylmorpholine (243 mg, 2.4 mmol) in DCE (10 mL) was stirred at room temperature for 10 mins, then diphenyl phosphorazidate (660 mg, 2.4 mmol) was added. After stirred at room temperature for 2 hours, the reaction mixture was heated to 75 ^oC for 6 hours, then diluted with H₂O and extracted with DCM (20 mL) two times. The combined organic layer was dried over Na₂SO₄ and concentrated in vacuo. The crude material was triturated in heptane (10 mL) to give compound 28b (300 mg) as a white solid. LCMS (M+H⁺): 227.1.

Preparation of (6S)-6-methyl-3-(2-oxo-1,3a,4,5,6,6a-hexahydrocyclopenta[d]imidazol- 3-yl)-N-(3,4,5-trifluorophenyl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide (Example 28)

The Example 28 was prepared in analogy to Example 27 by using tert-butyl 2-oxo- 1,3a,4,5,6,6a-hexahydrocyclopenta[d]imidazole-3-carboxylate (compound 28b) instead of (3aR,6aS)-3,3a,4,5,6,6a-hexahydrocyclopenta[d]oxazol-2-one (compound 27b). Example 28 (120 mg) was obtained as a white solid, LCMS (M+H+): 435.2, ¹H NMR (400MHz,

METHANOL-d4) δ ppm 7.56 (d, J=3.3 Hz, 1H), 7.31-7.26 (m, 2H), 5.06 (d, J=16.6 Hz, 0.5H), 5.01 - 4.91 (m, 1.5H), 4.64 - 4.50 (m, 1.5H), 4.39 (d, J=16.6 Hz, 0.5H), 4.33 - 4.26 (m, 2H), 4.26 - 4.11 (m, 1H), 1.89 - 1.58 (m, 6H), 1.29 (d, J=6.8 Hz, 1.5H), 1.22 (d, J=6.8 Hz, 1.5H). Example 29

(6S)-3-[(3aS,6aR)-2-oxo-4,5,6,6a-tetrahydro-3aH-cyclopenta[d]oxazol-3-yl]-6-methyl-N- (3,4,5-trifluorophenyl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide

The Example 29 was prepared in analogy to Example 27 by using (1R,2S)-2- aminocyclopentanol hydrochloride instead of (1S,2R)-2-aminocyclopentanol hydrochloride (compound 27a). Example 29 (80 mg) was obtained as a white solid. LCMS (M+H⁺): 436.2, ¹H NMR (400MHz, METHANOL-d₄) δ ppm 7.52 (s, 1H), 7.19-7.12 (m, 2H), 5.11 - 5.03 (m, 1H), 4.95 (d, J=16.8 Hz, 1H), 4.90 - 4.83 (m, 1H), 4.54 (t, J=6.5 Hz, 1H), 4.28 (d, J=16.8 Hz, 1H), 4.23 - 4.14 (m, 1H), 4.11 - 4.00 (m, 1H), 2.05 - 1.95 (m, 1H), 1.84 - 1.65 (m, 4H), 1.63 - 1.51 (m, 1H), 1.11 (d, J=6.8 Hz, 3H). Example 30

(6S)-6-methyl-3-(2-oxo-3a,4,6,6a-tetrahydrofuro[3,4-d]oxazol-3-yl)-N-(3,4,5- trifluorophenyl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide

The title compound was prepared according to the following scheme:

Step 1: Preparation of 3a,4,6,6a-tetrahydro-3H-furo[3,4-d]oxazol-2-one (compound 30b)

The solution of tert-butyl N-(cis-4-hydroxytetrahydrofuran-3-yl)carbamate (CAS:

1631070-69-3, Pharmablock catalog PBLL8008, 220 mg, 1.08 mmol) in

hexanfluoroisopropanol (5 mL) was heated under microwave at 130 ^oC for 3h. The solvent was removed, and the residue was dissolved in DCM (10 mL). To the solution was added DIEA (140 mg, 189 µl, 1.08 mmol) and bis(4-nitrophenyl) carbonate (compound 30a, 329 mg, 1.08 mmol). The mixture was stirred at room temperature overnight. The solvent was removed to give crude compound 30b (430mg, purity 30%) which was directly used for next step.

Step 2: Preparation of tert-butyl (6S)-6-methyl-3-(2-oxo-3a,4,6,6a- tetrahydrofuro[3,4-d]oxazol-3-yl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate (compound 30c)

To a solution of (S)-tert-butyl 3-iodo-6-methyl-6,7-dihydropyrazolo[1,5-a]pyrazine- 5(4H)-carboxylate (compound 30b, 300 mg, 826 µmol), CuI (31.5 mg, 165 µmol), K₃PO₄ (351 mg, 1.65 mmol), (1R,2R)-N1,N2-dimethylcyclohexane-1,2-diamine (47 mg, 330 µmol, ) in DMSO (10 mL) was added 3a,4,6,6a-tetrahydro-3H-furo[3,4-d]oxazol-2-one (compound 30b, 430mg, purity 30%) under argon. The mixture was stirred at 110 ^oC for 2h, quenched with sat. aqueous solution of NH₄Cl and diluted with EtOAc. The organic layer was separated and washed with sat. NH₄Cl and brine, dried over Na₂SO₄ and concentrated to give crude compound 30c (420 mg) which was directly used in next step. LCMS (M+1): 365.

Step 3: Preparation of (6S)-6-methyl-3-(2-oxo-3a,4,6,6a-tetrahydrofuro[3,4- d]oxazol-3-yl)-N-(3,4,5-trifluorophenyl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5- carboxamide To a solution of tert-butyl (6S)-6-methyl-3-(2-oxo-3a,4,6,6a-tetrahydrofuro[3,4-d]oxazol- 3-yl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate (compound 30c, 420 mg, 1.15 mmol) in DCM (10 mL) was added TFA (3 mL), the mixture was stirred at room temperature for 30 min, then concentrated. The residue was further dried under high vacuum, and then dissolved in DCM (10 mL). To the solution was added DIEA (715 mg, 966 µl, 5.53 mmol) and phenyl (3,4,5-trifluorophenyl)carbamate (Intermediate I-4, 250 mg, 936 µmol). The mixture was stirred at room temperature overnight, then the solvent was removed to give a crude product, which was purified by prep-HPLC to give Example 30 (30 mg) as a white powder. LCMS (M+1): 438.¹H NMR (400MHz, METHANOL-d₄) δ ppm 7.66 (s, 0.5H), 7.65 (s, 0.5 H), 7.29 (dd, J=6.4, 10.3 Hz, 2H), 5.34 - 5.29 (m, 1H), 5.07 (d, J=16.9 Hz, 0.5H), 5.02 - 4.95 (m, 1H), 4.95 (d, J=16.9 Hz, 0.5H), 4.85 - 4.76 (m, 1H), 4.53 (d, J=16.9 Hz, 0.5H), 4.43 (d, J=16.9 Hz, 0.5H), 4.36 - 4.26 (m, 1H), 4.25 - 4.13 (m, 2H), 4.01 (d, J=4.6 Hz, 0.5H), 3.98 (d, J=4.3 Hz, 0.5H), 3.71 (d, J=3.9 Hz, 0.5H), 3.68 (d, J=3.8 Hz, 0.5H), 3.55 - 3.47 (m, 1H), 1.28 (d, J=6.8 Hz, 1.5H), 1.24 (d, J=6.8 Hz, 1.5H). Example 31

(6S)-6-methyl-3-(2-oxo-3a,4,6,6a-tetrahydro-1H-furo[3,4-d]imidazol-3-yl)-N-(3,4,5- trifluorophenyl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide

The title compound was prepared according to the following scheme:

Step 1: preparation of dimethyl 1,3-dibenzyl-2-oxo-imidazolidine-4,5-dicarboxylate (compound 31b)

To the mixture of 1,3-dibenzyl-2-oxo-imidazolidine-4,5-dicarboxylic acid (compound 31a, 2.0 g, 5.6 mmol) in MeOH (20.0 mL) was added SOCl₂ (2.0 mL), the reaction mixture was stirred at 60 ^oC for 16 hours, and then concentrated. The residue was dissolved in EtOAc (20 mL) and the organic layer was washed with sat.NaHCO₃ twice (5 mL), dried over Na₂SO₄, filtered and concentrated to give compound 31b (2.1 g) as a yellow solid. LCMS (M+H⁺): 383.1

Step 2: preparation of 1,3-dibenzyl-4,5-bis(hydroxymethyl)imidazolidin-2-one

(compound 31c)

To the mixture of dimethyl 1,3-dibenzyl-2-oxo-imidazolidine-4,5-dicarboxylate (compound 31b, 2.1 g, 5.5 mmol) in THF (20.0 mL) was added LiAlH₄ (0.2 g, 5.5 mmol) at 0 ^oC, the mixture was then warmed to room temperature and stirred for 2 hours. The mixture was quenched carefully with H₂O (1.0 mL), concentrated and the residue was purified by

chromatograph (EtOAc) to give compound 31c (1.6 g) as yellow solid. LCMS (M+H⁺): 327.1.^^ Step 3: preparation of 1,3-dibenzyl-3a,4,6,6a-tetrahydrofuro[3,4-d]imidazol-2-one (compound 31d)

To the mixture of 1,3-dibenzyl-4,5-bis(hydroxymethyl)imidazolidin-2-one (compound 31c, 1.5 g, 4.60 mmol) in THF (20 mL) was added NaH (275.7 mg, 6.89 mmol) and 1-(p- tolylsulfonyl)imidazole (222.3 mg, 3.22 mmol) at 0 ^oC, the reaction mixture was stirred at room temperature for 16 hours and then concentrated. The residue was purified by prep-TLC

(PE/EtOAc=3/1) to give compound 31d (1.1 g) as a white solid, LCMS (M+H⁺): 309.1.^{^^}

Step 4: preparation of 3-benzyl-3a,4,6,6a-tetrahydro-1H-furo[3,4-d]imidazol-2-one (compound 31e)

To the mixture of 1,3-dibenzyl-3a,4,6,6a-tetrahydrofuro[3,4-d]imidazol-2-one (compound 31d, 1.10 g, 3.57 mmol) in THF (20 mL) was bubbled in NH₃ for 10 minutes at -78 ^oC, then Na (856.0 mg, 35.67 mmol) and EtOH (1.0 mL) was added to the mixture. The resulting mixture was stirred at -78 ^oC for 30 mins and quenched with sat. NH₄Cl (5 mL). Then the reaction mixture was concentrated and the residue was suspended and stirred in THF (20 mL). After 30 mins, the mixture was filtered and the filtrate was concentrated to give compound 31e (0.60 g) as a white solid. LCMS (M+H⁺): 219.1.

Step 5: preparation of tert-butyl (6S)-3-(1-benzyl-2-oxo-3a,4,6,6a-tetrahydrofuro[3,4- d]imidazol-3-yl)-6-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate

(compound 31f)

A mixture of 3-benzyl-3a,4,6,6a-tetrahydro-1H-furo[3,4-d]imidazol-2-one (compound 31e, 0.6 g, 2.7 mmol), tert-butyl (6S)-3-iodo-6-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5- carboxylate (Intermediate I-1,1.0 g, 2.7 mmol), (1R,2R)-N1,N2-dimethylcyclohexane-1,2- diamine (38.4 mg, 0. 3 mmol), CuI (51.4 mg, 0.3 mmol) and K₃PO₄ (1.2 g, 5.5 mmol) in NMP (30 mL) was stirred at 100 ^oC for 6 hours under N₂. The reaction mixture was filtered, and the filtrate was diluted with brine (20 mL) and extracted with EtOAc three times (20 mL). The combined organic layer was dried over Na₂SO₄, filtered and concentrated, the residue was purified by chromatograph (EtOAc) to give compound 31f (0.7 g) as a yellow solid. LCMS (M+H⁺): 454.1.

Step 6: preparation of tert-butyl (6S)-6-methyl-3-(2-oxo-3a,4,6,6a-tetrahydro-1H- furo[3,4-d]imidazol-3-yl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate

(compound 31g)

To the mixture of tert-butyl (6S)-3-(1-benzyl-2-oxo-3a,4,6,6a-tetrahydrofuro[3,4- d]imidazol-3-yl)-6-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate (compound 31f, 100.0 mg, 0.22 mmol) in THF (10 mL) was bubbled in NH₃ for 10 mins at - 78 ^oC, then Na (50.7 mg, 2.20 mmol) and EtOH (0.1 mL) was added and the mixture was stirred at -78 ^oC for 30 mins. The reaction was quenched with sat. NH₄Cl and then concentrated in vacuo. The residue was suspended in THF (20 mL) and stirred for 30 minutes, then the solid was filtered and filtrate was concentrated to give compound 31g (55.0 mg) as a yellow solid. LCMS (M+H⁺): 364.1 Step 7: preparation of (6S)-6-methyl-3-(2-oxo-3a,4,6,6a-tetrahydro-1H-furo[3,4- d]imidazol-3-yl)-N-(3,4,5-trifluorophenyl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5- carboxamide (Example 31)

The Example 31 was prepared in analogy to Example 1 by using tert-butyl (6S)-6-methyl- 3-(2-oxo-3a,4,6,6a-tetrahydro-1H-furo[3,4-d]imidazol-3-yl)-6,7-dihydro-4H-pyrazolo[1,5- a]pyrazine-5-carboxylate (compound 31g) instead of tert-butyl (6S)-6-methyl-3-[(4S)-4,5,5- trimethyl-2-oxo-oxazolidin-3-yl]-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate (compound 1f). Example 31 (6.2 mg) was obtained as white solid. LCMS (M+H⁺): 437.1, ¹H NMR (400MHz, METHANOL-d₄) δ ppm 7.59 (d, J=3.6 Hz, 1H), 7.39 - 7.20 (m, 2H), 5.11 - 4.94 (m, 2H), 4.78 - 4.72 (m, 1H), 4.55 (d, J=16.8 Hz, 1H), 4.47 - 4.39 (m, 1H), 4.29 (td, J=4.1, 12.7 Hz, 1H), 4.21 - 4.13 (m, 1H), 4.00 - 3.89 (m, 2H), 3.64 (dd, J=4.6, 9.4 Hz, 1H), 3.56 - 3.47 (m, 1H), 1.33 - 1.17 (m, 3H). Example 32

(6S)-3-(5-hydroxy-2-oxo-1,3a,4,5,6,6a-hexahydrocyclopenta[d]imidazol-3-yl)-6-methyl-N- (3,4,5-trifluorophenyl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide

The title compound was prepared according to the following scheme:

Step 1: preparation of cyclopent-3-en-1-yloxymethylbenzene (compound 32b)

To a solution of cyclopent-3-en-1-ol (compound 32a, 5.0 g, 59.4 mmol) in THF (100.0 ml) was added NaH (3.1 g, 77.2 mmol) in portions at 0 ^oC. The reaction was stirred at the same temperature for 30 minutes, then BnBr (10.2 g, 59.4 mmol) was added dropwise. The reaction w^{as warmed to room temperature and stirred for 12 hours. The reaction was quenched with H} ₂ ^O (300 mL) and extracted with EtOAc twice (200 mL). The combined organic layer was dried over Na₂SO₄, concentrated to give compound 32b (12.5 g, crude) as a brown oil.

Step 2: preparation of 3-benzyloxy-6-oxabicyclo[3.1.0]hexane (compound 32c)

To a solution of cyclopent-3-en-1-yloxymethylbenzene (compound 32b, 0.3 g, crude) in DCM (200 mL) was added m-CPBA (25.6 g, 118.8 mmol). The reaction was stirred for 12 hours at room temperature. The reaction was quenched with saturated aqueous Na2SO3, diluted with H₂O (200 mL) and adjusted to pH=10 with Na₂CO₃. Then the mixture was extracted with DCM (200.0 mL) two times, dried and concentrated in vacuo, the residue was purified by column chromatography (EtOAc/PE=1/10) to give compound 32c (4.0 g) as a brown oil. LCMS:^ (M+Na⁺): 213.2

Step 3: preparation of 2-azido-4-benzyloxy-cyclopentanol (compound 32d)

To a solution of 3-benzyloxy-6-oxabicyclo[3.1.0]hexane (compound 32c, 3.0 g, 15.7 mmol) in EtOH/H₂O (40/10 mL) was added NH₄Cl (2.5 g, 47.1 mmol) and NaN₃ (3.0 g, 47.1mmol). The reaction mixture was stirred at 90 ^oC for 12 hours and then cooled to room temperature, H₂O (100 mL) was added, then EtOH was removed under reduced pressure. The obtained solution (70 mL), which contained compound 32d, was used for next step without further purification.

Step 4: preparation of 2-amino-4-benzyloxy-cyclopentanol (compound 32e)

To a solution of (1S,2S)-2-azido-4-benzyloxy-cyclopentanol (compound 32d in 70 mL H₂O from previous step) in THF (100.0 mL) was added PPh₃ (5.7 g, 21.9 mmol). The reaction was stirred at 80 ^oC for 5 hours. Then the reaction was diluted with H₂O (200 mL), and extracted with EtOAc twice (200 mL). The combined organic phase was dried and concentrated to give compound 32e (10.6 g, crude) as a brown oil which was used for next step without further purification.

Step 5: preparation of tert-butyl N-[4-benzyloxy-2-hydroxy-cyclopentyl]carbamate (compound 32f)

To a solution of (1S,2S)-2-amino-4-benzyloxy-cyclopentanol (compound 32e, 10.6 g, 14.6 mmol, crude) in THF (100 mL) was added Na₂CO₃ (3.1 g, 29.2 mmol) and Boc₂O (4.8 g, 21.9 mmol). The reaction was stirred at room temperature for 3 hours. Then the reaction mixture was partitioned between H₂O (200 mL) and EtOAc (400 mL). Organic layer was separated and concentrated, the residue was purified by column chromatography (PE/EtOAc=5/1) to give a crude product (10.0 g), which was further purified by prep-HPLC to give compound 32f (3.8 g) as a white solid. LCMS:^(M+H⁺): 308.1

Step 6: preparation of [4-benzyloxy-2-(tert-butoxycarbonylamino)cyclopentyl] methanesulfonate (compound 32g)

To a solution of tert-butyl N-[4-benzyloxy-2-hydroxy-cyclopentyl]carbamate (compound 32f, 2.0 g, 6.51 mmol) in DCM (50.0 mL) were added TEA (1.3 g, 13.02 mmol) and then MsCl (0.9 g, 7.81 mmol) slowly at 0 ^oC. The reaction was stirred for 0.5 hour at 0 ^oC. The reaction mixture was poured into H₂O (200 mL), and extracted with DCM (400 mL). The organic layer was dried over Na₂SO₄ and then concentrated to give compound 32g (2.9 g, crude) as a brown oil. Step 7: preparation of tert-butyl N-(2-azido-4-benzyloxy-cyclopentyl)carbamate (compound 32h)

To a solution of [4-benzyloxy-2-(tert-butoxycarbonylamino)cyclopentyl] methanesulfonate (compound 32g, 290 g, 6.51 mmol, crude) in DMF (50.0 mL) was added K₂CO₃ (1.17 g, 8.46 mmol) and NaN3 (0.55 g, 8.46 mmol). The reaction was stirred for 12 hours at 90 ^oC, then poured into H₂O (200 mL), extracted with EtOAc (400 mL). The organic layer was dried over Na₂SO₄ and then concentrated to give compound 32h (2.6 g, crude) as a brown oil.

Step 8: preparation of tert-butyl N-[2-amino-4-benzyloxy-cyclopentyl]carbamate (compound 32i)

To a solution of tert-butyl N-(2-azido-4-benzyloxy-cyclopentyl)carbamate (compound 32h, 2.6 g, 6.51 mmol, crude) in MeOH (50.0 mL) was added Pd (2.7 g, 2.60 mmol, 10% on carbon). The reaction was stirred for 2 hours at room temperature under 1 atm. of H₂. The reaction mixture was filtered and the filtrate was concentrated, the residue was purified by column chromatography (DCM/MeOH=10/1) to give compound 32i (1.2 g) as a white solid. LCMS: (M+H⁺): 307.2

Step 9: preparation of 5-benzyloxy-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[d]imidazol- 2-one (compound 32j)

To a solution of tert-butyl N-[2-amino-4-benzyloxy-cyclopentyl]carbamate (compound 32i, 800.0 mg, 2.61 mmol) in CH₃CN (20.0 mL) was added t-BuOK (586.0 mg, 5.22 mmol). The reaction was stirred for 12 hours at 80 ^oC. Then the reaction mixture was concentrated and the residue was treated with H₂O (200 mL), extracted with EtOAc (200 mL) three times. The combined organic layer was concentrated and the residue was purified by prep-TLC

(DCM/MeOH=10/1) to give compound 32j (0.3 g) as a white solid.

Step 10: preparation of tert-butyl (6S)-3-(5-benzyloxy-2-oxo-1,3a,4,5,6,6a- hexahydrocyclopenta[d]imidazol-3-yl)-6-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine- 5-carboxylate (compound 32k)

Compound 32k was prepared in analogy to tert-butyl (6S)-6-methyl-3-[(4S)-4,5,5- trimethyl-2-oxo-oxazolidin-3-yl]-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate (compound 1f) by using 5-benzyloxy-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[d]imidazol-2-one (compound 32j) instead of (4S)-4,5,5-trimethyloxazolidin-2-one (compound 1e). Compound 32k was obtained as a brown solid (115.0 mg). LCMS (M+H⁺): 468.2.

