HK1250031B - Cyclized sulfamoylarylamide derivatives and the use thereof as medicaments for the treatment of hepatitis b - Google Patents

Description

Cyclic sulfamoyl arylamide derivatives and their use as drugs for treating hepatitis B

Field of the Invention

The present invention relates to inhibitors of HBV replication, processes for preparing said compounds, pharmaceutical compositions containing said compounds, and their use alone or in combination with other HBV inhibitors in HBV therapy.

Background of the Invention

Hepatitis B virus (HBV) is an enveloped, partially double-stranded DNA (dsDNA) virus of the hepadnaviridae family. Its genome consists of four overlapping reading frames: the precore/core gene; the polymerase gene; the L, M, and S genes, which encode three envelope proteins; and the X gene.

After infection, the partially double-stranded DNA genome (relaxed circular DNA; rcDNA) is converted into covalently closed circular DNA (cccDNA) in the host cell nucleus and the viral mRNA is transcribed. Once encapsidated, the pregenomic RNA (pgRNA) (which also encodes core protein and Pol) serves as a template for reverse transcription, which regenerates the partially double-stranded dsDNA genome (rcDNA) in the nucleocapsid.

HBV has caused epidemics in parts of Asia and Africa, and it is endemic in China. HBV has infected approximately 2 billion people worldwide, of which approximately 350 million people have developed into chronic infectious diseases. The virus causes the disease hepatitis B and chronic infectious diseases are associated with the strongly increased risk of developing cirrhosis of the liver and hepatocellular carcinoma. In addition, HBV is a helper virus of hepatitis D virus (HDV), and it is estimated that more than 15 million people worldwide may be HBV/HDV co-infected, compared with patients who only suffer from HBV, with an increased risk of rapidly developing cirrhosis of the liver and increased liver decompensation (Hughes, S.A. et al., Lancet 2011, 378, 73-85).

Hepatitis B virus is transmitted through exposure to infectious blood or body fluids, and viral DNA has been detected in the saliva, tears, and urine of chronic carriers with high titers of DNA in the serum.

An effective and well-tolerated vaccine exists, but immediate treatment options are currently limited to interferon and the following antivirals: tenofovir, lamivudine, adefovir, entecavir, and telbivudine.

Additionally, heteroaryldihydropyrimidines (HAPs) were identified as a class of HBV inhibitors in tissue culture and animal models (Weber et al., Antiviral Res. 54:69-78).

WO 2013/006394 published on January 10, 2013 relates to a subclass of sulfamoyl-arylamide active against HBV.

WO 2013/096744 published on June 26, 2013 relates to active compounds against HBV.

Among the problems that may be encountered with these direct HBV antiviral drugs are toxicity, mutagenicity, lack of selectivity, poor efficacy, poor bioavailability, low solubility, and synthetic difficulties.

There is a need for additional HBV inhibitors that overcome at least one of these disadvantages or that possess additional advantages, such as increased potency or an increased safety window.

SUMMARY OF THE INVENTION

The present invention relates to a compound having chemical formula (I-A)

or one of its stereoisomers or tautomeric forms, wherein

represents a monocyclic 5- or 6-membered aryl group which may optionally contain one or two heteroatoms, which aryl group may be optionally substituted by one or more substituents each independently selected from the group consisting of C ₁ -C ₃ alkyl, in particular methyl, C ₃ -C ₄ cycloalkyl, -CN and halogen;

represents a 6-membered aromatic group which may optionally contain one nitrogen atom;

X represents -CR ² R ³ -;

Y represents C ₁ -C ₇ alkanediyl or C ₂ -C ₇ alkenediyl, each of which may be optionally substituted with one or more substituents each independently selected from the group consisting of C ₁ -C ₄ alkyl, fluorine, and -OH;

Z represents a heteroatom, preferably NH or oxygen and more preferably oxygen, or a single bond;

^Ra , ^Rb , ^Rc and ^Rd are each independently selected from the group consisting of hydrogen, halogen, _-CHF2 , _-CF2 -methyl, _-CH2F , _-CF3 , -OCF3, -CN, _C3 - _{C4 cycloalkyl} and _-C1 - _C4 alkyl;

R ¹ is hydrogen or C ₁ -C ₁₀ alkyl which may be optionally substituted by one or more substituents each independently selected from the group consisting of -OH, fluorine, and oxygen;

R ² is selected from the group consisting of hydrogen; C ₁ -C ₁₀ alkyl which may be optionally substituted by one or more substituents each independently selected from the group consisting of: -OH, fluorine, methoxy, oxygen, and -C(═O)OC ₁ -C ₄ alkyl; C ₁ -C ₃ alkyl-R ⁷ ; C ₂ -C ₄ alkynyl; a 3-7 membered saturated ring which may optionally contain one or more heteroatoms each independently selected from the group consisting of O, S and N; and a monocyclic aryl which may optionally contain one or two heteroatoms; wherein the C ₁ -C ₃ alkyl-R ⁷ , the 3-7 membered saturated ring or the monocyclic aryl may each be optionally substituted by one or more R ⁸ substituents;

R ³ is hydrogen or C _1-6 alkyl which may be optionally substituted by -OH; in particular hydrogen or methyl;

or R ² and R ³ together with the carbon atom to which they are attached form a 3-7 membered saturated ring, which may optionally contain one or more heteroatoms, each independently selected from the group consisting of O, S and N, and may be optionally substituted with one or more substituents, each independently selected from the group consisting of -OH, fluorine, methoxy, oxygen, -C(═O)OC ₁ -C ₄ alkyl, benzyl, and C ₁ -C ₄ alkyl which may be optionally substituted with one or more substituents, each independently selected from the group consisting of fluorine and/or -OH;

R ⁷ represents a monocyclic aromatic group, which may optionally contain one or two heteroatoms and may be optionally substituted by one or two substituents each independently selected from the group consisting of halogen and C _1-3 alkyl; a 3-7 membered saturated ring optionally containing one or more heteroatoms each independently selected from the group consisting of O, S and N; or -NR ⁹ R ¹⁰ ;

wherein R ⁹ and R ¹⁰ are each independently selected from hydrogen and C ₁ -C ₃ alkyl optionally substituted with one or more fluorine substituents;

each R ⁸ is independently selected from the group consisting of: -OH, fluoro, methoxy, oxygen, -C(=O)OC ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ alkoxy, and C ₁ -C ₄ alkyl optionally substituted with one or more substituents each independently selected from the group consisting of fluoro and/or -OH;

or a pharmaceutically acceptable salt or solvate thereof.

The present invention further relates to a pharmaceutical composition comprising a compound of formula (I-A) and a pharmaceutically acceptable carrier.

The present invention also relates to a compound of formula (I-A) for use as a medicament, preferably for use in the prevention and treatment of HBV infection in mammals.

In another aspect, the present invention relates to a combination of a compound of formula (I-A) and another HBV inhibitor.

Detailed Description of the Invention

The present invention relates to a compound of formula (I-A) as defined above.

More specifically, the present invention relates to a compound of formula (I-A)

or one of its stereoisomers or tautomeric forms, wherein

represents a monocyclic 5- or 6-membered aryl group which may optionally contain one or two heteroatoms, which aryl group may be optionally substituted by one or more substituents each independently selected from the group consisting of C ₁ -C ₃ alkyl, in particular methyl, C ₃ -C ₄ cycloalkyl, -CN and halogen;

represents a 6-membered aromatic group which may optionally contain one nitrogen atom;

X represents -CR ² R ³ -;

Y represents C ₁ -C ₇ alkanediyl or C ₂ -C ₇ alkenediyl, each of which may be optionally substituted by one or more substituents each independently selected from the group consisting of C ₁ -C ₄ alkyl and -OH;

Z represents a heteroatom, preferably oxygen, or a single bond;

^Ra , ^Rb , ^Rc and ^Rd are each independently selected from the group consisting of hydrogen, halogen, _-CHF2 , _-CF2 -methyl, _-CH2F , _-CF3 , -OCF3, -CN, _C3 - _{C4 cycloalkyl} and _-C1 - _C4 alkyl;

R ¹ is hydrogen or C ₁ -C ₆ alkyl, which may be optionally substituted with one or more substituents each independently selected from the group consisting of -OH, fluorine, oxygen, and C _{1 -C 4 alkyl} which may be optionally substituted with one or more fluorine and/or -OH;

R ² is selected from the group consisting of hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₃ alkyl-R ⁷ , a 3-7 membered saturated ring which may optionally contain one or more heteroatoms each independently selected from the group consisting of O, S and N, and a monocyclic aryl which may optionally contain one or two heteroatoms, and this C ₁ -C ₆ alkyl, C ₁ -C ₃ alkyl-R ⁷ , a 3-7 membered saturated ring or a monocyclic aryl may be optionally substituted with one or more R ⁸ ;

R ³ is hydrogen or C _1-6 alkyl; in particular hydrogen or methyl;

or R ² and R ³ together with the carbon atoms to which they are attached form a 3-7 membered saturated ring, which 3-7 membered saturated ring may optionally contain one or more heteroatoms each independently selected from the group consisting of O, S and N, and which 3-7 membered saturated ring may be optionally substituted with one or more R ⁸ ;

R ⁷ represents a monocyclic aromatic group which may optionally contain one or two heteroatoms; a 3-7 membered saturated ring which may optionally contain one or more heteroatoms each independently selected from the group consisting of O, S and N; or -NR ⁹ R ¹⁰ ;

wherein R ⁹ and R ¹⁰ are each independently selected from hydrogen and C ₁ -C ₃ alkyl;

each R ⁸ is independently selected from the group consisting of: -OH, fluoro, methoxy, oxygen, -C(=O)OC ₁ -C ₄ alkyl, and C ₁ -C ₄ alkyl optionally substituted with one or more substituents each independently selected from: fluoro and/or -OH;

or a pharmaceutically acceptable salt or solvate thereof.

In a specific embodiment, the present invention relates to a compound having the chemical formula (I-A)

or one of its stereoisomers or tautomeric forms, wherein:

represents a monocyclic 5- or 6-membered aryl group which may optionally contain one or two heteroatoms, which aryl group may be optionally substituted by one or more substituents each independently selected from the group consisting of C ₁ -C ₃ alkyl, in particular methyl, C ₃ -C ₄ cycloalkyl, -CN and halogen;

represents a 6-membered aromatic group which may optionally contain one nitrogen atom;

X represents -CR ² R ³ -;

Y represents C ₁ -C ₇ alkanediyl or C ₂ -C ₇ alkenediyl, each of which may be optionally substituted by one or more substituents each independently selected from the group consisting of C ₁ -C ₄ alkyl and -OH;

Z represents a heteroatom, preferably oxygen, or a single bond;

^Ra , ^Rb , ^Rc and ^Rd are each independently selected from the group consisting of hydrogen, halogen, _-CHF2 , _-CF2 -methyl, _-CH2F , _-CF3 , -OCF3, -CN, _C3 - _{C4 cycloalkyl} and _-C1 - _C4 alkyl;

R ¹ is hydrogen or C ₁ -C ₆ alkyl, which may be optionally substituted with one or more substituents each independently selected from the group consisting of -OH, fluorine, oxygen, and C _{1 -C 4 alkyl} which may be optionally substituted with one or more fluorine and/or -OH;

R ² is selected from the group consisting of hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₃ alkyl-R ⁷ , a 3-7 membered saturated ring (which may optionally contain one or more heteroatoms each independently selected from the group consisting of O, S and N), and a monocyclic aryl (the monocyclic aryl may optionally contain one or two heteroatoms), and this C ₁ -C ₆ alkyl, C ₁ -C ₃ alkyl-R ⁷ , a 3-7 membered saturated ring or a monocyclic aryl may be optionally substituted with one or more R ⁸ ;

^R3 is hydrogen;

or R ² and R ³ together with the carbon atoms to which they are attached form a 3-7 membered saturated ring, which 3-7 membered saturated ring may optionally contain one or more heteroatoms each independently selected from the group consisting of O, S and N, and which 3-7 membered saturated ring may be optionally substituted with one or more R ⁸ ;

R ⁷ represents a monocyclic aromatic group which may optionally contain one or two heteroatoms; a 3-7 membered saturated ring which may optionally contain one or more heteroatoms each independently selected from the group consisting of O, S and N; or -NR ⁹ R ¹⁰ ;

wherein R ⁹ and R ¹⁰ are each independently selected from hydrogen and C ₁ -C ₃ alkyl;

each R ⁸ is independently selected from the group consisting of: -OH, fluoro, methoxy, oxygen, -C(=O)OC ₁ -C ₄ alkyl, and C ₁ -C ₄ alkyl optionally substituted with one or more substituents each independently selected from: fluoro and/or -OH;

or a pharmaceutically acceptable salt or solvate thereof.

In another specific embodiment, the invention relates to a compound of formula (I-A) as defined herein, or one of its stereoisomers or tautomeric forms, wherein:

represents a monocyclic 5- or 6-membered aryl group which may optionally contain one or two heteroatoms, which aryl group may be optionally substituted by one or more substituents each independently selected from the group consisting of C ₁ -C ₃ alkyl, in particular methyl, C ₃ -C ₄ cycloalkyl, -CN and halogen;

represents a 6-membered aromatic group which may optionally contain one nitrogen atom;

X represents -CR ² R ³ -;

Y represents C ₁ -C ₇ alkanediyl or C ₂ -C ₇ alkenediyl, each of which may be optionally substituted with one or more C ₁ -C ₄ alkyl groups or -OH;

Z represents a heteroatom, preferably oxygen, or a single bond;

^Ra , ^Rb , ^Rc and ^Rd are independently selected from the group consisting of hydrogen, halogen, _-CHF2 , _-CF2 -methyl, _-CH2F , _-CF3 , _-OCF3 , -CN, _C3 - _C4 cycloalkyl and _-C1 - _C4 alkyl;

R ¹ is hydrogen or C ₁ -C ₆ alkyl, which may be optionally substituted with one or more substituents each independently selected from the group consisting of -OH, fluorine, oxygen, and C _{1 -C 4 alkyl} which may be optionally substituted with one or more fluorine and/or -OH;

R ² is selected from the group consisting of hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₃ alkyl-R ⁷ , a 3-7 membered saturated ring (which may optionally contain one or more heteroatoms each independently selected from the group consisting of O, S and N), and a monocyclic aryl (the monocyclic aryl may optionally contain one or two heteroatoms), and this C ₁ -C ₆ alkyl, C ₁ -C ₃ alkyl-R ⁷ , a 3-7 membered saturated ring or a monocyclic aryl may be optionally substituted with one or more R ⁸ ;

^R3 is hydrogen;

or R ² and R ³ together with the carbon atoms to which they are attached form a 3-7 membered saturated ring, which 3-7 membered saturated ring may optionally contain one or more heteroatoms each independently selected from the group consisting of O, S and N, and which 3-7 membered saturated ring may be optionally substituted with one or more R ⁸ ;

R ⁷ represents a monocyclic aromatic group which may optionally contain one or two heteroatoms;

Each R ⁸ is independently selected from the group consisting of: -OH, fluorine, methoxy, oxygen, -C(=O)OC ₁ -C ₄ alkyl, and C ₁ -C ₄ alkyl optionally substituted with one or more fluorine and/or -OH;

or a pharmaceutically acceptable salt or solvate thereof.

In a further embodiment, the present invention relates to a compound of formula (I-A) as defined herein and stereoisomers or tautomeric forms thereof, wherein:

Indicates that

R ⁴ is hydrogen, C ₁ -C ₃ alkyl or C ₃ -C ₄ cycloalkyl; in particular methyl;

R ⁵ is hydrogen or halogen; in particular fluorine;

and wherein R ⁶ is selected from hydrogen, methyl, -CN and halogen; in particular hydrogen or methyl; in particular hydrogen or fluorine, in particular hydrogen;

and all other variables are as defined in formula (I-A);

or a pharmaceutically acceptable salt or solvate thereof.

The present invention further relates to a compound having the chemical formula (A)

or one of its stereoisomers or tautomeric forms, wherein:

represents a monocyclic 5- or 6-membered aryl group which may optionally contain one or two heteroatoms and which may be optionally substituted by one or more methyl, -CN or halogen;

represents a 6-membered aromatic group which may optionally contain one nitrogen atom;

X represents -CR ² R ³ -;

Y represents C ₁ -C ₇ alkanediyl or C ₂ -C ₇ alkenediyl, each of which may be optionally substituted with one or more C ₁ -C ₄ alkyl groups or -OH;

Z represents a heteroatom, preferably oxygen, or a single bond;

^Ra , ^Rb , ^Rc and ^Rd are independently selected from the group consisting of hydrogen, halogen, _-CHF2 , _-CF2 -methyl, _-CH2F , _-CF3 , _-OCF3 , -CN, _C3 - _C4 cycloalkyl and _-C1 - _C4 alkyl;

R ¹ is hydrogen or C ₁ -C ₆ alkyl, which may be optionally substituted with one or more substituents each independently selected from the group consisting of -OH, fluorine, oxygen, and C _{1 -C 4 alkyl} which may be optionally substituted with one or more fluorine and/or -OH;

R ² is selected from the group consisting of hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₃ alkyl-R ⁷ , a 3-7 membered saturated ring (which may optionally contain one or more heteroatoms each independently selected from the group consisting of O, S and N), and a monocyclic aryl (the monocyclic aryl may optionally contain one or two heteroatoms), and this C ₁ -C ₆ alkyl, C ₁ -C ₃ alkyl-R ⁷ , a 3-7 membered saturated ring or a monocyclic aryl may be optionally substituted with one or more R ⁸ ;

^R3 is hydrogen;

or R ² and R ³ together with the carbon atoms to which they are attached form a 3-7 membered saturated ring, which 3-7 membered saturated ring may optionally contain one or more heteroatoms each independently selected from the group consisting of O, S and N, and which 3-7 membered saturated ring may be optionally substituted with one or more R ⁸ ;

R ⁷ represents a monocyclic aromatic group which may optionally contain one or two heteroatoms;

Each R ⁸ is independently selected from the group consisting of: -OH, fluorine, methoxy, oxygen, -C(=O)OC ₁ -C ₄ alkyl, and C ₁ -C ₄ alkyl optionally substituted with one or more fluorine and/or -OH;

or a pharmaceutically acceptable salt or solvate thereof.

The present invention further relates to a pharmaceutical composition comprising a compound of formula (A) and a pharmaceutically acceptable carrier.

The present invention also relates to a compound of formula (A) for use as a medicament, preferably for use in the prevention or treatment of HBV infection in mammals.

In another aspect, the present invention relates to a combination of a compound of formula (A) and another HBV inhibitor.

Whenever used hereinafter, the term "compound of formula (I-A)" or "compound of formula (A)"

or "compounds of the present invention" or similar terms are meant to include all compounds having the general formula (I-A), (A), (A*), (B), or (C), their salts, stereoisomeric forms, and racemic mixtures or any subgroup thereof.

The present invention particularly relates to compounds of formula (A)

or one of its stereoisomers or tautomeric forms, wherein:

represents a monocyclic 5- or 6-membered aryl group which may optionally contain one or two heteroatoms and which may be optionally substituted by one or more methyl, -CN or halogen;

represents a 6-membered aromatic group which may optionally contain one nitrogen atom;

X represents -CR ² R ³ -;

Y represents C ₁ -C ₇ alkanediyl or C ₂ -C ₇ alkenediyl, each of which may be optionally substituted with one or more C ₁ -C ₄ alkyl groups or -OH;

Z represents a heteroatom, preferably oxygen, or a single bond;

^Ra , ^Rb , ^Rc and ^Rd are independently selected from the group consisting of hydrogen, halogen, _-CHF2 , _-CF2 -methyl, _-CH2F , _-CF3 , _-OCF3 , -CN, _C3 - _C4 cycloalkyl and _-C1 - _C4 alkyl;

R ¹ is hydrogen or C ₁ -C ₆ alkyl, which may be optionally substituted with one or more substituents each independently selected from the group consisting of -OH, fluorine, oxygen, and C _{1 -C 4 alkyl} which may be optionally substituted with one or more fluorine and/or -OH;

R ² is selected from the group consisting of hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₃ alkyl-R ⁷ , a 3-7 membered saturated ring which may optionally contain one or more heteroatoms each independently selected from the group consisting of O, S and N, and a monocyclic aryl which may optionally contain one or two heteroatoms, and this C ₁ -C ₆ alkyl, C ₁ -C ₃ alkyl-R ⁷ , a 3-7 membered saturated ring or a monocyclic aryl may be optionally substituted with one or more R ⁸ ;

^R3 is hydrogen;

or R ² and R ³ together with the carbon atoms to which they are attached form a 3-7 membered saturated ring, which 3-7 membered saturated ring may optionally contain one or more heteroatoms each independently selected from the group consisting of O, S and N, and which 3-7 membered saturated ring may be optionally substituted with one or more R ⁸ ;

R ⁷ represents a monocyclic aromatic group which may optionally contain one or two heteroatoms;

Each R ⁸ is independently selected from the group consisting of: -OH, fluorine, methoxy, oxygen, -C(=O)OC ₁ -C ₄ alkyl, and C ₁ -C ₄ alkyl optionally substituted with one or more fluorine and/or -OH;

or a pharmaceutically acceptable salt or solvate thereof.

In one embodiment, the present invention relates to compounds of formula (A)

or one of its stereoisomers or tautomeric forms, wherein:

represents a monocyclic 5- or 6-membered aryl group which may optionally contain one or two heteroatoms and which may be optionally substituted by one or more methyl, -CN or halogen;

represents a 6-membered aromatic group which may optionally contain one nitrogen atom;

X represents -CR ² R ³ -;

Y represents a C ₁ -C ₇ alkanediyl group or a C ₂ -C ₇ alkenediyl group, each of which may be optionally substituted with one or more C ₁ -C ₄ alkyl groups;

Z represents a heteroatom, preferably oxygen, or a single bond;

^Ra , ^Rb , ^Rc and ^Rd are independently selected from the group consisting of hydrogen, halogen, _-CHF2 , _-CF2 -methyl, _-CH2F , _-CF3 , _-OCF3 , -CN, _C3 - _C4 cycloalkyl and _-C1 - _C4 alkyl;

R ¹ is hydrogen or C ₁ -C ₆ alkyl, which may be optionally substituted with one or more substituents each independently selected from the group consisting of -OH, fluorine, oxygen, and C _{1 -C 4 alkyl} which may be optionally substituted with one or more fluorine and/or -OH;

R ² is selected from the group consisting of hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₃ alkyl-R ⁷ and a monocyclic aryl group which may optionally contain one or two heteroatoms, and this C ₁ -C ₆ alkyl, C ₁ -C ₃ alkyl-R ⁷ or monocyclic aryl group may be optionally substituted with one or more R ⁸ ;

^R3 is hydrogen;

or R ² and R ³ together with the carbon atoms to which they are attached form a 3-7 membered saturated ring, which may optionally contain one or more heteroatoms each independently selected from the group consisting of O, S and N, and which may optionally be substituted with one or more fluorine and/or -OH, or C ₁ -C ₄ alkyl which may optionally be substituted with one or more fluorine and/or -OH;

R ⁷ represents a monocyclic aromatic group which may optionally contain one or two heteroatoms;

Each R ⁸ is independently selected from the group consisting of: -OH, fluorine, methoxy, oxygen, and C _{1 -C 4} alkyl optionally substituted with one or more fluorine and/or -OH;

or a pharmaceutically acceptable salt or solvate thereof.

In one embodiment, the present invention relates to a compound having formula (B)

or a compound of formula (C)

wherein ^Ra , ^Rb , ^Rc and ^Rd are independently selected from the group consisting of hydrogen, halogen, _-CHF2 , _-CF2 -methyl, _-CH2F , _-CF3 , -OCF3, -CN, _C3 - _{C4 cycloalkyl} and _-C1 - _C4 alkyl;

R ¹ is hydrogen or C ₁ -C ₆ alkyl, which may be optionally substituted with one or more substituents each independently selected from the group consisting of -OH, fluorine, oxygen, and C _{1 -C 4 alkyl} which may be optionally substituted with one or more fluorine and/or -OH;

R ² is selected from the group consisting of hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₃ alkyl-R ⁷ and a monocyclic aryl group which may optionally contain one or two heteroatoms, and this C ₁ -C ₆ alkyl, C ₁ -C ₃ alkyl-R ⁷ or monocyclic aryl group may be optionally substituted with one or more R ⁸ ;

^R3 is hydrogen;

or R ² and R ³ together with the carbon atoms to which they are attached form a 3-7 membered saturated ring, the 3-7 membered saturated ring may optionally contain one or more heteroatoms each independently selected from the group consisting of O, S and N, the 3-7 membered saturated ring may optionally be substituted with one or more fluorine and/or -OH, C ₁ -C ₄ alkyl which may optionally be substituted with one or more fluorine and/or -OH;

R ⁴ is hydrogen, -C ₁ -C ₃ alkyl or C ₃ -C ₄ cycloalkyl, preferably methyl;

R ⁵ is hydrogen or halogen, preferably fluorine;

^R6 is selected from hydrogen, methyl, -CN and halogen;

R ⁷ represents a monocyclic aromatic group which may optionally contain one or two heteroatoms;

and each R ⁸ is independently selected from the group consisting of: -OH, fluorine, methoxy, oxygen, and C ₁ -C ₄ alkyl optionally substituted with one or more fluorine and/or -OH;

or a pharmaceutically acceptable salt or solvate thereof.

In further embodiments, the invention relates to compounds of formula (IA), (A), (A*), (B) or (C) as described herein, wherein R ¹ is hydrogen or C ₁ -C ₆ alkyl optionally substituted with one or more substituents, in particular 1-3 substituents each independently selected from the group consisting of -OH, and fluorine.

Another embodiment of the present invention relates to compounds of formula (I-A), in particular compounds of formula (I-AA1) or (I-AA2)

in

Ring B represents phenyl or 4-pyridyl;

wherein in the chemical formula (I-AA2), represents a single bond or a double bond;

R ² is selected from the group consisting of hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₃ alkyl-R ⁷ , a 3-7 membered saturated ring which may optionally contain one or more heteroatoms each independently selected from the group consisting of O, S and N, and a monocyclic aryl which may optionally contain one or two heteroatoms, and this C ₁ -C ₆ alkyl, C ₁ -C ₃ alkyl-R ⁷ , a 3-7 membered saturated ring or a monocyclic aryl may be optionally substituted with one or more R ⁸ ;

R ₃ is hydrogen or -C ₁ -C ₆ alkyl, especially hydrogen or methyl;

R ⁴ is C ₁ -C ₃ alkyl, especially methyl;

^R6 is hydrogen or methyl;

R ⁷ is selected from the group consisting of: a monocyclic aromatic group optionally containing one or two heteroatoms; a 3-7 membered saturated ring optionally containing one or more heteroatoms each independently selected from the group consisting of O, S and N;

or -NR ⁹ R ¹⁰ ;

wherein R ⁹ and R ¹⁰ are each independently selected from hydrogen and C ₁ -C ₃ alkyl;

each R ⁸ is independently selected from the group consisting of: -OH, fluoro, methoxy, oxygen, -C(=O)OC ₁ -C ₄ alkyl, and C ₁ -C ₄ alkyl optionally substituted with one or more substituents each independently selected from: fluoro and/or -OH;

R ^a is selected from hydrogen and halogen, especially hydrogen;

When ring B is pyridyl, R ^b is absent or when ring B is phenyl, R ^b is hydrogen or halogen, especially hydrogen;

R ^c is selected from halogen, CH ₃ , CHF ₂ , CF ₃ , and -CN;

R ^d is selected from hydrogen and halogen, especially hydrogen;

or a pharmaceutically acceptable salt or solvate thereof.

Another embodiment of the present invention relates to compounds of formula (I-A), in particular compounds of formula (I-A1) or (I-A2)

in

Ring B represents phenyl or 4-pyridyl;

wherein in chemical formula (I-A2), represents a single bond or a double bond;

R ² is selected from the group consisting of hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₃ alkyl-R ⁷ , a 3-7 membered saturated ring which may optionally contain one or more heteroatoms each independently selected from the group consisting of O, S and N, and a monocyclic aryl which may optionally contain one or two heteroatoms, and this C ₁ -C ₆ alkyl, C ₁ -C ₃ alkyl-R ⁷ , a 3-7 membered saturated ring or a monocyclic aryl may be optionally substituted with one or more R ⁸ ;

R ⁴ is C _{1 -} C ₃ alkyl, especially methyl;

^R6 is hydrogen or methyl;

R ⁷ is selected from the group consisting of: a monocyclic aromatic group optionally containing one or two heteroatoms; a 3-7 membered saturated ring optionally containing one or more heteroatoms each independently selected from the group consisting of O, S and N; or

-NR ⁹ R ¹⁰ ;

wherein R ⁹ and R ¹⁰ are each independently selected from hydrogen and C ₁ -C ₃ alkyl;

each R ⁸ is independently selected from the group consisting of: -OH, fluoro, methoxy, oxygen, -C(=O)OC ₁ -C ₄ alkyl, and C ₁ -C ₄ alkyl optionally substituted with one or more substituents each independently selected from: fluoro and/or -OH;

R ^a is selected from hydrogen and halogen, especially hydrogen;

When ring B is pyridyl, R ^b is absent or when ring B is phenyl, R ^b is hydrogen or halogen, especially hydrogen;

R ^c is selected from halogen, CH ₃ , CHF ₂ , CF ₃ , and -CN;

R ^d is selected from hydrogen and halogen, especially hydrogen;

or a pharmaceutically acceptable salt or solvate thereof.

In a further embodiment, the present invention relates to compounds of formula (I-A), in particular compounds of formula (I-A1') or (I-A2')

in

Ring B represents phenyl or 4-pyridyl;

wherein in chemical formula (I-A2), represents a single bond or a double bond;

R ² is selected from the group consisting of: C ₁ -C ₆ alkyl, C ₁ -C ₃ alkyl-R ⁷ , a 3-7 membered saturated ring (which may optionally contain one or more heteroatoms each independently selected from the group consisting of O, S and N), and a monocyclic aryl (the monocyclic aryl may optionally contain one or two heteroatoms), and this C ₁ -C ₆ alkyl, C ₁ -C ₃ alkyl-R ⁷ , a 3-7 membered saturated ring or a monocyclic aryl may be optionally substituted with one or more R ⁸ ;

R ⁴ is C ₁ -C ₃ alkyl, especially methyl;

^R6 is hydrogen or methyl;

R ⁷ is selected from the group consisting of: a monocyclic aromatic group optionally containing one or two heteroatoms; a 3-7 membered saturated ring optionally containing one or more heteroatoms each independently selected from the group consisting of O, S and N; or

-NR ⁹ R ¹⁰ ;

wherein R ⁹ and R ¹⁰ are each independently selected from hydrogen and C ₁ -C ₃ alkyl;

each R ⁸ is independently selected from the group consisting of: -OH, fluoro, methoxy, oxygen, -C(=O)OC ₁ -C ₄ alkyl, and C ₁ -C ₄ alkyl optionally substituted with one or more substituents each independently selected from: fluoro and/or -OH;

R ^a is selected from hydrogen and halogen, especially hydrogen;

When ring B is pyridyl, R ^b is absent or when ring B is phenyl, R ^b is hydrogen or halogen, especially hydrogen;

R ^c is selected from halogen, CH ₃ , CHF ₂ , CF ₃ , and -CN;

R ^d is selected from hydrogen and halogen, especially hydrogen;

or a pharmaceutically acceptable salt or solvate thereof.

In a further embodiment, the invention relates to compounds of formula (IA) as defined herein, in particular formula (I-A1') or formula (I-A2'), wherein R ² is C ₁ -C ₆ alkyl optionally substituted by 1-4 substituents each independently selected from the group consisting of: -OH, fluorine, and methoxy, in particular -OH and fluorine; Ring B represents phenyl; ^Ra is selected from hydrogen and halogen;

R ^b is hydrogen or halogen, particularly halogen; and R ^c is selected from halogen, CH ₃ , CHF ₂ , CF ₃ , and -CN; and the remaining variables are as defined herein.

Another embodiment of the present invention relates to compounds of Formula (I-A), Formula (I-AA1), Formula (I-AA2), Formula (I-A1), Formula (I-A2), Formula (I-A1′), Formula (I-A2′), Formula (A), Formula (B), or Formula (C), or any subgroup thereof, as mentioned in any other embodiment, wherein one or more of the following limitations apply:

(a) Ring C consists of 6 to 8 atoms, preferably 7 atoms.

(b) Y represents a linear C ₁ -C ₇ alkanediyl or C ₂ -C ₇ alkenediyl, each of which may be optionally substituted with 1 to 3 substituents each independently selected from the group consisting of fluorine and -OH.

(c) Y represents a linear C ₁ -C ₇ alkanediyl or C ₂ -C ₇ alkenediyl, each of which may be optionally substituted by -OH.

(d) R ² is C ₁ -C ₆ alkyl, optionally substituted with one or more independently selected fluorine and/or -OH substituents. Preferably, R ² is a branched C ₁ -C ₆ alkyl substituted with one or more fluorine substituents.

(e) R ² is C ₁ -C ₆ alkyl which may be optionally substituted with one or more -OH substituents. In particular, R ² is C _1-6 alkyl substituted with one -OH.

(f) R ² is C ₁ -C ₄ alkyl which may be optionally substituted with one or more fluorine substituents.

(g) R ² is C ₃ -C ₆ alkyl which may be optionally substituted with one or more fluorine substituents.

(h) R ³ is C ₁ -C ₄ alkyl, especially methyl.

(i) R ³ is C ₁ -C ₄ alkyl, especially methyl; and R ² is selected from the group consisting of C ₁ -C ₆ alkyl, and monocyclic aryl which may optionally contain one or two heteroatoms, which C ₁ -C ₆ alkyl or monocyclic aryl may be optionally substituted with one or more R ⁸ , wherein R ⁸ is as defined herein.

(j) R ⁴ is C ₁ -C ₃ alkyl, preferably methyl.

(k) R ^b is hydrogen or fluorine.

(1) R ^b and R ^c are independently selected from hydrogen, fluorine and -CN.

(m) R ^b and R ^c are independently selected from hydrogen or fluorine.

(n) R ^b and R ^c are independently selected from fluoro and -CN.

(o) ^Ra and/or ^Rd are hydrogen

(p) ^Ra and ^Rd are both hydrogen.

(q) R ^b and/or R ^c are fluorine.

(r) R ¹ is hydrogen or C ₁ -C ₆ alkyl which may be optionally substituted with one or more substituents, in particular 1 to 4 substituents, each independently selected from the group consisting of -OH and fluorine.

(s) ^R1 is hydrogen.

(t) represents a phenyl group.

(u) represents a phenyl group substituted by one or more halogen substituents.

(v) represents phenyl substituted by at least one halogen, more preferably at least one fluorine, even more preferably at least 2 fluorines.

(w) R ⁷ is a 3-7 membered saturated ring, especially cyclopropyl.

(x) R ² is selected from the group consisting of methyl, ethyl, isopropyl, CF ₃ , CHF ₂ , CF ₂ CH ₃ , CH ₂ OH, CH ₂ OCH ₃ ,

(y) R ² is selected from the group consisting of methyl, ethyl, isopropyl, CF ₃ , CF ₂ CH ₃ , CH ₂ OH,

(z) represents phenyl, and ^Ra , ^Rb , ^Rc and ^Rd are each independently selected from the group consisting of hydrogen, halogen _{, -CHF2} , _-CF2 -methyl, _-CF3 , -OCF3, -CN, _C3 - _C4 cycloalkyl and _-C1 - _C4 alkyl.

(aa) represents phenyl, and ^Ra is selected from hydrogen and halogen; ^Rb is hydrogen or halogen, in particular halogen; ^Rc is selected from halogen, _CH3 , _CHF2 , _CF3 , and -CN; and ^Rd is selected from hydrogen and halogen, in particular hydrogen.

(bb) represents phenyl, and ^Ra is selected from hydrogen and halogen; ^Rb is hydrogen or halogen, in particular halogen; ^Rc is selected from halogen, _CH3 , _CF3 , and -CN; and ^Rd is selected from hydrogen and halogen, in particular hydrogen.

Further combinations of any of these embodiments are also contemplated to be within the scope of the present invention.

In further embodiments, the present invention relates to a compound of formula (I-A) as defined herein, or a stereoisomer or tautomeric form thereof, wherein

represents a monocyclic 5- or 6-membered aryl or heteroaryl group selected from the group consisting of pyrrolyl, phenylthio, pyrazolyl, phenyl, and pyridinyl, each of which may be optionally substituted with one or two substituents each independently selected from the group consisting of C ₁ -C ₃ alkyl (especially methyl), C ₃ -C ₄ cycloalkyl, -CN and halogen;

represents a phenyl or pyridyl group;

X represents -CR ² R ³ -;

Y represents a linear C ₁ -C ₇ alkanediyl or C ₂ -C ₇ alkenediyl, each optionally substituted by one, two or three substituents each independently selected from the group consisting of fluorine and -OH;

Z represents oxygen or a single bond;

^Ra , ^Rb , ^Rc and ^Rd are each independently selected from the group consisting of hydrogen, halogen, _-CHF2 , _-CF2 -methyl, _-CH2F , _-CF3 , -OCF3, -CN, _C3 - _{C4 cycloalkyl} and _-C1 - _C4 alkyl;

R ¹ is hydrogen or C ₁ -C ₆ alkyl which may be optionally substituted by one, two, three or four substituents each independently selected from the group consisting of -OH and fluorine;

R ² is selected from the group consisting of hydrogen; C ₁ -C ₆ alkyl which may be optionally substituted with 1-4 substituents each independently selected from the group consisting of: -OH, fluorine, methoxy, oxygen, and -C(═O)OC ₁ -C ₄ alkyl; C ₁ -C ₃ alkyl-R ⁷ ; C ₂ -C ₄ alkynyl; a 3-7 membered saturated ring which may optionally contain one or two heteroatoms each independently selected from the group consisting of O, S and N; and a monocyclic aryl which may optionally contain one or two heteroatoms; wherein the C ₁ -C ₃ alkyl-R ⁷ , the 3-7 membered saturated ring or the monocyclic aryl may each be optionally substituted with one or more R ⁸ substituents;

R ³ is hydrogen or C _1-6 alkyl which may be optionally substituted by -OH; in particular hydrogen or methyl;

or R ² and R ³ together with the carbon atom to which they are attached form a 3-7 membered saturated ring, which may optionally contain one or more heteroatoms, each independently selected from the group consisting of O, S and N, and may be optionally substituted with one or more substituents, each independently selected from the group consisting of -OH, fluoro, methoxy, oxygen, benzyl, and C ₁ -C ₄ alkyl;

R ⁷ represents a monocyclic aromatic group, which may optionally contain one or two heteroatoms and may be optionally substituted by one or two substituents each independently selected from the group consisting of halogen and C _1-3 alkyl; a 3-7 membered saturated ring optionally containing one or more heteroatoms each independently selected from the group consisting of O, S and N; or -NR ⁹ R ¹⁰ ;

wherein R ⁹ and R ¹⁰ are each independently selected from hydrogen and C ₁ -C ₃ alkyl optionally substituted with one or more fluorine substituents;

each R ⁸ is independently selected from the group consisting of: -OH, fluoro, methoxy, oxygen, -C(=O)OC ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ alkoxy, and C ₁ -C ₄ alkyl optionally substituted with one or more substituents each independently selected from the group consisting of fluoro and/or -OH;

or a pharmaceutically acceptable salt or solvate thereof.

In further embodiments, the present invention relates to a compound of formula (I-A) as defined herein, or a stereoisomer or tautomeric form thereof, wherein

represents a monocyclic 5-membered heteroaryl group selected from the group consisting of pyrrolyl, phenylthio, and pyrazolyl, each of which may be optionally substituted by one or two substituents each independently selected from the group consisting of C ₁ -C ₃ alkyl, in particular methyl;

represents a phenyl or pyridyl group;

X represents -CR ² R ³ -;

Y represents a linear C ₁ -C ₇ alkanediyl or C ₂ -C ₇ alkenediyl, each of which may be optionally substituted with one or two substituents each independently selected from the group consisting of fluorine and -OH;

Z represents oxygen or a single bond;

^Ra , ^Rb , ^Rc and ^Rd are each independently selected from the group consisting of hydrogen, halogen, _-CHF2 , _-CF2 -methyl, _-CH2F , _-CF3 , -OCF3, -CN, _C3 - _{C4 cycloalkyl} and _-C1 - _C4 alkyl;

R ¹ is hydrogen or C ₁ -C ₃ alkyl which may be optionally substituted by one, two, or three substituents each independently selected from the group consisting of: -OH and fluorine; more particularly hydrogen;

R ² is selected from the group consisting of: hydrogen; C ₁ -C ₆ alkyl which may be optionally substituted by one, two, three or four substituents each independently selected from the group consisting of

-OH, fluoro, and methoxy; C ₁ -C ₃ alkyl-R ⁷ ; C ₂ -C ₄ alkynyl; a 3-7 membered saturated ring optionally containing one or two heteroatoms each independently selected from the group consisting of O, S and N, the saturated ring selected from the group consisting of cyclopropyl, tetrahydropyranyl and piperidinyl; and a monocyclic aryl group optionally containing one or two heteroatoms selected from the group consisting of phenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyrazolyl, imidazolyl, and oxazolyl; wherein the C ₁ -C ₃ alkyl-R ⁷ , the 3-7 membered saturated ring or the monocyclic aryl group may each be optionally substituted with one or more R ⁸ substituents;

R ³ is hydrogen or C _1-3 alkyl which may be optionally substituted by -OH; in particular hydrogen or methyl;

or R ² and R ³ together with the carbon atom to which they are attached form a cyclopropyl, glycidyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl or piperidinyl ring, each of which may be optionally substituted with benzyl;

R ⁷ is selected from the group consisting of phenyl, pyridyl, pyrazolyl, imidazolyl, and oxazolyl, each of which may be optionally substituted with one or two substituents each independently selected from the group consisting of halogen and C _1-3 alkyl; cyclopropyl; and -NR ⁹ R ¹⁰ ;

wherein R ⁹ and R ¹⁰ are each independently selected from hydrogen and C ₁ -C ₃ alkyl optionally substituted with one or more fluorine substituents;

each R ⁸ is independently selected from the group consisting of: -OH, fluoro, methoxy, oxygen, -C(=O)OC ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ alkoxy, and C ₁ -C ₄ alkyl optionally substituted with one or more substituents each independently selected from the group consisting of fluoro and/or -OH;

or a pharmaceutically acceptable salt or solvate thereof.

In a further embodiment, the invention relates to compounds of formula (I-A), (A) or (A*) as defined herein, wherein

Selected from the group consisting of pyrrolyl, thienyl and pyrazolyl, each optionally substituted with one or two substituents each independently selected from the group consisting of C ₁ -C ₃ alkyl (especially methyl) -CN and halogen.

In a further embodiment, the invention relates to a compound of the invention as defined herein, wherein

R ² is selected from the group consisting of hydrogen, C ₁ -C ₆ alkyl optionally substituted with 1-4 substituents each independently selected from the group consisting of -OH, fluoro and methoxy; C ₁ -C ₃ alkyl-R ⁷ optionally substituted with -OH; heterocyclyl selected from piperidinyl and tetrahydropyranyl, each optionally substituted with C ₁ -C ₄ alkyl, the C ₁ -C ₄ alkyl optionally substituted with 1-3 fluoro substituents; and aryl or heteroaryl is selected from the group consisting of phenyl, pyridinyl, pyrazinyl, pyrimidinyl, and oxazolyl, each optionally substituted with methyl; wherein R ⁷ is selected from the group consisting of cyclopropyl, phenyl, pyridinyl, oxazolyl, pyrazolyl and imidazolyl, each optionally substituted with 1-3 substituents each independently selected from halogen and methyl; and -NR ⁹ R ¹⁰ , wherein R ⁹ and R ¹⁰ are each independently selected from hydrogen, C ₁ -C ₃ alkyl, and C ₁ -C ₃ alkyl substituted with 1 to 3 fluorine substituents;

R ³ is hydrogen or C _1-6 alkyl which may be optionally substituted by -OH; in particular hydrogen or methyl;

or ^R2 and ^R3 together with the carbon atom to which they are attached form a cyclopropyl, glycidyl, tetrahydrofuranyl or pyrrolidinyl ring which may be optionally substituted with a benzyl group, in particular a glycidyl or tetrahydrofuranyl ring.

In a further embodiment, the invention relates to a compound of the invention as defined herein, wherein

R ² is selected from the group consisting of: C ₁ -C ₆ alkyl which may be optionally substituted with 1 to 4 substituents (these substituents are each independently selected from the group consisting of: -OH and fluorine); C ₁ -C ₃ alkyl-R ⁷ which may be optionally substituted with -OH;

piperidinyl or tetrahydropyranyl, each of which may be optionally substituted with C ₁ -C ₄ alkyl, which may be optionally substituted with ₁ to ₃ fluorine substituents;

phenyl, pyridyl, pyrazinyl, pyrimidinyl, oxazolyl, each of which may be optionally substituted with methyl;

wherein R ⁷ is selected from cyclopropyl, phenyl, pyridyl, oxazolyl, pyrazolyl and imidazolyl, each of which may be optionally substituted with 1-3 substituents independently selected from halogen and methyl; and -NR ⁹ R ¹⁰ , wherein R ⁹ and R ¹⁰ are independently selected from hydrogen and C ₁ -C ₃ alkyl;

R ³ is hydrogen or C _1-6 alkyl; in particular hydrogen or methyl;

or R ² and R ³ together with the carbon atom to which they are attached form a cyclopropyl, propylene oxide or tetrahydrofuranyl, in particular an propylene oxide or tetrahydrofuranyl ring.

Preferred compounds according to the present invention are compounds having a chemical formula as shown in the compound synthesis section or a stereoisomer or tautomeric form thereof, and their activities are shown in Table 1.

definition

The term "aryl" refers to a monocyclic or polycyclic aromatic ring comprising carbon atoms and hydrogen atoms. If indicated, the aromatic ring may comprise one or more heteroatoms (also referred to as heteroaryl), preferably 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, preferably nitrogen. As is well known to those skilled in the art, heteroaryl rings have less aromaticity than their all-carbon counterparts. Therefore, for the purposes of the present invention, heteroaryl groups only need to have a certain degree of aromaticity. Illustrative examples of aryl groups may optionally be substituted with phenyl. Illustrative examples of heteroaryl groups according to the present invention include pyrrole, pyridine, and imidazole, which may optionally be substituted. Therefore, the term monocyclic aryl, which may optionally comprise one or more heteroatoms (e.g., one or two heteroatoms), for example, refers to a 5- or 6-membered aryl or heteroaryl group, such as, but not limited to, phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, and oxazolyl.

The terms "C _1-X alkyl" and C ₁ -C _x alkyl are used interchangeably.

The terms "Ci _-10 ) alkyl", "Ci _-6 alkyl", "Ci _-3 alkyl" as a group or part of a group refer to a hydrocarbon group having the formula _{CnH2n +1} , where n is a number ranging from 1 to 10, from 1 to 6, or from 1 to 3. For example, where a Ci _-3 alkyl group is coupled to another group, it refers to _the formula _CnH2n . _Ci-3 alkyl groups include from 1 to 3 carbon atoms, more preferably 1 to 2 carbon atoms. _Ci-3 alkyl includes all linear or branched alkyl groups having between 1 and 3 carbon atoms, and thus includes, for example, methyl, ethyl, n-propyl, and isopropyl.

_C1-4 alkyl as a group or part of a group defines a straight or branched chain saturated hydrocarbon group having from 1 to 4 carbon atoms, such as the groups defined for _C1-3 alkyl and butyl etc.

_C1-6alkyl and _C2-6alkyl as a group or part of a group define straight or branched chain saturated hydrocarbon groups having from 1 to 6 carbon atoms, or from 2 to 6 carbon atoms, such as the groups defined for _C1-4alkyl and pentyl, hexyl, 2-methylbutyl, etc.

The term " _{C1-7alkanediyl} " as a group or part of a group defines a divalent straight or branched chain saturated hydrocarbon group having from 1 to 7 carbon atoms, such as methanediyl, ethanediyl, propanediyl, butanediyl, pentanediyl, hexanediyl and heptanediyl.

The term " _C2-7 alkenediyl" as a group or part of a group defines a straight or branched divalent hydrocarbon group having from 2 to 7 carbon atoms and having at least one double bond, preferably one double bond, such as ethylenediyl, propylenediyl, butenediyl, pentenediyl, hexenediyl and heptenediyl, etc.

The term "C ₃ -C ₄ cycloalkyl" is generic to cyclopropane and cyclobutane.

As used herein, the term "3-7 membered saturated ring" means a saturated cyclic hydrocarbon (cycloalkyl) having 3, 4, 5, 6 or 7 carbon atoms and is general to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

Such saturated rings optionally contain one or more heteroatoms (also referred to as heterocyclyls), such that at least one carbon atom is replaced by a heteroatom selected from N, O and S, in particular from N and O. Examples include glycidyl, tetrahydro-2H-pyranyl, piperidinyl, tetrahydrofuranyl, morpholinyl, thiolane 1,1-dioxide and pyrrolidinyl. Preferred are saturated cyclic hydrocarbons having 3 or 4 carbon atoms and 1 oxygen atom. Examples include glycidyl and tetrahydrofuranyl.

It should be noted that different isomers of different heterocycles may exist in the definitions as used throughout this specification.For example, pyrrolyl may be 1H-pyrrolyl or 2H-pyrrolyl.

The terms halo and halogen are generally fluorine, chlorine, bromine or iodine. Preferred halogens are bromine, fluorine and chlorine.

The term "heteroatom" refers to an atom other than carbon or hydrogen in a ring structure or saturated backbone as defined herein. Typical heteroatoms include N (H), O or S.

The *R and *S depicted in the structural formula indicate that a racemic mixture of a compound was separated into its two enantiomers. The first-eluting enantiomer is indicated by *R, and the second-eluting enantiomer is indicated by *S. Therefore, both *R and *S indicate specific isolated enantiomers, but do not determine the configuration of the stereocenter.

It should also be noted that the residue positions on any molecular moiety used in the definitions can be any position on such moiety as long as it is chemically stable. For example, pyridyl includes 2-pyridyl, 3-pyridyl and 4-pyridyl; pentyl includes 1-pentyl, 2-pentyl and 3-pentyl.

The term or ring B represents a 6-membered aromatic group optionally containing one nitrogen atom. Thus ring B may be referred to as phenyl or pyridyl.

" represents a monocyclic 5- or 6-membered aryl group optionally containing one or two heteroatoms, which is optionally substituted with one or more substituents each independently selected from the group consisting of C ₁ -C ₃ alkyl (particularly methyl), C ₃ -C ₄ cycloalkyl, -CN, and halogen. Such monocyclic 5- or 6-membered aryl or heteroaryl groups as defined herein include, but are not limited to, phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, and oxazolyl. Ring A may alternatively be described as having optional substituents C ₁ -C ₃ alkyl, C ₃ -C ₄ cycloalkyl, -CN, and halogen at specific positions, as defined herein, such substituents being referred to as R ⁴ , R ⁵ , and R ⁶ , if applicable.

Lines drawn from substituents to the ring system indicate that the bond can be attached to any suitable ring atom.

The positions indicated on ring B (e.g., ortho, meta, and/or para) are indicated relative to the bond connecting the aryl group B to the main structure. For an example of the position of meta position ^Ra , as shown in formula (A*), the position is indicated relative to the nitrogen (*) connected to the main structure.

When any variable (eg, halogen or C _1-4 alkyl) occurs more than one time in any constituent, each definition is independent.

The phrase "one or more substituents" specifically refers to 1, 2, 3, 4 or more substituents, particularly 1, 2, 3, or 4 substituents, more particularly 1, 2, or 3 substituents.

Combinations of substituents and/or variables are permissible only if such combinations result in chemically stable compounds."Stable compound" is intended to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture and formulation into a therapeutic agent.

For therapeutic use, salts of compounds of formula (I-A), (A), (B), (C) are those in which the counterion is pharmaceutically or physiologically acceptable. However, salts with non-pharmaceutically acceptable counterions may also find use, for example, in the preparation or purification of pharmaceutically acceptable compounds of formula (I-A), (A), (B), (C). All salts, whether pharmaceutically acceptable or not, are included within the scope of the present invention.

The pharmaceutically acceptable or physiologically tolerable addition salt forms that the compounds of the present invention are able to form can be conveniently prepared using appropriate acids, such as, for example, inorganic acids, such as hydrohalic acids (for example, hydrochloric acid or hydrobromic acid), sulfuric acid, hemisulfuric acid, nitric acid, phosphoric acid and the like; or organic acids, such as, for example, acetic acid, aspartic acid, dodecylsulfuric acid, heptanoic acid, hexanoic acid, nicotinic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid, oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclamic acid, salicylic acid, p-aminosalicylic acid, pamoic acid and the like.

Conversely said acid addition salt forms can be converted by treatment with an appropriate base into the free base form.

The term "solvate" comprises the solvent addition forms and the salts that the compounds of the present invention are able to form. Examples of such solvent addition forms are, for example, hydrates, alcoholates, and the like.

The compounds of the present invention may also exist in tautomeric forms. For example, the tautomeric form of an amide (-C(=O)-NH-) group is an iminoalcohol (-C(OH)=N-). Tautomeric forms, although not explicitly indicated in the structural formulas represented herein, are intended to be encompassed by the present invention.

As used herein, the term "stereochemically isomeric forms of the compounds of the present invention" defines all possible compounds consisting of the same atoms bonded by the same sequence of bonds but having different three-dimensional structures that are not interchangeable, and the compounds of the present invention may have these characteristics. Unless otherwise mentioned or indicated, the chemical nomenclature of a compound encompasses a mixture of all possible stereochemically isomeric forms that the compound may have. The mixture may contain all diastereomers and/or enantiomers of the basic molecular structure of the compound. All stereochemically isomeric forms of the compounds of the present invention, in pure form or admixed with each other, are intended to be included within the scope of the present invention.

Pure stereoisomeric forms of the compounds and intermediates referred to herein are defined as isomers that are substantially free of other enantiomeric or diastereomeric forms of the same basic molecular structure of the compound or intermediate. In particular, the term 'stereoisomerically pure' relates to compounds or intermediates having at least 80% stereoisomeric excess (i.e., at least 90% of one isomer and 10% of other possible isomers) to 100% stereoisomeric excess (i.e., 100% of one isomer and no other isomers), more particularly compounds or intermediates having 90% to 100% stereoisomeric excess, even more particularly 94% to 100% stereoisomeric excess and most particularly 97% to 100% stereoisomeric excess. The terms 'enantiomerically pure' and 'diastereomerically pure' should be understood in a similar manner, but the discussion is about enantiomeric excess or diastereomeric excess, respectively, in a mixture.

Pure stereoisomeric forms of the compounds of the present invention and intermediates can be obtained by the application of procedures known in the art. For example, enantiomers can be separated from each other by selective crystallization of their diastereomeric salts with optically active acids or bases. Examples thereof are tartaric acid, dibenzoyltartaric acid, ditoluoyltartaric acid, and camphorsulfonic acid. Alternatively, enantiomers can be separated by chromatographic techniques using chiral stationary phases. The pure stereochemical isomeric forms can also be derived from the corresponding pure stereochemical isomeric forms of appropriate starting materials, provided that the reaction occurs stereospecifically. Preferably, if a specific stereoisomer is desired, the compound will be synthesized by a stereospecific preparation method. These methods will advantageously use enantiomerically pure starting materials.

Stereoisomeric forms of compounds of formula (I-A), (A), (B), or (C) can be obtained individually by conventional methods. Suitable physical separation methods that may be advantageously employed are, for example, selective crystallization and chromatography (e.g., column chromatography).

The present invention is also intended to include all isotopes of atoms present in the compounds of the present invention. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, hydrogen includes tritium and deuterium isotopes. Carbon includes C-13 and C-14 isotopes.

In another aspect, the present invention relates to a pharmaceutical composition comprising a therapeutic or preventive effective amount of a compound as specified herein with chemical formula (I-A) or chemical formula (A), (B) or (C), and a pharmaceutically acceptable carrier. In this context, a preventive effective amount is an amount sufficient to prevent the HBV infection of a subject at risk of infection. In this context, a therapeutically effective amount is an amount sufficient to stabilize HBV infection, alleviate HBV infection, or eradicate HBV infection in an infected subject. In yet another aspect, the present invention relates to a method for preparing a pharmaceutical composition as specified herein, the method comprising closely mixing a pharmaceutically acceptable carrier with a therapeutic or preventive effective amount of a compound as specified herein with chemical formula (I-A), (A), (B) or (C).

Therefore, the compounds of the present invention or any subgroup thereof can be formulated into different pharmaceutical forms for administration purposes. As appropriate compositions, all compositions commonly used for systemic administration can be cited. In order to prepare the pharmaceutical compositions of the present invention, an effective amount of a specific compound (optionally in the form of an addition salt or a solvate) is combined as an active ingredient with a pharmaceutically acceptable carrier in an intimate mixture, and the carrier can take a variety of forms, depending on the form of the desired preparation for administration. It is desirable that these pharmaceutical compositions are in a unit dosage form suitable for, in particular suitable for, oral, rectal, transdermal or parenteral administration. For example, in the preparation of a composition in an oral dosage form, any common pharmaceutical medium can be used, such as water, glycols, oils, alcohols and the like in the case of oral liquid preparations (such as suspensions, syrups, elixirs, emulsions and solutions); or in the case of powders, pills, capsules and tablets, solid carriers such as starch, sugar, kaolin, lubricants, binders, disintegrants, etc. Because they are easy to administer, tablets and capsules represent the most advantageous oral unit dosage forms, in which case solid pharmaceutical carriers are used. For parenteral compositions, the carrier will typically include at least a substantial portion of sterile water, but may also include other ingredients, such as to aid solubility. For example, injectable solutions can be prepared in which the carrier includes a physiological saline solution, a glucose solution, or a mixture of a physiological saline solution and a glucose solution. Injectable suspensions can also be prepared, in which case appropriate liquid carriers, suspending agents, and the like can be used. Also included are solid form products that are intended to be converted into liquid form products shortly before use. In compositions suitable for transdermal administration, the carrier may optionally include a penetration enhancer and/or a suitable wetting agent, optionally in combination with a small proportion of suitable additives of any nature that do not introduce significant adverse effects on the skin. The compounds of the present invention can also be administered by oral inhalation or insufflation in the form of a solution, suspension, or dry powder using any delivery system known in the art.

For ease of administration and uniformity of dosage, it is particularly advantageous to formulate the above-mentioned pharmaceutical compositions in unit dosage form. As used herein, unit dosage form refers to a physically discrete unit suitable as a unit dosage, each unit containing a predetermined amount of the active ingredient calculated to produce the desired therapeutic effect in combination with the required pharmaceutical carrier. Examples of such unit dosage forms are tablets (including scored or coated tablets), capsules, pills, suppositories, powder packets, wafers, injectable solutions or suspensions, and the like, as well as separate multiples thereof.

Compounds of formula (I-A), (A), (B), or (C) are active as inhibitors of the HBV replication cycle and can be used to treat and prevent HBV infection or diseases associated with HBV. The latter include progressive liver fibrosis, inflammation and necrosis leading to cirrhosis, end-stage liver disease, and hepatocellular carcinoma. HBV acts as a helper virus for HDV, and HDV only infects subjects infected with HBV. Therefore, in a specific embodiment, the compounds of formula (I-A), (A), (B), or (C) can be used to treat and/or prevent HBV/HDV co-infection, or diseases associated with HBV/HDV co-infection.

Due to their antiviral properties, in particular their anti-HBV properties, compounds of formula (I-A), (A), (B), or (C), or any subgroup thereof, are useful in inhibiting the HBV replication cycle, in particular in the treatment of warm-blooded animals (in particular humans) infected with HBV and for the prevention of HBV infection. Furthermore, the present invention relates to a method for treating a warm-blooded animal (in particular humans) infected with HBV or at risk of HBV infection, comprising administering a therapeutically effective amount of a compound of formula (I-A), (A), (B), or (C). In a specific embodiment, the warm-blooded animal (in particular humans) may be co-infected with HBV/HDV or at risk of HBV/HDV co-infection.

Thus, the compounds of formula (I-A), (A), (B), or (C) as specified herein can be used as a medicament, in particular as a medicament for treating or preventing HBV infection. The use as a medicament or treatment method comprises systemically administering to a subject infected with HBV or susceptible to HBV infection an amount effective to combat HBV infection-related conditions or an amount effective to prevent HBV infection. In a specific embodiment, the HBV infection is specifically HBV/HDV co-infection.

The present invention also relates to the use of the compounds of the present invention in the manufacture of a medicament. The present invention also relates to the use of the compounds of the present invention in the manufacture of a medicament for treating or preventing HBV infection. In a specific embodiment, the present invention relates to the use of the compounds of the present invention in the manufacture of a medicament for treating or preventing HBV/HDV co-infection.

In general, it is contemplated that the antiviral effective daily dose will be from about 0.01 mg/kg to about 50 mg/kg body weight, or from about 0.01 mg/kg to about 30 mg/kg body weight. The desired dose may be suitably administered as two, three, four, or more sub-doses at appropriate intervals throughout the day. The sub-doses may be formulated as unit dosage forms, for example, containing from about 1 mg to about 500 mg, or from about 1 mg to about 300 mg, or from about 1 mg to about 100 mg, or from about 2 mg to about 50 mg of active ingredient per unit dosage form.

The present invention also relates to combinations of compounds of formula (I-A), (A), (B), or (C) as specified herein, or any subgroup thereof, with other anti-HBV agents. The term "combination" also relates to a product or kit comprising (a) a compound of formula (I-A), (A), (B), or (C) as specified above, and (b) at least one other compound/agent capable of treating HBV infection (referred to herein as an anti-HBV agent), as a combined preparation for simultaneous, separate, or sequential use in the treatment of HBV infection. In one embodiment, the present invention relates to a combination of a compound of formula (I-A), (A), (B), or (C), or any subgroup thereof, with at least one anti-HBV agent. In a specific embodiment, the present invention relates to a combination of a compound of formula (I-A), (A), (B), or (C), or any subgroup thereof, with at least two anti-HBV agents. In a specific embodiment, the present invention relates to a combination of a compound of formula (I-A), (A), (B), or (C), or any subgroup thereof, with at least three anti-HBV agents. In a specific embodiment, the present invention relates to a combination of a compound of Formula (I-A), (A), (B), or (C) or any subgroup thereof and at least four anti-HBV agents.

The term anti-HBV agent also includes compounds that are therapeutic nucleic acids, antibodies, or proteins, in their native form or chemically modified and/or stabilized. The term therapeutic nucleic acid includes, but is not limited to, nucleotides and nucleosides, oligonucleotides, polynucleotides, non-limiting examples of which are antisense oligonucleotides, miRNA, siRNA, shRNA, therapeutic vectors, and DNA/RNA editing components.

The term anti-HBV agent also includes compounds that can treat HBV infection via immunomodulation. Examples of immunomodulators are interferon-α (IFN-α), pegylated interferon-α, or stimulators of the innate immune system, such as Toll-like receptor 7 and/or 8 agonists, and therapeutic or prophylactic vaccines. One embodiment of the present invention relates to a combination of a compound of formula (I-A), (A), (B), or (C), or any subgroup thereof, as specified herein, and an immunomodulatory compound, more specifically a Toll-like receptor 7 and/or 8 agonist.

The additional one or more HBV antiviral drugs can be, for example, selected from: therapeutic vaccines, RNA interference therapeutics/antisense oligonucleotides (siRNA, ddRNA, shRNA), immunomodulators (TLR agonists (TLR7, TLR8 or TLR9 agonists), STING agonists, RIG-I modulators, NKT modulators, IL agonists, interleukins or other immune active proteins, therapeutic and preventive vaccines, and immune checkpoint regulators), HBV entry inhibitors, cccDNA regulators, capsid assembly inhibitors/regulators, core or X protein targeting agents; nucleotide analogs, nucleoside analogs, interferons or modified interferons, HBV antiviral drugs with different or unknown mechanisms, cyclophilin inhibitors, and sAg release inhibitors.

Specifically, a combination of previously known anti-HBV agents (e.g., interferon-α (IFN-α), pegylated interferon-α, 3TC, tenofovir, lamivudine, entecavir, telbivudine, and adefovir, or a combination thereof) and a compound of Formula (I-A), (A), (B), or (C), or any subgroup thereof, can be used as one drug in combination therapy.

Specific examples of such HBV antiviral drugs include, but are not limited to:

- RNA interference (RNAi) therapeutics: TKM-HBV (also known as ARB-1467), ARB-1740, ARC-520, ARC-521, BB-HB-331, REP-2139, ALN-HBV, ALN-PDL, LUNAR-HBV, GS3228836, and GS3389404;

-HBV entry inhibitors: Myrcludex B, IVIG-Tonrol, GC-1102;

- HBV capsid inhibitors/modulators, core or X protein targeting agents, forward cccDNA inhibitors, cccDNA formation inhibitors, or cccDNA epigenetic modifiers: BAY 41-4109, NVR 3-778, GLS-4, NZ-4 (also known as W28F), Y101, ARB-423, ARB-199, ARB-596, JNJ-56136379, ASMB-101 (also known as AB-V102), ASMB-103, CHR-101, CC-31326; AT-130

- HBV polymerase inhibitors: entecavir (Baraclude, Entavir), lamivudine (3TC, Zeffix, Heptovir, Epivir, and Epivir-HBV), telbivudine (Tyzeka, Sebivo), clavudine, besifovir, adefovir (hepsera), tenofovir (particularly tenofovir disoproxil fumarate (Viread), tenofovir alafenamide fumarate (TAF)), tenofovir disoproxil orotate (also known as DA-2802), tenofovir disoproxil aspartate (also known as CKD-390), AGX-1009, and CMX157);

- Zidovudine, didanosine, zalcitabine, stavudine, and abacavir;

- Cyclophilin inhibitors: OCB-030 (also known as NVP-018), SCY-635, SCY-575, and CPI-431-32;

-dinucleotide: SB9200;

- Compounds with different or unknown mechanisms, such as, but not limited to, AT-61 ((E)-N-(1-chloro-3-oxo-1-phenyl-3-(piperidin-1-yl)prop-1-en-2-yl)benzamide), ((E)-N-(1-bromo-1-(2-methoxyphenyl)-3-oxo-3-(piperidin-1-yl)prop-1-en-2-yl)-4-nitrobenzamide), and similar analogs; REP-9AC (also known as REP-2055), REP-9AC′ (also known as REP-2139), REP-2165, and HBV-0259;

-TLR agonists (TLR7, 8, and/or 9): RG7795 (also known as RO-6864018), GS-9620, SM360320 (9-benzyl-8-hydroxy-2-(2-methoxy-ethoxy)adenine), and AZD 8848 (methyl [3-({[3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-pyridin-9-yl)propyl][3-(4-morpholinyl)propyl]amino}methyl)phenyl]acetate); ARB-1598;

-RIG-I modulator: SB-9200;

-SMAC inhibitor: Birinapant

- Checkpoint inhibitors: BMS-936558 (OpdiVo (nivolumab)), (pembrolizumab);

- Therapeutic vaccines: HBsAG-HBIG, HB-Vac, ABX203, NASVAC, GS-4774, GX-110 (also known as HB-110E), CVI-HBV-002, RG7944 (also known as INO-1800), TG-1050, FP-02 (Hepsyn-B), AIC649, VGX-6200, KW-2, TomegaVax-HBV, ISA-204, NU-500, INX-102-00557 HBV MVA, PepTcell;

-IL agonists and immune-affecting proteins: INO-9112; recombinant IL12;

-Interferon: interferon alpha (IFN-α), interferon alpha-2a, recombinant interferon alpha-2a, pegylated interferon alpha-2a (Pegasys), interferon alpha-2b (Intron A), recombinant interferon alpha-2b, interferon alpha-2b XL, pegylated interferon alpha-2b, glycated interferon alpha-2b, interferon alpha-2c, recombinant interferon alpha-2c, interferon beta, interferon beta-1a, pegylated interferon beta-1a, interferon delta, interferon lambda (IFN-λ), pegylated interferon lambda-1, interferon omega, interferon tau, interferon gamma (IFN-γ), composite alpha interferon-1 (interferon alfacon-1), albinterferon alpha-n1, interferon alpha-n3, alb interferon alpha-2b, BLX-883, DA-3021, P1101 (also known as AOP2014), PEG-infurin, Belerofon, INTEFEN-IFN, albumin/interferon alpha 2a fusion protein, rHSA-IFN alpha 2a, rHSA-IFN alpha 2b, PEG-IFN-SA, interferon alpha biobetter; in particular, pegylated interferon alpha-2a, pegylated interferon alpha-2b, glycated interferon alpha-2b, pegylated interferon beta-1a, and pegylated interferon lambda-1; more particularly pegylated interferon alpha-2a;

-HDV targeting agent: lonafarnib.

In another embodiment, the additional HBV antiviral compound is selected from the compounds disclosed in WO2013102655, WO 2013174962, WO 2014033167, WO 2014033170, WO 2014033176, WO2014131847, WO 2014161888, WO 2014184350, WO 2014184365, WO 2015011281, WO2015059212, WO 2015118057, WO 2013/096744, WO 2014/165128, WO 2015/073774, WO2015/109130.

In another embodiment, the additional HBV antiviral compound is selected from compounds based on the HAP backbone, in particular Roche US 20160083383 (in particular compounds 19, 21, 22, 25, 27, 30, 34, 36; 38, 42, 43, 54, 55, 59, 62, 73, 76, 82B, 86B, 87B, 88B, and 91B), WO 2014184328, WO 2014037480, US20150252057, WO 2015132276 (A1), WO 2013144129

Medshine Discovery

WO 2015180631

Sunshine Lake Pharmaceutical Co., Ltd.

Those disclosed in WO 2015144093.

Universal synthesis

The substituents represented by Ra ^{, b, c, d} or ^R in this general synthesis section are intended to include any substituent or reactive species suitable for conversion into any Ra ^{, b, c, d} or ^R substituent according to the present invention without undue burden to one of ordinary skill in the art.

One possible synthesis of compounds of general formula (I) is described in Schemes 1, 2, 3 and 4.

Compounds of general formula (II) can be reacted with an amine of general formula (III) (wherein X has the meaning as defined in the claims (e.g., C 1 -C 6 alkanediyl optionally substituted with one or more substituents independently selected from the group consisting of -OH, fluorine, and oxygen)) in an organic solvent such as acetonitrile or DCM, possibly in the presence of an organic base such as _{triethylamine} or _DIPEA , or an inorganic base such as sodium bicarbonate. The compound of general formula (IV) formed can be ring-closed under Heck conditions with a ligand such as bis(tri-tert-butylphosphine)palladium(0) to give compounds of general formula (V). Compounds of formula (IV) can be reacted with potassium allyltrifluoroborate under Suzuki conditions with a ligand such as bis(tri-tert-butylphosphine)palladium(0) in the presence of _an inorganic base such as _Cs2CO3 to give a mixture of compounds of formula (VII) and compounds of formula (VIII). Compounds of formula (VII) or (VIII) can be ring-closed under metathesis conditions with a catalyst such as the 2nd generation Grubbs catalyst to form compounds of formula (V). Compounds of formula (V) can be reacted with an amine of formula (VI) in the presence of a base such as lithium bis(trimethylsilyl)amide in a solvent such as THF to form compounds of formula (Ia) (wherein Y ^* represents an alkenediyl group and Z represents a single bond). The hydrogenation of the double bond forms a compound of the general formula (Ib) (wherein Y ^** represents an alkanediyl group and Z represents a single bond). Alternatively, the amide can be formed via classical routes known to those skilled in the art, such as (without any limitation) via the acid and a coupling reagent such as HATU or via activation of the acid chloride and reaction with an amine of the general formula (VI).

Compounds of formula (IV) can also be reacted with an amine of formula (VI) in the presence of a base such as lithium bis(trimethylsilyl)amide in a solvent such as THF to form compounds of formula (XXXIV). The resulting compounds of formula (XXXIV) can be ring-closed under Heck reaction conditions with a ligand such as bis(tri-tert-butylphosphine)palladium(0) to give compounds of formula (Ia) (wherein Y ^* represents an alkenediyl group and Z represents a single bond).

Compounds of general formula (II) can be reacted with an amino alcohol of general formula (XXXI) (wherein X has the meaning as defined in the claims (e.g., C 1 -C 6 alkanediyl optionally substituted with one or more substituents each independently selected from the group consisting of -OH, fluorine, and oxygen), for example, in an organic solvent such as acetonitrile or DCM, possibly in the presence of an organic base such as triethylamine or DIPEA, or an inorganic base such as sodium bicarbonate. The resulting compound of general formula (XXXII) can be oxidized with an oxidizing agent such as ₂ - _{iodoacylbenzoic} acid in a solvent such as THF to produce compounds of general formula (XXXIII). Compounds of general formula (XXXIII) can be reacted under Wittig conditions to give compounds of general formula (IV).

Solution 1

Alternatively, as described in Scheme 2, compounds of general formula (II) can be reacted with an amine of general formula (IX) in an organic solvent such as acetonitrile or DCM, possibly in the presence of an organic base such as triethylamine or DIPEA, or in the presence of an inorganic base such as sodium bicarbonate. The compound of general formula (X) formed can be reacted with potassium allyltrifluoroborate under Suzuki reaction conditions with a ligand such as bis(tri-tert-butylphosphine)palladium(0) in the presence of an inorganic base such as _Cs2CO3 to give a mixture of _compounds of general formula (XI) and compounds of general formula (XII). Compounds of general formula (XI) or compounds of general formula (XII) can be reacted with an amine of general formula (VI) in the presence of a base such as lithium bis(trimethylsilyl)amide in a solvent such as THF, resulting in the formation of compounds of general formula (XIII) or compounds of general formula (XV). Under Mitsunobu conditions, a compound of formula (XIII) or (XV) can be reacted with an alcohol of formula (XVII), wherein X has the meaning as defined in the claims (e.g., C1- _{C6 alkanediyl} optionally substituted with one or more substituents each independently selected from the group consisting of -OH, fluorine, and oxygen), to produce a compound of formula (XIV) or (XVI). Under metathesis conditions, using a catalyst such as a 2nd generation Grubbs catalyst, a ring closure of the compound of formula (Ia) can be performed, resulting in the formation of a compound of formula (Ia), wherein Y ^* represents an alkenediyl group and Z represents a single bond. Hydrogenation of the double bond forms a compound of formula (Ib), wherein Y ^** represents an alkanediyl group and Z represents a single bond.

Option 2

Alternatively, as described in Scheme 3, compounds of general formula (XVIII) can be reacted with an alcohol of general formula (XIX) in an organic solvent such as THF or DCM, possibly in the presence of an organic base such as triethylamine or DIPEA, or in the presence of an inorganic base such as sodium bicarbonate. The formed compound of general formula (XX) can be coupled with an amine of general formula (VI) in the presence of a base such as lithium bis(trimethylsilyl)amide in a solvent such as THF. The formed compound of general formula (XXI) can be ring-closed in the presence of a base such as CsF to produce compounds of general formula (Ic), wherein Z is oxygen.

Compounds of general formula (XXII) can be reacted with alcohols of general formula (XIX) in a mixture of an organic solvent such as THF or DCM and water, possibly in the presence of an organic base such as triethylamine or DIPEA, or in the presence of an inorganic base such as sodium carbonate. The compound of general formula (XXIII) formed can be coupled with an amine of general formula (VI) in the presence of an activating reagent such as HATU and an organic base such as triethylamine or DIPEA to give compounds of general formula (XXI).

Option 3

Alternatively, as described in Scheme 4, compounds of formula (II) can be treated with ammonia in a solvent such as dioxane to provide compounds of formula (XXIV). The formed compound (XXIV) can be coupled with 1-3-diketoalkanes such as pentane-2,4-dione or heptane-3,5-dione to provide compounds of formula (XXV) (wherein Ry is C ₁ -C ₄ alkyl), or coupled with stannanes such as (Z)-1-ethoxy-2-(tributylstannyl)ethylene under Stille conditions to provide compounds of formula (XXIX). Compounds of formula (XXV) can be ring-closed under acidic conditions using an acid such as TFA to provide compounds of formula (XXVI) (wherein Rz is C ₁ -C ₄ alkyl). Compounds of formula (XXIX) can be ring-closed under acidic conditions using an acid such as TFA to provide compounds of formula (XXVI) (wherein Rz is hydrogen). The compound of formula (XXVI) formed can also be hydrogenated to form a compound of formula (XXVII), or coupled with an amine of formula (VI) in the presence of a base such as, for example, lithium bis(trimethylsilyl)amide in a solvent such as THF to obtain a compound of formula (XXX). The compound of formula (XXVII) can be alkylated, for example, with an alkyl bromide, and then coupled with an amine of formula (VI) in the presence of a base such as, for example, lithium bis(trimethylsilyl)amide in a solvent such as THF to obtain a compound of formula (Ib) (wherein Y ^** represents an alkanediyl group and Z represents a single bond). The compound of formula (XXX) can be hydrogenated to obtain a compound of formula (Id) (wherein Y ^** represents an alkanediyl group and Z represents a single bond). Compounds of general formula (XXVII) can be coupled with an amine of general formula (VI) in the presence of a base such as, for example, lithium bis(trimethylsilyl)amide in a solvent such as, for example, THF to give compounds of general formula (Id) (wherein Y ^** represents an alkanediyl group and Z represents a single bond).

Option 4

Alternatively, as described in Scheme 5, compounds of formula (XXXV) can be reacted with compounds of formula (XXXVI) (wherein X has the meaning as defined in the claims (e.g., C 1 -C 6 alkanediyl optionally substituted with one or more substituents each independently selected from the group consisting of -OH, fluorine, and oxygen)) using a ligand such as bis( _tri - _tert -butylphosphine)palladium(0) in the presence of an organic base such as Hunigs' base under Suzuki reaction conditions, for example, in a solvent such as DMF. The resulting compound of formula (XXXVII) can be reduced using palladium on carbon under catalytic conditions under a hydrogen atmosphere. Compounds of formula (XXXVIII) can be deprotected using a reagent such as ethylenediamine in a solvent such as n-butanol to form compounds of formula (XXXIX). Compounds of general formula (XXXIX) can be chlorosulfonated in the presence of chlorosulfonic acid and thionyl chloride and then ring-closed in a saturated aqueous solution of an inorganic base such as NaHCO ₃ or Na ₂ CO ₃ by quenching to give compounds of general formula (XXXX) (wherein Y ^** represents an alkanediyl group and Z represents a single bond). Compounds of general formula (XXXX) can be reacted with an amine of general formula (VI) in the presence of a base such as, for example, lithium bis(trimethylsilyl)amide in a solvent such as THF, resulting in the formation of compounds of general formula (Ib).

