Provided herein are compounds of formula (IA) and (III) useful for the treatment of HBV infection in a subject in need thereof, pharmaceutical compositions thereof, and methods of inhibiting, suppressing, or preventing HBV infection in the subject. [structure]

Description

80 parts

›RELATED APPLICATIONS

This application is a 35 U.S.C. § 371 filing of International Application No. PCT/US2017/040130, filed Jun. 29, 2017, which claims the benefit of U.S. provisional patent application No. 62/356,487, filed Jun. 29, 2016; and U.S. provisional patent application No. 62/511,565, filed May 26, 2017; the entire contents of each of which are incorporated herein by reference.

›BACKGROUND

Chronic hepatitis B virus (HBV) infection is a significant global health problem, affecting over 5% of the world population (over 350 million people worldwide and 1.25 million individuals in the U.S.).

Despite the availability of a prophylactic HBV vaccine, the burden of chronic HBV infection continues to be a significant unmet worldwide medical problem, due to suboptimal treatment options and sustained rates of new infections in most parts of the developing world. Current treatments do not provide a cure and are limited to only two classes of agents (interferon alpha and nucleoside analogues/inhibitors of the viral polymerase); drug resistance, low efficacy, and tolerability issues limit their impact. The low cure rates of HBV are attributed at least in part to the fact that complete suppression of virus production is difficult to achieve with a single antiviral agent. However, persistent suppression of HBV DNA slows liver disease progression and helps to prevent hepatocellular carcinoma. Current therapy goals for HBV-infected patients are directed to reducing serum HBV DNA to low or undetectable levels, and to ultimately reducing or preventing the development of cirrhosis and hepatocellular carcinoma.

The HBV capsid protein plays essential functions during the viral life cycle. HBV capsid/core proteins form metastable viral particles or protein shells that protect the viral genome during intercellular passage, and also play a central role in viral replication processes, including genome encapsidation, genome replication, and virion morphogenesis and egress. Capsid structures also respond to environmental cues to allow un-coating after viral entry. Consistently, the appropriate timing of capsid assembly and dis-assembly, the appropriate capsid stability and the function of core protein have been found to be critical for viral infectivity.

There is a need in the art for therapeutic agents that can increase the suppression of virus production and that can treat, ameliorate, or prevent HBV infection. Administration of such therapeutic agents to an HBV infected patient, either as monotherapy or in combination with other HBV treatments or ancillary treatments, will lead to significantly reduced virus burden, improved prognosis, diminished progression of the disease and enhanced seroconversion rates.

›SUMMARY · 1 of 2

Provided herein are compounds useful for the treatment of HBV infection in a subject in need thereof. Thus, in an aspect, provided herein is a compound of Formula Ia:

or a pharmaceutically acceptable salt thereof, wherein

A is N or C(H);

R 1 is H, C 1 -C 6 -alkyl, C 1 -C 6 -alkenyl, or C 1 -C 6 -alkyl-OH;

R 2 is, at each occurrence, independently selected from —OH, halo, C 1 -C 6 -alkyl, C 1 -C 6 -alkylene, C 0 -C 6 -alkyl-C 3 -C 6 -cycloalkyl, C 0 -C 6 -alkyl-C 2 -C 6 -heterocycloalkyl, C 0 -C 6 -alkyl-OR 6 , C 0 -C 6 -alkyl-N(R 7 ) 2 , C 0 -C 6 -alkyl-S(O)R 8 , C 0 -C 6 -alkyl-S(O) 2 R 8 , C 0 -C 6 -alkyl-C(O)OR 9 , C 0 -C 6 -alkyl-OC(O)R 9 , C 0 -C 6 -alkyl-OC(O)OR 9 , C 0 -C 6 -alkyl-OC(O)N(R 7 ) 2 , and C 0 -C 6 -alkyl-C(O)N(R 7 ) 2 , wherein alkyl, cycloalkyl, and heterocycloalkyl are optionally substituted with 1, 2, or 3 groups, each independently selected from —OH and halo;

R 3 is, at each occurrence, independently selected from —OH, halo, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, —O—C 1 -C 6 -alkyl, and C 1 -C 6 -alkyl-OH;

R 5 is selected from H, C 1 -C 6 -alkyl, and C 1 -C 6 -alkyl-OH;

R 6 is selected from H, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, C 1 -C 6 -alkenyl, and C 0 -C 6 -alkyl-C 3 -C 6 -cycloalkyl;

R 7 is selected from H, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, C 1 -C 6 -alkyl-OR 10 , —C(O)C 1 -C 6 -alkyl, —C(O)C 1 -C 6 -haloalkyl, —C(O)C 1 -C 6 -alkyl-OR 10 , —C(O)C 1 -C 6 -alkyl-CN, —C(O)C 3 -C 7 -cycloalkyl, —C(O)O—C 1 -C 6 -alkyl, —C(O)O—C 1 -C 6 -haloalkyl, —C(O)O—C 3 -C 7 -cycloalkyl, —C(O)N(R 10 ) 2 , —S(O) 2 C 1 -C 6 -alkyl, —S(O) 2 C 1 -C 6 -haloalkyl and —S(O) 2 C 3 -C 7 -cycloalkyl;

R 8 is selected from H and C 1 -C 6 -alkyl;

R 9 is selected from H and C 1 -C 6 -alkyl;

R 10 is selected from H and C 1 -C 6 -alkyl;

R a is, at each occurrence, independently selected from H, —OH, halo, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, —O—C 1 -C 6 -alkyl, and C 1 -C 6 -alkyl-OH;

R b is, at each occurrence, independently selected from H and C 1 -C 6 -alkyl;

m is 0, 1, 2, 3, or 4;

n is 0, 1, 2, 3, or 4; and

p is 0, 1, 2, 3, or 4.

In another aspect, provided herein is a compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein

R 1 is H, C 1 -C 6 -alkyl, C 1 -C 6 -alkenyl, or C 1 -C 6 -alkyl-OH;

R 2 is, at each occurrence, independently selected from —OH, halo, C 1 -C 6 -alkyl, C 1 -C 6 -alkylene, C 0 -C 6 -alkyl-C 3 -C 6 -cycloalkyl, C 0 -C 6 -alkyl-C 2 -C 6 -heterocycloalkyl, C 0 -C 6 -alkyl-OR 6 , C 0 -C 6 -alkyl-N(R 7 ) 2 , C 0 -C 6 -alkyl-SR 8 , C 0 -C 6 -alkyl-S(O)R 8 , C 0 -C 6 -alkyl-S(O) 2 R 8 , C 0 -C 6 -alkyl-C(O)OR 9 , C 0 -C 6 -alkyl-OC(O)R 9 , C 0 -C 6 -alkyl-OC(O)OR 9 , C 0 -C 6 -alkyl-OC(O)N(R 7 ) 2 , and C 0 -C 6 -alkyl-C(O)N(R 7 ) 2 , wherein alkyl, cycloalkyl, and heterocycloalkyl are optionally substituted with 1, 2, or 3 groups, each independently selected from —OH and halo;

R 3 is, at each occurrence, independently selected from —OH, halo, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, —O—C 1 -C 6 -alkyl, and C 1 -C 6 -alkyl-OH;

R 5 is selected from H, C 1 -C 6 -alkyl, and C 1 -C 6 -alkyl-OH;

R 6 is selected from H, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, C 1 -C 6 -alkenyl, and C 0 -C 6 -alkyl-C 3 -C 6 -cycloalkyl;

R 7 is selected from H, C 1 -C 6 -alkyl, and C 1 -C 6 -alkyl-OH;

R 8 is selected from H and C 1 -C 6 -alkyl;

R 9 is selected from H and C 1 -C 6 -alkyl;

R a is, at each occurrence, independently selected from H, —OH, halo, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, —O—C 1 -C 6 -alkyl, and C 1 -C 6 -alkyl-OH;

R b is, at each occurrence, independently selected from H and C 1 -C 6 -alkyl;

m is 0, 1, 2, 3, or 4;

n is 0, 1, 2, 3, or 4; and

p is 0, 1, 2, 3, or 4.

In an embodiment, the compound of Formula Ia has the structure of Formula II:

or a pharmaceutically acceptable salt thereof.

In another aspect, provided herein is a compound of Formula III:

or a pharmaceutically acceptable salt thereof, wherein

is a single or double bond;

X is N—R c ;

R 1 is H, C 1 -C 6 -alkyl, C 1 -C 6 -alkenyl, or C 1 -C 6 -alkyl-OH;

R 2 is, at each occurrence, independently selected from —OH, halo, C 1 -C 6 -alkyl, C 1 -C 6 -alkylene, C 0 -C 6 -alkyl-C 3 -C 6 -cycloalkyl, C 0 -C 6 -alkyl-C 2 -C 6 -heterocycloalkyl, C 0 -C 6 -alkyl-OR 6 , C 0 -C 6 -alkyl-N(R 7 ) 2 , C 0 -C 6 -alkyl-SR 8 , C 0 -C 6 -alkyl-S(O)R 8 , C 0 -C 6 -alkyl-S(O) 2 R 8 , C 0 -C 6 -alkyl-C(O)OR 9 , C 0 -C 6 -alkyl-OC(O)R 9 , C 0 -C 6 -alkyl-OC(O)OR 9 , C 0 -C 6 -alkyl-OC(O)N(R 7 ) 2 , and C 0 -C 6 -alkyl-C(O)N(R 7 ) 2 , wherein alkyl, cycloalkyl, and heterocycloalkyl are optionally substituted with 1, 2, or 3 groups, each independently selected from —OH and halo;

R 3 is, at each occurrence, independently selected from —OH, halo, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, —O—C 1 -C 6 -alkyl, and C 1 -C 6 -alkyl-OH;

›SUMMARY · 2 of 2

R 5 is selected from H, C 1 -C 6 -alkyl, and C 1 -C 6 -alkyl-OH;

R 6 is selected from H, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, C 1 -C 6 -alkenyl, and C 0 -C 6 -alkyl-C 3 -C 6 -cycloalkyl;

R 8 is selected from H and C 1 -C 6 -alkyl;

R 9 is selected from H and C 1 -C 6 -alkyl;

R 10 is selected from H and C 1 -C 6 -alkyl;

R a is, at each occurrence, independently selected from H, —OH, halo, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, —O—C 1 -C 6 -alkyl, and C 1 -C 6 -alkyl-OH;

R b is, at each occurrence, independently selected from H and C 1 -C 6 -alkyl;

R c is absent, H, C 1 -C 6 -alkyl, C 1 -C 6 -alkenyl, C 1 -C 6 -haloalkyl, or C 1 -C 6 -alkyl-OH;

m is 0, 1, 2, 3, or 4;

n is 0, 1, 2, 3, or 4; and

p is 0, 1, 2, 3, or 4.

In another aspect, provided herein is a pharmaceutical composition comprising at least one compound of Formula Ia, Formula I, Formula II, or Formula III, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier.

In another aspect, provided herein is a pharmaceutical composition comprising at least one disclosed compound, together with a pharmaceutically acceptable carrier. In another aspect, provided herein is a method of treating an HBV infection in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a compound of Formula Ia, Formula I, Formula II, or Formula III, or a pharmaceutically acceptable salt thereof.

In another aspect, provided herein is a method of inhibiting or reducing the formation or presence of HBV DNA-containing particles or HBV RNA-containing particles in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a compound of Formula Ia, Formula I, Formula II, or Formula III, or a pharmaceutically acceptable salt thereof.

In an embodiment, any of the methods provided herein can further comprising administering to the individual at least one additional therapeutic agent selected from the group consisting of an HBV polymerase inhibitor, immunomodulatory agents, interferon, viral entry inhibitor, viral maturation inhibitor, capsid assembly modulator, reverse transcriptase inhibitor, a cyclophilin/TNF inhibitor, a TLR-agonist, an HBV vaccine, and any combination thereof.

›BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the X-ray crystal structure of the iodo-benzoic acid analogue of Intermediate 18, also referred to as compound 215.

›DETAILED DESCRIPTION

Provided herein are compounds, e.g., the compounds of Formula Ia, Formula I, Formula II, or Formula III, or pharmaceutically acceptable salts thereof, that are useful in the treatment and prevention of HBV infection in subject.

Without being bound to any particular mechanism of action, these compounds are believed to modulate or disrupt HBV assembly and other HBV core protein functions necessary for HBV replication or the generation of infectious particles. In addition, or alternatively, the compounds may disrupt HBV capsid assembly to induce production of defective viral particles with greatly reduced infectivity or replication capacity. In other words, the compounds provided herein may act as capsid assembly modulators by modulating (e.g., accelerating, delaying, inhibiting, disprupting or reducing) normal viral capsid assembly or disassembly, binding capsids, and/or altering metabolism of cellular polyproteins and precursors. The modulation may occur when the capsid protein is mature, or during viral infectivity. The disclosed compounds can be used in methods of modulating the activity or properties of HBV cccDNA, or the generation or release of HBV RNA particles from within an infected cell.

In one embodiment, the compounds described herein are suitable for monotherapy and are effective against natural or native HBV strains and against HBV strains resistant to currently known drugs. In another embodiment, the compounds described herein are suitable for use in combination therapy.

›Definitions · 1 of 19

Listed below are definitions of various terms used to describe this invention. These definitions apply to the terms as they are used throughout this specification and claims, unless otherwise limited in specific instances, either individually or as part of a larger group.

Unless defined otherwise, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Generally, the nomenclature used herein and the laboratory procedures in cell culture, molecular genetics, organic chemistry, and peptide chemistry are those well-known and commonly employed in the art.

As used herein, the articles “a” and “an” refer to one or to more than one (i.e. to at least one) of the grammatical object of the article. By way of example, “an element” means one element or more than one element. Furthermore, use of the term “including” as well as other forms, such as “include”, “includes,” and “included,” is not limiting.

As used herein, the term “about” will be understood by persons of ordinary skill in the art and will vary to some extent on the context in which it is used. As used herein when referring to a measurable value such as an amount, a temporal duration, and the like, the term “about” is meant to encompass variations of ±20% or ±10%, including ±5%, ±1%, and ±0.1% from the specified value, as such variations are appropriate to perform the disclosed methods.

As used herein, the term “capsid assembly modulator” refers to a compound that disrupts or accelerates or inhibits or hinders or delays or reduces or modifies normal capsid assembly (e.g., during maturation) or normal capsid disassembly (e.g., during infectivity) or perturbs capsid stability, thereby inducing aberrant capsid morphology and function. In one embodiment, a capsid assembly modulator accelerates capsid assembly or disassembly, thereby inducing aberrant capsid morphology. In another embodiment, a capsid assembly modulator interacts (e.g. binds at an active site, binds at an allosteric site, modifies or hinders folding and the like) with the major capsid assembly protein (CA), thereby disrupting capsid assembly or disassembly. In yet another embodiment, a capsid assembly modulator causes a perturbation in structure or function of CA (e.g., ability of CA to assemble, disassemble, bind to a substrate, fold into a suitable conformation, or the like), which attenuates viral infectivity or is lethal to the virus.

As used herein, the term “treatment” or “treating” is defined as the application or administration of a therapeutic agent, i.e., a disclosed compound (alone or in combination with another pharmaceutical agent), to a patient, or application or administration of a therapeutic agent to an isolated tissue or cell line from a patient (e.g., for diagnosis or ex vivo applications), who has an HBV infection, a symptom of HBV infection or the potential to develop an HBV infection, with the purpose to cure, heal, alleviate, relieve, alter, remedy, ameliorate, improve or affect the HBV infection, the symptoms of HBV infection, or the potential to develop an HBV infection. Such treatments may be specifically tailored or modified, based on knowledge obtained from the field of pharmacogenomics.

As used herein, the term “prevent” or “prevention” means no disorder or disease development if none had occurred, or no further disorder or disease development if there had already been development of the disorder or disease. Also considered is the ability of one to prevent some or all of the symptoms associated with the disorder or disease.

As used herein, the term “patient,” “individual” or “subject” refers to a human or a non-human mammal. Non-human mammals include, for example, livestock and pets, such as ovine, bovine, porcine, canine, feline and murine mammals. Preferably, the patient, subject, or individual is human.

As used herein, the terms “effective amount,” “pharmaceutically effective amount,” and “therapeutically effective amount” refer to a nontoxic but sufficient amount of an agent to provide the desired biological result. That result may be reduction or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. An appropriate therapeutic amount in any individual case may be determined by one of ordinary skill in the art using routine experimentation.

As used herein, the term “pharmaceutically acceptable” refers to a material, such as a carrier or diluent, which does not abrogate the biological activity or properties of the compound, and is relatively non-toxic, i.e., the material may be administered to an individual without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.

As used herein, the term “pharmaceutically acceptable salt” refers to derivatives of the disclosed compounds wherein the parent compound is modified by converting an existing acid or base moiety to its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts of the present invention include the conventional non-toxic salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418 and Journal of Pharmaceutical Science, 66, 2 (1977), each of which is incorporated herein by reference in its entirety.

›Definitions · 2 of 19

As used herein, the term “composition” or “pharmaceutical composition” refers to a mixture of at least one compound useful within the invention with a pharmaceutically acceptable carrier. The pharmaceutical composition facilitates administration of the compound to a patient or subject. Multiple techniques of administering a compound exist in the art including, but not limited to, intravenous, oral, aerosol, parenteral, ophthalmic, pulmonary, and topical administration.

As used herein, the term “pharmaceutically acceptable carrier” means a pharmaceutically acceptable material, composition or carrier, such as a liquid or solid filler, stabilizer, dispersing agent, suspending agent, diluent, excipient, thickening agent, solvent or encapsulating material, involved in carrying or transporting a compound useful within the invention within or to the patient such that it may perform its intended function. Typically, such constructs are carried or transported from one organ, or portion of the body, to another organ, or portion of the body. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation, including the compound useful within the invention, and not injurious to the patient. Some examples of materials that may serve as pharmaceutically acceptable carriers include: sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol; polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; surface active agents; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol; phosphate buffer solutions; and other non-toxic compatible substances employed in pharmaceutical formulations.

As used herein, “pharmaceutically acceptable carrier” also includes any and all coatings, antibacterial and antifungal agents, and absorption delaying agents, and the like that are compatible with the activity of the compound useful within the invention, and are physiologically acceptable to the patient. Supplementary active compounds may also be incorporated into the compositions. The “pharmaceutically acceptable carrier” may further include a pharmaceutically acceptable salt of the compound useful within the invention. Other additional ingredients that may be included in the pharmaceutical compositions used in the practice of the invention are known in the art and described, for example in Remington's Pharmaceutical Sciences (Genaro, Ed., Mack Publishing Co., 1985, Easton, Pa.), which is incorporated herein by reference. As used herein, the term “alkyl,” by itself or as part of another substituent means, unless otherwise stated, a straight or branched chain hydrocarbon having the number of carbon atoms designated (i.e., C 0 -C 6 -alkyl means null or an alkyl having one to six carbon atoms) and includes straight and branched chains. Examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, neopentyl, and hexyl. Other examples of C 1 -C 6 -alkyl include ethyl, methyl, isopropyl, isobutyl, n-pentyl, and n-hexyl.

As used herein, the term “alkenyl,” denotes a monovalent group derived from a hydrocarbon moiety containing at least two carbon atoms and at least one carbon-carbon double bond. The double bond may or may not be the point of attachment to another group. Alkenyl groups (e.g., C 2 -C 8 -alkenyl) include, but are not limited to, for example, ethenyl, propenyl, prop-1-en-2-yl, butenyl, 1-methyl-2-buten-1-yl, heptenyl, octenyl and the like.

As used herein, the term “halo” or “halogen” alone or as part of another substituent means, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom, preferably, fluorine, chlorine, or bromine, more preferably, fluorine or chlorine.

As used herein, the term “haloalkyl” refers to alkl radicals wherein any one or more of the alkyl carbon atoms is substituted with halo as defined above. Haloalkyl embraces monohaloalkyl, dihaloalkyl, and polyhaloalkyl radicals. The term “haloalkyl” includes, but is not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, and pentafluoroethyl.

As used herein, the term “cycloalkyl” refers to a mono cyclic or polycyclic non-aromatic radical, wherein each of the atoms forming the ring (i.e., skeletal atoms) is a carbon atom. In one embodiment, the cycloalkyl group is saturated or partially unsaturated. In another embodiment, the cycloalkyl group is fused with an aromatic ring. Cycloalkyl groups include groups having 3 to 10 ring atoms (C 3 -C 10 -cycloalkyl), groups having 3 to 8 ring atoms (C 3 -C 8 -cycloalkyl), groups having 3 to 7 ring atoms (C 3 -C 7 -cycloalkyl), and groups having 3 to 6 ring atoms (C 3 -C 6 -cycloalkyl). Monocyclic cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Dicyclic cycloalkyls include, but are not limited to, tetrahydronaphthyl, indanyl, and tetrahydropentalene. Polycyclic cycloalkyls include adamantine and norbornane. The term cycloalkyl includes unsaturated nonaromatic cyclic groups, which contain at least one carbon carbon double bond or one carbon carbon triple bond.

As used herein, the term “heterocycloalkyl” or “heterocyclyl” refers to a heteroalicyclic group containing one to four ring heteroatoms each selected from O, S, and N. In one embodiment, each heterocyclyl group has from 3 to 10 atoms in its ring system, with the proviso that the ring of said group does not contain two adjacent O or S atoms. Heterocyclyl substituents may be alternatively defined by the number of carbon atoms, e.g., C 2 -C 8 -heterocyclyl indicates the number of carbon atoms contained in the heterocyclic group without including the number of heteroatoms. For example, a C 2 -C 8 -heterocyclyl will include an additional one to four heteroatoms. Preferably, the heterocyclyl group has less than three heteroatoms. More preferably, the heterocyclyl group has one to two heteroatoms. In another embodiment, the heterocycloalkyl group is fused with an aromatic ring. In one embodiment, the nitrogen and sulfur heteroatoms may be optionally oxidized, and the nitrogen atom may be optionally quaternized. The heterocyclic system may be attached, unless otherwise stated, at any heteroatom or carbon atom that affords a stable structure.

›Definitions · 3 of 19

An example of a 3-membered heterocyclyl group includes, and is not limited to, aziridine. Examples of 4-membered heterocycloalkyl groups include, and are not limited to, azetidine and a beta lactam. Examples of 5-membered heterocyclyl groups include, and are not limited to, pyrrolidine, oxazolidine and thiazolidinedione. Examples of 6-membered heterocycloalkyl groups include, and are not limited to, piperidine, morpholine, and piperazine.

Other non-limiting examples of heterocyclyl groups include monocyclic groups such as aziridine, oxirane, thiirane, azetidine, oxetane, thietane, pyrrolidine, pyrroline, pyrazolidine, imidazoline, dioxolane, sulfolane, 2,3-dihydrofuran, 2,5-dihydrofuran, tetrahydrofuran, thiophane, piperidine, 1,2,3,6-tetrahydropyridine, 1,4-dihydropyridine, piperazine, morpholine, thiomorpholine, pyran, 2,3-dihydropyran, tetrahydropyran, 1,4-dioxane, 1,3-dioxane, homopiperazine, homopiperidine, 1,3-dioxepane, 4,7-dihydro-1,3-dioxepin, and hexamethyleneoxide.

As used herein, the term “aromatic” refers to a carbocycle or heterocycle with one or more polyunsaturated rings and having aromatic character, i.e., having (4n+2) delocalized π (pi) electrons, where n is an integer.

As used herein, the term “aryl,” employed alone or in combination with other terms, means, unless otherwise stated, a carbocyclic aromatic system containing one or more rings (typically one, two, or three rings), wherein such rings may be attached together in a pendent manner, such as a biphenyl, or may be fused, such as naphthalene. Examples of aryl groups include phenyl, anthracyl, and naphthyl. Preferred examples are phenyl (e.g., C 6 -aryl) and biphenyl (e.g., C 12 -aryl). In some embodiments, aryl groups have from six to sixteen carbon atoms. In some embodiments, aryl groups have from six to twelve carbon atoms (e.g., C 6 -C 12 -aryl). In some embodiments, aryl groups have six carbon atoms (e.g., C 6 -aryl).

As used herein, the term “heteroaryl” or “heteroaromatic” refers to a heterocycle having aromatic character. Heteroaryl substituents may be defined by the number of carbon atoms, e.g., C 1 -C 9 -heteroaryl indicates the number of carbon atoms contained in the heteroaryl group without including the number of heteroatoms. For example, a C 1 -C 9 -heteroaryl will include an additional one to four heteroatoms. Preferably, the heteroaryl group has less than three heteroatoms. More preferably, the heteroaryl group has one to two heteroatoms. A polycyclic heteroaryl may include one or more rings that are partially saturated. Non-limiting examples of heteroaryls include pyridyl, pyrazinyl, pyrimidinyl (including, e.g., 2- and 4-pyrimidinyl), pyridazinyl, thienyl, furyl, pyrrolyl (including, e.g., 2-pyrrolyl), imidazolyl, thiazolyl, oxazolyl, pyrazolyl (including, e.g., 3- and 5-pyrazolyl), isothiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,3,4-triazolyl, tetrazolyl, 1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl, 1,3,4-thiadiazolyl and 1,3,4-oxadiazolyl.

Non-limiting examples of polycyclic heterocycles and heteroaryls include indolyl (including, e.g., 3-, 4-, 5-, 6- and 7-indolyl), indolinyl, quinolyl, tetrahydroquinolyl, isoquinolyl (including, e.g., 1- and 5-isoquinolyl), 1,2,3,4-tetrahydroisoquinolyl, cinnolinyl, quinoxalinyl (including, e.g., 2- and 5-quinoxalinyl), quinazolinyl, phthalazinyl, 1,8-naphthyridinyl, 1,4-benzodioxanyl, coumarin, dihydrocoumarin, 1,5-naphthyridinyl, benzofuryl (including, e.g., 3-, 4-, 5-, 6- and 7-benzofuryl), 2,3-dihydrobenzofuryl, 1,2-benzisoxazolyl, benzothienyl (including, e.g., 3-, 4-, 5-, 6-, and 7-benzothienyl), benzoxazolyl, benzothiazolyl (including, e.g., 2-benzothiazolyl and 5-benzothiazolyl), purinyl, benzimidazolyl (including, e.g., 2-benzimidazolyl), benzotriazolyl, thioxanthinyl, carbazolyl, carbolinyl, acridinyl, pyrrolizidinyl, and quinolizidinyl.

As used herein, the term “substituted” means that an atom or group of atoms has replaced hydrogen as the substituent attached to another group.

As used herein, the terminology “selected from . . . ” (e.g., “R 4 is selected from A, B and C”) is understood to be equivalent to the terminology “selected from the group consisting of . . . ” (e.g., “R 4 is selected from the group consisting of A, B and C”).

Compounds

Provided herein are compounds having the structure of Formula Ia:

or a pharmaceutically acceptable salt thereof.

A may be N or C(H). In embodiments, A is N. In embodiments, A is C(H).

R 1 may be H, C 1 -C 6 -alkyl, C 1 -C 6 -alkenyl, or C 1 -C 6 -alkyl-OH. In embodiments, R 1 is H. In embodiments, R 1 is C 1 -C 6 -alkyl. In embodiments, R 1 is C 1 -C 6 -alkenyl. In embodiments, R 1 is C 1 -C 6 -alkyl-OH.

In embodiments, there may be 0, 1, 2, 3, or 4 R 2 substituents: m is 0, 1, 2, 3, or 4. Each R 2 may be independently selected from —OH, halo, C 1 -C 6 -alkyl, C 1 -C 6 -alkylene, C 0 -C 6 -alkyl-C 3 -C 6 -cycloalkyl, C 0 -C 6 -alkyl-C 2 -C 6 -heterocycloalkyl, C 0 -C 6 -alkyl-OR 6 , C 0 -C 6 -alkyl-N(R 7 ) 2 , C 0 -C 6 -alkyl-S(O)R 8 , C 0 -C 6 -alkyl-S(O) 2 R 8 , C 0 -C 6 -alkyl-C(O)OR 9 , C 0 -C 6 -alkyl-OC(O)R 9 , C 0 -C 6 -alkyl-OC(O)OR 9 , C 0 -C 6 -alkyl-OC(O)N(R 7 ) 2 , or C 0 -C 6 -alkyl-C(O)N(R 7 ) 2 . In certain embodiments, m is 0 and there is no R 2 substitution. In certain embodiments, m is 1 and there is one R 2 substitution. In certain embodiments, m is 2 and there are two R 2 substitutions. In certain embodiments, m is 3 and there are three R 2 substitutions. In certain embodiments, m is 4 and there are four R 2 substitutions. In embodiments, there may be 0, 1, 2, 3, or 4 R 3 substituents: n is 0, 1, 2, 3, or 4. In certain embodiments, n is 0 and there is no R 3 substitution. In certain embodiments, n is 1 and there is one R 3 substitution. In certain embodiments, n is 2 and there are two R 3 substitutions. In certain embodiments, n is 3 and there are three R 3 substitutions. In certain embodiments, n is 4 and there are four R 3 substitutions.

In certain embodiments, R 2 may be C 1 -C 6 -alkyl optionally substituted with 1, 2, or 3 halo groups. In certain embodiments, R 2 may be C 0 -C 6 -alkyl-OR 6 , wherein R 6 is C 1 -C 6 -haloalkyl. In certain embodiments, R 2 may be (CH 2 ) 1-2 —O—C 1 -C 3 -alkyl, wherein C 1 -C 3 -alkyl is optionally substituted with 1, 2, or 3 halo groups. In certain embodiments, m is 1 or 2.

›Definitions · 4 of 19

Each R 3 may be independently selected from —OH, halo, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, —O—C 1 -C 6 -alkyl, and C 1 -C 6 -alkyl-OH. In certain embodiments, at least one R 3 is —OH. In certain embodiments, at least one R 3 is halo. In certain embodiments, at least one R 3 is C 1 -C 6 -alkyl. In certain embodiments, at least one R 3 is C 1 -C 6 -haloalkyl. In certain embodiments, at least one R 3 is —O—C 1 -C 6 -alkyl. In certain embodiments, at least one R 3 is C 1 -C 6 -alkyl-OH.

R 4 is selected from (CR a R b ) p —C 1 -C 9 -heteroaryl, (CR a R b ) p —C 6 -C 12 -aryl, (CR a R b ) p —C 3 -C 7 -cycloalkyl, and (CR a R b ) p —C 2 -C 6 -heterocycloalkyl, wherein heteroaryl, aryl, cycloalkyl, and heterocycloalkyl are optionally substituted with 1, 2, 3, or 4 groups, each independently selected from —OH, halo, —CN, —SF 5 , C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, —O—C 1 -C 6 -alkyl, and C 1 -C 6 -alkyl-OH. In certain embodiments, R 4 is (CR a R b ) p —C 1 -C 9 -heteroaryl optionally substituted with 1, 2, 3, or 4 groups, each independently selected from —OH, halo, —CN, —SF 5 , C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, —O—C 1 -C 6 -alkyl, and C 1 -C 6 -alkyl-OH. In certain embodiments, R 4 is (CR a R b ) p —C 6 -C 12 -aryl optionally substituted with 1, 2, 3, or 4 groups, each independently selected from —OH, halo, —CN, —SF 5 , C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, —O—C 1 -C 6 -alkyl, and C 1 -C 6 -alkyl-OH. In certain embodiments, R 4 is (CR a R b ) p —C 3 -C 7 -cycloalkyl optionally substituted with 1, 2, 3, or 4 groups, each independently selected from —OH, halo, —CN, —SF 5 , C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, —O—C 1 -C 6 -alkyl, and C 1 -C 6 -alkyl-OH. In certain embodiments, R 4 is (CR a R b ) p —C 2 -C 6 -heterocycloalkyl optionally substituted with 1, 2, 3, or 4 groups, each independently selected from —OH, halo, —CN, —SF 5 , C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, —O—C 1 -C 6 -alkyl, and C 1 -C 6 -alkyl-OH. In certain embodiments, R 4 is phenyl or pyridyl, wherein said phenyl or pyridyl is optionally substituted with 1, 2, 3, or 4 groups, each independently selected from halo, —CN, C 1 -C 6 -alkyl and C 1 -C 6 -haloalkyl. In a particular embodiment, R 4 is phenyl, wherein the phenyl is substituted with 1, 2, 3, or 4 groups, each independently selected from halo, —CN, C 1 -C 6 -alkyl and C 1 -C 6 -haloalkyl. In another particular embodiment, R 4 is pyridyl, wherein the pyridyl is substituted with 1, 2, 3, or 4 groups, each independently selected from halo, —CN, C 1 -C 6 -alkyl and C 1 -C 6 -haloalkyl.

R 5 may be selected from H, C 1 -C 6 -alkyl, and C 1 -C 6 -alkyl-OH. In a particular embodiment, R 5 is H.

R 6 may be selected from H, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, C 1 -C 6 -alkenyl, and C 0 -C 6 -alkyl-C 3 -C 6 -cycloalkyl. In a particular embodiment, R 6 is selected from H, C 1 -C 6 -alkyl, and C 1 -C 6 -haloalkyl.

R 7 may be independently selected from H, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, C 1 -C 6 -alkyl-OR 10 , —C(O)C 1 -C 6 -alkyl, —C(O)C 1 -C 6 -haloalkyl, —C(O)C 1 -C 6 -alkyl-OR 10 , —C(O)C 1 -C 6 -alkyl-CN, —C(O)C 3 -C 7 -cycloalkyl, —C(O)O—C 1 -C 6 -alkyl, —C(O)O—C 1 -C 6 -haloalkyl, —C(O)O—C 3 -C 7 -cycloalkyl, —C(O)N(R 10 ) 2 , —S(O) 2 C 1 -C 6 -alkyl, —S(O) 2 C 1 -C 6 -haloalkyl and —S(O) 2 C 3 -C 7 -cycloalkyl;

or wherein two R 7 groups together with the N to which they are attached form a C 2 -C 6 heterocycle, wherein the C 2 -C 6 heterocycle is further independently and optionally substituted with 1 or 2 oxo or halogen substituents. In an embodiment, R 7 is, at each occurrence, independently selected from H and C 1 -C 6 -alkyl. In a further embodiment, R 7 is, at each occurrence, independently selected from H, C 1 -C 6 -haloalkyl, C 1 -C 6 -alkyl-OR 10 , —C(O)C 1 -C 6 -alkyl, —C(O)C 1 -C 6 -haloalkyl, —C(O)C 1 -C 6 -alkyl-OR 10 , —C(O)C 1 -C 6 -alkyl-CN, —C(O)C 3 -C 7 -cycloalkyl, —C(O)O—C 1 -C 6 -alkyl, —C(O)O—C 1 -C 6 -haloalkyl, —C(O)O—C 3 -C 7 -cycloalkyl, —C(O)N(R 10 ) 2 , —S(O) 2 C 1 -C 6 -alkyl, —S(O) 2 C 1 -C 6 -haloalkyl or —S(O) 2 C 3 -C 7 -cycloalkyl. In an embodiment, R 7 is, at each occurrence, independently selected from C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, —C(O)C 1 -C 6 -alkyl, —C(O)C 1 -C 6 -haloalkyl, —C(O)C 1 -C 6 -alkyl-OR 10 , —C(O)C 1 -C 6 -alkyl-CN, —C(O)C 3 -C 7 -cycloalkyl, —C(O)O—C 1 -C 6 -alkyl, —C(O)O—C 1 -C 6 -haloalkyl, —C(O)O—C 3 -C 7 -cycloalkyl, —C(O)N(R 10 ) 2 , —S(O) 2 C 1 -C 6 -alkyl, —S(O) 2 C 1 -C 6 -haloalkyl or —S(O) 2 C 3 -C 7 -cycloalkyl.

R 8 may be selected from H and C 1 -C 6 -alkyl.

R 9 may be selected from H and C 1 -C 6 -alkyl.

R 10 may be selected from H and C 1 -C 6 -alkyl.

R a may be independently selected from H, —OH, halo, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, —O—C 1 -C 6 -alkyl, and C 1 -C 6 -alkyl-OH.

R b may be independently selected from H and C 1 -C 6 -alkyl.

m may be 0, 1, 2, 3, or 4.

n may be 0, 1, 2, 3, or 4.

p may be 0, 1, 2, 3, or 4.

In another aspect, provided herein are compounds having the structure of Formula I:

or a pharmaceutically acceptable salt thereof.

In embodiments, there may be 0, 1, 2, 3, or 4 R 2 substituents: m is 0, 1, 2, 3, or 4. Each R 2 may be independently selected from —OH, halo, C 1 -C 6 -alkyl, C 1 -C 6 -alkylene, C 0 -C 6 -alkyl-C 3 -C 6 -cycloalkyl, C 0 -C 6 -alkyl-C 2 -C 6 -heterocycloalkyl, C 0 -C 6 -alkyl-OR 6 , C 0 -C 6 -alkyl-N(R 7 ) 2 , C 0 -C 6 -alkyl-SR 8 , C 0 -C 6 -alkyl-S(O)R 8 , C 0 -C 6 -alkyl-S(O) 2 R 8 , C 0 -C 6 -alkyl-C(O)OR 9 , C 0 -C 6 -alkyl-OC(O)R 9 , C 0 -C 6 -alkyl-OC(O)OR 9 , C 0 -C 6 -alkyl-OC(O)N(R 7 ) 2 , or C 0 -C 6 -alkyl-C(O)N(R 7 ) 2 . In certain embodiments, m is 0 and there is no R 2 substitution. In certain embodiments, m is 1 and there is one R 2 substitution. In certain embodiments, m is 2 and there are two R 2 substitutions. In certain embodiments, m is 3 and there are three R 2 substitutions. In certain embodiments, m is 4 and there are four R 2 substitutions. In embodiments, there may be 0, 1, 2, 3, or 4 R 3 substituents: n is 0, 1, 2, 3, or 4. In certain embodiments, n is 0 and there is no R 3 substitution. In certain embodiments, n is 1 and there is one R 3 substitution. In certain embodiments, n is 2 and there are two R 3 substitutions. In certain embodiments, n is 3 and there are three R 3 substitutions. In certain embodiments, n is 4 and there are four R 3 substitutions.

›Definitions · 5 of 19

R 5 may be selected from H, C 1 -C 6 -alkyl, and C 1 -C 6 -alkyl-OH. In a particular embodiment, R 5 is H.

R 7 may be independently selected from H, C 1 -C 6 -alkyl, and C 1 -C 6 -alkyl-OH. In a particular embodiment, R 7 is, at each occurrence, independently selected from H, and C 1 -C 6 -alkyl.

R 8 may be selected from H and C 1 -C 6 -alkyl.

R 9 may be selected from H and C 1 -C 6 -alkyl.

R a may be independently selected from H, —OH, halo, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, —O—C 1 -C 6 -alkyl, and C 1 -C 6 -alkyl-OH.

R b may be independently selected from H and C 1 -C 6 -alkyl.

m may be 0, 1, 2, 3, or 4.

n may be 0, 1, 2, 3, or 4.

p may be 0, 1, 2, 3, or 4.

In another aspect, provided herein are compounds having the structure of Formula III:

or a pharmaceutically acceptable salt thereof.

may be a single bond or a double bond. In embodiments, is a single bond. In embodiments, is a double bond.

X is N—R c .

In embodiments, there may be 0, 1, 2, 3, or 4 R 2 substituents: m is 0, 1, 2, 3, or 4. Each R 2 may be independently selected from —OH, halo, C 1 -C 6 -alkyl, C 1 -C 6 -alkylene, C 0 -C 6 -alkyl-C 3 -C 6 -cycloalkyl, C 0 -C 6 -alkyl-C 2 -C 6 -heterocycloalkyl, C 0 -C 6 -alkyl-OR 6 , C 0 -C 6 -alkyl-N(R 7 ) 2 , C 0 -C 6 -alkyl-SR 8 , C 0 -C 6 -alkyl-S(O)R 8 , C 0 -C 6 -alkyl-S(O) 2 R 8 , C 0 -C 6 -alkyl-C(O)OR 9 , C 0 -C 6 -alkyl-OC(O)R 9 , C 0 -C 6 -alkyl-OC(O)OR 9 , C 0 -C 6 -alkyl-OC(O)N(R 7 ) 2 , or C 0 -C 6 -alkyl-C(O)N(R 7 ) 2 . In certain embodiments, m is 0 and there is no R 2 substitution. In certain embodiments, m is 1 and there is one R 2 substitution. In certain embodiments, m is 2 and there are two R 2 substitutions. In certain embodiments, m is 3 and there are three R 2 substitutions. In certain embodiments, m is 4 and there are four R 2 substitutions. In embodiments, there may be 0, 1, 2, 3, or 4 R 3 substituents: n is 0, 1, 2, 3, or 4. In certain embodiments, n is 0 and there is no R 3 substitution. In certain embodiments, n is 1 and there is one R 3 substitution. In certain embodiments, n is 2 and there are two R 3 substitutions. In certain embodiments, n is 3 and there are three R 3 substitutions. In certain embodiments, n is 4 and there are four R 3 substitutions.

›Definitions · 6 of 19

R 5 may be selected from H, C 1 -C 6 -alkyl, and C 1 -C 6 -alkyl-OH. In a particular embodiment, R 5 is H.

R 7 may be independently selected from H, C 1 -C 6 -alkyl, and C 1 -C 6 -alkyl-OH. In a particular embodiment, R 7 is, at each occurrence, independently selected from H, and C 1 -C 6 -alkyl.

R 8 may be selected from H and C 1 -C 6 -alkyl.

R 9 may be selected from H and C 1 -C 6 -alkyl.

R a may be independently selected from H, —OH, halo, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, —O—C 1 -C 6 -alkyl, and C 1 -C 6 -alkyl-OH.

R b may be independently selected from H and C 1 -C 6 -alkyl.

R c may be selected from absent, H, C 1 -C 6 -alkyl, C 1 -C 6 -alkenyl, C 1 -C 6 -haloalkyl, or C 1 -C 6 -alkyl-OH.

m may be 0, 1, 2, 3, or 4.

n may be 0, 1, 2, 3, or 4.

p may be 0, 1, 2, 3, or 4.

In an embodiment of the compound of Formula III, n is 0, 1, or 2; and each R 3 is independently C 1 -C 6 -alkyl.

In another embodiment of the compound of Formula III, R 4 is phenyl, pyridinyl, or cyclohexyl, wherein R 4 is optionally substituted with 1, 2, or 3 groups, each independently selected from —F, —Br, —Cl, —I, —CN, —CH 3 , —CH 2 CH 3 , —CF 3 , —CHF 2 , and —SF 5 . In yet another embodiment of the compound of Formula III, R 1 is CH 3 ;

R 2 is selected from the group consisting of: H, C 1-4 haloalkyl, OH, C 1-4 alkyl, CH 2 OH, CH(OH)CH 3 , CH(OH)CH 2 CH 3 , CH(OH)cyclopropyl, and CH 2 OCH 2 CHF 2 ;

R 3 is H or CH 3 ;

R 4 is

R 5 is H;

R c is absent, H, C 1-4 alkyl, CH 2 CH═CH 2 , CH 3 CHF 2 , CH 2 CH 2 OH, CH 2 CH 2 CH 2 OH, or CH 2 CH(OH)CH 3 ;

m is 0, 1, or 2; and

n is 0 or 1.

In an embodiment of the compound of Formula Ia, R 1 is C 1 -C 6 -alkyl, or C 1 -C 6 -alkenyl.

In another embodiment of the compound of Formula Ia, R 1 is —CH 3 , —CH 2 CH 3 , —CH 2 CH 2 CH 3 , —CH 2 CH═CH 2 , or —CD 3 .

In an embodiment of the compound of Formula Ia, m is 1 or 2; and

each R 2 is independently selected from C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, C 0 -C 6 -alkyl-OR 6 ; C 1 -C 6 -alkyl-N(R 7 ) 2 , C 0 -C 6 -alkyl-S(O)R 8 , C 0 -C 6 -alkyl-S(O) 2 R 8 , C 0 -C 6 -alkyl-C(O)OR 9 , C 0 -C 6 -alkyl-OC(O)R 9 , C 0 -C 6 -alkyl-OC(O)OR 9 , C 0 -C 6 -alkyl-OC(O)N(R 7 ) 2 , and C 0 -C 6 -alkyl-C(O)N(R 7 ) 2 .

In an embodiment of the compound of Formula I, R 1 is C 1 -C 6 -alkyl, or C 1 -C 6 -alkenyl.

In another embodiment of the compound of Formula I, R 1 is —CH 3 , —CH 2 CH 3 , —CH 2 CH 2 CH 3 , —CH 2 CH═CH 2 , or —CD 3 .

In an embodiment of the compound of Formula I, m is 1 or 2; and

In an embodiment, the compound of Formula Ia has the structure of Formula II:

or a pharmaceutically acceptable salt thereof.

In an embodiment of the compound of Formula Ia or Formula II, R 2 is C 0 -C 6 -alkyl-OR 6 , C 0 -C 6 -alkyl-C(O)N(R 7 ) 2 and C 1 -C 6 -alkyl-N(R 7 ) 2 .

In an embodiment of the compound of Formula Ia or Formula II, R 2 is selected from the group consisting of —CH 2 OH, —CH 2 OCF 3 , —C(O)-3,3-difluoroazetidine, —C(O)-3,3-difluoropyrrolidine, —C(O)N(CH 3 )(CH 2 CHF 2 ), —C(O)N(CH 3 )(CH 2 CF 3 ), —C(O)N(H)(CH 2 CHF 2 ), —C(O)N(H)(CH 3 ), —C(O)N(H)(CH 2 CF 3 ), —CH 2 N(H)(C(O)CH 3 ), —CH 2 N(H)(C(O)CF 3 ), —CH 2 N(H)(C(O)OCH 3 ), —CH 2 N(H)(S(O) 2 CH 3 ), —CH 2 N(H)(S(O) 2 CF 3 ), —CH 2 -pyrrolidin-2-one, —CH 2 N(H)(C(O)CH 2 CH 3 ), —CH 2 N(H)(C(O)-cyclopropyl), —CH 2 N(H)(C(O)CH 2 CF 3 ), —CH 2 N(H)(C(O)CH(CH 3 ) 2 ), —CH 2 N(H)(C(O)C(CH 3 ) 3 ), —CH 2 N(H)(C(O)OCH 2 CH 3 ), —CH 2 N(H)(C(O)O-cyclopropyl), —CH 2 N(H)(C(O)N(CH 3 ) 2 ), —CH 2 N(H)(C(O)CH 2 CN), —CH 2 N(H)(C(O)CH 2 OH), —CH 2 N(H)(C(O)OCH 2 CF 3 ), —CH 2 N(H)(S(O) 2 CH 2 CH 3 ), CH 2 N(H)(S(O) 2 CH 2 CF 3 ) and —CH 2 N(H)(S(O) 2 -cyclopropyl).

›Definitions · 7 of 19

In an embodiment of the compound of Formula Ia or Formula II, R 2 is selected from the group consisting of —CH 3 , —CH 2 OH, —CH 2 F, —CH 2 OCH 3 , —CH 2 OCH 2 CH 3 , —CH 2 OCH 2 CH 2 CH 3 , —CH 2 OCH 2 -cyclopropyl, —CH 2 OCH 2 CHF 2 , —CH 2 OCH 2 CF 3 , —CH 2 OCH 2 CH═CH 2 , —CH 2 SCH 3 , —CH 2 S(O)CH 3 , —CH 2 —S(O) 2 CH 3 , —CH 2 OC(O)OCH 3 , —CH 2 OC(O)OCH(CH 3 ) 2 , —CH 2 OC(O)OC(CH 3 ) 3 , —CH 2 OC(O)OCH 2 CH 3 , —CH 2 OC(O)CH 3 , —CH 2 OC(O)C(CH 3 ) 3 , —C(O)OH, —C(O)OCH 3 , —CH 2 OC(O)NH 2 , —CH 2 OC(O)N(CH 3 ) 2 , —C(O)NH 2 , —C(O)NHCH 3 , —C(O)N(CH 3 ) 2 , and —CH 2 N(CH 3 ) 2 .

In an embodiment of the compound of Formula Ia or Formula II, R 2 is C 1 -C 6 -alkyl optionally substituted with 1, 2, or 3 halo groups. In an embodiment of the compound of Formula Ia or Formula II, R 2 is C 0 -C 6 -alkyl-OR 6 , wherein R 6 is C 1 -C 6 -haloalkyl. In certain embodiments, R 2 is (CH 2 ) 1-2 —O—C 1 -C 3 -alkyl, wherein C 1 -C 3 -alkyl is optionally substituted with 1, 2, or 3 halo groups. In certain embodiments, m is 1 or 2.

In an embodiment of the compound of Formula Ia or Formula II, n is 0, 1, or 2; and each R 3 is independently C 1 -C 6 -alkyl.

In an embodiment of the compound of Formula Ia or Formula II, each R 3 is independently C 1 -C 3 -alkyl. In a further embodiment of the compound of Formula I or Formula II, R 3 is independently —CH 3 .

In an embodiment of the compound of Formula Ia or Formula II, n is 1, and R 3 is in the following position:

In an embodiment of the compound of Formula Ia or Formula II, R 4 is (CR a R b ) p —C 1 -C 5 -heteroaryl, (CR a R b ) p —C 6 -aryl, or (CR a R b ) p —C 3 -C 7 -cycloalkyl, wherein heteroaryl, aryl, and cycloalkyl are optionally substituted with 1, 2, or 3 groups, each independently selected from —OH, halo, —CN, —SF 5 , C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, —O—C 1 -C 6 -alkyl, and C 1 -C 6 -alkyl-OH;

R a is H or C 1 -C 6 -alkyl;

R b is H or C 1 -C 6 -alkyl; and

p is 0 or 1.

In an embodiment of the compound of Formula I or Formula II, R 2 is selected from the group consisting of —CH 3 , —CH 2 OH, —CH 2 F, —CH 2 OCH 3 , —CH 2 OCH 2 CH 3 , —CH 2 OCH 2 CH 2 CH 3 , —CH 2 OCH 2 -cyclopropyl, —CH 2 OCH 2 CHF 2 , —CH 2 OCH 2 CF 3 , —CH 2 OCH 2 CH═CH 2 , —CH 2 SCH 3 , —CH 2 S(O)CH 3 , —CH 2 —S(O) 2 CH 3 , —CH 2 OC(O)OCH 3 , —CH 2 OC(O)OCH(CH 3 ) 2 , —CH 2 OC(O)OC(CH 3 ) 3 , —CH 2 OC(O)OCH 2 CH 3 , —CH 2 OC(O)CH 3 , —CH 2 OC(O)C(CH 3 ) 3 , —C(O)OH, —C(O)OCH 3 , —CH 2 OC(O)NH 2 , —CH 2 OC(O)N(CH 3 ) 2 , —C(O)NH 2 , —C(O)NHCH 3 ,

—C(O)N(CH 3 ) 2 , and —CH 2 N(CH 3 ) 2 . In an embodiment of the compound of Formula I or Formula II, n is 0, 1, or 2; and each R 3 is independently C 1 -C 6 -alkyl. In an embodiment of the compound of Formula I or Formula II, each R 3 is independently C 1 -C 3 -alkyl. In a further embodiment of the compound of Formula I or Formula II, R 3 is independently —CH 3 .

In another embodiment of the compound of Formula Ia or Formula II, R 4 is C 1 -C 5 -heteroaryl, C 6 -aryl, or C 3 -C 7 -cycloalkyl any of which is optionally substituted with 1, 2, or 3 groups, each independently selected from —OH, halo, —CN, —SF 5 , C 1 -C 6 -alkyl, and C 1 -C 6 -haloalkyl.

In an embodiment of the compound of Formula Ia or Formula II, R 4 is phenyl, pyridinyl, or cyclohexyl, any of which is optionally substituted with 1, 2, or 3 groups, each independently selected from —F, —Br, —Cl, —I, —CN, —CH 3 , —CH 2 CH 3 , —CF 3 , —CHF 2 , and —SF 5 .

In an embodiment of the compound of Formula Ia or Formula II, R 4 is selected from the group consisting of:

In an embodiment of the compound of Formula I or Formula II, R 4 is (CR a R b ) p —C 1 -C 5 -heteroaryl, (CR a R b ) p —C 6 -aryl, or (CR a R b ) p —C 3 -C 7 -cycloalkyl, wherein heteroaryl, aryl, and cycloalkyl are optionally substituted with 1, 2, or 3 groups, each independently selected from —OH, halo, —CN, —SF 5 , C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, —O—C 1 -C 6 -alkyl, and C 1 -C 6 -alkyl-OH;

R a is H or C 1 -C 6 -alkyl;

R b is H or C 1 -C 6 -alkyl; and

p is 0 or 1. In another embodiment of the compound of Formula I or Formula II, R 4 is C 1 -C 5 -heteroaryl, C 6 -aryl, or C 3 -C 7 -cycloalkyl, any of which is optionally substituted with 1, 2, or 3 groups, each independently selected from —OH, halo, —CN, —SF 5 , C 1 -C 6 -alkyl, and C 1 -C 6 -haloalkyl. In an embodiment of the compound of Formula I or Formula II, R 4 is phenyl, pyridinyl, or cyclohexyl, any of which is optionally substituted with 1, 2, or 3 groups, each independently selected from —F, —Br, —Cl, —I, —CN, —CH 3 , —CH 2 CH 3 , —CF 3 , —CHF 2 , and —SF 5 .

In an embodiment of the compound of Formula I or Formula II, R 4 is selected from the group consisting of:

In another embodiment of the compound of Formula Ia or Formula II, R 4 is

In another embodiment of the compound of Formula Ia or Formula II, R 5 is H or —CH 3 .

In an embodiment of the compound of Formula Ia or Formula II, R 5 is H or C 1 -C 6 -alkyl. In an embodiment of the compound of Formula I or Formula II, R 5 is H or C 1 -C 6 -alkyl. In another embodiment of the compound of Formula I or Formula II, R 5 is H or —CH 3 .

In another embodiment of the compound of Formula Ia,

A is N or C(H)

R 1 is C 1 -C 6 -alkyl;

R 2 is, independently selected from the group consisting of C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, C 0 -C 6 -alkyl-OR 6 , C 1 -C 6 -alkyl-N(R 7 ) 2 , C 0 -C 6 -alkyl-SR 8 , C 0 -C 6 -alkyl-S(O)R 8 , C 0 -C 6 -alkyl-S(O) 2 R 8 , C 0 -C 6 -alkyl-C(O)OR 9 , C 0 -C 6 -alkyl-OC(O)R 9 , C 0 -C 6 -alkyl-OC(O)OR 9 , C 0 -C 6 -alkyl-OC(O)N(R 7 ) 2 , and C 0 -C 6 -alkyl-C(O)N(R 7 ) 2 ;

R 3 is, at each occurrence, independently selected from C 1 -C 6 -alkyl;

R 4 is selected from (CR a R b ) p —C 1 -C 9 -heteroaryl and (CR a R b ) p —C 6 -C 12 -aryl, wherein the heteroaryl or aryl is optionally substituted with 1, 2, 3, or 4 groups, each independently selected from halo, —CN, —SF 5 , C 1 -C 6 -alkyl, and C 1 -C 6 -haloalkyl;

›Definitions · 8 of 19

R 5 is H or C 1 -C 6 -alkyl;

R 6 is selected from H, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, C 1 -C 6 -alkenyl, and C 0 -C 6 -alkyl-C 3 -C 6 -cycloalkyl;

R 7 is selected from H, C 1 -C 6 -alkyl, and C 1 -C 6 -alkyl-OH;

R 8 is selected from H and C 1 -C 6 -alkyl;

R 9 is selected from H and C 1 -C 6 -alkyl;

R a is, at each occurrence, independently selected from H, —OH, halo, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, —O—C 1 -C 6 -alkyl, and C 1 -C 6 -alkyl-OH;

R b is, at each occurrence, independently selected from H and C 1 -C 6 -alkyl;

m is 0, 1 or 2;

n is 0, 1 or 2; and

p is 0 or 1. In another embodiment of the compound of Formula Ia,

R 1 is C 1 -C 6 -alkyl;

R 2 is, at each occurrence, independently selected from —CH 2 OH, —CH 2 OCF 3 , —C(O)-3,3-difluoroazetidine, —C(O)-3,3-difluoropyrrolidine, —C(O)N(CH 3 )(CH 2 CHF 2 ), —C(O)N(CH 3 )(CH 2 CF 3 ), —C(O)N(H)(CH 2 CHF 2 ), —C(O)N(H)(CH 3 ), —C(O)N(H)(CH 2 CF 3 ), —CH 2 N(H)(C(O)CH 3 ), —CH 2 N(H)(C(O)CF 3 ), —CH 2 N(H)(C(O)OCH 3 ), —CH 2 N(H)(S(O) 2 CH 3 ), —CH 2 N(H)(S(O) 2 CF 3 ), —CH 2 -pyrrolidin-2-one, —CH 2 N(H)(C(O)CH 2 CH 3 ), —CH 2 N(H)(C(O)-cyclopropyl), —CH 2 N(H)(C(O)CH 2 CF 3 ), —CH 2 N(H)(C(O)CH(CH 3 ) 2 ), —CH 2 N(H)(C(O)C(CH 3 ) 3 ), —CH 2 N(H)(C(O)OCH 2 CH 3 ), —CH 2 N(H)(C(O)O-cyclopropyl), —CH 2 N(H)(C(O)N(CH 3 ) 2 ), —CH 2 N(H)(C(O)CH 2 CN), —CH 2 N(H)(C(O)CH 2 OH), —CH 2 N(H)(C(O)OCH 2 CF 3 ), —CH 2 N(H)(S(O) 2 CH 2 CH 3 ), —CH 2 N(H)(S(O) 2 CH 2 CF 3 ) and —CH 2 N(H)(S(O) 2 -cyclopropyl);

R 3 is, at each occurrence, independently selected from C 1 -C 6 -alkyl;

R 5 is H;

m is 0, 1 or 2;

n is 0, 1 or 2; and

p is 0.

In further embodiment of the compound of Formula Ia,

R 1 is C 1 -C 6 -alkyl;

R 2 is, at each occurrence, independently selected from —CH 3 , —CH 2 OH, —CH 2 F, —CH 2 OCH 3 , —CH 2 OCH 2 CH 3 , —CH 2 OCH 2 CH 2 CH 3 , —CH 2 OCH 2 -cyclopropyl, —CH 2 OCH 2 CHF 2 , —CH 2 OCH 2 CF 3 , —CH 2 OCH 2 CH═CH 2 , —CH 2 SCH 3 , —CH 2 S(O)CH 3 , —CH 2 —S(O) 2 CH 3 , —CH 2 OC(O)OCH 3 , —CH 2 OC(O)OCH(CH 3 ) 2 , —CH 2 OC(O)OC(CH 3 ) 3 , —CH 2 OC(O)OCH 2 CH 3 , —CH 2 OC(O)CH 3 , —CH 2 OC(O)C(CH 3 ) 3 , —C(O)OH, —C(O)OCH 3 , —CH 2 OC(O)NH 2 , —CH 2 OC(O)N(CH 3 ) 2 , —C(O)NH 2 , —C(O)NHCH 3 , —C(O)N(CH 3 ) 2 , and —CH 2 N(CH 3 ) 2 ;

R 3 is, at each occurrence, independently selected from C 1 -C 6 -alkyl;

R 5 is H;

m is 0, 1 or 2;

n is 0, 1 or 2; and

p is 0.

In another embodiment of the compound of Formula I,

R 1 is C 1 -C 6 -alkyl;

R 3 is, at each occurrence, independently selected from C 1 -C 6 -alkyl;

R 5 is H;

m is 0, 1 or 2;

n is 0, 1 or 2; and

p is 0.

In a particular embodiment, R 1 is methyl and R 4 is 3-chloro-4-fluorophenyl.

In another particular embodiment, R 1 is methyl, R 2 is —CH 2 OH and m is 1.

In yet another particular embodiment, R 1 is methyl, R 2 is —CH 2 F and m is 1.

Provided herein are compounds according to the following embodiments:

In a particular embodiment of Formula I, R 1 is C 1 -C 6 -alkyl, R 2 is —CH 3 , R 4 is phenyl, wherein the phenyl is substituted with at least one halogen, R 5 is H, m is 1 and n is 0.

In another particular embodiment of Formula I, R 1 is C 1 -C 6 -alkyl, R 2 is —CH 3 , R 4 is phenyl, wherein the phenyl is substituted with at least one halogen, R 5 is H, m is 2 and n is 0.

In another particular embodiment of Formula I, R 1 is C 1 -C 6 -alkyl, R 2 is —CH 2 F, R 4 is phenyl or pyridyl, wherein the phenyl or pyridyl is substituted with 1-3 groups independently selected from halo, —CN, —SF 5 , C 1 -C 6 -alkyl, and C 1 -C 6 -haloalkyl, R 5 is H, and n is 0.

In another particular embodiment of Formula Ia, R 1 is C 1 -C 6 -alkyl, R 2 is —CH 2 OCH 2 CHF 2 , R 4 is phenyl or pyridyl, wherein the phenyl or pyridyl is substituted with 1-3 groups independently selected from halo, —CN, —SF 5 , C 1 -C 6 -alkyl, and C 1 -C 6 -haloalkyl, R 5 is H, n is 1, and R 3 is C 1 -C 6 -alkyl.

In another particular embodiment of Formula I, R 1 is C 1 -C 6 -alkyl; R 2 is C 1 -C 6 -alkyl or C 0 -C 6 -alkyl-OR 6 , wherein alkyl is substituted with halo, and R 6 is H or C 1 -C 6 -haloalkyl; R 3 is C 1 -C 6 -alkyl; R 4 is phenyl substituted with 1 or 2 groups, each independently selected from halo and —CN; R 5 is H; m is 1; and n is 1.

In another particular embodiment of Formula I, R 1 is methyl; R 2 is —CH 2 F or CH 2 —O—CH 2 CHF 2 ; R 3 is methyl; R 4 is phenyl substituted with 1 or 2 groups, each independently selected from F and —CN; R 5 is H; m is 1; and n is 1.

In a particular embodiment of Formula II, R 1 is C 1 -C 6 -alkyl, R 2 is —CH 2 OH, R 4 is phenyl or pyridyl, wherein the phenyl or pyridyl is substituted with 1-3 groups independently selected from halo, —CN, —SF 5 , C 1 -C 6 -alkyl, and C 1 -C 6 -haloalkyl, R 5 is H, and n is 0.

›Definitions · 9 of 19

In a particular embodiment of Formula II, R 1 is —CD 3 , R 2 is —CH 2 OH, R 4 is phenyl, wherein the phenyl is substituted with at least one halogen, R 5 is H, and n is 0.

In another particular embodiment of Formula II, R 1 is C 1 -C 6 -alkyl, R 2 is —CH 2 F, R 4 is phenyl or pyridyl, wherein the phenyl or pyridyl is substituted with 1-3 groups independently selected from halo, —CN, —SF 5 , C 1 -C 6 -alkyl, and C 1 -C 6 -haloalkyl, R 5 is H, and n is 0.

In another particular embodiment of Formula II, R 1 is C 1 -C 6 -alkyl, R 2 is —CH 2 OCH 2 CHF 2 , R 4 is phenyl or pyridyl, wherein the phenyl or pyridyl is substituted with 1-3 groups independently selected from halo, —CN, —SF 5 , C 1 -C 6 -alkyl, and C 1 -C 6 -haloalkyl, R 5 is H, n is 1, and R 3 is C 1 -C 6 -alkyl.

In another particular embodiment of Formula II, R 1 is C 1 -C 6 -alkyl, R 2 is —CH 2 OH, R 3 is C 1 -C 6 -alkyl, R 4 is phenyl, wherein the phenyl is substituted with at least one halogen, R 5 is H, and n is 1.

In another particular embodiment of Formula II, R 1 is C 1 -C 6 -alkyl, R 2 is —CH 2 S(O) 2 CH 3 , R 4 is phenyl, wherein the phenyl is substituted with at least one halogen, R 5 is H, and n is 0.

In another particular embodiment of Formula II, R 1 is C 1 -C 6 -alkyl, R 2 is —CH 2 OC(O)O—C 1 -C 6 -alkyl, R 4 is phenyl, wherein the phenyl is substituted with at least one halogen, R 5 is H, and n is 0.

In another particular embodiment of Formula II, R 1 is C 1 -C 6 -alkyl, R 2 is —CH 2 OC(O)NH 2 , R 4 is phenyl, wherein the phenyl is substituted with at least one halogen, R 5 is H, and n is 0.

In another particular embodiment of Formula II, R 1 is C 1 -C 6 -alkyl, R 2 is —C(O)NH 2 , —C(O)NHCH 3 , or —C(O)N(CH 3 ) 2 , R 4 is phenyl, wherein the phenyl is substituted with at least one halogen, R 5 is H, and n is 0.

In another particular embodiment of Formula II, R 1 is C 1 -C 6 -alkyl, R 2 is —CH 2 OC(O)N(CH 3 ) 2 , R 4 is phenyl, wherein the phenyl is substituted with at least one halogen, R 5 is H, and n is 0.

In another particular embodiment of Formula I, R 1 is C 1 -C 6 -alkyl, R 4 is phenyl, wherein the phenyl is substituted with at least one halogen, R 5 is H, m is 0 and n is 0.

In another particular embodiment of Formula I, R 1 is C 1 -C 6 -alkyl, R 3 is C 1 -C 6 -alkyl, R 4 is phenyl or pyridyl, wherein the phenyl or pyridyl is substituted with 1-3 groups independently selected from halo, —CN, C 1 -C 6 -alkyl, and C 1 -C 6 -haloalkyl, R 5 is H, m is 0 and n is 1. In a more particular embodiment, R 3 is (R)-methyl.

In another particular embodiment of Formula II, R 1 is C 1 -C 6 -alkyl, R 2 is —CH 2 F, R 3 is C 1 -C 6 -alkyl, R 4 is phenyl or pyridyl, wherein the phenyl or pyridyl is substituted with 1-3 groups independently selected from halo, —CN, C 1 -C 6 -alkyl, and C 1 -C 6 -haloalkyl, R 5 is H, and n is 1. In a more particular embodiment, R 3 is (R)-methyl.