Step 11: preparation of 5-benzyloxy-3-[(6S)-6-methyl-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrazin-3-yl]-1,3a,4,5,6,6a-hexahydrocyclopenta[d]imidazol-2-one (compound 32l) To a solution of tert-butyl (6S)-3-(5-benzyloxy-2-oxo-1,3a,4,5,6,6a- hexahydrocyclopenta[d]imidazol-3-yl)-6-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5- carboxylate (compound 32k, 115.0 mg, 0.25 mmol) in MeOH (5 mL) was added HCl (2 mL, 8.0 mmol), the reaction mixture was stirred at room temperature for 2 hours under N₂ atmosphere, then concentrated to give compound 32l (124.0 mg, crude) as a brown solid. LCMS (M+H⁺): 368.3.

Step 12: preparation of 5-hydroxy-3-[(6S)-6-methyl-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrazin-3-yl]-1,3a,4,5,6,6a-hexahydrocyclopenta[d]imidazol-2-one (compound 32m)

To a mixture of 5-benzyloxy-3-[(6S)-6-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3- yl]-1,3a,4,5,6,6a-hexahydrocyclopenta[d]imidazol-2-one (compound 32l, 115.0 mg, 0.28 mmol) in MeOH (20.0 mL) was added Pd(OH)₂ (40.0 mg, 0.057 mmol), the reaction mixture was stirred at room temperature for 12 hours under H₂ (50Psi) atmosphere, then adjust to pH=8 by NaHCO₃ and filtered, the filtrate was concentrated and the residue was purified by prep-HPLC (DCM/MeOH=5/1) to give compound 32m (24.0 mg) as brown solid. LCMS (M+H⁺): 278.0.

Step 13: preparation of (6S)-3-(5-hydroxy-2-oxo-1,3a,4,5,6,6a- hexahydrocyclopenta[d]imidazol-3-yl)-6-methyl-N-(3,4,5-trifluorophenyl)-6,7-dihydro-4H- pyrazolo[1,5-a]pyrazine-5-carboxamide (Example 32)

To a mixture of 5-hydroxy-3-[(6S)-6-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3- yl]-1,3a,4,5,6,6a-hexahydrocyclopenta[d]imidazol-2-one (compound 32m, 24.0 mg, 0.087 mmol) in DMF (2.0 mL) was added DIPEA (22.5 mg, 0.174 mmol) and phenyl N-(3,4,5- trifluorophenyl)carbamate (Intermediate I-4, 25.4 mg, 0.095 mmol), the reaction mixture was stirred at room temperature for 12 hours, then filtered and the filtrate was purified by prep-HPLC to give Example 32 (3.8 mg) as a white solid. LCMS (M+H⁺): 451.0.¹H NMR (400MHz, METHANOL-d₄) δ ppm 7.62 - 7.54 (m, 1H), 7.36 - 7.21 (m, 2H), 5.08 - 4.95 (m, 1H), 4.69 - 4.61 (m, 1H), 4.58 - 4.39 (m, 2H), 4.38 - 4.26 (m, 2H), 4.20 - 4.10 (m, 1H), 2.06 - 1.97 (m, 2H), 1.97 - 1.88 (m, 1H), 1.81 (td, J=6.8, 14.0 Hz, 1H), 1.86 - 1.76 (m, 1H), 1.36 - 1.19 (m, 3H). Example 33

(6S)-3-[3-hydroxy-2-oxo-4-(2-pyridyl)pyrrolidin-1-yl]-6-methyl-N-(3,4,5-trifluorophenyl)- 6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide

The title compound was prepared according to the following scheme:

Preparation of ethyl 3-cyano-2-hydroxy-3-(2-pyridyl)propanoate (compound 33b) To a solution of 2-(2-pyridyl)acetonitrile (compound 33a, 2.0 g, 17.0 mmol) and NaHCO3 (1.4 g, 17.0 mmol) in MeCN (20 mL) was added ethyl 2-oxoacetate (3.8 g, 18.6 mmol). The reaction mixture was stirred at 25 ^oC for 5 hours, then filtered and the filtrate was concentrated to afford compound 33b (4.0 g, crude) as a yellow oil. LCMS (M+H⁺): 221.1.

Preparation of 3-hydroxy-4-(2-pyridyl)pyrrolidin-2-one (compound 33c):

To a solution of ethyl 3-cyano-2-hydroxy-3-(2-pyridyl)propanoate (compound 33b, 3.0 g, 13.6 mmol) and NH3.H2O (0.5 ml) in MeOH (50.0 ml) was added Raney Ni (2.0 g), then the mixture was stirred at 30 ^oC for 34 hours under H₂ (50 psi). The mixture was concentrated and the residue was purified by column chromatography (DCM:MeOH=10:1) and then prep-HPLC to afford cis- isomer 33c-1 (50 mg) and trans- isomer 33c-2 (300 mg) as yellow solids. LCMS (M+H⁺): 179.1. Preparation of ((6S)-3-[3-hydroxy-2-oxo-4-(2-pyridyl)pyrrolidin-1-yl]-6-methyl-N- (3,4,5-trifluorophenyl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide (Example 33):

The Example 33 was prepared in analogy to Example 1 by using 3-hydroxy-4-(2- pyridyl)pyrrolidin-2-one (compound 33c-1 or 33c-2) instead of (4S)-4,5,5-trimethyloxazolidin-2- one (compound 1e).

Cis-isomer 33c-1 gave two isomers of Example 33, Example 33-1 and Example 33-2, after SFC separation (Chiralcel OD-3100×4.6 mm ID, 3um; mobile phase, methanol (0.05% DEA) in CO₂ from 5% to 40%).

Example 33-1 (6 mg), white solid. LCMS (M+H⁺): 487.3.¹H NMR (400MHz, MeOD) δ ppm 8.60 (d, J=4.5 Hz, 1H), 7.94 (t, J=7.7 Hz, 1H), 7.71 (s, 1H), 7.53 (d, J=8.0 Hz, 1H), 7.46 - 7.38 (m, 1H), 7.30 (dd, J=6.4, 10.3 Hz, 2H), 5.16 (d, J=17.1 Hz, 1H), 4.97 (d, J=5.6 Hz, 1H), 4.81 (d, J=7.3 Hz, 1H), 4.59 (d, J=17.2 Hz, 1H), 4.33 (dd, J=4.5, 12.7 Hz, 1H), 4.27 - 4.09 (m, 4H), 1.32 (d, J=6.9 Hz, 3H).

Example 33-2 (6 mg), white solid, LCMS (M+H⁺): 487.3. ¹H NMR (400MHz, MeOD) δ ppm 8.44 (d, J=4.9 Hz, 1H), 7.77 - 7.68 (m, 1H), 7.58 (s, 1H), 7.33 (d, J=7.8 Hz, 1H), 7.26 - 7.13 (m, 3H), 5.02 (d, J=16.9 Hz, 1H), 4.90 - 4.84 (m, 1H), 4.69 (d, J=7.5 Hz, 1H), 4.47 (d, J=17.1 Hz, 1H), 4.21 (dd, J=4.5, 12.7 Hz, 1H), 4.13 - 3.86 (m, 4H), 1.16 (d, J=6.9 Hz, 3H).

Trans-isomer 33c-2 gave another two isomers of Example 33, Example 33-3 and Example 33-4, after SFC separation (Chiralpak AS-3100×4.6mm ID, 3um; mobile phase, ethanol (0.05% DEA) in CO₂ from 5% to 40%)

Example 33-3 (7 mg), white solid. LCMS (M+H⁺): 487.3. ¹H NMR (400MHz, DMSO-d₆) δ ppm 9.29 (br. s., 1H), 8.66 (d, J=4.8 Hz, 1H), 7.87 (t, J=7.6 Hz, 1H), 7.75 (s, 1H), 7.60 - 7.48 (m, 3H), 7.39 (dd, J=4.8, 7.5 Hz, 1H), 6.03 (d, J=6.7 Hz, 1H), 5.18 (d, J=17.2 Hz, 1H), 5.00 - 4.89 (m, 1H), 4.64 (dd, J=6.4, 9.5 Hz, 1H), 4.44 (d, J=17.3 Hz, 1H), 4.34 - 4.26 (m, 1H), 4.21 (s, 1H), 4.11 - 4.02 (m, 1H), 3.93 (t, J=9.4 Hz, 1H), 3.75 - 3.65 (m, 1H), 1.20 (d, J=6.7 Hz, 3H).

Example 33-4 (7 mg), white solid, LCMS (M+H⁺): 487.3. ¹H NMR (400MHz, DMSO-d₆) δ ppm 9.37 (br. s., 1H), 8.66 (d, J=3.9 Hz, 1H), 7.87 (dt, J=1.8, 7.7 Hz, 1H), 7.73 (s, 1H), 7.59 - 7.48 (m, 3H), 7.39 (dt, J=0.9, 6.2 Hz, 1H), 6.06 (d, J=5.9 Hz, 1H), 5.12 (d, J=17.2 Hz, 1H), 5.02 - 4.93 (m, 1H), 4.61 (dd, J=5.5, 9.4 Hz, 1H), 4.54 (d, J=17.2 Hz, 1H), 4.33 - 4.24 (m, 1H), 4.22 - 4.15 (m, 1H), 3.99 (d, J=9.2 Hz, 2H), 3.71 (q, J=9.3 Hz, 1H), 1.23 (d, J=6.8 Hz, 3H). Example 37 (6S)-3-[(2S,3S)-3-hydroxy-2-methyl-5-oxo-pyrrolidin-1-yl]-6-methyl-N-(3,4,5- trifluorophenyl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide

The title compound was prepared according to the following scheme:

Step 1: preparation of tert-butyl N-[(1S)-2-(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5- ylidene)-2-hydroxy-1-methyl-ethyl]carbamate (compound 37b)

To a stirred solution of (2S)-2-(tert-butoxycarbonylamino)propanoic acid (compound 37a, 1.7 g, 11.63 mmol) and DMAP (2.0 g, 15.86 mmol) in DCM (50 mL) was added 2,2-dimethyl- 1,3-dioxane-4,6-dione (2.0 g, 10.57 mmol) at 0 °C. EDCI (4.9 g, 25.37 mmol) was then added. The reaction mixture was stirred at room temperature for 15 hours. The yellow reaction mixture was cooled to 0°C and washed with cold 5% KHSO₄ (100 mL) three times and brine. The organic layer was dried over Na₂SO₄, filtered and concentrated to afford crude compound 37b (11.4 g), which was used directly in the next step. LCMS: (M+Na⁺): 338.2

Step 2: preparation of tert-butyl (2S)-2-methyl-3,5-dioxo-pyrrolidine-1-carboxylate (compound 37c)

A stirred solution of tert-butyl N-[(1S)-2-(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-ylidene)-2- hydroxy-1-methyl-ethyl]carbamate (compound 37b, 10.0 g, 31.7 mmol) in EtOAc (150 mL) was refluxed for 0.5 hour. The reaction mixture was concentrated to afford compound 37c (6.7 g, crude) as a yellow solid. LCMS (M+Na⁺): 236.2.

Step 3: preparation of tert-butyl (2S,3S)-3-hydroxy-2-methyl-5-oxo-pyrrolidine-1- carboxylate (compound 37d)

To a stirred solution of tert-butyl (2S)-2-methyl-3,5-dioxo-pyrrolidine-1-carboxylate (compound 37c, 6.2 g, 29.08 mmol) in DCM (300 mL) was added HOAc (30 mL) at 0 ^oC. Then NaBH₄ (2.2 g, 58.15 mmol) was added slowly in three portions. After being stirred at 0°C for 5 hours, the reaction mixture was quenched with cold 5% NaHCO₃ aqueous solution at 0°C. The reaction mixture was extracted with DCM (100 mL) three times. The combined organic layer was washed with 5% NaHCO₃ aqueous solution, brine and then concentration. The residue was purified by flash chromatography (DCM/MeOH=10:1) to afford compound 37d (2.7 g) as a white solid. LCMS (2M+Na⁺): 453.1.

Step 4: preparation of (4S,5S)-4-hydroxy-5-methyl-pyrrolidin-2-one (compound 37e) To a stirred solution of tert-butyl (2S,3S)-3-hydroxy-2-methyl-5-oxo-pyrrolidine-1- carboxylate (compound 37d, 1.8 g, 8.36 mmol) in DCM (60 mL) was added TFA (6 mL) dropwise at 0°C. The reaction was stirred at 0°C for 1 hour and then stirred at room temperature for 14 hours. The reaction was concentrated and then toluene (50mL) was added to the residue, and the solution was concentrated to afford crude compound 37e (1.0 g) as a brown oil.

Preparation of (6S)-3-[(2S,3S)-3-hydroxy-2-methyl-5-oxo-pyrrolidin-1-yl]-6-methyl-N- (3,4,5-trifluorophenyl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide (Example 37)

The title compound was prepared in analogy to Example 1 by using (4S,5S)-4-hydroxy-5- methyl-pyrrolidin-2-one (compound 37e) instead of (4S)-4,5,5-trimethyloxazolidin-2-one (compound 1e). Example 37 was obtained (628.0 mg) as a yellow solid. LCMS (M+H)⁺: 424.3, ¹H NMR (400MHz, METHANOL-d₄) δ ppm 7.53 (s, 1H), 7.36 - 7.23 (m, 2H), 5.04 - 4.94 (m, 2H), 4.52 - 4.45 (m, 1H), 4.40 - 4.28 (m, 2H), 4.21 - 4.12 (m, 2H), 2.88 (dd, J=6.3, 17.3 Hz, 1H), 2.52 - 2.39 (m, 1H), 1.22 (d, J=6.7 Hz, 3H), 1.20 (d, J=6.7 Hz, 3H). Example 38

(6S)-6-methyl-3-[(2S,3S)-2-methyl-3-(morpholine-4-carbonyl)-5-oxo-pyrrolidin-1-yl]-N- (3,4,5-trifluorophenyl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide

Preparation of tert-butyl (6S)-3-[(2S,3S)-3-methoxycarbonyl-2-methyl-5-oxo-pyrrolidin-1- yl]-6-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate (Intermediate I-38) and tert-butyl (6S)-3-[(2S,3R)-3-methoxycarbonyl-2-methyl-5-oxo-pyrrolidin-1-yl]-6- methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate (Intermediate I-39)

Intermediate I-38 and Intermediate I-39 were prepared according to the following scheme:

Step 1: preparation of methyl 3-[benzyl-[(1S)-1-phenylethyl]amino]butanoate (compound 38b)

n-Butyllithium solution (46.0 mL, 115.0 mmol) was added dropwise to a solution of (1S)- N-benzyl-1-phenyl-ethanamine (compound 38a, 25.0 g, 118.3 mmol) in THF (270 mL) at -10 ^oC under nitrogen. The resulting red solution of lithium amide was cooled to -78 ^oC and a solution of methyl (E)-but-2-enoate (10.7 g, 106.5 mmol) in THF (30 mL) was added by cannula. The reaction mixture was stirred at -78 ^oC for 1 hour, then quenched with saturated ammonium chloride solution, and extracted with EtOAc twice. The combined organic layer was dried over Na₂SO₄ and concentrated. The residue was purified by silica gel chromatograph (eluting with 5% EtOAc in petroleum ether) to give compound 38b (25.6 g) as a yellow oil. LCMS (M+H⁺): 312.

Step 2: preparation of O4-ethyl O1-methyl 2-[1-[benzyl-[(1S)-1- phenylethyl]amino]ethyl]butanedioate (compound 38c)

To a stirred solution of methyl 3-[benzyl-[(1S)-1-phenylethyl]amino]butanoate (compound 38b, 25.0 g, 80.3 mmol) in THF (250.0 mL) was added LDA (120 mL, 240.8 mmol) dropwise at -78 ^oC. After 1 hour, trimethyl borate (25.0 g, 240.8 mmol) was added and the reaction mixture was stirred for 30 minutes at the same temperature. Then a solution of ethyl 2-bromoacetate (26.8 g, 160.6 mmol) in THF (50.0 mL) was added dropwise at -78 ^oC, the temperature was maintained for 1 hour. The reaction mixture was quenched with saturated ammonium chloride solution and extracted by EtOAc three times. The combined organic layer was dried over Na₂SO₄ and concentrated. The residue was purified by silica gel chromatograph (eluting with 10% EtOAc in petroleum ether) to give compound 38c (22.0 g, crude) as a yellow oil. LCMS (M+H⁺): 398.

Step 3: preparation of methyl (2S)-2-methyl-5-oxo-pyrrolidine-3-carboxylate

(compound 38d)

A mixture of O4-ethyl O1-methyl 2-[1-[benzyl-[(1S)-1- phenylethyl]amino]ethyl]butanedioate (compound 38c, 22.0 g, 55.3 mmol) and palladium on carbon (2.2 g) in MeOH (500 mL) was stirred at room temperature under hydrogen (50 psi) for 16 hours. The reaction mixture was filtered and the filtrate was concentrated. The residue was purified by silica gel chromatograph (eluting with 5% methanol in dichloromethane) to give compound 38d (5.5 g, crude) as a yellow oil. LCMS (M+H⁺): 158.

Step 4: preparation of tert-butyl (6S)-3-[(2S,3S)-3-methoxycarbonyl-2-methyl-5-oxo- pyrrolidin-1-yl]-6-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate

(Intermediate I-38) and tert-butyl (6S)-3-[(2S,3R)-3-methoxycarbonyl-2-methyl-5-oxo- pyrrolidin-1-yl]-6-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate (Intermediate I-39)

An oven-dried re-sealable Schlenk tube was charged with tert-butyl (6S)-3-iodo-6-methyl- 6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate (Intermediate I-1, 2.9 g, 8.0 mmol), K3PO4 (3.4 g, 16.0 mmol), CuI (304.7 mg, 1.6 mmol), (1R,2R)-N1,N2-dimethylcyclohexane- 1,2-diamine (227.6 mg, 1.6 mmol), evacuated and backfilled with argon. Methyl (2S)-2-methyl- 5-oxo-pyrrolidine-3-carboxylate (compound 38d,1.25 g, 8.0 mmol) in dioxane (40.0 ml) were added under nitrogen. The mixture was stirred at 110 ^oC for 15 hours. The reaction mixture was filtered and the filtrate was concentrated. The residue was purified first by silica gel

chromatograph, and then by SFC (Column: Chiralcel OD-3100×4.6 mm, I.D.3um, mobile phase: ethanol (0.05% DEA) in CO₂ from 5% to 40%, Wavelength: 220 nm) to give two isomers, Intermediate I-38 (520 mg) as a yellow solid and Intermediate I-39 (594 mg) as a yellow solid.

Intermediate I-38, LCMS (M+H⁺): 393.¹H NMR (400MHz, DMSO-d₆) δ ppm 7.53 (s, 1H), 4.81 (d, J=17.4 Hz, 1H), 4.64 (d, J=5.1 Hz, 1H), 4.36 - 4.27 (m, 1H), 4.22 - 4.14 (m, 1H), 4.09 - 3.96 (m, 2H), 3.70 - 3.67 (m, 3H), 3.62 (q, J=8.4 Hz, 1H), 2.72 (dd, J=8.3, 16.8 Hz, 1H), 2.54 (d, J=8.7 Hz, 1H), 1.45 (s, 9H), 1.00 (d, J=6.8 Hz, 3H), 0.96 (d, J=6.5 Hz, 3H).

Intermediate I-39, LCMS (M+H⁺): 393.¹H NMR (400MHz, DMSO-d₆) δ ppm 7.53 - 7.45 (m, 1H), 4.78 (d, J=17.5 Hz, 1H), 4.65 (br. s., 1H), 4.21 - 4.14 (m, 1H), 4.11 (t, J=6.1 Hz, 1H), 4.08 - 3.99 (m, 2H), 3.70 (s, 3H), 3.10 - 3.02 (m, 1H), 2.81 - 2.72 (m, 1H), 2.65 - 2.57 (m, 1H), 1.44 (s, 9H), 1.20 (d, J=6.2 Hz, 3H), 1.01 (d, J=6.8 Hz, 3H). Preparation of (6S)-6-methyl-3-[(2S,3S)-2-methyl-3-(morpholine-4-carbonyl)-5-oxo- pyrrolidin-1-yl]-N-(3,4,5-trifluorophenyl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5- carboxamide (Example 38)

Example 38 was prepared according to the following scheme:

Step 1: preparation of (2S,3S)-1-[(6S)-5-tert-butoxycarbonyl-6-methyl-6,7-dihydro- 4H-pyrazolo[1,5-a]pyrazin-3-yl]-2-methyl-5-oxo-pyrrolidine-3-carboxylic acid (compound 38f)

To a solution of tert-butyl (6S)-3-[(2S,3S)-3-methoxycarbonyl-2-methyl-5-oxo-pyrrolidin- 1-yl]-6-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate (Intermediate I-38, 110 mg, 280 µmol) in tetrahydrofuran (280 µL) was added a solution of lithium hydroxide monohydrate in water (2.0 M, 280 µL, 561 µmol). The reaction mixture was stirred at room temperature for 2 hours and then diluted with DCM/i-PrOH (V/V=5/1), acidified to pH=4-5 with 1N aqueous solution of HCl, and washed with water. The organic phase was dried and concentrated to give crude compound 38f (106 mg). LCMS (M+H⁺): 379.