Option 5

Alternatively, as described in Scheme 6, compounds of formula (XXXXI) can be reacted with compounds of formula (XXXXII) (wherein X has the meaning as defined in the claims (e.g., C 1 -C 6 alkanediyl optionally substituted with one or more substituents each independently selected from the group consisting of -OH, fluorine, and oxygen), for example in a solvent such as ACN in the presence of an organic base such as _{Hunigs '} base. The resulting compound of formula (XXXXIII) can be ring-closed under Mitsunobu reaction conditions. The resulting compound of formula (XXXXIV) can be reacted, after deprotection, with an amine of formula (VI) in the presence of a base such as lithium bis(trimethylsilyl)amide in a solvent such as THF to form compounds of formula (Ic).

Option 6

Alternatively, as described in Scheme 7, for example, in a solvent such as dioxane, in the presence of silver carbonate, a compound with formula (XXXXV) can be reacted with a compound with general formula (XXXXVI). The tert-butyl ester of the compound with general formula (XXXXVII) formed can be cleaved using TFA in a solvent such as DCM. The continuous esterification with methyl iodide in the presence of an inorganic base such as _{Cs CO} in a solvent such as DMF can give a compound with general formula (XXXXVIII). The compound with general formula (XXXXVIII) can be chlorosulfonated in the presence of chlorosulfonic acid and thionyl chloride and then quenched in a saturated aqueous solution of an inorganic base such as _{NaHCO or Na CO} for ring closure. In a solvent such as THF, the compound with general formula (XXXXIX) obtained can be reacted with a Grignard reagent such as methylmagnesium bromide to form a compound with general formula (XXXXX). The formed compound of general formula (XXXXX) can be reacted with an amine of general formula (VI) in the presence of a base such as, for example, lithium bis(trimethylsilyl)amide in a solvent such as, for example, THF, resulting in the formation of a compound of general formula (XXXXXI).

Option 7

General Procedure LCMS Method

High performance liquid chromatography (HPLC) measurements were performed using an LC pump, a diode array (DAD) or UV detector and a column as specified in the corresponding methods. Additional detectors were included if necessary (see method table below).

The flow from the column is taken to a mass spectrometer (MS) equipped with an atmospheric pressure ion source. Setting the tuning parameters (e.g., scan range, dwell time, etc.) to obtain ions of the nominal monoisotopic molecular weight (MW) that allow identification of the compound is within the knowledge of the skilled person. Data acquisition is performed using appropriate software.

Compounds are described by experimental retention time ( _Rt ) and ion. If not specified differently in the data table, the reported molecular ions correspond to [M+H] ⁺ (protonated molecule) and/or [MH] ⁻ (deprotonated molecule). In cases where the compound is not directly ionizable, the type of adduct is specified (i.e., [M+NH ₄ ] ⁺ , [M+HCOO] ⁻ , etc.). All results obtained are subject to the experimental uncertainty typically associated with the methods used.

Hereinafter, “SQD” means single quadrupole detector, “MSD” mass selective detector, “RT” room temperature, “BEH” bridged ethylsiloxane/silica hybrid, “DAD” diode array detector, “HSS” high intensity silica, “Q-Tof” quadrupole time-of-flight mass spectrometer, “CLND” chemiluminescent nitrogen detector, “ELSD” evaporative light scanning detector,

LCMS method

(Flow rate is expressed in mL/min; column temperature (T) is expressed in °C; run time is expressed in minutes).

General procedure for SFC-MS methods

Use analytical supercritical fluid chromatography (SFC) system to carry out SFC measurement, this system is made up of: for delivering carbon dioxide (CO 2) and the binary pump of modifier, automatic sample injector, column drying oven, be equipped with the diode array detector of the high pressure flow cell that can withstand 400 bar.If be configured with mass spectrometer (MS), the stream from post is brought to this (MS).Tuning parameters (such as scan range, dwell time etc.) are set to obtain the ion of the nominal monoisotopic molecular weight (MW) that allows to differentiate compound within the knowledge of technician.Use suitable software to carry out data acquisition.

Analytical SFC-MS method (flow rate in mL/min; column temperature (T) in °C; run time in minutes, back pressure (BPR) in bar).

Melting points (MP) reported in °C refer to the peak observed in differential scanning calorimetry (DSC): 30°C to 300°C at 10°C/min.

Synthesis of compounds

Compound 1: (9E)-N-(3,4-difluorophenyl)-4,14-dimethyl-2,2-dioxo-2λ ⁶ -thia-3,14-diazepine Heterobicyclo[10.3.0]pentadeca-1(15),9,12-triene-13-carboxamide.

Methyl 3-bromo-4-chlorosulfonyl-1-methyl-pyrrole-2-carboxylate (500 mg, 1.58 mmol), oct-7-en-2-amine (221 mg, 1.74 mmol) and Hunin's base (0.82 mL, 0.75 g/mL, 4.74 mmol) were dissolved in THF (5 mL) and stirred at room temperature overnight. The volatiles were removed under reduced pressure, and the residue was purified on silica using a heptane to EtOAc gradient to give methyl 3-bromo-1-methyl-4-(1-methylhept-6-enylsulfamoyl)pyrrole-2-carboxylate (507 mg) as an oil that solidified upon standing. ¹ H NMR (400 MHz, chloroform-d) δ ppm 1.09 (d, J = 6.6 Hz, 3H), 1.22-1.36 (m, 4H), 1.37-1.50 (m, 2H), 1.89-2.06 (m, 2H), 3.11-3.38 (m, 1H), 3.91 (s, 3H), 3.92-3.95 (m, 3H), 4.53 (d, J = 7.7 Hz, 1H), 4.89-5.01 (m, 2H), 5.76 (ddt, J = 17.1, 10.3, 6.7, 6.7 Hz, 1H), 7.35 (s, 1H).

Methyl 3-bromo-1-methyl-4-(1-methylhept-6-enylsulfamoyl)pyrrole-2-carboxylate (100 mg, 0.25 mmol), potassium allyltrifluoroborate (109 mg, 0.74 mmol), bis(tri-tert-butylphosphine)palladium(0) (12.6 mg, 0.025 mmol) and Cs ₂ CO ₃ (240 mg, 0.74 mmol) were dissolved in a mixture of DME (5 mL) and water (1 mL) and heated in a microwave oven at 120° C. for 30 minutes. The volatiles were removed under reduced pressure, and the residue was purified on silica using a heptane to EtOAc gradient to give methyl 3-allyl-1-methyl-4-(1-methylhept-6-enylsulfamoyl)pyrrole-2-carboxylate (62 mg) as a clear oil.

Methyl 3-allyl-1-methyl-4-(1-methylhept-6-enylsulfamoyl)pyrrole-2-carboxylate (62 mg, 0.17 mmol) was dissolved in DCE (50 mL) and heated to 80° C. while N ₂ was bubbled through the reaction mixture. 2nd generation Grubbs catalyst (14.3 mg, 0.017 mmol) was added and heating was continued for 2 hours. Volatiles were removed under reduced pressure and the residue was purified on silica using a heptane to EtOAc gradient to produce methyl (9Z)-4,14-dimethyl-2,2-dioxo-2-thia-3,14-diazabicyclo[10.3.0]pentadeca-1(15),9,12-triene-13-carboxylate (35 mg). Method B; Rt: 1.19 min. m/z: 341 (M+H) ⁺ exact mass: 340.1.

By methyl (9Z) -4,14- dimethyl -2,2- dioxo -2- thia -3,14- diazabicyclo [10.3.0] 15-1 (15), 9,12- triene -13- carboxylate (35mg, 0.1mmol) and 3,4- difluoroaniline (12.4 μ L, 1.29g / mL, 0.12mmol) were dissolved in THF (5mL). Bis (trimethylsilyl) amide lithium (0.31mL, 1M in THF, 0.31mmol) was added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was quenched with NH ₄ Cl (aqueous, saturated, 5mL). The organic layer was removed and the aqueous layer was extracted with DCM (2X5mL). The combined organic layer was evaporated to dryness and the residue was purified using heptane to EtOAc gradient on silica. The obtained product was crystallized from a DCM:DIPE mixture to yield compound 1 as an off-white powder. ¹ H NMR (600MHz, chloroform-d) δppm 1.15-1.21 (m, 1H) 1.22 (d, J = 6.5Hz, 3H) 1.23-1.30 (m, 1H) 1.41- 1.49 (m, 3H) 1.66-1.73 (m, 1H) 2.02-2.10 (m, 1H) 2.32 (br d, J = 13.5 Hz, 1H) 3.27 (dt, J = 12.3, 6.2Hz, 1H) 3.64 (br d, J = 18.5Hz, 1H) 3.85 (br dd, J＝18.3, 5.0Hz, 1H) 3.91 (s, 3H) 4.24 (d, J＝6.2Hz, 1H) 5.28- 5.36 (m, 1H) 5.93 (br d, J = 15.6 Hz, 1H) 7.01-7.06 (m, 1H) 7.06-7.12 (m, 1H) 7.31 (s, 1H) 7.58 (ddd, J = 12.0, 7.1, 2.6 Hz, 1H) 7.94 (br s, 1H). Method B; Rt: 1.17 min. m/z: 438 (M+H) ⁺ exact mass: 437.2.

Compounds 2a and 2b: 8Z-N-(3,4-difluorophenyl)-4,13-dimethyl-2,2-dioxo-2λ ⁶ -thia-3,13- Diazabicyclo[9.3.0]tetradeca-1(14),8,11-triene-12-carboxamide and 8E-N-(3,4-difluorophenyl)-4,13-diol Methyl-2,2-dioxo-2λ ⁶ -thia-3,13-diazabicyclo[9.3.0]tetradeca-1(14),8,11-triene-12-carboxamide.

Methyl 3-bromo-1-methyl-4-(1-methylhept-6-enylsulfamoyl)pyrrole-2-carboxylate (420 mg, 1.03 mmol), potassium allyl trifluoroborate (458 mg, 3.09 mmol), bis(tri-tert-butylphosphine)palladium(0) (52.7 mg, 0.1 mmol) and Cs ₂ CO ₃ (1008 mg, 3.09 mmol) were dissolved in a mixture of DME (5 mL) and water (1 mL) and heated in a microwave oven at 120° C. for 30 minutes. The volatiles were removed under reduced pressure, and the residue was purified on silica using a heptane to EtOAc gradient to give methyl 3-allyl-1-methyl-4-[[(E)-1-methylhept-5-enyl]sulfamoyl]pyrrole-2-carboxylate (258 mg) as a clear oil.

Methyl 3-allyl-1-methyl-4-[[(E)-1-methylhept-5-enyl]sulfamoyl]pyrrole-2-carboxylate (258 mg, 0.7 mmol) was dissolved in DCE (50 mL) and _N2 was bubbled through the reaction mixture. 2nd generation Grubbs catalyst (38.7 mg, 0.046 mmol) was added and the reaction mixture was heated for 5 hours. Volatiles were removed under reduced pressure and the residue was purified on silica using a heptane to EtOAc gradient to yield methyl (8Z)-4,13-dimethyl-2,2-dioxo-2-thia-3,13-diazabicyclo[9.3.0]tetradeca-1(14),8,11-triene-12-carboxylate as an off-white powder.

By methyl (8Z) -4,13- dimethyl -2,2- dioxo -2- thia -3,13- diazabicyclo [9.3.0] fourteen -1 (14), 8,11- triene -12- carboxylate (22mg, 0.067mmol) and 3,4- difluoroaniline (8.2 μ L, 1.29g/mL, 0.081mmol) are dissolved in THF (5mL). Add bis (trimethylsilyl) amide lithium (1M in THF) (202 μ L, 1M in THF, 0.2mmol) and the reaction mixture is stirred at room temperature overnight. The reaction mixture is quenched with NH ₄ Cl (aqueous, saturated, 5mL). The organic layer is removed and the aqueous layer is extracted with DCM (2X 5mL). The combined organic layer is evaporated to dryness and the residue is purified using heptane to EtOAc gradient on silica. The obtained product was purified by preparative HPLC (stationary phase: RP XBridge Prep C18 ODB-5 μm, 30×250 mm, mobile phase: 0.25% NH ₄ HCO ₃ solution in water, ACN) to yield compound 2a (7.2 mg) ¹ H NMR (400 MHz, chloroform-d) δ ppm 1.30 (d, J=6.4 Hz, 3H), 1.36-1.48 (m, 4H), 1.84 (br dd, J=13.0, 5.1 Hz, 1H), 1.93-2.10 (m, 1H), 3.30-3.41 (m, 1H), 3.56-3.68 (m, 1H), 3.77-3.84 (m, 1H), 3.85(s, 3H), 4.02-4.26(m, 1H), 5.54-5.74(m, 2H), 7.09-7.19(m, 2H), 7.26(s, 1H), 7.65-7.72(m, 1H), 8.11(br s, 1H). Method D; Rt: 2.05 min. m/z: 424 (M+H) ⁺ exact mass: 423.1 and compound 2b (18.2 mg) ¹ H NMR (400 MHz, chloroform-d) δ ppm-0.05-0.05 (m, 1H), 1.25 (d, J=6.2 Hz, 3H), 1.36-1.45 (m, 1H), 1.47-1.65 (m, 3H), 2.00-2.27 (m, 2H), 3.05 (br s, 1H), 3.48-3.69 (m, 2H), 3.75-3.90 (m, 3H), 4.34 (br s, 1H), 5.34 (dt, dt, J = 15.6, 7.5 Hz, 1H), 5.84 (dt, J = 15.7, 4.1 Hz, 1H), 7.08-7.22 (m, 2H), 7.63-7.72 (m, 1H), 7.91 (br s, 1H). Method D; Rt: 2.09 min. m/z: 424 (M+H) ⁺ exact mass: 423.1.

Compound 3: (5Z)-N-(3,4-difluorophenyl)-8-methyl-1,1-dioxo-2-[(1R)-2,2,2-trifluoro-1-methyl]- [3,4-dihydropyrrolo[3,4-g]thiazocine-7-carboxamide.

In a 150 mL pressure tube, methyl 3-bromo-4-chlorosulfonyl-1-methyl-pyrrole-2-carboxylate (5 g, 15.79 mmol), (R)-1,1,1-trifluoro-2-propylamine (2.68 g, 23.7 mmol), NaHCO ₃ (3.98 g, 47.4 mmol) and molecular sieves (10 g) were distributed in ACN (75 mL). The suspension was stirred at 80 ° C overnight. The reaction mixture was filtered and volatiles were removed under reduced pressure. The residue was purified on silica using a heptane to EtOAc gradient. The fractions containing the product were evaporated to dryness to produce methyl 3-bromo-1-methyl-4-[[(1R)-2,2,2-trifluoro-1-methyl-ethyl]sulfamoyl]pyrrole-2-carboxylate (4.89 g) as a white powder.

Methyl 3-bromo-1-methyl-4-[[(1R)-2,2,2-trifluoro-1-methyl-ethyl]sulfamoyl]pyrrole-2-carboxylate (2 g, 5.09 mmol), potassium allyltrifluoroborate (2.26 g, 15.3 mmol), bis(tri-tert-butylphosphine)palladium(0) (260 mg, 0.51 mmol) and _{Cs2CO3 (} 4.97 g, 15.3 mmol) were dissolved in a mixture of DME (15 mL) and water (3 mL) and heated in a microwave oven at 100°C for 30 min. The volatiles were removed under reduced pressure, and the residue was purified on silica using a heptane to EtOAc gradient to give methyl 1-methyl-3-[(E)-prop-1-enyl]-4-[[(1R)-2,2,2-trifluoro-1-methyl-ethyl]sulfamoyl]pyrrole-2-carboxylate (1.18 g) as a light brown powder.

Methyl 1-methyl-3-[(E)-prop-1-enyl]-4-[[(1R)-2,2,2-trifluoro-1-methyl-ethyl]sulfamoyl]pyrrole-2-carboxylate (1.18 g, 3.33 mmol) and 3,4-difluoroaniline (404 μL, 1.29 g/mL, 4 mmol) were dissolved in THF (25 mL). Lithium bis(trimethylsilyl)amide (10 mL, 1 M in THF, 10 mmol) was added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was quenched with NH ₄ Cl (aqueous, saturated, 10 mL). The organic layer was removed and the aqueous layer was extracted with DCM (2×5 mL). The combined organic layers were evaporated to dryness, and the residue was purified on silica using a heptane to EtOAc gradient to give N-(3,4-difluorophenyl)-1-methyl-3-[(E)-prop-1-enyl]-4-[[(1R)-2,2,2-trifluoro-1-methyl-ethyl]sulfamoyl]pyrrole-2-carboxamide (1.08 g) as a brown powder.

DIAD (0.12 mL, 1.04 g/mL, 0.6 mmol) was added to a solution of N-(3,4-difluorophenyl)-1-methyl-3-[(E)-prop-1-enyl]-4-[[(1R)-2,2,2-trifluoro-1-methyl-ethyl]sulfamoyl]pyrrole-2-carboxamide (180 mg, 0.4 mmol), 3-butene-1-ol (31.6 mg, 0.44 mmol) and triphenylphosphine (157 mg, 0.6 mmol) in THF (5 mL). The reaction mixture was stirred at room temperature overnight. LCMS showed 60% conversion to the desired product. 3-Butene-1-ol (31.6 mg, 0.44 mmol), triphenylphosphine (157 mg, 0.6 mmol) and DIAD (0.12 mL, 1.04 g/mL, 0.6 mmol) were added and the reaction mixture was stirred for 1 hour. The volatiles were removed under reduced pressure, and the residue was purified on silica using a heptane to EtOAc gradient to give 4-[but-3-enyl-[(1R)-2,2,2-trifluoro-1-methyl-ethyl]sulfamoyl]-N-(3,4-difluorophenyl)-1-methyl-3-[(E)-prop-1-enyl]pyrrole-2-carboxamide (120 mg) as a clear oil.

4-[But-3-enyl-[(1R)-2,2,2-trifluoro-1-methyl-ethyl]sulfamoyl]-N-(3,4-difluorophenyl)-1-methyl-3-[(E)-prop-1-enyl]pyrrole-2-carboxamide (120 mg, 0.24 mmol) was dissolved in DCE (150 mL) and N ₂ was bubbled through the reaction mixture. 2nd generation Grubbs catalyst (20.2 mg, 0.024 mmol) was added and the reaction mixture was heated at 80 ° C. overnight. Volatiles were removed under reduced pressure and the residue was purified on silica using a heptane to EtOAc gradient to give Compound 3 (92 mg) as a white powder. ^1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.37 (br d, J = 7.0 Hz, 3H), 2.39 (br s, 2H), 3.49-3.61 (m, 2H), 3.99 (s, 3H), 4.71 (dt, J = 14.9, 7.6 Hz, 1H), 6.24 (dt, J = 10.6, 8.8 Hz, 1H), 6.75 (d, J = 10.8 Hz, 1H), 7.07-7.17 (m, 2H), 7.30 (s, 1H), 7.60-7.70 (m, 2H); Method B; Rt: 1.13 min. m/z: 464 (M+H) ⁺ exact mass: 463.1.

Compound 4: N-(3,4-difluorophenyl)-8-methyl-1,1-dioxo-2-[(1R)-2,2,2-trifluoro-1-methyl-ethyl] yl]-3,4,5,6-tetrahydropyrrolo[3,4-g]triazocine-7-carboxamide.

Compound 3 (80 mg, 0.17 mmol) was dissolved in MeOH (20 mL), Pd/C (10%) (18 mg, 0.017 mmol) was added and the reaction mixture was stirred under a hydrogen atmosphere overnight. The volatiles were removed under reduced pressure and the residue was purified on silica using a heptane to EtOAc gradient to yield compound 4 (63.1 mg) as a white powder after crystallization from DCM:DIPE. ¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.36 (d, J = 7.0 Hz, 3H), 1.63-1.73 (m, 2H), 1.73-1.86 (m, 2H), 3.13-3.34 (m, 2H), 3.51-3.60 (m, 2H), 3.84 (s, 3H), 4.76 (dt, J = 15.1, 7.5 Hz, 1H), 7.08-7.20 (m, 3H), 7.53 (s, 1H), 7.67 (ddd, J = 12.0, 7.2, 2.4 Hz, 1H); Method B; Rt: 1.18 min. m/z: 466 (M+H) ⁺ exact mass: 465.1; MP: 137.3°C.

Compound 5: (4Z)-N-(3,4-difluorophenyl)-3,8-dimethyl-1,1-dioxo-3,6-dihydro-2H-pyrrolo[3,6-dihydro-2H-pyrrolo] ...]-1, [3,4-g]Triazocine-7-carboxamide.

Methyl 3-bromo-4-chlorosulfonyl-1-methyl-pyrrole-2-carboxylate (1000 mg, 3.16 mmol) and 3-butene-2-amine hydrochloride (374 mg, 3.47 mmol) were dissolved in THF (5 mL). Hunin's base (1.63 mL, 0.75 g/mL, 9.48 mmol) was added and the reaction mixture was stirred at room temperature overnight. _NH4Cl (saturated, aqueous, 5 mL) was added and the organic layer was removed. The aqueous layer was extracted with DCM (2 x 5 mL) and the combined organic layers were evaporated to dryness. The residue was purified on silica using a heptane to EtOAc gradient to produce methyl 3-bromo-1-methyl-4-(1-methylallylsulfamoyl)pyrrole-2-carboxylate (981 mg) as a white powder.

Methyl 3-bromo-1-methyl-4-(1-methylallylsulfamoyl)pyrrole-2-carboxylate (200 mg, 0.57 mmol), potassium allyltrifluoroborate (253 mg, 1.71 mmol), bis(tri-tert-butylphosphine)palladium(0) (29 mg, 0.057 mmol) and _Cs2CO3 (557 mg, 1.71 mmol) were dissolved in a mixture of DME (5 mL) and water (1 mL) and heated in a microwave oven at 80 _° C for 30 min. The volatiles were removed under reduced pressure, and the residue was purified on silica using a heptane to EtOAc gradient to yield methyl 3-allyl-1-methyl-4-(1-methylallylsulfamoyl)pyrrole-2-carboxylate (47 mg) and methyl 3,7-dimethyl-1,1-dioxo-2,3-dihydropyrrolo[3,4-f]triazepine-6-carboxylate (79 mg).

Methyl 3-allyl-1-methyl-4-(1-methylallylsulfamoyl)pyrrole-2-carboxylate (47 mg, 0.15 mmol) was dissolved in DCE (100 mL) and _N was bubbled through the reaction mixture. 2nd generation Grubbs catalyst (26 mg, 0.03 mmol) was added and the reaction mixture was heated at 80° C. overnight. Volatiles were removed under reduced pressure and the residue was purified on silica using a heptane to EtOAc gradient to yield methyl (4Z)-3,8-dimethyl-1,1-dioxo-3,6-dihydro-2H-pyrrolo[3,4-g]triazocine-7-carboxylate (31 mg).

Methyl (4Z)-3,8-dimethyl-1,1-dioxo-3,6-dihydro-2H-pyrrolo[3,4-g]triazocine-7-carboxylate (31 mg, 0.11 mmol) and 3,4-difluoroaniline (13.2 μL, 1.29 g/mL, 0.13 mmol) were dissolved in THF (5 mL). Lithium bis(trimethylsilyl)amide (0.33 mL, 1 M in THF, 0.33 mmol) was added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was quenched with _NH4Cl (aqueous, saturated, 5 mL). The organic layer was removed and the aqueous layer was extracted with DCM (2 x 5 mL). The combined organic layers were evaporated to dryness and the residue was purified on silica using a heptane to EtOAc gradient. The obtained product was purified by preparative HPLC (stationary phase: RP XBridge PrepC18 OBD-10 μm, 30×150 mm, mobile phase: 0.25% NH ₄ HCO ₃ solution in water, MeOH) to give compound 5 (9.7 mg) as a white powder. ¹ H NMR (400MHz, DMSO-d ₆ ) δppm 1.23 (d, J=6.8Hz, 3H), 3.16 -3.29 (m, 1H), 3.58 (dd, J=13.5, 10.2Hz, 1H), 3.68 (s, 3H), 4.37-4.48 (m, 1H), 5.30 (dd, J=10.0, 7.6Hz, 1H), 5.69 (q, J=9.1Hz, 1H), 7.28 (br d, J=9.9Hz, 1H), 7.39 (s, 1H), 7.40-7.46 (m, 2H), 7.81-7.90 (m, 1H), 10.56 (s, 1H); Method B; Rt: 0.97 min. m/z: 382 (M+H) ⁺ exact mass: 381.1.

Compound 6: N-(3,4-difluorophenyl)-7-methyl-1,1-dioxo-2-[(1R)-2,2,2-trifluoro-1-methyl-ethyl] 1H-pyrrolo[3,4-f]triazepine-6-carboxamide.

DIAD (0.16 mL, 1.04 g/mL, 0.8 mmol) is added to a solution of N-(3,4-difluorophenyl)-1-methyl-3-[(E)-prop-1-enyl]-4-[[(1R)-2,2,2-trifluoro-1-methyl-ethyl]sulfamoyl]pyrrole-2-carboxamide (180 mg, 0.4 mmol), 2-propen-1-ol (25.5 mg, 0.44 mmol) and triphenylphosphine (209 mg, 0.8 mmol) in THF (5 mL). The reaction mixture is stirred at room temperature overnight. Volatiles are removed under reduced pressure and the residue is purified using heptane to EtOAc gradient on silica. The obtained residue was purified by preparative HPLC (stationary phase: RPXBridge Prep C18 OBD-10 μm, 30 x 150 mm, mobile phase: 0.25% NH4HCO3 solution in water, MeOH) to give 4-[allyl-[(1R)-2,2,2-trifluoro-1-methyl-ethyl]sulfamoyl]-N-(3,4-difluorophenyl)-1-methyl-3-[(E)-prop-1-enyl]pyrrole-2-carboxamide (81 mg).

4-[Allyl-[(1R)-2,2,2-trifluoro-1-methyl-ethyl]sulfamoyl]-N-(3,4-difluorophenyl)-1-methyl-3-[(E)-prop-1-enyl]pyrrole-2-carboxamide (81 mg, 0.16 mmol) was dissolved in DCE (100 mL) and N ₂ was bubbled through the reaction mixture. 2nd generation Grubbs catalyst (28 mg, 0.033 mmol) was added and the reaction mixture was heated at 80° C. overnight. Volatiles were removed under reduced pressure and the residue was purified by preparative HPLC (stationary phase: RPXBridge Prep C18 OBD-10 μm, 30×150 mm, mobile phase: 0.25% NH ₄ HCO ₃ solution in water, MeOH) to give compound 6 (50.1 mg) as a white powder after crystallization from DCM:DIPE. ^1H NMR (360 MHz, DMSO- _d6 ) δ ppm 1.17 (d, J = 7.0 Hz, 3H), 3.74 (s, 3H), 4.10 (dd, J = 21.2, 4.8 Hz, 1H), 4.28-4.37 (m, 1H), 4.37-4.45 (m, 1H), 5.68-5.75 (m, 1H), 6.57 (br d, J = 12.8 Hz, 1H), 7.40-7.49 (m, 2H), 7.67 (s, 1H), 7.81-7.89 (m, 1H), 10.76 (s, 1H); Method B; Rt: 1.13 min. m/z: 450 (M+H) ⁺ exact mass: 449.1.

Compound 7: N-(3,4-difluorophenyl)-3,7-dimethyl-1,1-dioxo-2,3-dihydropyrrolo[3,4-f]triazol-2-yl] ... Azepine-6-carboxamide.

Methyl 3,7-dimethyl-1,1-dioxo-2,3-dihydropyrrolo[3,4-f]triazepine-6-carboxylate (79 mg, 0.29 mmol) and 3,4-difluoroaniline (36 μL, 1.29 g/mL, 0.35 mmol) were dissolved in THF (5 mL). Lithium bis(trimethylsilyl)amide (0.88 mL, 1 M in THF, 0.88 mmol) was added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was quenched with NH ₄ Cl (aqueous, saturated, 5 mL). The organic layer was removed and the aqueous layer was extracted with DCM (2×5 mL). The combined organic layers were evaporated to dryness and the residue was purified on silica using a heptane to EtOAc gradient. The obtained product was purified by preparative HPLC (stationary phase: RP XBridge Prep C18 ODB-5 μm, 30×250 mm, mobile phase: 0.25% NH ₄ HCO ₃ solution in water, ACN) to yield Compound 7. ^1H NMR (360 MHz, CHLOROFORM-d) δ ppm 1.41 (d, J = 7.3 Hz, 3H), 3.71 (q, J = 7.0 Hz, 1H), 3.76 (s, 3H), 4.40 (br s, 1H), 5.61 (dd, J = 12.4, 2.6 Hz, 1H), 6.53 (dd, J = 12.4, 2.2 Hz, 1H), 7.10-7.26 (m, 3H), 7.71 (ddd, J = 12.0, 7.2, 2.4 Hz, 1H), 8.20 (br s, 1H); Method D; Rt: 1.72 min. m/z: 368 (M+H) ⁺ exact mass: 367.1. The racemic mixture was separated into enantiomers 7a (19.5 mg) and 7b (13.4 mg) by preparative SFC (stationary phase: Chiralpak Diacel AD 20 x 250 mm, mobile phase: _CO2 , EtOH with 0.4% _iPrNH2 ).Method E; Rt: 7a: 1.80 min, 7b: 2.33 min.

Compound 8: N-(3,4-difluorophenyl)-7-methyl-1,1-dioxo-3-(trifluoromethyl)-2,3-dihydropyrrolo[3-(1,4-difluorophenyl) ... [3,4-f]Triazepine-6-carboxamide.

Methyl 3-bromo-4-chlorosulfonyl-1-methyl-pyrrole-2-carboxylate (1000 mg, 3.16 mmol), 1,1,1-trifluorobut-3-en-2-ylamine (612 mg, 3.79 mmol), NaHCO ₃ (1062 mg, 12.64 mmol) and molecular sieves (2 g) were partitioned in ACN (30 mL) and the reaction mixture was stirred at 80° C. for 4 days. The reaction mixture was filtered and the filtrate was evaporated to dryness. The residue was purified on silica using a heptane to EtOAc gradient to yield methyl 3-bromo-1-methyl-4-[1-(trifluoromethyl)allylsulfamoyl]pyrrole-2-carboxylate (894 mg) as a white powder.

Methyl 3-bromo-1-methyl-4-[1-(trifluoromethyl)allylsulfamoyl]pyrrole-2-carboxylate (837 mg, 2.07 mmol), bis(tri-tert-butylphosphine)palladium(0) (211 mg, 0.41 mmol) and TEA (286 μL, 0.73 g/mL, 2.07 mmol) were dissolved in DMF (5 mL). The reaction mixture was heated in a microwave oven at 120° C. for 30 minutes. Volatiles were removed under reduced pressure and the residue was purified on silica using a heptane to EtOAc gradient to yield methyl 7-methyl-1,1-dioxo-3-(trifluoromethyl)-2,3-dihydropyrrolo[3,4-f]triazepine-6-carboxylate (470 mg).

Methyl 7-methyl-1,1-dioxo-3-(trifluoromethyl)-2,3-dihydropyrrolo[3,4-f]triazepine-6-carboxylate (470 mg, 1.45 mmol) and 3,4-difluoroaniline (176 μL, 1.29 g/mL, 1.74 mmol) were dissolved in THF (5 mL). Lithium bis(trimethylsilyl)amide (4.35 mL, 1 M in THF, 4.35 mmol) was added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was quenched with NH ₄ Cl (aqueous, saturated, 5 mL). The organic layer was removed and the aqueous layer was extracted with DCM (2×5 mL). The combined organic layers were evaporated to dryness and the residue was purified by preparative HPLC (stationary phase: RP XBridge Prep C18 OBD-10 μm, 30 x 150 mm, mobile phase: 0.25% NH ₄ HCO ₃ solution in water, MeOH) to give compound 8 (28.1 mg) as a white powder. ¹ H NMR (360 MHz, DMSO-d ₆ ) δ ppm 3.75 (s, 3H), 4.88 (br s, 1H), 5.80 (dd, J=12.2, 3.0 Hz, 1H), 6.77-6.83 (m, 1H), 7.41-7.49 (m, 2H), 7.73 (s, 1H), 7.81-7.89 (m, 1H), 8.64 (br d, J=10.1 Hz, 1H), 10.83 (s, 1H); Method D; Rt: 1.89 min. m/z: 420 (MH) ^- Exact mass: 421.1; MP: 245.6° C.

Compound 9: N-(3,4-difluorophenyl)-7-methyl-1,1-dioxo-2,3-dihydropyrrolo[3,4-f]triazepine 6-Methyl-2-piperidinamide.

Methyl 3-bromo-4-chlorosulfonyl-1-methyl-pyrrole-2-carboxylate (500 mg, 1.58 mmol) and allylamine (223 mg, 3.79 mmol) were dissolved in THF (5 mL). Hunin's base (1.63 mL, 0.75 g/mL, 9.48 mmol) was added and the reaction mixture was stirred at room temperature overnight. _NH4Cl (saturated, aqueous, 5 mL) was added and the organic layer was removed. The aqueous layer was extracted with DCM (2 x 5 mL) and the combined organic layers were evaporated to dryness. The residue was purified on silica using a heptane to EtOAc gradient to produce methyl 4-(allylsulfamoyl)-3-bromo-1-methyl-pyrrole-2-carboxylate (488 mg) as a white powder.

Methyl 4-(allylsulfamoyl)-3-bromo-1-methyl-pyrrole-2-carboxylate (430 mg, 1.28 mmol), bis(tri-tert-butylphosphine)palladium(0) (130 mg, 0.26 mmol) and TEA (177 μL, 0.73 g/mL, 1.28 mmol) were dissolved in DMF (5 mL) and heated in a microwave at 140° C. for 30 minutes. The reaction mixture was directly purified by preparative HPLC (stationary phase: RP XBridge Prep C18 OBD-10 μm, 30×150 mm, mobile phase: 0.25% NH ₄ HCO ₃ solution in water, ACN) to give methyl 7-methyl-1,1-dioxo-2,3-dihydropyrrolo[3,4-f]triazepine-6-carboxylate (75 mg).

Methyl 7-methyl-1,1-dioxo-2,3-dihydropyrrolo[3,4-f]triazepine-6-carboxylate (75 mg, 0.29 mmol) and 3,4-difluoroaniline (36 μL, 1.29 g/mL, 0.35 mmol) were dissolved in THF (5 mL). Lithium bis(trimethylsilyl)amide (0.88 mL, 1 M in THF, 0.88 mmol) was added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was quenched with NH ₄ Cl (aqueous, saturated, 5 mL). The organic layer was removed and the aqueous layer was extracted with DCM (2×5 mL). The combined organic layers were evaporated to dryness and the residue was purified on silica using a heptane to EtOAc gradient to produce Compound 9 as a light brown powder after crystallization from a DCM:DIPE mixture. ¹ H NMR (360 MHz, DMSO-d ₆ ) δ ppm 3.71 (s, 3H), 3.89 (ddd, J=6.4, 3.9, 1.8 Hz, 2H), 5.65 (dt, J=12.5, 4.0 Hz, 1H), 6.52 (dt, J=12.8, 1.7 Hz, 1H), 7.39-7.48 (m, 2H), 7.55 (s, 1H), 7.62 (t, J=6.5 Hz, 1H), 7.82-7.89 (m, 1H), 10.76 (s, 1H); Method B; Rt: 0.84 min. m/z: 352 (MH) ^- Exact mass: 353.1; MP: 221.9° C.

Compound 10: N-(3,4-difluorophenyl)-3,7-dimethyl-1,1-dioxo-2,3,4,5-tetrahydropyrrolo[3,4- f] Triazepine-6-carboxamide.

Compound 7a (120 mg, 0.33 mmol) and Pd/C (10%) (35 mg, 0.033 mmol) were distributed in MeOH (20 mL). The reaction mixture was placed under a hydrogen atmosphere and stirred for 2 hours. The reaction mixture was filtered and evaporated to dryness to produce compound 10a (111 mg) as a white powder. ^1H NMR (400 MHz, DMSO- _d6 ) δ ppm 1.13 (d, J = 6.8 Hz, 3H), 1.23-1.40 (m, 1H), 1.84 (br dd, J = 14.2, 6.5 Hz, 1H), 2.78-3.01 (m, 2H), 3.58-3.66 (m, 1H), 3.69 (s, 3H), 6.89-7.17 (m, 1H), 7.37-7.45 (m, 3H), 7.81-7.89 (m, 1H), 10.49 (br s, 1H); Method B; Rt: 0.90 min. m/z: 368 (MH) ^- Exact mass: 369.1; MP: 231.6°C.

Compound 10b (35.6 mg) was prepared similarly as described for compound 10a using compound 7b instead of compound 7a. ^1H NMR (400 MHz, DMSO- _d6 ) δ ppm 1.13 (d, J = 6.8 Hz, 3H), 1.29-1.40 (m, 1H), 1.84 (br dd, J = 14.2, 6.5 Hz, 1H), 2.78-3.02 (m, 2H), 3.58-3.66 (m, 1H), 3.69 (s, 3H), 7.01 (br s, 1H), 7.36-7.44 (m, 3H), 7.81-7.88 (m, 1H), 10.48 (br s, 1H); Method B; Rt: 0.90 min. m/z: 368 (MH) ^- Exact mass: 369.1; MP: 229.8°C.

Compound 11: N-(3,4-difluorophenyl)-3,6-dimethyl-1,1-dioxo-3,4-dihydro-2H-pyrrolo[3,4- e] Thiazine-5-carboxamide.

Methyl 3-bromo-4-chlorosulfonyl-1-methyl-pyrrole-2-carboxylate (2.2 g, 6.95 mmol) was dissolved in aqueous ammonia (60 mL, 0.5 M in dioxane, 30 mmol). The reaction mixture was stirred at room temperature for 4 days. Volatiles were removed, and the residue was dissolved in 2-Me-THF and washed with water. The organic layer was dried (MgSO ₄ ), filtered, and evaporated to dryness to give methyl 3-bromo-1-methyl-4-sulfamoyl-pyrrole-2-carboxylate (2 g) as a white powder. Method B; Rt: 0.55 min. m/z: 295 (MH) ^- Exact mass: 296.

A mixture of methyl 3-bromo-1-methyl-4-sulfamoyl-pyrrole-2-carboxylate (1.20 g, 3.92 mmol), pentane-2,4-dione (1.18 g, 11.8 mmol), copper (I) iodide (74.6 mg, 0.39 mmol) and tripotassium phosphate (1.66 g, 7.83 mmol) in DMSO (18 mL) was stirred overnight at 90 ° C. under an _N atmosphere. The mixture was quenched with HCl (aqueous, 1 M, 20 mL) and the solution was extracted with EtOAc (3 × 50 mL). The organic layers were combined, dried over sodium sulfate and evaporated to dryness. The brown residue was purified using silica gel column chromatography (EtOAc in heptane from 0 to 100%) to give methyl 3-acetylmethyl-4-(acetylsulfamoyl)-1-methyl-pyrrole-2-carboxylate (1.22 g) as a light brown powder. Method B; Rt: 0.41 min. m/z: 315 (MH) ^- Exact mass: 316.0.

Methyl 3-acetylmethyl-4-(acetylsulfamoyl)-1-methyl-pyrrole-2-carboxylate (1.22 g, 3.86 mmol) was dissolved in TFA and heated under reflux for 2 hours. The reaction mixture was concentrated. The residue was dissolved in DCM (20 mL) and washed with NaHCO ₃ (aqueous, saturated, 2×5 mL), dried (Na ₂ SO ₄ ), filtered, the filtrate was concentrated in vacuo, and the crude residue was purified using silica gel column chromatography (EtOAc in heptane from 0 to 100%) to give methyl 3,6-dimethyl-1,1-dioxo-2H-pyrrolo[3,4-e]thiazine-5-carboxylate (203 mg). ¹ H NMR (360 MHz, DMSO-d ₆ ) δ ppm 2.02 (d, J=1.1 Hz, 3H), 3.81 (s, 3H), 3.92 (s, 3H), 6.24 (br s, 1H), 7.86 (s, 1H), 10.52 (br s, 1H); Method B; Rt: 0.59 min. m/z: 255 (MH) ^- Exact mass: 256.0.

To a solution of methyl 3,6-dimethyl-1,1-dioxo-2H-pyrrolo[3,4-e]thiazine-5-carboxylate (203 mg, 0.79 mmol) and 3,4-difluoroaniline (123 mg, 0.95 mmol) in THF (5 mL) was added lithium bis(trimethylsilyl)amide (3.17 mL, 1 M in THF, 3.17 mmol). The reaction mixture was stirred at room temperature for 40 minutes and quenched with _NH4Cl (aqueous, saturated, 5 mL). The aqueous layer was extracted with DCM (3 x 50 mL). The combined organic layers were dried ( _Na2SO4 ), concentrated, and the residue was purified on silica using a heptane to EtOAc gradient _to give a brown powder, which was triturated with methanol. The precipitate was filtered and the solid was washed with methanol to give N-(3,4-difluorophenyl)-3,6-dimethyl-1,1-dioxo-2H-pyrrolo[3,4-e]thiazine-5-carboxamide (33 mg) as a white powder.Method B; Rt: 0.80 min. m/z: 354 (M+H) ⁺ exact mass: 353.0.

N-(3,4-difluorophenyl)-3,6-dimethyl-1,1-dioxo-2H-pyrrolo[3,4-e]thiazine-5-carboxamide (33 mg, 0.093 mmol) was dissolved in THF (40 mL) and Pd/C (10%) (56 mg, 0.053 mmol) was added under a nitrogen atmosphere. The reaction mixture was hydrogenated for 1 hour. The reaction mixture was filtered through celite. The filtrate was washed with THF (3 x 50 mL). The filtrate was evaporated to dryness and the residue was purified using silica gel column chromatography (EtOAc in heptane from 0 to 100%) to give Compound 11 (18 mg) as a white powder. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.26 (d, J=6.6 Hz, 3H), 2.51-2.58 (m, 1H), 2.83 (dd, J=16.3, 3.5 Hz, 1H), 3.55-3.70 (m, 1H), 3.77 (br s, 3H), 7.08 (br d, J=10.9 Hz, 1H), 7.37-7.46 (m, 2H), 7.61 (s, 1H), 7.77-7.85 (m, 1H), 10.15 (s, 1H); Method B; Rt: 0.87 min. m/z: 354 (MH) ^- Exact mass: 355.0.

Compound 12: N-(3,4-difluorophenyl)-7-fluoro-3-methyl-1,1-dioxo- 3,4-dihydro-2H-5,1λ ⁶ ,2- benzoxatriazepine -6-carboxamide.

Na ₂ CO ₃ (2.06g, 19.5mmol) is dissolved in water (30mL). Immediately to this is added DL-alaninol (2.93g, 39.0mmol) followed by THF (30mL). The solution obtained is stirred and cooled in an ice bath. 3-(chlorosulfonyl)-2,6-difluorobenzoic acid (5.00g, 19.5mmol) is dissolved in THF (40mL) and this is added dropwise to the stirred solution. While continuing to cool, the resulting mixture is stirred for 30 minutes. The mixture is then stirred at room temperature for 3 hours. The mixture is concentrated in a vacuum until only water remains. 20mL of water is then added and the mixture is acidified with 20mL of HCl (aqueous, 1M). This is extracted with 2-Me-THF (3X 50mL). The combined organics were washed with brine (50 mL), dried _{( Na2SO4} ), filtered and concentrated in vacuo to yield 2,6-difluoro-3-[(2-hydroxy-1-methyl-ethyl)sulfamoyl]benzoic acid (4.9 g) as a yellow powder.Method D; Rt: 0.75 min. m/z: 294 (MH) ^- Exact mass: 295.0.

2,6-Difluoro-3-[(2-hydroxy-1-methyl-ethyl)sulfamoyl]benzoic acid (1.00 g, 3.18 mmol), 3,4-difluoroaniline (623 mg, 4.78 mmol), HATU (1.33 mg, 3.5 mmol) and DIPEA (1.65 mL, 0.75 g/mL, 9.55 mmol) were dissolved in DMF (2 mL) and stirred at room temperature for 2 hours. The mixture was injected directly onto a silica plug and purified using silica gel column chromatography (gradient elution: EtOAc: heptane 0:100 to 100:0) to give N-(3,4-difluorophenyl)-2,6-difluoro-3-[(2-hydroxy-1-methyl-ethyl)sulfamoyl]benzamide (987 mg) as an oil.

N-(3,4-difluorophenyl)-2,6-difluoro-3-[(2-hydroxy-1-methyl-ethyl)sulfamoyl]benzamide (887 mg, 2.18 mmol) in DMF (8 mL) was treated with NaH (437 mg, 60% dispersion in mineral oil, 10.9 mmol) at room temperature and stirred for 2 minutes. It was then heated to 110° C. under microwave irradiation for 40 minutes. The reaction mixture was poured into ice water (100 mL) and extracted with EtOAc (3×100 mL). The combined extracts were washed with brine (100 mL), dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. The crude product was purified using silica gel column chromatography (gradient elution: EtOAc:heptane 0:100 to 30:70) to give an oil, which was crystallized from boiling diisopropyl ether/acetonitrile to give Compound 12 (191 mg) as a white powder. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.10 (d, J=7.04 Hz, 3H) 3.66 (dd, J=12.32, 9.68 Hz, 1H) 3.77-3.88 (m, 1H) 4.45 (dd, J=12.43, 2.31 Hz, 1H) 7.32 (t, J=8.69 Hz, 1H) 7.35-7.50 (m, 2H) 7.79-7.91 (m, 3H) 10.97 (s, 1H); Method B; Rt: 0.89 min. m/z: 387 (M+H) ⁺ exact mass: 386.1.

Compound 13: N-(3,4-difluorophenyl)-6-methyl-1,1-dioxo-3,4-dihydro-2H-pyrrolo[3,4-e]thiazolyl Oxazine-5-carboxamide.

To a solution of methyl 3-bromo-1-methyl-4-sulfamoyl-pyrrole-2-formate (300mg, 0.98 mmol) in DMF (10mL), (Z)-1-ethoxy-2-(tributylstannyl)ethylene (490 μL, 1.08g/mL, 1.47mmol) was added. The reaction mixture was purified with nitrogen for 5 minutes and bis(tri-tert-butylphosphine)palladium(0) (150mg, 0.29mmol) was added. The reaction mixture was heated at 140°C for 20 minutes. The reaction mixture was poured into water and extracted with EtOAc (3x 30mL). The organic layer was washed with salt water, dried (Na ₂ SO ₄ ) and concentrated to give a brown oil. The oil was dissolved in acetonitrile and washed with heptane. The solution was concentrated to dryness to give methyl 3-[(E)-2-ethoxyvinyl]-1-methyl-4-sulfamoyl-pyrrole-2-carboxylate (707 mg) as a brown oil.Method B; Rt: 0.63 min. m/z: 289 (M+H) ⁺ exact mass: 288.0.

Methyl 3-[(Z)-2-ethoxyvinyl]-1-methyl-4-sulfamoyl-pyrrole-2-carboxylate (707 mg, 1.15 mmol) was dissolved in TFA (5 mL) and stirred at room temperature for 1 hour. The reaction mixture was concentrated and dissolved in THF (50 mL) and concentrated to give methyl 6-methyl-1,1-dioxo-2H-pyrrolo[3,4-e]thiazine-5-carboxylate (600 mg) as a brown oil. Method D; Rt: 1.10 min. m/z: 243 (M+H) ⁺ exact mass: 242.0.

Methyl 6-methyl-1,1-dioxo-2H-pyrrolo[3,4-e]thiazine-5-carboxylate (70 mg, 0.29 mmol) was dissolved in THF (20 mL) and Pd/C (10%) (26.4 mg, 0.025 mmol) was added under a nitrogen atmosphere. The reaction mixture was hydrogenated for 18 hours. The reaction mixture was filtered through celite. The filtrate was washed with THF (3 x 20 mL). The combined filtrates were evaporated to dryness. The residue was purified using silica gel column chromatography (EtOAc in heptane from 0 to 100%) to give methyl 6-methyl-1,1-dioxo-3,4-dihydro-2H-pyrrolo[3,4-e]thiazine-5-carboxylate (73 mg) as a white powder. Method B; Rt: 0.62 min. m/z: 243 (MH) ^- exact mass: 244.0.

To a solution of methyl 6-methyl-1,1-dioxo-3,4-dihydro-2H-pyrrolo[3,4-e]thiazine-5-carboxylate (20 mg, 0.078 mmol) and 3,4-difluoroaniline (12.1 mg, 0.093 mmol) in THF (2 mL) was added lithium bis(trimethylsilyl)amide (0.31 mL, 1 M in THF, 0.31 mmol). The reaction mixture was stirred at room temperature for 30 minutes and quenched with NH ₄ Cl (aqueous, saturated, 2 mL). The aqueous layer was extracted with DCM (3 x 5 mL) and ethyl acetate (15 mL). The combined organic layers were concentrated, and the residue was purified twice on silica (EtOAc in heptane from 0 to 100%) and by preparative HPLC (stationary phase: RP XBridge Prep C18 OBD-10 μm, 30 x 150 mm, mobile phase: 0.25% NH ₄ HCO ₃ solution in water, ACN) to give compound 13 (15 mg) as a white powder. ¹ H NMR (360 MHz, DMSO-d ₆ ) δ ppm 2.72-2.79 (m, 2H), 3.42-3.50 (m, 2H), 3.78 (br s, 3H), 7.18 (br s, 1H), 7.37-7.47 (m, 2H), 7.63 (s, 1H), 7.78-7.85 (m, 1H), 10.21 (br s, 1H); Method B; Rt: 0.82 min. m/z: 340 (MH) ^- exact mass: 341.0.

Compound 14: N-(3,4-difluorophenyl)-3,7-dimethyl-1,1-dioxo-3,4-dihydro-2H-pyrrolo[3,4- b] [1,4,5]oxatriazepine-6-carboxamide.

Ethyl 4-chlorosulfonyl-3-fluoro-1-methyl-pyrrole-2-carboxylate (500 mg, 1.85 mmol), DL-alaninol (209 mg, 2.78 mmol) and Hunin's base (0.96 mL, 0.75 g/mL, 5.56 mmol) were dissolved in THF and stirred at room temperature overnight. The resulting precipitate was filtered off and the filtrate was evaporated to dryness. The residue was purified on silica using a heptane to EtOAc gradient to yield ethyl 3-fluoro-4-[(2-hydroxy-1-methyl-ethyl)sulfamoyl]-1-methyl-pyrrole-2-carboxylate (513 mg) as a white powder.

Ethyl 3-fluoro-4-[(2-hydroxy-1-methyl-ethyl)sulfamoyl]-1-methyl-pyrrole-2-carboxylate (240 mg, 0.78 mmol) and 3,4-difluoroaniline (0.094 mL, 1.29 g/mL, 0.93 mmol) were dissolved in THF (5 mL). Lithium bis(trimethylsilyl)amide (2.34 mL, 1 M in THF, 2.34 mmol) was added and the reaction mixture was stirred at room temperature overnight. Lithium bis(trimethylsilyl)amide (0.5 mL, 1 M in THF, 0.5 mmol) was added and the reaction mixture was stirred for 1 hour. NH ₄ Cl (saturated, aqueous, 5 mL) was added and the organic layer was removed. The aqueous layer was extracted with DCM (2×5 mL) and the combined organic layers were evaporated to dryness. The residue was purified on silica using a heptane to EtOAc gradient to yield after crystallization from a DCM:DIPE mixture N-(3,4-difluorophenyl)-3-fluoro-4-[(2-hydroxy-1-methyl-ethyl)sulfamoyl]-1-methyl-pyrrole-2-carboxamide as a white powder (225 mg).

N-(3,4-Difluorophenyl)-3-fluoro-4-[(2-hydroxy-1-methyl-ethyl)sulfamoyl]-1-methyl-pyrrole-2-carboxamide (183 mg, 0.47 mmol) and cesium fluoride (15.5 mg, 0.94 mmol) were partitioned in DMF (3 mL). The reaction mixture was heated in a microwave oven at 140° C. for 2 hours. The reaction mixture was purified by preparative HPLC (stationary phase: RP XBridgePrep C18 OBD-10 μm, 30×150 mm, mobile phase: 0.25% NH ₄ HCO ₃ solution in water, ACN) to give Compound 14 (130 mg). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.10-1.20 (m, 3H), 3.78-3.86 (m, 5H), 4.51-4.59 (m, 1H), 7.36-7.48 (m, 3H), 7.61 (br s, 1H), 7.85 (ddd, J=13.1, 7.4, 2.3 Hz, 1H), 9.44 (s, 1H); Method D; Rt: 1.82 min. m/z: 372 (M+H) ⁺ exact mass: 371.1. The racemic mixture was separated into enantiomers 14a (40.6 mg) and 14b (36.9 mg) by preparative SFC (stationary phase: Chiralpak Diacel AD 20 x 250 mm, mobile phase: _CO2 , EtOH with 0.4% _iPrNH2 ).Method F; Rt: 14a: 1.52 min, 14b: 2.14 min.

Compound 15: (5Z)-N-(3,4-difluorophenyl)-3,8-dimethyl-1,1-dioxo-3,4-dihydro-2H-pyrrolo[3,4-difluorophenyl] ... [3,4-g]Triazocine-7-carboxamide.

Methyl 3-bromo-4-chlorosulfonyl-1-methyl-pyrrole-2-carboxylate (1000 mg, 3.16 mmol) and pent-4-en-2-ylamine hydrochloride (423 mg, 3.47 mmol) were dissolved in THF (5 mL). Hunin's base (1.63 mL, 0.75 g/mL, 9.48 mmol) was added and the reaction mixture was stirred at room temperature overnight. _NH4Cl (saturated, aqueous, 5 mL) was added and the organic layer was removed. The aqueous layer was extracted with DCM (2 x 5 mL) and the combined organic layers were evaporated to dryness. The residue was purified on silica using a heptane to EtOAc gradient to produce methyl 3-bromo-1-methyl-4-(1-methylbut-3-enylsulfamoyl)pyrrole-2-carboxylate (965 mg) as a white powder.

Methyl 3-bromo-1-methyl-4-(1-methylbut-3-enylsulfamoyl)pyrrole-2-carboxylate (97 mg, 0.28 mmol), bis(tri-tert-butylphosphine)palladium(0) (13.6 mg, 0.027 mmol) and TEA (36.8 μL, 0.73 g/mL, 0.27 mmol) were dissolved in DMF (5 mL) and heated in a microwave oven at 150° C. for 30 minutes. The reaction mixture was purified by preparative HPLC (stationary phase: RP XBridge Prep C18 OBD-10 μm, 30×150 mm, mobile phase: 0.25% NH ₄ HCO ₃ solution in water, ACN) to give methyl (5Z)-3,8-dimethyl-1,1-dioxo-3,4-dihydro-2H-pyrrolo[3,4-g]triazocine-7-carboxylate (41 mg).

Methyl (5Z)-3,8-dimethyl-1,1-dioxo-3,4-dihydro-2H-pyrrolo[3,4-g]triazocine-7-carboxylate (41 mg, 0.14 mmol) and 3,4-difluoroaniline (17.5 μL, 1.29 g/mL, 0.17 mmol) were dissolved in THF (5 mL). Lithium bis(trimethylsilyl)amide (433 μL, 1 M in THF, 0.43 mmol) was added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was quenched with NH ₄ Cl (aqueous, saturated, 5 mL). The organic layer was removed and the aqueous layer was extracted with DCM (2×5 mL). The combined organic layers were evaporated to dryness and the residue was purified by preparative HPLC (stationary phase: RP XBridge Prep C18 OBD-10 μm, 30 x 150 mm, mobile phase: 0.25% NH ₄ HCO ₃ solution in water, MeOH) to give compound 15. ¹ H NMR (400MHz, DMSO-d ₆ ) δppm 1.32 (d, J=7.0Hz, 3H), 2.08-2.16 (m, 1H), 2.46 (ddd, J=13.6, 8.6, 1.8Hz, 1H), 3.51 (quind, J=6.9, 6.9, 6.9, 6.9, 1.8Hz, 1H), 3.92 (s, 3H), 6.08 (dt, J=11.0, 8.8Hz, 1H), 6.77 (d, J=11.0Hz, 1H), 7.31 (dt, J-10.4, 9.0Hz, 1H), 7.38-7.44 (m, 2H), 7.89 (ddd, J-13.0, 7.4, 2.6 Hz, 1H); Method D; Rt: 1.78 min. m/z: 382 (M+H) ⁺ exact mass: 381.1. The racemic mixture was separated into enantiomers 15a (4.7 mg) and 15b (4.2 mg) by preparative SFC (stationary phase: Kromasil (R,R) Whelk-O 1 10/100, mobile phase: CO 2 , MeOH + 0.4iPrNH ₂ ). Method G; Rt: 15a: 2.31 min, 15b: 2.75 min.

Compound 16: N-(3,4-difluorophenyl)-2-isopropyl-6-methyl-1,1-dioxo-3,4-dihydropyrrolo[3, 4-e]thiazine-5-carboxamide.

Methyl 6-methyl -1,1-dioxo -3,4-dihydro -2H- pyrrolo [3,4-e] thiazine -5- carboxylate (40 mg, 0.11 mmol) was dissolved in DMF (1 mL) and 2-bromopropane (17.2 μL, 2.28 g/mL, 0.32 mmol) was added. The reaction mixture was stirred at room temperature for 66 hours. The reaction mixture was diluted with water and extracted with EtOAc (3 x 10 mL). The combined organic layers were dried and concentrated to dryness. The white solid was purified using silica gel column chromatography (EtOAc in heptane from 0 to 100%) to obtain methyl 2-isopropyl -6-methyl -1,1-dioxo -3,4-dihydro pyrrolo [3,4-e] thiazine -5- carboxylate (20 mg) as a white powder. Method B; Rt: 0.84 min. m/z: 287 (M+H) ⁺ exact mass: 286.0.

To a solution of methyl 2-isopropyl-6-methyl-1,1-dioxo-3,4-dihydropyrrolo[3,4-e]thiazine-5-carboxylate (20 mg, 0.07 mmol) and 3,4-difluoroaniline (10.82 mg, 0.084 mmol) in THF (2 mL) was added lithium bis(trimethylsilyl)amide (0.28 mL, 1 M in THF, 0.28 mmol) and the reaction mixture was stirred at room temperature for 1 hour. Lithium bis(trimethylsilyl)amide (0.28 mL, 1 M in THF, 0.28 mmol) was added and the reaction mixture was stirred at room temperature for 5 minutes and quenched with NH ₄ Cl (aqueous, saturated, 2 mL). The aqueous layer was extracted with DCM (3 x 5 mL). The combined organic layers were concentrated and the residue was purified on silica (EtOAc in heptane from 0 to 100%) to give a brown powder. This was triturated in hot methanol. The white suspension was filtered to give compound 16 (18 mg) as an off-white solid. ^1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.16 (d, J=6.8 Hz, 6H), 2.83-2.90 (m, 2H), 3.58-3.65 (m, 2H), 3.78 (s, 3H), 4.09-4.21 (m, 1H), 7.36-7.46 (m, 2H), 7.63 (s, 1H), 7.77-7.83 (m, 1H), 10.08 (br s, 1H); Method B; Rt: 0.98 min. m/z: 384 (M+H) ⁺ exact mass: 383.0.

Compound 17: N-(3,4-difluorophenyl)-3-ethyl-6-methyl-1,1-dioxo-3,4-dihydro-2H-pyrrolo[3,4-difluorophenyl] ...2H-pyrrolo[3,4-difluorophenyl]-3-ethyl-6-methyl-1,1-dioxo- [3,4-e]thiazine-5-carboxamide.

Methyl 3-ethyl-6-methyl-1,1-dioxo-2H-pyrrolo[3,4-e]thiazine-5-carboxylate was prepared similarly to that described for methyl 3,6-dimethyl-1,1-dioxo-2H-pyrrolo[3,4-e]thiazine-5-carboxylate using heptane-3,5-dione instead of pentane-2,4-dione.

Methyl 3-ethyl-6-methyl-1,1-dioxo-2H-pyrrolo[3,4-e]thiazine-5-carboxylate (128 mg, 0.18 mmol) was dissolved in MeOH (10 mL) and Pd/C (10%) (20 mg, 0.018 mmol) was added under a nitrogen atmosphere. The reaction mixture was hydrogenated for 18 hours. Pd/C (10%) (20 mg, 0.018 mmol) was added under a nitrogen atmosphere. The reaction mixture was hydrogenated at 50° C. for 18 hours. The reaction mixture was filtered through celite. The filter cake was washed with MeOH (3 x 20 mL). The filtrate was evaporated to dryness and the residue was purified using silica gel column chromatography (EtOAc in heptane from 0 to 100%) to obtain methyl 3-ethyl-6-methyl-1,1-dioxo-3,4-dihydro-2H-pyrrolo[3,4-e]thiazine-5-carboxylate (20 mg). Method B; Rt: 0.74 min. m/z: 271 (MH) ^- exact mass: 272.0.

To a solution of methyl 3-ethyl-6-methyl-1,1-dioxo-3,4-dihydro-2H-pyrrolo[3,4-e]thiazine-5-carboxylate (20 mg, 0.073 mmol) and 3,4-difluoroaniline (9.5 mg, 0.073 mmol) in THF (2 mL) was added lithium bis(trimethylsilyl)amide (0.29 mL, 1 M in THF, 0.29 mmol). The reaction mixture was stirred at room temperature for 30 minutes and quenched with NH ₄ Cl (aqueous, saturated, 2 mL). The aqueous layer was extracted with DCM (3 x 5 mL). The combined organic layers were concentrated and the residue was purified by preparative HPLC (stationary phase: RP XBridge Prep C18 OBD-10 μm, 30 x 150 mm, mobile phase: 0.25% NH ₄ HCO ₃ in water, ACN) to give compound 17 (4.5 mg) as an off-white powder. ^1H NMR (400 MHz, DMSO- _d6 ) δ ppm 0.96 (tt, J=7.3, 1.0 Hz, 3H), 1.54-1.63 (m, 2H), 2.45-2.55 (m, 1H), 2.80-2.92 (m, 1H), 3.16-3.44 (m, 1H), 3.77 (s, 3H), 6.92-7.05 (m, 1H), 7.37-7.46 (m, 2H), 7.60 (s, 1H), 7.77-7.84 (m, 1H), 10.09-10.19 (m, 1H); Method B; Rt: 0.91 min. m/z: 368 (MH) ^- Exact mass: 369.1.

Compound 18: N-(3,4-difluorophenyl)-2,3,7-trimethyl-1,1-dioxo-3H-pyrrolo[3,4-f]triazine Mizorelin-6-carboxamide.

At 50 ℃, trimethylsulfonium iodide (123mg, 0.56mmol) and potassium tert-butoxide (58mg, 0.52mmol) are dissolved in DMSO (5mL). Compound 7 (100mg, 0.27mmol) dissolved in DMSO (5mL) is added dropwise and the reaction mixture is stirred overnight at 50 ℃. Trimethylsulfonium iodide (123mg, 0.56mmol) and potassium tert-butoxide (58mg, 0.52mmol) are dissolved in DMSO (5mL), and this is added in the reaction mixture, which is stirred for another hour. The reaction mixture is purified through preparative HPLC (stationary phase: RP XBridge Prep C18 OBD-10μm, 30x 150mm, mobile phase: 0.25% _{NH4HCO3 solution} in water, MeOH) to produce compound 18 (23.7mg). ¹ H NMR (400MHz, acetone-d ₆ ) δppm 1.41 (d, J=7.5Hz, 3H), 2.53 (s, 3H), 3.86 (s, 3H), 4.88 (qt, J=7.5, 2.6Hz, 1H), 5.40 (dd, J=12.4, 2.5Hz, 1H), 6.67 (dd, J=12.5, 2.9Hz, 1H), 7.34 (dt, J=10.4, 9.0Hz, 1H), 7.44 (s, 1H), 7.47-7.56 (m, 1H), 7.94 (ddd, J=12.9, 7.5, 2.6 Hz, 1H), 9.84(br s, 1H); Method B; Rt: 0.99 min. m/z: 382 (M+H) ⁺ exact mass: 381.1.

Compound 19: N-(3,4-difluorophenyl)-7-methyl-1,1-dioxo-spiro[2,4-dihydropyrrolo[3,4-b][1, [4,5]oxatriazepine-3,1′-cyclopropane]-6-carboxamide.

Compound 19 (18.1 mg) was prepared similarly as described for compound 14, using 1-amino-cyclopropanemethanol instead of DL-alaninol. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.91-1.04 (m, 4H), 3.83 (s, 3H), 4.15 (s, 2H), 7.36-7.47 (m, 2H), 7.49 (s, 1H), 7.84 (ddd, J=13.2, 7.5, 2.2 Hz, 1H), 8.23 (s, 1H), 9.51 (s, 1H); Method B; Rt: 0.94 min. m/z: 384 (M+H) ⁺ exact mass: 383.1.

Compound 20: (3R)-N-(3,4-difluorophenyl)-3-ethyl-7-methyl-1,1-dioxo-3,4-dihydro-2H-pyrrolidone Pyrrolidine[3,4-b][1,4,5]oxatriazepine-6-carboxamide.

Compound 20 (36.6 mg) was prepared similarly as described for compound 14, using (R)-(-)-2-amino-1-butanol instead of DL-alaninol. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.98 (t, J=7.4 Hz, 3H), 1.37-1.55 (m, 2H), 3.47-3.59 (m, 1H), 3.82 (s, 3H), 3.83-3.89 (m, 1H), 4.56-4.62 (m, 1H), 7.36-7.49 (m, 3H), 7.54 (br d, J=8.4 Hz, 1H), 7.85 (ddd, J=13.2, 7.5, 2.4 Hz, 1H), 9.43 (s, 1H); Method B; Rt: 0.99 min. m/z: 386 (M+H) ⁺ exact mass: 385.1.

Compound 21: N-(3,4-difluorophenyl)-3,8-dimethyl-1,1-dioxo-2,3,4,5-tetrahydropyrrolo[3,4- b] [1,4,5]oxatriazocine-7-carboxamide.

Compound 21 (137.3 mg) was prepared similarly as described for compound 14, using 3-aminobutan-1-ol instead of DL-alaninol. ¹ H NMR (400MHz, DMSO-d ₆ ) δ ppm 1.04 (d, J=5.9Hz, 3H), 1.21 (d, J=6.6Hz, 3H), 1.66-1.76 (m, 1H), 1.97-2.05 (m, 1H), 3.78-3.85 (m, 4H), 4.21 (ddd, J=11.8, 8.4, 3.2Hz, 1H), 4.31-4.38 (m, 1H), 7.36-748 (m, 3H), 7.63 (d, J=9.2Hz, 1H), 7.86 (ddd, J=13.3, 7.4, 2.4Hz, 1H), 9.54 (s, 1H); Method B; Rt: 0.96min. m/z: 386 (M+H) ⁺ exact mass: 385.1.

Compound 22: (3S)-N-(3,4-difluorophenyl)-3-isopropyl-7-methyl-1,1-dioxo-3,4-dihydro-2H- Pyrrolo[3,4-b][1,4,5]oxatriazepine-6-carboxamide.

Compound 22 (46.5 mg) was prepared similarly as described for compound 14, using (S)-(+)-2-amino-3-methyl-1-butanol instead of DL-alaninol. ^1H NMR (400 MHz, DMSO- _d6 ) δ ppm 0.94 (d, J = 6.8 Hz, 3H), 0.97 (d, J = 6.6 Hz, 3H), 1.85 (dq, J = 13.4, 6.8 Hz, 1H), 3.46 (br s, 1H), 3.83 (s, 3H), 3.94 (dd, J = 12.7, 9.1 Hz, 1H), 4.70 (dd, J = 12.5, 1.5 Hz, 1H), 7.36-7.55 (m, 4H), 7.86 (ddd, J = 13.1, 7.4, 2.5 Hz, 1H), 9.42 (s, 1H); Method B; Rt: 1.05 min. m/z: 400 (M+H) ⁺ exact mass: 399.1.

Compound 23: (3S)-N-(3,4-difluorophenyl)-7-methyl-3 - [(1S)-1-methylpropyl]-1,1-dioxo- 3,4-dihydro-2H-pyrrolo[3,4-b][1,4,5]oxatriazepine-6-carboxamide.

Compound 23 (30.8 mg) was prepared similarly as described for compound 14, using L-isoleucinol instead of DL-alaninol. ¹ H NMR (400MHz, DMSO-d ₆ ) δppm 0.87 (t, J=7.4Hz, 3H), 0.94 (d, J=6.8Hz, 3H), 1.22-1.33 (m, 1H), 1.46 -1.56 (m, 1H), 1.56-1.65 (m, 1H), 3.53 (br s, 1H), 3.83 (s, 3H), 3.94 (dd, J=12.8, 9.0Hz, 1H), 4.71 (d, J=11.0Hz, 1H), 7.36-7.45 (m, 1H), 7.45-7.52 (m, 2H), 7.56 (br s, 1H), 7.86 (ddd, J=13.2, 7.4, 2.5Hz, 1H), 9.42 (s, 1H); Method B; Rt: 1.10 min. m/z: 414 (M+H) ⁺ exact mass: 413.1.

Compound 24: N-(3,4-difluorophenyl)-7-methyl-1,1-dioxo-spiro[2,4-dihydropyrrolo[3,4-b][1, 4,5]oxatriazepine-3,3'-oxetane]-6-carboxamide.

Compound 24 (51.6 mg) was prepared similarly as described for compound 14 using (3-aminooxetan-3-yl)methanol instead of DL-alaninol. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 3.82 (s, 3H), 4.47 (d, J=6.8 Hz, 2H), 4.65 (d, J=6.8 Hz, 2H), 4.76 (s, 2H), 7.38-7.46 (m, 1H), 7.49 (s, 1H), 7.50-7.54 (m, 1H), 7.89 (ddd, J=13.1, 7.4, 2.5 Hz, 1H), 8.47 (s, 1H), 9.46 (s, 1H); Method B; Rt: 0.88 min. m/z: 400 (M+H) ⁺ exact mass: 399.1.

Compound 25: (3R)-N-(3,4-difluorophenyl)-7-methyl-1,1-dioxo-3-phenyl-3,4-dihydro-2H-pyrrolidone Pyrrolidine[3,4-b][1,4,5]oxatriazepine-6-carboxamide.

Compound 25 (5 mg) was prepared similarly as described for compound 14, using (D)-β-aminophenethanol instead of DL-alaninol. ^1H NMR (400 NHz, DMSO- _d6 ) δ ppm 3.86 (br s, 3H), 4.15-4.26 (m, 1H), 4.74 (br d, J = 11.7 Hz, 1H), 4.92 (br d, J = 9.2 Hz, 1H), 7.28-7.44 (m, 4H), 7.48 (br s, 3H), 7.58 (s, 1H), 7.85 (br s, 1H), 9.43 (br s, 1H); Method B; Rt: 1.07 min. m/z: 432 (MH) ^- Exact mass: 433.1.

Compound 26: (3S)-N-(3,4-difluorophenyl)-7-methyl-1,1-dioxo-3-phenyl-3,4-dihydro-2H-pyrrolidone Pyrrolidine[3,4-b][1,4,5]oxatriazepine-6-carboxamide.

Compound 26 (8.8 mg) was prepared similarly as described for compound 14, using (S)-(+)-2-phenylglycinol instead of DL-alaninol. ^1H NMR (400 MHz, DMSO- _d6 ) δ ppm 3.86 (s, 3H), 4.20 (dd, J = 12.8, 9.7 Hz, 1H), 4.74 (dd, J = 12.8, 2.0 Hz, 1H), 4.92 (br d, J = 8.1 Hz, 1H), 7.31-7.44 (m, 4H), 7.44-7.51 (m, 3H), 7.56 (s, 1H), 7.85 (ddd, J = 13.2, 7.5, 2.4 Hz, 1H), 8.24 (br s, 1H), 9.43 (br s, 1H); Method B; Rt: 1.07 min. m/z: 432 (MH) ^- Exact mass: 433.1.

Compound 27: (3R)-N-(3,4-difluorophenyl)-3-isopropyl-7-methyl-1,1-dioxo-3,4-dihydro-2H- Pyrrolo[3,4-b][1,4,5]oxatriazepine-6-carboxamide.

Compound 27 (22.7 mg) was prepared similarly as described for compound 14, with D-valinol replacing DL-alaninol. ^1H NMR (400 MHz, DMSO- _d6 ) δ ppm 0.96 (dd, J = 12.1, 6.8 Hz, 6H), 1.85 (dq, J = 13.3, 6.7 Hz, 1H), 3.46 (br d, J = 6.8 Hz, 1H), 3.83 (s, 3H), 3.94 (dd, J = 12.8, 9.2 Hz, 1H), 4.69 (dd, J = 12.8, 1.5 Hz, 1H), 7.36-7.54 (m, 4H), 7.86 (ddd, J = 13.2, 7.4, 2.5 Hz, 1H), 9.42 (s, 1H); Method D; Rt: 2.00 min. m/z: 400 (M+H) ⁺ exact mass: 399.1.

Compound 28: N-(3,4-difluorophenyl)-3,4,7-trimethyl-1,1-dioxo-3,4-dihydro-2H-pyrrolo[3, 4-b][1,4,5]oxatriazepine-6-carboxamide.

Compound 28 (18.1 mg) was prepared similarly as described for compound 14 using 3-amino-2-butanol instead of DL-alaninol. Method B; Rt: 0.94 min. m/z: 384 (M+H) ⁺ exact mass: 383.1.

Compound 29: (*S)-3,7-dimethyl-1,1-dioxo-N-(3,4,5-trifluorophenyl)-2,3-dihydropyrrolo[3,4,5-trifluorophenyl] ... [3,4-f]Triazepine-6-carboxamide.

3-Chloro-1-butene (88.1 g, 973 mmol) was added to an overhead stirred suspension of potassium phthalimide (157 g, 848 mmol) and K ₂ CO ₃ (23.5 g, 170 mmol) in DMF (1.3 L). The reaction mixture was heated to 120° C. for 5 hours. The reaction mixture was allowed to cool to room temperature and stirred at room temperature overnight. The reaction mixture was quenched with ice-cold water (6 L) and filtered. The filter cake was washed with cold water (300 mL) and air-dried for one hour and then dried in a vacuum oven for 3 days to produce 2-(1-methylallyl)isoindoline-1,3-dione (148 g) as a white powder. ¹ H NMR (400 MHz, DMSO-d ₆ ) δppm 1.51 (d, J=7.0Hz, 3H), 4.79-4.87 (m, 1H), 5.10-5.20 (m, 2H), 6.11 (ddd, J=17.3, 10.5, 5.7Hz, 1H), 7.82-7.89 (m, 4H). The racemic mixture was separated into the enantiomers (*R)-2-(1-methylallyl)isoindoline-1,3-dione (43.6 g) and (*S)-2-(1-methylallyl)isoindoline-1,3-dione (48 g) by preparative chiral HPLC (stationary phase: Chiralpak Diacel AD 20 microm 2000 gr, mobile phase: isocratic 100% MeOH), where *R refers to the first eluting enantiomer and *S refers to the second eluting enantiomer.

To a solution of (*S)-2-(1-methylallyl)isoindoline-1,3-dione (5.03 g, 25 mmol) in EtOH (10 mL) was added ethanolamine (6.34 mL, 1.01 g/mL, 105 mmol). The mixture was heated at 45°C for 20 h and allowed to reach room temperature, and then heated at 90°C for 5 h. The flask was equipped with a short-path distillation apparatus, and ethanol and free amine were distilled as an azeotropic mixture at atmospheric pressure. The pot temperature was 120°C, and the boiling point of the ethanol + amine distillate was 80°C. To the distillate (6.8 mol% in ethanol) was added a solution of methyl 3-bromo-4-chlorosulfonyl-1-methyl-pyrrole-2-carboxylate (5.00 g, 15.8 mmol) in DCM (100 mL) and Hunin's base (5.44 mL, 0.75 g/mL, 31.6 mmol). The reaction mixture was stirred at room temperature for 18h. The reaction mixture was concentrated to dryness and the residue was dissolved in DCM (100mL) and washed with saturated aqueous ammonium chloride solution. The organic layer was separated and dried (Na ₂ SO ₄ ), filtered and concentrated to dryness. The residue was purified using silica gel column chromatography (EtOAc in heptane from 0 to 100%) to obtain methyl 3- bromo-1-methyl -4- [[(1 * S) -1- methylallyl] sulfamoyl] pyrrole-2-carboxylate (4.08g) as a white powder.

Compound 29 (139 mg) was prepared similarly as described for compound 8, using methyl 3-bromo-1-methyl-4-[[(1*S)-1-methylallyl]sulfamoyl]pyrrole-2-carboxylate instead of methyl 3-bromo-1-methyl-4-[1-(trifluoromethyl)allylsulfamoyl]pyrrole-2-carboxylate and heating for 5 minutes instead of 30 minutes, and using 3,4,5-trifluoroaniline instead of 3,4-difluoroaniline. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.31 (d, J 7.3 Hz, 3H), 3.71 (s, 3H), 4.20-4.33 (m, 1H), 5.59 (dd, J=12.6, 2.4 Hz, 1H), 6.43 (dd, J=12.6, 2.6 Hz, 1H), 7.48-7.68 (m, 4H), 10.86 (s, 1H); Method B; Rt: 0.97 min. m/z: 384 (MH) ^- Exact mass: 385.1.

Compound 30: (*S)-N-[4-fluoro-3-(trifluoromethyl)phenyl]-3,7-dimethyl-1,1-dioxo-2,3-dihydro Pyrrolo[3,4-f]triazepine-6-carboxamide.

