HK40004613B - 6,7-dihydro-4h-pyrazolo[1,5-a]pyrazine and 6,7-dihydro-4h-triazolo[1,5-a]pyrazine compounds for the treatment of infectious diseases - Google Patents

Description

6,7-Dihydro-4H-pyrazolo[1,5-a]pyrazine and 6,7-Dihydro-4H-triazolo[1,5-a]pyrazine compounds for treating infectious diseases

The present invention relates to organic compounds for treating and/or preventing, in particular for treating, hepatitis B virus infection in mammals, and also relates to their pharmaceutical activity, preparation, pharmaceutical compositions containing them and their potential use as drugs.

Field of the Invention

The present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof,

wherein ^R1 to ^R4 and Q are as described below. The compounds of the present invention can be used to treat or prevent hepatitis B virus infection.

Hepatitis B virus (HBV) infection is a significant public health concern worldwide, with approximately 30% of the world's population showing serological evidence of current or past infection. Despite the introduction of safe and effective vaccines against the virus in the early 1980s, it is estimated that over 240 million chronic HBV carriers remain worldwide, with a high risk of developing cirrhosis or hepatocellular carcinoma (HCC) (WHO Hepatitis B. Fact Sheet No. 204). In the 2010 Global Burden of Disease study (R. Lozano et al., Lancet, 380 (2012), 2095–2128), HBV infection ranked among the top global health concerns and the 10th leading cause of death (780,000 deaths annually). Recent studies have shown that the progression of cirrhosis and HCC in patients with chronic HBV infection is closely correlated with circulating HBV DNA levels. Therefore, antiviral therapy against HBV is crucial for preventing the progression of cirrhosis or the development of HCC.

HBV is a small enveloped virus belonging to the Hepadnaviridae family. It contains a partially double-stranded DNA genome of approximately 3200 base pairs. HBV has a strong propensity to infect human hepatocytes. Its life cycle begins when HBV binds to the host cell membrane via its envelope proteins. The precise mechanism of viral entry remains unclear. The viral relaxed circular DNA (rcDNA), containing the nucleocapsid, is released into the cytoplasm and transported to the nucleus. Within the nucleus, the rcDNA is repaired by both viral and cellular enzymes to form covalently closed circular DNA (cccDNA). Evidence suggests that each infected cell contains 1–50 cccDNA molecules as unique episomal minichromosomes. Both subgenomic RNA (sgRNA) and pregenomic RNA (pgRNA) can be transcribed from cccDNA using the cellular transcriptional machinery. After nuclear export, the pgRNA is translated into core proteins and the viral polymerase. The sgRNA is translated into the regulatory X protein and three envelope proteins. The self-assembly of the viral nucleocapsid containing RNA occurs through the formation of a complex of pgRNA with core protein and polymerase. In the nucleocapsid, the pgRNA is reverse transcribed into negative-strand DNA. rcDNA is then produced by positive-strand synthesis of the negative-strand DNA. The nucleocapsid can then be added to the cell nucleus for cccDNA amplification or can be released through the endoplasmic reticulum (ER). Reverse transcriptase lacks proofreading activity; therefore, mutations in the viral genome occur frequently, leading to the coexistence of genetically different viral species (quasispecies) in infected individuals.

Currently, seven treatments are approved for chronic hepatitis B (CHB), including two interferon (IFN) formulations (conventional IFN and PEG-IFN) and five nucleoside analogs (NUCs: lamivudine, adefovir dipivoxil, entecavir, telbivudine, and tenofovir disoproxil fumarate). The primary difference between immunomodulators and NUCs is that PEG-IFN has a defined duration of use, while NUC use is indefinite. The main disadvantage of PEG-IFN is the high incidence of adverse reactions. Certain viral genotypes do not respond well to interferon therapy. Furthermore, long-term use of NUCs may pose a risk of drug resistance. The ultimate goal of antiviral therapy for CHB is to prevent progression to cirrhosis or HCC by eradicating HBV or achieving sustained viral suppression. However, this goal is currently unattainable in the majority of treated patients. As mentioned above, nucleocapsid assembly is a critical step in HBV genome replication. Because viral DNA synthesis occurs exclusively within the nucleocapsid, precise control and regulation of nucleocapsid assembly and disassembly are essential to ensure proper packaging and release of the viral genome. Nucleocapsid assembly is a progressive, restricted process that limits HBV diversity and is highly sensitive to even subtle molecular perturbations. The assembly and disassembly of the nucleocapsid make it an attractive therapeutic target for the development of new antiviral therapies against various HBV genotypes and drug-resistant isolates. Several anti-HBV compounds related to the capsid have been reported. For example, heteroaryldihydropyrimidines (HAPs), including compounds designated Bay 41-4109, Bay 38-7690, and Bay 39-5493 (Deres K. et al., Science 2003, 893), and phenylacrylamide derivatives, such as AT-61 and AT-130 (Feld J. et al., Antiviral Research 2007, 168-177), have emerged as promising drug targets for several molecules currently under clinical investigation. There remains a need for new therapies for the prevention and treatment of HBV infection.

SUMMARY OF THE INVENTION

The present invention relates to novel compounds of formula (I), or pharmaceutically acceptable salts, enantiomers or diastereomers thereof,

in

R ¹ is dioxothiazinyl, dioxotetrahydro[1,2,5]thiadiazolo[3,2-c][1,4]oxazinyl, dioxothiadiazinyl, dioxothiadiazolidinyl, dioxothiadiazolidinyl, dioxothiazolidinyl, oxothiazolidinyl or trioxotetrahydropyrrolo[2,1-d][1,2,5]thiadiazinyl, said dioxothiazinyl, dioxotetrahydro[1,2,5]thiadiazolo[3,2-c][1,4]oxazinyl, dioxothiadiazinyl, dioxothiadiazolidinyl, dioxothiadiazolidinyl, oxothiazolidinyl and trioxotetrahydropyrrolo[2,1-d][1,2,5]thiadiazinyl being unsubstituted or substituted once, twice or three times with substituents independently selected from hydroxy, C 1-6 alkyl, C 1-6 alkyl, C 1-6 alkyl, C 1-6 alkyl, C 1-6 alkyl, C 1-6 alkyl, C 1-6 alkyl, C 1-6 alkyl, C 1-6 alkyl, C 1-6 alkyl, C 1-6 alkyl, C 1-6 alkyl, C 1-6 alkyl, C 1-6 alkyl, C 1-6 alkyl, C 1-6 alkyl, C 1-6 alkyl, C 1-6 alkyl, C _1-6 alkyl, C 1-6 alkyl, C C _1-6 alkoxy, C _1-6 alkylcarbonyl, benzyloxycarbonyl, carboxyphenyl, carboxypyrrolidinyl and pyrimidinyloxy;

^R2 is H or _C1-6 alkyl;

^R3 is _C1-6 alkyl;

^R4 is benzothiazolyl, phenyl _C1-6 alkyl, phenyl, pyridyl, thienyl or thienyl _C1-6 alkyl, wherein the benzothiazolyl, phenyl C1-6 alkyl, phenyl, pyridyl, thienyl and thienyl _C1-6 alkyl are substituted once, twice or three times by substituents independently selected from the group consisting of halogen, cyano, _C1-6 alkyl and halo _C1-6 alkyl _;

Q is CH or N.

The present invention relates to novel compounds of formula (I), their preparation, medicaments based on the compounds of the invention and their preparation, and the use of the compounds of formula (I) as HBV inhibitors and for the treatment or prevention of HBV infections.

Detailed Description of the Invention

definition

The term "C _1-6 alkyl" refers to a monovalent straight or branched chain saturated hydrocarbon group of 1 to 6 carbon atoms. In particular embodiments, the C _1-6 alkyl group has 1 to 6 carbon atoms, and in more particular embodiments, has 1 to 4 carbon atoms. Examples of C _1-6 alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, or tert-butyl.

The term "C _1-6 alkoxy" refers to C _1-6 alkyl-O-.

The term "pyrimidinyloxy" refers to pyrimidinyl-O-.

The terms "halo" or "halogen" are used interchangeably herein to refer to fluoro, chloro, bromo, or iodo.

The term "halogenated C _1-6 alkyl" refers to a C _1-6 alkyl group in which at least one hydrogen atom of the C _1-6 alkyl group is replaced by the same or different halogen atoms, in particular fluorine atoms. Examples of halosubstituted C _1-6 alkyl groups include monofluoro-, difluoro- or trifluoro-methyl, -ethyl or -propyl groups, such as 3,3,3-trifluoropropyl, 2-fluoroethyl, trifluoroethyl, fluoromethyl, difluoromethyl, difluoroethyl or trifluoromethyl.

The term "oxo" refers to a divalent oxygen atom =0.

The term "heterocyclyl" refers to a monovalent saturated or partially unsaturated mono- or bicyclic ring system of 3-10 ring atoms containing 1-5 ring heteroatoms selected from N, O and S, with the remaining ring atoms being carbon. In certain embodiments, the heterocyclyl is a monovalent monocyclic ring system of 4-7 ring atoms containing 1, 2 or 3 ring heteroatoms selected from N, O and S, with the remaining ring atoms being carbon. Examples of monocyclic heterocyclyls are aziridinyl, oxiranyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, morpholinyl, thiomorpholinyl, 1,1-dioxo-thiomorpholin-4-yl, azepanyl, diazepanyl, homopiperazinyl, oxazepanyl, Cycloheptyl; dioxooxathiazinyl, dioxotetrahydro[1,2,5]thiadiazolo[3,2-c][1,4]oxazinyl, dioxothiadiazinyl, dioxothiadiazolidinyl, dioxothiazetidinyl, dioxothiazolidinyl, oxothiazolidinyl or trioxotetrahydropyrrolo[2,1-d][1,2,5]thiadiazinyl; the monocyclic saturated heterocycle may be further substituted by benzyl, cyano, hydroxyl, C _1-6 alkyl, halogen, halogenated C _1-6 alkyl, C _1-6 alkylcarbonyl, benzyloxycarbonyl, C _1-6 alkoxy, carboxyphenyl, carboxypyrrolidinyl or pyrimidinyloxy. Examples of substituted monocyclic heterocyclyl groups include, but are not limited to, hydroxydioxothiadiazinyl, acetyldioxothiadiazinyl, benzyloxycarbonyldioxothiadiazinyl, methyldioxothiadiazolidinyl, dimethyldioxothiadiazolidinyl, methyldioxothiazetidinyl, hydroxydioxothiazolidinyl, hydroxy(methyl)dioxothiazolidinyl, methoxy(methyl)dioxothiazolidinyl, methyldioxothiazolidinyl, carboxyphenyldioxothiazolidinyl, carboxypyrrolidinyldioxothiazolidinyl, and pyrimidinyloxy(methyl)dioxothiazolidinyl.

The term "diastereomer" refers to stereoisomers with two or more chiral centers whose molecules are not mirror images of one another. Diastereomers have different physical properties, such as melting points, boiling points, spectral characteristics, activities, and reactivities.

The term "enantiomers" refers to two stereoisomers of a compound that are non-superimposable mirror images of one another.

The term "pharmaceutically acceptable salts" refers to salts that are not biologically or otherwise undesirable. Pharmaceutically acceptable salts include acid addition salts and base addition salts.

The term "pharmaceutically acceptable acid addition salts" refers to 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 the group consisting of aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic acids such as formic acid, acetic acid, propionic acid, glycolic acid, gluconic acid, lactic acid, pyruvic acid, oxalic acid, malic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, aspartic acid, ascorbic acid, glutamic acid, anthranilic acid, benzoic acid, cinnamic acid, mandelic acid, pamoic acid, phenylacetic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid and salicylic acid.

The term "pharmaceutically acceptable base addition salts" refers to those pharmaceutically acceptable salts formed with organic or inorganic bases. Examples of acceptable inorganic bases include salts of sodium, potassium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines; salts of substituted amines (including naturally occurring substituted amines); salts of cyclic amines and salts of basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-diethylaminoethanol, trimethylamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydroxylamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, and polyamine resins.

Compounds of formula (I) containing one or more chiral centers may exist as racemates, diastereomeric mixtures or optically active single isomers. Racemates can be separated into enantiomers according to known methods. In particular, diastereomeric salts that can be separated by crystallization methods can be formed from the racemic mixture by reaction with an optically active acid, such as D- or L-tartaric acid, mandelic acid, malic acid, lactic acid or camphorsulfonic acid.

HBV inhibitors

The present invention provides (i): a novel compound having the general formula (I), or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof,

in:

R ¹ is dioxooxathiazinyl, dioxotetrahydro[1,2,5]thiadiazolo[3,2-c][1,4]oxazinyl, dioxothiadiazinyl, dioxothiadiazolidinyl, dioxothiaazetidinyl, dioxothiazolidinyl, oxothiazolidinyl or trioxotetrahydropyrrolo[2,1-d][1,2,5]thiadiazinyl, said dioxooxathiazinyl, dioxotetrahydro[1,2,5]thiadiazolo[3,2-c][1,4]oxazinyl, dioxothiadiazinyl, dioxothiadiazolidinyl, dioxothiazetidinyl, dioxothiazolidinyl, oxothiazolidinyl and trioxotetrahydropyrrolo[2,1-d][1,2,5]thiadiazinyl being substituted one, two or three times with substituents independently selected from the group consisting of hydroxy, C 1-6 alkyl, C 1-6 alkyl, C 1-6 alkyl, C 1-6 alkyl, C 1-6 alkyl, C 1-6 alkyl, C 1-6 alkyl, C 1-6 alkyl, C 1-6 alkyl, C 1-6 alkyl, C 1-6 alkyl, C 1-6 alkyl, C 1-6 alkyl, C 1-6 alkyl, C 1-6 alkyl, C 1-6 alkyl, C 1-6 alkyl, C _1-6 alkyl, C 1-6 alkyl, C C _1-6 alkoxy, C _1-6 alkylcarbonyl, benzyloxycarbonyl, carboxyphenyl, carboxypyrrolidinyl and pyrimidinyloxy;

^R2 is H or _C1-6 alkyl;

^R3 is _C1-6 alkyl;

^R4 is benzothiazolyl, phenyl _C1-6 alkyl, phenyl, pyridyl, thienyl or thienyl _C1-6 alkyl, wherein the benzothiazolyl, phenyl C1-6 alkyl, phenyl, pyridyl, thienyl and thienyl _C1-6 alkyl are substituted once, twice or three times by substituents independently selected from the group consisting of halogen, cyano, _C1-6 alkyl and halo _C1-6 alkyl _;

Q is CH or N.

Another embodiment of the present invention is (ii): a compound of formula (I), or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof,

in

^R1 is

dioxothiazininyl;

dioxotetrahydro[1,2,5]thiadiazolo[3,2-c][1,4]oxazinyl;

a dioxothiadiazinyl group which is unsubstituted or substituted with a hydroxyl group, a C _1-6 alkylcarbonyl group, or a benzyloxycarbonyl group;

Dioxothiadiazolidinyl, which is unsubstituted or substituted once or twice with C _1-6 alkyl;

dioxothiazetidinyl, which is unsubstituted or substituted with C _1-6 alkyl;

a dioxothiazolidinyl group, wherein the dioxothiadiazolidinyl group is unsubstituted or substituted once or twice with substituents independently selected from the group consisting of hydroxy, C _1-6 alkyl, C _1-6 alkoxy, carboxyphenyl, carboxypyrrolidinyl, and pyrimidinyloxy;

Oxothiazolidinyl; or

trioxotetrahydropyrrolo[2,1-d][1,2,5]thiadiazinyl;

^R2 is H;

^R3 is _C1-6 alkyl;

^R4 is

benzothiazolyl;

Phenyl C _1-6 alkyl;

Phenyl, substituted once, twice or three times with substituents independently selected from the group consisting of halogen, cyano, C _1-6 alkyl and halo-substituted C _1-6 alkyl;

Pyridyl, wherein the pyridyl is substituted by halogen or halogenated C _1-6 alkyl;

thienyl; or

Thienyl C _1-6 alkyl;

Q is CH or N.

Another embodiment of the present invention is (iii): a compound of formula (I), or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof,

in

^R1 is dioxothiazinyl, dioxotetrahydro[1,2,5]thiadiazolo[3,2-c][1,4]oxazinyl, dioxothiadiazinyl, hydroxydioxothiadiazinyl, acetyldioxothiadiazinyl, benzyloxycarbonyldioxothiadiazinyl, dioxothiadiazinyl, methyldioxothiadiazinyl, dimethyldioxothiadiazinyl, dioxothiazetidinyl, methyldioxothiadiazinyl, dioxothiazolidine 1,1-dioxo-3a,4,6,7-tetrahydro-3H-[1,2,5]thiadiazolo[3,2-c][1,4]oxazin-2-yl;

^R2 is H;

^R3 is methyl;

^R4 is benzothiazolyl, benzyl, fluorophenyl, fluorochlorophenyl, fluorocyanophenyl, fluoro(methyl)phenyl, fluoro(trifluoromethyl)phenyl, trifluorophenyl, chloropyridyl, difluoromethylpyridyl, thienyl or thienylmethyl;

Q is CH or N.

Another embodiment of the present invention is (iv): a compound of formula (I), wherein Q is CH.

Another embodiment of the present invention is (v): a compound of formula (I), wherein R ¹ is a dioxothiazolidinyl group, said dioxothiadiazolidinyl group being unsubstituted or substituted once or twice with substituents independently selected from the group consisting of hydroxy, C _1-6 alkyl, C _1-6 alkoxy, carboxyphenyl, carboxypyrrolidinyl and pyrimidinyloxy.

Another embodiment of the present invention is (vi): a compound of formula (I), wherein R ¹ is dioxothiazolidinyl, hydroxydioxothiazolidinyl, hydroxy(methyl)dioxothiazolidinyl, methoxy(methyl)dioxothiazolidinyl, methyldioxothiazolidinyl, carboxyphenyldioxothiazolidinyl, carboxypyrrolidinyldioxothiazolidinyl or pyrimidinyloxy(methyl)dioxothiazolidinyl.

In another embodiment of the present invention, the specific compound of the present invention is (vii), selected from:

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

(6S)-N-(2-chloro-4-pyridinyl)-3-(1,1-dioxo-1,2-thiazolidin-2-yl)-6-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide;

(6S)-N-(4-chloro-3-fluoro-phenyl)-3-(1,1-dioxo-1,2-thiazolidin-2-yl)-6-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide;

(6S)-3-(1,1-dioxo-1,2-thiazolidin-2-yl)-N-(4-fluoro-3-methyl-phenyl)-6-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide;

(6S)-N-(3-Cyano-4-fluoro-phenyl)-3-(1,1-dioxo-1,2-thiazolidin-2-yl)-6-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide;

(6S)-N-[2-(difluoromethyl)-4-pyridinyl]-3-(1,1-dioxo-1,2-thiazolidin-2-yl)-6-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide;

(6S)-3-(1,1-dioxo-1,2-thiazolidin-2-yl)-N-[4-fluoro-3-(trifluoromethyl)phenyl]-6-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide;

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

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

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

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

(6S)-3-(1,1-dioxo-3a,4,6,7-tetrahydro-3H-[1,2,5]thiadiazolo[3,2-c][1,4]oxazin-2-yl)-6-methyl-N-(3,4,5-trifluorophenyl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide;

benzyl 2-[(6S)-6-methyl-5-[(3,4,5-trifluorophenyl)carbamoyl]-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-3-yl]-1,1-dioxo-1,2,5-thiadiazinane-5-carboxylate;

(6S)-6-methyl-N-(3,4,5-trifluorophenyl)-3-(3,3,6-trioxo-4,7,8,8a-tetrahydro-1H-pyrrolo[2,1-d][1,2,5]thiadiazin-2-yl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide;

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

(6S)-N-[2-(difluoromethyl)-4-pyridinyl]-3-(4-hydroxy-3-methyl-1,1-dioxo-1,2-thiazolidin-2-yl)-6-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide;

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

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

(6S)-N-[2-(difluoromethyl)-4-pyridinyl]-3-(4-methoxy-3-methyl-1,1-dioxo-1,2-thiazolidin-2-yl)-6-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide;

(6S)-N-[2-(difluoromethyl)-4-pyridinyl]-3-(4-methoxy-3-methyl-1,1-dioxo-1,2-thiazolidin-2-yl)-6-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide;

3-(1,1-dioxo-1,2-thiazolidin-2-yl)-6-methyl-N-(3,4,5-trifluorophenyl)-6,7-dihydro-4H-triazolo[1,5-a]pyrazine-5-carboxamide;

3-(1,1-dioxo-1,2-thiazolidin-2-yl)-6-methyl-N-(3,4,5-trifluorophenyl)-6,7-dihydro-4H-triazolo[1,5-a]pyrazine-5-carboxamide;

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

(2S)-1-[2-[(6S)-6-methyl-5-[(3,4,5-trifluorophenyl)carbamoyl]-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-3-yl]-1,1-dioxo-1,2-thiazolidin-4-yl]pyrrolidine-2-carboxylic acid; and

2-[2-[(6S)-6-Methyl-5-[(3,4,5-trifluorophenyl)carbamoyl]-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-3-yl]-1,1-dioxo-1,2-thiazolidin-4-yl]benzoic acid.