In another particular embodiment of Formula II, R 1 is C 1 -C 6 -alkyl, R 2 is —CH 2 N(CH 3 ) 2 , R 3 is C 1 -C 6 -alkyl, R 4 is phenyl or pyridyl, wherein the phenyl or pyridyl is substituted with 1-3 groups independently selected from halo, —CN, C 1 -C 6 -alkyl, and C 1 -C 6 -haloalkyl, R 5 is H, and n is 1. In a more particular embodiment, R 3 is (R)-methyl. In another particular embodiment of Formula II, R 1 is C 1 -C 6 -alkyl, R 2 is selected from —CH 2 OCH 3 , —CH 2 OCH 2 CH 3 , —CH 2 OCH 2 CH═CH 2 , —CH 2 OCH 2 CH 2 CH 3 , —CH 2 OCH 2 -cyclopropyl, —CH 2 OCH 2 CHF 2 , and —CH 2 OCH 2 CF 3 , R 4 is phenyl, wherein the phenyl is substituted with at least one halogen, R 5 is H, and n is 0.

In another particular embodiment of Formula Ia, R 1 is C 1 -C 6 -alkyl, R 4 is phenyl, wherein the phenyl is substituted with at least one halogen, R 5 is H, m is 0 and n is 0.

In another particular embodiment of Formula Ia, R 1 is C 1 -C 6 -alkyl, R 3 is C 1 -C 6 -alkyl, R 4 is phenyl or pyridyl, wherein the phenyl or pyridyl is substituted with 1-3 groups independently selected from halo, —CN, C 1 -C 6 -alkyl, and C 1 -C 6 -haloalkyl, R 5 is H, m is 0 and n is 1. In a more particular embodiment, R 3 is (R)-methyl.

In an embodiment of Formula II, R 1 is C 1 -C 6 -alkyl, R 2 is C 0 -C 6 -alkyl-OR 6 , R 4 is phenyl, wherein the phenyl is substituted with at least one halogen, R 5 is H, R 6 is H, and n is 0.

In an embodiment of Formula II, R 1 is C 1 -C 6 -alkyl, R 2 is C 0 -C 6 -alkyl-OR 6 , R 4 is phenyl, wherein the phenyl is substituted with at least one halogen, R 5 is H, R 6 is C 1 -C 6 -haloalkyl, and n is 0.

In another embodiment of Formula II, R 1 is C 1 -C 6 -alkyl, R 2 is C 0 -C 6 -alkyl-C(O)N(R 7 ) 2 , wherein two R 7 groups together form a C 2 -C 6 heterocycle with the N to which they are attached, wherein the C 2 -C 6 heterocycle is further independently and optionally substituted with 1 or 2 oxo or halogen substituents, R 4 is phenyl, wherein the phenyl is substituted with at least one halogen, R 5 is H, and n is 0.

In another embodiment of Formula II, R 1 is C 1 -C 6 -alkyl, R 2 is C 0 -C 6 -alkyl-C(O)N(C 1 -C 6 -alkyl)(C 1 -C 6 -haloalkyl), R 4 is phenyl, wherein the phenyl is substituted with at least one halogen,

R 5 is H, and n is 0.

In another embodiment of Formula II, R 1 is C 1 -C 6 -alkyl, R 2 is C 0 -C 6 -alkyl-C(O)N(H)(C 1 -C 6 -haloalkyl), R 4 is phenyl, wherein the phenyl is substituted with at least one halogen, R 5 is H, and n is 0.

In another embodiment of Formula II, R 1 is C 1 -C 6 -alkyl, R 2 is C 0 -C 6 -alkyl-C(O)N(H)(C 1 -C 6 -alkyl), R 4 is phenyl, wherein the phenyl is substituted with at least one halogen, R 5 is H, and n is 0.

In yet another embodiment of Formula II, R 1 is C 1 -C 6 -alkyl, R 2 is C 1 -C 6 -alkyl-N(R 7 ) 2 , is phenyl, wherein the phenyl is substituted with at least one halogen, R 5 is H, wherein two R 7 groups together form a C 2 -C 6 heterocycle with the N to which they are attached, wherein the C 2 -C 6 heterocycle is further independently and optionally substituted with 1 or 2 oxo or halogen substituents and n is 0.

In yet another embodiment of Formula II, R 1 is C 1 -C 6 -alkyl, R 2 is C 1 -C 6 -alkyl-N(H)(C 1 -C 6 -alkyl), R 4 is phenyl, wherein the phenyl is substituted with at least one halogen, R 5 is H, and n is 0.

›Definitions · 10 of 19

In yet another embodiment of Formula II, R 1 is C 1 -C 6 -alkyl, R 2 is C 1 -C 6 -alkyl-N(H)(C 1 -C 6 -haloalkyl), R 4 is phenyl, wherein the phenyl is substituted with at least one halogen, R 5 is H, and n is 0.

In yet another embodiment of Formula II, R 1 is C 1 -C 6 -alkyl, R 2 is C 1 -C 6 -alkyl-N(H)(—C(O)C 1 -C 6 -alkyl), R 4 is phenyl, wherein the phenyl is substituted with at least one halogen, R 5 is H, and n is 0.

In yet another embodiment of Formula II, R 1 is C 1 -C 6 -alkyl, R 2 is C 1 -C 6 -alkyl-N(H)(—C(O)C 1 -C 6 -haloalkyl), R 4 is phenyl, wherein the phenyl is substituted with at least one halogen, R 5 is H, and n is 0.

In yet another embodiment of Formula II, R 1 is C 1 -C 6 -alkyl, R 2 is C 1 -C 6 -alkyl-N(H)(—C(O)C 1 -C 6 -alkyl-OH), R 4 is phenyl, wherein the phenyl is substituted with at least one halogen, R 5 is H, and n is 0.

In yet another embodiment of Formula II, R 1 is C 1 -C 6 -alkyl, R 2 is C 1 -C 6 -alkyl-N(H)(—C(O)C 1 -C 6 -alkyl-CN), R 4 is phenyl, wherein the phenyl is substituted with at least one halogen, R 5 is H, and H, and n is 0.

In yet another embodiment of Formula II, R 1 is C 1 -C 6 -alkyl, R 2 is C 1 -C 6 -alkyl-N(H)(—C(O)C 3 -C 7 -cycloalkyl), R 4 is phenyl, wherein the phenyl is substituted with at least one halogen, R 5 is H, and n is 0.

In yet another embodiment of Formula II, R 1 is C 1 -C 6 -alkyl, R 2 is C 1 -C 6 -alkyl-N(H)(—C(O)O—C 1 -C 6 -alkyl), R 4 is phenyl, wherein the phenyl is substituted with at least one halogen, R 5 is H, and n is 0.

In yet another embodiment of Formula II, R 1 is C 1 -C 6 -alkyl, R 2 is C 1 -C 6 -alkyl-N(H)(—C(O)O—C 1 -C 6 -haloalkyl), R 4 is phenyl, wherein the phenyl is substituted with at least one halogen, R 5 is H, and n is 0.

In yet another embodiment of Formula II, R 1 is C 1 -C 6 -alkyl, R 2 is C 1 -C 6 -alkyl-N(H)(—C(O)O—C 3 -C 7 -cycloalkyl), R 4 is phenyl, wherein the phenyl is substituted with at least one halogen, R 5 is H, and n is 0.

In yet another embodiment of Formula II, R 1 is C 1 -C 6 -alkyl, R 2 is C 1 -C 6 -alkyl-N(H)(—C(O)N(C 1 -C 6 -alkyl) 2 ), R 4 is phenyl, wherein the phenyl is substituted with at least one halogen, R 5 is H, and n is 0.

In yet another embodiment of Formula II, R 1 is C 1 -C 6 -alkyl, R 2 is C 1 -C 6 -alkyl-N(H)(—S(O) 2 C 1 -C 6 -alkyl), R 4 is phenyl, wherein the phenyl is substituted with at least one halogen, R 5 is H, and n is 0.

In yet another embodiment of Formula II, R 1 is C 1 -C 6 -alkyl, R 2 is C 1 -C 6 -alkyl-N(H)(—S(O) 2 C 1 -C 6 -haloalkyl), R 4 is phenyl, wherein the phenyl is substituted with at least one halogen, R 5 is H, and n is 0.

In yet another embodiment of Formula II, R 1 is C 1 -C 6 -alkyl, R 2 is C 1 -C 6 -alkyl-N(H)(—S(O) 2 C 3 -C 7 -cycloalkyl), R 4 is phenyl, wherein the phenyl is substituted with at least one halogen, R 5 is H, R 7 is —S(O) 2 C 3 -C 7 -cycloalkyl, and H, and n is 0.

In another particular embodiment of Formula II, R 1 is C 1 -C 6 -alkyl, R 2 is selected from —CH 2 OH, —CH 2 OCF 3 , —C(O)-3,3-difluoroazetidine, —C(O)-3,3-difluoropyrrolidine, —C(O)N(CH 3 )(CH 2 CHF 2 ), —C(O)N(CH 3 )(CH 2 CF 3 ), —C(O)N(H)(CH 2 CHF 2 ), —C(O)N(H)(CH 3 ), —C(O)N(H)(CH 2 CF 3 ), —CH 2 N(H)(C(O)CH 3 ), —CH 2 N(H)(C(O)CF 3 ), —CH 2 N(H)(C(O)OCH 3 ), —CH 2 N(H)(S(O) 2 CH 3 ), —CH 2 N(H)(S(O) 2 CF 3 ), —CH 2 -pyrrolidin-2-one, —CH 2 N(H)(C(O)CH 2 CH 3 ), —CH 2 N(H)(C(O)-cyclopropyl), —CH 2 N(H)(C(O)CH 2 CF 3 ), —CH 2 N(H)(C(O)CH(CH 3 ) 2 ), —CH 2 N(H)(C(O)C(CH 3 ) 3 ), —CH 2 N(H)(C(O)OCH 2 CH 3 ), —CH 2 N(H)(C(O)O-cyclopropyl), —CH 2 N(H)(C(O)N(CH 3 ) 2 ), —CH 2 N(H)(C(O)CH 2 CN), —CH 2 N(H)(C(O)CH 2 OH), —CH 2 N(H)(C(O)OCH 2 CF 3 ), —CH 2 N(H)(S(O) 2 CH 2 CH 3 ), —CH 2 N(H)(S(O) 2 CH 2 CF 3 ) and —CH 2 N(H)(S(O) 2 -cyclopropyl), R 4 is phenyl, wherein the phenyl is substituted with at least one halogen, R 5 is H, and n is 0.

In an embodiment of Formula II, R 1 is C 1 -C 6 -alkyl, R 2 is C 0 -C 6 -alkyl-OR 6 , R 3 is C 1 -C 6 -alkyl, R 4 is phenyl, wherein the phenyl is substituted with at least one halogen, R 5 is H, R 6 is H, and n is 1. In a more particular embodiment, R 3 is (R)-methyl.

In another embodiment of Formula II, R 1 is C 1 -C 6 -alkyl, R 2 is C 0 -C 6 -alkyl-C(O)N(C 1 -C 6 -haloalkyl)(C 1 -C 6 -alkyl), R 3 is C 1 -C 6 -alkyl, R 4 is phenyl, wherein the phenyl is substituted with at least one halogen, R 5 is H, and n is 1. In a more particular embodiment, R 3 is (R)-methyl.

In another embodiment of Formula II, R 1 is C 1 -C 6 -alkyl, R 2 is C 0 -C 6 -alkyl-C(O)N(C 1 -C 6 -haloalkyl)(H), R 3 is C 1 -C 6 -alkyl, R 4 is phenyl, wherein the phenyl is substituted with at least one halogen, R 5 is H, and n is 1. In a more particular embodiment, R 3 is (R)-methyl.

In another embodiment of Formula II, R 1 is C 1 -C 6 -alkyl, R 2 is C 0 -C 6 -alkyl-C(O)N(C 1 -C 6 -alkyl)(H), R 3 is C 1 -C 6 -alkyl, R 4 is phenyl, wherein the phenyl is substituted with at least one halogen, R 5 is H, and n is 1. In a more particular embodiment, R 3 is (R)-methyl.

In yet another embodiment of Formula II, R 1 is C 1 -C 6 -alkyl, R 2 is C 1 -C 6 -alkyl-N(—C(O)C 1 -C 6 -alkyl)(H), R 3 is C 1 -C 6 -alkyl, R 4 is phenyl, wherein the phenyl is substituted with at least one halogen, R 5 is H, and n is 1. In a more particular embodiment, R 3 is (R)-methyl.

In yet another embodiment of Formula II, R 1 is C 1 -C 6 -alkyl, R 2 is C 1 -C 6 -alkyl-N(—S(O) 2 C 1 -C 6 -alkyl)(H), R 3 is C 1 -C 6 -alkyl, R 4 is phenyl, wherein the phenyl is substituted with at least one halogen, R 5 is H, and n is 1. In a more particular embodiment, R 3 is (R)-methyl.

In yet another embodiment of Formula II, R 1 is C 1 -C 6 -alkyl, R 2 is C 1 -C 6 -alkyl-N(—C(O)O—C 1 -C 6 -alkyl)(H), R 3 is C 1 -C 6 -alkyl, R 4 is phenyl, wherein the phenyl is substituted with at least one halogen, R 5 is H, and n is 1. In a more particular embodiment, R 3 is (R)-methyl.

In another particular embodiment of Formula II, R 1 is C 1 -C 6 -alkyl, R 2 is selected from —CH 2 OH, —C(O)N(CH 3 )(CH 2 CHF 2 ), —C(O)N(H)(CH 2 CHF 2 ), —C(O)N(H)(CH 3 ), —CH 2 N(H)(C(O)CH 3 ), —CH 2 N(H)(C(O)OCH 3 ), —CH 2 N(H)(S(O) 2 CH 3 ), R 3 is C 1 -C 6 -alkyl, R 4 is phenyl, wherein the phenyl is substituted with at least one halogen, R 5 is H, and n is 1. In a more particular embodiment, R 3 is (R)-methyl.

›Definitions · 11 of 19

In an embodiment of Formula III, R 1 is C 1 -C 6 -alkyl, R 3 is C 1 -C 6 -alkyl, R 4 is phenyl, wherein the phenyl is substituted with at least one halogen, R 5 is H, R c is H, C 1-4 alkyl, CH 2 CH═CH 2 , CH 3 CHF 2 , CH 2 CH 2 OH, CH 2 CH 2 CH 2 OH, or CH 2 CH(OH)CH 3 , m is 0, and n is 1. In a more particular embodiment, R 3 is (R)-methyl.

In an embodiment of Formula III, R 1 is C 1 -C 6 -alkyl, R 2 is selected from —C 1-4 haloalkyl, OH, C 1-4 alkyl, CH 2 OH, CH(OH)CH 3 , CH(OH)CH 2 CH 3 , CH(OH)cyclopropyl, CH 2 OCH 2 CHF 2 , R 3 is C 1 -C 6 -alkyl, R 4 is phenyl, wherein the phenyl is substituted with at least one halogen, R 5 is H, R c is H, C 1-4 alkyl, CH 2 CH═CH 2 , CH 3 CHF 2 , CH 2 CH 2 OH, CH 2 CH 2 CH 2 OH, CH 2 CH(OH)CH 3 , and n is 1. In a more particular embodiment, R 3 is (R)-methyl.

In an embodiment of Formula III, R 1 is C 1 -C 6 -alkyl, R 3 is C 1 -C 6 -alkyl, R 4 is phenyl, wherein the phenyl is substituted with at least one halogen, R 5 is H, R c is absent, m is 0, and n is 1. In a more particular embodiment, R 3 is (R)-methyl.

In an embodiment of Formula III, R 1 is C 1 -C 6 -alkyl, R 2 is selected from —C 1-4 haloalkyl, OH, C 1-4 alkyl, CH 2 OH, CH(OH)CH 3 , CH(OH)CH 2 CH 3 , CH(OH)cyclopropyl, CH 2 OCH 2 CHF 2 , R 3 is C 1 -C 6 -alkyl, R 4 is phenyl, wherein the phenyl is substituted with at least one halogen, R 5 is H, R c is absent, and n is 1. In a more particular embodiment, R 3 is (R)-methyl.

Certain embodiments of Formulas I and II are shown below in Table 1.

In an embodiment, compounds of Formulas I and II are selected from:

Compound ID Compound Name 001 N-(3-bromophenyl)-4-(hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine- 10(2H)-carboxamide 002 4-(hydroxymethyl)-2-methyl-1-oxo-N-(m-tolyl)-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine- 10(2H)-carboxamide 003 N-(2-chloro-3-fluoropyridin-4-yl)-4-(hydroxymethyl)-2-methyl-1- oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5] oxadiazepine-10(2H)-carboxamide 004 N-(3-bromo-2-fluorophenyl)-4-(hydroxymethyl)-2-methyl-1-oxo- 1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5] oxadiazepine-10(2H)-carboxamide 005 N-(3,4-difluorophenyl)-4-(hydroxymethyl)-2-methyl-1-oxo- 1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5] oxadiazepine-10(2H)-carboxamide 006 4-(hydroxymethyl)-2-methyl-1-oxo-N-(3,4,5-trifluorophenyl)- 1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5] oxadiazepine-10(2H)-carboxamide 007 N-(3-chloro-2,4-difluorophenyl)-4-(hydroxymethyl)-2-methyl-1-oxo- 1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5] oxadiazepine-10(2H)-carboxamide 008 4-(hydroxymethyl)-2-methyl-1-oxo-N-(3-(trifluoromethyl)phenyl)- 1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5] oxadiazepine-10(2H)-carboxamide 009 N-(3-ethylphenyl)-4-(hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine- 10(2H)-carboxamide 010 N-(3-bromo-2,4-difluorophenyl)-4-(hydroxymethyl)-2-methyl-1-oxo- 1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5] oxadiazepine-10(2H)-carboxamide 011_E1 (S*)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-4-(hydroxymethyl)-2- methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo [5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide 011_E2 (R*)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-4-(hydroxymethyl)-2- methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo [5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide 012 N-(3,4-dichlorophenyl)-4-(hydroxymethyl)-2-methyl-1-oxo- 1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5] oxadiazepine-10(2H)-carboxamide 013 N-(5-chloro-2,4-difluorophenyl)-4-(hydroxymethyl)-2-methyl-1-oxo- 1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5] oxadiazepine-10(2H)-carboxamide 014 N-(5-bromo-2,4-difluorophenyl)-4-(hydroxymethyl)-2-methyl-1-oxo- 1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5] oxadiazepine-10(2H)-carboxamide 015 N-(3-bromo-4,5-difluorophenyl)-4-(hydroxymethyl)-2-methyl-1-oxo- 1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5] oxadiazepine-10(2H)-carboxamide 016 N-(2,5-dimethylphenyl)-4-(hydroxymethyl)-2-methyl-1-oxo- 1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5] oxadiazepine-10(2H)-carboxamide 017 N-(5-bromo-2-methylphenyl)-4-(hydroxymethyl)-2-methyl-1-oxo- 1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5] oxadiazepine-10(2H)-carboxamide 018 N-(5-bromo-4-fluoro-2-methylphenyl)-4-(hydroxymethyl)-2-methyl- 1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5] oxadiazepine-10(2H)-carboxamide 019 4-(hydroxymethyl)-2-methyl-N-(3-methylcyclohexyl)-1-oxo- 1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5] oxadiazepine-10(2H)-carboxamide 020 4-(hydroxymethyl)-N-(3-iodophenyl)-2-methyl-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine- 10(2H)-carboxamide 021 N-(3-(difluoromethyl)phenyl)-4-(hydroxymethyl)-2-methyl-1-oxo- 1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5] oxadiazepine-10(2H)-carboxamide 022 N-(3-chloro-4-fluoro-5-(trifluoromethyl)phenyl)-4-(hydroxymethyl)- 2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo [5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide 023 N-(2,3-dichloro-4-fluorophenyl)-4-(hydroxymethyl)-2-methyl-1-oxo- 1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5] oxadiazepine-10(2H)-carboxamide 024 N-(3,4-dichloro-2-fluorophenyl)-4-(hydroxymethyl)-2-methyl-1-oxo- 1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5] oxadiazepine-10(2H)-carboxamide 025 N-(4-chloro-3-(trifluoromethyl)phenyl)-4-(hydroxymethyl)-2- methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo [5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide 026 N-(3-chloro-4-methylphenyl)-4-(hydroxymethyl)-2-methyl-1-oxo- 1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5] oxadiazepine-10(2H)-carboxamide 027 N-(4,5-dichloro-2-fluorophenyl)-4-(hydroxymethyl)-2-methyl-1-oxo- 1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5] oxadiazepine-10(2H)-carboxamide 028_E1 (S*)-N-(3-chloro-4,5-difluorophenyl)-4-(hydroxymethyl)-2-methyl- 1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5] oxadiazepine-10(2H)-carboxamide 029 4-(hydroxymethyl)-2-methyl-1-oxo-N-(3-(pentafluoro-16-sulfanyl) phenyl)-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d] [1,2,5]oxadiazepine-10(2H)-carboxamide 030 N-(3-chlorophenyl)-4-(hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine- 10(2H)-carboxamide 031_E1 (S*)-N-(3-chloro-4-fluorophenyl)-4-(hydroxymethyl)-2-methyl-1- oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5] oxadiazepine-10(2H)-carboxamide 031_E2 (R*)-N-(3-chloro-4-fluorophenyl)-4-(hydroxymethyl)-2- methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo [5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide 032_E1 (S*)-N-(3-bromo-4-fluorophenyl)-4-(hydroxymethyl)-2-methyl-1- oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5] oxadiazepine-10(2H)-carboxamide 033_E1 (S*)-N-(2-bromo-3-fluoropyridin-4-yl)-4-(hydroxymethyl)-2-methyl- 1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5] oxadiazepine-10(2H)-carboxamide 034_E1 (S*)-N-(3-cyano-4-fluorophenyl)-4-(hydroxymethyl)-2-methyl-1- oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5] oxadiazepine-10(2H)-carboxamide 035_E1 (S*)-N-(4-fluoro-3-methylphenyl)-4-(hydroxymethyl)-2-methyl-1- oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5] oxadiazepine-10(2H)-carboxamide 036 4-(fluoromethyl)-2-methyl-1-oxo-N-(3-(trifluoromethyl)phenyl)- 1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5] oxadiazepine-10(2H)-carboxamide 037_E1 (S*)-N-(3-chlorophenyl)-4-(fluoromethyl)-2-methyl-1-oxo- 1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5] oxadiazepine-10(2H)-carboxamide 038_E1 (S*)-N-(3-chloro-4-fluorophenyl)-4-(fluoromethyl)-2-methyl-1-oxo- 1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5] oxadiazepine-10(2H)-carboxamide 039_E1 (S*)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-4-(fluoromethyl)-2- methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo [5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide 040_E1 (S*)-N-(3-bromo-4-fluorophenyl)-4-(fluoromethyl)-2-methyl-1-oxo- 1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5] oxadiazepine-10(2H)-carboxamide 041_E1 (S*)-N-(2-bromo-3-fluoropyridin-4-yl)-4-(fluoromethyl)-2-methyl-1- oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5] oxadiazepine-10(2H)-carboxamide 042_E1 (S*)-N-(3-cyano-4-fluorophenyl)-4-(fluoromethyl)-2-methyl-1-oxo- 1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5] oxadiazepine-10(2H)-carboxamide 043_E1 (S*)-N-(4-fluoro-3-methylphenyl)-4-(fluoromethyl)-2-methyl-1-oxo- 1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5] oxadiazepine-10(2H)-carboxamide 044_E1 (S*)-N-(3-chloro-4,5-difluorophenyl)-4-(fluoromethyl)-2-methyl-1- oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5] oxadiazepine-10(2H)-carboxamide 045 N-(3-chloro-4-fluorophenyl)-4-(hydroxymethyl)-N,2-dimethyl-1- oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5] oxadiazepine-10(2H)-carboxamide 046 N-(3-chlorophenyl)-4-(hydroxymethyl)-2,8,8-trimethyl-1-oxo- 1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5] oxadiazepine-10(2H)-carboxamide 047 N-(3-chlorophenyl)-4-(hydroxymethyl)-2,8-dimethyl-1-oxo- 1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5] oxadiazepine-10(2H)-carboxamide 048 N-(3-chloro-4-fluoro-phenyl)-2-methyl-4-(methylsulfanylmethyl)- 1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5] oxadiazepine-10-carboxamide 049_E1 (S*)-N-(3-chloro-4-fluorophenyl)-2-methyl-4-(((S*)- methylsulfinyl)methyl)-1-oxo-1,4,5,8,9,11-hexahydropyrido [4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide 049_E2 (S*)-N-(3-chloro-4-fluorophenyl)-2-methyl-4-(((R*)- methylsulfinyl)methyl)-1-oxo-1,4,5,8,9,11-hexahydropyrido [4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide 049_E3 (R*)-N-(3-chloro-4-fluorophenyl)-2-methyl-4-(((R*)- methylsulfinyl)methyl)-1-oxo-1,4,5,8,9,11-hexahydropyrido [4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide 049_E4 (R*)-N-(3-chloro-4-fluorophenyl)-2-methyl-4-(((S*)- methylsulfinyl)methyl)-1-oxo-1,4,5,8,9,11-hexahydropyrido [4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide 050 N-(3-chloro-4-fluorophenyl)-2-methyl-4-((methylsulfonyl)methyl)- 1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5] oxadiazepine-10(2H)-carboxamide 051 (10-((3-chloro-4-fluorophenyl)carbamoyl)-2-methyl-1-oxo- 1,2,4,5,8,9,10,11-octahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5] oxadiazepin-4-yl)methyl methyl carbonate 052 (10-((3-chloro-4-fluorophenyl)carbamoyl)-2-methyl-1-oxo- 1,2,4,5,8,9,10,11-octahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5] oxadiazepin-4-yl)methyl acetate 053 (10-((3-chloro-4-fluorophenyl)carbamoyl)-2-methyl-1-oxo- 1,2,4,5,8,9,10,11-octahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5] oxadiazepin-4-yl)methyl isopropyl carbonate 054 tert-butyl((10-((3-chloro-4-fluorophenyl)carbamoyl)-2-methyl-1- oxo-1,2,4,5,8,9,10,11-octahydropyrido[4′,3′:3,4]pyrazolo[5,1-d] [1,2,5]oxadiazepin-4-yl)methyl) carbonate 055 (10-((3-chloro-4-fluorophenyl)carbamoyl)-2-methyl-1-oxo- 1,2,4,5,8,9,10,11-octahydropyrido[4′,3′:3,4]pyrazolo[5,1-d] [1,2,5]oxadiazepin-4-yl)methyl pivalate 056 (10-((3-chloro-4-fluorophenyl)carbamoyl)-2-methyl-1-oxo- 1,2,4,5,8,9,10,11-octahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5] oxadiazepin-4-yl)methyl ethyl carbonate 057 (10-((3-chloro-4-fluorophenyl)carbamoyl)-2-methyl-1-oxo- 1,2,4,5,8,9,10,11-octahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5] oxadiazepin-4-yl)methyl carbamate 058 N-(3-chloro-4-fluoro-phenyl)-4-[(dimethylamino)methyl]-2-methyl- 1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5] oxadiazepine-10-carboxamide 059 [10-[(3-chloro-4-fluoro-phenyl)carbamoyl]-2-methyl-1-oxo- 5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5] oxadiazepin-4-yl]methyl N,N-dimethylcarbamate 060_E1 (S*)-N-(3-chloro-4-fluorophenyl)-2-ethyl-4-(hydroxymethyl)-1-oxo- 1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5] oxadiazepine-10(2H)-carboxamide 060_E2 (R*)-N-(3-chloro-4-fluorophenyl)-2-ethyl-4-(hydroxymethyl)-1-oxo- 1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5] oxadiazepine-10(2H)-carboxamide 061 N-(3-chloro-4-fluoro-phenyl)-2,5-dimethyl-1-oxo-5,8,9,11- tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10- carboxamide 062 N-(3-chloro-4-fluorophenyl)-2,4-dimethyl-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine- 10(2H)-carboxamide 063 N-(3-chlorophenyl)-2,4-dimethyl-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine- 10(2H)-carboxamide 064 N-(3-chloro-4-fluoro-phenyl)-2,4,4-trimethyl-1-oxo-5,8,9,11- tetrahydropyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10- carboxamide 065 N-(3-chloro-4-fluoro-phenyl)-4-(methoxymethyl)-2-methyl-1-oxo- 5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5] oxadiazepine-10-carboxamide 066 N-(3-chloro-4-fluoro-phenyl)-2-methyl-1-oxo-5,8,9,11-tetrahydro- 4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxamide 067 2-allyl-N-(3-chloro-4-fluoro-phenyl)-1-oxo-5,8,9,11-tetrahydro-4H- pyrido[2,3]pyrazolo[2,4-c][1,2,5]oxadiazepine-10-carboxamide 068 N-(3-chloro-4-fluoro-phenyl)-1-oxo-2-propyl-5,8,9,11-tetrahydro- 4H-pyrido[2,3]pyrazolo[2,4-c][1,2,5]oxadiazepine-10-carboxamide 069_E1 (4S*,9S*)-N-(3-chloro-4-fluorophenyl)-4-(hydroxymethyl)-2,9- dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo [5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide 069_E2 (4R*,9S*)-N-(3-chloro-4-fluorophenyl)-4-(hydroxymethyl)-2,9- dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo [5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide 069_E3 (4R*,9R*)-N-(3-chloro-4-fluorophenyl)-4-(hydroxymethyl)-2,9- dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo [5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide 069_E4 (4S*,9R*)-N-(3-chloro-4-fluorophenyl)-4-(hydroxymethyl)-2,9- dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo [5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide 070 N-(3-chloro-4-fluoro-phenyl)-4-(hydroxymethyl)-2,9-dimethyl-1- oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5] oxadiazepine-10-carboxamide 071 methyl 10-[(3-chloro-4-fluoro-phenyl)carbamoyl]-2-methyl-1-oxo- 5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5] oxadiazepine-4-carboxylate 072 N10-(3-chloro-4-fluoro-phenyl)-2-methyl-1-oxo-5,8,9,11-tetrahydro- 4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-4,10- dicarboxamide 073 N10-(3-chloro-4-fluoro-phenyl)-N4,2-dimethyl-1-oxo-5,8,9,11- tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-4,10- dicarboxamide 074 N10-(3-chloro-4-fluoro-phenyl)-N4,N4,2-trimethyl-1-oxo-5,8,9,11- tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-4,10- dicarboxamide 075 (9R)-N-(3-chloro-4-fluoro-phenyl)-2,9-dimethyl-1-oxo-5,8,9,11- tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-4,10- carboxamide 076 (R)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-2,9-dimethyl-1-oxo- 1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5] oxadiazepine-10(2H)-carboxamide 077 (R)-N-(3-bromo-4-fluorophenyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine- 10(2H)-carboxamide 078 (R)-N-(2-bromo-3-fluoropyridin-4-yl)-2,9-dimethyl-1-oxo- 1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5] oxadiazepine-10(2H)-carboxamide 079 (R)-N-(3-cyano-4-fluorophenyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine- 10(2H)-carboxamide 080 (R)-N-(4-fluoro-3-methylphenyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine- 10(2H)-carboxamide 081 (R)-N-(3-chloro-4,5-difluorophenyl)-2,9-dimethyl-1-oxo- 1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5] oxadiazepine-10(2H)-carboxamide 082_E1 (4S*,9R)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-4-(hydroxymethyl)- 2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4] pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide 082_E2 (4R*,9R)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-4- (hydroxymethyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine- 10(2H)-carboxamide 083_E1 (4S*,9R)-N-(4-fluoro-3-methylphenyl)-4-(hydroxymethyl)-2,9- dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo [5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide 083_E2 (4R*,9R)-N-(4-fluoro-3-methylphenyl)-4-(hydroxymethyl)-2,9- dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo [5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide 084_E1 (4S*,9R)-N-(3-cyano-4-fluorophenyl)-4-(hydroxymethyl)-2,9- dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo [5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide 08_4E2 (4R*,9R)-N-(3-cyano-4-fluorophenyl)-4-(hydroxymethyl)-2,9- dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo [5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide 085_E1 (4S*,9R)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-4-(fluoromethyl)- 2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4] pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide 085_2 (4R*,9R)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-4-(fluoromethyl)- 2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4] pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide 086_E1 (4S*,9R)-N-(4-fluoro-3-methylphenyl)-4-(fluoromethyl)-2,9- dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo [5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide 086_E2 (4R*,9R)-N-(4-fluoro-3-methylphenyl)-4-(fluoromethyl)-2,9- dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo [5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide 087_E1 (4S*,9R)-N-(3-cyano-4-fluorophenyl)-4-(fluoromethyl)-2,9- dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo [5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide 087_E2 (4R*,9R)-N-(3-cyano-4-fluorophenyl)-4-(fluoromethyl)-2,9- dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo [5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide 088_E1 (4S*,9R)-N-(3-chloro-4-fluorophenyl)-4-(fluoromethyl)-2,9- dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo [5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide 088 (4R*,9R)-N-(3-chloro-4-fluorophenyl)-4-(fluoromethyl)-2,9- dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo [5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide 089_E1 (4S*,9R)-N-(5-bromo-2,4-difluorophenyl)-4-(hydroxymethyl)-2,9- dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo [5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide 089_E2 (4R*,9R)-N-(5-bromo-2,4-difluorophenyl)-4-(hydroxymethyl)-2,9- dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo [5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide 090_E1 (4S*,9R)-N-(5-chloro-2,4-difluorophenyl)-4-(hydroxymethyl)-2,9- dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo [5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide 090_E2 (4R*,9R)-N-(5-chloro-2,4-difluorophenyl)-4-(hydroxymethyl)-2,9- dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo [5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide 091_E1 (4S*,9R)-N-(3-chloro-2,4-difluorophenyl)-4-(hydroxymethyl)-2,9- dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo [5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide 091_E2 (4R*,9R)-N-(3-chloro-2,4-difluorophenyl)-4-(hydroxymethyl)-2,9- dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo [5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide 092_E1 (4S*,9R)-N-(3-bromo-2,4-difluorophenyl)-4-(hydroxymethyl)-2,9- dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo [5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide 092_E2 (4R*,9R)-N-(3-bromo-2,4-difluorophenyl)-4-(hydroxymethyl)-2,9- dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo [5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide 093_D1 (4S*,9R)-N-(3-chloro-4-fluorophenyl)-4-((dimethylamino)methyl)- 2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4] pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide 093_D2 (4R*,9R)-N-(3-chloro-4-fluorophenyl)-4-((dimethylamino)methyl)- 2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4] pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide 094_D1 (4S*,9R)-N-(3-bromo-4-fluorophenyl)-4-((dimethylamino)methyl)- 2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4] pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide 094_D2 (4R*,9R)-N-(3-bromo-4-fluorophenyl)-4-((dimethylamino)methyl)- 2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4] pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide 095_D1 (4S*,9R)-N-(2-bromo-3-fluoropyridin-4-yl)-4-((dimethylamino) methyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4] pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide 10(2H)-carboxamide 095_D2 (4R*,9R)-N-(2-bromo-3-fluoropyridin-4-yl)-4-((dimethylamino) methyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4] pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide 096_D1 (4S*,9R)-N-(3-cyano-4-fluorophenyl)-4-((dimethylamino)methyl)- 2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4] pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide 096_D2 (4R*,9R)-N-(3-cyano-4-fluorophenyl)-4-((dimethylamino)methyl)- 2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4] pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide 097_D1 (4S*,9R)-4-((dimethylamino)methyl)-N-(4-fluoro-3-methylphenyl)- 2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4] pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide 097_D2 (4R*,9R)-4-((dimethylamino)methyl)-N-(4-fluoro-3-methylphenyl)- 2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4] pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide 098_D1 (4S*,9R)-4-((dimethylamino)methyl)-N-(4-fluoro-3- (trifluoromethyl)phenyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine- 10(2H)-carboxamide 098_D2 (4R*,9R)-4-((dimethylamino)methyl)-N-(4-fluoro-3- (trifluoromethyl)phenyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine- 10(2H)-carboxamide 099_D1 (4S*,9R)-N-(5-chloro-2,4-difluorophenyl)-4-((dimethylamino) methyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4] pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide 099_D2 (4R*,9R)-N-(5-chloro-2,4-difluorophenyl)-4-((dimethylamino) methyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4] pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide 100_D1 (4S*,9R)-N-(5-bromo-2,4-difluorophenyl)-4-((dimethylamino) methyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4] pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide 100_D2 (4R*,9R)-N-(5-bromo-2,4-difluorophenyl)-4-((dimethylamino) methyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4] oxadiazepine-10(2H)-carboxamide 101 N-(3-chloro-4-fluoro-phenyl)-4-(ethoxymethyl)-2-methyl-1-oxo- 5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5] oxadiazepine-10-carboxamide 102 4-(allyloxymethyl)-N-(3-chloro-4-fluoro-phenyl)-2-methyl-1-oxo- 5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5] oxadiazepine-10-carboxamide 103 N-(3-chloro-4-fluoro-phenyl)-2-methyl-1-oxo-4-(propoxymethyl)- 5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5] oxadiazepine-10-carboxamide 104 N-(3-chloro-4-fluoro-phenyl)-4-(cyclopropylmethoxymethyl)-2- methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido [2,4-d][1,2,5]oxadiazepine-10-carboxamide 105 N-(3-chloro-4-fluoro-phenyl)-4-(2,2-difluoroethoxymethyl)-2- methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo [2,4-d][1,2,5]oxadiazepine-10-carboxamide 106 N-(3-chloro-4-fluoro-phenyl)-2-methyl-1-oxo-4-(2,2,2- trifluoroethoxymethyl)-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo [2,4-d][1,2,5]oxadiazepine-10-carboxamide 107 N-(3-chloro-4-fluoro-phenyl)-4-(hydroxymethyl)-1-oxo-2- (trideuteriomethyl)-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo [2,4-d][1,2,5]oxadiazepine-10-carboxamide *Pure but unknown enantiomer or diastereomer.

›Definitions · 12 of 19

and pharmaceutically acceptable salts thereof.

Certain embodiments of Formulae I and II are shown below in Table 2.

In an embodiment, compounds of Formulae I and II are selected from:

Compound ID Compound Name 108_D1 (4S*,9R)-N-(5-bromo-2,4-difluorophenyl)-4-((2,2- difluoroethoxy)methyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)- carboxamide 108_D2 (4R*,9R)-N-(5-bromo-2,4-difluorophenyl)-4-((2,2- difluoroethoxy)methyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)- carboxamide 109_D1 (4S*,9S*)-N-(3-chloro-4-fluorophenyl)-9-ethyl-4-(hydroxymethyl)-2- methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d] [1,2,5]oxadiazepine-10(2H)-carboxamide 109_D2 (4S*,9R*)-N-(3-chloro-4-fluorophenyl)-9-ethyl-4-(hydroxymethyl)-2- methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d] [1,2,5]oxadiazepine-10(2H)-carboxamide 109_D3 (4R*,9R*)-N-(3-chloro-4-fluorophenyl)-9-ethyl-4-(hydroxymethyl)-2- methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d] [1,2,5]oxadiazepine-10(2H)-carboxamide 109_D4 (4R*,9S*)-N-(3-chloro-4-fluorophenyl)-9-ethyl-4-(hydroxymethyl)-2- methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d] [1,2,5]oxadiazepine-10(2H)-carboxamide 110_D1 (4S*,9R)-N10-(3-chloro-2,4-difluorophenyl)-N4,2,9-trimethyl-1-oxo- 1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d] [1,2,5]oxadiazepine-4,10(2H)-diacarboxamide 110_D2 (4R*,9R)-N10-(3-chloro-2,4-difluorophenyl)-N4,2,9-trimethyl-1-oxo- 1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d] [1,2,5]oxadiazepine-4,10(2H)-diacarboxamide 111_D1 (4S*,9R)-N10-(5-chloro-2,4-difluorophenyl)-N4,2,9-trimethyl-1-oxo- 1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d] [1,2,5]oxadiazepine-4,10(2H)-diacarboxamide 111_D2 (4R*,9R)-N10-(5-chloro-2,4-difluorophenyl)-N4,2,9-trimethyl-1-oxo- 1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d] [1,2,5]oxadiazepine-4,10(2H)-diacarboxamide 112_D1 (4S*,9R)-N10-(3-cyano-4-fluorophenyl)-N4,2,9-trimethyl-1-oxo- 1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d] [1,2,5]oxadiazepine-4,10(2H)-diacarboxamide 112_D2 (4R*,9R)-N10-(3-cyano-4-fluorophenyl)-N4,2,9-trimethyl-1-oxo- 1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d] [1,2,5]oxadiazepine-4,10(2H)-diacarboxamide 113 4-(aminomethyl)-N-(3-chloro-4-fluoro-phenyl)-2-methyl-1-oxo-5,8,9,11- tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10- carboxamide 114_E1 (S*)-4-(aminomethyl)-N-(3-cyano-4-fluoro-phenyl)-2-methyl-1-oxo- 5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine- 10-carboxamide 115_D1 (4S*,9R)-4-(aminomethyl)-N-(3-cyano-4-fluorophenyl)-2,9-dimethyl-1- oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d] [1,2,5]oxadiazepine-10(2H)-carboxamide 115_D2 (4R*,9R)-4-(aminomethyl)-N-(3-cyano-4-fluorophenyl)-2,9-dimethyl-1- oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d] [1,2,5]oxadiazepine-10(2H)-carboxamide 116_D1 (4S*,9R)-4-(aminomethyl)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-2,9- dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d] [1,2,5]oxadiazepine-10(2H)-carboxamide 116_D2 (4R*,9R)-4-(aminomethyl)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-2,9- dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d] [1,2,5]oxadiazepine-10(2H)-carboxamide 117_D1 (4S*,9R)-4-(aminomethyl)-N-(3-bromo-4-fluorophenyl)-2,9-dimethyl-1- oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d] [1,2,5]oxadiazepine-10(2H)-carboxamide 117_D2 (4R*,9R)-4-(aminomethyl)-N-(3-bromo-4-fluorophenyl)-2,9-dimethyl-1- oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d] [1,2,5]oxadiazepine-10(2H)-carboxamide 118 N10-(3-chloro-2,4-difluorophenyl)-N4,2-dimethyl-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadizepine-4,10(2H)- dicarboxamide 119 N10-(5-chloro-2,4-difluorophenyl)-N4,2-dimethyl-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadizepine-4,10(2H)- dicarboxamide 120 N10-(3-cyano-4-fluorophenyl)-N4,2-dimethyl-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadizepine-4,10(2H)- dicarboxamide 121_D1 (4S*,9R)-N-(3-chloro-4-fluorophenyl)-4-((2,2-difluoroethoxy)methyl)- 2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d] [1,2,5]oxadiazepine-10(2H)-carboxamide 121_D2 (4R*,9R)-N-(3-chloro-4-fluorophenyl)-4-((2,2-difluoroethoxy)methyl)- 2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d] [1,2,5]oxadiazepine-10(2H)-carboxamide 122_D1 (4S*,9R)-N-(3-bromo-4-fluorophenyl)-4-((2,2-difluoroethoxy)methyl)- 2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d] [1,2,5]oxadiazepine-10(2H)-carboxamide 122_D2 (4R*,9R)-N-(3-bromo-4-fluorophenyl)-4-((2,2-difluoroethoxy)methyl)- 2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d] [1,2,5]oxadiazepine-10(2H)-carboxamide 123_D1 (4S*,9R)-N-(2-bromo-3-fluoropyridin-4-yl)-4-((2,2-difluoroethoxy) methyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4] pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide 123_D2 (4R*,9R)-N-(2-bromo-3-fluoropyridin-4-yl)-4-((2,2-difluoroethoxy) methyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido [4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide 124_D1 (4S*,9R)-N-(3-cyano-4-fluorophenyl)-4-((2,2-difluoroethoxy)methyl)- 2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d] [1,2,5]oxadiazepine-10(2H)-carboxamide 124_D2 (4R*,9R)-N-(3-cyano-4-fluorophenyl)-4-((2,2-difluoroethoxy)methyl)- 2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d] [1,2,5]oxadiazepine-10(2H)-carboxamide 125_D1 (4S*,9R)-4-((2,2-difluoroethoxy)methyl)-N-(4-fluoro-3-methylphenyl)- 2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d] [1,2,5]oxadiazepine-10(2H)-carboxamide 125_D2 (4R*,9R)-4-((2,2-difluoroethoxy)methyl)-N-(4-fluoro-3-methylphenyl)- 2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d] [1,2,5]oxadiazepine-10(2H)-carboxamide 126_D1 (4S*,9R)-4-((2,2-difluoroethoxy)methyl)-N-(4-fluoro-3-(trifluoromethyl) phenyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido [4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide 126_D2 (4R*,9R)-4-((2,2-difluoroethoxy)methyl)-N-(4-fluoro-3-(trifluoromethyl) phenyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido [4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide 127_D1 (4S*,9R)-N-(5-chloro-2,4-difluorophenyl)-4-((2,2-difluoroethoxy) methyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido [4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide 127_D2 (4R*,9R)-N-(5-chloro-2,4-difluorophenyl)-4-((2,2-difluoroethoxy) methyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4] pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide *Pure but unknown enantiomer or diastereomer.

›Definitions · 13 of 19

and pharmaceutically acceptable salts thereof.

Certain embodiments of Formula Ia and Formula II are shown below in Table 3.

In an embodiment, compounds of Formulas Ia and II are selected from:

Compound ID Compound Name 128 N-(3-chloro-4-fluoro-phenyl)-2-methyl-1-oxo-4-(trifluoromethoxymethyl)- 5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10- carboxamide 129 N-(3-chloro-4-fluorophenyl)-4-(ethylsulfonamidomethyl)-2-methyl-1-oxo- 1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine- 10(2H)-carboxamide 130 N-(3-chloro-4-fluorophenyl)-2-methyl-1-oxo-4-(((2,2,2-trifluoroethyl) sulfonamido)methyl)-1,4,5,8,9,11-hexahydropyrido [4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide 131 N-(3-chloro-4-fluorophenyl)-4-(3,3-difluoroazetidine-1-carbonyl)-2-methyl-1- oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d] [1,2,5]oxadiazepine-10(2H)-carboxamide 132 N-(3-chloro-4-fluorophenyl)-4-(3,3-difluoropyrrolidine-1-carbonyl)-2-methyl- 1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5] oxadiazepine-10(2H)-carboxamide 133 N10-(3-chloro-4-fluorophenyl)-N4,2-dimethyl-1-oxo-N4-(2,2,2- trifluoroethyl)-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5] oxadiazepine-4,10(2H)-dicarboxamide 134 N10-(3-chloro-4-fluorophenyl)-N4-(2,2-difluoroethyl)-N4,2-dimethyl-1-oxo- 1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine- 4,10(2H)-dicarboxamide 135 N10-(3-chloro-4-fluorophenyl)-2-methyl-1-oxo-N4-(2,2,2-trifluoroethyl)- 1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine- 4,10(2H)-dicarboxamide 136 N10-(3-chloro-4-fluorophenyl)-N4-(2,2-difluoroethyl)-2-methyl-1-oxo- 1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine- 4,10(2H)-dicarboxamide 137_E1 (S*)-N-(3-chloro-2,4,5-trifluorophenyl)-4-(hydroxymethyl)-2-methyl-1-oxo- 1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine- 10(2H)-carboxamide 138_E1 (S*)-N-(3-chloro-2,6-difluorophenyl)-4-(hydroxymethyl)-2-methyl-1-oxo- 1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine- 10(2H)-carboxamide 139_E1 (S*)-N-(5-chloro-2-fluorophenyl)-4-(hydroxymethyl)-2-methyl-1-oxo- 1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine- 10(2H)-carboxamide 140_E1 (S*)-N-(5-bromo-2,3-difluorophenyl)-4-(hydroxymethyl)-2-methyl-1-oxo- 1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine- 10(2H)-carboxamide 141_E1 (S*)-N-(5-bromo-2-fluorophenyl)-4-(hydroxymethyl)-2-methyl-1-oxo- 1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine- 10(2H)-carboxamide 142_E1 (S*)-N-(2,4-difluoro-3-methylphenyl)-4-(hydroxymethyl)-2-methyl-1-oxo- 1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine- 10(2H)-carboxamide 143_E1 (S*)-N-(2,4-difluoro-5-methylphenyl)-4-(hydroxymethyl)-2-methyl-1-oxo- 1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine- 10(2H)-carboxamide 144_E1 (S*)-4-(hydroxymethyl)-2-methyl-1-oxo-N-(2,4,5-trifluoro-3-methylphenyl)- 1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine- 10(2H)-carboxamide 145_E1 (S*)-N-(5-cyano-2-fluorophenyl)-4-(hydroxymethyl)-2-methyl-1-oxo- 1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine- 10(2H)-carboxamide 146_E1 (S*)-N-(3-cyano-2-fluorophenyl)-4-(hydroxymethyl)-2-methyl-1-oxo- 1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine- 10(2H)-carboxamide 147_E1 (S*)-N-(2,4-difluoro-5-(trifluoromethyl)phenyl)-4-(hydroxymethyl)-2-methyl- 1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d] [1,2,5]oxadiazepine-10(2H)-carboxamide 148_E1 (S*)-N-(2-fluoro-5-(trifluoromethyl)phenyl)-4-(hydroxymethyl)-2-methyl-1- oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d] [1,2,5]oxadiazepine-10(2H)-carboxamide 149_E1 (S*)-N-(2,4-difluoro-3-(trifluoromethyl)phenyl)-4-(hydroxymethyl)-2-methyl- 1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d] [1,2,5]oxadiazepine-10(2H)-carboxamide 150_E1 (S*)-N-(2-bromo-5-fluoropyridin-4-yl)-4-(hydroxymethyl)-2-methyl-1-oxo- 1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine- 10(2H)-carboxamide 151_E1 (S*)-4-(hydroxymethyl)-2-methyl-1-oxo-N-(2,3,4,5-tetrafluorophenyl)- 1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine- 10(2H)-carboxamide 152_D1 (4S*,9R)-N10-(3-chloro-2,4-difluorophenyl)-N4-(2,2-difluoroethyl)-N4,2,9- trimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d] [1,2,5]oxadiazepine-4,10(2H)-carboxamide 152_D2 (4R*,9R)-N10-(3-chloro-2,4-difluorophenyl)-N4-(2,2-difluoroethyl)-N4,2,9- trimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d] [1,2,5]oxadiazepine-4,10(2H)-carboxamide 153_D1 (4S*,9R)-N10-(3-cyano-2,4-difluorophenyl)-N4-(2,2-difluoroethyl)-N4,2,9- trimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d] [1,2,5]oxadiazepine-4,10(2H)-carboxamide 153_D2 (4R*,9R)-N10-(3-cyano-2,4-difluorophenyl)-N4-(2,2-difluoroethyl)-N4,2,9- trimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d] [1,2,5]oxadiazepine-4,10(2H)-carboxamide 154_D1 (4S*,9R)-N10-(5-chloro-2,4-difluorophenyl)-N4-(2,2-difluoroethyl)-N4,2,9- trimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d] [1,2,5]oxadiazepine-4,10(2H)-carboxamide 154_D2 (4R*,9R)-N10-(5-chloro-2,4-difluorophenyl)-N4-(2,2-difluoroethyl)-N4,2,9- trimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d] [1,2,5]oxadiazepine-4,10(2H)-carboxamide 155_D1 (4S*,9R)-N10-(3-cyano-4-fluorophenyl)-N4-(2,2-difluoroethyl)-N4,2,9- trimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d] [1,2,5]oxadiazepine-4,10(2H)-carboxamide 155_D2 (4R*,9R)-N10-(3-cyano-4-fluorophenyl)-N4-(2,2-difluoroethyl)-N4,2,9- trimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d] [1,2,5]oxadiazepine-4,10(2H)-carboxamide 156_D1 (4S*,9R)-N10-(3-cyano-2,4-difluorophenyl)-N4,2,9-trimethyl-1-oxo- 1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine- 4,10(2H)-dicarboxamide 156_D2 (4R*,9R)-N10-(3-cyano-2,4-difluorophenyl)-N4,2,9-trimethyl-1-oxo- 1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine- 4,10(2H)-dicarboxamide 157_D1 (4S*,9R)-N-[2-fluoro-5-(trifluoromethyl)phenyl]-4-(hydroxymethyl)-2,9- dimethyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d] [1,2,5]oxadiazepine-10(2H)-carboxamide 157_D2 (4R*,9R)-N-[2-fluoro-5-(trifluoromethyl)phenyl]-4-(hydroxymethyl)-2,9- dimethyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d] [1,2,5]oxadiazepine-10(2H)-carboxamide 158 N10-(3-chloro-2,4-difluorophenyl)-N4-(2,2-difluoroethyl)-N4,2-dimethyl-1- oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d] [1,2,5]oxadiazepine-4,10(2H)-carboxamide 159 N10-(5-chloro-2,4-difluorophenyl)-N4-(2,2-difluoroethyl)-N4,2-dimethyl-1- oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d] [1,2,5]oxadiazepine-4,10(2H)-carboxamide 160 N10-(3-cyano-4-fluorophenyl)-N4-(2,2-difluoroethyl)-N4,2-dimethyl-1-oxo- 1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d] 4,10(2H)-dicarboxamide 161 N10-(3-cyano-2,4-difluorophenyl)-N4-(2,2-difluoroethyl)-N4,2-dimethyl-1- oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d] [1,2,5]oxadiazepine-4,10(2H)-carboxamide 162 4-(acetamidomethyl)-N-(3-chloro-4-fluorophenyl)-2-methyl-1-oxo- 1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine- 10(2H)-carboxamide 163 N-(3-chloro-4-fluorophenyl)-2-methyl-1-oxo-4-((2,2,2-trifluoroacetamido) methyl)-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d] [1,2,5]oxadiazepine-10(2H)-carboxamide 164 N-(3-chloro-4-fluorophenyl)-2-methyl-1-oxo-4- (((trifluoromethyl)sulfonamido)methyl)-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)- carboxamide 165 N-(3-chloro-4-fluorophenyl)-2-methyl-4-(methylsulfonamidomethyl)-1-oxo- 1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine- 10(2H)-carboxamide 166 methyl ((10-(3-chloro-4-fluorophenyl)carbamoyl)-2-methyl-1-oxo- 1,2,4,5,8,9,10,11-octahydropyrido[4′,3′:3,4]pyrazolo[5,1-d] [1,2,5]oxadizaepin-4-yl)methyl)carbamate 167_E1 (S*)-4-(acetamidomethyl)-N-(3-cyano-2,4-difluorophenyl)-2-methyl-1-oxo- 1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine- 10(2H)-carboxamide 168_E1 (S*)-4-(acetamidomethyl)-N-(3-cyano-4-fluorophenyl)-2-methyl-1-oxo- 1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine- 10(2H)-carboxamide 169_E1 (S*)-4-(acetamidomethyl)-N-(3-chloro-2,4-difluorophenyl)-2-methyl-1-oxo- 1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine- 10(2H)-carboxamide 170_E1 (S*)-4-(acetamidomethyl)-N-(3-bromo-2,4-difluorophenyl)-2-methyl-1-oxo- 1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine- 10(2H)-carboxamide 171_E1 (S*)-4-(acetamidomethyl)-N-(3-bromo-4-fluorophenyl)-2-methyl-1-oxo- 1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine- 10(2H)-carboxamide 172_E1 (S*)-4-(acetamidomethyl)-N-(2,4-difluoro-3-(trifluoromethyl)phenyl)-2- methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d] [1,2,5]oxadiazepine-10(2H)-carboxamide 173_E1 (S*)-4-(acetamidomethyl)-N-(5-chloro-2,4-difluorophenyl)-2-methyl-1-oxo- 1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine- 10(2H)-carboxamide 174_E1 (S*)-4-(acetamidomethyl)-N-(5-bromo-2,4-difluorophenyl)-2-methyl-1-oxo- 1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine- 10(2H)-carboxamide 175_E1 (S*)-4-(acetamidomethyl)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-2-methyl-1- oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d] [1,2,5]oxadiazepine-10(2H)-carboxamide 176_D1 (4S*,9R)-4-(acetamidomethyl)-N-(3-cyano-4-fluorophenyl)-2,9-dimethyl-1- oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d] [1,2,5]oxadiazepine-10(2H)-carboxamide 176_D2 (4R*,9R)-4-(acetamidomethyl)-N-(3-cyano-4-fluorophenyl)-2,9-dimethyl-1- oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d] [1,2,5]oxadiazepine-10(2H)-carboxamide 177_D1 (4S*,9R)-4-(acetamidomethyl)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-2,9- dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d] [1,2,5]oxadiazepine-10(2H)-carboxamide 177_D2 (4R*,9R)-4-(acetamidomethyl)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-2,9- dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d] [1,2,5]oxadiazepine-10(2H)-carboxamide 178_D1 (4S*,9R)-N-(3-cyano-4-fluorophenyl)-2,9-dimethyl-4- (methylsulfonamidomethyl)-1-oxo-1,4,5,8,9,11-hexahydropyrido [4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide 178_D2 (4R*,9R)-N-(3-cyano-4-fluorophenyl)-2,9-dimethyl-4- (methylsulfonamidomethyl)-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)- carboxamide 179_D1 (4S*,9R)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-2,9-dimethyl-4- (methylsulfonamidomethyl)-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)- carboxamide 179_D2 (4R*,9R)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-2,9-dimethyl-4- (methylsulfonamidomethyl)-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)- carboxamide 180_D1 methyl (((4S*,9R)-10-((3-cyano-4-fluorophenyl)carbamoyl)-2,9-dimethyl-1- oxo-1,2,4,5,8,9,10,11-octahydropyrido[4′,3′:3,4]pyrazolo[5,1-d] [1,2,5]oxadiazepin-4-yl)methyl)carbamate 180_D2 methyl (((4R*,9R)-10-((3-cyano-4-fluorophenyl)carbamoyl)-2,9-dimethyl-1- oxo-1,2,4,5,8,9,10,11-octahydropyrido[4′,3′:3,4]pyrazolo[5,1-d] [1,2,5]oxadiazepin-4-yl)methyl)carbamate 181_D1 methyl (((4S*,9R)-10-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)-2,9- dimethyl-1-oxo-1,2,4,5,8,9,10,11-octahydropyrido[4′,3′:3,4]pyrazolo[5,1-d] [1,2,5]oxadiazepin-4-yl)methyl)carbamate 181_D2 methyl (((4R*,9R)-10-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)-2,9- dimethyl-1-oxo-1,2,4,5,8,9,10,11-octahydropyrido[4′,3′:3,4]pyrazolo[5,1-d] [1,2,5]oxadiazepin-4-yl)methyl)carbamate 182_D1 (4S*,9R)-4-(((2,2-difluoroethyl)amino)methyl)-N-(4-fluoro-3- (trifluoromethyl)phenyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)- carboxamide 182_D2 (4R*,9R)-4(((2,2-difluoroethyl)amino)methyl)-N-(4-fluoro-3- (trifluoromethyl)phenyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[1,2,5]oxadiazepine-10(2H)- carboxamide 183_D1 (4S*,9R)-N-(3-cyano-4-fluorophenyl)-4-(((2,2-difluoroethyl)amino)methyl)- 2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d] [1,2,5]oxadiazepine-10(2H)-carboxamide 183_D2 (4R*,9R)-N-(3-cyano-4-fluorophenyl)-4-(((2,2-difluoroethyl)amino)methyl)- 2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d] [1,2,5]oxadiazepine-10(2H)-carboxamide 184_D1 (4S*,9R)-N-(3-bromo-4-fluorophenyl)-4-(((2,2-difluoroethyl)amino)methyl)- 2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d] [1,2,5]oxadiazepine-10(2H)-carboxamide 184_D2 (4R*,9R)-N-(3-bromo-4-fluorophenyl)-4-(((2,2-difluoroethyl)amino)methyl)- 2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d] [1,2,5]oxadiazepine-10(2H)-carboxamide 185_D1 (4S*,9R)-4-(((2,2-difluoroethyl)amino)methyl)-N-(4-fluoro-3-methylphenyl)- 2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d] [1,2,5]oxadiazepine-10(2H)-carboxamide 185_D2 (4R*,9R)-4-(((2,2-difluoroethyl)amino)methyl)-N-(4-fluoro-3-methylphenyl)- 2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d] [1,2,5]oxadiazepine-10(2H)-carboxamide 186_E1 (S*)-N-(3-cyano-2,4-difluorophenyl)-4-(((2,2-difluoroethyl)amino)methyl)-2- methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d] [1,2,5]oxadiazepine-10(2H)-carboxamide 187_E1 (S*)-N-(3-cyano-4-fluorophenyl)-4-(((2,2-difluoroethyl)amino)methyl)-2- methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d] [1,2,5]oxadiazepine-10(2H)-carboxamide 188_E1 (S*)-N-(3-chloro-2,4-difluorophenyl)-4-(((2,2-difluoroethyl)amino)methyl)-2- methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d] [1,2,5]oxadiazepine-10(2H)-carboxamide 189_E1 (S*)-N-(3-bromo-2,4-difluorophenyl)-4-(((2,2-difluoroethyl)amino)methyl)-2- methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d] [1,2,5]oxadiazepine-10(2H)-carboxamide 190_E1 (S*)-N-(3-bromo-4-fluorophenyl)-4-(((2,2-difluoroethyl)amino)methyl)-2- methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d] [1,2,5]oxadiazepine-10(2H)-carboxamide 191_E1 (S*)-N-(2,4-difluoro-3-(trifluoromethyl)phenyl)-4-(((2,2- difluoroethyl)amino)methyl)-2-methyl-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)- carboxamide 192_E1 (S*)-N-(5-chloro-2,4-difluorophenyl)-4-(((2,2-difluoroethyl)amino)methyl)-2- methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d] [1,2,5]oxadiazepine-10(2H)-carboxamide 193_E1 (S*)-N-(5-bromo-2,4-difluorophenyl)-4-(((2,2-difluoroethyl)amino)methyl)-2- methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d] [1,2,5]oxadiazepine-10(2H)-carboxamide 194_E1 (S*)-4-(((2,2-difluoroethyl)amino)methyl)-N-(4-fluoro-3- (trifluoromethyl)phenyl)-2-methyl-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)- carboxamide 195 N10-(3-cyano-2,4-difluorophenyl)-N4,2-dimethyl-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-4,10(2H)- dicarboxamide 196 N-(3-chloro-4-fluoro-phenyl)-2-methyl-1-oxo-4-[(2-oxopyrrolidin-1-yl) methyl]-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d] [1,2,5]oxadiazepine-10-carboxamide 197 N-(3-chloro-4-fluorophenyl)-2-methyl-1-oxo-4-(propionamidomethyl)- 1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine- 10(2H)-carboxamide 198 N-(3-chloro-4-fluorophenyl)-4-(cyclopropanecarboxamidomethyl)-2-methyl- 1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d] [1,2,5]oxadiazepine-10(2H)-carboxamide 199 N-(3-chloro-4-fluorophenyl)-2-methyl-1-oxo-4-((3,3,3- trifluoropropanamido)methyl)-1,4,5,8,9,11-hexahydropyrido [4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide 200 N-(3-chloro-4-fluorophenyl)-4-(isobutyramidomethyl)-2-methyl-1-oxo- 1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine- 10(2H)-carboxamide 201 N-(3-chloro-4-fluorophenyl)-2-methyl-1-oxo-4-(pivalamidomethyl)- 1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine- 10(2H)-carboxamide 202 ethyl ((10-((3-chloro-4-fluorophenyl)carbamoyl)-2-methyl-1-oxo- 1,2,4,5,8,9,10,11-octahydropyrido[4′,3′:3,4]pyrazolo[5,1-d] [1,2,5]oxadiazepin-4-yl)methyl)carbamate 203 cyclopropyl ((10-((3-chloro-4-fluorophenyl)carbamoyl)-2-methyl-1-oxo- 1,2,4,5,8,9,10,11-octahydropyrido[4′,3′:3,4]pyrazolo[5,1-d] [1,2,5]oxadiazepin-4-yl)methyl)carbamate 204 N-(3-chloro-4-fluorophenyl)-4-((3,3-dimethylureido)methyl)-2-methyl-1-oxo- 1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine- 10(2H)-carboxamide 205 N-(3-chloro-4-fluorophenyl)-4-((2-cyanoacetamido)methyl)-2-methyl-1-oxo- 1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine- 10(2H)-carboxamide 206 N-(3-chloro-4-fluorophenyl)-4-((2-hydroxyacetamido)methyl)-2-methyl-1- oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d] [1,2,5]oxadiazepine-10(2H)-carboxamide 207 2,2,2-trifluoroethyl ((10-((3-chloro-4-fluorophenyl)carbamoyl)-2-methyl-1- oxo-1,2,4,5,8,9,10,11-octahydropyrido[4′,3′:3,4]pyrazolo[5,1-d] [1,2,5]oxadiazepine-4-yl)methyl)carbamate 208 N-(3-chloro-4-fluorophenyl)-4-(ethylsulfonamidomethyl)-2-methyl-1-oxo- 1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine- 10(2H)-carboxamide 209 N-(3-chloro-4-fluoro-phenyl)-4-(hydroxymethyl)-2-methyl-1-oxo- 4,5,8,9,10,11-hexahydro-[1,2,5]oxadiazepino[5,4-b]indazole-10-carboxamide

›Definitions · 14 of 19

and pharmaceutically acceptable salts thereof.

Certain embodiments of Formula Ia are shown below in Table 4.

In an embodiment, compounds of Formula Ia are selected from:

Compound ID Compound Name 210 (4S*,9R)-N-(3-cyano-4-fluorophenyl)-2,9-dimethyl-1-oxo-4-((2,2,2- trifluoroethoxy)methyl)-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo [5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide 211 (S*)-N-(3-cyano-4-fluorophenyl)-4-((2,2-difluoroethoxy)methyl)-2-methyl-1- oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5] oxadiazepine-10(2H)-carboxamide 212 (5*)-4-((2,2-difluoroethoxy)methyl)-N-(4-fluoro-3-(trifluoromethyl)phenyl)- 2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d] [1,2,5]oxadiazepine-10(2H)-carboxamide 213 (R)-N-(3-cyano-4-fluorophenyl)-2,4,4,9-tetramethyl-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)- carboxamide 214 (R)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-2,4,4,9-tetramethyl-1-oxo- 1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d] 10(2H)-carboxamide *Pure but unknown enantiomer or diastereomer.

and pharmaceutically acceptable salts thereof.

Certain embodiments of Formula III are shown below in Table 5.