Compound 30 (126 mg) was prepared similarly as described for compound 29 using 4-fluoro-3-(trifluoromethyl)aniline instead of 3,4,5-trifluoroaniline. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.31 (d, J=7.3 Hz, 3H), 3.72 (s, 3H), 4.22-4.32 (m, 1 H), 5.58 (dd, J=12.6, 2.4 Hz, 1 H), 648 (dd, J=12.6, 2.6 Hz, 1 H), 7.48-7.61 (m, 3H), 7.92-8.00 (m, 1 H), 8.20 (dd, J=6.5, 2.7 Hz, 1 H), 10.84 (br s, 1 H); Method B; Rt: 1.00 min. m/z: 416 (MH) ^- Exact mass: 417.1.

Compound 31: (*S)-N-(4-fluoro-3-methyl-phenyl)-3,7-dimethyl-1,1-dioxo-2,3-dihydropyrrolo[3 ... [3,4-f]Triazepine-6-carboxamide.

Compound 31 (106 mg) was prepared similarly as described for compound 29 using 4-fluoro-3-methylaniline instead of 3,4,5-trifluoroaniline. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.31 (d, J=7.3 Hz, 3H), 2.19-2.26 (m, 3H), 3.70 (s, 3H), 4.22-4.31 (m, 1H), 5.55 (dd, J=12.5, 2.4 Hz, 1H), 6.43 (dd, J=12.6, 2.6 Hz, 1H), 7.11 (t, J=9.2 Hz, 1H), 7.37-7.79 (m, 4H), 10.50 (br s, 1H); Method B; Rt: 0.92 min. m/z: 362 (MH) ^- Exact mass: 363.1.

Compound 32: (*S)-N-(3-cyano-4-fluoro-phenyl)-3,7-dimethyl-1,1-dioxo-2,3-dihydropyrrolo[3-(4-fluoro-3-nitrophenyl)-1,7-dihydro-2,3-dihydropyrrolo[3-nitro-4-nitrophenyl)-1,1-dioxo-2,3-dihydropyrrolo[3-nitro-2,3-dihydropyrrolo]- [3,4-f]Triazepine-6-carboxamide.

Compound 32 (78 mg) was prepared similarly as described for compound 29 using 5-amino-2-fluorobenzonitrile instead of 3,4,5-trifluoroaniline. ^1H NMR (400 MHz, DMSO- _d6 ) δ ppm 1.31 (d, J = 7.5 Hz, 3H), 3.72 (s, 3H), 4.23-4.32 (m, 1H), 5.58 (dd, J = 12.6, 2.4 Hz, 1H), 6.47 (dd, J = 12.6, 2.6 Hz, 1H), 7.51-7.60 (m, 3H), 7.97 (ddd, J = 9.2, 4.9, 2.7 Hz, 1H), 8.19 (dd, J = 5.8, 2.7 Hz, 1H), 10.86 (br s, 1H); Method B; Rt: 0.84 min. m/z: 373 (MH) ^- Exact mass: 374.1.

Compound 33: (3R)-N-(3,4-difluorophenyl)-3-[(1R)-1-hydroxyethyl]-7-methyl-1,1-dioxo-3, 4-Dihydro-2H-pyrrolo[3,4-b][1,4,5]oxatriazepine-6-carboxamide.

Compound 33 (44.1 mg) was prepared similarly as described for compound 14, using L-threoninol instead of DL-alaninol. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.10 (d, J = 6.4 Hz, 3H), 3.60-3.70 (m, 1H), 3.83 (s, 3H), 3.85-4.00 (m, 2H), 4.74 (d, J = 11.4 Hz, 1H), 4.96 (d, J = 4.6 Hz, 1H), 7.35-7.44 (m, 2H), 7.44-7.50 (m, 2H), 7.87 (ddd, J = 13.2, 7.5, 2.4 Hz, 1H), 9.44 (s, 1H); Method B; Rt: 0.87 min. m/z: 402 (M+H) ⁺ exact mass: 401.1.

Compound 34: (3S)-N-(3,4-difluorophenyl)-3-[(1R)-1-hydroxyethyl]-7-methyl-1,1-dioxo- 3,4-dihydro-2H-pyrrolo[3,4-b][ 1,4,5]oxatriazepine-6-carboxamide.

Compound 34 (93.6 mg) was prepared similarly as described for compound 14, using D-allo-threonine alcohol instead of DL-propanenitroalcohol. ¹ H NMR (400MHz, DMSO-d ₆ ) δ ppm 1.21 (d, J=6.2Hz, 3H), 3.38-3.45 (m, 1H), 3.56-3.64 (m, 1H), 3.82 (s, 3H), 3.97 (dd, J=12.5, 9.0Hz, 1H), 4.89 (dd, J=12.8, 2.0Hz, 1H), 5.05 (d, J=5.9Hz, 1H), 7.36-7.44 (m, 1H), 7.44-7.49 (m, 2H), 7.61 (d, J=9.7Hz, 1H), 7.87 (ddd, J=13.2, 7.5, 2.4Hz, 1H), 9.42 (s, 1 H); Method B; Rt: 0.86 min. m/z: 402 (M+H) ⁺ exact mass: 401.1.

Compound 35: (3R)-N-(3,4-difluorophenyl)-3-[(1S)-1-hydroxyethyl]-7-methyl-1,1-dioxo-3, 4-Dihydro-2H-pyrrolo[3,4-b][1,4,5]oxatriazepine-6-carboxamide.

Compound 35 (68.5 mg) was prepared similarly as described for compound 14 using L-allo-threoninol instead of DL-alaninol. ¹ H NMR (400MHz, DMSO-d ₆ ) δppm 1.21 (d, J=6.2Hz, 3H), 3.35-3.44 (m, 1H), 3.60 (dt, J=8.1, 6.1Hz, 1H), 3.82 (s, 3H), 3.97 (dd, J=12.8, 9.0Hz, 1H), 4.89 (dd, J=12.7, 1.9 Hz, 1H), 5.04 (d, J=5.9Hz, 1H), 7.36-7.44 (m, 1H), 7.44-7.49 (m, 2 H), 7.61 (d, J=9.7Hz, 1H), 7.87 (ddd, J=13.1, 7.5, 2.4Hz, 1H), 9.42 (s, 1H); Method B; Rt: 0.86 min. m/z: 402 (M+H) ⁺ exact mass: 401.1.

Compound 36: (3R)-N-(3,4-difluorophenyl)-3-[(R)-hydroxy(phenyl)methyl]-7-methyl-1,1-difluorophenyl Oxy-3,4-dihydro-2H-pyrrolo[3,4-b][1,4,5]oxatriazepine-6-carboxamide.

Compound 36 (81.4 mg) was prepared similarly as described for compound 14 using (1R,2R)-(-)-2-amino-1-phenyl-1,3-propanediol instead of DL-alaninol. Method B; Rt: 1.00 min. m/z: 464 (M+H) ⁺ exact mass: 463.1.

Compound 37: (3S)-N-(3,4-difluorophenyl)-3-[(1S)-1-hydroxyethyl]-7-methyl-1,1-dioxo-3, 4-Dihydro-2H-pyrrolo[3,4-b][1,4,5]oxatriazepine-6-carboxamide.

Compound 37 (105.5 mg) was prepared similarly as described for compound 14, using D-threoninol instead of DL-alaninol. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.10 (d, J = 6.4 Hz, 3H), 3.61-3.70 (m, 1H), 3.82 (s, 3H), 3.85-3.99 (m, 2H), 4.74 (d, J = 11.4 Hz, 1H), 4.96 (d, J = 4.6 Hz, 1H), 7.36-7.44 (m, 2H), 7.44-7.50 (m, 2H), 7.87 (ddd, J = 13.2, 7.5, 2.6 Hz, 1H), 9.44 (s, 1H); Method B; Rt: 0.87 min. m/z: 402 (M+H) ⁺ exact mass: 401.1.

Compound 38: (3S)-N-(3,4-difluorophenyl)-7-methyl-1,1-dioxo-3-(3-pyridylmethyl)-3,4- Dihydro-2H-pyrrolo[3,4-b][1,4,5]oxatriazepine-6-carboxamide.

Compound 38 (7.1 mg) was prepared similarly as described for compound 14 using (2S)-2-amino-3-(3-pyridyl)propan-1-ol instead of DL-alaninol. ¹ H NMR (400 MHz, chloroform-d) δppm 2.86-3.10 (m, 2H), 3.94 (s, 3H), 4.13 (br s, 1H), 4.36 (dd, J=13.0, 9.0Hz, 1H), 4.66 (dd, J=12.9, 3.0Hz, 1H), 5.35 (br s, 1H), 7.03 (s, 1H), 7.06-7.16 (m, 2H), 7.27-7.34 (m, 1H), 7.61-7.70 (m, 2H), 8.45 (d, J=1.5Hz, 1H), 8.51 (dd, J=4.8, 1.5Hz, 1H), 8.66 (s, 1 H); Method B; Rt: 0.91 min. m/z: 449 (M+H) ⁺ exact mass: 448.1.

Compound 39: (3*S)-3,7-dimethyl-1,1-dioxo-N-(3,4,5-trifluorophenyl)-2,3,4,5-tetrahydropyridine Pyrro[3,4-f]triazepine-6-carboxamide.

Compound 39 (41 mg) was prepared similarly as described for compound 10, using compound 29 instead of compound 7. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.13 (d, J=6.8 Hz, 3H), 1.34 (q, J=12.2 Hz, 1H), 1.84 (br dd, J=14.0, 6.4 Hz, 1H), 2.78-2.99 (m, 1H), 3.57-3.66 (m, 1H), 3.69 (s, 3H), 7.03 (d, J=9.6 Hz, 1H), 7.44 (s, 1H), 7.54-7.66 (m, 1H), 10.59 (s, 1H); Method B; Rt: 0.91 min. m/z: 386 (MH) ^- exact mass: 387.1.

Compound 40: (3*S)-N-[4-fluoro-3-(trifluoromethyl)phenyl]-3,7-dimethyl-1,1-dioxo-2,3,4,5- Tetrahydropyrrolo[3,4-f]triazepine-6-carboxamide.

Compound 40 (49 mg) was prepared similarly as described for compound 10, using compound 30 instead of compound 7. ¹ H NMR (400MHz, DMSO-d ₆ ) δppm 1.13 (d, J=6.8Hz, 3H), 1.27-1.41 (m, 1H), 1.81-1.88 (m, 1H), 2.80-2.89 (m, 1H), 2.94-3.02 (m, 1H), 3.59-3.67 (m, 1H), 3.69 (s, 3H), 7.02 (d, J=9.6Hz, 1H), 7.43 (s, 1H), 7.51 (t, J=9.8Hz, 1H), 7.91-7.96 (m, 1H), 8.20 (dd, J=6.6, 2.7Hz, 1H), 10.58 (s, 1H); Method B; Rt: 1.01min.m/z: 418(MH) ^- Exact mass: 419.1.

Compound 41: (3*S)-N-(4-fluoro-3-methyl-phenyl)-3,7-dimethyl-1,1-dioxo-2,3,4,5-tetrahydro Pyrrolo[3,4-f]triazepine-6-carboxamide.

Compound 41 (52 mg) was prepared similarly as described for compound 10, using compound 31 instead of compound 7. ¹ H NMR (400MHz, DMSO-d ₆ ) δppm 1.13 (d, J=6.8Hz, 3H), 1.35 (q, J=12.3Hz, 1H), 1.84 (br dd, J=14.0, 6.4Hz, 1H), 2.20-2.24 (m, 3H), 2.78-2.98 (m, 2H), 3.59-3.73 (m, 4H), 7.00 (d, J=9.5Hz, 1H), 7.10 (t, J=9.2Hz, 1H), 7.39 (s, 1H), 7.45-7.52 (m, 1 H), 7.62 (dd, J=7.1, 2.7Hz, 1H), 10.23 (s, 1H); Method B; Rt: 0.92min. m/z: 364 (MH) ^- exact mass: 365.1.

Compound 42: (3*S)-3,7-dimethyl-1,1-dioxo-N-[2-(trifluoromethyl)-4-pyridinyl]-2,3-dihydro Pyrrolo[3,4-f]triazepine-6-carboxamide.

Compound 42 (115 mg) was prepared similarly as described for compound 29 using 4-amino-2-trifluoromethylpyridine instead of 3,4,5-trifluoroaniline. ^1H NMR (400 MHz, DMSO- _d6 ) δ ppm 1.32 (d, J = 7.3 Hz, 3H), 3.74 (s, 3H), 4.22-4.34 (m, 1H), 5.61 (dd, J = 12.6, 2.4 Hz, 1H), 6.49 (dd, J = 12.6, 2.6 Hz, 1H), 7.56-7.63 (m, 2H), 7.89 (dd, J = 5.5, 2.0 Hz, 1H), 8.20 (d, J = 2.0 Hz, 1H), 8.67 (d, J = 5.5 Hz, 1H), 11.21 (br s, 1H); Method B; Rt: 0.86 min. m/z: 401 (M+H) ⁺ exact mass: 400.1.

Compound 43: N-(3,4-difluorophenyl)-7-methyl-3-(1-methylpyrazol-4-yl)-1,1-dioxo-3,4-difluorophenyl Hydrogen-2H-pyrrolo[3,4-b][1,4,5]oxatriazepine-6-carboxamide.

Compound 43 (53.6 mg) was prepared similarly to that described for compound 14, using 2-amino-2-(1-methyl-1h-pyrazol-4-yl)ethan-1-ol instead of DL-alaninol. Ring closure was obtained in DMA after heating at 140° C. overnight, and compound 43 was purified using a heptane to EtOAc: EtOH 3: 1 gradient. ^1H NMR (400 MHz, DMSO- _d6 ) δ ppm 3.81 (s, 3H), 3.84 (s, 3H), 3.98-4.11 (m, 1H), 4.72 (dd, J = 12.5, 2.2 Hz, 1H), 4.86 (td, J = 9.6, 1.9 Hz, 1H), 7.36-7.44 (m, 1H), 7.44-7.51 (m, 2H), 7.53 (s, 1H), 7.72 (s, 1H), 7.82-7.89 (m, 1H), 8.02 (d, J = 9.7 Hz, 1H), 9.46 (s, 1H); Method B; Rt: 0.90 min. m/z: 438 (M+H) ⁺ exact mass: 437.1.

Compound 44: (3S)-N-(3,4-difluorophenyl)-7-fluoro-3-isopropyl-1,1-dioxo-3,4-dihydro-2H-5,1 λ ⁶ ,2-Benzoxitriazepine-6-carboxamide.

Compound 44 (11.5 mg) was prepared similarly as described for compound 12, using L-valinol instead of DL-alaninol. ¹ H NMR (400MHz, DMSO-d ₆ ) δppm 0.94 (dd, J=6.71, 1.65Hz, 6H) 1.80 (dq, J=13.70, 6.80Hz, 1H) 3.43- 3.56 (m, 1H) 3.80 (dd, J = 12.43, 10.01Hz, 1H) 4.55 (dd, J = 12.54, 2.20 Hz, 1H) 7.31 (t, J = 8.69Hz, 1H) 7.35-7.51 (m, 2H) 7.70 (br d, J = 8.58 Hz, 1H) 7.80-7.92 (m, 2H) 10.98 (s, 1H); Method B; Rt: 1.03min.m/z: 413 (MH) ^- Exact mass: 414.1.

Compound 45: (3S)-N-(3-Cyano-4-fluoro-phenyl)-7-fluoro-3-isopropyl-1,1-dioxo - 3,4-dihydro- 2H-5,1λ ⁶ ,2-benzoxetriazepine-6-carboxamide.

Compound 45 (378.5 mg) was prepared similarly as described for compound 44 using 5-amino-2-fluorobenzonitrile instead of 3,4-difluoroaniline. ¹ H NMR (400MHz, DMSO-d ₆ ) δppm 0.94 (dd, J=6.82, 2.20Hz, 6H) 1.80 (dq, J=13.78, 6.78 Hz, 1H) 3.48 (br s, 1H) 3.80 (dd, J = 12.54, 10.12Hz, 1H) 4.56 (dd, J = 12.54, 2.20Hz, 1H) 7.33 (t, J = 8.69Hz, 1H) 7.56 (t, J = 9.13Hz, 1H) 7.70 (br s, 1H) 7.85-7.98 (m, 2H) 8.20 (dd, J=5.72, 2.64Hz, 1H) 11.14 (s, 1H); Method B; Rt: 0.98 min. m/z: 420 (MH) ^- Exact mass: 421.1.

Compound 46: (3R)-7-Fluoro-N-(3-fluoro-4-methyl-phenyl)-3-isopropyl-1,1-dioxo-3,4-dihydro- 2H-5,1λ ⁶ ,2-Benzooxatriazepine-6-carboxamide.

Compound 46 (155.1 mg) was prepared similarly as described for compound 44 using 4-fluoro-3-methylaniline instead of 3,4-difluoroaniline. ¹ H NMR (400MHz, DMSO-d ₆ ) δppm 0.94 (dd, J=6.82, 1.98Hz, 6H) 1.80 (dq, J=13.78, 6.78Hz, 1H) 2.24 (d, J=1.54Hz, 3H) 3.41-3.60 (m, 1H) 3.80 (dd, J=12.32, 9.90Hz, 1H) 4.53 (dd, J=12.54, 2.20Hz, 1H) 7.13 (t, J=9.24Hz, 1H) 7.29 (t, J=8.58Hz, 1H)7.40-7.52 (m, 1H)7.63 (dd, J=6.93, 2.53Hz, 1H)7.68 (br d, J = 7.48 Hz, 1H) 7.87 (dd, J = 8.80, 6.38 Hz, 1H) 10.70 (s, 1H); Method B; Rt: 1.04 min. m/z: 409 (MH) ^- Exact mass: 410.1.

Compound 47: N-(3,4-difluorophenyl)-7-methyl-1,1-dioxo-3-(trifluoromethyl)-2,3,4,5-tetrahydropyridine Pyrro[3,4-f]triazepine-6-carboxamide.

1,1,1-trifluorobut-3-ene-2-ylamine (306 mg, 1.90 mmol) was dissolved in pyridine (5 mL). Methyl 3-bromo-4-chlorosulfonyl-1-methyl-pyrrole-2-carboxylate (500 mg, 1.58 mmol) was added and the mixture was stirred at room temperature for 16 hours. The reaction mixture was filtered and the filtrate was evaporated to dryness. The residue was purified by column chromatography using a gradient of 0 to 50% EtOAc in heptane over 15 column volumes. The product fractions were concentrated in vacuo to produce methyl 3-bromo-1-methyl-4-[1-(trifluoromethyl)allylsulfamoyl]pyrrole-2-carboxylate (385 mg) as a white powder. Method D; Rt: 1.74 min. m/z: 405 (M+H) ⁺ exact mass: 404.0.

Methyl 3-bromo-1-methyl-4-[1-(trifluoromethyl)allylsulfamoyl]pyrrole-2-carboxylate (385 mg), bis(tri-tert-butylphosphine)palladium(0) (211 mg, 0.41 mmol) and trimethylamine (286 μL, 2.07 mmol) were dissolved in DMF (5 mL). The reaction mixture was heated in a microwave oven at 120 ° C for 30 minutes. The volatiles were removed under reduced pressure and the residue was purified by column chromatography using a gradient of 0 to 50% EtOAc in heptane over 15 column volumes. The product fractions were concentrated in vacuo to produce methyl 7-methyl-1,1-dioxo-3-(trifluoromethyl)-2,3-dihydropyrrolo[3,4-f]triazepine-6-carboxylate (152 mg) as a white solid. Method D; Rt: 1.64 min. m/z: 405 (M+H) ⁺ exact mass: 404.0.

Methyl 7-methyl-1,1-dioxo-3-(trifluoromethyl)-2,3-dihydropyrrolo[3,4-f]triazepine-6-carboxylate (152 mg) and Pd/C (10%) (50 mg, 0.047 mmol) were partitioned in MeOH (50 mL). The reaction mixture was placed under a hydrogen atmosphere and stirred for 2 hours. The reaction mixture was filtered and the volatiles were removed under reduced pressure to yield methyl 7-methyl-1,1-dioxo-3-(trifluoromethyl)-2,3,4,5-tetrahydropyrrolo[3,4-f]triazepine-6-carboxylate (153 mg) as a white powder.

Methyl 7-methyl-1,1-dioxo-3-(trifluoromethyl)-2,3,4,5-tetrahydropyrrolo[3,4-f]triazepine-6-carboxylate (153 mg) and 3,4-difluoroaniline (57 μL, 0.56 mmol) were dissolved in THF (10 mL). Lithium bis(trimethylsilyl)amide (1.41 mL, 1 M in THF, 1.41 mmol) was added and the reaction mixture was stirred at room temperature for 4 hours. NH ₄ Cl (saturated, aqueous, 5 mL) was added and the organic layer was removed. The aqueous layer was extracted with DCM (2×5 mL) and the combined organic layers were evaporated to dryness. The residue was purified by preparative HPLC (stationary phase: RP XBridge Prep C18 OBD-10 μm, 30 x 150 mm, mobile phase: 0.25% NH ₄ HCO ₃ solution in water, MeOH) to give compound 47 (73 mg) as a white powder. ^1H NMR (400 MHz, DMSO- _d6 ) δ ppm 1.58-1.69 (m, 1H), 2.11 (br dd, J = 13.8, 6.3 Hz, 1H), 2.84-2.95 (m, 1H), 3.12 (br dd, J = 15.6, 6.2 Hz, 1H), 3.70 (s, 3H), 4.18-4.31 (m, 1H), 7.37-7.50 (m, 2H), 7.54 (s, 1H), 7.79-7.88 (m, 1H), 8.04 (d, J = 10.4 Hz, 1H), 10.54 (s, 1H); Method D; Rt: 1.82 min. m/z: 422 (MH) ^- Exact mass: 423.1.

Compound 48: (3R)-N-(3,4-difluorophenyl)-7-fluoro-3-isopropyl-1,1-dioxo-3,4-dihydro-2H-5,1 λ ⁶ ,2-Benzoxitriazepine-6-carboxamide.

Compound 48 (75.5 mg) was prepared similarly as described for compound 12, using D-valinol instead of DL-alaninol. ^1H NMR (400 MHz, DMSO- _d6 ) δ ppm 0.94 (dd, J = 6.71, 1.87 Hz, 6H) 1.66-1.94 (m, 1H) 3.48 (br t, J = 7.59 Hz, 1H) 3.80 (dd, J = 12.43, 10.01 Hz, 1H) 4.55 (dd, J = 12.54, 2.20 Hz, 1H) 7.23-7.35 (m, 1H) 7.36-7.51 (m, 2H) 7.70 (s, 1H) 7.79-7.94 (m, 2H) 10.97 (s, 1H); Method B; Rt: 1.02 min. m/z: 413 (MH) ^- Exact mass: 414.1.

Compound 49: (3R)-N-(3-cyano-4-fluoro-phenyl)-7-fluoro-3-isopropyl-1,1-dioxo-3,4-dihydro- 2H-5,1λ ⁶ ,2-Benzooxatriazepine-6-carboxamide.

Compound 49 (39.7 mg) was prepared similarly as described for compound 48 using 5-amino-2-fluorobenzonitrile instead of 3,4-difluoroaniline. ¹ H NMR (400MHz, DMSO-d ₆ ) δppm 0.94 (dd, J=6.82, 2.20Hz, 6H) 1.80 (dq, J=13.64, 6.82 Hz, 1H) 3.43-3.54 (m, 1H) 3.81 (dd, J=12.43, 10.01Hz, 1H) 4.56 (dd, J=12.54, 2.20Hz, 1H) 7.32 (t, J=8.58Hz, 1H) 7.56 (t, J=9.13Hz, 1H) 7.71 (br s, 1H) 7.84-8.04 (m, 2H) 8.20 (dd, J=5.61, 2.75Hz, 1H) 11.15 (br s, 1H); Method B; Rt: 0.97 min. m/z: 420 (MH) ^- exact mass: 421.1.

Compound 50: (3*S)-N-(2-bromo-4-pyridinyl)-3,7-dimethyl-1,1-dioxo-2,3-dihydropyrrolo[2 ... [3,4-f]Triazepine-6-carboxamide.

Compound 50 (42 mg) was prepared similarly as described for compound 29 using 4-amino-2-bromopyridine instead of 3,4,5-trifluoroaniline. ^1H NMR (400 MHz, DMSO- _d6 ) δ ppm 1.31 (d, J = 7.5 Hz, 3H), 3.72 (s, 3H), 4.19-4.33 (m, 1H), 5.61 (dd, J = 12.5, 2.4 Hz, 1H), 6.45 (dd, J = 12.8, 2.6 Hz, 1H), 7.55-7.60 (m, 2H), 7.63 (dd, J = 5.6, 1.9 Hz, 1H), 7.96 (d, J = 1.8 Hz, 1H), 8.29 (d, J = 5.6 Hz, 1H), 11.05 (s, 1H); Method D; Rt: 1.52 min. m/z: 411 (M+H) ⁺ exact mass: 410.0.

Compound 51: (3*S)-N-[3-(difluoromethyl)-4-fluoro-phenyl]-3,7-dimethyl-1,1-dioxo-2,3-diol Hydropyrrolo[3,4-f]triazepine-6-carboxamide.

Compound 51 (46 mg) was prepared similarly as described for compound 29 using 3-(difluoromethyl)-4-fluoro-aniline instead of 3,4,5-trifluoroaniline. ¹ H NMR (400MHz, DMSO-d ₆ ) δppm 1.31 (d, J=7.5Hz, 3H), 3.71 (s, 3H), 4.20-4.33 (m, 1 H), 5.57 (dd, J=12.5, 2.4Hz, 1H), 646 (dd, J=12.6, 2.6Hz, 1H), 7.23 (br t, J=54.4Hz, 1H), 7.38 (t, J=9.6Hz, 1H), 7.51-7.58 (m, 2H), 7.77- 7.87 (m, 1H), 8.06 (dd, J=6.3, 2.7Hz, 1H), 10.75 (s, 1H); Method B; Rt: 0.90min.m/z: 398 (MH) ^- Exact mass: 399.1.

Compound 52: (3*S)-N-(3-chloro-2,4-difluoro-phenyl)-3,7-dimethyl-1,1-dioxo-2,3-dihydropyridine Pyrro[3,4-f]triazepine-6-carboxamide.

Compound 52 (40 mg) was prepared similarly as described for compound 29 using 3-chloro-2,4-difluoroaniline instead of 3,4,5-trifluoroaniline. ^1H NMR (400 MHz, DMSO- _d6 ) δ ppm 1.31 (d, J = 7.5 Hz, 3H), 3.73 (s, 3H), 4.20-4.33 (m, 1H), 5.60 (dd, J = 12.5, 2.4 Hz, 1H), 6.58 (dd, J = 12.7, 2.5 Hz, 1H), 7.36 (td, J = 9.0, 2.0 Hz, 1H), 7.55 (s, 1H), 7.57 (d, J = 9.3 Hz, 1H), 7.64 (td, J = 8.7, 5.8 Hz, 1H), 10.45 (br s, 1H); Method B; Rt: 0.93 min. m/z: 400 (MH) ^- Exact mass: 401.0.

Compound 53: (3*S)-3,7-dimethyl-1,1-dioxo-N-[2-(trifluoromethyl)-4-pyridinyl]-2,3,4,5- Tetrahydropyrrolo[3,4-f]triazepine-6-carboxamide.

To a solution of methyl 3-bromo-1-methyl-4-[[(1*S)-1-methylallyl]sulfamoyl]pyrrole-2-carboxylate (3.5 g, 10 mmol) in DMA (200 mL) in a nitrogen-purged pressure tube was added Hunin's base (1.89 mL, 0.75 g/mL, 11.0 mmol) and bis(tri-tert-butylphosphine)palladium(0) (0.76 g, 1.49 mmol). The reaction mixture was heated at 140° C. for 10 minutes. The reaction mixture was poured into HCl (aqueous, 0.5 M, 150 mL). The resulting suspension was extracted with ethyl acetate (3×100 mL). The combined organic layers were dried (Na ₂ SO ₄ ), concentrated, and the residue (8 g) was purified using silica gel column chromatography (ethyl acetate in heptane from 0 to 40%). The desired fractions were combined and concentrated. This was purified by preparative HPLC (stationary phase: RP XBridge Prep C18 OBD-10 μm, 30 x 150 mm, mobile phase: 0.25% NH ₄ HCO ₃ solution in water, MeOH) to yield methyl (3*S)-3,7-dimethyl-1,1-dioxo-2,3-dihydropyrrolo[3,4-f]triazepine-6-carboxylate (640 mg) as a white powder. Method B; Rt: 0.74 min. m/z: 269 (MH) ^- exact mass: 270.1.

Methyl (3*S)-3,7-dimethyl-1,1-dioxo-2,3-dihydropyrrolo[3,4-f]triazepine-6-carboxylate (400 mg, 1.48 mmol) was dissolved in MeOH (40 mL). Pd/C (10%) (157 mg, 0.15 mmol) was added under a nitrogen atmosphere. The reaction mixture was hydrogenated for 30 minutes. The reaction mixture was filtered through Celite. The filtrate was evaporated to dryness to give methyl (3S)-3,7-dimethyl-1,1-dioxo-2,3,4,5-tetrahydropyrrolo[3,4-f]triazepine-6-carboxylate (360 mg) as a white powder.

To a solution of methyl (3S)-3,7-dimethyl-1,1-dioxo-2,3,4,5-tetrahydropyrrolo[3,4-f]triazepine-6-carboxylate (72 mg) and 4-amino-2-trifluoromethylpyridine (51 mg, 0.32 mmol) in THF (5 mL) was added lithium bis(trimethylsilyl)amide (1.06 mL, 1 M in THF, 1.06 mmol) and the reaction mixture was stirred at room temperature for 1 hour. NH ₄ Cl (saturated, aqueous, 5 mL) was added and the organic layer was separated. The aqueous layer was extracted with DCM (2×5 mL) and the combined organic layers were evaporated to dryness. The residue was purified by preparative HPLC (stationary phase: RP XBridge Prep C18 OBD-10 μm, 30×150 mm, mobile phase: 0.25% NH ₄ HCO ₃ solution in water, ACN) to give compound 53 (60 mg) as a white powder. ¹ H NMR (400MHz, DMSO-d ₆ ) δppm 1.13 (d, J=6.8Hz, 3H), 1.29-1.42 (m, 1H), 1.79-1.89 (m, 1H), 2.80-2.91 (m, 1H), 2.94-3.05 (m, 1H), 3.56-3.67 (m, 1H), 3.71 (s, 3H), 7.04 (d, J=9.6Hz, 1H), 7.47 (s, 1H), 7.86 (dd, J=5.6, 2.0 Hz, 1H), 8.19 (d, J=2.0Hz, 1H), 8.64 (d, J=5.5Hz, 1H), 10.94 (br s, 1 H); Method D; Rt: 1.63 min. m/z: 403 (M+H) ⁺ exact mass: 402.1.

Compound 54: (3*S)-N-(3-chloro-2,4-difluoro-phenyl)-3,7-dimethyl-1,1-dioxo-2,3,4,5-tetrakis Hydropyrrolo[3,4-f]triazepine-6-carboxamide.

Compound 54 (24 mg) was prepared similarly as described for compound 53 using 3-chloro-2,4-difluoroaniline instead of 4-nitro-2-trifluoromethylpyridine. ¹ H NMR (400MHz, DMSO-d ₆ ) δppm 1.14 (d, J=6.8Hz, 3H), 1.38 (q, J=12.4Hz, 1H), 1.87 (br dd, J＝14.1, 6.6Hz, 1H), 2.76-2.89 (m, 1H), 3.12 (brdd, J＝15.5, 6.6 Hz, 1H), 3.56-3.68 (m, 1H), 3.69 (s, 3H), 7.02 (d, J=9.6Hz, 1H), 7.35 (td, J=9.0, 2.0Hz, 1H), 7.42 (s, 1H), 7.65 (td, J=8.8, 5.8Hz, 1H), 10.18 (br s, 1H); Method B; Rt: 0.94 min. m/z: 402 (MH) ^- exact mass: 403.1.

Compound 55: (3*S)-N-[3-(difluoromethyl)-4-fluoro-phenyl]-3,7-dimethyl-1,1-dioxo-2,3,4, 5-Tetrahydropyrrolo[3,4-f]triazepine-6-carboxamide.

Compound 55 (55 mg) was prepared similarly as described for compound 53 using 3-(difluoromethyl)-4-fluoro-aniline instead of 4-amino-2-trifluoromethylpyridine. ¹ H NMR (400 MHz, DMSO-d ₆ ) δppm 1.13 (d, J=6.8Hz, 3H), 1.36 (q, J=12.3Hz, 1H), 1.85 (br dd, J=13.9, 6.4Hz, 1H), 2.76-2.90 (m, 1H), 2.92-3.02 (m, 1 H), 3.57-3.74 (m, 4H), 7.01 (d, J=9.6Hz, 1H), 7.22 (t, J=54.4Hz, 1H), 7.33-7.40 (m, 1H), 7.41 (s, 1H), 7.74-7.86 (m, 1H), 8.06 (dd, J=6.4, 2.7 Hz, 1H), 10.48 (s, 1H); Method B; Rt: 0.91 min. m/z: 400 (MH) ^- Exact mass: 401.1.

Compound 56: (3*S)-N-(3-cyano-4-fluoro-phenyl)-3,7-dimethyl-1,1-dioxo-2,3,4,5-tetrahydro Pyrrolo[3,4-f]triazepine-6-carboxamide.

Compound 56 (53 mg) was prepared similarly as described for compound 53 using 5-amino-2-fluorobenzonitrile instead of 4-amino-2-trifluoromethylpyridine. ¹ H NMR (400MHz, DMSO-d ₆ ) δppm 1.13 (d, J=6.8Hz, 3H), 1.35 (br q, J=12.5Hz, 1H), 1.84 (br dd, J=14.1, 6.4Hz, 1H), 2.78-2.89 (m, 1H), 2.92-3.02 (m, 1 H), 3.56-3.66 (m, 1H), 3.69 (s, 3H), 7.02 (d, J=9.5Hz, 1H), 7.43 (s, 1H), 7.53 (t, J=9.1Hz, 1H), 7.95 (ddd, J=9.2, 4.9, 2.7Hz, 1H), 8.19 (dd, J = 5.8, 2.7 Hz, 1H), 10.59 (s, 1H); Method B; Rt: 0.84 min. m/z: 375 (MH) ^- Exact mass: 376.1.

Compound 57: (3*S)-N-(2-bromo-4-pyridinyl)-3,7-dimethyl-1,1-dioxo-2,3,4,5-tetrahydropyrrole 1,3-[3,4-f]triazepine-6-carboxamide.

Compound 57 (25 mg) was prepared similarly as described for compound 53 using 4-amino-2-bromopyridine instead of 4-amino-2-trifluoromethylpyridine. ¹ H NMR (400MHz, DMSO-d ₆ ) δppm 1.13 (d, J=6.8Hz, 3H), 1.35 (q, J=12.3Hz, 1H), 1.79- 1.91 (m, 1H), 2.79-2.89 (m, 1H), 2.91-3.00 (m, 1H), 3.55-3.67 (m, 1 H), 3.70 (s, 3H), 7.04 (d, J=9.6Hz, 1H), 7.46 (s, 1H), 7.61 (dd, J=5.6, 1.9Hz, 1H), 7.95 (d, J=1.8Hz, 1H), 8.27 (d, J=5.6Hz, 1H), 10.78 (s, 1 H); Method B; Rt: 0.84 min. m/z: 411 (MH) ^- exact mass: 412.0.

Compound 58: 7-methyl-1,1-dioxo-3-(trifluoromethyl)-N-[2-(trifluoromethyl)-4-pyridinyl]-2,3- Dihydropyrrolo[3,4-f]triazepine-6-carboxamide.

Methyl 7-methyl-1,1-dioxo-3-(trifluoromethyl)-2,3-dihydropyrrolo[3,4-f]triazepine-6-carboxylate (200 mg) and 4-amino-2-trifluoromethylpyridine (102 mg, 0.62 mmol) were dissolved in THF (4 mL). Lithium bis(trimethylsilyl)amide (1.85 mL, 1 M in THF, 1.85 mmol) was added dropwise to the reaction mixture and stirred at room temperature for 2 hours. The reaction was quenched with _NH4Cl (saturated, aqueous, 5 mL) and the organic layer was separated, dried ( _MgSO4 ), filtered, and concentrated in vacuo. The residue was purified by preparative HPLC (stationary phase: RP _XBridge Prep C18 OBD-10 μm, 30 x 150 mm, mobile phase: _0.25 % _NH4HCO3 solution in water, ACN) to yield Compound 58 (10 mg). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 3.78 (s, 3H), 4.89 (br dd, J=11.1, 8.2 Hz, 1H), 5.82 (dd, J=12.2, 3.0 Hz, 1H), 6.86 (dd, J=12.2, 2.7 Hz, 1H), 7.79 (s, 1H), 7.89 (dd, J=5.5, 2.0 Hz, 1H), 8.20 (d, J=1.9 Hz, 1H), 8.67 (d, J=5.2 Hz, 1H), 8.69 (s, 1H), 11.27-11.32 (m, 1H); Method D; Rt: 1.76 min. m/z: 455 (M+H) ⁺ exact mass: 454.1.

Compound 59: 7-methyl-1,1-dioxo-3-(trifluoromethyl)-N-[2-(trifluoromethyl)-4-pyridinyl]-2,3- 4,5-Tetrahydropyrrolo[3,4-f]triazepine-6-carboxamide.

Compound 59 (118 mg) was prepared similarly as described for compound 47 using 4-amino-2-trifluoromethylpyridine instead of 3,4-difluoroaniline. ¹ H NMR (400MHz, DMSO-d ₆ ) δppm 1.64 (q, J=12.2Hz, 1H), 2.06-2.15 (m, 1H), 2.87- 2.98 (m, 1H), 3.13-3.29 (m, 1H), 3.68-3.80 (m, 3H), 4.20-4.32 (m, 1 H), 7.61 (s, 1H), 7.87 (dd, J=5.5, 2.0Hz, 1H), 8.07 (br d, J=9.9Hz, 1H), 8.19 (d, J=2.0Hz, 1H), 8.66 (d, J=5.5Hz, 1H), 11.03 (s, 1H); Method D; Rt: 1.75 min. m/z: 457 (M+H) ⁺ exact mass: 456.1. The racemic mixture was separated into enantiomers 59a and 59b by preparative SFC (stationary phase: Chiralpak Diacel AD 20x250 mm, mobile phase: _CO2 , EtOH with 0.4% _iPrNH2 ). Method H; Rt: 59a: 1.65 min, 59b: 2.36 min.

Compound 60: N-(3-cyano-4-fluoro-phenyl)-7-methyl-1,1-dioxo-3-(trifluoromethyl)-2,3,4,5-tetrakis Hydropyrrolo[3,4-f]triazepine-6-carboxamide.

Compound 60 (139 mg) was prepared similarly as described for compound 47 using 5-amino-2-fluorobenzonitrile instead of 3,4-difluoroaniline. ¹ H NMR (400MHz, DMSO-d ₆ ) δppm 1.59-1.70 (m, 1H), 2.06-2.16 (m, 1H), 2.84-2.96 (m, 1H), 3.10-3.21 (m, 1H), 3.66-3.78 (m, 3H), 4.19-4.32 (m, 1H), 7.51-7.58 (m, 2H), 7.96 (ddd, J=9.2, 4.8, 2.6Hz, 1H), 8.05 (d, J=10.3 Hz, 1H), 8.19 (dd, J=5.8, 2.7Hz, 1H), 10.61-10.71 (m, 1H); Method D; Rt: 1.73min.m/z: 429 (MH) ^- Exact mass: 430.1. The racemic mixture was separated into enantiomers 60a and 60b by preparative SFC (stationary phase: Chiralpak Diacel AD 20x250 mm, mobile phase: CO ₂ , EtOH with 0.4% iPrNH ₂ ). Method I; Rt: 60a: 1.16 min, 60b: 1.61 min.

Compound 61: (3S)-N-(3,4-difluorophenyl)-7-methyl-1,1-dioxo-3-(trifluoromethyl)-3,4-dihydro- 2H-Pyrrolo[3,4-b][1,4,5]oxatriazepine-6-carboxamide.

Ethyl 4-chlorosulfonyl-3-fluoro-1-methyl-pyrrole-2-carboxylate (250 mg) and (2S)-2-amino-3,3,3-trifluoropropan-1-ol hydrochloride (153 mg, 0.93 mmol) were dissolved in pyridine (2 mL) and stirred at room temperature overnight. The volatiles were removed under reduced pressure and the residue was purified on silica using a heptane to EtOAc gradient to yield ethyl 3-fluoro-1-methyl-4-[[(1S)-2,2,2-trifluoro-1-(hydroxymethyl)ethyl]sulfamoyl]pyrrole-2-carboxylate (254 mg).

Ethyl 3-fluoro-1-methyl-4-[[(1S)-2,2,2-trifluoro-1-(hydroxymethyl)ethyl]sulfamoyl]pyrrole-2-carboxylate (254 mg) and 3,4-difluoroaniline (0.071 mL, 0.7 mmol) were dissolved in THF (5 mL). Lithium bis(trimethylsilyl)amide (2.8 mL, 1 M in THF, 2.8 mmol) was added and the reaction mixture was stirred at room temperature overnight. NH ₄ Cl (saturated, aqueous, 50 mL) was added and the organic layer was removed. The aqueous layer was extracted with DCM (2×5 mL) and the combined organic layers were evaporated to dryness. The residue was purified on silica using a heptane to EtOAc:EtOH 3:1 gradient to yield N-(3,4-difluorophenyl)-3-fluoro-1-methyl-4-[[(1S)-2,2,2-trifluoro-1-(hydroxymethyl)ethyl]sulfamoyl]pyrrole-2-carboxamide (198 mg). Method B; Rt: 0.91 min. m/z: 446 (M+H) ⁺ exact mass: 445.1.

N-(3,4-Difluorophenyl)-3-fluoro-1-methyl-4-[[(1S)-2,2,2-trifluoro-1-(hydroxymethyl)ethyl]sulfamoyl]pyrrole-2-carboxamide (198 mg) and cesium fluoride (173 mg, 1.14 mmol) were dissolved in DMF (5 mL) and heated at 100° C. overnight. The reaction mixture was purified by preparative HPLC (stationary phase: RP XBridge Prep C18 OBD-10 μm, 30×150 mm, mobile phase: 0.25% NH ₄ HCO ₃ solution in water, ACN) to give Compound 61 as a white powder. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 3.83 (s, 3H), 4.29 (dd, J=12.7, 9.4 Hz, 1H), 4.49-4.62 (m, 1H), 4.91 (dd, J=13.0, 2.0 Hz, 1H), 7.37-7.46 (m, 1H), 7.46-7.52 (m, 1H), 7.58 (s, 1H), 7.86 (ddd, J=13.2, 7.5, 2.4 Hz, 1H), 8.75 (br s, 1H), 9.47 (s, 1H); Method B; Rt: 0.99 min. m/z: 426 (M+H) ⁺ exact mass: 425.1.

Compound 62: (3R)-N-(3,4-difluorophenyl)-3-[(1R)-1-methoxyethyl]-7-methyl-1,1-dioxo- 3,4-Dihydro-2H-pyrrolo[3,4-b][1,4,5]oxatriazepine-6-carboxamide.

Ethyl 4-chlorosulfonyl-3-fluoro-1-methyl-pyrrole-2-carboxylate (250 mg), O-methyl-L-threonine (119 mg, 0.89 mmol) and Hunin's base (0.46 mL, 2.68 mmol) were dissolved in DCM (5 mL) and stirred at room temperature overnight. The reaction mixture was directly loaded onto a silica cartridge and a gradient was applied from heptane to EtOAc:EtOH:AcOH 3:1:0.1 to yield (2S,3R)-2-[(5-ethoxycarbonyl-4-fluoro-1-methyl-pyrrol-3-yl)sulfonylamino]-3-methoxy-butanoic acid (310 mg) as an off-white powder.

(2S,3R)-2-[(5-Ethoxycarbonyl-4-fluoro-1-methyl-pyrrol-3-yl)sulfonylamino]-3-methoxy-butanoic acid (310 mg) and 3,4-difluoroaniline (86 μL, 0.85 mmol) were dissolved in THF (5 mL). Lithium bis(trimethylsilyl)amide (4.23 mL, 1 M in THF, 4.23 mmol) was added and the reaction mixture was stirred at room temperature for 2 hours. NH ₄ Cl (saturated, aqueous, 50 mL) was added and the organic layer was removed. The aqueous layer was extracted with DCM (2×5 mL) and the combined organic layers were evaporated to dryness. The residue was purified on silica using a gradient from heptane to EtOAc:EtOH:AcOH 3:1:0.1 to yield (2S,3R)-2-[[5-[(3,4-difluorophenyl)carbamoyl]-4-fluoro-1-methyl-pyrrol-3-yl]sulfonylamino]-3-methoxy-butanoic acid (324 mg) as an off-white powder.

(2S,3R)-2-[[5-[(3,4-difluorophenyl)carbamoyl]-4-fluoro-1-methyl-pyrrol-3-yl]sulfonylamino]-3-methoxy-butanoic acid was dissolved in THF (10 mL) and lithium aluminum hydride solution (1.44 mL, 1 M in THF, 1.44 mmol) was added dropwise, and the reaction mixture was stirred at room temperature overnight. Sodium sulfate decahydrate (348 mg, 1.08 mmol) was added followed _{by Na2SO4} . The reaction mixture was filtered and evaporated to dryness. The residue was purified using a heptane to EtOAc:EtOH 3:1 gradient to yield N-(3,4-difluorophenyl)-3-fluoro-4-[[(1R,2R)-1-(hydroxymethyl)-2-methoxy-propyl]sulfamoyl]-1-methyl-pyrrole-2-carboxamide (50 mg).

N-(3,4-Difluorophenyl)-3-fluoro-4-[[(1R,2R)-1-(hydroxymethyl)-2-methoxy-propyl]sulfamoyl]-1-methyl-pyrrole-2-carboxamide (50 mg) was dissolved in DMF (5 mL). Cesium fluoride (70 mg, 0.46 mmol) was added and the reaction mixture was heated at 100° C. overnight. The reaction mixture was directly loaded onto a silica cartridge and a gradient from heptane to EtOAc was used to produce compound 62 (23.9 mg) as an off-white powder. ¹ H NMR (400MHz, DMSO-d ₆ ) δppm 1.13 (d, J=6.4Hz, 3H), 3.28 (s, 3H), 3.55-3.65 (m, 1H), 3.77 (br dd, J=7.9, 3.3Hz, 1H), 3.82 (s, 3H), 4.00 (dd, J=12.5, 9.0Hz, 1H), 4.70 (dd, J=12.7, 1.2Hz, 1H), 7.36-7.44 (m, 1H), 7.44-7.51 (m, 2H), 7.51-7.62 (m, 1H), 7.86 (ddd, J=13.3, 7.5, 2.5Hz, 1 H), 9.42 (s, 1H); Method B; Rt: 0.99 min. m/z: 416 (M+H) ⁺ exact mass: 415.1.

Compound 63: (3S)-N-(3,4-difluorophenyl)-3-[(S)-hydroxy(phenyl)methyl]-7-methyl-1,1-difluorophenyl Oxy-3,4-dihydro-2H-pyrrolo[3,4-b][1,4,5]oxatriazepine-6-carboxamide.

Compound 63 (32.7 mg) was prepared similarly to that described for compound 14, using (1S,2S)-(+)-2-amino-1-phenyl-1,3-propanediol instead of DL-alaninol. Ring closure was achieved in DMF after heating at 100° C. overnight, and compound 63 was purified by preparative HPLC (stationary phase: RP XBridge Prep C18 OBD-10 μm, 30×150 mm, mobile phase: 0.25% NH ₄ HCO ₃ solution in water, ACN). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 3.80 (s, 3H), 3.85-3.96 (m, 1H), 4.01 (dd, J=12.4, 9.1 Hz, 1H), 4.72 (br d, J=11.9 Hz, 1H), 4.86 (t, J=4.3 Hz, 1H), 5.67 (d, J=4.6 Hz, 1H), 7.25-7.31 (m, 1H), 7.31-7.48 (m, 8H), 7.79-7.90 (m, 1H), 9.44 (s, 1H); Method B; Rt: 0.98 min. m/z: 462 (MH) ^- Exact mass: 463.1.

Compound 64: (3R)-N-[3-(Difluoromethyl)-4-fluoro-phenyl]-3-[(1S)-1-hydroxyethyl]-7-methyl- 1,1-Dioxo-3,4-dihydro-2H-pyrrolo[3,4-b][1,4,5]oxatriazepine-6-carboxamide.

Compound 64 (124.8 mg) was prepared similarly as described for compound 35, using 3-(difluoromethyl)-4-fluoro-aniline instead of 3,4-difluoroaniline and heating at 100°C overnight. ¹ H NMR (400MHz, DMSO-d ₆ ) δppm 1.22 (d, J=6.2Hz, 3H), 3.35-3.46 (m, 1H), 3.55-3.67 (m, 1H), 3.83 (s, 3H), 3.99 (dd, J=12.8, 9.0Hz, 1H), 4.89 (dd, J=12.8, 1.8Hz, 1H), 5.05 (br s, 1H), 7.21 (t, J=54.4Hz, 1H), 7.35 (t, J=9.5Hz, 1H), 7.47 (s, 1H), 7.61 (br s, 1H), 7.82 (dt, J=8.1, 4.1 Hz, 1H), 8.04 (dd, J=6.3, 2.5 Hz, 1H), 9.41-9.51 (m, 1H); Method B; Rt: 0.87 min. m/z: 432 (MH) ^- Exact mass: 433.1.

Compound 65: (3R)-N-(3-cyano-4-fluoro-phenyl)-3-[(1S)-1-hydroxyethyl]-7-methyl-1,1-diol Oxy-3,4-dihydro-2H-pyrrolo[3,4-b][1,4,5]oxatriazepine-6-carboxamide.

Compound 65 (29.2 mg) was prepared similarly as described for compound 64 using 5-amino-2-fluorobenzonitrile instead of 3-(difluoromethyl)-4-fluoro-aniline. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.21 (d, J=6.2Hz, 3H), 3.41 (br t, J=8.0Hz, 1H), 3.61 (br s, 1H), 3.83 (s, 3H), 3.97 (dd, J=12.9, 9.1Hz, 1H), 4.88-4.96 (m, 1H), 5.06 (br s, 1H), 7.49 (s, 1H), 7.51 (t, J=9.2Hz, 1H), 7.64 (br s, 1H), 8.05 (ddd, J=9.2, 4.9, 2.9Hz, 1H), 8.20 (dd, J=5.7, 2.6Hz, 1H), 9.51 (s, 1H); Method B; Rt: 0.81 min. m/z: 407 (MH) ^- Exact mass: 408.1.

Compound 66: (3R)-N-(2-bromo-4-pyridinyl)-3-[(1S)-1-hydroxyethyl]-7-methyl-1,1-dioxo- 3,4-Dihydro-2H-pyrrolo[3,4-b][1,4,5]oxatriazepine-6-carboxamide.

Compound 66 (82.9 mg) was prepared similarly as described for compound 64 using 4-amino-2-bromopyridine instead of 3-(difluoromethyl)-4-fluoro-aniline. ¹ H NMR (400MHz, DMSO-d ₆ ) δppm 1.21 (d, J=6.2Hz, 3H), 3.34-3.46 (m, 1H), 3.56-3.66 (m, 1H), 3.83 (s, 3H), 4.01 (dd, J=12.8, 9.0Hz, 1H), 4.92 (dd, J=12.7, 1.9Hz, 1H), 5.07 (d, J=5.5Hz, 1H), 7.54 (s, 1H), 7.61-7.70 (m, 1H), 7.72 (dd, J=5.6, 1.9Hz, 1H), 8.02 (d, J=1.8Hz, 1H), 8.24 (d, J=5.5Hz, 1H), 9.65 (br s, 1H); Method B; Rt: 0.75 min. m/z: 443 (MH) ^- exact mass: 444.0.

Compound 67: N-(3,4-difluorophenyl)-3,7-dimethyl-1,1-dioxo-2,3,4,5-tetrahydropyrrolo[3,4- f] [1,2,5]thiadiazepine-6-carboxamide.

Carbamic acid, n-(2-aminopropyl)-, 1,1-dimethylethyl ester (850 mg, 4.64 mmol) was dissolved in DCM (20 mL). Hunin's base (1.92 mL, 11.1 mmol) was added and then ethyl 4-chlorosulfonyl-3-fluoro-1-methyl-pyrrole-2-carboxylate (1 g) was added. The mixture was stirred at room temperature for 2 hours. The mixture was washed with water and the organic layer was separated, dried (MgSO ₄ ), filtered and concentrated in vacuo. The residue was purified by column chromatography using a gradient of 0 to 50% EtOAc in heptane over 15 column volumes. The product fractions were concentrated in vacuo to produce ethyl 4-[[2-(tert-butoxycarbonylamino)-1-methyl-ethyl]sulfamoyl]-3-fluoro-1-methyl-pyrrole-2-carboxylate (1.3 g) as a white powder.

Ethyl 4-[[2-(tert-butoxycarbonylamino)-1-methyl-ethyl]sulfamoyl]-3-fluoro-1-methyl-pyrrole-2-carboxylate (1.3 g) was dissolved in 1,4-dioxane (15 mL). HCl (8 mL, 4 M in dioxane, 31.9 mmol) was added and the mixture was stirred at room temperature for 16 hours. The precipitated product was filtered off and dried under vacuum to yield ethyl 4-[(2-amino-1-methyl-ethyl)sulfamoyl]-3-fluoro-1-methyl-pyrrole-2-carboxylate hydrochloride (1 g) as a white solid. Method B; Rt: 0.50 min. m/z: 208 (M+H) ⁺ exact mass: 307.1.

Ethyl 4-[(2-amino-1-methyl-ethyl)sulfamoyl]-3-fluoro-1-methyl-pyrrole-2-carboxylate hydrochloride (539 mg) and 3,4-difluoroaniline (0.19 mL, 1.88 mmol) were dissolved in THF (20 mL). Lithium bis(trimethylsilyl)amide (7.8 mL, (1 M in THF), 7.8 mmol) was added dropwise to the reaction mixture. The mixture was stirred at room temperature for 1 hour. The mixture was quenched with _NH4Cl (saturated, aqueous, 15 mL). The reaction mixture was diluted with 2-MeTHF and the organic layer was separated, dried ( _MgSO4 ), filtered, and concentrated in vacuo. The residue was triturated with DIPE, filtered off and dried under vacuum to yield 4-[(2-amino-1-methyl-ethyl)sulfamoyl]-N-(3,4-difluorophenyl)-3-fluoro-1-methyl-pyrrole-2-carboxamide (500 mg) as a light brown solid.

A microwave vial was filled with 4-[(2-amino-1-methyl-ethyl)sulfamoyl]-N-(3,4-difluorophenyl)-3-fluoro-1-methyl-pyrrole-2-carboxamide (200 mg), water (15 mL) and 1,4-dioxane (3 mL). The vial was capped and the mixture was irradiated at 150° C. for 6 hours. The mixture was neutralized with HCl (aqueous, 1 M). The mixture was extracted with DCM and the organic phase was separated, dried (MgSO 4 ), filtered and concentrated in vacuo. The residue was purified by preparative HPLC (stationary phase: RP XBridge Prep C18 OBD-10 μm, 30×150 mm, mobile phase: 0.25% NH ₄ HCO ₃ solution in water, MeOH) to give compound 67 (16 mg). ¹ H NMR (400MHz, DMSO-d ₆ ) δppm 1.12 (d, J=6.9Hz, 3H), 2.80 (dd, J=14.1, 8.5Hz, 1H), 3.39 (dd, J=13.7, 1.6Hz, 1H), 3.48-3.60(m, 1H), 3.78(s, 3H), 5.45(br s, 1H), 7.26- 7.31(m, 1H), 7.31-7.35(m, 1H), 7.35(s, 1H), 7.36-7.43(m, 1H), 7.78 (ddd, J=13.4, 7.4, 2.2Hz, 1H), 10.45 (br s, 1H); Method B; Rt: 0.91 min. m/z: 369 (MH) ^- exact mass: 370.1.

Compound 68: N-(3,4-difluorophenyl)-4-hydroxy-7-methyl-1,1-dioxo-2,3,4,5-tetrahydropyrrolo[3,4-d]- ... [3,4-f]Triazepine-6-carboxamide.

1-Pentene-4-yne (6.2 g) and ethyl isocyanoacetate (35.3 g, 297 mmol) dissolved in dioxane (100 mL) were added dropwise to a suspension of silver carbonate (3.88 g, 14.1 mmol) in dioxane (200 mL) between 80° C. and 90° C. over 45 minutes. The reaction mixture was stirred at 80° C. for 2 hours. The reaction mixture was filtered and concentrated. The residue was subjected to column chromatography using a gradient from 10% to 100% EtOAc in heptane over 10 column volumes to produce ethyl 3-allyl-1H-pyrrole-2-carboxylate (15.7 g) as an oil. ^1H NMR (400 MHz, DMSO- _d6 ) δ ppm 1.28 (t, J = 7.2 Hz, 3H), 3.48 (d, J = 6.6 Hz, 2H), 4.22 (q, J = 7.2 Hz, 2H), 4.93-4.98 (m, 1H), 4.98-5.06 (m, 1H), 5.93 (ddt, J = 16.9, 10.1, 6.6, 6.6 Hz, 1H), 6.01 (t, J = 2.4 Hz, 1H), 6.88 (t, J = 2.9 Hz, 1H), 11.51 (br s, 1H); Method D; Rt: 1.83 min. m/z: 180 (M+H) ⁺ exact mass: 179.1.

Ethyl 3-allyl-1H-pyrrole-2-formate (15.7g) and methyl iodide (14.3g, 100mmol) are dissolved in DMF (150mL) and stirred in ice bath.In 10 minutes, add NaH (4.37g, 60% is dispersed in mineral oil, 109mmol) in batches and this reaction mixture is stirred 1 hour.Add the NaH (2.27g of other amount, 60% is dispersed in mineral oil, 56.8mmol) followed by methyl iodide (7.19g, 50.6mmol) in batches, and this reaction mixture is stirred 1 hour in ice bath.This reaction mixture is quenched with ethanol (10mL) and diluted with water (500mL).This mixture is extracted with EtOAc (3X200mL).By the organic layer drying (MgSO ₄ ) that merges, filter and concentrate. The residue was subjected to column chromatography using a gradient from 0 to 100% EtOAc in heptane over 10 column volumes to yield ethyl 3-allyl-1-methyl-pyrrole-2-carboxylate (13.2 g) as a light yellow oil. ^1H NMR (400 MHz, DMSO- _d6 ) δ ppm 1.28 (t, J = 7.2 Hz, 3H), 3.45 (d, J = 6.6 Hz, 2H), 3.80 (s, 3H), 4.21 (q, J = 7.1 Hz, 2H), 4.93-5.04 (m, 2H), 5.86-5.97 (m, 2H), 6.97 (d, J = 2.4 Hz, 1H); Method D; Rt: 2.07 min. m/z: 194 (M+H) ⁺ exact mass: 193.1.

Osmium tetroxide (2.43 g, 2.5% in tert-butanol, 0.239 mmol) is added to ethyl 3-allyl-1-methyl-pyrrole-2-carboxylate (1156 mg, 5.982 mmol) in ACN (50 mL) and stirred for 10 minutes. Water (10 mL) is added followed by benzyloxycarbonylamino 4-chlorobenzoate (1.83 g, 5.98 mmol). The reaction mixture is stirred for 2 hours and then quenched with K ₂ S ₂ O ₅ (aqueous, saturated, 10 mL), diluted with water (100 mL) and extracted with EtOAc (2×100 mL). The combined organic layers are washed with saturated NaHCO ₃ solution, dried (MgSO ₄ ), filtered and concentrated. The residue was subjected to column chromatography using a gradient from 10% to 100% EtOAc in heptane over 10 column volumes to yield ethyl 3-[3-(benzyloxycarbonylamino)-2-hydroxy-propyl]-1-methyl-pyrrole-2-carboxylate (1.25 g) as a clear oil. ¹ H NMR (400MHz, DMSO-d ₆ ) δppm 1.27 (t, J=7.2Hz, 3H), 2.67 (dd, J=14.0, 7.2Hz, 1H), 2.81-2.96 (m, 2H), 3.00- 3.08 (m, 1H), 3.60-3.75 (m, 1H), 3.78 (s, 3H), 4.19 (q, J=7.0Hz, 2H), 4.57 (d, J=5.5Hz, 1H), 5.00 (s, 2H), 6.01 (d, J=2.4Hz, 1H), 6.94 (d, J=2.4Hz, 1H), 7.06 (brt, J=5.6Hz, 1H), 7.28-7.39 (m, 5H); Method D; Rt: 1.76 min. m/z: 361 (M+H) ⁺ exact mass: 360.1.

Ethyl 3-[3-(benzyloxycarbonylamino)-2-hydroxy-propyl]-1-methyl-pyrrole-2-carboxylate (920 mg) was dissolved in EtOH (100 mL). Pd/C (10%) (100 mg, 0.094 mmol) was added under a nitrogen atmosphere. The reaction mixture was hydrogenated for 3 hours. The reaction mixture was filtered through Celite. The filtrate was evaporated to dryness to give ethyl 3-(3-amino-2-hydroxy-propyl)-1-methyl-pyrrole-2-carboxylate (549 mg) as an oil. Method D; Rt: 1.00 min. m/z: 227 (M+H) ⁺ exact mass: 226.1.

In an ice bath, chlorosulfonic acid (2.06 g, 17.7 mmol) dissolved in dichloromethane (10 mL) was added to ethyl 3-(3-amino-2-hydroxy-propyl)-1-methyl-pyrrole-2-carboxylate (500 mg) in DCM (25 mL) and stirred for 1 hour. ACN (150 mL) was added and the reaction mixture was stirred for 1 hour. Na ₂ CO ₃ (2.58 g, 24.3 mmol) was added and the reaction mixture was stirred for 1 hour. Na ₂ CO ₃ (2.58 g, 24.3 mmol) was added and the reaction mixture was stirred for another 2 hours. 5 g of Na ₂ CO ₃ was added and the reaction mixture was stirred over the weekend. The reaction mixture was filtered and concentrated. The residue was dissolved in DMF (5 mL), filtered and subjected to column chromatography as is using a gradient from 10% to 100% EtOAc in heptane over 10 column volumes to give ethyl 4-hydroxy-7-methyl-1,1-dioxo-2,3,4,5-tetrahydropyrrolo[3,4-f]triazepine-6-carboxylate (51 mg) as a clear resin.

Lithium bis(trimethylsilyl)amide (1.4 mL, 1 M in THF, 1.4 mmol) was added to a solution of ethyl 4-hydroxy-7-methyl-1,1-dioxo-2,3,4,5-tetrahydropyrrolo[3,4-f]triazepine-6-carboxylate (51 mg) and 3,4-difluoroaniline (40 mg, 0.31 mmol) in THF (10 mL) and stirred for 1 hour. The reaction mixture was quenched with NH ₄ Cl (saturated, aqueous, 25 mL) and extracted with EtOAc (50 mL). The organic layer was dried (Na ₂ SO ₄ ), filtered and concentrated. The residue was subjected to column chromatography using a gradient from 10% to 100% EtOAc in heptane. The product fractions were concentrated and the residue was dissolved in methanol (5 mL), and water was added until the product crystallized. Compound 68 (15.5 mg) was filtered off as beige crystals and dried in vacuo at 50° C. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 2.92-3.09 (m, 2H), 3.21-3.27 (m, 2H), 3.49-3.59 (m, 1H), 3.68 (s, 3H), 5.06 (d, J=4.4 Hz, 1H), 7.34 (brt, J=6.7 Hz, 1H), 7.38-7.47 (m, 3H), 7.82-7.90 (m, 1H), 10.48 (s, 1H); Method D; Rt: 1.76 min. m/z: 372 (M+H) ⁺ exact mass: 371.1; MP: 229.0° C.

Compound 69: (3R)-N-(3,4-difluorophenyl)-3-[(1R)-1-hydroxyethyl]-7-methyl-1,1-dioxo-2, 3-Dihydropyrrolo[3,4-f]triazepine-6-carboxamide.

To a solution of N-(tert-butyloxycarbonyl)-L-threonine methyl ester (10 g, 42.9 mmol) in CH ₂ Cl ₂ (100 mL) was added 2-methoxypropylene (8.22 mL, 85.7 mmol) and camphorsulfonic acid (100 mg, 0.43 mmol) at 0° C. under a nitrogen atmosphere. The resulting solution was stirred at room temperature for 2 hours. The reaction was then quenched with Et ₃ N (5 mL) and the organic solvent was removed in vacuo. The residue was purified by flash chromatography (silica gel, 0 to 15% EtOAc in heptane) to give O 3 -tert-butyl O 4 -methyl (4S,5R)-2,2,5-trimethyloxazolidine-3,4-dicarboxylate (10.5 g) as a colorless oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.25-1.54 (m, 18H), 3.66-3.72 (m, 3H), 3.86-3.91 (m, 1H), 4.06-4.13 (m, 1H) (rotamers).

To a stirred solution of methyltriphenylphosphonium bromide (27.4 g, 76.7 mmol) in THF (77 mL) at 0°C was added KOtBu (8.39 g, 74.8 mmol) in one portion. The resulting mixture was stirred at the same temperature for another hour before use. To a stirred solution of O3-tert-butyl O4-methyl (4S,5R)-2,2,5-trimethyloxazolidine-3,4-dicarboxylate (10.5 g, 38.42 mmol) in _CH2Cl2 (125 mL) at -78° _C under a nitrogen atmosphere was added DIBAL-H (1 M in heptane, 77 mL) dropwise over 1 hour. After an additional 2 hours, the THF suspension of the ylide was added dropwise over 40 minutes at the same temperature. After an additional 15 minutes, the reaction mixture was warmed to room temperature, and after an additional 3 hours, the reaction mixture was warmed to 50°C at the same temperature. At the same temperature for another 14 hours, the reaction mixture was cooled to room temperature, washed with H ₂ O (50 mL), then with an aqueous HCl solution (aqueous, 1 M, 150 mL), and the layers were separated. The aqueous residue was extracted with EtOAc (4×100 mL). The combined organic layers were washed with brine (1×250 mL), dried (Na ₂ SO ₄ ), filtered, and concentrated under reduced pressure. The resulting residue was purified on silica gel by flash chromatography (1% to 23% EtOAc in heptane) to produce tert-butyl (4R, 5R)-2,2,5-trimethyl-4-vinyl-oxazolidine-3-carboxylate (4.5 g). ¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.28 (d, J=6.0 Hz, 3H), 1.36-1.49 (m, 9H), 1.49-1.53 (m, 3H), 1.57-1.63 (m, 3H), 3.72 (br s, 1H), 3.78-3.89 (m, 1H), 5.08-5.29 (m, 2H), 5.44-5.92 (m, 1H).

Tert-butyl (4R, 5R) -2,2,5-trimethyl-4-vinyl-oxazolidine-3-carboxylate (4.5 g) was dissolved in diethyl ether (150 mL) and HCl (47 mL, 4 M in dioxane, 186 mmol) was added. The reaction mixture was stirred at room temperature overnight and concentrated to dryness. The residue was triturated with diethyl ether and concentrated to dryness. To the residue was added a premixed solution of 4.7 mL _{H 2} O in 47 mL 4 M HCl in dioxane cooled to 0° C. using an ice/water bath, and the resulting mixture was stirred for 2 hours, allowed to warm to room temperature. The mixture was then diluted with toluene (50 mL) and concentrated to dryness under reduced pressure. The residue was then azeotroped with toluene (3×50 mL) to remove all remaining water to obtain (2R, 3R) -3- aminopent-4-ene-2-ol hydrochloride (3.35 g). ¹ H NMR (400MHz, DMSO-d ₆ ) δppm 1.09 (d, J=6.3Hz, 3H), 3.32-3.48 (m, 1H), 3.62-3.78 (m, 1H), 5.22- 5.50 (m, 2H), 5.80 (ddd, J=17.3, 10.5, 7.9Hz, 1H), 8.16 (br s, 3H).

Methyl 3-bromo-4-chlorosulfonyl-1-methyl-pyrrole-2-carboxylate (2.12 g) was dissolved in DCM (200 mL) and (2R,3R)-3-aminopent-4-en-2-ol (3.35 g, 32.1 mmol) and Hunin's base (13.9 mL, 80.4 mmol) were added. The reaction mixture was stirred at room temperature for 1 hour. The reaction was quenched with _NH4Cl (saturated, aqueous, 40 _mL ). The layers were separated and the organics were dried ( _Na2SO4 ), filtered, and concentrated to give a brown residue, which was purified using silica gel column chromatography (ethyl acetate in heptane from 0 to 100%) to give methyl 3-bromo-4-[[(1R)-1-[(1R)-1-hydroxyethyl]allyl]sulfamoyl]-1-methyl-pyrrole-2-carboxylate (2.60 g) as an off-white powder. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.96 (d, J=6.0 Hz, 3H), 3.55-3.67 (m, 2H), 3.82 (s, 3H), 3.86 (s, 3H), 4.57-4.77 (m, 1H), 4.97-5.10 (m, 2H), 5.71 (ddd, J=17.3, 10.5, 5.7 Hz, 1H), 7.35 (br s, 1H), 7.70 (s, 1H); Method B; Rt: 0.70 min. m/z: 379 (MH) ^- Exact mass: 380.0.

To a nitrogen-purged solution of methyl 3-bromo-4-[[(1R)-1-[(1R)-1-hydroxyethyl]allyl]sulfamoyl]-1-methyl-pyrrole-2-carboxylate (600 mg) in DMA (5 mL) was added Hunin's base (0.3 mL, 1.73 mmol) and bis(tri-tert-butylphosphine)palladium(0) (0.16 g, 0.31 mmol). The reaction mixture was heated at 140° C. in a microwave for 5 minutes. The reaction mixture was diluted with methanol (60 mL) and purified by preparative HPLC (stationary phase: RP XBridge Prep C18 ODB-5 μm, 30×250 mm, mobile phase: 0.25% NH 4 HCO ₃ solution in water, ACN) to give methyl (3R)-3-[(1R)-1-hydroxyethyl]-7-methyl-1,1-dioxo-2,3-dihydropyrrolo[3,4-f]triazepine-6-carboxylate (160 mg). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.09 (d, J=6.4 Hz, 3H) 3.73-3.87 (m, 6H) 3.87-3.93 (m, 1H) 4.09 (br s, 1H) 4.94 (br d, J=4.0 Hz, 1H) 5.93 (dd, J=12.8, 2.6 Hz, 1H) 7.17 (dd, J=12.9, 2.8 Hz, 1H) 7.31 (br s, 1H) 7.69 (s, 1H); Method B; Rt: 0.60 min. m/z: 299 (MH) ^- Exact mass: 300.1.

Methyl (3R)-3-[(1R)-1-hydroxyethyl]-7-methyl-1,1-dioxo-2,3-dihydropyrrolo[3,4-f]triazepine-6-carboxylate (160 mg) and 3,4-difluoroaniline (76 mg, 0.59 mmol) were dissolved in THF (5 mL). Lithium bis(trimethylsilyl)amide (2.4 mL, 1 M in THF, 2.4 mmol) was added and the reaction mixture was stirred at room temperature for 60 minutes. 3,4-Difluoroaniline (21 mg, 0.16 mmol) was added followed by lithium bis(trimethylsilyl)amide (1 mL, 1 M in THF, 1 mmol). The reaction mixture was stirred at room temperature for 30 minutes. _NH4Cl (saturated, aqueous, 5 mL) was added and the organic layer was separated. The aqueous layer was extracted with DCM (2 x 5 mL) and the combined organic layers were evaporated to dryness. The residue was purified twice using silica gel column chromatography (ethyl acetate in heptane from 0 to 100%) and then purified by preparative HPLC (Hypersyl C18 BDS-3 μm, 100x4.6 mm) mobile phase ( _{NH4HCO3 0.2} % in water, ACN) to give compound 69 (68 mg). ^1H NMR (400 MHz, DMSO- _d6 ) δ ppm 1.10 (d, J = 6.4 Hz, 3H), 3.71 (s, 3H), 3.85-3.94 (m, 1H), 4.11 (br s, 1H), 4.92 (br s, 1H), 5.81 (dd, J = 12.7, 2.5 Hz, 1H), 6.59 (dd, J = 12.5, 2.6 Hz, 1H), 7.22 (br s, 1H), 7.39-7.47 (m, 2H), 7.57 (s, 1H), 7.82-7.88 (m, 1H), 10.74 (br s, 1H); Method B; Rt: 0.79 min. m/z: 396 (MH) ^- Exact mass: 397.1.

Compound 70: (3R)-N-(3,4-difluorophenyl)-3-[(1R)-1-hydroxyethyl]-7-methyl-1,1-dioxo-2, 3,4,5-Tetrahydropyrrolo[3,4-f]triazepine-6-carboxamide.

Compound 69 (32 mg) was dissolved in MeOH (40 mL). Pd/C (10%) (24 mg, 0.022 mmol) was added under a nitrogen atmosphere. The reaction mixture was hydrogenated for 60 minutes. The reaction mixture was filtered through celite and the filtrate was evaporated to dryness to give a white residue, which was purified using silica gel column chromatography (ethyl acetate in heptane from 0 to 100%) to produce compound 70 (23 mg) as a white powder. ¹ H NMR (400 MHz, DMSO-d ₆ ) δppm 1.04 (d, J=6.2Hz, 3H), 1.44 (q, J=12.1Hz, 1H), 1.90 (br dd, J=14.1, 6.6Hz, 1H), 2.78 (br t, J=13.2Hz, 1H), 3.02 (br dd, J=15.3, 5.4Hz, 1H), 3.38-3.48 (m, 1H), 3.63-3.73 (m, 4H), 4.61 (br d, J=3.7Hz, 1H), 6.69 (br d, J=8.6Hz, 1H), 7.38-7.47 (m, 3H), 7.81- 7.89(m,1H),10.48(br s, 1H); Method B; Rt: 0.79 min. m/z: 398 (MH) ^- Exact mass: 399.1

Compound 71: (3S)-N-(3-cyano-4-fluoro-phenyl)-7-methyl-1,1-dioxo-3-(3-pyridylmethyl)- 3,4-Dihydro-2H-pyrrolo[3,4-b][1,4,5]oxatriazepine-6-carboxamide.

Compound 71 (11.2 mg) was prepared similarly as described for compound 38 using 5-amino-2-fluorobenzonitrile instead of 3,4-difluoroaniline. ¹ H NMR (400MHz, DMSO-d ₆ ) δppm 2.66-2.76 (m, 1H) 2.88 (dd, J=14.1, 4.8Hz, 1H) 3.82 (s, 3H) 3.86-3.98 (m, 1H) 4.03 (dd, J=12.7, 9.1Hz, 1H) 4.67 (br d, J=12.3Hz, 1H) 7.37 (dd, J=7.7, 4.8Hz, 1H) 7.48-7.55 (m, 2H) 7.68- 7.81 (m, 2H) 7.99-8.04 (m, 1H) 8.18 (dd, J=5.7, 2.6Hz, 1H) 8.45- 8.50 (m, 2H) 9.55 (s, 1H); Method B; Rt: 0.85 min. m/z: 456 (M+H) ⁺ exact mass: 455.1.

Compound 72: tert-Butyl 4-[6-[(3,4-difluorophenyl)carbamoyl]-7-methyl-1,1-dioxo-3,4-diol Hydrogen-2H-pyrrolo[3,4-b][1,4,5]oxatriazepin-3-yl]piperidine-1-carboxylate.

To a cooled (-78°C) solution of tert-butyl 4-(1-amino-2-methoxy-2-oxoethyl)piperidine-1-carboxylate (1 g) in THF (50 mL) was added lithium aluminum hydride (3.56 mL, 1 M in THF, 3.562 mmol) at -78°C. The mixture was stirred at -78°C for 3 hours and allowed to warm to room temperature. The mixture was further stirred at room temperature for 16 hours. Sodium sulfate decahydrate (1.72 g, 5.34 mmol) was carefully added and the mixture was stirred at room temperature for 10 minutes. Na ₂ SO ₄ was added and the mixture was filtered. The filtrate was concentrated in vacuo and the residue was purified by column chromatography using a gradient of 0 to 100% MeOH/NH ₃ (90/10) in DCM over 10 column volumes. The product fractions were concentrated in vacuo to yield tert-butyl 4-(1-amino-2-hydroxy-ethyl)piperidine-1-carboxylate (513 mg) as an oil.

Compound 72 (127 mg) was prepared similarly as described for compound 14, using tert-butyl 4-(1-amino-2-hydroxy-ethyl)piperidine-1-carboxylate instead of DL-alaninol and heating at 110° C. for 6 hours instead of 140° C. for 2 hours. ¹ H NMR (400 MHz, DMSO-d ₆ ) δppm 1.12-1.27 (m, 2H), 1.40 (s, 9H), 1.71 (br t, J=12.7Hz, 3H), 2.67 (br s, 2H), 3.47-3.55 (m, 1H), 3.82 (s, 3H), 3.90- 4.05 (m, 2H), 3.96-4.01 (m, 1H), 4.71 (d, J=10.9Hz, 1H), 7.35-7.45 (m, 1H), 7.45-7.51 (m, 2H), 7.62 (d, J=9.7Hz, 1H), 7.85 (ddd, J=13.2, 7.4, 2.4 Hz, 1H), 9.42 (s, 1H); Method B; Rt: 1.13 min. m/z: 539 (MH) ^- Exact mass: 540.2.

Compound 73: N-(3,4-difluorophenyl)-7-methyl-1,1-dioxo-3-(4-piperidinyl)-3,4-dihydro-2H-pyridine Pyrrol[3,4-b][1,4,5]oxatriazepine-6-carboxamide.