In another embodiment of the present invention, the specific compound of the present invention is (viii), selected from:

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

(6S)-3-(1,1-dioxo-1,2-thiazolidin-2-yl)-N-(4-fluoro-3-methyl-phenyl)-6-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide;

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

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

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

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

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

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

(2S)-1-[2-[(6S)-6-Methyl-5-[(3,4,5-trifluorophenyl)carbamoyl]-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-3-yl]-1,1-dioxo-1,2-thiazolidin-4-yl]pyrrolidine-2-carboxylic acid.

synthesis

The compounds of the present invention can be prepared by any conventional method. Suitable methods and starting materials for synthesizing these compounds are provided in the following schemes and examples. Unless otherwise indicated, all substituents (particularly R ¹ -R ⁴ and Q) are as defined above. In addition, unless otherwise expressly provided, all reactions, reaction conditions, abbreviations, and symbols have the meanings known to those skilled in the art of organic chemistry.

Scheme 1: General synthetic route for the compounds of the present invention

^R5 and ^R6 together with the nitrogen and sulfur to which they are attached form a 4-10 membered heterocyclic group.

Formula (VII) and (X) compound can be prepared according to process 1.Bicyclo (II) is processed with iodinating agent such as N-iodosuccinimide to obtain iodide (III), and in the presence of a copper catalyst such as CuI, it and sulfinamide (IV) carry out copper-catalyzed coupled reaction to obtain formula (V) compound.Deprotection intermediate (V) under acidic conditions, such as the HCl in EtOAc and the TFA in DCM, then react with phenyl carbamate (VI) to obtain final formula (VII) compound.On the other hand, the copper-catalyzed coupled reaction between iodide (III) and sulfonamide (VIII) obtains formula (IX) compound, which undergoes deprotection under acidic conditions, such as the EtOAc solution of HCl and the DCM solution of TFA, then react with phenyl carbamate (VI) to obtain final formula (X) compound.

The present invention also relates to a process for preparing a compound of formula (I), (VII) or (X), comprising any one of the following steps:

(a) Compound of formula (V)

Reaction with acid, followed by reaction with phenyl carbamate (VI);

(b) Compound of formula (IX)

Reaction with acid, followed by reaction with phenyl carbamate (VI);

In steps (a) and (b), the acid can be, for example, a solution of HCl in EtOAc or a solution of TFA in DCM.

Compounds of formula (I), (VII) or (X) prepared according to the above-described process are also an object of the present invention.

Pharmaceutical compositions and administration

Another embodiment provides a pharmaceutical composition or medicine, which comprises the compounds of this invention and a therapeutically inert carrier, diluent or excipient, and also provides a method for preparing such compositions and medicines using the compounds of this invention. In one example, the compound of formula (I) can be prepared as a galenic dosage form at ambient temperature, in an appropriate pH and with the required purity by mixing with a physiologically acceptable carrier (i.e., a nontoxic carrier to the recipient at the dosage and concentration used). The pH of the preparation depends primarily on the specific use and concentration of the compound, but the preferred range is from about 3 to about 8. In one example, the compound of formula (I) is prepared in an acetic acid buffer at pH 5. In one example, the compound of formula (I) is sterile. The compound can be stored as, for example, a solid or amorphous composition, a freeze-dried formulation or an aqueous solution.

The composition can be formulated, dispensed, and administered in a manner consistent with good medical practice. Factors considered herein include the specific disease to be treated, the specific mammal to be treated, the clinical condition of the individual patient, the cause of the disease, the site of drug delivery, the method of administration, the time schedule for administration, and other factors well known to practitioners. The "effective amount" of the compound to be administered depends on the above-mentioned considerations and is the minimum amount necessary to suppress serum HBV DNA levels, or seroconversion of HBeAg to HBeAb, or reduction of HBsAg, or normalization of alanine aminotransferase levels, and improvement in liver histology. For example, the amount may be less than an amount that would be toxic to normal cells or the mammal as a whole.

In one example, the pharmaceutically effective amount of the compound of the present invention administered parenterally per dose is in the range of about 0.01-100 mg/kg, or about 0.1-20 mg/kg of patient body weight/day, with a typical initial dose of 0.3-15 mg/kg/day. In another embodiment, oral unit dosage forms (e.g., tablets and capsules) contain about 0.1 to about 1000 mg of the compound of the present invention.

The compounds of the present invention can be administered by any appropriate method, including oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, subcutaneous, intraperitoneal, intrapulmonary, intradermal, intrathecal, epidural and intranasal, and if local treatment is required, also including intralesional administration. Parenteral infusion includes intramuscular, intravenous, intraarterial, intraperitoneal or subcutaneous administration.

The compounds of the present invention can be administered in any convenient form, such as tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, etc. Such compositions may contain ingredients commonly used in pharmaceutical preparations, such as diluents, carriers, pH adjusters, sweeteners, fillers and other active ingredients.

Typical formulations are prepared by mixing a compound of the invention with a carrier or excipient. Suitable carriers and excipients are well known to those skilled in the art and are described in detail, for example, in 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 preparation may also include one or more buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifiers, processing aids, colorants, sweeteners, aromas, flavorings, diluents and other known additives to provide a drug (i.e., a compound of the present invention or a pharmaceutical composition thereof) with a good appearance or to facilitate the production of a pharmaceutical product (i.e., a drug).

An example of a suitable oral dosage form is a tablet containing the following ingredients: about 0.1 mg to 1000 mg of a compound of the invention, along with about 30 mg to 90 mg of anhydrous lactose, about 5 mg to 40 mg of croscarmellose sodium, about 5 mg to 30 mg of polyvinylpyrrolidone (PVP) K30, and about 1 mg to 10 mg of magnesium stearate. The powdered ingredients are first blended together and then mixed with the PVP solution. The resulting composition is dried, granulated, mixed with the magnesium stearate, and compressed into tablet form using conventional equipment. An example of an aerosol formulation can be prepared by dissolving, for example, 5 mg to 400 mg of a compound of the invention in a suitable buffer (e.g., phosphate buffer) and, if desired, adding a tonicity adjuster (e.g., a salt such as sodium chloride). The solution can be filtered, for example, using a 0.2 micron filter, to remove impurities and contaminants.

Thus, one embodiment includes a pharmaceutical composition comprising a compound of formula (I) or a stereoisomer or pharmaceutically acceptable salt thereof.Another embodiment includes a pharmaceutical composition comprising a compound of formula (I) or a stereoisomer or pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient.

Indications and treatments

The compounds of the present invention can inhibit HBV DNA synthesis and reduce HBV DNA levels. Therefore, the compounds of the present invention can be used to treat or prevent HBV infection.

The present invention relates to the use of the compound of formula (I) in treating or preventing HBV infection.

The use of the compound of formula (I) in the preparation of a medicament for treating or preventing diseases associated with HBV infection is also an object of the present invention.

The present invention particularly relates to the use of the compound of formula (I) in the preparation of a medicament for treating or preventing HBV infection.

Another embodiment includes a method of treating or preventing HBV infection comprising administering an effective amount of a compound of formula (I), a stereoisomer, tautomer, prodrug, or pharmaceutically acceptable salt thereof.

Example

The present invention may be more fully understood with reference to the following examples, which, however, should not be construed as limiting the scope of the invention.

The abbreviations used in this article are as follows:

General experimental conditions

Intermediates and final compounds were purified by flash chromatography using one of the following instruments: i) Biotage SP1 system with Quad 12/25 cartridge module; ii) ISCO combi-flash chromatography instrument. Silica gel brands and pore sizes: i) KP-SIL, particle size: 40-60 μm; ii) CAS Registry Number: 63231-67-4, particle size: 47-60 μm; iii) ZCX, obtained from Qingdao Haiyang Chemical Co., Ltd., pore size: 200-300 or 300-400 μm.

Intermediates and final compounds were purified by preparative HPLC on a reverse phase column using an XBridge ^™ Prep-C18 (5 μm, OBD™ 30×100 mm) or SunFire ^™ Prep-C18 (5 μm, OBD ^™ 30×100 mm) column. Waters AutoP purification system (column: XBridge ^™ Prep-C18, 30×100 mm, sample processor 2767, pump 2525, detector: Micromass ZQ and UV 2487, solvent system: acetonitrile and 0.1% aqueous ammonium hydroxide). LC/MS spectra of the compounds were obtained using LC/MS (Waters ^™ Alliance 2795-Micromass ZQ) under the following LC/MS conditions (run time 6 minutes):

Acidic conditions: A: 0.1% formic acid in water; B: 0.1% formic acid in acetonitrile;

Basic conditions: A: 0.1% NH ₃ ·H ₂ O aqueous solution; B: acetonitrile;

Neutral conditions: A: H ₂ O; B: acetonitrile.

Mass Spectrometry (MS): Generally, only ions representing the parent mass are reported. Unless otherwise specified, the mass ion quoted is the positively charged mass ion (MH) ⁺ .

NMR spectra were obtained using a Bruker Avance 400 MHz.

Microwave-assisted reactions were performed on a Biotage Initiator Sixty microwave synthesizer.

All reactions involving air-sensitive reagents were performed under argon or nitrogen atmosphere. Unless otherwise stated, reagents obtained from commercial suppliers were used directly without further purification.

The following examples are intended to illustrate the meaning of the present invention, but are by no means intended to limit the meaning of the present invention.

Preparation Example

The present invention may be more fully understood with reference to the following examples, which, however, should not be construed as limiting the scope of the invention.

Intermediate I-1

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

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

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). The reaction mixture was stirred at 25°C for 1 hour. _NaBH₄ (25.9 g, 675 mmol) was added at 0°C and the reaction mixture was stirred for another hour. _H₂O (300 mL) and _Boc₂O (147.1 g, 675 mmol) were then added. The resulting mixture was stirred at room temperature for 12 hours and extracted with EtOAc (600 mL). The organic layer was dried _over anhydrous _Na₂SO₄ , filtered, and concentrated. The residue was purified by column chromatography (eluting with 0% to 5% MeOH in DCM) to provide Compound I-1b (80 g) as a colorless oil. MS found (ESI ⁺ ) [(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 g, 117.2 mmol) and Et ₃ N (100.5 g, 995.6 mmol) in DCM (800 mL) was slowly added MsCl (57.3 g, 497.8 mmol) at 0°C. The resulting mixture was stirred at room temperature for 2 hours, then washed with water (500 mL), brine (500 mL), and dried over anhydrous Na ₂ SO _4. The organic layer was concentrated to give compound I-1c (100 g, crude material), which was used directly in the 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 g, 313.4 mmol) in DMF (1000 mL) at 0°C was added NaH (15 g, 376.2 mmol) portionwise. The reaction mixture was then stirred at room temperature for 12 hours, poured into water (2000 mL), and extracted twice with EtOAc (1000 mL). The combined organic layers were concentrated, and the residue was purified by column chromatography (eluting with 10% to 80% EtOAc in petroleum ether) to afford Compound I-1d (18 g) as a colorless oil. MS found (ESI ⁺ ) [(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 (Intermediate I-1):

To a solution of tert-butyl 6-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate (Compound I-1d, 3.3 g, 14.8 mmol) in CH ₃ CN (40 mL) was slowly added NIS (5.0 g, 22.1 mmol). The reaction mixture was stirred at room temperature for 16 hours, then extracted with EtOAc (50 mL) and washed with brine (50 mL). The organic layer was dried over Na ₂ SO ₄ and concentrated, and the residue was purified by column chromatography (eluting with 10% to 80% EtOAc in petroleum ether) to afford Intermediate I-1 (4.8 g) as a white solid.

Intermediate I-2

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

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

To a solution of 3,4,5-trifluoroaniline (1.47 g, 10 mmol) in DCM (30 mL) was added DIPEA (2 mL, 12 mmol), followed by the dropwise addition of phenyl chloroformate (1.4 mL, 11 mmol) at 0°C _. After the addition was complete, the reaction mixture was warmed to room temperature and stirred overnight. The reaction mixture was diluted with DCM and washed with water. The organic phase was separated, dried over anhydrous _Na₂SO₄ , and concentrated. The residue was purified by column chromatography to afford intermediate I-2 (1.87 g) as a white solid. MS found (ESI ⁺ )[(M+H) ⁺ ]: 268.

Intermediate I-3

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

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

To a mixture of 4-bromo-2-(difluoromethyl)pyridine (compound I-3a, 416 mg, 2.0 mmol) and diphenylmethane (725 mg, 4.0 mmol) in toluene (15 mL) were added Pd ₂ (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 heated at 100 ° C for 2 hours. The reaction mixture was cooled, diluted with EtOAc (30 mL), and washed with water. The organic layer was separated and concentrated to give crude compound I-3b (617 mg). MS measured value (ESI ⁺ ) [(M+H) ⁺ ]: 309. Compound I-3b (617 mg, 2 mmol) was dissolved in THF (10 mL) and hydrochloric acid (2 mL, 12 M). The resulting mixture was stirred at room temperature for 2 hours and then concentrated. The residue was dissolved in DCM (5 mL), and DIPEA (1 mL, 5.8 mmol) and benzoyl chloride (251 μL, 2.0 mmol) were added at 0°C. The resulting mixture was stirred at room temperature for 2 hours, then poured into water (20 mL) and extracted twice with EtOAc (20 mL). The organic layers were combined and concentrated, and the residue was purified by column chromatography (eluting with 0% to 20% EtOAc in petroleum ether) to obtain intermediate I-3 (264 mg) as a white solid. MS found (ESI ⁺ ) [(M+H) ⁺ ]: 265.

Intermediate I-4

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

Intermediate I-4 was prepared similarly to Intermediate I-2, using 2-chloropyridin-4-amine instead of 3,4,5-trifluoroaniline. Intermediate I-4 (1.74 g) was obtained as a white solid. MS found (ESI ⁺ ) [(M+H) ⁺ ]: 249.

Intermediate I-5

N-(4-Chloro-3-fluoro-phenyl)carbamic acid phenyl ester

Intermediate I-5 was prepared according to the following process:

To a mixture of 4-chloro-3-fluoroaniline (1.0 g, 6.87 mmol) and phenyl chloroformate (1.0 g, 6.87 mmol) in DCM (64 mL) was added _Et₃N (1.4 g, 13.74 mmol). The mixture was stirred at 20°C for 4 hours and then concentrated under reduced pressure. The residue was partitioned between EtOAc (50 mL) and water (50 mL). The organic layer was washed with brine, dried over _{anhydrous Na₂SO₄} , and concentrated under reduced pressure. The residue was purified by silica gel chromatography to afford phenyl N-(4-chloro-3-fluoro-phenyl)carbamate (Intermediate I-5, 550 mg) as a white solid. MS measured ( ^ESI⁺ ) [(M+H) ^⁺ ]: 266.

Intermediate I-6

N-(4-Fluoro-3-methyl-phenyl)carbamic acid phenyl ester

Intermediate I-6 was prepared according to the following process:

To a mixture of 4-fluoro-3-methylaniline (1.0 g, 8.0 mmol) and phenyl chloroformate (1.25 g, 8.0 mmol) in DCM (70 mL) was added _Et₃N (1.6 g, 16 mmol). The mixture was stirred at 20°C for 16 hours and then concentrated under reduced pressure. The residue was dissolved in EtOAc (20 mL) and PE (20 mL) was added. The resulting suspension was stirred for 5 minutes and then filtered. The filtrate was concentrated under reduced pressure and the residue was recrystallized from EtOAc and PE to obtain phenyl N-(4-fluoro-3-methyl-phenyl)carbamate (Intermediate I-6, 730 mg) as a white solid. MS measured value (ESI ⁺ )[(M+H) ⁺ ]: 246.

Intermediate I-7

N-(3-Cyano-4-fluoro-phenyl)carbamic acid phenyl ester

Intermediate I-7 was prepared similarly to Intermediate I-6, using 5-amino-2-fluoro-benzonitrile instead of 4-fluoro-3-methylaniline. Intermediate I-7 (200 mg) was obtained as a white solid. MS measured value (ESI ⁺ ) [(M+H) ⁺ ]: 257.

Intermediate I-8

Phenyl N-[4-fluoro-3-(trifluoromethyl)phenyl]carbamate

Intermediate I-8 was prepared similarly to compound I-5, using 4-fluoro-3-(trifluoromethyl)aniline instead of 4-chloro-3-fluoroaniline. Intermediate I-8 (100 mg) was obtained as a white solid. MS found (ESI ⁺ ) [(M+H) ⁺ ]: 300.

Intermediate I-9

Phenyl N-(2-fluorophenyl)carbamate

Intermediate I-9 was prepared similarly to compound I-5, using 2-fluoroaniline instead of 4-chloro-3-fluoroaniline. Intermediate I-9 (100 mg) was obtained as a white solid. MS found (ESI ⁺ ) [(M+H) ⁺ ]: 232.

Intermediate I-10

Phenyl N-(1,3-benzothiazol-6-yl)carbamate

Intermediate I-10 was prepared similarly to compound I-5, using 1,3-benzothiazol-6-amine instead of 4-chloro-3-fluoroaniline. Intermediate I-10 (50 mg) was obtained as a white solid. MS found (ESI ⁺ ) [(M+H) ⁺ ]: 271.

Intermediate I-11

Phenyl N-(3-thienyl)carbamate

Intermediate I-11 was prepared similarly to compound I-5, using thiophene-3-amine instead of 4-chloro-3-fluoroaniline. Intermediate I-11 (150 mg) was obtained as a white solid. MS found (ESI ⁺ ) [(M+H) ⁺ ]: 220.

Intermediate I-12

N-Benzylcarbamic acid phenyl ester

Intermediate I-12 was prepared similarly to compound I-6, using phenylmethylamine instead of 4-fluoro-3-methylaniline. Intermediate I-12 (900 mg) was obtained as a white solid. MS found (ESI ⁺ ) [(M+H) ⁺ ]: 228.