In an embodiment, compounds of Formula III are selected from:

Compound ID Compound Name 216 N-(3-chloro-4-fluorophenyl)-2-methyl-1-oxo-1,2,3,4,5,8,9,11-octahydro-10H- pyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]triazepine-10-carboxamide 217 N-(3-chloro-4-fluorophenyl)-2,3-dimethyl-1-oxo-1,2,3,4,5,8,9,11-octahydro- 10H-pyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]triazepine-10-carboxamide 218 (R)-3-allyl-N-(3-cyano-4-fluorophenyl)-2,9-dimethyl-1-oxo-1,2,3,4,5,8,9,11- octahydro-10H-pyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]triazepine-10- carboxamide 219 (R)-N-(3-cyano-4-fluorophenyl)-3-(2,2-difluoroethyl)-2,9-dimethyl-1-oxo- 1,2,3,4,5,8,9,11-octahydro-10H-pyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5] triazepine-10-carboxamide 220 (R)-N-(3-cyano-4-fluorophenyl)-3-(2-hydroxyethyl)-2,9-dimethyl-1-oxo- 1,2,3,4,5,8,9,11-octahydro-10H-pyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5] triazepine-10-carboxamide 221 (R)-N-(3-cyano-4-fluorophenyl)-2,9-dimethyl-1-oxo-3-propyl- 1,2,3,4,5,8,9,11-octahydro-10H-pyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5] triazepine-10-carboxamide 222 (R)-N-(3-cyano-4-fluorophenyl)-3-(3-hydroxypropyl)-2,9-dimethyl-1-oxo- 1,2,3,4,5,8,9,11-octahydro-10H-pyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5] triazepine-10-carboxamide 223 (9R)-N-(3-cyano-4-fluorophenyl)-3-(2-hydroxypropyl)-2,9-dimethyl-1-oxo- 1,2,3,4,5,8,9,11-octahydro-10H-pyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5] triazepine-10-carboxamide 224 (R)-N-(3-cyano-4-fluorophenyl)-2,3,9-trimethyl-1-oxo-1,2,3,4,5,8,9,11- octahydro-10H-pyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]triazepine-10- carboxamide 225 (R)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-2,3,9-trimethyl-1-oxo- 1,2,3,4,5,8,9,11-octahydro-10H-pyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5] triazepine-10-carboxamide 226 N-(3-chloro-4-fluorophenyl)-4-hydroxy-2-methyl-1-oxo-4-(trifluoromethyl)- 1,2,3,4,5,8,9,11-octahydro-10H-pyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5] triazepine-10-carboxamide 227 N-(3-chloro-4-fluorophenyl)-4-(hydroxymethyl)-2-methyl-1-oxo-1,2,5,8,9,11- hexahydro-10H-pyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]triazepine-10- carboxamide 228 N-(3-cyano-4-fluorophenyl)-4-(hydroxymethyl)-2-methyl-1-oxo-1,2,5,8,9,11- hexahydro-10H-pyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]triazepine-10- carboxamide 229 N-(3-chloro-4-fluorophenyl)-4-(1-hydroxypropyl)-2-methyl-1-oxo- 1,2,5,8,9,11-hexahydro-10H-pyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]triazepine- 10-carboxamide 230 N-(3-chloro-4-fluorophenyl)-4-(1-hydroxyethyl)-2-methyl-1-oxo-1,2,5,8,9,11- hexahydro-10H-pyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]triazepine-10- carboxamide 231 N-(3-chloro-4-fluorophenyl)-4-(cyclopropyl(hydroxy)methyl)-2-methyl-1- oxo-1,2,5,8,9,11-hexahydro-10H-pyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5] triazepine-10-carboxamide 232 N-(3-chloro-4-fluorophenyl)-2,4-dimethyl-1-oxo-1,2,5,8,9,11-hexahydro- 10H-pyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]triazepine-10-carboxamide 233 (R)-N-(3-cyano-4-fluorophenyl)-4-(hydroxymethyl)-2,9-dimethyl-1-oxo- 1,2,5,8,9,11-hexahydro-10H-pyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]triazepine- 10-carboxamide 234 (R)-N-(3-bromo-4-fluorophenyl)-4-(hydroxymethyl)-2,9-dimethyl-1-oxo- 1,2,5,8,9,11-hexahydro-10H-pyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]triazepine- 10-carboxamide 235 (R)-N-(3-chloro-4-fluorophenyl)-4-(hydroxymethyl)-2,9-dimethyl-1-oxo- 1,2,5,8,9,11-hexahydro-10H-pyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]triazepine- 10-carboxamide 236 (R)-N-(3-bromo-4-fluorophenyl)-4((2,2-difluoroethoxy)methyl)-2,9- dimethyl-1-oxo-1,2,5,8,9,11-hexahydro-10H-pyrido[4′,3′:3,4]pyrazolo[5,1-d] [1,2,5]triazepine-10-carboxamide 237 (R)-N-(3-cyano-4-fluorophenyl)-4-((2,2-difluoroethoxy)methyl)-2,9-dimethyl- 1-oxo-1,2,5,8,9,11-hexahydro-10H-pyrido[4′,3′:3,4]pyrazolo[5,1-d] [1,2,5]triazepine-10-carboxamide 238 (R)-4((2,2-difluoroethoxy)methyl)-N-(4-fluoro-3-(trifluoromethyl)phenyl)- 2,9-dimethyl-1-oxo-1,2,5,8,9,11-hexahydro-10H- pyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]triazepine-10-carboxamide *Pure but unknown enantiomer or diastereomer.

and pharmaceutically acceptable salts thereof.

The disclosed compounds may possess one or more stereocenters, and each stereocenter may exist independently in either the R or S configuration. In one embodiment, compounds described herein are present in optically active or racemic forms. It is to be understood that the compounds described herein encompass racemic, optically-active, regioisomeric and stereoisomeric forms, or combinations thereof that possess the therapeutically useful properties described herein.

Preparation of optically active forms is achieved in any suitable manner, including by way of non-limiting example, by resolution of the racemic form with recrystallization techniques, synthesis from optically-active starting materials, chiral synthesis, or chromatographic separation using a chiral stationary phase. In one embodiment, a mixture of one or more isomer is utilized as the disclosed compound described herein. In another embodiment, compounds described herein contain one or more chiral centers. These compounds are prepared by any means, including stereoselective synthesis, enantioselective synthesis or separation of a mixture of enantiomers or diastereomers. Resolution of compounds and isomers thereof is achieved by any means including, by way of non-limiting example, chemical processes, enzymatic processes, fractional crystallization, distillation, and chromatography.

›Definitions · 15 of 19

In one embodiment, the disclosed compounds may exist as tautomers. All tautomers are included within the scope of the compounds presented herein.

Compounds described herein also include isotopically-labeled compounds wherein one or more atoms is replaced by an atom having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes suitable for inclusion in the compounds described herein include and are not limited to 2 H, 3 , 11 C, 13 C, 14 C, 36 Cl, 18 F, 123 I, 125 I, 13 N, 15 N, 15 O, 17 O, 18 O, 32 P, and 35 S. In one embodiment, isotopically-labeled compounds are useful in drug or substrate tissue distribution studies. In another embodiment, substitution with heavier isotopes such as deuterium affords greater metabolic stability (for example, increased in vivo half-life or reduced dosage requirements).

In yet another embodiment, substitution with positron emitting isotopes, such as 11 C, 18 F, 15 O and 13 N, is useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy. Isotopically-labeled compounds are prepared by any suitable method or by processes using an appropriate isotopically-labeled reagent in place of the non-labeled reagent otherwise employed.

In one embodiment, the compounds described herein are labeled by other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.

The compounds described herein, and other related compounds having different substituents are synthesized using techniques and materials described herein and as described, for example, in Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd's Chemistry of Carbon Compounds, Volumes 1-5 and Supplementals (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989), March, Advanced Organic Chemistry 4 th Ed., (Wiley 1992); Carey and Sundberg, Advanced Organic Chemistry 4th Ed., Vols. A and B (Plenum 2000, 2001), and Green and Wuts, Protective Groups in Organic Synthesis 3rd Ed., (Wiley 1999) (all of which are incorporated by reference for such disclosure). General methods for the preparation of compound as described herein are modified by the use of appropriate reagents and conditions, for the introduction of the various moieties found in the formula as provided herein.

Compounds described herein are synthesized using any suitable procedures starting from compounds that are available from commercial sources, or are prepared using procedures described herein.

Methods

Provided herein is a method of treating an HBV infection in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a disclosed compound.

Also provided herein is a method of eradicating an HBV infection in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a disclosed compound.

Provided herein is a method of reducing viral load associated with an HBV infection in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a disclosed compound.

Further, provided herein is a method of reducing reoccurrence of an HBV infection in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a disclosed compound.

Provided herein is a method of inhibiting or reducing the formation or presence of HBV DNA-containing particles or HBV RNA-containing particles in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a disclosed compound.

In certain aspects, the methods and/or compositions described herein are effective for inhibiting or reducing the formation or presence of HBV-associated particles in vitro or in vivo (e.g., in a cell, in a tissue, in an organ (e.g., in the liver), in an organism or the like). HBV-associated particles may contain HBV DNA (i.e., linear and/or covalently closed circular DNA (cccDNA)) and/or HBV RNA (i.e., pre-genomic RNA and/or sub-genomic RNA). Accordingly, HBV-associated particles include HBV DNA-containing particles or HBV RNA-containing particles.

As used herein, “HPV-associated particles” refer to both infectious HBV virions (i.e., Dane particles) and non-infectious HBV subviral particles (i.e., HBV filaments and/or HBV spheres). HBV virions comprise an outer envelope including surface proteins, a nucleocapsid comprising core proteins, at least one polymerase protein, and an HBV genome. HBV filaments and HBV spheres comprise HBV surface proteins, but lack core proteins, polymerase and an HBV genome. HBV filaments and HBV spheres are also known collectively as surface antigen (HBsAg) particles. HBV spheres comprise middle and small HBV surface proteins. HBV filaments also include middle, small and large HBV surface proteins.

HBV subviral particles can include the nonparticulate or secretory HBeAg, which serves as a marker for active replication of HBV.

Provided herein is a method of reducing an adverse physiological impact of an HBV infection in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a disclosed compound.

Also provided herein is a method of reducing, slowing, or inhibiting an HBV infection in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a disclosed compound.

Provided herein is a method of inducing reversal of hepatic injury from an HBV infection in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a disclosed compound.

Provided herein is a method of reducing the physiological impact of long-term antiviral therapy for HBV infection in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a disclosed compound.

›Definitions · 16 of 19

Provided herein is a method of prophylactically treating an HBV infection in an individual in need thereof, wherein the individual is afflicted with a latent HBV infection, comprising administering to the individual a therapeutically effective amount of a disclosed compound.

In one embodiment, the individual is refractory to other therapeutic classes of HBV drugs (e.g, HBV polymerase inhibitors, interferons, viral entry inhibitors, viral maturation inhibitors, literature-described capsid assembly modulators, antiviral compounds of distinct or unknown mechanism, and the like, or combinations thereof). In another embodiment, the disclosed method reduces viral load in an individual suffering from an HBV infection to a greater extent or at a faster rate compared to the extent that other therapeutic classes of HBV drugs reduce viral load in the individual.

In one embodiment, the administering of a disclosed compound, or a pharmaceutically acceptable salt thereof, allows for administering of the at least one additional therapeutic agent at a lower dose or frequency as compared to the administering of the at least one additional therapeutic agent alone that is required to achieve similar results in prophylactically treating an HBV infection in an individual in need thereof.

In one embodiment, the administering of a disclosed compound, or a pharmaceutically acceptable salt thereof, reduces the viral load in the individual to a greater extent or at a faster rate compared to the administering of a compound selected from the group consisting of an HBV polymerase inhibitor, interferon, viral entry inhibitor, viral maturation inhibitor, distinct capsid assembly modulator, antiviral compounds of distinct or unknown mechanism, and any combination thereof.

In one embodiment, the disclosed method reduces viral load in an individual suffering from an HBV infection, thus allowing lower doses or varying regimens of combination therapies to be used.

In one embodiment, the disclosed method causes a lower incidence of viral mutation or viral resistance compared to other classes of HBV drugs, thereby allowing for long term therapy and minimizing the need for changes in treatment regimens.

In one embodiment, the administering of a compound the invention, or a pharmaceutically acceptable salt thereof, causes a lower incidence of viral mutation or viral resistance than the administering of a compound selected from the group consisting of an HBV polymerase inhibitor, interferon, viral entry inhibitor, viral maturation inhibitor, distinct capsid assembly modulator, antiviral compounds of distinct or unknown mechanism, and combination thereof.

In one embodiment, the disclosed method increases the seroconversion rate from HBV infected to non-HBV infected or from detectable HBV viral load to non-detectable HBV viral load beyond that of current treatment regimens. As used herein, “seroconversion” refers to the period of time during which HBV antibodies develop and become detectable.

In one embodiment, the disclosed method increases or normalizes or restores normal health, elicits full recovery of normal health, restores life expectancy, or resolves the viral infection in the individual in need thereof.

In one embodiment, the disclosed method eliminates or decreases the number of HBV RNA particles that are released from HBV infected cells thus enhancing, prolonging, or increasing the therapeutic benefit of the disclosed compounds.

In one embodiment, the disclosed method eradicates HBV from an individual infected with HBV, thereby obviating the need for long term or life-long treatment, or shortening the duration of treatment, or allowing for reduction in dosing of other antiviral agents.

In another embodiment, the disclosed method further comprises monitoring or detecting the HBV viral load of the subject, and wherein the method is carried out for a period of time including until such time that the HBV virus is undetectable.

Accordingly, in one embodiment, provided herein is a method of treating an HBV infection in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a compound of Formula Ia, or a pharmaceutically acceptable salt thereof.

In another embodiment, provided herein is a method of treating an HBV infection in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a compound of Formula II, or a pharmaceutically acceptable salt thereof.

In another embodiment, provided herein is a method of treating an HBV infection in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a compound of Table 1, or a pharmaceutically acceptable salt thereof.

In another embodiment, provided herein is a method of treating an HBV infection in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a compound of Table 2, or a pharmaceutically acceptable salt thereof.

In another embodiment, provided herein is a method of treating an HBV infection in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a compound of Table 3, or a pharmaceutically acceptable salt thereof.

In another embodiment, provided herein is a method of treating an HBV infection in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a compound of Table 4, or a pharmaceutically acceptable salt thereof.

›Definitions · 17 of 19

In another embodiment, provided herein is a method of treating an HBV infection in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a compound of Table 5, or a pharmaceutically acceptable salt thereof.

In an embodiment of any of the methods provided herein, the method can further comprise monitoring the HBV viral load of the subject, wherein the method is carried out for a period of time such that the HBV virus is undetectable.

Combination Therapies

The disclosed compounds may be useful in combination with one or more additional compounds useful for treating HBV infection. These additional compounds may comprise other disclosed compounds and/or compounds known to treat, prevent, or reduce the symptoms or effects of HBV infection. Such compounds include, but are not limited to, HBV polymerase inhibitors, interferons, viral entry inhibitors, viral maturation inhibitors, literature-described capsid assembly modulators, reverse transcriptase inhibitors, immunomodulatory agents, TLR-agonists, and other agents with distinct or unknown mechanisms that affect the HBV life cycle or affect the consequences of HBV infection.

In non-limiting examples, the disclosed compounds may be used in combination with one or more drugs (or a salt thereof) selected from the group comprising:

HBV reverse transcriptase inhibitors, and DNA and RNA polymerase inhibitors including, but not limited to, lamivudine (3TC, Zeffix, Heptovir, Epivir, and Epivir-HBV), entecavir (Baraclude, Entavir), adefovir dipivoxil (Hepsara, Preveon, bis-POM PMEA), tenofovir disoproxil fumarate (Viread, TDF or PMPA);

interferons including, but not limited to, interferon alpha (IFN-α), interferon beta (IFN-β), interferon lambda (IFN-λ), and interferon gamma (IFN-γ);

viral entry inhibitors;

viral maturation inhibitors;

literature-described capsid assembly modulators, such as, but not limited to, BAY 41-4109;

reverse transcriptase inhibitors;

immunomodulatory agents such as TLR-agonists; and

agents of distinct 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), AT-130 ((E)-N-(1-bromo-1-(2-methoxyphenyl)-3-oxo-3-(piperidin-1-yl)prop-1-en-2-yl)-4-nitrobenzamide), and similar analogs.

In one embodiment, the additional therapeutic agent is an interferon. The term “interferon” or “IFN” refers to any member of the family of highly homologous species-specific proteins that inhibit viral replication and cellular proliferation and modulate immune response. Human interferons are grouped into three classes: Type I, which includes interferon-alpha (IFN-α), interferon-beta (IFN-β), and interferon-omega (IFN-ω), Type II, which includes interferon-gamma (IFN-γ), and Type III, which includes interferon-lambda (IFN-λ). Recombinant forms of interferons that have been developed and are commercially available are encompassed by the term “interferon” as used herein. Subtypes of interferons, such as chemically modified or mutated interferons, are also encompassed by the term “interferon” as used herein. Chemically modified interferons may include pegylated interferons and glycosylated interferons. Examples of interferons also include, but are not limited to, interferon-alpha-2a, interferon-alpha-2b, interferon-alpha-n1, interferon-beta-1a, interferon-beta-1b, interferon-lamda-1, interferon-lamda-2, and interferon-lamda-3. Examples of pegylated interferons include pegylated interferon-alpha-2a and pegylated interferon alpha-2b.

Accordingly, in one embodiment, the compounds of Formula Ia, Formula I, or Formula II can be administered in combination with an interferon selected from the group consisting of interferon alpha (IFN-α), interferon beta (IFN-β), interferon lambda (IFN-λ), and interferon gamma (IFN-γ). In one specific embodiment, the interferon is interferon-alpha-2a, interferon-alpha-2b, or interferon-alpha-n1. In another specific embodiment, the interferon-alpha-2a or interferon-alpha-2b is pegylated. In a preferred embodiment, the interferon-alpha-2a is pegylated interferon-alpha-2a (PEGASYS).

In another embodiment, the additional therapeutic agent is selected from immune modulator or immune stimulator therapies, which includes biological agents belonging to the interferon class.

Further, the additional therapeutic agent may be an agent of distinct or unknown mechanism including agents that disrupt the function of other essential viral protein(s) or host proteins required for HBV replication or persistence.

In another embodiment, the additional therapeutic agent is an antiviral agent that blocks viral entry or maturation or targets the HBV polymerase such as nucleoside or nucleotide or non-nucleos(t)ide polymerase inhibitors. In a further embodiment of the combination therapy, the reverse transcriptase inhibitor or DNA or RNA polymerase inhibitor is Zidovudine, Didanosine, Zalcitabine, ddA, Stavudine, Lamivudine, Abacavir, Emtricitabine, Entecavir, Apricitabine, Atevirapine, ribavirin, acyclovir, famciclovir, valacyclovir, ganciclovir, valganciclovir, Tenofovir, Adefovir, PMPA, cidofovir, Efavirenz, Nevirapine, Delavirdine, or Etravirine.

In an embodiment, the additional therapeutic agent is an immunomodulatory agent that induces a natural, limited immune response leading to induction of immune responses against unrelated viruses. In other words, the immunomodulatory agent can effect maturation of antigen presenting cells, proliferation of T-cells and cytokine release (e.g., IL-12, IL-18, IFN-alpha, -beta, and -gamma and TNF-alpha among others),

In a further embodiment, the additional therapeutic agent is a TLR modulator or a TLR agonist, such as a TLR-7 agonist or TLR-9 agonist. In further embodiment of the combination therapy, the TLR-7 agonist is selected from the group consisting of 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-purin-9-yl)propyl][3-(4-morpholinyl)propyl]amino}methyl)phenyl]acetate).

›Definitions · 18 of 19

In any of the methods provided herein, the method may further comprise administering to the individual at least one HBV vaccine, a nucleoside HBV inhibitor, an interferon or any combination thereof. In an embodiment, the HBV vaccine is at least one of RECOMBIVAX HB, ENGERIX-B, ELOVAC B, GENEVAC-B, or SHANVAC B.

In one embodiment, the methods described herein further comprise administering at least one additional therapeutic agent selected from the group consisting of nucleotide/nucleoside analogs, entry inhibitors, fusion inhibitors, and any combination of these or other antiviral mechanisms.

In another aspect, provided herein is method of treating an HBV infection in an individual in need thereof, comprising reducing the HBV viral load by administering to the individual a therapeutically effective amount of a disclosed compound alone or in combination with a reverse transcriptase inhibitor; and further administering to the individual a therapeutically effective amount of HBV vaccine. The reverse transcriptase inhibitor may be at least one of Zidovudine, Didanosine, Zalcitabine, ddA, Stavudine, Lamivudine, Abacavir, Emtricitabine, Entecavir, Apricitabine, Atevirapine, ribavirin, acyclovir, famciclovir, valacyclovir, ganciclovir, valganciclovir, Tenofovir, Adefovir, PMPA, cidofovir, Efavirenz, Nevirapine, Delavirdine, or Etravirine.

In another aspect, provided herein is a method of treating an HBV infection in an individual in need thereof, comprising reducing the HBV viral load by administering to the individual a therapeutically effective amount of a disclosed compound alone or in combination with a antisense oligonucleotide or RNA interference agent that targets HBV nucleic acids; and further administering to the individual a therapeutically effective amount of HBV vaccine. The antisense oligonucleotide or RNA interference agent possesses sufficient complementarity to the the target HBV nucleic acids to inhibit replication of the viral genome, transcription of viral RNAs, or translation of viral proteins.

In another embodiment, the disclosed compound and the at least one additional therapeutic agent are co-formulated. In yet another embodiment, the disclosed compound and the at least one additional therapeutic agent are co-administered.

For any combination therapy described herein, synergistic effect may be calculated, for example, using suitable methods such as the Sigmoid-E max equation (Holford & Scheiner, 19981, Clin. Pharmacokinet. 6: 429-453), the equation of Loewe additivity (Loewe & Muischnek, 1926, Arch. Exp. Pathol Pharmacol. 114: 313-326) and the median-effect equation (Chou & Talalay, 1984, Adv. Enzyme Regul. 22: 27-55). Each equation referred to above may be applied to experimental data to generate a corresponding graph to aid in assessing the effects of the drug combination. The corresponding graphs associated with the equations referred to above are the concentration-effect curve, isobologram curve and combination index curve, respectively.

In an embodiment of any of the methods of administering combination therapies provided herein, the method can further comprise monitoring or detecting the HBV viral load of the subject, wherein the method is carried out for a period of time including until such time that the HBV virus is undetectable.

Administration/Dosage/Formulations

In another aspect, provided herein is a pharmaceutical composition comprising at least one disclosed compound, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier.

Actual dosage levels of the active ingredients in the pharmaceutical compositions of this invention may be varied so as to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.

In particular, the selected dosage level will depend upon a variety of factors including the activity of the particular compound employed, the time of administration, the rate of excretion of the compound, the duration of the treatment, other drugs, compounds or materials used in combination with the compound, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well, known in the medical arts.

A medical doctor, e.g., physician or veterinarian, having ordinary skill in the art may readily determine and prescribe the effective amount of the pharmaceutical composition required. For example, the physician or veterinarian could begin administration of the pharmaceutical composition to dose the disclosed compound at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.

In particular embodiments, it is especially advantageous to formulate the compound in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the patients to be treated; each unit containing a predetermined quantity of the disclosed compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical vehicle. The dosage unit forms of the invention are dictated by and directly dependent on (a) the unique characteristics of the disclosed compound and the particular therapeutic effect to be achieved, and (b) the limitations inherent in the art of compounding/formulating such a disclosed compound for the treatment of HBV infection in a patient.

In one embodiment, the compositions of the invention are formulated using one or more pharmaceutically acceptable excipients or carriers. In one embodiment, the pharmaceutical compositions of the invention comprise a therapeutically effective amount of a disclosed compound and a pharmaceutically acceptable carrier.

In some embodiments, the dose of a disclosed compound is from about 1 mg to about 2,500 mg. In some embodiments, a dose of a disclosed compound used in compositions described herein is less than about 10,000 mg, or less than about 8,000 mg, or less than about 6,000 mg, or less than about 5,000 mg, or less than about 3,000 mg, or less than about 2,000 mg, or less than about 1,000 mg, or less than about 500 mg, or less than about 200 mg, or less than about 50 mg. Similarly, in some embodiments, a dose of a second compound (i.e., another drug for HBV treatment) as described herein is less than about 1,000 mg, or less than about 800 mg, or less than about 600 mg, or less than about 500 mg, or less than about 400 mg, or less than about 300 mg, or less than about 200 mg, or less than about 100 mg, or less than about 50 mg, or less than about 40 mg, or less than about 30 mg, or less than about 25 mg, or less than about 20 mg, or less than about 15 mg, or less than about 10 mg, or less than about 5 mg, or less than about 2 mg, or less than about 1 mg, or less than about 0.5 mg, and any and all whole or partial increments thereof.

›Definitions · 19 of 19

In one embodiment, the present invention is directed to a packaged pharmaceutical composition comprising a container holding a therapeutically effective amount of a disclosed compound, alone or in combination with a second pharmaceutical agent; and instructions for using the compound to treat, prevent, or reduce one or more symptoms of HBV infection in a patient.

Routes of administration of any of the compositions of the invention include oral, nasal, rectal, intravaginal, parenteral, buccal, sublingual or topical. The compounds for use in the invention may be formulated for administration by any suitable route, such as for oral or parenteral, for example, transdermal, transmucosal (e.g., sublingual, lingual, (trans)buccal, (trans)urethral, vaginal (e.g., trans- and perivaginally), (intra)nasal and (trans)rectal), intravesical, intrapulmonary, intraduodenal, intragastrical, intrathecal, subcutaneous, intramuscular, intradermal, intra-arterial, intravenous, intrabronchial, inhalation, and topical administration.

Suitable compositions and dosage forms include, for example, tablets, capsules, caplets, pills, gel caps, troches, dispersions, suspensions, solutions, syrups, granules, beads, transdermal patches, gels, powders, pellets, magmas, lozenges, creams, pastes, plasters, lotions, discs, suppositories, liquid sprays for nasal or oral administration, dry powder or aerosolized formulations for inhalation, compositions and formulations for intravesical administration and the like. It should be understood that the formulations and compositions that would be useful in the present invention are not limited to the particular formulations and compositions that are described herein.

For oral application, particularly suitable are tablets, dragees, liquids, drops, suppositories, or capsules, caplets and gelcaps. The compositions intended for oral use may be prepared according to any method known in the art and such compositions may contain one or more agents selected from the group consisting of inert, non-toxic pharmaceutically excipients that are suitable for the manufacture of tablets. Such excipients include, for example an inert diluent such as lactose; granulating and disintegrating agents such as cornstarch; binding agents such as starch; and lubricating agents such as magnesium stearate. The tablets may be uncoated or they may be coated by known techniques for elegance or to delay the release of the active ingredients. Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert diluent.

For parenteral administration, the disclosed compounds may be formulated for injection or infusion, for example, intravenous, intramuscular or subcutaneous injection or infusion, or for administration in a bolus dose or continuous infusion. Suspensions, solutions or emulsions in an oily or aqueous vehicle, optionally containing other formulatory agents such as suspending, stabilizing or dispersing agents may be used.

Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, numerous equivalents to the specific procedures, embodiments, claims, and examples described herein. Such equivalents were considered to be within the scope of this invention and covered by the claims appended hereto. For example, it should be understood, that modifications in reaction conditions, including but not limited to reaction times, reaction size/volume, and experimental reagents, such as solvents, catalysts, pressures, atmospheric conditions, e.g., nitrogen atmosphere, and reducing/oxidizing agents, with art-recognized alternatives and using no more than routine experimentation, are within the scope of the present application.

It is to be understood that wherever values and ranges are provided herein, all values and ranges encompassed by these values and ranges, are meant to be encompassed within the scope of the present invention. Moreover, all values that fall within these ranges, as well as the upper or lower limits of a range of values, are also contemplated by the present application.

The following examples further illustrate aspects of the present invention. However, they are in no way a limitation of the teachings or disclosure of the present invention as set forth herein.

›EXAMPLES

Exemplary compounds useful in methods of the invention will now be described by reference to the illustrative synthetic schemes for their general preparation below and the specific examples that follow. Artisans will recognize that, to obtain the various compounds herein, starting materials may be suitably selected so that the ultimately desired substituents will be carried through the reaction scheme with or without protection as appropriate to yield the desired product. Alternatively, it may be necessary or desirable to employ, in the place of the ultimately desired substituent, a suitable group that may be carried through the reaction scheme and replaced as appropriate with the desired substituent. Unless otherwise specified, the variables are as defined above in reference to Formula (Ia). Reactions may be performed between the melting point and the reflux temperature of the solvent, and preferably between 0° C. and the reflux temperature of the solvent. Reactions may be heated employing conventional heating or microwave heating. Reactions may also be conducted in sealed pressure vessels above the normal reflux temperature of the solvent.

Abbreviations and acronyms used herein include the following:

›PREPARATIVE EXAMPLES · 1 of 53

According to SCHEME 1, a commercially available or synthetically accessible compound of formula (Xa), where R a is —C 1-6 alkyl, C 1-6 haloalkyl, or C 1-6 alkenyl, and PG is a suitable nitrogen protecting group such as BOC, Bn, and the like, is alkylated with an alkylating agent such as methyl 2-bromo-2-methylpropanoate, and the like, to provide a compound of formula (XIa), where R b is C 1-6 alkyl optionally substituted with CO 2 Me. A compound of formula (Xb), where PG is a suitable nitrogen protecting group such as BOC, Bn, and the like, is alkylated under conditions known to one skilled in the art, for example, reaction with or without a base such as NaH, Cs 2 CO 3 , K 2 CO 3 , and the like, in a suitable solvent such as THF, DMF and the like, with an alkylating agent such as deuterium methyl iodide, allyl bromide, and the like, to provide a compound of formula (XIb), where R a is C 1-6 alkyl, C 1-6 haloalkyl, or C 1-6 alkenyl.

Deprotection of the nitrogen protecting group, employing conditions known to one skilled in the art provides a compound of formula (XIIa) and (XIIb). For example, the BOC protecting group is removed with acid such as TFA, HCl, and the like, in a suitable solvent such as DCM, and the like.

According to SCHEME 2, a commercially available or synthetically accessible compound of Formula (XIII), where R 3 is H or C 1-6 alkyl, is coupled with a compound of Formula (XIIb), where R a is C 1-6 alkyl, C 1-6 haloalkyl, or C 1-6 alkenyl, under amide bond coupling conditions to provide a compound of Formula (XIV). For example, an acid compound of Formula (XIII) is reacted with an amine of Formula (XII), in the presence of a dehydrating agent such as HOBt/EDAC, CDI, PyBOP, HATU, HOAT, propylphosphonic anhydride (T 3 P), a suitably selected base such as DIPEA, TEA, and the like, in a solvent such as toluene, MeCN, EtOAc, DMF, THF, DCM, or a mixture thereof, to afford a compound of Formula (XIV).

A compound of Formula (XIV), where R 3 is H or C 1-6 alkyl, R a is C 1-6 alkyl, C 1-6 haloalkyl, or C 1-6 alkenyl, is reacted with oxetane bromide, with a base such as cesium carbonate, with a phase transfer catalyst such as TBAI, in a solvent such as DMF, at a temperature of about 60-80° C. for a period of 5-6 h provides a compound of Formula (XVa) where R 3 is H or C 1-6 alkyl and R 1 is C 1-6 alkyl, C 1-6 haloalkyl, or C 1-6 alkenyl.

A compound of Formula (XIV), where R 3 is H or C 1-6 alkyl, R a is C 1-6 alkyl, C 1-6 haloalkyl, or C 1-6 alkenyl, is reacted with 1-methyl-dibromoethane, with a base such as potassium carbonate, solvent such as DMF, at a temperature of about 20° C. provides a compound of Formula (XVb) where R 3 is H or C 1-6 alkyl and R 1 is C 1-6 alkyl, C 1-6 haloalkyl, or C 1-6 alkenyl.

A compound of Formula (XIV), where R 3 is H or C 1-6 alkyl, R a is C 1-6 alkyl, C 1-6 haloalkyl, or C 1-6 alkenyl, is reacted with ethyl 2-bromopropanoate, with a base such as cesium carbonate, with a phase transfer catalyst such as TBAI, in a solvent such as DMF, at a temperature of about 40-60° C. for a period of 14-18 h provides a compound of Formula (XVc) where R 3 is H or C 1-6 alkyl and R 1 is C 1-6 alkyl, C 1-6 haloalkyl, or C 1-6 alkenyl.

A compound of Formula (XIV), where R 3 is H or C 1-6 alkyl, R a is C 1-6 alkyl, C 1-6 haloalkyl, or C 1-6 alkenyl, is reacted with 1-methyl-dibromoethane, with a base such as cesium carbonate, with a phase transfer catalyst such as TBAI, solvent such as DMF, at a temperature of about 20° C. provides a compound of Formula (XVd) where R 3 is H or C 1-6 alkyl and R 1 is C 1-6 alkyl, C 1-6 haloalkyl, or C 1-6 alkenyl.

A commercially available or synthetically accessible compound of Formula (XIII), where R 3 is H or C 1-6 alkyl, is coupled with a compound of Formula (XIIa), where R a is C 1-6 alkyl, C 1-6 haloalkyl, or C 1-6 alkenyl, and R b is C 1-6 alkyl optionally substituted with CO 2 Me, under amide bond coupling conditions to provide a compound of Formula (XIVa). For example, an acid compound of Formula (XIII) is reacted with an amine of Formula (XIaI), in the presence of a dehydrating agent such as HOBt/EDAC, CDI, PyBOP, HATU, HOAT, propylphosphonic anhydride (T 3 P), a suitably selected base such as DIPEA, TEA, and the like, in a solvent such as toluene, MeCN, EtOAc, DMF, THF, DCM, or a mixture thereof, to afford a compound of Formula (XIVa).

A compound of Formula (XIV), where R 3 is H or C 1-6 alkyl, R a is C 1-6 alkyl, C 1-6 haloalkyl, or C 1-6 alkenyl, and R b is C 1-6 alkyl optionally substituted with CO 2 Me is reacted with a trialkyl phosphate such as tributyl phosphate, a coupling reagent such as DIAD, solvent such as THF, at a temperature of about reflux provides a compound of Formula (XVe) where R 3 is H or C 1-6 alkyl and R 1 is C 1-6 alkyl, C 1-6 haloalkyl, or C 1-6 alkenyl.

According to SCHEME 3, a compound of Formula (XVI) where Ar is an optionally substituted aryl ring, R 3 is H or C 1-6 alkyl, and R 1 is C 1-6 alkyl, C 1-6 haloalkyl, or C 1-6 alkenyl, can be prepared in two steps. For example, a compound of Formula (XVa) is reacted with an acid such as TFA, in a solvent such as DCM, at a temperature of about about 15° C. for about 30 minutes to provide a compound of Formula (XVI) where the Boc group has been removed. The resulting product can then be reacted with an optionally substituted N-aryl phenyl carbamate such as phenyl (3-chloro-4-fluorophenyl)carbamate and a base such as TEA in a solvent such as DCM to provide a compound of Formula (XVI) where Ar is an optionally substituted aryl ring.

According to SCHEME 4, a compound of Formula (XVI) where Ar is an optionally substituted aryl ring, R 3 is H or C 1-6 alkyl, and R 1 is C 1-6 alkyl, C 1-6 haloalkyl, or C 1-6 alkenyl is reacted with a fluorinating reagent such as DAST, in a solvent such as DCM to provide a compound of Formula (XVII) where R 2 is CH 2 F.

›PREPARATIVE EXAMPLES · 2 of 53

A compound of Formula (XVII) where Ar is an optionally substituted aryl ring, R 3 is H or C 1-6 alkyl, R 1 is C 1-6 alkyl, C 1-6 haloalkyl, or C 1-6 alkenyl, R 2 is CH 2 SC 1 -C 6 alkyl, and m is 1 was prepared in two steps. First, a compound of Formula (XVI) was coupled with a sulfonating reagent such as MsCl, in presence of a base such as TEA, in a solvent such as DCM, at a temperature of about 25° C. for about 2 h to provide a compound of Formula (XVII) where R 2 is CH 2 OMs and m is 1. Second, adding a sulfide nucleophile such as sodium methyl sulfide, in a solvent such as DMF, at a temperature of about 15° C. for about 16 h to provide a compound of Formula (XVII) where R 2 is CH 2 SC 1 -C 6 alkyl, and m is 1.

A compound of Formula (XVII) where Ar is an optionally substituted aryl ring, R 3 is H or C 1-6 alkyl, R 1 is C 1-6 alkyl, C 1-6 haloalkyl, or C 1-6 alkenyl, R 2 is CH 2 SC 1 -C 6 alkyl, and m is 1 is reacted with an oxidant such as m-CPBA, in a solvent such as DCM, at a temperature of about 30° C. for about 16 h to provide a compound of Formula (XVII) where R 2 is CH 2 S(O)C 1 -C 6 alkyl or CH 2 SO 2 C 1 -C 6 alkyl and m is 1.

A compound of Formula (XVI) where Ar is an optionally substituted aryl ring, R 3 is H or C 1-6 alkyl, and R 1 is C 1-6 alkyl, C 1-6 haloalkyl, or C 1-6 alkenyl is reacted with NaOCN, with an acid such as TFA, in a solvent such as DCM, at a temperature of about 25° C. for about 32 h to provide a compound of Formula (XVII) where R 2 is CH 2 O(O)NH 2 .

A compound of Formula (XVII) where Ar is an optionally substituted aryl ring, R 3 is H or C 1-6 alkyl, R 1 is C 1-6 alkyl, C 1-6 haloalkyl, or C 1-6 alkenyl, R 2 is COOH, and m is 1 is reacted with an N(C 1-6 alkyl) 0-2 such as methyl amine or dimethyl amine, using a coupling agent such as HATU, with a base such as DIPEA, in a solvent such as DMF to provide a compound of Formula (XVII) where R 2 is C(O)N(C 1-6 alkyl) 0-2 and m is 1.

A compound of Formula (XVII) where Ar is an optionally substituted aryl ring, R 3 is H or C 1-6 alkyl, R 1 is C 1-6 alkyl, C 1-6 haloalkyl, or C 1-6 alkenyl, R 2 is C 3-6 lactam, and m is 1 is prepared in 2 steps. First, a compound of Formula (XVII) where R 2 is CH 2 NH 2 is reacted with haloalkyl acid chloride such as C 1 CH 2 CH 2 CH 2 C(O)Cl, with a base such as TEA, in a solvent such as DCM to provide a compound of Formula (XVII) where R 2 is CH 2 NHC(O)CH 2 CH 2 CH 2 Cl and m is 1. Second, reacting with a strong base such as NaH, in a solvent such as THF to provide a compound of Formula (XVII) R 2 is C 3-6 lactam, and m is 1.

A compound of Formula (XVII) where Ar is an optionally substituted aryl ring, R 3 is H or C 1-6 alkyl, R 1 is C 1-6 alkyl, C 1-6 haloalkyl, or C 1-6 alkenyl, R 2 is CH 2 N 3 , and m is 1 is reacted with with a phosphine such as triphenyl phosphine, in a solvent such a THF, water, or a mixture of both to provide a compound of Formula (XVII) where R 2 is CH 2 NH 2 .

According to SCHEME 5, a compound of Formula (XIX) where R 3 is H or C 1-6 alkyl, R 1 is C 1-6 alkyl, C 1-6 haloalkyl, or C 1-6 alkenyl, R 2 is CH 2 N(C 1-6 alkyl) 0-2 or C(O)N(C 1-6 alkyl) 0-2 , and m is 1 is prepared in two steps. First, a compound of Formula (XVIII) is reacted with a sulfonating reagent such as MsCl, with a base such as TEA, in a solvent such as DCM to provide a compound of Formula (XIX) where R 2 is CH 2 OH. Second, reacting with an amine such as N(C 1-6 alkyl) 0-2 , with a base such as potassium carbonate, in a solvent such as DMF, at a temperature of about 80° C. for about 24 h to provide a compound of (XIX) where R 2 is CH 2 N(C 1-6 alkyl) 0-2 or C(O)N(C 1-6 alkyl) 0-2 , and m is 1.

A compound of Formula (XVIII) where R 3 is H or C 1-6 alkyl, and R 1 is C 1-6 alkyl, C 1-6 haloalkyl, or C 1-6 alkenyl is reacted with a C 1-6 alkyl halide, C 1-6 alkenyl halide, C 1-6 haloalkyl triflate or halo-C 1-6 alkyl-C 1-6 cycloalkyl such as MeI, EtI, n-propyliodide, allylbromide, CHF 2 CH 2 OTf, CF 3 CH 2 OTf or c-PrCH 2 Br with a strong base such as NaH, in a solvent such as DMF to provide a compound of Formula (XIX) where R 2 is CH 2 OC 1-6 alkyl, CH 2 OC 1-6 alkenyl, CH 2 OC 1-6 haloalkyl, or CH 2 OC 1-6 alkyl-C 1-6 cycloalkyl.

A compound of Formula (XIX) where R 3 is H or C 1-6 alkyl, R 1 is C 1-6 alkyl, C 1-6 haloalkyl, or C 1-6 alkenyl, R 2 is COOC 1-6 alkyl, and m is 1 is prepared in 2 steps. First, a compound of Formula (XVIII) is reacted with an oxidant such as TPAP, a co-oxidant such as NMO, in a solvent such as MeCN to provide a compound of Formula (XIX) where R 2 is COOH. Second, reacting with a C 1-6 alkyl-halide such as Met with a base such as potassium carbonate, in a solvent such as MeCN to provide a compound of (XIX) where R 2 is COOC 1-6 alkyl, and m is 1.

A compound of Formula (XVIII) where R 3 is H or C 1-6 alkyl, and R 1 is C 1-6 alkyl, C 1-6 haloalkyl, or C 1-6 alkenyl is reacted with a silane such as TMSCF 3 , a triflate salt such as silver triflate, a base such as 2-fluropyridine, a desilation reagent such as potassium fluoride, a fluorinating reagent suc has Selectfluor®, in a solvent such as Ethyl Acetate to provide a compound of Formula (XIX) where R 2 is CH 2 OCF 3 and m is 1.

A compound of Formula (XIX) where R 3 is H or C 1-6 alkyl, R 1 is C 1-6 alkyl, C 1-6 haloalkyl, or C 1-6 alkenyl, R 2 is CH 2 OMs, and m is 1 is reacted with an amine such as N(C 1-6 alkyl) 0-2 or N(C 1-6 haloalkyl) 0-2 , a base such as potassium carbonate, in a solvent such as MeCN, at a temperature of about 80° C. for about 16 h to provide a compound of Formula (XIX) where R 2 is CH 2 N(C 1-6 alkyl) 0-2 or N(C 1-6 haloalkyl) 0-2 and m is 1.

A compound of Formula (XIX) where R 3 is H or C 1-6 alkyl, R 1 is C 1-6 alkyl, C 1-6 haloalkyl, or C 1-6 alkenyl, R 2 is COOH, and m is 1 is reacted with an amine such as N(C 1-6 alkyl) 0-2 , N(C 1-6 haloalkyl) 0-2 , or N(C 1-6 alkyl)(C 1-6 haloalkyl), a base such as 3-picoline, a sulfonating reagent such as MsCl, in a solvent such as MeCN, at a temperature of about 0° C. to 30° C. for about 1 h to provide a compound of Formula (XIX) where R 2 is C(O)N(C 1-6 alkyl) 0-2 , C(O)N(C 1-6 haloalkyl) 0-2 , or C(O)N(C 1-6 alkyl)(C 1-6 haloalkyl) and m is 1.

›PREPARATIVE EXAMPLES · 3 of 53

A compound of Formula (XIX) where R 3 is H or C 1-6 alkyl, R 1 is C 1-6 alkyl, C 1-6 haloalkyl, or C 1-6 alkenyl, R 2 is CH 2 NHC(O)C 1-6 alkyl, and m is 1 is prepared in three steps. First, a compound of Formula (XIX) where R 2 is CH 2 OMs and m is 1 is reacted with a nucleophilic azide such as sodium azide, in a solvent such as DMF, at a temperature of about 70° C. for about 16 h to provide a compound of Formula (XIX) where R 2 is CH 2 N 3 . Second, reacting with a phosphine such as triphenyl phosphine, in a solvent such a THF, water, or a mixture of both to provide a compound of Formula (XIX) where R 2 is CH 2 NH 2 . Third, reacting with a C 1-6 alkyl anhydride such as acetic anhydride, a base such as TEA, in a solvent such as DCM to provide a compound of Formula (XIX) where R 2 is CH 2 NHC(O)C 1-6 alkyl.

A compound of Formula (XIX) where R 3 is H or C 1-6 alkyl, R 1 is C 1-6 alkyl, C 1-6 haloalkyl, or C 1-6 alkenyl, R 2 is CH 2 NH 2 , and m is 1 is reacted with a C 1-6 alkyl-SO 2 -halide such as MsCl, a base such as TEA, in a solvent such as DCM to provide a compound of Formula (XIX) where R 2 is CH 2 NH(SO 2 C 1-6 alkyl), and m is 1.

Method A:

According to SCHEME 6, a compound of Formula (XVII) where Ar is an optionally substituted aryl ring, R 3 is H or C 1-6 alkyl, R 1 is C 1-6 alkyl, C 1-6 haloalkyl, or C 1-6 alkenyl, R 2 is as described in any of the examples above, and m is 1 is prepared in 2 steps. First, a compound of Formula (XIX) is reacted with an acid such as TFA, in a solvent such as DCM, at a temperature of about 15° C. for about 30 min to provide a compound of Formula (XIX) where the Boc has been removed. Second, adding a reagent useful for forming an isocyanate such as triphosgene, an optionally substituted aryl amine such as analine, a base such as TEA, in a solvent such as DCM, at a temperature of about 25° C. for about 15 min to provide a compound of Formula (XVII) where Ar is an optionally substituted aryl ring.

Method B:

a compound of Formula (XVII) where Ar is an optionally substituted aryl ring, R 3 is H or C 1-6 alkyl, R 1 is C 1-6 alkyl, C 1-6 haloalkyl, or C 1-6 alkenyl, R 2 is as described in any of the examples above, and m is 1 is prepared in 2 steps. First, a compound of Formula (XIX) is reacted with an acid such as TFA, in a solvent such as DCM, at a temperature of about about 15° C. for about 30 min to provide a compound of Formula (XIX) where the Boc has been removed. Second, adding an optionally substituted N-aryl phenyl carbamate such as phenyl (3-chloro-4-fluorophenyl)carbamate, as base such as TEA, in a solvent such as DCM to provide a compound of Formula (XVII) where Ar is an optionally substituted aryl ring.

According to SCHEME 7, a commercially available or synthetically accessible compound of formula (XXa), where R a is C 1-6 alkyl, and PG is a suitable nitrogen protecting group such as BOC, Bn, and the like, is protected with an a suitable nitrogen protecting group such as carboxybenzyl (Cbz), and the like, to provide a compound of formula (XXIa), where PG 2 is a suitable nitrogen protecting group such as carboxybenzyl (Cbz), and the like.

A compound of formula (XXIIa), where R a is C 1-6 alkyl, PG is a suitable nitrogen protecting group such as BOC, Bn, and the like, PG 2 is a suitable nitrogen protecting group such as carboxybenzyl (Cbz), and the like, and R b is CH 2 CH 2 OH is prepared in two steps from (XXIa). First, (XXIa) is alkylated under conditions known to one skilled in the art, for example, reaction with or without a base such as NaH, Cs 2 CO 3 , K 2 CO 3 , and the like, in a suitable solvent such as THF, DMF and the like, with an alkylating agent such as 1-bromo-methyl acetate, and the like, to provide a compound of formula (XXIIa) where R b is CH 2 (O)OMe. Second, reduction under conditions known to one skilled in the art, for example, reduction using lithium borohydride, and the like, in a suitable solvent such as THF, and the like to provide a compound of formula (XXIIa), where R a is C 1-6 alkyl, PG is a suitable nitrogen protecting group such as BOC, Bn, and the like, PG 2 is a suitable nitrogen protecting group such as carboxybenzyl (Cbz), and the like, and R b is CH 2 CH 2 OH.

A commercially available or synthetically accessible compound of formula (XXb), where R a is C 1-6 alkyl, and PG is a suitable nitrogen protecting group such as BOC, Bn, and the like, is alkylated under conditions known to one skilled in the art, for example, reaction with or without a base such as diisopropyl ethyl amine, NaH, Cs 2 CO 3 , K 2 CO 3 , and the like, in a suitable solvent such as THF, DMF and the like, with an alkylating agent such as (2-bromoethoxy)(tert-butyl)dimethylsilane, and the like, to provide a compound of formula (XXIb), where R c is CH 2 CH 2 OTBS, and the like.

A compound of formula (XXIIb), where R a is C 1-6 alkyl, PG is a suitable nitrogen protecting group such as BOC, Bn, and the like, R b is Me or CH 2 CH═CH 2 , and R c is a CH 2 CH 2 OH, and the like, is prepared in two steps. First, alkylating under conditions known to one skilled in the art, for example, reaction with or without a base such as diisopropyl ethyl amine, NaH, Cs 2 CO 3 , K 2 CO 3 , and the like, in a suitable solvent such as THF, DMF and the like, with an alkylating agent such as allyl bromide, methyl iodide, and the like, to provide a compound of formula (XXIIb) where R b is Me or CH 2 CH═CH 2 . Second, deprotection under conditions known to one skilled in the art, for example, deprotection using hydrochloric acid, and the like, in a suitable solvent such as ethyl acetate, and the like to provide a compound of formula (XXIIb), where R a is C 1-6 alkyl, PG is a suitable nitrogen protecting group such as BOC, Bn, and the like, R c is CH 2 CH 2 OH and R b is Me or CH 2 CH═CH 2 .

Deprotection of the nitrogen protecting group, employing conditions known to one skilled in the art provides a compound of formula (XXIIIa) and (XXIIIb). For example, the BOC protecting group is removed with acid such as TFA, HCl, and the like, in a suitable solvent such as DCM, and the like.

›PREPARATIVE EXAMPLES · 4 of 53

Any of the above alkylation steps are optional. In absence of alkylation, a proton is understood to be in the place of R b or R c .

According to SCHEME 8, a commercially available or synthetically accessible compound of Formula (XIII), where R 3 is H or C 1-6 alkyl, is coupled with a compound of Formula (XXIIIa), where R a is C 1-6 alkyl, PG 2 is a suitable nitrogen protecting group such as carboxybenzyl (Cbz), and the like, and R b is 2-ethanol, under amide bond coupling conditions to provide a compound of Formula (XXIVa). For example, an acid compound of Formula (XIII) is reacted with an amine of Formula (XXIIIa), in the presence of a dehydrating agent such as HOBt/EDAC, CDI, PyBOP, HATU, HOAT, propylphosphonic anhydride (T 3 P), a suitably selected base such as DIPEA, TEA, and the like, in a solvent such as toluene, MeCN, EtOAc, DMF, THF, DCM, or a mixture thereof, to afford a compound of Formula (XXIVa).

A commercially available or synthetically accessible compound of Formula (XIII), where R 3 is H or C 1-6 alkyl, is coupled with a compound of Formula (XXIIIb), where R a is C 1-6 alkyl, R c is CH 2 CH 2 OH and R b is Me or CH 2 CH═CH 2 , under amide bond coupling conditions to provide a compound of Formula (XXIVb). For example, an acid compound of Formula (XIII) is reacted with an amine of Formula (XXIIIb), in the presence of a dehydrating agent such as HOBt/EDAC, CDI, PyBOP, HATU, HOAT, propylphosphonic anhydride (T 3 P), a suitably selected base such as DIPEA, TEA, and the like, in a solvent such as toluene, MeCN, EtOAc, DMF, THF, DCM, or a mixture thereof, to afford a compound of Formula (XXIVb).

A compound of Formula (XXIVa), where R 3 is H or C 1-6 alkyl, where R a is C 1-6 alkyl, PG 2 is a suitable nitrogen protecting group such as carboxybenzyl (Cbz), and the like, and R b is 2-ethanol, is reacted with MsCl, with a base such as triethyl amine, in a solvent such as DCM, to provide a compound of Formula (XXVa) where R 3 is H or C 1-6 alkyl and R 1 is C 1-6 alkyl, and R 2 is a suitable nitrogen protecting group such as carboxybenzyl (Cbz).

A compound of Formula (XXIVb), where R 3 is H or C 1-6 alkyl, where R a is C 1-6 alkyl, R c is CH 2 CH 2 OH and R b is Me or CH 2 CH═CH 2 , is reacted with MsCl, with a base such as triethyl amine, in a solvent such as DCM, to provide a compound of Formula (XXVa) where R 3 is H or C 1-6 alkyl and R 1 is C 1-6 alkyl, and R 2 is Me or CH 2 CH═CH 2 .

Deprotection of the nitrogen protecting group, employing conditions known to one skilled in the art provides a compound of formula (XXVa) where R 2 is H. For example, the Cbz protecting group is removed with hydrogen and palladium over carbon, and the like, in a suitable solvent such as MeOH, and the like.

According to SCHEME 9, a compound of Formula (XXVI) where Ar is an optionally substituted aryl ring, R 3 is H or C 1-6 alkyl, and R 1 is C 1-6 alkyl, is reacted with a reducing reagent such as hydrogen and palladium over carbon, in a solvent such as MeOH to provide a compound of Formula (XXVII) where R 2 is CH 2 CH 2 CH 3 .

A compound of Formula (XXVII) where Ar is an optionally substituted aryl ring, R 3 is H or C 1-6 alkyl, R 1 is C 1-6 alkyl, and R 2 is CH 2 CH 2 OH, was prepared in two steps. First, a compound of Formula (XXVI) was oxidized with a reagent such as OsO 4 , in presence of NaIO 4 , in a solvent such as THF and water mixture, to provide a compound of Formula (XXVII) where R 2 is CH 2 CH═O. Second, adding a reducing reagent such as sodium borohydride, in a solvent such as a THF and ethanol mixture, to provide a compound of Formula (XXVII) where R 2 is CH 2 CH 2 OH.

A compound of Formula (XXVII) where Ar is an optionally substituted aryl ring, R 3 is H or C 1-6 alkyl, R 1 is C 1-6 alkyl, and R 2 is CH 2 CHF 2 , was prepared in two steps. First, a compound of Formula (XXVI) was oxidized with a reagent such as OsO 4 , in presence of NaIO 4 , in a solvent such as THF and water mixture, to provide a compound of Formula (XXVII) where R 2 is CH 2 CH═O. Second, adding a fluorinating agent such as DAST, in a solvent such as DCM, to provide a compound of Formula (XXVII) where R 2 is CH 2 CHF 2 .

According to SCHEME 9, a compound of Formula (XXVIII) where R 3 is H or C 1-6 alkyl, and R 1 is C 1-6 alkyl, is reacted under hydroboration conditions, using reagents such as BH 3 -DMS, in a solvent such as THF, followed by a base such as sodium hydroxide, and an oxidant such as hydrogen peroxide to provide a compound of Formula (XXIX) where R 2 is CH 2 CH 2 CH 2 OH.

A compound of Formula (XXVIII) where R 3 is H or C 1-6 alkyl, and R 1 is C 1-6 alkyl, is reacted under hydroboration conditions, using reagents such as BH 3 -DMS, in a solvent such as THF, followed by a base such as sodium hydroxide, and an oxidant such as hydrogen peroxide to provide a compound of Formula (XXIX) where R 2 is CH 2 CHOHCH 3 .

A compound of Formula (XXXI) where R 3 is H or C 1-6 alkyl, R 1 is C 1-6 alkyl, and R 2 is CH 2 OH, was prepared in three steps. First, a compound of Formula (XXX) was coupled with a reagent such as 3-chloro-2-oxopropyl acetate, in presence of a suitable acid such as p-toluenesulfonic acid, in a solvent such as DCM. Second, adding a reagent such as MsCl, in presence of a suitable base such as pyridine, in a solvent such as DCM. Third, adding a suitable base such as sodium hydride, in a solvent such as THF, to provide a compound of Formula (XXXI) where R 3 is H or C 1-6 alkyl, R 1 is C 1-6 alkyl, and R 2 is CH 2 OH.

A compound of Formula (XXXI) where R 3 is H or C 1-6 alkyl, R 1 is C 1-6 alkyl, and R 2 is Me, was prepared in three steps. First, a compound of Formula (XXX) was coupled with a reagent such as 1-hydroxypropan-2-one, in presence of a suitable acid such as p-toluenesulfonic acid, in a solvent such as DCM. Second, adding a reagent such as MsCl, in presence of a suitable base such as pyridine, in a solvent such as DCM. Third, adding a suitable base such as sodium hydride, in a solvent such as THF, to provide a compound of Formula (XXXI) where R 3 is H or C 1-6 alkyl, R 1 is C 1-6 alkyl, and R 2 is Me.

›PREPARATIVE EXAMPLES · 5 of 53

A compound of Formula (XXXI) where R 3 is H or C 1-6 alkyl, R 1 is C 1-6 alkyl, and R 2 is CH(Et)OH, CH(Me)OH, or CH(cPr)OH was prepared in two steps. First, a compound of Formula (XXXII) was oxidized with a reagent such as DMP, in a solvent such as DCM. Second, adding a Grignard reagent such as EtMgBr, MeMgBr, or cPrMgBr, in a solvent such as THF to provide a compound of Formula (XXXI) where R 3 is H or C 1-6 alkyl, R 1 is C 1-6 alkyl, and R 2 is CH(Et)OH, CH(Me)OH, or CH(cPr)OH.

Method A:

According to SCHEME 13, a compound of Formula (XXXIII) or Formula (XXVII) where Ar is an optionally substituted aryl ring, R 3 is H or C 1-6 alkyl, R 1 is C 1-6 alkyl, and R 2 is as described in any of the examples above is prepared in 2 steps. First, a compound of Formula (XXXI) or Formula (XXIX) is reacted with an acid such as TFA, in a solvent such as DCM, at a temperature of about 15° C. for about 30 min to provide a compound of Formula (XXXI) or Formula (XXIX) where the Boc has been removed. Second, adding a reagent useful for forming an isocyanate such as triphosgene, an optionally substituted aryl amine such as analine, a base such as TEA, in a solvent such as DCM, at a temperature of about 25° C. for about 15 min to provide a compound of Formula (XXXIII) or Formula (XXVII) where Ar is an optionally substituted aryl ring.

Method B:

A compound of Formula (XXXIII) or Formula (XXVII) where Ar is an optionally substituted aryl ring, R 3 is H or C 1-6 alkyl, R 1 is C 1-6 alkyl, C 1-6 haloalkyl, or C 1-6 alkenyl, R 2 is as described in any of the examples above, and m is 1 is prepared in 2 steps. First, a compound of Formula (XXXI) or Formula (XXIX) is reacted with an acid such as TFA, in a solvent such as DCM, at a temperature of about 15° C. for about 30 min to provide a compound of Formula (XXXI) or Formula (XXIX) where the Boc has been removed. Second, adding an optionally substituted N-aryl phenyl carbamate such as phenyl (3-chloro-4-fluorophenyl)carbamate, as base such as TEA, in a solvent such as DCM to provide a compound of Formula (XXXIII) or Formula (XXVII) where Ar is an optionally substituted aryl ring.

Intermediate 1. tert-butyl 4-(hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxylate

Step 1. Preparation of tert-butyl 3-(2-ethoxy-2-oxoacetyl)-4-oxo-piperidine-1-carboxylate. To LiHMDS (1 M, 652.44 mL, 1.30 eq) was added a solution of tert-butyl 4-oxopiperidine-1-carboxylate (100.00 g, 501.88 mmol, 1.00 eq) in THF (1.00 L) was added dropwise at −78° C. under N 2 . The reaction mixture was stirred at −78° C. for 30 minutes under N 2 . Diethyl oxalate (95.35 g, 652.44 mmol, 1.30 eq) was added dropwise. After addition, the reaction mixture was warmed to 15° C. over a period of 30 minutes and stirred at 15° C. for another 2 hours. TLC showed the reaction was completed. The reaction was quenched with aqueous saturated NH 4 Cl (1.5 L) and then neutralized with dilute hydrochloric acid, the aqueous layer was extracted with EtOAc (800 mL*3). The combined organic phase was dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuum to give the title compound (165.00 g, crude) as a yellow oil and used directly for next step.

Step 2. Preparation of 5-tert-butyl-3-ethyl 1,4,6,7-tetrahydropyrazolo [4,3-c]pyridine-3,5-dicarboxylate. A mixture of tert-butyl 3-(2-ethoxy-2-oxo-acetyl)-4-oxo-piperidine-1-carboxylate (165.00 g, 551.25 mmol, 1.00 eq) and NH 2 NH 2 .H 2 O (35.71 g, 606.37 mmol, 1.10 eq) in AcOH (1.00 L) was degassed and purged with N 2 for 3 times. Then the mixture was stirred at 80° C. for 1 hour under N 2 atmosphere. TLC and LCMS showed the reaction was completed. The mixture was concentrated under reduced pressure. The residue was dissolved in EtOAc (800 mL) and washed with Na 2 CO 3 (1 N, 1.2 L). The aqueous phase was extracted with ethyl acetate (800 mL*2). The combined organic phase was washed with brine (1 L*2), dried with anhydrous Na 2 SO 4 , filtered and concentrated in vacuum to give the title compound (130.00 g, 440.19 mmol, 79.85% yield) as a yellow solid. 1 H NMR (400 MHz, METHANOL-d 4 ) δ=4.57-4.65 (m, 2H), 4.36 (d, J=7.03 Hz, 2H), 3.67-3.74 (m, 2H), 2.75 (t, J=5.65 Hz, 2H), 1.49 (s, 9H), 1.36-1.40 (m, 3H). LCMS: 296 [M+1]

Step 3. Preparation of tert-butyl 3-[hydroxy(methyl)carbamoyl]-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylate. Sodium metal (7.78 g, 338.60 mmol, 8.02 mL, 10.00 eq) was added to MeOH (100.00 mL) portionwise at 0° C., and the mixture was stirred at 15° C. for 0.5 hr under N 2 . Then N-methylhydroxylamine (8.48 g, 101.58 mmol, 3.00 eq, HCl) was added to the mixture and the mixture was stirred at 15° C. for 0.5 hr under N 2 . Then 5-tert-butyl 3-ethyl 1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-3,5-dicarboxylate (10.00 g, 33.86 mmol, 1.00 eq) was added, the mixture was stirred at 70° C. for 16 hr under N 2 atmosphere. TLC showed the starting material was consumed completely and a new spot was detected mainly. The mixture was poured into ice-water (300 mL) and stirred at 5 min. Then the mixture was concentrated in vacuum to give the residue. The pH of the aqueous phase was adjusted to around 6 with diluted hydrochloride acid (1 N) and extracted with ethyl acetate (100 mL*3). The combined organic phase was washed with brine (300 mL), dried with anhydrous Na 2 SO 4 , filtered and concentrated in vacuum to give the title compound (8.00 g, 27.00 mmol, 79.73% yield) as a yellow solid. 1 H NMR (400 MHz, METHANOL-d 4 ) δ=4.62 (brs, 2H) 3.70 (t, J=5.52 Hz, 2H) 3.31-3.58 (m, 3H) 2.74 (s, 2H) 1.48 (s, 9H). LCMS: 297 [M+1]

Step 4. Preparation of tert-butyl 4-(hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxylate. A mixture of tert-butyl 3-[hydroxy(methyl)carbamoyl]-1,4,6,7-tetrahydroPyrazolo [4,3-c]pyridine-5-carboxylate (8.00 g, 27.00 mmol, 1.00 eq), 3-bromooxetane (4.07 g, 29.70 mmol, 1.10 eq), TBAI (997.22 mg, 2.70 mmol, 0.10 eq) and Cs 2 CO 3 (13.19 g, 40.50 mmol, 1.50 eq) in DMF (80.00 mL) was degassed and purged with N 2 for 3 times, and then the mixture was stirred at 70° C. for 3 hr under N 2 atmosphere. TLC showed the starting material was consumed completely, desired product was major. The mixture was poured into water (200 mL) and stirred for 5 min. The aqueous phase was extracted with ethyl acetate (100 mL*3). The combined organic phase was washed with brine (300 mL*2), dried with anhydrous Na 2 SO 4 , filtered and concentrated in vacuum. The residue was purified by column chromatography (SiO 2 , Petroleum ether/Ethyl acetate=100/1 to 1/2) to give the title compound (4.50 g, 12.39 mmol, 45.88% yield, 97% purity) as a yellow solid. 1 H NMR (400 MHz, CHLOROFORM-d) δ=4.62 (brs, 2H) 4.53 (brs, 2H) 4.32-4.42 (m, 1H) 3.57-3.88 (m, 4H) 3.29 (br. s., 3H) 2.68-2.79 (m, 2H) 1.41-1.53 (m, 9H). LCMS: 353 [M+1].

›PREPARATIVE EXAMPLES · 6 of 53

The racemate of tert-butyl 4-(hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxylate (2.6 g) was separated by SFC to get both enantiomers E1 (1.2 g, the first peak one) and E2 (1.3 g, the second one) (SFC separation condition: Column: Chiralpak AD-3 100×4.6 mm I.D., 3 um Mobile phase: methanol (0.05% DEA) in CO 2 from 5% to 40% Flow rate: 3 mL/min Wavelength: 220 nm). Each of the enantiomers were separately used to prepare the urea targets with the two sequential Boc protection and urea formation steps.

Intermediate 2. 3-chloro-4-fluoro-N-methylaniline

Step 1. Preparation of tert-butyl N-(3-chloro-4-fluoro-phenyl)carbamate. To a mixture of 3-chloro-4-fluoro-aniline (1.00 g, 6.87 mmol, 1.00 eq) and (Boc) 2 O (3.00 g, 13.74 mmol, 3.16 mL, 2.00 eq) in H 2 O (10.00 mL) was added TEA (2.09 g, 20.61 mmol, 2.86 mL, 3.00 eq) dropwise at 15° C. under N 2 . The mixture was stirred at 10-20° C. for 3 h. LCMS showed 3.6% starting material remained and 93.2% desired product was generated. The reaction mixture was extracted with DCM (10 mL*2). The combined organic phase was dried with ydrous Na 2 SO 4 , filtered and concentrated in vacuum. The residue was rinsed with PE (2 mL). The solid was collected by filtration, and dried in high vacuo to give the title compound (1.10 g, 4.48 mmol, 65.21% yield) as white solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.59 (br s, 1H), 7.60-7.81 (m, 1H), 7.23-7.44 (m, 2H), 3.33 (s, 2H), 2.37-2.60 (m, 11H), 1.47 (s, 9H).