Compound 72 (119 mg) was suspended in DCM (5 mL). TFA (0.25 mL, 3.30 mmol) was added and the mixture was stirred at room temperature for 1 hour. The mixture was washed with saturated _NaHCO solution. The organic layer was separated, dried ( _MgSO ), filtered and concentrated in vacuo. The residue was purified by preparative HPLC (stationary phase: RP XBridge Prep C18 OBD-10 μm, 30x150 mm, mobile phase: 0.25% NH ₄ HCO ₃ solution in water, ACN). The product fractions were collected to produce compound 73 (21 mg) as a white solid. ¹ H NMR (400MHz, DMSO-d ₆ ) δppm 1.10 -1.25 (m, 2H), 1.51-1.71 (m, 3H), 1.75 (s, 1H), 2.34-2.45 (m, 2H), 2.89-2.97 (m, 2H), 3.39-3.49 (m, 1H), 3.80-3.85 (m, 3H), 3.95 (dd, J=12.8, 9.0Hz, 1H), 4.72 (dd, J=12.9, 1.9Hz, 1H), 7.36-7.57 (m, 4H), 7.86 (ddd, J=13.2, 7.5, 2.5 Hz, 1H), 9.34-9.48 (m, 1H); Method B; Rt: 0.72 min. m/z: 441 (M+H) ⁺ exact mass: 440.1.

Compound 74: (3S)-N-(4-Fluoro-3-methyl-phenyl)-7-methyl-1,1-dioxo-3-(3-pyridylmethyl)- 3,4-Dihydro-2H-pyrrolo[3,4-b][1,4,5]oxatriazepine-6-carboxamide.

Compound 74 (29 mg) was prepared similarly as described for compound 38 using 4-fluoro-3-methylaniline instead of 3,4-difluoroaniline. ¹ H NMR (400MHz, DMSO-d ₆ ) δ ppm 2.23 (d, J=1.5Hz, 3H), 2.66-2.75 (m, 1H), 2.85-2.92 (m, 1H), 3.82 (s, 3H), 3.93 (br s, 1H), 3.99-4.11 (m, 1H), 4.67 (dd, J=12.5, 2.0 Hz, 1H), 7.10 (t, J=9.1Hz, 1H), 7.37 (dd, J=7.7, 5.1Hz, 1H), 7.45 (s, 1 H), 7.49 (br d, J＝4.6Hz, 1H), 7.53-7.58(m, 1H), 7.70-7.80(m, 2H), 8.46 (d, J=5.1 Hz, 1H), 8.49 (s, 1H), 9.24 (s, 1H); Method B; Rt: 0.91 min. m/z: 445 (M+H) ⁺ exact mass: 444.1.

Compound 75: (3S)-N-[3-(difluoromethyl)-4-fluoro-phenyl]-7-methyl-1,1-dioxo-3-(3-pyridyl)- methyl)-3,4-dihydro-2H-pyrrolo[3,4-b][1,4,5]oxatriazepine-6-carboxamide.

Compound 75 (5 mg) was prepared similarly as described for compound 38 using 3-(difluoromethyl)-4-fluoro-aniline instead of 3,4-difluoroaniline. ¹ H NMR (400MHz, DMSO-d ₆ ) δppm 2.65-2.76 (m, 1H), 2.87 (br dd, J=14.3, 4.8Hz, 1H), 3.83 (s, 3H), 3.93 (br s, 1H), 4.00-4.08 (m, 1H), 4.65 (dd, J=12.8, 2.2 Hz, 1H), 7.20 (t, J=48.0Hz, 1H), 7.35-7.40 (m, 2H), 7.47 (s, 1H), 7.70 -7.83 (m, 3H), 8.02 (dd, J=6.3, 2.5Hz, 1H), 8.46 (dd, J=4.8, 1.5Hz, 1 H), 8.49 (d, J=2.0 Hz, 1H), 9.49 (s, 1H); Method B; Rt: 0.90 min. m/z: 481 (M+H) ⁺ exact mass: 480.1.

Compound 76: N-(3,4-difluorophenyl)-7-methyl-3-(1-methyl-4-piperidinyl)-1,1-dioxo-3,4-difluorophenyl Hydrogen-2H-pyrrolo[3,4-b][1,4,5]oxatriazepine-6-carboxamide

Compound 73 (109 mg) is dissolved in MeOH (1 mL) and DCE (2 mL). The mixture is cooled on an ice bath and formaldehyde (22 μL, 1.09 g/mL, 0.297 mmol) is added followed by sodium cyanoborohydride (33 mg, 0.50 mmol). The mixture is stirred at room temperature for 16 hours. The solvent is evaporated and the residue is distributed in NaOH (aqueous, 1 M) and Me-THF. The organic layer is separated, dried (MgSO ), filtered and evaporated. The residue is purified by column chromatography using a gradient of from 0 to 100% DCM/NH ₃ solution in MeOH (90/10) in DCM through 10 column volumes. The product fractions are concentrated in a vacuum. The product is crystallized from water:MeOH to produce compound 76 (51 mg) as a white solid. ¹ H NMR (400MHz, DMSO-d ₆ ) δppm 1.24-1.47 (m, 3 H), 1.64-1.83 (m, 4H), 2.09-2.16 (m, 3H), 2.71-2.84 (m, 2H), 3.39- 3.53 (m, 1H), 3.82 (s, 3H), 3.95 (dd, J=12.9, 9.1Hz, 1H), 4.73 (dd, J=13.0, 2.0Hz, 1H), 7.36-7.53 (m, 3H), 7.58 (d, J=9.7Hz, 1H), 7.86 (ddd, J=13.2, 7.4, 2.5 Hz, 1H), 9.38-9.43 (m, 1H); Method B; Rt: 0.75 min. m/z: 455 (M+H) ⁺ exact mass: 454.1.

Compound 77: (3R)-N-[2-(difluoromethyl)-4-pyridinyl]-3-[(1S)-1-hydroxyethyl]-7-methyl-1, 1-Dioxo-3,4-dihydro-2H-pyrrolo[3,4-b][1,4,5]oxatriazepine-6-carboxamide

Compound 77 (72.7 mg) was prepared similarly as described for compound 64 using 2-(difluoromethyl)pyridin-4-amine instead of 3-(difluoromethyl)-4-fluoro-aniline. ¹ H NMR (400MHz, DMSO-d ₆ ) δppm 143 (d, J=6.4Hz, 3H), 2.12 (s, 1H), 3.85 (tdd, J=9.2, 9.2, 4.8, 2.4Hz, 1H), 3.96 (s, 3H), 4.19 (quin, J=6.1Hz, 1H), 4.35 (dd, J=13.0, 8.8Hz, 1H), 4.90 (dd, J=13.0, 2.4Hz, 1H), 5.18 (d, J=9.5Hz, 1H), 6.62 (t, J=55.5Hz, 1H), 7.10 (s, 1H), 7.71-7.73 (m, 1 H), 7.74-7.75 (m, 1H), 8.53 (d, J=5.5 Hz, 1H), 9.05 (s, 1H); Method B; Rt: 0.71 min. m/z: 415 (MH) ^- Exact mass: 416.1.

Compound 78: N-(3,4-difluorophenyl)-7-methyl-1,1-dioxo-3-[1-(2,2,2-trifluoroethyl )-4- piperidinyl]-3,4-dihydro-2H-pyrrolo[3,4-b][1,4,5]oxatriazepine-6-carboxamide

A microwave vial was filled with compound 73 (50 mg, 0.11 mmol), 2,2,2-trifluoroethyl trichloromethanesulfonate (34 mg, 0.11 mmol), K ₂ CO ₃ (19 mg, 0.14 mmol) in acetone (1 mL). The vial was capped and the mixture was stirred at 60 ° C for 16 hours. The mixture was concentrated and the residue was purified by column chromatography using a gradient of 0 to 100% EtOAc in heptane over 10 column volumes. The product fractions were concentrated in vacuo. The product was ground in DIPE, filtered off and dried under vacuum to give compound 78 (38 mg) as a white solid. ¹ H NMR (400MHz, DMSO-d ₆ ) δppm 1.28-1.44 (m, 2H), 1.44-1.54 (m, 1H), 1.64-1.76 (m, 2H), 2.20-2.36 (m, 2H), 2.89-2.98 (m, 2H), 3.05-3.20 (m, 2H), 3.42-3.56 (m, 1H), 3.82 (s, 3H), 3.92-4.04 (m, 1H), 4.68-4.76 (m, 1H), 7.36- 7.51 (m, 3H), 7.59 (d, J=9.8Hz, 1H), 7.86 (ddd, J=13.2, 7.5, 2.5Hz, 1H), 9.38-9.43 (m, 1H); Method D; Rt: 2.06 min. m/z: 521 (M+H) ⁺ exact mass: 522.1.

Compound 79: N-(3,4-difluorophenyl)-3-isopropyl-7-methyl-1,1-dioxo-2,3-dihydropyrrolo[3, 4-f]Triazepine-6-carboxamide

Methyl 3-bromo-4-chlorosulfonyl-1-methyl-pyrrole-2-carboxylate (2 g, 6.32 mmol) was dissolved in DCM (100 mL). Hunin's base (4.36 mL, 25.3 mmol) was added. 4-Methyl-1-penten-3-amine (1.71 g, 12.6 mmol) was added in DCM (100 mL). The resulting mixture was stirred overnight and concentrated in vacuo. The residue was purified using silica gel column chromatography (gradient elution: EtOAc:heptane 0:100 to 100:0) to produce methyl 3-bromo-4-(1-isopropylallylsulfamoyl)-1-methyl-pyrrole-2-carboxylate (1.88 g) as a beige powder, which was used as is. Method B; Rt: 0.98 min. m/z: 379 (M+H) ⁺ exact mass: 378.0.

By methyl 3- bromo- 4- (1- isopropyl allyl sulfamoyl) -1- methyl - pyrrole -2- formate (1.70g, 4.48mmol) and TEA (0.62mL, 0.73g/mL, 4.48mmol) in DMF (10mL) stir and purify with nitrogen for 5 minutes.Then add bis (tri- tert- butylphosphine) palladium (0) (458mg, 0.90mmol) and continue stirring and purify for 5 minutes again.The mixture is heated to 100 ℃ under microwave radiation and continues 75 minutes.The reaction mixture is cooled to room temperature and filtered through diatomaceous earth pad and rinsed with 150mL of EtOAc.Then the filtrate is concentrated in vacuo and uses silica gel column chromatography (gradient elution: EtOAc: heptane 0: 100 to 100: 0) to purify and produce a mixture of 2 kinds of isomers. The mixture was purified by preparative HPLC (stationary phase: RP XBridge Prep C18 OBD-10 μm, 30 x 150 mm, mobile phase: 0.25% NH ₄ HCO ₃ in water, ACN) to give methyl 3-isopropyl-7-methyl-1,1-dioxo-2,3-dihydropyrrolo[3,4-f]triazepine-6-carboxylate (203 mg). Method B; Rt: 0.88 min. m/z: 299 (M+H) ⁺ exact mass: 298.1.

A mixture of methyl 3-isopropyl-7-methyl-1,1-dioxo-2,3-dihydropyrrolo[3,4-f]triazepine-6-carboxylate (101 mg, 0.34 mmol) and 3,4-difluoroaniline (49 mg, 0.37 mmol) in THF (5 mL) was treated with LiHMDS (0.64 mL, 1.06 M in THF, 0.68 mmol) and stirred at room temperature for 2 hours. The resulting mixture was quenched with _NH4Cl (aqueous, saturated, 5 mL). Brine (5 mL) was then added and the layers separated. The aqueous layer was extracted with EtOAc (2 x 10 mL). The combined extracts were concentrated in vacuo and the resulting crude product was purified using silica gel column chromatography (gradient elution: EtOAc: heptane 0:100 to 100:0). The desired fractions were concentrated in vacuo and the obtained residue was purified by preparative HPLC (stationary phase: RP XBridge Prep C18 OBD-10 μm, 30 x 150 mm, mobile phase: 0.25% NH ₄ HCO ₃ solution in water, ACN) to yield compound 79 (60.3 mg) as a bright white color. ¹ H NMR (400MHz, DMSO-d ₆ ) δppm 1.47-1.51 (m, 3H) 1.51-1.56 (m, 3H) 3.20-3.24 (m, 1H) 3.20-3.24 (m, 2H) 4.30 (s, 2H) 4.53-4.63 (m, 1H) 6.21 (dd, J=12.32, 2.86Hz, 1H) 6.49 (d, J=10.56Hz, 1H) 7.15 (dd, J=12.32, 2.64Hz, 1H) 7.76-7.89 (m, 2H) 7.95-8.05 (m, 1H) 8.43 (ddd, J=12.87, 7.37, 2.64Hz, 1H) 10.23(br s, 1H); Method D; Rt: 1.90 min. m/z: 396 (M+H) ⁺ exact mass: 395.1. The racemic mixture was separated into its enantiomers by preparative SFC (stationary phase: Chiralpak Diacel AD 20x250 mm, mobile phase: _CO2 , EtOH + 0.4iPrNH2) to produce compounds 79a and _79b . Method E; Rt: 79a: 1.22 min, 79b: 2.09 min.

Compound 80: N-(3,4-difluorophenyl)-3-(1-methoxy-1-methyl-ethyl)-7-methyl-1,1-dioxo-3, 4-Dihydro-2H-pyrrolo[3,4-b][1,4,5]oxatriazepine-6-carboxamide

Ethyl 4-chlorosulfonyl-3-fluoro-1-methyl-pyrrole-2-carboxylate (250 mg, 0.89 mmol), 2-amino-3-methoxy-3-methylbutanoic acid (131 mg, 0.89 mmol) and Hunin's base (0.46 mL, 0.75 g/mL, 2.68 mmol) were dissolved in DCM (5 mL) and stirred at room temperature overnight. The reaction mixture was directly loaded onto a silica cartridge and a gradient was applied from heptane to EtOAc:EtOH:AcOH 3:1:0.02 to yield 2-[(5-ethoxycarbonyl-4-fluoro-1-methyl-pyrrol-3-yl)sulfonylamino]-3-methoxy-3-methyl-butanoic acid (143 mg).

2-[(5-Ethoxycarbonyl-4-fluoro-1-methyl-pyrrol-3-yl)sulfonylamino]-3-methoxy-3-methyl-butanoic acid (143 mg, 0.38 mmol) and 3,4-difluoroaniline (38 μL, 1.29 g/mL, 0.38 mmol) were dissolved in THF (5 mL). Lithium bis(trimethylsilyl)amide (1.88 mL, 1 M in THF, 1.88 mmol) was added and the reaction mixture was stirred at room temperature overnight. NH ₄ Cl (saturated, aqueous, 5 mL) was added and the organic layer was removed. The aqueous layer was extracted with DCM (2×5 mL) and the combined organic layers were evaporated to dryness. The residue was purified on silica using a heptane to EtOAc:EtOH:AcOH 3:1:0.02 gradient to give 2-[[5-[(3,4-difluorophenyl)carbamoyl]-4-fluoro-1-methyl-pyrrol-3-yl]sulfonylamino]-3-methoxy-3-methyl-butanoic acid (123 mg).

2-[[5-[(3,4-Difluorophenyl)carbamoyl]-4-fluoro-1-methyl-pyrrol-3-yl]sulfonylamino]-3-methoxy-3-methyl-butanoic acid (123 mg, 0.27 mmol) was dissolved in THF (10 mL) and LAH (0.27 mL, 1 M in THF, 0.27 mmol) was added dropwise. The reaction mixture was stirred at room temperature overnight. LAH (0.27 mL, 1 M in THF, 0.27 mmol) was added and stirring was continued for 24 hours. The reaction mixture was quenched with sodium sulfate decahydrate (128 mg, 0.4 mmol) followed by the addition _{of Na2SO4} . Filtration and evaporation gave an oily residue which was purified on silica using a heptane to EtOAc:EtOH 3:1 gradient to yield N-(3,4-difluorophenyl)-3-fluoro-4-[[1-(hydroxymethyl)-2-methoxy-2-methyl-propyl]sulfamoyl]-1-methyl-pyrrole-2-carboxamide (17 mg).

N-(3,4-Difluorophenyl)-3-fluoro-4-[[1-(hydroxymethyl)-2-methoxy-2-methyl-propyl]sulfamoyl]-1-methyl-pyrrole-2-carboxamide (17 mg, 0.038 mmol) and cesium fluoride (23 mg, 0.15 mmol) were partitioned in DMF (5 mL) and heated to 100° C. for 4 hours. The reaction mixture was directly purified by preparative HPLC (stationary phase: RPXBridge Prep C18 OBD-10 μm, 30×150 mm, mobile phase: 0.25% NH ₄ HCO ₃ solution in water, ACN) to give Compound 80 (6.3 mg) as a white powder. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.31-1.43 (m, 6H), 3.19 (s, 3H), 3.85 (br s, 1H), 3.95 (s, 3H), 4.04 (dd, J=12.8, 8.8 Hz, 1H), 4.82-4.93 (m, 2H), 7.05 (s, 1H), 7.08-7.14 (m, 2H), 7.62-7.69 (m, 1H), 8.81 (s, 1H); Method B; Rt: 1.04 min. m/z: 428 (MH) ^- Exact mass: 429.1.

Compound 81: N-(3,4-difluorophenyl)-3-isopropyl-7-methyl-1,1-dioxo-2,3,4,5-tetrahydropyrrolo[2-(2-(4-(difluorophenyl)-3-isopropyl)-7-methyl-1,1-dioxo-2,3,4,5-tetrahydropyrrolo[2-(4-(difluorophenyl)-3-isopropyl)-7-methyl-1,1-dioxo-2, [3,4-f]Triazepine-6-carboxamide

The hydrogenation flask was flushed with nitrogen and then filled with Pd/C (10%) (10 mg, 0.0094 mmol). Under nitrogen, compound 79 (50 mg, 0.13 mmol) in MeOH (30 mL) was added thereto. The resulting suspension was then stirred at room temperature for 90 minutes under a hydrogen atmosphere. The mixture was then filtered through a diatomaceous earth pad under a constant nitrogen stream and the pad was rinsed with MeOH (50 mL). The filtrate was concentrated in a vacuum and the obtained residue was purified using silica gel column chromatography (gradient elution: EtOAc: heptane 0: 100 to 100: 0). The desired fraction was concentrated in a vacuum and dried in a vacuum oven at 55 ° C to produce compound 81 (36 mg) as a bright white powder. ¹ H NMR (400MHz, DMSO-d ₆ ) δ ppm 0.88 (d, J = 3.74Hz, 3H) 0.90 (d, J = 3.52Hz, 3H) 1.31- 1.48 (m, 1H) 1.68 (dq, J = 12.90, 6.56Hz, 1H) 1.79-1.95 (m, 1H) 2.72- 2.86 (m, 1H) 2.94-3.07 (m, 1H) 3.18-3.29 (m, 1H) 3.68 (s, 3H) 6.90 (d, J=10.12Hz, 1H) 7.35-7.49 (m, 3H) 7.78-7.92 (m, 1H) 10.48 (s, 1 H); Method B; Rt: 1.03 min. m/z: 396 (MH) ^- exact mass: 397.1.

Compound 82: N-[3-(Difluoromethyl)-4-fluoro-phenyl]-3-isopropyl-7-methyl-1,1-dioxo-2,3-dihydro Pyrrolo[3,4-f]triazepine-6-carboxamide

Compound 82 (70.9 mg) was prepared similarly as described for compound 79, using 3-(difluoromethyl)-4-fluoro-aniline instead of 3,4-difluoroaniline. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.95 (d, J=6.82 Hz, 3H) 0.98 (d, J=6.60 Hz, 3H) 1.85-2.01 (m, 1H) 3.72 (s, 3H) 3.91-3.98 (m, 1H) 5.70 (dd, J=12.43, 2.75 Hz, 1H) 6.57 (dd, J=12.43, 2.75 Hz, 1H) 7.06-7.43 (m, 3H) 7.58 (s, 1H) 7.78-7.87 (m, 1H) 8.06 (dd, J=6.27, 2.53 Hz, 1H) 10.75 (s, 1H); Method B; Rt: 1.02 min. m/z: 426 (MH) ^- Exact mass: 427.1.

Compound 83: N-(3,4-difluorophenyl)-3-(hydroxymethyl)-7-methyl-1,1-dioxo-3,4-dihydro-2H-pyrrolidone Pyrrolidine[3,4-b][1,4,5]oxatriazepine-6-carboxamide

Compound 83 (216 mg) was prepared similarly to that described for compound 14 using 2-amino-1,3-propanediol instead of DL-alaninol. Ring closure was achieved after heating in DMF at 100° C. overnight and compound 83 was purified on silica using a gradient from heptane to EtOAc: EtOH 3: 1. ¹ H NMR (400MHz, DMSO-d ₆ ) δppm 3.35-3.42 (m, 1H), 3.56 (dt, J=10.8, 5.2Hz, 1H), 3.63-3.73 (m, 1H), 3.82 (s, 3H), 3.94 (dd, J=12.8, 8.8Hz, 1H), 4.74 (dd, J=12.7, 1.9Hz, 1H), 5.10 (dd, J=6.5, 5.0Hz, 1H), 7.36-7.50 (m, 3H), 7.61 (d, J=9.7Hz, 1H), 7.87 (ddd, J=13.2, 7.5, 2.6Hz, 1H), 9.44 (s, 1H); Method B; Rt: 0.81 min. m/z: 386 (MH) ^- exact mass: 387.1.

Compound 84: (3R)-N-(3,4-difluorophenyl)-3-[(1S)-1-hydroxyethyl]-7-methyl-1,1-dioxo-2, 3-Dihydropyrrolo[3,4-f]triazepine-6-carboxamide

Methyl 3-bromo-4-chlorosulfonyl-1-methyl-pyrrole-2-carboxylate (10.8 g, 34.1 mmol) was dissolved in ACN (200 mL) and (2S,3R)-3-aminopent-4-en-2-ol hydrochloride (4.99 g, 36.2 mmol) and Hunin's base (14.7 mL, 0.75 g/mL, 85.3 mmol) were added. The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated and the residue was purified using silica gel column chromatography (EtOAc in heptane from 0 to 100%) to give methyl 3-bromo-4-[[(1R)-1-[(1S)-1-hydroxyethyl]allyl]sulfamoyl]-1-methyl-pyrrole-2-carboxylate (11.4 g) as an off-white powder. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.99 (d, J=6.4 Hz, 3H), 3.41-3.50 (m, 1H), 3.53-3.63 (m, 1H), 3.81 (s, 3H), 3.85 (s, 3H), 4.62 (br d, J=5.1 Hz, 1H), 4.91-4.95 (m, 1H), 4.97 (d, J=0.7 Hz, 1H), 5.63-5.74 (m, 1H), 7.33 (br s, 1H), 7.69 (s, 1H); Method B; Rt: 0.68 min. m/z: 379 (MH) ^- Exact mass: 380.0.

To a nitrogen-purged solution of methyl 3-bromo-4-[[(1R)-1-[(1S)-1-hydroxyethyl]allyl]sulfamoyl]-1-methyl-pyrrole-2-carboxylate (1.10 g, 2.89 mmol) in DMF (5 mL) was added Hunin's base (0.55 mL, 0.75 g/mL, 3.17 mmol) and bis(tri-tert-butylphosphine)palladium(0) (147 mg, 0.29 mmol). The reaction mixture was heated at 130° C. in a microwave for 10 minutes. The reaction mixture was purified by preparative HPLC (stationary phase: RP XBridge Prep C18 OBD-10 μm, 50 x 150 mm, mobile phase: 0.25% NH ₄ HCO ₃ solution in water, ACN) to give methyl (3R)-3-[(1S)-1-hydroxyethyl]-7-methyl-1,1-dioxo-2,3-dihydropyrrolo[3,4-f]triazepine-6-carboxylate (380 mg). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.19 (d, J = 6.2 Hz, 3 H), 3.62-3.72 (m, 1 H), 3.76-3.88 (m, 7 H), 4.98 (br d, J = 3.7 Hz, 1 H), 6.07 (dd, J = 12.9, 2.8 Hz, 1 H), 7.12 (dd, J = 12.8, 2.6 Hz, 1 H), 7.49 (br s, 1 H), 7.69 (s, 1 H); Method B; Rt: 0.59 min. m/z: 299 (MH) ^- Exact mass: 300.1 and methyl 3-acetyl-7-methyl-1,1-dioxo-2,3,4,5-tetrahydropyrrolo[3,4-f]triazepine-6-carboxylate. ¹ H NMR (400 MHz, DMSO-d ₆ ) ppm 1.46-1.59 (m, 1H), 2.12-2.20 (m, 1H), 2.22 (s, 3H), 2.77-2.87 (m, 1H), 3.58 (br dd, J=15.7, 7.7 Hz, 1H), 3.80 (s, 3H), 3.79 (s, 3H), 4.19 (brt, J=9.5 Hz, 1H), 7.59 (s, 1H), 7.68 (br d, J=9.3 Hz, 1H); Method B; Rt: 0.67 min. m/z: 299 (MH) ^- Exact mass: 300.1

Methyl (3R)-3-[(1S)-1-hydroxyethyl]-7-methyl-1,1-dioxo-2,3-dihydropyrrolo[3,4-f]triazepine-6-carboxylate (95 mg, 0.32 mmol) and 3,4-difluoroaniline (53 mg, 0.41 mmol) were dissolved in THF (5 mL). Lithium bis(trimethylsilyl)amide (2 mL, 1 M in THF, 2 mmol) was added and the reaction mixture was stirred at room temperature. After 1 hour, the reaction was quenched with _NH4Cl (saturated, aqueous, 5 mL) and the organic layer was separated. The aqueous layer was extracted with DCM (2 x 4 mL) and _the combined organic layers were dried ( _Na2SO4 ) and evaporated to dryness. The residue was purified by preparative HPLC (stationary phase: RP XBridge Prep C18 OBD-10 μm, 50 x 150 mm, mobile phase: 0.25% NH ₄ HCO ₃ solution in water, ACN). The obtained product was purified using silica gel column chromatography ( _EtOAc in heptane from 0 to 100%) to give compound 84 (62 mg). ^1H NMR (400 MHz, DMSO- _d6 ) δ ppm 1.20 (d, J = 6.2 Hz, 3H), 3.60-3.77 (m, 4H), 3.77-3.87 (m, 1H), 4.97 (br d, J = 5.7 Hz, 1H), 5.96 (dd, J = 12.5, 2.6 Hz, 1H), 6.54 (dd, J = 12.5, 2.6 Hz, 1H), 7.35-7.52 (m, 3H), 7.57 (s, 1H), 7.81-7.89 (m, 1H), 10.73 (br s, 1H); Method B; Rt: 0.78 min. m/z: 396 (MH) ^- Exact mass: 397.1.

Compound 85: N-(3-cyano-4-fluoro-phenyl)-3-isopropyl-7-methyl-1,1-dioxo-2,3,4,5-tetrahydropyridine Pyrro[3,4-f]triazepine-6-carboxamide

To the methyl 3-bromo-1-methyl-pyrrole-2-formate (2.44g in DMF (5mL), tert-butyl N-(1-isopropyl allyl) carbamate (2.65g, 13.3 mmol) and TEA (3mL, 0.73g/mL, 22.2mmol) stir and purify 5 minutes with nitrogen.Then add bis(tri-tert-butylphosphine) palladium (0) (1.13g, 2.22mmol) and continue to stir and purify 5 minutes again.This mixture was heated to 100 ℃ and continued 60 minutes under microwave radiation.This reaction mixture was cooled to room temperature and filtered through diatomite pad and used EtOAc rinsing (150mL). The filtrate was then concentrated in vacuo and purified using silica gel column chromatography (gradient elution: EtOAc: heptane 0: 100 to 100: 0) to give methyl 3-[(E)-3-(tert-butoxycarbonylamino)-4-methyl-pent-1-enyl]-1-methyl-pyrrole-2-carboxylate (3.31 g) as an oil. Method B; Rt: 1.18 min. m/z: 335 (MH) ^- exact mass: 336.2.

The hydrogenation flask was flushed with nitrogen and then filled with Pd/C (10%) (733 mg, 0.69 mmol). To this was added methyl 3-[(E)-3-(tert-butyloxycarbonylamino)-4-methyl-pent-1-enyl]-1-methyl-pyrrole-2-carboxylate (2.20 g, 6.54 mmol) in MeOH (35 mL) under nitrogen. The resulting suspension was then stirred at room temperature for 90 minutes under a hydrogen atmosphere. The mixture was then filtered through a celite pad under a constant nitrogen stream and the pad was rinsed with MeOH (150 mL). The filtrate was concentrated in vacuo and the obtained residue was purified using silica gel column chromatography (gradient elution: EtOAc: heptane 0: 100 to 100: 0). The desired fractions were concentrated in vacuo to yield methyl 3-[3-(tert-butoxycarbonylamino)-4-methyl-pentyl]-1-methyl-pyrrole-2-carboxylate (2.16 g) as a bright white powder.

Methyl 3-[3-(tert-butoxycarbonylamino)-4-methyl-pentyl]-1-methyl-pyrrole-2-carboxylate (250 mg, 0.74 mmol) in DCM (10 mL) was treated with chlorosulfonic acid (246 μL, 1.75 g/mL, 3.69 mmol) in DCM (5 mL) at 0° C. The mixture was then allowed to reach room temperature and stirred for another hour. The mixture was added dropwise to ice water (20 mL) and extracted with 2-MeTHF (2×20 mL). The combined extracts were dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to yield methyl 3-isopropyl-7-methyl-1,1-dioxo-2,3,4,5-tetrahydropyrrolo[3,4-f]triazepine-6-carboxylate (80 mg).

Methyl 3-isopropyl-7-methyl-1,1-dioxo-2,3,4,5-tetrahydropyrrolo[3,4-f]triazepine-6-carboxylate (80 mg, 0.27 mmol) and 5-amino-2-fluoro-benzonitrile (36 mg, 0.27 mmol) in dry THF (5 mL) were treated with lithium bis(trimethylsilyl)amide (1.3 mL, 1 M in THF, 1.3 mmol) and stirred at room temperature for 2 hours. The resulting mixture was quenched with _NH4Cl (aqueous, saturated, 5 mL). Brine (5 mL) was then added and the layers separated. The aqueous layer was extracted with EtOAc (2 x 20 mL). The combined extracts were concentrated in vacuo and the resulting crude product was purified using silica gel column chromatography (gradient elution: EtOAc: heptane 0:100 to 100:0). The desired fractions were concentrated in vacuo and the obtained residue was purified by preparative HPLC (stationary phase: RP XBridge Prep C18 OBD-10 μm, 30×150 mm, mobile phase: 0.25% NH ₄ HCO ₃ solution in water, ACN) to yield compound 85 (17 mg) as a bright white solid. ¹ H NMR (400MHz, DMSO-d ₆ ) δppm 0.88 (d, J=3.30Hz, 3H) 0.90 (d, J=3.08Hz, 3H) 1.32-1.47 (m, 1H) 1.69 (dq, J=12.96, 6.54Hz, 1H) 1.79-1.93 (m, 1H) 2.72-2.85 (m, 1H) 2.98-3.11 (m, 1H) 3.19-3.28 (m, 1H) 3.69 (s, 3H) 6.91 (d, J=10.34Hz, 1H) 7.44 (s, 1H) 7.54 (t, J = 9.13 Hz, 1H) 7.95 (ddd, J = 9.24, 4.84, 2.64 Hz, 1H) 8.18 (dd, J = 5.83, 2.75 Hz, 1H) 10.59 (s, 1H); Method B; Rt: 0.97 min. m/z: 403 (MH) ^- Exact mass: 404.1.

Compound 86: N-[3-(Difluoromethyl)-4-fluoro-phenyl]-3-isopropyl-7-methyl-1,1-dioxo-2,3,4,5- Tetrahydropyrrolo[3,4-f]triazepine-6-carboxamide

Compound 86 (17 mg) was prepared similarly as described for compound 81 using compound 82 instead of compound 79. ¹ H NMR (400MHz, DMSO-d ₆ ) δppm 0.88 (d, J=3.30Hz, 3H) 0.90 (d, J=3.30Hz, 3H) 1.32-1.46 (m, 1H) 1.69 (dq, J=13.04, 6.73Hz, 1H) 1.79-1.95 (m, 1H) 2.71-2.88 (m, 1H) 2.95-3.11 (m, 1H) 3.19-3.28 (m, 1H) 3.69 (s, 3H) 6.89 (d, J= 10.34Hz, 1H) 7.22 (t, J = 54.36Hz, 1H) 7.36 (t, J = 9.46Hz, 1H) 7.42 (s, 1H) 7.76-7.85 (m, 1H) 8.02-8.08 (m, 1H) 10.49 (s, 1H); Method B; Rt: 1.02 min. m/z: 428 (MH) ^- Exact mass: 429.1.

Compound 87: (3R)-N-(3-cyano-4-fluoro-phenyl)-3-[(1S)-1-hydroxyethyl]-7-methyl-1,1-diol Oxy-2,3-dihydropyrrolo[3,4-f]triazepine-6-carboxamide

Compound 87 (55 mg) was prepared similarly as described for compound 84 using 5-amino-2-fluoro-benzonitrile instead of 3,4-difluoroaniline. ¹ H NMR (400MHz, DMSO-d ₆ ) δppm 1.20 (d, J=6.2Hz, 3H), 3.60-3.77 (m, 4H), 3.77-3.87 (m, 1H), 4.97 (d, J=5.7Hz, 1H), 5.97 (dd, J=12.5, 2.6Hz, 1H), 6.57 (dd, J=12.5, 2.4Hz, 1H), 7.40 (br d, J=9.5Hz, 1H), 7.55 (t, J=9.1Hz, 1H), 7.59 (s, 1 H), 7.98 (ddd, J=9.2, 4.8, 2.8Hz, 1H), 8.20 (dd, J=5.7, 2.6Hz, 1H), 10.85 (br s, 1H); Method B; Rt: 0.74 min. m/z: 403 (MH) ^- Exact mass: 404.1.

Compound 88: (3R)-N-(3,4-difluorophenyl)-3-[(1S)-1-hydroxyethyl]-7-methyl-1,1-dioxo-2, 3,4,5-tetrahydropyrrolo[3,4-f]triazepine-6-carboxamide

Methyl (3R)-3-[(1S)-1-hydroxyethyl]-7-methyl-1,1-dioxo-2,3-dihydropyrrolo[3,4-f]triazepine-6-carboxylate (200 mg, 0.67 mmol) was dissolved in MeOH (30 mL). Pd/C (10%) (71 mg, 0.067 mmol) was added under a nitrogen atmosphere. The reaction mixture was placed under a hydrogen atmosphere for 60 minutes. The reaction mixture was filtered through celite and the solid was washed with methanol (4 x 100 mL) and THF (4 x 100 mL). The filtrate was evaporated to dryness to give methyl (3R)-3-[(1S)-1-hydroxyethyl]-7-methyl-1,1-dioxo-2,3,4,5-tetrahydropyrrolo[3,4-f]triazepine-6-carboxylate (180 mg) as a white powder. Method B; Rt: 0.59 min. m/z: 301 (MH) ^- exact mass: 302.1.

Methyl (3R)-3-[(1S)-1-hydroxyethyl]-7-methyl-1,1-dioxo-2,3,4,5-tetrahydropyrrolo[3,4-f]triazepine-6-carboxylate (90 mg, 0.24 mmol) and 3,4-difluoroaniline (40 mg, 0.31 mmol) were dissolved in THF (5 mL). Lithium bis(trimethylsilyl)amide (1.6 mL, 1 M in THF, 1.6 mmol) was added and the reaction mixture was stirred at room temperature for 1 hour. The reaction was quenched with _NH4Cl (saturated, aqueous, 5 mL) and the organic layer was separated. The aqueous layer was extracted with DCM (2 x 4 mL) and _the combined organic layers were dried ( _Na2SO4 ) and evaporated to dryness. The residue was purified by preparative HPLC (stationary phase: RP XBridge Prep C18 OBD-10 μm, 50 x 150 mm, mobile phase: 0.25% NH ₄ HCO ₃ solution in water, ACN). The obtained product was purified using silica gel column chromatography (ethyl acetate in heptane from 0 to 100%) to give Compound 88 (35 mg). ¹ H NMR (400MHz, DMSO-d ₆ ) δppm 1.13 (d, J=6.2 Hz, 3H), 1.20-1.35 (m, 1H), 2.18 (br dd, J=14.3, 6.8Hz, 1H), 2.67- 2.80 (m, 1H), 3.02 (br dd, J=14.9, 6.5Hz, 1H), 3.14-3.27 (m, 1H), 3.43 -3.51 (m, 1H), 3.68 (s, 3H), 4.67 (d, J=5.9Hz, 1H), 6.89 (d, J=10.1Hz, 1H), 7.38-7.46 (m, 3H), 7.81-7.89 (m, 1H), 10.47 (s, 1H); Method B; Rt: 0.78 min. m/z: 398 (MH) ^- Exact mass: 399.1.

Compound 89: N-(3,4-difluorophenyl)-7-methyl-1,1-dioxo-3-tetrahydropyran-4-yl-3,4-dihydro- 2H-Pyrrolo[3,4-b][1,4,5]oxatriazepine-6-carboxamide

Compound 89 (320 mg) was prepared similarly to that described for compound 14 using 2-amino-2-(alkyl-4-yl)ethan-1-ol hydrochloride instead of DL-alaninol. Ring closure was achieved after heating in DMF at 110° C. for 90 minutes and compound 83 was purified on silica using a gradient from heptane to EtOAc. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.24-1.44 (m, 2H), 1.60-1.79 (m, 3H), 3.20-3.29 (m, 2H), 3.42-3.51 (m, 1H), 3.81-4.04 (m, 6H), 4.72 (d, J=12.5 Hz, 1H), 7.36-7.50 (m, 3H), 7.62 (d, J=9.6 Hz, 1H), 7.86 (ddd, J=13.2, 7.5, 2.5 Hz, 1H), 9.42 (s, 1H); Method D; Rt: 1.80 min. m/z: 440 (MH) ^- exact mass: 441.1. The racemic mixture was separated into enantiomers 89a (101 mg) and 89b (75 mg) by preparative SFC (stationary phase: Chiralpak Diacel AD 20 x 250 mm, mobile phase: CO2, EtOH + _0.4iPrNH2 ).Method J; Rt: 89a: 1.39 min, 89b: 2.96 min.

Compound 90: (3R)-N-(3-cyano-4-fluoro-phenyl)-3-[(1S)-1-hydroxyethyl]-7-methyl-1,1-diol Oxy-2,3,4,5-tetrahydropyrrolo[3,4-f]triazepine-6-carboxamide

Compound 90 (38 mg) was prepared similarly as described for compound 88 using 5-amino-2-fluoro-benzonitrile instead of 3,4-difluoroaniline. ¹ H NMR (400MHz, DMSO-d ₆ ) δppm 1.13 (d, J=6.2Hz, 3H), 1.20-1.35 (m, 1H), 2.19 (br dd, J=14.2, 6.9Hz, 1H), 2.71-2.81 (m, 1H), 3.05 (br dd, J=15.0, 6.4Hz, 1H), 3.16- 3.27 (m, 1H), 3.47 (sxt, J=6.4Hz, 1H), 3.69 (s, 3H), 4.67 (d, J=5.7Hz, 1 H), 6.90 (d, J=10.1Hz, 1H), 7.44 (s, 1H), 7.54 (t, J=9.1Hz, 1H), 7.96 (ddd, J = 9.1, 4.8, 2.8 Hz, 1 H), 8.19 (dd, J = 5.7, 2.6 Hz, 1 H), 10.59 (s, 1 H); Method B; Rt: 0.73 min. m/z: 405 (MH) ^- Exact mass: 406.1.

Compound 91: N-(3-cyano-4-fluoro-phenyl)-7-methyl-1,1-dioxo-3,4-dihydro-2H-pyrrolo[3,4- b][1,4,5]oxatriazepine-6-carboxamide

Ethyl 3-hydroxyl-1-methyl-pyrrole-2-formate (200mg, 1.0 mmol) under nitrogen is dissolved in THF (8mL) and at room temperature adds NaH (60% is dispersed in mineral oil) (64mg, 1.61mmol) and stirs 10 minutes, adds 2-(uncle-Butoxycarbonylamino) ethyl methanesulfonate (361mg, 1.51mmol) afterwards.This solution is heated at 80 DEG C and spend the night.This solution is diluted with frozen water cancellation EtOAc, extracted twice with EtOAc, and by the organic matter _MgSO4 that merges drying, filter, and concentrate in a vacuum.This residue is purified to produce the ethyl 3-[2-(uncle-Butoxycarbonylamino) ethoxy]-1-methyl-pyrrole-2-formate (238mg) in oily state using gradient elution (heptane/EtOAc from 100/0 to 50/50) on silica.

Ethyl 3-[2-(tert-butoxycarbonylamino)ethoxy]-1-methyl-pyrrole-2-carboxylate (235 mg, 0.68 mmol) was dissolved in DCM (4 mL) and chlorosulfonic acid (0.090 mL, 1.75 g/mL, 1.354 mmol) was added under an inert atmosphere at 0° C. and stirred for 2 hours. The solution was concentrated in vacuo to give 4-(2-aminoethoxy)-5-ethoxycarbonyl-1-methyl-pyrrole-3-sulfonic acid (197 mg).

4-(2-aminoethoxy)-5-ethoxycarbonyl-1-methyl-pyrrole-3-sulfonic acid (197 mg, 0.6 mmol) is dissolved in DCM (4 mL) and SOCl ₍ 0.218 mL, 1.64 g/mL, 2.999 mmol) is added and the solution is heated at 70 ° C for 2 hours. The solution is co-evaporated with toluene until dry. The residue is redissolved in MeOH and quenched with _NaHCO (aqueous, saturated). Excess salt is filtered out and the residue is concentrated in a vacuum. The crude product is then further purified using DCM/MeOH from 100/0 to 90/10 gradient on silica to give ethyl 7-methyl-1,1-dioxo-3,4-dihydro-2H-pyrrolo[3,4-b][1,4,5]oxatriazepine-6-carboxylate (85 mg) as a yellow solid. ¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.36 (t, J=7.2 Hz, 3H) 3.62-3.70 (m, 2H) 3.83 (s, 3H) 4.28-4.36 (m, 4H) 4.87 (br s, 1H) 7.03 (s, 1H).

At room temperature, under inert atmosphere, ethyl 7-methyl-1,1-dioxo-3,4-dihydro-2H-pyrrolo[3,4-b][1,4,5]oxatriazepine-6-carboxylate (67 mg, 0.22 mmol) was dissolved in THF (4 mL) and 5-amino-2-fluorobenzonitrile (33 mg, 0.24 mmol) was added followed by lithium bis(trimethylsilyl)amide (0.87 mL, 1 M in THF, 0.87 mmol) and stirred for 2 hours. The solution was quenched with NH ₄ Cl (saturated, aqueous) and the organics were removed in vacuo, diluted with DCM, separated, dried over Na ₂ SO ₄ , filtered off, and concentrated in vacuo. The crude product was then purified by preparative HPLC to give compound 91 (15 mg). ¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 3.77-3.83 (m, 2H), 3.97 (s, 3H), 4.43-4.47 (m, 2H), 4.72 (t, J=6.9 Hz, 1H), 7.11 (s, 1H), 7.18-7.22 (m, 1H), 7.72 (ddd, J=9.1, 4.5, 2.8 Hz, 1H), 7.96 (dd, J=5.4, 2.8 Hz, 1H), 8.86 (s, 1H); Method B; Rt: 0.82 min. m/z: 363 (MH) ^- Exact mass: 364.1.

Compound 92: (3S)-3-[Cyclopropyl(hydroxy)methyl]-N-(3,4-difluorophenyl)-7-methyl-1,1-dioxo- 3,4-Dihydro-2H-pyrrolo[3,4-b][1,4,5]oxatriazepine-6-carboxamide

At -78 ° C, to a cold solution of (S)-(-)-3-boc-2,2-dimethyloxazolidine-4-carboxaldehyde in dry THF (20 mL), cyclopropylmagnesium bromide (4.83 mL, 1 M in THF, 4.83 mmol) was added. The reaction mixture was slowly warmed to room temperature and stirred for 4 hours. The reaction mixture was quenched with water (20 ml) and then EtOAc (10 ml) was added to extract the product (some NaCl was added to remove all THF in the water layer). The water layer was extracted once with EtOAc. The combined organic layers were dried over Na ₂ SO ₄ , filtered and evaporated to dryness and the crude oil was purified on silica (from 0% to 40% EtOAc in heptane). All pure fractions were collected and evaporated to give tert-butyl (4S)-4-[cyclopropyl(hydroxy)methyl]-2,2-dimethyl-oxazolidine-3-carboxylate (679 mg) as a clear yellow oil. ¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.20-0.65 (m, 4H), 0.75-0.99 (m, 1H), 1.38-1.78 (m, 15H), 2.98-3.57 (m, 2H), 3.87-4.35 (m, 3H).

HCl (2.35 mL, 4M in dioxane, 9.41 mmol) was added to a solution of tert-butyl (4S)-4-[cyclopropyl(hydroxy)methyl]-2,2-dimethyl-oxazolidine-3-carboxylate (679 mg, 2.35 mmol) in 1,4-dioxane (10 mL). The reaction mixture was stirred at room temperature for 150 minutes. The reaction mixture was concentrated under reduced pressure to produce (2S)-2-amino-1-cyclopropyl-propane-1,3-diol hydrochloride (308 mg), which was used as is.

Ethyl 4-chlorosulfonyl-3-fluoro-1-methyl-pyrrole-2-carboxylate (667 mg, 2.47 mmol) was added to a solution of (2S)-2-amino-1-cyclopropyl-propane-1,3-diol hydrochloride (308.26 mg, 2.35 mmol) and Hunin's base (2.56 mL, 0.75 g/mL, 14.8 mmol) in DCM (15 mL) at room temperature under a nitrogen atmosphere. The reaction mixture was stirred at room temperature overnight. A portion of the DCM was concentrated and the reaction mixture was purified directly on silica (heptane/ethyl acetate 100/0 to 0/100) to give ethyl 4-[[(1S)-2-cyclopropyl-2-hydroxy-1-(hydroxymethyl)ethyl]sulfamoyl]-3-fluoro-1-methyl-pyrrole-2-carboxylate (756 mg). Method B; Rt: 0.66 min. m/z: 363 (MH) ^- exact mass: 364.1.

Lithium bis(trimethylsilyl)amide (5.5 mL, 1 M in THF, 5.5 mmol) was added dropwise to a solution of ethyl 4-[[(1S)-2-cyclopropyl-2-hydroxy-1-(hydroxymethyl)ethyl]sulfamoyl]-3-fluoro-1-methyl-pyrrole-2-carboxylate (400 mg, 1.1 mmol) and 3,4-difluoroaniline (0.13 mL, 1.29 g/mL, 1.32 mmol) in THF (15 mL). The reaction mixture was stirred at room temperature for 30 min. The reaction mixture was quenched by adding water and diluted in ethyl acetate. The aqueous layer was extracted twice with ethyl acetate. The combined organic layers were dried over Na ₂ SO ₄ , filtered off and concentrated under reduced pressure. The residue was purified on silica (heptane/ethyl acetate 100/0 to 0/100) to give 4-[[(1S)-2-cyclopropyl-2-hydroxy-1-(hydroxymethyl)ethyl]sulfamoyl]-N-(3,4-difluorophenyl)-3-fluoro-1-methyl-pyrrole-2-carboxamide (250 mg).

Cesium fluoride (272 mg, 1.79 mmol) was added to a solution of 4-[[(1S)-2-cyclopropyl-2-hydroxy-1-(hydroxymethyl)ethyl]sulfamoyl]-N-(3,4-difluorophenyl)-3-fluoro-1-methyl-pyrrole-2-carboxamide (200 mg, 0.45 mmol) in DMF (5 mL). The reaction mixture was stirred at 110° C. for 7 hours. The reaction mixture was concentrated and purified on silica (heptane/ethyl acetate 100/0 to 0/100). The obtained product was purified by preparative SFC (stationary phase: Chiralpak Diacel AD 20×250 mm, mobile phase: CO ₂ , EtOH-iPrOH (50-50) + 0.4% iPrNH ₂ ) to give compound 92a (34 mg); ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.25-0.50 (m, 4H), 0.98-1.10 (m, 1H), 3.03-3.14 (m, 1H), 3.56-3.67 (m, 1H), 3.83 (s, 3H), 4.00 (dd, J=12.8, 9.2 Hz, 1H), 4.91 (dd, J=12.8, 1.8 Hz, 1H), 5.00 (d, 5.7 Hz, 1H), 7.35-7.50 (m, 3H), 7.60 (d, J=9.9 Hz, 1H), 7.87 (ddd, J=13.3, 7.5, 2.5 Hz, 1H), 9.43 (s, 1H); Method D; Rt: 1.78 min. m/z: 426 (MH) ^- Exact mass: 427.1, and 92b (11 mg); ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.17-0.47 (m, 4H), 0.95-1.08 (m, 1H), 3.04-3.18 (m, 1H), 3.82 (s, 4H), 3.93-4.10 (m, 1H), 4.74 (dd, J = 12.7, 1.4 Hz, 1H), 5.00 (d, J = 5.1 Hz, 1H), 7.34-7.49 (m, 4H), 7.86 (ddd, J = 13.2, 7.5, 2.4 Hz, 1H), 9.35-9.48 (m, 1H); Method D; Rt: 1.77 min. m/z: 426 (MH) ^- Exact mass: 427.1, two epimers of compound 92. Method P; Rt: 92a: 1.88 min, 92b: 2.27 min.

Compound 93: (3R)-N-(3,4-difluorophenyl)-3-(1-hydroxy-1-methyl-ethyl)-7-methyl-1,1-difluorophenyl Oxy-3,4-dihydro-2H-pyrrolo[3,4-b][1,4,5]oxatriazepine-6-carboxamide

At -20 ° C, under a nitrogen atmosphere, methylmagnesium bromide (12.7 mL, 3M, 38.2 mmol) was added to a solution of (R)-3-tert-butyl 4-methyl 2,2-dimethyloxazolidine-3,4-dicarboxylate (3 g, 1.08 g/mL, 11.6 mmol) in THF (100 mL). The reaction mixture was stirred at 0 ° C for 4 h and then quenched with NH ₄ Cl (saturated, aqueous) and diluted in EtOAc. The two layers were separated and the aqueous layer was extracted with EtOAc (twice). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified on silica (heptane/EtOAc 100/0 to 70/30) to give tert-butyl (4R)-4-(1-hydroxy-1-methyl-ethyl)-2,2-dimethyl-oxazolidine-3-carboxylate (2.11 g) as a light yellow oil.

Compound 93 (188 mg) was prepared similarly as described for compound 92 using tert-butyl (4R)-4-(1-hydroxy-1-methyl-ethyl)-2,2-dimethyl-oxazolidine-3-carboxylate instead of tert-butyl (4S)-4-[cyclopropyl(hydroxy)methyl]-2,2-dimethyl-oxazolidine-3-carboxylate. ¹ H NMR (400MHz, DMSO-d ₆ ) δppm 1.13 (d, J=6.2Hz, 3H), 1.20-1.35 (m, 1H), 2.19 (br dd, J=14.2, 6.9Hz, 1H), 2.71-2.81 (m, 1H), 3.05 (br dd, J=15.0, 6.4Hz, 1H), 3.16-3.27 (m, 1H), 3.47 (sxt, J=6.4Hz, 1H), 3.69 (s, 3H), 4.67 (d, J=5.7Hz, 1H), 6.90 (d, J=10.1Hz, 1H), 7.44 (s, 1 H), 7.54 (t, J=9.1 Hz, 1H), 7.96 (ddd, J=9.1, 4.8, 2.8 Hz, 1H), 8.19 (dd, J=5.7, 2.6 Hz, 1H), 10.59 (s, 1H); Method B; Rt: 0.73 min. m/z: 405 (MH) ^- Exact mass: 406.1.

Compound 94: (3S)-N-(3,4-difluorophenyl)-3-(1-hydroxy-1-methyl-ethyl)-7-methyl-1,1-difluorophenyl Oxy-3,4-dihydro-2H-pyrrolo[3,4-b][1,4,5]oxatriazepine-6-carboxamide

Compound 94 (300 mg) was prepared similarly as described for compound 93 using (S)-(-)-3-tert-butoxycarbonyl-4-methoxycarbonyl-2,2-dimethyl-1,3-oxazolidine instead of (R)-3-tert-butyl 4-methyl 2,2-dimethyloxazolidine-3,4-dicarboxylate. ^1H NMR (400 MHz, DMSO- _d6 ) δ ppm 1.06 (s, 3H), 1.25 (s, 3H), 3.55 (t, J = 9.4 Hz, 1H), 3.83 (s, 3H), 3.92 (dd, J = 12.5, 9.0 Hz, 1H), 4.85 (s, 1H), 4.96 (d, J = 11.4 Hz, 1H), 7.33-7.54 (m, 4H), 7.87 (ddd, J = 13.2, 7.5, 2.4 Hz, 1H), 9.43 (s, 1H); Method B; Rt: 0.88 min. m/z: 414 (MH) ^- Exact mass: 415.1. MP: 234.1°C.

Compound 95: N-(3,4-difluorophenyl)-3-[hydroxy(3-pyridyl)methyl]-7-methyl-1,1-dioxo-3,4- Dihydro-2H-pyrrolo[3,4-b][1,4,5]oxatriazepine-6-carboxamide

To a solution of KOH (2.48 g, 44.2 mmol) in EtOH (100 mL) at 0° C., 3-pyridinecarboxaldehyde (4.66 mL, 1.14 g/mL, 48.6 mmol) and ethyl isocyanoacetate (4.85 mL, 1.03 g/mL, 44.2 mmol) were added. The reaction mixture was stirred for 3 hours and then concentrated to produce an oil. This was redissolved in HCl (37% in H ₂ O, 50 mL) and heated at 60° C. for 2 hours. The resulting precipitate was filtered off to give 2-amino-3-hydroxy-3-(3-pyridyl)propionic acid (8.3 g).

In a 250mL flask, 2-amino-3-hydroxy-3-(3-pyridyl)propionic acid (8.3g, 32.5mmol) was dissolved in dry MeOH (50mL) and cooled to 5°C. _SOCl (11.8mL, 1.64g/mL, 163mmol) was added dropwise and the reaction was heated under reflux for 3 hours after addition. The reaction mixture was concentrated to dryness and distributed between DCM and _NaHCO (saturated, aqueous). The organic layer was dried over _MgSO and evaporated to dryness to produce methyl 2-amino-3-hydroxy-3-(3-pyridyl)propanoate (8.76g) as a light yellow oil.

Methyl 2-amino-3-hydroxy-3-(3-pyridyl)propanoate (8.76 g, 32.5 mmol), BOC-anhydride (7.32 g, 32.5 mmol), and _Et3N (22.6 mL, 0.73 g/mL, 163 mmol) were dissolved in THF (150 mL) and stirred at room temperature for 3 hours. Volatiles were removed under reduced pressure, and the residue was partitioned between water and 2-MeTHF. The organic layer was removed and concentrated under reduced pressure. The residue was purified on silica using a heptane to EtOAc:EtOH 3:1 gradient to yield methyl 2-(tert-butoxycarbonylamino)-3-hydroxy-3-(3-pyridyl)propanoate (3.3 g). Method B; Rt: 0.65 min. m/z: 295 (MH) ^- Exact mass: 296.1.

Methyl 2-(tert-butoxycarbonylamino)-3-hydroxy-3-(3-pyridyl)propanoate (3.3g, 11.1mmol) is distributed in dioxane (100mL). LAH (12mL, 1M in THF, 12mmol) is added and the reaction mixture is stirred at 80°C overnight. The reaction mixture is quenched with sodium sulfate decahydrate (550mg, 1.7mmol) and then dried over _MgSO4 . The solid is filtered out and the filtrate is evaporated to dryness. The residue is purified on silica using heptane to EtOAc: EtOH 3: 1 gradient to produce tert-butyl N-[2-hydroxy-1-(hydroxymethyl)-2-(3-pyridyl)ethyl]carbamate (763mg) as a white powder.

Tert-butyl N-[2-hydroxy-1-(hydroxymethyl)-2-(3-pyridyl)ethyl]carbamate (350 mg, 1.3 mmol) was dissolved in DCM (10 mL). TFA (300 μL, 1.49 g/mL, 3.91 mmol) was added and the reaction mixture was stirred overnight. TFA (300 μL, 1.49 g/mL, 3.91 mmol) was added and the reaction mixture was stirred at 40° C. for 2 days. Hunin's base (2.25 mL, 0.75 g/mL, 13.04 mmol) was added and the reaction mixture was used as is in further synthesis.

Compound 95 (15.2 mg) was prepared similarly as described for compound 63, using the previously described reaction mixture in place of (1S,2S)-(+)-2-amino-1-phenyl-1,3-propanediol. ¹ H NMR (400MHz, DMSO-d ₆ ) δppm 3.80 (s, 3H), 3.91-3.97 (m, 1 H), 3.97-4.06 (m, 1H), 4.82 (d, J = 11.7Hz, 1H), 4.99 (d, J = 3.3Hz, 1H), 5.91 (br s, 1H), 7.36-7.50 (m, 4H), 7.53 (br s, 1H), 7.78 (dt, J=7.7, 1.8 Hz, 1H), 7.82-7.90 (m, 1H), 8.48 (dd, J=4.8, 1.5Hz, 1H), 8.59 (d, J = 1.8 Hz, 1H), 9.49 (s, 1H); Method B; Rt: 0.84 min. m/z: 463 (MH) - exact mass: 464.1.

Compound 96: (3R)-N-[3-(Difluoromethyl)-4-fluoro-phenyl]-3-[(1S)-1-hydroxyethyl]-7-methyl- 1,1-Dioxo-2,3-dihydropyrrolo[3,4-f]triazepine-6-carboxamide

Compound 96 (177 mg) was prepared similarly as described for compound 84 using 3-(difluoromethyl)-4-fluoro-aniline instead of 3,4-difluoroaniline. ¹ H NMR (400MHz, DMSO-d ₆ ) δppm 1.20 (d, J=6.2Hz, 3H), 3.64-3.76 (m, 4H), 3.76-3.88 (m, 1H), 4.96 (d, J=5.9Hz, 1H), 5.96 (dd, J=12.5, 2.9Hz, 1H), 6.56 (dd, J=12.5, 2.6Hz, 1H), 7.23 (t, J=54.4Hz, 1H), 7.32-7.44 (m, 2H), 7.57 (s, 1H), 7.80-7.85(m, 1H), 8.07(dd, J=6.4, 2.4Hz, 1H), 10.75(br s, 1H); Method B; Rt: 0.81 min. m/z: 428 (MH) - Exact mass: 429.1. MP: 182.3°C.

Compound 97: (3R)-N-(2-bromo-4-pyridinyl)-3-[(1S)-1-hydroxyethyl]-7-methyl-1,1-dioxo- 2,3-Dihydropyrrolo[3,4-f]triazepine-6-carboxamide

Compound 97 (134 mg) was prepared similarly as described for compound 84 using 4-amino-2-bromopyridine instead of 3,4-difluoroaniline. ^1H NMR (400 MHz, DMSO- _d6 ) δ ppm 1.21 (d, J = 6.2 Hz, 3H), 3.64-3.91 (m, 5H), 4.98 (d, J = 5.7 Hz, 1H), 5.99 (dd, J = 12.5, 2.9 Hz, 1H), 6.56 (dd, J = 12.5, 2.6 Hz, 1H), 7.42 (d, J = 10.3 Hz, 1H), 7.59-7.67 (m, 2H), 7.97 (d, J = 1.8 Hz, 1H), 8.29 (d, J = 5.7 Hz, 1H), 11.04 (s, 1H); Method B; Rt: 0.69 min. m/z: 439 (MH) ^- Exact mass: 440.0.

Compound 98: (3R)-3-[(1S)-1-hydroxyethyl]-7-methyl-1,1-dioxo-N-(3,4,5-trifluorophenyl)- 2,3-Dihydropyrrolo[3,4-f]triazepine-6-carboxamide

Compound 98 (146 mg) was prepared similarly as described for compound 84 using 3,4,5-trifluoroaniline instead of 3,4-difluoroaniline. ^1H NMR (400 MHz, DMSO- _d6 ) δ ppm 1.21 (d, J = 6.2 Hz, 3H), 3.54-3.74 (m, 4H), 3.76-3.90 (m, 1H), 4.98 (d, J = 5.7 Hz, 1H), 5.98 (dd, J = 12.5, 2.6 Hz, 1H), 6.54 (dd, J = 12.5, 2.4 Hz, 1H), 7.40 (br d, J = 10.1 Hz, 1H), 7.54-7.66 (m, 3H), 10.85 (br s, 1H); Method B; Rt: 0.86 min. m/z: 414 (MH) ^- Exact mass: 415.1. MP: 244.0°C.

Compound 99: (3R)-N-(4-Fluoro-3-methyl-phenyl)-3-[(1S)-1-hydroxyethyl]-7-methyl-1,1-diol Oxy-2,3-dihydropyrrolo[3,4-f]triazepine-6-carboxamide

Compound 99 (134 mg) was prepared similarly as described for compound 84 using 4-fluoro-3-methylaniline instead of 3,4-difluoroaniline. ¹ H NMR (400MHz, DMSO-d ₆ ) δppm 1.20 (d, J=6.2Hz, 3H), 2.23 (d, J=1.5Hz, 3H), 3.64-3.76 (m, 4H), 3.76-3.88 (m, 1H), 4.96 (br d, J=5.5Hz, 1H), 5.94 (dd, J=12.5, 2.6 Hz, 1H), 6.53 (dd, J=12.5, 2.6Hz, 1H), 7.12 (t, J=9.2Hz, 1H), 7.37 (br d, J=8.1Hz, 1H), 7.48-7.53 (m, 1H), 7.54 (s, 1H), 7.63 (dd, J=6.9, 2.3Hz, 1H), 10.49 (s, 1H); Method B; Rt: 0.80 min. m/z: 392 (MH) ^- Exact mass: 393.1.

Compound 100: (3R)-N-[3-(difluoromethyl)-4-fluoro-phenyl]-3-(1-hydroxy-1-methyl-ethyl)-7-methyl 1,1-dioxo-3,4-dihydro-2H-pyrrolo[3,4-b][1,4,5]oxatriazepine-6-carboxamide

Compound 100 (216 mg) was prepared similarly as described for the preparation of compound 93 using 3-(difluoromethyl)-4-fluoro-aniline instead of 3,4-difluoroaniline. ^1H NMR (400 MHz, DMSO- _d6 ) δ ppm 1.06 (s, 3H), 1.25 (s, 3H), 3.55 (br t, J = 9.5 Hz, 1H), 3.83 (s, 3H), 3.94 (dd, J = 12.5, 8.8 Hz, 1H), 4.86 (s, 1H), 4.95 (d, J = 11.4 Hz, 1H), 7.06-7.37 (m, 2H), 7.47-7.53 (m, 2H), 7.77-7.85 (m, 1H), 8.04 (dd, J = 6.3, 2.5 Hz, 1H), 9.47 (s, 1H); Method B; Rt: 0.90 min. m/z: 446 (MH) ^- Exact mass: 447.1.

Compound 101: (3S)-N-[3-(difluoromethyl)-4-fluoro-phenyl]-3-(1-hydroxy-1-methyl-ethyl)-7-methyl 1,1-dioxo-3,4-dihydro-2H-pyrrolo[3,4-b][1,4,5]oxatriazepine-6-carboxamide

Compound 101 (132.8 mg) was prepared similarly as described for the preparation of compound 94 using 3-(difluoromethyl)-4-fluoro-aniline instead of 3,4-difluoroaniline. ^1H NMR (400 MHz, DMSO- _d6 ) δ ppm 1.06 (s, 3H), 1.25 (s, 3H), 3.55 (t, J = 9.4 Hz, 1H), 3.83 (s, 3H), 3.93 (dd, J = 12.5, 9.0 Hz, 1H), 4.86 (s, 1H), 4.95 (d, J = 11.4 Hz, 1H), 7.05-7.39 (m, 2H), 7.45-7.55 (m, 2H), 7.77-7.85 (m, 1H), 8.04 (dd, J = 6.3, 2.5 Hz, 1H), 9.47 (s, 1H); Method B; Rt: 0.89 min. m/z: 446 (MH) ^- Exact mass: 447.1. MP: 214.4℃.

Compound 102: (3R)-N-(3,4-difluorophenyl)-3-(1-hydroxy-1-methyl-ethyl)-7-methyl-1,1-difluorophenyl Oxy-2,3,4,5-tetrahydropyrrolo[3,4-f]triazepine-6-carboxamide

At 90 ° C, over 45 minutes, tert-butyl (2R) -2- (benzyloxycarbonylamino) hexyl-5-ynoate (5.03g, 15.8mmol) and ethyl isocyanoacetate (5.10g, 42.8mmol) in dioxane (15mL) were added dropwise to a solution of ethyl isocyanoacetate (1.50g, 12.6mmol) in dioxane (20mL), wherein silver carbonate (947mg, 3.44mmol) was suspended. The reaction mixture was heated and further stirred at this temperature for 3 hours. The reaction mixture was filtered while hot and concentrated. The residue was subjected to silica column chromatography using a gradient from 10% to 100% EtOAc in heptane to produce ethyl 3- [(3R) -3- (benzyloxycarbonylamino) -4- tert- butoxy -4- oxo -butyl] -1H- pyrrole -2-carboxylate (1.98g) as a clear oil.

TFA (5.3 mL, 1.49 g/mL, 69 mmol) is added to ethyl 3-[(3R)-3-(benzyloxycarbonylamino)-4-tert-butoxy-4-oxo-butyl]-1H-pyrrole-2-carboxylate (1.98 g, 4.6 mmol) in DCM (50 mL) and stirred for 3 hours. The reaction mixture is concentrated and redissolved in DMF (50 mL). MeI (6.24 mL, 2.28 g/mL, 100 mmol) and Cs ₂ CO ₃ (13 g, 40 mmol) are added and the reaction mixture is stirred overnight. The reaction mixture is filtered and directly loaded onto a silica cartridge. Ethyl 3-[(3R)-3-(benzyloxycarbonylamino)-4-methoxy-4-oxo-butyl]-1-methyl-pyrrole-2-carboxylate (1.70 g) is produced using a gradient from 0 to 100% EtOAc in heptane. ¹ H NMR (400MHz, DMSO-d ₆ ) δppm 1.26 (t, J=7.2Hz, 3H), 1.76-1.87 (m, 1H), 1.87-2.00 (m, 1H), 2.67-2.78 (m, 2H), 3.62 (s, 3H), 3.78 (s, 3H), 3.94-4.06 (m, 1H), 4.19 (q, J=7.0Hz, 2H), 5.05 (s, 2H), 5.93 (d, J=2.4Hz, 1H), 6.96 (d, J=2.4Hz, 1H), 7.27-7.42 (m, 5H), 7.77 (d, J=7.7Hz, 1H); Method D; Rt: 2.07 min. m/z: 401 (MH) ^- exact mass: 402.2.

Chlorosulfonic acid (112 mg, 0.96 mmol) was added to a solution of ethyl 3-[(3R)-3-(benzyloxycarbonylamino)-4-methoxy-4-oxo-butyl]-1-methyl-pyrrole-2-carboxylate (193 mg, 0.48 mmol) in DCM (20 mL) and stirred for 1 hour. Thionyl chloride (285 mg, 2.4 mmol) was added and the reaction mixture was stirred and refluxed for 2 hours and then cooled in an ice bath and quenched with methanol (1 mL). The mixture was poured into NaHCO ₃ (aqueous saturated, 100 mL). The mixture was extracted with DCM (2×50 mL) and the combined organic layers were dried over magnesium sulfate, filtered and concentrated. The residue was purified by column chromatography using a gradient from 0 to 100% EtOAc in heptane to give O6-ethyl O3-methyl (3R)-7-methyl-1,1-dioxo-2,3,4,5-tetrahydropyrrolo[3,4-f]triazepine-3,6-dicarboxylate (58.8 mg) as a white powder. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.29 (t, J=7.0 Hz, 3H), 1.61-1.74 (m, 1H), 2.16-2.26 (m, 1H), 2.81 (br dd, J=14.1, 12.1 Hz, 1H), 3.62-3.72 (m, 4H), 3.80 (s, 3H), 4.22-4.30 (m, 3H), 7.56 (s, 1H), 7.74 (d, J=9.9 Hz, 1H); Method D; Rt: 1.60 min. m/z: 329 (MH) ^- Exact mass: 330.1.

At -78 ° C, methylmagnesium chloride (0.12mL, 3M, 0.35mmol) is added to O6-ethyl O3-methyl (3R) -7-methyl -1,1-dioxo -2,3,4,5- tetrahydropyrrolo [3,4-f] triazepine -3,6- dicarboxylate (58.8mg, 0.168mmol) in THF (10mL). The reaction mixture is allowed to reach room temperature immediately. At -78 ° C, another equal amount of methylmagnesium chloride (0.12mL, 3M, 0.35mmol) is added and the reaction mixture is allowed to reach room temperature. At 20 ° C, methylmagnesium chloride (0.04mL, 3M, 0.12mmol) is added and the reaction mixture is stirred for 15 minutes. The reaction mixture is quenched with HCl (aqueous, 1M, 30mL), diluted with brine (50mL) and extracted with EtOAc (3 × 50mL). The combined organic layer is dried over _MgSO4 , filtered and concentrated. The residue was subjected to silica gel column chromatography using a gradient from 0 to 100% EtOAc in heptane to yield ethyl (3R)-3-(1-hydroxy-1-methyl-ethyl)-7-methyl-1,1-dioxo-2,3,4,5-tetrahydropyrrolo[3,4-f]triazepine-6-carboxylate (26 mg) as a clear oil. Method D; Rt: 1.46 min. m/z: 329 (MH) ^- Exact mass: 330.1.

Lithium bis(trimethylsilyl)amide (0.32 mL, 1 M in THF, 0.32 mmol) was added to a solution of ethyl (3R)-3-(1-hydroxy-1-methyl-ethyl)-7-methyl-1,1-dioxo-2,3,4,5-tetrahydropyrrolo[3,4-f]triazepine-6-carboxylate (26 mg, 0.0787 mmol) and 3,4-difluoroaniline (21 mg, 0.16 mmol) in THF (2 mL) and stirred for 30 minutes. After 3 more times, this amount of 3,4-difluoroaniline (21 mg, 0.16 mmol) and lithium bis(trimethylsilyl)amide (0.32 mL, 1 M in THF, 0.32 mmol) was added and the reaction mixture was stirred for 1 hour. The reaction mixture was quenched with _NH4Cl solution (aqueous saturation, 10 mL), washed with brine (10 mL) and extracted with EtOAc (50 mL). The organic layer was dried over _MgSO4 , filtered and concentrated. The residue was subjected to silica gel column chromatography using a gradient from 0 to 100% EtOAc in heptane. The product fraction was concentrated and the residue was subjected to silica gel column chromatography using a gradient from 5% to 30% iPrOH in heptane, producing compound 102 (12 mg) as a beige resin. ¹ H NMR (400MHz, DMSO-d ₆ ) δppm1.20-1.31 (m, 6H), 1.47-1.59 (m, 1H), 1.70 (br s, 1H), 2.09-2.18 (m, 1H), 2.89-2.99 (m, 1H), 3.17 (td, J=7.7, 5.5Hz, 1H), 3.39-3.51 (m, 1H), 3.74 (s, 3H), 4.67 (d, J=10.3 Hz, 1H), 7.09-7.18 (m, 2H), 7.19-7.25 (m, 1H), 7.70 (ddd, J=12.0, 7.2, 2.4 Hz, 1H), 8.20 (s, 1H); Method D; Rt: 1.58 min. m/z: 412 (MH) ^- exact mass: 413.1; MP: 218.2°C.

Compound 103: (3R)-N-[3-(Difluoromethyl)-4-fluoro-phenyl]-3-[(1S)-1-hydroxyethyl]-7-methyl- 1,1-Dioxo-2,3,4,5-tetrahydropyrrolo[3,4-f]triazepine-6-carboxamide

Compound 96 (109 mg, 0.25 mmol) was dissolved in MeOH (30 mL). Pd/C (10%) (27 mg, 0.025 mmol) was added under a nitrogen atmosphere. The reaction mixture was hydrogenated for 60 minutes. The reaction mixture was filtered through celite and the solids were washed with THF (4x80 mL). The filtrate was evaporated to dryness and the residue was purified using silica gel column chromatography (EtOAc in heptane from 0 to 100%) to obtain compound 103 (70 mg) as a white powder. ¹ H NMR (400MHz, DMSO-d ₆ ) δppm 1.13 (d, J=6.2Hz, 3H), 1.19-1.37 (m, 1H), 2.19 (br dd, J=14.3, 6.8Hz, 1H), 2.71-2.81 (m, 1H), 3.05 (br dd, J＝15.3, 6.1Hz, 1H), 3.16-3.29 (m, 1H), 3.40-3.54 (m, 1H), 3.69 (s, 3H), 4.67 (d, J＝5.7Hz, 1H), 6.89 (d, J=10.1Hz, 1H), 7.22 (t, J=54.2Hz, 1H), 7.37 (t, J=9.6Hz, 1H), 7.42 (s, 1H), 7.78-7.84 (m, 1H), 8.04-8.09 (m, 1H), 10.48 (s, 1H); Method B; Rt: 0.80 min. m/z: 430 (MH) ^- Exact mass: 431.1. MP: 274.7°C.

Compound 104: (2R)-3-[(1S)-1-hydroxyethyl]-7-methyl-1,1-dioxo-N-(3,4,5-trifluorophenyl)- 1-[4-[4-[4-(2-[4-(2-methyl-1-oxo-2-yl)-2,3,4,5-tetrahydropyrrolo[3,4-f]triazepine-6-carboxamide]]

Compound 98 (75 mg, 0.18 mmol) was dissolved in MeOH (30 mL). Pd/C (10%) (19 mg, 0.018 mmol) was added under a nitrogen atmosphere. The reaction mixture was hydrogenated for 60 minutes. The reaction mixture was filtered through celite and the solids were washed with THF (4x80 mL). The filtrate was evaporated to dryness and the residue was purified using silica gel column chromatography (EtOAc in heptane from 0 to 100%) to obtain compound 104 (37 mg) as a white powder. ¹ H NMR (400MHz, DMSO-d ₆ ) δppm 1.13 (d, J=6.4Hz, 3H), 1.19-1.36 (m, 1H), 2.18 (br dd, J=14.2, 7.2Hz, 1H), 2.71-2.80 (m, 1H), 3.02 (br dd, J＝15.4, 5.9Hz, 1H), 3.16-3.28 (m, 1H), 3.33-3.54 (m, 1H), 3.68 (s, 3H), 4.67 (d, J＝5.9Hz, 1H), 6.90 (d, J = 10.3 Hz, 1H), 7.44 (s, 1H), 7.56-7.64 (m, 2H), 10.58 (s, 1H); Method B; Rt: 0.85 min. m/z: 416 (MH) - exact mass: 417.1.

Compound 105: (3R)-3-[Cyclopropyl(hydroxy)methyl]-N-(3,4-difluorophenyl)-7-methyl-1,1-dioxo- 3,4-Dihydro-2H-pyrrolo[3,4-b][1,4,5]oxatriazepine-6-carboxamide

Compound 105 (310 mg) was prepared similarly as described for compound 92 using (R)-(-)-3-boc-2,2-dimethyloxazolidine-4-carbaldehyde instead of (S)-(-)-3-boc-2,2-dimethyloxazolidine-4-carbaldehyde. The obtained product was purified by preparative SFC (stationary phase: Chiralpak Diacel AD 20x250 mm, mobile phase: _CO2 , EtOH+0.4% _iPrNH2 ) to give compound 105a (60 mg); ^1H NMR (400 MHz, DMSO- _d6 ) δ ppm 0.16-0.27 (m, 1H), 0.27-0.36 (m, 1H), 0.36-0.48 (m, 2H), 0.94-1.09 (m, 1H), 3.13 (dt, J=7.5, 4.0 Hz, 1H), 3.72-3.80 (m, 1H), 3.83 (s, 3H), 4.04 (dd, J = 12.8, 9.2 Hz, 1H), 4.75 (dd, J = 12.7, 1.4 Hz, 1H), 5.01 (d, J = 4.8 Hz, 1H), 7.33-7.52 (m, 4H), 7.86 (ddd, J = 13.2, 7.5, 2.4 Hz, 1H), 9.45 (s, 1H); Method D; Rt: 1.77 min. m/z: 426 (MH) ^- Exact mass: 427.1; MP: 243.0°C, and 105b (203 mg); ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.22-0.41(m, 3H), 0.41-0.53(m, 1H), 0.98-1.11(m, 1H), 3.03-3.14 (m, 1H), 3.56-3.70 (m, 1H), 3.83 (s, 3H), 4.00 (dd, J=12.8, 9.2Hz, 1H), 4.91 (dd, J=12.8, 1.8Hz, 1H), 5.01 (d, J=5.5Hz, 1H), 7.34-7.51 (m, 3 H), 7.61 (d, J=9.7Hz, 1H), 7.87 (ddd, J=13.2, 7.5, 2.4Hz, 1H), 9.43 (s, 1 H); Method D; Rt: 1.77 min. m/z: 426 (MH) ^- Exact mass: 427.1; MP: 244.8°C, two epimers of compound 105. Method K; Rt: 105a: 1.98 min, 105b: 1.68 min.

Compound 106: (3R)-N-(3-cyano-4-fluoro-phenyl)-3-(1-hydroxy-1-methyl-ethyl)-7-methyl-1, 1-Dioxo-3,4-dihydro-2H-pyrrolo[3,4-b][1,4,5]oxatriazepine-6-carboxamide

Compound 106 (134 mg) was prepared similarly as described for compound 93 using 5-amino-2-fluoro-benzonitrile instead of 3,4-difluoroaniline. ¹ H NMR (400MHz, DMSO-d ₆ ) δppm 1.06 (s, 3H), 1.25 (s, 3H), 3.55 (brt, J=9.5Hz, 1H), 3.84 (s, 3H), 3.93 (dd, J=12.5, 9.0Hz, 1H), 4.86 (s, 1H), 4.99 (d, J=11.4 Hz, 1H), 7.46-7.56 (m, 3H), 8.06 (ddd, J=9.2, 4.8, 2.9Hz, 1H), 8.21 (dd, J=5.7, 2.9Hz, 1H), 9.52 (s, 1H); Method B; Rt: 0.83min.m/z: 421 (MH) ^-Exact mass: 422.1; MP: 260.1°C.