Intermediate I-13

3-Methyl-1,2-thiazolidine 1,1-dioxide

Intermediate I-13 was prepared according to the following process:

Step 1: Preparation of tert-butyl N-(3-hydroxybutylsulfonyl)carbamate (Compound I-13b)

To a solution of diisopropylamine (15.54 g, 163.66 mmol) in THF (150 mL) at -78°C was added n-BuLi (61.5 mL, 153.75 mmol, 2.5 M solution in hexane). The mixture was stirred at -78°C for 20 minutes. A solution of tert-butyl methylsulfonylcarbamate (Compound I-13a, 15.0 g, 76.8 mmol) in THF (150 mL) was then added dropwise over 20 minutes. The mixture was stirred at -50°C for 30 minutes, followed by the addition of a solution of propylene oxide (5.58 g, 96.03 mmol, 6.72 mL) in THF (90 mL) at -78°C over 30 minutes. The mixture was warmed to room temperature and stirred for 15 hours. The mixture was poured into an aqueous NH ₄ Cl solution (210 mL). The resulting precipitate was collected and dissolved in water, then acidified to pH 3 with 2M HCl. The resulting aqueous mixture was extracted five times with DCM (100 mL). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ , and concentrated under reduced pressure. The residue was purified by column chromatography to afford compound I-13b (17 g) as a colorless oil. MS found (ESI ⁺ ) [(M+H) ⁺ ]: 254

Step 2: Preparation of tert-butyl N-(3-oxobutylsulfonyl)carbamate (Compound I-13c)

A mixture of tert-butyl N-(3-hydroxybutylsulfonyl)carbamate (compound I-13b, 17.0 g, 67.1 mmol) and pyridinium chlorochromate (30.4 g, 140.9 mmol) in DCM (500 mL) was stirred at 15 ° C for 16 hours. The reaction mixture was filtered through celite. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography to obtain crude compound I-13c (15 g) as a black solid. MS measured value (ESI ⁺ )[(M+H) ⁺ ]: 252

Step 3: Preparation of 3-methyl-4,5-dihydroisothiazole 1,1-dioxide (Compound I-13d)

A mixture of tert-butyl N-(3-oxobutylsulfonyl)carbamate (Compound I-13c, 10.0 g, 39.8 mmol) and TFA (15.4 g, 159.2 mmol) in DCM (375 mL) was refluxed for 48 hours. The mixture was concentrated under reduced pressure, and the residue was dissolved in EtOH (50 mL). The solution was concentrated under reduced pressure to leave 25 mL of the mixture, which was cooled to -20°C. The mixture was filtered. The filter cake was washed with cooled EtOH (25 mL, -20°C) and dried under reduced pressure to give Compound I-13d (3.7 g) as a white solid. MS found (ESI ⁺ )[(M+H) ⁺ ]: 134

Step 4: Preparation of 3-methyl-1,2-thiazolidine 1,1-dioxide (Intermediate I-13)

To a solution of 3-methyl-4,5-dihydroisothiazole 1,1-dioxide (3.7 g. 27.7 mmol) in THF (90 mL) was added NaBH ₄ (1.2 g, 30.5 mmol) in batches at -20 ° C. The mixture was stirred at -20 ° C for 20 minutes in an N ₂ atmosphere and then poured into a saturated NaHCO ₃ solution (500 mL). The resulting mixture was extracted 5 times with EtOAc (400 mL). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ , and concentrated under reduced pressure. The residue was purified by column chromatography to obtain 3-methyl-1,2-thiazolidine 1,1-dioxide (intermediate I-13, 2.5 g) as a colorless oil. MS measured value (ESI ⁺ )[(M+H) ⁺ ]: 136

Intermediate I-14

1,2-thiazolidine 1-oxide

Intermediate I-14 was prepared according to the following scheme:

Step 1: Preparation of 3-(3-aminopropyldisulfanyl)propan-1-amine (Compound I-14b)

_{A solution of 3-bromopropan-1-amine hydrobromide (30 g, 137 mmol) and Na₂S₂O₃·5H₂O ( 37.4 g} , 151 mmol) in MeOH/ _H₂O (200 mL, V/V = 1:1) was heated at 90°C with stirring for 12 hours. A solution of iodine (19.1 g, 75.4 mmol) in MeOH (200 mL) was slowly added to the refluxing solution via a dropping funnel over 10 hours. The mixture was concentrated under reduced pressure. The residue was dissolved in 6N aqueous NaOH (100 mL), and the resulting solution was extracted twice with DCM (500 mL). The combined organic layers were concentrated under reduced pressure. The residue was treated with HCl in EA (100 mL, 4 N) and filtered. The filter cake was dissolved in 6N aqueous NaOH (100 mL), and the solution was extracted twice with DCM (500 mL). The combined organic layers were dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to give compound I-14b (10.6 g) as a yellow oil. MS found (ESI ⁺ ) [(M+H) ⁺ ]: 181

Step 2: Preparation of 1,2-thiazolidine 1-oxide (Intermediate I-14)

To a solution of 3-(3-aminopropyldisulfanyl)propan-1-amine (3.0 g, 16.6 mmol) and _NaIO₄ (16 g, 75 mmol) in _H₂O (500 mL) was added B(OH) _₃ / _H₂O (0.2 M) until pH = 8. The mixture was stirred at 25°C for 3 days and then filtered. The filtrate was extracted three times with DCM (100 mL). The combined organic layers were dried over _{anhydrous Na₂SO₄} and concentrated under reduced pressure. The residue was purified by column chromatography to give 1,2-thiazolidine 1-oxide (Intermediate I-14, 60 mg) as a yellow oil. MS found ( ^ESI⁺ ) [(M+H) ^⁺ ]: 106.

Intermediate I-15

1,1-Dioxo-1,2-thiazolidin-4-ol

Intermediate I-15 was prepared according to the following scheme:

Step 1: Preparation of methyl 2-chlorosulfonylacetate (Compound I-15b)

To a solution of methyl 2-mercaptoacetate (Compound I-15a, 34 g, 320 mmol) in DCM (50 mL) was added _H₂O (150 mL). Chlorine gas was gently bubbled through the solution, maintaining the temperature below 5°C, until the solution remained light green for 4 hours. The solution was extracted twice with DCM (100 mL). The combined _organic layers were dried over anhydrous _Na₂SO₄ and concentrated to afford Compound I-15b (56.6 g, crude) as a yellow oil, which was used in the next step without further purification.

Step 2: Preparation of ethyl 2-[benzyl-(2-methoxy-2-oxo-ethyl)sulfonyl-amino]acetate (Compound I-15c)

A mixture of ethyl 2-(benzylamino)acetate (30.9 g, 159.9 mmol), methyl 2-chlorosulfonylacetate (Compound I-15b, 27.6 g, 159.9 mmol), and triethylamine (32.4 g, 319.8 mmol) in DCM (300 mL) was stirred at 18°C for 12 hours. The mixture was diluted with DCM (500 mL) and washed twice with _1N brine (200 mL). The organic layer was dried over anhydrous _Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel chromatography to obtain Compound I-15c (25.1 g) as a yellow oil. MS found (ESI ⁺ ) [(M+H) ⁺ ]: 330.

Step 3: Preparation of 2-benzyl-1,1-dioxo-1,2-thiazolidin-4-one (Compound I-15d)

To a solution of Na (7.0 g, 303.6 mmol) in MeOH (400 mL) was slowly added a solution of ethyl 2-[benzyl-(2-methoxy-2-oxo-ethyl)sulfonyl-amino]acetate (Compound I-15c, 20 g, 60.7 mmol) in MeOH (100 mL). The reaction mixture was stirred at 18°C for 4 hours and then quenched by the addition of _H₂O (50 mL). The resulting mixture was acidified to pH = 3 with concentrated HCl and then stirred at 18°C for 4 hours. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography to afford Compound I-15d (1.8 g) as a yellow solid. MS found (ESI ⁺ ) [(M+H) ⁺ ]: 226.

Step 4: Preparation of 2-benzyl-1,1-dioxo-1,2-thiazolidin-4-ol (Compound I-15e)

To a mixture of 2-benzyl-1,1-dioxo-1,2-thiazolidin-4-one (Compound I-15d, 200 mg, 0.89 mmol) in anhydrous MeOH (3 mL) was added NaBH ₄ (169 mg, 4.4 mmol). The reaction mixture was stirred at 15° C. for 1 hour and then quenched with H ₂ O (2 mL). The resulting mixture was purified by preparative HPLC to afford Compound I-15e (170 mg) as a yellow oil.

Step 5: Preparation of 1,1-dioxo-1,2-thiazolidin-4-ol (Intermediate I-15)

Na (14 mg, 3.5 mmol) was added to liquid NH ₃ (5 mL) at -70 ° C. The mixture was stirred at -70 ° C for 10 hours, and then a solution of 2-benzyl-1,1-dioxo-1,2-thiazolidine-4-ol (compound I-15e, 80 mg, 0.35 mmol) in THF (1 mL) was added. The reaction mixture was stirred at -70 ° C for 3 hours and then quenched by adding NH ₄ Cl aqueous solution (5 mL). The mixture was heated to 15 ° C, then concentrated, and then THF (30 mL) was added. The resulting mixture was stirred for 20 minutes and filtered. The filtrate was concentrated under reduced pressure to obtain crude intermediate I-15 (50 mg), which was used directly without further purification. MS measured value (ESI ⁺ ) [(M+H) ⁺ ]: 138.

Intermediate I-16

2-Benzyl-1,2,5-thiadiazolidine 1,1-dioxide

Intermediate I-16 was prepared according to the following scheme:

To a refluxing solution of sulfonamide (2.0 g, 20.8 mmol) in anhydrous pyridine (60 mL) was added N-benzylethane-1,2-diamine (3.1 g, 20.8 mmol) dropwise over 2 hours. The resulting mixture was refluxed for an additional 10 hours. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography to afford intermediate I-16 (2.2 g) as a yellow oil. MS found (ESI ⁺ ) [(M+H) ⁺ ]: 213.

Intermediate I-17

2-Methyl-1,2,5-thiadiazolidine 1,1-dioxide

Intermediate I-17 was prepared according to the following scheme:

To a mixture of sulfonamide (5 g, 52.1 mmol) in pyridine (120 mL) was added a solution of N-methylethylenediamine (3.85 g, 52.1 mmol) in pyridine (30 mL) at 100°C. The mixture was stirred at 100°C for 16 hours and then concentrated under reduced pressure. The residue was purified by column chromatography to afford Intermediate I-17 (2.7 g) as a colorless oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 4.37 (brs, 1H), 4.45-4.58 (m, 2H), 3.34-3.42 (m, 2H), 2.76 (s, 3H).

Intermediate I-18

(3S)-3-Methylthiazetidine 1,1-dioxide

Intermediate I-18 was prepared according to the following scheme:

Step 1: Preparation of tert-butyl N-[(1S)-2-hydroxy-1-methyl-ethyl]carbamate (Compound I-18b)

To a mixture of (2S)-2-aminopropan-1-ol (Compound I-18a, 10 g, 133 mmol) in dioxane (100 mL) and saturated aqueous _NaHCO₃ (100 mL) was added _Boc₂O (29.1 g, 133 mmol) at 20°C. The mixture was stirred at 20°C for 3 hours and then extracted three times with EtOAc (100 mL). The combined organic layers were dried _over anhydrous _Na₂SO₄ , filtered, and concentrated to afford Compound I-18b (18.5 g) as a yellow oil.

Step 2: Preparation of S-[(2S)-2-(tert-butoxycarbonylamino)propyl]thioacetate (Compound I-18c)

To a mixture of tert-butyl N-[(1S)-2-hydroxy-1-methyl-ethyl]carbamate (compound I-18b, 10 g, 57.1 mmol) and TEA (6.4 g, 62.8 mmol) in DCM (100 mL) at 0°C was added MsCl (7.2 g, 62.8 mmol). After the addition was complete, the mixture was stirred at 20°C for 1 hour and then quenched with saturated aqueous NaHCO ₃ solution. The organic layer was separated, and the aqueous layer was extracted three times with EtOAc (30 mL). The combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated. The residue (11 g) was dissolved in DMF (100 mL), and thioacetic acid (5 g, 65 mmol) and Cs ₂ CO ₃ (21.2 g, 65.1 mmol) were added. The mixture was stirred at 20°C for 16 hours, then filtered, and the filtrate was concentrated. The residue was purified by column chromatography to give compound I-18c (7.5 g) as a yellow oil. ¹ H NMR (400 MHz, CHLOROFORM-d) δ 4.56 (br s, 1H), 3.87 (br s, 1H), 3.04 (q, 2H), 2.37 (s, 3H), 1.45 (s, 8H), 1.60-1.37 (m, 1H), 1.18 (d, 3H).

Step 3: Preparation of tert-butyl N-[(1S)-1-methyl-2-sulfanyl-ethyl]carbamate (Compound I-18d)

To a mixture of S-[(2S)-2-(tert-butoxycarbonylamino)propyl]thioacetate (Compound I-18c, 7.5 g, 32 mmol) in MeOH (100 mL) was added NaOH (4 g, 100 mmol). The mixture was stirred at 20°C for 16 hours and then concentrated under reduced pressure. The residue was dissolved in _H₂O and adjusted to pH = 7. The resulting mixture was extracted three times with EtOAc (20 mL). The combined organic layers were dried over anhydrous _{Na₂SO₄ ,} filtered, and concentrated. The residue was purified by column chromatography to afford Compound I-18d (5.3 g) as a yellow oil. ¹ H NMR (400 MHz, CHLOROFORM-d) δ 4.69 (br s, 1H), 3.87 (br s, 1H), 2.67 (brdd, 2H), 1.46 (s, 9H), 1.35-1.28 (m, 1H), 1.20 (d, 3H).

Step 4: Preparation of (2S)-2-aminopropane-1-thiol hydrochloride (Compound I-18e)

A mixture of tert-butyl N-[(1S)-1-methyl-2-sulfanyl-ethyl]carbamate (compound I-18d, 0.52 g, 2.7 mmol) in HCl/EtOAc (5.0 mL) was stirred at 25°C for 2 hours and then concentrated under reduced pressure to afford compound I-18e (0.5 g, crude) as a white solid. MS found (ESI ⁺ ) [(M+H) ⁺ ]: 92.

Step 5: Preparation of (2S)-2-aminopropane-1-sulfonyl chloride hydrochloride (Compound I-18f)

Chlorine gas was bubbled into a mixture of (2S)-2-aminopropane-1-thiol hydrochloride (Compound I-18e, 340 mg, 2.7 mmol) in methanol (25 mL) at 0°C for 30 minutes. The reaction mixture was stirred at 15°C for 2 hours and then flushed with nitrogen. The mixture was concentrated to give Compound I-18f (0.5 g, crude material), which was used directly in the next step without purification. MS found (ESI ⁺ ) [(M+H) ⁺ ]: 158.

Step 6: Preparation of (3S)-3-methylthiazetidine 1,1-dioxide (Intermediate I-18)

To a solution of (2S)-2-aminopropane-1-sulfonyl chloride hydrochloride (Compound I-18f, 0.4 g, 2.1 mmol) in DCM (25 mL) was added TEA (0.64 g, 6.3 mmol). The mixture was stirred at 15 ° C for 15 hours and then concentrated. The residue was triturated in EtOAc (30 mL) and then filtered. The filtrate was concentrated to give Intermediate I-18 (0.25 g) as a yellow oil. MS measured value (ESI ⁺ ) [(M+H) ⁺ ]: 122.

Intermediate I-19

(4S)-2-[(4-Methoxyphenyl)methyl]-4-methyl-1,2,5-thiadiazolidine 1,1-dioxide

Intermediate I-19 was prepared according to the following scheme:

Step 1: Preparation of (2S)-N1-[(4-methoxyphenyl)methyl]propane-1,2-diamine (Compound I-19b)

To a solution of tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate (Compound I-19a, 3 g, 17.3 mmol) in MeOH (30 mL) at 20°C was added (4-methoxyphenyl)methanamine (4.8 g, 34.6 mmol). The mixture was stirred at 20°C for 1 hour, followed by the addition of NaBH(AcO) ₃ (5.5 g, 26 mmol). The reaction mixture was stirred at 20°C for 1 hour, then quenched with saturated aqueous NaHCO ₃ (20 mL) and extracted three times with EtOAc (20 mL). The combined organic layers were concentrated, and the residue was purified by column chromatography to give a yellow oil, which was dissolved in EtOAc (20 mL), followed by the addition of HCl/EtOAc (40 mL). The resulting mixture was stirred at 20° C. for 2 hours and then concentrated to give (2S)-N1-[(4-methoxyphenyl)methyl]propane-1,2-diamine (compound I-19b, 3.65 g, crude material) as a yellow solid, which was used in the next step without further purification.

Step 2: Preparation of (4S)-2-[(4-methoxyphenyl)methyl]-4-methyl-1,2,5-thiadiazolidine 1,1-dioxide (Intermediate I-19)

To a solution of sulfonamide (1.1 g, 11.5 mmol) in pyridine (20 mL) at 120°C was added (2S)-N1-[(4-methoxyphenyl)methyl]propane-1,2-diamine (Compound I-19b, 2.65 g, 11.5 mmol). The reaction mixture was stirred at 120°C for 16 hours, then cooled to room temperature and concentrated. The residue was partitioned between _H2O (10 mL) and EtOAc (10 mL). The aqueous layer was extracted twice with EtOAc. The combined organic layers were dried _over anhydrous _Na2SO4 and concentrated. The residue was purified by column chromatography to give (4S)-2-[(4-methoxyphenyl)methyl]-4-methyl-1,2,5-thiadiazolidine 1,1-dioxide (Intermediate I-19, 400 mg) as a yellow oil. MS found (ESI ⁺ ) [(M+H) ⁺ ]: 279.

Intermediate I-20

(4S)-2-[(4-Methoxyphenyl)methyl]-3,4-dimethyl-1,2,5-thiadiazolidine 1,1-dioxide

Intermediate I-20 was prepared according to the following process:

Step 1: Preparation of tert-butyl N-[(1S)-2-[methoxy(methyl)amino]-1-methyl-2-oxo-ethyl]carbamate (Compound I-20b)

To a solution of (2S)-2-(tert-butoxycarbonylamino)propanoic acid (Compound I-20a, 10 g, 52.85 mmol) in THF (200 mL) at 0°C was added HATU (30.1 g, 79 mmol), TEA (13.4 g, 132 mmol), and N-methoxymethylamine hydrochloride (7.7 g, 79 mmol). The reaction mixture was stirred at 20°C under nitrogen for 15 hours and then extracted three times with EtOAc (200 mL). The combined organic layers were washed with brine, dried _over anhydrous _Na2SO4 , filtered, and concentrated. The residue was purified by column chromatography to afford Compound I-20b (11.5 g) as a white solid. MS found (ESI ⁺ ) [(M+H) ⁺ ]: 233.

Step 2: Preparation of tert-butyl N-[(1S)-1-methyl-2-oxo-propyl]carbamate (Compound I-20c)

To a solution of tert-butyl N-[(1S)-2-[methoxy(methyl)amino]-1-methyl-2-oxo-ethyl]carbamate (compound I-20b, 11.5 g, 49.5 mmol) in THF (200 mL) at 0°C was added MeMgBr (35 mL, 104 mmol). The reaction mixture was stirred at 20°C for 18 hours, then quenched by the addition of aqueous _NH4Cl (100 mL) and extracted three times with EtOAc (100 mL). The combined organic layers were washed with brine, dried _over anhydrous _Na2SO4 , filtered, and concentrated. The residue was purified by column chromatography to afford compound I-20c (6.8 g) as a yellow oil. MS observed (ESI ⁺ ) [(M+H) ⁺ ]: 188.

Step 3-4: Preparation of (4S)-2-[(4-methoxyphenyl)methyl]-3,4-dimethyl-1,2,5-thiadiazolidine 1,1-dioxide (Intermediate I-20)

Intermediate I-20 was prepared similarly to compound I-19, substituting tert-butyl N-[(1S)-1-methyl-2-oxo-propyl]carbamate (compound I-20c) for tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate (compound I-19a). Intermediate I-20 (3.8 g) was obtained as a colorless oil. MS observed value (ESI ⁺ ) [(M+H) ⁺ ]: 271.

Intermediate I-21

1,3,4-Oxazoline 3,3-dioxide

Intermediate I-21 was prepared according to the following scheme:

Step 1: Preparation of N-benzyl-1-chloro-N-(2-hydroxyethyl)methanesulfonamide (Compound I-21b)

To a solution of 2-(benzylamino)ethanol (1 g, 6.6 mmol) and DIPEA (1.7 g, 13 mmol) in THF (20 mL) was added chloromethanesulfonyl chloride (1.1 g, 7.3 mmol) dropwise at 0 ° C. The mixture was stirred at 15 ° C for 15 hours and then concentrated under reduced pressure. The residue was partitioned between ethyl acetate (30 mL) and water (20 mL). The organic layer was washed with water and brine, dried over anhydrous Na ₂ SO ₄ , and concentrated to give compound I-21b (1.7 g, crude material) as a yellow oil. MS measured value (ESI ⁺ ) [(M+H) ⁺ ]: 263.

Step 2: Preparation of 4-benzyl-1,3,4-oxathiazinane 3,3-dioxide (Compound I-21c)

To a solution of N-benzyl-1-chloro-N-(2-hydroxyethyl)methanesulfonamide (Compound I-21b, 1.7 g, 6.5 mmol) in DMF (20 mL) was added Cs ₂ CO ₃ (4.2 g, 13 mmol). The mixture was stirred at 80° C. for 15 hours and then concentrated under reduced pressure. The residue was partitioned between ethyl acetate (30 mL) and water (20 mL). The organic layer was washed with water and brine, dried over anhydrous Na ₂ SO ₄ , and concentrated. The residue was purified by column chromatography to afford Compound I-21c (1.1 g) as a yellow oil. MS observed (ESI ⁺ ) [(M+H) ⁺ ]: 228.