Step 6: preparation of tert-butyl (6S)-6-methyl-3-[(2S,3S)-2-methyl-3-(morpholine-4- carbonyl)-5-oxo-pyrrolidin-1-yl]-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate (compound 38g)

To a solution of (2S,3S)-1-[(6S)-5-tert-butoxycarbonyl-6-methyl-6,7-dihydro-4H- pyrazolo[1,5-a]pyrazin-3-yl]-2-methyl-5-oxo-pyrrolidine-3-carboxylic acid (compound 38f, 106 mg, 0.28 mmol) in dry DMF (5.0 ml) were added morpholine (36.6 mg, 420 µmol), N1- ((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (69.8 mg, 364 µmol), 1H-benzo[d][1,2,3]triazol-1-ol (11.4 mg, 84 µmol) and DIPEA (1.0 ml, 5.83 mmol). The reaction mixture was heated to 50 °C and stirred for 2 hours, then cooled down, washed with ice- water, and extracted with DCM twice. The organic phase was concentrated. The residue was purified by column chromatography to give compound 38g (80 mg). LCMS (M+H⁺): 448. Step 7: preparation of (6S)-6-methyl-3-[(2S,3S)-2-methyl-3-(morpholine-4-carbonyl)- 5-oxo-pyrrolidin-1-yl]-N-(3,4,5-trifluorophenyl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5- carboxamide (Example 38)

The mixture of tert-butyl (6S)-6-methyl-3-[(2S,3S)-2-methyl-3-(morpholine-4-carbonyl)- 5-oxo-pyrrolidin-1-yl]-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate (compound 38g, 80 mg, 179 µmol), 2,2,2-trifluoroacetic acid (2.0 mL) and solvent DCM (1.0 mL) was stirred at room temperature for 30 minutes. The reaction mixture was concentrated, the residue was dissolved in DCE (3.0 ml), then added DIPEA (0.5 mL), phenyl (3,4,5- trifluorophenyl)carbamate (Intermediate I-4, 52.5 mg, 197 µmol). The reaction mixture was stirred at 50^oC for 1 hour and then cooled down, washed with ice-water, extracted with DCM twice. The combined organic phase was concentrated. The residue was purified sequentially by column chromatography, and then pre-HPLC to give Example 38 (38 mg). LCMS (M+H⁺): 521. ¹H NMR (400MHz, METHANOL-d₄) δ = 7.60 (s, 1H), 7.34 - 7.26 (m, 2H), 5.05 - 4.96 (m, 2H), 4.48 - 4.38 (m, 1H), 4.36 - 4.29 (m, 2H), 4.21 - 4.15 (m, 1H), 4.02 (q, J=8.5 Hz, 1H), 3.77 - 3.63 (m, 8H), 3.21 - 3.11 (m, 1H), 2.57 (dd, J=8.7, 17.2 Hz, 1H), 1.20 (d, J=6.8 Hz, 3H), 1.10 (d, J=6.6 Hz, 3H) Example 39

(6S)-6-methyl-3-[(2S,3R)-2-methyl-3-(morpholine-4-carbonyl)-5-oxo-pyrrolidin-1-yl]-N- (3,4,5-trifluorophenyl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide

The title compound was prepared in analogy to Example 38 by using tert-butyl (6S)-3- [(2S,3R)-3-methoxycarbonyl-2-methyl-5-oxo-pyrrolidin-1-yl]-6-methyl-6,7-dihydro-4H- pyrazolo[1,5-a]pyrazine-5-carboxylate (Intermediate I-39) instead of tert-butyl (6S)-3-[(2S,3S)- 3-methoxycarbonyl-2-methyl-5-oxo-pyrrolidin-1-yl]-6-methyl-6,7-dihydro-4H-pyrazolo[1,5- a]pyrazine-5-carboxylate (Intermediate I-38). Example 39 was obtained as a solid (38.6 mg). LCMS (M+H⁺): 521. ¹H NMR (400MHz, METHANOL-d₄) δ = 7.58 (s, 1H), 7.34 - 7.26 (m, 2H), 5.04 - 4.93 (m, 2H), 4.39 - 4.26 (m, 3H), 4.20 - 4.14 (m, 1H), 3.76 - 3.59 (m, 8H), 3.48 - 3.41 (m, 1H), 2.95 (dd, J=9.3, 17.1 Hz, 1H), 2.65 (dd, J=6.1, 17.1 Hz, 1H), 1.33 (d, J=6.4 Hz, 3H), 1.24 (d, J=6.8 Hz, 3H) Example 40

(6S)-3-(3,4-trans-4-cyano-3-hydroxy-2-oxo-pyrrolidin-1-yl)-6-methyl-N-(3,4,5- trifluorophenyl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide

trans-isomers Preparation of tert-butyl (6S)-3-[3-[tert-butyl(dimethyl)silyl]oxy-4-ethoxycarbonyl-2-oxo- pyrrolidin-1-yl]-6-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate

(Intermediate I-40)

Intermediate I-40 was prepared according to the following scheme:

Step 1: preparation of ethyl 1-[(2,4-dimethoxyphenyl)methyl]-4-hydroxy-5-oxo-2H- pyrrole-3-carboxylate (compound 40a)

To a solution of (2,4-dimethoxyphenyl)methanamine (33.4 g, 199.8 mmol) in EtOH(100 mL) was added ethyl prop-2-enoate (20.0 g, 199.8 mmol) in portions at 0 ^oC. The reaction mixture was stirred at room temperature for 2 hours, and then EtOH was removed to give a residue. A solution of NaOEt in EtOH (fresh prepared by dissolving Na (5.51 g, 239.71 mmol) in EtOH (50.0 ml)) was added to a mixture of above residue and diethyl oxalate (29.2 g, 199.8 mmol). The resulting reaction mixture was heated to 80 ^oC for 2 hours. After cooled to room temperature, the reaction mixture was concentrated, and treated with saturated NH₄Cl aqueous solution (200 mL) and extracted with DCM three times. The organic layer was dried over Na₂SO₄, filtered and concentrated to give compound 40a (60.0g) as a yellow solid. LCMS (M+H⁺): 322.

Step 2: preparation of ethyl 4-hydroxy-5-oxo-1,2-dihydropyrrole-3-carboxylate (compound 40b)

The mixture of ethyl 1-[(2,4-dimethoxyphenyl)methyl]-4-hydroxy-5-oxo-2H-pyrrole-3- carboxylate (compound 40a, 60.0 g, 186.7 mmol) and 2,2,2-trifluoroacetic acid (400 mL) was stirred at 80 ^oC for 4 hours under nitrogen. The solvent was removed under vacuum to give compound 40b (35.0 g, crude) which was used in next step directly. LCMS (M+H⁺): 172.

Step 3: preparation of ethyl 4-hydroxy-5-oxo-pyrrolidine-3-carboxylate (compound 40c) To a solution of ethyl 4-hydroxy-5-oxo-1,2-dihydropyrrole-3-carboxylate (compound 40b, 15.0 g, 87.7 mmol) in EtOH (200 mL) were added water (20 mL) and ammonium chloride (23.4 g, 438.2 mmol) and zinc powder (28.6 g, 438.2 mmol). The mixture was stirred at 80 ^oC for 18 hours and filtered. The filtrate was concentrated and purified by reversed-phase column chromatography to give compound 40c (63.0 g, crude) as a yellow oil. LCMS (M+H⁺): 174.

Step 4: preparation of ethyl 4-[tert-butyl(dimethyl)silyl]oxy-5-oxo-pyrrolidine-3- carboxylate (compound 40d)

To a solution of ethyl 4-hydroxy-5-oxo-pyrrolidine-3-carboxylate (compound 40c, 30.0 g, 174.0 mmol) and imidazole (36.0 g, 261.0 mmol) in DMF (150 ml) was added tert- butyldimethylsilyl chloride (36.0 g, 192.0 mmol). The reaction mixture was stirred at room temperature for 24 hours, and then concentrated, treated with water (50 ml) and extracted with EtOAc twice. The combine organic phase was dried over Na₂SO₄ and concentrated to afford compound 40d (10.0 g, crude) as a yellow oil. LCMS (M+H⁺): 288.

Step 5: tert-butyl (6S)-3-[3-[tert-butyl(dimethyl)silyl]oxy-4-ethoxycarbonyl-2-oxo- pyrrolidin-1-yl]-6-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate (I-40) An oven-dried sealable Schlenk tube was charged with (1R,2R)-N1,N2- dimethylcyclohexane-1,2-diamine (0.42 g, 3.0 mmol), K₃PO₄ (7.0 g, 33.0 mmol), evacuated and backfilled with argon. Then CuI (0.45 g, 3.0 mmol), tert-butyl (6S)-3-iodo-6-methyl-6,7- dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate (Intermediate I-1, 6.0 g, 16.5 mmol), ethyl 4- [tert-butyl(dimethyl)silyl]oxy-5-oxo-pyrrolidine-3-carboxylate (compound 40d, 4.8 g, 16.5 mmol) and toluene (60.0 ml) were added under nitrogen. The mixture was stirred at 100 ^oC for 15 hours. The mixture was filtered and the filtrated was concentrated. The residue was purified by column chromatography (eluting with 50% EtOAc in petroleum ether) to afford trans-isomers (Intermediate trans-I-40, 1.77 g) and cis-isomers (Intermediate cis-I-40, 0.56 g).

tert-butyl (6S)-3-[3,4-trans-3-[tert-butyl(dimethyl)silyl]oxy-4-ethoxycarbonyl-2-oxo- pyrrolidin-1-yl]-6-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate (Intermediate trans-I-40,): LCMS (M+H⁺): 523.¹H NMR (400MHz, DMSO-d₆) δ ppm 7.59 (d, J=1.4 Hz, 1H), 4.98 - 4.78 (m, 1H), 4.73 - 4.58 (m, 2H), 4.36 - 4.12 (m, 3H), 4.10 - 3.93 (m, 2H), 3.82 - 3.79 (m, 1H), 3.57 - 3.51 (m, 1H), 3.46 - 3.37 (m, 1H), 1.44 (s, 9H), 1.21 (dt, J=1.1, 6.5 Hz, 3H), 1.11 - 1.02 (m, 3H), 0.86 (d, J=1.1 Hz, 9H), 0.18 - 0.10 (m, 6H).

tert-butyl (6S)-3-[3,4-cis-3-[tert-butyl(dimethyl)silyl]oxy-4-ethoxycarbonyl-2-oxo- pyrrolidin-1-yl]-6-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate (Intermediate cis-I-40,): LCMS (M+H⁺): 523.¹H NMR (400MHz, DMSO-d₆) δ ppm 7.61 (s, 1H), 5.02 - 4.76 (m, 1H), 4.66 (dd, J=1.4, 8.8 Hz, 2H), 4.46 - 4.27 (m, 1H), 4.20 - 4.13 (m, 3H), 4.08 - 4.02 (m, 1H), 3.86 - 3.76 (m, 1H), 3.41 (d, J=2.8 Hz, 1H), 3.30 - 3.27 (m, 1H), 3.22 - 3.05 (m, 1H), 1.44 (s, 9H), 1.26 - 1.21 (m, 3H), 1.06 (dd, J=6.9, 9.9 Hz, 3H), 0.89 (s, 9H), 0.14 (d, J=9.7 Hz, 6H). Preparation of (6S)-3-(3,4-trans-4-cyano-3-hydroxy-2-oxo-pyrrolidin-1-yl)-6-methyl-N- (3,4,5-trifluorophenyl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide (Example 40)

Example 40 was prepared according to the following scheme.

Step 1: preparation of 1-[(6S)-5-tert-butoxycarbonyl-6-methyl-6,7-dihydro-4H- pyrazolo[1,5-a]pyrazin-3-yl]-4-[tert-butyl(dimethyl)silyl]oxy-5-oxo-pyrrolidine-3- carboxylic acid (compound 40f)

To a solution of tert-butyl (6S)-3-[3,4-trans-3-[tert-butyl(dimethyl)silyl]oxy-4- ethoxycarbonyl-2-oxo-pyrrolidin-1-yl]-6-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5- carboxylate (Intermediate trans-I-40, 250 mg, 0.49 mmol) in THF (1.0 mL) was added lithium hydroxide solution in water (1.0 ml, 2 M). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with EtOAc, and acidified to pH=4-5 with 1N hydrogen chloride solution. The organic phase was dried and concentrated to give compound 40f (200 mg). LCMS (M+H⁺): 495.

Step 2: preparation of tert-butyl (6S)-3-[3-[tert-butyl(dimethyl)silyl]oxy-4-carbamoyl- 2-oxo-pyrrolidin-1-yl]-6-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate (compound 40g)

To a solution of 1-[(6S)-5-tert-butoxycarbonyl-6-methyl-6,7-dihydro-4H-pyrazolo[1,5- a]pyrazin-3-yl]-4-[tert-butyl(dimethyl)silyl]oxy-5-oxo-pyrrolidine-3-carboxylic acid (compound 40f, 200 mg, 0.40 mmol) in DCE (5 ml) was added ammonium chloride (216 mg, 4.0 mmol), N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (101 mg, 0.53 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (16.4 mg, 0.12 mmol and DIPEA (2.0 mL). The reaction mixture was heated to 50 °C and stirred at for 2 hours, and then cooled down, washed with brine, extracted with DCM twice. The combined organic phase was dried over Na₂SO₄, filtrated and concentrated. The residue was purified by column chromatography to give compound 40g (110 mg). LCMS (M+H⁺): 494.

Step 3: preparation of tert-butyl (6S)-3-[3-[tert-butyl(dimethyl)silyl]oxy-4-cyano-2- oxo-pyrrolidin-1-yl]-6-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate (compound 40h)

To a solution of tert-butyl (6S)-3-[3-[tert-butyl(dimethyl)silyl]oxy-4-carbamoyl-2-oxo- pyrrolidin-1-yl]-6-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate (compound 40g, 110 mg, 223 µmol) in dry THF (3.0 mL) was added pyridine (0.2 mL). The mixture was flushed with nitrogen and cooled to 0^oC, then to which was added dropwise trifluoroacetic anhydride (0.2 mL). The reaction mixture was stirred at 0 ^oC for another 30 minutes. The reaction mixture was quenched with ice-water, extracted with EtOAc twice. The organic phase was dried over Na₂SO₄, concentrated. The crude product was purified by column

chromatography to give compound 40h (95 mg). LCMS (M+H⁺): 476.

Step 4: preparation of (6S)-3-[3-[tert-butyl(dimethyl)silyl]oxy-4-cyano-2-oxo- pyrrolidin-1-yl]-6-methyl-N-(3,4,5-trifluorophenyl)-6,7-dihydro-4H-pyrazolo[1,5- a]pyrazine-5-carboxamide (compound 40i)

The mixture of tert-butyl (6S)-3-[3-[tert-butyl(dimethyl)silyl]oxy-4-cyano-2-oxo- pyrrolidin-1-yl]-6-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate (compound 40h, 95 mg, 200 µmol), 2,2,2-trifluoroacetic acid (3.0 mL) and DCM (1.5 mL) was stirred at room temperature for 1 hour. The reaction mixture was concentrated, and the residue was dissolved in DMF (3 mL), to which were then added DIPEA (1.0 mL), phenyl (3,4,5- trifluorophenyl)carbamate (Intermediate I-4, 58.7 mg, 220 µmol). The reaction mixture was stirred at 50^oC for 1 hour, and then cooled down, directly purified by column chromatography to give compound 40i (95 mg). LCMS (M+H⁺): 549.

Step 5: preparation of (6S)-3-(3,4-trans-4-cyano-3-hydroxy-2-oxo-pyrrolidin-1-yl)-6- methyl-N-(3,4,5-trifluorophenyl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide (Example 40)

A mixture of (6S)-3-[3-[tert-butyl(dimethyl)silyl]oxy-4-cyano-2-oxo-pyrrolidin-1-yl]-6- methyl-N-(3,4,5-trifluorophenyl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide (compound 40i, 88 mg, 160 µmol) and tetrabutylammonium fluoride 1.0 M solution in tetrahydrofuran (1.0 mL) was stirred at room temperature for 2 hours. The reaction mixture was concentrated and the residue was purified by column chromatography to give Example 40 (40.0 mg). LCMS (M+H⁺): 435.¹H NMR (400MHz, METHANOL-d₄) δ = 7.66 (s, 1H), 7.33 - 7.24 (m, 2H), 5.12 - 4.93 (m, 2H), 4.75 - 4.70 (m, 1H), 4.59 - 4.43 (m, 1H), 4.30 (td, J=4.6, 12.8 Hz, 1H), 4.20 - 4.14 (m, 1H), 4.09 - 3.94 (m, 2H), 3.50 (dq, J=4.7, 9.2 Hz, 1H), 1.27 (dd, J=6.8, 16.1 Hz, 3H). Example 41

(6S)-3-(3,4-cis-4-cyano-3-hydroxy-2-oxo-pyrrolidin-1-yl)-6-methyl-N-(3,4,5- trifluorophenyl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide

The title compound was prepared in analogy to Example 40 by using tert-butyl (6S)-3- [3,4-cis-3-[tert-butyl(dimethyl)silyl]oxy-4-ethoxycarbonyl-2-oxo-pyrrolidin-1-yl]-6-methyl-6,7- dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate (Intermediate cis-I-40) instead of tert-butyl (6S)-3-[3,4-trans-3-[tert-butyl(dimethyl)silyl]oxy-4-ethoxycarbonyl-2-oxo-pyrrolidin-1-yl]-6- methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate (Intermediate trans-I-40).

Example 41 was obtained as a solid (9.7 mg). LCMS (M+H⁺): 435.¹H NMR (400MHz,

METHANOL-d₄) δ = 7.66 (s, 1H), 7.33 - 7.24 (m, 2H), 5.12 - 4.92 (m, 2H), 4.76 - 4.71 (m, 1H), 4.59 - 4.42 (m, 1H), 4.30 (td, J=4.6, 12.7 Hz, 1H), 4.21 - 4.13 (m, 1H), 4.09 - 3.95 (m, 2H), 3.50 (dq, J=5.0, 9.2 Hz, 1H), 1.30 - 1.22 (m, 3H). Example 42

(6S)-3-[(2S,3S)-3-cyano-2-methyl-5-oxo-pyrrolidin-1-yl]-N-[2-(difluoromethyl)-4-pyridyl]- 6-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide

The title compound was prepared according to the following scheme:

Step 1: preparation of tert-butyl (6S)-3-[(2S,3S)-3-carbamoyl-2-methyl-5-oxo- pyrrolidin-1-yl]-6-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate

(compound 42b)

To a solution of (2S,3S)-1-[(6S)-5-tert-butoxycarbonyl-6-methyl-6,7-dihydro-4H- pyrazolo[1,5-a]pyrazin-3-yl]-2-methyl-5-oxo-pyrrolidine-3-carboxylic acid (compound 38f, 193.0 mg, 0.51 mmol) in DCE (5.0 ml) was added ammonium chloride (81.8 mg, 1.53 mmol), N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (127.0 mg, 0.66 mmol), DIPEA (0.5 mL) and 1H-benzo[d][1,2,3]triazol-1-ol (20.7 mg, 0.15 mmol). The reaction mixture was stirred at 45^oC for 2 hours and then washed with ice-water, extracted with DCM twice. The combined organic phase was dried

filtered and concentrated to give compound 42b (173 mg, crude), which was used directly in next step. LCMS (M+H⁺): 378.

Step 2: preparation of tert-butyl (6S)-3-[(2S,3S)-3-cyano-2-methyl-5-oxo-pyrrolidin-1- yl]-6-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate (compound 42c)

To a solution of tert-butyl (6S)-3-[(2S,3S)-3-carbamoyl-2-methyl-5-oxo-pyrrolidin-1-yl]-6- methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate (compound 42b, 1.2 g, 3.18 mmol) in dry THF (8.0 mL) was added pyridine (1.2 ml, 14.8 mmol). The mixture was flushed with nitrogen and cooled to 0^oC, to which was then added dropwise of trifluoroacetic anhydride (1.2 mL, 8.59 mmol). The reaction mixture was stirred at 0^oC for another 3 hours. The reaction mixture was quenched by adding ice-water, extracted with EtOAc twice. The organic phase was dried over Na₂SO₄, concentrated. The residue was purified by column chromatography {eluting with 60% EtOAc (containing 10% MeOH) in petroleum ether} to afford compound 42c (670.0 mg). LCMS (M+H⁺): 360.

Step 3: preparation of (6S)-3-[(2S,3S)-3-cyano-2-methyl-5-oxo-pyrrolidin-1-yl]-N-[2- (difluoromethyl)-4-pyridyl]-6-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5- carboxamide (Example 42)

The mixture of tert-butyl (6S)-3-[(2S,3S)-3-cyano-2-methyl-5-oxo-pyrrolidin-1-yl]-6- methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate (compound 41c, 40.0 mg, 111 µmol), 2,2,2-trifluoroacetic acid (2.0 mL) and DCM (1.0 mL) was stirred at room temperature for 1 hour. The reaction mixture was concentrated, the residue was dissolved in DCE (3.0 mL), to which were then added DIPEA (0.5 mL), and phenyl N-[2-(difluoromethyl)-4- pyridyl]carbamate (Intermediate I-8, 44.1 mg, 167 µmol). The reaction mixture was stirred at 50^oC for 2 hours, then cooled down, washed with water, extracted with EtOAc three times. The combined organic layer was dried over Na₂SO₄ and concentrated under vacuum. The residue was purified by silica gel column and then preparative HPLC to give Example 42 (26.6 mg). LCMS (M+H⁺): 430.¹H NMR (400MHz, METHANOL-d₄) δ = 8.43 (d, J=5.7 Hz, 1H), 7.87 (d, J=2.1 Hz, 1H), 7.68 (dd, J=2.1, 5.7 Hz, 1H), 7.59 (s, 1H), 6.84 - 6.51 (m, 1H), 5.10 - 4.97 (m, 2H), 4.42 - 4.32 (m, 3H), 4.20 (dd, J=1.2, 12.8 Hz, 1H), 3.92 (td, J=7.0, 9.0 Hz, 1H), 3.04 - 2.88 (m, 2H), 1.43 (d, J=6.5 Hz, 3H), 1.25 (d, J=6.8 Hz, 3H). Example 43 (6S)-3-(3,3-difluoro-2-oxo-pyrrolidin-1-yl)-6-methyl-N-(3,4,5-trifluorophenyl)-6,7-dihydro- 4H-pyrazolo[1,5-a]pyrazine-5-carboxamide

The title compound was prepared according to the following scheme:

Step 1: Preparation of tert-butyl (6S)-3-(3,3-difluoro-2-oxo-pyrrolidin-1-yl)-6- methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate (compound 43a)

To a solution of tert-butyl (6S)-3-iodo-6-methyl-6,7-dihydro-4H-pyrazolo[1,5- a]pyrazine-5-carboxylate (Intermediate I-1, 300 mg, 826 µmol), K₃PO₄ (526 mg, 2.48 mmol), (1R,2R)-N1,N2-dimethylcyclohexane-1,2-diamine (47 mg, 330 µmol), CuI (31.5 mg, 165 µmol) in DMSO (10 mL) was added 3,3-difluoropyrrolidin-2-one (150 mg, 1.24 mmol) under argon. The mixture was stirred at 110 ^oC for 6h, then quenched with sat. aqueous solution of NH₄Cl and diluted with EtOAc. The organic layer was separated and washed with sat NH₄Cl and brine, dried over Na₂SO₄ and concentrated to give the crude compound 43a (280 mg) which was directly used in next step. LCMS (M+1): 357.