Compound 107: (3S)-N-(3-cyano-4-fluoro-phenyl)-3-(1-hydroxy-1-methyl-ethyl)-7-methyl-1, 1-Dioxo-3,4-dihydro-2H-pyrrolo[3,4-b][1,4,5]oxatriazepine-6-carboxamide

Compound 107 (111.4 mg) was prepared similarly as described for compound 94 using 5-amino-2-fluoro-benzonitrile instead of 3,4-difluoroaniline. ^1H NMR (400 MHz, DMSO- _d6 ) δ ppm 1.06 (s, 3H), 1.25 (s, 3H), 3.55 (brt, J = 7.6 Hz, 1H), 3.84 (s, 3H), 3.93 (dd, J = 12.4, 8.9 Hz, 1H), 4.86 (s, 1H), 4.99 (d, J = 11.4 Hz, 1H), 7.46-7.56 (m, 3H), 8.06 (ddd, J = 9.2, 4.9, 2.9 Hz, 1H), 8.21 (dd, J = 5.7, 2.9 Hz, 1H), 9.52 (s, 1H); Method B; Rt: 0.85 min. m/z: 421 (MH) ^- Exact mass: 422.1. MP: 259.8℃.

Compound 108: N-[2-(difluoromethyl)-4-pyridinyl]-3-isopropyl-7-methyl-1,1-dioxo-2,3,4,5- Tetrahydropyrrolo[3,4-f]triazepine-6-carboxamide

Compound 108 (10.8 mg) was prepared similarly as described for compound 85 using 2-(difluoromethyl)pyridin-4-amine instead of 5-amino-2-fluoro-benzonitrile. ¹ H NMR (400MHz, DMSO-d ₆ ) δppm 0.86-0.89 (m, 3H) 0.89-0.92 (m, 3H) 1.32-1.47 (m, 1H)1.62-1.74(m,1H)1.82-1.93(m,1H)2.74-2.88(m,1H)2.99-3.10(m,1H)3.19-3.27(m,1H)3.71(s,3H)6.73-7.08(m,2H)7.47 (s, 1H) 7.70-7.82 (m, 1H) 8.03 (d, J = 1.76Hz, 1H) 8.56 (d, J = 5.72Hz, 1H) 10.85 (s, 1H); Method B; Rt: 0.88 min. m/z: 411 (MH) ^- Exact mass: 412.1.

Compound 109: N-(4-Fluoro-3-methyl-phenyl)-3-isopropyl-7-methyl-1,1-dioxo-2,3,4,5-tetrahydro Pyrrolo[3,4-d]triazepine-6-carboxamide

Compound 109 (16.1 mg) was prepared similarly as described for compound 85 using 4-fluoro-3-methylaniline instead of 5-amino-2-fluoro-benzonitrile. ¹ H NMR (400MHz, DMSO-d ₆ ) δppm 0.89 (dd, J=6.82, 3.52Hz, 6H) 1.38 (q, J=11.88Hz, 1H) 1.62-1.74 (m, 1H) 1.86 (br dd, J＝13.97, 6.71Hz, 1H) 2.22 (d, J＝1.32 Hz, 3H) 2.73-2.84 (m, 1H) 2.95-3.06 (m, 1H) 3.18-3.28 (m, 1H) 3.68 (s, 3H) 6.87 (br d, J＝10.12Hz, 1H) 7.10 (t, J＝9.13Hz, 1H) 7.39 (s, 1H) 7.45-7.54 (m, 1H) 7.58-7.66 (m, 1H) 10.23 (s, 1H); Method B; Rt: 1.03 min. m/z: 392 (MH) ^- Exact mass: 393.1.

Compound 110: N-(3,4-difluorophenyl)-3-(dimethylaminomethyl)-7-methyl-1,1-dioxo-3,4-diol Hydrogen-2H-pyrrolo[3,4-b][1,4,5]oxatriazepine-6-carboxamide

Compound 83 (105 mg, 0.27 mmol), MsCl (31 μL, 1.48 g/mL, 0.41 mmol) and TEA (150 μL, 0.73 g/mL, 1.08 mmol) were dissolved in DCM (10 mL) and stirred for 2 hours. Water was added and a precipitate formed. The precipitate was filtered off, triturated with DIPE and dried to yield [6-[(3,4-difluorophenyl)carbamoyl]-7-methyl-1,1-dioxo-3,4-dihydro-2H-pyrrolo[3,4-b][1,4,5]oxatriazepin-3-yl]methyl methanesulfonate (64 mg) as a white powder.

[6-[(3,4-difluorophenyl)carbamoyl]-7-methyl-1,1-dioxo-3,4-dihydro-2H-pyrrolo[3,4-b][1,4,5]oxatriazepin-3-yl]methyl methanesulfonate (10 mg, 0.021 mmol) was dissolved in dimethylamine (3 mL, 2M in THF) and stirred at room temperature for 4 hours. The volatiles were removed under reduced pressure and the residue was purified on silica using a heptane to EtOAc gradient to yield compound 110 (2 mg). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 2.32 (s, 6H), 2.42 (dd, J=12.2, 5.8 Hz, 1H), 2.66 (dd, J=12.2, 9.6 Hz, 1H), 3.62-3.79 (m, 1H), 3.86-3.97 (m, 4H), 4.14 (dd, J=13.0, 5.7 Hz, 1H), 4.85 (dd, J=13.0, 2.4 Hz, 1H), 7.05 (s, 1H), 7.07-7.15 (m, 2H), 7.61-7.67 (m, 1H), 8.72 (s, 1H); Method B; Rt: 0.86 min. m/z: 413 (MH) ^- Exact mass: 414.1.

Compound 111: (3R)-N-(2-bromo-4-pyridinyl)-3-[(1S)-1-hydroxyethyl]-7-methyl-1,1-dioxo- 2,3,4,5-tetrahydropyrrolo[3,4-f]triazepine-6-carboxamide

Compound 111 (20.5 mg) was prepared similarly as described for compound 90 using 4-amino-2-bromopyridine instead of 5-amino-2-fluoro-benzonitrile. ¹ H NMR (400MHz, DMSO-d ₆ ) δppm 1.13 (d, J=6.2Hz, 3H), 1.22-1.34 (m, 1H), 2.18 (br dd, J=14.2, 6.7Hz, 1H), 2.72-2.81 (m, 1H), 3.03 (br dd, J=14.7, 6.4Hz, 1H), 3.16-3.28 (m, 1H), 3.47 (sxt, J=6.2Hz, 1H), 3.70 (s, 3H), 4.68 (d, J=5.9Hz, 1H), 6.92 (d, J=10.3Hz, 1H), 7.47 (s, 1H), 7.62 (dd, J=5.6, 1.9 Hz, 1H), 7.96 (d, J=1.8 Hz, 1H), 8.27 (d, J=5.5 Hz, 1H), 10.78 (s, 1H); Method B; Rt: 0.67 min. m/z: 441 (MH) ^- Exact mass: 442.0.

Compound 112: (3R)-N-(4-fluoro-3-methyl-phenyl)-3-[(1S)-1-hydroxyethyl]-7-methyl-1,1-diol Oxy-2,3,4,5-tetrahydropyrrolo[3,4-f]triazepine-6-carboxamide

Compound 112 (56 mg) was prepared similarly as described for compound 90 using 4-fluoro-3-methylaniline instead of 5-amino-2-fluoro-benzonitrile. ¹ H NMR (400MHz, DMSO-d ₆ ) δppm 1.13 (d, J=6.2Hz, 3H), 1.29 (q, J=11.9Hz, 1H), 2.13-2.24 (m, 4H), 2.70-2.79 (m, 1H), 3.02 (br dd, J＝14.9, 6.5Hz, 1H), 3.16 -3.25 (m, 1H), 3.47 (sxt, J＝6.2Hz, 1H), 3.67 (s, 3H), 4.66 (d, J＝5.7Hz, 1H), 6.87 (d, J=10.1Hz, 1H), 7.10 (t, J=9.2Hz, 1H), 7.39 (s, 1H), 7.47- 7.52 (m, 1H), 7.62 (dd, J=7.0, 2.2 Hz, 1H), 10.23 (s, 1H); Method B; Rt: 0.79 min. m/z: 394 (MH) ^- Exact mass: 395.1. MP: 287.3°C.

Compound 113: (3S)-N-(3,4-difluorophenyl)-3-(1-hydroxy-1-methyl-ethyl)-7-methyl-1,1-difluorophenyl Oxy-2,3,4,5-tetrahydropyrrolo[3,4-f]triazepine-6-carboxamide

Under nitrogen atmosphere, at -78 ℃, to methyl 3-acetyl-7-methyl-1,1-dioxo-2,3,4,5-tetrahydropyrrolo[3,4-f]triazepine-6-carboxylate (1000mg, 3.33mmol) in THF (15mL) solution, add methylmagnesium bromide (2.55mL, 3M in diethyl ether, 7.66mmol).The reaction mixture is stirred at -78 ℃ for 90 minutes.Methylmagnesium bromide (2.55mL, 3M in diethyl ether, 7.66mmol) is added in the reaction mixture and the reaction is quenched with NH ₄ Cl (saturated, aqueous, 4mL) and allowed to reach room temperature.The reaction mixture is filtered and these solids are washed with THF (3x100mL).The filtrate is washed with salt water and dried (Na ₂ SO ₄ ), and concentrated to obtain white foam. The residue was purified using silica gel column chromatography (EtOAc in heptane from 0 to 100%) to give methyl 3-(1-hydroxy-1-methyl-ethyl)-7-methyl-1,1-dioxo-2,3,4,5-tetrahydropyrrolo[3,4-f]triazepine-6-carboxylate (910 mg) as a white powder.

Methyl 3-(1-hydroxy-1-methyl-ethyl)-7-methyl-1,1-dioxo-2,3,4,5-tetrahydropyrrolo[3,4-f]triazepine-6-carboxylate (220 mg, 0.63 mmol) and 3,4-difluoroaniline (106 mg, 0.82 mmol) were dissolved in THF (5 mL). Lithium bis(trimethylsilyl)amide (4.11 mL, 1 M in THF, 4.11 mmol) was added and the reaction mixture was stirred at room temperature for 4 hours. The reaction was quenched with _NH4Cl (saturated, aqueous, 5 mL) and the organic layer was separated. The aqueous layer was extracted with 2-MeTHF (2 x 4 mL) and the combined organic layers were evaporated to dryness. The residue was purified using preparative HPLC (stationary phase: RP XBridge Prep C18 OBD-10 μm, 50×150 mm, mobile phase: 0.25% NH ₄ HCO ₃ solution in water, ACN). The obtained product (222 mg) was separated into its enantiomers by preparative SFC (stationary phase: Chiralpak Diacel AD20x250 mm, mobile phase: CO ₂ , EtOH+0.4 iPrNH ₂ ) to yield compound 113 (105 mg), ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.03 (s, 3H), 1.17 (s, 3H), 1.24-1.39 (m, 1H), 2.16 (br dd, J=13.9, 6.8 Hz, 1H), 2.66-2.78 (m, 1H), 3.03 (br dd, J=14.6, 6.1 Hz, 1H), 3.22-3.35 (m, 1H), 3.69 (s, 3H), 4.39 (s, 1H), 6.83 (br d, J=10.1 Hz, 1H), 7.38-7.46 (m, 3H), 7.81-7.88 (m, 1H), 10.47 (br s, 1H); Method D; Rt: 1.60 min. m/z: 412 (MH) - exact mass: 413.1; MP: 217.7°C and compound 102 (105 mg). Method F; Rt: 113: 1.15 min, 102: 1.85 min.

Compound 114: N-(3,4-difluorophenyl)-3-(1-hydroxy-2-methyl-propyl)-7-methyl-1,1-dioxo-3, 4-Dihydro-2H-pyrrolo[3,4-b][1,4,5]oxatriazepine-6-carboxamide

To a cold solution (-78°C) of ethyl 2-(dibenzylamino)acetate (2.0 g, 7.1 mmol) in dry THF was added lithium bis(trimethylsilyl)amide (24.7 mL, 1 M in THF, 24.7 mmol) dropwise while maintaining the temperature below -50°C. The solution was stirred at -78°C for 30 min. Maintaining the temperature below -50°C, isobutyraldehyde (2.32 mL, 0.79 g/mL, 24.7 mmol) was slowly added and the reaction mixture was stirred for 3 hours. The reaction mixture was warmed to 0°C and then quenched with _NH4Cl (saturated, aqueous). EtOAc was then added to extract the product. The combined organic layers were dried over _Na2SO4 , _filtered and evaporated. The residue was purified by silica gel column chromatography (0% to 50% EtOAc in heptane) and separated into its two diastereomers to yield diastereomer 1 (492 mg); ^1H NMR (400 MHz, chloroform-d) δ ppm 0.60 (d, J = 6.8 Hz, 3H), 0.87-1.02 (m, 3H), 1.39 (t, J = 7.2 Hz, 3H), 1.50-1.62 (m, 1H), 3.27 (d, J = 9.9 Hz, 1H), 3.41 (d, J = 13.2 Hz, 2H), 3.84 (dd, J = 9.9, 3.1 Hz, 1H), 4.04 (d, 3H), 3.44 (d, J=13.4 Hz, 2H), 3.83 (d, J=13.7 Hz, 2H), 3.96 (d, J=13.6 Hz, 2H), 3.13 (d, J=13.9 Hz, 2H), 3.21 (d, J=13.2 Hz, 2H), 4.21 (m, 2H), 7.18 (m, 10H); Method D; Rt: 2.54 min. m/z: 356 (M+H) ⁺ exact mass: 355.2 and 2 diastereomers (1.45 g); ¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.35 (d, J=6.8 Hz, 3H), 0.92 (d, J=7.0 Hz, 3H), 1.43 (t, J=7.2 Hz, 3H), 2.08 (m, 2H), 3.32 (d, J=9.2 Hz, 1H), 3.44 (d, J=13.4 Hz, 2H), 3.83 (m, 1H), 3.90 (d, J = 13.6 Hz, 2H), 4.23-4.45 (m, 2H), 7.20-7.28 (m, 2H), 7.29-7.38 (m, 8H); Method D; Rt: 2.47 min. m/z: 356 (M+H) ⁺ exact mass: 355.2

At -70 ° C, LAH (2.29 mL, 1 M in THF, 4.57 mmol) was added to a solution of diastereomer 2 (1.35 g, 3.81 mmol) in dry THF (30 mL). The reaction mixture was slowly heated to room temperature and stirred overnight. LAH (0.20 mL, 1 M in THF, 0.20 mmol) was added and the reaction mixture was stirred for 4.5 hours. The reaction mixture was carefully quenched with EtOAc (30 mL) and stirred for 5 minutes. Na ₂ SO ₄ .10H ₂ O was then added and the mixture was stirred again for 15 min. Anhydrous Na ₂ SO ₄ was then added. The solid was filtered out and the filtrate was evaporated to dryness. The residue was purified on silica (0% to 50% EtOAc in DCM) to produce 2- (dibenzylamino) -4-methyl-pentane-1,3-diol (1.19 g) as a clear oil. ¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.65 (d, J = 6.8 Hz, 3H), 0.89 (d, J = 6.8 Hz, 3H), 1.44-1.73 (m, 2H), 1.99 (dtd, J = 13.6, 6.8, 6.8, 4.8 Hz, 1H), 2.79 (q, J = 5.9 Hz, 1H), 3.61-3.86 (m, 6H), 3.96 (dd, J = 11.1, 6.3 Hz, 1H), 7.14-7.45 (m, 10H); Method D; Rt: 2.19 min. m/z: 314 (M+H) ⁺ exact mass: 313.2.

Pd (OH) ₂ / C (50% w / w relative to A) was added to a solution of 2- (dibenzylamino) -4-methyl-pentane-1,3-diol in degassed MeOH and the resulting suspension was stirred at room temperature under a hydrogen atmosphere for 1 hour. The reaction mixture was filtered through a pad of celite and concentrated in vacuo to give 2-amino-4-methyl-pentane-1,3-diol (485 mg). ¹ HNMR (400MHz, chloroform-d) δppm 0.93 (d, J=6.6Hz, 3H), 1.00 (d, J=6.6Hz, 3H), 1.79 (dq, J=13.5, 6.8Hz, 1H), 2.44 (br s, 4H), 3.00 (q, J=4.7Hz, 1H), 3.28 (dd, J=7.2, 5.0Hz, 1H), 3.65-3.81 (m, 2H).

2-Amino-4-methyl-pentane-1,3-diol (485 mg, 3.64 mmol) was suspended in DCM (20 mL) and DIPEA (1.26 mL, 0.75 g/mL, 7.28 mmol) was added. The reaction mixture was stirred for 5 minutes. Ethyl 4-chlorosulfonyl-3-fluoro-1-methyl-pyrrole-2-carboxylate (982 mg, 3.64 mmol) was added. The suspension was stirred at room temperature for 5 hours. The reaction mixture was diluted with some DCM and then extracted with _NaHCO (aqueous, saturated). The water layer was extracted twice more with DCM. The combined organic layers were evaporated to dryness and the residue was purified by silica gel chromatography (0% to 100% EtOAc in DCM) to give ethyl 3-fluoro-4-[[2-hydroxy-1-(hydroxymethyl)-3-methyl-butyl]sulfamoyl]-1-methyl-pyrrole-2-carboxylate (870 mg) as a white sticky solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δppm 0.68 (d, J=6.6Hz, 3H), 0.83 (d, J=6.8Hz, 3H), 1.28 (t, J=7.0Hz, 3H), 1.74-1.84 (m, 1H), 3.05-3.17 (m, 1H), 3.17- 3.25 (m, 1H), 3.41-3.51 (m, 2H), 3.81 (s, 3H), 4.27 (q, J=7.0Hz, 2H), 4.33 (t, J=5.5Hz, 1H), 4.53 (d, J=5.7Hz, 1H), 7.28 (br d, J=8.1Hz, 1H), 7.52 (d, J=4.8 Hz, 1H); Method D; Rt: 1.45 min. m/z: 367 (M+H) ⁺ exact mass: 366.1.

To a solution of ethyl 3-fluoro-4-[[2-hydroxy-1-(hydroxymethyl)-3-methyl-butyl]sulfamoyl]-1-methyl-pyrrole-2-carboxylate (410 mg, 1.06 mmol) and 3,4-difluoroaniline (0.13 mL, 1.29 g/mL, 1.28 mmol) in dry THF (10 mL) was added lithium bis(trimethylsilyl)amide (5.3 mL, 1 M in THF, 5.3 mmol) dropwise at room temperature under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 30 min. The reaction mixture was quenched with _NH4Cl (aqueous saturated) and then diluted with EtOAc. The aqueous layer was extracted twice with EtOAc. The combined organic layers were dried over _Na2SO4 , _filtered , and concentrated under reduced pressure. The residue was triturated with diethyl ether to give N-(3,4-difluorophenyl)-3-fluoro-4-[[2-hydroxy-1-(hydroxymethyl)-3-methyl-butyl]sulfamoyl]-1-methyl-pyrrole-2-carboxamide (253 mg) as a white solid.

N-(3,4-difluorophenyl)-3-fluoro-4-[[2-hydroxy-1-(hydroxymethyl)-3-methyl-butyl]-sulfamoyl]-1-methyl-pyrrole-2-carboxamide (253 mg, 0.55 mmol) and cesium fluoride (335 mg, 2.21 mmol) were dissolved in dry DMF and heated at 110 ° C overnight. The reaction mixture was slowly added to an ice/water mixture. When the suspension had reached room temperature, the yellow solid formed was filtered out. The aqueous layer was extracted with ether. The solid and the ether crude product were redissolved in MeOH and evaporated with diatomaceous earth to purify by silica gel chromatography (0% to 75% EtOAc in DCM) to produce compound 114. The racemic mixture was separated into enantiomers 114a (69 mg); ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.83 (d, J=6.8 Hz, 3H), 0.92 (d, J=6.8 Hz, 3H), 2.01 (quind, J=6.8, 6.8, 6.8, 6.8, 3.0 Hz, 1H), 3.21-3.29 (m, 1H), 3.47-3.62 (m, 1H), 3.82 (s, 3H), 3.97 (dd, J=12.7, 8.9 Hz, 1H), 4.89 (dd, J=12.7, 1.9 Hz, 1H), 4.95 (d, ppm 0.83 (d, J = 6.8 Hz, 3H), 0.92 (d, J = 7.0 Hz ^, 3H), 2.01 (quind, J = 6.8 ^, _... 6.8, 3.1 Hz, 1H), 3.23-3.30 (m, 1H), 3.49-3.62 (m, 1H), 3.82 (s, 3H), 3.97 (dd, J = 12.7, 8.9 Hz, 1H), 4.89 (dd, J = 12.5, 1.8 Hz, 1H), 4.95 (d, J = 6.6 Hz, 1H), 7.33-7.51 (m, 3H), 7.52-7.65 (m, 1H), 7.87 (ddd, J = 13.2, 7.5, 2.4 Hz, 1H), 9.43 (s, 1H); Method D; Rt: 1.84 min. m/z: 430 (M+H) ⁺ exact mass: 429.1; MP: 247.3 °C, by preparative SFC (stationary phase: Chiralpak Diacel AD 20x250 mm, mobile phase: _CO2 , EtOH with 0.4% _iPrNH2 ). Method K; Rt: 114a: 1.18 min, 114b: 1.79 min.

Compound 115: (3R)-3-[Cyclopropyl(hydroxy)methyl]-N-[3-(difluoromethyl)-4-fluoro-phenyl]-7-methyl 1,1-dioxo-3,4-dihydro-2H-pyrrolo[3,4-b][1,4,5]oxatriazepine-6-carboxamide

Compound 115 (541 mg) was prepared similarly as described for the preparation of compound 105 using 3-(difluoromethyl)-4-fluoro-aniline instead of 3,4-difluoroaniline. The racemic mixture was separated into its epimers by preparative SFC (stationary phase: Chiralpak Diacel AD 20x250 mm, mobile phase: _CO2 , EtOH + _0.4iPrNH2 ) to yield 115a (130 mg) ^1H NMR (400 MHz, DMSO- _d6 ) δ ppm 0.20-0.55 (m, 4H), 0.98-1.12 (m, 1H), 3.02-3.16 (m, 1H), 3.55-3.70 (m, 1H), 3.83 (s, 3H), 4.02 (dd, J = 12.9, 9.1 Hz, 1H), 4.90 (dd, J = 12.8, 1.8 Hz, 1H), 5.01 (br d, J = 4.6 Hz, 1H), 4.77 (br d, J = 5.9 Hz, 1H), 4.91 (br d, J = 6.8 Hz, 1H), 4. 1H), 7.02-7.40 (m, 2H), 7.47 (s, 1H), 7.60 (br s, 1H), 7.76-7.89 (m, 1H), 8.05 (dd, J=6.3, 2.5 Hz, 1H), 9.47 (s, 1H); Method D; Rt: 1.76 min. m/z: 458 (MH) ^- Exact mass: 459.1 and 115b (44 mg) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.16-0.27 (m, 1H), 0.27-0.36 (m, 1H), 0.37-0.50 d, J = 4.2 Hz, 1H), 7.02-7.57 (m, 4H), 7.75-7.86 (m, 1H), 8.03 (dd, J = 6.4, 2.6 Hz, 1H), 9.48 (s, 1H); Method D; Rt: 1.76 min. m/z: 458 (MH) - Exact mass: 459.1; MP: 240.7°C. Method N; Rt: 115a: 1.75 min, 115b: 2.01 min.

Compound 116: N-(3-cyano-4-fluoro-phenyl)-3-(1-hydroxy-1-methyl-ethyl)-7-methyl-1,1-diol Oxy-2,3,4,5-tetrahydropyrrolo[3,4-f]triazepine-6-carboxamide

Compound 116 (200 mg) was prepared similarly as described for compound 113 using 5-amino-2-fluoro-benzonitrile instead of 3,4-difluoroaniline. The racemic mixture was separated into its enantiomers and purified by preparative SFC (stationary phase: Chiralpak Diacel AD 20x250 mm, mobile phase: _CO2 , EtOH + 0.4iPrNH2) to yield 116a (54 mg); ^1H NMR (400 MHz, DMSO- _d6 ) δ ppm 1.03 (s, 3H), 1.17 (s, 3H), 1.28-1.39 (m, 1H), 2.17 ₍ br dd, J = 14.0, 6.5 Hz, 1H), 2.66-2.79 (m, 1H), 3.06 (br dd, J = 14.9, 6.3 Hz, 1H), 3.22-3.29 (m, 1H), 3.69 (s, 3H), 4.39 (s, 1H), 6.84 (br d, J = 10.6 Hz, 1H), 7.45 (s, 1H), 7.54 (t, J = 9.1 Hz, 1H), 7.96 (ddd, J = 9.2, 4.9, 2.6 Hz, 1H), 8.19 (dd, J = 5.9, 2.6 Hz, 1H), 10.59 (s, 1H); Method D; Rt: 1.49 min. m/z: 419 (MH) - Exact mass: 420.1 and 116b (52 _mg ); ¹ H NMR (400 MHz, DMSO- _d6 ) δ ppm 1.03 (s, 3H), 1.17 (s, 3H), 1.34 (q, J = 11.5 Hz, 1H), 2.17 (br d, J = 10.6 Hz, 1H), 7.45 (s, 1H), 7.54 (t, J = 9.1 Hz, 1H), 7.96 (ddd, J = 9.1 , 4.8 , 2.8 Hz, 1H), 8.19 (dd, J = 5.7 , 2.6 Hz, 1H), 10.59 (s, 1H); Method D; Rt: 1.49 min. m/z: 419 (MH) ^- Exact mass: 420.1. Method F; Rt: 116a: 1.29 min, 116b: 2.03 min.

Compound 117: N-(3-cyano-4-fluoro-phenyl)-7-methyl-1,1-dioxo-3-(2,2,2-trifluoro-1-hydroxy- 1-methyl-ethyl)-2,3,4,5-tetrahydropyrrolo[3,4-f]triazepine-6-carboxamide

A solution of methyl 3-acetyl-7-methyl-1,1-dioxo-2,3,4,5-tetrahydropyrrolo[3,4-f]triazepine-6-carboxylate (156 mg, 0.52 mmol), (trifluoromethyl)trimethylsilane (220 mg, 1.55 mmol) and TBAF (13.5 mg, 0.052 mmol) in DMF (5 ml) was stirred at 100° C. for 2 hours. (Trifluoromethyl)trimethylsilane (220 mg, 1.55 mmol) and CsF (79 mg, 0.52 mmol) were added to the reaction mixture. The reaction mixture was heated at 100° C. for 1 hour. The mixture was then cooled to room temperature and HCl (aqueous, 1 M, 2 ml) was added. After 18 hours, the mixture was quenched with NaHCO ₃ (aqueous saturated, 20 mL) and the product was extracted with (4 x 6 mL). The combined organic layers were dried over Na ₂ SO ₄ , evaporated and purified by silica gel column chromatography (EtOAc in heptane from 0 to 100%) to give methyl 7-methyl-1,1-dioxo-3-(2,2,2-trifluoro-1-hydroxy-1-methyl-ethyl)-2,3,4,5-tetrahydropyrrolo[3,4-f]triazepine-6-carboxylate (36 mg) as a yellow powder. Method B; Rt: 0.76 min. m/z: 369 (MH) ^- Exact mass: 370.1.

Methyl 7-methyl-1,1-dioxo-3-(2,2,2-trifluoro-1-hydroxy-1-methyl-ethyl)-2,3,4,5-tetrahydropyrrolo[3,4-f]triazepine-6-carboxylate (36 mg, 0.097 mmol) and 5-amino-2-fluoro-benzonitrile (17 mg, 0.13 mmol) were dissolved in THF (5 mL). Lithium bis(trimethylsilyl)amide (0.63 mL, 1 M in THF, 0.63 mmol) was added and the reaction mixture was stirred at room temperature for 1 hour. The reaction was quenched with NH ₄ Cl (saturated, aqueous, 5 mL) and the organic layer was separated. The aqueous layer was extracted with EtOAc (2×10 mL) and the combined organic layers were evaporated to dryness. The residue was purified using preparative HPLC (stationary phase: RP XBridge Prep C18 OBD-10 μm, 50 x 150 mm, mobile phase: 0.25% NH ₄ HCO ₃ solution in water, ACN). The obtained product was purified using silica gel column chromatography (EtOAc in heptane from 0 to 100%) to give compound 117 (18 mg) as a white powder. ¹ H NMR (600MHz, DMSO-d ₆ ) δppm 1.20 (s, 3H), 1.38-1.46 (m, 1H), 2.13 (br dd, J=13.8, 7.0Hz, 1H), 2.75-2.80 (m, 1H), 3.07-3.15 (m, 1H), 3.70 (s, 3H), 3.78 (br t, J=10.8 Hz, 1H), 6.16 (s, 1H), 7.23 (d, J=11.2Hz, 1H), 7.49 (s, 1H), 7.55 (t, J=9.1Hz, 1H), 7.96 (ddd, J=9.2, 4.8, 2.7Hz, 1H), 8.19 (dd, J=5.7, 2.6 Hz, 1H), 10.63 (s, 1H); Method B; Rt: 0.86 min. m/z: 473 (MH) ^- Exact mass: 474.1.

Compound 118: N-(3-cyano-4-fluoro-phenyl)-3-(1,1-difluoroethyl)-7-methyl-1,1-dioxo-2,3- 4,5-Tetrahydropyrrolo[3,4-f]triazepine-6-carboxamide

To a solution of methyl 3-acetyl-7-methyl-1,1-dioxo-2,3,4,5-tetrahydropyrrolo[3,4-f]triazepine-6-carboxylate (518 mg, 1.72 mmol) in DCM (7 mL) was added DAST (0.69 mL, 1.32 g/mL, 5.7 mmol) at room temperature. The reaction mixture was stirred for 18 hours. DAST (0.69 mL, 1.32 g/mL, 5.7 mmol) was added and the reaction mixture was stirred for 18 hours, cooled to 0°C and quenched by the addition of NaCl (aqueous saturated, 2 mL). The aqueous phase was separated and extracted with DCM (3 x 8 mL). The combined organic layers were dried over _Na2SO4 , _filtered and concentrated. The residue was purified by silica gel column chromatography (EtOAc in heptane 0-50%) to give methyl 3-(1,1-difluoroethyl)-7-methyl-1,1-dioxo-2,3,4,5-tetrahydropyrrolo[3,4-f]triazepine-6-carboxylate (56 mg). Method B; Rt: 0.84 min. m/z: 321 (MH) ^- Exact mass: 322.1.

Methyl 3-(1,1-difluoroethyl)-7-methyl-1,1-dioxo-2,3,4,5-tetrahydropyrrolo[3,4-f]triazepine-6-carboxylate (56 mg, 0.15 mmol) and 5-amino-2-fluoro-benzonitrile (26 mg, 0.19 mmol) were dissolved in THF (3 mL). Lithium bis(trimethylsilyl)amide (1 mL, 1 M in THF, 1 mmol) was added and the reaction mixture was stirred at room temperature for 1 hour. The reaction was quenched with _NH4Cl (saturated, aqueous, 5 mL) and the organic layer was separated. The aqueous layer was extracted with EtOAc (2 x 10 mL) and the combined organic layers were evaporated to dryness. The residue was purified using silica gel column chromatography (EtOAc in heptane from 0 to 100%). The obtained product was purified by HPLC (stationary phase: RP XBridge Prep C18 OBD-10 μm, 50×150 mm, mobile phase: 0.25% NH ₄ HCO ₃ in water, ACN) to give Compound 118 (21 mg). ^1H NMR (600 MHz, DMSO- _d6 ) δ ppm 1.48-1.59 (m, 1H), 1.64 (t, J = 19.3 Hz, 3H), 2.04-2.11 (m, 1H), 2.77-2.88 (m, 1H), 3.09-3.19 (m, 1H), 3.69-3.86 (m, 4H), 7.50-7.70 (m, 3H), 7.96 (ddd, J = 9.2, 4.8, 2.6 Hz, 1H), 8.19 (dd, J = 5.8, 2.8 Hz, 1H), 10.64 (br s, 1H); Method B; Rt: 0.93 min. m/z: 425 (MH) ^- Exact mass: 426.1.

Compound 119: N-(3-cyano-4-fluoro-phenyl)-3-(1-hydroxy-2-methyl-propyl)-7-methyl-1,1-diol Oxy-3,4-dihydro-2H-pyrrolo[3,4-b][1,4,5]oxatriazepine-6-carboxamide

Compound 119 (165 mg) was prepared similarly as described for compound 114 using 5-amino-2-fluoro-benzonitrile instead of 3,4-difluoroaniline. The racemic mixture was separated into its epimers by preparative SFC (stationary phase: Chiralpak Diacel AD20 x 250 mm, mobile phase: CO ₂ , EtOH + 0.4iPrNH ₂ ) to yield 119a (49 mg); ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.83 (d, J = 6.8 Hz, 3H), 0.92 (d, J = 6.8 Hz, 3H), 1.95-2.08 (m, 1H), 3.23-3.30 (m, 1H), 3.48-3.62 (m, 1H), 3.83 (s, 3H), 3.97 (dd, J = 12.8, 9.0 Hz, 1H), 4.87-4.99 (m, 2H), 7.46-7.55 (m, 2H); H), 7.60 (d, J = 9.9 Hz, 1H), 8.05 (ddd, J = 9.1, 4.8, 2.8 Hz, 1H), 8.21 (dd, J = 5.7, 2.6 Hz, 1H), 9.52 (s, 1H); Method D; Rt: 1.75 min. m/z: 435 (MH) ^- Exact mass: 436.1; MP: 213.7 °C and 119b (44 mg); ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.84 (d, J = 6.8 Hz, 3H), 0.92 (d, J = 7.0 Hz, 3H), 2.02 (quind, J=6.8, 6.8, 6.8, 6.8, 3.0Hz, 1H), 3.24-3.30 (m, 1H), 3.56 (qd, J=9.4, 1.7Hz, 1H), 3.83 (s, 3H), 3.97 (dd, J=12.8, 9.0Hz, 1H), 4.86- 5.01 (m, 2H), 7.45-7.55 (m, 2H), 7.60 (d, J=9.9Hz, 1H), 8.05 (ddd, J=9.2, 4.9, 2.6Hz, 1H), 8.21 (dd, J=5.8, 2.8Hz, 1H), 9.52 (s, 1H); Method D; Rt: 1.75min.m/z: 435 (MH) ^Exact mass: 436.1; MP: 213.7°C. Method N; Rt: 119a: 1.50 min, 119b: 2.78 min.

Compound 120: (3R)-N-(3-cyano-4-fluoro-phenyl)-3-[cyclopropyl(hydroxy)methyl]-7-methyl-1,1- 6-Dioxo-3,4-dihydro-2H-pyrrolo[3,4-b][1,4,5]oxatriazepine-2-carboxamide

Compound 120 (225 mg) was prepared similarly as described for compound 105 using 5-amino-2-fluoro-benzonitrile instead of 3,4-difluoroaniline. The racemic mixture was separated into its diastereomers by preparative SFC (stationary phase: Chiralpak Diacel AD20 x 250 mm, mobile phase: CO ₂ , EtOH + 0.4iPrNH ₂ ) to yield 120a (84 mg) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.23-0.52 (m, 4H), 0.98-1.11 (m, 1H), 3.03-3.14 (m, 1H), 3.57-3.69 (m, 1H), 3.83 (s, 3H), 4.01 (dd, J=12.8, 9.2 Hz, 1H), 4.94 (dd, J=12.8, 1.8 Hz, 1H), 5.01 (d, J=5.5 Hz, 1H), 7.45-7.55 (m, 1H). (m, 2H), 7.62 (d, J = 9.9 Hz, 1H), 8.06 (ddd, J = 9.2, 4.8, 2.9 Hz, 1H), 8.21 (dd, J = 5.8, 2.8 Hz, 1H), 9.52 (s, 1H); Method D; Rt: 1.69 min. m/z: 433 (MH) ^- Exact mass: 434.1 and 120b (36 mg) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.15-0.28 (m, 1H), 0.28-0.36 (m, 1H), 0.36-0.49 (m, 2H), 3H), 0.95-1.08 (m, 1H), 3.09-3.16 (m, 1H), 3.73-3.81 (m, 1H), 3.83 (s, 3H), 4.05 (dd, J=12.8, 9.2 Hz, 1H), 4.77 (dd, J=12.5, 1.3 Hz, 1H), 5.02 (d, J=5.1 Hz, 1H), 7.41-7.58 (m, 3H), 8.04 (ddd, J=9.2, 4.8, 2.9 Hz, 1H), 8.19 (dd, J=5.7, 2.6 Hz, 1H), 9.54 (s, 1H); Method D; Rt: 1.69 min. m/z: 433 (MH) ^- Exact mass: 434.1; MP: 233.9°C. Method O; Rt: 120a: 1.81 min, 120b: 2.77 min.

Compound 121: (3S)-N-(3,4-difluorophenyl)-3-(1-fluoro-1-methyl-ethyl)-7-methyl-1,1-dioxo- 3,4-Dihydro-2H-pyrrolo[3,4-b][1,4,5]oxatriazepine-6-carboxamide

At 0 ° C, under a nitrogen atmosphere, diethylaminosulfur trifluoride (90 μL, 1M, 0.09 mmol) was added dropwise to a solution of compound 94 (25 mg, 0.06 mmol) in DCM (0.46 mL, 1.33 g/mL, 7.2 mmol). The reaction mixture was stirred at 0 ° C for 15 minutes. The reaction mixture was allowed to reach room temperature and concentrated under reduced pressure. The residue was purified by preparative HPLC (stationary phase: RP Vydac Denali C18-10 μm, 200 g, 5 cm, mobile phase: 0.25 _{% NH4HCO3} solution in water, MeOH). The obtained product was purified by preparative SFC (stationary phase: Chiralpak Diacel AD 20 microm 2000 gr, mobile phase: _CO2 , EtOH + _0.4iPrNH2 ) to produce compound 121 (46.9 mg). ¹ H NMR (400MHz, DMSO-d ₆ ) δppm 1.41 (dd, J=39.2, 22.2Hz, 6 H), 3.72-3.81 (m, 1H), 3.83 (s, 3H), 4.01 (dd, J=12.4, 9.1Hz, 1H), 4.88 (d, J=11.4Hz, 1H), 7.34-7.54 (m, 3H), 7.82-7.93 (m, 2H), 9.43 (s, 1H); ¹⁹ F NMR (377MHz, DMSO-d ₆ ) δppm 144.56 (d, J=23.1Hz, 1F), -141.28 (s, 1F), -137.61 (d, J=23.1 Hz, 1F); Method D; Rt: 1.96 min. m/z: 416 (MH) ^- Exact mass: 417.1; MP: 239.8°C.

Compound 122: (3R)-N-(3-cyano-4-fluoro-phenyl)-3-(1-hydroxypropyl)-7-methyl-1,1-dioxo-3, 4-Dihydro-2H-pyrrolo[3,4-b][1,4,5]oxatriazepine-6-carboxamide

Compound 122 (262 mg) was prepared similarly as described for compound 105 using ethylmagnesium bromide instead of cyclopropylmagnesium bromide and 5-amino-2-fluoro-benzonitrile instead of 3,4-difluoroaniline. The racemic mixture was separated into its epimers by preparative SFC (stationary phase: Kromasil (R, R) Whelk-O 1 10/100, mobile phase: CO ₂ , EtOH + 0.4% iPrNH ₂ ) to yield compound 122a (113 mg); ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.92 (t, J = 7.4 Hz, 3H), 1.44 (dquin, J = 14.2, 7.2, 7.2, 7.2 Hz, 1 H), 1.65-1.79 (m, 1H), 3.35-3.44 (m, 1H), 3.44-3.56 (m, 1H), 3.83 (s, 3H), 3.98 (dd, J = 12.7, 8.9 Hz, 1H), 4.93 (dd, J = 12.8, 1.8 Hz, 1H), 4.98 (br d, J = 5.9 Hz, 1H), 7.44-7.55 (m, 2H), 7.61 (br d, J = 9.0 Hz, 1H), 8.05 (ddd, J = 9.2, 5.0, 2.8 Hz, 1H), 8.21 (dd, J = 5.7, 2.6 Hz, 1H), 9.51 (s, 1H); Method D; Rt: 1.67 min. m/z: 421 (MH) - exact mass: 422.1; MP: 222.3°C, and 122b (102 mg); ^1H NMR (400 MHz, DMSO- _d6 ) δ ppm 0.88(t, J=7.4 Hz, 3H), 1.28-1.44(m, 1H), 1.50-1.63(m, 1H), 3.54-3.66(m, 1H), 3.66-3.76 (m, 1H), 3.83 (s, 3H), 3.99 (dd, J=12.7, 9.1Hz, 1H), 4.74 (dd, J=12.7, 1.0Hz, 1H), 4.87 (d, J=5.3Hz, 1H), 7.37 (br s, 1H), 7.49 (s, 1 H), 7.52 (t, J=9.1Hz, 1H), 8.05 (ddd, J=9.3, 4.9, 2.8Hz, 1H), 8.19 (dd, J = 5.7, 2.6 Hz, 1H), 9.54 (s, 1H); Method D; Rt: 1.69 min. m/z: 421 (MH) ^- Exact mass: 422.1; MP: 252.2° C. Method L; Rt: 122a: 2.81 min, 122b: 3.50 min.

Compound 123: (3S)-N-(3,4-difluorophenyl)-7-methyl-1,1-dioxo-3-(2,2,2-trifluoro-1-hydroxy- ethyl)-3,4-dihydro-2H-pyrrolo[3,4-b][1,4,5]oxatriazepine-6-carboxamide

At room temperature, under nitrogen atmosphere, (trifluoromethyl) trimethylsilane (0.82mL, 0.96 g/mL, 5.6mmol) is added to tert-butyl (4S)-4-formyl-2,2-dimethyl-oxazolidine-3-formate (1.06g, 4.62mmol) and TBAF (0.11mL, 1M in THF, 0.11 mmol) in THF (28mL).The reaction mixture is stirred at room temperature overnight.Tetrabutylammonium fluoride (9.25mL, 1M, 9.25mmol) is added in the reaction mixture and continues to stir overnight.The reaction mixture is quenched with _NaHCO (aqueous saturation) and extracted with _EtOAc (3 times).The organic layer merged is through Na _SO dry, filter and under reduced pressure concentrate.

The residue was purified by silica gel column chromatography (heptane/ethyl acetate 100/0 to 0/100) to give tert-butyl (4S)-2,2-dimethyl-4-(2,2,2-trifluoro-1-hydroxy-ethyl)oxazolidine-3-carboxylate (1.42 g) as an oil.

HCl (4.6 mL, 4 M in dioxane, 18 mmol) was added dropwise to a solution of tert-butyl (4S)-2,2-dimethyl-4-(2,2,2-trifluoro-1-hydroxy-ethyl)oxazolidine-3-carboxylate (1.38 g, 4.62 mmol) in 1,4-dioxane (40 mL). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure to produce (2S)-2-amino-4,4,4-trifluoro-butane-1,3-diol (735 mg).

Ethyl 4-chlorosulfonyl-3-fluoro-1-methyl-pyrrole-2-carboxylate (1.06 g, 3.93 mmol) was added in portions to a solution of (2S)-2-amino-4,4,4-trifluoro-butane-1,3-diol (735 mg, 4.62 mmol) and DIPEA (4.78 mL, 0.75 g/mL, 27.7 mmol) in DCM (30 mL). The reaction mixture was stirred at room temperature overnight. The reaction mixture was quenched with NH ₄ Cl (saturated, aqueous) and dissolved in DCM. The two layers were separated and the aqueous layer was extracted twice with DCM. The combined organic layers were dried over Na2SO4, filtered off and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (heptane/ethyl acetate 100/0 to 0/100) to give ethyl 3-fluoro-1-methyl-4-[[3,3,3-trifluoro-2-hydroxy-1-(hydroxymethyl)propyl]sulfamoyl]pyrrole-2-carboxylate (610 mg) as a beige solid. ^1H NMR (400 MHz, DMSO- _d6 ) δ ppm 1.28 (s, 3H), 3.33-3.42 (m, 1H), 3.36 (s, 1H), 3.43-3.58 (m, 2H), 3.81 (s, 3H), 4.04 (dt, J=7.0, 3.7 Hz, 1H), 4.27 (d, J=7.0 Hz, 2H), 4.56 (br t, J=5.2 Hz, 1H), 6.51 (br d, J=6.6 Hz, 1H), 7.52 (d, J=4.6 Hz, 1H), 7.75 (br s, 1H); Method B; Rt: 0.73 min. m/z: 391 (MH) ^- Exact mass: 392.1.

Lithium bis(trimethylsilyl)amide (7.8 mL, 1 M in THF, 7.8 mmol) was added dropwise to a solution of ethyl 3-fluoro-1-methyl-4-[[3,3,3-trifluoro-2-hydroxy-1-(hydroxymethyl)propyl]sulfamoyl]pyrrole-2-carboxylate (610 mg, 1.55 mmol) and 3,4-difluoroaniline (0.19 mL, 1.29 g/mL, 1.9 mmol) in THF (20 mL). The reaction mixture was stirred at room temperature overnight. Lithium bis(trimethylsilyl)amide (4.7 mL, 1 M in THF, 4.7 mmol) was added and the reaction mixture was stirred for another 30 minutes. The reaction mixture was quenched with NH ₄ Cl (saturated, aqueous) and diluted with EtOAc. The two layers were separated and the aqueous layer was extracted twice with EtOAc. The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was precipitated in DCM (a small amount) and diethyl ether to give N-(3,4-difluorophenyl)-3-fluoro-1-methyl-4-[[3,3,3-trifluoro-2-hydroxy-1-(hydroxymethyl)propyl]sulfamoyl]pyrrole-2-carboxamide (300 mg) as a beige solid. After purification of the filtrate by silica gel column chromatography (heptane/ethyl acetate 100/0 to 0/100), a second crop of product (280 mg) was obtained.

Cesium fluoride (741 mg, 4.88 mmol) was added to a solution of N-(3,4-difluorophenyl)-3-fluoro-1-methyl-4-[[3,3,3-trifluoro-2-hydroxy-1-(hydroxymethyl)propyl]sulfamoyl]pyrrole-2-carboxamide (580 mg, 1.22 mmol) in DMF (13 mL). The reaction mixture was heated at 105° C. overnight. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (heptane/ethyl acetate 100/0 to 0/100). The obtained product was purified by preparative SFC (stationary phase: Chiralpak Diacel AS 20×250 mm, mobile phase: CO ₂ , iPrOH+0.4iPrNH ₂ ) to produce one epimer of compound 123 (30.7 mg). ¹ H NMR (400MHz, DMSO-d ₆ ) δppm 3.82 (s, 3H), 3.83-3.88 (m, 1H), 4.08 (br s, 1H), 4.18 (dd, J=13.0, 9.5 Hz, 1H), 4.86 (dd, J=12.9, 2.5Hz, 1H), 6.93 (br d, J=6.1Hz, 1H), 7.35-7.44 (m, 1H), 7.44-7.50 (m, 1H), 7.50 (s, 1H), 7.87 (ddd, J=13.3, 7.5, 2.5Hz, 1H), 8.00 (br s, 1H), 9.43 (s, 1H); method D; Rt: 1.82min.m/z: 454(MH) ^- Exact mass: 455.1.

Compound 124: (3R)-N-[3-(Difluoromethyl)-4-fluoro-phenyl]-3-(1-hydroxypropyl)-7-methyl-1,1- 6-Dioxo-3,4-dihydro-2H-pyrrolo[3,4-b][1,4,5]oxatriazepine-2-carboxamide

Compound 124 (445 mg) was prepared similarly as described for compound 122 using 3-(difluoromethyl)-4-fluoro-aniline instead of 5-amino-2-fluoro-benzonitrile. The racemic mixture was separated into its epimers by preparative SFC (stationary phase: Kromasil (R, R) Whelk-O 1 10/100, mobile phase: CO ₂ , EtOH + 0.4% iPrNH ₂ ) to yield compound 124a (209 mg); ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.92 (t, J = 7.3 Hz, 3H), 1.44 (dquin, J = 14.2, 7.3, 7.3, 7.3 Hz, 1H), 1.72 (dqd, J = 14.1, 7.2, 7.2, 7.2, 3.1 Hz, 1H), 3.26-3.44 (m, 1H), 3.49 (br t, J = 7.9 Hz, 1H), 3.83 (s, 3H), 3.99 (dd, J = 12.7, 8.9 Hz, 1H), 4.89 (dd, J = 12.7, 1.9 Hz, 1H), 4.98 (d, J = 6.2 Hz, 1H), 7.03-7.40 (m, 2H), 7.47 (s, 1H), 7.58 (br s, 1H), 7.76-7.88 (m, 1H), 8.04 (dd, J = 6.4, 2.6 Hz, 1H), 9.47 (s, 1H); Method D; Rt: 1.74 min. m/z: 446 (MH) ^- exact mass: 447.1, and 124b (159 mg); ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.88(t, J=7.4Hz, 3H), 1.29-1.44 (m, 1H), 1.49-1.64 (m, 1H), 3.55-3.65 (m, 1H), 3.66-3.77 (m, 1H), 3.83 (s, 3H), 4.00 (dd, J=12.7, 9.1Hz, 1H), 4.62-4.76 (m, 1H), 4.86 (br d, J＝4.8Hz, 1H), 7.04-7.41(m, 3H), 7.46(s, 1H), 7.77-7.87(m, 1H), 8.03 (dd, J=6.3, 2.5 Hz, 1H), 9.49 (s, 1H); Method D; Rt: 1.77 min. m/z: 446 (MH) ^- Exact mass: 447.1; MP: 224.5° C. Method M; Rt: 124a: 2.53 min, 124b: 3.56 min.

Compound 125: N-(3,4-difluorophenyl)-3,7-dimethyl-1,1-dioxo-3-phenyl-2,4-dihydropyrrolo[3-hydroxy-2-nitro-1-nitrophenyl] ... [3,4-b][1,4,5]oxatriazepine _- 6 _- carboxamide

Compound 125 (85 mg) was prepared similarly to that described for compound 14, using 2-amino-2-phenylpropan-1-ol hydrochloride instead of DL-alaninol and DCM instead of THF as solvent in the first step. Ring closure was achieved after heating in DMF at 110° C. for 90 minutes and compound 125 was purified on silica using a gradient from heptane to EtOAc. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.60 (s, 3H), 3.82 (s, 3H), 4.89-5.00 (m, 2H), 7.25-7.49 (m, 6H), 7.58 (d, J=7.6 Hz, 2H), 7.82 ^- 7.89 (m, 1H), 8.35 (s, 1H), 9.43 (s, 1H); Method D; Rt: 2.05 min. m/z: 446 (MH) ^- exact mass: 447.1; MP: 256.6° C.

Compound 126: (3R)-N-(3,4-difluorophenyl)-3,7-dimethyl-1,1-dioxo-3-(2-pyridyl)-2,4- Dihydropyrrolo[3,4-b][1,4,5]oxatriazepine-6-carboxamide

Compound 126 (115 mg) was prepared similarly to that described for compound 125 using (2R)-2-amino-2-(2-pyridyl)propan-1-ol instead of 2-amino-2-phenylpropan-1-ol hydrochloride. After heating for 3 hours, ring closure was achieved and compound 126 was purified on silica using a gradient from heptane to EtOAc:EtOH 3:1. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.59 (s, 3H), 3.82 (s, 3H), 4.99 (d, J=13.3 Hz, 1H), 5.21 (d, J=13.3 Hz, 1H), 7.29-7.51 (m, 4H), 7.78-7.92 (m, 3H), 8.46-8.54 (m, 2H), 9.39 (s, 1H); Method D; Rt: 1.97 min. m/z: 447 (MH) ^- exact mass: 448.1; MP: 270.5° C.

Compound 127: (3S)-N-(3,4-difluorophenyl)-3,7-dimethyl-1,1-dioxo-3-(2-pyridyl)-2,4- Dihydropyrrolo[3,4-b][1,4,5]oxatriazepine-6-carboxamide

Compound 127 (145 mg) was prepared similarly as described for compound 126 using (2S)-2-amino-2-(2-pyridinyl)propan-1-ol instead of (2R)-2-amino-2-(2-pyridinyl)propan-1-ol hydrochloride. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.55-1.62 (m, 3H), 3.82 (s, 3H), 4.99 (d, J=13.3 Hz, 1H), 5.21 (d, J=13.3 Hz, 1H), 7.29-7.50 (m, 4H), 7.79-7.92 (m, 3H), 8.47-8.53 (m, 2H), 9.39 (s, 1H); Method D; Rt: 1.98 min. m/z: 447 (MH) ^- exact mass: 448.1; MP: 270.8° C.

Compound 128: (3S)-N-(3-cyano-4-fluoro-phenyl)-3,7-dimethyl-1,1-dioxo-3-(2-pyridinyl)- 2,4-Dihydropyrrolo[3,4-b][1,4,5]oxatriazepine-6-carboxamide

Compound 128 (55 mg) was prepared similarly as described for compound 127 using 5-amino-2-fluoro-benzonitrile instead of 3,4-difluoroaniline. ¹ H NMR (400MHz, DMSO-d ₆ ) δppm 1.59 (s, 3H), 3.83 (s, 3H), 4.99 (d, J=13.3Hz, 1H), 5.25 (d, J=13.3Hz, 1H), 7.31 (ddd, J=7.4, 4.8, 1.2Hz, 1H), 7.48-7.55 (m, 2H), 7.78-7.84 (m, 1H), 7.84-7.90 (m, 1H), 8.08 (ddd, J=9.2, 4.9, 2.7Hz, 1H), 8.21 (dd, J=5.7, 2.7Hz, 1H), 8.47-8.51 (m, 1H), 8.53 (s, 1 H), 9.47 (s, 1H); Method D; Rt: 1.89 min. m/z: 454 (MH) ^- Exact mass: 455.1: MP: 235.0°C

Compound 129: N-(3,4-difluorophenyl)-3-[methoxymethoxy(2-pyridyl)methyl]-7-methyl-1,1- Dioxo-3,4-dihydro-2H-pyrrolo[3,4-b][1,4,5]oxatriazepine-6-carboxamide.

At -70 ° C, to a cold solution of ethyl 2-(dibenzylamino) acetate (2.0 g, 7.1 mmol) in dry THF (40 mL), lithium bis(trimethylsilyl)amide (24.7 mL, 1 M in THF, 24.7 mmol) was added dropwise. The solution was slowly heated to -5 ° C and stirred for 3 hours. The reaction mixture was then cooled to -70 ° C again and 2-pyridinecarboxaldehyde (2.36 mL, 24.7 mmol) was slowly added and stirred at -70 ° C for 45 minutes. The reaction mixture was slowly heated to room temperature and quenched with NH ₄ Cl (aqueous, saturated, 50 mL). This was extracted with EtOAc (3 × 75 mL). The combined organic layers were dried over Na ₂ SO ₄ , filtered and evaporated to dryness. The residue was purified by silica gel column chromatography (0% to 20% EtOAc in heptane) and separated into its 2 diastereomers to yield diastereomer 1 (827 mg); Method B; Rt: 1.23 min. m/z: 391 (M+H) ⁺ exact mass: 390.2 and diastereomer 2 (813 mg); Method B; Rt: 1.19 min. m/z: 391 (M+H) ⁺ exact mass: 390.2.

To the solution of diastereomer 1 (827mg, 0.72mmol) in dry DCM (5mL), add DIPEA (1.12mL, 6.48mmol) followed by chloromethyl methyl ether (0.49 mL, 6.48mmol) and the reaction mixture was stirred at room temperature for 3 days. Add DIPEA (1.12mL, 6.48mmol) and chloromethyl methyl ether (0.49mL, 6.48mmol) and the reaction mixture was stirred for another 3 days. The reaction mixture was quenched with _NaHCO (aqueous, saturated, 25mL) and extracted with EtOAc (3 × 25mL). The organic layer merged was dried over Na ₂ SO ₄ , filtered and evaporated to dryness. The residue was purified using heptane to EtOAc gradient on silica, producing ethyl 2- (dibenzylamino) -3- (methoxymethoxy) -3- (2-pyridyl) propanoate (418mg) in a clear oily state. Method B; Rt: 1.35 min. m/z: 435 (M+H) ⁺ exact mass: 434.2.

At -70 ° C, LAH (0.72 mL, 2M in THF, 1.44 mmol) was added to a solution of ethyl 2-(dibenzylamino)-3-(methoxymethoxy)-3-(2-pyridyl) propanoate (418 mg, 0.96 mmol) in dry THF. After addition, the reaction mixture was slowly warmed to room temperature and stirred for 4.5 hours. The reaction mixture was carefully quenched with EtOAc and the mixture was stirred for 5 min. Na ₂ SO ₄ .10H ₂ O was then added and the mixture was stirred for another 15 min. Anhydrous Na ₂ SO ₄ was then added. The solid was filtered out and the filtrate was evaporated to dryness. The residue was purified using a DCM to EtOAc gradient on silica to produce 2-(dibenzylamino)-3-(methoxymethoxy)-3-(2-pyridyl) propan-1-ol (316 mg) as a transparent yellow oil.

Pd(OH) ₂ /C (150 mg) was added to a solution of 2-(dibenzylamino)-3-(methoxymethoxy)-3-(2-pyridyl)propan-1-ol (316 mg, 0.81 mmol) in degassed MeOH and the resulting suspension was stirred at room temperature overnight under H _2. The reaction mixture was filtered through a pad of celite and concentrated in vacuo to yield 2-amino-3-(methoxymethoxy)-3-(2-pyridyl)propan-1-ol (119 mg).

2-Amino-3-(methoxymethoxy)-3-(2-pyridyl)propan-1-ol (119 mg, 0.56 mmol) was dissolved in DCM (4 mL) and Hunin's base (0.193 mL, 1.12 mmol) was added followed by ethyl 4-chlorosulfonyl-3-fluoro-1-methyl-pyrrole-2-carboxylate (151 mg, 0.56 mmol). After 4 hours, the reaction mixture was diluted with DCM (5 mL) and then quenched with _NaHCO (aqueous, saturated, 5 mL). The aqueous layer was extracted with DCM (2 x 5 mL). The combined organic layers were evaporated to give a yellow foam. The crude product was recrystallized/triturated in DCM and stirred for 3 days. The white solid formed was filtered off and washed with some DIPE to give ethyl 3-fluoro-4-[[1-(hydroxymethyl)-2-(methoxymethoxy)-2-(2-pyridinyl)ethyl]sulfamoyl]-1-methyl-pyrrole-2-carboxylate (140 mg).

To a solution of ethyl 3-fluoro-4-[[1-(hydroxymethyl)-2-(methoxymethoxy)-2-(2-pyridyl)ethyl]sulfamoyl]-1-methyl-pyrrole-2-carboxylate (98 mg, 0.22 mmol) and 3,4-difluoroaniline (0.027 mL, 0.26 mmol) in dry THF (3 mL) was added lithium bis(trimethylsilyl)amide (0.88 mL, 1 M in THF, 0.88 mmol) dropwise under nitrogen and stirred at room temperature for 2.5 hours. The reaction mixture was then quenched with NH ₄ Cl (aqueous, saturated, 3 mL) and extracted with EtOAc (3×3 mL). The combined organic layers were dried over Na ₂ SO ₄ , filtered and evaporated to dryness. The residue was purified on silica using a DCM to EtOAc gradient to give N-(3,4-difluorophenyl)-3-fluoro-4-[[1-(hydroxymethyl)-2-(methoxymethoxy)-2-(2-pyridinyl)ethyl]sulfamoyl]-1-methyl-pyrrole-2-carboxamide as a brown solid (128 mg).

By N-(3,4-difluorophenyl)-3-fluoro-4-[[1-(hydroxymethyl)-2-(methoxymethoxy)-2-(2-pyridyl)ethyl]sulfamoyl]-1-methyl-pyrrole-2-carboxamide (128mg, 0.24mmol) and cesium fluoride (216mg, 1.42mmol) are dissolved in dry DMF (3mL) and immediately heated at 110 DEG C.The mixture is stirred at 110 DEG C for 7 hours.The reaction mixture is quenched with water (3mL) and the product is extracted with EtOAc (3X 3mL).The organic layer merged is evaporated and the residue is purified using DCM to EtOAc gradient on silica. The crude product was purified by preparative HPLC (stationary phase: RP XBridge Prep C18 OBD-10 μm, 30 x 150 mm, mobile phase: 0.25% NH ₄ HCO ₃ solution in water, ACN) to give crude compound 129 and crude compound 141. The obtained crude compound 129 was purified on silica using a DCM to EtOAc gradient to give compound 129 (14 mg) as a beige solid. ¹ HNMR (400MHz, chloroform-d) δppm 3.47 (s, 3H), 3.85-4.03 (m, 4H), 4.37-4.48 (m, 1H), 4.74 (dd, J=12.8, 2.0Hz, 1H), 4.78-4.96 (m, 2H), 5.10 (d, J=4.0Hz, 1H), 6.58-6.89 (m, 1H), 6.97-7.16 (m, 3H), 7.19-7.26 (m, 1H), 7.52- 7.64(m, 2H), 7.74(td, J=7.7, 1.8Hz, 1H), 8.42-8.53(m, 1H), 8.64(s, 1 H); Method D; Rt: 1.88 min. m/z: 509 (M+H) ⁺ exact mass: 508.1.

Compound 130: (3R)-N-(3,4-difluorophenyl)-3-(1-hydroxypropyl)-7-methyl-1,1-dioxo-3,4-difluorophenyl Hydrogen-2H-pyrrolo[3,4-b][1,4,5]oxatriazepine-6-carboxamide

Compound 130 (414 mg) was prepared similarly as described for compound 122 using 3,4-difluoroaniline instead of 5-amino-2-fluoro-benzonitrile. The racemic mixture was separated into its diastereomers by preparative SFC (stationary phase: Kromasil (R, R) Whelk-O 110/100, mobile phase: CO ₂ , EtOH-iPrOH (50-50) + 0.4% iPrNH ₂ ) to yield compound 130a (130 mg); ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.91 (t, J=7.4 Hz, 3H), 1.43 (dquin, J=14.2, 7.3, 7.3, 7.3, 7.3 Hz, 1H), 1.62-1.82 (m, 1H), 3.34-3.44 (m, 1H), 3.44-3.56 (m, 1H), 3.82 (s, 3H), 3.98 (dd, 3H). 1H), 4.90 (dd, J = 12.7, 1.9 Hz, 1H), 4.98 (d, J = 6.4 Hz, 1H), 7.34-7.44 (m, 1H), 7.44-7.51 (m, 2H), 7.60 (d, J = 9.7 Hz, 1H), 7.87 (ddd, J = 13.3, 7.5, 2.5 Hz, 1H), 9.42 (s, 1H); Method D; Rt: 1.76 min. m/z: 414 (MH) ^- exact mass: 415.1; MP: 217.4°C, and 130b (104 mg); ^1H NMR (400 MHz, DMSO- _d6 ) δ ppm 3H), 0.88 (t, J = 7.4 Hz, 3H), 1.29-1.44 (m, 1H), 1.49-1.65 (m, 1H), 3.54-3.66 (m, 1H), 3.66-3.77 (m, 1H), 3.83 (s, 3H), 3.99 (dd, J = 12.8, 9.0 Hz, 1H), 4.63-4.79 (m, 1H), 4.86 (d, J = 5.3 Hz, 1H), 7.25-7.55 (m, 4H), 7.86 (ddd, J = 13.1, 7.4, 2.5 Hz, 1H), 9.45 (s, 1H); Method D; Rt: 1.78 min. m/z: 414 (MH) ^- Exact mass: 415.1; MP: 214.6° C. Method S; Rt: 130a: 2.65 min, 130b: 3.46 min.

Compound 131: N-(3,4-difluorophenyl)-7-methyl-1,1-dioxo-spiro[4,5-dihydro-2H-pyrrolo[3,4- f]triazepine-3,3′-oxetane-6-carboxamide

Methyl 7-methyl-1,1-dioxo-spiro[2H-pyrrolo[3,4-f]triazepine-3,3'-oxetane]-6-carboxylate (450 mg, 1.51 mmol) was dissolved in methanol (200 mL). Under a nitrogen atmosphere, _Et3N (420 μL, 0.73 g/mL, 3 mmol) and Pd/C (10%) (161 mg, 0.15 mmol) were added. The reaction mixture was hydrogenated for 1 hour and then filtered through celite and the solids were washed with THF (4 x 80 mL). The filtrate was evaporated to dryness to give methyl 7-methyl-1,1-dioxo-spiro[4,5-dihydro-2H-pyrrolo[3,4-f]triazepine-3,3'-oxetane]-6-carboxylate (430 mg) as a white powder.

Methyl 7-methyl-1,1-dioxo-spiro[4,5-dihydro-2H-pyrrolo[3,4-f]triazepine-3,3'-oxetane]-6-carboxylate (107 mg, 0.36 mmol) and 3,4-difluoroaniline (51 mg, 0.39 mmol) were dissolved in THF (3 mL). Lithium bis(trimethylsilyl)amide (2.1 mL, 1 M in THF, 2.1 mmol) was added and the reaction mixture was stirred at room temperature for 30 minutes. The reaction was quenched with _NH4Cl (saturated, aqueous, 5 mL) and the organic layer was separated. The aqueous layer was extracted with EtOAc (2 x 5 mL) and the combined organic layers were concentrated to dryness. The residue was purified using preparative HPLC (stationary phase: RP XBridge Prep C18 OBD-10 μm, 50 x 150 mm, mobile phase: 0.25% NH ₄ HCO ₃ solution in water, ACN) to yield compound 131 as a white powder after recrystallization from DCM (80 mg). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 2.13-2.25 (m, 2H), 2.84-2.99 (m, 2H), 3.69 (s, 3H), 4.29 (d, J=6.4 Hz, 2H), 4.64 (d, J=6.2 Hz, 2H), 7.39-7.46 (m, 3H), 7.78-7.89 (m, 2H), 10.49 (br s, 1H); Method B; Rt: 0.81 min. m/z: 396 (MH) ^- Exact mass: 397.1.

Compound 132: N-(3,4-difluorophenyl)-7-methyl-1,1-dioxo-spiro[2H-pyrrolo[3,4-f]triazepine [3,3'-oxetane]-6-carboxamide

Compound 132 (84 mg) was prepared similarly as described for compound 84 using 3-vinyloxetane-3-amine hydrochloride instead of (2S,3R)-3-aminopent-4-en-2-ol hydrochloride. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 3.70 (s, 3H), 4.50 (d, J=6.4 Hz, 2H), 4.78 (d, J=6.2 Hz, 2H), 6.27 (d, J=12.8 Hz, 1H), 6.50 (d, J=12.8 Hz, 1H), 7.40-7.47 (m, 2H), 7.52 (s, 1H), 7.82-7.88 (m, 1H), 8.44 (br s, 1H), 10.76 (br s, 1H); Method B; Rt: 0.82 min. m/z: 394 (MH) ^- Exact mass: 395.1.

Compound 133: N-(3,4-difluorophenyl)-3,3,7-trimethyl-1,1-dioxo-2,4-dihydropyrrolo[3,4- b][1,4,5]oxatriazepine-6-carboxamide

Compound 133 (111 mg) was prepared similarly to that described for compound 83, using 2-amino-2-methyl-1-propanol instead of 2-amino-1,3-propanediol and ACN instead of THF in the first step. Ring closure was achieved after heating at 110° C. for 2 hours in DMF, and compound 133 was purified on silica using a gradient from heptane to EtOAc. ^1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.29 (s, 6H), 3.81 (s, 3H), 4.40 (s, 2H), 7.37-7.45 (m, 3H), 7.76-7.88 (m, 2H), 9.38 (s, 1H); Method B; Rt: 1.01 min. m/z: 384 (MH) ^- Exact mass: 385.1.

Compound 134: N-(3,4-difluorophenyl)-3-ethyl-3,7-dimethyl-1,1-dioxo-2,4-dihydropyrrolo[3-(4-fluorophenyl)-1-[4-(4-fluorophenyl)-2-(4-fluorophenyl)-3-ethyl-2,4-dihydropyrrolo]-1-[4-fluorophenyl)-1-[4-fluorophenyl]-3-ethyl-2,4-dihydropyrrolo]-1- [3,4-b][1,4,5]oxatriazepine-6-carboxamide

Compound 134 (121 mg) was prepared similarly as described for compound 133 using 2-amino-2-methylbutan-1-ol instead of 2-amino-2-methyl-1-propanol. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.92 (t, J=7.4 Hz, 3H), 1.22 (s, 3H), 1.41-1.50 (m, 1H), 1.71-1.80 (m, 1H), 3.81 (s, 3H), 4.31-4.53 (m, 2H), 7.37-7.44 (m, 3H), 7.64 (s, 1H), 7.81-7.88 (m, 1H), 9.35 (s, 1H); Method B; Rt: 1.07 min. m/z: 398 (MH) ^- Exact mass: 399.1. The racemic mixture was separated into enantiomers 134a (49 mg) and 134b (52 mg) by preparative SFC (stationary phase: Chiralpak Diacel AS 20 x 250 mm, mobile phase: _CO2 , EtOH with _0.4 % iPrNH2). Method T; Rt: 134a: 2.75 min, 134b: 2.92 min.

Compound 135: N-(3-cyano-4-fluoro-phenyl)-3,3,7-trimethyl-1,1-dioxo-2,4-dihydropyrrolo[3-(4-fluoro-2-phenyl)-3-nitro-1,1-dioxo-2,4-dihydropyrrolo]-1,1-dioxo-2,4-dihydropyrrolo[3-nitro-1,1-dioxo-2,4-dihydropyrrolo]-1 [3,4-b][1,4,5]oxatriazepine-6-carboxamide

Compound 135 (39 mg) was prepared similarly as described for compound 133 using 5-amino-2-fluoro-benzonitrile instead of 3,4-difluoroaniline. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.30 (s, 6H), 3.82 (s, 3H), 4.41 (s, 2H), 7.45 (s, 1H), 7.53 (t, J=9.1 Hz, 1H), 7.80 (s, 1H), 8.03 (ddd, J=9.2, 4.8, 2.9 Hz, 1H), 8.16 (dd, J=5.7, 2.6 Hz, 1H), 9.46 (s, 1H); Method B; Rt: 0.94 min. m/z: 391 (MH) ^- Exact mass: 392.1.

Compound 136: 7-methyl-1,1-dioxo-N-(3,4,5-trifluorophenyl)spiro[4,5-dihydro-2H-pyrrolo[3, 4-f]triazepine-3,3'-oxetane-6-carboxamide

Compound 136 (41 mg) was prepared similarly as described for compound 131 using 3,4,5-trifluoroaniline instead of 3,4-difluoroaniline. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 2.10-2.25 (m, 2H), 2.85-2.97 (m, 2H), 3.69 (s, 3H), 4.29 (d, J=6.4 Hz, 2H), 4.64 (d, J=6.2 Hz, 2H), 7.47 (s, 1H), 7.54-7.65 (m, 2H), 7.84 (s, 1H), 10.61 (s, 1H); Method D; Rt: 1.67 min. m/z: 414 (MH) ^- Exact mass: 415.1.

Compound 137: N-[3-(Difluoromethyl)-4-fluoro-phenyl]-7-methyl-1,1-dioxo-spiro[4,5-dihydro-2H- Pyrrolo[3,4-f]triazepine-3,3'-oxetane]-6-carboxamide

Compound 137 (64 mg) was prepared similarly as described for compound 131 using 3-(difluoromethyl)-4-fluoro-aniline instead of 3,4-difluoroaniline. ^1H NMR (400 MHz, DMSO- _d6 ) δ ppm 2.10-2.33 (m, 2H), 2.86-3.00 (m, 2H), 3.70 (s, 3H), 4.29 (d, J = 6.4 Hz, 2H), 4.65 (d, J = 6.2 Hz, 2H), 7.23 (br t, J = 54.2 Hz, 1H), 7.37 (t, J = 9.5 Hz, 1H), 7.45 (s, 1H), 7.77-7.89 (m, 2H), 8.06 (dd, J = 6.2, 2.4 Hz, 1H), 10.51 (s, 1H); Method D; Rt: 1.59 min. m/z: 428 (MH) ^- Exact mass: 429.1.

Compound 138: N-(3-cyano-4-fluoro-phenyl)-7-methyl-1,1-dioxo-spiro[4,5-dihydro -2H-pyrrolo[3,4-f]triazepine-3,3'-oxetane]-6-carboxamide

Compound 138 (23 mg) was prepared similarly as described for compound 131 using 5-amino-2-fluoro-benzonitrile instead of 3,4-difluoroaniline. ^1H NMR (400 MHz, DMSO- _d6 ) δ ppm 2.14-2.27 (m, 2H), 2.87-2.99 (m, 2H), 3.70 (s, 3H), 4.29 (d, J = 6.4 Hz, 2H), 4.64 (d, J = 6.2 Hz, 2H), 7.46 (s, 1H), 7.55 (t, J = 9.1 Hz, 1H), 7.84 (s, 1H), 7.97 (ddd, J = 9.2, 4.8, 2.9 Hz, 1H), 8.19 (dd, J = 5.8, 2.8 Hz, 1H), 10.61 (s, 1H); Method D; Rt: 1.48 min. m/z: 403 (MH) ^- Exact mass: 404.1.

Compound 139: N-[3-(Difluoromethyl)-4-fluoro-phenyl]-7-methyl-1,1-dioxo-spiro[2H-pyrrolo[3, 4-f]triazepine-3,3'-oxetane-6-carboxamide

Compound 139 (108 mg) was prepared similarly as described for compound 132 using 3-(difluoromethyl)-4-fluoro-aniline instead of 3,4-difluoroaniline. ¹ H NMR (400MHz, DMSO-d ₆ ) δppm 3.71 (s, 3H), 4.50 (d, J = 6.2Hz, 2H), 4.79 (d, J = 6.4Hz, 2H), 6.27 (d, J=12.8Hz, 1H), 6.53 (d, J=12.8Hz, 1H), 7.23 (t, J=54.2 Hz, 1H), 7.39 (t, J=9.6Hz, 1H), 7.52 (s, 1H), 7.81-7.86 (m, 1H), 8.06 (dd, J=6.2, 2.4Hz, 1H), 8.45 (br s, 1H), 10.78 (br s, 1H); Method B; Rt: 0.83min.m/z: 426 (MH) ^- Exact mass: 427.1.

Compound 140: N-(3-cyano-4-fluoro-phenyl)-7-methyl-1,1-dioxo-spiro[2H-pyrrolo-[3,4-f]triazol- [Azepine-3,3'-oxetane]-6-carboxamide

Compound 140 (23 mg) was prepared similarly as described for compound 132 using 5-amino-2-fluoro-benzonitrile instead of 3,4-difluoroaniline. ^1H NMR (400 MHz, DMSO- _d6 ) δ ppm 3.71 (s, 3H), 4.51 (d, J = 6.4 Hz, 2H), 4.79 (d, J = 6.4 Hz, 2H), 6.28 (d, J = 12.8 Hz, 1H), 6.54 (d, J = 12.8 Hz, 1H), 7.53-7.58 (m, 2H), 7.98 (ddd, J = 9.2, 4.9, 2.6 Hz, 1H), 8.19 (dd, J = 5.8, 2.8 Hz, 1H), 8.46 (br s, 1H), 10.88 (br s, 1H); Method D; Rt: 1.48 min. m/z: 401 (MH) ^- Exact mass: 402.1.

Compound 141: N-(3,4-difluorophenyl)-3-[hydroxy(2-pyridyl)methyl]-7-methyl-1,1-dioxo-3, 4-Dihydro-2H-pyrrolo[3,4-b][1,4,5]oxatriazepine-6-carboxamide

The crude compound 141 obtained in the synthesis of compound 129 was purified on silica eluting with a DCM to EtOAc gradient to afford compound 141a (3 mg) as a beige solid. ¹ H NMR (400 MHz, chloroform-d) δ ppm 3.87-4.04 (m, 3H), 4.25 (dd, J=12.8, 9.0 Hz, 1H), 4.40-4.53 (m, 1H), 4.82-4.97 (m, 1H), 5.00-5.12 (m, 1H), 6.96-7.21 (m, 3H), 7.27-7.37 (m, 1H), 7.42-7.49 (m, 1H), 7.58-7.73 (m, 1H), 7.76-7.88 (m, 1H), 8.49-8.60 (m, 1H), 8.80 (s, 1H); Method B; Rt: 0.91 min. m/z: 465 (M+H) ⁺ Exact mass: 464.1.