Step 3: Preparation of 1,3,4-oxathiazinane 3,3-dioxide (Intermediate I-21)

To a solution of 4-benzyl-1,3,4-oxathiazinane 3,3-dioxide (Compound I-21c, 0.45 g, 2.0 mmol) in THF (30.0 mL) and EtOH (30.0 mL) was added Pd/C (0.1 g) and concentrated aqueous HCl (1.0 mL). The mixture was stirred at 45°C under _H2 (50 psi) for 24 hours and then filtered. The filtrate was concentrated to afford Intermediate I-21 (0.5 g, crude) as a yellow solid. MS found (ESI ⁺ ) [(M+H) ⁺ ]: 138.

Intermediate I-22

Thiazetidine 1,1-dioxide

Intermediate I-22 was prepared according to the following scheme:

Step 1: Preparation of 2-aminoethanesulfonyl chloride hydrochloride (Compound I-22b)

Chlorine gas was blown into a mixture of 2-aminoethanethiol (Compound I-22a, 2.5 g, 32.5 mmol) in methanol (25 mL) and water (1.75 g, 97.4 mmol) at 0°C for 30 minutes. The resulting mixture was stirred at 15°C for 2 hours, then flushed with nitrogen, and tert-butyl methyl ether (80 mL) was added. The precipitated solid was collected, washed with diethyl ether, and dried under pressure to obtain Compound I-22b (0.8 g). MS found (ESI ⁺ ) [(M+H) ⁺ ]: 144.

Step 1: Preparation of thiazetidine 1,1-dioxide (Intermediate I-22)

To a solution of 2-aminoethanesulfonyl chloride hydrochloride (Compound I-22b, 0.8 g, 4.5 mmol) in DCM (25 mL) was added TEA (1.36 g, 13.5 mmol). The mixture was stirred at 15°C for 5 hours and then concentrated. The residue was triturated in EtOAc (30.0 mL) and then filtered. The filtrate was concentrated to give Intermediate I-22 (0.3 g) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 4.29 (t, 2H), 3.19-3.11 (m, 2H)

Intermediate I-23

1,1-Dioxo-1,2,6-thiadiazin-4-ol

Intermediate I-23 was prepared according to the following scheme:

To a solution of sulfonamide (1 g, 10.4 mmol) in pyridine (5 mL) at 120°C was added 1,3-diaminopropan-2-ol (0.94 g, 10.4 mmol). The reaction mixture was stirred at 120°C for 16 hours. After cooling to room temperature, the mixture was concentrated, and the residue was dissolved in _H₂O (3 mL). The resulting mixture was extracted 10 times with _EtOAc (5 mL). The combined organic layers were dried over _Na₂SO₄ and concentrated to afford Intermediate I-23 (0.3 g, crude) as a yellow solid. ^1H NMR (400 MHz, DMSO- _d₆ ) δ 6.65-6.54 (m, 1H), 5.05 (d, 1H), 3.45 (d, 1H), 3.31-3.22 (m, 2H), 3.15-3.04 (m, 2H).

Intermediate I-24

1,2,6-Thiadiazinane 1,1-dioxide

Intermediate I-24 was prepared according to the following scheme:

To a mixture of sulfonamide (0.96 g, 10 mmol) in pyridine (30 mL) at 110°C was added propane-1,3-diamine (0.74 g, 10 mmol). The reaction mixture was stirred at 110°C for 16 hours and then concentrated. The residue was purified by column chromatography to afford Intermediate I-24 (0.5 g) as a yellow solid. ^1H NMR (400 MHz, DMSO-d ₆ ) δ 6.35 (br t, 2H), 3.31-3.20 (m, 4H), 1.49-1.33 (m, 2H).

Intermediate I-25

tert-Butyl 3-iodo-6-methyl-6,7-dihydro-4H-triazolo[1,5-a]pyrazine-5-carboxylate

Intermediate I-25 was prepared according to the following scheme:

Step 1: Preparation of 2-(benzylamino)propan-1-ol (Compound I-25b)

To a suspension of 2-aminopropan-1-ol (compound I-25a, 20 g, 266 mmol) in toluene (200 mL) was added benzaldehyde (28 g, 266 mmol). The mixture was stirred at 110 ° C for 2 hours, then cooled to 20 ° C and concentrated. The residue was dissolved in MeOH (200 mL), and then NaBH ₄ (10 g, 266 mmol) was added at 0 ° C. The reaction mixture was heated to 20 ° C and stirred for 16 hours, then concentrated. The residue was diluted with ice water (100 mL) and stirred for 30 minutes. The resulting mixture was extracted 5 times with ethyl acetate (200 mL). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The residue was purified by column chromatography to obtain compound I-25b (18 g) as a yellow solid. LCMS (M+H ⁺ ): 166.

Step 2: Preparation of 2-[benzyl(prop-2-ynyl)amino]propan-1-ol (Compound I-25c)

To a solution of 2-(benzylamino)propan-1-ol (compound I-25b, 18 g, 109 mmol) and 3-bromoprop-1-yne (15.6 g, 130 mmol) in MeCN (20 mL) was added K ₂ CO ₃ (22.6 g, 163 mmol) at 20°C. The mixture was stirred at 80°C for 16 hours, then cooled to 20°C and filtered. The filtrate was concentrated, and the residue was purified by column chromatography to afford compound I-25c (19 g) as a yellow oil. LCMS (M+H ⁺ ): 204.

Step 3: Preparation of N-benzyl-1-chloro-N-prop-2-ynyl-prop-2-amine (Compound I-25d)

To a solution of pyridine (11.7 g, 148 mmol) and _SOCl₂ (21 g, 177 mmol) in DCM (200 mL) at 0°C was added 2-[benzyl(prop-2-ynyl)amino]propan-1-ol (Compound I-25c, 20 g, 98 mmol). The reaction mixture was stirred at 20°C for 3 hours and then washed with saturated aqueous _NaHCO₃ (300 mL). The organic layer was washed three times with water (100 mL), dried _over anhydrous _Na₂SO₄ , and concentrated. The residue was purified by column chromatography to afford Compound I-25d (17.3 g) as a yellow oil. LCMS (M+ ^H⁺ ): 222.

Step 4: Preparation of 5-benzyl-6-methyl-6,7-dihydro-4H-triazolo[1,5-a]pyrazine (Compound I-25e)

To a solution of N-benzyl-1-chloro-N-prop-2-ynyl-prop-2-amine (Compound I-25d, 18 g, 81 mmol) in DMSO (200 mL) was slowly added NaN ₃ (5.28 g, 81 mmol) at 25° C. The reaction mixture was stirred at 150° C. for 3 hours. After cooling to room temperature, the reaction mixture was partitioned between EtOAc (800 mL) and saturated aqueous Na ₂ CO ₃ solution (200 mL). The organic layer was washed three times with water (100 mL), dried over anhydrous Na ₂ SO ₄ , and concentrated. The residue was purified by column chromatography to obtain Compound I-25e (15 g) as a red oil. LCMS (M+H ⁺ ): 229.

Step 5: Preparation of tert-butyl 6-methyl-6,7-dihydro-4H-triazolo[1,5-a]pyrazine-5-carboxylate (Compound I-25f)

To a solution of 5-benzyl-6-methyl-6,7-dihydro-4H-triazolo[1,5-a]pyrazine (compound I-25e, 15 g, 66 mmol) in MeOH (200 mL) was added Boc ₂ O (17 g, 79 mmol) and Pd/C (1.20 g). The reaction mixture was stirred at 50° C. under H ₂ (50 psi) for 24 hours. It was then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography to give a light yellow oil, which was further purified and separated by SFC (column: Chiralpak AD-3 100×4.6 mm ID, 3 μm, mobile phase: methanol (0.05% DEA) in CO ₂ , from 5% to 40%) to give compound I-25f-1 (1 g) as a yellow solid and compound I-25f-2 (2 g) as a yellow oil.

Compound I-25f-1: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.66 (s, 1H), 4.92 (d, 1H), 4.74 (br. s., 1H), 4.50-4.43 (m, 1H), 4.41-4.29 (m, 2H), 1.45 (s, 9H), 1.02 (d, 3H). LCMS (M+H ⁺ ): 239.

Compound I-25f-2: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.66 (s, 1H), 4.92 (d, 1H), 4.74 (br. s., 1H), 4.50-4.43 (m, 1H), 4.41-4.29 (m, 2H), 1.51-1.40 (m, 9H), 1.02 (d, 3H). LCMS (M+H ⁺ ): 239.

Step 6: Preparation of tert-butyl 3-iodo-6-methyl-6,7-dihydro-4H-triazolo[1,5-a]pyrazine-5-carboxylate (Intermediate I-25)

To a mixture of 2,2,6,6-tetramethylpiperidine (249 mg, 1.26 mmol) in THF (3 mL) was added BuLi (0.6 mL, 1.5 mmol) at 0°C. The mixture was then cooled to -70°C before the addition of a solution of compound I-25f-2 (300 mg, 1.26 mmol) in THF (3 mL). The mixture was stirred at -70°C for 1 hour before the addition of a solution of I ₂ (1.6 g, 6.3 mmol) in THF (6 mL). The reaction mixture was warmed to 15°C and stirred for 1 hour. The mixture was quenched by the addition of an aqueous NH ₄ Cl solution (2 mL) and an aqueous Na ₂ SO ₃ solution (4 mL), then extracted with EtOAc (50 mL). The organic layer was washed with brine (30 mL), dried over anhydrous Na ₂ SO ₄ , and concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA=5:1) and preparative TLC (PE:EA=1:1) to give intermediate I-25-2 (60 mg) as a white sticky solid. LCMS (M+H ⁺ ): 365.

Intermediate I-25-1 was prepared similarly to compound I-25-2, using compound I-25f-1 instead of compound I-25f-2 to obtain intermediate I-25-1 (60 mg) as a white sticky solid. LCMS (M+H ⁺ ): 365.

Intermediate I-26

Phenyl N-(3-thienylmethyl)carbamate

Intermediate I-26 was prepared similarly to compound I-5, using 3-thienylmethylamine instead of 4-chloro-3-fluoroaniline. Intermediate I-26 (60 mg) was obtained as a yellow oil. MS found (ESI ⁺ ) [(M+H) ⁺ ]: 234.

Example 1

(6S)-3-(1,1-dioxo-1,2-thiazolidin-2-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 (6S)-3-(1,1-dioxo-1,2-thiazolidin-2-yl)-6-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylic acid tert-butyl ester (Compound 1b)

To a mixture of (6S)-3-iodo-6-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylic acid tert-butyl ester (Intermediate I-1, 100 mg, 0.28 mmol), 1,2-thiazolidine 1,1-dioxide (Compound 1a, 50 mg, 0.41 mmol), trans-N,N′-dimethylcyclohexane-1,2-diamine (8 mg, 0.055 mmol) and CuI (10 mg, 0.055 mmol) in DMSO (5 mL) was added K ₂ CO ₃ (114 mg, 0.83 mmol). The reaction mixture was stirred at 100° C. for 12 hours and then concentrated under reduced pressure. The residue was purified by preparative HPLC to afford tert-butyl (6S)-3-(1,1-dioxo-1,2-thiazolidin-2-yl)-6-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate (Compound 1b, 72 mg) as a yellow solid. MS found (ESI ⁺ ) [(M+H) ⁺ ]: 357.

Step 2: Preparation of 2-[(6S)-6-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl]-1,2-thiazolidine 1,1-dioxide (Compound 1c)

A mixture of tert-butyl (6S)-3-(1,1-dioxo-1,2-thiazolidin-2-yl)-6-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate (Compound 1b, 72 mg, 0.20 mmol) in HCl/EtOAc (4N, 10 mL) was stirred at 20°C for 2 hours. The reaction mixture was then concentrated under reduced pressure to afford 2-[(6S)-6-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl]-1,2-thiazolidine 1,1-dioxide (Compound 1c, 55 mg, crude) as a brown oil. MS found (ESI ⁺ ) [(M+H) ⁺ ]: 257.

Step 3: Preparation of (6S)-3-(1,1-dioxo-1,2-thiazolidin-2-yl)-6-methyl-N-(3,4,5-trifluorophenyl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide

To a mixture of 2-[(6S)-6-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl]-1,2-thiazolidine 1,1-dioxide (Compound 1c, 55 mg, crude) and phenyl N-(3,4,5-trifluorophenyl)carbamate (Intermediate I-2, 57 mg, 0.21 mmol) in DMF (5 mL) was added _Et₃N (65 mg, 0.64 mmol). The reaction mixture was stirred at 20°C for 4 hours and then concentrated under reduced pressure. The residue was purified by preparative HPLC to afford (6S)-3-(1,1-dioxo-1,2-thiazolidin-2-yl)-6-methyl-N-(3,4,5-trifluorophenyl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide (Example 1, 45 mg) as a white solid. ¹ H NMR (400 MHz, CHLOROFORM-d) δ 7.59 (s, 1H), 7.13-7.25 (m, 2H), 7.01-7.13 (m, 1H), 5.10 (m, 1H), 5.00 (d, 1H), 4.52 (d, 1H), 4.27 (dd, 1H), 4.09 (d, 1H), 3.60-3.79 (m, 2H), 3.31-3.46 (m, 2H), 2.46-2.66 (m, 2H), 1.33 (d, 3H). MS found (ESI ⁺ ) [(M+H) ⁺ ]: 430.

Example 2

(6S)-N-(2-chloro-4-pyridinyl)-3-(1,1-dioxo-1,2-thiazolidin-2-yl)-6-methyl-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 2-[(6S)-6-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl]-1,2-thiazolidine 1,1-dioxide (Compound 1c, 20 mg, 0.078 mmol) in DMF (1.0 mL) was added TEA (24.0 mg, 0.234 mmol) and phenyl N-(2-chloro-4-pyridyl)carbamate (Intermediate I-4, 29.0 mg, 0.117 mmol). The mixture was stirred at 15 ° C for 18 hours and then partitioned between water (5.0 mL) and EtOAc (10.0 mL). The aqueous layer was extracted twice with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ , and concentrated under reduced pressure. The residue was purified by preparative-HPLC to give (6S)-N-(2-chloro-4-pyridinyl)-3-(1,1-dioxo-1,2-thiazolidin-2-yl)-6-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide (Example 2, 21 mg) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.17 (d, 1H), 7.56 (s, 1H), 7.55-7.47 (m, 2H), 7.29 (dd, 1H), 5.03-5.01 (m, 2H), 4.52-4.48 (m, 1H), 4.31-4.18 (m, 1H), 4.07 (d, 1H), 3.76-3.58 (m, 2H), 3.36 (t, 2H), 2.61-2.46 (m, 2H), 1.30 (d, 3H). MS found (ESI ⁺ ) [(M+H) ⁺ ]: 411.

Example 3

(6S)-N-(4-Chloro-3-fluoro-phenyl)-3-(1,1-dioxo-1,2-thiazolidin-2-yl)-6-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide

The title compound was prepared in a similar manner to Example 2, using N-(4-chloro-3-fluoro-phenyl)carbamic acid phenyl ester (Intermediate I-5) instead of N-(2-chloro-4-pyridyl)carbamic acid phenyl ester (Intermediate I-4). Example 3 (8.0 mg) was obtained as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.50 (s, 1H), 7.39 (dd, 1H), 7.15-7.24 (m, 1H), 6.99 (m, 1H), 6.78 (s, 1H), 4.97-5.05 (m, 1H), 4.92 (d, 1H), 4.45 (d, 1H), 4.19 (m, 1H), 4.01 (d, 1H), 3.54-3.67 (m, 2H), 3.26-3.33 (m, 2H), 2.42-2.51 (m, 2H), 1.24 (d, 3H). MS found (ESI ⁺ ) [(M+H) ⁺ ]: 428.

Example 4

(6S)-3-(1,1-dioxo-1,2-thiazolidin-2-yl)-N-(4-fluoro-3-methyl-phenyl)-6-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide

The title compound was prepared in a similar manner to Example 2, using N-(4-fluoro-3-methyl-phenyl)carbamic acid phenyl ester (Intermediate I-6) instead of N-(2-chloro-4-pyridyl)carbamic acid phenyl ester (Intermediate I-4). Example 4 (10.7 mg) was obtained as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 7.58 (s, 1H), 7.23-7.27 (m, 1H), 7.08-7.16 (m, 1H), 6.93 (t, 1H), 6.60 (s, 1H), 5.04-5.14 (m, 1H), 4.98 (d, 1H), 4.55 (d, 1H), 4.28 (dd, 1H), 4.10 (d, 1H), 3.62-3.74 (m, 2H), 3.31-3.41 (m, 2H), 2.54 (quin, 2H), 2.26 (s, 3H), 1.28 (d, 3H). MS observed (ESI) [(M+H) ⁺ ]: 408.

Example 5

(6S)-N-(3-Cyano-4-fluoro-phenyl)-3-(1,1-dioxo-1,2-thiazolidin-2-yl)-6-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide

The title compound was prepared in a similar manner to Example 2, using N-(3-cyano-4-fluoro-phenyl)carbamic acid phenyl ester (Intermediate I-7) instead of N-(2-chloro-4-pyridyl)carbamic acid phenyl ester (Intermediate I-4). Example 5 (11 mg) was obtained as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.73 (m, 1H), 7.64 (m, 1H), 7.57 (s, 1H), 7.21-7.05 (m, 2H), 5.14-4.91 (m, 2H), 4.50 (d, 1H), 4.25 (dd, 1H), 4.06 (d, 1H), 3.81-3.58 (m, 2H), 3.37 (t, 2H), 2.65-2.44 (m, 2H), 1.32 (d, 3H), MS found (ESI ⁺ ) [(M+H) ⁺ ]: 419.

Example 6

(6S)-N-[2-(Difluoromethyl)-4-pyridinyl]-3-(1,1-dioxo-1,2-thiazolidin-2-yl)-6-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide

A mixture of (6S)-tert-butyl 3-(1,1-dioxo-1,2-thiazolidin-2-yl)-6-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate (Compound 1b, 100 mg, 0.28 mmol) in DCM (1 mL) and TFA (1 mL) was stirred at room temperature for 30 minutes. The reaction mixture was concentrated, and the residue was dissolved in DMF (2.5 mL), followed by the addition of N-ethyl-N-isopropylpropan-2-amine (181 mg, 1.4 mmol) and phenyl (2-(difluoromethyl)pyridin- ⁴ -yl)carbamate (Intermediate I-3, 89 mg, 0.34 mmol). The reaction mixture was stirred at 70 ° C for 1 hour and purified by preparative HPLC to give Example 6 (45 mg) as a white solid. NMR(400MHz,METHANOL-d4)δppm8.50(d,J＝6.1Hz,1H),8.02(d,J＝2.2Hz,1H),7.83(dd,J ＝2.3,6.1Hz,1H),7.66(s,1H),6.83(t,J＝54.8Hz,1H),5.18(d,J＝17.0Hz,1H),5.07-4.9 6 (m, 1H), 4.63 (d, J = 17.1 Hz, 1H), 4.34 (dd, J = 4.4, 12.8 Hz, 1H), 4.18 (dd, J = 1.0, 12.8 Hz, 1H), 3.70 (t, J = 6.7 Hz, 2H), 3.45-3.36 (m, 2H), 2.58-2.43 (m, 2H), 1.28 (d, J = 6.8 Hz, 3H). MS found (ESI ⁺ ) [(M+H) ⁺ ]: 427.

Example 7

(6S)-3-(1,1-Dioxo-1,2-thiazolidin-2-yl)-N-[4-fluoro-3-(trifluoromethyl)phenyl]-6-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide

The title compound was prepared in a similar manner to Example 2, using phenyl N-[4-fluoro-3-(trifluoromethyl)phenyl]carbamate (Intermediate I-8) instead of phenyl N-(2-chloro-4-pyridyl)carbamate (Intermediate I-4). Example 7 (17 mg) was obtained as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.70 (dd, 1H), 7.54-7.62 (m, 2H), 7.13 (t, 1H), 6.93 (s, 1H), 5.06-5.16 (m, 1H), 5.01 (d, 1H), 4.54 (d, 1H), 4.27 (dd, 1H), 4.10 (d, 1H), 3.61-3.77 (m, 2H), 3.38 (t, 2H), 2.49-2.62 (m, 2H), 1.31 (d, 3H). MS found (ESI ⁺ ) [(M+H) ⁺ ]: 462.