Step 2: Preparation of (6S)-3-(3,3-difluoro-2-oxo-pyrrolidin-1-yl)-6-methyl-N-(3,4,5- trifluorophenyl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide (Example 43) To a solution of tert-butyl (6S)-3-(3,3-difluoro-2-oxo-pyrrolidin-1-yl)-6-methyl-6,7- dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate (compound 43a, 280 mg, 786 µmol) in DCM (10 mL) was added TFA (3 mL). The mixture was stirred at room temperature for 30 mins, then solvent was removed under reduced pressure. The residue was dissolved in DCM (10 mL), to which were added DIEA (508 mg, 686 µL, 3.93 mmol), and phenyl (3,4,5- trifluorophenyl)carbamate (Intermediate I-4, 252 mg, 943 µmol). The mixture was stirred at room temperature overnight, and then concentrated. The residue was purified by prep-HPLC to give Example 43 (38 mg) as a white powder. LCMS (M+1): 430. ¹H NMR (400MHz,

METHANOL-d₄) δ ppm 7.75 (s, 1H), 7.28 (dd, J=6.4, 10.3 Hz, 2H), 5.09 (d, J=17.0 Hz, 1H), 5.02 - 4.92 (m, 1H), 4.56 (d, J=17.1 Hz, 1H), 4.38 - 4.27 (m, 1H), 4.19 (dd, J=1.0, 12.8 Hz, 1H), 4.02 - 3.85 (m, 2H), 2.77 (tt, J=6.7, 15.5 Hz, 2H), 1.28 (d, J=7.0 Hz, 3H). Example 44

(6S)-3-[(2S,3S,4R)-3-cyano-4-hydroxy-2-methyl-5-oxo-pyrrolidin-1-yl]-6-methyl-N-(3,4,5- trifluorophenyl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide

The title compound was prepared according to following scheme:

Preparation of O1-ethyl O4-methyl (2R,3S)-3-[1-[benzyl-[(1S)-1-phenylethyl]amino]ethyl]- 2-methyl-butanedioate (compound 44c)

To a stirring solution of methyl 3-[benzyl-[(1S)-1-phenylethyl]amino]butanoate

(compound 38b, 5.0 g, 16.1 mmol) in THF (100.0 mL) was added dropwise of LDA (24.1 mL, 48.2 mmol) at -78 ^oC. After being stirred for 1 hour, trimethyl borate (5.0 g, 48.2 mmol) was added and the mixture was stirred for another 30 minutes. Then a solution of ethyl 2-oxoacetate (3.3 g, 32.1 mmol) in THF (20 mL) was added dropwise at -78 ^oC, the temperature was maintained for 1 hour. The reaction was quenched by saturated aqueous ammonium chloride solution and extracted by EtOAc three times. The combined organic layer was dried over Na₂SO₄ and concentrated. The residue was purified by silica gel chromatography (eluting with 10% EtOAc in petroleum ether) to give compound 44c (3.6 g) as a yellow oil. LCMS (M+H⁺): 414.

Preparation of methyl (2S,3R,4R)-4-hydroxy-2-methyl-5-oxo-pyrrolidine-3-carboxylate (compound 44d)

To a solution of O1-ethyl O4-methyl (2R,3S)-3-[1-[benzyl-[(1S)-1- phenylethyl]amino]ethyl]-2-methyl-butanedioate (compound 44c, 4.8 g, 11.6 mmol) in MeOH (100.0 mL) was added palladium on carbon (0.5 g) in one portion under nitrogen. Then hydrogen (50 psi) was introduced to the system, the reaction mixture was stirred at room temperature for 16 hours, then filtered and the filtrate was concentrated. The residue was purified by silica gel chromatography (eluting with 5% methanol in dichloromethane) to give compound 44d (1.7 g). LCMS (M+H⁺): 174.

Preparation of methyl (2S,3R,4R)-4-[tert-butyl(dimethyl)silyl]oxy-2-methyl-5-oxo- pyrrolidine-3-carboxylate (compound 44e)

To a mixture of methyl (2S,3R,4R)-4-hydroxy-2-methyl-5-oxo-pyrrolidine-3-carboxylate (1.8 g, 10.4 mmol) and imidazole (1.4 g, 20.8 mmol) in DMF (20 mL) was added TBSCl (1.9 g, 12.5 mmol). The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with EtOAc (50 mL) and washed with brine (20 mL). The organic layer was dried over Na₂SO₄ and concentrated. The residue was purified by silica gel chromatograph (DCM: MeOH= 40:1) to give compound 44e (2.8 g, 93.3% yield) as colorless oil. LCMS (M+ H⁺): 288.2

Preparation of tert-butyl (6S)-3-[(2S,3R,4R)-4-[tert-butyl(dimethyl)silyl]oxy-3- methoxycarbonyl-2-methyl-5-oxo-pyrrolidin-1-yl]-6-methyl-6,7-dihydro-4H-pyrazolo[1,5- a]pyrazine-5-carboxylate (compound 44f) An oven-dried Schlenk tube were charged with (1R,2R)-N1,N2-dimethylcyclohexane-1,2- diamine (64.0 mg, 0.45 mmol), K₃PO₄ (959.5 mg, 4.52 mmol, 2.0 eq), CuI (85.7 mg, 0.45 mmol), (2S,3R,4R)-4-[tert-butyl(dimethyl)silyl]oxy-2-methyl-5-oxo-pyrrolidine-3-carboxylate

(compound 44e, 650.0 mg, 2.26 mmol), tert-butyl (6S)-3-iodo-6-methyl-6,7-dihydro-4H- pyrazolo[1,5-a]pyrazine-5-carboxylate (820.8 mg, 2.26 mmol, 1.0 eq) and toluene (15 mL). The mixture was stirred at 90 ^oC for 72 hours under N₂. The reaction mixture was filtered, and the filtrate was concentrated. The residue was purified by silica gel chromatograph (PE: EtOAc= 1: 1). To give compound 44f (177.5 mg, 15.0% yield) as a yellow oil. LCMS (M+H⁺) = 523.3, ¹H NMR (400MHz, DMSO-d6) δ = 7.45 (s, 1H), 4.83 (d, J=17.3 Hz, 1H), 4.75 - 4.60 (m, 2H), 4.25 - 4.12 (m, 2H), 4.11 - 3.98 (m, 2H), 3.62 (s, 3H), 3.57 (t, J=6.4 Hz, 1H), 1.45 (s, 9H), 1.06 (d, J=6.3 Hz, 3H), 1.01 (d, J=6.5 Hz, 3H), 0.86 (s, 9H), 0.13 (d, J=12.3 Hz, 6H)

Preparation of (6S)-3-[(2S,3S,4R)-3-cyano-4-hydroxy-2-methyl-5-oxo-pyrrolidin-1-yl]-6- methyl-N-(3,4,5-trifluorophenyl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide (Example 44)

The title compound was prepared in analogy to Example 40 by using tert-butyl (6S)-3- [(2S,3R,4R)-4-[tert-butyl(dimethyl)silyl]oxy-3-methoxycarbonyl-2-methyl-5-oxo-pyrrolidin-1- yl]-6-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate (compound 44f) instead of tert-butyl (6S)-3-[3,4-trans-3-[tert-butyl(dimethyl)silyl]oxy-4-ethoxycarbonyl-2-oxo-pyrrolidin- 1-yl]-6-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate (Intermediate trans-I-40. Example 44 was obtained as a solid (14.6 mg). LCMS (M+H⁺): 449.¹H NMR (400MHz, METHANOL-d₄) δ = 7.57 (s, 1H), 7.31 - 7.22 (m, 2H), 5.07 - 4.93 (m, 2H), 4.76 (d, J=9.8 Hz, 1H), 4.37 (d, J=16.9 Hz, 1H), 4.33 - 4.27 (m, 1H), 4.25 - 4.15 (m, 2H), 3.09 (t, J=9.5 Hz, 1H), 1.37 (d, J=6.2 Hz, 3H), 1.21 (d, J=6.8 Hz, 3H). Example 45

(6S)-3-[(2S,3S)-3-cyano-2-methyl-5-oxo-pyrrolidin-1-yl]-N-(2,6-difluoro-4-pyridyl)-6- methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide

The Example 45 was prepared in analogy to Example 42 by using phenyl N-(2,6-difluoro- 4-pyridyl)carbamate (Intermediate I-9) instead of phenyl N-[2-(difluoromethyl)-4- pyridyl]carbamate (Intermediate I-8). Example 52 (50 mg) was obtained as white solid. LCMS (M+H)⁺: 416.2, ¹H NMR (400MHz, METHANOL-d₄) δ ppm 7.59 (s, 1H), 7.11 (s, 2H), 5.12 - 4.93 (m, 2H), 4.45 - 4.30 (m, 3H), 4.20 (dd, J=1.3, 12.9 Hz, 1H), 3.91 (td, J=6.9, 9.0 Hz, 1H), 3.06 - 2.85 (m, 2H), 1.42 (d, J=6.5 Hz, 3H), 1.25 (d, J=6.8 Hz, 3H). Example 47

(6S)-3-[(5S)-3-hydroxy-5-methyl-2-oxo-pyrrolidin-1-yl]-6-methyl-N-(3,4,5-trifluorophenyl)- 6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide

The title compound was prepared according to the following scheme:

Step 1: preparation of ethyl 4-[(S)-tert-butylsulfinyl]iminopentanoate (compound 47b) A mixture of 5-methyl-3H-furan-2-one (compound 47a, 2.0 g, 20.4 mmol), (S)-2- methylpropane-2-sulfinamide (2.7 g, 22.4 mmol), EtOH (940.0 mg, 20.4 mmol) and Ti(OEt)₄ (9.3 g, 40.8 mmol) in THF (150.0 mL) was stirred at 60 ^oC for 16 hours under N₂. The reaction was quenched with saturated aqueous NaHCO3 (60.0 mL) and then filtered. The filtrate was extracted with EtOAc (40 mL) three times. The organic layer was concentrated, and the residue was purified by column chromatography (PE: EtOAc=5: 1~2: 1) to give compound 47b (3.3 g) as yellow oil. LCMS (M+H⁺): 248.3.

Step 2: preparation of ethyl (4S)-4-[[(S)-tert-butylsulfinyl]amino]pentanoate

(compound 47c)

To a solution of ethyl (4Z)-4-[(S)-tert-butylsulfinyl]iminopentanoate (compound 47b, 3.3 g, 13.3 mmol) in THF (60 mL) was added L-selectride (16 mL, 16.0 mmol) dropwise at -78 ^oC under N₂. Then the mixture was stirred at -78 ^oC for 6 hours. The reaction was quenched with saturated aqueous NaHCO₃ (50 mL) and filtered. The filtrate was diluted with water (40 mL) and extracted with EtOAc (30 mL) three times. The organic layer was concentrated, and the residue was purified by column chromatography (PE: EtOAc=5: 1~1: 1) to give compound 47c (1.0 g) as yellow oil.

Step 3: preparation of (5S)-5-methylpyrrolidin-2-one (compound 47d)

To a solution of ethyl (4S)-4-[[(S)-tert-butylsulfinyl]amino]pentanoate (compound 47c, 1.0 g, 4.0 mmol) in THF (15 mL) was added 1 N HCl (10 mL). The mixture was stirred at room temperature for 16 hours. The reaction was basified to pH=12 with saturated aqueous K₂CO₃ and then washed with EtOAc (10 mL) three times. The aqueous layer was concentrated to dryness. The residue was suspended in THF (50 mL) and filtered. The filtrate was concentrated to give compound 47d (200 mg) as a light yellow oil.

Step 4: preparation of tert-butyl (6S)-6-methyl-3-[(2S)-2-methyl-5-oxo-pyrrolidin-1- yl]-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate (compound 47e)

A mixture of (5S)-5-methylpyrrolidin-2-one (compound 47d, 70.0 mg, 0.7 mmol), tert-butyl (6S)-3-iodo-6-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate (Intermediate I-1, 254.2 mg, 0.7 mmol), (1R,2R)-N1,N2-dimethylcyclohexane-1,2-diamine (10.0 mg, 0.07 mmol), CuI (13.3 mg, 0.07 mmol) and K₃PO₄ (297.0 mg, 1.4 mmol) in dioxane (3 mL) was stirred at 100 ^oC for 16 hours under N₂. The reaction solution was filtered, and the filtrate was

concentrated. The residue was purified by prep-TLC to give compound 47e (60.0 mg), LCMS (M+H⁺): 335.2 Step 5: preparation of tert-butyl (6S)-3-[(5S)-3-hydroxy-5-methyl-2-oxo-pyrrolidin-1- yl]-6-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate (compound 47f)

To a solution of tert-butyl (6S)-6-methyl-3-[(2S)-2-methyl-5-oxo-pyrrolidin-1-yl]-6,7- dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate (compound 47e, 40.0 mg, 0.12 mmol) in THF (2 mL) was added LiHMDS (0.48 mL, 0.48 mmol) dropwise at -78 ^oC under N2. The mixture was stirred at -78 ^oC for 30 mins. A solution of 2-(phenylsulfonyl)-3-phenyl- oxaziridine( Davis reagent, 48.0 mg, 0.18 mmol) in THF (1 mL) was added dropwise. The resulting mixture was stirred at -78 ^oC-20 ^oC for 16 hours. The reaction was quenched with water (0.5 mL) and then concentrated, the residue was purified by prep-TLC (EtOAc as the eluent) to give compound 47f (25.0 mg) as a yellow oil. LCMS (M+H⁺): 351.1.

Step 6: preparation of (6S)-3-[(5S)-3-hydroxy-5-methyl-2-oxo-pyrrolidin-1-yl]-6- methyl-N-(3,4,5-trifluorophenyl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide (Example 47)

To a solution of tert-butyl (6S)-3-[(5S)-3-hydroxy-5-methyl-2-oxo-pyrrolidin-1-yl]-6- methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate (compound 47f, 40.0 mg, 0.11 mmol) in DCM (2.0 mL) was added HCl/dioxane (0.5 mL, 2.0 mmol). The mixture was stirred at room temperature for 1h, and then concentrated to a yellow solid (30.0 mg, crude). The crude solid (27.5 mg, 0.11 mmol) was dissolved in DMF (2 mL), to which were added Et₃N (33.0 mg, 0.33 mmol) and phenyl N-(3,4,5-trifluorophenyl)carbamate (30.0 mg, 0.11 mmol). The mixture was stirred at room temperature for 2 hours, and then filtered. The filtrate was purified by prep- HPLC to give (6S)-3-[(5S)-3-hydroxy-5-methyl-2-oxo-pyrrolidin-1-yl]-6-methyl-N-(3,4,5- trifluorophenyl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide (20.0 mg, 42.9%) as a white solid. The product was further separated by SFC to give two isomers: Example 47-1 and Example 47-2.

Example 47-1 (7.1 mg), white solid; LCMS (M+H⁺): 424.1, ¹H NMR: (400MHz, MeOD) δ ppm 7.60 (s, 1H), 7.28 - 7.25 (m, 2H), 5.01 - 4.94 (m, 1H), 4.85 (d, J=17.1 Hz, 1H), 4.56 - 4.42 (m, 2H), 4.33 - 4.25 (m, 1H), 4.20 - 4.09 (m, 2H), 2.35 - 2.18 (m, 2H), 1.28 (d, J=7.0 Hz, 3H), 1.24 (d, J=6.3 Hz, 3H).

Example 47-2 (1.8 mg), white solid; LCMS (M+H⁺): 424.1, ¹H NMR: (400MHz, MeOD) δ ppm 7.58 (s, 1H), 7.37 - 7.25 (m, 2H), 5.03-4.95 (m, 1H), 4.60 - 4.48 (m, 2H), 4.38 - 4.26 (m, 2H), 4.21 - 4.07 (m, 2H), 2.32 - 2.20 (m, 2H), 1.25 (d, J=6.6 Hz, 3H), 1.21 (d, J=6.8 Hz, 3H). Example 49 (6S)-6-methyl-3-(5-oxo-4-azaspiro[2.4]heptan-4-yl)-N-(3,4,5-trifluorophenyl)-6,7-dihydro- 4H-pyrazolo[1,5-a]pyrazine-5-carboxamide

The title compound was prepared in analogy to the preparation of Example 43 by using 4-azaspiro[2.4]heptan-5-one instead of 3,3-difluoropyrrolidin-2-one. Example 49 was obtained as a a white solid (32 mg). LCMS (M+1): 420.¹H NMR (400MHz, METHANOL-d₄) δ ppm 7.44 (s, 1H), 7.29 (dd, J=6.4, 10.3 Hz, 2H), 5.01 - 4.92 (m, 1H), 4.84 (d, J=17.0 Hz, 1H), 4.33 (d, J=17.0 Hz, 1H), 4.34 - 4.28 (m, 1H), 4.22 - 4.07 (m, 1H), 2.78 - 2.62 (m, 2H), 2.41 - 2.25 (m, 2H), 1.24 (d, J=6.8 Hz, 3H), 0.72 (m, 4H). Example 50

(6S)-6-methyl-3-[(2S)-2-(methylcarbamoyl)-5-oxo-pyrrolidin-1-yl]-N-(3,4,5- trifluorophenyl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide

The title compound was prepared according to the following scheme:

Preparation of methyl (2S)-1-[(6S)-6-methyl-5-[(3,4,5-trifluorophenyl)carbamoyl]-6,7- dihydro-4H-pyrazolo[1,5-a]pyrazin-3-yl]-5-oxo-pyrrolidine-2-carboxylate (compound 50b) Compound 50b was prepared in analogy to the preparation of Example 43 by using methyl (2S)-5-oxopyrrolidine-2-carboxylate instead of 3,3-difluoropyrrolidin-2-one. Crude compound 50b (350 mg) was obtained, 100mg of which was purified by prep-HPLC to give compound 50b (35 mg) as a white powder. LCMS (M+1): 452.

Preparation of (2S)-1-[(6S)-6-methyl-5-[(3,4,5-trifluorophenyl)carbamoyl]-6,7-dihydro-4H- pyrazolo[1,5-a]pyrazin-3-yl]-5-oxo-pyrrolidine-2-carboxylic acid (compound 50c)

To the solution of methyl (2S)-1-[(6S)-6-methyl-5-[(3,4,5-trifluorophenyl)carbamoyl]-6,7- dihydro-4H-pyrazolo[1,5-a]pyrazin-3-yl]-5-oxo-pyrrolidine-2-carboxylate (compound 50b, 250 mg crude, 554 µmol) in THF (5 mL) was added aq. LiOH solution (0.5 M, 5 mL). The mixture was stirred at room temperature overnight, then neutralized with aq. HCl and concentrated. The residue was purified by prep-HPLC to give compound 50c (110 mg) as a white powder. LCMS (M+1): 438.