Step 2. Preparation of tert-butyl N-(3-chloro-4-fluoro-phenyl)-N-methyl-carbamate. To a mixture of tert-butyl N-(3-chloro-4-fluoro-phenyl)carbamate (600.00 mg, 2.44 mmol, 1.00 eq) in DMF (5.00 mL) was added NaH (195.38 mg, 4.88 mmol, 60% purity, 2.00 eq) at 0-5° C. under N 2 . The resulting mixture was stirred at 20° C. for 1 hr. Then CH 3 I (1.04 g, 7.32 mmol, 455.70 μL, 3.00 eq) was added dropwise at 15-20° C. The resulting mixture was stirred for 2 hr. LCMS showed starting material consumed and 98.55% desired product formed. The mixture was poured into water (20 mL), and extracted with EtOAc (3*5 mL). The combined organic phase was dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure to give the title compound (500.00 mg, 1.93 mmol, 78.91% yield) as yellow oil, which was used directly in next step. 1 H NMR (400 MHz, CHLOROFORM-d) δ 7.30 (dd, J=2.01, 6.53 Hz, 1H), 7.26 (s, 1H), 7.04-7.14 (m, 2H), 3.22 (s, 3H), 1.39-1.52 (m, 9H)

Step 3. Preparation of 3-chloro-4-fluoro-N-methyl-aniline. To a solution of HCl in dioxane (4 M, 5.00 mL, 11.56 eq), was added tert-butyl N-(3-chloro-4-fluoro-phenyl)-N-methyl-carbamate (450.00 mg, 1.73 mmol, 1.00 eq) below 0° C. The resulted mixture was stirred at 0-5° C. for 1 h, then warmed naturally to 15-20° C. and stirred at 15-20° C. for 2 hr. LCMS showed the starting material was consumed and 98% desired product was formed. The resulting mixture was concentrated under reduced pressure to give the title compound (240.00 mg, 1.22 mmol, 70.76% yield, HCl) as white solid which was used directly in the next step without further purification.

Intermediate 3. tert-butyl 4-(hydroxymethyl)-2,8,8-trimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxylate

Step 1. Preparation of tert-butyl-5-(2-ethoxy-2-oxo-acetyl)-3,3-dimethyl-4-oxo-piperidine-1-carboxylate. To LiHMDS (1 M, 5.72 mL, 1.30 eq) was added a solution of tert-butyl 3,3-dimethyl-4-oxo-piperidine-1-carboxylate (1.00 g, 4.40 mmol, 1.00 eq) in THF (10.00 mL) at −78° C. under N 2 . The reaction mixture was stirred at −78° C. for 30 minutes. Diethyl oxalate (835.82 mg, 5.72 mmol, 781.14 μL 1.30 eq) was added dropwise. After addition, the reaction mixture was warmed to 15° C. and stirred for another 2 hours. TLC indicated starting material was consumed completely, and a major new spot with larger polarity was detected. The reaction was quenched with diluted HCl (1N, 40 mL) and then extracted with EtOAc (100 mL*3). The combined organic phase was dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuum to afford the title compound (1.00 g, crude) as yellow oil. The product was used in the next step without purification.

Step 2. Preparation of 5-(tert-butyl) 3-ethyl 7,7-dimethyl-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-3,5-dicarboxylate. To a solution of tert-butyl 5-(2-ethoxy-2-oxo-acetyl)-3,3-dimethyl-4-oxo-piperidine-1-carboxylate (800.00 mg, 2.44 mmol, 1.00 eq) in EtOH (10.00 mL) was added NH 2 NH 2 .H 2 O (143.70 mg, 2.44 mmol, 139.51 μL 85% purity, 1.00 eq). The reaction mixture was stirred at 15° C. for 2 hours. TLC indicated the starting material was consumed completely, and one major new spot with larger polarity was detected. The reaction mixture was diluted with EtOAc (150 mL) and washed with water (80 mL*2), the organic phase was dried with anhydrous Na 2 SO 4 , filtered and concentrated in vacuum. The residue was purified by silica gel chromatography to afford the title compound (760.00 mg, 2.23 mmol, 91.50% yield, 95% purity) as yellow solid. 1 H NMR (400 MHz, METHANOL-d 4 ) δ=4.61 (s, 2H) 4.33-4.38 (q, J=7.11 Hz, 2H) 3.44 (brs, 2H) 1.49 (s, 9H) 1.37-1.40 (t, J=7.09 Hz, 3H) 1.28 (s, 6H). LCMS: 324 [M+1].

Step 3. Preparation of 5-tert-butoxycarbonyl-7,7-dimethyl-4,6-dihydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylic acid. To a solution of 5-(tert-butyl) 3-ethyl 7,7-dimethyl-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-3,5-dicarboxylate (900.00 mg, 2.78 mmol, 1.00 eq) in THF (10.00 mL) was added a solution of NaOH (222.64 mg, 5.57 mmol, 2.00 eq) in H 2 O (2.00 mL), the reaction mixture was warmed to 50° C. and stirred at 50° C. for 5 hours. TLC showed the reaction was completed. The pH of the reaction mixture was adjusted to around 6 by adding diluted hydrochloride acid (2N, 10 mL), then extracted with EtOAc (100 mL*4) and water (20 mL), the organic phase was dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuum to afford the title compound (780.00 mg, 2.59 mmol, 93.10% yield, 98% purity) as white solid. The product was used in the next step directly without further purification. LCMS: 296 [M+1].

›PREPARATIVE EXAMPLES · 7 of 53

Step 4. Preparation of tert-butyl 3-[hydroxy(methyl)carbamoyl]-7,7-dimethyl-4,6-dihydro-1H-pyrazolo[4,3-c]pyridine-5-carboxylate. To a mixture of 5-tert-butoxycarbonyl-7,7-dimethyl-4,6-dihydro-1H-pyrazolo[4,3-c] pyridine-3-carboxylic acid (200.00 mg, 677.21 μmol, 1.00 eq) in THF (5.00 mL) was added T 3 P (1.72 g, 2.71 mmol, 1.61 mL, 50% purity, 4.00 eq) and TEA (342.63 mg, 3.39 mmol, 469.36 μL5.00 eq), followed by N-methylhydroxylamine (113.12 mg, 1.35 mmol, 2.00 eq, HCl), the reaction mixture was stirred at 40° C. for 16 hours. LCMS showed the starting material was consumed completely and one main peak with desired MS was detected. The reaction mixture was diluted with EtOAc (80 mL) and washed with water (50 mL*2), the organic phase was dried with anhydrous Na 2 SO 4 , filtered and concentrated in vacuum. The residue was purified by silica gel chromatography to afford the title compound (70.00 mg, 215.80 μmol, 31.87% yield) as white solid. 1 H NMR (400 MHz, CHLOROFORM-d) δ=4.64 (s, 2H) 3.39 (brs, 5H) 1.47 (s, 9H) 1.27 (s, 6H). LCMS: 269 [M+1-56].

Step 5. Preparation of tert-butyl 4-(hydroxymethyl)-2,8,8-trimethyl-1-oxo-1,2,4,5,8,9-hexahydro pyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(11H)-carboxylate. To a mixture of tert-butyl 3-[hydroxy(methyl)carbamoyl]-7,7-dimethyl-4,6-dihydro-1H-pyrazolo[4,3-c]pyridine-5-carboxylate (70.00 mg, 215.80 μmol, 1.00 eq) and 3-bromooxetane (35.47 mg, 258.96 μmol, 1.20 eq) in DMF (2.00 mL) was added Cs 2 CO 3 (105.47 mg, 323.70 μmol, 1.50 eq) and TBAI (7.97 mg, 21.58 μmol, 0.10 eq), the reaction mixture was warmed to 75° C. and stirred at 75° C. for 3 hours. LCMS showed 50% of the starting material was remained. The reaction mixture was stirred at 75° C. for another 3 hours. LCMS showed the starting material was consumed completely and one main peak with desired MS was detected. The reaction mixture was diluted with EtOAc (100 mL) and washed with water (50 mL*3), the organic phase was dried with anhydrous Na 2 SO 4 , filtered and concentrated in vacuum to afford the title compound (53.00 mg, crude) as yellow oil. The product was used in the next step directly without further purification. LCMS: 381 [M+1].

Intermediate 4. tert-butyl 4-(hydroxymethyl)-2,8-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxylate

Step 1. Preparation of tert-butyl 3-methyl-4-oxo-piperidine-1-carboxylate. To a solution of 1-benzyl-3-methyl-piperidin-4-one (2.00 g, 9.84 mmol, 1.00 eq) and Boc 2 O (2.15 g, 9.84 mmol, 2.26 mL, 1.00 eq) in MeOH (50.00 mL) was added Pd/C (9.84 mmol, 1.00 eq) under N 2 . The suspension was degassed under vacuum and purged with H 2 several times. The mixture was stirred under H 2 (50 psi) at 20° C. for 16 hours. TLC (PE:EA=5:1) showed the reaction was completed. The mixture was filtrated. The filtrate was concentrated in vacuum. The residue was purified by column chromatography (PE:EA=0%˜15%) to afford the title compound (2.00 g, 9.38 mmol, 95.33% yield) as colorless oil. 1 H NMR (400 MHz, CHLOROFORM-d) δ=4.16-4.24 (m, 1H), 3.22-3.33 (m, 1H), 2.86 (brs, 1H), 2.38-2.61 (m, 3H), 1.51 (s, 9H), 1.06 (d, J=6.7 Hz, 3H).

Step 2. Preparation of tert-butyl 3-(2-ethoxy-2-oxo-acetyl)-5-methyl-4-oxo-piperidine-1-carboxylate. To a solution of tert-butyl 3-methyl-4-oxo-piperidine-1-carboxylate (2.00 g, 9.38 mmol, 1.00 eq) in THF (40.00 mL) was added LiHMDS (1 M, 11.26 mL, 1.20 eq) dropwise at −60° C. The mixture was stirred at −60° C. for 30 min. Diethyl oxalate (1.51 g, 10.32 mmol, 1.41 mL, 1.10 eq) was added dropwise at −60° C. Then the mixture was stirred at 20° C. for 1 hr. TLC (PE:EA=5:1) showed the reaction was completed. The reaction was quenched by saturated NH 4 Cl (20 mL) and extracted with EtOAc (60 mL*2). The combined organic layer was dried over Na 2 SO 4 , filtrated. The filtrate was concentrated in vacuum to afford the title compound (2.00 g, crude) as yellow oil.

Step 3. Preparation of 5-(tert-butyl) 3-ethyl 7-methyl-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-3,5-dicarboxylate. To a solution of tert-butyl 3-(2-ethoxy-2-oxo-acetyl)-5-methyl-4-oxo-piperidine-1-carboxylate (2.00 g, 6.38 mmol, 1.00 eq) in EtOH (40.00 mL) was added NH 2 NH 2 .H 2 O (394.59 mg, 6.70 mmol, 383.10 μL85% purity, 1.05 eq). The mixture was stirred at 20° C. for 16 hr. Major desired product was detected via LCMS. The mixture was concentrated in vacuum. The residue was diluted with EtOAc (80 mL) and H 2 O (30 mL). The organic phase was dried over Na 2 SO 4 , filtrated. The filtrate was concentrated in vacuum. The residue was purified by column chromatography (PE:EA:10%˜50%) to afford the title compound (1.00 g, 3.23 mmol, 50.61% yield) as white solid. 1 H NMR (400 MHz, CHLOROFORM-d) δ=1.30-1.34 (m, 3H) 1.41 (t, J=7.09 Hz, 3H) 1.49-1.55 (m, 9H) 2.98-3.38 (m, 2H) 3.74-4.08 (m, 1H) 4.40 (q, J=6.78 Hz, 2H) 4.47-4.68 (m, 1H) 4.78 (d, J=17.19 Hz, 1H).

Step 4. Preparation of 5-tert-butoxycarbonyl-7-methyl-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-3-carboxylic acid. To a solution of 5-(tert-butyl) 3-ethyl 7-methyl-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-3,5-dicarboxylate (1.00 g, 3.23 mmol, 1.00 eq) in THF (10.00 mL) was added a solution of NaOH (258.40 mg, 6.46 mmol, 2.00 eq) in H 2 O (2.00 mL). The mixture was stirred at 40° C. for 16 hr. TLC (PE:EA=1:1) showed the reaction was completed and one major spot appeared. Adjusted the pH of the mixture to 5-6 with 1N HCl (10 mL) and extracted with EtOAc (20 mL*2). The combined organic layer was dried over Na 2 SO 4 , filtrated. The filtrate was concentrated in vacuum to afford the title compound (850.00 mg, 2.95 mmol, 91.21% yield, 97.5% purity) as white solid. LCMS: 282 [M+1].

Step 5. Preparation of tert-butyl 3-[hydroxy(methyl)carbamoyl]-7-methyl-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylate. To a solution of 5-tert-butoxycarbonyl-7-methyl-1,4,6,7-tetrahydropyrazolo[4,3-c] pyridine-3-carboxylic acid (200.00 mg, 710.96 μmol, 1.00 eq) and N-methylhydroxylamine (237.52 mg, 2.84 mmol, 4.00 eq, HCl) in THF (5.00 mL) was added T 3 P (1.81 g, 2.84 mmol, 1.69 mL, 50% purity, 3.99 eq) followed by TEA (575.54 mg, 5.69 mmol, 788.41 μL8.00 eq). The mixture was heated to 40° C. for 16 hr. TLC (DCM:MeOH=10:1) showed two main spots appeared. The mixture was extracted with EtOAc (20 mL*2) and H 2 O (20 mL). The combined organic layer was dried over Na 2 SO 4 , filtrated. The filtrate was concentrated. The residue was purified by column chromatography (PE:EA=50%˜100%) to afford the title compound (66.00 mg, 212.66 μmol, 29.91% yield) as white solid. LCMS: 312 [M+1].

›PREPARATIVE EXAMPLES · 8 of 53

Step 6. Preparation of tert-butyl 4-(hydroxymethyl)-2,8-dimethyl-1-oxo-1,2,4,5,8,9-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(11H)-carboxylate. To a solution of tert-butyl 3-[hydroxy(methyl)carbamoyl]-7-methyl-1,4,6,7-tetra hydropyrazolo[4,3-c]pyridine-5-carboxylate (60.00 mg, 193.33 μmol, 1.00 eq) in DMF (2.00 mL) was added Cs 2 CO 3 (188.97 mg, 579.99 μmol, 3.00 eq) followed by 3-bromooxetane (31.78 mg, 232.00 μmol, 1.20 eq). The mixture was stirred at 75° C. for 4 hr. LCMS showed the reaction was completed, major desired product was detected. The mixture was diluted with EtOAc (60 mL) and H 2 O (30 mL). Separated the organic layer and washed with H 2 O (30 mL*3), dried over Na 2 SO 4 , filtrated. The filtrate was concentrated in vacuum to afford the title compound (60.00 mg, crude) as yellow oil. LCMS: 367 [M+1].

Intermediate 5. tert-butyl 2-ethyl-4-(hydroxymethyl)-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxylate

Step 1. Preparation of tert-butyl 3-[ethyl(hydroxy)carbamoyl]-2,4,6,7-tetrahydropyrazolo[4,3-c] pyridine-5-carboxylate. To a solution of 5-tert-butoxycarbonyl-2,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-3-carboxylic acid (100.00 mg, 374.14 μmol, 1.00 eq) in DMF (3.00 mL) was added HATU (184.94 mg, 486.38 μmol, 1.30 eq), DIPEA (241.77 mg, 1.87 mmol, 326.72 μL5.00 eq) and N-ethylhydroxylamine (109.48 mg, 1.12 mmol, 3.00 eq, HCl). The mixture was stirred at 80° C. for 16 hr. LCMS showed the desired product was detected and −20% starting material was remained. The mixture was poured into water (20 mL), and extracted with DCM (20 mL*2). The organic layer was washed with brine (30 mL*3), dried over anhydrous Na 2 SO 4 and concentrated in vacuum. The crude was purified by Prep-TLC (Dichloromethane:Methanol=10:1) to give the title compound (36.00 mg, 115.65 μmol, 30.91% yield, 99.7% purity) as colorless oil. LCMS: 311[M+1].

Step 2. Preparation of tert-butyl 2-ethyl-4-(hydroxymethyl)-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxylate. To a solution of tert-butyl 3-[ethyl(hydroxy)carbamoyl]-2,4,6,7-tetrahydropyrazolo [4,3-c]pyridine-5-carboxylate (36.00 mg, 116.00 μmol, 1.00 eq) and 3-bromooxetane (19.07 mg, 139.20 μmol, 1.20 eq) in DMF (2.00 mL) was added Cs 2 CO 3 (45.35 mg, 139.20 μmol, 1.20 eq) and TBAI (4.28 mg, 11.60 μmol, 0.10 eq). The mixture was stirred at 75° C. for 3 hr. LCMS showed about 40% starting material 2 was remained. The mixture was stirred at 75° C. for another 3 hr. The mixture was diluted with ethyl acetate (40 mL), washed with brine (30 mL*3). The organic layer was dried over anhydrous Na 2 SO 4 , concentrated in vacuum. The crude was purified by prep-TLC (100% Ethyl acetate). The title compound (25.00 mg, 68.23 μmol, 58.82% yield) was obtained as the colorless oil.

Intermediate 6. tert-butyl 3-(hydroxy(methyl)carbamoyl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate

Step 1. Preparation of tert-butyl 3-(2-ethoxy-2-oxo-acetyl)-4-oxo-piperidine-1-carboxylate. To LiHMDS (1 M, 652.44 mL, 1.30 eq) was added a solution of tert-butyl 4-oxopiperidine-1-carboxylate (100.00 g, 501.88 mmol, 1.00 eq) in THF (1.00 L) dropwise at −78° C. under N 2 . The reaction mixture was stirred at −78° C. for 30 minutes under N 2 . Then diethyl oxalate (95.35 g, 652.44 mmol, 1.30 eq) was added dropwise. After addition, the reaction mixture was warmed to 15° C. over a period of 30 minutes and stirred at 15° C. for another 2 hours. TLC (PE/EA=3/1) showed the reaction was completed. The reaction was quenched with NH 4 Cl (sat. aq, 1.5 L) and then neutralized with diluted hydrochloric acid, the aqueous layer was extracted with EtOAc (800 mL×3). The combined organic phase was dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuum to afford the title compound (165.00 g, crude) as yellow oil and used directly for next step.

Step 2. Preparation of 5-tert-butyl 3-ethyl 1,4,6,7-tetrahydropyrazolo [4,3-c]pyridine-3,5-dicarboxylate. A mixture of tert-butyl 3-(2-ethoxy-2-oxo-acetyl)-4-oxo-piperidine-1-carboxylate (165.00 g, crude, 551.25 mmol, 1.00 eq) and NH 2 NH 2 .H 2 O (35.71 g, 606.37 mmol, 1.10 eq) in AcOH (1.00 L) was degassed and purged with N 2 for 3 times. Then the mixture was stirred at 80° C. for 1 hour under N 2 atmosphere. TLC (PE/EA=1/1) and LCMS showed the reaction was completed. The mixture was concentrated under reduced pressure. The residue was dissolved in EtOAc (800 mL) and washed with Na 2 CO 3 (1 N, 1.2 L). The aqueous phase was extracted with ethyl acetate (800 mL×2). The combined organic phase was washed with brine (1 L×2), dried with anhydrous Na 2 SO 4 , filtered and concentrated in vacuum to afford the title compound (130.00 g, 440.19 mmol, 79.85% yield) as a yellow solid. LCMS: 296 [M+1]. 1 H NMR (400 MHz, METHANOL-d 4 ) δ=4.57-4.65 (m, 2H), 4.36 (d, J=7.03 Hz, 2H), 3.67-3.74 (m, 2H), 2.75 (t, J=5.65 Hz, 2H), 1.49 (s, 9H), 1.36-1.40 (m, 3H).

Step 3. Preparation of 5-tert-butoxycarbonyl-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-3-carboxylic acid. A mixture of 5-tert-butyl 3-ethyl 1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-3,5-dicarboxylate (10.00 g, 33.86 mmol, 1.00 eq) and NaOH (2.03 g, 50.79 mmol, 1.50 eq) in THF (100.00 mL) and H 2 O (20.00 mL) was degassed and purged with N 2 for 3 times, and then the mixture was stirred at 40° C. for 16 hr under N 2 atmosphere. Then the mixture was stirred at 50° C. for 4 hr, LCMS showed the reaction was completed. The mixture was diluted in water (100 mL) and extracted with EA (50 mL×2). The aqueous phase was separated and adjusted the pH˜6 by adding diluted hydrochloride acid (1 N), solid was precipitated out. The mixture was filtered and the cake was concentrated in vacuum to afford the title compound (8.00 g, 29.93 mmol, 88.40% yield, 100% purity) as a yellow solid. LCMS: 268 [M+1]

Step 4. Preparation of tert-butyl 3-(hydroxy(methyl)carbamoyl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate. A mixture of 5-tert-butoxycarbonyl-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-3-carboxylic acid (3.00 g, 11.22 mmol, 1.00 eq), N-methylhydroxylamine (1.41 g, 16.83 mmol, 1.50 eq, HCl), T 3 P (17.86 g, 56.10 mmol, 16.69 mL, 5.00 eq) and TEA (11.35 g, 112.20 mmol, 15.55 mL, 10.00 eq) in THF (30.00 mL) was degassed and purged with N 2 for 3 times, and then the mixture was stirred at 50° C. for 16 hour under N 2 atmosphere. LCMS showed the reaction was completed. The mixture was poured into water (80 mL), the aqueous layer was adjusted pH˜4 by 1N HCl, then the aqueous layer was extracted with DCM (40 mL×3), the combined organic layer was dried with anhydrous Na 2 SO 4 , filtered and concentrated in vacuum. The residue was purified by column chromatography (SiO 2 , PE/EA=100/1 to 1/1) to give the crude product which was rinsed with EtOAc to afford the title compound (1.30 g, 4.39 mmol, 39.10% yield, 100% purity) as a white solid. LCMS: 319 [M+23].

›PREPARATIVE EXAMPLES · 9 of 53

Intermediate 7. tert-butyl 2,5-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxylate

To a solution of tert-butyl 3-(hydroxy(methyl)carbamoyl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (Intermediate 6, 50.00 mg, 168.74 μmol, 1.00 eq) in DMF (2.00 mL) was added TBAI (6.23 mg, 16.87 μmol, 0.10 eq). The reaction mixture was stirred at 15° C. for 3 hr. LCMS showed ˜77% of the starting material remained and −8.5% of desired product was detected. The reaction mixture was stirred at 50° C. for another 24 hr. TLC indicated the starting material remained and two new spots formed. The reaction mixture was quenched by water (20 mL) and extracted with EtOAc (30 mL×3). The combined organic layers were washed with saturated NH 4 Cl. The residue was purified by prep-TLC (PE/EA, 1/3) to give the title compound (10.00 mg, 29.73 μmol, 17.62% yield) was obtained as a white solid. LCMS: 337 [M+1]. 1 H NMR (400 MHz, CHLOROFORM-d) (pilot run EW4043-68) δ 4.60-4.76 (m, 3H), 4.48 (dd, J=5.52, 11.42 Hz, 1H), 3.88-4.04 (m, 1H), 3.73-3.85 (m, 1H), 3.66 (s, 1H), 3.31 (s, 3H), 2.79 (s, 2H), 1.62 (d, J=6.65 Hz, 3H), 1.49 (s, 9H).

Intermediate 8. tert-butyl 2,4-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxylate

Step 1. Preparation of tert-butyl 3-[(2-ethoxy-1-methyl-2-oxo-ethoxy)-methyl-carbamoyl]-2,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylate. To a solution of tert-butyl 3-(hydroxy(methyl)carbamoyl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (Intermediate 6, 400.00 mg, 1.35 mmol, 1.00 eq) in THF (20.00 mL) was added t-BuOK (151.50 mg, 1.35 mmol, 1.00 eq) under N 2 . The reaction mixture was stirred at 0° C. for 1 hr. Then ethyl 2-bromopropanoate (232.00 mg, 1.28 mmol, 166.91 μL0.95 eq) in THF (4.00 mL) was added dropwise under N 2 . After addition, the reaction mixture was stirred at 15° C. for 2 hr. TLC (PE/EA, 1/2) indicated the starting material was consumed completely and two new spots formed. The reaction mixture was quenched by sat. aq. NH 4 Cl (15 mL) and extracted with EtOAc (30 mL×3). The combined organic layers were washed with water (15 mL) and brine (20 mL), dried with anhydrous Na 2 SO 4 , filtered and concentrated in vacuo. The residue was purified by column chromatography (PE/EA, 2/1 to 1/1) to give the title compound (510.00 mg, 1.29 mmol, 95.29% yield) as a white solid.

Step 2. Preparation of tert-butyl 3-[(2-hydroxy-1-methyl-ethoxy)-methyl-carbamoyl]-2,4,6,7-tetra hydropyrazolo[4,3-c]pyridine-5-carboxylate. To a solution of tert-butyl 3-[(2-ethoxy-1-methyl-2-oxo-ethoxy)-methyl-carbamoyl]-2,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylate (400.00 mg, 706.29 μmol, 1.00 eq) in THF (5.00 mL) was added NaBH 4 (26.72 mg, 706.29 μmol, 1.00 eq) followed by MeOH (200.00 μL at −10° C. The mixture was stirred at 10° C. for 2 hr. TLC showed the starting material was consumed and three spots appeared. The mixture was quenched by saturated NH 4 Cl (10 mL) and extracted with EtOAc (20 mL*2). The combined organic layer was dried over Na 2 SO 4 , filtrated. The filtrate was concentrated in vacuum. The residue was purified by prep-TLC (EA:MeOH=10:1) to get the title compound (80.00 mg, 225.73 μmol, 31.96% yield) as colorless oil.

Step 3. Preparation of tert-butyl 2,4-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxylate. To a solution of tert-butyl 3-[(2-hydroxy-1-methyl-ethoxy)-methyl-carbamoyl]-2,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylate (70.00 mg, 197.52 μmol, 1.00 eq) in THF (4.00 mL) was added tributylphosphane (79.92 mg, 395.04 μmol, 97.46 μL2.00 eq) followed by DIAD (79.88 mg, 395.04 μmol, 76.81 μL2.00 eq) under N 2 . The mixture was heated to 60° C. for 16 hr. TLC showed the starting material consumed and one main spot appeared. The mixture was extracted with EtOAc (30 mL*2) and H 2 O (20 mL). The combined organic layer was dried over Na 2 SO 4 , filtrated. The filtrate was concentrated in vacuum. The residue was purified by prep-TLC (PE:EA=1:2) to get the title compound (42.00 mg, 124.86 μmol, 63.21% yield) as colorless oil.

Intermediate 9. tert-butyl 2,4,4-trimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxylate

Step 1. Preparation of methyl-2-[tert-butoxycarbonyl(methyl)amino]oxy-2-methyl-propanoate. To a solution of CH 3 ONa (587.78 mg, 10.88 mmol, 1.00 eq) in MeOH (20.00 mL) was added methyl 2-bromo-2-methyl-propanoate (1.97 g, 10.88 mmol, 1.41 mL, 1.00 eq) and tert-butyl N-hydroxy-N-methyl-carbamate (1.60 g, 10.88 mmol, 1.00 eq) at 15° C. The mixture was heated to 60° C. with stirring for 16 h. TLC (PE:EtOAc=5:1) showed that starting material was consumed completely and one main new spot formed. The mixture was evaporated to remove the solvent and get the residue. The residue was purified by column chromatography (SiO 2 , Petroleum ether/Ethyl acetate=100/1 to 20/1) to obtain the title compound (2.30 g, 9.30 mmol, 85.49% yield) as off-white liquid. 1 H NMR (400 MHz, CHLOROFORM-d) δ=3.74 (s, 3H), 3.11 (s, 3H), 1.48 (d, J=4.9 Hz, 15H).

Step 2. Preparation of tert-butyl N-(2-hydroxy-1,1-dimethyl-ethoxy)-N-methyl-carbamate. LiBH 4 (704.60 mg, 32.35 mmol, 4.00 eq) was charged to a cooled three-necked round bottom flask at −78° C. under N 2 , then a solution of methyl 2-[tert-butoxycarbonyl(methyl)amino]oxy-2-methyl-propanoate (2.00 g, 8.09 mmol, 1.00 eq) in THF (20.00 mL) was added dropwise. After addition, the reaction mixture was warmed to 0° C. and stirred at 0° C. for 2 hours. TLC (PE:EtOAc=2:1) showed that reactant 3 was consumed completely and one main spot formed. The mixture was quenched with 20 mL of water and filtered to get the filtrate. The filtrate was extracted with EtOAc (20 mL*3) and the organic phases were combined. The combined organic phase was dried over anhydrous Na 2 SO 4 , filtered and concentrated to get the residue. The residue was purified by column chromatography (SiO 2 , Petroleum ether/Ethyl acetate=1/0 to 15/1) to obtain the title compound (1.30 g, 5.93 mmol, 73.32% yield) as off-white liquid. 1 H NMR (400 MHz, CHLOROFORM-d) δ=4.60 (brs, 1H), 3.59 (br d, J=12.35 Hz, 1H), 3.01-3.21 (m, 4H), 1.49 (s, 9H), 1.15-1.33 (m, 6H).

›PREPARATIVE EXAMPLES · 10 of 53

Step 3. Preparation of 2-methyl-2-(methylaminooxy)propan-1-ol. To a solution of tert-butyl N-(2-hydroxy-1,1-dimethyl-ethoxy)-N-methyl-carbamate (1.30 g, 5.93 mmol, 1.00 eq) in dioxane (2.00 mL) was added HCl/dioxane (4 M, 6.00 mL, 4.05 eq) under stirring at 15° C. for 2 h. TLC (PE:EtOAc=3:1) showed that the starting material was consumed completely and one main spot formed. The mixture was directly evaporated to get the title compound (1.10 g, crude, HCl) as yellow oil. 1 H NMR (400 MHz, METHANOL-d 4 ) δ=3.75 (s, 2H), 2.95 (s, 3H), 1.37 (s, 6H).

Step 4. Preparation of tert-butyl 3-[(2-hydroxy-1,1-dimethyl-ethoxy)-methyl-carbamoyl]-2,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylate. To a solution of 5-tert-butoxycarbonyl-2,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-3-carboxylic acid (800.00 mg, 2.99 mmol, 1.00 eq) and 2-methyl-2-(methylaminooxy)propan-1-ol (604.89 mg, 3.89 mmol, 1.30 eq, HCl) in THF (8.00 mL) was added T 3 P (3.81 g, 5.98 mmol, 3.56 mL, 50% purity, 2.00 eq) and TEA (2.42 g, 23.92 mmol, 3.32 mL, 8.00 eq). The mixture was stirred at 30° C. for 2 hr. LCMS showed 30% desired product and 40% byproduct with MS+1=747. The mixture was diluted with saturated NH 4 Cl (50 mL) and extracted with EtOAc (50 mL*2). The combined organic layer was dried over Na 2 SO 4 , filtrated. The filtrate was concentrated in vacuum. The residue was purified by column chromatography (PE:EA:30%˜100%) to get the title compound (200.00 mg, 542.84 μmol, 18.16% yield) as white solid. 1 H NMR (400 MHz, CHLOROFORM-d) δ=4.70 (brs, 2H), 3.60-3.77 (m, 4H), 3.50 (brs, 3H), 2.77 (t, J=5.32 Hz, 2H), 1.49 (s, 9H), 1.36 (s, 6H).

Step 5. Preparation of tert-butyl 2,4,4-trimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxylate. To a solution of tert-butyl 3-[(2-hydroxy-1,1-dimethyl-ethoxy)-methyl-carbamoyl]-2,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylate (200.00 mg, 542.84 μmol, 1.00 eq) in THF (2.00 mL) was added tributylphosphane (219.66 mg, 1.09 mmol, 267.87 μL2.00 eq) followed by DIAD (219.54 mg, 1.09 mmol, 211.09 μL2.00 eq) under N 2 . The mixture was heated to 80° C. for 16 hr. TLC (PE:EA=0:1) showed the starting material was consumed and one main spot appeared. The mixture was extracted with EtOAc (10 mL*2) and H 2 O (10 mL). The combined organic layer was dried over Na 2 SO 4 , filtrated. The filtrate was concentrated in vacuum. The residue was purified by prep-TLC (PE:EA=0:1) to give the title compound (150.00 mg, 428.07 μmol, 78.86% yield) as colorless oil.

Intermediate 10. tert-butyl 2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxylate

To a mixture of tert-butyl 3-(hydroxy(methyl)carbamoyl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (Intermediate 6, 100.00 mg, 337.47 μmol, 1.00 eq) and K 2 CO 3 (93.28 mg, 674.94 μmol, 2.00 eq) in DMF (3.00 mL) was added 1,2-dibromoethane (69.74 mg, 371.22 μmol, 28.01 μL1.10 eq) in one portion at 15° C. The mixture was stirred at 15° C. for 36 hours. LCMS and TLC (dichloromethane:methanol=10:1) showed the reaction was completed. The mixture was poured into water (15 mL) and stirred for 2 min. The aqueous phase was extracted with ethyl acetate (15 mL*2). The combined organic phase was washed with brine (10 mL*2), dried with anhydrous Na 2 SO 4 , filtered and concentrated in vacuum. The residue was purified by prep-TLC (dichloromethane:methanol=10:1) to afford the title compound (55.00 mg, 170.62 μmol, 50.56% yield, 100% purity) as a yellow solid. LCMS: 323 [M+1].

Intermediate 11. N-allylhydroxylamine

Step 1. Preparation of [allyl(tert-butoxycarbonyl)amino] tert-butyl carbonate. To a solution of (tert-butoxycarbonylamino) tert-butyl carbonate (5.50 g, 23.58 mmol, 1.00 eq) in DMF (30.00 mL) was added K 2 CO 3 (6.52 g, 47.16 mmol, 2.00 eq) and 3-bromoprop-1-ene (3.71 g, 30.65 mmol, 1.30 eq) under N 2 , the reaction mixture was stirred at 50° C. for 12 hr. TLC indicated the starting material was consumed completely and one new spot formed. The reaction mixture was filtered and the filter cake was washed with EtOAc (100 mL×3), the organic layer was added water (200 mL) and extracted with EtOAc (200 mL×3), the combined layers were washed with water (50 mL×3) and brine (150 mL), dried with anhydrous Na 2 SO 4 , filtered and concentrated in vacuum. The residue was purified by column chromatography to give the title compound (5.20 g, 19.03 mmol, 80.68% yield) as colorless oil. 1 H NMR (400 MHz, CHLOROFORM-d) δ=5.76-6.00 (m, 1H) 5.18-5.31 (m, 2H) 4.19 (d, J=5.77 Hz, 2H) 1.52 (s, 9H) 1.49 (s, 9H).

Step 2. Preparation of N-allylhydroxylamine. To a solution of [allyl(tert-butoxycarbonyl)amino] tert-butyl carbonate (1.90 g, 6.95 mmol, 1.00 eq) in DCM (35.00 mL) was added TFA (53.90 g, 472.74 mmol, 35.00 mL, 68.02 eq), the reaction mixture was stirred at 15° C. for 3 hr. TLC indicated the starting material was consumed completely and one new spot formed. The reaction mixture was concentrated in vacuum to give the title compound (1.31 g, crude, TFA) as a light yellow oil.

Intermediate 12. tert-butyl 2-allyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxylate

Step 1. Preparation of tert-butyl3-[allyl(hydroxy)carbamoyl]-2,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylate. To a solution of N-allylhydroxylamine (Intermediate 11, 1.05 g, 5.61 mmol, 1.50 eq, TFA) and TEA (3.07 g, 30.29 mmol, 4.20 mL, 8.10 eq) in THF (50.00 mL) was added T 3 P (9.64 g, 15.15 mmol, 9.01 mL, 50% purity, 4.05 eq) and 5-tert-butoxycarbonyl-2,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-3-carboxylic acid (1.00 g, 3.74 mmol, 1.00 eq), the reaction mixture was stirred at 30° C. for 40 min. LCMS showed the starting material was consumed completely and a peak (about 69%) with desired MS was detected. The reaction mixture was quenched with water (40 mL) and extracted with EtOAc (40 mL×3), the combined organic layers were washed with water (50 mL×3) and brine (50 mL), filtered, dried with anhydrous Na 2 SO 4 and concentrated in vacuum to give the title compound (900.00 mg, 2.29 mmol, 61.21% yield, 82% purity) as a light yellow solid. 1 H NMR (400 MHz, CHLOROFORM-d) δ=5.90 (s, 1H) 5.20-5.35 (m, 2H) 4.23-4.77 (m, 4H) 3.67 (s, 2H) 2.71 (s, 2H) 1.48 (s, 9H). LCMS: 323 [M+1].

›PREPARATIVE EXAMPLES · 11 of 53

Step 2. Preparation of tert-butyl 2-allyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-c] [1,2,5]oxadiazepine-10-carboxylate. To a mixture of tert-butyl 3-[allyl(hydroxy)carbamoyl]-2,4,6,7-tetrahydropyrazolo [4,3-c]pyridine-5-carboxylate (80.00 mg, 248.17 μmol, 1.00 eq) and 1,2-dibromoethane (69.93 mg, 372.25 μmol, 28.08 μL1.50 eq) in DMF (2.00 mL) was added Cs 2 CO 3 (242.58 mg, 744.51 μmol, 3.00 eq) and TBAI (9.17 mg, 24.82 μmol, 0.10 eq), the reaction mixture was stirred at 30° C. for 16 hours. LCMS showed the starting material was consumed completely and about 60% of desired compound was detected. The reaction mixture was diluted with EtOAc (80 mL) and washed with water (50 mL*2), the organic phase was dried with anhydrous Na 2 SO 4 , filtered and concentrated in vacuum. The residue was purified by silica gel chromatography to give the title compound (53.00 mg, 136.91 μmol, 55.17% yield, 90% purity) as yellow oil. LCMS: 349 [M+1].

Intermediate 13. 5-(tert-butoxycarbonyl)-6-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylic acid

Step 1. Preparation of ethyl 3-aminobutanoate. SOCl 2 (28.84 g, 242.43 mmol, 17.59 mL, 2.50 eq) was added to EtOH (100.00 mL) dropwise at 0° C. under N 2 . The mixture was stirred at 0° C. for 0.5 hr under N 2 . Then 3-aminobutanoic acid (10.00 g, 96.97 mmol, 1.00 eq) was added to the mixture and the mixture was stirred at 25° C. for 1.5 hr under N 2 . And then the mixture was stirred at 50° C. for 1 hr under N 2 atmosphere. TLC (DCM/MeOH=10/1) showed the reaction was completed. The mixture was concentrated in vacuum to afford the title compound (16.00 g, 95.45 mmol, 98.43% yield, HCl) as black brown oil. 1 H NMR (400 MHz, METHANOL-d 4 ) δ=2.66 (d, J=7.15 Hz, 2H), 2.09-2.19 (m, 1H), 1.17 (d, J=6.53 Hz, 2H), −0.18 (d, J=6.65 Hz, 3H), −0.27 (s, 3H)

Step 2. Preparation of ethyl 3-[(3-ethoxy-3-oxo-propyl) amino]butanoate. To a solution of ethyl 3-aminobutanoate (10.00 g, 59.66 mmol, 11.24 mL, 1.00 eq, HCl) in EtOH (100.00 mL) was added NaOH (2.51 g, 62.64 mmol, 1.05 eq) followed by ethyl prop-2-enoate (7.17 g, 71.59 mmol, 7.79 mL, 1.20 eq). The mixture was heated to 80° C. and stirred at 80° C. for 16 hr. TLC (DCM:MeOH=10:1) showed the starting material remained and a new spot was appeared. The pH of the mixture was adjusted to 4 with HCl (1N) and extracted with EA (200 mL). The aqueous phase was adjust to pH˜8 with Na 2 CO 3 (sat. aq) and then extracted with EA (200 mL×2). The combined organic layer was dried over Na 2 SO 4 , filtered and concentrated to afford the title compound (9.00 g, 38.91 mmol, 65.22% yield) as colorless oil.

Step 3. Preparation of ethyl 3-[tert-butoxycarbonyl-(3-ethoxy-3-oxo-propyl)amino]butanoate. To a mixture of ethyl 3-[(3-ethoxy-3-oxo-propyl)amino]butanoate (9.00 g, 38.91 mmol, 1.00 eq) and TEA (5.51 g, 54.47 mmol, 7.55 mL, 1.40 eq) in THF (50.00 mL) was added Boc 2 O (8.49 g, 38.91 mmol, 8.94 mL, 1.00 eq) at 30° C. The mixture was stirred at 30° C. for 12 hours. TLC (PE/EA=5/1) and LCMS showed the reaction was completed. The mixture was poured into water (30 mL) and stirred for 1 min. The aqueous phase was extracted with ethyl acetate (30 mL×2). The combined organic phase was washed with brine (30 mL×2), dried with anhydrous Na 2 SO 4 , filtered and concentrated in vacuum. The residue was purified by silica gel chromatography (PE/EA=10/1) to afford the title compound (7.00 g, 21.12 mmol, 54.29% yield) as yellow oil.

Step 4. Preparation of 1-tert-butyl 3-ethyl 6-methyl-4-oxo-piperidine-1,3-dicarboxylate. To a mixture of ethyl 3-[tert-butoxycarbonyl-(3-ethoxy-3-oxo-propyl)amino] butanoate (7.20 g, 21.73 mmol, 1.00 eq) in THF (200.00 mL) was added t-BuOK (2.68 g, 23.90 mmol, 1.10 eq) in one portion at −40° C. under N 2 . The mixture was stirred at −40° C. for 1 hr. LCMS showed the reaction was completed. The mixture was poured into water (50 mL) and stirred for 3 min. The aqueous phase was extracted with ethyl acetate (50 mL×2). The combined organic phase was washed with brine (50 mL×2), dried with anhydrous Na 2 SO 4 , filtered and concentrated in vacuum to afford the title compound (5.00 g, 17.52 mmol, 80.64% yield) as yellow oil. LCMS: 186 [M−99].

Step 5. Preparation of tert-butyl 3-hydroxy-6-methyl-1,4,6,7-tetrahydropyrazolo [4,3-c]pyridine-5-carboxylate. To a mixture of 1-tert-butyl 3-ethyl 6-methyl-4-oxo-piperidine-1,3-dicarboxylate (5.00 g, 17.52 mmol, 1.00 eq) in MeOH (30.00 mL) was added N 2 H 4 .H 2 O (1.03 g, 17.52 mmol, 1.00 mL, 85% purity, 1.00 eq) in one portion at 30° C. under N 2 . The mixture was stirred at 30° C. for 12 hours. LCMS showed the reaction was completed. The mixture was concentrated in vacuum. The residue was purified by prep-HPLC(FA) to afford the title compound (1.50 g, 5.92 mmol, 33.80% yield) as yellow solid. LCMS: 254 [M+1]. 1 H NMR (400 MHz, METHANOL-d 4 ) δ 4.70-4.82 (m, 1H), 4.58-4.68 (m, 1H), 3.76-3.89 (m, 1H), 2.75-2.88 (m, 1H), 2.37-2.50 (m, 1H), 1.49 (s, 9H), 1.13 (d, J=6.90 Hz, 3H)

Step 6. Preparation of tert-butyl 6-methyl-3-(trifluoromethylsulfonyloxy)-1,4,6,7-tetrahydropyrazolo [4,3-c]pyridine-5-carboxylate. To a mixture of tert-butyl 3-hydroxy-6-methyl-1,4,6,7-tetrahydropyrazolo[4,3-c] pyridine-5-carboxylate (1.50 g, 5.92 mmol, 1.00 eq) in Py (5.00 mL) was added 1,1,1-trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)methanesulfonamide (3.17 g, 8.88 mmol, 1.50 eq) in one portion under N 2 . The mixture was stirred at 20° C. for 12 hours. TLC (PE/EA=2/1) showed the reaction was completed. The mixture was concentrated in vacuum. The residue was diluted with ethyl acetate (150 mL) and poured into HCl (0.5 N, 20 mL) and stirred for 1 min. The aqueous phase was extracted with ethyl acetate (100 mL×2). The combined organic phase was washed with brine (100 mL×2), dried with anhydrous Na 2 SO 4 , filtered and concentrated in vacuum. The residue was purified by silica gel chromatography (PE/EA=10/1) to afford the title compound (1.40 g, 3.63 mmol, 61.37% yield) as yellow solid.

Step 7. Preparation of tert-butyl 6-methyl-3-vinyl-1,4,6,7-tetrahydropyrazolo[4,3-c] pyridine-5-carboxylate. To a mixture of tert-butyl 6-methyl-3-(trifluoromethylsulfonyloxy)-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylate (200.00 mg, 519.00 μmol, 1.00 eq) and [trifluoro(vinyl)-boranyl]potassium (1+) (208.56 mg, 1.56 mmol, 3.00 eq) in dioxane (2.00 mL) and H 2 O (200.00 μL) were added XPHOS-Pd-G2 (Chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)) (40.83 mg, 51.90 μmol, 0.10 eq) and K 3 PO 4 (330.50 mg, 1.56 mmol, 3.00 eq) in one portion under N 2 . The reaction vessel was sealed and heated under microwave at 140° C. for 2 hours. TLC (PE/EA=2/1) showed ˜10% of the starting material remained, 80% of the title compound was detected. The mixture was poured into water (30 mL) and stirred for 2 min. The aqueous phase was extracted with ethyl acetate (30 mL×2). The combined organic phase was washed with brine (30 mL×2), dried with anhydrous Na 2 SO 4 , filtered and concentrated in vacuum. The residue was purified by silica gel chromatography (PE/EA=10/1) to afford the title compound (190.00 mg, 656.59 μmol, 42.17% yield, 91% purity) as yellow oil. LCMS: 264 [M+1].

›PREPARATIVE EXAMPLES · 12 of 53

Step 8. Preparation of tert-butyl 3-formyl-6-methyl-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylate. To a mixture of tert-butyl 6-methyl-3-vinyl-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylate (400.00 mg, 1.52 mmol, 1.00 eq) in THF (40.00 mL) and H 2 O (8.00 mL) was added NaIO 4 (1.30 g, 6.08 mmol, 336.79 μL4.00 eq) and OsO 4 (38.62 mg, 152.00 μmol, 7.88 μL0.10 eq) in one portion at 20° C. The mixture was stirred at 20° C. for 3 hours. LCMS showed the reaction was completed. The mixture was quenched with Na 2 SO 3 (sat. aq, 20 mL) and stirred for 5 min. The aqueous phase was extracted with ethyl acetate (20 mL×2). The combined organic phase was washed with brine (20 mL×2), dried with anhydrous Na 2 SO 4 , filtered and concentrated in vacuum to afford the title compound (400.00 mg, crude) as yellow oil.

Step 9. Preparation of 5-tert-butoxycarbonyl-6-methyl-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-3-carboxylic acid. To a mixture of tert-butyl 3-formyl-6-methyl-1,4,6,7-tetrahydropyrazolo[4,3-c] pyridine-5-carboxylate (400.00 mg, crude, 1.51 mmol, 1.00 eq) in t-BuOH (20.00 mL) was added 2-methylbut-2-ene (1PD0.56 g, 150.58 mmol, 16.00 mL, 99.72 eq) dropwise at 0° C., then a solution of NaH 2 PO 4 (905.85 mg, 7.55 mmol, 5.00 eq) and sodium; chlorite (1.37 g, 15.10 mmol, 10.00 eq) in H 2 O (10.00 mL) was added to the above mixture dropwise at 0° C. The mixture was stirred at 0° C. for 2 hours. LCMS showed the reaction was completed. The mixture was adjusted to pH˜9 with solid NaHCO 3 , the aqueous phase was extracted with ethyl acetate (10 mL×2). The aqueous layer was acidified to pH˜4 with 2N HCl and extracted with ethyl acetate (10 mL×2). The combined organic phase was washed with brine (10 mL×2), dried with anhydrous Na 2 SO 4 , filtered and concentrated in vacuum to afford the title compound (320.00 mg, 910.03 μmol, 60.27% yield, 80% purity) as yellow solid. LCMS: 282 [M+1].

Intermediate 14. tert-butyl 4-(hydroxymethyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxylate

To a mixture of 5-(tert-butoxycarbonyl)-6-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylic acid (Intermediate 13, 400.00 mg, 1.42 mmol, 1.00 eq) and N-(oxetan-3-yloxy) methanamine (585.72 mg, 5.68 mmol, 4.00 eq) in THF (5.00 mL) was added T 3 P (2.71 g, 4.26 mmol, 2.53 mL, 50% purity, 3.00 eq) and TEA (7.29 g, 72.05 mmol, 9.99 mL, 50.74 eq) in one portion under N 2 . The mixture was stirred at 50° C. for 12 hours. LCMS showed the reaction was completed and one peak was detected, whereas TLC (dichloromethane:methanol=10:1) showed three new points. The residue was poured into water (30 mL) and stirred for 2 min. The aqueous phase was extracted with ethyl acetate (30 mL*2). The combined organic phase was washed with brine (20 mL*2), dried with anhydrous Na 2 SO 4 , filtered and concentrated in vacuum. The residue was purified by silica gel chromatography (Petroleum ether/Ethyl acetate=100/1, 50/1), followed by prep-HPLC(base) to give the title compound (50.00 mg, 136.46 μmol, 9.61% yield) as a white solid. LCMS: 367 [M+1]. 1 H NMR (400 MHz, CHLOROFORM-d) 4.63-5.16 (m, 3H), 4.09-4.61 (m, 4H), 3.60-3.94 (m, 2H), 3.30 (s, 3H), 2.85-3.02 (m, 1H), 2.50-2.66 (m, 1H), 1.48 (s, 9H), 1.13 (dd, J=3.64, 6.78 Hz, 3H).

Intermediate 15. tert-butyl 6-methyl-3-(methyl(oxetan-3-yloxy)carbamoyl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate

To a mixture of 5-(tert-butoxycarbonyl)-6-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylic acid (Intermediate 13, 400.00 mg, 1.42 mmol, 1.00 eq) and N-(oxetan-3-yloxy) methanamine (585.72 mg, 5.68 mmol, 4.00 eq) in THF (5.00 mL) was added T 3 P (2.71 g, 4.26 mmol, 2.53 mL, 50% purity, 3.00 eq) and TEA (7.29 g, 72.05 mmol, 9.99 mL, 50.74 eq) in one portion under N 2 . The mixture was stirred at 50° C. for 12 hours. LCMS showed the reaction was completed and one peak was detected, whereas TLC (dichloromethane:methanol=10:1) showed three new points. The residue was poured into water (30 mL) and stirred for 2 min. The aqueous phase was extracted with ethyl acetate (30 mL*2). The combined organic phase was washed with brine (20 mL*2), dried with anhydrous Na 2 SO 4 , filtered and concentrated in vacuum. The residue was purified by silica gel chromatography (Petroleum ether/Ethyl acetate=100/1, 50/1), followed by prep-HPLC(base) to give the title compound (160.00 mg, 436.67 μmol, 30.75% yield) as white solid. LCMS: 367 [M+1]. 1 H NMR (400 MHz, CHLOROFORM-d) δ 5.11 (d, J=5.14 Hz, 2H), 4.86 (d, J=6.15 Hz, 3H), 4.75 (dd, J=5.02, 7.65 Hz, 2H), 4.08-4.26 (m, 1H), 3.48 (br. s., 3H), 2.91-3.05 (m, 1H), 2.52-2.65 (m, 1H), 1.49 (s, 9H), 1.13 (d, J=6.90 Hz, 3H).

Intermediate 16. 10-(tert-butyl) 4-methyl 2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-4,10(2H)-dicarboxylate

Step 1. Preparation of 10-tert-butoxycarbonyl-2-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-4-carboxylic acid. To a mixture of tert-butyl 4-(hydroxymethyl)-2-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxylate (1.00 g, 2.84 mmol, 1.00 eq) and NMO (2.50 g, 21.30 mmol, 2.25 mL, 7.50 eq) in MeCN (30.00 mL) was added TPAP (199.61 mg, 568.00 μmol, 0.20 eq) in one portion at 0° C. under N 2 . The mixture was stirred at 0° C. for 2 hr. LCMS showed the reaction was completed. The residue was concentrated in vacuum to afford the title compound (1.04 g, crude) as black brown solid. LCMS: 367 [M+1].

Step 2. Preparation of 10-(tert-butyl) 4-methyl 2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-4,10(2H)-dicarboxylate. To a mixture of 10-tert-butoxycarbonyl-2-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-4-carboxylic acid (1.04 g, 2.84 mmol, 1.00 eq) and K 2 CO 3 (1.18 g, 8.52 mmol, 3.00 eq) in MeCN (5.00 mL) was added MeI (1.21 g, 8.52 mmol, 530.70 μL3.00 eq) in one portion at 25° C. under N 2 . The mixture was stirred at 25° C. 12 hours. LCMS showed the reaction was not reacted. The starting material was recovered from the reaction mixture by extracted with ethyl acetate (20 mL*2) after neutralized with 1N HCl to pH 3. Then reacted again (To a mixture of 10-tert-butoxycarbonyl-2-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido [2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-4-carboxylic acid (1.04 g, 2.84 mmol, 1.00 eq) and K 2 CO 3 (1.18 g, 8.52 mmol, 3.00 eq) in MeCN (5.00 mL) was added MeI (1.21 g, 8.52 mmol, 530.70 μL3.00 eq) in one portion at 25° C. under N 2 . The mixture was stirred at 25° C. for 12 hours). LCMS and TLC (ethyl acetate:petroleum ether=2:1) showed the reaction was completed. The residue was poured into water (20 mL) and stirred for 2 min. The aqueous phase was extracted with ethyl acetate (20 mL*2). The combined organic phase was washed with brine (20 mL*2), dried with anhydrous Na 2 SO 4 , filtered and concentrated in vacuum. The residue was purified by silica gel chromatography (Petroleum ether/Ethyl acetate=10/1, 2/1) to afford the title compound (150.00 mg, 394.33 μmol, 13.88% yield, 100% purity) as yellow oil. LCMS: 381 [M+1]. 1 H NMR (400 MHz, CHLOROFORM-d) 4.79-4.98 (m, 2H), 4.45-4.75 (m, 3H), 3.88 (s, 3H), 3.54-3.85 (m, 2H), 3.38 (s, 3H), 2.67-2.89 (m, 2H), 1.49 (s, 9H).

›PREPARATIVE EXAMPLES · 13 of 53

Intermediate 17. tert-butyl(R)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxylate

Step 1. Preparation of tert-butyl(2R)-5-(2-ethoxy-2-oxo-acetyl)-2-methyl-4-oxo-piperidine-1-carboxylate. To a solution of tert-butyl (2R)-2-methyl-4-oxo-piperidine-1-carboxylate (4.00 g, 18.76 mmol, 1.00 eq) in THF (50.00 mL) was added LiHMDS (1 M, 22.51 mL, 1.20 eq) dropwise at −70° C. The mixture was stirred at −70° C. for 0.5 hr. Then diethyl oxalate (3.56 g, 24.38 mmol, 3.33 mL, 1.30 eq) was added dropwise at −70° C. The mixture was stirred at 10° C. for 1 hr. TLC (petroleum ether:ethyl acetate=5:1) showed the starting material consumed and one new spot appeared. The mixture was quenched by 1N HCl (500 mL) and extracted with ethyl acetate (300 mL*5). The combined organic layer was dried over Na 2 SO 4 , filtrated. The filtrate was concentrated in vacuum to get the title compound (5.00 g, crude) as yellow oil.

Step 2. Preparation of 5-tert-butyl 3-ethyl (6R)-6-methyl-1,4,6,7-tetrahydropyrazolo[4,3-c] Pyridine-3,5-dicarboxylate. To a solution of tert-butyl (2R)-5-(2-ethoxy-2-oxo-acetyl)-2-methyl-4-oxo-piperidine-1-carboxylate (5.00 g, 15.96 mmol, 1.00 eq) in EtOH (30.00 mL) was added NH 2 NH 2 .H 2 O (939.75 mg, 15.96 mmol, 912.38 μL85% purity, 1.00 eq). The mixture was stirred at 10° C. for 1 hr. TLC (petroleum ether (PE):ethyl acetate (EA)=1:1) showed the starting material consumed and one main spot appeared. The reaction mixture was concentrated in vacuum. The residue was purified by column chromatography (PE:EA: 20%˜60%) to get the title compound (3.60 g, 11.64 mmol, 72.91% yield) as a yellow solid.

Step 3. Preparation of (6R)-5-tert-butoxycarbonyl-6-methyl-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-3-carboxylic acid. To a solution of 5-tert-butyl 3-ethyl (6R)-6-methyl-1,4,6,7-tetrahydropyrazolo [4,3-c]pyridine-3,5-dicarboxylate (3.60 g, 11.64 mmol, 1.00 eq) in THF (30.00 mL) was added a solution of NaOH (930.95 mg, 23.27 mmol, 2.00 eq) in H 2 O (7.00 mL). The mixture was stirred at 50° C. for 16 hr. TLC (PE:EA=1:1) showed the starting material consumed and one main spot with higher polarity appeared. The pH of the mixture was adjusted to 5-6 with 1N HCl. The mixture was diluted with ethyl acetate (300 mL) and H 2 O (100 mL). The organic layer was separated, dried with Ns 2 SO 4 , and filtered. The filtrate was concentrated in vacuum to get the title compound (3.00 g, 10.66 mmol, 91.62% yield) as a white solid. 1 H NMR (400 MHz, METHANOL-d 4 ) δ=4.93 (d, J=17.24 Hz, 1H), 4.68-4.75 (m, 1H), 4.04 (d, J=16.51 Hz, 1H), 2.82 (dd, J=6.05, 15.96 Hz, 1H), 2.52 (d, J=15.89 Hz, 1H), 1.39 (s, 9H), 1.02 (d, J=6.97 Hz, 3H).

Step 4. Preparation of tert-butyl(6R)-3-[hydroxy(methyl)carbamoyl]-6-methyl-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylate. To a solution of (6R)-5-tert-butoxycarbonyl-6-methyl-1,4,6,7-tetrahydropyrazolo [4,3-c]pyridine-3-carboxylic acid (2.70 g, 9.60 mmol, 1.00 eq) and N-methylhydroxylamine (2.40 g, 28.79 mmol, 3.00 eq, HCl) in DMF (20.00 mL) was added HOBt (1.95 g, 14.40 mmol, 1.50 eq), PyBOP (7.49 g, 14.40 mmol, 1.50 eq) and DIEA (6.20 g, 47.99 mmol, 8.38 mL, 5.00 eq). The mixture was stirred at 30° C. for 3 hr. TLC (DCM:MeOH=10:1) showed the starting material was consumed and one main spot appeared. The mixture was extracted with ethyl acetate (150 mL*3) and H 2 O (150 mL). The combined organic layer was washed with H 2 O (150 mL*2), 1N HCl (80 mL) and saturated Na 2 CO 3 (50 mL). The organic layer was dried with Na 2 SO 4 , filtrated. The filtrate was concentrated in vacuum. The residue was purified by column chromatography (petroleum ether:ethyl acetate: 60%˜100%) to get the title compound (2.00 g, 6.44 mmol, 67.13% yield) as white solid. 1 H NMR (400 MHz, METHANOL-d 4 ) δ=5.06 (d, J=13.82 Hz, 1H), 4.78-4.84 (m, 1H), 4.20 (brs, 1H), 3.40 (brs, 3H), 2.93 (dd, J=5.93, 15.71 Hz, 1H), 2.63 (d, J=15.89 Hz, 1H), 1.50 (s, 9H), 1.14 (d, J=6.85 Hz, 3H).

Step 5. Preparation of tert-butyl (R)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxylate. To a solution of tert-butyl (6R)-3-[hydroxy(methyl)carbamoyl]-6-methyl-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylate (2.00 g, 6.44 mmol, 1.00 eq) in DMF (20.00 mL) was added Cs 2 CO 3 (6.30 g, 19.32 mmol, 3.00 eq) followed by 1,2-dibromoethane (1.81 g, 9.66 mmol, 728.81 μL1.50 eq) and TBAI (238.03 mg, 644.00 μmol, 0.10 eq). The mixture was stirred at 50° C. for 16 hr. TLC (PE:EA=0:1) showed the starting material was consumed and one main spot appeared. The mixture was extracted with ethyl acetate (20 mL*2) and H 2 O (20 mL). The combined organic layer was washed with H 2 O (20 mL*2), dried with Na 2 SO 4 , filtrated. The filtrate was concentrated in vacuum. The residue was purified by column chromatography (petroleum ether:ethyl acetate=50%˜100%) to get the title compound (1.50 g, 4.19 mmol, 65.09% yield, 94% purity) as a white solid. 1 H NMR (400 MHz, CHLOROFORM-d) δ=4.73-5.06 (m, 1H), 4.38-4.52 (m, 1H), 4.21-4.36 (m, 1H), 4.11 (d, J=17.48 Hz, 1H), 3.21 (s, 3H), 2.84-2.93 (m, 1H), 2.51 (d, J=15.77 Hz, 1H), 1.41 (s, 10H), 1.06 (d, J=6.97 Hz, 3H).

Intermediate 18. tert-butyl(9R)-4-(hydroxymethyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxylate

To a solution of (R)-5-(tert-butoxycarbonyl)-6-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylic acid (Intermediate 13, 2.30 g, 7.41 mmol, 1.00 eq) in DMF (20.00 mL) was added Cs 2 CO 3 (7.24 g, 22.23 mmol, 3.00 eq) followed by 3-bromooxetane (1.32 g, 9.63 mmol, 1.30 eq) and TBAI (273.74 mg, 741.00 μmol, 0.10 eq). The mixture was stirred at 75° C. for 4 hr. LCMS showed 70% desired product. The mixture was extracted with ethyl acetate (20 mL*2) and H 2 O (20 mL). The combined organic layer was washed with H 2 O (20 mL*2), dried with Na 2 SO 4 , filtrated. The filtrate was concentrated in vacuum. The residue was purified by column chromatography (Petroleum ether:ethyl acetate=50%˜100%) to get 1.8 g desired product with 85% purity. 1.5 g was re-purified by prep-HPLC (FA) to get 1.1 g of pure desired product, which was separated by SFC to afford both diastereomers (420 mg) and (470 mg).

›PREPARATIVE EXAMPLES · 14 of 53

SFC separation condition: Instrument: SFC Thar_80_Q; Column: OD-10 μm; Mobile phase: A for CO 2 and B for Isopropanol (0.1% Ammonia); Isocratic: B 20%; Flow rate: 50 mL/min; Back pressure: 100 bar; Column temperature: 35° C.; Wavelength: 220 nm.

Intermediate 19. 2,2-difluoroethyl trifluoromethanesulfonate

To a solution of 2,2-difluoroethanol (500.00 mg, 6.09 mmol, 1.00 eq) and DIPEA (945.08 mg, 7.31 mmol, 1.28 mL, 1.20 eq) in DCM (5.00 mL) was added Tf 2 O (1.89 g, 6.70 mmol, 1.11 mL, 1.10 eq) at 0° C. under N 2 , and the mixture was stirred at 10° C. for 3 h. The starting material have lower boiling point and the reaction was not detected. The mixture was diluted with DCM (10 mL) and washed with water (20 mL*2) and brine (20 mL*1). The organic phase was dried over anhydrous Na 2 SO 4 and filtered. DMF (1 mL) was added. The resulting mixture was concentrated in vacuo to get a DMF solution of (2,2,2-trifluoroethyl trifluoromethanesulfonate (5.68 mmol, 1 mL), which directly used in the next step.

Intermediate 20. 2,2,2-trifluoroethyl trifluoromethanesulfonate

To a solution of 2,2,2-trifluoroethanol (2.09 g, 20.84 mmol, 1.50 mL, 1.00 eq) and DIPEA (3.23 g, 25.01 mmol, 4.36 mL, 1.20 eq) in DCM (10.00 mL) was added Tf 2 O (6.47 g, 22.92 mmol, 3.78 mL, 1.10 eq) at 0° C. under N 2 , and the mixture was stirred at 10° C. for 3 h. The starting material have lower boiling point and the reaction was not detected. The mixture was diluted with DCM (10 mL) and washed with water (20 mL*2) and brine (20 mL*1). The organic phase was dried over anhydrous Na 2 SO 4 and filtered. DMF (1.00 mL) was added. The resulting mixture was concentrated in vacuo to get a DMF solution of 2,2,2-trifluoroethyl trifluoromethanesulfonate (14.19 mmol, 1 mL) was obtained, directly used in the next step.

Intermediate 21. tert-butyl 4-(hydroxymethyl)-2-(methyl-d3)-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxylate

Step 1. Preparation of [tert-butoxycarbonyl (trideuteriomethyl)amino] tert-butyl carbonate. A mixture of (tert-butoxycarbonylamino) tert-butyl carbonate (100.00 mg, 428.71 μmol, 1.00 eq), CD 3 I (138.04 mg, 857.42 μmol, 2.00 eq) and K 2 CO 3 (88.88 mg, 643.07 μmol, 1.50 eq) in DMF (3.00 mL) was degassed and purged with N 2 for 3 times, and then the mixture was stirred at 50° C. for 16 hour under N 2 atmosphere. TLC showed the starting material was consumed completely and a new spot appeared. The mixture was poured into water (5 mL) and stirred at 5 min. The aqueous phase was extracted with ethyl acetate (3 mL*3). The combined organic phase was washed with brine (5 mL), dried with anhydrous Na 2 SO 4 , filtered and concentrated in vacuum to give the title compound (100.00 mg, 399.50 μmol, 93.19% yield) as a colorless oil, which was used directly for the next step.

Step 2. Preparation of N-(trideuteriomethyl)hydroxylamine. A mixture of [tert-butoxycarbonyl(trideuteriomethyl)amino] tert-butyl carbonate (100.00 mg, 399.50 μmol, 1.00 eq) in DCM (3.00 mL) was added TFA (3.08 g, 27.01 mmol, 2.00 mL, 67.62 eq). The mixture was stirred at 15° C. for 2 hour. TLC showed the starting material was consumed completely and a new spot appeared. The mixture was concentrated in vacuum to give (65.56 mg, 399.51 μmol, 100.00% yield, TFA) as a yellow oil, which was used directly for the next step.