Example 8

(6S)-3-(1,1-dioxo-1,2-thiazolidin-2-yl)-N-(2-fluorophenyl)-6-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide

The title compound was prepared by a method similar to that used in Example 2, using phenyl N-(2-fluorophenyl)carbamate (Intermediate I-9) instead of phenyl N-(2-chloro-4-pyridyl)carbamate (Intermediate I-4). Example 8 (18 mg) was obtained as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.06-7.98 (m, 1H), 7.59 (s, 1H), 7.16-6.97 (m, 3H), 6.65 (br. s., 1H), 5.10-4.95 (m, 2H), 4.66 (s, 1H), 4.31 (dd, 1H), 4.20-4.10 (m, 1H), 3.66 (dt, 2H), 3.35 (t, 2H), 2.58-2.47 (m, 2H), 1.27 (d, 3H). MS found (ESI ⁺ ) [(M+H) ⁺ ]: 394.

Example 9

(6S)-N-(1,3-Benzothiazol-6-yl)-3-(1,1-dioxo-1,2-thiazolidin-2-yl)-6-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide

The title compound was prepared by a method similar to that of Example 2, using phenyl N-(1,3-benzothiazol-6-yl)carbamate (Intermediate I-10) instead of phenyl N-(2-chloro-4-pyridyl)carbamate (Intermediate I-4), to afford Example 9 (4.7 mg) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.88 (s, 1H), 8.28 (d, 1H), 8.02 (d, 1H), 7.58 (s, 1H), 7.37 (dd, 1H), 6.99 (s, 1H), 5.13 (quin, 1H), 5.05 (d, 1H), 4.66-4.53 (m, 1H), 4.34-4.24 (m, 1H), 4.11 (d, 1H), 3.76-3.61 (m, 2H), 3.37 (t, 2H), 2.62-2.48 (m, 2H), 1.31 (d, 3H). MS found (ESI ⁺ ) [(M+H) ⁺ ]: 433.

Example 10

(6S)-3-(1,1-dioxo-1,2-thiazolidin-2-yl)-6-methyl-N-(3-thienyl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide

The title compound was prepared in a similar manner to Example 2, using phenyl N-(3-thienyl)carbamate (Intermediate I-11) instead of phenyl N-(2-chloro-4-pyridyl)carbamate (Intermediate I-4). Example 10 (3.5 mg) was obtained as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.57 (s, 1H), 7.31 (d, 1H), 7.21 (dd, 1H), 7.03 (d, 1H), 7.00-6.94 (m, 1H), 5.15-5.02 (m, 1H), 4.94 (d, 1H), 4.54 (d, 1H), 4.27 (dd, 1H), 4.10 (d, 1H), 3.75-3.60 (m, 2H), 3.41-3.30 (m, 2H), 2.61-2.46 (m, 2H), 1.27 (d, 3H). MS found (ESI ⁺ ) [(M+H) ⁺ ]: 382.

Example 11

(6S)-N-Benzyl-3-(1,1-dioxo-1,2-thiazolidin-2-yl)-6-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide

The title compound was prepared by a method similar to that used in Example 2, using phenyl N-benzylcarbamate (Intermediate I-12) instead of phenyl N-(2-chloro-4-pyridyl)carbamate (Intermediate I-4). Example 11 (6.4 mg) was obtained as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.49 (s, 1H), 7.30-7.20 (m, 5H), 5.09-4.97 (m, 1H), 4.96-4.87 (m, 1H), 4.73 (d, 1H), 4.45-4.31 (m, 3H), 4.15 (dd, 1H), 3.99 (d, 1H), 3.62-3.49 (m, 2H), 3.22 (t, 2H), 2.48-2.31 (m, 2H), 1.11 (d, 3H). MS found (ESI ⁺ ) [(M+H) ⁺ ]: 390.

Example 12

(6S)-3-(1,1-dioxo-3a,4,6,7-tetrahydro-3H-[1,2,5]thiadiazolo[3,2-c][1,4]oxazin-2-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 3-[(sulfamoylamino)methyl]morpholine-4-carboxylate (Compound 12b)

To a solution of tert-butyl 3-(aminomethyl)morpholine-4-carboxylate hydrochloride (compound 12a, 388 mg, 1.54 mmol) in DCE (5.0 mL) was added TEA (777 mg, 7.68 mmol), DMAP (94 mg, 0.77 mmol) and sulfamoyl chloride (355 mg, 3.07 mmol) at 0°C. The reaction mixture was slowly heated to room temperature and stirred for 1 hour, then quenched by the addition of ice water. The resulting mixture was extracted with DCM. The organic layer was concentrated. The residue was purified by column chromatography (8%-10% methanol in dichloromethane elution) to give compound 12b (227 mg). MS measured value (ESI ⁺ )[(M+H) ⁺ ]: 296.

Step 2: Preparation of 2,3,3a,4,6,7-hexahydro-[1,2,5]thiadiazolo[3,2-c][1,4]oxazine 1,1-dioxide (Compound 12c)

A solution of tert-butyl 3-[(sulfamoylamino)methyl]morpholine-4-carboxylate (compound 12b, 200 mg, 0.68 mmol) in 1,1,1,3,3,3-hexafluoro-2-propanol (8.0 mL) was heated in a sealed vial at 140° C. under microwave conditions for 2 hours. The reaction mixture was concentrated to afford crude compound 12c (121 mg). MS observed (ESI ⁺ ) [(M+H) ⁺ ]: 179.

Step 3: Preparation of (6S)-3-(1,1-dioxo-3a,4,6,7-tetrahydro-3H-[1,2,5]thiadiazolo[3,2-c][1,4]oxazin-2-yl)-6-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylic acid tert-butyl ester (Compound 12d)

A mixture of (6S)-3-iodo-6-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylic acid tert-butyl ester (Intermediate I-1, 100 mg, 0.28 mmol), K ₃ PO ₄ (117 mg, 0.55 mmol), CuI (10.5 mg, 55 μmol), (1R,2R)-N1,N2-dimethylcyclohexane-1,2-diamine (7.8 mg, 55 μmol) and 2,3,3a,4,6,7-hexahydro-[1,2,5]thiadiazolo[3,2-c][1,4]oxazine 1,1-dioxide (Compound 12c, 59 mg, 0.33 mmol) in DMSO (6.0 ml) was heated at 120° C. for 2 hours. The reaction mixture was cooled, quenched by the addition of ice water, and extracted twice with EtOAc. The combined organic layers were concentrated, and the residue was purified by column chromatography to give compound 12d (45 mg). MS found (ESI ⁺ ) [(M+H) ⁺ ]: 414.

Step 4: Preparation of (6S)-3-(1,1-dioxo-3a,4,6,7-tetrahydro-3H-[1,2,5]thiadiazolo[3,2-c][1,4]oxazin-2-yl)-6-methyl-N-(3,4,5-trifluorophenyl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide (Example 12)

A mixture of (6S)-tert-butyl 3-(1,1-dioxo-3a,4,6,7-tetrahydro-3H-[1,2,5]thiadiazolo[3,2-c][1,4]oxazin-2-yl)-6-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate (Compound 12d, 45 mg, 109 μmol), 2,2,2-trifluoroacetic acid (2 mL) and DCM (1 mL) was stirred at room temperature for 1 hour. The reaction mixture was concentrated, and the residue was dissolved in DCE (3.0 mL), followed by the addition of DIPEA (0.5 mL) and phenyl (3,4,5-trifluorophenyl)carbamate (Intermediate I-2, 44 mg, 163 μmol). The reaction mixture was stirred at 45 ° C for 2 hours and then washed with ice water. The aqueous solution was extracted three times with EtOAc. The combined organic layers were dried over _{anhydrous Na2SO4} and concentrated under reduced pressure. The residue was purified by column chromatography to afford Example 12 (22 mg). ^1H NMR (400 MHz, METHANOL- _d4 ) δ 7.57 (s, 1H), 7.22-7.11 (m, 2H), 4.99 (d, 1H), 4.89-4.80 (m, 1H), 4.46 (d, 1H), 4.20 (dd, 1H), 4.05 (dd, 1H), 3.92 (dd, 1H), 3.81 (td, 1H), 3.69-3.59 (m, 3H), 3.55-3.47 (m, 2H), 3.30-3.25 (m, 1H), 3.04-2.95 (m, 1H), 1.12 (d, 3H). MS found (ESI ⁺ ) [(M+H) ⁺ ]: 487.

Example 13

Benzyl 2-[(6S)-6-methyl-5-[(3,4,5-trifluorophenyl)carbamoyl]-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-3-yl]-1,1-dioxo-1,2,5-thiadiazinane-5-carboxylate

The title compound was prepared according to the following scheme:

Step 1: Preparation of (6S)-3-[2-(benzyloxycarbonylamino)ethylamino]-6-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylic acid tert-butyl ester (Compound 13b)

To a mixture of (6S)-3-iodo-6-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylic acid tert-butyl ester (Intermediate I-1, 1.09 g, 3.0 mmol), K ₃ PO ₄ (1.27 g, 6.0 mmol), CuI (114 mg, 0.6 mmol), and 2-((2,6-dimethylphenyl)amino)-2-oxoacetic acid (232 mg, 1.2 mmol) in DMSO (15.0 mL) was added benzyl (2-aminoethyl)carbamate (Compound 13a, 874 mg, 4.5 mmol) under argon. The mixture was heated at 120° C. in a microwave for 2 hours. The reaction mixture was diluted with ice water and then extracted twice with EtOAc. The combined organic layers were separated and concentrated. The residue was purified by column chromatography to give Compound 13b (450 mg). MS found (ESI ⁺ ) [(M+H) ⁺ ]: 430.

Step 2: Preparation of (6S)-3-[2-(benzyloxycarbonylamino)ethyl-(bromomethylsulfonyl)amino]-6-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylic acid tert-butyl ester (Compound 13c)

To a solution of (6S)-3-[2-(benzyloxycarbonylamino)ethylamino]-6-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylic acid tert-butyl ester (compound 13b, 450 mg, 1.05 mmol) in THF (10.0 mL) was added TEA (0.44 mL, 3.14 mmol). The reaction mixture was cooled to 0 ° C., and bromomethanesulfonyl chloride (507 mg, 2.62 mmol) was added dropwise. The reaction mixture was slowly heated to room temperature and stirred for 2 hours, then quenched by adding ice water. The resulting mixture was extracted twice with EtOAc, the combined organic layer was separated, and concentrated. The residue was purified by column chromatography to obtain compound 13c (540 mg). MS measured value (ESI ⁺ )[(M+H) ⁺ ]: 587.

Step 3: Preparation of 2-[(6S)-5-tert-butoxycarbonyl-6-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-3-yl]-1,1-dioxo-1,2,5-thiadiazinane-5-carboxylic acid benzyl ester (Compound 13d)

To a solution of (6S)-3-[2-(benzyloxycarbonylamino)ethyl-(bromomethylsulfonyl)amino]-6-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylic acid tert-butyl ester (compound 13c, 540 mg, 0.92 mmol) in DMF (8.0 mL) was added sodium hydride (92 mg, 2.3 mmol) at 0°C. The reaction mixture was stirred at 0°C for 1 hour, then warmed to room temperature and stirred for 2 hours. The reaction mixture was quenched by adding ice water and then extracted twice with EtOAc. The combined organic layers were dried over _{anhydrous Na2SO4} , filtered and concentrated. The residue was purified by column chromatography to give compound 13d (300 mg, crude material). MS found (ESI ⁺ ) [(M+H) ⁺ ]: 506.

Step 4: Preparation of 2-[(6S)-6-methyl-5-[(3,4,5-trifluorophenyl)carbamoyl]-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-3-yl]-1,1-dioxo-1,2,5-thiadiazinane-5-carboxylic acid benzyl ester (Example 13)

A mixture of 2-[(6S)-5-tert-butoxycarbonyl-6-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-3-yl]-1,1-dioxo-1,2,5-thiadiazinane-5-carboxylic acid benzyl ester (compound 13d, 123 mg, 0.24 mmol) in 2,2,2-trifluoroacetic acid (2.0 mL) and DCM (1.0 mL) was stirred at room temperature for 1 hour and then concentrated. The residue was dissolved in DCE (3.0 mL), and DIPEA (0.5 mL) and phenyl (3,4,5-trifluorophenyl)carbamate (intermediate I-2, 78 mg, 0.29 mmol) were added. The reaction mixture was stirred at 45 ° C for 2 hours and then diluted with EtOAc. The mixture was washed with water, and the aqueous layer was extracted three times with EtOAc. The combined organic layers were dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by preparative HPLC to give Example 13 (70 mg). ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ 7.63 (br s, 1H), 7.33-7.13 (m, 7H), 5.14 (br s, 2H), 4.97-4.81 (m, 4H), 4.42 (d, J=17.0 Hz, 1H), 4.17 (dd, J=4.3, 12.9 Hz, 1H), 4.06-3.99 (m, 1H), 3.87-3.62 (m, 4H), 1.10 (d, J=6.8 Hz, 3H). MS found (ESI ⁺ ) [(M+H) ⁺ ]: 579.

Example 14

(6S)-6-Methyl-N-(3,4,5-trifluorophenyl)-3-(3,3,6-trioxo-4,7,8,8a-tetrahydro-1H-pyrrolo[2,1-d][1,2,5]thiadiazin-2-yl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide

The title compound was prepared according to the following scheme:

The title compound was prepared in a manner similar to Example 13 using 5-(aminomethyl)pyrrolidin-2-one (Compound 14a) instead of benzyl N-(2-aminoethyl)carbamate (Compound 13a). Example 14 (11.1 mg) was obtained as a solid. ¹ H NMR (400MHz, METHANOL-d ₄ )δ7.70(s,0.5H),7.65(s,0.5H),7.23-7.13(m,2H),5.19-5.09(m,1H),4.99-4.90(m,1H),4.90-4.82(m,1H),4.48-4.36(m,2H),4.3 1-4.11(m,2H),4.09-3.89(m,2H),3.59-3.42(m,1H),2.59-2.38(m,2H),2.31-2.18(m,1H),1.75-1.63(m,1H),1.11(d,J＝6.8Hz,3H). MS found (ESI ⁺ ) [(M+H) ⁺ ]: 499.

Example 15

(6S)-3-(5-Acetyl-1,1-dioxo-1,2,5-thiadiazin-2-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:

The title compound was prepared in a manner similar to Example 13 using N-(2-aminoethyl)acetamide (Compound 15a) instead of benzyl N-(2-aminoethyl)carbamate (Compound 13a) to afford Example 15 (15.0 mg) as a solid. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ 7.65–7.62 (m, 1H), 7.22–7.13 (m, 2H), 5.02–4.92 (m, 3H), 4.91–4.78 (m, 1H), 4.43 (d, J = 17.0 Hz, 1H), 4.18 (dd, J = 4.1, 12.7 Hz, 1H), 4.08–4.01 (m, 1H), 3.92–3.80 (m, 2H), 3.74–3.69 (m, 1H), 3.66–3.61 (m, 1H), 2.18–2.12 (m, 3H), 1.11 (d, J = 7.0 Hz, 3H). MS found (ESI ⁺ ) [(M+H) ⁺ ]: 487.

Example 16

(6S)-6-Methyl-3-(3-methyl-1,1-dioxo-1,2-thiazolidin-2-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 (6S)-6-methyl-3-(3-methyl-1,1-dioxo-1,2-thiazolidin-2-yl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylic acid tert-butyl ester (Compound 16a)

To a solution of (6S)-3-iodo-6-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylic acid tert-butyl ester (Intermediate I-1, 100.0 mg, 0.275 mmol) in NMP (5.0 mL) was added CuI (10.0 mg, 0.055 mmol), K ₃ PO ₄ (175.0 mg, 0.825 mmol), N,N'-dimethyl-1,2-cyclohexanediamine (8.0 mg, 0.055 mmol) and 3-methyl-1,2-thiazolidine 1,1-dioxide (Intermediate I-13, 56.0 mg, 0.413 mmol). The reaction mixture was then heated under microwave conditions at 140° C. and stirred for 3 hours. The reaction was repeated 10 times on the same scale. The reaction mixture was partitioned between H ₂ O (80.0 mL) and EA (80.0 mL). The aqueous solution was extracted twice with EA (80.0 mL). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ , and concentrated under reduced pressure. The residue was purified by column chromatography and preparative HPLC to give (6S)-6-methyl-3-(3-methyl-1,1-dioxo-1,2-thiazolidin-2-yl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylic acid tert-butyl ester (Compound 16a, 100.0 mg) as a yellow oil. MS measured value (ESI ⁺ )[(M+H) ⁺ ]: 371.

Step 2: Preparation of 3-methyl-2-[(6S)-6-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl]-1,2-thiazolidine 1,1-dioxide (Compound 16b)

To a solution of tert-butyl (6S)-6-methyl-3-(3-methyl-1,1-dioxo-1,2-thiazolidin-2-yl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate (compound 16a, 50 mg, 0.135 mmol) in EtOAc (2.0 mL) was added a solution of HCl in EtOAc (5.0 mL, 20.0 mmol). The mixture was stirred at 15°C for 4 hours and then concentrated under reduced pressure to afford 3-methyl-2-[(6S)-6-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl]-1,2-thiazolidine 1,1-dioxide (compound 16b, 60 mg, crude) as a yellow solid. MS found (ESI ⁺ ) [(M+H) ⁺ ]: 271.

Step 3: Preparation of (6S)-6-methyl-3-(3-methyl-1,1-dioxo-1,2-thiazolidin-2-yl)-N-(3,4,5-trifluorophenyl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide

To a mixture of 3-methyl-2-[(6S)-6-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl]-1,2-thiazolidine 1,1-dioxide (60.0 mg, 0.222 mmol) in DMF (5 mL) was added Et ₃ N (67.4 mg, 0.666 mmol) and phenyl N-(3,4,5-trifluorophenyl)carbamate (59.3 mg, 0.222 mmol). The mixture was stirred at 15° C. for 15 hours and then partitioned between EA (100 mL) and water (30 mL). The organic layer was washed with brine (30 mL), dried over anhydrous Na ₂ SO ₄ , and concentrated under reduced pressure. The residue was purified by preparative-HPLC to give (6S)-6-methyl-3-(3-methyl-1,1-dioxo-1,2-thiazolidin-2-yl)-N-(3,4,5-trifluorophenyl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide (Example 16, 11.5 mg) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.58-7.51 (m, 1H), 7.21-7.08 (m, 2H), 7.02 (s, 1H), 5.05 (m, 1H), 5.00-4.82 (m, 1H), 4.56-4.35 (m, 1H), 4.31-4.19 (m, 1H), 4.14-4.02 (m, 1H), 3.89-3.69 (m, 1H), 3.50-3.27 (m, 2H), 2.66-2.55 (m, 1H), 2.16 (m, 1H), 1.35-1.26 (m, 3H), 1.26-1.17 (m, 3H), MS found (ESI ⁺ ) [(M+H) ⁺ ]: 444.

Example 17

(6S)-6-Methyl-3-(1-oxo-1,2-thiazolidin-2-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:

The title compound was prepared by a method similar to Example 1, using 1,2-thiazolidine 1-oxide (Intermediate I-14) instead of 1,2-thiazolidine 1,1-dioxide (Compound 1a) and N,N'-dimethyl-1,2-cyclohexanediamine instead of trans-N,N'-dimethyl-1,2-cyclohexanediamine. Example 17 (11 mg) was obtained as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.56-8.05 (m, 1H), 7.41-7.46 (d, 1H), 7.22-7.27 (m, 2H), 4.87-5.23 (m, 2H), 4.66-4.35 (m, 1H), 4.02-4.27 (m, 2H), 3.66-3.72 (m, 2H), 3.17-3.22 (m, 2H), 2.82 (m, 1H), 1.25-1.37 (m, 3H). MS found (ESI ⁺ ) [(M+H) ⁺ ]: 414.

Example 18

(6S)-3-(4-Hydroxy-1,1-dioxo-1,2-thiazolidin-2-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:

The title compound was prepared in a similar manner to Example 16, using 1,1-dioxo-1,2-thiazolidin-4-ol (Intermediate I-15) instead of 3-methyl-1,2-thiazolidine 1,1-dioxide (Intermediate I-13), to afford Example 18 (4 mg) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.62 (d, 1H), 7.19-7.22 (m, 2H), 7.02-7.08 (m, 1H), 5.11 (m, 1H), 5.01-5.06 (m, 1H), 4.99 (s, 1H), 4.52-4.56 (m, 1H), 4.27 (m, 1H), 4.10-4.13 (m, 1H), 4.01 (m, 1H), 3.66-3.70 (m, 2H), 3.47 (m, 1H), 1.31-1.33 (d, 3H). MS found (ESI ⁺ ) [(M+H) ⁺ ]: 446.