Alternatively, this compound can be synthesized as described for compound 129 using 6-bromopyridine-2-carboxaldehyde instead of 2-pyridinecarboxaldehyde. The individual diastereomers were separated at the final step during the synthesis using preparative HPLC (stationary phase: RPXBridge Prep C18 OBD-10 μm, 30 x 150 mm, mobile phase: 0.25% NH ₄ HCO ₃ solution in water, MeOH) to yield compound 141a (5 mg); ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 3.87-4.04 (m, 3H), 4.25 (dd, J=12.8, 9.0 Hz, 1H), 4.40-4.53 (m, 1H), 4.82-4.97 (m, 1H), 5.00-5.12 (m, 1H), 6.96-7.21 (m, 3H), 7.27-7.83 (m, 1H). -7.37 (m, 1H), 7.42-7.49 (m, 1H), 7.58-7.73 (m, 1H), 7.76-7.88 (m, 1H), 8.49-8.60 (m, 1H), 8.80 (s, 1H); Method D; Rt: 1.76 min. m/z: 465 (M+H) ⁺ exact mass: 464.1 and compound 141b (14 mg); ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 3.81 (s, 3H), 4.03 (dd, J=12.6, 9.3 Hz, 1H), 4.13-4.21 δ 5.77-5.64 (m, 2H), 4.62-4.79 (m, 4H), 4.30-4.93 (m, 3H), 4.93-4.97 (m, 4H), 4.79-4.99 (m, 5H), 4.11-4.79 (m, 2H), 4.90-4.79 (m, 4H), 4.91-4.79 (m, 5H), 4.82-4.79 (m, 1H), 4.82-4.79 (m, 1H), 4.90-4.79 (m, 5H), 4.91-4.79 (m, 4H), 4.91-4.79 (m, 5H), 4.91-4.79 (m, 5H), 4.91-4.79 (m, 5H), 4.91-4.79 (m, 5H), 4.91-4.79 (m, 5H), ^4.91-4.79 (m, 5H), 4.91-4.79 (m, 5H), 4.91-4.79 (m, 5H), 4.91-4.79 (m, 5H), 4.91-4.79 (m, 5H), 4.91-4.79 (m, 5H), 4.91-4.79 (m, 5H),

Compound 142: N-(3,4-difluorophenyl)-3-(1-hydroxypropyl)-7-methyl-1,1-dioxo-3,4-dihydro- 2H-Pyrrolo[3,4-b][1,4,5]oxatriazepine-6-carboxamide

Compound 142 (387 mg) was prepared similarly as described for compound 92 using ethylmagnesium bromide instead of cyclopropylmagnesium bromide. The racemic mixture was separated into its epimers by preparative SFC (stationary phase: Daicel Chiralpak ID 20×250 mm, mobile phase: CO ₂ , EtOH+0.4 iPrNH ₂ ) to yield compound 142a (141 mg); ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.91 (t, J=7.4 Hz, 3H), 1.44 (dquin, J=14.3, 7.3, 7.3, 7.3 Hz, 1H), 1.64-1.79 (m, 1H), 3.34-3.44 (m, 1H), 3.44-3.55 (m, 1H), 3.82 (s, 3H), 3.98 (dd, J=12.8, 8.8 Hz, 1H), 4.90 (dd, δ ppm; 1H NMR (400 MHz, DMSO ^- d6) ^δ _ppm 0.88 (t, J=7.4Hz, 3H), 1.29-143 (m, 1H), 1.49-1.63 (m, 1H), 3.55- 3.64 (m, 1H), 3.66-3.75 (m, 1H), 3.82 (s, 3H), 3.99 (dd, J=12.7, 9.1Hz, 1H), 4.68-4.75 (m, 1H), 4.86 (br d, J=4.2Hz, 1H), 7.26-7.52 (m, 4H), 7.86 (ddd, J=13.2, 7.5, 2.4Hz, 1H), 9.45 (s, 1H); Method D; Rt: 1.77min. m/z：414(MH) ^- Exact mass: 415.1; MP: 212.6°C. Method U; Rt: 142a: 3.06 min, 142b: 3.64 min.

Compound 143: 7-Methyl-1,1-dioxo-N-(3,4,5-trifluorophenyl)spiro[2H-pyrrolo[3,4-f]triazepine [3,3′-oxetane]-6-carboxamide

Compound 143 (28 mg) was prepared similarly as described for compound 132 using 3,4,5-trifluoroaniline instead of 3,4-difluoroaniline. ^1H NMR (400 MHz, DMSO- _d6 ) δ ppm 3.70 (s, 3H), 4.51 (d, J = 6.4 Hz, 2H), 4.78 (d, J = 6.2 Hz, 2H), 6.28 (d, J = 12.8 Hz, 1H), 6.50 (d, J = 12.8 Hz, 1H), 7.54 (s, 1H), 7.56-7.66 (m, 2H), 8.45 (br s, 1H), 10.88 (br s, 1H); Method B; Rt: 0.88 min. m/z: 412 (MH) ^- Exact mass: 413.1.

Compound 144: N-[3-(Difluoromethyl)-4-fluoro-phenyl]-3-(1-hydroxypropyl)-7-methyl-1,1-dioxo- 3,4-Dihydro-2H-pyrrolo[3,4-b][1,4,5]oxatriazepine-6-carboxamide

Compound 144 (420 mg) was prepared similarly as described for the preparation of compound 142 using 3-(difluoromethyl)-4-fluoro-aniline instead of 3,4-difluoroaniline. The racemic mixture was separated into its epimers by preparative SFC (stationary phase: Daicel Chiralpak ID 20×250 mm, mobile phase: CO ₂ , EtOH+0.4 iPrNH ₂ ) to yield compound 144a (176 mg); ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.92 (t, J=7.3 Hz, 3H), 1.44 (dquin, J=14.2, 7.1, 7.1, 7.1, 7.1 Hz, 1H), 1.64-1.79 (m, 1H), 3.35-3.44 (m, 1H), 3.44-3.56 (m, 1H), 3.83 (s, 3H), 3.99 (dd, J=12.7, 8.9 Hz, 1H); 1H), 4.89 (dd, J = 12.8, 1.8 Hz, 1H), 4.98 (d, J = 6.4 Hz, 1H), 7.03-7.41 (m, 2H), 7.47 (s, 1H), 7.59 (br s, 1H), 7.73-7.89 (m, 1H), 8.04 (dd, J = 6.3, 2.5 Hz, 1H), 9.47 (s, 1H); Method D; Rt: 1.75 min. m/z: 446 (MH) ^- exact mass: 447.1, and 144b (156 mg); ^1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.88 (t, J=7.4Hz, 3H), 1.30-1.43 (m, 1H), 1.49-1.63 (m, 1H), 3.56-3.64 (m, 1H), 3.66-3.76 (m, 1H), 3.83 (s, 3H), 4.00 (dd, J=12.7, 9.1Hz, 1H), 4.64-4.77 (m, 1H), 4.86 (d, J=5.5Hz, 1H), 7.02-7.42 (m, 3H), 7.46 (s, 1H), 7.76-7.88 (m, 1H), 8.03 (dd, J=6.3, 2.5Hz, 1H), 9.49 (s, 1H); Method D; Rt: 1.78 min. m/z: 446 (MH) ^- Exact mass: 447.1; MP: 224.6° C. Method U; Rt: 144a: 2.92 min, 144b: 3.49 min.

Synthesis of 2-amino-2-pyrazin-2-yl-propan-1-ol

100ml flask is filled with acetyl pyrazine (2.00g, 16.4mmol), NH ₃ (33mL, 7M in MeOH, 229mmol) and ammonium chloride (2.63g, 49.1mmol). Trimethylsilyl cyanide (6.2mL, 0.793g/mL, 49mmol) is added and the mixture is stirred at room temperature for 16 hours. The mixture is concentrated in a vacuum. The residue is absorbed in DCM and the precipitation is filtered out. The filtrate is concentrated in a vacuum and the residue is purified by column chromatography using a gradient from 0 to 100% EtOAc-EtOH (3-1) in heptane. The product fraction is concentrated in a vacuum to produce 2-amino-2-pyrazine-2-yl-propionitrile (1.9g) as a light yellow oil.

2-amino-2-pyrazine-2-base-propionitrile (1.9g, 12.8mmol) is dissolved in acetic acid (6.3mL).The hydrobromic acid in acetic acid (30mL) is carefully added and the mixture is stirred at 80 DEG C for 1 hour.The mixture is cooled and poured into EtOAc (400mL).Precipitation is filtered out and washed with EtOAc and ACN and dried under vacuum to produce 2-amino-2-pyrazine-2-base-propionamide trihydrobromide (5.2g) as a yellow solid.

2-amino-2-pyrazine-2-base-propionamide trihydrobromide (5.2g, 12.7mmol) is dissolved in MeOH (50mL). Carefully add H ₂ SO ₄ (5mL) (exothermic) and the mixture is heated under reflux for 16 hours. The mixture is cooled and concentrated in a vacuum. The residue is dissolved in water (50mL) and washed with EtOAc. The aqueous portion is neutralized with Na ₂ CO ₃ and extracted with Me-THF (2X 50mL). The combined organic layer is dried (MgSO 4 ), filtered and concentrated in a vacuum. The residue is purified by column chromatography using a gradient from 0 to 100% EtOAc-EtOH (3-1) in heptane. The product fraction is concentrated in a vacuum to produce methyl 2-amino-2-pyrazine-2-base-propionic acid ester (371mg) as a yellow oil.

Under _N2 atmosphere, methyl 2-amino-2-pyrazine-2-yl-propionic acid ester (371 mg, 2.05 mmol) was dissolved in MeOH (10 mL). Sodium borohydride (155 mg, 4.10 mmol) was added and the mixture was stirred at room temperature for 16 hours. The mixture was concentrated in vacuo. The residue was dissolved in Me-THF, dried ( _MgSO4 ), filtered and concentrated in vacuo to produce 2-amino-2-pyrazine-2-yl-propan-1-ol (285 mg).

Compound 145: N-(3,4-difluorophenyl)-3,7-dimethyl-1,1-dioxo-3-pyrazin-2-yl-2,4-dihydropyrazin- Pyrrolidine[3,4-b][1,4,5]oxatriazepine-6-carboxamide

Compound 145 (221 mg) was prepared similarly to that described for compound 125, using 2-amino-2-pyrazin-2-yl-propan-1-ol instead of 2-amino-2-phenylpropan-1-ol hydrochloride. Ring closure was achieved after heating for 3 hours and compound 145 was crystallized from ACN. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.63 (s, 3H), 3.82 (s, 3H), 4.98-5.14 (m, 2H), 7.38-7.52 (m, 3H), 7.88 (ddd, J=13.2, 7.5, 2.5 Hz, 1H), 8.56-8.60 (m, 2H), 8.68 (s, 1H), 9.03 (d, J=1.1 Hz, 1H), 9.43 (s, 1H); Method B; Rt: 0.96 min. m/z: 448 (MH) ^- Exact mass: 449.1. The racemic mixture was separated into its epimers by preparative SFC (stationary phase: Daicel Chiralpak AS 20 x 250 mm, mobile phase: CO ₂ , EtOH + 0.4 iPrNH ₂ ) to produce compounds 145a (89 mg); Method D; Rt: 1.83 min. m/z: 448 (MH) ^- exact mass: 449.1, MP: 199.4° C., and 145b (156 mg); Method D; Rt: 1.83 min. m/z: 448 (MH) ^- exact mass: 449.1; MP: 199.4° C. Method T; Rt: 145a: 3.51 min, 145b: 4.34 min.

Compound 146: (3R)-N-(2-chloro-4-pyridinyl)-3-(1-hydroxy-1-methyl-ethyl)-7-methyl-1,1-diol Oxy-3,4-dihydro-2H-pyrrolo[3,4-b][1,4,5]oxatriazepine-6-carboxamide

Compound 146 (214 mg) was prepared similarly as described for compound 93 using 4-amino-2-chloropyridine instead of 3,4-difluoroaniline. ¹ H NMR (400MHz, DMSO-d ₆ ) δppm 1.07 (s, 3H), 1.25 (s, 3H), 3.50-3.61 (m, 1H), 3.84 (s, 3H), 3.96 (dd, J=12.5, 8.8Hz, 1H), 4.87 (s, 1H), 4.98 (dd, J=12.4, 1.0Hz, 1H), 7.47-7.61 (m, 2H), 7.69 (dd, J=5.6, 1.9Hz, 1H), 7.88 (d, J=1.8Hz, 1H), 8.27 (d, J=5.7Hz, 1H), 9.69 (s, 1H); Method D; Rt: 1.53min.m/z: 413 (MH) ^- Exact mass: 414.1, MP: 246.6°C.

Compound 147: (3R)-3-(1-hydroxy-1-methyl-ethyl)-7-methyl-1,1-dioxo-N-(3,4,5-trifluorophenyl)- 1-[3,4-b][1,4,5]oxatriazepine-6-carboxamide]-3,4-dihydro-2H-pyrrolo[3,4-b][1,4,5]oxatriazepine-6-carboxamide

Compound 147 (259 mg) was prepared similarly as described for compound 93 using 3,4,5-trifluoroaniline instead of 3,4-difluoroaniline. ^1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.07 (s, 3H), 1.25 (s, 3H), 3.50-3.60 (m, 1H), 3.83 (s, 3H), 3.92 (dd, J=12.4, 8.9 Hz, 1H), 4.86 (s, 1H), 4.95-5.04 (m, 1H), 7.43-7.59 (m, 2H), 7.65-7.79 (m, 2H), 9.49 (s, 1H); Method D; Rt: 1.84 min. m/z: 432 (MH) ^- Exact mass: 433.1.

Compound 148: N-(3,4-difluorophenyl)-4,4-difluoro-7-methyl-1,1-dioxo-3,5-dihydro-2H-pyrrole 6-[3,4-f]triazepine-3-carboxamide

2-Iodoacylbenzoic acid (3.71 g, 13.3 mmol) was added to a solution of ethyl 3-[3-(benzyloxycarbonylamino)-2-hydroxy-propyl]-1-methyl-pyrrole-2-carboxylate (2.12 g, 5.89 mmol) in EtOAc (50 mL) and stirred at reflux temperature for 5 hours and 30 minutes. The reaction mixture was filtered while hot. The precipitate was washed with EtOAc (150 mL). The organic layer was washed with NaHCO ₃ (aqueous, saturated, 200 mL), dried over magnesium sulfate, filtered and concentrated. The residue was purified on silica using a gradient from 0 to 100% EtOAc in heptane to produce ethyl 3-[3-(benzyloxycarbonylamino)-2-oxo-propyl]-1-methyl-pyrrole-2-carboxylate (1.49 g) as a clear oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.24 (t, J = 7.0 Hz, 3H), 3.76-3.93 (m, 7H), 4.16 (q, J = 7.2 Hz, 2H), 5.03 (s, 2H), 6.00 (d, J = 2.4 Hz, 1H), 7.01 (d, J = 2.4 Hz, 1H), 7.27-7.50 (m, 6H); Method D; Rt: 1.90 min. m/z: 357 (MH) ^- exact mass: 358.2.

Diethylaminosulfur trifluoride (3.35 g, 20.8 mmol) was added to a solution of ethyl 3-[3-(benzyloxycarbonylamino)-2-oxo-propyl]-1-methyl-pyrrole-2-carboxylate (1.49 g, 4.16 mmol) in DCM (100 mL) and stirred at room temperature overnight. The reaction mixture was quenched by pouring into NaHCO ₃ (aqueous, saturated, 300 mL). The organic layer was dried over sodium sulfate, filtered and concentrated. The residue was purified on silica using a gradient from 0 to 100% EtOAc in heptane to give ethyl 3-[3-(benzyloxycarbonylamino)-2,2-difluoro-propyl]-1-methyl-pyrrole-2-carboxylate (371 mg) as a clear oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.27 (t, J = 7.0 Hz, 3H), 3.32-3.49 (m, 4H), 3.80 (s, 3H), 4.20 (q, J = 7.0 Hz, 2H), 5.04 (s, 2H), 6.08 (d, J = 2.2 Hz, 1H), 7.01 (d, J = 2.6 Hz, 1H), 7.27-7.40 (m, 5H), 7.68 (br t, J = 6.2 Hz, 1H); Method D; Rt: 2.07 min. m/z: 379 (MH) ^- exact mass: 380.2.

Chlorosulfonic acid (7.8 g, 67 mmol) was added to a solution of ethyl 3-[3-(benzyloxycarbonylamino)-2,2-difluoro-propyl]-1-methyl-pyrrole-2-carboxylate (365 mg, 0.96 mmol) in DCM (50 mL) and the reaction mixture was stirred for 20 minutes. The reaction mixture was poured into water (300 mL) and the organic layer was washed with NaHCO ₃ (aqueous, saturated, 250 mL), dried over magnesium sulfate, filtered and concentrated. The residue was purified on silica using a gradient of 0 to 100% EtOAc in heptane to give ethyl 4,4-difluoro-7-methyl-1,1-dioxo-3,5-dihydro-2H-pyrrolo[3,4-f]triazepine-6-carboxylate (17 mg) as white crystals. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.31 (t, J=7.2 Hz, 3H), 3.66 (td, J=11.6, 7.2 Hz, 2H), 3.76-3.89 (m, 5H), 4.30 (q, J=7.1 Hz, 2H), 7.65 (s, 1H), 8.18 (t, J=6.8 Hz, 1H); Method D; Rt: 1.65 min. m/z: 307 (MH) ^- exact mass: 308.1.

Lithium bis(trimethylsilyl)amide (0.33 mL, 1 M in THF, 0.33 mmol) was added to a solution of ethyl 4,4-difluoro-7-methyl-1,1-dioxo-3,5-dihydro-2H-pyrrolo[3,4-f]triazepine-6-carboxylate (17 mg, 0.055 mmol) and 3,4-difluoroaniline (22 mg, 0.17 mmol) in THF (3 mL) and stirred for 30 minutes. The reaction mixture was quenched with NH ₄ Cl solution (aqueous, saturated, 10 mL) and extracted with EtOAc (50 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated. The residue was purified on silica using a gradient from 10% to 100% EtOAc in heptane to produce compound 148 (9.8 mg). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 3.39-3.50 (m, 2H), 3.61-3.70 (m, 2H), 3.72 (s, 3H), 7.39-7.49 (m, 2H), 7.55 (s, 1H), 7.81-7.88 (m, 1H), 8.14 (t, J=6.9 Hz, 1H), 10.62 (s, 1H); Method D; Rt: 1.72 min. m/z: 390 (MH) ^- exact mass: 391.1.

Compound 149: 3-(1-Hydroxy-1-methyl-ethyl)-7-methyl-1,1-dioxo-N-(3,4,5-trifluorophenyl)- 2,3,4,5-tetrahydropyrrolo[3,4-f]triazepine-6-carboxamide

Compound 149 (140 mg) was prepared similarly as described for compound 113 using 3,4,5-trifluoroaniline instead of 3,4-difluoroaniline. The racemic mixture was separated into its enantiomers by preparative SFC (stationary phase: Daicel Chiralpak AD 20×250 mm, mobile phase: CO ₂ , EtOH + 0.4 iPrNH ₂ ) to yield compound 149a (66 _mg ); ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.03 (s, 3H), 1.17 (s, 3H), 1.33 (br q, J=11.5 Hz, 1H), 2.17 (brdd, J=14.0, 6.9 Hz, 1H), 2.67-2.78 (m, 1H), 2.98-3.08 (m, 1H), 3.21-3.29 (m, 1H), 3.69 (s, 3H), 4.39 (s, 1H), 6.85 (d, J = 10.8 Hz, 1H), 7.45 (s, 1H), 7.56-7.64 (m, 2H), 10.59 (s, 1H); Method D; Rt: 1.70 min. m/z: 430 (MH) ^- Exact mass: 431.1, and 149b (63 mg); ^1H NMR (400 MHz, DMSO- _d6 ) δ ppm 1.03 (s, 3H), 1.17 (s, 3H), 1.27-1.38 (m, 1H), 2.17 (br dd, J = 14.0, 6.9 Hz, 1H), 2.67-2.78 (m, 1H), 2.98 -3.08 (m, 1H), 3.23-3.30 (m, 1H), 3.69 (s, 3H), 4.39 (s, 1H), 6.85 (d, J=10.6 Hz, 1H), 7.45 (s, 1H), 7.56-7.64 (m, 2H), 10.59 (s, 1H); Method D; Rt: 1.70 min. m/z: 430 (MH) ^- Exact mass: 431.1. Method R; Rt: 149a: 2.83 min, 149b: 3.64 min.

Compound 150: N-[3-(Difluoromethyl)-4-fluoro-phenyl]-3-(1-hydroxy-1-methyl-ethyl)-7-methyl-1, 1-Dioxo-2,3,4,5-tetrahydropyrrolo[3,4-f]triazepine-6-carboxamide

Compound 150 (45 mg) was prepared similarly as described for compound 113 using 3-(difluoromethyl)-4-fluoro-aniline instead of 3,4-difluoroaniline. The racemic mixture was separated into its enantiomers by preparative SFC (stationary phase: Daicel Chiralpak AD20 x 250 mm, mobile phase: CO ₂ , EtOH + 0.4 iPrNH ₂ ) to yield compound 150a (23 mg); ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.03 (s, 3H), 1.17 (s, 3H), 1.34 (q, J = 11.6 Hz, 1H), 2.17 (brdd, J = 14.1, 6.8 Hz, 1H), 2.66-2.79 (m, 1H), 3.06 (br dd, J = 14.4, 6.5 Hz, 1H), 3.21-3.30 (m, 1H), 3.69 (s, 3H), 4.39 (m, 1H). (s, 1H), 6.83 (d, J = 10.8 Hz, 1H), 7.22 (t, J = 54.2 Hz, 1H), 7.37 (t, J = 9.6 Hz, 1H), 7.43 (s, 1H), 7.78-7.84 (m, 1H), 8.06 (dd, J = 6.3, 2.3 Hz, 1H), 10.49 (s, 1H); Method D; Rt: 1.61 min. m/z: 444 (MH) ^- Exact mass: 445.1, and 150b (22 mg); ^1H NMR (400 MHz, DMSO- _d6 ) δ ppm 1.03 (s, 3H), 1.17 (s, 3H), 1.34 (br q, J=12.0Hz, 1H), 2.17 (brdd, J=13.9, 6.8Hz, 1H), 2.68-2.79 (m, 1H), 3.01-3.11 (m, 1H), 3.19-3.30 (m, 1H), 3.69 (s, 3H), 4.39 (s, 1H), 6.83 (br d, J=10.6Hz, 1H), 7.22 (t, J=54.2Hz, 1H), 7.37 (t, J=9.6Hz, 1H), 7.43 (s, 1H), 7.78-7.84 (m, 1H), 8.06 (dd, J=6.2, 2.4 Hz, 1H), 10.49 (s, 1H); Method D; Rt: 1.61 min. m/z: 444 (MH) ^- Exact mass: 445.1. Method R; Rt: 150a: 2.92 min, 150b: 3.74 min.

Compound 151: (3R)-N-[2-(difluoromethyl)-4-pyridinyl]-3-(1-hydroxy-1-methyl-ethyl)-7-methyl 1,1-dioxo-3,4-dihydro-2H-pyrrolo[3,4-b][1,4,5]oxatriazepine-6-carboxamide

Compound 151 (359 mg) was prepared similarly as described for compound 93 using 2-(difluoromethyl)pyridin-4-amine instead of 3,4-difluoroaniline. ¹ H NMR (400MHz, DMSO-d ₆ ) δppm 1.06 (s, 3H), 1.25 (s, 3H), 3.49-3.61 (m, 1H), 3.85 (s, 3H), 3.97 (dd, J=12.5, 8.9Hz, 1H), 4.88 (s, 1H), 4.97 (dd, J=12.9, 0.5 Hz, 1H), 6.91 (t, J=55.0Hz, 1H), 7.48-7.61 (m, 2H), 7.77-7.85 (m, 1 H), 8.09 (d, J=2.1Hz, 1H), 8.53 (d, J=5.6Hz, 1H), 9.75 (s, 1H); Method B; Rt: 0.73 min. m/z: 429 (MH) ^- exact mass: 430.1.

Compound 152: (3S)-N-(3,4-difluorophenyl)-3,7,8-trimethyl-1,1-dioxo-2,3,4,5-tetrahydropyrrolo[3,4-f]triazepine-6-carboxamide

Methyl (3S)-3,7-dimethyl-1,1-dioxo-2,3,4,5-tetrahydropyrrolo[3,4-f]triazepine-6-carboxylate (200 mg, 0.73 mmol) was dissolved in acetic acid (5 mL) and bromine (0.057 mL, 3.10 g/mL, 1.10 mmol) was added. The solution was then refluxed for 4 hours and stirred at room temperature for 16 hours. The solution was then cooled to 0°C, quenched with _NaHCO3 and extracted with EtOAc. The combined organics were dried _{over Na2SO4} , filtered and concentrated in vacuo. The crude product was then purified on silica using heptane/EtOAc from 100/0 to 50/50 to give methyl (3S)-8-bromo-3,7-dimethyl-1,1-dioxo-2,3,4,5-tetrahydropyrrolo[3,4-f]triazepine-6-carboxylate (202 mg).

Methyl (3S)-8-bromo-3,7-dimethyl-1,1-dioxo-2,3,4,5-tetrahydropyrrolo[3,4-f]triazepine-6-carboxylate (202 mg, 0.58 mmol) and 3,4-difluoroaniline (0.069 mL, 1.29 g/mL, 0.69 mmol) were dissolved in THF (5 mL) and LiHMDS (1.7 mL, 1 M, 1.7 mmol) was added. After 2 hours, the solution was quenched with NH ₄ Cl (aqueous, saturated) and stirred for 5 min. The solution was then diluted with EtOAc, extracted, and the combined organics were dried over MgSO ₄ , filtered off, and concentrated in vacuo. The crude product was then purified on silica using heptane/EtOAc 100/0 to 0/100 to give (3S)-8-bromo-N-(3,4-difluorophenyl)-3,7-dimethyl-1,1-dioxo-2,3,4,5-tetrahydropyrrolo[3,4-f]triazepine-6-carboxamide (228 mg). Method B; Rt: 0.97 min. m/z: 446 (MH) ^- exact mass: 447.0.

By (3S) -8- bromo- N - (3,4- difluorophenyl) -3,7- dimethyl -1,1- dioxo -2,3,4,5- tetrahydro pyrrolo [3,4-f] triazapine -6- formamide (54mg, 0.12mmol) is dissolved in DMF (2mL). Tetramethyltin (0.025mL, 0.18mmol) is added and the solution is flushed with nitrogen in 5 minutes, tetrakis (triphenylphosphine) palladium (0) is added afterwards.Then the bottle is heated in 30 minutes at 140 DEG C by microwave radiation.Then the solution is filtered through diatomite and washed with EtOAc.The filtrate is concentrated in a vacuum and purified using heptane/EtOAc 100/0 to 80/20 on silica and further ground with diethyl ether to give compound 152 (37mg) as a white solid. ¹ H NMR (400MHz, DMSO-d ₆ ) δppm 1.12 (d, J=6.8Hz, 3H) 1.15-1.39 (m, 1H) 1.83 (br dd, J=14.0, 7.2Hz, 1H) 2.39 -2.45 (m, 1H) 2.42 (s, 2H) 2.73-2.84 (m, 1H) 2.88-2.98 (m, 1H) 3.53 (s, 3H) 3.56-3.65 (m, 1H) 7.07 (d, J = 9.5Hz, 1H) 7.35-7.46 (m, 2H) 7.79-7.91 (m, 1H) 10.46 (s, 1H); Method B; Rt: 0.93min.m/z: 382 (MH) ^- Exact mass: 383.1.

Compound 153: N-(3,4-difluorophenyl)-3,7-dimethyl-1,1-dioxo-3-pyrimidin-2-yl-2,4-dihydropyrimidin-2 Pyrrolidine[3,4-b][1,4,5]oxatriazepine-6-carboxamide

Compound 153 (205 mg) was prepared similarly as described for compound 125 using 2-amino-2-pyrimidin-2-yl-propan-1-ol to replace 2-amino-2-phenylpropan-1-ol hydrochloride. 2-amino-2-pyrimidin-2-yl-propan-1-ol was synthesized as described for 2-amino-2-pyrazine-2-yl-propan-1-ol using 2-acetyl pyrimidine to replace acetyl pyrazine. Ring closure was obtained after heating for 3 hours and compound 153 was crystallized from ACN. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.63 (s, 3H), 3.80 (s, 3H), 5.07-5.20 (m, 2H), 7.36-7.43 (m, 2H), 7.43-7.48 (m, 2H), 7.80-7.87 (m, 1H), 8.30-8.36 (m, 1H), 8.86 (d, J=4.9 Hz, 2H), 9.38 (s, 1H); Method B; Rt: 1.01 min. m/z: 448 (MH) ^- Exact mass: 449.1. The racemic mixture was separated into its enantiomers by preparative SFC (stationary phase: Daicel Chiralpak AD 20 x 250 mm, mobile phase: CO ₂ , EtOH + 0.4 iPrNH ₂ ) to produce compounds 153a (75 mg); Method D; Rt: 1.93 min. m/z: 448 (MH) ^- exact mass: 449.1, MP: 228.3° C., and 153b (73 mg); Method D; Rt: 1.94 min. m/z: 448 (MH) ^- exact mass: 449.1; MP: 228.6° C. Method R; Rt: 153a: 4.67 min, 153b: 5.97 min.

Synthesis of (2R)-2-amino-2-methyl-3-phenyl-propan-1-ol

A solution of ZL-alanine (5 g, 22.4 mmol) and benzaldehyde dimethyl acetal (5.11 g, 33.6 mmol) in diethyl ether (50 mL) was cooled to -78°C. Boron trifluoride etherate (23.5 mL, 1.15 g/mL, 190 mmol) was added while maintaining the temperature below -70°C. After addition, the reaction mixture was allowed to warm to -15°C and stirred continuously at this temperature over the weekend. The reaction mixture was quenched with cold _NaHCO₃ (saturated, aqueous, 100 mL) and stirred for 30 minutes. The organic layer was removed and evaporated under reduced pressure. The residue was purified on silica using heptane to heptane:EtOAc 1:1 to produce benzyl (2S,4S)-4-methyl-5-oxo-2-phenyl-oxazolidine-3-carboxylate (6.2 g) as an oil that solidified upon standing. ¹ H NMR (400MHz, DMSO-d ₆ ) δppm 1.52 (d, J=7.0Hz, 3H), 4.56 (q, J=6.9Hz, 1H), 5.10 (br s, 2H), 6.58 (s, 1H), 7.31 (br s, 4H), 7.40-7.50 (m, 6H).

Benzyl (2S, 4S) -4- methyl -5- oxygen -2- phenyl - oxazolidine -3- formate (1.5g, 4.82mmol) and benzyl bromide (572μL, 1.44g/mL, 4.82mmol) solution was added dropwise to a solution of bis (trimethylsilyl) amide lithium (5.78mL, 1M in THF, 5.78mmol) in THF (5mL) and stirred for 1 hour. The reaction mixture was quenched with _NH4Cl (saturated, aqueous, 10mL) and the organic layer was removed. The aqueous layer was extracted with DCM (2X 5mL) and the combined organic layer was evaporated to dryness, and the residue was purified using heptane to an EtOAc gradient on silica to produce benzyl (2S, 4R) -4- methyl -5- oxygen -2- phenyl - oxazolidine -3- formate (1.01g). Method D; Rt: 2.38 min. m/z: 402 (M+H) ⁺ exact mass: 401.1.

LiOH (121 mg, 5.03 mmol) dissolved in water (1 mL) was added to a solution of benzyl (2S, 4R) -4-benzyl-4-methyl-5-oxo-2-phenyl-oxazolidine-3-carboxylate (1.01 g, 2.52 mmol) in MeOH (10 mL). The reaction mixture was stirred for 2 hours. HCl (aqueous, 1 M, 5 mL) was added and the volatiles were removed under reduced pressure. The residue was purified on silica using a heptane to EtOAc gradient to produce methyl (2R) -2- (benzyloxycarbonylamino) -2-methyl-3-phenyl-propanoate (691 mg). Method B; Rt: 1.13 min. m / z: 328 (M + H) ⁺ exact mass: 327.2.

Methyl (2R)-2-(benzyloxycarbonyl amino)-2-methyl-3-phenyl-propionic acid ester (560mg, 1.71mmol) is dissolved in THF (10mL).Add lithium aluminum hydride (5.13mL, 1M in THF, 5.13mmol) and the reaction mixture is stirred 2 hours.Add THF (100mL) and then add the tetrahydrate potassium sodium tartrate (2.17g, 7.7mmol) that is dissolved in the water (3mL) and the reaction mixture is stirred 15 minutes.Add Na ₂ SO ₄ and the reaction mixture is stirred 15 minutes.Precipitation is removed by filtration and the filtrate is evaporated to dryness.This residue is used heptane to EtOAc gradient to carry out purification on silica, produce benzyl N-[(1R)-1-benzyl-2-hydroxy-1-methyl-ethyl] carbamate (186 mg).

Benzyl N-[(1R)-1-benzyl-2-hydroxy-1-methyl-ethyl]carbamate (186 mg, 0.62 mmol) and Pd/C (10%) (33 mg, 0.031 mmol) were partitioned in MeOH (40 mL) and placed under a hydrogen atmosphere overnight. The reaction mixture was filtered and evaporated to dryness to yield (2R)-2-amino-2-methyl-3-phenyl-propan-1-ol, which was used as is.

Compound 154: (3R)-3-Benzyl-N-(3,4-difluorophenyl)-3,7-dimethyl-1,1-dioxo-2,4-dihydropyridine Pyrrolidine[3,4-b][1,4,5]oxatriazepine-6-carboxamide

Compound 154 (111 mg) was prepared similarly as described for compound 133 using (2R)-2-amino-2-methyl-3-phenyl-propan-1-ol instead of 2-amino-2-methyl-1-propanol. ^1H NMRR (400 MHz, DMSO- _d6 ) δ ppm 1.15 (s, 3H), 2.80 (d, J = 13.0 Hz, 1H), 3.00 (d, J = 13.0 Hz, 1H), 3.82 (s, 3H), 4.40 (d, J = 13.2 Hz, 1H), 4.57 (d, J = 13.0 Hz, 1H), 7.24-7.38 (m, 5H), 7.38-7.46 (m, 2H), 7.47 (s, 1H), 7.57-7.80 (m, 1H), 7.81-7.90 (m, 1H), 9.40 (s, 1H); Method B; Rt: 1.19 min. m/z: 460 (MH) ^- Exact mass: 461.1.

Compound 155: (3S)-3-Benzyl-N-(3,4-difluorophenyl)-3,7-dimethyl-1,1-dioxo-2,4-dihydropyridine Pyrrolidine[3,4-b][1,4,5]oxatriazepine-6-carboxamide

Compound 155 (92 mg) was prepared similarly as described for compound 133, using (2S)-2-amino-2-methyl-3-phenyl-propan-1-ol instead of 2-amino-2-methyl-1-propanol. (2S)-2-amino-2-methyl-3-phenyl-propan-1-ol was synthesized as described for (2S)-2-amino-2-methyl-3-phenyl-propan-1-ol, using ZD-alanine instead of ZL-alanine. ^1H NMR (400 MHz, DMSO- _d6 ) δ ppm 1.15 (s, 3H), 2.80 (d, J = 13.0 Hz, 1H), 3.00 (d, J = 13.2 Hz, 1H), 3.82 (s, 3H), 4.40 (d, J = 13.2 Hz, 1H), 4.57 (d, J = 13.2 Hz, 1H), 7.25-7.36 (m, 5H), 7.40-7.46 (m, 2H), 7.47 (s, 1H), 7.71-7.89 (m, 2H), 9.40 (s, 1H); Method B; Rt: 1.19 min. m/z: 460 (MH) ^- Exact mass: 461.1.

Compound 156: (3S)-3-Benzyl-N-(3-cyano-4-fluoro-phenyl)-3,7-dimethyl-1,1-dioxo-2,4-diol Hydropyrrolo[3,4-b][1,4,5]oxatriazepine-6-carboxamide

Compound 156 (41 mg) was prepared similarly as described for compound 155 using 5-amino-2-fluoro-benzonitrile instead of 3,4-difluoroaniline. ¹ H NMR (400MHz, DMSO-d ₆ ) δppm 1.16 (s, 3H), 2.79 (d, J=13.2Hz, 1H), 3.01 (d, J=13.2 Hz, 1H), 3.83 (s, 3H), 4.40 (d, J=13.2Hz, 1H), 4.59 (d, J=13.0Hz, 1H), 7.24-7.36 (m, 5H), 7.49 (s, 1H), 7.55 (t, J=9.1Hz, 1H), 7.75 (s, 1H), 8.02 (ddd, J=9.2, 4.8, 2.9Hz, 1H), 8.18 (dd, J=5.7, 2.6Hz, 1H), 9.49 (s, 1H); Method B; Rt: 1.13 min. m/z: 467 (MH) ^- Exact mass: 468.1.

Synthesis of (S)-2-(1-methylallyl)isoindoline-1,3-dione.

At -78 ° C, DIBAL (11mL, 1M in heptane, 11mmol) is added dropwise to the anhydrous solution of methyl (2S) -2- (benzyloxycarbonyl amino) propanoate (2.50g, 10.5mmol) in THF (50 mL). After addition, at -78 ° C, the solution is carefully quenched with NaF (aqueous, saturated). The mixture stirred by the obtained mixture is allowed to warm to room temperature. More water is added and the reaction mixture is extracted with EtOAc (3 × 25mL). The combined extracts are evaporated to dryness, and the residue is purified using heptane to EtOAc gradient on silica to produce benzyl N- [(1S) -1- methyl -2- oxygen-ethyl] carbamate (1.13g) in an oily state.

Methyltriphenylphosphonium bromide (3.11 g, 8.69 mmol) is suspended in toluene (50 mL) and cooled to 0° C. Add lithium bis(trimethylsilyl)amide (8.2 mL, 1 M in toluene, 8.2 mmol). The reaction is stirred at 0° C. for 30 minutes, then cooled to -78° C. and a solution of benzyl N-[(1S)-1-methyl-2-oxygen-ethyl] carbamate (1.13 g, 5.43 mmol) in toluene (5 mL) is added. Allow the solution to warm to room temperature, stir for 30 min, then quench with saturated NH ₄ Cl (aqueous, saturated) (20 mL). Each layer is separated and the aqueous layer is washed with EtOAc (10 mL). The combined organic layers were evaporated to dryness and the residue was purified on silica using a heptane to EtOAc gradient to give benzyl N-[(1S)-1-methylallyl]carbamate (230 mg) as an oil which solidified on standing.

Benzyl N-[(1S)-1-methylallyl]carbamate (100 mg, 0.49 mmol) was dissolved in HCl (37% in _H₂O , 3 mL) and heated at 100°C for 30 minutes. Volatiles were removed under reduced pressure and the residue was dissolved in THF (5 mL). Hunier's base (0.84 mL, 0.75 g/mL, 4.9 mmol) and 1,3-isobenzofurandione (79 mg, 0.54 mmol) were added and the reaction mixture was stirred over the weekend. Hunier's base (0.84 mL, 0.75 g/mL, 4.9 mmol) was added and the reaction mixture was heated at 50°C for 2 hours. The (S)-2-(1-methylallyl)isoindoline-1,3-dione formed in this reaction mixture was found to be identical to the (*S)-2-(1-methylallyl)isoindoline-1,3-dione described in the synthesis of compound 29. Method Q; Rt: (*R)-2-(1-methylallyl)isoindoline-1,3-dione: 1.65 min, (*S)-2-(1-methylallyl)isoindoline-1,3-dione and (S)-2-(1-methylallyl)isoindoline-1,3-dione: 1.89 min.

Compound 157: (3S)-N-(3-cyano-2,4-difluoro-phenyl)-3,7-dimethyl-1,1-dioxo-2,3,4,5- Tetrahydropyrrolo[3,4-f]triazepine-6-carboxamide

To methyl 3-bromo-1-methyl-pyrrole-2-carboxylate (10.0 g, 45.9 mmol) and 2-[(1S)-1-methylallyl]isoindoline-1,3-dione (10.2 g, 50.5 mmol) in DMF (50 mL) was added TEA (12.7 mL, 0.73 g/mL, 91.7 mmol) and stirred and purged with nitrogen for 5 minutes. Bis(tri-tert-butylphosphine)palladium(0) (1.17 g, 2.29 mmol) was then added and the mixture was stirred and heated in an oil bath at 110° C. for 90 minutes. The resulting mixture was filtered through a pad of celite, rinsed with EtOAc (300 mL) and concentrated in vacuo. The crude product was purified on silica (gradient elution: EtOAc: heptane 0:100 to 100:0). The desired fractions were concentrated under reduced pressure to yield methyl 3-[(E,3S)-3-(1,3-dioxoisoindolin-2-yl)but-1-enyl]-1-methyl-pyrrole-2-carboxylate (15.1 g) as a yellow oil.

The hydrogenation flask was flushed with nitrogen and then charged with Pd/C (10%) (2.37 g, 2.22 mmol). To this was added methyl 3-[(E,3S)-3-(1,3-dioxoisoindolin-2-yl)but-1-enyl]-1-methyl-pyrrole-2-carboxylate (15.4 g, 44.5 mmol) in THF (200 mL) under nitrogen. The resulting suspension was then stirred at room temperature under a hydrogen atmosphere for 2 hours. The mixture was then filtered through a pad of celite under a constant stream of nitrogen and the pad was rinsed with THF (250 mL). The filtrate was concentrated in vacuo to yield methyl 3-[(3S)-3-(1,3-dioxoisoindolin-2-yl)butyl]-1-methyl-pyrrole-2-carboxylate (15.0 g).

Methyl 3-[(3S)-3-(1,3-dioxoisoindolin-2-yl)butyl]-1-methyl-pyrrole-2-carboxylate (15.0 g, 44.1 mmol) was dissolved in n-butanol (150 mL). Ethylenediamine (118 mL) was added and stirred at room temperature for 5 minutes and then heated at 90° C. for 3 hours. The mixture was cooled and concentrated in vacuo. The residue was purified by column chromatography on silica using a gradient of 0 to 10% MeOH/NH ₃ in DCM. The product fractions were concentrated in vacuo to give methyl 3-[(3S)-3-aminobutyl]-1-methyl-pyrrole-2-carboxylate (9.1 g) as an oil. Method B; Rt: 0.52 min. m/z: 211 (M+H) ⁺ exact mass: 210.1.

Chlorosulfonic acid (55 mL, 1.75 g/mL, 832 mmol) is stirred and cooled in an ice acetone bath. A gentle nitrogen stream is maintained. Methyl 3-[(3S)-3-aminobutyl]-1-methyl-pyrrole-2-carboxylate (3.50 g, 16.6 mmol) in DCM (65 mL) is added dropwise. After addition, the resulting mixture is added dropwise to an ice-cold and stirred solution of Na ₂ CO ₃ (176 g) in ice-cold water (1 L). After addition, the layers are separated and the aqueous layer is extracted with DCM (2 × 500 mL). The combined extracts are dried over Na ₂ SO ₄ , filtered, and concentrated in vacuo. The crude product was purified on silica gel using a gradient elution (heptane/iPrOH 100:0 to 20:80) to give methyl (3S)-3,7-dimethyl-1,1-dioxo-2,3,4,5-tetrahydropyrrolo[3,4-f]triazepine-6-carboxylate (1.95 g) as a clear oil. Method B; Rt: 0.73 min. m/z: 271 (MH) ^- exact mass: 272.1.

Methyl (3S)-3,7-dimethyl-1,1-dioxo-2,3,4,5-tetrahydropyrrolo[3,4-f]triazepine-6-carboxylate (200 mg, 0.73 mmol) and 3-amino-2,6-difluoro-benzonitrile (0.16 g, 0.88 mmol) in dry THF (5 mL) were treated with lithium bis(trimethylsilyl)amide (2.2 mL, 1 M in THF, 2.2 mmol) and stirred at room temperature overnight. The resulting mixture was quenched with _NH4Cl (aqueous, saturated, 5 mL). 5 mL of brine was then added and the layers separated. The aqueous layer was extracted with EtOAc (2 x 30 mL). The combined extracts were concentrated in vacuo and the resulting crude product was purified using silica gel column chromatography (gradient elution: EtOAc: heptane 0:100 to 100:0). The desired fractions were concentrated in vacuo and the residue obtained was purified by preparative HPLC (stationary phase: RP XBridge Prep C18 OBD-10 μm, 30×150 mm, mobile phase: 0.25% NH ₄ HCO ₃ solution in water, ACN).

The desired fractions were concentrated under reduced pressure, co-evaporated with methanol (2 X 25 mL) and dried in a vacuum oven at 55 °C for 18 hours to yield compound 157 (7.6 mg). ^1H NMR (400 MHz, DMSO- _d6 ) δ ppm 1.14 (d, J = 6.82 Hz, 3H) 1.31-1.45 (m, 1H) 1.81-1.91 (m, 1H) 2.77-2.89 (m, 1H) 3.07-3.18 (m, 1H) 3.58-3.67 (m, 1H) 3.70 (s, 3H) 7.03 (d, J = 9.68 Hz, 1H) 7.40-7.51 (m, 2H) 8.06 (td, J = 8.97, 6.05 Hz, 1H) 10.31 (s, 1H); Method B; Rt: 0.85 min. m/z: 393 (MH) ^- Exact mass: 394.1, MP: 247.5°C.

Methyl (3S)-3,7-dimethyl-1,1-dioxo-2,3,4,5-tetrahydropyrrolo[3,4-f]triazepine-6-carboxylate (140 mg, 0.51 mmol) and 5-amino-2-fluorobenzonitrile (77 mg, 0.57 mmol) in THF (8 mL) were treated with LiHMDS (1 mL, 1 M in THF, 1 mmol) and stirred at room temperature for 2 hours. The resulting mixture was quenched with _NH4Cl (aqueous, saturated, 5 mL). Brine (5 mL) was then added and the layers separated. The aqueous layer was extracted with EtOAc (2 x 10 mL). The combined extracts were concentrated in vacuo and the resulting crude product was purified using silica gel column chromatography (EtOAc: heptane 0: 100 to 100: 0). The desired fractions were concentrated in vacuo and the obtained residue was purified by preparative HPLC (stationary phase: RP XBridge Prep C18 OBD-10 μm, 30 x 150 mm, mobile phase: 0.25% NH ₄ HCO ₃ solution in water, ACN) to yield (3S)-N-(3-cyano-4-fluoro-phenyl)-3,7-dimethyl-1,1-dioxo-2,3,4,5-tetrahydropyrrolo[3,4-f]triazepine-6-carboxamide (41 mg), which is equivalent to compound 56. ¹ HNMR (400 MHz, DMSO-d ₆ ) δppm 1.13 (d, J=6.60Hz, 3H) 1.28-1.42 (m, 1H) 1.77 -1.92 (m, 1H) 2.77-2.90 (m, 1H) 2.92-3.04 (m, 1H) 3.56-3.66 (m, 1 H) 3.69 (s, 3H) 7.02 (d, J = 9.68Hz, 1H) 7.43 (s, 1H) 7.54 (t, J = 9.13Hz, 1H) 7.95 (ddd, J = 9.19, 4.90, 2.86Hz, 1H) 8.19 (dd, J = 5.72, 2.64Hz, 1H) 10.59 (s, 1H); Method B; Rt: 0.85 min. m/z: 375 (MH) ^- Exact mass: 376.1.

Compound 158: N-[2-(difluoromethyl)-4-pyridinyl]-3,3,7-trimethyl-1,1-dioxo-2,4-dihydropyridinyl Pyrrolidine[3,4-b][1,4,5]oxatriazepine-6-carboxamide

Compound 158 (610 mg) was prepared similarly as described for compound 133 using 2-(difluoromethyl)pyridin-4-amine instead of 3,4-difluoroaniline. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.30 (s, 6H), 3.82 (s, 3H), 4.43 (s, 2H), 6.91 (t, J=55.0 Hz, 1H), 7.49 (s, 1H), 7.77-7.81 (m, 1H), 7.82 (s, 1H), 8.03 (d, J=2.0 Hz, 1H), 8.54 (d, J=5.5 Hz, 1H), 9.69 (s, 1H); Method B; Rt: 0.82 min. m/z: 399 (MH) ^- Exact mass: 400.1, MP: 229.9° C.

Compound 159: (3R)-N-(3-cyano-2,4-difluoro-phenyl)-3-[(1S)-1-hydroxyethyl]-7-methyl-1, 1-Dioxo-2,3,4,5-tetrahydropyrrolo[3,4-f]triazepine-6-carboxamide

Compound 159 (7 mg) was prepared similarly as described for compound 88 using 3-amino-2,6-difluoro-benzonitrile instead of 3,4-difluoroaniline. ¹ H NMR (400MHz, DMSO-d ₆ ) δppm 1.13 (d, J=6.2Hz, 3H), 1.25-1.37 (m, 1H), 2.17-2.24 (m, 1H), 2.71-2.79 (m, 1H), 3.15-3.24 (m, 2H), 3.42-3.53 (m, 1H), 3.70 (s, 3H), 4.68 (d, J=5.7Hz, 1H), 6.91 (d, J=10.1Hz, 1H), 7.43-7.49 (m, 2H), 8.06 (td, J=8.9, 6.2Hz, 1H), 10.31 (s, 1H); Method D; Rt: 1.71 min.m/z: 423 (MH) ^- Exact mass: 424.1.

Compound 160: N-(3,4-difluorophenyl)-3,7-dimethyl-3-oxazol-2-yl-1,1-dioxo-2,4-dihydropyridine Pyrrolidine[3,4-b][1,4,5]oxatriazepine-6-carboxamide

Compound 160 (240 mg) was prepared similarly as described for compound 153 using 1-(oxazol-2-yl)ethanone instead of 2-acetylpyrimidine. ^1H NMR (400 MHz, DMSO- _d6 ) δ ppm 1.63 (s, 3H), 3.81 (s, 3H), 4.88 (d, J = 13.3 Hz, 1H), 5.11 (d, J = 13.3 Hz, 1H), 7.18 (d, J = 0.8 Hz, 1H), 7.38-7.50 (m, 3H), 7.87 (ddd, J = 13.2, 7.5, 2.4 Hz, 1H), 8.13 (d, J = 0.8 Hz, 1H), 8.68 (s, 1H), 9.46 (s, 1H); Method B; Rt: 0.93 min. m/z: 439 (M+H) ⁺ exact mass: 438.1. The racemic mixture was separated into its enantiomers by preparative SFC (stationary phase: Daicel Chiralpak OD 20 x 250 mm, mobile phase: CO ₂ , EtOH + 0.4 iPrNH ₂ ) to yield compounds 160a (88 mg); MP: 239.5° C., and 160b (80 mg); MP: 240.2° C. Method Y; Rt: 160a: 3.43 min, 160b: 3.73 min.

Synthesis of 2-amino-3-(2,2,2-trifluoroethylamino)butan-1-ol.

By tert-butyl 4-acetyl-2,2-dimethyl oxazolidine-3-formate (3.0g, 12mmol) and 2,2,2-trifluoroethylamine (1.47mL, 1.24g/mL, 18.5mmol) are dissolved in DCM (50 mL) and at room temperature stir 30min.Then add NaBH (OAc) ₃ (3-40g, 16.0mmol) and the reaction mixture is stirred overnight.The reaction mixture is diluted with DCM (40mL) and quenched with Na ₂ CO ₃ (aqueous, saturated, 60mL).The organic layer is separated, through Na ₂ SO ₄ is dried, filtered and evaporated to dryness.The crude oil is purified using heptane to EtOAc gradient on silica, produces tert-butyl 2,2-dimethyl-4-[1-(2,2,2-trifluoroethylamino) ethyl] oxazolidine-3-formate (4.2g) in a clear oily state. ¹ H NMR (400 MHz, chloroform-d) δ ppm 1.04 (d, J=6.6 Hz, 3H), 1.35-1.57 (m, 15H), 3.00-4.21 (m, 6H).

Tert-butyl 2,2-dimethyl-4-[1-(2,2,2-trifluoroethylamino)ethyl]oxazolidine-3-carboxylate (3.73 g, 11.43 mmol) was dissolved in 1,4-dioxane (50 mL) and HCl (17 mL, 4 M in 1,4-dioxane, 68.6 mmol) was added at room temperature. After stirring for 5 hours, the solvent was removed to produce crude 2-amino-3-(2,2,2-trifluoroethylamino)butan-1-ol hydrochloride, which was used as is in the next step.

Compound 161: N-(3-cyano-4-fluoro-phenyl)-7-methyl-1,1-dioxo-3-[1-(2,2,2-trifluoroethylamino]- [3,4-dihydro-2H-pyrrolo[3,4-b][1,4,5]oxatriazepine-6-carboxamide]

A mixture of 2-amino-3-(2,2,2-trifluoroethylamino)butan-1-ol hydrochloride (2.13 g, 11.4 mmol) and Hunin's base (12.4 mL, 0.75 g/mL, 72.2 mmol) in dry DCM (75 mL) was stirred for 15 min to give a clear yellow solution. Ethyl 4-chlorosulfonyl-3-fluoro-1-methyl-pyrrole-2-carboxylate (3.08 g, 11.43 mmol) was then added and the solution was stirred at room temperature for 4 hours. The reaction mixture was quenched with _NaHCO (aqueous, saturated, 75 mL). The aqueous layer was extracted with DCM (2 x 50 mL). The combined organic layers were _dried over _NaSO , filtered, and evaporated to give a yellow oil. The crude product was purified on silica using a DCM to EtOAc gradient to give ethyl 3-fluoro-4-[[1-(hydroxymethyl)-2-(2,2,2-trifluoroethylamino)propyl]sulfamoyl]-1-methyl-pyrrole-2-carboxylate (4.55 g) as a yellow oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.84-0.97 (m, 3H), 1.28 (t, J=7.0 Hz, 3H), 1.85-2.10 (m, 1H), 2.76-2.91 (m, 1H), 2.99-3.52 (m, 5H), 3.82 (s, 3H), 4.27 (q, J=7.0 Hz, 2H), 4.54-4.77 (m, 1H), 7.44 (br s, 1H), 7.51-7.60 (m, 1H); Method D; Rt: 1.64 min. m/z: 418 (MH) ^- Exact mass: 419.1.

To a solution of ethyl 3-fluoro-4-[[1-(hydroxymethyl)-2-(2,2,2-trifluoroethylamino)propyl]sulfamoyl 1-1-methyl-pyrrole-2-carboxylate (1.00 g, 2.38 mmol) and 5-amino-2-fluoro-benzonitrile (389 mg, 2.86 mmol) in dry THF (25 mL) was added lithium bis(trimethylsilyl)amide (1 M in THF) [4039-32-1]#JNJ-70824# (12 mL, 1 M in THF, 12 mmol). The reaction mixture was stirred at room temperature for 5 hours. NH ₄ Cl (aqueous, saturated, 30 mL) was then added followed by EtOAc (30 mL), and the mixture was stirred for 15 min. The two layers were separated and the aqueous layer was extracted with EtOAc (2×30 mL). The combined organic layers were dried over _Na2SO4 , _filtered and concentrated under reduced pressure to give a brown oil. The crude product was purified on silica using a DCM to EtOAc gradient to yield N-(3-cyano-4-fluoro-phenyl)-3-fluoro-4-[[1-(hydroxymethyl)-2-(2,2,2-trifluoroethylamino)propyl]sulfamoyl]-1-methyl-pyrrole-2-carboxamide (818 mg).

By N-(3-cyano-4-fluoro-phenyl)-3-fluoro-4-[[1-(hydroxymethyl)-2-(2,2,2-trifluoroethylamino) propyl group] sulfamoyl]-1-methyl-pyrrole-2-carboxamide (818mg, 1.61mmol) and cesium fluoride (976mg, 6.42mmol) are dissolved in dry DMF (12mL) and heated at 110 ℃ for 18 hours.The reaction mixture is quenched with cold water (15mL) and extracted with EtOAc (3 × 15mL).The organic layer merged is evaporated and this residue is used DCM to EtOAc gradient on silica to be purified to obtain yellow foam. The four isomers were separated by preparative SFC (stationary phase: Daicel Chiralpak AS 20 microm 500gr, mobile phase: CO ₂ , EtOH + 0.4iPrNH ₂ ) to give compound 161a (89 mg); ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.08 (d, J = 6.4 Hz, 3H), 2.30-2.43 (m, 1H), 2.71-2.84 (m, 1H), 3.12-3.41 (m, 2H), 3.53-3.63 (m, 1H), 3.83 (s, 3H), 4.00 (dd, J = 12.7, 8.9 Hz, 1H), 4.84 (dd, J = 12.8, 1.9 Hz, 1 1H), 7.44-7.56 (m, 2H), 7.60 (br s, 1H), 8.00 (ddd, J=9.2, 4.9, 2.7 Hz, 1H), 8.18 (dd, J=5.8, 2.7 Hz, 1H), 9.55 (s, 1H); Method D; Rt: 1.92 min. m/z: 488 (MH) - exact mass: 489.1, compound 161b (70 mg); ^1H NMR (400 MHz, DMSO- _d6 ) ppm 1.08 (d, J=6.4 Hz, 3H), 2.31-2.43 (m, 1H), 2.70-2.85 δ 5.77 (s, 1H), 4.11 (m, 2H), 3.57 (m, 1H), 3.09 (s, 3H), 4.11 (m, 2H), 3.07 (m, 1H), 3.09 (s, 3H), 4.12 (m, 2H), 3.06 (m, 1H), 3.05 (m, 2H), 3.04 (m, 1H), 3.06 (m, 2H), 3.08 (m, 1H), 3.09 (m, 2H), 3.10 (m, 1H), 3.13 (m, 2H), 3.53 (m, 1H), 3.83 (s, 3H), 4.00 (dd, J = 12.7, 8.9 Hz, 1H), 4.84 (dd, J = 12.7, 2.0 Hz, 1H), 7.47 (m, 2H), 7.62 (br s, 1H), 8.00 (ddd, J = 9.2, 4.9, 2.8 Hz, 1H), 8.18 (dd, J = 5.8, 2.7 Hz, 1H), 9.55 (s, 1H); Method D; Rt: 1.92 min. m/z: 488 (MH) ^- Exact mass: 489.1, Compound 161c (15 mg); ¹ H NMR (400 MHz, DMSO-d ₆ ) δppm 1.07 (d, J=6.5Hz, 3H), 2.35 (q, J=7.4Hz, 1H), 2.88-3.02 (m, 1H), 3.12 -3.44 (m, 2H), 3.62-3.72 (m, 1H), 3.83 (s, 3H), 4.01 (dd, J=12.8, 9.0 Hz, 1H), 4.72 (dd, J=12.8, 1.3Hz, 1H), 7.42-7.56 (m, 2H), 7.59 (br s, 1 H), 8.02 (ddd, J=9.2, 4.9, 2.7Hz, 1H), 8.18 (dd, J=5.8, 2.7Hz, 1H), 9.56 (s, 1H); Method D; Rt: 1.93 min. m/z: 488 (MH) ^- Exact mass: 489.1 and compound 161d (18 mg); ^1H NMR (400 MHz, DMSO- _d6 ) δ ppm 1.07 (d, J = 6.5 Hz, 3H), 2.35 (q, J = 7.3 Hz, 1H), 2.89-3.03 (m, 1H), 3.13-3.45 (m, 2H), 3.63-3.73 (m, 1H), 3.83 (s, 3H), 4.01 (dd, J = 12.8, 9.0 Hz, 1H), 4.72 (dd, J = 13.1, 1.2 Hz, 1H), 7.43-7.56 (m, 2H), 7.60 (br s, 1H), 8.02 (ddd, J=9.2, 4.9, 2.7 Hz, 1H), 8.18 (dd, J=5.8, 2.7 Hz, 1H), 9.56 (s, 1H); Method D; Rt: 1.93 min. m/z: 488 (MH) ^- Exact mass: 489.1. Method AA; Rt: 161a: 3.69 min, 161b: 3.61 min, 161c: 3.75 min, 161d: 4.02 min.

Compound 162: N-(3,4-difluorophenyl)-3,7-dimethyl-3-[(5-methylisoxazol-3-yl)methyl]-1, 1-Dioxo-2,4-dihydropyrrolo[3,4-b][1,4,5]oxatriazepine-6-carboxamide

DL-alanine methyl ester hydrochloride (12.8 g, 91.7 mmol) is finely ground and added to DCM (250 mL). Benzophenone imine (14.4 g, 1.62 g/mL, 79.5 mmol) is added and the mixture is stirred at room temperature overnight. The mixture is filtered and the filtrate is washed with water. The organic layer is separated and concentrated in vacuo. The residue is purified on silica using a gradient of 0 to 50% EtOAc in heptane to produce methyl 2-(benzylideneamino) propionate (15.7 g) as a clear oil.

Potassium tert-butoxide (3.74 g, 33.3 mmol) is added to a cold (-10 ° C) solution of methyl 2-(benzylideneamino) propionate (7.42 g, 27.8 mmol) and 3-(chloromethyl)-5-methylisoxazole (3.77 g, 27.8 mmol) in NMP (20 mL). The reaction mixture is stirred for 1 hour and HCl (67 mL, 1 M in H ₂ O, 67 mmol) is added and the reaction mixture is stirred overnight. The reaction mixture is then diluted with EtOAc (100 mL) and washed with brine (3×100 mL). The combined organic layers are evaporated to dryness and the residue is purified on silica using a heptane to EtOAc gradient to produce methyl 2-(benzylideneamino)-2-methyl-3-(5-methylisoxazol-3-yl) propionate (4.44 g) as an oil. ¹ H NMR (400MHz, DMSO-d ₆ ) δppm 1.55 (s, 3H), 2.37-2.41 (m, 3H), 3.22 (s, 2H), 3.69-3.79 (m, 3H), 6.15 (s, 1H), 8.78 (br s, 3H).

Methyl 2-(benzylideneamino)-2-methyl-3-(5-methylisoxazol-3-yl)propanoate (4.44 g, 18.9 mmol) was dissolved in MeOH (50 mL) cooled in an ice bath (-10°C). Sodium borohydride (2.15 g, 56.8 mmol) was added and the reaction mixture was stirred overnight. Incomplete conversion was observed. Volatiles were removed under reduced pressure and the residue was redistributed in THF (100 mL) and lithium aluminum hydride (18.9 mL, 1 M in THF, 18.9 mmol) was added dropwise. The reaction mixture was stirred overnight. Sodium sulfate decahydrate (27.4 g, 85.1 mmol) was added followed _{by Na2SO4} . The reaction mixture was filtered and the volatiles were removed under reduced pressure, and the residue was purified on silica using a DCM to DCM: MeOH/NH ₃ 9: 1 gradient to produce 2-amino-2-methyl-3-(5-methylisoxazol-3-yl)propan-1-ol (1.41 g) as a clear oil. The filter cake was washed with MeOH and the volatiles were removed from the filtrate. The residue was purified on silica using a DCM to DCM: MeOH/NH ₃ 9: 1 gradient to produce a second batch of 2-amino-2-methyl-3-(5-methylisoxazol-3-yl)propan-1-ol (455 mg) as a light yellow oil.

The two fractions (1.44 g and 455 mg, 11.1 mmol), ethyl 4-chlorosulfonyl-3-fluoro-1-methyl-pyrrole-2-carboxylate (2.74 g, 10.2 mmol) and Hunin's base (4.37 mL, 0.75 g/mL, 25.4 mmol) were dissolved in ACN (25 mL) and the reaction mixture was stirred overnight. The volatiles were removed under reduced pressure and the residue was purified on silica using a heptane to EtOAc gradient to give ethyl 3-fluoro-4-[[1-(hydroxymethyl)-1-methyl-2-(5-methylisoxazol-3-yl)ethyl]sulfamoyl]-1-methyl-pyrrole-2-carboxylate (2.42 g) as a yellow oil which solidified overnight.

Ethyl 3-fluoro-4-[[1-(hydroxymethyl)-1-methyl-2-(5-methylisoxazol-3-yl)ethyl]sulfamoyl]-1-methyl-pyrrole-2-carboxylate (484 mg, 1.20 mmol) and 3,4-difluoroaniline (0.12 mL, 1.29 g/mL, 1.2 mmol) were partitioned in THF (5 mL). Lithium bis(trimethylsilyl)amide (6 mL, 1 M in THF, 6 mmol) was added and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was quenched with NH ₄ Cl (saturated, aqueous, 10 mL) and the organic layer was removed. The aqueous layer was extracted with DCM (2 x 5 mL) and the combined organic layers were evaporated to dryness and the residue was purified on silica using a heptane to EtOAc gradient to yield N-(3,4-difluorophenyl)-3-fluoro-4-[[1-(hydroxymethyl)-1-methyl-2-(5-methylisoxazol-3-yl)ethyl]sulfamoyl]-1-methyl-pyrrole-2-carboxamide (175 mg).

N-(3,4-Difluorophenyl)-3-fluoro-4-[[1-(hydroxymethyl)-1-methyl-2-(5-methylisoxazol-3-yl)ethyl]sulfamoyl]-1-methyl-pyrrole-2-carboxamide (175 mg, 0.36 mmol) and cesium fluoride (219 mg, 1.44 mmol) were partitioned in DMF (3 mL) and heated in a microwave tube at 110° C. for 2 hours. The reaction mixture was loaded directly onto a silica cartridge and a heptane to EtOAc gradient was employed to produce compound 162. This was separated into its enantiomers by preparative SFC (stationary phase: Chiralpak Diacel AD 20×250 mm, mobile phase: CO ₂ , MeOH+0.4iPrNH ₂ ) to yield compound 162a (32 mg); ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.21 (s, 3H), 2.38-2.41 (m, 3H), 2.87 (d, J=13.9 Hz, 1H), 3.04 (d, J=13.9 Hz, 1H), 3.82 (s, 3H), 4.41 (d, J=13.0 Hz, 1H), 4.60 (d, J=13.0 Hz, 1H), 6.21 (d, J=0.9 Hz, 1H), 7.40-7.44 (m, 2H), 7.48 (s, 1H), 7.81-7.93 (m, 2H), 9.39 (s, 1H); Method B; Rt: 1.04 min. m/z: 465 (MH) ^- Exact mass: 466.1 and compound 162b (33 mg); ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.21 (s, 3H), 2.37-2.41 (m, 3H), 2.87 (d, J=13.9 Hz, 1H), 3.04 (d, J=13.9 Hz, 1H), 3.82 (s, 3H), 4.41 (d, J=13.2 Hz, 1H), 4.60 (d, J = 13.0 Hz, 1H), 6.21 (d, J = 0.9 Hz, 1H), 7.38-7.45 (m, 2H), 7.48 (s, 1H), 7.80-7.93 (m, 2H), 9.39 (s, 1H); Method B; Rt: 1.04 min. m/z: 465 (MH) ^- Exact mass: 466.1, white powder after crystallization from an EtOAc:DIPE mixture. Method V; Rt: 162a: 3.82 min, 162b: 4.21 min.

Compound 163: N-(3-cyano-4-fluoro-phenyl)-3-(1-hydroxypropyl)-7-methyl-1,1-dioxo-3,4-diol Hydrogen-2H-pyrrolo[3,4-b][1,4,5]oxatriazepine-6-carboxamide

Compound 163 (132 mg) was prepared similarly as described for compound 142 using 5-amino-2-fluoro-benzonitrile instead of 3,4-difluoroaniline. The racemic mixture was separated into its diastereomers by preparative SFC (stationary phase: Daicel Chiralpak AD 20x250 mm, mobile phase: _CO2 , EtOH + _0.4iPrNH2 ) to yield compound 163a (41 mg); ^1H NMR (400 MHz, DMSO- _d6 ) δ ppm 0.92 (t, J = 7.4 Hz, 3H), 1.44 (dquin, J = 14.2, 7.3, 7.3, 7.3, 7.3 Hz, 1H), 1.65-1.78 (m, 1H), 3.35-3.44 (m, 1H), 3.44-3.57 (m, 1H), 3.83 (s, 3H), 3.98 (dd, J = 12.6, 8.8 Hz, 1H), 4.93 (dd, J = 12.8, 2.0 Hz, 1H), 4.99 (d, J = 6.2 Hz, 1H), 7.45-7.56 (m, 2 H), 7.62 (br d, J = 8.6 Hz, 1H), 8.05 (ddd, J = 9.2, 4.9, 2.8 Hz, 1H), 8.21 (dd, J = 5.8, 2.7 Hz, 1H), 9.51 (s, 1H); Method D; Rt: 1.69 min. m/z: 421 (MH) ^- Exact mass: 422.1, and 163b (21 mg); ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.88 (t, J=7.3Hz, 3H), 1.29-1.43 (m, 1H), 1.50-1.63 (m, 1H), 3.55-3.64 (m, 1H), 3.67-3.76 (m, 1H), 3.83 (s, 3H), 3.99 (dd, J=12.7, 9.1Hz, 1H), 4.74 (dd, J=13.1, 0.5Hz, 1H), 4.88 (br d, J=5.3Hz, 1H), 7.35 (br s, 1H), 7.49 (s, 1H), 7.52 (t, J=9.1Hz, 1H), 8.05 (ddd, J = 9.2, 4.9, 2.8 Hz, 1H), 8.19 (dd, J = 5.8, 2.7 Hz, 1H), 9.54 (s, 1H); Method D; Rt: 1.70 min. m/z: 421 (MH) ^- Exact mass: 422.1; MP: 247.0° C. Method R; Rt: 163a: 4.44 min, 163b: 4.60 min.

Compound 164: (3S)-N-[3-(Difluoromethyl)-2,4-difluoro-phenyl]-3,7-dimethyl-1,1-dioxo-2, 3,4,5-tetrahydropyrrolo[3,4-f]triazepine-6-carboxamide

Compound 164 (87 mg) was prepared similarly as described for compound 157 using 3-(difluoromethyl)-2,4-difluoro-aniline instead of 3-amino-2,6-difluoro-benzonitrile. ^1H NMR (400 MHz, DMSO- _d6 ) δ ppm 1.14 (d, J = 6.82 Hz, 3H) 1.29-1.52 (m, 1H) 1.79-1.99 (m, 1H) 2.74-2.93 (m, 1H) 3.12 (br dd, J = 15.07, 6.05 Hz, 1H) 3.55-3.67 (m, 1H) 3.70 (s, 3H) 7.02 (br d, J = 9.02 Hz, 1H) 7.17-7.56 (m, 3H) 7.77-7.99 (m, 1H) 10.13 (br s, 1H); Method B; Rt: 0.89 min. m/z: 418 (MH) ^- Exact mass: 419.1, MP: 227.7°C.

Compound 165: (3S)-N-[2-(difluoromethyl)-4-pyridinyl]-3,7-dimethyl-1,1-dioxo-2,3,4,5- Tetrahydropyrrolo[3,4-f]triazepine-6-carboxamide

Compound 165 (84 mg) was prepared similarly as described for compound 157 using 2-(difluoromethyl)pyridin-4-amine instead of 3-amino-2,6-difluoro-benzonitrile. ¹ H NMR (400 MHz, DMSO-d ₆ ) δppm 1.13 (d, J=6.82Hz, 3H) 1.29-1.44 (m, 1H) 1.79-1.93 (m, 1H) 2.78-2.91 (m, 1H) 2.92-3.03 (m, 1H) 3.56-3.68 (m, 1H) 3.71 (s, 3H) 6.73-7.12 (m, 2H) 7.47 (s, 1H) 7.75 (dd, J = 5.50, 1.76Hz, 1H) 8.03 (d, J = 1.76Hz, 1H) 8.56 (d, J = 5.50Hz, 1H) 10.84 (s, 1H); Method B; Rt: 0.74 min. m/z: 385 (MH) ^- Exact mass: 384.1.

Compound 166: (3S)-N-(2-chloro-4-pyridinyl)-3,7-dimethyl-1,1-dioxo-2,3,4,5-tetrahydropyrrole 6-[3,4-f]triazepine-3-carboxamide

Compound 166 (107 mg) was prepared similarly as described for compound 157 using 2-chloropyridin-4-amine instead of 3-amino-2,6-difluoro-benzonitrile. ¹ H NMR (400MHz, DMSO-d ₆ ) δppm 1.13 (d, J=6.82Hz, 3H) 1.27-1.47 (m, 1H) 1.79-1.91 (m, 1H) 2.78-2.90 (m, 1H) 2.91-3.04 (m, 1H) 3.55-3.67 (m, 1H) 3.70 (s, 3H) 7.04 (d, J = 9.46Hz, 1H) 7.47 (s, 1H) 7.58 (dd, J = 5.72, 1.76 Hz, 1H) 7.80 (d, J = 1.76Hz, 1H) 8.29 (d, J = 5.50Hz, 1H) 10.81 (br s, 1 H); Method B; Rt: 0.76 min. m/z: 367 (MH) ^- Exact mass: 368.1.

Compound 167: N-(3,4-difluorophenyl)-3,7-dimethyl-3-[(1-methylpyrazol-3-yl)methyl]-1,1- 2,4-dihydropyrrolo[3,4-b][1,4,5]oxatriazepine-6-carboxamide

Compound 167 (435 mg) was prepared similarly as described for compound 162 using 3-(chloromethyl)-1-methyl-1H-pyrazole hydrochloride instead of 3-(chloromethyl)-5-methylisoxazole. The racemic mixture was separated into its enantiomers by preparative SFC (stationary phase: Daicel Chiralpak AD 20 x 250 mm, mobile phase: CO ₂ , MeOH + 0.4iPrNH ₂ ) to yield compound 167a (154.1 mg); ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.21 (s, 3H), 2.83 (d, J = 13.9 Hz, 1H), 2.98 (d, J = 13.9 Hz, 1H), 3.80 (s, 3H), 3.82 (s, 3H), 4.40 (d, J = 13.0 Hz, 1H), 4.53 (d, J = 13.2 Hz, 1H), 6.14 (s, 4H). (d, J = 2.2 Hz, 1H), 7.38-7.45 (m, 2H), 7.46 (s, 1H), 7.60 (d, J = 2.0 Hz, 1H), 7.80 (s, 1H), 7.81-7.88 (m, 1H), 9.37 (s, 1H); Method B; Rt: 0.99 min. m/z: 464 (MH) ^- Exact mass: 465.1, and 167b (151.4 mg); ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.21 (s, 3H), 2.83 (d, J = 13.9 Hz, 1H), 2.98 (d, δ = 1.5 Hz, 1H), 3.7 (s, 3H), 4.6 (s, 1H), 5.9 (s, 2H), 4.1 (s, 3H), 4.7 (s, 1H), 4.9 (s, 2H), 3.1 (s, 3H), 4.9 (s, 3H), 4.0 (s, 1H), 4.1 (s, 1H), 4.2 (s, 1H), 4.4 (s, 1H), 3.9 (s, 2H), 4.6 (s, 1H), 4.9 (s, 3H), 4.1 (s, 1H), 4.2 (s, 1H), 4.1 (s, 1H), 4.2 (s, 1H) ^, 4.1 (s, 1H), 4.3 (s, 1H), 4.7 (s, 1H), 4.1 (s, 1H);

Compound 168: N-(3,4-difluorophenyl)-3,7-dimethyl-3-(6-methyl-2-pyridinyl)-1,1-dioxo-2, 4-Dihydropyrrolo[3,4-b][1,4,5]oxatriazepine-6-carboxamide

Compound 168 (118 mg) was prepared similarly as described for compound 153 using 2-acetyl-6-methylpyridine instead of 2-acetylpyrimidine. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.54-1.59 (m, 3H), 2.44-2.47 (m, 3H), 3.79-3.84 (m, 3H), 4.97 (d, J=13.4 Hz, 1H), 5.21 (d, J=13.3 Hz, 1H), 7.16 (d, J=7.6 Hz, 1H), 7.37-7.51 (m, 3H), 7.60 (d, J=7.9 Hz, 1H), 7.75 (t, J=7.8 Hz, 1H). H), 7.89 (ddd, J=13.2, 7.5, 2.5 Hz, 1H), 8.47 (s, 1H), 9.40 (s, 1H); Method B; Rt: 1.26 min. m/z: 463 (M+H) ⁺ exact mass: 462.1. The racemic mixture was separated into its enantiomers by preparative SFC (stationary phase: Daicel Chiralpak AS 20 x 250 mm, mobile phase: CO ₂ , EtOH + 0.4iPrNH ₂ ) to produce compounds 168a (37 mg); MP: 221.9° C., and 168b (35 mg); MP: 221.5° C. Method T; Rt: 168a: 3.67 min, 168b: 4.66 min.

Compound 169: (3S)-N-[3-(Difluoromethyl)-4-fluoro-phenyl]-3,7-dimethyl-1,1-dioxo-3-(2-pyridinium chloride) pyridyl)-2,4-dihydropyrrolo[3,4-b][1,4,5]oxatriazepine-6-carboxamide

Compound 169 (131 mg) was prepared similarly as described for compound 127 using 3-(difluoromethyl)-4-fluoro-aniline instead of 3,4-difluoroaniline. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.55-1.62 (m, 3H), 3.82 (s, 3H), 4.99 (d, J=13.4 Hz, 1H), 5.20 (d, J=13.3 Hz, 1H), 7.04-7.41 (m, 3H), 7.47 (s, 1H), 7.79-7.89 (m, 3H), 8.05 (dd, J=6.3, 2.6 Hz, 1H), 8.48-8.52 (m, 2H), 9.44 (s, 1H); Method B; Rt: 1.07 min. m/z: 479 (MH) ^- Exact mass: 480.1; MP: 208.8° C.

Compound 170: 3,7-dimethyl-3-[(5-methylisoxazol-3-yl)methyl]-1,1-dioxo-N-(3,4,5-trioxo- (fluorophenyl)-2,4-dihydropyrrolo[3,4-b][1,4,5]oxatriazepine-6-carboxamide

Compound 170 (102 mg) was prepared similarly as described for compound 162, using 3,4,5-trifluoroaniline instead of 3,4-difluoroaniline. This was separated into its enantiomers by preparative SFC (stationary phase: Kromasil (R, R) Whelk-O 1 10/100, mobile phase: CO ₂ , iPrOH + 0.4iPrNH ₂ ) to yield compound 170a (18 mg), ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.22 (s, 3H), 2.40 (s, 3H), 2.88 (d, J = 14.1 Hz, 1H), 3.05 (d, J = 13.9 Hz, 1H), 3.82 (s, 3H), 4.43 (d, J = 13.2 Hz, 1H), 4.61 (d, 1H), 6.22 (s, 1H), 7.51 (s, 1H), 7.62-7.75 (m, 2H), 7.93 (s, 1H), 9.45 (s, 1H); method B; Rt: 1.13 min. m/z: 483 (MH) ^- exact mass: 484.1 and compound 170b (29 mg), ^1H NMR (400 MHz, DMSO- _d6 ) δ ppm 1.17-1.27 (m, 3H), 2.40 (s, 3H), 2.88 (d, J = 13.9 Hz, 1H), 3.05 (d, δ = 1.13 min. m/z: 483 (MH) - exact mass: 484.1 ^. Method X; Rt: 170a: 4.81 min, 170b: 5.12 min.