Preparation of (6S)-6-methyl-3-[(2S)-2-(methylcarbamoyl)-5-oxo-pyrrolidin-1-yl]-N-(3,4,5- trifluorophenyl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide (Example 50) To a solution of (2S)-1-[(6S)-6-methyl-5-[(3,4,5-trifluorophenyl)carbamoyl]-6,7-dihydro- 4H-pyrazolo[1,5-a]pyrazin-3-yl]-5-oxo-pyrrolidine-2-carboxylic acid (compound 50c, 20 mg, 45.7 µmol), methylamine hydrochloride (6.17 mg, 91.5 µmol) in DCM (5 mL) was added DIEA (17.7 mg, 24 µl, 137 µmol) and HATU (34.8 mg, 91.5 µmol). The resulting mixture was stirred overnight at room temperature, and then concentrated. The residue was purified by prep-HPLC to give Example 50 (6 mg) as a white powder. LCMS (M+1): 451.¹H NMR (400MHz,

METHANOL-d₄) δ ppm 7.51 (s, 1H), 7.32 (dd, J=6.4, 10.3 Hz, 2H), 4.99 (d, J=17.1 Hz, 1H), 5.03 - 4.95 (m, 1H), 4.56 (dd, J=3.7, 8.3 Hz, 1H), 4.50 (d, J=17.0 Hz, 1H), 4.27 (dd, J=4.5, 12.5 Hz, 1H), 4.16 - 4.08 (m, 1H), 2.73 - 2.65 (m, 1H), 2.69 (s, 3H), 2.61 - 2.47 (m, 2H), 2.19 - 2.09 (m, 1H), 1.29 (d, J=7.0 Hz, 3H). Example 51

(6S)-6-methyl-3-[(2S,3S)-2-methyl-5-oxo-3-pyrimidin-2-yloxy-pyrrolidin-1-yl]-N-(3,4,5- trifluorophenyl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide

The tittle compound was prepared according to following scheme:

To a microwave vial was added (6S)-3-[(2S,3S)-3-hydroxy-2-methyl-5-oxo-pyrrolidin-1- yl]-6-methyl-N-(3,4,5-trifluorophenyl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide (Example 37, 151.0 mg, 1.06 mmol) and sodium carbonate (67.6 mg, 638 µmol) in dioxane (8 mL). The vial was capped and heated to 110 °C for 3hours. The reaction mixture was cooled down, washed with ice-water, extracted with EtOAc twice. The combined organic phase was concentrated and the residue was purified by prep-HPLC to give Example 51 (29.7 mg). LCMS (M+H⁺): 502.¹H NMR (400MHz, METHANOL-d₄) δ = 8.64 (d, J=4.8 Hz, 2H), 7.59 (s, 1H), 7.34 - 7.26 (m, 2H), 7.19 (t, J=4.9 Hz, 1H), 5.92 - 5.87 (m, 1H), 5.06 - 4.97 (m, 2H), 4.59 - 4.49 (m, 1H), 4.43 (d, J=16.8 Hz, 1H), 4.34 (dd, J=4.3, 12.8 Hz, 1H), 4.19 (dd, J=1.3, 12.8 Hz, 1H), 3.13 (dd, J=6.5, 17.7 Hz, 1H), 2.73 (dd, J=3.1, 17.6 Hz, 1H), 1.26 (d, J=6.7 Hz, 3H), 1.23 (d, J=6.8 Hz, 3H). Example 53

tert-butyl 6-[(6S)-5-[[2-(difluoromethyl)-4-pyridyl]carbamoyl]-6-methyl-6,7-dihydro-4H- pyrazolo[1,5-a]pyrazin-3-yl]-7-oxo-2,6-diazaspiro[3.4]octane-2-carboxylate

The title compound was prepared according to the following scheme:

Step 1: preparation of tert-butyl 6-[(6S)-6-methyl-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrazin-3-yl]-7-oxo-2,6-diazaspiro[3.4]octane-2-carboxylate (compound 53b)

To a solution of tert-butyl 6-oxo-2,7-diazaspiro[3.4]octane-2-carboxylate (271.5 mg, 1.2 mmol) in dioxane (15 mL) were added (6S)-3-iodo-6-methyl-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrazine(Intermediate I-1-1, 263.0 mg, 1.0 mmol), (1R,2R)-N1,N2-dimethylcyclohexane-1,2- diamine (14.2 mg, 0.1 mmol), K₃PO₄ (637.0 mg, 3.0 mmol) and CuI (19.0 mg, 0.1 mmol) under N₂, and the mixture was stirred at room temperature for 12 hours and then filtered and concentrated under reduced pressure, the residue was purified by column chromatograph on silica gel (DCM/MeOH=50/1 to 20/1) to give compound 53b (200 mg) as a white oil. LCMS (M+H⁺): 362.

Step 2: preparation of tert-butyl 6-[(6S)-5-[(3-chloro-4-fluoro-phenyl)carbamoyl]-6- methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-3-yl]-7-oxo-2,6-diazaspiro[3.4]octane-2- carboxylate (Example 53)

To a solution of tert-butyl 6-[(6S)-6-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl]- 7-oxo-2,6-diazaspiro[3.4]octane-2-carboxylate (compound 53b, 150 mg, 332 µmol) and DIPEA (290 µl, 1.66 mmol) in DCE (5 mL) was added phenyl (2-(difluoromethyl)pyridin-4- yl)carbamate (105 mg, 398 µmol) at 20 °C, and then the mixture was stirred at 60 °C for 1 hour. The crude reaction mixture was concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 12 g, 10% to 80% EtOAc in hexanes, EtOAc contain 10% MeOH) to give Example 53 (53 mg) as a white solid. LCMS (M+H⁺): 532.2.¹H NMR (400MHz,

METHANOL-d₄) δ ppm 8.43 (d, J=5.7 Hz, 1H), 7.87 (d, J=2.1 Hz, 1H), 7.73 - 7.61 (m, 2H), 6.67 (d, J=56.0 Hz, 1H), 5.09 (d, J=17.0 Hz, 1H), 5.02 - 4.96 (m, 1H), 4.55 (d, J=17.0 Hz, 1H), 4.32 (dd, J=4.4, 12.8 Hz, 1H), 4.17 (dd, J=1.1, 12.8 Hz, 1H), 4.12 - 3.98 (m, 6H), 2.88 (s, 2H), 1.47 (s, 9H), 1.29 (d, J=6.8 Hz, 3H). Example 54

(6S)-3-(4-cyano-2-oxo-pyrrolidin-1-yl)-N-(2,6-difluoro-4-pyridyl)-6-methyl-6,7-dihydro-4H- pyrazolo[1,5-a]pyrazine-5-carboxamide

The title compound was prepared according to the following scheme:

Step 1: preparation of tert-butyl (6S)-3-(4-methoxycarbonyl-2-oxo-pyrrolidin-1-yl)-6- methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate (compound 54a ) A mixture of tert-butyl (6S)-3-iodo-6-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5- carboxylate (Intermediate I-1, 364 mg, 1.0 mmol), methyl 5-oxopyrrolidine-3-carboxylate (286 mg, 2.0 mmol), (1S,2S)-cyclohexane-1,2-diamine (46 mg, 0.4 mmol), CuI (38 mg, 0.2 mmol) and K₃PO₄ (636 mg, 3 mmol) in DMSO (10 mL) under N₂ was stirred at microwave for 2 hours at room temperature. The reaction mixture was diluted with EtOAc (20 mL) and washed with water and brine. The organic layer was concentrated to afford compound 54a (200 mg) as a slight yellow oil. LCMS (M+H⁺): 379.

Step 2: preparation of 1-[(6S)-5-tert-butoxycarbonyl-6-methyl-6,7-dihydro-4H- pyrazolo[1,5-a]pyrazin-3-yl]-5-oxo-pyrrolidine-3-carboxylic acid (compound 54b )

A mixture of tert-butyl (6S)-3-(4-methoxycarbonyl-2-oxo-pyrrolidin-1-yl)-6-methyl-6,7- dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate (compound 54a, 200 mg,0.53 mmol ) and LiOH·H₂O (110 mg, 2.62 mmol) in THF/H₂O (10 mL, 5:1) was stirred at room temperature for 2 hours. Then the reaction was adjusted to pH = 4, extracted with DCM (20 mL) two times, the organic layer was dried and concentrated to compound 54b (183 mg) as slight yellow solid LCMS (M+H⁺): 365.

Step 3: preparation of tert-butyl (6S)-3-(4-carbamoyl-2-oxo-pyrrolidin-1-yl)-6- methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate (compound 54c )

A mixture of 1-[(6S)-5-tert-butoxycarbonyl-6-methyl-6,7-dihydro-4H-pyrazolo[1,5- a]pyrazin-3-yl]-5-oxo-pyrrolidine-3-carboxylic acid (compound 54b, 183 mg, 0.5 mmol), HATU (210 mg, 0.6 mmol), NH₄Cl (138 mg, 2.5 mmol) and DIPEA (770 mg, 6 mmol) in THF (10 mL) was stirred at 60 ^oC for 2 hours. The reaction mixture was diluted with hydrochloride acid (0.5 M, 15 mL), and extracted with EtOAc (20 mL) twice. The organic layer was concentrated to afford compound 54c (150 mg) as a slight yellow solid. LCMS (M+H⁺): 364.

Step 4: preparation of tert-butyl (6S)-3-(4-cyano-2-oxo-pyrrolidin-1-yl)-6-methyl-6,7- dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate (compound 54d )

To a solution of tert-butyl (6S)-3-(4-carbamoyl-2-oxo-pyrrolidin-1-yl)-6-methyl-6,7- dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate (compound 54c, 150 mg, 0.41 mmol) in dry tetrahydrofuran (5.0 mL) at 0 ^oC under nitrogen was added pyridine (0.5 mL, 6.2 mmol) followed by dropwise addition of a solution of trifluoroacetic anhydride (0.5 mL, 3.5 mmol) in dry tetrahydrofuran (1.0 mL). The resulting reaction mixture was allowed to warm slowly to room temperature, and stirred overnight, then quenched with ice-water, and extracted with EtOAc (20 mL) twice. The organic layer was concentrated to afford compound 54d (138 mg) as a slight yellow solid. LCMS (M+H⁺): 346. Step 5: preparation of (6S)-3-(4-cyano-2-oxo-pyrrolidin-1-yl)-N-(2,6-difluoro-4- pyridyl)-6-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide (Example 54) A mixture of tert-butyl (6S)-3-(4-cyano-2-oxo-pyrrolidin-1-yl)-6-methyl-6,7-dihydro-4H- pyrazolo[1,5-a]pyrazine-5-carboxylate (compound 54d, 200 mg, 579 µmol) and 2,2,2- trifluoroacetic acid (446 µL, 5.79 mmol) in isopropyl acetate (1 mL) was stirred at 70 ^oC for 2 hours. The reaction mixture was concentrated to remove most of the TFA, the residue was dissolved in isopropyl acetate (1 mL), then added DIPEA (374 mg, 2.9 mmol) and phenyl (2,6- difluoropyridin-4-yl)carbamate (Intermediate I-9, 174 mg, 695 µmol). The reaction mixture was stirred at 70 ^oC for 1 hour. The reaction mixture was concentrated in vacuo and the residue was purified by flash chromatography (silica gel, 40 g, 10% to 70% EtOAc in hexanes, EtOAc contain 10% MeOH), and then by SFC to give Example 54 as two isomers, Example 54-1 and Example 54-2.

Example 54-1, 70 mg, white solid. LCMS (M+H⁺): 402.1.¹H NMR (400MHz,

METHANOL-d₄) δ ppm 7.65 (s, 1H), 7.10 (s, 2H), 5.09 (d, J=17.1 Hz, 1H), 5.04 - 4.94 (m, 1H), 4.53 (d, J=17.0 Hz, 1H), 4.32 (dd, J=4.5, 12.8 Hz, 1H), 4.24 - 4.14 (m, 2H), 4.05 (dd, J=6.1, 9.8 Hz, 1H), 3.84 - 3.72 (m, 1H), 3.05 - 2.94 (m, 1H), 2.93 - 2.83 (m, 1H), 1.29 (d, J=7.0 Hz, 3H).

Example 54-2, 70 mg, white solid. LCMS (M+H⁺): 402.1.¹H NMR (400MHz, DMSO-d₆) δ ppm 9.77 (s, 1H), 7.62 (s, 1H), 7.16 (s, 2H), 4.99 (d, J=17.2 Hz, 1H), 4.91 - 4.81 (m, 1H), 4.42 (d, J=17.1 Hz, 1H), 4.31 - 3.96 (m, 4H), 3.81 (quin, J=7.9 Hz, 1H), 2.96 - 2.70 (m, 2H), 1.16 (d, J=6.7 Hz, 3H). Example 56

(6S)-N-(2,6-difluoro-4-pyridyl)-6-methyl-3-[(2S,3S)-2-methyl-5-oxo-3-pyrimidin-2-yloxy- pyrrolidin-1-yl]-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide

The title compound was prepared according to the following scheme:

Step 1: preparation of tert-butyl (6S)-6-methyl-3-[(2S,3S)-2-methyl-5-oxo-3- pyrimidin-2-yloxy-pyrrolidin-1-yl]-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate (compound 56a)

A mixture of tert-butyl (6S)-3-[(2S,3S)-3-hydroxy-2-methyl-5-oxo-pyrrolidin-1-yl]-6- methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate (compound 37f, 70 mg, 200 µmol), 2-(methylsulfinyl)pyrimidine (56.8 mg, 400 µmol) and sodium carbonate (63.5 mg, 599 µmol,) in dioxane (2 mL) was heated at 110 ºC for16 hours. The crude reaction mixture was concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 12 g, 20% to 80% EtOAc in hexanes, EtOAc contain 10% MeOH) to give compound 56a (50 mg) as light yellow oil, LCMS (M+H⁺): 429.2.

Step 2: preparation of (6S)-N-(2,6-difluoro-4-pyridyl)-6-methyl-3-[(2S,3S)-2-methyl-5- oxo-3-pyrimidin-2-yloxy-pyrrolidin-1-yl]-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5- carboxamide (Example 56)

A mixture of (S)-tert-butyl 6-methyl-3-((2S,3S)-2-methyl-5-oxo-3-(pyrimidin-2- yloxy)pyrrolidin-1-yl)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate (compound 56a, 20 mg, 46.7 µmol) and 2,2,2-trifluoroacetic acid (121 µl) in DCM (2 mL) was stirred at room temperature for 30 minutes. The reaction mixture was concentrated, the residue was dissolved in DMF (2 mL), to which were then added DIPEA (30.2 mg, 233 µmol) and phenyl (2,6- difluoropyridin-4-yl)carbamate (Intermediate I-9, 14 mg, 56 µmol). The reaction mixture was stirred at 60 ^oC for 1 hour. The reaction mixture was purified by prep-HPLC to give Example 56 (7 mg) as white solid. LCMS (M+H⁺): 485.2.¹H NMR (400MHz, METHANOL-d₄) δ ppm 8.65 (d, J=4.9 Hz, 2H), 7.60 (s, 1H), 7.19 (t, J=4.8 Hz, 1H), 7.13 (s, 2H), 5.94 - 5.85 (m, 1H), 5.13 - 5.00 (m, 2H), 4.54 (dd, J=5.4, 6.6 Hz, 1H), 4.47 (d, J=16.9 Hz, 1H), 4.36 (dd, J=4.2, 12.8 Hz, 1H), 4.21 (dd, J=1.3, 12.8 Hz, 1H), 3.14 (dd, J=6.5, 17.7 Hz, 1H), 2.73 (dd, J=3.0, 17.7 Hz, 1H), 1.26 (d, J=6.7 Hz, 3H), 1.24 (d, J=6.7 Hz, 3H). Example 57

(6S)-N-[2-(difluoromethyl)-4-pyridyl]-6-methyl-3-[(2S,3S)-2-methyl-5-oxo-3-pyrimidin-2- yloxy-pyrrolidin-1-yl]-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide

A mixture of (S)-tert-butyl 6-methyl-3-((2S,3S)-2-methyl-5-oxo-3-(pyrimidin-2- yloxy)pyrrolidin-1-yl)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate (compound 56a, 20 mg, 46.7 µmol) and 2,2,2-trifluoroacetic acid (121 µL) in DCM (2 mL) was stirred at room temperature for 30 mins. The reaction mixture was concentrated, the residue was dissolved in DMF (2 mL), to which were then then added DIPEA (30.2 mg, 233 µmol) and phenyl (2,6- difluoropyridin-4-yl)carbamate (Intermediate I-8, 14.8 mg, 56 µmol). The reaction mixture was stirred at 60 ^oC for 1 hour. The reaction mixture was purified by prep-HPLC to give Example 57 (7 mg) as a white solid. LCMS (M+H⁺): 499.2, ¹H NMR (400MHz, METHANOL-d₄) δ ppm 8.53 (d, J=4.9 Hz, 2H), 8.31 (d, J=5.7 Hz, 1H), 7.77 (d, J=2.2 Hz, 1H), 7.58 (dd, J=2.1, 5.7 Hz, 1H), 7.48 (s, 1H), 7.07 (t, J=4.8 Hz, 1H), 6.74 - 6.37 (m, 1H), 5.83 - 5.70 (m, 1H), 5.05 - 4.85 (m, 2H), 4.52 - 4.33 (m, 2H), 4.25 (dd, J=4.3, 12.8 Hz, 1H), 4.09 (d, J=12.8 Hz, 1H), 3.02 (dd, J=6.5, 17.7 Hz, 1H), 2.62 (dd, J=3.1, 17.7 Hz, 1H), 1.15 (d, J=6.7 Hz, 3H), 1.13 (d, J=6.7 Hz, 3H). Example 62

(6S)-3-(4-cyano-4-methyl-2-oxo-pyrrolidin-1-yl)-N-(2,6-difluoro-4-pyridyl)-6-methyl-6,7- dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide

The title compound was prepared according to the following scheme:

Preparation of dimethyl 2-cyano-2-methyl-butanedioate (compound 62b)

To a solution of dimethyl 2-cyanobutanedioate (compound 62a, 513 mg, 3 mmol) in acetone (5 mL) was added iodomethane (639 mg, 4.5 mmol) and potassium carbonate (829 mg, 6 mmol). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was extracted with EtOAc twice, washed with water. The combined organic phase was dried over Na₂SO₄, filtrated and concentrated to give compound 62b (556 mg, crude). LCMS (M+H⁺): 186.

Preparation of methyl 3-methyl-5-oxo-pyrrolidine-3-carboxylate (compound 62c)

To a suspension of Raney nickel (85.7 mg, 1.0 mmol) (pre-washed with methanol) in solvent MeOH (10 mL) was added dimethyl 2-cyano-2-methyl-butanedioate (compound 46b, 185.0 mg, 1.0 mmol) in MeOH (5 mL). The reaction mixture was heated at 40 ^oC under 1 atmosphere of H₂ overnight. The reaction mixture was filtered and concentrated to give compound 62c (157.1 mg, crude). LCMS (M+H⁺): 158.

Preparation of (6S)-3-(4-cyano-4-methyl-2-oxo-pyrrolidin-1-yl)-N-(2,6-difluoro-4-pyridyl)- 6-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide (Example 62)

The title compound was prepared in analogy to Example 54 by using methyl 3-methyl-5- oxo-pyrrolidine-3-carboxylate (compound 62c) instead of methyl 5-oxopyrrolidine-3- carboxylate. Example 62 was obtained as a solid (25.0 mg). LCMS (M+H⁺): 416. ¹H NMR (400MHz, METHANOL-d₄) δ = 7.64 (s, 1H), 7.10 (s, 2H), 5.16 - 5.04 (m, 1H), 5.02 - 4.93 (m, 1H), 4.60 - 4.50 (m, 1H), 4.32 (dd, J=4.4, 12.7 Hz, 1H), 4.26 - 4.15 (m, 2H), 3.93 - 3.85 (m, 1H), 3.13 - 3.05 (m, 1H), 2.79 - 2.72 (m, 1H), 1.69 (s, 3H), 1.29 (d, J=6.8 Hz, 3H). Example 63

(6S)-3-(4-cyano-4-methyl-2-oxo-pyrrolidin-1-yl)-N-[2-(difluoromethyl)-4-pyridyl]-6- methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide

The title compound was prepared in analogy to Example 62 by using phenyl N-(2- difluoromethyl-4-pyridyl)carbamate (Intermediate I-8) instead of phenyl N-(2,6-difluoro-4- pyridyl)carbamate (Intermediate I-9). Example 62 (35 mg) was obtained. LCMS (M+H⁺): 430. ¹H NMR (400MHz, METHANOL-d₄) δ = 8.42 (d, J=5.6 Hz, 1H), 7.87 (s, 1H), 7.70 - 7.63 (m, 2H), 6.67 (t, J=56 Hz, 1H), 5.13 (d, J=8.0 Hz, 0.5H), .5.09 (d, J=8.0 Hz, 0.5H), 5.05 - 4.96 (m, 1H), 4.58 (d, J=8.0 Hz, 0.5H), 4.54 (d, J=8.0 Hz, 0.5H), 4.33 (dd, J=4.5, 12.8 Hz, 1H), 4.27 - 4.15 (m, 2H), 3.93 - 3.84 (m, 1H), 3.13 - 3.05 (m, 1H), 2.79 - 2.71 (m, 1H), 1.69 (s, 3H), 1.30 (d, J=6.8 Hz, 3H). Example 64

tert-butyl 6-[(6S)-5-[(2,6-difluoro-4-pyridyl)carbamoyl]-6-methyl-6,7-dihydro-4H- pyrazolo[1,5-a]pyrazin-3-yl]-7-oxo-2,6-diazaspiro[3.4]octane-2-carboxylate

The Example 64 was prepared in analogy to Example 53 by using phenyl N-(2,6-difluoro- 4-pyridyl)carbamate (Intermediate I-9) instead of phenyl N-[2-(difluoromethyl)-4- pyridyl]carbamate (Intermediate I-8). Example 64 (60 mg) was obtained as a white solid. LCMS (M+H)⁺: 518.2, ¹H NMR (400MHz, METHANOL-d₄) δ ppm 7.64 (s, 1H), 7.10 (s, 2H), 5.07 (d, J=17.0 Hz, 1H), 5.03 - 4.94 (m, 1H), 4.53 (d, J=17.0 Hz, 1H), 4.31 (dd, J=4.4, 12.8 Hz, 1H), 4.17 (dd, J=1.2, 12.8 Hz, 1H), 4.10 - 4.00 (m, 6H), 2.87 (s, 2H), 1.47 (s, 9H), 1.29 (d, J=6.8 Hz, 3H). Example 65

(6S,7S)-3-(4-cyano-2-oxo-pyrrolidin-1-yl)-6,7-dimethyl-N-(3,4,5-trifluorophenyl)-6,7- dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide

The Example 65 and 66 was prepared in analogy to Example 54 by using tert-butyl (6S,7S)-3-iodo-6,7-dimethyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate

(intermediate I-2) instead of tert-butyl (6S)-3-iodo-6-methyl-6,7-dihydro-4H-pyrazolo[1,5- a]pyrazine-5-carboxylate (intermediate I-1) and phenyl N-(3,4,5-trifluorophenyl)carbamate (intermediate I-4) instead of phenyl N-(2,6-difluoro-4-pyridyl)carbamate (intermediate I-9). Separation of the final product by SFC (chiral column, chiralpak® IC, 5 µm, 30 × 250 mm; mobile phase, 60% CO2 and 40% MeOH (MeOH+0.5% NH3H2O); flow rate 80 mL/min, back pressure 100 bar) gave Example 65 as two isomers, Example 65-1 and Example 65-2.