Step 3. Preparation of tert-butyl 3-[hydroxy(trideuteriomethyl)carbamoyl]-2,4,6,7-tetrahydropyrazolo [4,3-c]pyridine-5-carboxylate. A mixture of 5-tert-butoxycarbonyl-2,4,6,7-tetrahydropyrazolo [4,3-c]pyridine-3-carboxylic acid (100.00 mg, 374.14 μmol, 1.00 eq), N-(trideuteriomethyl)hydroxylamine (61.40 mg, 374.14 μmol, 1.00 eq, TFA), T 3 P (357.13 mg, 1.12 mmol, 333.77 μL3.00 eq) and TEA (189.30 mg, 1.87 mmol, 259.32 μL5.00 eq) in THF (3.00 mL) was degassed and purged with N 2 for 3 times, and then the mixture was stirred at 15° C. for 16 hour under N 2 atmosphere. LCMS showed the starting material was consumed completely and desired product was major. The mixture was poured into ice-water (5 mL) and stirred at 5 min. Then the mixture was concentrated in vacuum to give the residue. The pH of the aqueous phase was adjusted to around 6 by adding diluted hydrochloride acid (1 N) and extracted with ethyl acetate (3 mL*3). The combined organic phase was washed with brine (5 mL), dried with anhydrous Na 2 SO 4 , filtered and concentrated in vacuum to give the title compound (75.00 mg, 238.02 μmol, 63.62% yield, 95% purity) as a white solid. 1 H NMR (400 MHz, METHANOL-d 4 ) δ 4.62 (s, 2H) 3.71 (d, J=4.16 Hz, 2H) 2.70-2.78 (m, 2H) 1.48 (d, J=3.42 Hz, 9H). LCMS: 300 [M+1].

Step 4. Preparation of tert-butyl 4-(hydroxymethyl)-2-(methyl-d3)-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxylate. A mixture of tert-butyl 3-[hydroxy(trideuteriomethyl)carbamoyl]-2,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylate (75.00 mg, 250.55 μmol, 1.00 eq), 3-bromooxetane (41.18 mg, 300.66 μmol, 1.20 eq), TBAI (9.25 mg, 25.06 μmol, 0.10 eq) and Cs 2 CO 3 (122.45 mg, 375.83 μmol, 1.50 eq) in DMF (3.00 mL) was degassed and purged with N 2 for 3 times, and then the mixture was stirred at 70° C. for 3 hour under N 2 atmosphere. TLC showed the starting material was consumed completely and two new spots appeared. The mixture was poured into water (10 mL) and stirred at 5 min. The aqueous phase was extracted with ethyl acetate (5 mL*3). The combined organic phase was washed with brine (10 mL), dried with anhydrous Na 2 SO 4 , filtered and concentrated in vacuum. The residue was purified by Prep-TLC (DCM/MeOH=10/1) to give the title compound (41.00 mg, 98.06 μmol, 39.14% yield, 85% purity) as a white solid. 1 H NMR (400 MHz, CHLOROFORM-d) δ 4.47-4.72 (m, 4H) 4.31-4.43 (m, 1H) 3.59-3.95 (m, 4H) 2.77 (br. s., 2H) 1.49 (s, 9H). LCMS: 356 [M+1].

Intermediate 22. 10-(tert-butyl) 4-methyl 2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-4,10(2H)-dicarboxylate

Step 1. Preparation of 10-tert-butoxycarbonyl-2-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-4-carboxylic acid. To a mixture of tert-butyl 4-(hydroxymethyl)-2-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxylate (Intermediate 1, 1.00 g, 2.84 mmol, 1.00 eq) and NMO (2.50 g, 21.30 mmol, 2.25 mL, 7.50 eq) in MeCN (30.00 mL) was added TPAP (199.61 mg, 568.00 μmol, 0.20 eq) in one portion at 0° C. under N 2 . The mixture was stirred at 0° C. for 2 hr. LCMS showed the reaction was completed. The mixture was concentrated in vacuum to afford the title compound (1.04 g, crude) as black brown solid. LCMS: 367 [M+1].

›PREPARATIVE EXAMPLES · 15 of 53

Step 2. Preparation of 10-tert-butyl 4-methyl 2-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-4,10-dicarboxylate. To a mixture of 10-tert-butoxycarbonyl-2-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-4-carboxylic acid (1.04 g, crude, 2.84 mmol, 1.00 eq) and K 2 CO 3 (1.18 g, 8.52 mmol, 3.00 eq) in MeCN (20.00 mL) was added MeI (1.21 g, 8.52 mmol, 530.70 μL3.00 eq) in one portion at 25° C. under N 2 . The mixture was stirred at 25° C. 12 hours. LCMS showed the reaction didn't react. The starting material was recovered: the reaction mixture was neutralized with HCl (1 N, aq) to pH=3, then extracted with ethyl acetate (20 mL×2). The combined organic layer was dried over Na 2 SO 4 , filtered and concentrated to dryness. The reaction was performed again. To the recovered the starting material and K 2 CO 3 (1.18 g, 8.52 mmol, 3.00 eq) in MeCN (20.00 mL) was added MeI (1.21 g, 8.52 mmol, 530.70 μL3.00 eq) in one portion at 25° C. under N 2 . The mixture was stirred at 25° C. for 12 hours. LCMS and TLC (EA/PE=2/1) showed the reaction was completed, and 45% of the title compound was detected. The residue was poured into water (20 mL) and stirred for 2 min. The aqueous phase was extracted with ethyl acetate (20 mL×2). The combined organic phase was washed with brine (20 mL×2), dried with anhydrous Na 2 SO 4 , filtered and concentrated in vacuum. The residue was purified by silica gel chromatography (PE/EA=10/1, 2/1) to afford the title compound (150.00 mg, 394.33 μmol, 13.88% yield, 100% purity) as yellow oil. LCMS: 381 [M+1]. 1 H NMR (400 MHz, CHLOROFORM-d) 4.79-4.98 (m, 2H), 4.45-4.75 (m, 3H), 3.88 (s, 3H), 3.54-3.85 (m, 2H), 3.38 (s, 3H), 2.67-2.89 (m, 2H), 1.49 (s, 9H).

Intermediate 23. tert-butyl 9-ethyl-4-(hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxylate

Step 1. Preparation of tert-butyl 4-oxopyridine-1-carboxylate. To a solution of pyridin-4-ol (5.00 g, 52.58 mmol, 1.00 eq) in t-BuOH (250.00 mL) was added NaH (2.73 g, 68.35 mmol, 60% purity, 1.30 eq) under N 2 , and the mixture was warmed to 50° C. in hot water bath until the mixture turned to a slurry. A solution of (Boc) 2 O (14.92 g, 68.35 mmol, 15.71 mL, 1.30 eq) in t-BuOH (100.00 mL) was added dropwise, the mixture was stirred at 30° C. for 16 h. TLC indicated 50% of pyridin-4-ol was remained, and one major new spot with lower polarity was detected. The reaction mixture was quenched with water (200 mL), acidified to PH=7 with 10% HCl, and then extracted with ethyl acetate (300 mL*3), the combined organic phase was dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuum. The residue was purified by silica gel chromatography. The title compound (2.90 g, 14.86 mmol, 28.25% yield) was obtained as white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ=8.03-8.09 (m, 2H) 6.25-6.33 (m, 2H) 1.61 (s, 9H).

Step 2. Preparation of tert-butyl 4-oxo-2-vinyl-2,3-dihydropyridine-1-carboxylate. To a mixture of tert-butyl 4-oxopyridine-1-carboxylate (5.80 g, 29.71 mmol, 1.00 eq) and TMSCl (9.68 g, 89.13 mmol, 11.26 mL, 3.00 eq) in THF (50.00 mL) was added bromo(vinyl)magnesium (1 M, 44.57 mL, 1.50 eq) dropwise under N 2 at −78° C. The reaction mixture was warmed to 10° C. and stirred at 10° C. for 2 hours. TLC indicated the starting material consumed completely, and one major new spot with lower polarity was detected. The reaction was quenched with aqueous solution of NH 4 Cl (120 mL) and then extracted with ethyl acetate (150 mL*3). The combined organic phase was dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuum. The residue was purified by silica gel chromatography to give the title compound (4.60 g, 20.19 mmol, 67.96% yield, 98% purity) as yellow oil. LCMS: 224 [M+1].

Step 3. Preparation of tert-butyl 4-oxo-2-vinyl-piperidine-1-carboxylate. To a solution of tert-butyl 4-oxo-2-vinyl-2,3-dihydropyridine-1-carboxylate (4.60 g, 20.60 mmol, 1.00 eq) in AcOH (30.00 mL) was added Zn (6.74 g, 103.00 mmol, 5.00 eq) under N 2 , the reaction mixture was stirred at 70° C. for 4 hours. TLC indicated the starting material consumed completely, and two new spots with lower polarity were detected. The reaction mixture was filtered and the filtrate was diluted with ethyl acetate (200 mL) and washed with aqueous solution of NaHCO 3 (100 mL*3), the organic phase was dried with anhydrous Na 2 SO 4 , filtered and concentrated in vacuum. The residue was purified by silica gel chromatography to afford the title compound (3.05 g, 13.40 mmol, 65.06% yield, 99% purity) as yellow oil. LCMS: 170 [M−56+1].

Step 4. Preparation of tert-butyl 5-(2-ethoxy-2-oxo-acetyl)-4-oxo-2-vinyl-piperidine-1-carboxylate. Cooled the three-necked round bottom flask to −78° C., LiHMDS (1 M, 11.54 mL, 1.30 eq) was added under N 2 , then a solution of tert-butyl 4-oxo-2-vinyl-piperidine-1-carboxylate (2.00 g, 8.88 mmol, 1.00 eq) in THF (15.00 mL) was added dropwise, the reaction mixture was stirred at −78° C. for 30 minutes under N 2 . Then a solution of diethyl oxalate (1.56 g, 10.66 mmol, 1.46 mL, 1.20 eq) in THF (10.00 mL) was added dropwise. After addition, the reaction mixture was stirred at −78° C. for 30 minutes, then at 10° C. for another 2 hours. TLC indicated tert-butyl 4-oxo-2-vinyl-piperidine-1-carboxylate consumed completely, and one major new spot with larger polarity was detected. The reaction mixture was quenched with aqueous solution of NH 4 Cl (100 mL) and then extracted with ethyl acetate (150 mL*2). The combined organic phase was dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuum to give the title compound (2.00 g, crude) was obtained as yellow oil, which was used in the next step directly without further purification.

Step 5. Preparation of 5-tert-butyl 3-ethyl 6-vinyl-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-3,5-dicarboxylate. To a solution of tert-butyl 5-(2-ethoxy-2-oxo-acetyl)-4-oxo-2-vinyl-piperidine-1-carboxylate (2.00 g, 6.15 mmol, 1.00 eq) in EtOH (20.00 mL) was added a solution of NH 2 NH 2 .H 2 O (289.76 mg, 4.92 mmol, 281.32 μL85% purity, 0.80 eq) in EtOH (2.00 mL) dropwise. The reaction mixture was stirred at 10° C. for one hour. LCMS showed one main peak with desired MS was detected. The reaction mixture was diluted with ethyl acetate (150 mL) and washed with water (80 mL*2), the organic phase was dried with anhydrous Na 2 SO 4 , filtered and concentrated in vacuum. The residue was purified by silica gel chromatography to give the title compound (1.30 g, 3.92 mmol, 63.74% yield, 97% purity) was obtained as yellow solid. 1 H NMR (400 MHz, CHLOROFORM-d) δ=5.71 (ddd, J=17.32, 10.54, 4.89 Hz, 1H) 5.04-5.18 (m, 3H) 4.09-4.44 (m, 4H) 2.98-3.05 (m, 2H) 1.51 (s, 9H) 1.38 (t, J=7.09 Hz, 3H); LCMS: 322 [M+1].

›PREPARATIVE EXAMPLES · 16 of 53

Step 6. Preparation of 5-tert-butyl 3-ethyl 6-ethyl-1,4,6,7-tetrahydropyrazolo [4,3-c]pyridine-3,5-dicarboxylate. To a solution of 5-tert-butyl 3-ethyl 6-vinyl-1,4,6,7-tetrahydropyrazolo[4,3-c] pyridine-3,5-dicarboxylate (1.50 g, 4.67 mmol, 1.00 eq) in MeOH (60.00 mL) was added Pd/C (200.00 mg, 10% purity) under N 2 , The suspension was degassed under vacuum and purged with H 2 three times, the mixture was stirred under H 2 (15 psi) at 10° C. for 16 hours. LCMS showed the starting material consumed completely and desired product was detected. The reaction mixture was filtered and the filtrate was concentrated to give the title compound (1.42 g, 4.22 mmol, 90.26% yield, 96% purity) as yellow solid, which was combined with another batch (187 mg) to separated by SFC to get a pair of enantiomers (E1: 0.76 g and E2: 0.77 g). SFC separation condition: Instrument: SFC Thar_80_Q; Column: IC-10 μm; Mobile phase: A for CO 2 and B for Methanol (0.1% Ammonia); Isocratic: B 25%; Flow rate: 55 mL/min; Back pressure: 100 bar; Column temperature: 35° C.; Wavelength: 220 nm.

E1: 1H NMR (400 MHz, CHLOROFORM-d) δ=4.92-5.25 (m, 1H) 4.47-4.76 (m, 1H) 4.32-4.45 (m, 2H) 3.95-4.18 (m, 1H) 2.95 (dd, J=16.02, 5.99 Hz, 1H) 2.74 (d, J=16.02 Hz, 1H) 1.43-1.54 (m, 11H) 1.39 (t, J=7.09 Hz, 3H) 0.90 (t, J=7.34 Hz, 3H).

E2: 1H NMR (400 MHz, CHLOROFORM-d) δ=4.97-5.25 (m, 1H) 4.46-4.75 (m, 1H) 4.28-4.45 (m, 2H) 3.95-4.18 (m, 1H) 2.89-3.01 (m, 1H) 2.76 (d, J=16.02 Hz, 1H) 1.42-1.57 (m, 11H) 1.38 (t, J=7.09 Hz, 3H) 0.87-0.94 (m, 3H).

Step 7. Preparation of 5-tert-butoxycarbonyl-6-ethyl-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-3-carboxylic acid. To a solution of 5-tert-butyl 3-ethyl 6-ethyl-1,4,6,7-tetrahydropyrazolo[4,3-c] pyridine-3,5-dicarboxylate (750.00 mg, 2.32 mmol, 1.00 eq) in MeOH (15.00 mL) was added a solution of NaOH (139.20 mg, 3.48 mmol, 1.50 eq) in H 2 O (3.00 mL), the reaction mixture was stirred at 50° C. for 16 hours. LCMS showed one main peak with desired MS was detected. The pH of the reaction mixture was adjusted to around 6 by adding diluted HCl (1N, 15 mL). The resulting mixture was extracted with ethyl acetate (50 mL*3). The combined organic phase was dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuum to give the title compound (630.00 mg, crude) as white solid used in next step directly without further purification. LCMS: 296 [M+1].

Step 8. Preparation of tert-butyl 6-ethyl-3-[hydroxy(methyl) carbamoyl]-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylate. To a mixture of 5-tert-butoxycarbonyl-6-ethyl-1,4,6,7-tetrahydropyrazolo[4,3-c] pyridine-3-carboxylic acid (600.00 mg, 2.03 mmol, 1.00 eq) and N-methylhydroxylamine (339.09 mg, 4.06 mmol, 2.00 eq, HCl) in DMF (8.00 mL) was added PyBOP (1.27 g, 2.44 mmol, 1.20 eq), HOBt (329.15 mg, 2.44 mmol, 1.20 eq) and DIPEA (1.05 g, 8.12 mmol, 1.42 mL, 4.00 eq), the reaction mixture was stirred at 25° C. for 2 hours. LCMS showed about 40% of desired compound was detected. The reaction mixture was diluted with ethyl acetate (100 mL) and washed with water (50 mL*3), the organic phase was dried with anhydrous Na 2 SO 4 , filtered and concentrated in vacuum. The residue was purified by silica gel chromatography to give the title compound (560.00 mg, 1.55 mmol, 76.54% yield, 90% purity) as white solid. LCMS: 325 [M+1].

Step 9. Preparation of tert-butyl 9-ethyl-4-(hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxylate. To a mixture of tert-butyl 6-ethyl-3-[hydroxy(methyl)carbamoyl]-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylate (500.00 mg, 1.54 mmol, 1.00 eq) and 3-bromooxetane (253.14 mg, 1.85 mmol, 1.20 eq) in DMF (3.00 mL) was added Cs 2 CO 3 (752.64 mg, 2.31 mmol, 1.50 eq) and TBAI (56.88 mg, 154.00 μmol, 0.10 eq), the reaction mixture was stirred at 55° C. for 4 hours. LCMS showed one main peak with desired MS was detected. The reaction mixture was diluted with ethyl acetate (100 mL) and washed with water (50 mL*3). The organic phase was dried with anhydrous Na 2 SO 4 , filtered and concentrated in vacuum. The residue was purified by silica gel chromatography to give the title compound (430.00 mg, 1.13 mmol, 73.39% yield) as white solid. LCMS: 381 [M+1].

Intermediate 24. (9R)-10-(tert-butoxycarbonyl)-2,9-dimethyl-1-oxo-1,2,4,5,8,9,10,11-octahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-4-carboxylic acid

Step 1. Preparation of (9R)-10-tert-butoxycarbonyl-2,9-dimethyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-4-carboxylic acid. To a solution of tert-butyl (9R)-4-(hydroxymethyl)-2,9-dimethyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxylate (Intermediate 18, 500.00 mg, 1.36 mmol, 1.00 eq, diastereomer separated by SFC) and NMO (1.19 g, 10.20 mmol, 1.08 mL, 7.50 eq) in MeCN (10.00 mL) was added TPAP (119.49 mg, 340.00 μmol, 0.25 eq). The mixture was stirred at 30° C. for 12 hr. LCMS showed the starting material was consumed completely, desired mass was major. The mixture was poured into water (20 mL) and washed with tert-butyl methyl ether (10 mL), the aqueous layer was acidified by 0.5 N HCl to pH˜3, extracted with DCM (20 mL×2), the organic layer was washed with brine (10 mL), dried over anhydrous Na 2 SO 4 and concentrated in vacuum to afford the title compound (520.00 mg, crude) as a black brown solid. LCMS: 381[M+1].

Intermediate 25. tert-butyl(9R)-2,9-dimethyl-4-(methylcarbamoyl)-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxylate

A mixture of (9R)-10-(tert-butoxycarbonyl)-2,9-dimethyl-1-oxo-1,2,4,5,8,9,10,11-octahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-4-carboxylic acid (Intermediate 24, 256.00 mg, 672.99 μmol, 1.00 eq, diastereomer separated by SFC), methanamine (227.20 mg, 3.36 mmol, 5.00 eq, HCl), T 3 P (856.53 mg, 1.35 mmol, 800.50 μL50% purity, 2.00 eq), TEA (681.00 mg, 6.73 mmol, 932.88 μL10.00 eq) in THF (10.00 mL) was degassed and purged with N 2 for 3 times, and then the mixture was stirred at 70° C. for 16 hour under N 2 atmosphere. LCMS showed the starting material was consumed completely, desired product was major. The mixture was poured into water (20 mL) and extracted with ethyl acetate (10 mL*2). The combined organic phase was washed with brine (30 mL), dried with anhydrous Na 2 SO 4 , filtered and concentrated in vacuum to give the title compound (220.00 mg, 525.62 μmol, 78.10% yield, 94% purity) as a black blown solid. LCMS: 394[M+1].

›PREPARATIVE EXAMPLES · 17 of 53

Intermediate 26. 10-(tert-butoxycarbonyl)-2-methyl-1-oxo-1,2,4,5,8,9,10,11-octahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-4-carboxylic acid

To a solution of tert-butyl 4-(hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxylate (Intermediate 1, 400.00 mg, 1.14 mmol, 1.00 eq) and NMO (1.00 g, 8.55 mmol, 902.37 μL7.50 eq) in MeCN (20.00 mL) was added TPAP (100.16 mg, 285.00 μmol, 0.25 eq). The mixture was stirred at 20° C. for 12 h. The mixture was poured into water (40 mL) and washed with tert-butyl methyl ether (20 mL), the aqueous layer was acidified by 0.5 N HCl to pH=3, extracted with DCM (40 mL*2). The organic layer was washed with brine (20 mL), dried over anhydrous Na 2 SO 4 and concentrated in vacuum to afford the title compound (550.00 mg, crude) as brown oil. LCMS: 367 [M+1].

Intermediate 27. tert-butyl 4-((2,2-difluoroethyl)(methyl)carbamoyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxylate

To a mixture of 10-(tert-butoxycarbonyl)-2-methyl-1-oxo-1,2,4,5,8,9,10,11-octahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-4-carboxylic acid (Intermediate 26, 340.00 mg, 928.02 μmol, 1.00 eq), 3-PICOLINE (259.28 mg, 2.78 mmol, 270.08 μL3.00 eq) and 2,2-difluoro-N-methyl-ethanamine (244.16 mg, 1.86 mmol, 2.00 eq, HCl) in MeCN (10.00 mL) was added MsCl (212.61 mg, 1.86 mmol, 143.66 μL2.00 eq) at 0° C. The mixture was stirred at 25° C. for 1 h under N 2 . The mixture was adjusted to pH=6 by 1N HCl, then diluted with H 2 O (30 mL) and extracted Ethyl acetate (30 mL*2). The combined organic layers was dried over Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by column chromatography (Petroleum ether:Ethyl acetate=1/1) to afford the title compound (290.00 mg, 634.36 μmol, 68.36% yield, 97% purity) as white solid. LCMS: 444 [M+1].

Intermediate 28. tert-butyl 4-(azidomethyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxylate

Step 1. Preparation of tert-butyl 2-methyl-4-(methylsulfonyloxymethyl)-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxylate. A mixture of tert-butyl 4-(hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxylate (Intermediate 1, 500.00 mg, 1.42 mmol, 1.00 eq, single enatiomer separated by SFC), TEA (574.76 mg, 5.68 mmol, 787.34 μL4.00 eq) in DCM (10.00 mL) was added MsCl (487.98 mg, 4.26 mmol, 329.72 μL3.00 eq) dropwise at 0° C. under N 2 , and then the mixture was stirred at 15° C. for 3 hour under N 2 atmosphere. TLC showed the starting material was consumed completely and new spot formed. The mixture was poured into ice-water (40 mL) and stirred at 5 min. The aqueous phase was extracted with DCM (10 mL*2). The combined organic phase was washed with brine (50 mL), dried with anhydrous Na 2 SO 4 , filtered and concentrated in vacuum to give the title compound (611.00 mg, crude) as a yellow solid. LCMS: 431[M+1]

Step 2. Preparation of tert-butyl 4-(azidomethyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxylate. A mixture of tert-butyl2-methyl-4-(methylsulfonyloxymethyl)-1-oxo-5,8,9,11-tetra hydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxylate (611.00 mg, 1.42 mmol, 1.00 eq), NaN 3 (553.63 mg, 8.52 mmol, 6.00 eq) in DMF (10.00 mL) was degassed and purged with N 2 for 3 times, and then the mixture was stirred at 70° C. for 16 hr under N 2 atmosphere. TLC showed the starting material was consumed completely, desired product was major. The mixture was diluted with ethyl acetate (10 mL) and washed with brine (30 mL, *3). The organic phase was dried over Na 2 SO 4 , filtered and concentrated in vacuo. The residue was purified by column chromatography (Petroleum ether/Ethyl acetate=100/1 to 1:1) to give the title compound (500.00 mg, 1.26 mmol, 88.63% yield, 95% purity) as a colorless oil. LCMS: 378[M+1].

Intermediate 29. tert-butyl(9R)-4-(azidomethyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxylate

Step 1. Preparation of tert-butyl (9R)-2,9-dimethyl-4-(methylsulfonyloxymethyl)-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxylate. A mixture of tert-butyl (9R)-4-(hydroxymethyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxylate (Intermediate 18, 3.00 g, 8.19 mmol, 1.00 eq), TEA (4.14 g, 40.95 mmol, 5.67 mL, 5.00 eq) in DCM (40.00 mL) was added MsCl (3.75 g, 32.76 mmol, 2.53 mL, 4.00 eq) dropwise at 0° C. under N 2 , and then the mixture was stirred at 30° C. for 3 hour under N 2 atmosphere. TLC showed the starting material was consumed completely, a new spot appeared. The mixture was poured into ice-water (50 mL) and stirred at 5 min. The aqueous phase was extracted with DCM (40 mL*2). The combined organic phase was washed with brine (50 mL), dried with anhydrous Na 2 SO 4 , filtered and concentrated in vacuum. The residue was purified by column chromatography (SiO 2 , Petroleum ether/Ethyl acetate=100/1 to 1:2) to give the title compound (3.40 g, 7.34 mmol, 89.66% yield, 96% purity) as a white solid. LCMS: 445 [M+1].

Step 2. Preparation of tert-butyl (9R)-4-(azidomethyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxylate. A mixture of tert-butyl(9R)-2,9-dimethyl-4-(methylsulfonyloxymethyl)-1-oxo-5,8, 9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxylate (1.20 g, 2.70 mmol, 1.00 eq), NaN 3 (877.53 mg, 13.50 mmol, 5.00 eq) in DMF (20.00 mL) was degassed and purged with N 2 for 3 times, and then the mixture was stirred at 70° C. for 16 hr under N 2 atmosphere. LCMS showed ˜10% starting material, ˜85% desired product. NaN 3 (351.01 mg, 5.40 mmol, 2.00 eq) was added to the mixture, the mixture was stirred at 70° C. for another 5 hr. LCMS showed the starting material was consumed completely, desired product was major. The mixture was diluted with ethyl acetate (60 mL) and washed with brine (100 mL, *3). The organic phase was dried over Na 2 SO 4 , filtered and concentrated in vacuo to give the title compound (1.24 g, crude) as a yellow solid. LCMS: 392 [M+1]

›PREPARATIVE EXAMPLES · 18 of 53

Intermediate 30. tert-butyl(9R)-4-(aminomethyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxylate

A mixture of tert-butyl (9R)-4-(azidomethyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxylate (Intermediate 29, 1.06 g, 2.71 mmol, 1.00 eq), PPh 3 (1.42 g, 5.42 mmol, 2.00 eq) in THF (12.00 mL) and H 2 O (2.00 mL) was degassed and purged with N 2 for 3 times, and then the mixture was stirred at 30° C. for 16 hour under N 2 atmosphere. LCMS showed the starting material was consumed completely, desired product was major. The mixture was concentrated in vacuum. The residue was purified by column chromatography (SiO 2 , Petroleum ether/Ethyl acetate=100/1 to 0:1) to give the title compound (827.00 mg, 2.20 mmol, 81.00% yield, 97% purity) as a white solid. LCMS: 366 [M+1]

Compound 001: N-(3-bromophenyl)-4-(hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

Step 1. 4-(hydroxymethyl)-2-methyl-4,5,8,9,10,11-hexahydropyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepin-1-one. A mixture of tert-butyl 3-[methyl(oxetan-3-yloxy)carbamoyl]-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylate (Intermediate 1, 244.00 mg, 692.41 μmol, 1.00 eq) in DCM (3.00 mL) was added TFA (2.31 g, 20.26 mmol, 1.50 mL, 29.26 eq), and then the mixture was stirred at 30° C. for 1 hour. LCMS showed the reaction was completed. The mixture was concentrated in vacuum to afford the title compound (253.00 mg, 690.71 μmol, 99.75% yield, TFA) as yellow oil which was used directly for next step. LCMS: 253 [M+1].

Step 2. N-(3-bromophenyl)-4-(hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide. A mixture of N-methyl-N-(oxetan-3-yloxy)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c] pyridine-3-carboxamide (50.00 mg, 136.50 μmol, 1.00 eq, TFA), phenyl N-(3-bromophenyl)carbamate (39.88 mg, 136.50 μmol, 1.00 eq), TEA (20.72 mg, 204.75 μmol, 28.38 μL1.50 eq) in DCM (2.00 mL) was degassed and purged with N 2 for 3 times, and then the mixture was stirred at 30° C. for 16 hour under N 2 atmosphere. LCMS showed desired mass was detected. The mixture was poured into water (5 mL) and stirred for 5 min. The aqueous phase was extracted with DCM (3 mL×3). The combined organic phase was washed with brine (5 mL), dried with anhydrous Na 2 SO 4 , filtered and concentrated in vacuum. The residue was purified by Prep-HPLC (FA) to afford the title compound (25.00 mg, 54.96 μmol, 40.27% yield, 99% purity) as a white solid. LCMS: 450/452 [M+1]. 1 H NMR (400 MHz, MeOD) 7.68 (s, 1H), 7.33-7.35 (m, 1H), 7.15-7.17 (m, 2H), 4.86 (s, 2H), 4.53-4.73 (m, 2H), 4.35-4.37 (m, 1H), 3.82-3.84 (m, 2H), 3.71-3.73 (m, 1H), 3.66-3.67 (m, 1H), 3.32 (s, 3H), 2.81-2.84 (m, 2H).

Compounds 002, 003, 004, 005, 006, 007, 008, 009, 010, 011, 012, 013, 014, 015, 016, 017, 018, 020, 021, 022, 023, 024, 025, 026, 027, 028, 029, 030, 031, 032, 033, 034, and 035 were prepared in a manner analogous to Compound 001.

Compound 002: 4-(hydroxymethyl)-2-methyl-1-oxo-N-(m-tolyl)-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS (M+1): 386.2

Compound 003: N-(2-chloro-3-fluoropyridin-4-yl)-4-(hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS (M+1): 424.1,

Compound 004: N-(3-bromo-2-fluorophenyl)-4-(hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS (M+1): 468.1.

Compound 005: N-(3,4-difluorophenyl)-4-(hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS (M+1): 408.1.

Compound 006: 4-(hydroxymethyl)-2-methyl-1-oxo-N-(3,4,5-trifluorophenyl)-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS (M+1): 426.1. 1H NMR (400 MHz, METHANOL-d 4 ) δ=7.24 (dd, J=10.29, 6.53 Hz, 2H) 4.71 (s, 2H) 4.48-4.62 (m, 2H) 4.32-4.41 (m, 1H) 3.82 (t, J=4.89 Hz, 2H) 3.70-3.77 (m, 1H) 3.62-3.68 (m, 1H) 3.31-3.33 (m, 3H) 2.82 (t, J=5.77 Hz, 2H).

Compound 007: N-(3-chloro-2,4-difluorophenyl)-4-(hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS (M+1): 442.1.

Compound 008: 4-(hydroxymethyl)-2-methyl-1-oxo-N-(3-(trifluoromethyl)phenyl)-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS (M+1): 440.1. 1 H NMR (400 MHz, METHANOL-d 4 ) δ=7.82 (s, 1H) 7.66 (d, J=8.03 Hz, 1H) 7.46 (t, J=8.03 Hz, 1H) 7.31 (d, J=7.53 Hz, 1H) 4.77 (s, 2H) 4.51-4.64 (m, 2H) 4.33-4.43 (m, 1H) 3.82-3.93 (m, 2H) 3.63-3.81 (m, 2H) 3.33-3.36 (m, 3H) 2.86 (t, J=5.77 Hz, 2H).

Compound 009: N-(3-ethylphenyl)-4-(hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS (M+1): 400.2. 1 H NMR (400 MHz, METHANOL-d 4 ) δ=7.22 (s, 1H) 7.17 (m, 2H) 6.88 (m, 1H) 4.73 (s, 2H) 4.50-4.63 (m, 2H) 4.31-4.41 (m, 1H) 3.80-3.89 (m, 2H) 3.70-3.77 (m, 1H) 3.62-3.69 (m, 1H) 3.31-3.34 (m, 3H) 2.83 (t, J=5.65 Hz, 2H) 2.61 (q, J=7.53 Hz, 2H) 1.22 (t, J=7.65 Hz, 3H)

Compound 010: N-(3-bromo-2,4-difluorophenyl)-4-(hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS (M+1): 486.0.

Compound 011: N-(4-fluoro-3-(trifluoromethyl)phenyl)-4-(hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS (M+1): 458.1.

Compound 011_E1: (S*)—N-(4-fluoro-3-(trifluoromethyl)phenyl)-4-(hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS (M+1): 458. 1 H NMR (400 MHz, CHLOROFORM-d) δ=7.68 (dd, J=2.8, 6.0 Hz, 1H), 7.56-7.64 (m, 1H), 7.15 (t, J=9.3 Hz, 1H), 6.63 (s, 1H), 4.74 (d, J=3.4 Hz, 2H), 4.54-4.65 (m, 2H), 4.39-4.48 (m, 1H), 3.84-3.96 (m, 3H), 3.72-3.83 (m, 1H), 3.35 (s, 3H), 2.89 (t, J=5.8 Hz, 2H), 1.92 (brs, 1H).

›PREPARATIVE EXAMPLES · 19 of 53

*Pure but unknown enantiomer.

Compound 011_E2: (R*)—N-(4-fluoro-3-(trifluoromethyl)phenyl)-4-(hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS (M+1): 458. 1 H NMR (400 MHz, CHLOROFORM-d) δ=7.66 (dd, J=6.09, 2.70 Hz, 1H) 7.55-7.61 (m, 1H) 7.13 (t, J=9.41 Hz, 1H) 6.64 (s, 1H) 4.72 (s, 2H) 4.51-4.62 (m, 2H) 4.37-4.46 (m, 1H) 3.75-3.93 (m, 4H) 3.33 (s, 3H) 2.86 (t, J=5.71 Hz, 2H) 2.02 (br. s., 1H).

*Pure but unknown enantiomer.

Compound 012: N-(3,4-dichlorophenyl)-4-(hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS (M+1): 440.0.

Compound 013: N-(5-chloro-2,4-difluorophenyl)-4-(hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS (M+1): 442.1 1 H NMR (400 MHz, METHANOL-d 4 ) δ=7.60 (t, J=7.91 Hz, 1H) 7.19 (t, J=9.66 Hz, 1H) 4.73 (s, 2H) 4.49-4.63 (m, 2H) 4.30-4.44 (m, 1H) 3.84 (s, 2H) 3.61-3.78 (m, 2H) 3.33-3.39 (m, 3H) 2.83 (t, J=5.65 Hz, 2H).

Compound 014: N-(5-bromo-2,4-difluorophenyl)-4-(hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS (M+1): 486.0.

Compound 015: N-(3-bromo-4,5-difluorophenyl)-4-(hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS (M+1): 486.0.

Compound 016: N-(2,5-dimethylphenyl)-4-(hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS (M+1): 400.2.

Compound 017: N-(5-bromo-2-methylphenyl)-4-(hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS (M+1): 464.1.

Compound 018: N-(5-bromo-4-fluoro-2-methylphenyl)-4-(hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS (M+1): 482.0. 1 H NMR (400 MHz, METHANOL-d 4 ) δ=7.42 (d, J=6.78 Hz, 1H) 7.09 (d, J=9.54 Hz, 1H) 4.74 (s, 2H) 4.50-4.64 (m, 2H) 4.34-4.44 (m, 1H) 3.84 (t, J=5.14 Hz, 2H) 3.71-3.78 (m, 1H) 3.63-3.69 (m, 1H) 3.32 (m, 3H) 2.83 (t, J=5.52 Hz, 2H) 2.19 (s, 3H).

Compound 019: 4-(hydroxymethyl)-2-methyl-N-(3-methylcyclohexyl)-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

Step 1. 4-(hydroxymethyl)-2-methyl-4,5,8,9,10,11-hexahydropyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepin-1-one. A mixture of tert-butyl 4-(hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxylate (Intermediate 1, 200.00 mg, 567.55 μmol, 1.00 eq) in DCM (2.00 mL) was added TFA (1.54 g, 13.51 mmol, 1.00 mL, 23.80 eq) and then the mixture was stirred at 15° C. for 30 min. TLC showed the starting material was consumed completely, and major desired product. The mixture was concentrated in vacuum to give the title compound (207.00 mg, 565.13 μmol, 99.57% yield, TFA) as a yellow oil, which was used directly for next step.

Step 2: 4-(hydroxymethyl)-2-methyl-N-(3-methylcyclohexyl)-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide. A mixture of 3-methylcyclohexanamine (30.00 mg, 235.79 μmol, 1.00 eq, HCl) and TEA (146.00 mg, 1.44 mmol, 200.00 μL9.25 eq) in DCM (2.0 mL) was added triphosgene (46.27 mg, 155.92 μmol, 1.00 eq) at 0° C. The mixture was stirred at 25° C. for 12 min. Then 4-(hydroxymethyl)-2-methyl-4,5,8,9,10,11-hexahydropyrido [2,3] pyrazolo[2,4-d][1,2,5]oxadiazepin-1-one (50.00 mg, 136.50 μmol, 0.5 eq, TFA) and TEA (100.00 μL3.06 eq) was added to the reaction. The resulting mixture was stirred at 25° C. for 12 min. LCMS showed the reaction was completed. The solvent was evaporated in vacuo. The residue was adjusted to pH=6 and purified by prep-HPLC (FA) to afford the title compound. LCMS (M+1): 392.2.

Compound 020: 4-(hydroxymethyl)-N-(3-iodophenyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS (M+1): 498.0.

Compound 021: N-(3-(difluoromethyl)phenyl)-4-(hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS (M+1): 422. 1 H NMR (400 MHz, CHLOROFORM-d) δ=ppm 7.58-7.63 (m, 1H) 7.48 (s, 1H) 7.37 (t, J=7.84 Hz, 1H) 7.15-7.22 (m, 1H) 6.79 (s, 1H) 6.61 (s, 1H) 6.47 (s, 1H) 4.73 (s, 2H) 4.49-4.60 (m, 2H) 4.42 (s, 1H) 3.70-3.95 (m, 4H) 3.31 (s, 3H) 2.86 (s, 2H) 2.24-2.52 (m, 1H).

Compound 022: N-(3-chloro-4-fluoro-5-(trifluoromethyl)phenyl)-4-(hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS [M+1]: 492. 1 H NMR (400 MHz, CHLOROFORM-d) δ=7.84 (dd, J=6.02, 2.64 Hz, 1H) 7.52 (dd, J=5.21, 2.57 Hz, 1H) 6.76 (s, 1H) 4.71 (d, J=3.89 Hz, 2H) 4.56 (d, J=13.30 Hz, 2H) 4.43 (s, 1H) 3.86 (dd, J=7.15, 5.52 Hz, 4H) 3.33 (s, 3H) 2.87 (t, J=5.71 Hz, 2H) 1.89-2.11 (m, 1H).

Compound 023: N-(2,3-dichloro-4-fluorophenyl)-4-(hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS[M+1]: 458/460. 1 H NMR (400 MHz, CHLOROFORM-d) δ=8.05 (dd, J=9.35, 5.21 Hz, 1H) 7.09 (t, J=8.78 Hz, 1H) 6.97 (s, 1H) 4.73-4.82 (m, 2H) 4.51-4.62 (m, 2H) 4.36-4.46 (m, 1H) 3.75-3.93 (m, 4H) 3.33 (s, 3H) 2.89 (t, J=5.71 Hz, 2H) 1.94 (brs, 1H).

Compound 024: N-(3,4-dichloro-2-fluorophenyl)-4-(hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS[M+1]: 458. 1 H NMR (400 MHz, CHLOROFORM-d) δ=7.88-8.01 (m, 1H), 7.23 (dd, J=1.9, 9.1 Hz, 1H), 6.70 (d, J=3.1 Hz, 1H), 4.76 (s, 2H), 4.51-4.65 (m, 2H), 4.34-4.48 (m, 1H), 3.72-3.96 (m, 4H), 3.34 (s, 3H), 2.89 (t, J=5.7 Hz, 2H).

Compound 025: N-(4-chloro-3-(trifluoromethyl)phenyl)-4-(hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

›PREPARATIVE EXAMPLES · 20 of 53

LCMS[M+1]: 474/476 1 H NMR (400 MHz, CHLOROFORM-d) δ=7.75 (d, J=2.38 Hz, 1H) 7.60 (dd, J=8.72, 2.45 Hz, 1H) 7.41 (d, J=8.66 Hz, 1H) 6.74 (s, 1H) 4.72 (s, 2H) 4.51-4.61 (m, 2H) 4.37-4.47 (m, 1H) 3.77-3.93 (m, 4H) 3.32 (s, 3H) 2.86 (t, J=5.71 Hz, 2H) 2.04 (d, J=15.06 Hz, 1H).

Compound 026: N-(3-chloro-4-methylphenyl)-4-(hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS[M+1]: 420. 1 H NMR (400 MHz, CHLOROFORM-d) δ=7.51 (d, J=1.8 Hz, 1H), 7.12-7.20 (m, 2H), 6.48 (s, 1H), 4.72 (s, 2H), 4.51-4.64 (m, 2H), 4.35-4.47 (m, 1H), 3.74-3.97 (m, 4H), 3.34 (s, 3H), 2.87 (t, J=5.7 Hz, 2H), 2.33 (s, 3H), 1.98 (brs, 1H).

Compound 027: N-(4,5-dichloro-2-fluorophenyl)-4-(hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS (M+1): 458/460. 1 H NMR (400 MHz, CHLOROFORM-d) δ=8.25-8.38 (m, 1H), 7.21 (d, J=10.54 Hz, 1H), 6.61-6.69 (m, 1H), 4.74 (s, 2H), 4.51-4.63 (m, 2H), 4.35-4.47 (m, 1H), 3.86 (d, J=16.06 Hz, 4H), 3.33 (s, 3H), 2.88 (t, J=5.77 Hz, 2H), 1.81-1.92 (m, 1H).

Compound 028: N-(3-chloro-4,5-difluorophenyl)-4-(hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS [M+1]: 442. 1 H NMR (400 MHz, CHLOROFORM-d) δ=7.30-7.40 (m, 1H) 7.19-7.24 (m, 1H) 6.39-6.74 (m, 1H) 4.69 (d, J=2.38 Hz, 2H) 4.50-4.62 (m, 2H) 4.36-4.48 (m, 1H) 3.72-3.95 (m, 4H) 3.33 (s, 3H) 2.86 (t, J=5.58 Hz, 2H) 1.81-1.99 (m, 1H).

Compound 028_E1: (S*)—N-(3-chloro-4,5-difluorophenyl)-4-(hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS (M+1):442. 1 H NMR (400 MHz, CHLOROFORM-d) δ=7.33 (ddd, J=2.8, 6.4, 12.0 Hz, 1H), 7.21 (td, J=2.4, 5.2 Hz, 1H), 6.74 (brs, 1H), 4.69 (s, 2H), 4.49-4.62 (m, 2H), 4.37-4.47 (m, 1H), 3.71-3.92 (m, 4H), 3.31 (s, 3H), 2.84 (t, J=5.6 Hz, 2H), 2.28 (s, 1H).

*Pure but unknown enantiomer.

Compound 029: 4-(hydroxymethyl)-2-methyl-1-oxo-N-(3-(pentafluoro-16-sulfanyl)phenyl)-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS [M+1]: 498. 1 H NMR (400 MHz, CHLOROFORM-d) δ=7.86 (t, J=1.94 Hz, 1H) 7.60 (d, J=8.03 Hz, 1H) 7.34-7.45 (m, 2H) 6.80 (brs, 1H) 4.74 (s, 2H) 4.51-4.61 (m, 2H) 4.38-4.47 (m, 1H) 3.74-3.94 (m, 4H) 3.32 (s, 3H) 2.87 (t, J=5.77 Hz, 2H) 2.13 (brs, 1H).

Compound 030: N-(3-chlorophenyl)-4-(hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS (M+1): 406. 1 H NMR (400 MHz, CHLOROFORM-d) δ=7.51 (s, 1H), 7.16-7.25 (m, 2H), 7.01 (m, 1H), 6.69 (s, 1H), 4.70 (s, 2H), 4.49-4.60 (m, 2H), 4.36-4.45 (m, 1H), 3.70-3.93 (m, 4H), 3.31 (s, 3H), 2.85 (t, J=8.0 Hz, 2H), 2.40 (s, 1H).

Compound 031_E1: (S*)—N-(3-chloro-4-fluorophenyl)-4-(hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS (M+1): 424. 1 H NMR (400 MHz, CHLOROFORM-d) δ=7.55 (dd, J=4.0, 8.0 Hz, 1H), 7.15-7.23 (m, 1H), 6.99-7.08 (m, 1H), 6.69 (s, 1H), 4.69 (s, 2H), 4.60-4.49 (m, 2H), 4.36-4.46 (m, 1H), 3.71-3.92 (m, 4H), 3.29-3.34 (m, 3H), 2.84 (t, J=8.0 Hz, 2H), 2.42 (s, 1H).

*Pure but unknown enantiomer.

Compound 031_E2: (R*)—N-(3-chloro-4-fluorophenyl)-4-(hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS (M+1): 424. 1 H NMR (400 MHz, CHLOROFORM-d) δ=7.56-7.58 (dd, J=6.53, 2.64 Hz, 1H) 7.17-7.20 (dt, J=8.88, 3.40 Hz, 1H) 7.03-7.08 (m, 1H) 6.49 (s, 1H) 4.57-4.70 (s, 2H) 4.52-4.54 (m, 2H) 4.40-4.42 (m, 1H) 3.79-3.89 (m, 4H) 3.32 (s, 3H) 2.84-2.87 (t, J=5.77 Hz, 2H) 1.89-1.94 (m, 1H).

*Pure but unknown enantiomer.

Compound 032_E1: (S*)—N-(3-bromo-4-fluorophenyl)-4-(hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS (M+1): 468/470. 1 H NMR (400 MHz, CHLOROFORM-d) δ=7.68 (dd, J=4.0, 8.0 Hz, 1H), 7.22-7.26 (m, 1H), 7.03 (t, J=8.0 Hz, 1H), 6.69 (s, 1H), 4.69 (s, 2H), 4.49-4.61 (m, 2H), 4.36-4.45 (m, 1H), 3.71-3.92 (m, 4H), 3.31 (s, 3H), 2.84 (t, J=8.0 Hz, 2H), 2.42 (s, 1H).

*Pure but unknown enantiomer.

Compound 033_E1: (S*)—N-(2-bromo-3-fluoropyridin-4-yl)-4-(hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS (M+1): 469/471. 1 H NMR (400 MHz, CHLOROFORM-d) δ=8.10-8.18 (m, 1H), 8.06 (d, J=5.52 Hz, 1H), 6.99-7.10 (m, 1H), 4.76 (s, 2H), 4.50-4.62 (m, 2H), 4.37-4.46 (m, 1H), 3.71-3.95 (m, 4H), 3.32 (s, 3H), 2.89 (t, J=5.71 Hz, 2H), 2.20 (d, J=19.58 Hz, 1H).

*Pure but unknown enantiomer.

Compound 034_E1: (S*)—N-(3-cyano-4-fluorophenyl)-4-(hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS (M+1): 415. 1 H NMR (400 MHz, CHLOROFORM-d) δ=7.75 (dd, J=4.0, 8.0 Hz, 1H), 7.55-7.62 (m, 1H), 7.14 (t, J=8.0 Hz, 1H), 6.73 (s, 1H), 4.71 (d, J=4.0 Hz, 2H), 4.51-4.62 (m, 2H), 4.37-4.47 (m, 1H), 3.74-3.94 (m, 4H), 3.33 (s, 3H), 2.86 (t, J=8.0 Hz, 2H), 2.02 (s, 1H).

*Pure but unknown enantiomer.

Compound 035_E1: (S*)—N-(4-fluoro-3-methylphenyl)-4-(hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS (M+1): 404. 1 H NMR (400 MHz, CHLOROFORM-d) δ=7.22 (dd, J=4.0, 8.0 Hz, 1H), 7.05-7.12 (m, 1H), 6.91 (t, J=8.0 Hz, 1H), 6.57 (s, 1H), 4.69 (s, 2H), 4.48-4.59 (m, 2H), 4.35-4.43 (m, 1H), 3.68-3.92 (m, 4H), 3.29 (s, 3H), 2.83 (t, J=5.6 Hz, 2H), 2.66 (brs, 1H), 2.23 (d, J=1.6 Hz, 3H).

*Pure but unknown enantiomer.

Compound 038_E1: (S*)—N-(3-chloro-4-fluorophenyl)-4-(fluoromethyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

To a solution of N-(3-chloro-4-fluoro-phenyl)-4-(hydroxymethyl)-2-methyl-1-oxo-5,8,9,11-tetrahydro-4Hpyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxamide (Compound 031_E1, 20.00 mg, 47.19 μmol, 1.00 eq) in DCM (1.00 mL) was added DAST (45.64 mg, 283.14 μmol, 37.41 μL6.00 eq) at −30° C. under N 2 , the reaction mixture was stirred at 10° C. for 2 hours. TLC indicated the starting material was consumed completely and one major new spot with lower polarity was detected. The reaction mixture was quenched with water (10 mL) and then extracted with DCM (20 mL*3), the combined organic phase was dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuum. The residue was purified via prep-TLC, followed by prep-HPLC (FA) to afford the title compound as white solid.

›PREPARATIVE EXAMPLES · 21 of 53

LCMS (M+1): 426/428. 1 H NMR (400 MHz, CHLOROFORM-d) δ=7.58 (dd, J=6.53, 2.63 Hz, 1H) 7.15-7.22 (m, 1H) 7.03-7.10 (m, 1H) 6.45 (s, 1H) 4.53-4.73 (m, 6H) 4.42 (dd, J=14.43, 6.78 Hz, 1H) 3.81-3.91 (m, 2H) 3.33 (s, 3H) 2.87 (t, J=5.71 Hz, 2H).

*Pure but unknown enantiomer.

Compounds 036, 037, 039, 040, 041, 042, 043, and 044 were prepared in a manner analogous to Compound 038.

Compound 036: 4-(fluoromethyl)-2-methyl-1-oxo-N-(3-(trifluoromethyl)phenyl)-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS: 442 [M+1]. 1 H NMR (400 MHz, CHLOROFORM-d) δ=7.72 (s, 1H) 7.59 (d, J=7.53 Hz, 1H) 7.41 (t, J=7.91 Hz, 1H) 7.30 (d, J=7.78 Hz, 1H) 6.71 (s, 1H) 4.54-4.76 (m, 6H) 4.42 (dd, J=14.43, 6.90 Hz, 1H) 3.81-3.94 (m, 2H) 3.33 (s, 3H) 2.88 (t, J=5.77 Hz, 2H).

Compound 037_E1: (S*)—N-(3-chlorophenyl)-4-(fluoromethyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS (M+1): 408/410. 1 H NMR (400 MHz, CHLOROFORM-d) δ=7.52-7.55 (m, 1H) 7.18-7.25 (m, 2H) 7.00-7.05 (m, 1H) 6.49 (s, 1H) 4.54-4.73 (m, 6H) 4.42 (dd, J=14.49, 6.84 Hz, 1H) 3.82-3.91 (m, 2H) 3.33 (s, 3H) 2.87 (t, J=5.77 Hz, 2H).

*Pure but unknown enantiomer.

Compound 039_E1: (S*)—N-(4-fluoro-3-(trifluoromethyl)phenyl)-4-(fluoromethyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS (M+1): 460. 1 H NMR (400 MHz, CHLOROFORM-d) δ=7.57-7.61 (m, 1H), 7.47-7.54 (m, 1H), 7.06 (t, J=9.4 Hz, 1H), 6.46 (s, 1H), 4.57-4.67 (m, 4H), 4.45-4.56 (m, 2H), 4.34 (dd, J=6.9, 14.5 Hz, 1H), 3.80 (q, J=5.7 Hz, 2H), 3.25 (s, 3H), 2.80 (t, J=5.7 Hz, 2H).

*Pure but unknown enantiomer.

Compound 040_E1: (S*)—N-(3-bromo-4-fluorophenyl)-4-(fluoromethyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS (M+1): 470/472. 1 H NMR (400 MHz, CHLOROFORM-d) δ=7.70 (dd, J=2.57, 5.96 Hz, 1H), 7.22-7.27 (m, 1H), 7.04 (t, J=8.53 Hz, 1H), 6.53 (s, 1H), 4.50-4.82 (m, 6H), 4.41 (dd, J=6.90, 14.43 Hz, 1H), 3.86 (q, J=5.56 Hz, 2H), 3.32 (s, 3H), 2.86 (t, J=5.71 Hz, 2H).

*Pure but unknown enantiomer.

Compound 041_E1: (S*)—N-(2-bromo-3-fluoropyridin-4-yl)-4-(fluoromethyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS (M+1): 471/473. 1 H NMR (400 MHz, CHLOROFORM-d) δ=8.14-8.18 (m, 1H), 8.07 (d, J=5.5 Hz, 1H), 6.96 (d, J=3.4 Hz, 1H), 4.77 (s, 2H), 4.53-4.72 (m, 4H), 4.42 (dd, J=6.7, 14.5 Hz, 1H), 3.88 (t, J=5.9 Hz, 2H), 3.33 (s, 3H), 2.90 (t, J=5.7 Hz, 2H).

*Pure but unknown enantiomer.

Compound 042_E1: (S*)—N-(3-cyano-4-fluorophenyl)-4-(fluoromethyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS (M+1): 417. 1 H NMR (400 MHz, CHLOROFORM-d) δ=7.71-7.81 (m, 1H), 7.53-7.64 (m, 1H), 7.15 (s, 1H), 6.58 (s, H), 4.72 (d, J=2.08 Hz, 4H), 4.56 (d, J=5.14 Hz, 2H), 4.37-4.48 (m, 1H), 3.80-3.93 (m, 2H), 3.33 (s, 3H), 2.88 (t, J=5.81 Hz, 2H).

*Pure but unknown enantiomer.

Compound 043_E1: (S*)—N-(4-fluoro-3-methylphenyl)-4-(fluoromethyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS (M+1):406, 1 H NMR (CHLOROFORM-d, 400 MHz): δ=7.16 (d, J=2.9 Hz, 1H), 6.99-7.06 (m, 1H), 6.85 (t, J=8.9 Hz, 1H), 6.28 (s, 1H), 4.46-4.65 (m, 7H), 4.34 (dd, J=14.4, 6.8 Hz, 1H), 3.79 (q, J=5.4 Hz, 2H), 3.25 (s, 3H), 2.79 (t, J=5.7 Hz, 2H), 2.18 ppm (d, J=1.3 Hz, 3H).

*Pure but unknown enantiomer.

Compound 044_E1: (S*)—N-(3-chloro-4,5-difluorophenyl)-4-(fluoromethyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS (M+1): 444. 1 H NMR (400 MHz, CHLOROFORM-d) δ=7.34 (ddd, J=11.76, 6.43, 2.64 Hz, 1H) 7.21 (dt, J=5.30, 2.43 Hz, 1H) 6.49 (s, 1H) 4.54-4.73 (m, 6H) 4.42 (dd, J=14.49, 6.96 Hz, 1H) 3.81-3.91 (m, 2H) 3.33 (s, 3H) 2.87 (t, J=5.71 Hz, 2H).

*Pure but unknown enantiomer.

Compound 045: N-(3-chloro-4-fluorophenyl)-4-(hydroxymethyl)-N,2-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

To a solution of 3-chloro-4-fluoro-N-methyl-aniline (Intermediate 2, 45.00 mg, 229.53 μmol, 1.00 eq, HCl) and triphosgene (34.06 mg, 114.77 μmol, 0.50 eq) in DCM (3.00 mL) was added TEA (116.13 mg, 1.15 mmol, 159.08 μL5.00 eq) dropwise. The resulting mixture was stirred for 0.5 h at 0° C. and then stirred at 20° C. for 0.5 hr. 4-(hydroxymethyl)-2-methyl-4,5,8,9,10,11-hexahydropyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepin-1-one (Intermediate 1, 66.27 mg, 229.53 μmol, 1.00 eq, HCl) was added portionwise at 0° C., then warmed back to 20° C. and stirred for 1 hr. LCMS showed starting material consumed and 77.5% product was formed. Two batches of reaction mixture were poured into H 2 O (5 mL), and extracted with DCM (3*5 ml). The combined organic phase was dried over anhydrous Na 2 SO 4 , and concentrated under reduced pressure. The residue was purified by prep-HPLC to obtain the title compound (70 mg, 84.92 μmol, 99.77% purity) as a white solid. 1 H NMR (400 MHz, METHANOL-d 4 ) δ 7.33 (dd, J=2.70, 6.46 Hz, 1H), 7.19-7.26 (m, 1H), 7.12-7.18 (m, 1H), 4.43-4.55 (m, 2H), 4.23-4.36 (m, 3H), 3.66-3.75 (m, 1H), 3.55-3.66 (m, 3H), 3.31 (s, 6H), 3.26 (s, 3H), 3.18 (s, 3H). LCMS [M+1]: 438.

Compound 046: N-(3-chlorophenyl)-4-(hydroxymethyl)-2,8,8-trimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

Step 1. 4-(hydroxymethyl)-2,8,8-trimethyl-4,5,8,9,10,11-hexahydropyrido[4′,3′:3,4] pyrazolo[5,1-d][1,2,5]oxadiazepin-1(2H)-one. To a solution of tert-butyl 4-(hydroxymethyl)-2,8,8-trimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxylate (Intermediate 3, 43.00 mg, 113.03 μmol, 1.00 eq) in DCM (300.00 μL was added a solution of TFA (462.00 mg, 4.05 mmol, 300.00 μL35.85 eq) in DCM (300.00 μL at 0° C., the reaction mixture was stirred at 10° C. for one hour. TLC indicated starting material was consumed completely. The solvent was removed on a rotary evaporator to afford the title compound (40.00 mg, crude, TFA) as yellow oil. The product was used in the next step directly without further purification.

›PREPARATIVE EXAMPLES · 22 of 53

Step 2. N-(3-chlorophenyl)-4-(hydroxymethyl)-2,8,8-trimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide. To a mixture of 4-(hydroxymethyl)-2,8,8-trimethyl-4,5,8,9,10,11-hexahydropyrido [4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepin-1(2H)-one (40.00 mg, 101.43 μmol, 1.00 eq, TFA) in DCM (2.00 mL) was added TEA (41.06 mg, 405.73 μmol, 56.24 μL4.00 eq), followed by phenyl N-(3-chlorophenyl)carbamate (25.12 mg, 101.43 μmol, 1.00 eq), the reaction mixture was stirred at 10° C. for 16 hours. LCMS showed the starting material was consumed completely and about 50% of desired compound was detected. The mixture was extracted with DCM (50 mL*3) and water (30 mL), the organic phase was dried with anhydrous Na 2 SO 4 , filtered and concentrated in vacuum. The residue was purified by prep-HPLC(FA) to afford the title compound (28.00 mg, 63.24 μmol, 62.35% yield, 98% purity) as white solid. 1 H NMR (400 MHz, CHLOROFORM-d) δ=7.56 (s, 1H) 7.18-7.24 (m, 2H) 7.00-7.02 (d, J=7.78 Hz, 1H) 6.64 (s, 1H) 4.71 (s, 2H) 4.52-4.56 (m, 2H) 4.38-4.41 (m, 1H) 3.85-3.86 (m, 1H) 3.76-3.77 (m, 1H) 3.52-3.62 (m, 2H) 3.30 (s, 3H) 2.18 (brs, 1H) 1.34-1.36 (d, J=4.64 Hz, 6H). LCMS: 434/436 [M+1].

Compound 047: N-(3-chlorophenyl)-4-(hydroxymethyl)-2,8-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

To a solution of tert-butyl 4-(hydroxymethyl)-2,8-dimethyl-1-oxo-1,2,4,5,8,9-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(11H)-carboxylate (Intermediate 4, 60.00 mg, 163.75 μmol, 1.00 eq) in DCM (3.00 mL) was added TFA (1.32 g, 11.58 mmol, 857.16 μL70.70 eq). The mixture was stirred at 15° C. for 1 hr. TLC (PE:EA=0:1) showed the starting material consumed. The mixture was concentrated in vacuum to afford 4-(hydroxymethyl)-2,8-dimethyl-4,5,8,9,10,11-hexahydropyrido [4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepin-1(2H)-one (64.00 mg, 168.28 μmol, 102.77% yield, TFA) as yellow oil. The resulting solid was dissolved with DCM (5.00 mL), and added TEA (82.48 mg, 815.10 μmol, 112.99 μL5.00 eq) followed by phenyl N-(3-chlorophenyl)carbamate (40.38 mg, 163.02 μmol, 1.00 eq). The mixture was stirred at 15° C. for 16 hr. LCMS showed major product. The mixture was concentrated in vacuum. The residue was purified by prep-HPLC (FA) to afford the title compound (25.00 mg, 59.25 μmol, 36.34% yield, 99.5% purity) as white solid. 1 H NMR (400 MHz, CHLOROFORM-d) δ=7.56 (s, 1H), 7.19-7.27 (m, 2H), 7.03 (d, J=7.5 Hz, 1H), 6.60 (brs, 1H), 4.72-4.86 (m, 1H), 4.51-4.69 (m, 3H), 4.33-4.48 (m, 1H), 4.07-4.19 (m, 1H), 3.67-3.93 (m, 2H), 3.33 (s, 3H), 3.24 (ddd, J=8.3, 13.2, 17.4 Hz, 1H), 3.10 (d, J=6.7 Hz, 1H), 2.07 (brs, 1H), 1.36 (dd, J=2.3, 6.8 Hz, 1H). LCMS: 420/422 [M+1].

Compound 048: N-(3-chloro-4-fluoro-phenyl)-2-methyl-4-(methylsulfanylmethyl)-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxamide

Step 1. [10-[(3-chloro-4-fluoro-phenyl)carbamoyl]-2-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepin-4-yl]methylmethanesulfonate. To a solution of N-(3-chloro-4-fluoro-phenyl)-4-(hydroxymethyl)-2-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxamide (Compound 031, 500.00 mg, 1.18 mmol, 1.00 eq) in DCM (4.00 mL) was added Et3N (716.43 mg, 7.08 mmol, 981.40 μL6.00 eq) followed by MsCl (540.68 mg, 4.72 mmol, 365.32 μL4.00 eq) at 15° C. The resulting mixture was stirred for 20 hours at 25° C. TLC (Dichloromethane/Methanol=10/1) showed the starting material consumed nearly and major desired product was generated. The reaction mixture was diluted with dichloromethane (30 mL), and washed with 1N HCl (30 mL*2) and brine (30 mL). The organic layer was dried with Na 2 SO 4 , and concentrated to give the title compound (590.00 mg, 1.02 mmol, 86.67% yield, 87% purity) as a yellow solid.

Step 2. N-(3-chloro-4-fluoro-phenyl)-2-methyl-4-(methylsulfanylmethyl)-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxamide

To a solution of [10-[(3-chloro-4-fluoro-phenyl)carbamoyl]-2-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepin-4-yl]methylmethanesulfonate (150.00 mg, 298.85 μmol, 1.00 eq) in DMF (8.00 mL) was added NaSMe (125.68 mg, 1.79 mmol, 114.25 μL6.00 eq). The resulting mixture was stirred for 16 hours at 15° C. TLC (Dichloromethane/Methanol=10/1) showed the starting material consumed nearly and desired product was generated mainly. The reaction mixture was diluted with EtOAc (30 mL) and washed with water (30 mL*2) and brine (30 mL). The organic layer was dried with Na 2 SO 4 , and concentrated tin vacuo. The residue was purified by column chromatography (Dichloromethane:Methanol=20:1˜10:1) to give 145.00 mg of the desired product with 70.5% purity as a yellow liquid, 30 mg of which was further purified via Prep-HPLC (TFA) to give 14.81 mg of the title compound with 98% purity. 1 H NMR: (CDCl 3 , 400 MHz) δ=7.57-7.59 (m, 1H), 7.28-7.30 (m, 1H), 7.13 (t, J=9.20 Hz, 1H), 4.84 (s, 2H), 4.59-4.71 (m, 2H), 4.42-4.45 (m, 1H), 3.80-3.84 (t, J=6.00 Hz, 2H), 3.31 (s, 3H), 2.81-2.84 (m, 3H), 2.67-2.70 (m, 1H), 2.19 (s, 3H). LCMS [M+1]: 454.1

Compound 049_E1: (S*)—N-(3-chloro-4-fluorophenyl)-2-methyl-4-(((S*)-methylsulfinyl)methyl)-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

To a solution of N-(3-chloro-4-fluoro-phenyl)-2-methyl-4-(methylsulfanylmethyl)-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxamide (Compound 048, 80.00 mg, 123.37 μmol, 1.00 eq) in DCM (5.00 mL) was added m-CPBA (29.27 mg, 135.71 μmol, 80% purity, 1.10 eq) at 15° C. The resulting mixture was stirred for 16 hours at 30° C. TLC (Dichloromethane/Methanol=10/1) and LCMS showed the starting material was consumed completely and sulfone and sulfoxide were generated. The reaction mixture was diluted with dichloromethane (20 mL), then washed with water (10 mL), brine (10 mL), dried with Na 2 SO 4 , filtered, concentrated in vacuo. The residue was purified by Prep-TLC (Dichloromethane/Methanol=15/1), followed by prep-HPLC to 9.77 mg of Compound 050 and 29.09 mg of racemic Compound 049. 29.09 mg of racemic Compound 049 was separated by two rounds of SFC, and further purified by prep-HPLC (TFA condition) to give 4 enantiomers: Compound 049_E1 (6.86 mg), Compound 049_E2 (5.78 mg); Compound 049_E3 (7.15 mg) and Compound 049_E4 (6.79 mg). 1 H NMR: (CDCl 3 , 400 MHz) δ=7.56-7.59 (m, 1H), 7.15-7.22 (m, 1H), 7.07 (t, J=9.20 Hz, 1H), 6.46 (s, 1H), 5.03-5.12 (m, 1H), 4.65-4.78 (m, 3H), 4.45 (dd, J=7.60 Hz, J=7.60 Hz, 1H), 3.75-3.96 (m, 2H), 3.34 (s, 3H), 2.85-3.05 (m, 4H), 2.69 (s, 3H).

›PREPARATIVE EXAMPLES · 23 of 53

* pure but unknown stereochemistry

Compound 049_E2: (S*)—N-(3-chloro-4-fluorophenyl)-2-methyl-4-(((R*)-methylsulfinyl)methyl)-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

Compound 049_E2 was separated from the mixture described above.

1 H NMR: (CDCl 3 , 400 MHz) δ=7.56-7.59 (m, 1H), 7.15-7.22 (m, 1H), 7.07 (t, J=9.20 Hz, 1H), 6.46 (s, 1H), 5.03-5.12 (m, 1H), 4.65-4.78 (m, 3H), 4.45 (dd, J=7.60 Hz, J=7.60 Hz, 1H), 3.75-3.96 (m, 2H), 3.34 (s, 3H), 2.85-3.05 (m, 4H), 2.69 (s, 3H).

* pure but unknown stereochemistry

Compound 049_E3: (R*)—N-(3-chloro-4-fluorophenyl)-2-methyl-4-(((R*)-methylsulfinyl)methyl)-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

Compound 049_E3 was separated from the mixture described above.