Compound 171: 3-[(6-bromo-3-pyridyl)methyl]-N-(3,4-difluorophenyl)-3,7-dimethyl-1,1-difluorophenyl Oxy-2,4-dihydropyrrolo[3,4-b][1,4,5]oxatriazepine-6-carboxamide

Compound 171 (102 mg) was prepared similarly as described for compound 162 using 2-bromo-5-(bromomethyl)pyridine instead of 3-(chloromethyl)-5-methylisoxazole. ¹ H NMR (400MHz, DMSO-d ₆ ) δppm 1.13 (s, 3H), 2.72 (d, J = 13.2Hz, 1H), 3.04 (d, J = 13.2Hz, 1H), 3.82 (s, 3H), 4.41 (d, J = 13.2Hz, 1H), 4.64 (d, J=13.2Hz, 1H), 7.38-7.47 (m, 2H), 7.49 (s, 1H), 7.63-7.67 (m, 1H), 7.67-7.73 (m, 1H), 7.76 (s, 1H), 7.80-7.88 (m, 1H), 8.31 (d, J=2.2Hz, 1H), 9.40 (s, 1H); Method B; Rt: 1.11 min. m/z: 539 (MH) ^- Exact mass: 540.0, MP: 259.2°C.

Compound 172: N-(3,4-difluorophenyl)-3,7-dimethyl-3-[(6-methyl-2-pyridyl)methyl]-1,1- 2,4-dihydropyrrolo[3,4-b][1,4,5]oxatriazepine-6-carboxamide

Compound 172 (196 mg) was prepared similarly as described for compound 162 using 2-(bromomethyl)-6-methyl-pyridine instead of 3-(chloromethyl)-5-methylisoxazole. ¹ H NMR (400MHz, DMSO-d ₆ ) δppm 1.23 (s, 3H), 2.42 (s, 3H), 2.99-3.11 (m, 2H), 3.81 (s, 3H), 4.49 (d, J=13.0Hz, 1H), 4.62 (d, J=13.2Hz, 1H), 7.12 (d, J=7.7Hz, 1H), 7.20 (d, J=7.7Hz, 1H), 7.38-7.45 (m, 2H), 7.46 (s, 1H), 7.62 (t, J=7.6Hz, 1H), 7.79-7.86 (m, 1H), 8.02 (s, 1H), 9.30 (s, 1H); Method B; Rt: 1.13 min. m/z: 475 (MH) ^- Exact mass: 476.1, MP: 206.0°C. This was separated into its enantiomers by preparative SFC (stationary phase: Chiralpak Diacel AD 20 x 250 mm, mobile phase: CO ₂ , iPrOH + 0.4 iPrNH ₂ ) to produce Compound 172a (65 mg) and Compound 172b (36 mg). Method W; Rt: 172a: 4.20 min, 172b: 4.40 min.

Compound 173: N-(3,4-difluorophenyl)-3,7-dimethyl-3-[(1-methylimidazol-2-yl)methyl]-1,1- 2,4-dihydropyrrolo[3,4-b][1,4,5]oxatriazepine-6-carboxamide

Compound 173 (109 mg) was prepared similarly as described for compound 162 using 2-chloromethyl-1-methyl-1H-imidazole instead of 3-(chloromethyl)-5-methylisoxazole. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.29-1.36 (m, 3H), 2.96-3.10 (m, 2H), 3.64 (s, 3H), 3.75-3.83 (m, 3H), 4.51-4.66 (m, 2H), 6.82 (d, J=1.1 Hz, 1H), 7.06 (d, J=1.1 Hz, 1H), 7.38-7.46 (m, 3H), 7.79-7.87 (m, 1H), 8.07 (br s, 1H), 9.37 (s, 1H); Method B; Rt: 0.92 min. m/z: 464 (MH) ^- Exact mass: 465.1, MP: 297.1° C.

Compound 174: N-(3,4-difluorophenyl)-3,7-dimethyl-3-[(3-methylimidazol-4-yl)methyl]-1,1- 2,4-dihydropyrrolo[3,4-b][1,4,5]oxatriazepine-6-carboxamide

Compound 174 (109 mg) was prepared similarly as described for compound 162 using 5-chloromethyl-1-methyl-1H-imidazole instead of 3-(chloromethyl)-5-methylisoxazole. ¹ H NMR (400MHz, DMSO-d ₆ ) δppm 1.03-1.24 (m, 3H), 2.83 (d, J=15.0Hz, 1H), 2.97 (d, J=15.0Hz, 1H), 3.60 (s, 3H), 3.81 (s, 3H), 4.38 (d, J=13.4 Hz, 1H), 4.65 (d, J=13.0Hz, 1H), 6.80 (s, 1H), 7.38-7.45 (m, 2H), 7.46 (s, 1H), 7.53 (s, 1H), 7.79-7.91 (m, 2H), 9.39 (s, 1H); Method B; Rt：0.87min.m/z：464(MH) ^- Exact mass: 465.1, MP: 265.5°C.

Compound 175: N-(3,4-difluorophenyl)-3-[(2,5-dimethylpyrazol-3-yl)methyl]-3,7-dimethyl- 1,1-Dioxo-2,4-dihydropyrrolo[3,4-b][1,4,5]oxatriazepine-6-carboxamide

Compound 175 (182 mg) was prepared similarly as described for compound 162 using 5-(chloromethyl)-1,3-dimethyl-1H-pyrazole instead of 3-(chloromethyl)-5-methylisoxazole. ^1H NMR (400 MHz, DMSO- _d6 ) δ ppm 1.22 (s, 3H), 2.11 (s, 3H), 2.85 (d, J = 14.5 Hz, 1H), 3.01 (d, J = 14.7 Hz, 1H), 3.72 (s, 3H), 3.81 (s, 3H), 4.38 (d, J = 13.2 Hz, 1H), 4.65 (d, J = 13.2 Hz, 1H), 5.96 (s, 1H), 7.38-7.48 (m, 3H), 7.81-7.92 (m, 2H), 9.39 (s, 1H); Method B; Rt: 0.98 min. m/z: 478 (MH) ^- Exact mass: 479.1. This was separated into its enantiomers by preparative SFC (stationary phase: Chiralpak Diacel AD 20 x 250 mm, mobile phase: _CO2 , EtOH + _0.4iPrNH2 ) to yield compound 175a (74 mg) and compound 175b (63 mg).Method R; Rt: 172a: 3.88 min, 172b: 5.31 min.

Compound 176: N-[3-(Difluoromethyl)-4-fluoro-phenyl]-3-[(2,5-dimethylpyrazol-3-yl)methyl]-3, 7-Dimethyl-1,1-dioxo-2,4-dihydropyrrolo[3,4-b][1,4,5]oxatriazepine-6-carboxamide

Compound 176 was prepared similarly as described for compound 175 using 3-(difluoromethyl)-4-fluoro-aniline instead of 3,4-difluoroaniline. ¹ H NMR (400MHz, DMSO-d ₆ ) δ ppm 1.22 (s, 3H), 2.11 (s, 3H), 2.94 (dd, J=55.6, 14.6Hz, 2H), 3.72 (s, 3 H), 3.82 (s, 3H), 4.38 (d, J = 13.2Hz, 1H), 4.63 (d, J = 13.6Hz, 1H), 5.96 (s, 1H), 7.23 (t, J=54.8Hz, 1H), 7.32-7.42 (m, 1H), 7.46 (s, 1H), 7.76-7.84 (m, 1H), 7.76-7.84 (m, 1H), 7.88 (s, 1H), 7.97-8.03 (m, 1H), 9.44 (s, 1H); Method B; Rt: 0.98 min. m/z: 510 (MH) ^- Exact mass: 511.2. This was separated into its enantiomers by preparative SFC (stationary phase: Chiralpak Diacel AD 20 x 250 mm, mobile phase: CO ₂ , EtOH + 0.4iPrNH ₂ ) to produce compound 176a (97 mg) and compound 176b (83 mg). Method R; Rt: 176a: 3.61 min, 176b: 5.13 min.

Compound 177: N-[3-(Difluoromethyl)-4-fluoro-phenyl]-3,7-dimethyl-3-(6-methyl-2-pyridinyl)- 1,1-Dioxo-2,4-dihydropyrrolo[3,4-b][1,4,5]oxatriazepine-6-carboxamide

Compound 177 (273 mg) was prepared similarly as described for compound 168 using 3-(difluoromethyl)-4-fluoro-aniline instead of 3,4-difluoroaniline. ¹ H NMR (400MHz, DMSO-d ₆ ) δppm 1.52-1.62 (m, 3H), 2.44-2.48 (m, 3H), 3.78-3.86 (m, 3H), 4.97 (d, J=13.4Hz, 1H), 5.20 (d, J=13.4Hz, 1H), 7.04-7.42 (m, 2H), 7.47 (s, 1H), 7.60 (d, J=7.9Hz, 1H), 7.75 (br t, J=7.7Hz, 1H), 7.79-7.87 (m, 1H), 8.05 (dd, J=6.4, 2.7Hz, 1H), 8.46 (s, 1H), 9.41- 9.47 (m, 1H); Method B; Rt: 1.15 min. m/z: 493 (MH) ^- Exact mass: 494.1; MP: 210.2°C. This was separated into its enantiomers by preparative SFC (stationary phase: Chiralpak Diacel AS 20 x 250 mm, mobile phase: CO ₂ , EtOH + 0.4iPrNH ₂ ) to produce compound 177a (66 mg) and compound 177b (86 mg). Method T; Rt: 177a: 3.09 min, 177b: 3.88 min.

Compound 178: (3R)-N-(3-cyano-2,4-difluoro-phenyl)-3-[(1S)-1-hydroxyethyl]-7-methyl-1, 1-Dioxo-2,3-dihydropyrrolo[3,4-f]triazepine-6-carboxamide

Compound 178 (26 mg) was prepared similarly as described for compound 84 using 3-amino-2,6-difluorobenzonitrile instead of 3,4-difluoroaniline. ¹ H NMR (400MHz, DMSO-d ₆ ) δppm 1.21 (d, J=6.2Hz, 3H), 3.64-3.78 (m, 4H), 3.82 (ddt, J=10.1, 7.4, 2.7, 2.7Hz, 1H), 4.98 (d, J=5.9Hz, 1H), 5.98 (dd, J=12.5, 2.9Hz, 1H), 6.70 (dd, J=12.5, 2.4Hz, 1H), 7.41 (d, J=9.9Hz, 1H), 7.47 (t, J=9.0Hz, 1H), 7.59 (s, 1H), 8.06 (td, J=8.9, 6.2Hz, 1H), 10.59 (br s, 1H); Method B; Rt: 0.73 min. m/z: 421 (MH) ^- Exact mass: 422.1.

Compound 179: N-(3-Bromo-2,4-difluoro-phenyl)-3-(1-hydroxy-1-methyl-ethyl)-7-methyl-1,1-difluoro-phenyl)-1-methyl- Oxy-2,3,4,5-tetrahydropyrrolo[3,4-f]triazepine-6-carboxamide

Compound 179 (274 mg) was prepared similarly as described for compound 113 using 3-bromo-2,4-difluoro-aniline instead of 3,4-difluoroaniline. ¹ H NMR (400MHz, DMSO-d ₆ ) δppm 1.04 (s, 3H), 1.17 (s, 3H), 1.37 (q, J=11.7Hz, 1H), 2.18 (br dd, J=14.2, 7.2Hz, 1H), 2.67-2.78 (m, 1H), 3.16-3.30 (m, 2H), 3.70 (s, 3H), 4.40 (s, 1H), 6.85 (br d, J=10.3Hz, 1H), 7.31 (td, J=8.6, 1.9Hz, 1H), 7.44(s, 1H), 7.70(td, J=8.7, 5.9Hz, 1H), 10.15(br s, 1H); Method B; Rt: 0.86 min. m/z: 490 (MH) ^- exact mass: 491.0, MP: 236.8°C.

Compound 180: (3R)-N-(3-chloro-4-fluoro-phenyl)-3-(1-hydroxy-1-methyl-ethyl)-7-methyl-1,1- 6-Dioxo-3,4-dihydro-2H-pyrrolo[3,4-b][1,4,5]oxatriazepine-2-carboxamide

Compound 180 (289 mg) was prepared similarly as described for compound 93 using 3-chloro-4-fluoro-aniline instead of 3,4-difluoroaniline. ¹ H NMR (400MHz, DMSO-d ₆ ) δppm 1.06 (s, 3H), 1.25 (s, 3H), 3.55 (br t, J=8.5Hz, 1H), 3.83 (s, 3H), 3.93 (dd, J=12.5, 8.9Hz, 1H), 4.85 (s, 1H), 4.96 (d, J=12.4Hz, 1H), 7.38 (t, J=9.1Hz, 1H), 7.45-7.57 (m, 2H), 7.65 (ddd, J=9.0, 4.3, 2.6Hz, 1H), 8.00 (dd, J=6.8, 2.6Hz, 1H), 9.41 (s, 1H); Method D; Rt: 1.82min. m/z: 430 (MH) ^- exact mass: 431.1, MP: 234.1°C.

Compound 181: N-[3-(Difluoromethyl)-4-fluoro-phenyl]-3,7-dimethyl-3-(5-methylisoxazole-3- 1,1-dioxo-2,4-dihydropyrrolo[3,4-b][1,4,5]oxatriazepine-6-carboxamide

Compound 181 (151 mg) was prepared similarly as described for compound 153 using 1-(5-methylisoxazol-3-yl)ethanone instead of 2-acetylpyrimidine. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.60 (s, 3H), 2.39-2.43 (m, 3H), 3.82 (s, 3H), 4.83 (d, J=13.3 Hz, 1H), 4.99 (d, J=13.3 Hz, 1H), 6.34 (d, J=1.1 Hz, 1H), 7.22 (t, J=54.2 Hz, 1H), 7.37 (t, J=9.5 Hz, 1H), 7.47 (s, 1H), 7.80-7.85 (m, 1H), 8.05 (dd, J=6.4, 2.7 Hz, 1H), 8.56 (s, 1H), 9.47 (s, 1H); Method B; Rt: 1.03 min. m/z: 483 (M+H) ⁺ exact mass: 484.1. The racemic mixture was separated into its epimers by preparative SFC (stationary phase: Daicel Chiralpak OD 20 x 250 mm, mobile phase: CO ₂ , EtOH + 0.4iPrNH ₂ ) to produce compounds 181a (47 mg) and 181b (48 mg). Method Y; Rt: 181a: 3.07 min, 181b: 3.53 min.

Compound 182: (3R)-N-[3-(Difluoromethyl)-2,4-difluoro-phenyl]-3-(1-hydroxy-1-methyl-ethyl)- 7-Methyl-1,1-dioxo-3,4-dihydro-2H-pyrrolo[3,4-b][1,4,5]oxatriazepine-6-carboxamide

Compound 182 (153 mg) was prepared similarly as described for compound 93 using 3-(difluoromethyl)-2,4-difluoro-aniline instead of 3,4-difluoroaniline. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.04 (s, 3H), 1.25 (s, 3H), 3.53-3.63 (m, 1H), 3.87 (s, 3H), 3.99 (dd, J=12.5, 8.8 Hz, 1H), 4.83-5.03 (m, 2H), 7.15-7.78 (m, 4H), 8.17-8.34 (m, 1H), 9.36 (s, 1H); Method D; Rt: 1.79 min. m/z: 464 (MH) ^- Exact mass: 465.1, MP: 182.1° C.

Compound 183: N-(3,4-difluorophenyl)-3-[hydroxy(4-pyridyl)methyl]-7-methyl-1,1-dioxo-3, 4-Dihydro-2H-pyrrolo[3,4-b][1,4,5]oxatriazepine-6-carboxamide

At -70 ° C, bis(trimethylsilyl)amide lithium (100 mL, 1M in THF, 100 mmol) was added dropwise to a cold solution of ethyl 2-(dibenzylamino)acetate (10 g, 35.3 mmol) in dry THF (200 mL). The solution was stirred for 1 hour. Then 4-pyridinecarboxaldehyde (6.6 mL, 1.137 g/mL, 70.6 mmol) was slowly added. After the addition was complete, the reaction mixture was heated to 0 ° C over 1 hour. NH ₄ Cl solution (aqueous, saturated, 150 mL) was added and the product was extracted with EtOAc (3×200 mL). The combined organic layers were dried over Na ₂ SO ₄ , filtered and evaporated. The residue was purified on silica using a DCM to EtOAc gradient to produce ethyl 2-(dibenzylamino)-3-hydroxy-3-(4-pyridyl)propanoate (8.72 g) as a yellow oil.

To the solution of ethyl 2-(dibenzylamino)-3-hydroxy-3-(4-pyridyl) propanoate (1.30g, 2.56 mmol) in dry DCM/ pyridine, add imidazoles (524mg, 7.69mmol) followed by TBDMS-Cl (1.16g, 7.69mmol), and the reaction mixture was stirred at room temperature for 2 hours.Add more imidazoles (524mg, 7.69mmol) and TBDMS-Cl (1.16g, 7.69mmol) and the reaction mixture was stirred overnight.Add more imidazoles (524mg, 7.69mmol) and TBDMS-Cl (1.16g, 7.69mmol) and the reaction mixture was stirred overnight.Add pyridine (15mL) and the reaction mixture was stirred overnight.The reaction mixture was quenched with _NaHCO (aqueous, saturated) and the product was extracted with DCM (3 times). The combined organic layers were dried over _Na2SO4 , _filtered and evaporated to give a yellow oil, which was purified by silica gel column chromatography (0% to 50% EtOAc in heptane) and separated into its two enantiomers to yield diastereomer 1 (744 mg); ^1H NMR (400 MHz, chloroform-d) δ ppm -0.30 (s, 3H), -0.02 (s, 3H), 0.72 (s, 9H), 1.42 (t, J = 7.1 Hz, 3H), 3.31 (d, J = 14.0 Hz, 2H), 3.53 (d, J = 9.9 Hz, 1H), 3.91 (d, J = 14.0 Hz, 2H), 4.20-4.43 (m, 2H), 4.97 (d, J = 9.9 Hz, 1H), 6.89-7.02 (m, 6H), 7.15-7.24 (m, 6H), 8.48-8.57 (m, 2H); Method D; Rt: 3.11 min. m/z: 505 (M+H) ⁺ exact mass: 504.3 and diastereomer 2 (40 mg); ¹ H NMR (400 MHz, chloroform-d) δ ppm-0.23 (s, 3H), 0.03 (s, 3H), 0.88 (s, 9H), 1.32 (t, J = 7.1 Hz, 3H), 3.58 (d, J = 4.5 Hz, 1H), 3.81 (d, J = 14.3 Hz, 2H), 4.07-4.37 (m, 4H), 5.30 (d, J = 4.5 Hz, 1H), 7.00-7.09 (m, 6H), 7.14-7.25 (m, 6H), 8.45-8.53 (m, 2H); Method D; Rt: 3.29 min. m/z: 505 (M+H) ⁺ exact mass: 505.3.

At -78 ℃, under nitrogen atmosphere, to diastereomer 1 (744mg, 1.46mmol) in the cold solution in dry DCM, DIBAL (3.5mL, 1M in heptane, 3.5mmol) is slowly added and stirring is continued at this temperature for 4 hours.Add extra DIBAL (3.5 mL, 1M in heptane, 3.5mmol) and the reaction is stirred for 2 more hours.At -78 ℃, the reaction mixture is quenched with MeOH (6mL) followed by sodium potassium tartrate (15mL).Then the bath that becomes cold is removed and the reaction mixture is slowly heated to room temperature.The product is extracted with DCM (3X 20mL).The organic layer merged is evaporated and DCM is used to EtOAc gradient on silica to purify, to produce 3-[tert-butyl (dimethyl) silyl] oxy-2-(dibenzylamino)-3-(4-pyridyl) propan-1-ol (611 mg) in clear oil. Method B; Rt: 1.42 min. m/z: 463 (M+H) ⁺ exact mass: 462.3.

Palladium hydroxide on carbon (91 mg, 0.65 mmol) was added to a solution of 3-[tert-butyl(dimethyl)silyl]oxy-2-(dibenzylamino)-3-(4-pyridyl)propan-1-ol (300 mg, 0.65 mmol) in degassed MeOH (6.5 mL) and the resulting suspension was stirred at room temperature under a hydrogen atmosphere. After 18 hours, the reaction mixture was filtered through a pad of Celite (eluent MeOH) and concentrated in vacuo. The crude product was used as is in the next step.

To a mixture of 2-amino-3-[tert-butyl(dimethyl)silyl]oxy-3-(4-pyridinyl)propan-1-ol (162 mg, 0.57 mmol) and Hunin's base (0.62 mL, 0.75 g/mL, 3.6 mmol) in dry DCM (3.9 mL) was added ethyl 4-chlorosulfonyl-3-fluoro-1-methyl-pyrrole-2-carboxylate (0.16 g, 0.57 mmol) and the reaction mixture was stirred for 1 hour. The reaction mixture was quenched with NaHCO ₃ (aqueous, saturated, 5 mL). The two layers were separated. The aqueous layer was extracted with DCM (2×5 mL). The combined organic layers were evaporated and the crude product was purified on silica using a DCM to EtOAc gradient to give ethyl 4-[[2-[tert-butyl(dimethyl)silyl]oxy-1-(hydroxymethyl)-2-(4-pyridinyl)ethyl]sulfamoyl]-3-fluoro-1-methyl-pyrrole-2-carboxylate (120 mg) as an orange oil.

To a solution of ethyl 4-[[2-[tert-butyl(dimethyl)silyl]oxy-1-(hydroxymethyl)-2-(4-pyridyl)ethyl]sulfamoyl]-3-fluoro-1-methyl-pyrrole-2-carboxylate (120 mg, 0.23 mmol) and 3,4-difluoroaniline (0.035 mL, 1.29 g/mL, 0.35 mmol) in dry THF (2.8 mL) was slowly added lithium bis(trimethylsilyl)amide (1.4 mL, 1 M in THF, 1.4 mmol). The mixture was stirred at room temperature for 3 hours. It was then quenched with _NH4Cl solution (aqueous, saturated, 10 mL) and EtOAc (5 mL) was added. The two layers were separated and the aqueous layer was extracted with EtOAc (2 x 10 mL). The combined organic layers were concentrated under reduced pressure. The crude product was purified on silica using a DCM to EtOAc gradient to give 4-[[2-[tert-butyl(dimethyl)silyl]oxy-1-(hydroxymethyl)-2-(4-pyridinyl)ethyl]sulfamoyl]-N-(3,4-difluorophenyl)-3-fluoro-1-methyl-pyrrole-2-carboxamide as a brown solid (104 mg).

By 4-[[2-[tert-butyl(dimethyl)silyl]oxy-1-(hydroxymethyl)-2-(4-pyridyl)ethyl]sulfamoyl]-N-(3,4-difluorophenyl)-3-fluoro-1-methyl-pyrrole-2-carboxamide (104 mg, 0.17 mmol) and cesium fluoride (106 mg, 0.70 mmol) were dissolved in DMF (2 mL) and heated at 110 ° C for 18 hours. The reaction mixture was quenched with cold water (5 mL) and the product was extracted with EtOAc (3 × 5 mL). The combined organic layers were evaporated and the crude product was purified on silica using DCM to DCM: MeOH 9: 1 gradient to obtain a brown foam. A second purification was performed by preparative HPLC (stationary phase: RP XBridge Prep C18 OBD-10 μm, 30×150 mm, mobile phase: 0.25% NH ₄ HCO ₃ solution in water, ACN) to afford compound 183 (8 mg) as a mixture of 2 enantiomers. ^1H NMR (400 MHz, DMSO- _d6 ) δ ppm 3.73-3.80 (m, 1H), 3.81 (s, 3H), 4.17 (dd, J = 12.8, 9.2 Hz, 1H), 4.57 (d, J = 8.5 Hz, 1H), 4.93 (dd, J = 12.9, 2.3 Hz, 1H), 6.10 (br s, 1H), 7.33-7.51 (m, 5H), 7.71 (br s, 1H), 7.87 (ddd, J = 13.2, 7.5, 2.5 Hz, 1H), 8.53-8.62 (m, 2H), 9.42 (s, 1H); Method D; Rt: 1.62 min. m/z: 463 (MH) ^- Exact mass: 464.1.

Compound 184: (3R)-N-[3-(difluoromethyl)-4-fluoro-phenyl]-3-(hydroxymethyl)-7-methyl-1,1-difluoro-phenyl Oxy-2,3,4,5-tetrahydropyrrolo[3,4-f]triazepine-6-carboxamide

In 5 minutes, at -78 ℃, diisobutylaluminum hydride (1.5mL, 1M in heptane, 1.5mmol) is added dropwise to O6-ethyl O3-methyl (3R) -7-methyl -1,1-dioxo -2,3,4,5-tetrahydropyrrolo [3,4-f] triazepine -3,6- dicarboxylate (239mg, 0.70mmol) in 2-MeTHF (25mL, 0.86g/mL, 250mmol) and stir 1 hour.Add other amount diisobutylaluminum hydride (3mL, 1M, 3mmol) and the reaction mixture is stirred at -78 ℃ for 15 minutes.Allow the reaction mixture to reach room temperature in 10 minutes in a water-bath and quench with methanol (10mL).The reaction mixture is diluted with HCl (aqueous, 1M, 10mL) and extracted with EtOAc (50mL). The organic layer was separated, dried over magnesium sulfate, filtered, and concentrated. The residue was purified on silica using a gradient from 0 to 100% EtOAc in heptane to yield ethyl (3R)-3-(hydroxymethyl)-7-methyl-1,1-dioxo-2,3,4,5-tetrahydropyrrolo[3,4-f]triazepine-6-carboxylate (62 mg) as a white powder. Method D; Rt: 1.31 min. m/z: 301 (MH) ^- Exact mass: 302.1.

To a solution of ethyl (3R)-3-(hydroxymethyl)-7-methyl-1,1-dioxo-2,3,4,5-tetrahydropyrrolo[3,4-f]triazepine-6-carboxylate (62 mg, 0.205 mmol) and 3-(difluoromethyl)-4-fluoro-aniline hydrochloride (51 mg, 0.26 mmol) in THF (3 mL) was added lithium bis(trimethylsilyl)amide in THF (1 mL, 1 M in THF, 1 mmol) and stirred for 3 hours. More 3-(difluoromethyl)-4-fluoro-aniline hydrochloride (102 mg, 0.52 mmol) and lithium bis(trimethylsilyl)amide in THF (2 mL, 1 M in THF, 2 mmol) were added and stirred for 1 hour. The reaction mixture was quenched with _NH4Cl (aqueous, saturated), diluted with brine and extracted with EtOAc. The organic layer was dried over magnesium sulfate, filtered and concentrated. The residue was purified on silica using a gradient from 10% to 100% EtOAc in heptane and further by preparative HPLC (stationary phase: RP XBridge Prep C18 OBD-10 μm, 30 x 150 mm, mobile phase: 0.25% NH ₄ HCO ₃ solution in water, ACN) to produce compound 184 (11 mg). ¹ H NMR (400MHz, DMSO-d ₆ ) δppm 1.22-1.36 (m, 1H), 2.02 (br dd, J=14.3, 6.6Hz, 1H), 2.75-2.85 (m, 1H), 2.99-3.09 (m, 1H), 3.26 (dt, J=10.3, 6.8Hz, 1H), 3.38-3.53 (m, 2H), 3.69 (s, 3H), 4.76 (t, J=5.7Hz, 1H), 6.91 (d, J=9.7Hz, 1H), 7.07-7.40 (m, 2H), 7.42 (s, 1H), 7.78- 7.84 (m, 1H), 8.06 (dd, J=6.2, 2.4 Hz, 1H), 10.49 (s, 1H); Method D; Rt: 1.50 min. m/z: 416 (MH) ^- Exact mass: 417.1.

Compound 185: N-(3-cyano-2,4-difluoro-phenyl)-3-(1-hydroxy-1-methyl-ethyl)-7-methyl-1,1- 2,3,4,5-tetrahydropyrrolo[3,4-f]triazepine-6-carboxamide

Microwave tube was loaded with compound 179 (248 mg, 0.5 mmol), zinc cyanide (41 mg, 0.35 mmol) and DMF (5 mL). The solution was purified with nitrogen for 10 minutes and 1,1'-bis(diphenylphosphine)ferrocenedichloropalladium (II) (37 mg, 0.05 mmol) was added. The tube was sealed and stirred and heated at 160 °C for 30 minutes under microwave irradiation. The reaction mixture was cooled and purified with nitrogen for 10 minutes, and Pd(PPh ₃ ) ₄ (58 mg, 0.05 mmol) was added. The reaction mixture was sealed and stirred and heated at 160 °C for 50 minutes under microwave irradiation. The reaction mixture was filtered through a celite pad, rinsed with 10 mL of acetonitrile and concentrated in vacuo. The residue was purified using preparative HPLC (stationary phase: RP XBridge Prep C18 OBD-10 μm, 50 x 150 mm, mobile phase: 0.25% NH ₄ HCO ₃ solution in water, ACN) to give compound 185 (17 mg). ¹ H NMR (400MHz, DMSO-d ₆ ) δppm 1.03 (s, 3H), 1.17 (s, 3H), 1.31-1.42 (m, 1H), 2.18 (br dd, J=13.5, 6.9Hz, 1H), 2.67-2.78 (m, 1H), 3.15-3.29 (m, 2H), 3.70 (s, 3H), 4.40 (s, 1H), 6.85 (d, J=10.6Hz, 1H), 7.42-7.48 (m, 2H), 8.07 (td, J=8.9, 6.1Hz, 1H), 10.32 (br s, 1H); Method B; Rt: 0.76min.m/z: 437(MH) ^- Exact mass: 438.1.

Compound 186: (3R)-N-[3-(Difluoromethyl)-2,4-difluoro-phenyl]-3-[(1S)-1-hydroxyethyl]-7- Methyl-1,1-dioxo-2,3-dihydropyrrolo[3,4-f]triazepine-6-carboxamide

Compound 186 (72 mg) was prepared similarly as described for compound 84 using 3-(difluoromethyl)-2,4-difluoro-aniline instead of 3,4-difluoroaniline. ¹ H NMR (400 MHz, DMSO-d ₆ ) δppm 1.21 (d, J=6.2Hz, 3H), 3.64-3.74 (m, 1H), 3.75 (s, 3H), 3.78-3.85 (m, 1H), 4.98 (d, J=5.9Hz, 1H), 5.98 (dd, J=12.5, 2.6Hz, 1H), 6.69 (dd, J=12.7, 2.5Hz, 1H), 7.35 (t, J=52.0Hz, 1H), 7.29 -7.48 (m, 2H), 7.58 (s, 1H), 7.84-7.91 (m, 1H), 10.41 (br s, 1H); Method B; Rt: 0.78 min. m/z: 446 (MH) ^- exact mass: 447.1.

Compound 187: N-[3-(Difluoromethyl)-4-fluoro-phenyl]-3,7-dimethyl-3-[(1-methylimidazol-2-yl) methyl]-1,1-dioxo-2,4-dihydropyrrolo[3,4-b][1,4,5]oxatriazepine-6-carboxamide

Compound 187 (75 mg) was prepared similarly as described for compound 173 using 3-(difluoromethyl)-4-fluoro-aniline instead of 3,4-difluoroaniline. ¹ H NMR (400MHz, DMSO-d ₆ ) δppm 1.33 (s, 3H), 3.01-3.06 (m, 2H), 3.64 (s, 3H), 3.81 (s, 3H), 4.54 (d, J=13.2Hz, 1H), 4.64 (d, J=13.4Hz, 1H), 6.82 (d, J=1.1Hz, 1H), 7.05 (d, J=1.1Hz, 1H), 7.22 (t, J=54.4Hz, 1H), 7.36 (t, J=9.5Hz, 1 H), 7.45 (s, 1H), 7.76-7.81 (m, 1H), 8.00 (dd, J=6.3, 2.5Hz, 1H), 8.08 (br s, 1H), 9.41 (s, 1H); Method B; Rt: 0.93 min. m/z: 496 (MH) ^- Exact mass: 497.1, MP: 282.8°C.

Compound 188: (3R)-N-[3-(Difluoromethyl)-2,4-difluoro-phenyl]-3-[(1S)-1-hydroxyethyl]-7- Methyl-1,1-dioxo-2,3,4,5-tetrahydropyrrolo[3,4-fL-triazepine-6-carboxamide

Compound 188 (96 mg) was prepared similarly as described for compound 88 using 3-(difluoromethyl)-2,4-difluoro-aniline instead of 3,4-difluoroaniline. ¹ H NMR (400 MHz, DMSO-d ₆ ) δppm 1.13 (d, J=6.2Hz, 3H), 1.27-1.38 (m, 1H), 2.21 (br dd, J=14.0, 6.9Hz, 1H), 2.66-2.80 (m, 1H), 3.16-3.27 (m, 2H), 3.44-3.52 (m, 1H), 3.70 (s, 3H), 4.67 (d, J=5.7Hz, 1H), 6.90 (br d, J=10.1Hz, 1H), 7.34 (br t, J=52.2Hz, 1H), 7.30 (br t, J=9.5Hz, 1H), 7.43 (s, 1H), 7.85-7.92 (m, 1H), 10.14 (br s, 1H); Method B; Rt: 0.88 min. m/z: 448 (MH) ^- Exact mass: 449.1, MP: 277.1°C.

Compound 189: N-(3-cyano-4-fluoro-phenyl)-3-(difluoromethyl)-7-methyl-1,1-dioxo-2,3-dihydro Pyrrolo[3,4-f]triazepine-6-carboxamide

(S)-(-)-2-methyl-2-propanesulfenamide (21.2 g, 175 mmol) was mixed with 1-ethoxy-2,2-difluoroethanol (20.1 g, 159 mmol). Titanium (IV) ethoxide (50 mL, 1.09 g/mL, 238 mmol) was added to form a transparent thick solution, which was heated to 80 ° C for 2 days under nitrogen with a reflux condenser. The mixture was cooled to room temperature and diluted with EtOAc (500 mL). Under vigorous stirring, this was poured into salt water (500 mL). The two-phase mixture was filtered through a celite pad and rinsed with EtOAc (500 mL). The layers of the filtrate were separated and the organic layer was dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude product was purified on silica using gradient elution (EtOAc:heptane 0:100 to 100:0) to give N-(1-ethoxy-2,2-difluoro-ethyl)-2-methyl-propane-2-sulfenamide (18.3 g). Method B; Rt: 0.69 min. m/z: 230 (M+H) ⁺ exact mass: 229.1.

N-(1-ethoxy-2,2-difluoro-ethyl)-2-methyl-propane-2-sulfinamide (18.0 g, 78.5 mmol) in DCM (300 mL) was cooled to -50°C under a stream of nitrogen. Under nitrogen, vinylmagnesium bromide (118 mL, 1 M, 118 mmol) was added dropwise and stirred, maintaining the temperature below -47°C. After the addition was complete, stirring was continued for 3 hours, allowed to reach 0°C and stirred for 2 hours. The reaction mixture was quenched with NH ₄ Cl (aqueous, saturated) and diluted with EtOAc (500 mL). The layers were separated and the aqueous layer was extracted with EtOAc (2×250 mL). The combined organics were dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified on silica using a gradient from heptane to EtOAc to yield N-[1-(difluoromethyl)allyl]-2-methyl-propane-2-sulfenamide (8.86 g).Method B; Rt: 0.71 min. m/z: 212 (M+H) ⁺ exact mass: 211.1.

N-[1-(difluoromethyl)allyl]-2-methyl-propane-2-sulfinamide (8.86 g, 42.0 mmol) was dissolved in MeOH (100 mL) and cooled to 0 ° C. This was treated with HCl (21 mL, 4M in dioxane, 84 mmol). The resulting mixture was stirred for 2 hours. The mixture was concentrated in a vacuum. The obtained residue was ground with diethyl ether, filtered, rinsed with diethyl ether (100 mL) and dried in a vacuum oven to produce 1,1-difluorobut-3-ene-2-amine hydrochloride (5.4 g) as a white solid.

Methyl 3-bromo-4-chlorosulfonyl-1-methyl-pyrrole-2-carboxylate (3.68 g, 11.6 mmol) was dissolved in pyridine (10 mL). 1,1-Difluorobut-3-en-2-amine hydrochloride (2 g, 13.9 mmol) was added and the mixture was stirred at room temperature for 19 hours. The resulting mixture was concentrated in vacuo and the residue was purified on silica (gradient elution: EtOAc: heptane 0:100 to 100:0) to produce methyl 3-bromo-4-[1-(difluoromethyl)allylsulfamoyl]-1-methyl-pyrrole-2-carboxylate (1200 mg). Method B; Rt: 0.84 min. m/z: 385 (MH) ^- Exact mass: 386.0.

At room temperature, methyl 3-bromo-4-[1-(difluoromethyl)allylsulfamoyl]-1-methyl-pyrrole-2-carboxylate (200mg, 0.52mmol) and 5-amino-2-fluoro-benzonitrile (84mg, 0.62mmol) in dry THF (5mL) are treated with bis(trimethylsilyl)amide lithium (1.6mL, 1M in THF, 1.6mmol). After 1 hour at room temperature, bis(trimethylsilyl)amide lithium (1mL, 1M in THF, 1mmol) is added and the mixture is stirred at room temperature for 1 hour. The mixture is quenched with NH ₄ Cl (aqueous, saturated, 10mL) and salt solution (10mL). Each layer is separated and the aqueous layer is extracted with EtOAc (3×20mL). The combined extracts are dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude product was purified on silica (gradient elution: EtOAc:heptane 0:100 to 100:0) to give 3-bromo-N-(3-cyano-4-fluoro-phenyl)-4-[1-(difluoromethyl)allylsulfamoyl]-1-methyl-pyrrole-2-carboxamide (210 mg).

3-Bromo-N-(3-cyano-4-fluoro-phenyl)-4-[1-(difluoromethyl)allylsulfamoyl]-1-methyl-pyrrole-2-carboxamide (210 mg, 0.43 mmol) and TEA (0.12 mL, 0.73 g/mL, 0.85 mmol) in DMF (1 mL) were purged with nitrogen for 5 minutes. Bis(tri-tert-butylphosphine)palladium(0) (11 mg, 0.021 mmol) was then added and the mixture was heated at 90° C. in a sealed tube under nitrogen for 2 hours. The mixture was poured onto a silica plug as is and a gradient from heptane to EtOAc was used to produce compound 189 (86 mg). ^1H NMR (400 MHz, DMSO- _d6 ) δ ppm 3.74 (s, 3H) 4.38-4.59 (m, 1H) 5.74 (dd, J = 12.54, 2.86 Hz, 1H) 6.07-6.49 (m, 1H) 6.76 (dd, J = 12.54, 2.64 Hz, 1H) 7.56 (t, J = 9.13 Hz, 1H) 7.68 (s, 1H) 7.98 (ddd, J = 9.19, 4.90, 2.64 Hz, 1H) 8.03-8.34 (m, 2H) 10.93 (br s, 1H); Method B; Rt: 0.88 min. m/z: 409 (MH) ^- Exact mass: 410.1.

Compound 190: 3-[(2-chloro-4-pyridyl)methyl]-1-N-(3,4-difluorophenyl)-3,7-dimethyl-1,1-difluorophenyl]- Oxy-2,4-dihydropyrrolo[3,4-b][1,4,5]oxatriazepine-6-carboxamide

Compound 190 (90 mg) was prepared similarly as described for compound 162 using 2-chloro-4-(chloromethyl)pyridine instead of 3-(chloromethyl)-5-methylisoxazole. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.37 (s, 3H) 2.65 (d, J = 12.9 Hz, 1H) 3.35 (d, J = 13.2 Hz, 1H) 3.97 (s, 3H) 4.38 (d, J = 13.2 Hz, 1H) 4.65 (s, 1H) 4.98 (br d, J=13.4Hz, 1H) 7.07 (s, 1H) 7.09-7.18 (m, 2H) 7.26 (d, J= 1.3Hz, 1H) 7.32 (s, 1H) 7.61-7.69 (m, 1H) 8.39 (d, J= 5.1Hz, 1H) 8.61 (s, 1 H); Method B; Rt: 1.07min.m/z: 495(MH) ^- Exact mass: 496.1, MP: 225.0°C.

Compound 191: N-(3,4-difluorophenyl)-3,7-dimethyl-1,1-dioxo-3-(4-pyridylmethyl)-2,4- dihydropyrrolo[3,4-b1[1,4,5]oxatriazepine-6-carboxamide

Compound 190 (70 mg, 0.14 mmol) was dissolved in MeOH (25 mL) and Pd/C (10%) (15 mg, 0.014 mmol) was added and the reaction mixture was placed under a hydrogen atmosphere. After 2 h, the solution was filtered through celite, concentrated in vacuo, redissolved in DCM (30 mL), neutralized with NaHCO ₃ (aq., saturated), and the combined organics were concentrated in vacuo and purified on silica using DCM/MeOH 100/0 to 90/10 to yield compound 191 (23 mg). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.15 (s, 3H) 2.74 (d, J = 13.0Hz, 1H) 3.07 (d, J = 12.8Hz, 1H) 3.82 (s, 3H) 4.40 (d, J = 13.2Hz, 1H) 4.63 (d, J = 13.6Hz, 1H) 7.30-7.36 (m, 2H) 7.40-7.46 (m, 2H) 7.49 (s, 1H) 7.78 (br s, 1H) 7.82-7.90 (m, 1H) 8.51-8.53 (m, 2H) 9.41 (s, 1H); Method B; Rt: 0.96 min.m/z：461(MH) ^- Exact mass: 462.1, MP: 276.0°C.

Synthesis of 2-amino-2-(1-methylpyrazol-3-yl)propan-1-ol.

A 30ml tube was filled with ethyl N-(diphenylmethylene) glycine ester (2.5g, 9.35mmol), 3-bromo-1-methyl-1h-pyrazole (1.51g, 9.35mmol), tripotassium phosphate (6g, 27.7mmol) in toluene (15mL), and the mixture was purged with _N2 for 5 minutes. Bis(tri-tert-butylphosphine) palladium (0) (526mg, 1.03mmol) was added and the vial was capped, and the mixture was stirred at 100°C for 16 hours. The mixture was cooled and filtered through celite. The filtrate was concentrated in vacuo. The residue was purified by column chromatography using a gradient from 0 to 100% EtOAc in heptane. The product fraction was concentrated in vacuo to produce ethyl 2-(diphenylmethyleneamino)-2-(1-methylpyrazole-3-yl)acetic acid (1.95g) as a light yellow oil.

Under _N2 atmosphere, ethyl 2-(diphenylmethyleneamino)-2-(1-methylpyrazole-3-yl) acetic acid (1.95g, 5.61mmol) is dissolved in DMF (30mL). The mixture is cooled on an ice bath and NaH (60% is distributed in mineral oil) (269mg, 6.74mmol) is added in batches. The mixture is stirred at 5°C for 30 minutes. MeI (0.42mL, 2.28g/mL, 6.74mmol) is added dropwise and the mixture is stirred at 5°C for 15 minutes and then allowed to warm to room temperature. The mixture is stirred at room temperature for 16 hours. The mixture is quenched with water and the mixture is concentrated in vacuo. The residue is distributed between water and EtOAc and the organic layer is separated, washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The residue is purified by column chromatography using a gradient from 0 to 50% EtOAc in heptane. The product fractions were concentrated in vacuo to give ethyl 2-(benzylideneamino)-2-(1-methylpyrazol-3-yl)propanoate (1.1 g) as a yellow oil.

Ethyl 2-(benzylideneamino)-2-(1-methylpyrazol-3-yl)propanoate (1.1 g, 3.04 mmol) was dissolved in diethyl ether (20 mL). HCl (3.7 mL, 1 M in H ₂ O, 3.7 mmol) was added and the mixture was stirred at room temperature for 3 hours. The organic layer was separated and the aqueous layer was neutralized with NaHCO _3. The aqueous layer was extracted with 2-MeTHF and the organic layer was dried (MgSO 4 ), filtered and concentrated in vacuo. The residue was purified by column chromatography using a gradient from 0 to 100% MeOH/NH 3 (90/10) in DCM. The product fractions were concentrated in vacuo to produce ethyl 2-amino-2-(1-methylpyrazol-3-yl)propanoate (382 mg) as a clear oil. Method B; Rt: 0.52 min. m/z: 198 (M+H) ⁺ exact mass: 197.1.

Under N2, ethyl 2-amino-2-(1-methylpyrazole-3-yl) propanoate (382mg, 1.94mmol) is dissolved in MeOH (10mL). Sodium borohydride (147mg, 3.87mmol) is added and the mixture is stirred at room temperature for 16 hours. The mixture is concentrated in vacuo. The residue is purified by column chromatography using a gradient from 0 to 100% MeOH/NH3(90/10) in DCM. The product fractions are concentrated in vacuo to produce 2-amino-2-(1-methylpyrazole-3-yl) propan-1-ol (230mg) as a clear oil.

Compound 192: N-(3,4-difluorophenyl)-3,7-dimethyl-3-(1-methylpyrazol-3-yl)-1,1-dioxo-2, 4-Dihydropyrrolo[3,4-b][1,4,5]oxatriazepine-6-carboxamide

Compound 192 (223 mg) was prepared similarly as described for compound 125 using 2-amino-2-(1-methylpyrazol-3-yl)propan-1-ol instead of 2-amino-2-phenylpropan-1-ol hydrochloride. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.59 (s, 3H), 3.79 (s, 3H), 3.82 (s, 3H), 4.81-4.92 (m, 2H), 6.33 (d, J=2.2 Hz, 1H), 7.36-7.50 (m, 3H), 7.60 (d, J=2.2 Hz, 1H), 7.87 (ddd, J=13.2, 7.5, 2.5 Hz, 1H), 8.16 (s, 1H), 9.33-9.38 (m, 1H); Method B; Rt: 1.05 min. m/z: 450 (MH) ^- Exact mass: 451.1. The racemic mixture was separated into its enantiomers by preparative SFC (stationary phase: Daicel Chiralpak AD 20×250 mm, mobile phase: CO ₂ , EtOH+0.4iPrNH ₂ ) to produce compounds 192a (85 mg); Method D; Rt: 1.85 min. m/z: 450 (MH) ^- exact mass: 451.1, MP: 208.7° C., and 192b (85 mg); Method D; Rt: 1.86 min. m/z: 450 (MH) ^- exact mass: 451.1; MP: 209.2° C. Method R; Rt: 192a: 4.17 min, 192b: 4.96 min.

Compound 193: (3R)-N-(3-chloro-4-fluoro-phenyl)-3-[(1S)-1-hydroxyethyl]-7-methyl-1,1-dioxo- 2,3,4,5-tetrahydropyrrolo[3,4-f]triazepine-6-carboxamide

Compound 193 (101 mg) was prepared similarly as described for compound 88 using 3-chloro-4-fluoro-aniline instead of 3,4-difluoroaniline. ¹ H NMR (400MHz, DMSO-d ₆ ) δppm 1.13 (d, J=6.4Hz, 3H), 1.21-1.35 (m, 1H), 2.19 (br dd, J=14.3, 6.8Hz, 1H), 2.70-2.81 (m, 1H), 3.03 (br dd, J=14.9, 6.5Hz, 1H), 3.15- 3.26 (m, 1H), 3.47 (sxt, J=6.3Hz, 1H), 3.69 (s, 3H), 4.69 (d, J=5.7Hz, 1 H), 6.91 (d, J=10.1Hz, 1H), 7.38-7.45 (m, 2H), 7.61 (ddd, J=9.0, 4.4, 2.6 Hz, 1H), 8.00 (dd, J=6.9, 2.5 Hz, 1H), 10.46 (s, 1H); Method B; Rt: 0.92 min. m/z: 414 (MH) ^- Exact mass: 415.1, MP: 290.8°C.

Compound 194: (3R)-N-(3-chloro-4-fluoro-phenyl)-3-[(1S)-1-hydroxyethyl]-7-methyl-1,1-diol Oxy-2,3-dihydropyrrolo[3,4-f]triazepine-6-carboxamide

Compound 194 (89 mg) was prepared similarly as described for compound 84 using 3-chloro-4-fluoro-aniline instead of 3,4-difluoroaniline. ¹ H NMR (400MHz, DMSO-d ₆ ) δppm 1.20 (d, J=6.2Hz, 3H), 3.62-3.74 (m, 4H), 3.76-3.88 (m, 1H), 4.96 (d, J=5.7Hz, 1H), 5.96 (dd, J=12.5, 2.6Hz, 1H), 6.55 (dd, J=12.5, 2.4Hz, 1H), 7.34-7.46 (m, 2H), 7.57 (s, 1H), 7.62 (ddd, J=9.0, 4.3, 2.5 Hz, 1H), 8.00 (dd, J=6.8, 2.6Hz, 1H), 10.71 (s, 1H); Method D; Rt: 1.63 min.m/z: 412 (MH) ^- exact mass: 413.1; MP: 211.3°C.

Compound 195: (3R)-N-(4-Fluoro-3-methyl-phenyl)-3-(1-hydroxy-1-methyl-ethyl)-7-methyl-1, 1-Dioxo-3,4-dihydro-2H-pyrrolo[3,4-b][1,4,5]oxatriazepine-6-carboxamide

Compound 195 (274 mg) was prepared similarly as described for compound 93 using 4-fluoro-3-methyl-aniline instead of 3,4-difluoroaniline. ¹ H NMR (400MHz, DMSO-d ₆ ) δppm 1.06 (s, 3H), 1.25 (s, 3H), 2.23 (d, J=2.0Hz, 3H), 3.47 -3.61 (m, 1H), 3.83 (s, 3H), 3.93 (dd, J=12.5, 8.9Hz, 1H), 4.85 (s, 1H), 4.90-5.00 (m, 1H), 7.09 (t, J=9.2Hz, 1H), 7.46 (s, 1H), 7.47-7.55 (m, 2H), 7.57 (dd, J=7.0, 2.6Hz, 1H), 9.22 (s, 1H); Method D; Rt: 1.75min. m/z: 410 (MH) ^- Exact mass: 411.1.

Synthesis of ethyl 4-chlorosulfonyl-3-hydroxy-1-methyl-pyrrole-2-carboxylate.

Chlorosulfonic acid (2 mL, 1.753 g/mL, 30 mmol) is cooled to 0 ° C and ethyl 3-hydroxy-1-methyl-pyrrole-2-carboxylate (1 g, 5.9 mmol) is added portionwise to the stirred liquid. After addition, the mixture is allowed to reach room temperature and then stirred for another hour. The resulting mixture is added dropwise to a stirred ice-water mixture (100 mL), keeping the temperature below 5 ° C. The mixture is extracted with Me-THF, dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. The obtained crude product is ground in cyclohexane, filtered and dried to produce ethyl 4-chlorosulfonyl-3-hydroxy-1-methyl-pyrrole-2-carboxylate (1.1 g).

Compound 196: (3S)-N-(3,4-difluorophenyl)-3-(1-hydroxycyclopropyl)-7-methyl-1,1-dioxo-3,4- Dihydro-2H-pyrrolo[3,4-b][1,4,5]oxatriazepine-6-carboxamide

(S)-(-)-3-tert-butoxycarbonyl-4-methoxycarbonyl-2,2-dimethyl-1,3-oxazolidine (5 g, 19.3 mmol) was dissolved in THF (100 mL) and cooled to 0°C, followed by the addition of isopropoxytitanium (IV) (2.9 mL, 0.96 g/1 mL, 9.6 mmol) over 10 minutes while stirring. Ethylmagnesium bromide (16 mL, 3 M, 48 mmol) was then slowly added over 10 minutes to obtain a dark brown solution, which was stirred at 0°C and then allowed to reach room temperature. After 16 hours, the solution was quenched with _NH4Cl (aqueous, saturated) and extracted with EtOAc, dried over _MgSO4 , filtered, and concentrated in vacuo. The crude product obtained was purified on silica using heptane/EtOAc: 100/0 to 80/20 to give tert-butyl (4S)-4-(1-hydroxycyclopropyl)-2,2-dimethyl-oxazolidine-3-carboxylate (4.0 g) as a light oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.29-0.73 (m, 4H) 1.35-1.49 (m, 15H) 3.74 (br d, J=81.0 Hz, 1H) 3.93-4.09 (m, 2H) 5.30 (br s, 1H).

NaH (933 mg, 60% distribution in mineral oil, 23.3 mmol) is dissolved in DMF (45 mL) and cooled to 0 ° C., followed by addition of a solution of tert-butyl (4S)-4-(1-hydroxycyclopropyl)-2,2-dimethyl-oxazolidine-3-carboxylate (3.0 g, 11.7 mmol) in THF (10 mL). The solution is stirred for 30 minutes and then benzyl bromide (1.5 mL, 1.44 g/mL, 13 mmol) is added. The solution is allowed to reach room temperature and stirred for 16 hours. The solution is quenched with NH ₄ Cl (aqueous, saturated) and stirred for 10 minutes, then extracted with EtOAc and washed three times with salt water. The combined organic layers are dried over MgSO ₄ , filtered off, and concentrated in vacuo. The crude obtained was purified on silica using heptane/EtOac from 100/0 to 50/50 to yield tert-butyl (4S)-4-(1-benzyloxycyclopropyl)-2,2-dimethyl-oxazolidine-3-carboxylate (2.8 g).

Tert-butyl (4S)-4-(1-benzyloxycyclopropyl)-2,2-dimethyl-oxazolidine-3-carboxylate (2.8 g, 8.1 mmol) was dissolved in a mixture of MeOH (30 mL) and THF (65 mL). HCl (25 mL, 1 M in _H₂O , 24.176 mmol) was added dropwise and the solution was heated to 50° C. and stirred for 48 _hours . The solution was then basified with _K₂CO₃ and concentrated in vacuo. The crude product was then diluted with DCM and washed with water. The combined organic layers were concentrated in vacuo and purified on silica using a gradient from DCM to DCM/MeOH ( _NH₃ 7N) 9/1 to yield (2S)-2-amino-2-(1-benzyloxycyclopropyl)ethanol (1.2 g). Method B; Rt: 0.52 min. m/z: 208 (M+H) ⁺ exact mass: 207.1.

At room temperature, under an inert atmosphere, (2S)-2-amino-2-(1-benzyloxycyclopropyl)ethanol (950 mg, 4.6 mmol) was dissolved in dry DCM and 2 g of molecular sieves were added followed by 4-methoxybenzaldehyde (0.69 mL, 1.119 g/mL, 5.5 mmol) and the solution was stirred at room temperature for 16 hours. The solution was quickly filtered, concentrated in vacuo and redissolved in MeOH (18 mL) and cooled to 0° C., after which sodium borohydride (433 mg, 11.46 mmol) was added and the solution was allowed to reach room temperature. After 2 hours, the solution was quenched with water, extracted with DCM, dried over Na ₂ SO ₄ , filtered, concentrated and purified on silica using heptane/EtOAc 100/0 to 10/90 to yield (2S)-2-(1-benzyloxycyclopropyl)-2-[(4-methoxyphenyl)methylamino]ethanol (1.38 g). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.59-0.71 (m, 2H) 0.87-1.03 (m, 2H) 2.68 (dd, J=7.0, 4.6 Hz, 1H) 3.56 (dd, J=10.8, 7.0 Hz, 1H) 3.74 (dd, J=10.8, 4.6 Hz, 1H) 3.78-3.84 (m, 4H) 3.91-3.98 (m, 1H) 4.47-4.62 (m, 2H) 6.86 (d, J=7.7 Hz, 2H) 7.22-7.34 (m, 7H); Method B; Rt: 0.94 min. m/z: 328 (M+H) ⁺ exact mass: 327.2.

(2S)-2-(1-benzyloxycyclopropyl)-2-[(4-methoxyphenyl)methylamino]ethanol (1.13 g, 3.451 mmol) was dissolved in ACN (20 mL) and Hunin's base (1.78 mL, 0.75 g/mL, 10.4 mmol) was added followed by ethyl 4-chlorosulfonyl-3-hydroxy-1-methyl-pyrrole-2-carboxylate (924 mg, 3.45 mmol). After 16 hours, the solution was quenched with NaHCO ₃ (aqueous, saturated, 50 mL) and stirred for 10 minutes. The solution was then extracted with EtOAc (3×50 mL). The combined organics were dried _{over Na2SO4} , filtered, concentrated in vacuo and purified on silica using heptane/EtOAc 100/0 to 20/80 to give ethyl 4-[[(1S)-1-(1-benzyloxycyclopropyl)-2-hydroxy-ethyl]-[(4-methoxyphenyl)methyl]sulfamoyl]-3-hydroxy-1-methyl-pyrrole-2-carboxylate (800 mg).

Ethyl 4-[[(1S)-1-(1-benzyloxycyclopropyl)-2-hydroxy-ethyl]-[(4-methoxyphenyl)methyl]sulfamoyl]-3-hydroxy-1-methyl-pyrrole-2-carboxylate (800 mg, 1.43 mmol) was dissolved in THF (15 mL). Triphenylphosphine (413 mg, 1.58 mmol) and di-tert-butyl azodicarboxylate (363 mg, 1.58 mmol) were added. After 16 h, the solution was extracted with EtOAc, washed with water, and the combined organics were dried over MgSO ₄ , filtered, and concentrated in vacuo. The crude product was purified on silica using heptane/EtOAc 100/ to 0/100 to yield ethyl (3S)-3-(1-benzyloxycyclopropyl)-2-[(4-methoxyphenyl)methyl]-7-methyl-1,1-dioxo-3,4-dihydropyrrolo[3,4-b][1,4,5]oxatriazepine-6-carboxylate (774 mg).

Ethyl (3S)-3-(1-benzyloxycyclopropyl)-2-[(4-methoxyphenyl)methyl]-7-methyl-1,1-dioxo-3,4-dihydropyrrolo[3,4-b][1,4,5]oxatriazepine-6-carboxylate (774 mg, 1.43 mmol) was dissolved in THF (20 mL) and 3,4-difluoroaniline (0.16 mL, 1.29 g/mL, 1.58 mmol) and LiHMDS (7 mL, 1 M in THF, 7 mmol) were added. After 2 hours at room temperature, the solution was quenched with _NH4Cl (aqueous, saturated) and extracted with EtOAc. The combined organic layers were dried _{over MgSO4} , filtered, concentrated in vacuo, and the crude product was purified on silica using a gradient elution of heptane/EtOAc: 100/0 to 0/100. The crude product obtained was partitioned between EtOAc (50 ml), 10 mL of HCl (aqueous, 1 M) and water (20 mL) and stirred for 10 minutes. After extraction, the combined organic layers were dried over MgSO ₄ , filtered and concentrated in vacuo to yield (3S)-3-(1-benzyloxycyclopropyl)-N-(3,4-difluorophenyl)-2-[(4-methoxyphenyl)methyl]-7-methyl-1,1-dioxo-3,4-dihydropyrrolo[3,4-b][1,4,5]oxatriazepine-6-carboxamide (621 mg). Method B; Rt: 1.41 min. m/z: 624 (M+H) ⁺ exact mass: 623.1.

(3S)-3-(1-benzyloxycyclopropyl)-N-(3,4-difluorophenyl)-2-[(4-methoxyphenyl)methyl]-7-methyl-1,1-dioxo-3,4-dihydropyrrolo[3,4-b][1,4,5]oxatriazepine-6-carboxamide (100 mg, 0.16 mmol) was dissolved in DCM (2 mL) at room temperature and TFA (1.23 mL, 1.49 g/mL, 16.0 mmol) was added. After 16 hours, the reaction was quenched with water and NaHCO ₃ (aqueous, saturated) and extracted with DCM. The combined organic layers were dried over MgSO ₄ , filtered, concentrated in vacuo, and purified on silica to yield (3S)-3-(1-benzyloxycyclopropyl)-N-(3,4-difluorophenyl)-7-methyl-1,1-dioxo-3,4-dihydro-2H-pyrrolo[3,4-b][1,4,5]oxatriazepine-6-carboxamide (70 mg). Method B; Rt: 1.21 min. m/z: 504 (M+H) ⁺ exact mass: 503.1.

(3S)-3-(1-Benzyloxycyclopropyl)-N-(3,4-difluorophenyl)-7-methyl-1,1-dioxo-3,4-dihydro-2H-pyrrolo[3,4-b][1,4,5]oxatriazepine-6-carboxamide (70 mg, 0.139 mmol) was dissolved in MeOH (20 mL) and HOAc (0.4 mL, 1.049 g/mL, 7.0 mmol) and 5 drops of 0.4% thiophene in THF were added. Pd/C (10%) (15 mg, 0.014 mmol) was added. The solution was hydrogenated at room temperature over 1 hour. The reaction mixture was filtered through celite, concentrated in vacuo, and purified on silica using heptane/EtOAc 100/0 to 50/50 to produce compound 196 (12 mg). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.57-0.80 (m, 4H) 3.46-3.53 (m, 1H) 3.83 (s, 3H) 3.99-4.09 (m, 1H) 4.92 (dd, J=12.5, 1.3 Hz, 1H) 5.50 (s, 1H) 7.36-7.53 (m, 4H) 7.87 (ddd, J=13.1, 7.5, 2.4 Hz, 1H) 9.43 (s, 1H); Method B; Rt: 0.89 min. m/z: 412 (MH) ^- Exact mass: 413.1.

Compound 197: 3-[(6-chloro-3-pyridyl)methyl]-N-(3,4-difluorophenyl)-3,7-dimethyl-1,1-difluorophenyl Oxy-2,4-dihydropyrrolo[3,4-b][1,4,5]oxatriazepine-6-carboxamide

Compound 197 (331 mg) was prepared similarly as described for compound 162 using 2-chloro-5-(chloromethyl)pyridine instead of 3-(chloromethyl)-5-methylisoxazole. ^1H NMR (400 MHz, DMSO- _d6 ) δ ppm 1.13 (s, 3H), 2.75 (d, J = 13.2 Hz, 1H), 3.06 (d, J = 13.2 Hz, 1H), 3.82 (s, 3H), 4.41 (d, J = 13.0 Hz, 1H), 4.64 (d, J = 13.2 Hz, 1H), 7.38-7.46 (m, 2H), 7.49 (s, 1H), 7.52 (d, J = 8.1 Hz, 1H), 7.74-7.88 (m, 3H), 8.33 (d, J = 2.2 Hz, 1H), 9.40 (s, 1H); Method B; Rt: 1.08 min. m/z: 495 (MH) ^- Exact mass: 496.1.

Compound 198: N-(3-chloro-4-fluoro-phenyl)-3-[(6-chloro-3-pyridinyl)methyl]-3,7-dimethyl-1,1- 2,4-dihydropyrrolo[3,4-b][1,4,5]oxatriazepine-6-carboxamide

Compound 198 (109 mg) was prepared similarly as described for compound 197 using 3-chloro-4-fluoro-aniline instead of 3,4-difluoroaniline. ¹ H NMR (400MHz, DMSO-d ₆ ) δppm 1.14 (s, 3H), 2.74 (d, J=13.2Hz, 1H), 3.07 (d, J=13.4Hz, 1H), 3.82 (s, 3H), 4.42 (d, J = 13.2Hz, 1H), 4.64 (d, J = 13.2Hz, 1H), 7.41 (t, J = 9.0Hz, 1H), 7.49 (s, 1H), 7.51 (d, J = 8.5Hz, 1H), 7.63 (ddd, J = 9.0, 4.4, 2.6Hz, 1H), 7.76 (s, 1H), 7.80 (dd, J=8.4, 2.4Hz, 1H), 7.97 (dd, J = 6.8, 2.6 Hz, 1H), 8.33 (d, J = 2.4 Hz, 1H), 9.38 (s, 1H); Method B; Rt: 1.13 min. m/z: 511 (MH) ^- Exact mass: 512.1.

Compound 199: N-(3,4-difluorophenyl)-3,7-dimethyl-1,1-dioxo-3-(3-pyridylmethyl)-2,4- Dihydropyrrolo[3,4-b][1,4,5]oxatriazepine-6-carboxamide

Compound 197 (389 mg, 0.78 mmol), Pd/C (10%) (42 mg, 0.039 mmol) and TEA (0.22 mL, 0.73 g/mL, 1.57 mmol) were partitioned in THF (50 mL) and placed under a hydrogen atmosphere for 2 h. The reaction mixture was filtered and the residue was triturated in DIPE to yield compound 199 as an off-white powder. This was separated into its enantiomers by preparative SFC (stationary phase: Chiralpak Diacel AD 20×250 mm, mobile phase: CO ₂ , EtOH+0.4iPrNH ₂ ) to yield compound 199a (141 mg), ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.14 (s, 3H), 2.74 (d, J=13.2 Hz, 1H), 3.06 (d, J=13.4 Hz, 1H), 3.82 (s, 3H), 4.42 (d, J=13.2 Hz, 1H), 4.63 (d, J=13.2 Hz, 1H), 7.37 (dd, J=7.7, 5.3 Hz, 1H), 7.40-7.45 (m, 2H), 7.48 (s, 1H), 7.71-7.75 (m, 1H), 7.76 (s, 1H), 7.82-7.89 (m, 1H), 8.47 (d, J = 5.0 Hz, 1H), 8.52 (s, 1H), 9.41 (s, 1H); Method B; Rt: 0.94 min. m/z: 461 (MH) ^- Exact mass: 462.1, MP: 267.1 ° C and compound 199b (136 mg), ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.14 (s, 3H), 2.74 (d, J = 13.2 Hz, 1 3H), 3.06 (d, J = 13.2 Hz, 1H), 3.82 (s, 3H), 4.42 (d, J = 13.2 Hz, 1H), 4.63 (d, J = 13.2 Hz, 1H), 7.37 (dd, J = 7.8, 5.2 Hz, 1H), 7.40-7.47 (m, 2H), 7.49 (s, 1H), 7.71-7.75 (m, 1H), 7.76 (s, 1H), 7.82-7.89 (m, 1H), 8.46-8.53 (m, 2H), 9.41 (s, 1H); Method B; Rt: 0.94 min. m/z: 461 (MH) ^- Exact mass: 462.1, MP: 268.3°C, obtained after trituration from DIPE. Method R; Rt: 197a: 4.57 min, 197b: 5.09 min.

Compound 200: (3R)-N-(4-Fluoro-3-methyl-phenyl)-3-[(1S)-1-hydroxyethyl]-7-methyl-1,1-diol Oxy-3,4-dihydro-2H-pyrrolo[3,4-b][1,4,5]oxatriazepine-6-carboxamide

Compound 200 (241 mg) was prepared similarly to that described for compound 35, using 4-fluoro-3-methyl-aniline instead of 3,4-difluoroaniline and heating at 110° C. for 8 hours. The crude product was purified by preparative HPLC (stationary phase: RPXBridge Prep C18 ODB-5 μm, 30×250 mm, mobile phase: 0.1% TFA solution in water + 5% ACN, ACN) to yield compound 200 (241 mg). ¹ H NMR (400MHz, DMSO-d ₆ ) δppm 1.21 (d, J=6.2Hz, 3H), 2.23 (d, J=2.0Hz, 3H), 3.36-3.46 (m, 1 H), 3.55-3.66 (m, 1H), 3.83 (s, 3H), 3.98 (dd, J=12.7, 8.9Hz, 1H), 4.88 (dd, J=12.7, 2.0Hz, 1H), 5.04 (d, J=5.9Hz, 1H), 7.09 (t, J=9.2Hz, 1H), 7.44 (s, 1H), 7.48-7.55 (m, 1H), 7.55-7.67 (m, 2H), 9.21 (s, 1H); Method Z; Rt: 7.32 min. m/z: 396 (MH) ^- Exact mass: 397.1.

Compound 201: N-(3,4-difluorophenyl)-3,3-bis(hydroxymethyl)-7-methyl-1,1-dioxo-4,5-dihydro- 2H-Pyrrolo[3,4-f]triazepine-6-carboxamide

Compound 131 (55 mg, 0.14 mmol), water (0.200 ml), MeOH (3 mL), PTSA (0.57 mg, 0.003 mmol) and 2,6-di-tert-butyl-4-methyl-phenol (0.5 mg, 0.002 mmol) were placed in a sealed tube and the reaction was heated and stirred at 80° C. for 132 hours. The reaction mixture was purified by preparative HPLC (stationary phase: RP XBridgePrep C18 OBD-10 μm, 50 x 150 mm, _mobile phase: 0.25% _NH4HCO3 solution in water, ACN) to yield compound 201 (10 mg); ^1H NMR (400 MHz, DMSO- _d6 ) δ ppm 1.84-1.96 (m, 2H), 2.86-2.97 (m, 2H), 3.40-3.55 (m, 4H), 3.69 (s, 3H), 4.91 (br s, 1H), 7.35-7.46 (m, 3H), 7.80-7.87 (m, 1H); Method B; Rt: 0.71 min. m/z: 414 (MH) ^- exact mass: 415.1, and crude compound 202 (18 mg).

Compound 202: N-(3,4-difluorophenyl)-3-(hydroxymethyl)-3-(methoxymethyl)-7-methyl-1,1-difluorophenyl Oxy-4,5-dihydro-2H-pyrrolo[3,4-f]triazepine-6-carboxamide

Crude compound 202 (18 mg) obtained in the synthesis of compound 201 was purified on silica using a heptane to EtOAc gradient to yield compound 202 (12 mg); ^1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.82-1.97 (m, 2H), 2.86-2.98 (m, 2H), 3.27-3.29 (m, 3H), 3.35-3.53 (m, 4H), 3.69 (s, 3H), 4.72 (br s, 1H), 6.94 (br s, 1H), 7.37-7.46 (m, 3H), 7.79-7.87 (m, 1H), 10.36 (br s, 1H); Method B; Rt: 0.81 min. m/z: 428 (MH) ^- Exact mass: 429.1.

Compound 203: N-(3,4-difluorophenyl)-3-(hydroxymethyl)-3,7-dimethyl-1,1-dioxo-2,4-dihydro Pyrrolo[3,4-b1[1,4,5]oxatriazepine-6-carboxamide

Compound 203 (196 mg) was prepared similarly as described for compound 133 using 2-amino-2-methyl-propane-1,3-diol instead of 2-amino-1,3-propanediol. The racemic mixture was separated into its enantiomers using preparative SFC (stationary phase: Chiralpak Diacel AD 20 x 250 mm, mobile phase: _CO2 with 0.4% _iPrNH2EtOH ) to yield compound 203a (46.6 mg); ^1H NMR (400 MHz, DMSO- _d6 ) δ ppm 1.26 (s, 3H), 3.19-3.29 (m, 1H), 3.68 (dd, J = 10.9, 6.1 Hz, 1H), 3.81 (s, 3H), 4.47 (d, J = 13.2 Hz, 1H), 4.56 (d, J = 13.2 Hz, 1H), 5.06 (t, J = 5.8 Hz, 1H), 7.37-7.71 (m, 1H). 7.45 (m, 3H), 7.70 (s, 1H), 7.81-7.88 (m, 1H), 9.33 (s, 1H); Method B; Rt: 0.85 min. m/z: 400 (MH) ^- exact mass: 401.1; and compound 203b (44.7 mg); ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.26 (s, 3H), 3.22-3.28 (m, 1H), 3.68 (dd, J=10.7, 6.1 Hz, 1H), 3.81 (s, 3H), 4.44-4.59 (m, 2H), 5.06 (t, J = 5.8 Hz, 1H), 7.37-7.45 (m, 3H), 7.71 (s, 1H), 7.81-7.88 (m, 1H), 9.33 (s, 1H); Method B; Rt: 0.85 min. m/z: 400 (MH) ^- Exact mass: 401.1, obtained as a white powder after crystallization from an EtOAc:DIPE mixture. Method R; Rt: 203a: 3.86 min, 203b: 4.39 min.

Compound 204: N-(2-chloro-4-pyridinyl)-3-(hydroxymethyl)-3,7-dimethyl-1,1-dioxo-2,4-dihydro Pyrrolo[3,4-b][1,4,5]oxatriazepine-6-carboxamide

Compound 204 (205 mg) was prepared similarly to that described for compound 203, using 2-chloropyridin-4-amine instead of 3,4-difluoroaniline. The crude product was purified by preparative HPLC (stationary phase: RP XBridge Prep C18 ODB-5 μm, 50×150 mm, mobile phase: 0.25% NH ₄ HCO ₃ solution in water, MeOH) to yield compound 204. The racemic mixture was separated into its enantiomers using preparative SFC (stationary phase: Chiralpak Diacel AD 20 x 250 mm, mobile phase: CO ₂ , EtOH with 0.4% iPrNH ₂ ) to yield compound 204a (44.2 mg); ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.27 (s, 3H), 3.26-3.29 (m, 1H), 3.68 (dd, J=10.8, 5.9 Hz, 1H), 3.82 (s, 3H), 4.48-4.61 (m, 2H), 5.08 (t, J=5.8 Hz, 1H), 7.50 (s, 1H), 7.67 (dd, J=5.7, 5.8 Hz, 1H). 2.0 Hz, 1H), 7.75 (s, 1H), 7.83 (d, J=1.5 Hz, 1H), 8.28 (d, J=5.7 Hz, 1H), 9.58 (s, 1H); Method B; Rt: 0.72 min. m/z: 399 (MH) ^- Exact mass: 400.1; and compound 203b (48.7 mg); ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.27 (s, 3H), 3.25-3.29 (m, 1H), 3.64-3.72 (m, 1H), 3.82 (s, 3H), 4.48 -4.61 (m, 2H), 5.03-5.13 (m, 1H), 7.50 (s, 1H), 7.67 (dd, J = 5.6, 1.9 Hz, 1H), 7.75 (br s, 1H), 7.83 (d, J = 1.8 Hz, 1H), 8.28 (d, J = 5.5 Hz, 1H), 9.58 (br s, 1H); Method B; Rt: 0.85 min. m/z: 399 (MH) ^- Exact mass: 400.1, obtained as a white powder after crystallization from an EtOAc:DIPE mixture. Method R; Rt: 204a: 4.58 min, 204b: 5.15 min.

Compound 205: 3-But-2-ynyl-N-(3,4-difluorophenyl)-7-methyl-1,1-dioxo-3,4-dihydro-2H-pyrrolidone Pyrrolidine[3,4-b][1,4,5]oxatriazepine-6-carboxamide

Compound 205 (243 mg) was prepared similarly to that described for compound 14, using 2-aminohex-4-yn-1-ol instead of DL-alaninol and ACN instead of THF as solvent in the first step. Ring closure was achieved after heating in DMF at 110° C. overnight. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.78 (t, J=2.4 Hz, 3H), 2.32-2.47 (m, 2H), 3.68-3.78 (m, 1H), 3.81 (s, 3H), 3.95 (dd, J=13.0, 9.0 Hz, 1H), 4.67 (dd, J=12.8, 2.0 Hz, 1H), 7.36-7.48 (m, 3H), 7.77 (d, J=9.2 Hz, 1H), 7.82-7.88 (m, 1H), 9.45 (s, 1H); Method B; Rt: 1.03 min. m/z: 408 (MH) ^- Exact mass: 409.1.

Compound 206: 3-[Cyclopropyl(hydroxy)methyl]-N-(4-fluoro-3-methyl-phenyl)-7-methyl-1,1-dioxo- 3,4-Dihydro-2H-pyrrolo[3,4-b][1,4,5]oxatriazepine-6-carboxamide

Compound 206 (361 mg) was prepared similarly as described for compound 105 using 4-fluoro-3-methyl-aniline instead of 3,4-difluoroaniline. The racemic mixture was separated into its epimers by preparative SFC (stationary phase: Chiralpak Diacel ID20×250 mm, mobile phase: CO ₂ , EtOH + 0.4iPrNH ₂ ) to yield 206a (163 mg); ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.23-0.51 (m, 4H), 1.00-1.12 (m, 1H), 2.23 (d, J=2.0 Hz, 3H), 3.09 (q, J=6.5 Hz, 1H), 3.57-3.69 (m, 1H), 3.83 (s, 3H), 4.01 (dd, J=12.8, 9.1 Hz, 1H), 4.90 (dd, J=12.7, 2.0 Hz, 1H), 5.00 (d, J = 5.6 Hz, 1H), 7.09 (t, J = 9.2 Hz, 1H), 7.44 (s, 1H), 7.47-7.55 (m, 1H), 7.55-7.64 (m, 2H), 9.22 (s, 1H); Method D; Rt: 1.80 min. m/z: 422 (MH) ^- Exact mass: 423.1 and 206b (32 mg); ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.17-0.48 (m, 4H), 0.96-1.09 (m, 1H), 2.23 (d, J = 2.0 Hz, 3H), 3.05-3.18 (m, 1H), 3.71-3.81 (m, 1H), 3.83 (s, 3H), 4.05 (dd, J=12.7, 9.2 Hz, 1H), 4.74 (dd, J=13.2, 0.7 Hz, 1H), 4.90-5.08 (m, 1H), 7.09 (t, J=9.2 Hz, 1H), 7.35-7.47 (m, 2H), 7.47-7.54 (m, 1H), 7.56 (dd, J=6.9, 2.8 Hz, 1H), 9.24 (s, 1H); Method D; Rt: 1.81 min. m/z: 422 (MH) ^- Exact mass: 423.1; MP: 234.7°C. Method U; Rt: 206a: 4.19 min, 206b: 5.11 min.

Compound 207: N-(3-chloro-4-fluoro-phenyl)-3-[cyclopropyl(hydroxy)methyl]-7-methyl-1,1-dioxo-3, 4-Dihydro-2H-pyrrolo[3,4-b][1,4,5]oxatriazepine-6-carboxamide

Compound 207 (260 mg) was prepared similarly as described for compound 105 using 3-chloro-4-fluoro-aniline instead of 3,4-difluoroaniline. The racemic mixture was separated into its epimers by preparative SFC (stationary phase: Chiralpak Diacel ID 20x250 mm, mobile phase: _CO2 , EtOH + _0.4iPrNH2 ) to yield 207a (148 mg); ^1H NMR (400 MHz, DMSO- _d6 ) δ ppm 0.20-0.55 (m, 4H), 0.96-1.12 (m, 1H), 3.09 (q, J = 6.5 Hz, 1H), 3.56-3.69 (m, 1H), 3.83 (s, 3H), 4.00 (dd, J = 12.8, 9.2 Hz, 1H), 4.91 (dd, J = 12.7, 2.0 Hz, 1H), 5.00 (d, J = 5.6 Hz, 1H); H), 7.38 (t, J = 9.1 Hz, 1H), 7.47 (s, 1H), 7.60 (d, J = 9.9 Hz, 1H), 7.65 (ddd, J = 9.1, 4.3, 2.6 Hz, 1H), 8.00 (dd, J = 6.8, 2.6 Hz, 1H), 9.41 (s, 1H); Method D; Rt: 1.88 min. m/z: 442 (MH) ^- Exact mass: 443.1 and 207b (45 mg); ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.16-0.49 (m, 4H), 0.95- 1.09 (m, 1H), 3.08-3.17 (m, 1H), 3.71-3.81 (m, 1H), 3.83 (s, 3H), 4.04 (dd, J=12.7, 9.2Hz, 1H), 4.75 (dd, J=12.9, 1.1Hz, 1H), 5.00 (d, J＝4.9Hz, 1H), 7.39(t, J＝9.1Hz, 1H), 7.42-7.50(m, 2H), 7.64(ddd, J=9.0, 4.3, 2.6Hz, 1H), 7.99 (dd, J=6.8, 2.6Hz, 1H), 9.43 (s, 1H); Method D; Rt: 1.81min.m/z: 442 (MH) ^- Exact mass: 443.1; MP: 215.8°C. Method U; Rt: 206a: 4.30 min, 206b: 5.41 min.