Example 19

(6S)-3-(1,1-dioxo-1,2,5-thiadiazolidin-2-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 (6S)-3-(5-benzyl-1,1-dioxo-1,2,5-thiadiazolidin-2-yl)-6-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylic acid tert-butyl ester (Compound 19a)

To a solution of (6S)-3-iodo-6-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylic acid tert-butyl ester (Intermediate I-1, 100 mg, 0.275 mmol), _2- benzyl-1,2,5-thiadiazolidine 1,1-dioxide (Intermediate I-16, 117 mg, 0.413 mmol), N,N'-dimethyl-1,2-cyclohexanediamine (8 mg, 0.055 mmol) and CuI (10 mg, 0.055 mmol) in DMSO (5 mL) was added _K2CO3 (114 mg, 0.825 mmol). The reaction mixture was stirred at 110°C for 12 hours. After cooling to room temperature, the mixture was filtered and the filtrate was purified by preparative HPLC to give compound 19a (90 mg) as a yellow solid. MS found (ESI ⁺ ) [(M+H) ⁺ ]: 448.

Step 2: Preparation of (6S)-3-(1,1-dioxo-1,2,5-thiadiazolidin-2-yl)-6-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylic acid tert-butyl ester (Compound 19b)

To a solution of (6S)-3-(5-benzyl-1,1-dioxo-1,2,5-thiadiazolidin-2-yl)-6-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylic acid tert-butyl ester (compound 19a, 90 mg, 0.20 mmol) in MeOH (20 mL) was added Pd(OH) ₂ /C (10 mg). The reaction mixture was stirred at 40° C. under H ₂ (50 psi) for 12 hours, and then at 60° C. under H ₂ (50 psi) for 12 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to afford compound 19b (65 mg, crude material) as a yellow oil. MS observed value (ESI ⁺ )[(M+H) ⁺ ]: 358.

Step 3: Preparation of 2-[(6S)-6-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl]-1,2,5-thiadiazolidine 1,1-dioxide (Compound 19c)

A solution of tert-butyl (6S)-3-(1,1-dioxo-1,2,5-thiadiazolidin-2-yl)-6-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate (compound 19b, 65 mg, 0.18 mmol) in HCl/EA (10 mL, 4 N) was stirred at 20°C for 2 hours and then concentrated under reduced pressure to afford compound 19c (50 mg, crude) as a brown oil. MS found (ESI ⁺ ) [(M+H) ⁺ ]: 258.

Step 4: Preparation of (6S)-3-(1,1-dioxo-1,2,5-thiadiazolidin-2-yl)-6-methyl-N-(3,4,5-trifluorophenyl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide (Example 19)

To a solution of 2-[(6S)-6-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl]-1,2,5-thiadiazolidine 1,1-dioxide (Compound 19c, 47 mg, 0.183 mmol) and phenyl N-(3,4,5-trifluorophenyl)carbamate (Intermediate I-2, 49 mg, 0.183 mmol) in DMF (5 mL) was added _Et3N (56 mg, 0.549 mmol). The mixture was stirred at 20°C for 4 hours and then concentrated under reduced pressure. The residue was purified by preparative HPLC to afford Example 19 (33 mg) as a white solid. ¹ H NMR (400 MHz, CHLOROFORM-d) δ 7.62 (s, 1H), 7.15 (dd, 2H), 6.83 (s, 1H), 5.04-5.13 (m, 1H), 4.99 (d, 1H), 4.49-4.63 (m, 2H), 4.28 (dd, 1H), 4.10 (d, 1H), 3.78-3.94 (m, 2H), 3.72 (q, 2H), 1.24-1.39 (m, 3H). MS found (ESI ⁺ ) [(M+H) ⁺ ]: 431.

Example 20

(6S)-6-Methyl-3-(5-methyl-1,1-dioxo-1,2,5-thiadiazolidin-2-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:

The title compound was prepared by a method similar to Example 1, using 2-methyl-1,2,5-thiadiazolidine 1,1-dioxide (Intermediate I-17) instead of 1,2-thiazolidine 1,1-dioxide (Compound 1a), N,N'-dimethyl-1,2-cyclohexanediamine instead of trans-N,N'-dimethyl-1,2-cyclohexanediamine, and Cs ₂ CO ₃ instead of K ₂ CO _3. Example 20 (12 mg) was obtained as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.61 (s, 1H) 7.15 (dd, 2H) 6.78 (s, 1H) 5.06-5.16 (m, 1H) 4.99 (d, 1H) 4.53 (d, 1H) 4.27 (dd, 1H) 4.10 (d, 1H) 3.67-3.84 (m, 2H) 3.46-3.55 (m, 2H) 2.88 (s, 3H) 1.32 (d, 3H). MS found (ESI ⁺ ) [(M+H) ⁺ ]: 445.

Example 21

(6S)-6-Methyl-3-[(3S)-3-methyl-1,1-dioxo-thiazetidin-2-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:

The title compound was prepared in a similar manner to Example 1 using (3S)-3-methylthiazetidine 1,1-dioxide (Intermediate 1-18) instead of 1,2-thiazolidine 1,1-dioxide (Compound 1a), K ₃ PO ₄ instead of K ₂ CO ₃ , dioxane instead of DMSO (in Step 1), and DIPEA instead of Et ₃ N (in Step 3). Example 21 (36 mg) was obtained as a white solid. ¹ H NMR (400 MHz, METHANOL-d ₄ ) 7.68 (s, 1H), 7.29 (dd, 2H), 5.12 (d, 1H), 5.02-4.92 (m, 1H), 4.58 (d, 1H), 4.39 (dd, 1H), 4.31 (dd, 1H), 4.17 (dd, 1H), 4.03-3.90 (m, 2H), 1.46 (d, 3H), 1.23 (d, 3H). MS found (ESI ⁺ ) [(M+H) ⁺ ]: 430.

Example 22

(6S)-6-Methyl-3-[(3S)-3-methyl-1,1-dioxo-1,2,5-thiadiazolidin-2-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 (6S)-3-[(3S)-5-[(4-methoxyphenyl)methyl]-3-methyl-1,1-dioxo-1,2,5-thiadiazolidin-2-yl]-6-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylic acid tert-butyl ester (Compound 22a)

To a mixture of trans-N,N'-dimethyl-1,2-cyclohexanediamine (28.4 mg, 0.2 mmol), K ₃ PO ₄ (413.9 mg, 1.95 mmol), CuI (38.1 mg, 0.02 mmol), (4S)-2-[(4-methoxyphenyl)methyl]-4-methyl-1,2,5-thiadiazolidine 1,1-dioxide (Intermediate I-19, 250.0 mg, 0.98 mmol) in NMP (15.0 mL) was added (6S)-tert-butyl 3-iodo-6-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate (Intermediate I-1, 355.9 mg, 0.98 mmol). The mixture was stirred at 120° C. for 16 hours. After cooling to room temperature, the mixture was filtered. The filtrate was concentrated, and the residue was purified by column chromatography to give compound 22a (45.0 mg) as a yellow oil. MS found (ESI ⁺ ) [(M+H) ⁺ ]: 492.

Step 2: Preparation of (6S)-6-methyl-3-[(3S)-3-methyl-1,1-dioxo-1,2,5-thiadiazolidin-2-yl]-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylic acid tert-butyl ester (Compound 22b)

To a solution of compound 22a (20.0 mg, 0.04 mmol) in AcOH (5.0 mL) at 20°C was added Pd(OH) ₂ (2.0 mg). The mixture was stirred at 80°C under _H2 (50 psi) for 64 hours and then filtered. The filtrate was concentrated to afford compound 22b (30.0 mg, crude) as a colorless oil. MS found (ESI ⁺ ) [(M+H) ⁺ ]: 372.

Step 3: Preparation of (3S)-3-methyl-2-[(6S)-6-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl]-1,2,5-thiadiazolidine 1,1-dioxide (Compound 22c)

To a solution of tert-butyl (6S)-6-methyl-3-[(3S)-3-methyl-1,1-dioxo-1,2,5-thiadiazolidin-2-yl]-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate (compound 22b, 30.0 mg, 0.08 mmol) in EtOAc (1.0 mL) was added HCl/EtOAc (3.0 mL) at 20°C. The reaction mixture was stirred at 20°C for 2 hours and then concentrated to afford compound 22c (25.0 mg, crude) as a yellow solid. MS found (ESI ⁺ ) [(M+H) ⁺ ]: 272.

Step 4: Preparation of (6S)-6-methyl-3-[(3S)-3-methyl-1,1-dioxo-1,2,5-thiadiazolidin-2-yl]-N-(3,4,5-trifluorophenyl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide (Example 22)

To a solution of (3S)-3-methyl-2-[(6S)-6-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl]-1,2,5-thiadiazolidine 1,1-dioxide (compound 22c, 25.0 mg, 0.08 mmol) and DIPEA (20.7 mg, 0.16 mmol) in DMF (1.0 mL) at 20°C was added phenyl N-(3,4,5-trifluorophenyl)carbamate (Intermediate I- ₂ , 21.4 mg, 0.08 mmol). The reaction mixture was stirred at 20°C for 2 hours and then partitioned between EtOAc (5.0 mL) and brine (3.0 mL). The organic layer was dried over anhydrous _Na2SO4 and concentrated. The residue was purified by preparative HPLC to afford Example 22 as a colorless oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.57 (s, 1H), 7.62-7.56 (m, 2H), 7.54 (s, 1H), 5.13-5.05 (m, 1H), 5.03-4.95 (m, 1H), 4.41-4.32 (m, 1H), 4.30-4.23 (m, 1H), 4.13 (d, 1H), 3.93 (q, 1H), 3.64-3.56 (m, 1H), 3.03 (td, 1H), 1.12-1.07 (m, 6H). MS found (ESI ⁺ ) [(M+H) ⁺ ]: 445.

Example 23

(6S)-3-[(3S)-3,4-Dimethyl-1,1-dioxo-1,2,5-thiadiazolidin-2-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:

The title compound was prepared in a similar manner to Example 22, using (4S)-2-[(4-methoxyphenyl)methyl]-3,4-dimethyl-1,2,5-thiadiazolidine 1,1-dioxide (Intermediate I-20) instead of (4S)-2-[(4-methoxyphenyl)methyl]-4-methyl-1,2,5-thiadiazolidine 1,1-dioxide (Intermediate I-19). Example 23 (8.7 mg) was obtained as a colorless oil. ¹ H NMR (400MHz, DMSO-d ₆ ) δ9.21-9.06(m,1H),7.57(t,1H),7.43(br dd,1H),5.05-4.92(m,1H),4.85(br s,1H),4.34(br d,1H),4.26(br d,1H),4.16(br d,1H),3.90(br s,1H),3.57-3.41(m,2H),1.31-1.19(m,4H),1.16-1.03(m,5H). MS measured value (ESI ⁺ )[(M+H) ⁺ ]: 459.

Example 24

(6S)-3-(3,3-Dioxo-1,3,4-oxathiazin-4-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:

The title compound was prepared in a similar manner to Example 1 using 1,3,4-oxathiazinane 3,3-dioxide (Intermediate I-21) instead of 1,2-thiazolidine 1,1-dioxide (Compound 1a), K ₃ PO ₄ instead of K ₂ CO ₃ , dioxane instead of DMSO (in Step 1) and DIPEA instead of Et ₃ N (in Step 3). Example 24 (9.3 mg) was obtained as a white solid. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ 7.62 (s, 1H), 7.18 (dd, 2H), 4.97 (d, 1H), 4.89-4.83 (m, 1H), 4.76-4.75 (m, 2H), 4.44 (d, 1H), 4.23-4.13 (m, 1H), 4.09-3.92 (m, 3H), 3.79-3.70 (m, 2H), 1.11 (d, 3H). MS found (ESI ⁺ ) [(M+H) ⁺ ]: 446.

Example 25

(6S)-3-(1,1-dioxothiazetidin-2-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:

The title compound was prepared by a procedure analogous to Example 1, using thiazetidine 1,1-dioxide (Intermediate I-22) instead of 1,2-thiazolidine 1,1-dioxide (Compound 1a), K ₃ PO ₄ instead of K ₂ CO ₃ , dioxane instead of DMSO (in Step 1), and DIPEA instead of Et ₃ N (in Step 3). Example 25 (8.5 mg) was obtained as a white solid. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ 7.68 (s, 1H), 7.30 (dd, 2H), 5.13 (d, 1H), 4.96 (t, 1H), 4.56 (d, 1H), 4.38-4.26 (m, 3H), 4.19-4.13 (m, 1H), 3.69 (dt, 2H), 1.24 (d, 3H). MS found (ESI ⁺ ) [(M+H) ⁺ ]: 416.

Example 26

(6S)-3-(4-Hydroxy-1,1-dioxo-1,2,6-thiadiazin-2-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:

The title compound was prepared in a similar manner to Example 1, using 1,1-dioxo-1,2,6-thiadiazin-4-ol (Intermediate I-23) instead of 1,2-thiazolidine 1,1-dioxide (Compound 1a), K ₃ PO ₄ instead of K ₂ CO ₃ , dioxane instead of DMSO (in Step 1), and DIPEA instead of Et ₃ N (in Step 3). Example 26 (3.4 mg) was obtained as a white solid. ¹ H NMR (400 MHz, CHLOROFORM-d) δ 7.60 (d, 1H), 7.10-7.00 (m, 2H), 5.01-4.82 (m, 2H), 4.51-4.35 (m, 1H), 4.25-4.14 (m, 1H), 4.11-3.89 (m, 3H), 3.81 (d, 1H), 3.52-3.39 (m, 2H), 1.22 (d, 3H). MS found (ESI ⁺ ) [(M+H) ⁺ ]: 461.

Example 27

(6S)-3-(1,1-dioxo-1,2,6-thiadiazin-2-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:

The title compound was prepared in a similar manner to Example 1 using 1,2,6-thiadiazine 1,1-dioxide (Intermediate 1-24) instead of 1,2-thiazolidine 1,1-dioxide (Compound 1a), K ₃ PO ₄ instead of K ₂ CO ₃ , dioxane instead of DMSO (in Step 1), and DIPEA instead of Et ₃ N (in Step 3). Example 27 (8.8 mg) was obtained as a white solid. ^1H NMR (400 MHz, DMSO-d ₆ ) δ 9.17 (s, 1H), 7.63 (s, 1H), 7.50-7.34 (m, 2H), 7.21 (br t, 1H), 5.00 (d, 1H), 4.90-4.77 (m, 1H), 4.33 (d, 1H), 4.26-4.18 (m, 1H), 4.17-4.07 (m, 1H), 3.60-3.55 (m, 2H), 3.38 (br d, 2H), 1.78 (br s, 2H), 1.11 (d, 3H). MS found (ESI ⁺ ) [(M+H) ⁺ ]: 445.

Example 28

(6S)-3-(4-Hydroxy-3-methyl-1,1-dioxo-1,2-thiazolidin-2-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 (6S)-3-[[(1S)-2-methoxy-1-methyl-2-oxo-ethyl]amino]-6-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylic acid tert-butyl ester (Compound 28b)

An oven-dried resealable 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, 1 g, 2.75 mmol), K ₃ PO ₄ (1.46 g, 6.88 mmol), CuI (105 mg, 0.55 mmol) and 2-((2,6-dimethylphenyl)amino)-2-oxoacetic acid (213 mg, 1.10 mmol), then decanted and refilled with argon followed by the addition of a solution of (S)-methyl 2-aminopropanoate hydrochloride (compound 28a, 423 mg, 3.03 mmol) in DMSO (10.0 mL). The mixture was stirred at 110° C. in a microwave for 2 h, then quenched with saturated aqueous NH ₄ Cl and diluted with EtOAc. The organic layer was separated and washed with saturated aqueous NH ₄ Cl solution and brine, dried over Na ₂ SO ₄ and concentrated. The residue was purified by column chromatography to give compound 28b (323 mg). LCMS (M+H ⁺ ): 339.

Step 2: Preparation of (6S)-3-[[(1S)-2-methoxy-1-methyl-2-oxo-ethyl]-(2-methoxy-2-oxo-ethyl)sulfonyl-amino]-6-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylic acid tert-butyl ester (Compound 28c)

To a mixture of (6S)-3-[[(1S)-2-methoxy-1-methyl-2-oxo-ethyl]amino]-6-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylic acid tert-butyl ester (compound 28b, 323 mg, 0.954 mmol) and DIPEA (370 mg, 2.86 mmol) in DCM (10 mL) was added methyl 2-(chlorosulfonyl)acetate (181 mg, 1.05 mmol). The mixture was stirred at room temperature overnight and concentrated. The residue was purified by flash chromatography to give compound 28c (319 mg). LCMS (M+H ⁺ ): 475.

Step 3: Preparation of (6S)-6-methyl-3-(3-methyl-1,1,4-trioxo-1,2-thiazolidin-2-yl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylic acid tert-butyl ester (Compound 28d)

Sodium methoxide (182 mg, 3.36 mmol) was added to a solution of (6S)-3-[[(1S)-2-methoxy-1-methyl-2-oxo-ethyl]-(2-methoxy-2-oxo-ethyl)sulfonyl-amino]-6-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylic acid tert-butyl ester (compound 28c, 319 mg, 672 μmol) in MeOH (10 mL). The mixture was stirred at room temperature for 24 hours. The mixture was concentrated, and the residue was acidified to pH = 4 with hydrochloric acid. The resulting mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous Na ₂ SO ₄ and concentrated. The residue was purified by column chromatography to give compound 28d (80 mg). LCMS (M+H ⁺ ): 385.

Step 4: Preparation of (6S)-3-(4-hydroxy-3-methyl-1,1-dioxo-1,2-thiazolidin-2-yl)-6-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylic acid tert-butyl ester (Compound 28e)

NaBH ₄ (11.2 mg, 297 μmol) was added to a solution of (6S)-6-methyl-3-(3-methyl-1,1,4-trioxo-1,2-thiazolidin-2-yl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylic acid tert-butyl ester (compound 28d, 76 mg, 198 μmol) in MeOH (10 mL). The mixture was stirred at room temperature for 1 hour and then concentrated. The residue was partitioned between water and ethyl acetate. The organic layer was dried over anhydrous Na ₂ SO ₄ and concentrated to give compound 28e (69 mg, crude material), which was used directly in the next step without further purification. LCMS (M+H ⁺ ): 387.

Step 5: Preparation of 3-methyl-2-[(6S)-6-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl]-1,1-dioxo-1,2-thiazolidin-4-ol (Compound 28f)

A mixture of (6S)-tert-butyl 3-(4-hydroxy-3-methyl-1,1-dioxo-1,2-thiazolidin-2-yl)-6-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate (compound 28e, 69 mg, 623 μmol) and 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 28f (105 mg). LCMS (M+H ⁺ ): 287.

Step 6: Preparation of (6S)-3-(4-hydroxy-3-methyl-1,1-dioxo-1,2-thiazolidin-2-yl)-6-methyl-N-(3,4,5-trifluorophenyl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide

To a solution of 3-methyl-2-[(6S)-6-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl]-1,1-dioxo-1,2-thiazolidin-4-ol (compound 28f, 105 mg, crude material) in DCM (3.0 mL) was added DIPEA (0.5 mL) and phenyl N-(3,4,5-trifluorophenyl)carbamate (intermediate I-2, 57.2 mg, 214 μmol). The reaction mixture was stirred at 50 ° C for 3 hours and then partitioned between ice water and DCM. The aqueous layer was extracted with DCM. The combined organic layers were concentrated. The residue was purified by preparative HPLC to give Example 28-1 (35 mg) and Example 28-2 (6 mg).

Example 28-1: ¹ H NMR (400MHz, METHANOL-d ₄ ) δ7.63 (d, 1H), 7.30 (br dd, 2H), 5.07 (dd, 1H), 5.01-4.94 (m, 1H), 4.59 (br d,1H),4.33(td,1H),4.22-4.13(m,2H),3.99-3.92(m,1H),3.74(dd,1H),3.49-3.42(m,1H),1.32(t,3H),1.27-1.21(m,3H). LCMS(M+H ⁺ ):460.