* pure but unknown stereochemistry

Compound 049_E4: (R*)—N-(3-chloro-4-fluorophenyl)-2-methyl-4-(((S*)-methylsulfinyl)methyl)-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

Compound 049_E4 was separated from the mixture described above.

* pure but unknown stereochemistry

Compound 050: N-(3-chloro-4-fluorophenyl)-2-methyl-4-((methylsulfonyl)methyl)-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

Compound 050 was separated from the mixture described above.

1 H NMR: (CDCl 3 , 400 MHz) δ=7.53-7.57 (m, 1H), 7.15-7.20 (m, 1H), 7.07 (t, J=8.80 Hz, 1H), 6.45 (s, 1H), 5.12 (s, 1H), 4.65-4.78 (m, 3H), 4.53 (d, J=7.60 Hz, 1H), 3.75-3.90 (m, 3H), 3.32-3.45 (m, 3H), 3.27 (d, J=4.80 Hz, 1H), 3.03 (s, 3H), 2.88 (t, J=6.00 Hz, 2H). LCMS [M+1]: 486.3

Compound 051: (10-((3-chloro-4-fluorophenyl)carbamoyl)-2-methyl-1-oxo-1,2,4,5,8,9,10,11-octahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepin-4-yl)methyl methyl carbonate

To a solution of N-(3-chloro-4-fluoro-phenyl)-4-(hydroxymethyl)-2-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxamide (Compound 031, 50.00 mg, 117.97 μmol, 1.00 eq) in DCM (10.00 mL) was added Et 3 N (119.37 mg, 1.18 mmol, 163.53 μL 410.00 eq) followed by methyl carbonochloridate (111.48 mg, 1.18 mmol, 91.38 μL 10.00 eq) under ice-water bath (maintaining the inner temperature between 5˜10° C.). The resulting mixture was stirred for 2 hours at 30° C. TLC and LCMS showed the starting material was consumed, and the desired product was generated. The reaction mixture was concentrated in vacuo. The residue was purified by Prep-HPLC to give the purified product (50.00 mg, 102.73 μmol, 87.08% yield, 99% purity) as a white solid. LCMS: 482.1 [M+1]. 1 H NMR: (CDCl 3 , 400 MHz) δ=7.56-7.59 (m, 1H), 7.15-7.23 (m, 1H), 7.05 (t, J=8.80 Hz, 1H), 6.43 (s, 1H), 4.65-4.75 (m, 3H), 4.55-4.63 (m, 1H), 4.35-4.45 (m, 2H), 4.21-4.31 (m, 1H), 3.75-3.89 (m, 5H), 3.31 (s, 3H), 2.86 (t, J=6.00 Hz, 2H).

Compounds 052, 053, 054, 055 and 056 were prepared in a manner analogous to Compound 051.

Compound 052: (10-((3-chloro-4-fluorophenyl)carbamoyl)-2-methyl-1-oxo-1,2,4,5,8,9,10,11-octahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepin-4-yl)methyl acetate

LCMS: 466.1 [M+1]. 1 H NMR: (CDCl 3 , 400 MHz) δ=7.56-7.59 (m, 1H), 7.15-7.21 (m, 1H), 7.06 (t, J=8.80 Hz, 1H), 6.45 (s, 1H), 4.55-4.75 (m, 4H), 4.31-4.42 (m, 2H), 4.14-4.22 (m, 1H), 4.21-4.31 (m, 1H), 3.79-3.91 (m, 2H), 3.30 (s, 3H), 2.86 (t, J=6.40 Hz, 2H), 2.12 (s, 3H).

Compound 053: (10-((3-chloro-4-fluorophenyl)carbamoyl)-2-methyl-1-oxo-1,2,4,5,8,9,10,11-octahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepin-4-yl)methyl isopropyl carbonate

LCMS: 510 [M+1]. 1 H NMR (400 MHz, CHLOROFORM-d) δ=7.58 (dd, J=2.69, 6.48 Hz, 1H), 7.17-7.23 (m, 1H), 7.02-7.10 (m, 1H), 6.53 (s, 1H), 4.92 (m, J=6.24 Hz, 1H), 4.65-4.75 (m, 3H), 4.56-4.65 (m, 1H), 4.32-4.41 (m, 2H), 4.24 (dd, J=4.58, 11.92 Hz, 1H), 3.80-3.92 (m, 2H), 3.30 (s, 3H), 2.86 (t, J=5.75 Hz, 2H), 1.29-1.38 (m, 6H).

Compound 054: tert-butyl ((10-((3-chloro-4-fluorophenyl)carbamoyl)-2-methyl-1-oxo-1,2,4,5,8,9,10,11-octahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepin-4-yl)methyl) carbonate

LCMS: 546 [M+23]. 1 H NMR (400 MHz, CHLOROFORM-d) δ=7.58 (dd, J=2.63, 6.54 Hz, 1H), 7.16-7.23 (m, 1H), 7.02-7.10 (m, 1H), 6.55 (s, 1H), 4.65-4.77 (m, 3H), 4.56-4.64 (m, 1H), 4.27-4.41 (m, 2H), 4.18 (dd, J=4.65, 11.98 Hz, 1H), 3.77-3.93 (m, 2H), 3.30 (s, 3H), 2.86 (t, J=5.75 Hz, 2H), 1.51 (s, 9H).

Compound 055; (10-((3-chloro-4-fluorophenyl)carbamoyl)-2-methyl-1-oxo-1,2,4,5,8,9,10,11-octahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepin-4-yl)methyl pivalate

LCMS: 508 [M+1]. 1 H NMR (400 MHz, CHLOROFORM-d) δ=7.57 (dd, J=2.57, 6.48 Hz, 1H), 7.16-7.24 (m, 1H), 7.02-7.10 (m, 1H), 6.53 (s, 1H), 4.57-4.73 (m, 4H), 4.29-4.39 (m, 2H), 4.18-4.27 (m, 1H), 3.86 (t, J=5.81 Hz, 2H), 2.86 (t, J=5.75 Hz, 2H), 1.24 (s, 9H).

Compound 056: (10-((3-chloro-4-fluorophenyl)carbamoyl)-2-methyl-1-oxo-1,2,4,5,8,9,10,11-octahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepin-4-yl)methyl ethyl carbonate

LCMS: 496 [M+1]. 1 H NMR (400 MHz, CHLOROFORM-d) δ=7.57 (dd, J=2.69, 6.48 Hz, 1H), 7.16-7.23 (m, 1H), 7.02-7.10 (m, 1H), 6.52 (s, 1H), 4.65-4.76 (m, 3H), 4.56-4.65 (m, 1H), 4.32-4.43 (m, 2H), 4.21-4.30 (m, 3H), 3.77-3.95 (m, 2H), 3.31 (s, 3H), 2.86 (t, J=5.75 Hz, 2H), 1.35 (t, J=7.09 Hz, 3H).

Compound 057: (10-((3-chloro-4-fluorophenyl)carbamoyl)-2-methyl-1-oxo-1,2,4,5,8,9,10,11-octahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepin-4-yl)methyl carbamate

To a solution of N-(3-chloro-4-fluoro-phenyl)-4-(hydroxymethyl)-2-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxamide (Compound 031, 50.00 mg, 117.97 μmol, 1.00 eq) in DCM (8.00 mL) was added sodium cyanate (230.08 mg, 3.54 mmol, 30.00 eq) followed by CF 3 COOH (403.53 mg, 3.54 mmol, 262.03 μL30.00 eq) at 10° C. The resulting mixture was stirred for 48 hours at 30° C. LCMS and HPLC showed starting material/desired product=1/2. The reaction mixture was concentrated in vacuo. The residue was purified by Prep-HPLC (TFA condition) to give the desired product (16.74 mg, 35.86 μmol, 30.40% yield) as a white solid. 1 H NMR: (MeOD, 400 MHz) δ=7.57-7.59 (m, 1H), 7.23-7.39 (m, 1H), 7.13 (t, J=9.20 Hz, 1H), 4.65-4.75 (m, 3H), 4.59-4.64 (m, 1H), 4.33-4.41 (m, 1H), 4.25-4.32 (m, 1H), 4.13-4.20 (m, 1H), 3.82 (t, J=6.00 Hz, 2H), 3.31 (s, 3H), 2.82 (t, J=6.40 Hz, 2H). LCMS: 467 [M+1].

›PREPARATIVE EXAMPLES · 24 of 53

Compound 058: N-(3-chloro-4-fluoro-phenyl)-4-[(dimethylamino)methyl]-2-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxamide

Step 1. tert-butyl 2-methyl-4-(methylsulfonyloxymethyl)-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxylate. To a solution of tert-butyl 4-(hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxylate (Intermediate 1, 500.00 mg, 1.42 mmol, 1.00 eq) in DCM (2.00 mL) was added TEA (358.95 mg, 3.55 mmol, 491.72 μL2.50 eq) and MsCl (211.30 mg, 1.84 mmol, 142.77 μL1.30 eq). Then the mixture was stirred 20° C. for 2 hr. TLC (Ethyl acetate) showed the reaction was complete. The reaction mixture was diluted with DCM (20 mL) and washed with brine (10 mL), dried over anhydrous Na 2 SO 4 and concentrated in vacuum to give tert-butyl 2-methyl-4-(methylsulfonyloxymethyl)-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxylate (600.00 mg, 1.39 mmol, 98.16% yield) was obtained as yellow solid, which was used in the next step without further purification.

Step 2. tert-butyl 4-[(dimethylamino) methyl]-2-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxylate and tert-butyl 4-(dimethylcarbamoyloxymethyl)-2-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxylate. To a solution of tert-butyl 2-methyl-4-(methylsulfonyloxymethyl)-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxylate (50.00 mg, 116.15 μmol, 1.00 eq) and Me 2 NH (94.71 mg, 1.16 mmol, 106.42 μL10.00 eq, HCl) in DMF (3.00 mL) was added K 2 CO 3 (160.53 mg, 1.16 mmol, 161.00 μL10.00 eq). The mixture was stirred at 80° C. for 12 hr. LCMS showed the starting material was consumed and 19% 3 and 65% 3a were generated. The mixture was filtered and the filtrate was concentrated in vacuum. The crude was purified by prep-TLC (Dichloromethane:Methanol=10:1) to give the first titled compound (9.00 mg, 22.53 μmol, 19.40% yield, 95% purity) as the colorless oil, and the second titled compound (15.00 mg, 35.42 μmol, 30.50% yield) was obtained as colorless oil.

tert-butyl 4-[(dimethylamino)methyl]-2-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxylate: 1 H NMR (400 MHz, CHLOROFORM-d) δ 4.62-4.70 (m, 2H), 4.47-4.59 (m, 2H), 4.23-4.35 (m, 1H), 3.58-3.86 (m, 2H), 3.19-3.36 (m, 3H), 2.77 (t, J=5.44 Hz, 2H), 2.41-2.67 (m, 2H), 2.34 (s, 6H), 1.49 (s, 9H).

tert-butyl 4-(dimethylcarbamoyloxymethyl)-2-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxylate: 1 H NMR (400 MHz, CHLOROFORM-d) δ 4.51-4.72 (m, 4H), 4.27-4.39 (m, 2H), 4.15-4.25 (m, 1H), 3.71 (s, 2H), 3.28 (s, 3H), 2.92 (d, J=17.73 Hz, 5H), 2.70-2.80 (m, 2H), 1.48 (s, 9H).

Step 3. 4-[(dimethylamino)methyl]-2-methyl-4,5,8,9,10,11-hexahydropyrido[2,3] pyrazolo[2,4-d][1,2,5]oxadiazepin-1-one. To a solution of tert-butyl 4-[(dimethylamino)methyl]-2-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxylate (67.00 mg, 176.57 μmol, 1.00 eq) in DCM (2.00 mL) was added TFA (3.08 g, 27.01 mmol, 2.00 mL, 152.99 eq). The mixture was stirred at 15° C. for 30 min. TLC (ethyl acetate) showed the reaction was complete. The mixture was evaporated to give the crude title compound (80.00 mg, crude, TFA) as colorless oil, which was used in the next step without further purification.

Step 4. N-(3-chloro-4-fluoro-phenyl)-4-[(dimethylamino)methyl]-2-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxamide. To a solution of 4-[(dimethylamino)methyl]-2-methyl-4,5,8,9,10,11-hexahydropyrido [2,3]pyrazolo[2,4-d][1,2,5]oxadiazepin-1-one (49.00 mg, 175.41 μmol, 1.00 eq) and phenyl N-(3-chloro-4-fluoro-phenyl)carbamate (46.60 mg, 175.41 μmol, 1.00 eq) in DCM (2.00 mL) was added TEA (53.25 mg, 526.23 μmol, 72.95 μL3.00 eq). The mixture was stirred at 15° C. for 16 hr. LCMS showed the reaction was completed. The mixture was evaporated in vacuo. The residue was purified by prep-HPLC (column: Boston Green ODS 150*30 5 u; mobile phase: [water (0.225% FA)-ACN]; B %: 11%-41%, 10 min) The title compound (48.00 mg, 106.24 μmol, 60.57% yield, 99.8% purity) was obtained as white solid. 1 H NMR (400 MHz, CHLOROFORM-d) δ 7.57 (dd, J=2.63, 6.54 Hz, 1H), 7.17-7.22 (m, 1H), 7.03-7.09 (m, 1H), 6.53 (s, 1H), 4.77 (quin, J=5.81 Hz, 1H), 4.70 (s, 2H), 4.59 (dd, J=5.93, 14.61 Hz, 1H), 4.34 (dd, J=4.89, 14.67 Hz, 1H), 3.77-3.96 (m, 2H), 3.32 (s, 3H), 2.86 (t, J=5.75 Hz, 2H), 2.73 (d, J=6.72 Hz, 2H), 2.48 (s, 6H). LCMS: 451[M+1].

Compound 059: [10-[(3-chloro-4-fluoro-phenyl)carbamoyl]-2-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepin-4-yl]methyl N,N-dimethylcarbamate

Step 1. (2-methyl-1-oxo-4,5,8,9,10,11-hexahydropyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepin-4-yl)methyl N,N-dimethylcarbamate

To a solution of tert-butyl 4-(dimethylcarbamoyloxymethyl)-2-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxylate (As described above, 55.00 mg, 129.88 μmol, 1.00 eq) in DCM (2.00 mL) was added TFA (14.81 mg, 129.88 μmol, 9.62 μL1.00 eq). Then the mixture was stirred at 10° C. for 30 min. TLC (ethyl acetate) showed the reaction was complete. The mixture was evaporated to give the title compound (70.00 mg, crude, TFA) was obtained as colorless oil.

Step 2. [10-[(3-chloro-4-fluoro-phenyl)carbamoyl]-2-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepin-4-yl]methyl N,N-dimethylcarbamate

To a solution of (2-methyl-1-oxo-4,5,8,9,10,11-hexahydropyrido[2,3]pyrazolo[2,4-d] [1,2,5]oxadiazepin-4-yl)methyl N,N-dimethylcarbamate (42.00 mg, 96.03 μmol, 1.00 eq, TFA) and phenyl N-(3-chloro-4-fluoro-phenyl)carbamate (25.51 mg, 96.03 μmol, 1.00 eq) in DCM (2.00 mL) was added TEA (29.15 mg, 288.09 μmol, 39.93 μL3.00 eq). Then the mixture was stirred at 15° C. for 12 hr. LCMS showed the reaction was complete. The mixture was concentrated in vacuo. The residue was purified by prep-HPLC (column: Phenomenex Synergi C18 150*25*10 um; mobile phase: [water (0.225% FA)-ACN]; B %: 35%-65%, 10 min) to give the title compound (35.00 mg, 69.17 μmol, 72.02% yield, 97.8% purity) as a white solid. 1 H NMR (400 MHz, CHLOROFORM-d) δ 7.57 (dd, J=2.69, 6.48 Hz, 1H), 7.17-7.24 (m, 1H), 7.02-7.08 (m, 1H), 6.56 (s, 1H), 4.64-4.73 (m, 3H), 4.55-4.63 (m, 1H), 4.32-4.40 (m, 2H), 4.21-4.27 (m, 1H), 3.86 (t, J=5.87 Hz, 2H), 3.30 (s, 3H), 2.93 (d, J=16.99 Hz, 6H), 2.86 (t, J=5.69 Hz, 2H). LCMS: 495[M+1].

›PREPARATIVE EXAMPLES · 25 of 53

Compound 060_E1: (S*)—N-(3-chloro-4-fluorophenyl)-2-ethyl-4-(hydroxymethyl)-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

Step 1. 2-ethyl-4-(hydroxymethyl)-4,5,8,9,10,11 hexahydropyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepin-1-one. A solution of tert-butyl 2-ethyl-4-(hydroxymethyl)-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxylate (Intermediate 5, 51.00 mg, 139.19 μmol, 1.00 eq) in DCM (2.00 mL) was added TFA (770.00 mg, 6.75 mmol, 500.00 μL48.52 eq). Then the mixture was stirred at 10° C. for 1 hr. LCMS showed the reaction was completed. The mixture was evaporated to give the title compound (60.00 mg, crude) as the colorless oil which was used in the next step directly without further purification.

Step 2. (S*)—N-(3-chloro-4-fluorophenyl)-2-ethyl-4-(hydroxymethyl)-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide. To a solution of 2-ethyl-4-(hydroxymethyl)-4,5,8,9,10,11-hexahydropyrido[2,3] pyrazolo[2,4-d][1,2,5]oxadiazepin-1-one (60.00 mg, 135.19 μmol, 1.00 eq) and phenyl N-(3-chloro-4-fluoro-phenyl)carbamate (22.27 mg, 83.82 μmol, 0.62 eq) in DCM (3.00 mL) was added TEA (27.36 mg, 270.38 μmol, 37.48 μL2.00 eq). Then the mixture was stirred at 10° C. for 16 hr. LCMS showed the reaction was completed. The mixture was concentrated in vacuo. The residue was purified by Prep-HPLC (column: Phenomenex Synergi C18 150*25*10 um; mobile phase: [water (0.225% FA)-ACN]; B %: 30%-60%, 10 min). N-(3-chloro-4-fluoro-phenyl)-2-ethyl-4-(hydroxymethyl)-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxamide (34.00 mg, 76.88 μmol, 56.87% yield, 99% purity) was obtained as white solid. 30 mg of the racemate was separated by SFC (column: Phenomenex Synergi Max-RP 250*80 10 u; mobile phase: [Base-MeOH]; B %: 40%-40%, 3 MIN; 90 min), followed by prep-HPLC to give both enantiomers (each 12.00 mg, 27.41 μmol, 40.00% yield) as white solid.

1 H NMR (400 MHz, CHLOROFORM-d) δ 7.54-7.62 (m, 1H), 7.16-7.24 (m, 1H), 7.02-7.12 (m, 1H), 6.53 (s, 1H), 4.63-4.79 (m, 2H), 4.43-4.60 (m, 3H), 3.78-3.96 (m, 4H), 3.74 (dd, J=4.52, 11.54 Hz, 1H), 3.64 (qd, J=6.84, 13.85 Hz, 1H), 2.85 (t, J=5.40 Hz, 2H), 2.03 (s, 1H), 1.34 (t, J=7.03 Hz, 3H). LCMS: 438/440[M+1].

*Pure but unknown enantiomer.

Compound 060_E2: (R*)—N-(3-chloro-4-fluorophenyl)-2-ethyl-4-(hydroxymethyl)-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

Compound 060_E2 was isolated from the above-described mixture.

1 H NMR (400 MHz, CHLOROFORM-d) δ 7.55 (dd, J=2.51, 6.40 Hz, 1H), 7.15-7.23 (m, 1H), 6.99-7.09 (m, 1H), 6.63 (s, 1H), 4.62-4.77 (m, 2H), 4.44-4.60 (m, 3H), 3.76-3.94 (m, 4H), 3.69-3.76 (m, 1H), 3.63 (qd, J=7.00, 14.13 Hz, 1H), 2.84 (t, J=5.58 Hz, 2H), 2.29 (s, 1H), 1.33 (t, J=7.09 Hz, 3H). LCMS: 438/440[M+1].

*Pure but unknown enantiomer.

Compound 061: N-(3-chloro-4-fluoro-phenyl)-2,5-dimethyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxamide

Step 1. 2,5-dimethyl-4,5,8,9,10,11-hexahydropyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepin-1-one. To a solution of tert-butyl 2,5-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxylate (Intermediate 7, 30.00 mg, 89.18 μmol, 1.00 eq) in DCM (2.00 mL) was added TFA (3.08 g, 27.01 mmol, 2.00 mL, 302.90 eq). The reaction 192mixture was stirred at 15° C. for 12 hr. LCMS showed the starting material was consumed completely and ˜84% desired product was detected. The reaction mixture was concentrated in vacuo to give the title compound (35.00 mg, crude, TFA) as a off-white solid. LCMS: 237 [M+1].

Step 2. N-(3-chloro-4-fluoro-phenyl)-2,5-dimethyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxamide. To a solution of 2,5-dimethyl-4,5,8,9,10,11-hexahydropyrido[2,3]pyrazolo [2,4-d][1,2,5]oxadiazepin-1-one (35.00 mg, 99.92 μmol, 1.00 eq, TFA) and phenyl N-(3-chloro-4-fluoro-phenyl)carbamate (26.00 mg, 97.92 μmol, 0.98 eq) in DCM (3.00 mL) was added TEA (73.00 mg, 721.42 μmol, 100.00 μL7.22 eq). The reaction mixture was stirred at 30° C. for 12 hr. LCMS showed compound 4 was consumed completely and ˜75% desired product was detected. The reaction mixture was concentrated in vacuo. The residue was purified by prep-HPLC (HCl) to give the title compound (15.00 mg, 34.21 μmol, 34.23% yield, 93% purity) as a white solid. 1 H NMR (400 MHz, CHLOROFORM-d) 7.49-7.65 (m, 1H), 7.19 (s, 1H), 7.00-7.09 (m, 1H), 6.61 (s, 1H), 4.62-4.81 (m, 4H), 4.53 (dd, J=5.01, 11.62 Hz, 1H), 4.04 (dd, J=8.25, 11.43 Hz, 1H), 3.86 (s, 2H), 3.33 (s, 3H), 2.88 (s, 2H), 1.64 (d, J=6.36 Hz, 3H). LCMS: 408 [M+1].

Compound 062: N-(3-chloro-4-fluorophenyl)-2,4-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

Step 1. 2,4-dimethyl-4,5,8,9,10,11-hexahydropyrido[2,3] pyrazolo[2,4-d][1,2,5]oxadiazepin-1-one. Tert-butyl 2,4-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxylate (Intermediate 8, 50.00 mg, 148.64 μmol, 1.00 eq) was dissolved in TFA (5.13 g, 45.02 mmol, 3.33 mL, 302.90 eq). The mixture was stirred at 10° C. for 1 hr. TLC (PE:EA=0:1) showed the starting material consumed. The mixture was concentrated in vacuum to obtain the title compound (53.00 mg, crude, TFA) as colorless oil.

Step 2. N-(3-chloro-4-fluorophenyl)-2,4-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide. To a solution of 2,4-dimethyl-4,5,8,9,10,11-hexahydropyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepin-1-one (45.00 mg, 128.46 μmol, 1.00 eq, TFA) in DCM (5.00 mL) was added TEA (65.00 mg, 642.32 μmol, 89.04 μL5.00 eq) followed by phenyl N-(3-chloro-4-fluoro-phenyl)carbamate (34.13 mg, 128.46 μmol, 1.00 eq). The mixture was stirred at 30° C. for 16 hr. LCMS showed one main peak with desired Ms detected. The mixture was concentrated in vacuum. The residue was purified by prep-HPLC (HCl) to get N-(3-chloro-4-fluoro-phenyl)-2,4-dimethyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxamide 062 (43.00 mg, 105.23 μmol, 81.91% yield, 99.8% purity) as white solid.

›PREPARATIVE EXAMPLES · 26 of 53

1 H NMR (400 MHz, METHANOL-d 4 ) δ=7.60 (dd, J=2.5, 6.7 Hz, 1H), 7.28-7.36 (m, 1H), 7.15 (t, J=8.9 Hz, 1H), 4.74 (s, 2H), 4.65-4.69 (m, 1H), 4.59 (dd, J=5.3, 14.4 Hz, 1H), 4.24 (dd, J=5.3, 14.5 Hz, 1H), 3.85 (t, J=5.6 Hz, 2H), 3.30 (s, 3H), 2.85 (t, J=5.6 Hz, 2H), 1.29-1.37 (m, 3H). LCMS: 408[M+1].

Compound 063 was prepared in a manner analogous to Compound 062.

Compound 063: N-(3-chlorophenyl)-2,4-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazole [5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

1 H NMR (400 MHz, METHANOL-d 4 ) δ=7.54 (t, J=2.0 Hz, 1H), 7.29-7.35 (m, 1H), 7.21-7.27 (m, 1H), 7.02 (d, J=7.8 Hz, 1H), 4.74 (s, 2H), 4.64-4.71 (m, 1H), 4.59 (dd, J=5.7, 14.4 Hz, 1H), 4.24 (dd, J=5.5, 14.3 Hz, 1H), 3.85 (t, J=5.9 Hz, 2H), 3.30 (s, 3H), 2.85 (t, J=5.8 Hz, 2H), 1.34 (d, J=6.2 Hz, 3H). LCMS: 390[M+1].

Compound 064: N-(3-chloro-4-fluoro-phenyl)-2,4,4-trimethyl-1-oxo-5,8,9,11-tetrahydro pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxamide

Step 1. 2,4,4-trimethyl-8,9,10,11-tetrahydro-5H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepin-1-one. To a solution of tert-butyl 2,4,4-trimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxylate (Intermediate 9, 70.00 mg, 199.77 μmol, 1.00 eq) in DCM (3.00 mL) was added TFA (1.54 g, 13.51 mmol, 1.00 mL, 67.61 eq). The mixture was stirred at 10° C. for 1 hr. TLC (PE:EA=0:1) showed Compound 8 consumed. The mixture was concentrated in vacuum to get the title compound (73.00 mg, crude, TFA) as yellow oil.

Step 2. N-(3-chloro-4-fluoro-phenyl)-2,4,4-trimethyl-1-oxo-5,8,9,11-tetrahydro pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxamide. To a solution of 2,4,4-trimethyl-8,9,10,11-tetrahydro-5H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepin-1-one (73.00 mg, 200.37 μmol, 1.00 eq, TFA) and phenyl N-(3-chloro-4-fluoro-phenyl)carbamate (53.23 mg, 200.37 μmol, 1.00 eq) in DCM (10.00 mL) was added TEA (101.38 mg, 1.00 mmol, 138.88 μL5.00 eq). The mixture was stirred at 10° C. for 16 hr. LCMS showed 50% desired product detected. The mixture was concentrated in vacuum. The residue was purified by prep-HPLC (FA) to get the title compound (50.20 mg, 118.29 μmol, 59.03% yield, 99.4% purity) as white solid. 1 H NMR (400 MHz, CHLOROFORM-d) δ=7.60 (dd, J=2.64, 6.53 Hz, 1H), 7.21 (ddd, J=2.76, 4.02, 8.91 Hz, 1H), 7.04-7.11 (m, 1H), 6.48 (s, 1H), 4.71 (s, 2H), 4.25 (s, 2H), 3.88 (t, J=5.77 Hz, 2H), 3.29 (s, 3H), 2.88 (t, J=5.77 Hz, 2H), 1.39 (s, 6H). LCMS (M+1): 422.

Compound 065: N-(3-chloro-4-fluoro-phenyl)-4-(methoxymethyl)-2-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxamide

Step 1. Preparation of tert-butyl4-(methoxymethyl)-2-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxylate. To a mixture of tert-butyl 4-(hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxylate (Intermediate 1, 50.00 mg, 141.89 μmol, 1.00 eq) in DMF (4.00 mL) was added NaH (8.51 mg, 212.83 μmol, 60% purity, 1.50 eq) in one portion at −40° C. under N 2 . The mixture was stirred at −40˜-10° C. for 30 min, then MeI (40.28 mg, 283.78 μmol, 17.67 μL2.00 eq) was added to the mixture. The mixture was stirred at 0° C. for 1 hour. TLC (ethyl acetate: petroleum ether=2:1) showed the reaction was completed. The residue was poured into water (10 mL) and stirred for 2 min. The aqueous phase was extracted with ethyl acetate (10 mL*2). The combined organic phase was washed with brine (5 mL*2), dried with anhydrous Na 2 SO 4 , filtered and concentrated in vacuum. The residue was purified by prep-TLC (ethyl acetate: petroleum ether=2:1) to afford the title compound (30.00 mg, 72.05 μmol, 50.78% yield, 88% purity) as a yellow solid. LCMS: 367 [M+1].

Step 2. Preparation of 4-(methoxymethyl)-2-methyl-4,5,8,9,10,11-hexahydropyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepin-1-one. To a mixture of tert-butyl 4-(methoxymethyl)-2-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxylate (30.00 mg, 81.88 μmol, 1.00 eq) in DCM (2.00 mL) was added TFA (616.00 mg, 5.40 mmol, 400.00 μL65.98 eq) in one portion at 0° C. under N 2 . The mixture was stirred at 0° C. for 2 hr. LCMS showed the reaction was completed. The residue was concentrated in vacuum to afford (31.34 mg, crude, TFA) as yellow solid. LCMS: 267 [M+1].

Step 3. Preparation of N-(3-chloro-4-fluoro-phenyl)-4-(methoxymethyl)-2-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxamide. To a mixture of 4-(methoxymethyl)-2-methyl-4,5,8,9,10,11-hexahydropyrido[2,3] pyrazolo[2,4-d][1,2,5]oxadiazepin-1-one (31.14 mg, 81.88 μmol, 1.00 eq, TFA) and phenyl N-(3-chloro-4-fluoro-phenyl)carbamate (21.75 mg, 81.88 μmol, 1.00 eq) in DCM (4.00 mL) was added TEA (82.85 mg, 818.78 μmol, 113.50 μL10.00 eq) under N 2 . The mixture was stirred at 25° C. for 10 hours. LCMS showed the reaction was completed. The residue was poured into water (10 mL) and stirred for 2 min. The aqueous phase was extracted with ethyl acetate (10 mL*2). The combined organic phase was washed with brine (10 mL*2), dried with anhydrous Na 2 SO 4 , filtered and concentrated in vacuum. The residue was purified by prep-HPLC(FA) to afford the title compound (24.00 mg, 54.16 μmol, 66.14% yield, 98.8% purity) as white solid. 1 H NMR (400 MHz, CHLOROFORM-d) 7.53-7.63 (m, 1H), 7.14-7.23 (m, 1H), 7.06 (s, 1H), 6.46 (s, 1H), 4.70 (s, 2H), 4.48-4.65 (m, 2H), 4.41 (s, 1H), 3.86 (d, J=12.67 Hz, 2H), 3.57-3.67 (m, 1H), 3.49-3.56 (m, 1H), 3.44 (s, 3H), 3.31 (s, 3H), 2.82-2.93 (m, 2H). LCMS: 438 [M+1].

Compound 066: N-(3-chloro-4-fluoro-phenyl)-2-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-c][1,2,5]oxadiazepine-10-carboxamide

Step 1. 2-methyl-4,5,8,9,10,11-hexahydropyrido[2,3] pyrazolo[2,4-c][1,2,5]oxadiazepin-1-one. To a mixture of tert-butyl 2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxylate (Intermediate 10, 55.00 mg, 170.62 μmol, 1.00 eq) in DCM (2.00 mL) was added TFA (616.00 mg, 5.40 mmol, 400.00 μL31.66 eq) in one portion at 0° C. under N 2 . The mixture was stirred at 0° C. for 2 hr. TLC (dichloromethane:methanol=10:1) showed the reaction was completed. The residue was concentrated to afford (57.37 mg, 170.61 μmol, 100.00% yield, TFA) as a yellow oil.

›PREPARATIVE EXAMPLES · 27 of 53

Step 2. N-(3-chloro-4-fluoro-phenyl)-2-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-c][1,2,5]oxadiazepine-10-carboxamide. To a mixture of 2-methyl-4,5,8,9,10,11-hexahydropyrido[2,3]pyrazolo[2,4-c][1,2,5] oxadiazepin-1-one (57.37 mg, 170.61 μmol, 1.00 eq, TFA) and phenyl N-(3-chloro-4-fluoro-phenyl)carbamate (45.33 mg, 170.61 μmol, 1.00 eq) in DCM (4.00 mL) was added TEA (172.64 mg, 1.71 mmol, 236.49 μL10.00 eq) under N 2 . The mixture was stirred at 25° C. for 10 hours. LCMS showed the reaction was completed. The residue was poured into water (10 mL) and stirred for 2 min. The aqueous phase was extracted with ethyl acetate (10 mL*2). The combined organic phase was washed with brine (10 mL*2), dried with anhydrous Na 2 SO 4 , filtered and concentrated in vacuum. The residue was purified by prep-HPLC (FA) to afford the title compound (42.00 mg, 105.05 μmol, 61.58% yield, 98.5% purity) as white solid. 1 H NMR (400 MHz, CHLOROFORM-d) 7.55-7.62 (m, 1H), 7.16-7.24 (m, 1H), 7.02-7.11 (m, 1H), 6.48-6.56 (m, 1H), 4.71 (s, 2H), 4.52-4.60 (m, 2H), 4.36-4.45 (m, 2H), 3.82-3.93 (m, 2H), 3.31 (s, 3H), 2.87 (s, 2H). LCMS:394 [M+1].

Compound 067: 2-allyl-N-(3-chloro-4-fluoro-phenyl)-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-c][1,2,5]oxadiazepine-10-carboxamide

Step 1. 2-allyl-4,5,8,9,10,11-hexahydropyrido[2,3]pyrazolo[2,4-c][1,2,5]oxadiazepin-1-one. To a solution of tert-butyl 2-allyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxylate (Intermediate 12, 30.00 mg, 86.11 μmol, 1.00 eq) in DCM (2.00 mL) was added TFA (770.00 mg, 6.75 mmol, 500.00 μL78.43 eq), the reaction mixture was stirred at 10° C. for one hour. TLC indicated Compound 7 was consumed completely, and one major new spot with larger polarity was detected. The solvent was removed on a rotary evaporator to give the title compound (30.00 mg, crude, TFA) as a yellow oil. The crude product was used in next step directly without purification.

Step 2. 2-allyl-N-(3-chloro-4-fluoro-phenyl)-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-c][1,2,5]oxadiazepine-10-carboxamide. To a solution of 2-allyl-4,5,8,9,10,11-hexahydropyrido[2,3]pyrazolo[2,4-c][1,2,5] oxadiazepin-1-one (30.00 mg, 82.80 μmol, 1.00 eq, TFA) in DCM (2.00 mL) was added TEA (33.52 mg, 331.22 μmol, 45.91 μL4.00 eq), followed by phenyl N-(3-chloro-4-fluoro-phenyl)carbamate (22.00 mg, 82.80 μmol, 1.00 eq). The reaction mixture was stirred at 10° C. for 16 hours. LCMS showed Compound 8 was consumed completely and one main peak with desired MS was detected. The mixture was extracted with DCM (30 mL*2) and water (20 mL), the organic phase was dried with anhydrous Na 2 SO 4 , filtered and concentrated in vacuum. Further purification by prep-HPLC(FA) to give the title compound (32.60 mg, 75.68 μmol, 91.41% yield, 97.47% purity) as a white solid. 1 H NMR (400 MHz, CHLOROFORM-d) δ=7.56-7.58 (dd, J=6.54, 2.63 Hz, 1H) 7.18-7.21 (m, 1H) 7.03-7.07 (m, 1H) 6.55 (s, 1H) 5.92-5.97 (ddt, J=16.93, 10.30, 6.31, 6.31 Hz, 1H) 5.32-5.34 (m, 2H) 4.71 (s, 2H) 4.54-4.57 (m, 2H) 4.36-4.39 (m, 2H) 4.28-4.30 (d, J=6.36 Hz, 2H) 3.85-3.87 (t, J=5.81 Hz, 2H) 2.85-2.87 (t, J=5.75 Hz, 2H). LCMS: 420/422 [M+1].

Compound 068: N-(3-chloro-4-fluoro-phenyl)-1-oxo-2-propyl-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-c][1,2,5]oxadiazepine-10-carboxamide

Step 1. tert-butyl 1-oxo-2-propyl-5,8,9,11-tetrahydro-4H-pyrido[2,3] pyrazolo[2,4-c][1,2,5]oxadiazepine-10-carboxylate. A mixture of tert-butyl 2-allyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo [2,4-c][1,2,5]oxadiazepine-10-carboxylate (Compound 067, 40.00 mg, 114.81 μmol, 1.00 eq) and Pd/C (20.00 mg, 10% purity) in MeOH (20.00 mL) was stirred under H 2 (15 psi) at 10° C. for 16 hours. LCMS showed Compound 7 was consumed completely and one main peak with desired MS was detected. The reaction mixture was filtered and the filter was concentrated to give the title compound (38.00 mg, 108.44 μmol, 94.46% yield) as a yellow oil. LCMS: 373 [M+23].

Step 2. 2-propyl-4,5,8,9,10,11-hexahydropyrido[2,3]pyrazolo[2,4-c][1,2,5]oxadiazepin-1-one. To a solution of tert-butyl 1-oxo-2-propyl-5,8,9,11-tetrahydro-4H-pyrido[2,3] pyrazolo[2,4-c][1,2,5]oxadiazepine-10-carboxylate (38.00 mg, 108.44 μmol, 1.00 eq) in DCM (2.00 mL) was added TFA (1.54 g, 13.51 mmol, 1.00 mL, 124.55 eq). The reaction mixture was stirred at 10° C. for one hour. TLC indicated Compound 9 was consumed completely, and one major new spot with larger polarity was detected. The solvent was removed on a rotary evaporator to give (38.00 mg, crude, TFA) as a yellow oil, which was used in next step directly without further purification.

Step 3. N-(3-chloro-4-fluoro-phenyl)-1-oxo-2-propyl-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-c][1,2,5]oxadiazepine-10-carboxamide. To a solution of 2-propyl-4,5,8,9,10,11-hexahydropyrido[2,3]pyrazolo[2,4-c][1,2,5]oxadiazepin-1-one (38.00 mg, 104.30 μmol, 1.00 eq, TFA) in DCM (2.00 mL) was added TEA (42.22 mg, 417.20 μmol, 57.84 μL4.00 eq), followed by phenyl N-(3-chloro-4-fluoro-phenyl)carbamate (27.71 mg, 104.30 μmol, 1.00 eq). The reaction mixture was stirred at 10° C. for 16 hours. LCMS showed Compound 10 was consumed completely and one main peak with desired MS was detected. The mixture was extracted with DCM (30 mL*2) and water (20 mL), the organic phase was dried with anhydrous Na 2 SO 4 , filtered and concentrated in vacuum. The residue was purification by prep-HPLC(FA) to give the title compound (35.39 mg, 82.06 μmol, 78.67% yield, 97.81% purity) was obtained as a white solid. 1 H NMR (400 MHz, CHLOROFORM-d) δ=7.56-7.58 (dd, J=6.53, 2.63 Hz, 1H) 7.17-7.19 (m, 1H) 7.03-7.08 (m, 1H) 6.52 (s, 1H) 4.70 (s, 2H) 4.54-4.57 (m, 2H) 4.38-4.41 (m, 2H) 3.85-3.88 (t, J=5.77 Hz, 2H) 3.64-3.68 (m, 2H) 2.85-2.87 (t, J=5.77 Hz, 2H) 1.74-1.83 (m, J=7.38 Hz, 2H) 1.00-1.04 (t, J=7.40 Hz, 3H). LCMS: 422/424 [M+1].

Compound 069_E1: (4S*,9S*)—N-(3-chloro-4-fluorophenyl)-4-(hydroxymethyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

›PREPARATIVE EXAMPLES · 28 of 53

Step 1. 4-(hydroxymethyl)-2,9-dimethyl-4,5,8,9,10,11-hexahydropyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepin-1-one. To a mixture of tert-butyl 4-(hydroxymethyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxylate (Intermediate 14, 100.00 mg, 272.92 μmol, 1.00 eq) in DCM (2.00 mL) was added TFA (616.00 mg, 5.40 mmol, 400.00 μL19.80 eq) in one portion at 0° C. under N 2 . The mixture was stirred at 0° C. for 2 hr. TLC and LCMS showed the reaction was completed. The mixture was concentrated in vacuum to afford the title compound (103.80 g, crude, TFA) as a yellow oil. LCMS: 267 [M+1].

Step 2. (4S*,9S*)—N-(3-chloro-4-fluorophenyl)-4-(hydroxymethyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide. To a mixture of 4-(hydroxymethyl)-2,9-dimethyl-4,5,8,9,10,11-hexahydropyrido [2,3]pyrazolo[2,4-d][1,2,5]oxadiazepin-1-one (103.80 mg, 272.93 μmol, 1.00 eq, TFA) and phenyl N-(3-chloro-4-fluoro-phenyl)carbamate (72.51 mg, 272.93 μmol, 1.00 eq) in DCM (6.00 mL) was added TEA (276.18 mg, 2.73 mmol, 378.32 μL10.00 eq) under N 2 . The mixture was stirred at 25° C. for 10 hours. LCMS and TLC (dichloromethane:methanol=10:1) showed the reaction was completed. The residue was poured into water (10 mL) and stirred for 2 min. The aqueous phase was extracted with ethyl acetate (10 mL*2). The combined organic phase was washed with brine (10 mL*2), dried with anhydrous Na 2 SO 4 , filtered and concentrated in vacuum. The residue was purified by silica gel chromatography (dichloromethane:methanol=100/1, 50/1) to afford the title compound (98.00 mg, 218.90 μmol, 80.20% yield, 97.8% purity) as a yellow solid, which was resolved by SFC (Instrument: SFC Waters 80_Q Column: OD-10 um. Mobile phase: A for CO 2 and B for Methanol (0.1% NH 3 H 2 O) Isocratic: B 25%. Flow rate: 55 mL/min. Back pressure: 100 bar. Column temperature: 35° C.; Wavelength: 220 nm) to give two fractions. The first fraction was separated by SFC (Instrument: SFC Thar_80_Q. Column: OJ-5 um. Mobile phase: A for CO 2 and B for Isopropanol (0.1% NH 3 H 2 O). Isocratic: B 25%. Flow rate: 55 mL/min. Back pressure: 100 bar. Column temperature: 35° C. Wavelength: 220 nm) to give Compound 070_E1(8.68 mg, 95.8% purity) and Compound 069_E2 (20.43 mg, 98.0% purity) as a white solid. LCMS: 438 [M+1]. 1 H NMR (400 MHz, CHLOROFORM-d) 7.55-7.63 (m, 1H), 7.16-7.24 (m, 1H), 7.02-7.10 (m, 1H), 6.43-6.52 (m, 1H), 5.09-5.21 (m, 1H), 4.80-4.93 (m, 1H), 4.52-4.65 (m, 2H), 4.33-4.50 (m, 2H), 3.74-3.96 (m, 2H), 3.34 (s, 3H), 2.98-3.10 (m, 1H), 2.63-2.74 (m, 1H), 1.82-1.99 (m, 1H), 1.18 (d, J=6.90 Hz, 3H).

* pure but unknown stereochemistry

Compound 069_E2: (4R*,9S*)—N-(3-chloro-4-fluorophenyl)-4-(hydroxymethyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

Obtained from the above-described mixture.

LCMS: 438 [M+1]. 1 H NMR (400 MHz, CHLOROFORM-d) 7.53-7.64 (m, 1H), 7.16-7.23 (m, 1H), 7.02-7.12 (m, 1H), 6.42-6.50 (m, 1H), 5.07-5.18 (m, 1H), 4.77-4.86 (m, 1H), 4.38-4.66 (m, 4H), 3.71-3.93 (m, 2H), 3.33 (s, 3H), 2.97-3.10 (m, 1H), 2.68 (d, J=15.94 Hz, 1H), 1.85-1.98 (m, 1H), 1.19 (d, J=6.90 Hz, 3H).

* pure but unknown stereochemistry

The second fraction was separated by SFC (Instrument: SFC Thar_80_Q. Column: OJ-5 um. Mobile phase: A for CO 2 and B for Methanol (0.1% NH 3 H 2 O). Isocratic: B 25%. Flow rate: 55 mL/min. Back pressure: 100 bar. Column temperature: 35° C. Wavelength: 220 nm) to give Compound 069_E3(15.37 mg, 97.3% purity) and Compound 069_E4 (21.86 mg, 99.26% purity) as white solid.

Compound 069_E3: (4R*,9R*)—N-(3-chloro-4-fluorophenyl)-4-(hydroxymethyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS: 438 [M+1]. 1 H NMR (400 MHz, CHLOROFORM-d) 7.55-7.65 (m, 1H), 7.16-7.23 (m, 1H), 7.01-7.13 (m, 1H), 6.40-6.52 (m, 1H), 5.07-5.23 (m, 1H), 4.80-4.92 (m, 1H), 4.52-4.63 (m, 2H), 4.34-4.50 (m, 2H), 3.74-3.96 (m, 2H), 3.02 (d, J=5.77 Hz, 1H), 2.71 (s, 1H), 1.80-1.96 (m, 1H), 1.18 (d, J=6.90 Hz, 3H).

* pure but unknown stereochemistry

Compound 069_E4: (4S*,9R*)—N-(3-chloro-4-fluorophenyl)-4-(hydroxymethyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS: 438 [M+1]. 1 H NMR (400 MHz, CHLOROFORM-d) 7.54-7.65 (m, 1H), 7.15-7.23 (m, 1H), 7.01-7.11 (m, 1H), 6.40-6.52 (m, 1H), 5.06-5.19 (m, 1H), 4.75-4.86 (m, 1H), 4.36-4.65 (m, 4H), 3.71-3.91 (m, 2H), 2.98-3.10 (m, 1H), 2.68 (d, J=15.69 Hz, 1H), 1.84-2.01 (m, 1H), 1.19 (d, J=6.90 Hz, 3H).

* pure but unknown stereochemistry

Compound 070 N-(3-chlorophenyl)-4-(hydroxymethyl)-2,9-dimethyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxamide

To a mixture of tert-butyl 6-methyl-3-(methyl(oxetan-3-yloxy)carbamoyl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (Intermediate 15, 40.00 mg, 109.17 μmol, 1.00 eq) in DCM (1.00 mL) was added TFA (770.00 mg, 6.75 mmol, 500.00 μL61.86 eq) in one portion at 0° C. under N 2 . The mixture was stirred at 0° C. for 2 hours. LCMS and TLC (dichloromethane:methanol=5:1) showed the reaction was completed. The reaction mixture was treated with TEA (1 mL) at −78° C. To the resulting mixture, was added phenyl N-(3-chlorophenyl)carbamate (27.04 mg, 109.16 μmol, 1.00 eq) in DCM (4.00 mL), followed by TEA (110.46 mg, 1.09 mmol, 151.32 μL10.00 eq) under N 2 . The mixture was stirred at 25° C. for 10 hours. LCMS showed the reaction was completed. The residue was poured into water (10 mL) and stirred for 5 min. The aqueous phase was extracted with ethyl acetate (10 mL*2). The combined organic phase was washed with brine (10 mL*2), dried with anhydrous Na 2 SO 4 , filtered and concentrated in vacuum. The residue was purified by prep-HPLC (FA) to afford the title compound (17.00 mg, 40.17 μmol, 36.80% yield, 99.2% purity) as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.79-8.94 (m, 1H), 7.62 (s, 1H), 7.35-7.42 (m, 1H), 7.22-7.29 (m, 1H), 6.93-7.02 (m, 1H), 5.13-5.22 (m, 1H), 4.96-5.07 (m, 1H), 4.80-4.91 (m, 1H), 4.38-4.60 (m, 2H), 4.09-4.34 (m, 2H), 3.44-3.69 (m, 2H), 3.23 (d, J=3.14 Hz, 3H), 2.84-2.95 (m, 1H), 2.58 (dd, J=4.20, 15.75 Hz, 1H), 1.09 (d, J=6.78 Hz, 3H). LCMS: 420 [M+1].

›PREPARATIVE EXAMPLES · 29 of 53

Compound 071: methyl 10-[(3-chloro-4-fluoro-phenyl)carbamoyl]-2-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-4-carboxylate

To a mixture of 10-(tert-butyl) 4-methyl 2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-4,10(2H)-dicarboxylate (Intermediate 16, 110.00 mg, 289.18 μmol, 1.00 eq) in DCM (2.00 mL) was added TFA (770.00 mg, 6.75 mmol, 500.00 μL23.35 eq) in one portion at 0° C. under N 2 . The mixture was stirred at 0° C. for 2 hr. TLC (Dichloromethane:Methanol=10:1) showed the reaction was completed. The residue was concentrated in vacuum to give 2-methyl-1-oxo-4,5,8,9,10,11-hexahydropyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-4-carboxylate (114.02 mg, 289.17 μmol, 1.00 eq, TFA) as yellow oil. The resulting oil and phenyl N-(3-chloro-4-fluoro-phenyl)carbamate (76.82 mg, 289.17 μmol, 1.00 eq) was dissolved in DCM (4.00 mL) and added TEA (292.61 mg, 2.89 mmol, 400.84 μL10.00 eq) under N 2 . The mixture was stirred at 25° C. for 10 hours. LCMS showed the reaction was completed. The residue was poured into water (10 mL) and stirred for 2 min. The aqueous phase was extracted with ethyl acetate (10 mL*2). The combined organic phase was washed with brine (10 mL*2), dried with anhydrous Na 2 SO 4 , filtered and concentrated in vacuum. The residue was purified by prep-HPLC(FA) to afford the title compound (60.00 mg, 131.99 μmol, 45.65% yield, 99.4% purity) as white solid. LCMS: 452[M+1]. 1 H NMR (400 MHz, CHLOROFORM-d) 7.57 (dd, J=2.64, 6.53 Hz, 1H), 7.15-7.24 (m, 1H), 7.01-7.11 (m, 1H), 6.48 (s, 1H), 4.92 (s, 2H), 4.74 (s, 1H), 4.50-4.68 (m, 2H), 3.90 (s, 3H), 3.86 (s, 2H), 3.40 (s, 3H), 2.77-2.98 (m, 2H).

Compound 072: N10-(3-chloro-4-fluoro-phenyl)-2-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-4,10-dicarboxamide

Step 1. 10-[(3-chloro-4-fluoro-phenyl)carbamoyl]-2-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-4-carboxylic acid. To a mixture of methyl 10-[(3-chloro-4-fluoro-phenyl)carbamoyl]-2-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-4-carboxylate (Compound 071, 40.00 mg, 88.53 μmol, 1.00 eq) in DCE (4.00 mL) was added hydroxyl (trimethyl) stannane (80.04 mg, 442.65 μmol, 5.00 eq) in one portion under N 2 . The mixture was stirred at 30° C. for 12 hours. LCMS showed the reaction was completed. The residue was concentrated in vacuum. The residue was purified by prep-HPLC(FA) to afford the title compound (30.00 mg, 65.13 μmol, 73.57% yield, 95.05% purity) as a yellow solid. 1 H NMR (400 MHz, CHLOROFORM-d) δ 7.52-7.58 (m, 1H), 7.16-7.23 (m, 1H), 7.02-7.11 (m, 1H), 6.47-6.56 (m, 1H), 4.84-5.03 (m, 1H), 4.59-4.78 (m, 1H), 3.85 (s, 1H), 3.40 (s, 3H), 2.87 (br d, J=5.50 Hz, 1H). LCMS: 438[M+1].

Step 2. N10-(3-chloro-4-fluoro-phenyl)-2-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-4,10-dicarboxamide. To a mixture of 10-[(3-chloro-4-fluoro-phenyl)carbamoyl]-2-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-4-carboxylic acid (20.00 mg, 45.68 μmol, 1.00 eq) and NH 4 Cl (24.44 mg, 456.82 μmol, 15.97 μL10.00 eq) in DMF (3.00 mL) was added HOBt (9.26 mg, 68.52 μmol, 1.50 eq), PyBOP (35.66 mg, 68.52 μmol, 1.50 eq) and DIPEA (88.56 mg, 685.23 μmol, 119.67 μL15.00 eq) in one portion under N 2 . The mixture was stirred at 30° C. for 12 hours. LCMS showed the reaction was completed, and desired product was detected. The residue was poured into water (10 mL). The aqueous phase was extracted with ethyl acetate (10 mL*2). The combined organic phase was washed with brine (10 mL*2), dried with anhydrous Na 2 SO 4 , filtered and concentrated in vacuum. The residue was purified by prep-HPLC (FA) to afford the title compound (14.00 mg, 31.92 μmol, 69.88% yield, 99.6% purity) as a white solid. 1 H NMR (400 MHz, CHLOROFORM-d) 7.54-7.61 (m, 1H), 7.15-7.23 (m, 1H), 7.01-7.11 (m, 1H), 6.44-6.55 (m, 1H), 6.01-6.12 (m, 1H), 5.55-5.67 (m, 1H), 4.86-5.01 (m, 2H), 4.64-4.79 (m, 3H), 3.71-3.98 (m, 2H), 3.37 (s, 3H), 2.87 (s, 2H). LCMS: 437 [M+1].

Compound 073: N10-(3-chloro-4-fluoro-phenyl)-N4,2-dimethyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-4,10-dicarboxamide

Step 1. 10-[(3-chloro-4-fluoro-phenyl)carbamoyl]-2-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-4-carboxylic acid. To a mixture of methyl 10-[(3-chloro-4-fluoro-phenyl)carbamoyl]-2-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-4-carboxylate (Compound 071, 40.00 mg, 88.53 μmol, 1.00 eq) in DCE (4.00 mL) was added hydroxyl (trimethyl) stannane (80.04 mg, 442.65 μmol, 5.00 eq) in one portion under N 2 . The mixture was stirred at 30° C. for 12 hours. LCMS showed the reaction was completed. The residue was concentrated in vacuum. The residue was purified by prep-HPLC(FA) to afford the title compound (30.00 mg, 65.13 μmol, 73.57% yield, 95.05% purity) as a yellow solid. 1 H NMR (400 MHz, CHLOROFORM-d) δ=7.52-7.58 (m, 1H), 7.16-7.23 (m, 1H), 7.02-7.11 (m, 1H), 6.47-6.56 (m, 1H), 4.84-5.03 (m, 1H), 4.59-4.78 (m, 1H), 3.85 (s, 1H), 3.40 (s, 3H), 2.87 (br d, J=5.50 Hz, 1H). LCMS: 438[M+1].

Step 2. N10-(3-chloro-4-fluoro-phenyl)-N4,2-dimethyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-4,10-dicarboxamide. To a mixture of 10-[(3-chloro-4-fluoro-phenyl)carbamoyl]-2-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-4-carboxylic acid (25.00 mg, 57.10 μmol, 1.00 eq) and methanamine (MeNH 2 ) (38.55 mg, 571.00 μmol, 10.00 eq, HCl) in DMF (2.00 mL) was added HATU (32.57 mg, 85.65 μmol, 1.50 eq) and DIPEA (110.69 mg, 856.50 μmol, 149.58 μL15.00 eq) in one portion under N 2 . The mixture was stirred at 30° C. for 12 hours. LCMS showed the reaction was not reacted. The mixture was stirred at 30° C. for another 12 hours, LCMS showed the reaction was completed. The residue was poured into water (10 mL) and stirred for 2 min. The aqueous phase was extracted with ethyl acetate (10 mL*2). The combined organic phase was washed with brine (10 mL*2), dried with anhydrous Na 2 SO 4 , filtered and concentrated in vacuum. The residue was purified by prep-HPLC (FA) to afford the title compound (20.00 mg, 44.01 μmol, 77.07% yield, 99.2% purity) as white solid. 1 H NMR (400 MHz, METHANOL-d 4 ) 7.56-7.64 (m, 1H), 7.26-7.36 (m, 1H), 7.08-7.21 (m, 1H), 4.98-5.05 (m, 1H), 4.74 (s, 4H), 3.72-3.96 (m, 2H), 3.34 (br. s., 4H), 2.80-2.90 (m, 2H), 2.76 (s, 3H). LCMS: 451 [M+1].

›PREPARATIVE EXAMPLES · 30 of 53

Compound 074: N10-(3-chloro-4-fluoro-phenyl)-N4,N4,2-trimethyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-4,10-dicarboxamide

Step 1. 10-[(3-chloro-4-fluoro-phenyl)carbamoyl]-2-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-4-carboxylic acid. To a mixture of methyl 10-[(3-chloro-4-fluoro-phenyl)carbamoyl]-2-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-4-carboxylate (Compound 071, 40.00 mg, 88.53 μmol, 1.00 eq) in DCE (4.00 mL) was added hydroxyl (trimethyl) stannane (80.04 mg, 442.65 μmol, 5.00 eq) in one portion under N 2 . The mixture was stirred at 30° C. for 12 hours. LCMS showed the reaction was completed. The residue was concentrated in vacuum. The residue was purified by prep-HPLC(FA) to afford the title compound (30.00 mg, 65.13 μmol, 73.57% yield, 95.05% purity) as a yellow solid. 1 H NMR (400 MHz, CHLOROFORM-d) δ=7.52-7.58 (m, 1H), 7.16-7.23 (m, 1H), 7.02-7.11 (m, 1H), 6.47-6.56 (m, 1H), 4.84-5.03 (m, 1H), 4.59-4.78 (m, 1H), 3.85 (s, 1H), 3.40 (s, 3H), 2.87 (br d, J=5.50 Hz, 1H). LCMS: 438[M+1].

Step 2. N10-(3-chloro-4-fluoro-phenyl)-N4,N4,2-trimethyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-4,10-dicarboxamide. To a mixture of 10-[(3-chloro-4-fluoro-phenyl)carbamoyl]-2-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-4-carboxylic acid (20.00 mg, 45.68 μmol, 1.00 eq) and N-methylmethanamine (18.62 mg, 228.40 μmol, 20.92 μL5.00 eq, HCl) in DMF (5.00 mL) was added HATU (26.05 mg, 68.52 μmol, 1.50 eq) and DIPEA (88.56 mg, 685.20 μmol, 119.68 μL15.00 eq) in one portion under N 2 . The mixture was stirred at 30° C. for 12 hours. LCMS showed the reaction was completed, and the desired product was detected. The residue was poured into water (10 mL). The aqueous phase was extracted with ethyl acetate (10 mL*2). The combined organic phase was washed with brine (10 mL*2), dried with anhydrous Na 2 SO 4 , filtered and concentrated in vacuum. The residue was purified by prep-HPLC(FA) to afford the title compound (16.00 mg, 33.94 μmol, 74.29% yield, 98.6% purity) as a white solid. 1 H NMR (400 MHz, METHANOL-d 4 ) 7.53-7.66 (m, 1H), 7.22-7.39 (m, 1H), 7.06-7.19 (m, 1H), 5.28-5.40 (m, 1H), 4.89-4.95 (m, 1H), 4.72 (s, 2H), 4.54-4.66 (m, 1H), 3.70-3.97 (m, 2H), 3.21 (d, J=9.41 Hz, 6H), 3.02 (s, 3H), 2.77-2.89 (m, 2H). LCMS: 465 [M+1].

Compound 075: (9R)—N-(3-chloro-4-fluoro-phenyl)-2,9-dimethyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-c][1,2,5]oxadiazepine-10-carboxamide

Step 1. (9R)-2,9-dimethyl-4,5,8,9,10,11-hexahydropyrido[2,3]pyrazolo[2,4-c][1,2,5]oxadiazepin-1-one. To a solution of tert-butyl (9R)-2,9-dimethyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido [2,3]pyrazolo[2,4-c][1,2,5]oxadiazepine-10-carboxylate (600.00 mg, 1.78 mmol, 1.00 eq) in DCM (5.00 mL) was added TFA (67.53 mmol, 5.00 mL, 37.94 eq). The mixture was stirred at 10° C. for 1 hr. TLC (petroleum ether:ethyl acetate=0:1) showed the starting material was consumed. The mixture was concentrated in vacuum to get the title compound (640.00 mg, crude, TFA) as yellow oil.

Step 2. (9R)—N-(3-chloro-4-fluoro-phenyl)-2,9-dimethyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-c][1,2,5]oxadiazepine-10-carboxamide. To a solution of (9R)-2,9-dimethyl-4,5,8,9,10,11-hexahydropyrido[2,3]pyrazolo [2,4-c][1,2,5]oxadiazepin-1-one (90.00 mg, 256.93 μmol, 1.00 eq, TFA) and phenyl N-(3-chloro-4-fluoro-phenyl)carbamate (71.67 mg, 269.78 μmol, 1.05 eq) in DCM (2.00 mL) was added TEA (78.00 mg, 770.79 μmol, 106.85 μL3.00 eq). The mixture was stirred at 30° C. for 1 h under N 2 atmosphere. TLC (DCM:MeOH=10:1) showed that (9R)-2,9-dimethyl-4,5,8,9,10,11-hexahydropyrido[2,3]pyrazolo[2,4-c][1,2,5]oxadiazepin-1-one was consumed completely and one major spot formed. LCMS indicated that MS of desired product was detected. The mixture was diluted with DCM (10 mL) and washed with HCl (1%, 10 mL*2) and brine (10 mL*1). The organic phase was dried over anhydrous Na 2 SO 4 , filtered and concentrated to get the residue. The residue was purified by prep-HPLC (FA) to obtain the title compound (53.00 mg, 129.44 μmol, 50.38% yield, 99.6% purity) as a white solid. LCMS: 408 (M+1). 1 H NMR (400 MHz, CHLOROFORM-d) δ=7.52-7.62 (m, 1H), 7.16-7.24 (m, 1H), 6.98-7.10 (m, 1H), 6.63 (s, 1H), 5.14 (quin, J=6.45 Hz, 1H), 4.85 (d, J=15.65 Hz, 1H), 4.53-4.59 (m, 2H), 4.35-4.50 (m, 3H), 3.23-3.35 (m, 3H), 3.03 (dd, J=5.81, 15.83 Hz, 1H), 2.67 (d, J=15.77 Hz, 1H), 1.17 (d, J=6.97 Hz, 3H).

Compounds 076, 077, 078, 079, 080, and 081 were prepared in a manner analogous to Compound 075.

Compound 076: (R)—N-(4-fluoro-3-(trifluoromethyl)phenyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS: 442 (M+1). 1 H NMR (400 MHz, CHLOROFORM-d) δ=7.68 (dd, J=2.69, 6.11 Hz, 1H), 7.53-7.62 (m, 1H), 7.12 (t, J=9.41 Hz, 1H), 6.72 (s, 1H), 5.15 (quin, J=6.42 Hz, 1H), 4.87 (d, J=15.65 Hz, 1H), 4.52-4.60 (m, 2H), 4.45-4.52 (m, 1H), 4.36-4.45 (m, 2H), 3.25-3.37 (m, 3H), 3.04 (dd, J=5.87, 15.89 Hz, 1H), 2.69 (d, J=15.89 Hz, 1H), 1.18 (d, J=6.97 Hz, 3H).

Compound 077: (R)—N-(3-bromo-4-fluorophenyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS: 452/454. 1 H NMR (400 MHz, CHLOROFORM-d) δ=7.64-7.77 (m, 1H), 7.24-7.29 (m, 2H), 7.04 (t, J=8.50 Hz, 1H), 6.52-6.62 (m, 1H), 5.14 (quin, J=6.45 Hz, 1H), 4.79-4.92 (m, 1H), 4.53-4.62 (m, 2H), 4.37-4.51 (m, 3H), 3.31 (s, 3H), 3.04 (dd, J=5.81, 15.83 Hz, 1H), 2.68 (d, J=15.77 Hz, 1H), 1.17 (d, J=6.97 Hz, 3H).

Compound 078: (R)—N-(2-bromo-3-fluoropyridin-4-yl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS: 453/455. 1 H NMR (400 MHz, CHLOROFORM-d) δ=8.10-8.19 (m, 1H), 7.97-8.08 (m, 1H), 6.95-7.11 (m, 1H), 5.00-5.15 (m, 1H), 4.92 (d, J=15.77 Hz, 1H), 4.48-4.61 (m, 3H), 4.31-4.47 (m, 2H), 3.25-3.38 (m, 3H), 2.94-3.13 (m, 1H), 2.63-2.79 (m, 1H), 1.12-1.30 (m, 3H).

›PREPARATIVE EXAMPLES · 31 of 53

Compound 079: (R)—N-(3-cyano-4-fluorophenyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS: 399 (M+1). 1 H NMR (400 MHz, CHLOROFORM-d) δ=7.75 (dd, J=2.75, 5.44 Hz, 1H), 7.60 (ddd, J=2.81, 4.58, 9.11 Hz, 1H), 7.11 (t, J=8.68 Hz, 1H), 6.94 (s, 1H), 5.11 (quin, J=6.45 Hz, 1H), 4.88 (d, J=15.77 Hz, 1H), 4.52-4.62 (m, 2H), 4.32-4.50 (m, 3H), 3.29 (s, 3H), 2.94-3.08 (m, 1H), 2.61-2.73 (m, 1H), 1.17 (d, J=6.85 Hz, 3H).

Compound 080: (R)—N-(4-fluoro-3-methylphenyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS: 388 (M+1). 1 H NMR (400 MHz, CHLOROFORM-d) δ=7.22-7.28 (m, 1H), 7.05-7.16 (m, 1H), 6.91 (t, J=8.99 Hz, 1H), 6.45 (br s, 1H), 5.15 (quin, J=6.45 Hz, 1H), 4.85 (d, J=15.65 Hz, 1H), 4.51-4.60 (m, 2H), 4.29-4.50 (m, 3H), 3.22-3.38 (m, 3H), 2.96-3.10 (m, 1H), 2.67 (d, J=15.77 Hz, 1H), 2.24 (d, J=1.34 Hz, 3H), 1.17 (d, J=6.85 Hz, 3H).

Compound 081: (R)—N-(3-chloro-4,5-difluorophenyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS: 426. 1 H NMR (400 MHz, CHLOROFORM-d) δ=7.35 (ddd, J=63, 6.45, 11.95 Hz, 1H, 7.22 (td, J=2.43, 5.29 Hz, 1H), 6.70 (s, 1H), 5.12 (quin, J=6.45 Hz, 1H), 4.85 (d, J=15.65 Hz, 1H), 4.52-4.61 (m, 2H), 4.34-4.49 (m, 3H), 3.24-3.35 (m, 3H), 2.95-3.10 (m, 1H), 2.59-2.77 (m, 1H), 1.09-1.22 (m, 3H).