Example 65-1 was obtained (60 mg) as white solid. LCMS (M+H)⁺: 433.2, ¹H NMR (400MHz, METHANOL-d₄) δ ppm 7.66 (s, 1H), 7.32 - 7.28 (m, 2H), 5.06 (d, J=17.0 Hz, 1H), 4.76 (q, J=6.5 Hz, 1H), 4.49 (d, J=17.0 Hz, 1H), 4.43 - 4.33 (m, 1H), 4.20 - 4.04 (m, 2H), 3.77 (td, J=7.8, 15.6 Hz, 1H), 3.04 - 2.94 (m, 1H), 2.93 - 2.83 (m, 1H), 1.45 (d, J=6.6 Hz, 3H), 1.25 (d, J=6.8 Hz, 3H).

Example 65-2 was obtained (60 mg) as white solid. LCMS (M+H)⁺: 433.2, ¹H NMR (400MHz, METHANOL-d₄) δ ppm 7.66 (s, 1H), 7.38 - 7.24 (m, 2H), 5.07 (d, J=16.9 Hz, 1H), 4.77 (q, J=6.7 Hz, 1H), 4.49 (d, J=16.9 Hz, 1H), 4.38 (q, J=6.9 Hz, 1H), 4.18 (dd, J=8.3, 9.8 Hz, 1H), 4.05 (dd, J=6.2, 9.8 Hz, 1H), 3.85 - 3.71 (m, 1H), 3.05 - 2.94 (m, 1H), 2.93 - 2.82 (m, 1H), 1.46 (d, J=6.6 Hz, 3H), 1.24 (d, J=7.0 Hz, 3H). Example 67 (6S,7S)-3-(4-cyano-2-oxo-pyrrolidin-1-yl)-N-(2,6-difluoro-4-pyridyl)-6,7-dimethyl-6,7- dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide

The Example 67 was prepared in analogy to Example 54 by using tert-butyl (6S,7S)-3- iodo-6,7-dimethyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate (Intermediate I-2) instead of tert-butyl (6S)-3-iodo-6-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5- carboxylate (Intermediate I-1). Separation of the final product with SFC ( chiral column, chiralpak® IC, 5 µm, 30 × 250 mm; mobile phase, 60% CO₂ and 40% MeOH (MeOH+0.5% NH₃H₂O); flow rate 80 mL/min, back pressure 100 bar) gave Example 67 as two isomers,

Example 67-1 and Example 67-2.

Example 67-1 was obtained (60 mg) as white solid. LCMS (M+H)⁺: 416.2, ¹H NMR (400MHz, METHANOL-d₄) δ ppm 7.66 (s, 1H), 7.13 (s, 2H), 5.12 (d, J=17.0 Hz, 1H), 4.79 (q, J=6.2 Hz, 1H), 4.53 (d, J=17.1 Hz, 1H), 4.44 - 4.35 (m, 1H), 4.21 - 4.02 (m, 2H), 3.87 - 3.70 (m, 1H), 3.05 - 2.95 (m, 1H), 2.92 - 2.83 (m, 1H), 1.45 (d, J=6.6 Hz, 3H), 1.27 (d, J=7.0 Hz, 3H).

Example 67-2 was obtained (40 mg) as white solid. LCMS (M+H)⁺: 416.2, ¹H NMR (400MHz, METHANOL-d4) δ = 7.66 (s, 1H), 7.13 (s, 2H), 5.12 (d, J=17.0 Hz, 1H), 4.80 (q, J=6.6 Hz, 1H), 4.54 (d, J=17.0 Hz, 1H), 4.40 (q, J=6.7 Hz, 1H), 4.19 (dd, J=8.4, 9.7 Hz, 1H), 4.05 (dd, J=6.2, 9.8 Hz, 1H), 3.78 (td, J=7.7, 15.5 Hz, 1H), 3.05 - 2.95 (m, 1H), 2.94 - 2.83 (m, 1H), 1.46 (d, J=6.6 Hz, 3H), 1.26 (d, J=6.8 Hz, 3H). Example 68

(6S,7R)-3-(4-cyano-2-oxo-pyrrolidin-1-yl)-N-(2,6-difluoro-4-pyridyl)-6,7-dimethyl-6,7- dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide

The Example 68 was prepared in analogy to Example 54 by using tert-butyl (6S,7R)-3- iodo-6,7-dimethyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate (intermediate I-3) instead of tert-butyl (6S)-3-iodo-6-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5- carboxylate (Intermediate I-1). Separation of the final product with SFC ( chiral column, chiralpak® IC, 5 µm, 30 × 250 mm; mobile phase, 70% CO2 and 30% MeOH (MeOH+0.5% NH₃H₂O); flow rate 80 mL/min, back pressure 100 bar) gave Example 68 as two isomers, Example 68-1 and Example 68-2.

Example 68-1 was obtained (48 mg) as white solid. LCMS (M+H)⁺: 416.2, ¹H NMR (400MHz, METHANOL-d₄) δ = 7.64 (s, 1H), 7.10 (s, 2H), 5.06 (d, J=17.1 Hz, 1H), 4.83 - 4.70 (m, 1H), 4.53 (d, J=17.2 Hz, 1H), 4.49 - 4.40 (m, 1H), 4.19 - 4.05 (m, 2H), 3.87 - 3.70 (m, 1H), 3.06 - 2.94 (m, 1H), 2.93 - 2.83 (m, 1H), 1.63 (d, J=6.7 Hz, 3H), 1.18 (d, J=7.0 Hz, 3H).

Example 68-2 was obtained (53 mg) as white solid. LCMS (M+H)⁺: 416.2, ¹H NMR (400MHz, METHANOL-d₄) δ = 7.64 (s, 1H), 7.11 (s, 2H), 5.06 (d, J=17.0 Hz, 1H), 4.76 (dd, J=4.1, 6.8 Hz, 1H), 4.53 (d, J=17.1 Hz, 1H), 4.50 - 4.42 (m, 1H), 4.19 (dd, J=8.4, 9.8 Hz, 1H), 4.03 (dd, J=6.2, 9.8 Hz, 1H), 3.85 - 3.72 (m, 1H), 3.06 - 2.95 (m, 1H), 2.92 - 2.84 (m, 1H), 1.63 (d, J=6.7 Hz, 3H), 1.17 (d, J=6.8 Hz, 3H). Example 71

(6S)-3-[2-[(dimethylamino)methyl]-5-oxo-pyrrolidin-1-yl]-6-methyl-N-(3,4,5- trifluorophenyl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide

The title compound was prepared according to the following scheme:

^{Example 71}

Step 1: preparation of tert-butyl (6S)-3-[2-(aminomethyl)-5-oxo-pyrrolidin-1-yl]-6- methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate (compound 71b)

A mixture of tert-butyl (6S)-3-iodo-6-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5- carboxylate (Intermediate I-1, 636.34 mg, 1.75 mmol), 5-(aminomethyl)pyrrolidin-2-one (compound 71a, 200.0 mg, 1.75 mmol, 1.0 eq), (1S,2S)-cyclohexane-1,2-diamine (99.69 mg, 0.700 mmol), CuI (66.4 mg, 0.35 mmol) and K₃PO₄ (1.11 g, 5.26 mmol, 3.0 eq) in DMSO (10 mL) was stirred at 110 ^oC for 12 hours under N₂ protection. Then the reaction mixture was filtered and the filtrate was purified by pre-HPLC to give compound 71b (100.0 mg) as white solid.

Step 2: preparation of tert-butyl (6S)-3-[2-[(dimethylamino)methyl]-5-oxo-pyrrolidin- 1-yl]-6-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate (compound 71c) To a solution of tert-butyl (6S)-3-[2-(aminomethyl)-5-oxo-pyrrolidin-1-yl]-6-methyl-6,7- dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate (compound 71b, 90.0 mg, 0.26 mmol) and 1,3,5-trioxane (232.01 mg, 2.58 mmol) in methanol (10 mL) was added palladium under carbon (2.74 mg, 0.03 mmol) under H₂. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was filtered, and the filtrate was concentrated to give crude compound 71c (40.0 mg).

Step 3: preparation of (6S)-3-[2-[(dimethylamino)methyl]-5-oxo-pyrrolidin-1-yl]-6- methyl-N-(3,4,5-trifluorophenyl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide (Example 71)

The Example 71 was prepared in analogy to Example 1 by using tert-butyl (6S)-3-[2- [(dimethylamino)methyl]-5-oxo-pyrrolidin-1-yl]-6-methyl-6,7-dihydro-4H-pyrazolo[1,5- a]pyrazine-5-carboxylate (compound 71c) instead of tert-butyl (6S)-6-methyl-3-[(4S)-4,5,5- trimethyl-2-oxo-oxazolidin-3-yl]-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate (compound 1f). Example 71 (6.1 mg) was obtained as a colorless oil. LCMS (M+H)⁺: 451.0, ¹H NMR (400MHz, METHANOL-d₄) δ ppm 8.43 (br s, 1H), 7.67 - 7.46 (m, 1H), 7.40 - 7.23 (m, 2H), 5.01 (br s, 2H), 4.48 (d, J=16.9 Hz, 1H), 4.39 - 4.26 (m, 2H), 4.23 - 4.10 (m, 1H), 2.87 - 2.62 (m, 3H), 2.60 - 2.53 (m, 1H), 2.52 - 2.40 (m, 6H), 2.16 - 2.06 (m, 2H), 1.40 - 1.13 (m, 3H). Example 72

(6S,7R)-3-(4-cyano-2-oxo-pyrrolidin-1-yl)-6,7-dimethyl-N-(3,4,5-trifluorophenyl)-6,7- dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide

The Example 72 was prepared in analogy to Example 54 by using tert-butyl (6S,7R)-3- iodo-6,7-dimethyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate (Intermediate I-3) instead of tert-butyl (6S)-3-iodo-6-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5- carboxylate (Intermediate I-1) and phenyl N-(3,4,5-trifluorophenyl)carbamate (Intermediate I-4) instead of phenyl N-(2,6-difluoro-4-pyridyl)carbamate (Intermediate I-9). Separation of the final product by SFC (chiral column, chiralpak® AD-H, 5 µm, 20 × 250 mm; mobile phase, 70% CO₂ and 30% MeOH (MeOH+0.5%NH₃H₂O); flow rate 65 mL/min, back pressure 100 bar) gave Example 72 as two isomers, Example 72-1 and Example 72-2.

Example 72-1 was obtained (40 mg) as a white solid. LCMS (M+H)⁺: 433.2, ¹H NMR (400MHz, METHANOL-d₄) δ ppm 7.51 (s, 1H), 7.24 - 7.09 (m, 2H), 4.89 (d, J=16.9 Hz, 1H), 4.68 - 4.56 (m, 1H), 4.45 - 4.28 (m, 2H), 4.07 (dd, J=8.4, 9.8 Hz, 1H), 3.91 (dd, J=6.2, 9.8 Hz, 1H), 3.74 - 3.58 (m, 1H), 2.93 - 2.82 (m, 1H), 2.81 - 2.69 (m, 1H), 1.51 (d, J=6.7 Hz, 3H), 1.03 (d, J=6.8 Hz, 3H).

Example 72-2 was obtained (27 mg) as a white solid. LCMS (M+H)⁺: 433.2, ¹H NMR (400MHz, METHANOL-d₄) δ ppm 7.64 (s, 1H), 7.39 - 7.20 (m, 2H), 5.01 (d, J=17.0 Hz, 1H), 4.82 - 4.69 (m, 1H), 4.58 - 4.39 (m, 2H), 4.21 - 4.03 (m, 2H), 3.85 - 3.70 (m, 1H), 3.06 - 2.94 (m, 1H), 2.92 - 2.81 (m, 1H), 1.63 (d, J=6.7 Hz, 3H), 1.16 (d, J=6.8 Hz, 3H). Examples 79 & 80

(6S)-6-methyl-3-[2-oxo-4-(2-pyridyl)imidazolidin-1-yl]-N-(3,4,5-trifluorophenyl)-6,7- dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide and (6S)-6-methyl-3-[2-oxo-5-(2- pyridyl)imidazolidin-1-yl]-N-(3,4,5-trifluorophenyl)-6,7-dihydro-4H-pyrazolo[1,5- a]pyrazine-5-carboxamide

^p

The title compounds were prepared according to the following scheme:

Step 1: preparation of tert-butyl (6S)-6-methyl-3-[2-oxo-4-(2-pyridyl)imidazolidin-1- yl]-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate & tert-butyl (6S)-6-methyl-3-[2- oxo-5-(2-pyridyl)imidazolidin-1-yl]-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate (compound 79b & 80b) An oven-dried sealable Schlenk tube were charged with (S)-tert-butyl 3-iodo-6-methyl-6,7- dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate (Intermediate I-1, 500 mg, 1.38 mmol), K₃PO₄ (584 mg, 2.75 mmol), CuI (78.7 mg, 0.41 mmol), (1R,2R)-N1,N2-dimethylcyclohexane- 1,2-diamine (78.3 mg, 0.55 mmol), 4-(2-pyridyl)imidazolidin-2-one (CAS: 503758-50-6, Accela ChemBio Co. Ltd. Cat. # SY0395182, 70 mg, 1.65 mmol) and DMSO (10 mL). The mixture was stirred at 110 ^oC for 2 hours under microwave under N₂, quenched with sat. aqueous solution of NH₄Cl and diluted with EtOAc. The organic layer was separated and washed with brine, dried over Na₂SO₄ and concentrated. The residue was purified by silica gel chromatograph to afford a mixture comprising compound 79b and compound 80b (236 mg). LCMS (M+H⁺): 399.

Step 2: preparation of (6S)-6-methyl-3-[2-oxo-4-(2-pyridyl)imidazolidin-1-yl]-N- (3,4,5-trifluorophenyl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide (Example 79) and (6S)-6-methyl-3-[2-oxo-5-(2-pyridyl)imidazolidin-1-yl]-N-(3,4,5-trifluorophenyl)- 6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide (Example 80)

The mixture of compound 79b and compound 80b obtained above (236 mg, 592 µmol) was treated with 2,2,2-trifluoroacetic acid (2 mL) in DCM (1mL) at room temperature for 30 minutes. The reaction mixture was then concentrated. The resulting residue was dissolved in DCM (3 mL), to which were then added DIPEA (0.5 mL), phenyl (3,4,5- trifluorophenyl)carbamate (Intermediate I-4, 52.5 mg, 197 µmol). The reaction mixture was stirred at 50^oC for 1 hour, then cooled down, washed with ice-water, extracted with DCM twice. The combined organic phase was dried and concentrated. The residue was purified by prep- HPLC to afford Example 79 (49 mg) and Example 80 (18 mg).

Example 79: ¹H NMR (400MHz, METHANOL-d₄) δ = 8.60 (dd, J=0.7, 4.2 Hz, 1H), 7.93 (dt, J=1.8, 7.7 Hz, 1H), 7.63 - 7.57 (m, 2H), 7.41 (ddd, J=1.1, 4.9, 7.6 Hz, 1H), 7.31 (ddd, J=2.3, 6.4, 10.2 Hz, 2H), 5.14 - 5.03 (m, 2H), 5.01 - 4.93 (m, 1H), 4.57 (dd, J=3.1, 16.7 Hz, 1H), 4.35 (dt, J=3.3, 9.3 Hz, 1H), 4.31 - 4.24 (m, 1H), 4.14 (dd, J=1.2, 12.7 Hz, 1H), 3.85 (ddd, J=3.3, 6.6, 9.0 Hz, 1H), 1.26 (t, J=7.2 Hz, 3H). LCMS (M+H⁺): 472.

Example 80: ¹H NMR (400MHz, METHANOL-d₄) δ = 8.59 - 8.52 (m, 1H), 7.80 (ddt, J=1.8, 3.2, 7.7 Hz, 1H), 7.47 (dd, J=7.8, 12.5 Hz, 1H), 7.38 - 7.26 (m, 4H), 5.37 - 5.27 (m, 1H), 5.02 - 4.89 (m, 1H), 4.57 (d, J=16.9 Hz, 0.5H), 4.28 (d, J=16.6 Hz, 0.5H), 4.24 - 4.10 (m, 1H), 4.07 - 3.94 (m, 2H), 3.71 - 3.56 (m, 1H), 1.23 (d, J=7.0 Hz, 2H), 0.92 (d, J=6.8 Hz, 2H). LCMS (M+H⁺): 472. Example 83 (6S)-6-methyl-3-(4-oxo-8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-N-(3,4,5-trifluorophenyl)-6,7- dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide

The title compound was prepared according to the following scheme:

8^{3a 83b} _{Example 83}

Step 1: preparation of 3-[(6S)-6-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3- yl]-8-oxa-3-azabicyclo[3.2.1]octan-4-one (compound 83b)

The compound 83b was prepared in analogy to compound 11d by using 8-oxa-3- azabicyclo[3.2.1]octan-4-one (compound 83a, for its synthesis refer to Synthesis, 2011, 1113) instead of (4S)-1-[(4-methoxyphenyl)methyl]-4-methyl-imidazolidin-2-one (compound 11c). Compound 83b (15 mg) was obtained as white solid.

Step 2: preparation of (6S)-6-methyl-3-(4-oxo-8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-N- (3,4,5-trifluorophenyl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide (Example 83)

To a solution of 3-[(6S)-6-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl]-8-oxa-3- azabicyclo[3.2.1]octan-4-one (compound 83b, 15.0 mg, 0.06 mmol, 1.0 eq) and DIPEA (15.5 mg, 0.12 mmol) in DMF (2.0 mL) was added phenyl (3,4,5-trifluorophenyl)carbamate (Intermediate I-4, 24.0 mg, 0.09 mmol) at room temperature. The reaction mixture was stirred at room temperature for 2 hours and purified by prep-HPLC to give Example 83 (5.2 mg) as a gray solid. LCMS (M+H)⁺: 436.3, ¹H NMR (400MHz, METHANOL-d₄) δ ppm 7.64 (d, J=2.3 Hz, 1H), 7.35 - 7.22 (m, 2H), 5.03 - 4.94 (m, 2H), 4.76 (d, J=4.5 Hz, 1H), 4.57 (d, J=5.8 Hz, 1H), 4.38 (d, J=16.8 Hz, 1H), 4.30 (d, J=12.8 Hz, 1H), 4.20 - 4.12 (m, 1H), 4.07 - 3.94 (m, 1H), 3.49 - 3.38 (m, 1H), 2.34 - 2.18 (m, 3H), 2.16 - 2.05 (m, 1H), 1.27 (t, J=5.9 Hz, 3H). Example 84 (6S)-3-(8-acetyl-4-oxo-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-methyl-N-(3,4,5- trifluorophenyl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide

The title compound was prepared according to the following scheme:

Step 1: Preparation of tert-butyl (6S)-6-methyl-3-(4-oxo-3,8- diazabicyclo[3.2.1]octan-3-yl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate (compound 84a)

The mixture of tert-butyl (6S)-3-iodo-6-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine- 5-carboxylate (Intermediate I-1,1.15 g, 3.17 mmol), (1R,5S)-3,8-diazabicyclo[3.2.1]octan-2-one (CAS: 22315-17-9, PharmaBlock Sciences, Cat. # PB05912, 400 mg, 3.17 mmol), K₃PO₄ (2.02 g, 9.51 mmol), (1R,2R)-N1,N2-dimethylcyclohexane-1,2-diamine (180 mg, 1.27 mmol) and CuI (121 mg, 634 µmol) in DMSO (5 mL) was heated at 110 ^oC for 5 hours. The mixture was diluted with EtOAc, washed with sat. aqueous solution of NH₄Cl and brine, dried over Na₂SO₄ and concentrated to give a crude product (1.0 g) which was directly used in next step. LCMS (M+1): 362.