Example 28-2: ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ 7.66-7.61 (m, 1H), 7.29 (dd, 2H), 5.05 (d, 1H), 5.00-4.94 (m, 1H), 4.58-4.50 (m, 1H), 4.32-4.26 (m, 1H), 4.20-4.14 (m, 2H), 3.83-3.76 (m, 1H), 3.66-3.61 (m, 1H), 1.30-1.19 (m, 6H). LCMS (M+H ⁺ ): 460.

Example 29

(6S)-N-[2-(Difluoromethyl)-4-pyridinyl]-3-(4-hydroxy-3-methyl-1,1-dioxo-1,2-thiazolidin-2-yl)-6-methyl-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 3-methyl-2-[(6S)-6-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl]-1,1-dioxo-1,2-thiazolidin-4-ol (compound 28f, 53 mg, crude material) in DCM (3.0 mL) was added DIPEA (0.5 mL) and phenyl N-[2-(difluoromethyl)-4-pyridinyl]carbamate (Intermediate I-3, 28 mg, 106 μmol). The reaction mixture was stirred at 50 ° C for 1 hour and then partitioned between ice water and DCM. The aqueous layer was extracted with DCM. The combined organic layers were concentrated. The residue was purified by preparative-HPLC to give Example 29 (7.6 mg). ¹ H NMR (400MHz, METHANOL-d ₄ ) δ8.35(d,1H),7.80(d,1H),7.61(br d,1H),7.56(d,1H),6.75-6.43(m,1H),5.04(dd,1H),4.96-4.89(m,1H),4.51(dd,1H),4.31- 4.17(m,2H),4.11(dd,1H),3.72(dd,1H),3.56(dt,1H),3.21-3.15(m,1H),1.20-1.13(m,6H). LCMS(M+H ⁺ ):457.

Example 30

(6S)-6-Methyl-3-(3-methyl-1,1-dioxo-4-pyrimidin-2-yloxy-1,2-thiazolidin-2-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 (6S)-6-methyl-3-(3-methyl-1,1-dioxo-4-pyrimidin-2-yloxy-1,2-thiazolidin-2-yl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylic acid tert-butyl ester (Compound 30a)

To a mixture of _K2CO3 (32.2 _mg , 233 μmol) and (6S)-tert-butyl 3-(4-hydroxy-3-methyl-1,1-dioxo-1,2-thiazolidin-2-yl)-6-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate (compound 28e, 30 mg, 77.6 μmol) in dioxane (10 mL) was added 2-(methylsulfinyl)pyrimidine (22.1 mg, 155 μmol). The mixture was stirred at room temperature overnight and then concentrated. The residue was partitioned between water and ethyl acetate. The organic layer was dried _over anhydrous _Na2SO4 and concentrated. The residue was purified by column chromatography to afford compound 30a (29 mg). LCMS (M+H ⁺ ): 465.

Step 2: Preparation of 3-methyl-2-[(6S)-6-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl]-4-pyrimidin-2-yloxy-1,2-thiazolidine 1,1-dioxide (Compound 30b)

A mixture of (6S)-6-methyl-3-(3-methyl-1,1-dioxo-4-pyrimidin-2-yloxy-1,2-thiazolidin-2-yl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylic acid tert-butyl ester (compound 30a, 25 mg, 53.8 μmol) and 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 give compound 30b (30 mg, crude material). LCMS (M+H ⁺ ): 365.

Step 3: Preparation of (6S)-6-methyl-3-(3-methyl-1,1-dioxo-4-pyrimidin-2-yloxy-1,2-thiazolidin-2-yl)-N-(3,4,5-trifluorophenyl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide

(Example 30)

To a solution of 3-methyl-2-[(6S)-6-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl]-4-pyrimidin-2-yloxy-1,2-thiazolidine 1,1-dioxide (compound 30b, 30 mg, crude material) in DCM (3.0 mL) was added DIPEA (0.5 mL) and phenyl N-(3,4,5-trifluorophenyl)carbamate (Intermediate I-2, 20 mg, 75.2 μmol). The reaction mixture was stirred at 50 ° C for 1 hour and then partitioned between ice water and DCM. The aqueous layer was extracted with DCM. The combined organic layers were concentrated. The residue was purified by preparative-HPLC to give Example 30 (7.5 mg). ¹ H NMR (400MHz, METHANOL-d ₄ )δ8.65(t,2H),7.70(d,1H),7.31(ddd,2H),7.22(dt,1H),5.61-5.52(m,1H),5.10(dd,1H),5.04-4. 95(m,1H),4.60(dd,1H),4.34(dd,1H),4.22-4.03(m,3H),3.63(ddd,1H),1.42(d,3H),1.24(t,3H). LCMS(M+H ⁺ ):538.

Example 31

(6S)-3-(4-methoxy-3-methyl-1,1-dioxo-1,2-thiazolidin-2-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 (6S)-3-(4-methoxy-3-methyl-1,1-dioxo-1,2-thiazolidin-2-yl)-6-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylic acid tert-butyl ester (Compound 31a)

NaH (60% in oil, 10 mg, 259 μmol) was added to a solution of (6S)-3-(4-hydroxy-3-methyl-1,1-dioxo-1,2-thiazolidin-2-yl)-6-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylic acid tert-butyl ester (compound 28e, 50 mg, 129 μmol) in THF (10 mL) at 0°C. The mixture was stirred at 0°C for 5 minutes, then iodomethane (55 mg, 388 μmol) was added. The reaction mixture was stirred at room temperature overnight and then concentrated. The residue was partitioned between water and ethyl acetate. The organic layer was dried over anhydrous Na ₂ SO ₄ and concentrated. The residue was purified by column chromatography to give compound 31a (42 mg, crude material). LCMS (M+H ⁺ ): 401.

Step 2: Preparation of 4-methoxy-3-methyl-2-[(6S)-6-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl]-1,2-thiazolidine 1,1-dioxide (Compound 31b)

A mixture of (6S)-3-(4-methoxy-3-methyl-1,1-dioxo-1,2-thiazolidin-2-yl)-6-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylic acid tert-butyl ester (Compound 31a, 25 mg, crude) and 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 give Compound 31b (25 mg). LCMS (M+H ⁺ ): 301.

Step 3: Preparation of (6S)-3-(4-methoxy-3-methyl-1,1-dioxo-1,2-thiazolidin-2-yl)-6-methyl-N-(3,4,5-trifluorophenyl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide (Example 31)

To a solution of 4-methoxy-3-methyl-2-[(6S)-6-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl]-1,2-thiazolidine 1,1-dioxide (compound 31b, 25 mg, crude material) in DCM (3.0 mL) was added DIPEA (0.5 mL) and phenyl N-(3,4,5-trifluorophenyl)carbamate (intermediate I-2, 16 mg, 60 μmol). The reaction mixture was stirred at 50 ° C for 1 hour and then partitioned between ice water and DCM. The aqueous layer was extracted with DCM. The combined organic layers were concentrated. The residue was purified by preparative-HPLC to give Example 31 (8.2 mg). ¹ H NMR (400MHz, METHANOL-d ₄ )δ7.64(d,1H),7.29(dd,2H),5.05(dd,1H),5.00-4.93(m,1H),4.53(d,1H),4.33(td,1H),4.17(dd,1H),4. 03(td,1H),3.82(m,1H),3.72(dt,1H),3.50-3.46(m,3H),3.41(ddd,1H),1.29(dd,3H),1.26-1.21(m,3H). LCMS(M+H ⁺ ):474.

Example 32

(6S)-N-[2-(Difluoromethyl)-4-pyridinyl]-3-(4-methoxy-3-methyl-1,1-dioxo-1,2-thiazolidin-2-yl)-6-methyl-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 4-methoxy-3-methyl-2-[(6S)-6-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl]-1,2-thiazolidine 1,1-dioxide (compound 31b, 25 mg, crude material) in DCM (3.0 mL) was added DIPEA (0.5 mL) and N-[2-(difluoromethyl)-4-pyridyl]phenylcarbamate (intermediate I-3, 16 mg, 60 μmol). The reaction mixture was stirred at 50 ° C for 1 hour and then partitioned between ice water and DCM. The aqueous layer was extracted with DCM. The combined organic layers were concentrated. The residue was purified by preparative-HPLC to give Example 32-1 (8.4 mg) and Example 32-2 (1.9 mg).

Example 32-1: ¹ H NMR (400MHz, METHANOL-d ₄ ) δ 8.53 (br s, 1H), 8.02 (s, 1H), 7.83 (brd, 1H), 7.68 (br s, 1H), 7.00-6.66 (m, 1H), 5.13 (dd, 1H), 5.01 (br dd,1H),4.59(d,1H),4.35(br s,1H),4.21(br d,1H),4.07-4.00(m,1H),3.87-3.79(m,1H),3.75-3.69(m,1H),3.47(d,3H),3.41(ddd,1H),1.28(dt,6H). LCMS(M+H ⁺ ):471.

Example 32-2: ¹ H NMR (400MHz, METHANOL-d ₄ ) δ 8.31 (d, 1H), 7.77 (d, 1H), 7.57 (br d,1H),7.53-7.49(m,1H),6.75-6.39(m,1H),5.04-4.96(m,1H),4.95-4 .87(m,1H),4.52-4.43(m,1H),4.28-4.20(m,1H),4.15(q,1H),4.07(br d,1H),3.93(dd,1H),3.55(d,2H),3.35(s,3H),1.16-1.06(m,6H). LCMS(M+H ⁺ ):471.

Example 33

3-(1,1-dioxo-1,2-thiazolidin-2-yl)-6-methyl-N-(3,4,5-trifluorophenyl)-6,7-dihydro-4H-triazolo[1,5-a]pyrazine-5-carboxamide

The title compound was prepared according to the following scheme:

The title compound was prepared by a method similar to that of Example 1, using tert-butyl 3-iodo-6-methyl-6,7-dihydro-4H-triazolo[1,5-a]pyrazine-5-carboxylate (Intermediate I-25) instead of tert-butyl (6S)-3-iodo-6-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate (Intermediate I-1) in step 1, and N,N'-dimethyl-1,2-cyclohexanediamine instead of trans-N,N'-dimethyl-1,2-cyclohexanediamine.

Example 33-1 (4.2 mg, obtained from intermediate I-25-1) was obtained as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 7.16 (dd, 2H), 6.95 (s, 1H), 5.21 (m, 1H), 5.02 (d, 1H), 4.61 (d, 1H), 4.37-4.47 (m, 2H), 4.16 (dt, 1H), 4.06 (dt, 1H), 3.31-3.45 (m, 2H), 2.68 (quin, 2H), 1.27 (d, 3H). MS found (ESI ⁺ ) [(M+H) ⁺ ]: 431.

Example 33-2 (5 mg, obtained from intermediate I-25-2) was obtained as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 7.08-7.21 (m, 2H), 6.89 (br. s., 1H), 5.21 (br. s., 1H), 5.02 (d, 1H), 4.61 (d, 1H), 4.43 (br. s., 2H), 4.12-4.23 (m, 1H), 4.01-4.11 (m, 1H), 3.38 (d, 2H), 2.68 (t, 2H), 1.27 (d, 3H). MS found (ESI ⁺ ) [(M+H) ⁺ ]: 431.

Example 34

(6S)-3-(1,1-dioxo-1,2-thiazolidin-2-yl)-6-methyl-N-(3-thienylmethyl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide

The title compound was prepared in a similar manner to Example 2, using phenyl N-(3-thienylmethyl)carbamate (Intermediate I-26) instead of phenyl N-(2-chloro-4-pyridyl)carbamate (Intermediate I-4). Example 34 (24 mg) was obtained as a white solid. ¹ H NMR (400MHz, CDCl ₃ )δ7.52(s,1H),7.28-7.24(m,1H),7.14(d,1H),7.04(dd,1H),5.04-4.87(m,1H),4.76(d,1H),4.46-4.33(m, 3H),4.19(dd,1H),4.03(d,1H),3.66-3.55(m,2H),3.41(s,1H),3.29(t,2H),2.53-2.40(m,2H),1.14(d,3H). (ESI ⁺ )[(M+H) ⁺ ]:396.

Example 35

(2S)-1-[2-[(6S)-6-Methyl-5-[(3,4,5-trifluorophenyl)carbamoyl]-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-3-yl]-1,1-dioxo-1,2-thiazolidin-4-yl]pyrrolidine-2-carboxylic acid

The title compound was prepared according to the following scheme:

Step 1: Preparation of methyl (2S)-1-(2-benzyl-1,1-dioxo-1,2-thiazolidin-4-yl)pyrrolidine-2-carboxylate (Compound 35a)

To a solution of 2-benzyl-1,1-dioxo-1,2-thiazolidin-4-one (Compound I-15d, 500 mg, 2.2 mmol) in MeOH (10 mL) was added (2S)-methyl pyrrolidine-2-carboxylate (860 mg, 6.66 mmol) and NaBH(OAc) _₃ (1411 mg, 6.66 mmol). The resulting mixture was stirred at 20°C for 18 hours, followed by the addition of _NaBH₃CN (418 mg, 6.66 mmol). The resulting mixture was stirred at 20°C for an additional 18 hours. The mixture was filtered, and the filtrate was purified by preparative HPLC to afford Compound 35a (500 mg) as a colorless oil. MS observed (ESI) [(M+H) ^⁺ ]: 337.

Step 2: Preparation of (2S)-1-(1,1-dioxo-1,2-thiazolidin-4-yl)pyrrolidine-2-carboxylic acid methyl ester (Compound 35b)

To a solution of (2S)-1-(2-benzyl-1,1-dioxo-1,2-thiazolidin-4-yl)pyrrolidine-2-carboxylic acid methyl ester (compound 35a, 100 mg, 0.3 mmol) in MeOH (5 mL) was added Pd/C (300 mg). The reaction mixture was stirred at 60°C under _H₂ (50 psi) for 18 hours and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by chromatography to afford compound 35b (30 mg) as a colorless oil. MS observed (ESI) [(M+H) ^⁺ ]: 249.

Step 3: Preparation of (6S)-3-[4-[(2S)-2-methoxycarbonylpyrrolidin-1-yl]-1,1-dioxo-1,2-thiazolidin-2-yl]-6-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylic acid tert-butyl ester (Compound 35c)

To a solution of (2S)-1-(1,1-dioxo-1,2-thiazolidin-4-yl)pyrrolidine-2-carboxylic acid methyl ester (compound 35b, 130 mg, 0.52 mmol) in DMSO (1 mL) were added K ₃ PO ₄ (330 mg, 1.56 mmol), N,N'-dimethyl-1,2-cyclohexanediamine (15 mg, 0.1 mmol), (6S)-3-iodo-6-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylic acid tert-butyl ester (Intermediate I-1, 380 mg) and CuI (20 mg, 0.1 mmol). The resulting mixture was stirred at 110° C. under N ₂ for 15 hours. The mixture was purified by preparative HPLC to give compound 35c (30 mg) as a white solid. MS observed (ESI) [(M+H) ⁺ ]: 484.

Step 4: Preparation of (2S)-1-[2-[(6S)-6-methyl-5-[(3,4,5-trifluorophenyl)carbamoyl]-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-3-yl]-1,1-dioxo-1,2-thiazolidin-4-yl]pyrrolidine-2-carboxylic acid methyl ester (Compound 35d)

To a solution of tert-butyl (6S)-3-[4-[(2S)-2-methoxycarbonylpyrrolidin-1-yl]-1,1-dioxo-1,2-thiazolidin-2-yl]-6-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate (compound 35c, 30 mg, 0.06 mmol) in EtOAc (5 mL) was added HCl/EtOAc (2 mL). The resulting mixture was stirred at 20°C for 2 hours and then concentrated under reduced pressure. The residue was dissolved in DMF (1 mL), and _Et3N (13 mg, 0.13 mmol) and phenyl N-(3,4,5-trifluorophenyl)carbamate (Intermediate I-2, 21 mg, 0.08 mmol) were added. The resulting mixture was stirred at 20°C for 15 hours and then partitioned between water (10 mL) and EtOAc (10 mL). The aqueous layer was extracted twice with EtOAc. The combined organic layers were washed with water (20 mL) and brine (20 mL), dried over anhydrous Na ₂ SO ₄ , and concentrated under reduced pressure to afford crude compound 35d (40 mg) as a yellow oil, which was used directly in the next step without purification. MS observed value (ESI) [(M+H) ⁺ ]: 557.

Step 5: Preparation of (2S)-1-[2-[(6S)-6-methyl-5-[(3,4,5-trifluorophenyl)carbamoyl]-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-3-yl]-1,1-dioxo-1,2-thiazolidin-4-yl]pyrrolidine-2-carboxylic acid (Example 35)

To a mixture of (2S)-1-[2-[(6S)-6-methyl-5-[(3,4,5-trifluorophenyl)carbamoyl]-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-3-yl]-1,1-dioxo-1,2-thiazolidin-4-yl]pyrrolidine-2-carboxylic acid methyl ester (compound 35d, 40 mg, 0.07 mmol) in THF (3 mL) and water (1 mL) was added LiOH· _H₂O (9 mg, 0.22 mmol ₎ . The resulting mixture was stirred at 20°C for 2 hours and then acidified to pH = 1 with 1N HCl. The mixture was extracted three times with EtOAc (20 mL). The combined organic layers were washed with brine, dried over anhydrous _Na₂SO₄ , and concentrated under reduced pressure. The residue was purified by preparative HPLC to afford Example 35 (20 mg) as a white solid. ¹ H NMR(400MHz,MeOD)δ7.66(d,1H),7.39-7.24(m,2H),5.21-5.02(m,1H),5.00-4.94(m ,1H),4.56(dd,1H),4.35-4.04(m,3H),3.92-3.81(m,1H),3.81-3.56(m,3H),3.60(br dd,1H),3.36(br s,1H),3.43(br s,1H),2.99-2.79(m,1H),2.38-2.23(m,1H),2.10(br s,1H),2.01-1.83(m,2H),1.22(br d,3H). MS found (ESI ⁺ ) [(M+H) ⁺ ]: 543.

Example 36

2-[2-[(6S)-6-Methyl-5-[(3,4,5-trifluorophenyl)carbamoyl]-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-3-yl]-1,1-dioxo-1,2-thiazolidin-4-yl]benzoic acid

The title compound was prepared according to the following scheme:

Step 1: Preparation of (2-benzyl-1,1-dioxo-3H-isothiazol-4-yl) trifluoromethanesulfonate (Compound 36a)

To a solution of 2-benzyl-1,1-dioxo-1,2-thiazolidin-4-one (compound I-15d, 5 g, 22 mmol) in DCM (100 mL) was added TEA (4.6 mL, 33 mmol). The solution was cooled to -78°C, and then Tf ₂ O (7.5 g, 26.6 mmol) was added dropwise under N ₂ over 5 minutes. The reaction mixture was stirred at -78°C for 1 hour and then quenched by the addition of water (50 mL). The resulting mixture was diluted with DCM (500 mL). The organic layer was separated and washed with water and 1N hydrochloric acid, dried over anhydrous Na ₂ SO ₄ , and concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA = 20:1 to 5:1) to give compound 36a (2.8 g) as a white solid. ¹ H NMR (400MHz, DMSO-d ₆ ) δ7.36-7.44 (m, 5H), 6.78 (s, 1H), 4.40 (s, 2H), 3.90 (s, 2H).

Step 2: Preparation of methyl 2-(2-benzyl-1,1-dioxo-3H-isothiazol-4-yl)benzoate (Compound 36b)

To a solution of (2-benzyl-1,1-dioxo-3H-isothiazol-4-yl) trifluoromethanesulfonate (compound 36a, 500 mg, 1.4 mmol) in 1,4-dioxane (10 mL) and water (2 mL) were added 2-methoxycarbonylphenylboronic acid (252 mg, 1.4 mmol), Pd(dppf) _Cl₂ (114 mg), and _K₃PO₄ (594 _mg , 2.8 mmol). The reaction mixture was stirred at 100°C under _N₂ for 4 hours and then concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA = 10:1 to 3:1) to afford compound 32b (420 mg) as a brown solid. MS observed ( ^ESI⁺ ) [(M+H) ^⁺ ]: 344.

Step 3: Preparation of methyl 2-(1,1-dioxo-1,2-thiazolidin-4-yl)benzoate (Compound 36c)

To a solution of methyl 2-(2-benzyl-1,1-dioxo-3H-isothiazol-4-yl)benzoate (compound 36b, 100 mg, 0.29 mmol) in methanol (5 mL) was added Pd/C (40 mg). The mixture was stirred at 60°C under _H2 (50 psi) for 18 hours. The reaction was repeated twice on the same scale. The reaction mixtures were combined and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by chromatography to afford compound 36c (60 mg) as a colorless oil.