Compound 208: 3-[Cyclopropyl(hydroxy)methyl]-7-methyl-1,1-dioxo-N-(3,4,5-trifluorophenyl)-3, 4-Dihydro-2H-pyrrolo[3,4-b][1,4,5]oxatriazepine-6-carboxamide

Compound 208 (289 mg) was prepared similarly as described for compound 105 using 3,4,5-trifluoroaniline instead of 3,4-difluoroaniline. The racemic mixture was separated into its epimers by preparative SFC (stationary phase: Chiralpak Diacel ID20 x 250 mm, mobile phase: CO ₂ , EtOH + 0.4iPrNH ₂ ) to yield 208a (124 mg); ^1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.25-0.53 (m, 4H), 0.99-1.11 (m, 1H), 3.08 (q, J=6.5 Hz, 1H), 3.63 (q, J=8.4 Hz, 1H), 3.82 (s, 3H), 3.99 (dd, J=12.8, 9.2 Hz, 1H), 4.94 (dd, J=12.8, 1.8 Hz, 1H), 5.02 (d, J=5.6 Hz, 1H); 1H), 7.50 (s, 1H), 7.62 (br d, J=9.5 Hz, 1H), 7.66-7.77 (m, 2H), 9.49 (s, 1H); Method D; Rt: 1.91 min. m/z: 444 (MH) ^- Exact mass: 445.1 and 208b (43 mg); ^1H NMR (400 MHz, DMSO- _d6 ) δ ppm 0.16-0.50 (m, 4H), 0.95-1.08 (m, 1H), 3.08-3.16 (m, 1H), 3.72-3.81 (m, 1H), 3.82 (s, 3 H), 4.04 (dd, J = 12.7, 9.2 Hz, 1H), 4.77 (dd, J = 12.5, 1.1 Hz, 1H), 5.02 (d, J = 4.9 Hz, 1H), 7.41-7.53 (m, 2H), 7.64-7.75 (m, 2H), 9.51 (s, 1H); Method D; Rt: 1.88 min. m/z: 444 (MH) ^- Exact mass: 445.1. Method U; Rt: 208a: 3.49 min, 208b: 4.27 min.

Compound 209: N-[2-(difluoromethyl)-4-pyridinyl]-3,7-dimethyl-3-[(5-methylisoxazol-3-yl) methyl]-1,1-dioxo-2,4-dihydropyrrolo[3,4-b][1,4,5]oxatriazepine-6-carboxamide

Compound 209 (92 mg) was prepared similarly as described for compound 162, using 2-(difluoromethyl)pyridin-4-amine instead of 3,4-difluoroaniline. This was separated into its enantiomers by preparative SFC (stationary phase: Kromasil (R, R) Whelk-O 1 10/100, mobile phase: CO ₂ , EtOH + 0.4 iPrNH ₂ ) to yield compound 209a (23 mg), ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.22 (s, 3H), 2.40 (s, 3H), 2.89 (d, J = 13.9 Hz, 1 H), 3.04 (d, J = 14.1 Hz, 1 H), 3.83 (s, 3H), 4.44 (d, J = 13.2 Hz, 1 H), 4.62 (d, J = 13.7 Hz, 1 H). (d, J = 13.2 Hz, 1H), 6.21 (d, J = 0.9 Hz, 1H), 6.91 (t, J = 55.0 Hz, 1H), 7.54 (s, 1H), 7.79 (br d, J = 5.6 Hz, 1H), 7.95 (br s, 1H), 8.03 (d, J = 1.8 Hz, 1H), 8.55 (d, J = 5.5 Hz, 1H), 9.71 (s, 1H); Method B; Rt: 0.88 min. m/z: 480 (MH) ^- Exact mass: 481.1 and compound 209b (19 mg), ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 3H), 1.22 (s, 3H), 2.40 (s, 3H), 2.91 (s, 1H), 3.04 (d, J = 14.1 Hz, 1H), 3.83 (s, 3H), 4.44 (d, J = 13.2 Hz, 1H), 4.61 (s, 1H), 6.21 (s, 1H), 6.91 (t, J = 55.0 Hz, 1H), 7.54 (s, 1H), 7.79 (d, J = 5.4 Hz, 1H), 7.95 (br s, 1H), 8.03 (d, J = 1.8 Hz, 1H), 8.55 (d, J = 5.7 Hz, 1H), 9.71 (s, 1H); Method B; Rt: 0.86 min. m/z: 480 (MH) ^- Exact mass: 481.1. Method X; Rt: 209a: 5.56 min, 209b: 5.91 min.

Compound 210: N-(3-cyano-4-fluoro-phenyl)-3-(hydroxymethyl)-3,7-dimethyl-1,1-dioxo-2,4- Dihydropyrrolo[3,4-b][1,4,5]oxatriazepine-6-carboxamide

Compound 210 (354 mg) was prepared similarly as described for compound 203 using 5-amino-2-fluoro-benzonitrile instead of 3,4-difluoroaniline. The racemic mixture was separated into its enantiomers using preparative SFC (stationary phase: Chiralpak Diacel AD20 x 250 mm, mobile phase: _CO2 , EtOH with 0.4% _iPrNH2 ) to yield compound 210a (96.6 mg); ^1H NMR (400 MHz, DMSO- _d6 ) δ ppm 1.27 (s, 3H), 3.19-3.28 (m, 1H), 3.68 (dd, J = 10.6, 6.2 Hz, 1H), 3.82 (s, 3H), 4.49 (d, J = 13.2 Hz, 1H), 4.57 (d, J = 13.0 Hz, 1H), 5.07 (t, J = 5.8 Hz, 1H), 7.45 (s, 1H), 7.52 (t, J = 7. J = 9.1 Hz, 1H), 7.73 (s, 1H), 8.03 (ddd, J = 9.2, 5.0, 2.8 Hz, 1H), 8.17 (dd, J = 5.7, 2.6 Hz, 1H), 9.42 (s, 1H); Method B; Rt: 0.79 min. m/z: 407 (MH) ^- Exact mass: 408.1; and compound 210b (73.4 mg); ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.27 (s, 3H), 3.21-3.29 (m, 1H), 3.64-3.71 (m, 1H), 3.82 (s, 3H), 4.49 (d, J = 13.2 Hz, 1H), 4.57 (d, J = 13.2 Hz, 1H), 5.07 (t, J = 5.8 Hz, 1H), 7.45 (s, 1H), 7.52 (t, J = 9.1 Hz, 1H), 7.73 (s, 1H), 8.01-8.05 (m, 1H), 8.16-8.19 (m, 1H), 9.42 (s, 1H); Method B; Rt: 0.80 min. m/z: 407 (MH) ^- Exact mass: 408.1, obtained as a white powder after crystallization from an EtOAc:DIPE mixture. Method R; Rt: 210a: 4.21 min, 210b: 4.67 min.

Compound 211: N-(3-chloro-4-fluoro-phenyl)-3,7-dimethyl-1,1-dioxo-3-(3-pyridylmethyl)-2, 4-Dihydropyrrolo[3,4-b][1,4,5]oxatriazepine-6-carboxamide

Compound 198 (252 mg, 0.49 mmol), Pd/C (10%) (26 mg, 0.025 mmol), TEA (0.14 mL, 0.73 g/mL, 0.98 mmol) and thiophene (2.15 mL, 0.72 g/mL, 0.4% in DIPE, 0.074 mmol) were distributed in THF (100 mL) and placed under a hydrogen atmosphere for 2 hours. More Pt/C (5%) (96 mg, 0.025 mmol) was added and the reaction mixture was stirred under a hydrogen atmosphere overnight. Pd/C (10%) (52 mg, 0.049 mmol) was added and the reaction mixture was stirred under a hydrogen atmosphere overnight. More Pd/C (10%) (52 mg, 0.049 mmol) was added and the reaction mixture was stirred under a hydrogen atmosphere for 2 days. The reaction mixture was filtered and the residue was purified on silica using a heptane to EtOAc gradient and again by preparative HPLC (stationary phase: RP XBridge Prep C18 OBD-10 μm, 30 x 150 mm, mobile phase: 0.25% NH ₄ HCO ₃ solution in water, ACN) to give compound 211 as a white powder (87 mg). ¹ HNMR (400MHz, DMSO-d ₆ ) δppm 1.14 (s, 3H), 2.74 (d, J=13.0Hz, 1H), 3.06 (d, J=13.2Hz, 1H), 3.82 (s, 3H), 4.42 (d, J=13.0 Hz, 1H), 4.63 (d, J=13.2Hz, 1H), 7.35-7.44 (m, 2H), 7.48 (s, 1H), 7.61-7.66 (m, 1H), 7.73 (br d, J=7.7Hz, 2H), 7.97 (dd, J=6.8, 2.6Hz, 1 H), 8.47 (dd, J=4.7, 1.7 Hz, 1H), 8.52 (d, J=1.5 Hz, 1H), 9.39 (s, 1H); Method B; Rt: 1.00 min. m/z: 477 (MH) ^- Exact mass: 478.1, MP: 211.5°C.

Compound 212: N-(3-chloro-4-fluoro-phenyl)-7-methyl-1,1-dioxo-spiro[2,4-dihydropyrrolo[3,4-b] [1,4,5]oxatriazepine-3,3'-tetrahydrofuran]-6-carboxamide

Compound 212 (243 mg) was prepared similarly to that described for compound 205 using (3-aminotetrahydrofuran-3-yl)methanol instead of 2-aminohex-4-yn-1-ol. Ring closure was achieved after heating in DMF at 110° C. for 2 h. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.99-2.19 (m, 2H), 3.73-3.89 (m, 7H), 4.40-4.53 (m, 2H), 7.40 (t, J=9.1 Hz, 1H), 7.49 (s, 1H), 7.66 (ddd, J=9.1, 4.2, 2.5 Hz, 1H), 7.98 (dd, J=6.8, 2.6 Hz, 1H), 8.24 (br s, 1H), 9.36 (s, 1H); Method B; Rt: 0.96 min. m/z: 428 (MH) ^- Exact mass: 429.1. This was separated into its enantiomers by preparative SFC (stationary phase: Chiralpak Diacel IC 20 x 250 mm, mobile phase: CO ₂ , EtOH + 0.4iPrNH ₂ ) to yield compound 212a (97 mg) and compound 212b (14 mg). Method AA; Rt: 212a: 4.78 min, 212b: 5.55 min.

Compound 213: N-(2-chloro-4-pyridinyl)-3,7-dimethyl-3-[(5-methylisoxazol-3-yl)methyl]-1, 1-Dioxo-2,4-dihydropyrrolo[3,4-b][1,4,5]oxatriazepine-6-carboxamide

Compound 213 (92 mg) was prepared similarly as described for compound 162, using 4-amino-2-chloropyridine instead of 3,4-difluoroaniline. This was separated into its enantiomers by preparative SFC (stationary phase: Chiralpak Diacel AD 20×250 mm, mobile phase: CO ₂ , EtOH+0.4iPrNH ₂ ) to yield compound 213a (25 mg), ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.22 (s, 3H), 2.38-2.41 (m, 3H), 2.88 (d, J=13.9 Hz, 1H), 3.04 (d, J=13.9 Hz, 1H), 3.82 (s, 3H), 4.44 (d, J=13.0 Hz, 1H), 4.62 (m, 3H), 4. d, J = 13.2 Hz, 1H), 6.21 (d, J = 0.9 Hz, 1H), 7.55 (s, 1H), 7.66 (dd, J = 5.7, 1.8 Hz, 1H), 7.82 (d, J = 1.8 Hz, 1H), 7.95 (br s, 1H), 8.28 (d, J = 5.5 Hz, 1H), 9.65 (br s, 1H); Method B; Rt: 0.92 min. m/z: 464 (MH) ^- Exact mass: 465.1 and compound 213b (23 mg), ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.19-1.24 (m, 3H), 2.37-2.43 (m, 3H), 2.88 (d, J=14.1Hz, 1H), 3.04 (d, J=14.1Hz, 1H), 3.82 (s, 3H), 4.44 (d, J=13.2Hz, 1H), 4.62 (d, J=13.2Hz, 1H), 6.21 (s, 1H), 7.55 (s, 1H), 7.67 (dd, J=5.7, 1.8Hz, 1H), 7.82 (d, J=1.8Hz, 1H), 7.95 (br s, 1H), 8.28 (d, J=5.7Hz, 1H), 9.65 (s, 1 H); Method B; Rt: 0.93 min. m/z: 464 (MH) ^- Exact mass: 465.1. Method R; Rt: 213a: 4.57 min, 213b: 4.87 min.

Compound 214: 3-(Hydroxymethyl)-3,7-dimethyl-1,1-dioxo-N-(3,4,5-trifluorophenyl)-2,4-dihydro- Hydropyrrolo[3,4-b][1,4,5]oxatriazepine-6-carboxamide

Compound 214 (474 mg) was prepared similarly as described for compound 203 using 3,4,5-trifluoroaniline instead of 3,4-difluoroaniline. The racemic mixture was separated into its enantiomers using preparative SFC (stationary phase: Chiralpak Diacel AS 20 x 250 mm, mobile phase: _CO2 , iPrOH _with 0.4% iPrNH2) to yield compound 214a (80 mg); ^1H NMR (400 MHz, DMSO- _d6 ) δ ppm 1.27 (s, 3H), 3.18-3.28 (m, 1H), 3.68 (dd, J = 10.9, 6.3 Hz, 1H), 3.81 (s, 3H), 4.49 (d, J = 13.2 Hz, 1H), 4.57 (d, J = 13.2 Hz, 1H), 5.07 (t, J = 5.8 Hz, 1H), 7.46 (s, 1H), 7.64-7.74 (m, 3H), 9.39 (s, 1H); Method B; Rt: 0.94 min. m/z: 418 (MH) ^- Exact mass: 419.1; and compound 214b (75 mg); ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.27 (s, 3H), 3.21-3.30 (m, 1H), 3.68 (dd, J=10.8, 6.2 Hz, 1H), 3.81 (s, 3H), 4.47-4.60 (m, 2H), 5.07 (t, J=5.8 Hz, 1H), 7.46 (s, 1H), 7.64-7.74 (m, 3H), 9.39 (s, 1H); Method B; Rt: 0.95 min. m/z: 418 (MH) ^- Exact mass: 419.1, obtained as a white powder after crystallization from an EtOAc:DIPE mixture. Method T; Rt: 214a: 2.90 min, 214b: 3.19 min.

Compound 215: N-[2-(difluoromethyl)-4-pyridinyl]-3-(hydroxymethyl)-3,7-dimethyl-1,1-dioxo- 2,4-Dihydropyrrolo[3,4-b][1,4,5]oxatriazepine-6-carboxamide

Compound 215 was prepared similarly as described for compound 203 using 2-(difluoromethyl)pyridin-4-amine instead of 3,4-difluoroaniline. The racemic mixture was separated into its enantiomers using preparative SFC (stationary phase: Chiralpak Diacel AD20 x 250 mm, mobile phase: CO ₂ , EtOH with 0.4% iPrNH ₂ ) to yield compound 215a (78.3 mg); ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.27 (s, 3H), 3.23-3.29 (m, 1H), 3.68 (dd, J=10.8, 6.2 Hz, 1H), 3.82 (s, 3H), 4.46-4.62 (m, 2H), 5.08 (t, J=5.7 Hz, 1H), 6.91 (t, J=55.0 Hz, 1H), 7.50 (s, 1H), 7.71-7.80 (m, 2H). H), 8.05 (d, J = 2.0 Hz, 1H), 8.54 (d, J = 5.5 Hz, 1H), 9.65 (s, 1H); Method B; Rt: 0.72 min. m/z: 415 (MH) ^- exact mass: 416.1; and compound 215b (79.3 mg); ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.27 (s, 3H), 3.24-3.29 (m, 1H), 3.68 (dd, J = 10.7, 6.1 Hz, 1H), 3.82 (s, 3H), 4.46-4.62 (m, 2H), 5.08 (t, J = 5.8 Hz, 1H), 6.91 (t, J = 55.0 Hz, 1H), 7.50 (s, 1H), 7.71-7.81 (m, 2H), 8.05 (d, J = 2.0 Hz, 1H), 8.54 (d, J = 5.5 Hz, 1H), 9.65 (s, 1H); Method B; Rt: 0.72 min. m/z: 415 (MH) ^- Exact mass: 416.1, obtained as a white powder after crystallization from an EtOAc:DIPE mixture. Method R; Rt: 215a: 3.83 min, 215b: 4.26 min.

Compound 216: 1'-Benzyl-N-(3,4-difluorophenyl)-7-methyl-1,1-dioxo-spiro[2,4-dihydropyrrolo] [3,4-b][1,4,5]oxatriazepine-3,3'-pyrrolidine]-6-carboxamide

Compound 216 (265 mg) was prepared similarly as described for compound 212 using (3-amino-1-benzyl-pyrrolidin-3-yl)methanol instead of (3-aminotetrahydrofuran-3-yl)methanol. ¹ H NMR (400MHz, DMSO-d ₆ ) ppm 1.93-2.05 (m, 2H), 2.45-2.48 (m, 1H), 2.54 (s, 1H), 2.68 (br d, J=8.1Hz, 1H), 2.86 (br d, J=9.7Hz, 1 H), 3.61 (q, J=13.1Hz, 2H), 3.81 (s, 3H), 4.37-4.55 (m, 2H), 7.25 (br d, J=4.0Hz, 1H), 7.32 (d, J=4.2Hz, 4H), 7.38-7.48 (m, 3H), 7.80-7.88 (m, 1H), 8.12 (s, 1H), 9.34 (s, 1H); Method B; Rt: 1.19 min. m/z: 501 (MH) ^- Exact mass: 502.2.

Compound 217: N-[2-(difluoromethyl)-4-pyridinyl]-3,7-dimethyl-3-[(1-methylpyrazol-3-yl)methyl 1,1-dioxo-2,4-dihydropyrrolo[3,4-b][1,4,5]oxatriazepine-6-carboxamide

Compound 217 (269 mg) was prepared similarly as described for compound 167 using 2-(difluoromethyl)pyridin-4-amine instead of 3,4-difluoroaniline. This was separated into its enantiomers by preparative SFC (stationary phase: Chiralpak Diacel IC 20x250 mm, mobile phase: _CO2 , EtOH+ _0.4iPrNH2 ) to yield compound 176a (62.2 mg); ^1H NMR (400 MHz, DMSO- _d6 ) δ ppm 1.21 (s, 3H), 2.83 (d, J=13.9 Hz, 1H), 2.99 (d, J=13.9 Hz, 1H), 3.80 (s, 3H), 3.83 (s, 3H), 4.42 (d, J=13.2 Hz, 1H), 4.56 (d, J=13.4 Hz, 1H), 6.15 (d, J=2.2 Hz, 1H), 6.92 (t, J=55.1 Hz, 1H), 7.52 (s, 1H), 7.59 (s, 1H), 7.75-7.87 (m, 2H), 8.02 (d, J=2.0 Hz, 1H), 8.55 (d, J=5.5 Hz, 1H), 9.68 (s, 1H); Method B; Rt: 0.85 min. m/z: 479 (MH) ^- Exact mass: 480.1. and compound 176b (59.4 mg); ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.22 (s, 3H), 2.83 (d, J=13.9 Hz, 1H), 2.99 (d, J=14.1 Hz, 1H), 3.80 (s, 3H), 3.83 (s, 3H), 4.42 (d, J=13.2 Hz, 1H), 4.56 (d, J=13.2 Hz, 1H), 6.15 (d, J=2.2 Hz, 1H), 6.92 (t, J=55.1 Hz, 1H), 7.52 (s, 1H), 7.59 (s, 1H), 7.78 (br d, J = 3.7 Hz, 1H), 7.84 (s, 1H), 8.02 (d, J = 2.0 Hz, 1H), 8.55 (d, J = 5.5 Hz, 1H), 9.68 (s, 1H); Method B; Rt: 0.85 min. m/z: 479 (MH) ^- Exact mass: 480.1. Method AA; Rt: 217a: 5.76 min, 217b: 6.29 min.

Compound 218: 7-methyl-1,1-dioxo-3-[1-(2,2,2-trifluoroethylamino)ethyl]-N-(3,4,5-trifluoroethylamino)ethyl (fluorophenyl)-2,3,4,5-tetrahydropyrrolo[3,4-f]triazepine-6-carboxamide

Methyl 3-acetyl-7-methyl-1,1-dioxo-2,3,4,5-tetrahydropyrrolo[3,4-f]triazepine-6-carboxylate (550 mg, 1.83 mmol) and 2,2,2-trifluoroethylamine (7.31 mL, 1.24 g/mL, 91.6 mmol) were dissolved in methanol (70 mL), and thiophene (1 mL, 4% in DiPE) and Pd/C (10%) (390 mg, 0.37 mmol) were added sequentially. The reaction mixture was hydrogenated for 38 hours. Under a nitrogen atmosphere, Pd/C (10%) (390 mg, 0.37 mmol) was added to the reaction mixture and hydrogenated for 20 hours. Under a nitrogen atmosphere, Pd/C (10%) (390 mg, 0.37 mmol) was added to the reaction mixture and hydrogenated for another 120 hours. The reaction mixture was filtered through celite and the solids were washed with THF (3 x 100 mL). The filtrate was concentrated to give methyl 7-methyl-1,1-dioxo-3-[1-(2,2,2-trifluoroethylamino)ethyl]-2,3,4,5-tetrahydropyrrolo[3,4-f]triazepine-6-carboxylate (1.50 g). This was separated into its four isomers by preparative SFC (stationary phase: Chiralpak Diacel AS 20 x 250 mm, mobile phase: CO ₂ , EtOH + 0.4 iPrNH ₂ ). The four isomers obtained were reacted with 3,4,5-trifluoroaniline in THF using LiHMDS as a base to produce compound 218a (33 mg); ^1H NMR (400 MHz, DMSO- _d6 ) δ ppm 1.00 (d, J = 6.6 Hz, 3H), 1.33 (br d, J = 13.2 Hz, 1H), 2.01-2.13 (m, 2H), 2.53-2.67 (m, 1H), 2.74-2.82 (m, 1H), 3.01 (br dd, J = 15.0, 6.6 Hz, 1H), 3.16-3.28 (m, 2H), 3.37-3.47 (m, 1H), 3.69 (s, 3H). H), 6.91 (d, J = 10.3 Hz, 1H), 7.46 (s, 1H), 7.56-7.64 (m, 2H), 10.60 (s, 1H); Method D; Rt: 1.99 min. m/z: 497 (MH) ^- Exact mass: 498.1, compound 218b (78 mg); ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.99 (d, J = 6.6 Hz, 3H), 1.38-1.48 (m, 1H), 1.92 (br dd, J = 14.4, 6.5 Hz, 1H), 2.20-2.30 (m, 1H), 2.67-2.82 (m, 2H), 3.00 (br dd, J = 14.4, 6.1 Hz, 1H), 3.15-3.36 (m, 2H), 3.37-3.47 (m, 1H), 3.69 (s, 3H), 6.94 (d, J = 10.3 Hz, 1H), 7.47 (s, 1H), 7.55-7.64 (m, 2H), 10.61 (br s, 1H); Method D; Rt: 2.00 min. m/z: 497 (MH) ^- Exact mass: 498.1, Compound 218c (38 mg); ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.99 (d, J = 6.6 Hz, 3H), 1.38-1.48 (m, 1H), 1.88 -1.95 (m, 1H), 2.24 (q, J = 7.4 Hz, 1H), 2.67-2.82 (m, 2H), 3.01 (br dd, J = 15.3, 5.8 Hz, 1H), 3.15-3.35 (m, 2H), 3.37-3.47 (m, 1H), 3.69 (s, 3H), 6.94 (d, J = 10.3 Hz, 1H), 7.47 (s, 1H), 7.56-7.64 (m, 2H), 10.61 (s, 1H); Method D; Rt: 2.00 min. m/z: 497 (MH) ^- Exact mass: 498.1; MP: 216.2 °C and compound 218d (34 mg); ¹ H NMR (400 MHz, DMSO-d ₆ )δppm 1.00 (d, J=6.6Hz, 3H), 1.28-1.38 (m, 1H), 2.01-2.13 (m, 2H), 2.54- 2.67 (m, 1H), 2.73-2.82 (m, 1H), 3.01 (br dd, J=15.2, 5.7Hz, 1H), 3.16 -3.29(m, 2H), 3.39-3.48(m, 1H), 3.69(s, 3H), 6.91(d, J=10.3Hz, 1H), 7.47(s, 1H), 7.56-7.64(m, 2H), 10.60(s, 1H); Method D; Rt: 1.99 min.m/z：497(MH) Exact mass: ^498.1 , obtained after purification by preparative HPLC (stationary phase: RP XBridge Prep C18 OBD-10 μm, 50 x 150 mm, mobile phase: 0.25% _NH₄HCO₃ solution in _water , MeOH). Method AB; Rt: 218a: 3.49 min, 218b: 3.15 min, 218c: 2.09 min, 218d: 2.26 min.

Compound 219: 3-[(6-chloro-3-pyridyl)methyl]-N-(3,4-difluorophenyl)-3,7-dimethyl-1,1-difluorophenyl Oxy-2H-pyrrolo[3,4-f]triazepine-6-carboxamide

2-Amino-3-(6-chloro-3-pyridinyl)-2-methyl-propan-1-ol (1.00 g, 4.98 mmol), methyl 3-bromo-4-chlorosulfonyl-1-methyl-pyrrole-2-carboxylate (1.58 mg, 4.98 mmol) and Hunin's base (2.58 mL, 0.75 g/mL, 15 mmol) were dissolved in ACN (20 mL) and the reaction mixture was stirred overnight. The volatiles were removed under reduced pressure and the residue was purified on silica using a heptane to EtOAc gradient to give methyl 3-bromo-4-[[1-[(6-chloro-3-pyridinyl)methyl]-2-hydroxy-1-methyl-ethyl]sulfamoyl]-1-methyl-pyrrole-2-carboxylate (777 mg) as a white powder.

Methyl 3-bromo-4-[[1-[(6-chloro-3-pyridinyl)methyl]-2-hydroxy-1-methyl-ethyl]sulfamoyl]-1-methyl-pyrrole-2-carboxylate (777 mg, 1.62 mmol) and 3,4-difluoroaniline (162 μL, 1.29 g/mL, 1.62 mmol) were dissolved in THF (5 mL). Lithium bis(trimethylsilyl)amide (1 M in THF) (8 mL, 1 M in THF, 8 mmol) was added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was quenched with NH ₄ Cl (saturated, aqueous, 10 mL) and the organic layer was removed. The aqueous layer was extracted with DCM (2 x 5 mL) and the combined organic layers were filtered and evaporated to dryness to yield crude 3-bromo-4-[[1-[(6-chloro-3-pyridinyl)methyl]-2-hydroxy-1-methyl-ethyl]sulfamoyl]-N-(3,4-difluorophenyl)-1-methyl-pyrrole-2-carboxamide (833 mg).

3-Bromo-4-[[1-[(6-chloro-3-pyridinyl)methyl]-2-hydroxy-1-methyl-ethyl]sulfamoyl]-N-(3,4-difluorophenyl)-1-methyl-pyrrole-2-carboxamide (833 mg, 1.44 mmol) was dissolved in ACN (15 mL). 2-Iodoacylbenzoic acid (606 mg, 2.16 mmol) was added and the reaction mixture was heated at 80° C. for 90 minutes. The reaction mixture was filtered while hot, evaporated to dryness and the residue was purified on silica using a heptane to EtOAc gradient to yield 3-Bromo-4-[[1-[(6-chloro-3-pyridinyl)methyl]-1-methyl-2-oxo-ethyl]sulfamoyl]-N-(3,4-difluorophenyl)-1-methyl-pyrrole-2-carboxamide (721 mg). ¹ H NMR (400MHz, DMSO-d ₆ ) δppm 1.07 (s, 3H), 2.96-3.04 (m, 2H), 3.74 (s, 3 H), 7.41-7.49 (m, 3H), 7.67 (s, 1H), 7.72 (dd, J=8.1, 2.4Hz, 1H), 7.80-7.88 (m, 1H), 8.24 (s, 1H), 8.27 (d, J=2.2Hz, 1H), 9.57 (s, 1H), 10.60 (s, 1H).

At 0 ℃, KOtBu (73.1mg, 0.65mmol) is added to the suspension of methyltriphenylphosphonium bromide (233mg, 0.65mmol) stirring in THF (5mL).The suspension is stirred at 0 ℃ for 10min, and then at room temperature for 1 hour.At 0 ℃, 3-bromo-4-[[1-[(6-chloro-3-pyridyl) methyl]-1-methyl-2-oxygen-ethyl] sulfamoyl]-N-(3,4-difluorophenyl)-1-methyl-pyrrole-2-carboxamide (150mg, 0.26mmol) in THF (5mL) is added dropwise to the solution.The reaction mixture is allowed to warm to room temperature and stir overnight.LCMS shows the product formed. The volatiles were removed under reduced pressure and the residue was purified on silica using a heptane to EtOAc gradient to give 3-bromo-4-[[1-[(6-chloro-3-pyridinyl)methyl]-1-methyl-allyl]sulfamoyl]-N-(3,4-difluorophenyl)-1-methyl-pyrrole-2-carboxamide (118 mg) as a white powder.

3-Bromo-4-[[1-[(6-chloro-3-pyridinyl)methyl]-1-methyl-allyl]sulfamoyl]-N-(3,4-difluorophenyl)-1-methyl-pyrrole-2-carboxamide (118 mg, 0.21 mmol), bis(tri-tert-butylphosphine)palladium(0) (5 mg, 0.01 mmol) and Hunin's base (39 μL, 0.75 g/mL, 0.23 mmol) were dissolved in DMF (1 mL) and heated in a microwave at 150° C. for 5 minutes. Bis(tri-tert-butylphosphine)palladium(0) (5 mg, 0.01 mmol) was added and the reaction mixture was heated in a microwave at 150° C. for 5 minutes. The reaction mixture was directly loaded onto a silica cartridge and compound 219 (54 mg) was produced after crystallization from a DCM:DIPE mixture using a gradient from heptane to EtOAc. ^1H NMR (400 MHz, DMSO- _d6 ) δ ppm 1.13 (s, 3H), 2.83 (d, J = 13.4 Hz, 1H), 3.42 (d, J = 13.4 Hz, 1H), 3.70 (s, 3H), 5.61 (d, J = 13.0 Hz, 1H), 6.40 (d, J = 13.0 Hz, 1H), 7.40-7.55 (m, 4H), 7.61 (s, 1H), 7.80-7.88 (m, 2H), 8.36 (d, J = 2.2 Hz, 1H), 10.70 (s, 1H); Method B; Rt: 1.06 min. m/z: 491 (MH) ^- Exact mass: 492.1.

Compound 220: N-(3-cyano-4-fluoro-phenyl)-3,7-dimethyl-3-[(5-methylisoxazol-3-yl)methyl] 1,1-dioxo-2,4-dihydropyrrolo[3,4-b][1,4,5]oxatriazepine-6-carboxamide

Compound 220 (124 mg) was prepared similarly as described for compound 162, using 5-amino-2-fluoro-benzonitrile instead of 3,4-difluoroaniline. This was separated into its enantiomers by preparative SFC (stationary phase: Chiralpak Diacel AS 20×250 mm, mobile phase: CO ₂ , iPrOH+0.4iPrNH ₂ ) to yield compound 220a (28 mg), ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.22 (s, 3H), 2.40 (s, 3H), 2.88 (d, J=13.9 Hz, 1H), 3.05 (d, J=13.9 Hz, 1H), 3.75-3.88 (m, 3H), 4.42 (d, J=13.2 Hz, 1H), 4.62 (d, J = 13.0 Hz, 1H), 6.22 (s, 1H), 7.49-7.56 (m, 2H), 7.93 (s, 1H), 8.02 (ddd, J = 9.2, 4.8, 2.9 Hz, 1H), 8.16 (dd, J = 5.7, 2.6 Hz, 1H), 9.47 (s, 1H); Method B; Rt: 1.01 min. m/z: 472 (MH) ^- Exact mass: 473.1 and compound 2210 (21 mg), ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.23 (s, 3H), 3H), 2.40 (s, 3H), 2.88 (d, J = 13.9 Hz, 1H), 3.05 (d, J = 13.9 Hz, 1H), 3.83 (s, 3H), 4.42 (d, J = 13.0 Hz, 1H), 4.62 (d, J = 13.2 Hz, 1H), 6.22 (d, J = 0.9 Hz, 1H), 7.49-7.56 (m, 2H), 7.93 (s, 1H), 8.02 (ddd, J = 9.2, 4.8, 2.9 Hz, 1H), 8.16 (dd, J = 5.7, 2.6 Hz, 1H), 9.47 (s, 1H); Method B; Rt: 1.00 min. m/z: 472 (MH) ^- Exact mass: 473.1. Method AC; Rt: 220a: 4.96 min, 220b: 5.40 min.

Compound 221: N-(3,4-difluorophenyl)-3,7-dimethyl-1,1-dioxo-3-(3-pyridylmethyl)-4,5- Dihydro-2H-pyrrolo[3,4-f]triazepine-6-carboxamide

Compound 219 (48 mg, 0.097 mmol), Pd/C (10%) (5 mg, 0.005 mmol) and TEA (0.027 mL, 0.73 g/mL, 0.19 mmol) were partitioned in MeOH (25 mL) and placed under a hydrogen atmosphere for 2 hours. The reaction mixture was filtered and evaporated to dryness. The residue was purified on silica using a heptane to EtOAc gradient to produce compound 221 (25 mg) as a white powder after crystallization from a DCM:DIPE mixture. ¹ H NMR (400MHz, DMSO-d ₆ ) δppm 1.02-1.09 (m, 5H), 2.64-2.68 (m, 1H), 3.00 (br s, 2H), 3.19-3.29 (m, 1H), 3.71 (s, 3H), 7.29 (s, 1H), 7.34 (t, J=6.2Hz, 1H), 7.40-7.46 (m, 3H), 7.73 (br d, J=7.3Hz, 1H), 7.80-7.91 (m, 1H), 8.44 (dd, J=4.7, 1.7Hz, 1H), 8.51 (d, J = 1.5 Hz, 1H), 10.38 (s, 1H); Method B; Rt: 0.94 min. m/z: 459 (MH) ^- Exact mass: 460.1.

Compound 222: 3-(1-aminoethyl)-7-methyl-1,1-dioxo-N-(3,4,5-trifluorophenyl)-2,3,4,5- Tetrahydropyrrolo[3,4-f]triazepine-6-carboxamide

To the suspension of compound 104 (740 mg, 1.42 mmol) in EtOAc (200 mL), 2-iodine acyl benzoic acid (477 mg, 1.70 mmol) was added. The suspension was heated under reflux for 2 hours. The reaction mixture was filtered and these solids were washed with THF. The filtrate was concentrated. To the residue in EtOAc (200 mL), 2-iodine acyl benzoic acid (1.99 g, 7.09 mmol) was added. The suspension was heated under reflux for 20 hours. The reaction mixture was filtered and these solids were washed with THF. The filtrate was concentrated in a vacuum. The residue was triturated in boiling DCM (20 mL) and the white solid was filtered and washed with DCM (3 mL) to yield (3R)-3-acetyl-7-methyl-1,1-dioxo-N-(3,4,5-trifluorophenyl)-2,3,4,5-tetrahydropyrrolo[3,4-f]triazepine-6-carboxamide (350 mg). Method B; Rt: 0.93 min. m/z: 414 (MH) ^- Exact mass: 415.1.

Under nitrogen, to (3R)-3-acetyl-7-methyl-1,1-dioxo-N-(3,4,5-trifluorophenyl)-2,3,4,5-tetrahydropyrrolo[3,4-f]triazepine-6-formamide (150mg, 0.36mmol) in dry MeOH (2mL) and dry THF (2mL) stirred solution, add zinc chloride (0.071mL, 1M in diethyl ether, 0.071mmol).After stirring at ambient temperature for 30 minutes, the mixture is treated with ammonium formate (274mg, 4.30mmol).After stirring at ambient temperature for another hour, molecular sieves (1g) are added followed by sodium cyanoborohydride (47mg, 0.71mmol).Then the reaction is stirred overnight at ambient temperature.The reaction mixture is filtered through diatomaceous earth and these solids are washed with 2-MeTHF (3X 20mL). The filtrate was washed with water, brine, dried _{( Na2SO4} ), filtered and concentrated. The residue was purified using preparative HPLC (stationary phase: RP XBridgePrep C18 OBD-10 μm, 50 x 150 mm, mobile phase: 0.25% _NH4HCO3 solution in water, ACN) to produce compound 222a (17 mg); _1H NMR (400 MHz, DMSO- _d6 ) δ ppm 0.99 (d, J = 6.6 Hz, 3H), 1.30 (q, ^J = 12.0 Hz, 1H), 2.01 (br dd, J = 14.0, 6.7 Hz, 1H), 2.66-2.81 (m, 2H), 3.02 (br dd, J = 15.1, 6.5 Hz, 1H), 3.16-3.25 (m, 1H), 3.69 (s, 3H), 7.44 (s, 1H), 7.55-7.64 (m, 2H), 10.07-11.08 (m, 1H); Method B; Rt: 0.75 min. m/z: 415 (MH) ^- Exact mass: 416.1; MP: 227.5°C and compound 222b (43 mg); ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.97 (d, J=6.4 Hz, 3H), 1.35-1.46 (m, 1H), 1.87 (brs, 1H), 2.75-2.86 (m, 2H), 2.95-3.04 (m, 1H), 3.23-3.29 (m, 1H), 3.69 (s, 3H), 7.45 (s, 1H), 7.56-7.64 (m, 2H), 10.60 (br s, 1H); Method B; Rt: 0.76 min. m/z: 415 (MH) ^- Exact mass: 416.1; MP: 281.2°C.

Compound 223: 3-[(2-chloro-4-pyridyl)methyl]-N-(3,4-difluorophenyl)-3,7-dimethyl-1,1-difluorophenyl Oxy-2H-pyrrolo[3,4-f]triazepine-6-carboxamide

2-Amino-3-(2-chloro-4-pyridinyl)-2-methyl-propan-1-ol (an intermediate for the synthesis of compound 190) (1047 mg, 5.22 mmol), methyl 3-bromo-4-chlorosulfonyl-1-methyl-pyrrole-2-carboxylate (1.65 g, 5.22 mmol) and Hunin's base (2.7 mL, 0.75 g/mL, 15.7 mmol) were dissolved in ACN (20 mL) and the reaction mixture was stirred overnight. Volatiles were removed under reduced pressure and the residue was purified on silica using a heptane to EtOAc gradient to yield methyl 3-bromo-4-[[1-[(2-chloro-4-pyridinyl)methyl]-2-hydroxy-1-methyl-ethyl]sulfamoyl]-1-methyl-pyrrole-2-carboxylate (880 mg) as a white powder.

Methyl 3-bromo-4-[[1-[(2-chloro-4-pyridinyl)methyl]-2-hydroxy-1-methyl-ethyl]sulfamoyl]-1-methyl-pyrrole-2-carboxylate (150 mg, 0.31 mmol) was dissolved in ACN (15 mL). 2-iodoacylbenzoic acid (131 mg, 0.47 mmol) was added and the reaction mixture was heated at 80° C. for 90 minutes. The reaction mixture was filtered while hot, evaporated to dryness and the residue was purified on silica using a heptane to EtOAc gradient to produce methyl 3-bromo-4-[[1-[(2-chloro-4-pyridinyl)methyl]-1-methyl-2-oxo-ethyl]sulfamoyl]-1-methyl-pyrrole-2-carboxylate (107 mg).

At 0 ℃, KOtBu (251mg, 2.23mmol) is added in the suspension of methyltriphenylphosphonium bromide (798mg, 2.23mmol) stirring in THF (10mL).This suspension is stirred 10min at 0 ℃, and then at room temperature stirred 1 hour.At 0 ℃, methyl 3-bromo-4-[[1-[(2-chloro-4-pyridyl) methyl]-1-methyl-2-oxygen-ethyl] sulfamoyl]-1-methyl-pyrrole-2-formate (107mg, 0.22mmol) in THF (5mL) is added dropwise in this solution.Allow this reaction mixture to warm to room temperature and stir overnight. The volatiles were removed under reduced pressure and the residue was purified on silica using a heptane to EtOAc gradient to give methyl 3-bromo-4-[[1-[(2-chloro-4-pyridinyl)methyl]-1-methyl-allyl]sulfamoyl]-1-methyl-pyrrole-2-carboxylate (78 mg).

Methyl 3-bromo-4-[[1-[(2-chloro-4-pyridinyl)methyl]-1-methyl-allyl]sulfamoyl]-1-methyl-pyrrole-2-carboxylate (78 mg, 0.16 mmol), bis(tri-tert-butylphosphine)palladium(0) (4 mg, 0.008 mmol) and Hunin's base (0.031 mL, 0.75 g/mL, 0.18 mmol) were dissolved in DMF (3 mL) and heated in a microwave at 150° C. for 10 minutes. The reaction mixture was loaded directly onto a silica cartridge and a gradient from heptane to EtOAc was used to give methyl 3-[(2-chloro-4-pyridinyl)methyl]-3,7-dimethyl-1,1-dioxo-2H-pyrrolo[3,4-f]triazepine-6-carboxylate (51 mg).

Methyl 3-[(2-chloro-4-pyridinyl)methyl]-3,7-dimethyl-1,1-dioxo-2H-pyrrolo[3,4-f]triazepine-6-carboxylate (51 mg, 0.13 mmol) and 3,4-difluoroaniline (0.014 mL, 1.29 g/mL, 0.14 mmol) were dissolved in THF (5 mL). Lithium bis(trimethylsilyl)amide (0.64 mL, 1 M in THF, 0.64 mmol) was added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was quenched with NH ₄ Cl (saturated, aqueous, 10 mL) and the organic layer was removed. The aqueous layer was extracted with DCM (2×5 mL) and the combined organic layers were filtered and evaporated to dryness. The residue was purified by preparative HPLC (stationary phase: RP XBridge Prep C18 OBD-10 μm, 30 x 150 mm, mobile phase: 0.25% NH ₄ HCO ₃ solution in water, ACN) to give compound 223 (11 mg). ^1H NMR (400 MHz, DMSO- _d6 ) δ ppm 1.15 (s, 3H), 2.84 (d, J = 12.8 Hz, 1H), 3.46 (d, J = 12.8 Hz, 1H), 3.71 (s, 3H), 5.59 (d, J = 13.0 Hz, 1H), 6.43 (br d, J = 13.9 Hz, 1H), 7.38-7.51 (m, 5H), 7.66 (br s, 1H), 7.81-7.88 (m, 1H), 8.35 (d, J = 4.8 Hz, 1H), 10.72 (br s, 1H); Method B; Rt: 1.02 min. m/z: 491 (MH) ^- Exact mass: 492.1

Compound 224: N-(3,4-difluorophenyl)-3-methyl-1,1-dioxo-2,3-dihydrothiophene[3,4-f]triazepine 6-Chloroformamide

Methyl 3-bromothiophene-2-carboxylate (5 g, 22.6 mmol) was added portionwise to chlorosulfonic acid (7.6 mL, 1.73 g/mL, 113 mmol) at 0° C. The reaction mixture was allowed to warm to room temperature and heated at 120° C. for 3 hours. The resulting mixture was added dropwise to a stirred mixture of ice and water (250 mL), maintaining the temperature below 5° C. The precipitate was filtered and dissolved in 2-MeTHF, dried (MgSO ₄ ), filtered and concentrated in vacuo to yield 3-bromo-4-chlorosulfonyl-thiophene-2-carboxylic acid (6.9 g) as a brown oil.

Oxalyl chloride (10 mL) was added to 3-bromo-4-chlorosulfonyl-thiophene-2-carboxylic acid (6.9 g, 22.582 mmol), DMF (87 μL, 0.944 g/mL, 1.13 mmol) in DCM (350 mL) and stirred overnight. The reaction mixture was concentrated to yield 3-bromo-4-chlorosulfonyl-thiophene-2-carbonyl chloride (7.5 g) as a yellow resin which was used as is.

3-Bromo-4-chlorosulfonyl-thiophene-2-carbonyl chloride (7.5 g, 23.1 mmol) was dissolved in toluene (180 mL). The mixture was refluxed and 3,4-difluoroaniline (2.34 mL, 1.29 g/mL, 23.1 mmol) was added. The mixture was heated under reflux for 45 minutes. The mixture was cooled and concentrated in vacuo. The residue was purified by column chromatography using a gradient of 0 to 100% EtOAc in heptane to produce 4-bromo-5-[(3,4-difluorophenyl)carbamoyl]thiophene-3-sulfonyl chloride (5.7 g).

3-Butene-2-amine hydrochloride (762mg, 7.08mmol) is added in ACN (20mL) and the mixture is cooled on an ice bath. Add DIPEA (3.66mL, 0.75g/mL, 21.2mmol) and the mixture is stirred until a clear solution is obtained. Add 4-bromo-5-[(3,4-difluorophenyl)carbamoyl]thiophene-3-sulfonyl chloride (2.95g, 7.08mmol) and the mixture is stirred at room temperature for 16 hours. The mixture is concentrated in a vacuum and the residue is distributed between water and DCM. The organic layer is separated, dried (MgSO ₄ ), filtered and concentrated in a vacuum. The residue is crystallized from ACN and the precipitation is filtered out to produce 3-bromo-N-(3,4-difluorophenyl)-4-(1-methylallylsulfamoyl)thiophene-2-carboxamide (800mg). Method B; Rt: 1.04 min. m/z: 451 (M+H) ⁺ exact mass: 450.0.

A microwave vial was charged with 3-bromo-N-(3,4-difluorophenyl)-4-(1-methylallylsulfamoyl)thiophene-2-carboxamide (200 mg, 0.443 mmol), Hunin's base (0.084 mL, 0.75 g/mL, 0.49 mmol) and DMF (5 mL) and purged with _N for 5 minutes. Bis(tri-tert-butylphosphine)palladium(0) (11 mg, 0.022 mmol) was added and the vial was capped. The mixture was irradiated at 150° C. for 10 minutes. The mixture was concentrated in vacuo and the residue was purified by preparative HPLC (stationary phase: RP XBridge Prep C18 OBD-10 μm, 50×150 mm, mobile phase: 0.25% NH ₄ HCO ₃ solution in water, MeOH) to yield Compound 224 (65 mg) as a white solid after crystallization from ACN. ^1H NMR (400 MHz, DMSO- _d6 ) δ ppm 1.33 (d, J = 7.3 Hz, 3H), 4.31 (br s, 1H), 5.79 (dd, J = 13.1, 2.3 Hz, 1H), 6.82 (dd, J = 13.1, 2.3 Hz, 1H), 7.43-7.44 (m, 1H), 7.44-7.46 (m, 1H), 7.79-7.84 (m, 1H), 8.07-8.11 (m, 1H), 8.30 (s, 1H), 10.76 (br s, 1H); Method B; Rt: 0.96 min. m/z: 369 (MH) ^- Exact mass: 370.0; MP: 220.8°C.

Compound 225: N-(3,4-difluorophenyl)-3,7-dimethyl-1,1-dioxo-3,4-dihydro-2H-thiophene[3,2- b][1,4,5]oxatriazepine-6-carboxamide

Chlorosulfonic acid (1 mL, 1.73 g/mL, 16.109 mmol) was added to chloroform (15 mL) and cooled on an ice bath. Ethyl 4-hydroxy-2-methylthiophene-3-carboxylate (1 g, 5.37 mmol) dissolved in chloroform (5 mL) was added dropwise to the cooled solution. The mixture was allowed to warm to room temperature and stirred at room temperature for 1 hour. The mixture was poured into ice water and the organic layer was separated. The organic layer was dried (MgSO ₄ ), filtered and concentrated in vacuo. The residue was purified by column chromatography using a gradient of 0 to 100% EtOAc in heptane to produce ethyl 5-chlorosulfonyl-4-hydroxy-2-methyl-thiophene-3-carboxylate (523 mg).

2-[(4-Methoxyphenyl)methylamino]propan-1-ol (286 mg, 1.46 mmol) and Hunin's base (0.757 mL, 0.75 g/mL, 4.39 mmol) were dissolved in ACN (7 mL). Ethyl 5-chlorosulfonyl-4-hydroxy-2-methyl-thiophene-3-carboxylate (417 mg, 1.46 mmol) was added and the mixture was stirred at room temperature for 16 hours. The mixture was concentrated in vacuo and the residue was purified by column chromatography using a gradient from 0 to 100% EtOAc in heptane to produce ethyl 4-hydroxy-5-[(2-hydroxy-1-methyl-ethyl)-[(4-methoxyphenyl)methyl]sulfamoyl]-2-methyl-thiophene-3-carboxylate (359 mg). Method B; Rt: 1.20 min. m/z: 442 (MH) ^- Exact mass: 443.1.

Ethyl 4-hydroxy-5-[(2-hydroxy-1-methyl-ethyl)-[(4-methoxyphenyl)methyl]sulfamoyl]-2-methyl-thiophene-3-carboxylate (359 mg, 0.81 mmol) was dissolved in dry THF (8 mL). Triphenylphosphine (234 mg, 0.89 mmol) and di-tert-butyl azodicarboxylate (205 mg, 0.89 mmol) were added at room temperature. The mixture was stirred for 30 minutes and then concentrated in vacuo. The residue was purified by column chromatography using a gradient from 0 to 100% EtOAc in heptane to produce ethyl 2-[(4-methoxyphenyl)methyl]-3,7-dimethyl-1,1-dioxo-3,4-dihydrothiopheno[3,2-b][1,4,5]oxatriazepine-6-carboxylate (275 mg).

Ethyl 2-[(4-methoxyphenyl)methyl]-3,7-dimethyl-1,1-dioxo-3,4-dihydrothiophene[3,2-b][1,4,5]oxatriazepine-6-carboxylate (275 mg, 0.65 mmol) and 3,4-difluoroaniline (0.078 mL, 1.29 g/mL, 0.78 mmol) were dissolved in THF (5 mL). Lithium bis(trimethylsilyl)amide (1.9 mL, 1 M in THF, 1.9 mmol) was added dropwise and the mixture was stirred at room temperature for 2 hours. The mixture was quenched with _NH4Cl (aqueous, saturated). The mixture was diluted with 2-MeTHF and the organic layer was separated, dried ( _MgSO4 ), filtered, and concentrated in vacuo. The product was purified by column chromatography using a gradient from 0 to 50% EtOAc in heptane to yield N-(3,4-difluorophenyl)-2-[(4-methoxyphenyl)methyl]-3,7-dimethyl-1,1-dioxo-3,4-dihydrothiopheno[3,2-b][1,4,5]oxatriazepine-6-carboxamide (232 mg).

Under N ₂ , N-(3,4-difluorophenyl)-2-[(4-methoxyphenyl)methyl]-3,7-dimethyl-1,1-dioxo-3,4-dihydrothiophene[3,2-b][1,4,5]oxatriazepine-6-carboxamide (116 mg, 0.23 mmol) was dissolved in dry DCM (3 mL) and TFA (3 mL, 1.49 g/mL, 39 mmol) was added. The mixture was stirred at room temperature for 16 hours. The mixture was concentrated in vacuo and the residue was purified by column chromatography using a gradient from 0 to 50% EtOAc in heptane to produce compound 225 (63 mg). ^1H NMR (400 MHz, DMSO- _d6 ) δ ppm 1.19 (d, J = 7.0 Hz, 3H), 2.50 (s, 3H), 3.79 (q, J = 7.5 Hz, 1H), 4.05 (dd, J = 12.8, 8.3 Hz, 1H), 4.50 (dd, J = 12.8, 2.6 Hz, 1H), 7.33-7.44 (m, 2H), 7.77-7.85 (m, 1H), 8.02 (d, J = 8.2 Hz, 1H), 10.18 (s, 1H); Method D; Rt: 1.90 min. m/z: 387 (MH) - Exact mass: 388.0. MP: 221.5°C.

Compound 226: N-(3,4-difluorophenyl)-3,7-dimethyl-1,1-dioxo-2,3-dihydropyrazolo[4,3-f] Triazepine-6-carboxamide

Methyl 5-amino-2-methyl-pyrazole-3-formate (2.00g, 12.9mmol) is dissolved in THF (50mL) and N-bromosuccinimide (2.52g, 14.2mmol) is added and stirred for 2 hours.The solution is concentrated in a vacuum, redissolved in DCM and washed with water.The organic matter merged is evaporated to dryness and the crude product is purified using DCM/MeOH 100/0 to 90/10 on silica.The crude product obtained is redissolved in DIPE, and the remaining salt is removed by filtration.Then the filtrate is concentrated in a vacuum to produce methyl 5-amino-4-bromo-2-methyl-pyrazole-3-formate (2.0g) as a light orange solid.

In a cold (0 ℃) aqueous solution (3.5mL), SOCl ₂ (0.642mL, 1.64 g/mL, 8.84mmol) was added and allowed to warm to room temperature and stirred for 1h. Then cuprous chloride (19mg, 0.20mmol) was added and the solution was cooled to -5 ℃. In another solution of HCl (1.97 mL, 37% in H ₂ O, 1.18g/mL, 23.6mmol), methyl 5-amino-4-bromo-2-methyl-pyrazole-3-formate (500mg, 1.97mmol) was added and cooled to -5 ℃, followed by addition of a solution of sodium nitrite (149mg, 2.16mmol) in water (1mL). The solution was then added dropwise to the first solution and kept cooling at -5 ℃. The solution was then allowed to warm to 0 ℃ and continued stirring at this temperature for 2 hours, followed by allowing it to warm to room temperature. EtOac (20mL) was added and the organic layer was concentrated in vacuo. The residue was purified on silica using a heptane to EtOAc gradient to give methyl 4-bromo-5-chlorosulfonyl-2-methyl-pyrazole-3-carboxylate (544 mg).

Methyl 4-bromo-5-chlorosulfonyl-2-methyl-pyrazole-3-formate (383mg, 1.04 mmol) is dissolved in ACN (5mL, 0.786g/mL, 104mmol).DIPEA (0.715mL, 0.75g/mL, 4.15mmol) and but-3-ene-2-amine hydrochloride (223mg, 2.08mmol) are added and the reaction mixture is stirred for 5 hours.Then the solution is concentrated in a vacuum and directly purified using heptane/EtOAc 100 to 50/50 on silica, to produce methyl 4-bromo-2-methyl-5-(1-methylallylsulfamoyl)pyrazole-3-formate (98 mg).

At room temperature, methyl 4-bromo-2-methyl-5-(1-methylallylsulfamoyl)pyrazole-3-formate (98mg, 0.278mmol) is dissolved in THF (5mL) and 3,4-difluoroaniline (0.030mL, 1.302g/mL, 0.31mmol) and LiHMDS (0.835mL, 1M in THF, 0.84mmol) are added. After 2 hours, the solution is diluted with EtOAc and washed with water. By the organic layer _MgSO4 that merges, filter, concentrate in a vacuum and use heptane/EtOAc 100/0 to 50/50 to purify on silica to produce 4-bromo-N-(3,4-difluorophenyl)-2-methyl-5-(1-methylallylsulfamoyl)pyrazole-3-carboxamide (70mg).

To a solution of 4-bromo-N-(3,4-difluorophenyl)-2-methyl-5-(1-methylallylsulfamoyl)pyrazole-3-carboxamide (70 mg, 0.16 mmol) in DMF (2 mL) was added Hunin's base (0.054 mL, 0.75 g/mL, 0.31 mmol) and flushed under nitrogen. The mixture was first heated to 100° C., after which bis(tri-tert-butylphosphine)palladium(0) (8 mg, 0.016 mmol) was added, and the solution was then heated to 150° C. in a microwave for 5 minutes. The reaction mixture was directly purified on preparative HPLC (stationary phase: RP XBridge Prep C18 ODB-5 μm, 30×250 mm, mobile phase: 0.25% NH ₄ HCO ₃ solution in water, ACN) to yield compound 226 (26 mg). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.36 (d, J=7.3 Hz, 3H) 3.97 (s, 3H) 4.20-4.29 (m, 1H) 5.75 (dd, J=12.2, 2.5 Hz, 1H) 6.40 (dd, J=12.1, 2.6 Hz, 1H) 7.41-7.50 (m, 2H) 8.02 (br s, 1H) 7.81-7.90 (m, 1H) 11.14 (br s, 1H); Method B; Rt: 0.90 min. m/z: 367 (MH) ^- Exact mass: 368.1.

The following compounds were also synthesized according to the procedure described above:

Biological Example - Anti-HBV Activity of Compounds of Formula (A)

Anti-HBV activity was determined using the HepG2.117 cell line, a stable, inducible HBV-producing cell line that replicates HBV in the absence of doxycycline (tetracycline-off system). For the antiviral assay, HBV replication was induced and then treated with a serial dilution of the compound in duplicate in 96-well plates. After 3 days of treatment, antiviral activity was determined by quantifying intracellular HBV DNA using real-time PCR and an HBV-specific primer set and probe.

The cytotoxicity of these compounds was tested using HepG2 cells, which were incubated in the presence of the compounds for 4 days. Cell viability was assessed using the resazurin assay. The results are shown in Table 1.

Table 1: Anti-HBV activity and cytotoxicity

.

Claims (38)

1. Compounds with chemical formulas (I-A) in This indicates a monocyclic 5- or 6-membered aryl group optionally containing one or two heteroatoms, which is optionally substituted by one or more substituents independently selected from the group consisting of: _C1 - _C3 alkyl, _C3 - _C4 cycloalkyl, -CN and halogen; This indicates an optional 6-membered aryl group containing one nitrogen atom; X represents -CR ² R ³ -; Y represents a _C1 - _C7 alkylene or _C2 - _C7 alkenylene, each optionally substituted by one or more substituents independently selected from the group consisting of: _C1 - _C4 alkyl, fluorine, and -OH; Z represents a heteroatom selected from NH, O, or S, or a single bond; ^Ra , ^Rb , ^Rc , and ^Rd are each independently selected from the group consisting of the following: hydrogen, halogen, _-CHF2 , _-CF2 -methyl, _-CH2F , _-CF3 , -OCF3, -CN, _C3 - _{C4 cycloalkyl} , and _-C1 - _C4 alkyl; ^R1 is a _C1 - _C10 alkyl group, which is hydrogen or optionally substituted with one or more substituents selected independently from the group consisting of -OH, fluorine, and oxo. ^R2 is selected from the group consisting of: hydrogen; _C1 - _C10 alkyl optionally substituted with one or more substituents independently selected from the group consisting of: -OH, fluorine, methoxy, oxo, and -C(=O) _OC1 - _C4 alkyl; _C1 - _C3 alkyl- ^R7 ; _C2 - _C4 alkynyl; a 3-7 membered saturated ring optionally containing one or more heteroatoms independently selected from the group consisting of: O, S, and N; and a monocyclic aryl optionally containing one or two heteroatoms; wherein the _C1 - _C3 alkyl- ^R7 , the 3-7 membered saturated ring, or the monocyclic aryl is optionally substituted with one or more ^R8 substituents; ^R3 is hydrogen or a _C1-6 alkyl group optionally substituted with -OH; Alternatively, ^R2 and ^R3 together with the carbon atoms to which they are attached form a 3-7 membered saturated ring, which optionally contains one or more heteroatoms each independently selected from the group consisting of O, S and N, and optionally substituted by one or more substituents each independently selected from the group consisting of -OH, fluorine, methoxy, oxo, -C(=O)OC1 _{- C4} alkyl, benzyl, and _C1 - _C4 alkyl optionally substituted by one or more substituents each independently selected from the group consisting of fluorine and/or -OH; R ⁷ represents a monocyclic aryl group, which optionally contains one or two heteroatoms and is optionally substituted by one or two substituents, each independently selected from the group consisting of: halogens and _C1-3 alkyl groups; a 3-7 membered saturated ring, optionally containing one or more heteroatoms, each independently selected from the group consisting of: O, S, and N; or -NR ⁹ R ¹⁰ ; ^R9 and ^R10 are each independently selected from hydrogen and _C1 - _C3 alkyl groups optionally substituted with one or more fluorine substituents; Each R ⁸ is independently selected from the group consisting of: -OH, fluorine, methoxy, oxo, -C(=O) _OC1 - _C4 alkyl, _C1 - _C4 alkoxy, _C1 - _C4 alkoxy, and _C1 - _C4 alkyl optionally substituted by one or more substituents each independently selected from: fluorine and/or -OH; The monocyclic aryl group is a 5- or 6-membered aryl group, optionally containing one or two heteroatoms selected from NH, O, or S. Or its pharmaceutically acceptable salt. 2. The compound according to claim 1, wherein the _C1 - _C3 alkyl group is methyl, or ^R3 is hydrogen or methyl, or Z represents NH or oxygen, or a single bond. 3. The compound according to claim 1, wherein Z represents oxygen, or a single bond. 4. The compound according to claim 1, wherein... This indicates a monocyclic 5- or 6-membered aryl group optionally containing one or two heteroatoms, which is optionally substituted by one or more substituents independently selected from the group consisting of: _C1 - _C3 alkyl, _C3 - _C4 cycloalkyl, -CN and halogen; This indicates an optional 6-membered aryl group containing one nitrogen atom; X represents -CR ² R ³ -; Y represents a _C1 - _C7 alkylene or _C2 - _C7 alkenylene, each optionally substituted by one or more substituents independently selected from: _C1 - _C4 alkyl and -OH; Z represents a heteroatom selected from NH, O, or S, or a single bond; ^Ra , ^Rb , ^Rc , and ^Rd are each independently selected from the group consisting of the following: hydrogen, halogen, _-CHF2 , _-CF2 -methyl, _-CH2F , _-CF3 , -OCF3, -CN, _C3 - _{C4 cycloalkyl} , and _-C1 - _C4 alkyl; ^R1 is _hydrogen or a _{C1 - C6} alkyl group, which is optionally substituted by one or more substituents selected independently from the group consisting of -OH, fluorine and oxo groups; ^R2 is selected from the group consisting of: hydrogen, _C1 - _C6 alkyl, _C1 - _C3 alkyl- ^R7 , optionally containing one or more heteroatoms selected from the group consisting of: O, S and N, and optionally containing one or two heteroatoms of a monocyclic aryl group, wherein the _C1 - _C3 alkyl- ^R7 , 3-7 alkyl-R7, or monocyclic aryl group is optionally substituted by one or more ^R8s ; ^R3 is hydrogen or a _C1-6 alkyl group; Alternatively, ^R2 and ^R3 together with the carbon atoms to which they are attached form a 3-7 membered saturated ring, which optionally contains one or more heteroatoms each independently selected from the group consisting of O, S and N, and this 3-7 membered saturated ring is optionally substituted by one or more ^R8s ; R ⁷ indicates a monocyclic aryl group optionally containing one or two heteroatoms; optionally containing one or more 3- to 7-membered saturated rings, each consisting of one or more heteroatoms independently selected from the group consisting of O, S, and N; or -NR ⁹ R ¹⁰ ; ^R9 and ^R10 are each independently selected from hydrogen and _C1 - _C3 alkyl groups; Each R ⁸ is independently selected from the group consisting of: -OH, fluorine, methoxy, oxo, -C(=O)OC1 _{- C4} alkyl and _{C1- C4} alkyl optionally substituted with one or more substituents each independently selected from: fluorine and/or -OH, The monocyclic aryl group is a 5- or 6-membered aryl group, optionally containing one or two heteroatoms selected from NH, O or S. 5. The compound according to claim 4, wherein the _C1 - _C3 alkyl group is methyl, or Z represents oxygen, or a single bond. 6. The compound according to claim 1 or 4, wherein This indicates a 5- or 6-membered aryl group of a monocyclic ring optionally containing one or two heteroatoms, which is optionally substituted by one or more substituents independently selected from the group consisting of: _C1 - _C3 alkyl, _C3 - _C4 cycloalkyl, -CN and halogen; This indicates an optional 6-membered aryl group containing one nitrogen atom; X represents -CR ² R ³ -; Y represents a _C1 - _C7 alkylene or _C2 - _C7 alkenylene, each optionally substituted by one or more substituents independently selected from: _C1 - _C4 alkyl and -OH; Z represents a heteroatom selected from NH, O, or S, or a single bond; ^Ra , ^Rb , ^Rc , and ^Rd are each independently selected from the group consisting of the following: hydrogen, halogen, _-CHF2 , _-CF2 -methyl, _-CH2F , _-CF3 , -OCF3, -CN, _C3 - _{C4 cycloalkyl} , and _-C1 - _C4 alkyl; ^R1 is _hydrogen or a _{C1 - C6} alkyl group, which is optionally substituted by one or more substituents selected independently from the group consisting of -OH, fluorine and oxo groups; ^R2 is selected from the group consisting of: hydrogen, _C1 - _C6 alkyl, _C1 - _C3 alkyl- ^R7 , optionally containing one or more heteroatoms selected from the group consisting of: O, S and N, and optionally containing one or two heteroatoms of a monocyclic aryl group, wherein the _C1 - _C3 alkyl- ^R7 , 3-7 alkyl-R7, or monocyclic aryl group is optionally substituted by one or more ^R8s ; ^R3 is hydrogen; Alternatively, ^R2 and ^R3 together with the carbon atoms to which they are attached form a 3-7 membered saturated ring, which optionally contains one or more heteroatoms each independently selected from the group consisting of O, S and N, and this 3-7 membered saturated ring is optionally substituted by one or more ^R8s ; R ⁷ indicates a monocyclic aryl group optionally containing one or two heteroatoms; optionally containing one or more 3- to 7-membered saturated rings, each consisting of one or more heteroatoms independently selected from the group consisting of O, S, and N; or -NR ⁹ R ¹⁰ ; ^R9 and ^R10 are each independently selected from hydrogen and _C1 - _C3 alkyl groups; Each R ⁸ is independently selected from the group consisting of: -OH, fluorine, methoxy, oxo, -C(=O)OC1 _{- C4} alkyl and _{C1- C4} alkyl optionally substituted with one or more substituents each independently selected from: fluorine and/or -OH, The monocyclic aryl group is a 5- or 6-membered aryl group, optionally containing one or two heteroatoms selected from NH, O or S. 7. The compound according to claim 6, wherein Z represents oxygen, or a single bond. 8. The compound according to claim 1 or 4, wherein the compound has chemical formula (A). in: This indicates a monocyclic 5- or 6-membered aryl group that optionally contains one or two heteroatoms, the aryl group optionally being substituted by one or more methyl groups, -CN groups, or halogens; This indicates an optional 6-membered aryl group containing one nitrogen atom; X represents -CR ² R ³ -; Y represents a _C1 - _C7 alkylene or _C2 - _C7 alkenylene, each optionally substituted with one or more _C1 - _C4 alkyl or -OH groups; Z represents a heteroatom selected from NH, O, or S, or a single bond; ^Ra , ^Rb , ^Rc , and ^Rd are independently selected from the group consisting of: hydrogen, halogen, _-CHF2 , _-CF2 -methyl, _-CH2F , _-CF3 , _-OCF3 , -CN, _C3 - _C4 cycloalkyl, and _-C1 - _C4 alkyl; ^R1 is _hydrogen or a _{C1 - C6} alkyl group, which is optionally substituted by one or more substituents selected independently from the group consisting of -OH, fluorine and oxo groups; ^R2 is selected from the group consisting of: hydrogen, _C1 - _C6 alkyl, _C1 - _C3 alkyl- ^R7 , optionally containing one or more heteroatoms selected from the group consisting of: O, S and N, and optionally containing one or two heteroatoms of a monocyclic aryl group, wherein the _C1 - _C3 alkyl- ^R7 , 3-7 alkyl-R7, or monocyclic aryl group is optionally substituted by one or more ^R8s ; ^R3 is hydrogen; Alternatively, ^R2 and ^R3 together with the carbon atoms to which they are attached form a 3-7 membered saturated ring, which optionally contains one or more heteroatoms each independently selected from the group consisting of O, S and N, and this 3-7 membered saturated ring is optionally substituted by one or more ^R8s ; R ⁷ indicates a monocyclic aryl group that optionally contains one or two heteroatoms; Each R ⁸ is independently selected from the group consisting of: -OH, fluorine, methoxy, oxo, -C(=O)OC1 _{- C4} alkyl and _{C1- C4} alkyl optionally substituted with one or more fluorine and/or -OH; The monocyclic aryl group is a 5- or 6-membered aryl group, optionally containing one or two heteroatoms selected from NH, O, or S. Or its pharmaceutically acceptable salt. 9. The compound according to claim 8, wherein Z represents oxygen, or a single bond. 10. The compound according to claim 1 or 4, wherein ^R4 is hydrogen, _-C1 - _C3 alkyl or _C3 - _C4 cycloalkyl; and ^R6 is selected from hydrogen, methyl, -CN and halogen. 11. The compound according to claim 1 or 4, wherein ^R5 is hydrogen or halogen; and ^R6 is selected from hydrogen, methyl, -CN and halogen. 12. The compound according to claim 1 or 4, wherein the ring C consists of 6 to 8 atoms. 13. The compound according to claim 12, wherein the ring C consists of 7 atoms. 14. The compound according to claim 10, wherein ^R4 is a methyl group. 15. The compound according to claim 10, wherein ^R6 is hydrogen. 16. The compound of claim 1, wherein ^R2 is a _C1 - _C6 alkyl group optionally substituted with one or more substituents selected independently from the group consisting of -OH, fluorine, and methoxy. 17. The compound according to claim 1 or 4, wherein the compound represents a phenyl group, and ^Ra is selected from hydrogen and halogens; ^Rb is hydrogen or halogens; ^Rc is selected from halogens, _CH3 , _CHF2 , _CF3 , and -CN; and ^Rd is selected from hydrogen and halogens. 18. The compound of claim 1, wherein ^R2 is a _C1 - _C4 alkyl group optionally substituted with one or more fluorine molecules. 19. The compound according to claim 1, wherein ^R2 is a _C1 - _C6 alkyl group optionally substituted with one or more -OH substituents. 20. The compound according to claim 1 or 4, wherein ^R1 is hydrogen. 21. The compound according to claim 1, wherein the compound is selected from the compounds numbered 1-250: Or its pharmaceutically acceptable salt. 22. The compound according to claim 1, wherein the compound is (3S)-N-(3-cyano-4-fluoro-phenyl)-7-methyl-1,1-dioxo-3-(3-pyridylmethyl)-3,4-dihydro-2H-pyrrolo[3,4-b][1,4,5]oxathazaza-6-carboxamide; (3R)-3-[(1S)-1-hydroxyethyl]-7-methyl-1,1-dioxo-N-(3,4,5-trifluorophenyl)-2,3-dihydropyrrolo[3,4-f]thiaza-6-carboxamide; (3R)-N-[3-(difluoromethyl)-4-fluoro-phenyl]-3-(1-hydroxy-1-methyl-ethyl)-7-methyl-1,1-dioxo-3,4-dihydro-2H-pyrrolo[3,4-b][1,4,5]oxathazaza-6-carboxamide; (3R)-N-(3-cyano-4-fluoro-phenyl)-3-(1-hydroxy-1-methyl-ethyl)-7-methyl-1,1-dioxo-3,4-dihydro-2H-pyrrolo[3,4-b][1,4,5]oxathazaza-6-carboxamide; (3S)-N-(3-cyano-4-fluoro-phenyl)-3,7-dimethyl-1,1-dioxo-2,3,4,5-tetrahydropyrrolo[3,4-f]thiaza-6-carboxamide; N-[3-(difluoromethyl)-4-fluoro-phenyl]-3-(1-hydroxy-1-methyl-ethyl)-7-methyl-1,1-dioxo-2,3,4,5-tetrahydropyrrolo[3,4-f]thiaza-6-carboxamide; N-[3-(difluoromethyl)-4-fluoro-phenyl]-3-[(2,5-dimethylpyrazol-3-yl)methyl]-3,7-dimethyl-1,1-dioxo-2,4-dihydropyrrolo[3,4-b][1,4,5]oxathazaza-6-carboxamide; or N-[3-(difluoromethyl)-4-fluoro-phenyl]-3,7-dimethyl-3-[(1-methylimidazol-2-yl)methyl]-1,1-dioxo-2,4-dihydropyrrolo[3,4-b][1,4,5]oxathazaza-6-carboxamide, Or its pharmaceutically acceptable salt. 23. The compound according to claim 1, wherein the compound is (3S)-N-(3-cyano-4-fluoro-phenyl)-7-methyl-1,1-dioxo-3-(3-pyridylmethyl)-3,4-dihydro-2H-pyrrolo[3,4-b][1,4,5]oxathazaza-6-carboxamide, Or its pharmaceutically acceptable salt. 24. The compound according to claim 1, wherein the compound is (3R)-3-[(1S)-1-hydroxyethyl]-7-methyl-1,1-dioxo-N-(3,4,5-trifluorophenyl)-2,3-dihydropyrrolo[3,4-f]thiaza-6-carboxamide, Or its pharmaceutically acceptable salt. 25. The compound according to claim 1, wherein the compound is (3R)-N-[3-(difluoromethyl)-4-fluoro-phenyl]-3-(1-hydroxy-1-methyl-ethyl)-7-methyl-1,1-dioxo-3,4-dihydro-2H-pyrrolo[3,4-b][1,4,5]oxathazaza-6-carboxamide, Or its pharmaceutically acceptable salt. 26. The compound according to claim 1, wherein the compound is (3R)-N-(3-cyano-4-fluoro-phenyl)-3-(1-hydroxy-1-methyl-ethyl)-7-methyl-1,1-dioxo-3,4-dihydro-2H-pyrrolo[3,4-b][1,4,5]oxathazaza-6-carboxamide, Or its pharmaceutically acceptable salt. 27. The compound according to claim 1, wherein the compound is (3S)-N-(3-cyano-4-fluoro-phenyl)-3,7-dimethyl-1,1-dioxo-2,3,4,5-tetrahydropyrrolo[3,4-f]thiaza-6-carboxamide, Or its pharmaceutically acceptable salt. 28. The compound according to claim 1, wherein the compound is (3*S)-N-[3-(difluoromethyl)-4-fluoro-phenyl]-3-(1-hydroxy-1-methyl-ethyl)-7-methyl-1,1-dioxo-2,3,4,5-tetrahydropyrrolo[3,4-f]thiaza-6-carboxamide, Or its pharmaceutically acceptable salt. 29. The compound according to claim 1, wherein the compound is (3*S)-N-[3-(difluoromethyl)-4-fluoro-phenyl]-3-[(2,5-dimethylpyrazol-3-yl)methyl]-3,7-dimethyl-1,1-dioxo-2,4-dihydropyrrolo[3,4-b][1,4,5]oxathazaza-6-carboxamide, Or its pharmaceutically acceptable salt. 30. The compound according to claim 1, wherein the compound is N-[3-(difluoromethyl)-4-fluoro-phenyl]-3,7-dimethyl-3-[(1-methylimidazol-2-yl)methyl]-1,1-dioxo-2,4-dihydropyrrolo[3,4-b][1,4,5]oxathazaza-6-carboxamide, Or its pharmaceutically acceptable salt. 31. The compound as defined in claim 1 or 4, used as a medicine. 32. The compound as defined in claim 1 or 4, for use in the prevention or treatment of HBV infection in mammals. 33. A pharmaceutical composition comprising a compound as defined in any one of claims 1 to 30, and a pharmaceutically acceptable carrier. 34. A product comprising (a) a compound as defined in any one of claims 1 to 30 or a pharmaceutical composition as described in claim 33 and (b) another HBV inhibitor, the product being used as a combination formulation for simultaneous, separate or sequential use in the treatment of HBV infection. 35. Use in the preparation of a medicament in a therapeutically effective amount of a compound as defined in any one of claims 1 to 30 or a pharmaceutical composition as defined in claim 33, said medicament for treating warm-blooded animals infected with HBV or at risk of HBV infection. 36. The use according to claim 35, wherein the warm-blooded animal is a human. 37. A method for preparing a compound as defined in any one of claims 1 to 20, the method comprising the following steps: (a) In the presence of a base, in a solvent, a compound having formula (V) is reacted with an amine having formula (VI) to form a compound having formula (Ia), and optionally the compound having formula (Ia) is subjected to hydrogenation. or (b) subjecting a compound having the chemical formula (XXXIV) to Heck reaction conditions to form a compound having the chemical formula (Ia), and optionally subjecting the compound having the chemical formula (Ia) to hydrogenation. or (c) In the presence of a suitable base and in a suitable solvent, a compound having the chemical formula (XXXX) is reacted with an amine having the chemical formula (VI). Among them, amines with chemical formula (VI) are In (a), Y* is a _C2 - _C7 alkenyl group; in (b), Y* is -CH=CH-; Y** is a _C1 - _C7 alkylene group; in (a) and (c), Z is as defined in any one of claims 1 to 20; in (b), Z is a single bond; and all other variables are as defined in any one of claims 1 to 20. 38. Compounds with the chemical formula (V) or (XXXX). in Y* is a _C2 - _C7 alkenyl group, Y** is a _C1 - _C7 alkylene group, and all other variables are as defined in any one of claims 1 to 20.