Step 2: Preparation of (6S)-3-(8-acetyl-4-oxo-3,8-diazabicyclo[3.2.1]octan-3-yl)-6- methyl-N-(3,4,5-trifluorophenyl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide (Example 84)

To a solution of tert-butyl (6S)-6-methyl-3-(4-oxo-3,8-diazabicyclo[3.2.1]octan-3-yl)- 6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate (compound 84a, 100 mg, 277 µmol,) in DCM (5 mL) was added DIEA (107 mg, 145 µl, 830 µmol) and acetyl chloride (32.6 mg, 415 µmol) at room temperature. The mixture was stirred at room temperature for 30 min, then quenched with sat. NH₄Cl, diluted with EtOAc, washed with sat NH₄Cl and brine, dried over Na₂SO₄, and then concentrated. The residue was dissolved in DCM (5 mL), and then TFA (5 mL) was added. After being stirred at room temperature for 30 min, the mixture was concentrated to give a crude product which was dissolved in DCM (5 mL), DIEA (0.5 mL) and phenyl (3,4,5- trifluorophenyl)carbamate (111 mg, 415 µmol) was added. The mixture was stirred at room temperature overnight, then concentrated to give a crude product which was purified by prep- HPLC to give Example 84 (25 mg) as a white powder. LCMS (M+1): 477. ¹H NMR (400MHz, METHANOL-d₄) δ ppm 7.67 - 7.63 (m, 1H), 7.33 - 7.19 (m, 2H), 5.02 - 4.94 (m, 2H), 4.91 - 4.83 (m, 1H), 4.79 - 4.64 (m, 1H), 4.43 - 4.25 (m, 2H), 4.21 - 4.11 (m, 1H), 4.10 - 3.95 (m, 1H), 3.64 - 3.42 (m, 1H), 2.50 - 2.03 (m, 7H), 1.34 - 1.19 (m, 3H). Example 85

(6S)-3-(8-ethylsulfonyl-4-oxo-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-methyl-N-(3,4,5- trifluorophenyl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide

The title compound was prepared in analogy to the preparation of Example 84 by using methanesulfonyl chloride instead of acetyl chloride. Example 85 (5 mg) was obtained as a white solid. LCMS (M+1): 527.¹H NMR (400MHz, METHANOL-d₄) δ ppm 7.63 (s, 0.5H), 7.62 (s, 0.5H), 7.31 - 7.22 (m, 2H), 4.98 - 4.90 (m, 2H), 4.56 - 4.50 (m, 1H), 4.46 - 4.41 (m, 1H), 4.36 (d, J=16.9 Hz, 1H), 4.33 - 4.26 (m, 1H), 4.16 (d, J=13.3 Hz, 1H), 4.09 - 3.97 (m, 1H), 3.61 - 3.52 (m, 1H), 3.31 - 3.25 (m, 2H), 2.41 - 2.32 (m, 2H), 2.31 - 2.22 (m, 1H), 2.12 - 2.07 (m, 1H), 1.40 (t, J=7.3 Hz, 3H), 1.29 (d, J=7.0 Hz, 1.5H), 1.25 (d, J=7.0 Hz, 1.5H). Example 86

(6S)-6-methyl-3-(8-methyl-4-oxo-3,8-diazabicyclo[3.2.1]octan-3-yl)-N-(3,4,5- trifluorophenyl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide

The title compound was prepared according to the following scheme:

To a solution of tert-butyl (6S)-6-methyl-3-(4-oxo-3,8-diazabicyclo[3.2.1]octan-3-yl)-6,7- dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate (compound 84a, 150 mg, 415 µmol) in MeOH (5 mL) was added formaldehyde (35% solution, 0.1 mL) and NaBH₃CN (52.2 mg, 830 µmol). The mixture was stirred at room temperature for 1h, then another portion of

formaldehyde and NaBH₃CN was added. After another hour, the reaction mixture was

concentrated under reduced pressure. The residue was dissolved in EtOAc and washed with sat NaHCO₃ and brine, dried over Na₂SO₄ and concentrated. The crude product was dissolved in DCM (5 mL) and TFA (5 mL) was added. was After being stirred at room temperature for 30min, the solvent was removed. The residue was dissolved in DCM (5 mL) and DIEA (268 mg, 2.08 mmol) and phenyl (3,4,5-trifluorophenyl)carbamate (166 mg, 623 µmol) were added. The mixture was stirred at room temperature overnight, solvent was removed under reduced pressure to give a crude product which was purified by prep-HPLC to give Example 86 (34 mg) as a white powder. LCMS (M+1): 449.¹H NMR (400MHz, METHANOL-d₄) δ ppm 7.62 (s, 1H), 7.27 (dd, J=6.4, 10.3 Hz, 2H), 4.98 - 4.90 (m, 2H), 4.36 (d, J=17.0 Hz, 1H), 4.33 - 4.26 (m, 1H), 4.15 (d, J=12.5 Hz, 1H), 4.01 - 3.89 (m, 1H), 3.62 - 3.52 (m, 2H), 3.44 - 3.35 (m, 1H), 2.54 (s, 1.5H), 2.53 (s, 1.5H), 2.43 - 2.27 (m, 2H), 2.17 - 2.07 (m, 1H), 2.04 - 1.92 (m, 1H), 1.32 - 1.21 (m, 3H). Example 87 (6S)-6-methyl-3-(4-oxo-3,7-diazabicyclo[3.3.1]nonan-3-yl)-N-(3,4,5-trifluorophenyl)-6,7- dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide

The title compound was prepared according to the following scheme:

Step 1: Preparation of tert-butyl 3-[(6S)-6-methyl-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrazin-3-yl]-4-oxo-3,7-diazabicyclo[3.3.1]nonane-7-carboxylate (compound 87a)

The mixture of (6S)-3-iodo-6-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine

(Intermediate I-1-1, 219 mg, 832 µmol), tert-butyl 6-oxo-3,7-diazabicyclo[3.3.1]nonane-3- carboxylate (CAS: 183277-52-2, Wuxi, Cat. #: WX120011, 200 mg, 832 µmol), (1R,2R)- N1,N2-dimethylcyclohexane-1,2-diamine (47.4 mg, 333 µmol), CuI (31.7 mg, 166 µmol) and potassium phosphate (530 mg, 2.5 mmol) in DMSO (5 mL) was stirred at 110 ^oC for 3 hours under argon. The mixture was cooled to room temperature and diluted with EtOAc (50 mL), washed with sat NH₄Cl and brine, dried over Na₂SO₄ and concentrated to give a crude compound 87a (312 mg) which was used in next step directly. LCMS (M+1): 376.

Step 2: Preparation of (6S)-6-methyl-3-(4-oxo-3,7-diazabicyclo[3.3.1]nonan-3-yl)-N- (3,4,5-trifluorophenyl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide (Example 87)

To a solution of tert-butyl 3-[(6S)-6-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3- yl]-4-oxo-3,7-diazabicyclo[3.3.1]nonane-7-carboxylate (compound 87a, 312 mg, 0.832mmol) in DCM (5 mL) was added DIEA (215 mg, 290 µl, 1.66 mmol) and phenyl (3,4,5- trifluorophenyl)carbamate (289 mg, 1.08 mmol). The reaction mixture was stirred overnight at room temperature, then TFA (5 mL) was added at 0 ^oC. After being stirred at room temperature for 30 min, the solvent was removed under reduced pressure to give a crude product, 100 mg of which was purified by prep-HPLC to give Example 87 as two isomers, Example 87-1 (10 mg) and Example 87-2 (8 mg) as white powders.

Example 87-1: LCMS (M+1): 449. ¹H NMR (400MHz, METHANOL-d4) δ ppm 7.72 (s, 1H), 7.28 (dd, J=6.4, 10.3 Hz, 2H), 4.96 (d, J=16.9 Hz, 1H), 4.99 - 4.90 (m, 1H), 4.37 (d, J=16.9 Hz, 1H), 4.35 - 4.28 (m, 1H), 4.21 - 4.14 (m, 1H), 4.00 (dd, J=5.9, 12.7 Hz, 1H), 3.73 (d, J=12.6 Hz, 1H), 3.31 - 3.23 (m, 2H), 3.20 - 3.10 (m, 2H), 2.79 - 2.71 (m, 1H), 2.40 - 2.24 (m, 2H), 2.12 - 2.06 (m, 1H), 1.27 (d, J=6.8 Hz, 3H).

Example 87-2: LCMS (M+1): 449. ¹H NMR (400MHz, METHANOL-d₄) δ ppm 7.74 (s, 1H), 7.28 (dd, J=6.4, 10.3 Hz, 2H), 5.00 - 4.90 (m, 2H), 4.42 (d, J=16.9 Hz, 1H), 4.34 - 4.27 (m, 1H), 4.20 - 4.13 (m, 1H), 3.95 (dd, J=5.6, 12.5 Hz, 1H), 3.76 (d, J=12.8 Hz, 1H), 3.30 - 3.21 (m, 2H), 3.16 - 3.06 (m, 2H), 2.75 - 2.69 (m, 1H), 2.36 - 2.22 (m, 2H), 2.09 (d, J=12.5 Hz, 1H), 1.30 (d, J=6.8 Hz, 3H). Example 88

(6S)-3-(7-acetyl-4-oxo-3,7-diazabicyclo[3.3.1]nonan-3-yl)-6-methyl-N-(3,4,5- trifluorophenyl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide

The title compound was prepared according to the following scheme:

To a solution of (6S)-6-methyl-3-(4-oxo-3,7-diazabicyclo[3.3.1]nonan-3-yl)-N-(3,4,5- trifluorophenyl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide (Example 87, 200 mg crude, 446 µmol) in DCM (5 mL) was added DIEA (288 mg, 2.23 mmol) and AcCl (70 mg, 892 µmol). The reaction mixture was stirred at room temperature for 1h, then quenched with sat NH₄Cl, and solvent was removed. The crude product was purified by prep-HPLC to give

Example 88 as two isomers, Example 88-1 (6 mg) and Example 88-2 (5 mg), as white powders.

Example 88-1: LCMS (M+1): 491. ¹H NMR (400MHz, METHANOL-d₄) δ ppm 7.62 - 7.50 (m, 1H), 7.47 - 7.32 (m, 2H), 5.06 - 4.93 (m, 2H), 4.77 (d, J=16.9 Hz, 0.6H), 4.67 (d, J=16.9Hz, 0.4H), 4.39 - 4.25 (m, 2H), 4.23 - 4.07 (m, 2.6H), 3.86 (dd, J=5.0, 12.5 Hz, 0.4H), 3.62 (d, J=12.8 Hz, 1H), 3.56 - 3.50 (m, 1H), 3.04 - 2.95 (m, 1H), 2.85 - 2.75 (m, 1H), 2.42 - 2.31 (m, 2H), 2.20 - 2.12 (m, 1H), 2.09 - 1.88 (m, 3H), 1.30 - 1.17 (m, 3H).

Example 88-2: LCMS (M+1): 491. ¹H NMR (400MHz, METHANOL-d₄) δ ppm 7.68 - 7.37 (m, 3H), 5.14 - 4.92 (m, 2H), 4.81 (d, J=16.3 Hz, 0.4H), 4.50 (d, J=16.5 Hz, 0.6H), 4.32 - 4.09 (m, 4.6H), 3.93 - 3.85 (m, 0.4H), 3.61 - 3.47 (m, 2H), 3.05 - 2.96 (m, 1H), 2.86 - 2.72 (m, 1H), 2.43 - 2.31 (m, 2H), 2.23 - 2.07 (m, 4H), 1.32 - 1.19 (m, 3H). Example 91

(6S)-3-(6-acetyl-4-oxo-3,6-diazabicyclo[3.1.1]heptan-3-yl)-6-methyl-N-(3,4,5- trifluorophenyl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide

The title compound was prepared in analogy to the preparation of Example 88 by using tert-butyl 4-oxo-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate (CAS: 1273562-74-5,

PharmaBlock, Cat.# PBN20111097) instead of tert-butyl 6-oxo-3,7-diazabicyclo[3.3.1]nonane- 3-carboxylate. Example 91 was obtained as a white solid (60 mg). LCMS (M+1): 463. ¹H NMR (400MHz, METHANOL-d₄) δ ppm 7.67 - 7.59 (m, 1H), 7.38 - 7.22 (m, 2H), 5.04 - 4.91 (m, 2H), 4.76 - 4.57 (m, 2H), 4.55 - 4.35 (m, 1H), 4.34 - 4.25 (m, 1H), 4.20 - 4.11 (m, 1H), 3.89 - 3.79 (m, 1H), 3.71 - 3.52 (m, 2H), 2.44 - 2.31 (m, 1H), 2.26 (s, 1H), 2.24 (s, 1H), 2.20 - 2.12 (m, 0.6H), 2.13 (s, 0.5H), 2.12 (s, 0.5H), 2.07 - 2.00 (m, 0.4H), 1.31 - 1.20 (m, 3H). Example 93 (6S)-3-(9-acetyl-6-oxo-3-oxa-7,9-diazabicyclo[3.3.1]nonan-7-yl)-6-methyl-N-(3,4,5- trifluorophenyl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide

The title compound was prepared according to the following scheme:

Step 1: preparation of benzyl 6-oxo-3-oxa-7,9-diazabicyclo[3.3.1]nonane-9- carboxylate (compound 93b)

To a solution of O9-benzyl O7-tert-butyl 6-oxo-3-oxa-7,9-diazabicyclo[3.3.1]nonane-7,9- dicarboxylate (compound 93a, 80.0 mg, the synthesis refer to PCT Int. Appl.,

2014184328) in DCM (1mL) was added HCl/EtOAc (4N, 0.53 mL). The reaction mixture was stirred at room temperature for 2 hours. The solvent was removed. The residue was dissolved in CH₃CN, basified with K₂CO₃, and then filtered and concentrated to give compound 93b (50 mg) as colorless oil. LCMS(M+H)⁺: 277.0

Step 2: preparation of benzyl 7-[(6S)-5-tert-butoxycarbonyl-6-methyl-6,7-dihydro- 4H-pyrazolo[1,5-a]pyrazin-3-yl]-6-oxo-3-oxa-7,9-diazabicyclo[3.3.1]nonane-9-carboxylate (compound 93c)

The compound 93c was prepared in analogy to compound 1f by using benzyl 6-oxo-3-oxa- 7,9-diazabicyclo[3.3.1]nonane-9-carboxylate (compound 93b) instead of(4S)-4,5,5- trimethyloxazolidin-2-one (compound 1e). Compound 93c (30 mg) was obtained as a white solid. LCMS (M+H)⁺:512.2.

Step 3: preparation of tert-butyl (6S)-6-methyl-3-(6-oxo-3-oxa-7,9- diazabicyclo[3.3.1]nonan-7-yl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate (compound 93d)

To a solution of benzyl 7-[(6S)-5-tert-butoxycarbonyl-6-methyl-6,7-dihydro-4H- pyrazolo[1,5-a]pyrazin-3-yl]-6-oxo-3-oxa-7,9-diazabicyclo[3.3.1]nonane-9-carboxylate

(compound 93c, 30.0 mg, 0.060 mmol) in methanol (10 mL) was added Pd/C(5 mg). The reaction mixture was stirred at room temperature for 16 hours under 50 psi of H₂. The mixture was filtered and the filtrate was concentrated to give crude compound 93d (30.0 mg). LCMS (M+H)⁺: 378.2.

Step 4: preparation of tert-butyl (6S)-3-(9-acetyl-6-oxo-3-oxa-7,9- diazabicyclo[3.3.1]nonan-7-yl)-6-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5- carboxylate (compound 93e)

To a solution of tert-butyl (6S)-6-methyl-3-(6-oxo-3-oxa-7,9-diazabicyclo[3.3.1]nonan-7- yl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate (compound 93d, 30.0 mg, 0.040 mmol) and triethylamine (0.01 mL, 0.080 mmol, 2 eq) in DCM (5.0 mL) was added acetyl chloride (4.7 mg, 0.060 mmol). The reaction mixture was stirred at room temperature for 0.5 hour, and then the solvent was removed to give crude compound 93e (20.0 mg). LCMS (M+H)⁺: 420.2.

Step 5: preparation of (6S)-3-(9-acetyl-6-oxo-3-oxa-7,9-diazabicyclo[3.3.1]nonan-7-yl)- 6-methyl-N-(3,4,5-trifluorophenyl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide (Example 93)

Example 93 was prepared in analogy to Example 1 by using b tert-butyl (6S)-3-(9-acetyl- 6-oxo-3-oxa-7,9-diazabicyclo[3.3.1]nonan-7-yl)-6-methyl-6,7-dihydro-4H-pyrazolo[1,5- a]pyrazine-5-carboxylate (compound 93e) instead of tert-butyl (6S)-6-methyl-3-[(4S)-4,5,5- trimethyl-2-oxo-oxazolidin-3-yl]-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate

(compound 1f). Example 93 (4.0 mg) was obtained as white solid. LCMS (M+H)⁺: 493.2, ¹H NMR (400MHz, METHANOL-d₄) δ ppm 7.72 - 7.67 (m, 1H), 7.30-7.24 (m, 2H), 5.07 (d, J=1.6 Hz, 1H), 5.00 - 4.94 (m, 1H), 4.87 - 4.83 (m, 1H), 4.68 - 4.06 (m, 7H), 4.24 - 4.06 (m, 3H), 3.93 - 3.71 (m, 3H), 2.27 - 2.20 (m, 3H). Example 94 (6S)-3-(5-cyano-5-methyl-2-oxo-1,3-oxazinan-3-yl)-6-methyl-N-(3,4,5-trifluorophenyl)-6,7- dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide

The title compound was prepared according to the following scheme:

Step 1: preparation of ethyl 2-cyano-3-hydroxy-2-methyl-propanoate (compound 94b) To a solution of ethyl 2-cyanopropanoate (40.0 g, 314.6 mmol) in ethanol (400 mL) was added potassium carbonate (124.4 g, 943.8 mmol) and paraformaldehyde (14.2 g, 471.9 mmol). The reaction mixture was stirred at 25 ^oC for 12 hours. The reaction mixture was filtered and the filtrate was concentrated. The residue was dissolved in ethyl acetate, washed with brine. The organic phase was concentrated, then purified by column chromatography to give compound 94b (16.0 g) as colorless oil. LCMS (M+H⁺): 158.

Step 2: preparation of ethyl 2-(aminomethyl)-3-hydroxy-2-methyl-propanoate hydrochloride (compound 94c) To a solution of ethyl 2-cyano-3-hydroxy-2-methyl-propanoate (compound 94b, 16.0 g, 101.8 mmol) in ethanol (200 mL) was added platinum oxide (2.3 g, 10.2 mmol) and hydrogen chloride (4 M in dioxane, 50.9 mL, 203.6 mmol). The reaction mixture was stirred at 25 ^oC for 12 hours under hydrogen atmosphere (50 Psi). The reaction mixture was filtered and the filtrate was concentrated to give compound 94c (19.4 g, crude) as a colorless oil. LCMS (M+H⁺): 198.

Step 3: preparation of O3-tert-butyl O5-ethyl 5-methyl-2-oxo-1,3-oxazinane-3,5- dicarboxylate (compound 94d)

To a solution of ethyl 2-(aminomethyl)-3-hydroxy-2-methyl-propanoate hydrochloride (compound 94c, 19.0 g, 96.1 mmol) in acetonitrile (200 mL) was added potassium carbonate (26.6 g, 192.2 mmol). After being stirred at 25 ^oC for 30 minutes, the mixture was added into a stirring mixture of di-tert-butyl dicarbonate (62.9 g, 288.4 mmol), triethylamine (29.2 g, 288.4 mmol) and 4-dimethylaminopyridine (2.4 g, 19.2 mmol) in acetonitrile (200 mL). The reaction mixture was stirred for 12 h at 25 ^oC. The reaction mixture was filtered and the filtrate was concentrated, the obtained residue was partitioned between water and ethyl acetate. The organic phase was washed with brine, concentrated and the residue was purified by column

chromatography to give compound 94d (11.0 g) as a colorless oil. LCMS (M+H⁺): 288.

Step 4: preparation of ethyl 5-methyl-2-oxo-1,3-oxazinane-5-carboxylate (compound 94e)

To a solution of O3-tert-butyl O5-ethyl 5-methyl-2-oxo-1,3-oxazinane-3,5-dicarboxylate (compound 94d, 11.0 g, 38.3 mmol) in DCM (70 mL) was added 2,2,2-trifluoroacetic acid (14 mL), the reaction mixture was stirred at 25 ^oC for 2 hours, and basified carefully to pH=10 by adding sodium hydroxide solution (2M). The organic phase was separated, washed with brine, concentrated to give compound 94e (4.2 g, crude) as an off white solid. LCMS (M+H⁺): 188.

Step 5: preparation of 5-methyl-2-oxo-1,3-oxazinane-5-carboxylic acid (compound 94f)

To a solution of ethyl 5-methyl-2-oxo-1,3-oxazinane-5-carboxylate (compound 94e, 560 mg, 3.0 mmol) in ethanol (10 mL) was added ammonia aqueous solution (25%- 28%, 10 mL). The reaction mixture was sealed and heated at 72^oC overnight. The reaction mixture was concentrated, and then 2-methyltetrahydrofuran was added to co-evaporate water to give compound 94f (428 mg, crude). LCMS (M+H⁺): 160.

Step 6: preparation of 5-methyl-2-oxo-1,3-oxazinane-5-carboxamide (compound 94g) To a mixture of 5-methyl-2-oxo-1,3-oxazinane-5-carboxylic acid (compound 94f, 500 mg, 3.14 mmol) and 4-methylmorpholine (518 µL, 4.71 mmol) in dry THF (20 mL) and DCM (20 mL) at -10 °C was added dropwise isobutyl chloroformate (491 µL, 3.77 mmol). The reaction mixture was stirred at -10 °C for 2 hours, then slowly warmed to 0 °C for 30 minutes. The reaction mixture was cooled down to -10 °C again, to which was added ammonia solution (0.4 M in THF, 8.0 mL). The reaction mixture was stirred at room temperature for 3 hours and then filtered, and the solid was collected to give compound 94g (300 mg). LCMS (M+H⁺): 159.

Step 7: preparation of 5-methyl-2-oxo-1,3-oxazinane-5-carbonitrile (compound 94h) To a mixture of 5-methyl-2-oxo-1,3-oxazinane-5-carboxamide (compound 94g, 300.0 mg, 1.9 mmol) and pyridine (1 mL) in dry THF (8 mL) at 0^oC was added dropwise trifluoroacetic anhydride (1 mL). After addition the reaction mixture was stirred at room temperature for 2 hours and then washed with ice-water, extracted with DCM/i-PrOH (V/V=5/1) twice, the organic phase was combined and concentrated. The residue was purified by column chromatography (eluting with 85%-100% EtOAc (containing 10% MeOH) in petroleum ether) to give compound 94h (100.0 mg). LCMS (M+H⁺): 141.