Step 4: Preparation of 2-[2-[(6S)-5-tert-butoxycarbonyl-6-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-3-yl]-1,1-dioxo-1,2-thiazolidin-4-yl]benzoic acid (Compound 36d)

To a solution of methyl 2-(1,1-dioxo-1,2-thiazolidin-4-yl)benzoate (compound 36c, 60 mg, 0.24 mmol) in DMSO (2 mL) was added CuI (9 mg, 0.05 mmol), (6S)-tert-butyl 3-iodo-6-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate (Intermediate I-1, 171 mg, 0.47 mmol), K ₃ PO ₄ (150 mg, 0.71 mmol) and N,N'-dimethyl-1,2-cyclohexanediamine (7 mg, 0.05 mmol). The mixture was stirred at 110° C. under N ₂ for 15 hours, then cooled to room temperature and purified by preparative HPLC to give compound 36d (30 mg) as a yellow oil. MS found (ESI ⁺ ) [(M+H) ⁺ ]: 477.

Step 5: Preparation of 2-[2-[(6S)-6-methyl-5-[(3,4,5-trifluorophenyl)carbamoyl]-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-3-yl]-1,1-dioxo-1,2-thiazolidin-4-yl]benzoic acid (Example 36)

To a solution of 2-[2-[(6S)-5-tert-butoxycarbonyl-6-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-3-yl]-1,1-dioxo-1,2-thiazolidin-4-yl]benzoic acid (Compound 36d, 25 mg, 0.05 mmol) in EtOAc (5 mL) was added EtOAc/HCl (2 mL). The resulting mixture was stirred at 25°C for 2 hours, then concentrated under reduced pressure, and the residue was dissolved in DMF (0.5 mL). To the resulting solution was added TEA (55 mg, 0.55 mmol) and phenyl N-(3,4,5-trifluorophenyl)carbamate (Intermediate I-2, 17 mg, 0.06 mmol). The mixture was stirred at 25°C for 18 hours, then purified by preparative HPLC to afford Example 36 (18.4 mg) as a white solid. ^1H NMR (400 MHz, MeOD) δ 7.88 (d, 1H), 7.74-7.67 (m, 2H), 7.65-7.56 (m, 1H), 7.43-7.35 (m, 1H), 7.34-7.22 (m, 2H), 5.19-5.09 (m, 1H), 5.01-4.95 (m, 2H), 4.65-4.51 (m, 1H), 4.35-4.23 (m, 1H), 4.20-4.08 (m, 1H), 4.05-3.94 (m, 1H), 3.90-3.72 (m, 2H), 3.66-3.53 (m, 1H), 1.23 (dd, 3H). MS found (ESI ⁺ ) [(M+H) ⁺ ]: 550.

Example 37: HBV inhibition test

Cell lines and culture conditions:

HepG2.2.15 is a stably transfected cell line containing the HBV genome, which was derived from the hepatoblastoma cell line Hep G2 (American Type Culture Collection, HB-8065 ^™ ) by a method described in 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 catalog number: 11320-033) supplemented with 10% fetal bovine serum (Gibco, catalog number: 10099-141), 100 U/mL penicillin, 100 μg/mL streptomycin (Gibco, catalog number: 15140-122), and 0.3 mg/mL G418 sulfate (Gibco, catalog number: 10131-027).

In vitro anti-HBV activity:

HepG2.2.15 cells were seeded at a density of 3 × 10 ⁴ cells per well in 96-well plates in 100 μL of DMEM/F-12 supplemented with 2.5% fetal bovine serum, 100 U/mL penicillin, and 100 μg/mL streptomycin and cultured overnight at 37°C. Test compounds were serially diluted half-logarithmically in DMSO and then diluted 100-fold in culture medium. 100 μL of culture medium containing the diluted compound was added to the plate to achieve a final DMSO concentration of 0.5% in each well. After 5 days of compound treatment, culture supernatants were collected for further testing.

For quantitative PCR detection of extracellular HBV DNA, culture supernatants were digested with 500 μg/mL Proteinase K (Sigma, Catalog No. P2308) at 50°C for 1 hour. After heating at 95°C for 15 minutes to inactivate the enzyme, samples were analyzed for HBV DNA quantification by qPCR. The effective compound concentration that inhibited HBV replication by 50% (EC ₅₀ ) was determined.

The embodiments of the present invention were tested according to the above assays described herein and found to have an _EC50 of less than 1 μM in the HepG2.2.15 assay, as shown in Table 1 below.

Table 1. Activity of the compounds of the present invention in the HepG2.2.15 assay

Example No. Example No. 1 0.0046 twenty one 0.046 2 0.079 twenty two 0.027 3 0.036 twenty three 0.052 4 0.006 twenty four 0.011 5 0.014 25 0.14 6 0.083 26 0.13 7 0.0098 27 0.044 8 0.30 28-1 0.021 9 0.26 28-2 0.018 10 0.57 29 0.32 11 0.11 30 0.0035 12 0.040 31 0.0097 13 0.052 32-1 0.17 14 0.028 33-2 0.093 15 0.026 33-1 0.024 16 0.009 33-2 0.41 17 0.086 34 0.099 18 0.012 35 0.0067 19 0.014 36 0.017 20 0.017

Claims (14)

1. A compound of formula (I), or a pharmaceutically acceptable salt, enantiomer, or diastereomer thereof, in ^R1 is a dioxathiazinyl group, a dioxathiazolyl group, a dioxathiazolyl group, a dioxathiazolyl group, a dioxathiazolyl group, a dioxathiazolyl group, a dioxathiazolyl group, a dioxathiazolyl group, a dioxathiazolyl group, a dioxathiazolyl group, or a trioxathiazolyl group, wherein the dioxathiazinyl group, the dioxathiazolyl group, the dioxathiazolyl group, the dioxathiazolyl group, the dioxathiazolyl group, the dioxathiazolyl group, the dioxathiazolyl group, the dioxathiazolyl group, and the trioxathiazolyl group are unsubstituted or substituted once, twice, or three times independently by substituents selected from the following: hydroxyl, C1-6 alkyl, _C1-6 alkyl, C2 ... _1-6 alkoxy, _C1-6 alkyl carbonyl, benzyloxy carbonyl, carboxyphenyl, carboxypyrrolidinyl and pyrimidinyloxy; ^R2 is H or _C1-6 alkyl; ^R3 is a _C1-6 alkyl group; R ⁴ is benzothiazolyl, phenyl _C1-6 alkyl, phenyl, pyridyl, thienyl, or thienyl _C1-6 alkyl, wherein the benzothiazolyl, phenyl _C1-6 alkyl, phenyl, pyridyl, thienyl, or thienyl C1-6 alkyl is independently substituted once, twice, or three times with a substituent selected from the following: halogen, cyano, _C1-6 alkyl, and halo _{-C1-6 alkyl} ; Q is CH or N. 2. The compound of formula (I) as claimed in claim 1, or a pharmaceutically acceptable salt, enantiomer, or diastereomer thereof, wherein... ^R1 is Dioxothiazine alkyl; Dioxotetrahydro[1,2,5]thiadiazo[3,2-c][1,4]oxazinyl; Dioxothiazine alkyl group, wherein the dioxothiazine alkyl group is unsubstituted or substituted with the following groups: hydroxyl, _C1-6 alkyl carbonyl or benzyloxy carbonyl; Dioxathiadiazole alkyl group, wherein the dioxathiadiazole alkyl group is unsubstituted or substituted once or twice with _C1-6 alkyl groups; Dioxazonium butyl group, wherein the dioxazonium butyl group is unsubstituted or substituted with _C1-6 alkyl groups; Dioxothiazolyl groups, wherein the dioxothiazolyl group is unsubstituted or substituted once or twice by substituents independently selected from the following: hydroxyl, _C1-6 alkyl, _C1-6 alkoxy, carboxyphenyl, carboxypyrrolidinyl and pyrimidinyloxy; oxothiazolyl; or Trioxotetrahydropyrrolo[2,1-d][1,2,5]thiadiazinyl; ^R2 is H; ^R3 is a _C1-6 alkyl group; ^R4 is Benzothiazolyl; Phenyl _C1-6 alkyl; Phenyl, wherein the phenyl group is independently substituted once, twice or three times with a substituent selected from the following: halogen, cyano, _C1-6 alkyl and halo- _C1-6 alkyl; Pyridyl group, wherein the pyridyl group is substituted with a halogen or a halogenated _C1-6 alkyl group; Thiophene group; or Thiophene group ( _C1-6 alkyl); Q is CH or N. 3. The compound of formula (I) as claimed in claim 2, or a pharmaceutically acceptable salt, enantiomer, or diastereomer thereof, wherein... R ¹ is a dioxothiazinyl group, dioxotetrahydro[1,2,5]thiadiazo[3,2-c][1,4]oxazinyl group, dioxothiazinyl group, hydroxydioxothiazinyl group, acetyldioxothiazinyl group, benzyloxycarbonyldioxothiazinyl group, dioxothiazolyl group, methyldioxothiazolyl group, dimethyldioxothiazolyl group, dioxothiazolyl cyclobutane group, methyldioxothiazolyl cyclobutane group, or dioxothiazolyl alkyl group. alkyl, hydroxydioxothiazolyl, hydroxy(methyl)dioxothiazolyl, methoxy(methyl)dioxothiazolyl, methyldioxothiazolyl, carboxyphenyldioxothiazolyl, carboxypyrrolidinyldioxothiazolyl, pyrimidinyloxy(methyl)dioxothiazolyl, oxothiazolyl or 1,1-dioxo-3a,4,6,7-tetrahydro-3H-[1,2,5]thiadiazo[3,2-c][1,4]oxazin-2-yl; ^R2 is H; ^R3 is a methyl group; R ⁴ is benzothiazolyl, benzyl, fluorophenyl, fluorochlorophenyl, fluorocyanophenyl, fluoro(methyl)phenyl, fluoro(trifluoromethyl)phenyl, trifluorophenyl, chloropyridyl, difluoromethylpyridyl, thienyl or thienylmethyl; Q is CH or N. 4. The compound of claim 2 or 3, wherein Q is CH. 5. The compound of claim 2, wherein ^R1 is a dioxothiazolyl group, said dioxothiazolyl group being unsubstituted or substituted once or twice by a substituent independently selected from the group consisting of hydroxyl, _C1-6 alkyl, _C1-6 alkoxy, carboxyphenyl, carboxypyrrolidinyl, and pyrimidinyloxy. 6. The compound of claim 5, wherein ^R1 is a dioxothiazolyl, hydroxydioxothiazolyl, hydroxy(methyl)dioxothiazolyl, methoxy(methyl)dioxothiazolyl, methyldioxothiazolyl, carboxyphenyldioxothiazolyl, carboxypyrrolidinyldioxothiazolyl, or pyrimidinyloxy(methyl)dioxothiazolyl. 7. Compounds, selected from: (6S)-3-(1,1-dioxo-1,2-thiazolidin-2-yl)-6-methyl-N-(3,4,5-trifluorophenyl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide; (6S)-N-(2-chloro-4-pyridinyl)-3-(1,1-dioxo-1,2-thiazolidin-2-yl)-6-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide; (6S)-N-(4-chloro-3-fluoro-phenyl)-3-(1,1-dioxo-1,2-thiazolidin-2-yl)-6-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide; (6S)-3-(1,1-dioxo-1,2-thiazolidin-2-yl)-N-(4-fluoro-3-methyl-phenyl)-6-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide; (6S)-N-(3-cyano-4-fluoro-phenyl)-3-(1,1-dioxo-1,2-thiazolidin-2-yl)-6-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide; (6S)-N-[2-(difluoromethyl)-4-pyridinyl]-3-(1,1-dioxo-1,2-thiazolidin-2-yl)-6-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide; (6S)-3-(1,1-dioxo-1,2-thiazolidin-2-yl)-N-[4-fluoro-3-(trifluoromethyl)phenyl]-6-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide; (6S)-3-(1,1-dioxo-1,2-thiazolidin-2-yl)-N-(2-fluorophenyl)-6-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide; (6S)-N-(1,3-benzothiazo-6-yl)-3-(1,1-dioxo-1,2-thiazolidin-2-yl)-6-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide; (6S)-3-(1,1-dioxo-1,2-thiazolidin-2-yl)-6-methyl-N-(3-thienyl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide; 6S)-N-benzyl-3-(1,1-dioxo-1,2-thiazolidin-2-yl)-6-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide; (6S)-3-(1,1-dioxo-3a,4,6,7-tetrahydro-3H-[1,2,5]thiadiazo[3,2-c][1,4]oxazin-2-yl)-6-methyl-N-(3,4,5-trifluorophenyl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-5-carboxamide; 2-[(6S)-6-methyl-5-[(3,4,5-trifluorophenyl)carbamoyl]-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-3-yl]-1,1-dioxo-1,2,5-thiadiazine-5-carboxylic acid benzyl ester; (6S)-6-methyl-N-(3,4,5-trifluorophenyl)-3-(3,3,6-trioxo-4,7,8,8a-tetrahydro-1H-pyrrolo[2,1-d][1,2,5]thiadiazin-2-yl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-5-carboxamide; (6S)-3-(5-acetyl-1,1-dioxo-1,2,5-thiadiazinyl-2-yl)-6-methyl-N-(3,4,5-trifluorophenyl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide; (6S)-6-methyl-3-(3-methyl-1,1-dioxo-1,2-thiazolidin-2-yl)-N-(3,4,5-trifluorophenyl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide; (6S)-6-methyl-3-(1-oxo-1,2-thiazolidin-2-yl)-N-(3,4,5-trifluorophenyl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide; (6S)-3-(4-hydroxy-1,1-dioxo-1,2-thiazolidin-2-yl)-6-methyl-N-(3,4,5-trifluorophenyl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide; (6S)-3-(1,1-dioxo-1,2,5-thiadiazolidine-2-yl)-6-methyl-N-(3,4,5-trifluorophenyl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide; (6S)-6-methyl-3-(5-methyl-1,1-dioxo-1,2,5-thiadiazolidine-2-yl)-N-(3,4,5-trifluorophenyl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide; (6S)-6-methyl-3-[(3S)-3-methyl-1,1-dioxo-thiazazonyl-2-yl]-N-(3,4,5-trifluorophenyl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide; (6S)-6-methyl-3-[(3S)-3-methyl-1,1-dioxo-1,2,5-thiadiazolidine-2-yl]-N-(3,4,5-trifluorophenyl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide; (6S)-3-[(3S)-3,4-dimethyl-1,1-dioxo-1,2,5-thiadiazolidine-2-yl]-6-methyl-N-(3,4,5-trifluorophenyl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide; (6S)-3-(3,3-dioxo-1,3,4-oxathiazin-4-yl)-6-methyl-N-(3,4,5-trifluorophenyl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide; (6S)-3-(1,1-dioxothiazazacyclobutane-2-yl)-6-methyl-N-(3,4,5-trifluorophenyl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide; (6S)-3-(4-hydroxy-1,1-dioxo-1,2,6-thiadiazin-2-yl)-6-methyl-N-(3,4,5-trifluorophenyl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide; (6S)-3-(1,1-dioxo-1,2,6-thiadiazin-2-yl)-6-methyl-N-(3,4,5-trifluorophenyl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide; (6S)-3-(4-hydroxy-3-methyl-1,1-dioxo-1,2-thiazolidin-2-yl)-6-methyl-N-(3,4,5-trifluorophenyl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide; (6S)-3-(4-hydroxy-3-methyl-1,1-dioxo-1,2-thiazolidin-2-yl)-6-methyl-N-(3,4,5-trifluorophenyl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide; (6S)-N-[2-(difluoromethyl)-4-pyridinyl]-3-(4-hydroxy-3-methyl-1,1-dioxo-1,2-thiazolidin-2-yl)-6-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide; (6S)-6-methyl-3-(3-methyl-1,1-dioxo-4-pyrimidin-2-yloxy-1,2-thiazolidin-2-yl)-N-(3,4,5-trifluorophenyl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide; (6S)-3-(4-methoxy-3-methyl-1,1-dioxo-1,2-thiazolidin-2-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-(4-methoxy-3-methyl-1,1-dioxo-1,2-thiazolidin-2-yl)-6-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide; (6S)-N-[2-(difluoromethyl)-4-pyridyl]-3-(4-methoxy-3-methyl-1,1-dioxo-1,2-thiazolidin-2-yl)-6-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide; 3-(1,1-dioxo-1,2-thiazolidin-2-yl)-6-methyl-N-(3,4,5-trifluorophenyl)-6,7-dihydro-4H-triazolo[1,5-a]pyrazine-5-carboxamide; 3-(1,1-dioxo-1,2-thiazolidin-2-yl)-6-methyl-N-(3,4,5-trifluorophenyl)-6,7-dihydro-4H-triazolo[1,5-a]pyrazine-5-carboxamide; (6S)-3-(1,1-dioxo-1,2-thiazolidin-2-yl)-6-methyl-N-(3-thienylmethyl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide; (2S)-1-[2-[(6S)-6-methyl-5-[(3,4,5-trifluorophenyl)carbamoyl]-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-3-yl]-1,1-dioxo-1,2-thiazolidin-4-yl]pyrrolidine-2-carboxylic acid; and 2-[2-[(6S)-6-methyl-5-[(3,4,5-trifluorophenyl)carbamoyl]-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-3-yl]-1,1-dioxo-1,2-thiazolidin-4-yl]benzoic acid. 8. Compounds, selected from: (6S)-3-(1,1-dioxo-1,2-thiazolidin-2-yl)-6-methyl-N-(3,4,5-trifluorophenyl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide; (6S)-3-(1,1-dioxo-1,2-thiazolidin-2-yl)-N-(4-fluoro-3-methyl-phenyl)-6-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide; (6S)-6-methyl-3-(3-methyl-1,1-dioxo-1,2-thiazolidin-2-yl)-N-(3,4,5-trifluorophenyl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide; (6S)-3-(4-hydroxy-1,1-dioxo-1,2-thiazolidin-2-yl)-6-methyl-N-(3,4,5-trifluorophenyl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide; (6S)-3-(1,1-dioxo-1,2,5-thiadiazolidine-2-yl)-6-methyl-N-(3,4,5-trifluorophenyl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide; (6S)-3-(3,3-dioxo-1,3,4-oxathiazin-4-yl)-6-methyl-N-(3,4,5-trifluorophenyl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide; (6S)-6-methyl-3-(3-methyl-1,1-dioxo-4-pyrimidin-2-yloxy-1,2-thiazolidin-2-yl)-N-(3,4,5-trifluorophenyl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide; (6S)-3-(4-methoxy-3-methyl-1,1-dioxo-1,2-thiazolidin-2-yl)-6-methyl-N-(3,4,5-trifluorophenyl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide; and (2S)-1-[2-[(6S)-6-methyl-5-[(3,4,5-trifluorophenyl)carbamoyl]-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-3-yl]-1,1-dioxo-1,2-thiazolidin-4-yl]pyrrolidine-2-carboxylic acid. 9. A method for preparing the compound according to any one of claims 1-8, comprising any one of the following steps: (a) Compound (V) It reacts with acid, and then with phenyl carbamate (VI); (b) Iodides (IX) It reacts with acid, and then with phenyl carbamate (VI); ^R2 and ^R3 are as defined in any one of claims 1-8; ^R5 and ^R6 together with the nitrogen and sulfur atoms to which they are attached form an ^R1 group as defined in any one of claims 1-8; and ^R4 is as defined in any one of claims 1-8. 10. The compound of any one of claims 1-8, or its pharmaceutically usable salt, enantiomer or diastereomer, for use as a therapeutically active substance. 11. A pharmaceutical composition comprising a compound of any one of claims 1-8 and a therapeutically inert carrier. 12. Use of the compound of any one of claims 1-8 in the preparation of a medicament for treating or preventing hepatitis B virus infection. 13. The compound of any one of claims 1-8 or its pharmaceutically usable salt, enantiomer or diastereomer, for the treatment or prevention of hepatitis B virus infection. 14. The compound of any one of claims 1-8 or the pharmaceutically acceptable salt, enantiomer or diastereomer thereof produced by the method of claim 9.