Compound 083: (9R)—N-(4-fluoro-3-methyl-phenyl)-4-(hydroxymethyl)-2,9-dimethyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxamide

Step 1. (9R)-4-(hydroxymethyl)-2,9-dimethyl-4,5,8,9,10,11-hexahydropyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepin-1-one. To a solution of tert-butyl (9R)-4-(hydroxymethyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxylate (Intermediate 18, 300.00 mg, (470.00 mg, 1.28 mmol, 1.00 eq) in DCM (5.00 mL) was added TFA (5.55 g, 48.67 mmol, 3.60 mL, 37.94 eq). The mixture was stirred at 10° C. for 1 hr. TLC (Ethyl acetate:MeOH=20:1) showed the starting material was consumed. The mixture was concentrated in vacuum to get the title compound (520.00 mg, crude, TFA) as yellow oil.

Step 2. (9R)—N-(4-fluoro-3-methyl-phenyl)-4-(hydroxymethyl)-2,9-dimethyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxamide. To a mixture of (9R)-4-(hydroxymethyl)-2,9-dimethyl-4,5,8,9,10,11-hexahydropyrido [2,3]pyrazolo[2,4-d][1,2,5]oxadiazepin-1-one (138.00 mg, 362.85 μmol, 1.00 eq, TFA) in DCM (2.00 mL) was added TEA (146.87 mg, 1.45 mmol, 201.19 μL4.00 eq), followed by phenyl N-(4-fluoro-3-methyl-phenyl)carbamate (88.99 mg, 362.85 μmol, 1.00 eq), the reaction mixture was stirred at 10° C. for 16 hours. LCMS showed the starting material was consumed completely and one main peak with desired MS was detected. The mixture was extracted with DCM (50 mL*2) and water (30 mL), the organic phase was dried with anhydrous Na 2 SO 4 , filtered and concentrated in vacuum. 1/3 of the residue was purified by prep-HPLC (FA) to afford the title compound (32.00 mg, 99.24% purity) as white solid. 1 H NMR (400 MHz, CHLOROFORM-d) d ppm δ=7.25 (d, J=2.45 Hz, 1H) 7.11 (dt, J=7.98, 3.90 Hz, 1H) 6.93 (t, J=8.99 Hz, 1H) 6.37 (s, 1H) 5.15 (quin, J=6.30 Hz, 1H) 4.86 (d, J=15.53 Hz, 1H) 4.52-4.62 (m, 2H) 4.34-4.49 (m, 2H) 3.75-3.93 (m, 2H) 3.33 (s, 3H) 3.04 (dd, J=15.77, 5.87 Hz, 1H) 2.68 (d, J=15.65 Hz, 1H) 2.26 (d, J=1.59 Hz, 3H) 1.82-2.04 (m, 1H) 1.17 (d, J=6.97 Hz, 3H). LCMS: 418 [M+1].

Compounds 069, 082, 084, 089, 090, and 091 were prepared in an analogous manner to Compound 083.

Compound 088: (9R)—N-(3-chloro-4-fluoro-phenyl)-4-(fluoromethyl)-2,9-dimethyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxamide

To a solution of (9R)—N-(3-chloro-4-fluoro-phenyl)-4-(hydroxymethyl)-2,9-dimethyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxamide, (Compound 069, 75.00 mg, 171.29 μmol, 1.00 eq) in DCM (5.00 mL) was added DAST (165.66 mg, 1.03 mmol, 135.79 μL6.00 eq) at −30° C. under N 2 , the reaction mixture was stirred at 15° C. for 2 hours. LCMS indicated that reactant was consumed completely and desired MS was detected. The mixture was washed with saturated NaHCO 3 (10 mL*1) and brine (10 mL*1). Then the organic phase was dried over anhydrous Na 2 SO 4 , filtered and concentrated to get the residue. The residue was purified by prep-HPLC (FA) to obtain the title compound (39.70 mg, 87.28 μmol, 50.96% yield, 96.7% purity) as a white solid.

Compounds 085, 086, and 087 were prepared in an analogous manner to Compound 088.

Compound 082_E1: (4S*,9R)—N-(4-fluoro-3-(trifluoromethyl)phenyl)-4-(hydroxymethyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS (M+1): 472. 1 H NMR (400 MHz, CHLOROFORM-d) δ=7.68 (dd, J=6.05, 2.75 Hz, 1H) 7.55-7.62 (m, 1H) 7.14 (t, J=9.41 Hz, 1H) 6.56 (s, 1H) 5.15 (m, J=6.45 Hz, 1H) 4.88 (d, J=15.53 Hz, 1H) 4.54-4.62 (m, 2H) 4.36-4.51 (m, 2H) 3.77-3.93 (m, 2H) 3.34 (s, 3H) 3.05 (dd, J=15.96, 5.81 Hz, 1H) 2.70 (d, J=15.65 Hz, 1H) 1.89 (br. s., 1H) 1.19 (d, J=6.97 Hz, 3H).

*Pure but unknown enantiomer.

Compound 082_E2: (4R*,9R)—N-(4-fluoro-3-(trifluoromethyl)phenyl)-4-(hydroxymethyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS (M+1): 472. 1 H NMR (400 MHz, CHLOROFORM-d) δ=7.66-7.73 (m, 1H), 7.56-7.65 (m, 1H), 7.15 (s, 1H), 6.59 (s, 1H), 5.09-5.22 (m, 1H), 4.76-4.92 (m, 1H), 4.55 (s, 4H), 3.87 (s, 2H), 3.35 (s, 3H), 3.00-3.12 (m, 1H), 2.71 (d, J=15.65 Hz, 1H), 1.88-2.01 (m, 1H), 1.21 (d, J=6.97 Hz, 3H).

*Pure but unknown enantiomer.

Compound 083_E1: (4S*,9R)—N-(4-fluoro-3-methylphenyl)-4-(hydroxymethyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS (M+1): 418. 1 H NMR (400 MHz, CHLOROFORM-d) δ=7.25 (d, J=2.45 Hz, 1H) 7.11 (dt, J=7.98, 3.90 Hz, 1H) 6.93 (t, J=8.99 Hz, 1H) 6.37 (s, 1H) 5.15 (m, J=6.30 Hz, 1H) 4.86 (d, J=15.53 Hz, 1H) 4.52-4.62 (m, 2H) 4.34-4.49 (m, 2H) 3.75-3.93 (m, 2H) 3.33 (s, 3H) 3.04 (dd, J=15.77, 5.87 Hz, 1H) 2.68 (d, J=15.65 Hz, 1H) 2.26 (d, J=1.59 Hz, 3H) 1.82-2.04 (m, 1H) 1.17 (d, J=6.97 Hz, 3H).

›PREPARATIVE EXAMPLES · 32 of 53

*Pure but unknown enantiomer.

Compound 083_E2: (4R*,9R)—N-(4-fluoro-3-methylphenyl)-4-(hydroxymethyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo [5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS (M+1): 472. 1 H NMR (400 MHz, CHLOROFORM-d) δ=7.24-7.27 (m, 1H), 7.08-7.15 (m, 1H), 6.89-6.97 (m, 1H), 6.37 (s, 1H), 5.04-5.25 (m, 1H), 4.82 (d, J=15.65 Hz, 1H), 4.29-4.65 (m, 4H), 3.68-3.93 (m, 2H), 3.33 (s, 3H), 2.94-3.13 (m, 1H), 2.56-2.74 (m, 1H), 2.26 (d, J=1.71 Hz, 3H), 1.89-2.01 (m, 1H), 1.18 (d, J=6.97 Hz, 3H).

*Pure but unknown enantiomer.

Compound 084_E1: (4S*,9R)—N-(3-cyano-4-fluorophenyl)-4-(hydroxymethyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo [5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS (M+1): 429. 1 H NMR (400 MHz, CHLOROFORM-d) δ=7.79 (dd, J=5.44, 2.75 Hz, 1H) 7.54-7.61 (m, 1H) 7.15 (t, J=8.68 Hz, 1H) 6.50-6.58 (m, 1H) 5.08-5.19 (m, 1H) 4.78-4.91 (m, 1H) 4.53-4.61 (m, 2H) 4.37-4.51 (m, 2H) 3.78-3.93 (m, 2H) 3.35 (s, 3H) 3.04 (dd, J=15.83, 5.93 Hz, 1H) 2.70 (d, J=15.53 Hz, 1H) 1.78 (br. s., 1H) 1.17-1.22 (m, 3H).

*Pure but unknown enantiomer.

Compound 084_E2: (4R*,9R)—N-(3-cyano-4-fluorophenyl)-4-(hydroxymethyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo [5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS [M+1]: 429. 1 H NMR (400 MHz, CHLOROFORM-d) δ=7.78 (br d, J=2.57 Hz, 1H), 7.59 (br d, J=4.40 Hz, 1H), 7.14 (br t, J=8.80 Hz, 1H), 6.62 (br d, J=16.14 Hz, 1H), 5.13 (br t, J=6.54 Hz, 1H), 4.82 (br d, J=15.77 Hz, 1H), 4.39-4.63 (m, 4H), 3.70-3.96 (m, 2H), 3.34 (s, 3H), 3.04 (br dd, J=5.99, 15.65 Hz, 1H), 2.70 (br d, J=16.02 Hz, 1H), 1.88 (br s, 1H), 1.20 (br d, J=6.97 Hz, 3H).

*Pure but unknown enantiomer.

Compound 085_E1: (4S*,9R)—N-(4-fluoro-3-(trifluoromethyl)phenyl)-4-(fluoromethyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS (M+1): 474. 1 H NMR (400 MHz, CHLOROFORM-d) δ=7.68 (dd, J=6.11, 2.69 Hz, 1H) 7.56-7.62 (m, 1H) 7.14 (t, J=9.35 Hz, 1H) 6.54 (s, 1H) 5.15 (m, J=6.45 Hz, 1H) 4.85 (d, J=15.65 Hz, 1H) 4.57-4.73 (m, 4H) 4.39-4.54 (m, 2H) 3.33 (s, 3H) 3.05 (dd, J=15.83, 5.81 Hz, 1H) 2.71 (d, J=16.02 Hz, 1H) 1.20 (d, J=6.97 Hz, 3H).

Compound 085_E2: (4R*,9R)—N-(4-fluoro-3-(trifluoromethyl)phenyl)-4-(fluoromethyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS (M+1): 474. 1 H NMR (400 MHz, CHLOROFORM-d) δ=7.65-7.73 (m, 1H), 7.56-7.63 (m, 1H), 7.14 (s, 1H), 6.54 (s, 1H), 5.08-5.22 (m, 1H), 4.82-4.92 (m, 1H), 4.37-4.79 (m, 6H), 3.34 (s, 3H), 2.99-3.13 (m, 1H), 2.62-2.79 (m, 1H), 1.19 (d, J=6.85 Hz, 3H).

*Pure but unknown enantiomer.

Compound 086_E1: (4S*,9R)—N-(4-fluoro-3-methylphenyl)-4-(fluoromethyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS (M+1): 420. 1 H NMR (400 MHz, CHLOROFORM-d) δ=7.25 (d, J=2.57 Hz, 1H) 7.11 (dt, J=7.89, 3.88 Hz, 1H) 6.93 (t, J=8.99 Hz, 1H) 6.34 (s, 1H) 5.09-5.19 (m, 1H) 4.79-4.89 (m, 1H) 4.56-4.73 (m, 4H) 4.37-4.52 (m, 2H) 3.33 (s, 3H) 3.04 (dd, J=15.71, 5.81 Hz, 1H) 2.69 (d, J=15.77 Hz, 1H) 2.26 (d, J=1.59 Hz, 3H) 1.18 (d, J=6.85 Hz, 3H).

Compound 086_E2: (4R*,9R)—N-(4-fluoro-3-methylphenyl)-4-(fluoromethyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS (M+1): 420. 1 H NMR (400 MHz, CHLOROFORM-d) δ=7.24-7.27 (m, 1H), 7.09-7.15 (m, 1H), 6.87-6.98 (m, 1H), 6.28-6.40 (m, 1H), 5.07-5.23 (m, 1H), 4.82-4.91 (m, 1H), 4.37-4.79 (m, 6H), 3.33 (s, 3H), 2.99-3.11 (m, 1H), 2.62-2.74 (m, 1H), 2.26 (d, J=1.71 Hz, 3H), 1.18 (d, J=6.85 Hz, 3H).

*Pure but unknown enantiomer.

Compound 087_E1: (4S*,9R)—N-(3-cyano-4-fluorophenyl)-4-(fluoromethyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS (M+1): 431. 1 H NMR (400 MHz, CHLOROFORM-d) δ=7.78 (dd, J=5.46, 2.82 Hz, 1H) 7.58 (ddd, J=9.13, 4.55, 2.89 Hz, 1H) 7.09-7.18 (m, 1H) 6.62 (s, 1H) 5.08-5.19 (m, 1H) 4.84 (d, J=15.69 Hz, 1H) 4.57-4.73 (m, 4H) 4.38-4.54 (m, 2H) 3.33 (s, 3H) 3.04 (dd, J=15.94, 5.90 Hz, 1H) 2.71 (d, J=16.19 Hz, 1H) 1.19 (d, J=6.90 Hz, 3H).

Compound 087_E2: (4R*,9R)—N-(3-cyano-4-fluorophenyl)-4-(fluoromethyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS [M+1]: 431. 1 H NMR (400 MHz, CHLOROFORM-d) δ=7.74-7.81 (m, 1H), 7.59 (ddd, J=2.82, 4.49, 9.13 Hz, 1H), 7.14 (t, J=8.66 Hz, 1H), 6.67 (s, 1H), 5.13 (quin, J=6.40 Hz, 1H), 4.87 (d, J=15.69 Hz, 1H), 4.58-4.78 (m, 3H), 4.39-4.57 (m, 3H), 3.33 (s, 3H), 3.04 (dd, J=5.77, 15.94 Hz, 1H), 2.69 (d, J=15.94 Hz, 1H), 1.19 (d, J=7.03 Hz, 3H).

Compound 088_E1: (4S*,9R)—N-(3-chloro-4-fluorophenyl)-4-(fluoromethyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS: 426. 1 H NMR (400 MHz, CHLOROFORM-d) δ=7.37 (ddd, J=2.8, 6.4, 12.0 Hz, 1H), 7.24 (td, J=2.4, 5.2 Hz, 1H), 6.64 (s, 1H), 5.14 (m, 1H), 4.84 (d, J=16.0 Hz, 1H), 4.54-4.59 (m, 2H), 4.39-4.50 (m, 3H), 3.32 (s, 3H), 3.04 (dd, J=8.0, 16.0 Hz, 1H), 2.69 (d, J=16.0 Hz, 1H), 1.18 (d, J=8.0 Hz, 3H).

Compound 088_E2: (4R*,9R)—N-(3-chloro-4-fluorophenyl)-4-(fluoromethyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS: 426. 1 H NMR (400 MHz, CHLOROFORM-d) δ=7.54-7.61 (m, 1H), 7.17-7.24 (m, 1H), 7.01-7.09 (m, 1H), 6.60 (s, 1H), 5.13 (quin, J=6.40 Hz, 1H), 4.86 (d, J=15.69 Hz, 1H), 4.57-4.75 (m, 3H), 4.52-4.56 (m, 1H), 4.37-4.48 (m, 2H), 3.25-3.38 (m, 3H), 2.96-3.10 (m, 1H), 2.67 (d, J=15.94 Hz, 1H), 1.17 (d, J=6.90 Hz, 3H).

*Pure but unknown enantiomer.

Compound 089_E1: (4S*,9R)—N-(5-bromo-2,4-difluorophenyl)-4-(hydroxymethyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS: 502/500 [M+1]. 1 H NMR (400 MHz, CHLOROFORM-d) δ=8.29 (t, J=7.89 Hz, 1H), 6.90 (dd, J=7.95, 10.64 Hz, 1H), 6.52 (br d, J=2.81 Hz, 1H), 4.97-5.18 (m, 1H), 4.82 (d, J=15.77 Hz, 1H), 4.35-4.65 (m, 4H), 3.66-3.86 (m, 2H), 3.30 (s, 3H), 3.02 (dd, J=5.75, 15.89 Hz, 1H), 2.66 (d, J=15.89 Hz, 1H), 1.18 (d, J=6.85 Hz, 3H).

›PREPARATIVE EXAMPLES · 33 of 53

*Pure but unknown enantiomer.

Compound 089_E2: (4R*,9R)—N-(5-bromo-2,4-difluorophenyl)-4-(hydroxymethyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS: 502/500[M+1]. 1 H NMR (400 MHz, CHLOROFORM-d) δ=8.32 (t, J=7.89 Hz, 1H), 6.94 (dd, J=7.95, 10.64 Hz, 1H), 6.57 (br d, J=2.69 Hz, 1H), 5.10 (br t, J=6.42 Hz, 1H), 4.91 (d, J=15.65 Hz, 1H), 4.33-4.61 (m, 4H), 3.70-3.97 (m, 2H), 3.33 (s, 3H), 3.05 (dd, J=5.81, 15.83 Hz, 1H), 2.70 (d, J=15.77 Hz, 1H), 1.20 (d, J=6.97 Hz, 3H).

Compound 090_E1: (4S*,9R)—N-(5-chloro-2,4-difluorophenyl)-4-(hydroxymethyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS: 456 [M+1]. 1 H NMR (400 MHz, CHLOROFORM-d) δ=8.19 (t, J=8.07 Hz, 1H), 6.95 (dd, J=8.50, 10.58 Hz, 1H), 6.54 (br s, 1H), 5.08 (br t, J=6.79 Hz, 1H), 4.85 (d, J=15.65 Hz, 1H), 4.41-4.67 (m, 4H), 3.68-3.94 (m, 2H), 3.34 (s, 2H), 2.97-3.12 (m, 1H), 2.70 (d, J=15.77 Hz, 1H), 1.21 (d, J=6.97 Hz, 3H).

Compound 090_E2: (4R*,9R)—N-(5-chloro-2,4-difluorophenyl)-4-(hydroxymethyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS: 456[M+1]. 1 H NMR (400 MHz, CHLOROFORM-d) δ=8.09-8.35 (m, 1H), 7.27 (s, 1H), 6.88-7.07 (m, 1H), 6.56 (br s, 1H), 5.11 (br d, J=6.27 Hz, 1H), 4.90 (br d, J=15.69 Hz, 1H), 4.32-4.73 (m, 4H), 3.69-4.00 (m, 2H), 3.33 (s, 3H), 3.05 (br dd, J=5.14, 16.06 Hz, 1H), 2.70 (br d, J=16.06 Hz, 1H), 1.20 (br d, J=6.78 Hz, 3H).

Compound 091_E1: (4S*,9R)—N-(3-chloro-2,4-difluorophenyl)-4-(hydroxymethyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS: 456[M+1]. 1 H NMR (400 MHz, CHLOROFORM-d) δ=7.89 (dt, J=5.62, 8.93 Hz, 1H), 6.90-7.02 (m, 1H), 6.55 (br s, 1H), 5.09 (br t, J=6.60 Hz, 1H), 4.89 (d, J=15.89 Hz, 1H), 4.42-4.64 (m, 4H), 3.69-3.93 (m, 2H), 3.35 (s, 3H), 3.07 (dd, J=6.05, 15.71 Hz, 1H), 2.71 (d, J=15.77 Hz, 1H), 1.23 (d, J=6.97 Hz, 3H).

Compound 091_E2: (4R*,9R)—N-(3-chloro-2,4-difluorophenyl)-4-(hydroxymethyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS: 456[M+1]. 1 H NMR (400 MHz, CHLOROFORM-d) δ=7.89 (dt, J=5.56, 8.89 Hz, 1H), 6.90-7.03 (m, 1H), 6.57 (br s, 1H), 5.10 (quin, J=6.27 Hz, 1H), 4.94 (d, J=15.77 Hz, 1H), 4.37-4.63 (m, 4H), 3.75-3.97 (m, 2H), 3.35 (s, 3H), 3.07 (dd, J=5.87, 15.77 Hz, 1H), 2.71 (d, J=15.77 Hz, 1H), 1.22 (d, J=6.85 Hz, 3H).

Compound 092_E1: (4S*,9R)—N-(3-bromo-2,4-difluorophenyl)-4-(hydroxymethyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS: 502/500[M+1] 1 H NMR (400 MHz, CHLOROFORM-d) δ=7.95 (dt, J=5.58, 8.94 Hz, 1H), 6.88-7.05 (m, 1H), 6.54 (br d, J=2.64 Hz, 1H), 5.09 (br t, J=6.53 Hz, 1H), 4.89 (d, J=15.94 Hz, 1H), 4.39-4.67 (m, 4H), 3.72-3.94 (m, 2H), 3.35 (s, 3H), 3.06 (dd, J=6.02, 15.81 Hz, 1H), 2.71 (d, J=15.81 Hz, 1H), 1.23 (d, J=6.90 Hz, 3H).

Compound 092_E2: (4R*,9R)—N-(3-bromo-2,4-difluorophenyl)-4-(hydroxymethyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS: 502/500[M+1]. 1 H NMR (400 MHz, CHLOROFORM-d) δ=7.95 (dt, J=5.69, 8.96 Hz, 1H), 6.88-7.03 (m, 1H), 6.60 (br s, 1H), 5.02-5.24 (m, 1H), 4.95 (d, J=15.65 Hz, 1H), 4.34-4.63 (m, 4H), 3.73-3.95 (m, 2H), 3.07 (dd, J=5.81, 15.96 Hz, 1H), 2.71 (d, J=16.02 Hz, 1H), 1.21 (d, J=6.85 Hz, 3H).

Compound 093_D1: (4S*,9R)—N-(3-chloro-4-fluorophenyl)-4-((dimethylamino)methyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

Step 1. tert-butyl (9R)-2,9-dimethyl-4-(methylsulfonyloxymethyl)-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxylate. To a solution of tert-butyl (9R)-4-(hydroxymethyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxylate (Intermediate 18, 1.50 g, 4.09 mmol, 1.00 eq) in DCM (4.00 mL) was added TEA (2.07 g, 20.47 mmol, 2.84 mL, 5.00 eq), and DMAP (50.01 mg, 409.38 μmol, 0.10 eq), followed by MsCl (1.41 g, 12.27 mmol, 949.68 μL3.00 eq) at 0° C. The mixture was stirred at 20° C. for 1 hr. TLC (petroleum ether:ethyl acetate=0:1) showed the starting material consumed and one main spot was generated. The mixture combined with another batch (1.3 g scale) was extracted with DCM (30 mL*2) and H 2 O (20 mL). The combined organic layer was dried over Na 2 SO 4 , filtrated. The filtrate was concentrated in vacuum. The residue was purified by column chromatography (petroleum ether:ethyl acetate: 30%˜50%) to get the title compound (1.50 g, 2.70 mmol, 66.01% yield) as a white solid.

Step 2. tert-butyl (9R)-4-[(dimethylamino)methyl]-2,9-dimethyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxylate. To a solution of tert-butyl (9R)-2,9-dimethyl-4-(methylsulfonyloxymethyl)-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxylate (1.10 g, 2.47 mmol, 1.00 eq) and Me 2 NH (2.01 g, 24.70 mmol, 2.26 mL, 10.00 eq, HCl) in MeCN (60.00 mL) was added K 2 CO 3 (4.44 g, 32.11 mmol, 13.00 eq). The mixture was heated to 80° C. for 16 hr. TLC (petroleum ether:ethyl acetate=0:1) showed the starting material consumed and one main spot was detected. The mixture was extracted with ethyl acetate (100 mL*2) and H 2 O (50 mL). The combined organic layer was dried over Na 2 SO 4 , filtrated. The filtrate was concentrated in vacuum. The residue was purified by column chromatography (Petroleum ether:Ethyl acetate:80%˜100%) to get the title compound (800.00 mg, 1.97 mmol, 79.76% yield, 96.7% purity) as yellow solid and (200.00 mg, 72% purity) as yellow oil.

The diastereomeric mixture (1.0 g) was separated via SFC to get both diasteremers (360 mg) and (360 mg). SFC separation method: Instrument: SFC Thar_80; Column: IC-10 um; Mobile phase: A for CO 2 and B for MeOH (0.1% Ammonia); Isocratic: B 25%; Flow rate: 55 mL/min; Back pressure: 100 bar; Column temperature: 35° C.; Wavelength: 220 nm.

›PREPARATIVE EXAMPLES · 34 of 53

Step 3. (9R)-4-[(dimethylamino)methyl]-2,9-dimethyl-4,5,8,9,10,11-hexahydropyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepin-1-one. To a solution of tert-butyl (9R)-4-[(dimethylamino)methyl]-2,9-dimethyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxylate (360.00 mg, 914.91 μmol, 1.00 eq) in DCM (4.00 mL) was added TFA (6.16 g, 54.03 mmol, 4.00 mL, 59.05 eq). The mixture was stirred at 20° C. for 1 hr. TLC (DCM:MeOH=10:1) showed the starting material was consumed. The mixture was concentrated in vacuum to get the title compound (380.00 mg, crude, TFA) as yellow oil.

Step 4. (9R)—N-(3-chloro-4-fluoro-phenyl)-4-[(dimethylamino)methyl]-2,9-dimethyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxamide. To a solution of (9R)-4-[(dimethylamino)methyl]-2,9-dimethyl-4,5,8,9,10,11-hexahydropyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepin-1-one (44.00 mg, 108.00 μmol, 1.00 eq, TFA) and phenyl N-(3-chloro-4-fluoro-phenyl)carbamate (28.69 mg, 108.00 μmol, 1.00 eq) in DCM (3.00 mL) was added TEA (54.64 mg, 540.00 μmol, 74.85 μL5.00 eq). The mixture was heated to 20° C. for 16 hr. LCMS showed one main peak with desired Ms. The mixture was concentrated in vacuum. The residue was purified by prep-HPLC (FA) to get the title compound (38.00 mg, 81.65 μmol, 75.60% yield, 99.9% purity) as a white solid. LCMS (M+1): 465. 1 H NMR (400 MHz, CHLOROFORM-d) δ=8.21 (s, 1H), 7.61 (dd, J=2.64, 6.53 Hz, 1H), 7.19-7.26 (m, 1H), 7.03-7.12 (m, 1H), 6.61 (s, 1H), 5.08-5.19 (m, 1H), 4.75-4.89 (m, 2H), 4.62 (dd, J=5.90, 14.68 Hz, 1H), 4.50 (d, J=15.69 Hz, 1H), 4.37 (dd, J=4.77, 14.56 Hz, 1H), 3.34 (s, 3H), 3.05 (br dd, J=5.96, 15.87 Hz, 2H), 2.66-2.77 (m, 3H), 2.48 (s, 6H).

* pure but unknown stereochemistry

Compounds 094, 095, 096, 097, 098, 099, and 100 were prepared in an analogous method to Compound 093_D1.

Compound 093_D2: (4R*,9R)—N-(3-chloro-4-fluorophenyl)-4-((dimethylamino)methyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS (M+1): 465. 1 H NMR (400 MHz, CHLOROFORM-d) δ=8.13 (s, 1H), 7.61 (dd, J=2.64, 6.53 Hz, 1H), 7.17-7.25 (m, 1H), 7.03-7.12 (m, 1H), 6.56 (s, 1H), 5.16 (quin, J=6.68 Hz, 1H), 4.87 (d, J=15.56 Hz, 1H), 4.56-4.75 (m, 2H), 4.47 (d, J=15.56 Hz, 1H), 4.33 (dd, J=5.90, 14.43 Hz, 1H), 3.34 (s, 3H), 3.05 (dd, J=5.90, 15.81 Hz, 1H), 2.58-2.81 (m, 4H), 2.43 (s, 6H), 1.20 (d, J=6.90 Hz, 3H).

* pure but unknown stereochemistry

Compound 094_D1: (4S*,9R)—N-(3-bromo-4-fluorophenyl)-4-((dimethylamino)methyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS (M+1): 509/511. 1 H NMR (400 MHz, CHLOROFORM-d) δ=8.22 (brs, 1H), 7.73 (dd, J=2.64, 6.02 Hz, 1H), 7.30 (dd, J=2.70, 4.20 Hz, 1H), 7.27 (d, J=2.64 Hz, 1H), 7.06 (t, J=8.53 Hz, 1H), 6.59 (br s, 1H), 5.14 (quin, J=6.49 Hz, 1H), 4.71-4.90 (m, 2H), 4.61 (dd, J=5.90, 14.56 Hz, 1H), 4.50 (d, J=15.56 Hz, 1H), 4.37 (dd, J=4.83, 14.62 Hz, 1H), 3.34 (s, 3H), 3.05 (dd, J=5.77, 15.81 Hz, 1H), 2.65-2.77 (m, 3H), 2.47 (s, 6H), 1.20 (d, J=6.90 Hz, 3H).

* pure but unknown stereochemistry

Compound 094_D2: (4R*,9R)—N-(3-bromo-4-fluorophenyl)-4-((dimethylamino)methyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS (M+1): 509/511. 1 H NMR (400 MHz, CHLOROFORM-d) δ=8.12 (s, 1H), 7.75 (dd, J=2.64, 6.02 Hz, 1H), 7.30 (dd, J=2.76, 4.14 Hz, 1H), 7.02-7.10 (m, 1H), 6.60 (s, 1H), 5.16 (quin, J=6.27 Hz, 1H), 4.75-4.93 (m, 2H), 4.62 (dd, J=5.90, 14.56 Hz, 1H), 4.45 (d, J=15.56 Hz, 1H), 4.35 (dd, J=5.33, 14.62 Hz, 1H), 3.35 (s, 3H), 3.05 (dd, J=5.71, 15.87 Hz, 1H), 2.67-2.83 (m, 3H), 2.53 (s, 5H), 1.20 (d, J=6.90 Hz, 3H).

* pure but unknown stereochemistry

Compound 096_D1: (4S*,9R)—N-(3-cyano-4-fluorophenyl)-4-((dimethylamino)methyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS (M+1): 456. 1 H NMR (400 MHz, CHLOROFORM-d) δ=8.18 (s, 1H), 7.80 (dd, J=2.76, 5.40 Hz, 1H), 7.62 (ddd, J=2.76, 4.58, 9.10 Hz, 1H), 7.09-7.20 (m, 1H), 6.76 (s, 1H), 5.14 (quin, J=6.40 Hz, 1H), 4.79-4.90 (m, 2H), 4.63 (dd, J=5.90, 14.68 Hz, 1H), 4.51 (d, J=15.69 Hz, 1H), 4.38 (dd, J=4.71, 14.62 Hz, 1H), 3.35 (s, 3H), 3.05 (dd, J=5.90, 15.94 Hz, 1H), 2.66-2.82 (m, 3H), 2.52 (s, 6H), 1.21 (d, J=6.90 Hz, 3H).

* pure but unknown stereochemistry

Compound 096_D2: (4R*,9R)—N-(3-cyano-4-fluorophenyl)-4-((dimethylamino)methyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS (M+1): 456. 1 H NMR (400 MHz, CHLOROFORM-d) δ=8.10 (s, 1H), 7.81 (dd, J=2.82, 5.46 Hz, 1H), 7.62 (ddd, J=2.76, 4.58, 9.10 Hz, 1H), 7.15 (t, J=8.72 Hz, 1H), 6.81 (s, 1H), 5.16 (quin, J=6.40 Hz, 1H), 4.78-4.96 (m, 2H), 4.62 (dd, J=6.02, 14.68 Hz, 1H), 4.31-4.48 (m, 2H), 3.35 (s, 3H), 3.05 (dd, J=5.77, 16.06 Hz, 1H), 2.87 (br d, J=6.15 Hz, 2H), 2.70 (d, J=16.06 Hz, 1H), 2.58 (s, 6H), 1.21 (d, J=6.90 Hz, 3H).

* pure but unknown stereochemistry

Compound 095_D1: (4S*,9R)—N-(2-bromo-3-fluoropyridin-4-yl)-4-((dimethylamino)methyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS (M+1): 510/512. 1 H NMR (400 MHz, CHLOROFORM-d) δ=8.14-8.18 (m, 1H) 8.07 (d, J=5.62 Hz, 1H) 6.97 (br s, 1H) 5.05 (br t, J=6.54 Hz, 1H) 4.89 (br d, J=16.02 Hz, 1H) 4.81 (br d, J=6.36 Hz, 1H) 4.51-4.64 (m, 2H) 4.38 (dd, J=14.61, 4.34 Hz, 1H) 3.33 (s, 3H) 3.06 (dd, J=15.89, 5.75 Hz, 1H) 2.69-2.78 (m, 3H) 2.49 (s, 6H) 1.24 (d, J=6.97 Hz, 3H).

* pure but unknown stereochemistry

Compound 095_D2: (4R*,9R)—N-(2-bromo-3-fluoropyridin-4-yl)-4-((dimethylamino)methyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS (M+1): 510/512. 1 H NMR (400 MHz, CHLOROFORM-d) δ=8.13-8.17 (m, 1H) 8.06 (d, J=5.52 Hz, 1H) 7.02 (br d, J=3.89 Hz, 1H) 5.07 (br t, J=6.40 Hz, 1H) 4.93 (d, J=15.81 Hz, 1H) 4.48-4.68 (m, 3H) 4.29 (dd, J=14.24, 6.09 Hz, 1H) 3.32 (s, 3H) 3.05 (dd, J=15.94, 5.90 Hz, 1H) 2.68-2.76 (m, 2H) 2.60 (dd, J=13.24, 5.08 Hz, 1H) 2.40 (s, 6H) 1.23 (d, J=6.90 Hz, 3H).

›PREPARATIVE EXAMPLES · 35 of 53

* pure but unknown stereochemistry

Compound 097_D1: (4 S*,9R)-4-((dimethylamino)methyl)-N-(4-fluoro-3-methylphenyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS (M+1): 445. 1 H NMR (400 MHz, CHLOROFORM-d) δ=7.23-7.27 (m, 1H) 7.08-7.14 (m, 1H) 6.92 (t, J=8.97 Hz, 1H) 6.48 (s, 1H) 5.12 (m, J=6.49 Hz, 1H) 4.79-4.92 (m, 2H) 4.61 (dd, J=14.68, 6.02 Hz, 1H) 4.48 (d, J=15.69 Hz, 1H) 4.37 (dd, J=14.68, 4.27 Hz, 1H) 3.33 (s, 3H) 3.03 (dd, J=15.87, 5.96 Hz, 1H) 2.83-2.91 (m, 1H) 2.73-2.81 (m, 1H) 2.67 (d, J=15.81 Hz, 1H) 2.51-2.56 (m, 6H) 2.25 (d, J=1.76 Hz, 3H) 1.18 (d, J=6.90 Hz, 3H).

* pure but unknown stereochemistry

Compound 097_D2: (4R*,9R)-4-((dimethylamino)methyl)-N-(4-fluoro-3-methylphenyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS (M+1): 445. 1 H NMR (400 MHz, CHLOROFORM-d) δ=7.23-7.27 (m, 1H) 7.11 (dt, J=7.87, 3.91 Hz, 1H) 6.92 (t, J=8.97 Hz, 1H) 6.56 (s, 1H) 5.13 (m, J=6.37 Hz, 1H) 4.86-4.98 (m, 2H) 4.62 (dd, J=14.81, 6.02 Hz, 1H) 4.32-4.43 (m, 2H) 3.33 (s, 3H) 2.98-3.09 (m, 2H) 2.92 (dd, J=13.55, 8.41 Hz, 1H) 2.62-2.70 (m, 7H) 2.24 (d, J=1.76 Hz, 3H) 1.17 (d, J=6.78 Hz, 3H).

* pure but unknown stereochemistry

Compound 098_D1: (4S*,9R)-4-((dimethylamino)methyl)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS (M+1): 499. 1 H NMR (400 MHz, CHLOROFORM-d) δ=7.69 (dd, J=6.15, 2.76 Hz, 1H) 7.60 (dt, J=8.56, 3.62 Hz, 1H) 7.12 (t, J=9.41 Hz, 1H) 6.82 (s, 1H) 5.14 (m, J=6.46 Hz, 1H) 4.86 (d, J=15.69 Hz, 1H) 4.76 (m, J=5.65 Hz, 1H) 4.60 (dd, J=14.68, 5.90 Hz, 1H) 4.49 (d, J=15.56 Hz, 1H) 4.34 (dd, J=14.62, 5.08 Hz, 1H) 3.32 (s, 3H) 3.04 (dd, J=15.94, 5.77 Hz, 1H) 2.65-2.71 (m, 3H) 2.44 (s, 6H) 1.18 (d, J=6.90 Hz, 3H)

* pure but unknown stereochemistry

Compound 098_D2: (4R*,9R)-4-((dimethylamino)methyl)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS (M+1): 499. 1 H NMR (400 MHz, CHLOROFORM-d) δ=7.69 (dd, J=6.05, 2.63 Hz, 1H) 7.57-7.64 (m, 1H) 7.12 (t, J=9.41 Hz, 1H) 6.85 (s, 1H) 5.15 (m, J=6.39 Hz, 1H) 4.85-4.96 (m, 2H) 4.61 (dd, J=14.67, 5.99 Hz, 1H) 4.32-4.46 (m, 2H) 3.33 (s, 3H) 3.03 (dd, J=15.96, 5.81 Hz, 1H) 2.83-2.96 (m, 2H) 2.67 (d, J=15.89 Hz, 1H) 2.60 (s, 6H) 1.18 (d, J=6.85 Hz, 3H).

* pure but unknown stereochemistry

Compound 099_D1: (4S*,9R)—N-(5-chloro-2,4-difluorophenyl)-4-((dimethylamino)methyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS (M+1): 483/485. 1H NMR (400 MHz, CHLOROFORM-d) δ=8.16-8.22 (m, 1H), 8.19 (t, J=7.72 Hz, 1H), 8.16 (s, 1H), 8.15-8.16 (m, 1H), 6.95 (dd, J=8.41, 10.54 Hz, 1H), 6.54 (d, J=3.26 Hz, 1H), 5.08 (s, 1H), 4.85 (d, J=15.69 Hz, 1H), 4.77 (dd, J=4.96, 5.96 Hz, 1H), 4.49-4.62 (m, 2H), 4.36 (dd, J=4.64, 14.56 Hz, 1H), 3.33 (s, 3H), 3.05 (dd, J=5.90, 15.81 Hz, 1H), 2.65-2.75 (m, 3H), 2.45 (s, 6H), 1.21 (d, J=6.90 Hz, 3H).

* pure but unknown stereochemistry

Compound 099_D2: (4R*,9R)—N-(5-chloro-2,4-difluorophenyl)-4-((dimethylamino)methyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS (M+1): 483/485. 1 H NMR (400 MHz, CHLOROFORM-d) δ=8.20 (t, J=7.98 Hz, 1H), 8.17-8.23 (m, 1H), 8.16 (s, 1H), 8.15-8.17 (m, 1H), 6.97 (dd, J=8.41, 10.54 Hz, 1H), 6.57 (br d, J=3.14 Hz, 1H), 5.11 (s, 1H), 4.91 (d, J=15.69 Hz, 1H), 4.78 (s, 1H), 4.62 (dd, J=5.96, 14.62 Hz, 1H), 4.49 (d, J=15.56 Hz, 1H), 4.33 (dd, J=5.71, 14.62 Hz, 1H), 3.34 (s, 3H), 3.05 (d, J=5.77 Hz, 1H), 2.63-2.86 (m, 3H), 2.51 (s, 6H), 1.22 (d, J=6.90 Hz, 3H).

* pure but unknown stereochemistry

Compound 100_D1: (4S*,9R)—N-(5-bromo-2,4-difluorophenyl)-4-((dimethylamino)methyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS (M+1): 527/529. 1 H NMR (400 MHz, CHLOROFORM-d) δ=8.33 (dd, J=7.59, 8.22 Hz, 1H), 8.22 (s, 1H), 7.29 (s, 1H), 6.95 (dd, J=7.91, 10.67 Hz, 1H), 6.57 (br d, J=3.01 Hz, 1H), 5.09 (br t, J=6.46 Hz, 1H), 4.79-4.91 (m, 2H), 4.49-4.65 (m, 2H), 4.38 (dd, J=4.45, 14.62 Hz, 1H), 3.34 (s, 3H), 3.02-3.10 (m, 1H), 2.68-2.83 (m, 3H), 2.50 (s, 6H), 1.22 (d, J=6.90 Hz, 3H).

* pure but unknown stereochemistry

Compound 100_D2: (4R*,9R)—N-(5-bromo-2,4-difluorophenyl)-4-((dimethylamino)methyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS (M+1): 527/529. 1 H NMR (400 MHz, CHLOROFORM-d) δ=8.34 (dd, J=7.53, 8.28 Hz, 1H), 8.17 (s, 1H), 6.95 (dd, J=7.91, 10.67 Hz, 1H), 6.57 (d, J=3.01 Hz, 1H), 5.11 (s, 1H), 4.91 (d, J=15.69 Hz, 1H), 4.74 (s, 1H), 4.62 (dd, J=5.90, 14.56 Hz, 1H), 4.49 (d, J=15.69 Hz, 1H), 4.33 (dd, J=5.96, 14.49 Hz, 1H), 3.34 (s, 3H), 3.02-3.10 (m, 1H), 2.62-2.83 (m, 3H), 2.55 (br s, 7H), 2.47 (s, 6H), 1.22 (d, J=6.90 Hz, 3H).

* pure but unknown stereochemistry

Compound 101: N-(3-chloro-4-fluoro-phenyl)-4-(ethoxymethyl)-2-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxamide

Step 1. tert-butyl 4-(ethoxymethyl)-2-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo [2,4-d][1,2,5]oxadiazepine-10-carboxylate. To a solution of tert-butyl 4-(hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5] oxadiazepine-10(2H)-carboxylate (Intermediate 1, 100.00 mg, 283.78 μmol, 1.00 eq) in DMF (2.00 mL) was added NaH (22.70 mg, 567.56 μmol, 22.70 μL60% purity, 2.00 eq) with stirring at −10° C. for 0.5 h under N 2 . And then a solution of iodoethane (66.39 mg, 425.67 μmol, 34.04 μL1.50 eq) in DMF (1.00 mL) was added into the mixture. The mixture was stirred at 15° C. for 1 h. TLC (Petroleum ether:Ethyl acetate=1:5) showed that the starting material was consumed completely and one main new spot formed. LCMS indicated that MS of desired product was detected. The mixture was quenched with 1 mL of water and extracted with EtOAc (10 mL*3). The organic layers was combined and dried over anhydrous Na 2 SO 4 , filtered and concentrated to give the residue. The residue was purified by prep-TLC (Petroleum ether:Ethyl acetate=1:5) to obtain the title compound (105.00 mg, crude) as off-white oil. LCMS [M+1]: 381.

›PREPARATIVE EXAMPLES · 36 of 53

Step 2. Preparation of 4-(ethoxymethyl)-2-methyl-4,5,8,9,10,11-hexahydropyrido[2,3]pyrazolo [2,4-d][1,2,5] oxadiazepin-1-one. To a solution of tert-butyl 4-(ethoxymethyl)-2-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxylate (50.00 mg, 131.43 μmol, 1.00 eq) in DCM (1.00 mL) was added TFA (1.54 g, 13.51 mmol, 1.00 mL, 102.76 eq) with stirring at 15° C. for 1 h. TLC (petroleum ether:ethyl acetate=1:5) showed that Reactant 2 was consumed completely and one main new spot formed. The mixture was directly evaporated to give the residue. The residue was not purified and directly used in the next step. The title compound (60.00 mg, crude, TFA) was obtained as a yellow oil.

Step 3. N-(3-chloro-4-fluoro-phenyl)-4-(ethoxymethyl)-2-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxamide. To a solution of 4-(ethoxymethyl)-2-methyl-4,5,8,9,10,11-hexahydropyrido [2,3]pyrazolo [2,4-d][1,2,5]oxadiazepin-1-one (60.00 mg, 152.15 μmol, 1.00 eq, TFA) in DCM (2.00 mL) was TEA (46.19 mg, 456.45 μmol, 63.27 μL3.00 eq) with stirring at 15° C., and then the resulting mixture was stirred at 30° C. for 1 h. TLC showed the starting material was consumed completely and LCMS indicated that MS of desired product was detected. The mixture was evaporated to get the residue. The residue was purified by prep-HPLC (FA) to obtain the title compound (28.00 mg, 61.78 μmol, 40.60% yield, 99.7% purity) as a white solid. 1 H NMR (400 MHz, CHLOROFORM-d) δ=7.58 (dd, J=2.8, 6.4 Hz, 1H), 7.20 (m, 1H), 7.03-7.10 (m, 1H), 6.55 (s, 1H), 4.70 (s, 2H), 4.51-4.64 (m, 2H), 4.35-4.46 (m, 1H), 3.79-3.94 (m, 2H), 3.51-3.67 (m, 4H), 3.31 (s, 3H), 2.86 (t, J=5.6 Hz, 2H), 1.24 (t, J=6.8 Hz, 3H). LCMS[M+1]: 452.

Compound 102: 4-(allyloxymethyl)-N-(3-chloro-4-fluoro-phenyl)-2-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxamide

Step 1. tert-butyl 4-(allyloxymethyl)-2-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxylate. To a solution of tert-butyl 4-(hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxylate (Intermediate 1, 200.00 mg, 567.57 μmol, 1.00 eq) in DMF (2.00 mL) was NaH (45.41 mg, 1.14 mmol, 22.70 μL60% purity, 2.00 eq) with stirring at −10° C. for 0.5 h under N 2 . And then 3-bromoprop-1-ene (103.00 mg, 851.35 μmol, 1.50 eq) was added into the mixture. The mixture was stirred at 15° C. for 1 h. TLC (petroleum ether:ethyl acetate=1:5) showed that the starting material was consumed completely and one main new spot formed. LCMS indicated that MS of desired product was detected. The mixture was quenched with 1 mL of water and extracted with ethyl acetate (10 mL*3). The organic layers was combined and dried over anhydrous Na 2 SO 4 , filtered and concentrated to obtain the title compound (160.00 mg, 407.70 μmol, 71.83% yield) as off-white oil. 1 H NMR (400 MHz, CHLOROFORM-d) δ=5.96-5.84 (m, 1H), 5.33-5.20 (m, 2H), 4.63 (brs, 2H), 4.60-4.48 (m, 2H), 4.40-4.31 (m, 1H), 4.04 (d, J=5.6 Hz, 2H), 3.70 (d, J=5.2 Hz, 2H), 3.64 (dd, J=6.0, 12.0 Hz, 1H), 3.57-3.50 (m, 1H), 3.27 (s, 3H), 2.81-2.72 (m, 2H), 1.47 (s, 9H). LCMS [M+1]: 393.

Step 2. Preparation of 4-(allyloxymethyl)-2-methyl-4,5,8,9,10,11-hexahydropyrido[2,3] pyrazolo[2,4-d][1,2,5]oxadiazepin-1-one. To a solution of tert-butyl 4-(allyloxymethyl)-2-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxylate (30.00 mg, 76.44 μmol, 1.00 eq) in DCM (1.00 mL) was added TFA (770.00 mg, 6.75 mmol, 500.00 μL88.35 eq) with stirring at 15° C. for 1 h. TLC indicated that the starting material was consumed completely and one main spot formed. The mixture was directly evaporated to obtain the title compound (50.00 mg, crude, TFA) as a yellow oil and directly used in the next step.

Step 3. 4-(allyloxymethyl)-N-(3-chloro-4-fluoro-phenyl)-2-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxamide. To a solution of 4-(allyloxymethyl)-2-methyl-4,5,8,9,10,11-hexahydropyrido [2,3]pyrazolo[2,4-d][1,2,5]oxadiazepin-1-one (31.00 mg, 76.29 μmol, 1.00 eq, TFA) and phenyl N-(3-chloro-4-fluoro-phenyl)carbamate (22.29 mg, 83.92 μmol, 1.10 eq) in DCM (2.00 mL) was added TEA (73.00 mg, 721.70 μmol, 100.00 μL9.46 eq) with stirring at 30° C. for 1 h. LCMS indicated that the starting material was consumed completely and MS of desired product was detected. The mixture was evaporated to get the residue. The residue was purified by prep-HPLC (FA) to obtain the title compound (25.70 mg, 55.01 μmol, 72.11% yield, 99.3% purity) as a yellow solid. 1 H NMR (400 MHz, CHLOROFORM-d) δ=7.51-7.63 (m, 1H), 7.16-7.25 (m, 1H), 6.98-7.08 (m, 1H), 6.61-6.79 (m, 1H), 5.83-5.98 (m, 1H), 5.19-5.34 (m, 2H), 4.69 (s, 2H), 4.48-4.64 (m, 2H), 4.31-4.44 (m, 1H), 4.00-4.11 (m, 2H), 3.76-3.94 (m, 2H), 3.52-3.69 (m, 2H), 3.29 (s, 3H), 2.85 (t, J=5.60 Hz, 2H). LCMS[M+1]: 464.

Compound 103: N-(3-chloro-4-fluoro-phenyl)-2-methyl-1-oxo-4-(propoxymethyl)-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxamide

Step 1. tert-butyl 2-methyl-1-oxo-4-(propoxymethyl)-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxylate. To a solution of tert-butyl 4-(hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxylate (Intermediate 1, 100.00 mg, 283.78 μmol, 1.00 eq) in DMF (2.00 mL) was added NaH (45.41 mg, 1.14 mmol, 22.70 μL60% purity, 2.00 eq) with stirring at −10° C. for 0.5 h under N 2 . And then 1-bromopropane (52.35 mg, 425.68 μmol, 38.78 μL1.50 eq) was added into the mixture. The mixture was stirred at 15° C. for 1 h. TLC (petroleum ether:ethyl acetate=1:5) showed that the starting material, was consumed completely and one main new spot formed. LCMS indicated that MS of desired product was detected. The mixture was quenched with 1 mL of water and extracted with ethyl acetate (10 mL*3). The organic layers was combined and dried over anhydrous Na 2 SO 4 , filtered and concentrated to obtain the title compound (60.00 mg, 152.11 μmol, 53.60% yield) as off-white oil. 1 H NMR (400 MHz, CHLOROFORM-d) δ=4.62 (brs, 2H), 4.46-4.58 (m, 2H), 4.29-4.39 (m, 1H), 3.69 (d, J=4.77 Hz, 2H), 3.58-3.64 (m, 1H), 3.47-3.55 (m, 1H), 3.39-3.47 (m, 2H), 3.26 (s, 3H), 2.74 (t, J=5.14 Hz, 2H), 1.55-1.64 (m, 2H), 1.46 (s, 9H), 0.86-0.97 (m, 3H). LCMS[M+1]: 395.

›PREPARATIVE EXAMPLES · 37 of 53

Step 2. 2-methyl-4-(propoxymethyl)-4,5,8,9,10,11-hexahydropyrido [2,3]pyrazolo[2,4-d][1,2,5]oxadiazepin-1-one. To a solution of tert-butyl 2-methyl-1-oxo-4-(propoxymethyl)-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxylate (60.00 mg, 152.11 μmol, 1.00 eq) in DCM (1.00 mL) was added TFA (1.54 g, 13.51 mmol, 1.00 mL, 88.79 eq) with stirring at 15° C. for 1 h. TLC indicated that the starting material was consumed completely and one main spot formed. The mixture was directly evaporated to obtain the title compound (70.00 mg, crude, TFA) as yellow oil and directly used in the next step. 1 H NMR (400 MHz, CHLOROFORM-d) δ=4.47-4.71 (m, 5H), 3.57-3.73 (m, 4H), 3.42-3.54 (m, 2H), 3.33 (s, 3H), 3.17 (t, J=6.0 Hz, 2H), 1.59-1.69 (m, 2H), 0.89-0.98 (m, 3H).

Step 3. N-(3-chloro-4-fluoro-phenyl)-2-methyl-1-oxo-4-(propoxymethyl)-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxamide. To a solution of 2-methyl-4-(propoxymethyl)-4,5,8,9,10,11-hexahydropyrido [2,3]pyrazolo[2,4-d][1,2,5]oxadiazepin-1-one (70.00 mg, 171.41 μmol, 1.00 eq, TFA) and phenyl N-(3-chloro-4-fluoro-phenyl)carbamate (45.54 mg, 171.41 μmol, 1.00 eq) in DCM (2.00 mL) was added TEA (164.09 mg, 1.62 mmol, 224.78 μL9.46 eq) with stirring at 30° C. for 1 h. LCMS indicated that the starting material was consumed completely and MS of desired product was detected. The mixture was evaporated to get the residue. The residue was purified by prep-HPLC (FA) to obtain the title compound (19.00 mg, 40.46 μmol, 23.60% yield, 99.2% purity) as a yellow solid. 1 H NMR (400 MHz, CHLOROFORM-d) δ=7.58 (dd, J=2.63, 6.54 Hz, 1H), 7.16-7.22 (m, 1H), 7.03-7.09 (m, 1H), 6.48 (s, 1H), 4.70 (s, 2H), 4.51-4.63 (m, 2H), 4.37-4.43 (m, 1H), 3.80-3.93 (m, 2H), 3.62-3.68 (m, 1H), 3.52-3.59 (m, 1H), 3.44-3.51 (m, 2H), 3.31 (s, 3H), 2.86 (t, J=5.81 Hz, 2H), 1.61-1.68 (m, 2H), 0.95 (t, J=7.40 Hz, 3H). LCMS[M+1]: 466.

Compound 104: N-(3-chloro-4-fluoro-phenyl)-4-(cyclopropylmethoxymethyl)-2-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxamide

Step 1. Preparation of tert-butyl4-(cyclopropylmethoxymethyl)-2-methyl-1-oxo-5,8,9,11-tetrahy-dro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxylate. To a solution of tert-butyl 4-(hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxylate (Intermediate 1, 500.00 mg, 1.42 mmol, 1.00 eq) in DMF (5.00 mL) was added NaH (113.51 mg, 2.84 mmol, 22.70 μL60% purity, 2.00 eq) with stirring at −10° C. for 0.5 h under N 2 . Then bromomethylcyclopropane (287.33 mg, 2.13 mmol, 203.78 μL1.50 eq) was added into the mixture. The mixture was stirred at 0° C. for 1 h. TLC showed that the starting material was consumed completely and one main new spot formed. The mixture was quenched with 1 mL of water and extracted with EtOAc (10 mL*3). The organic layers was combined and dried over anhydrous Na 2 SO 4 , filtered and concentrated to give a residue. The residue was purified by prep-TLC to obtain the title compound (290.00 mg, 713.46 μmol, 50.24% yield) as yellow oil. 1 H NMR (400 MHz, CHLOROFORM-d) δ=4.62 (brs, 2H), 4.46-4.59 (m, 2H), 4.28-4.38 (m, 1H), 3.66 (dt, J=5.50, 11.07 Hz, 3H), 3.53 (dd, J=5.26, 10.15 Hz, 1H), 3.33 (dd, J=2.32, 6.85 Hz, 2H), 3.27 (s, 3H), 2.74 (br s, 2H), 1.39-1.53 (m, 9H), 0.99-1.10 (m, 1H), 0.49-0.59 (m, 2H), 0.15-0.24 (m, 2H).

Step 2. Preparation of 4-(cyclopropylmethoxymethyl)-2-methyl-4,5,8,9,10,11-hexahydropyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepin-1-one. To a solution of tert-butyl 4-(cyclopropylmethoxymethyl)-2-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxylate (80.00 mg, 196.82 μmol, 1.00 eq) in DCM (2.00 mL) was added TFA (3.99 g, 34.95 mmol, 2.59 mL, 177.60 eq) with stirring at 15° C. for 1 h. TLC showed that the starting material was consumed completely. The mixture was directly evaporated to get the title compound (85.00 mg, crude, TFA) as a yellow oil and directly used in the next step.

Step 3. N-(3-chloro-4-fluoro-phenyl)-4-(cyclopropylmethoxymethyl)-2-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxamide. To a solution of 4-(cyclopropylmethoxymethyl)-2-methyl-4,5,8,9,10,11-hexahydropyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepin-1-one (83.00 mg, 197.44 μmol, 1.00 eq, TFA) and phenyl N-(3-chloro-4-fluoro-phenyl)carbamate (57.70 mg, 217.18 μmol, 1.10 eq) in DCM (2.00 mL) was added TEA (201.99 mg, 2.00 mmol, 276.70 μL10.11 eq) with stirring at 30° C. for 1 h. LCMS indicated that reactant was consumed completely and MS of desired product was detected. The mixture was evaporated to get the residue. The residue was purified by prep-HPLC (FA) to obtain the title compound (48.60 mg, 100.67 μmol, 50.99% yield, 99% purity) as white solid. 1 H NMR (400 MHz, CHLOROFORM-d) δ=7.54 (dd, J=2.63, 6.54 Hz, 1H), 7.14-7.23 (m, 1H), 7.03 (t, J=8.80 Hz, 1H), 6.71 (s, 1H), 4.69 (s, 2H), 4.51-4.63 (m, 2H), 4.34-4.44 (m, 1H), 3.75-3.91 (m, 2H), 3.52-3.72 (m, 2H), 3.33-3.39 (m, 2H), 3.29 (s, 3H), 2.84 (t, J=5.75 Hz, 2H), 1.01-1.12 (m, 1H), 0.52-0.61 (m, 2H), 0.19-0.26 (m, 2H). LCMS (M+1): 478.

Compound 105: N-(3-chloro-4-fluoro-phenyl)-4-(2,2-difluoroethoxymethyl)-2-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxamide

Step 1. tert-butyl 4-(2,2-difluoroethoxymethyl)-2-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxylate. To a solution of tert-butyl 4-(hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxylate (Intermediate 1, 200.00 mg, 567.57 μmol, 1.00 eq) in DMF (2.00 mL) was added NaH (68.11 mg, 1.70 mmol, 22.70 μL60% purity, 3.00 eq) with stirring at −10° C. for 0.5 h under N 2 . Then the resulting DMF solution of 2, 2-difluoroethyl trifluoromethanesulfonate (Intermediate 19, 5.68 mmol, 1.00 mL, 10.00 eq) was added into the mixture. The mixture was stirred at 0° C. for 2 h. TLC (PE:EtOAc=1:5) showed that the first reactant was consumed completely and some new spots formed. LCMS indicated that the desired product was detected. The mixture was poured into 10 mL of ice water and extracted with Ethyl acetate (10 mL*3). The organic layers was combined and dried over anhydrous Na 2 SO 4 , filtered and concentrated to give the residue. The residue was purified by prep-TLC to obtain the title compound (100.00 mg, 240.14 μmol, 42.31% yield) as yellow oil. 1 H NMR (400 MHz, CHLOROFORM-d) δ=5.69-6.04 (m, 1H), 4.45-4.63 (m, 4H), 4.27-4.40 (m, 1H), 3.59-3.79 (m, 6H), 3.24 (s, 3H), 2.64-2.78 (m, 2H), 1.45 (s, 9H).

›PREPARATIVE EXAMPLES · 38 of 53

Step 3. Preparation of 4-(2,2-difluoroethoxymethyl)-2-methyl-4,5,8,9,10,11-hexahydropyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepin-1-one. To a solution of tert-butyl 4-(2,2-difluoroethoxymethyl)-2-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxylate (100.00 mg, 240.14 μmol, 1.00 eq) in DCM (2.00 mL) was added TFA (1.54 g, 13.51 mmol, 1.00 mL, 56.24 eq) with stirring at 15° C. for 1 h. TLC showed that reactant was consumed completely and one new spot formed. The mixture was directly evaporated to get the title compound (110.00 mg, crude, TFA) as yellow oil and directly used in the next step.

Step 4. N-(3-chloro-4-fluoro-phenyl)-4-(2,2-difluoroethoxymethyl)-2-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxamide. To a solution of 4-(2,2-difluoroethoxymethyl)-2-methyl-4,5,8,9,10,11-hexahydropyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepin-1-one (103.00 mg, 239.35 μmol, 1.00 eq, TFA) in DCM (2.00 mL) was added TEA (193.76 mg, 1.91 mmol, 265.42 μL8.00 eq) with stirring at 30° C. for 1 h. LCMS indicated that reactant was consumed completely and the desired product was detected. The mixture was evaporated to get the residue. The residue was purified by prep-HPLC (FA) to obtain the title compound (61.00 mg, 124.29 μmol, 51.93% yield, 99.4% purity) as a white solid. 1 H NMR (400 MHz, CHLOROFORM-d) δ=7.54 (dd, J=2.70, 6.59 Hz, 1H), 7.19 (ddd, J=2.70, 4.05, 8.94 Hz, 1H), 6.99-7.08 (m, 1H), 6.73 (s, 1H), 5.72-6.06 (m, 1H), 4.69 (s, 2H), 4.51-4.64 (m, 2H), 4.33-4.43 (m, 1H), 3.81-3.90 (m, 2H), 3.66-3.80 (m, 4H), 3.24-3.35 (m, 3H), 2.77-2.91 (m, 2H). LCMS (M+1): 488.

Compound 106: N-(3-chloro-4-fluoro-phenyl)-2-methyl-1-oxo-4-(2,2,2-trifluoroethoxymethyl)-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxamide

Step 1. tert-butyl 2-methyl-1-oxo-4-(2,2,2-trifluoroethoxymethyl)-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxylate. To a solution of tert-butyl 4-(hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxylate (Intermediate 1, 500.00 mg, 1.42 mmol, 1.00 eq) in DMF (2.00 mL) was added NaH (170.27 mg, 4.26 mmol, 22.70 μL60% purity, 3.00 eq) at −10° C. The mixture was stirred for 0.5 h under N 2 . Then a DMF solution of 2,2,2-trifluoroethyl trifluoromethanesulfonate (Intermediate 20, 14.19 mmol, 1 mL, 10.00 eq) was added to the mixture. The mixture was stirred at 0° C. for 5 h. LCMS indicated that the MS of desired product was detected. The mixture was poured into 10 mL of ice water and extracted with Ethyl acetate (10 mL*3). The organic layers were combined and dried over anhydrous Na 2 SO 4 , filtered and concentrated to give the residue. The residue was purified by prep-TLC to obtain the title compound (160.00 mg, crude) as yellow oil. LCMS: 435 (M+1).

Step 3. Preparation of 2-methyl-4-(2,2,2-trifluoroethoxy methyl)-4,5,8,9,10,11-hexahydropyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepin-1-one. To a solution of tert-butyl 2-methyl-1-oxo-4-(2,2,2-trifluoroethoxymethyl)-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxylate (80.00 mg, 184.16 μmol, 1.00 eq) in DCM (2.00 mL) was added TFA (1.54 g, 13.51 mmol, 1.00 mL, 73.34 eq) with stirring at 15° C. for 1 h. TLC showed that reactant was consumed completely and one new spot formed. The mixture was directly evaporated to get the title compound (85.00 mg, crude, TFA) as yellow oil.

Step 4. Preparation of Compound 106: N-(3-chloro-4-fluoro-phenyl)-2-methyl-1-oxo-4-(2,2,2-trifluoroethoxymethyl)-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxamide. To a solution of 2-methyl-4-(2,2,2-trifluoroethoxymethyl)-4,5,8,9,10,11-hexahydropyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepin-1-one (30.00 mg, 66.92 μmol, 1.00 eq, TFA) and phenyl N-(3-chloro-4-fluoro-phenyl)carbamate (17.78 mg, 66.92 μmol, 1.00 eq) in DCM (2.00 mL) was added TEA (54.17 mg, 535.33 μmol, 74.21 μL8.00 eq) with stirring at 30° C. for 1 h. LCMS indicated that reactant was consumed completely and the desired product was detected. The mixture was evaporated in vacuo. The residue was purified by prep-HPLC (FA) to obtain the title compound (23.00 mg, 44.33 μmol, 33.12% yield, 97.5% purity) as a white solid. 1 H NMR (400 MHz, METHANOL-d 4 ) δ=7.58 (dd, J=2.51, 6.65 Hz, 1H), 7.23-7.36 (m, 1H), 7.06-7.19 (m, 1H), 4.65-4.75 (m, 1H), 4.59 (br dd, J=5.71, 14.49 Hz, 1H), 4.37 (dd, J=6.90, 14.56 Hz, 1H), 4.02 (q, J=8.87 Hz, 1H), 3.75-3.91 (m, 1H), 3.28 (s, 1H), 2.82 (br t, J=5.58 Hz, 1H). LCMS: 506 (M+1).

Compound 107: N-(3-chloro-4-fluoro-phenyl)-4-(hydroxymethyl)-1-oxo-2-(trideuteriomethyl)-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxamide

Step 1. Preparation of 4-(hydroxymethyl)-2-(trideuteriomethyl)-4,5,8,9,10,11-hexahydropyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepin-1-one. A mixture of tert-butyl 4-(hydroxymethyl)-2-(methyl-d3)-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxylate (Intermediate 21, 40.00 mg, 112.55 μmol, 1.00 eq) in DCM (2.00 mL) was added TFA (1.54 g, 13.51 mmol, 1.00 mL, 120.00 eq), and then the mixture was stirred at 10° C. for 1 hour. TLC showed the starting material was consumed completely and a new spot appeared. The mixture was concentrated in vacuum to give the title compound (41.57 mg, 112.56 μmol, 100.00% yield, TFA) as a yellow oil.

Step 2. N-(3-chloro-4-fluoro-phenyl)-4-(hydroxymethyl)-1-oxo-2-(trideuteriomethyl)-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxamide. A mixture of 4-(hydroxymethyl)-2-(trideuteriomethyl)-4,5,8,9,10,11-hexahydropyrido [2,3]pyrazolo[2,4-d][1,2,5]oxadiazepin-1-one (41.57 mg, 112.56 μmol, 1.00 eq, TFA), phenyl N-(3-chloro-4-fluoro-phenyl)carbamate (32.89 mg, 123.82 μmol, 1.10 eq), TEA (22.78 mg, 225.12 μmol, 31.21 μL2.00 eq) in DCM (3.00 mL) was degassed and purged with N 2 for 3 times, and then the mixture was stirred at 10° C. for 16 hour under N 2 atmosphere. LCMS showed the starting material was consumed completely and desired product was major. The mixture was poured into water (5 mL) and stirred at 5 min. The aqueous phase was extracted with DCM (3 mL*3). The combined organic phase was washed with brine (5 mL), dried with anhydrous Na 2 SO 4 , filtered and concentrated in vacuum. The residue was purified by prep-HPLC(FA) to give the title compound (21.00 mg, 48.21 μmol, 42.83% yield, 98% purity) as a white solid. 1 H NMR (400 MHz, CHLOROFORM-d) δ 7.54-7.59 (m, 1H) 7.16-7.22 (m, 1H) 7.06 (t, J=8.78 Hz, 1H) 6.51 (s, 1H) 4.70 (s, 2H) 4.51-4.62 (m, 2H) 4.34-4.47 (m, 1H) 3.74-3.93 (m, 4H) 2.86 (s, 2H) 1.87-2.07 (m, 1H). LCMS: 427 [M+1].