Step 8: preparation of tert-butyl (6S)-3-(5-cyano-5-methyl-2-oxo-1,3-oxazinan-3-yl)- 6-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate (compound 94i)

The mixture of 5-methyl-2-oxo-1,3-oxazinane-5-carbonitrile (compound 94h, 7.7 mg, 55 µmo), tert-butyl (6S)-3-iodo-6-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate (Intermediate I-1, 20.0 mg, 55 µmol), K₃PO₄ (23.4 mg, 110 µmol), CuI (2.1 mg, 11 µmol) and (1R,2R)-N1,N2-dimethylcyclohexane-1,2-diamine (1.6 mg, 11 µmol) in DMSO (5 mL) was flushed with nitrogen and sealed. The reaction mixture was heated to 105 ^oC under microwave for 2 hours. The reaction mixture was cooled down, poured into ice-water and extracted with EtOAc twice. The combined organic phase was dried over Na₂SO₄, filtrated and concentrated. The residue was purified by column chromatography to give compound 94i (8.3 mg). LCMS (M+H⁺): 376.

Step 9: preparation of (6S)-3-(5-cyano-5-methyl-2-oxo-1,3-oxazinan-3-yl)-6-methyl- N-(3,4,5-trifluorophenyl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide

(Example 94)

The mixture of tert-butyl (6S)-3-(5-cyano-5-methyl-2-oxo-1,3-oxazinan-3-yl)-6-methyl- 6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate (compound 94i, 60.0 mg, 160 µmol), 2,2,2-trifluoroacetic acid (2.0 mL) and DCM (1.0 mL) was stirred at room temperature for 30 minutes, and then concentrated. The residue was dissolved in DCE (3.0 mL), to which were added DIPEA (0.5 mL), and phenyl N-(3,4,5-trifluorophenyl)carbamate (Intermediate I-4, 85.4 mg, 320 µmol). The reaction mixture was stirred at 50 ^oC for 1 hour and then cooled down, diluted with DCM, washed with ice-water, and brine. Organic phase was concentrated and the residue was purified by column chromatography (eluting with 80% EtOAc (containing 10% MeOH) in petroleum ether( to give Example 94 (65.0 mg) as a white solid. LCMS (M+H⁺): 449. 1H NMR (400MHz, METHANOL-d₄) δ = 7.64 (s, 1H), 7.32 - 7.23 (m, 2H), 5.07 - 4.92 (m, 2H), 4.60 - 4.54 (m, 1H), 4.50 - 4.37 (m, 2H), 4.34 - 4.26 (m, 1H), 4.17 (d, J=12.7 Hz, 1H), 3.97 - 3.86 (m, 2H), 1.52 (s, 3H), 1.29 - 1.24 (m, 3H). Example 97

(6S)-6-methyl-3-(2-oxo-3H-benzimidazol-1-yl)-N-(3,4,5-trifluorophenyl)-6,7-dihydro-4H- pyrazolo[1,5-a]pyrazine-5-carboxamide

The title compound was prepared according to the following scheme:

Step 1: preparation of tert-butyl (6S)-6-methyl-3-(2-oxo-3H-benzimidazol-1-yl)-6,7- dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate (compound 97b)

An oven-dried sealable Schlenk tube were charged with (S)-tert-butyl 3-iodo-6-methyl-6,7- dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate (Intermediate I-1, 400 mg, 1.1 mmol), K₃PO₄ (468 mg, 2.2 mmol), CuI (83.9 mg, 0.44 mmol), (1R,2R)-N1,N2-dimethylcyclohexane-1,2- diamine (62.7 mg, 0.44 mmol), 1H-benzo[d]imidazol-2(3H)-one (591 mg, 4.41 mmol) and DMSO (5.0 ml) under nitrogen. The mixture was stirred at 110 ^oC for 2 hours under microwave, quenched with sat. aqueous solution of NH₄Cl and diluted with EtOAc. The organic layer was separated and washed with sat NH₄Cl and brine, dried over Na₂SO₄ and concentrated. The residue was purified by silica gel chromatograph to afford the product compound 97b (230 mg). LCMS (M+H⁺): 370.

Step 2: preparation of 3-[(6S)-6-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl]-1H- benzimidazol-2-one (compound 97c)

The mixture of tert-butyl (6S)-6-methyl-3-(2-oxo-3H-benzimidazol-1-yl)-6,7-dihydro-4H- pyrazolo[1,5-a]pyrazine-5-carboxylate (compound 97b, 230 mg, 623 µmol), 2,2,2-trifluoroacetic acid (2 mL) in DCM (5 mL) was stirred at room temperature for 30 minutes, and then concentrated to afford crude product 97c (250 mg). LCMS (M+H⁺): 270.

Step 3: preparation of (6S)-6-methyl-3-(2-oxo-3H-benzimidazol-1-yl)-N-(3,4,5- trifluorophenyl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide (compound 97) The mixture of crude compound 97c (96 mg, 0.25 mmol), DIPEA (0.5 mL), and phenyl (3,4,5-trifluorophenyl)carbamate (Intermediate I-4, 80.0 mg, 0.30 mol) in DCM (3.0 mL) was stirred at 50^oC for 1 hour. The reaction mixture was cooled down, diluted with DCM, washed with ice-water, and brine. The organic phase was separated and concentrated. The residue was purified by prepare-HPLC to afford product compound 97 (37 mg). LCMS (M+H⁺): 443.¹H NMR (400MHz, DMSO-d₆) δ ppm 7.00 (br d, J=2.6 Hz, 1H), 6.44 (br s, 2H), 6.34 (br s, 3H), 6.19 (br s, 1H), 4.41 - 4.14 (m, 2H), 3.84 - 3.54 (m, 2H), 3.47 (br s, 1H), 0.52 (br s, 3H). Example 99

(6S)-6-methyl-3-(2-oxo-1-pyridyl)-N-(3,4,5-trifluorophenyl)-6,7-dihydro-4H-pyrazolo[1,5- a]pyrazine-5-carboxamide

The Example 99 was prepared in analogy to Example 1 by using 1H-pyridin-2-one instead of (4S)-4,5,5-trimethyloxazolidin-2-one (compound 1e). Example 99 (47 mg) was obtained as white solid. LCMS (M+23)⁺: 426.1, ¹H NMR (400MHz, DMSO-d₆) δ ppm 9.13 (s, 1H), 7.71 (s, 1H), 7.69 (dd, J=1.3, 6.8 Hz, 1H), 7.56 - 7.48 (m, 1H), 7.42 (dd, J=6.5, 10.8 Hz, 2H), 6.52 (d, J=9.3 Hz, 1H), 6.34 (t, J=6.7 Hz, 1H), 4.98 - 4.91 (m, 1H), 4.88 (d, J=17.1 Hz, 1H), 4.34 (d, J=16.8 Hz, 1H), 4.30 - 4.23 (m, 1H), 4.22 - 4.16 (m, 1H), 1.17 (d, J=6.8 Hz, 3H).

Example 100: HBV inhibition assays

Cell line and culture conditions:

HepG2.2.15 is a stably-transfected cell line containing the HBV genome. It is derived from the hepatoblastoma cell line Hep G2 (American Type Culture Collection, ATCC® HB-8065™) by the published procedures described in reference: MA Selles et al. Proc. Natl. Acad. Sci. USA 1987, 84, 1005-1009. The cell line was maintained in Dulbecco's modified Eagle's medium and nutrient mixture F-12 (DMEM/F-12, Gibco, Cat.#:11320-033) supplemented with 10% fetal bovine serum (Gibco, Cat.#:10099-141), 100 U/mL penicillin, 100 μg/mL streptomycin (Gibco, Cat.#:15140-122), and 0.3 mg/mL of G418 Sulfate (Gibco, Cat.#: 10131-027).

Anti-HBV activity in vitro:

HepG2.2.15 cells were seeded into 96-well plates at a density of 3 × 10⁴ cells per well in culture media of 100 µL DMEM/F-12 supplemented with 2.5% fetal bovine serum, 100 U/mL penicillin, 100 μg/mL streptomycin and cultured overnight at 37 ºC. The test compounds were serially half-log diluted in DMSO, then diluted 100 times in culture media. 100 µL culture media containing diluted compounds were added into the plates to reach 0.5% final concentration of DMSO in every well. Five days after compound treatment, culture supernatant was collected for further analysis.

For quantitative PCR detection of extracellular HBV DNA, culture supernatant was processed by 500 µg/mL Proteinase K (Sigma, Cat.#:P2308) digestion at 50 ˚C for 1 hour. After heat inactivation of the enzyme at 95 ˚C for 15 minutes, the samples were subjected to HBV DNA quantification by qPCR. The effective compound concentration at which HBV replication was inhibited by 50% (EC₅₀) was determined.

The Examples of the present invention were tested in the above assays as described herein and found to have EC₅₀ less than 1 µM in HepG2.2.15 assay as shown in Table 1 below.

Table 1. Activity of compounds of this invention in HepG2.2.15 assay

Claims

CLAIMS 1. A compound of formula (I),

wherein

R¹ is , wherein R⁵, R⁶ and R⁷ are independently selected from H or C_1-

6a y ;

R² is H;

R³ is C_1-6alkyl;

or pharmaceutically acceptable salt, enantiomer or diastereomer thereof;

with the proviso that R⁵, R⁶ and R⁷ are not H simultaneously, and

(6S)-N-[2-(difluoromethyl)-4-pyridyl]-3-(5,5-dimethyl-2-oxo-oxazolidin-3-yl)-6-methyl- 6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide;

(6S)-N-[6-(difluoromethyl)-5-fluoro-2-pyridyl]-3-(5,5-dimethyl-2-oxo-oxazolidin-3-yl)-6- methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide;

(6S)-N-(2-chloro-4-pyridyl)-3-(5,5-dimethyl-2-oxo-oxazolidin-3-yl)-6-methyl-6,7- dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide; (6S)-3-(5,5-dimethyl-2-oxo-oxazolidin-3-yl)-6-methyl-N-[2-(trifluoromethyl)-4-pyridyl]- 6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide;

and their enantiomers or diastereomers are excluded.

2. A compound according to claim 1, wherein

R¹ is

R² is H;

R³ is methyl;

difluoromethylpyridinyl or trifluoromethylpyridinyl.

3. A compound according to claim 1, wherein

R¹ is wherein R⁵, R⁶ and R⁷ are C_1-6alkyl;

R² is H;

R³ is C_1-6alkyl;

R⁴ is phenyl three times substituted by halogen, or pyridinyl substituted by haloC_1-6alkyl.

4. A compound according to claim 1 or 3, wherein

R¹ is

R² is H;

R³ is methyl;

R⁴ is trifluorophenyl or difluoromethylpyridinyl.

5. A compound selected from:

(6S)-N-[2-(difluoromethyl)-4-pyridyl]-3-[(4S,5R)-4,5-dimethyl-2-oxo-oxazolidin-3-yl]-6- methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide;

(6S)-N-(2,6-difluoro-4-pyridyl)-3-[(4S,5S)-4,5-dimethyl-2-oxo-oxazolidin-3-yl]-6-methyl-6,7- dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide;

(6S)-N-(2,6-difluoro-4-pyridyl)-3-(5,5-dimethyl-2-oxo-oxazolidin-3-yl)-6-methyl-6,7-dihydro- 4H-pyrazolo[1,5-a]pyrazine-5-carboxamide.

6. A compound according to claim 3, selected from:

(6S)-N-[2-(difluoromethyl)-4-pyridyl]-6-methyl-3-[(4S)-4,5,5-trimethyl-2-oxo-oxazolidin-3-yl]- 6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide.

7. A compound of formula (I), wherein

R¹ is

R² is H;

R³ is C_1-6alkyl;

R⁴ is phenyl which is three times substituted by halogen;

or pharmaceutically acceptable salt, enantiomer or diastereomer thereof;

with the proviso that R⁸ and R⁹ are not H simultaneously.

8. A compound according to claim 7, wherein

R¹ is

, wherein R⁸ is H, pyridinyl or trifluoromethyl; R⁹ is H, pyridinyl or methyl;

R² is H;

R³ is methyl;

R⁴ is trifluorophenyl.

9. A compound selected from:

(6S)-6-methyl-3-[(4S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl]-N-(3,4,5-trifluorophenyl)- 6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide; (6S)-6-methyl-3-[(5S)-5-methyl-2-oxo-imidazolidin-1-yl]-N-(3,4,5-trifluorophenyl)-6,7-dihydro- 4H-pyrazolo[1,5-a]pyrazine-5-carboxamide;

(6S)-6-methyl-3-[2-oxo-5-(2-pyridyl)imidazolidin-1-yl]-N-(3,4,5-trifluorophenyl)-6,7-dihydro- 4H-pyrazolo[1,5-a]pyrazine-5-carboxamide.

10. A compound of formula (I), wherein

R¹ is

wherein R¹⁰ is H, halogen or hydroxy; R¹¹ is H or halogen; R¹² is H, cyano, hydroxy, pyridinyl or pyrimidinyloxy; R¹³ is H, C_1-6alkyl or morpholinylcarbonyl; R¹⁴ is H, C_1-6alkyl, C_1-6alkylaminocarbonyl or (C_1- ₆alkyl)₂aminoC_1-6alkyl;

R² is H or C_1-6alkyl;

R³ is C1-6alkyl;

(6S)-6-methyl-3-[2-oxo-4-(3-pyridyl)pyrrolidin-1-yl]-N-(3,4,5-trifluorophenyl)-6,7- dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide; (6S)-6-methyl-3-[2-oxo-4-(2-pyridyl)pyrrolidin-1-yl]-N-(3,4,5-trifluorophenyl)-6,7- dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide;

(6S)-6-methyl-3-[(4R)-2-oxo-4-pyrimidin-2-yloxy-pyrrolidin-1-yl]-N-(3,4,5- trifluorophenyl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide;

(6S)-3-[(3R,4R)-3,4-dihydroxy-2-oxo-pyrrolidin-1-yl]-6-methyl-N-(3,4,5-trifluorophenyl)- 6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide;

(6S)-3-[(2R,3R,4S)-4-hydroxy-2-methyl-5-oxo-3-pyrimidin-2-yloxy-pyrrolidin-1-yl]-6- methyl-N-(3,4,5-trifluorophenyl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide; and their enantiomers or diastereomers are excluded.

11. A compound according to claim 10, wherein R¹ is

morpholinylcarbonyl; R¹⁴ is H, methyl, methylaminocarbonyl or

dimethylaminomethyl;

R² is H or methyl;

R³ is methyl;

R⁴ is trifluorophenyl, difluoropyridinyl or difluoromethylpyridinyl.

12. A compound according to claim 10, wherein

R¹ is

, wherein R¹⁰ is H; R¹¹ is H; R¹² is cyano, hydroxy or

pyrimidinyloxy; R¹³ is H; R¹⁴ is H or C1-6alkyl;

R² is H or C_1-6alkyl;

R³ is C_1-6alkyl;

R⁴ is phenyl which is three times substituted by halogen; or pyridinyl which is once or

twice substituted by substituents independently selected from halogen and haloC_1- ₆alkyl.

13. A compound according to claim 12, wherein

R¹ is

R² is H or methyl; R³ is methyl;

R⁴ is trifluorophenyl, difluoropyridinyl or difluoromethylpyridinyl.

14. A compound selected from:

(6S)-3-(3,3-difluoro-2-oxo-pyrrolidin-1-yl)-6-methyl-N-(3,4,5-trifluorophenyl)-6,7-dihydro-4H- pyrazolo[1,5-a]pyrazine-5-carboxamide;

(6S)-3-(4-cyano-2-oxo-pyrrolidin-1-yl)-N-(2,6-difluoro-4-pyridyl)-6-methyl-6,7-dihydro-4H- pyrazolo[1,5-a]pyrazine-5-carboxamide; (6S)-N-(2,6-difluoro-4-pyridyl)-6-methyl-3-[(2S,3S)-2-methyl-5-oxo-3-pyrimidin-2-yloxy- pyrrolidin-1-yl]-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide;

(6S,7R)-3-(4-cyano-2-oxo-pyrrolidin-1-yl)-6,7-dimethyl-N-(3,4,5-trifluorophenyl)-6,7-dihydro- 4H-pyrazolo[1,5-a]pyrazine-5-carboxamide.

15. A compound selected from:

(6S,7S)-3-(4-cyano-2-oxo-pyrrolidin-1-yl)-6,7-dimethyl-N-(3,4,5-trifluorophenyl)-6,7-dihydro- 4H-pyrazolo[1,5-a]pyrazine-5-carboxamide; and (6S,7R)-3-(4-cyano-2-oxo-pyrrolidin-1-yl)-6,7-dimethyl-N-(3,4,5-trifluorophenyl)-6,7-dihydro- 4H-pyrazolo[1,5-a]pyrazine-5-carboxamide.

16. A compound of formula (I), wherein

R¹ is oxoazaspiro[2.4]heptanyl;

oxobenzimidazolyl;

oxodiazabicyclo[3.1.1]heptanyl;

oxohexahydrobenzimidazolyl;

oxooxazinanyl which is twice substituted by C_1-6alkyl and cyano;

oxopyridinyl;

oxotetrahydrocyclopenta[d]oxazolyl;

oxotetrahydrofuro[3,4-d]imidazolyl; or

oxotetrahydrofuro[3,4-d]oxazolyl;

R² is H;

R³ is C_1-6alkyl;

with the proviso that

Ethyl 6-[(6S)-6-methyl-5-[(3,4,5-trifluorophenyl)carbamoyl]-6,7-dihydro-4H- pyrazolo[1,5-a]pyrazin-3-yl]-7-oxo-2,6-diazaspiro[3.4]octane-2-carboxylate; (6S)-6-methyl-3-(5-oxo-4-oxa-6-azaspiro[2.4]heptan-6-yl)-N-(3,4,5-trifluorophenyl)-6,7- dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide;

and their enantiomers or diastereomers are excluded.

17. A compound according to claim 16, wherein

cyano(methyl)oxooxazinanyl; oxopyridinyl, 2-oxo-4,5,6,6a-tetrahydro-3aH- cyclopenta[d]oxazol-3-yl; 2-oxo-3a,4,6,6a-tetrahydro-1H-furo[3,4-d]imidazol-3-yl or 2-oxo-3a,4,6,6a-tetrahydrofuro[3,4-d]oxazol-3-yl;

R² is H;

R³ is methyl;

trifluoromethylpyridinyl.

18. A compound according to claim 16, wherein

R¹ is oxooxaazaspiro[2.4]heptanyl substituted by C_1-6alkyl;

R² is H;

R³ is C_1-6alkyl;

R⁴ is pyridinyl which is once or twice substituted by substituents independently selected from halogen and haloC_1-6alkyl.

19. A compound according to claim 18, wherein

R¹ is 7-methyl-5-oxo-4-oxa-6-azaspiro[2.4]heptan-6-yl;

R² is H; R³ is methyl;

R⁴ is difluoropyridinyl or difluoromethylpyridinyl.

20. A compound selected from:

(6S)-N-[2-(difluoromethyl)-4-pyridyl]-6-methyl-3-[(7S)-7-methyl-5-oxo-4-oxa-6- azaspiro[2.4]heptan-6-yl]-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide;

(6S)-3-[(3ar,7ar)-2-oxo-3a,4,5,6,7,7a-hexahydro-3H-benzimidazol-1-yl]-6-methyl-N-(3,4,5- trifluorophenyl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide;

(6S)-6-methyl-3-(5-oxo-4-azaspiro[2.4]heptan-4-yl)-N-(3,4,5-trifluorophenyl)-6,7-dihydro-4H- pyrazolo[1,5-a]pyrazine-5-carboxamide; Tert-butyl 6-[(6S)-5-[[2-(difluoromethyl)-4-pyridyl]carbamoyl]-6-methyl-6,7-dihydro-4H- pyrazolo[1,5-a]pyrazin-3-yl]-7-oxo-2,6-diazaspiro[3.4]octane-2-carboxylate;

(6S)-3-(7-acetyl-4-oxo-3,7-diazabicyclo[3.3.1]nonan-3-yl)-6-methyl-N-(3,4,5-trifluorophenyl)- 6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide;

(6S)-6-methyl-3-(2-oxo-1-pyridyl)-N-(3,4,5-trifluorophenyl)-6,7-dihydro-4H-pyrazolo[1,5- a]pyrazine-5-carboxamide.

21. A compound selected from: (6S)-N-(2,6-difluoro-4-pyridyl)-6-methyl-3-[(7S)-7-methyl-5-oxo-4-oxa-6-azaspiro[2.4]heptan- 6-yl]-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide; and

(6S)-N-[2-(difluoromethyl)-4-pyridyl]-6-methyl-3-[(7S)-7-methyl-5-oxo-4-oxa-6- azaspiro[2.4]heptan-6-yl]-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide.

22. A process for the preparation of a compound according to any one of claims 1 to 21 comprising the following step:

(a) the reaction of a compound of formula (IV),

with an acid followed by urea formation with amine R⁴NH₂ in the presence of a phosgene equivalent; wherein R¹ to R⁴ are defined as in any one of claims 1 to 21.

23. A compound or pharmaceutically acceptable salts, enantiomers or diastereomers according to any one of claims 1 to 21 for use as therapeutically active substance.

24. A pharmaceutical composition comprising a compound in accordance with any one of claims 1 to 21 and a therapeutically inert carrier.

25. The use of a compound according to any one of claims 1 to 21 for the treatment or prophylaxis of hepatitis B virus infection.

26. The use of a compound according to any one of claims 1 to 21 for the preparation of a medicament for the treatment or prophylaxis of hepatitis B virus infection.

27. A compound or pharmaceutically acceptable salt, enantiomer or diastereomer according to any one of claims 1 to 21 for the treatment or prophylaxis of hepatitis B virus infection.

28. A compound or pharmaceutically acceptable salt, enantiomer or diastereomer according to any one of claims 1 to 21, when manufactured according to a process of claim 22.

29. A method for the treatment or prophylaxis of hepatitis B virus infection, which method comprises administering a therapeutically effective amount of a compound as defined in any one of claims 1 to 21. 20. The invention as hereinbefore described.