›PREPARATIVE EXAMPLES · 39 of 53

Compound 108_D1: (4S*,9R)—N-(5-bromo-2,4-difluorophenyl)-4-((2,2-difluoroethoxy)methyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

Compound 108_D1 was prepared in an analogous manner to Compound 121.

LC-MS: 564/566 [M+1]. 1 H NMR (400 MHz, CHLOROFORM-d) δ=8.34 (t, J=7.89 Hz, 1H), 6.94 (dd, J=7.95, 10.64 Hz, 1H), 6.53 (br s, 1H), 5.68-6.13 (m, 1H), 5.09 (br t, J=6.17 Hz, 1H), 4.86 (d, J=15.77 Hz, 1H), 4.35-4.71 (m, 4H), 3.61-3.84 (m, 4H), 3.31 (s, 3H), 3.05 (dd, J=5.69, 15.71 Hz, 1H), 2.70 (d, J=15.89 Hz, 1H), 1.21 (d, J=6.85 Hz, 3H).

* pure but unknown stereochemistry

Compound 108_D2: (4R*,9R)—N-(5-bromo-2,4-difluorophenyl)-4-((2,2-difluoroethoxy)methyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

Compound 108_D1 was prepared in an analogous manner to Compound 121.

LCMS (M+1): 564/566. 1 H NMR (400 MHz, CHLOROFORM-d) δ=8.31-8.37 (m, 1H), 6.94 (dd, J=7.91, 10.67 Hz, 1H), 6.53 (br s, 1H), 5.75-6.06 (m, 1H), 5.10 (br t, J=6.09 Hz, 1H), 4.88 (d, J=15.69 Hz, 1H), 4.37-4.64 (m, 4H), 3.71-3.85 (m, 4H), 3.31 (s, 3H), 3.05 (dd, J=5.46, 16.00 Hz, 1H), 2.71 (d, J=15.81 Hz, 1H), 1.20 (d, J=6.90 Hz, 3H).

* pure but unknown stereochemistry

Compound 109: (4S*,9S*)—N-(3-chloro-4-fluorophenyl)-9-ethyl-4-(hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

Step 11. 9-ethyl-4-(hydroxymethyl)-2-methyl-4,5,8,9,10,11-hexahydropyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepin-1-one. To a solution of tert-butyl 9-ethyl-4-(hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxylate (Intermediate 23, 50.00 mg, 131.43 μmol, 1.00 eq) in DCM (2.00 mL) was added TFA (1.54 g, 13.51 mmol, 1.00 mL, 102.76 eq). The reaction mixture was stirred at 25° C. for 30 minutes. TLC indicated the starting material consumed completely, and one major new spot with larger polarity was detected. The reaction mixture was concentrated on a rotary evaporator to give the title compound (50.00 mg, crude, TFA) as yellow oil, used in next step directly.

Step 2. (4S*,9S*)—N-(3-chloro-4-fluorophenyl)-9-ethyl-4-(hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide. To a mixture of 9-ethyl-4-(hydroxymethyl)-2-methyl-4,5,8,9,10,11-hexahydro pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepin-1-one (50.00 mg, 126.79 μmol, 1.00 eq, TFA) in DCM (3.00 mL) was added TEA (51.32 mg, 507.16 μmol, 70.30 μL4.00 eq), followed by phenyl N-(3-chloro-4-fluoro-phenyl)carbamate (33.68 mg, 126.79 μmol, 1.00 eq), and the reaction mixture was stirred at 25° C. for 16 hours. LCMS showed one main peak with desired MS was detected. The mixture was extracted with DCM (50 mL) and water (30 mL*2), the organic phase was dried with anhydrous Na 2 SO 4 , filtered and concentrated in vacuum. The residue was purified by prep-HPLC(FA) to give the title compound (46.00 mg, 99.76 μmol, 78.68% yield, 98% purity) as white solid, which was separated by SFC, followed by prep-HPLC to get both diastereomers (109_D1: 20 mg and 109_D2: 20 mg).

SFC separation condition: Instrument: SFC 80; Column: AD-5 um; Mobile phase: A for CO 2 and B for IPA (0.1% NH 3 H 2 O); Gradient: B 30%; Flow rate: 60 mL/min; Back pressure: 100 bar; Column temperature: 35° C.; Wavelength: 220 nm. 1H NMR (400 MHz, CHLOROFORM-d) δ=7.59 (dd, J=2.70, 6.46 Hz, 1H), 7.16-7.23 (m, 1H), 7.03-7.10 (m, 1H), 6.50 (s, 1H), 4.81-4.89 (m, 2H), 4.51-4.63 (m, 2H), 4.40-4.48 (m, 2H), 3.72-3.89 (m, 2H), 3.33 (s, 3H), 3.00 (dd, J=5.77, 15.94 Hz, 1H), 2.77 (d, J=16.19 Hz, 1H), 1.95 (br s, 1H), 1.40-1.54 (m, 2H), 0.94 (t, J=7.40 Hz, 3H). LCMS: 452/454 [M+1]

* pure but unknown stereochemistry

Compound 109_D2: (4S*,9R*)—N-(3-chloro-4-fluorophenyl)-9-ethyl-4-(hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

1H NMR (400 MHz, CHLOROFORM-d) δ=7.60 (dd, J=2.64, 6.53 Hz, 1H), 7.18-7.23 (m, 1H), 7.03-7.09 (m, 1H), 6.58 (s, 1H), 4.84-4.93 (m, 2H), 4.52-4.60 (m, 2H), 4.35-4.43 (m, 2H), 3.75-3.92 (m, 2H), 3.33 (s, 3H), 3.00 (dd, J=6.02, 16.06 Hz, 1H), 2.77 (d, J=15.81 Hz, 1H), 1.92-2.08 (m, 1H), 1.42-1.55 (m, 2H), 0.94 (t, J=7.34 Hz, 3H). LCMS: 452/454 [M+1]

* pure but unknown stereochemistry

Compounds 109_D3/D4 were prepared through the similar procedure of 109_D1/D2. SFC separation condition: Instrument: SFC 80; Column: OJ-5 um; Mobile phase: A for CO 2 and B for EtOH (0.1% NH 3 H 2 O); Gradient: B 20%; Flow rate: 50 mL/min; Back pressure: 100 bar; Column temperature: 35° C.; Wavelength: 220 nm.

109_D3: (4R*,9R*)—N-(3-chloro-4-fluorophenyl)-9-ethyl-4-(hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

1H NMR (400 MHz, CHLOROFORM-d) δ=7.60 (dd, J=2.64, 6.53 Hz, 1H), 7.18-7.23 (m, 1H), 7.03-7.09 (m, 1H), 6.52 (s, 1H), 4.84-4.92 (m, 2H), 4.52-4.59 (m, 2H), 4.36-4.43 (m, 2H), 3.86-3.92 (m, 1H), 3.76-3.82 (m, 1H), 3.33 (s, 3H), 3.00 (dd, J=5.83, 16.00 Hz, 1H), 2.77 (d, J=15.94 Hz, 1H), 1.83-2.04 (m, 1H), 1.41-1.55 (m, 2H), 0.94 (t, J=7.40 Hz, 3H)

LCMS: 452 [M+1].

* pure but unknown stereochemistry

109_D4: (4R*,9S*)—N-(3-chloro-4-fluorophenyl)-9-ethyl-4-(hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

1H NMR (400 MHz, CHLOROFORM-d) δ=7.59 (dd, J=2.64, 6.53 Hz, 1H), 7.20 (ddd, J=2.70, 4.05, 8.94 Hz, 1H), 7.03-7.09 (m, 1H), 6.55 (br s, 1H), 4.84 (br d, J=15.69 Hz, 2H), 4.51-4.62 (m, 2H), 4.39-4.46 (m, 2H), 3.81-3.88 (m, 1H), 3.72-3.78 (m, 1H), 3.33 (s, 3H), 2.99 (dd, J=5.83, 16.00 Hz, 1H), 2.77 (d, J=15.94 Hz, 1H), 1.87-2.19 (m, 1H), 1.42-1.56 (m, 2H), 0.94 (t, J=7.40 Hz, 3H)

LCMS: 452 [M+1].

* pure but unknown stereochemistry

Compound 110_D1: (4S*,9R)—N10-(3-chloro-2,4-difluorophenyl)-N4,2,9-trimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-4,10(2H)-dicarboxamide

›PREPARATIVE EXAMPLES · 40 of 53

Step 1. (9R)—N,2,9-trimethyl-1-oxo-4,5,8,9,10,11-hexahydropyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-4-carboxamide. A solution of tert-butyl (9R)-2,9-dimethyl-4-(methylcarbamoyl)-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxylate (Intermediate 25, 165.00 mg, 419.38 μmol, 1.00 eq) in DCM (2.00 mL) was added TFA (1.54 g, 13.51 mmol, 1.00 mL, 32.21 eq), and then the mixture was stirred at 30° C. for 0.5 hour. TLC showed the starting material was consumed completely, desired product was major. The mixture was concentrated in vacuum to give the title compound (170.00 mg, 417.34 μmol, 99.51% yield, TFA) as a yellow oil, which was used directly for next step.

Step 2. (9R)—N10-(3-chloro-2,4-difluoro-phenyl)-N4,2,9-trimethyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-4,10-dicarboxamide. A mixture of (9R)—N,2,9-trimethyl-1-oxo-4,5,8,9,10,11-hexahydropyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-4-carboxamide (56.00 mg, 137.48 μmol, 1.00 eq, TFA), phenyl N-(3-chloro-2,4-difluoro-phenyl)carbamate (46.80 mg, 164.97 μmol, 1.20 eq), TEA (27.82 mg, 274.95 μmol, 38.11 μL2.00 eq) in DCM (3.00 mL) was degassed and purged with N 2 for 3 times, and then the mixture was stirred at 30° C. for 16 hour under N 2 atmosphere. LCMS showed the starting material was consumed completely and desired product was major. The mixture was poured into water (10 mL) and extracted with DCM (5 mL*3). The combined organic phase was washed with brine (10 mL), dried with anhydrous Na 2 SO 4 , filtered and concentrated in vacuum. The residue was purified by Prep-HPLC (FA) to give the title compound (40.00 mg, 80.35 μmol, 58.45% yield, 97% purity) as a white solid. LCMS: 483/484[M+1]. 1 H NMR (400 MHz, CHLOROFORM-d) δ 7.84-7.93 (m, 1H), 6.92-7.00 (m, 1H), 6.49-6.57 (m, 1H), 6.01-6.10 (m, 1H), 4.95-5.05 (m, 2H), 4.87-4.94 (m, 2H), 4.64-4.71 (m, 1H), 4.55 (s, 1H), 3.35 (s, 3H), 3.00-3.07 (m, 1H), 2.85 (d, J=4.89 Hz, 3H), 2.68-2.75 (m, 1H), 1.22 (d, J=6.90 Hz, 2H), 1.18-1.26 (m, 1H).

* pure but unknown stereochemistry

Compound 110_D2: (4R*,9R)—N10-(3-chloro-2,4-difluorophenyl)-N4,2,9-trimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-4,10(2H)-dicarboxamide

Compound 110_D2 was prepared in an analogous manner to 110_D1 using the opposite enantiomer of Intermediate 25.

LCMS: 483/484[M+1]. 1 H NMR (400 MHz, CHLOROFORM-d) δ=7.81-7.96 (m, 1H), 6.96 (br d, J=1.10 Hz, 1H), 6.49-6.61 (m, 1H), 6.07-6.22 (m, 1H), 5.02-5.11 (m, 1H), 4.84-5.00 (m, 3H), 4.75 (s, 1H), 4.48 (s, 1H), 3.35 (s, 3H), 3.00-3.10 (m, 1H), 2.89 (d, J=4.89 Hz, 3H), 2.72 (d, J=15.89 Hz, 1H), 1.19 (d, J=6.85 Hz, 3H).

* pure but unknown stereochemistry

Compounds 156, 111, and 112 were prepared in an analogous manner to Compound 110.

Compound 111_D1: (4S*,9R)—N10-(5-chloro-2,4-difluorophenyl)-N4,2,9-trimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-4,10(2H)-dicarboxamide

LCMS: 483/484[M+1]. 1 H NMR (400 MHz, CHLOROFORM-d) δ 8.15-8.24 (m, 1H), 6.91-7.01 (m, 1H), 6.51-6.57 (m, 1H), 6.00-6.08 (m, 1H), 4.95-5.05 (m, 2H), 4.85-4.94 (m, 2H), 4.64-4.71 (m, 1H), 4.48-4.55 (m, 1H), 3.35 (s, 3H), 2.99-3.08 (m, 1H), 2.85 (d, J=4.89 Hz, 3H), 2.68-2.76 (m, 1H), 1.19-1.25 (m, 3H).

* pure but unknown stereochemistry

Compound 111_D2: (4R*,9R)—N10-(5-chloro-2,4-difluorophenyl)-N4,2,9-trimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-4,10(2H)-dicarboxamide

LCMS: 483/484[M+1]. 1 H NMR (400 MHz, CHLOROFORM-d) δ=8.16-8.22 (m, 1H), 6.91-7.00 (m, 1H), 6.53-6.59 (m, 1H), 6.11-6.20 (m, 1H), 5.02-5.12 (m, 1H), 4.85-4.98 (m, 3H), 4.69-4.76 (m, 1H), 4.47 (s, 1H), 3.35 (s, 3H), 3.00-3.08 (m, 1H), 2.89 (d, J=4.89 Hz, 3H), 2.69-2.76 (m, 1H), 1.19 (d, J=6.90 Hz, 3H).

* pure but unknown stereochemistry

Compound 112_D1: (4S*,9R)—N10-(3-cyano-4-fluorophenyl)-N4,2,9-trimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-4,10(2H)-dicarboxamide

LCMS: 456[M+1]. 1 H NMR (400 MHz, CHLOROFORM-d) δ=7.73-7.79 (m, 1H), 7.57-7.64 (m, 1H), 7.10-7.19 (m, 1H), 6.67 (s, 1H), 6.01-6.10 (m, 1H), 4.81-5.12 (m, 4H), 4.64-4.74 (m, 1H), 4.51 (d, J=15.77 Hz, 1H), 3.35 (s, 3H), 2.98-3.08 (m, 1H), 2.86 (d, J=4.89 Hz, 3H), 2.66-2.75 (m, 1H), 1.20 (d, J=6.97 Hz, 3H).

* pure but unknown stereochemistry

Compound 112_D2: (4R*,9R)—N10-(3-cyano-4-fluorophenyl)-N4,2,9-trimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-4,10(2H)-dicarboxamide

LCMS: 456[M+1]. 1 H NMR (400 MHz, CHLOROFORM-d) δ=7.75-7.80 (m, 1H), 7.59-7.66 (m, 1H), 7.11-7.18 (m, 1H), 6.80 (s, 1H), 6.12-6.19 (m, 1H), 5.08-5.16 (m, 1H), 4.87-4.99 (m, 3H), 4.68-4.75 (m, 1H), 4.42 (d, J=15.69 Hz, 1H), 3.35 (s, 3H), 2.98-3.06 (m, 1H), 2.89 (d, J=4.89 Hz, 3H), 2.68-2.76 (m, 1H), 1.15-1.20 (m, 3H).

* pure but unknown stereochemistry

Compound 113: 4-(aminomethyl)-N-(3-chloro-4-fluoro-phenyl)-2-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxamide

Step 1. Preparation of [10-[(3-chloro-4-fluoro-phenyl)carbamoyl]-2-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepin-4-yl]methyl methanesulfonate. A mixture of N-(3-chloro-4-fluoro-phenyl)-4-(hydroxymethyl)-2-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5] oxadiazepine-10-carboxamide (Compound 031, 1.00 g, 2.36 mmol, 1.00 eq) and TEA (1.19 g, 11.80 mmol, 1.64 mL, 5.00 eq) in DCM (10.00 mL) was added MsCl (1.08 g, 9.44 mmol, 730.64 μL4.00 eq) at 0° C. under N 2 , and then the mixture was stirred at 30° C. for 2 hour under N 2 atmosphere. TLC showed the starting material was consumed completely and a new spot formed. The mixture was poured into ice-water (20 mL) and stirred at 5 min. The aqueous phase was extracted with DCM (10 mL*2). The combined organic phase was washed with brine (20 mL), dried with anhydrous Na 2 SO 4 , filtered and concentrated in vacuum to give the title compound (1.40 g, crude) as a yellow solid. LCMS: 502/504 [M+1].

›PREPARATIVE EXAMPLES · 41 of 53

Step 2. 4-(azidomethyl)-N-(3-chloro-4-fluoro-phenyl)-2-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[1,2,5]oxadiazepine-10-carboxamide. A solution of [10-[(3-chloro-4-fluoro-phenyl)carbamoyl]-2-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepin-4-yl]methylmethanesulfonate (1.18 g, 2.35 mmol, 1.00 eq) in DMF (15.00 mL) was added NaN 3 (458.51 mg, 7.05 mmol, 247.84 μL3.00 eq) at 0° C. under N 2 , and then the mixture was stirred at 50° C. for 16 hr under N 2 atmosphere. LCMS showed starting material/desired product=1/1. Then NaN 3 (458.32 mg, 7.05 mmol, 3.00 eq) was added to the mixture at 0° C. under N 2 , and the mixture was stirred at 70° C. for another 16 hr. LCMS showed the starting material was consumed completely, desired product was major. The mixture was diluted with ethyl acetate (20 mL) and washed with brine (20 mL, *3). The organic phase was dried over Na 2 SO 4 , filtered and concentrated in vacuo to give the title compound (1.40 g, crude) as a yellow oil. LCMS: 449/451 [M+1]

Step 3. 4-(aminomethyl)-N-(3-chloro-4-fluoro-phenyl)-2-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxamide. A solution of 4-(azidomethyl)-N-(3-chloro-4-fluoro-phenyl)-2-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxamide (1.06 g, 2.36 mmol, 1.00 eq) in THF (12.00 mL) and H 2 O (2.00 mL) was added PPh 3 (1.24 g, 4.72 mmol, 2.00 eq), and then the mixture was stirred at 30° C. for 16 hour under N 2 atmosphere. LCMS showed the starting material was consumed completely, desired product was major. The mixture was poured into water (30 mL) and stirred at 5 min. The aqueous phase was extracted with ethyl acetate (15 mL*2). The combined organic phase was washed with brine (30 mL), dried with anhydrous Na 2 SO 4 , filtered and concentrated in vacuum. The residue was purified by column chromatography (DCM/MeOH=100/1 to 20:1) to give the title compound (702.00 mg, 1.49 mmol, 63.31% yield, 90% purity) as a yellow solid, 75 mg of which was further purified by Prep-HPLC to give 25 mg pure desired product. LCMS: 423/425 [M+1]; 1 H NMR (400 MHz, METHANOL-d 4 ) δ 7.55-7.63 (m, 1H), 7.26-7.34 (m, 1H), 7.14 (s, 1H), 4.72 (br d, J=2.13 Hz, 4H), 4.38-4.47 (m, 1H), 3.73-3.92 (m, 2H), 3.33 (s, 3H), 2.96-3.18 (m, 2H), 2.80-2.87 (m, 2H).

Compound 114_E1: (S*)-4-(aminomethyl)-N-(3-cyano-4-fluoro-phenyl)-2-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxamide

Step 1. 4-(azidomethyl)-2-methyl-4,5,8,9,10,11-hexa hydropyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepin-1-one. A mixture of tert-butyl 4-(azidomethyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxylate (Intermediate 28, 120.00 mg, 317.97 μmol, 1.00 eq) in DCM (2.00 mL) was added TFA (1.54 g, 13.51 mmol, 1.00 mL, 42.48 eq), and then the mixture was stirred at 25° C. for 1 hour. TLC showed the starting material was consumed completely, a new spot appeared. The mixture was concentrated in vacuum to give the title compound (124.00 mg, 316.89 μmol, 99.66% yield, TFA) as a yellow oil, which was used directly for next step.

Step 2. Preparation of 4-(azidomethyl)-N-(3-cyano-4-fluoro-phenyl)-2-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxamide. A mixture of 4-(azidomethyl)-2-methyl-4,5,8,9,10,11-hexahydropyrido[2,3] pyrazolo[2,4-d][1,2,5]oxadiazepin-1-one (124.00 mg, 316.89 μmol, 1.00 eq, TFA), phenyl N-(3-cyano-4-fluoro-phenyl)carbamate (81.20 mg, 316.89 μmol, 1.00 eq), TEA (96.20 mg, 950.67 μmol, 131.78 μL3.00 eq) in DCM (5.00 mL) was degassed and purged with N 2 for 3 times, and then the mixture was stirred at 25° C. for 16 hour under N 2 atmosphere. TLC showed the starting material was consumed completely, desired product was major. The mixture was poured into water (10 mL). The aqueous phase was extracted with DCM (5 mL*3). The combined organic phase was washed with brine (10 mL), dried with anhydrous Na 2 SO 4 , filtered and concentrated in vacuum. The residue was purified by column chromatography (SiO 2 , Petroleum ether/Ethyl acetate=100/1 to 1:2) to give the title compound (115.00 mg, 235.55 μmol, 74.33% yield, 90% purity) as a yellow solid. LCMS: 440[M+1].

Step 3. (S*)-4-(aminomethyl)-N-(3-cyano-4-fluoro-phenyl)-2-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxamide. A solution of 4-(azidomethyl)-N-(3-cyano-4-fluoro-phenyl)-2-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxamide (120.00 mg, 273.10 μmol, 1.00 eq) in THF (6.00 mL) and H 2 O (1.00 mL) was added PPh 3 (143.26 mg, 546.20 μmol, 2.00 eq), and then the mixture was stirred at 30° C. for 16 hour under N 2 atmosphere. LCMS showed the starting material was consumed completely and the desired product was major. The mixture was poured into water (30 mL) and stirred at 5 min. The aqueous phase was extracted with ethyl acetate (15 mL*2). The combined organic phase was washed with brine (30 mL), dried with anhydrous Na 2 SO 4 , filtered and concentrated in vacuum. The residue was purified by column chromatography (DCM/MeOH=100/1 to 20:1), following by Prep-HPLC (HCl) to give the title compound (42.70 mg, 101.53 μmol, 37.18% yield, 98.3% purity) as a yellow solid. LCMS: 414[M+1]. 1 H NMR (400 MHz, METHANOL-d 4 ) δ 7.76-7.83 (m, 1H), 7.66-7.72 (m, 1H), 7.27 (s, 1H), 4.67-4.82 (m, 4H), 4.38-4.47 (m, 1H), 3.75-3.93 (m, 2H), 3.40-3.67 (m, 1H), 3.33 (s, 3H), 3.05-3.19 (m, 1H), 2.79-2.89 (m, 2H)

* pure but unknown stereochemistry

Compound 115_D1: (4S*,9R)-4-(aminomethyl)-N-(3-cyano-4-fluorophenyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

Step 1. (9R)-4-(azidomethyl)-2,9-dimethyl-4,5,8,9,10,11-hexahydropyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepin-1-one. A mixture of tert-butyl (9R)-4-(azidomethyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxylate (Intermediate 29, 120.00 mg, 306.57 μmol, 1.00 eq) in DCM (2.00 mL) was added TFA (1.54 g, 13.51 mmol, 1.00 mL, 44.06 eq), and then the mixture was stirred at 16° C. for 1 hour. TLC showed the starting material was consumed completely, a new spot appeared. The mixture was concentrated in vacuum to give the title compound (124.00 mg, 305.92 μmol, 99.79% yield, TFA) as a yellow oil, which was used directly for next step.

›PREPARATIVE EXAMPLES · 42 of 53

Step 2. (9R)-4-(azidomethyl)-N-(3-cyano-4-fluoro-phenyl)-2,9-dimethyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxamide. A mixture of (9R)-4-(azidomethyl)-2,9-dimethyl-4,5,8,9,10,11-hexahydropyrido[2,3] pyrazolo[2,4-d][1,2,5]oxadiazepin-1-one (124.00 mg, 305.92 μmol, 1.00 eq, TFA), phenyl N-(3-cyano-4-fluoro-phenyl)carbamate (78.39 mg, 305.92 μmol, 1.00 eq), TEA (92.87 mg, 917.77 μmol, 127.22 μL3.00 eq) in DCM (5.00 mL) was degassed and purged with N 2 for 3 times, and then the mixture was stirred at 25° C. for 16 hour under N 2 atmosphere. TLC showed the starting material was consumed completely, desired product was major. The mixture was poured into water (10 mL). The aqueous phase was extracted with DCM (5 mL*3). The combined organic phase was washed with brine (10 mL), dried with anhydrous Na 2 SO 4 , filtered and concentrated in vacuum. The residue was purified by column chromatography (SiO 2 , Petroleum ether/Ethyl acetate=100/1 to 1:2) to give the title compound (114.00 mg, 236.33 μmol, 77.25% yield, 94% purity) as a white solid. LCMS: 454[M+1]

Step 3. (4S*,9R)-4-(aminomethyl)-N-(3-cyano-4-fluorophenyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide. A solution of (9R)-4-(azidomethyl)-N-(3-cyano-4-fluoro-phenyl)-2,9-dimethyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxamide (114.00 mg, 251.42 μmol, 1.00 eq) in THF (6.00 mL) and H 2 O (1.00 mL) was added PPh 3 (131.89 mg, 502.83 μmol, 2.00 eq), and then the mixture was stirred at 15° C. for 16 hour under N 2 atmosphere. TLC showed the starting material was consumed completely, desired product was major. The mixture was poured into water (30 mL) and stirred at 5 min. The aqueous phase was extracted with ethyl acetate (15 mL*2). The combined organic phase was washed with brine (30 mL), dried with anhydrous Na 2 SO 4 , filtered and concentrated in vacuum. The residue was purified by column chromatography (DCM/MeOH=100/1 to 20:1), following by Prep-HPLC (HCl) to give the title compound (13.00 mg, 27.52 μmol, 10.94% yield, 90.47% purity) as a yellow solid. LCMS: 428[M+1]. 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.06 (br s, 1H), 8.23 (br s, 2H), 7.91-7.98 (m, 1H), 7.75-7.84 (m, 1H), 7.42 (t, J=9.10 Hz, 1H), 4.98-5.11 (m, 1H), 4.72 (br s, 3H), 4.31-4.43 (m, 1H), 4.11-4.21 (m, 1H), 3.28 (s, 3H), 3.03-3.19 (m, 2H), 2.88-2.95 (m, 1H), 2.61 (br d, J=15.81 Hz, 1H), 1.10 (d, J=6.78 Hz, 3H).

* pure but unknown stereochemistry

Compound 115_D2: (4R*,9R)-4-(aminomethyl)-N-(3-cyano-4-fluorophenyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

Compound 115_D2 was prepared using the other enantiomer of Intermediate 29.

LCMS: 428[M+1]. 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.06 (br s, 1H), 8.23 (br s, 2H), 7.91-7.98 (m, 1H), 7.75-7.84 (m, 1H), 7.42 (t, J=9.10 Hz, 1H), 4.98-5.11 (m, 1H), 4.72 (br s, 3H), 4.31-4.43 (m, 1H), 4.11-4.21 (m, 1H), 3.28 (s, 3H), 3.03-3.19 (m, 2H), 2.88-2.95 (m, 1H), 2.61 (br d, J=15.81 Hz, 1H), 1.10 (d, J=6.78 Hz, 3H)

* pure but unknown stereochemistry

Compounds 116 and 117 were prepared in an analogous manner to Compound 115.

Compound 116_D1: (4S*,9R)-4-(aminomethyl)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS: 471[M+1]. 1 H NMR (400 MHz, METHANOL-d 4 ) δ 7.77 (dd, J=2.45, 6.21 Hz, 1H), 7.54-7.67 (m, 1H), 7.54-7.69 (m, 1H), 7.24 (t, J=9.66 Hz, 1H), 5.03 (d, J=17.07 Hz, 1H), 4.93 (br d, J=5.77 Hz, 1H), 4.77-4.81 (m, 1H), 4.72 (br dd, J=6.09, 14.87 Hz, 1H), 4.31-4.50 (m, 2H), 3.32-3.37 (m, 4H), 2.97-3.16 (m, 2H), 2.69 (br d, J=15.69 Hz, 1H), 1.23 (d, J=6.90 Hz, 3H).

* pure but unknown stereochemistry

Compound 116_D2: (4R*,9R)-4-(aminomethyl)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS: 471[M+1]. 1 H NMR (400 MHz, METHANOL-d 4 ) δ 7.78 (dd, J=2.75, 6.17 Hz, 1H), 7.61-7.68 (m, 1H), 7.20-7.28 (m, 1H), 5.09 (s, 1H), 4.92-4.96 (m, 1H), 4.75-4.81 (m, 1H), 4.66-4.74 (m, 1H), 4.39-4.47 (m, 1H), 4.29-4.37 (m, 1H), 3.34 (s, 4H), 3.13-3.21 (m, 1H), 2.99-3.08 (m, 1H), 2.63-2.72 (m, 1H), 1.20 (d, J=6.85 Hz, 3H).

* pure but unknown stereochemistry

Compound 117_D1: (4S*,9R)-4-(aminomethyl)-N-(3-bromo-4-fluorophenyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS: 481/483[M+1]. 1 H NMR (400 MHz, METHANOL-d 4 ) δ 7.72 (dd, J=2.64, 6.27 Hz, 1H), 7.33 (td, J=3.40, 8.88 Hz, 1H), 7.12 (t, J=8.72 Hz, 1H), 5.01 (br d, J=16.81 Hz, 1H), 4.90-4.92 (m, 1H), 4.63-4.77 (m, 1H), 4.29-4.50 (m, 2H), 3.32-3.39 (m, 1H), 3.32-3.38 (m, 3H), 2.95-3.13 (m, 2H), 2.68 (d, J=16.06 Hz, 1H), 1.22 (d, J=6.90 Hz, 3H).

* pure but unknown stereochemistry

Compound 117_D2: (4R*,9R)-4-(aminomethyl)-N-(3-bromo-4-fluorophenyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS: 481/483[M+1]. 1 H NMR (400 MHz, METHANOL-d 4 ) δ 7.68-7.76 (m, 1H), 7.30-7.38 (m, 1H), 7.12 (t, J=8.68 Hz, 1H), 5.09 (d, J=16.87 Hz, 1H), 4.90-4.95 (m, 1H), 4.75-4.82 (m, 1H), 4.66-4.75 (m, 1H), 4.43 (dd, J=4.89, 14.79 Hz, 1H), 4.31 (d, J=16.87 Hz, 1H), 3.34 (s, 4H), 3.12-3.23 (m, 1H), 2.98-3.08 (m, 1H), 2.67 (br d, J=15.89 Hz, 1H), 1.19 (d, J=6.85 Hz, 3H).

* pure but unknown stereochemistry

Compound 118: N10-(3-chloro-2,4-difluorophenyl)-N4,2-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-4,10(2H)-dicarboxamide

Step 1. Preparation of tert-butyl 2-methyl-4-(methylcarbamoyl)-1-oxo-5,7,7a,8,9,11,11a,11b-octahydro-4H-pyrido[1,2]pyrazolo[3,5-c][1,2,5]oxadiazepine-10-carboxylate. A mixture of 10-(tert-butoxycarbonyl)-2-methyl-1-oxo-1,2,4,5,8,9,10,11-octahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-4-carboxylic acid (Intermediate 26, 500.00 mg, 1.35 mmol, 1.00 eq), T 3 P (1.72 g, 2.70 mmol, 1.61 mL, 50% purity, 2.00 eq) and Et3N (1.37 g, 13.50 mmol, 1.87 mL, 10.00 eq) in THF (8.00 mL) was added to methanamine;hydrochloride (455.72 mg, 6.75 mmol, 5.00 eq). The mixture was stirred at 70° C. for 16 h under N 2 in a sealed tube. The mixture was adjusted with HCl (1 M) to pH=6, then diluted with H 2 O (20 mL) and extracted Ethyl acetate (20 mL*2). The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by column chromatography (Petroleum ether:Ethyl acetate=1:3) to afford the title compound (235.00 mg, 612.87 μmol, 45.40% yield) as yellow solid. LCMS: 380 [M+1]

›PREPARATIVE EXAMPLES · 43 of 53

Step 2. Preparation of N,2-dimethyl-1-oxo-4,5,8,9,10,11-hexahydropyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-4-carboxamide. To a solution of tert-butyl 2-methyl-4-(methylcarbamoyl)-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxylate (259.00 mg, 682.64 μmol, 1.00 eq) in DCM (3.00 mL) was added TFA (4.43 g, 38.87 mmol, 2.88 mL, 56.94 eq) at 0° C. The mixture was stirred at 25° C. for 1 h. The mixture was concentrated under reduced pressure to afford the title compound (268.00 mg, 681.38 μmol, 99.82% yield, TFA) as yellow oil, the crude product was used directly for the next step. LCMS: 280 [M+1].

Step 3. N10-(3-chloro-2,4-difluoro-phenyl)-N4,2-dimethyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-4,10-dicarboxamide. To a solution of N,2-dimethyl-1-oxo-4,5,8,9,10,11-hexahydropyrido[2,3] pyrazolo[2,4-d][1,2,5]oxadiazepine-4-carboxamide (60.00 mg, 152.55 μmol, 1.00 eq, TFA) in DCM (3.00 mL) was added phenyl N-(3-chloro-2,4-difluoro-phenyl) carbamate (64.91 mg, 228.82 μmol, 1.50 eq) and Et3N (77.18 mg, 762.74 μmol, 105.73 μL5.00 eq). The mixture was stirred at 25° C. for 16 h. The mixture was adjusted to pH=6 with FA, filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC (FA), following by prep-TLC (DCM/MeOH=10/1) and prep-HPLC (FA) to afford (20.00 mg, 42.23 μmol, 27.68% yield, 99% purity) as white solid. LCMS [M+1]: 469/471. 1 H NMR (400 MHz, CHLOROFORM-d) δ 7.88 (dt, J=5.52, 8.97 Hz, 1H), 6.96 (ddd, J=2.13, 8.41, 9.29 Hz, 1H), 6.57 (br d, J=2.76 Hz, 1H), 6.08 (br d, J=5.02 Hz, 1H), 4.86-5.00 (m, 2H), 4.61-4.82 (m, 3H), 3.93 (td, J=5.49, 13.74 Hz, 1H), 3.72-3.82 (m, 1H), 3.34 (s, 3H), 2.80-2.94 (m, 5H).

Compounds 195, 119, and 120 were prepared in an analogous manner to Compound 118.

Compound 119: N10-(5-chloro-2,4-difluorophenyl)-N4,2-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-4,10(2H)-dicarboxamide

LCMS [M+1]: 469/471. 1 H NMR (400 MHz, CHLOROFORM-d) δ 8.18 (t, J=8.03 Hz, 1H), 6.95 (dd, J=8.41, 10.54 Hz, 1H), 6.57 (br d, J=3.14 Hz, 1H), 6.07 (br d, J=4.39 Hz, 1H), 4.87-4.99 (m, 2H), 4.64-4.77 (m, 3H), 3.92 (td, J=5.52, 13.68 Hz, 1H), 3.70-3.81 (m, 1H), 3.34 (s, 3H), 2.81-2.93 (m, 5H).

Compound 120: N10-(3-cyano-4-fluorophenyl)-N4,2-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-4,10(2H)-dicarboxamide

LCMS [M+1]: 442. 1 H NMR (400 MHz, CHLOROFORM-d) δ 7.75 (dd, J=2.76, 5.40 Hz, 1H), 7.61 (ddd, J=2.82, 4.58, 9.16 Hz, 1H), 7.14 (t, J=8.72 Hz, 1H), 6.77 (s, 1H), 6.10 (br d, J=4.89 Hz, 1H), 4.85-5.00 (m, 2H), 4.62-4.76 (m, 3H), 3.77-3.93 (m, 2H), 3.34 (s, 3H), 2.81-2.93 (m, 5H).

Compound 121_D1: (4S*,9R)—N-(3-chloro-4-fluorophenyl)-4-((2,2-difluoroethoxy)methyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

Step 1. tert-butyl (9R)-4-((2,2-difluoroethoxy)methyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxylate. To a solution of tert-butyl (9R)-4-(hydroxymethyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxylate (Intermediate 18, 700 mg, 1.91 mmol, 1.00 eq, single diastereomer separated by SFC) in DMF (5.00 mL) was added NaH (152.80 mg, 3.82 mmol, 60% purity, 2.00 eq) at −40° C. The mixture was stirred at −40° C. for 30 min. A solution of 2,2-difluoroethyl trifluoromethanesulfonate (1.23 g, 5.73 mmol, 3.00 eq) in was added dropwise at −40° C. The mixture was stirred at −20° C. for 0.5 hr. TLC (PE:ethyl acetate=1:1) showed the starting material consumed nearly and a new spot formed. The mixture was added into ice-water (50 mL) and extracted with ethyl acetate (50 mL*3). The combined organic layer was washed with H 2 O (50 mL*3), dried over Na 2 SO 4 , filtrated. The filtrate vs concentrated in vacuum. The residue was purified through column chromatography (PE:ethyl acetate: 30%˜50%) to get the title compound (580.00 mg, 1.35 mmol, 70.55% yield) as colorless oil.

Step 2. Preparation of (9R)-2-(2,2-difluoroethyl)-4-(hydroxymethyl)-9-methyl-4,5,8,9,10,11-hexahydropyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepin-1-one. To a solution of tert-butyl (9R)-2-(2,2-difluoroethyl)-4-(hydroxymethyl)-9-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxylate (440.00 mg, 1.06 mmol, 1.00 eq) in DCM (5.00 mL) was added TFA (8.06 g, 70.65 mmol, 5.23 mL, 66.86 eq). The mixture was stirred at 20° C. for 1 hr. TLC (PE:ethyl acetate=1:1) showed the starting material consumed. The mixture was concentrated in vacuum to get the title compound (460.00 mg, crude, TFA) as brown oil.

Step 3. (4S*,9R)—N-(3-chloro-4-fluorophenyl)-4-((2,2-difluoroethoxy)methyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide. To a solution of (9R)-4-(2,2-difluoroethoxymethyl)-2,9-dimethyl-4,5,8,9,10,11-hexahydropyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepin-1-one (55.00 mg, 123.78 μmol, 1.00 eq, TFA) and phenyl N-(3-chloro-4-fluoro-phenyl)carbamate (34.53 mg, 129.97 μmol, 1.05 eq) in DCM (3.00 mL) was added TEA (75.15 mg, 742.68 μmol, 102.95 μL6.00 eq) at 20° C. The mixture was stirred at 20° C. for 16 h. LCMS indicated desired product was detected. The mixture was directly concentrated in vacuo. The residue was purified by prep-HPLC (FA) to afford the title compound (42.30 mg, 82.17 μmol, 66.39% yield, 97.5% purity) as white solid. LCMS: 502 [M+1]. 1 H NMR (400 MHz, CHLOROFORM-d) δ=7.59 (dd, J=2.64, 6.53 Hz, 1H), 7.16-7.23 (m, 1H), 7.02-7.10 (m, 1H), 6.49 (s, 1H), 6.45-6.46 (m, 1H), 5.73-6.07 (m, 1H), 5.08-5.18 (m, 1H), 5.08-5.18 (m, 1H), 4.82-4.83 (m, 1H), 4.35-4.70 (m, 4H), 3.65-3.81 (m, 4H), 3.31 (s, 3H), 3.01-3.04 (m, 1H), 2.66-2.70 (m, 1H), 1.18 (d, J=6.90 Hz, 3H).

* pure but unknown stereochemistry

Compounds 108, 122, 123, 124, 125, 126, and 127 were prepared in an analogous method to Compound 121.

›PREPARATIVE EXAMPLES · 44 of 53

Compound 121_D2: (4R*,9R)—N-(3-chloro-4-fluorophenyl)-4-((2,2-difluoroethoxy)methyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS (M+1): 502. 1 H NMR (400 MHz, CHLOROFORM-d) δ=7.60 (dd, J=2.70, 6.59 Hz, 1H), 7.20 (ddd, J=2.76, 4.05, 8.88 Hz, 1H), 7.03-7.09 (m, 1H), 6.47 (s, 1H), 5.75-6.06 (m, 1H), 5.10-5.19 (m, 1H), 4.84 (d, J=15.43 Hz, 1H), 4.54-4.66 (m, 2H), 4.37-4.50 (m, 2H), 3.71-3.85 (m, 4H), 3.31 (s, 3H), 3.04 (dd, J=5.96, 15.87 Hz, 1H), 2.69 (d, J=15.94 Hz, 1H), 1.18 (d, J=6.90 Hz, 3H).

* pure but unknown stereochemistry

Compound 122_D1: (4S*,9R)—N-(3-bromo-4-fluorophenyl)-4-((2,2-difluoroethoxy)methyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LC-MS: 546/548 [M+1]. 1 H NMR (400 MHz, CHLOROFORM-d) δ=7.72 (dd, J=2.57, 6.09 Hz, 1H), 7.24-7.29 (m, 2H), 7.04 (t, J=8.47 Hz, 1H), 6.51 (br s, 1H), 5.73-6.06 (m, 1H), 5.13 (m, 1H), 4.83 (m, 1H), 4.35-4.68 (m, 4H), 3.64-3.81 (m, 4H), 3.50 (s, 1H), 3.31 (s, 3H), 3.04 (m, 1H), 2.68 (m, 1H), 1.18 (d, J=6.90 Hz, 3H).

* pure but unknown stereochemistry

Compound 122_D2: (4R*,9R)—N-(3-bromo-4-fluorophenyl)-4-((2,2-difluoroethoxy)methyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS (M+1): 546/548. 1 H NMR (400 MHz, CHLOROFORM-d) δ=7.73 (dd, J=2.64, 6.02 Hz, 1H), 7.23-7.27 (m, 1H), 7.05 (t, J=8.47 Hz, 1H), 6.45 (s, 1H), 5.74-6.06 (m, 1H), 5.14 (br t, J=6.59 Hz, 1H), 4.84 (d, J=15.56 Hz, 1H), 4.54-4.65 (m, 2H), 4.37-4.50 (m, 2H), 3.71-3.85 (m, 4H), 3.31 (s, 3H), 3.04 (dd, J=6.09, 16.12 Hz, 1H), 2.69 (d, J=16.31 Hz, 1H), 1.18 (d, J=6.90 Hz, 3H).

* pure but unknown stereochemistry

Compound 123_D1: (4S*,9R)—N-(2-bromo-3-fluoropyridin-4-yl)-4-((2,2-difluoroethoxy)methyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LC-MS: 547/549 [M+1]. 1 H NMR (400 MHz, CHLOROFORM-d) δ=8.02-8.21 (m, 2H), 6.99 (br s, 1H), 5.73-6.07 (m, 1H), 4.85-5.10 (m, 2H), 4.39-4.66 (m, 4H), 3.64-3.81 (m, 4H), 3.31 (s, 3H), 3.00-3.13 (m, 1H), 2.72 (br d, J=15.94 Hz, 1H), 1.23 (d, J=6.78 Hz, 3H).

* pure but unknown stereochemistry

Compound 123_D2: (4R*,9R)—N-(2-bromo-3-fluoropyridin-4-yl)-4-((2,2-difluoroethoxy)methyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS (M+1): 547/549. 1 H NMR (400 MHz, CHLOROFORM-d) δ=8.14-8.18 (m, 1H), 8.07 (d, J=5.52 Hz, 1H), 6.95 (br d, J=3.89 Hz, 1H), 5.74-6.07 (m, 1H), 5.07 (m, 1H), 4.92 (m, 1H), 4.35-4.66 (m, 4H), 3.69-3.87 (m, 4H), 3.31 (s, 3H), 3.06 (m, 1H), 2.73 (d, J=15.94 Hz, 1H), 1.23 (d, J=6.90 Hz, 3H.

* pure but unknown stereochemistry

Compound 124_D1: (4S*,9R)—N-(3-cyano-4-fluorophenyl)-4-((2,2-difluoroethoxy)methyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LC-MS: 493 [M+1]. 1 H NMR (400 MHz, CHLOROFORM-d) δ=7.77 (dd, J=2.76, 5.52 Hz, 1H), 7.59 (ddd, J=2.82, 4.55, 9.07 Hz, 1H), 7.14 (t, J=8.72 Hz, 1H), 6.71 (s, 1H), 5.71-6.08 (m, 1H), 5.06-5.19 (m, 1H), 4.85 (d, J=15.69 Hz, 1H), 4.36-4.69 (m, 4H), 3.62-3.85 (m, 4H), 3.31 (s, 3H), 3.04 (dd, J=5.77, 15.94 Hz, 1H), 2.69 (d, J=15.81 Hz, 1H), 1.19 (d, J=6.90 Hz, 3H).

* pure but unknown stereochemistry

Compound 124_D2: (4R*,9R)—N-(3-cyano-4-fluorophenyl)-4-((2,2-difluoroethoxy)methyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS (M+1): 493. 1 H NMR (400 MHz, CHLOROFORM-d) δ=7.79 (dd, J=2.76, 5.40 Hz, 1H), 7.59 (m, 1H), 7.11-7.18 (m, 1H), 6.64 (s, 1H), 5.74-6.06 (m, 1H), 5.15 (br t, J=6.21 Hz, 1H), 4.86 (d, J=15.43 Hz, 1H), 4.37-4.66 (m, 4H), 3.70-3.86 (m, 4H), 3.31 (s, 3H), 3.04 (dd, J=5.83, 15.75 Hz, 1H), 2.70 (d, J=16.31 Hz, 1H), 1.19 (d, J=6.90 Hz, 3H).

* pure but unknown stereochemistry

Compound 125_D1: (4S*,9R)-4-((2,2-difluoroethoxy)methyl)-N-(4-fluoro-3-methylphenyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LC-MS: 482 [M+1]. 1 H NMR (400 MHz, CHLOROFORM-d) δ=7.25 (br d, J=2.51 Hz, 1H), 7.08-7.14 (m, 1H), 6.93 (t, J=8.97 Hz, 1H), 6.38 (s, 1H), 5.74-6.07 (m, 1H), 5.14 (quin, J=6.40 Hz, 1H), 4.83 (d, J=15.69 Hz, 1H), 4.38-4.68 (m, 4H), 3.63-3.84 (m, 4H), 3.50 (s, 1H), 3.31 (s, 3H), 3.04 (dd, J=5.83, 15.87 Hz, 1H), 2.67 (d, J=15.81 Hz, 1H), 2.26 (d, J=1.63 Hz, 3H), 1.18 (d, J=6.90 Hz, 3H).

* pure but unknown stereochemistry

Compound 125_D2: (4R*,9R)-4-((2,2-difluoroethoxy)methyl)-N-(4-fluoro-3-methylphenyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS (M+1): 482. 1 H NMR (400 MHz, CHLOROFORM-d) δ=7.26 (d, J=2.89 Hz, 1H), 7.11 (td, J=3.87, 8.19 Hz, 1H), 6.89-6.96 (m, 1H), 6.37 (s, 1H), 5.74-6.06 (m, 1H), 5.15 (m, J=6.34 Hz, 1H), 4.85 (d, J=15.56 Hz, 1H), 4.54-4.66 (m, 2H), 4.36-4.50 (m, 2H), 3.71-3.85 (m, 4H), 3.31 (s, 3H), 3.04 (dd, J=5.84, 16.00 Hz, 1H), 2.68 (d, J=16.06 Hz, 1H), 2.26 (d, J=1.76 Hz, 3H), 1.17 (d, J=6.90 Hz, 3H).

* pure but unknown stereochemistry

Compound 126_D1: (4S*,9R)-4-((2,2-difluoroethoxy)methyl)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LC-MS: 536 [M+1]. 1 H NMR (400 MHz, CHLOROFORM-d) δ=7.68 (dd, J=2.70, 6.09 Hz, 1H), 7.56-7.62 (m, 1H), 7.13 (t, J=9.41 Hz, 1H), 6.61 (s, 1H), 5.72-6.11 (m, 1H), 5.15 (quin, J=6.43 Hz, 1H), 4.85 (d, J=15.56 Hz, 1H), 4.36-4.70 (m, 4H), 3.65-3.83 (m, 4H), 3.31 (s, 3H), 3.05 (dd, J=5.84, 15.87 Hz, 1H), 2.69 (d, J=15.81 Hz, 1H), 1.19 (d, J=6.90 Hz, 3H).

* pure but unknown stereochemistry

Compound 126_D2: (4R*,9R)-4-((2,2-difluoroethoxy)methyl)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS (M+1): 536. 1 H NMR (400 MHz, CHLOROFORM-d) δ=7.69 (dd, J=2.82, 6.21 Hz, 1H), 7.56-7.62 (m, 1H), 7.14 (t, J=9.29 Hz, 1H), 6.59 (s, 1H), 5.75-6.06 (m, 1H), 5.16 (m, J=6.78 Hz, 1H), 4.87 (d, J=15.56 Hz, 1H), 4.54-4.66 (m, 2H), 4.38-4.52 (m, 2H), 3.71-3.85 (m, 4H), 3.31 (s, 3H), 3.04 (dd, J=5.65, 15.81 Hz, 1H), 2.70 (d, J=16.19 Hz, 1H), 1.19 (d, J=6.90 Hz, 3H).

›PREPARATIVE EXAMPLES · 45 of 53

* pure but unknown stereochemistry

Compound 127_D1: (45*,9R)—N-(5-chloro-2,4-difluorophenyl)-4-((2,2-difluoroethoxy)methyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LC-MS: 520 [M+1]. 1 H NMR (400 MHz, CHLOROFORM-d) δ=8.19 (t, J=8.09 Hz, 1H), 6.95 (dd, J=8.47, 10.60 Hz, 1H), 6.55 (br d, J=2.76 Hz, 1H), 5.64-6.18 (m, 1H), 4.79-5.25 (m, 2H), 4.34-4.67 (m, 4H), 3.59-3.86 (m, 4H), 3.26-3.41 (m, 3H), 3.05 (dd, J=5.77, 15.81 Hz, 1H), 2.70 (d, J=15.81 Hz, 1H), 1.21 (d, J=6.90 Hz, 3H).

* pure but unknown stereochemistry

Compound 127_D2: (4R*,9R)—N-(5-chloro-2,4-difluorophenyl)-4-((2,2-difluoroethoxy)methyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS (M+1): 520/522. 1 H NMR (400 MHz, CHLOROFORM-d) δ=8.20 (t, J=8.09 Hz, 1H), 6.95 (dd, J=8.41, 10.54 Hz, 1H), 6.53 (br d, J=2.76 Hz, 1H), 5.74-6.06 (m, 1H), 5.06-5.14 (m, 1H), 4.88 (d, J=15.69 Hz, 1H), 4.37-4.63 (m, 4H), 3.71-3.85 (m, 4H), 3.31 (s, 3H), 3.05 (dd, J=5.83, 16.12 Hz, 1H), 2.71 (d, J=15.94 Hz, 1H), 1.20 (d, J=6.90 Hz, 3H).

* pure but unknown stereochemistry

Compound 128: N-(3-chloro-4-fluorophenyl)-2-methyl-1-oxo-4-((trifluoromethoxy)methyl)-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

Step 1 tert-butyl 2-methyl-1-oxo-4-(trifluoromethoxymethyl)-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyraz-olo[2,4-d][1,2,5]oxadiazepine-10-carboxylate. To a reaction bottle, AgOTf (192.50 mg, 749.19 μmol, 3.00 eq), Select Fluor® (301.60 mg, 851.36 μmol, 1.50 eq), KF (131.90 mg, 2.27 mmol, 53.19 μL4.00 eq), tert-butyl 4-(hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxylate (Intermediate 1, 200.00 mg, 567.57 μmol, 1.00 eq) were added successively in a nitrogen-filled glovebox. Then EtOAc (6.00 mL), 2-fluoropyridine (165.32 mg, 1.70 mmol, 146.30 μL3.00 eq) and TMSCF 3 (242.12 mg, 1.70 mmol, 3.00 eq) were added successively under N 2 atmosphere. The reaction mixture was stirred at 20° C. for 16 h. Several peaks showed on LCMS and 23% starting material remained and 13% desired product detected. The mixture was extracted with EtOAc (20 mL*2) and H 2 O (20 mL). The combined organic layer was dried over Na 2 SO 4 , filtrated. The filtrate was concentrated in vacuum. The residue was purified by prep-HPLC (FA) to get the title compound (30.00 mg, 71.36 μmol, 12.57% yield) as white solid.

Step 2. N-(3-chloro-4-fluoro-phenyl)-2-methyl-1-oxo-4-(trifluoromethoxymethyl)-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxamide. To a solution of tert-butyl 2-methyl-1-oxo-4-(trifluoromethoxymethyl)-5,8,9,11-tetra hydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxylate (45.00 mg, 107.05 μmol, 1.00 eq) in DCM (5.00 mL) was added TFA (5.00 mL). The mixture was stirred at 20° C. for 5 hr. TLC (PE:EtOAc=0:1) showed the starting material consumed. The mixture was concentrated in vacuum to get 2-methyl-4-(trifluoromethoxymethyl)-4,5,8,9,10,11-hexahydropyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepin-1-one (48.00 mg, crude, TFA) as brown oil. To a solution of 2-methyl-4-(trifluoromethoxymethyl)-4,5,8,9,10,11-hexaHydropyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepin-1-one (48.00 mg, 110.53 μmol, 1.00 eq, TFA) in DCM (3.00 mL) was added TEA (55.92 mg, 552.63 μmol, 76.60 μL5.00 eq) followed by phenyl N-(3-chloro-4-fluoro-phenyl)carbamate (35.24 mg, 132.64 μmol, 1.20 eq). The mixture was stirred at 20° C. for 16 hr. LCMS showed one main peak with desired MS detected. The mixture was concentrated in vacuum. The residue was purified by prep-HPLC (FA), repurified by prep-TLC (PE:EtOAc=1:1), further purification by prep-HPLC (base) to get the title compound (28.00 mg, 56.31 μmol, 50.94% yield, 98.9% purity) as white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ=7.59 (dd, J=2.69, 6.48 Hz, 1H), 7.18-7.25 (m, 1H), 7.03-7.11 (m, 1H), 6.61 (s, 1H), 4.68-4.78 (m, 3H), 4.59-4.67 (m, 1H), 4.39 (dd, J=6.60, 14.43 Hz, 1H), 4.14-4.22 (m, 1H), 4.05-4.13 (m, 1H), 3.80-3.94 (m, 2H), 3.32 (s, 3H), 2.88 (t, J=5.75 Hz, 2H)

LCMS: 492 [M+1].

Compound 129: N-(3-chloro-4-fluorophenyl)-4-(ethylsulfonamidomethyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

Compound 129 was prepared in an analogous manner to Compound 208.

LCMS: 527 [M+1]. 1 H NMR (400 MHz, DMSO-d 6 ) δ=8.90 (s, 1H), 7.72 (dd, J=2.57, 6.85 Hz, 1H), 7.48 (br s, 1H), 7.41 (ddd, J=2.69, 4.28, 9.05 Hz, 1H), 7.24-7.33 (m, 1H), 4.58-4.68 (m, 3H), 4.51 (quin, J=6.39 Hz, 1H), 4.29 (dd, J=7.40, 14.37 Hz, 1H), 3.66-3.82 (m, 2H), 3.24 (s, 5H), 2.72 (br t, J=5.38 Hz, 2H), 2.60-2.66 (m, 1H), 0.88-1.00 (m, 4H).

Compound 130: N-(3-chloro-4-fluorophenyl)-2-methyl-1-oxo-4-(((2,2,2-trifluoroethyl)sulfonamido)methyl)-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

Compound 130 was prepared in an analogous manner to Compound 208.

LCMS: 569 [M+1]. 1 H NMR (400 MHz, DMSO-d 6 ) δ=8.90 (s, 1H), 7.72 (dd, J=2.51, 6.78 Hz, 1H), 7.41 (td, J=4.36, 7.22 Hz, 1H), 7.25-7.31 (m, 1H), 4.58-4.65 (m, 3H), 4.44-4.57 (m, 3H), 4.29 (dd, J=6.96, 14.24 Hz, 1H), 3.70-3.79 (m, 2H), 3.28-3.30 (m, 2H), 3.24 (s, 3H), 2.72 (br t, J=5.58 Hz, 2H), 2.70-2.76 (m, 1H)

Compound 131: N-(3-chloro-4-fluorophenyl)-4-(3,3-difluoroazetidine-1-carbonyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

Step 1. methyl 2-methyl-1-oxo-4,5,8,9,10,11-hexahydropyrido[2,3]pyrazolo [2,4-d][1,2,5]oxadiazepine-4-carboxylate. To a solution of 10-(tert-butyl) 4-methyl 2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-4,10(2H)-dicarboxylate (Intermediate 22, 1.00 g, 2.63 mmol, 1.00 eq) in DCM (40.00 mL) was added TFA (135.08 mmol, 10.00 mL, 51.36 eq). The mixture was stirred at 10° C. for 1 hr. TLC(PE:ethyl acetate=0:1) showed the starting material consumed. The mixture was concentrated in vacuum to get the title compound (1.10 g, crude, TFA) as brown oil.

›PREPARATIVE EXAMPLES · 46 of 53

Step 2. methyl 10-[(3-chloro-4-fluoro-phenyl)carbamoyl]-2-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-4-carboxylate. To a mixture of methyl 2-methyl-1-oxo-4,5,8,9,10,11-hexahydropyrido[2,3]pyrazolo [2,4-d][1,2,5]oxadiazepine-4-carboxylate (1.10 g, 2.79 mmol, 1.00 eq, TFA) and phenyl N-(3-chloro-4-fluoro-phenyl)carbamate (741.15 mg, 2.79 mmol, 1.00 eq) in DCM (20.00 mL) was added TEA (1.41 g, 13.95 mmol, 1.93 mL, 5.00 eq). The mixture was heated to 20° C. for 16 hr. LCMS showed one main peak with desired MS was detected and TLC (PE: ethyl acetate=0:1) showed two spots formed. The mixture was diluted with H 2 O (30 mL). The organic phase was dried over Na 2 SO 4 , filtrated and concentrated in vacuum. The residue was purified by flash chromatography (PE:ethyl acetate: 50%˜80%) to get the title compound (1.00 g, 2.21 mmol, 79.33% yield) as white solid.

Step 3. 10-[(3-chloro-4-fluoro-phenyl)carbamoyl]-2-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-4-carboxylic acid. To a solution of methyl 10-[(3-chloro-4-fluoro-phenyl)carbamoyl]-2-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-4-carboxylate (900.00 mg, 1.99 mmol, 1.00 eq) in DCE (10.00 mL) was added hydroxy(trimethyl)stannane (1.44 g, 7.96 mmol, 4.00 eq). The mixture was stirred at 50° C. for 16 hr. TLC (PE:ethyl acetate=0:1) showed the starting material consumed. The mixture was diluted with DCM (100 mL) and quenched by a aqueous solution of KF (500 mg, 5 mL). The mixture was dried over Na 2 SO 4 and filtrated. The filtrate was concentrated in vacuum to get the title compound (700.00 mg, 1.60 mmol, 80.35% yield) as white solid.

Step 4. N-(3-chloro-4-fluoro-phenyl)-4-(3,3-difluoroazetidine-1-carbonyl)-2-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxamide. To a solution of 10-[(3-chloro-4-fluoro-phenyl)carbamoyl]-2-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-4-carboxylic acid (80.00 mg, 182.73 μmol, 1.00 eq) in DMF (3.00 mL) was added 3,3-difluoroazetidine hydrochloride (94.68 mg, 730.92 μmol, 4.00 eq), followed by DIEA (296.00 mg, 2.29 mmol, 400.00 μL12.53 eq), PyBOP (142.64 mg, 274.09 μmol, 1.50 eq) and HOBt (24.69 mg, 182.73 μmol, 1.00 eq). The mixture was stirred at 20° C. for 16 h. The mixture was diluted with 0.5 M HCl (30 mL) and extracted with ethyl acetate (20 mL*2), then washed with NaHCO 3 (30 mL). The combined organic was dried over Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by prep-TLC (DCM:MeOH=15:1), followed by prep-HPLC (FA) to get the title compound (15.50 mg, 30.04 μmol, 16.44% yield, 99.4% purity) as white solid. LCMS [M+1]: 513. 1 H NMR (400 MHz, CHLOROFORM-d) δ=7.54-7.59 (m, 1H), 7.17-7.23 (m, 1H), 7.06 (s, 1H), 6.50-6.54 (m, 1H), 4.86-5.02 (m, 2H), 4.62-4.77 (m, 3H), 4.33-4.61 (m, 4H), 3.85 (s, 2H), 3.31 (s, 3H), 2.88 (br s, 2H).

Compounds 132, 134, 135, and 136 were prepared in an analogous manner to Compound 131.

Compound 132: N-(3-chloro-4-fluorophenyl)-4-(3,3-difluoropyrrolidine-1-carbonyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS [M+1]: 527. 1 H NMR (400 MHz, CHLOROFORM-d) δ=7.55-7.59 (m, 1H), 7.19 (br s, 1H), 7.03-7.09 (m, 1H), 6.55 (s, 1H), 4.96-5.06 (m, 1H), 4.88-4.95 (m, 1H), 4.72-4.84 (m, 2H), 4.60-4.69 (m, 2H), 3.97-4.17 (m, 1H), 3.74-3.96 (m, 5H), 3.24 (s, 3H), 2.87 (br d, J=5.6 Hz, 2H), 2.36-2.61 (m, 2H).

Compound 133: N10-(3-chloro-4-fluorophenyl)-N4,2-dimethyl-1-oxo-N4-(2,2,2-trifluoroethyl)-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-4,10(2H)-dicarboxamide

To a mixture of 10-[(3-chloro-4-fluoro-phenyl)carbamoyl]-2-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-4-carboxylic acid (80.00 mg, 182.73 μmol, 1.00 eq), 2,2,2-trifluoro-N-methyl-ethanamine (27.33 mg, 182.73 μmol, 1.00 eq, HCl) and 3-picoline (51.05 mg, 548.18 μmol, 53.18 μL3.00 eq) in MeCN (5.00 mL) was added MsCl (29.30 mg, 255.82 μmol, 19.80 μL1.40 eq) dropwise at 0° C. under N 2 , and then the mixture was stirred at 20° C. for 0.5 hour under N 2 atmosphere. LCMS showed the starting material was consumed completely and major desired product formed. The mixture was poured into water (10 mL) and extracted with ethyl acetate (5 mL). The organic layer was washed with brine (10 mL), dried with anhydrous Na 2 SO 4 , filtered and concentrated in vacuum. The residue was purified by prep-HPLC to give the title compound (42.00 mg, 78.03 μmol, 42.70% yield, 99% purity) as a white solid. LCMS [M+1]: 533. 1 H NMR (400 MHz, CHLOROFORM-d) δ=7.55-7.60 (m, 1H), 7.16-7.22 (m, 1H), 7.03-7.09 (m, 1H), 6.51 (s, 1H), 4.94-5.10 (m, 2H), 4.75 (s, 1H), 4.49-4.70 (m, 3H), 3.86 (s, 3H), 3.16-3.37 (m, 6H), 2.88 (d, J=6.02 Hz, 2H).

Compound 134: N10-(3-chloro-4-fluorophenyl)-N4-(2,2-difluoroethyl)-N4,2-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-4,10(2H)-dicarboxamide

LCMS [M+1]: 515. 1 H NMR (400 MHz, CHLOROFORM-d) δ=7.54-7.61 (m, 1H), 7.16-7.23 (m, 1H), 7.06 (s, 1H), 6.55 (s, 1H), 6.04 (s, 1H), 5.03 (s, 2H), 4.74 (s, 1H), 4.65 (s, 2H), 3.93-4.15 (m, 1H), 3.86 (br t, J=5.7 Hz, 2H), 3.51-3.71 (m, 1H), 3.15-3.34 (m, 6H), 2.88 (br d, J=5.7 Hz, 2H).

Compound 135: N10-(3-chloro-4-fluorophenyl)-2-methyl-1-oxo-N4-(2,2,2-trifluoroethyl)-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-4,10(2H)-dicarboxamide

LCMS [M+1]: 519. 1 H NMR (400 MHz, CHLOROFORM-d) δ=7.54-7.58 (m, 1H), 7.17-7.23 (m, 1H), 7.07 (s, 1H), 6.47-6.52 (m, 1H), 6.34-6.41 (m, 1H), 4.95 (s, 2H), 4.72 (d, J=2.3 Hz, 3H), 3.78-4.04 (m, 4H), 3.35 (s, 3H), 2.86 (t, J=5.7 Hz, 2H).

Compound 136: N10-(3-chloro-4-fluorophenyl)-N4-(2,2-difluoroethyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-4,10(2H)-dicarboxamide

LCMS [M+1]: 501. 1 H NMR (400 MHz, CHLOROFORM-d) δ 7.57 (dd, J=2.63, 6.54 Hz, 1H), 7.18-7.25 (m, 1H), 7.04-7.11 (m, 1H), 6.57 (s, 1H), 6.37 (br t, J=6.17 Hz, 1H), 5.68-6.02 (m, 1H), 4.88-4.98 (m, 2H), 4.67-4.77 (m, 3H), 3.85 (t, J=5.81 Hz, 2H), 3.58-3.78 (m, 2H), 3.36 (s, 3H), 2.87 (t, J=5.75 Hz, 2H), 2.19 (s, 1H).

›PREPARATIVE EXAMPLES · 47 of 53

Compound 138_E1: (S*)—N-(3-chloro-2,6-difluorophenyl)-4-(hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

Step 1. 4-(hydroxymethyl)-2-methyl-4,5,8,9,10,11-hexahydropyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepin-1-one. A mixture of tert-butyl 4-(hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxylate (Intermediate 1, 320.00 mg, 908.08 μmol, 1.00 eq, sing enantiomer separated by SFC) in DCM (10.00 mL) was added TFA (7.70 g, 67.53 mmol, 5.00 mL, 74.37 eq) dropwise at 0° C., and then the mixture was stirred at 30° C. for 1 hour. TLC and LCMS showed the starting material was consumed completely, desired product was major. The mixture was concentrated in vacuum to give the title compound (332.60 mg, 908.02 μmol, 99.99% yield, TFA) as a yellow oil, which was used directly for next step.

Step 2. N-(3-chloro-2,6-difluoro-phenyl)-4-(hydroxymethyl)-2-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxamide. A mixture of 4-(hydroxymethyl)-2-methyl-4,5,8,9,10,11-hexahydropyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepin-1-one (40.00 mg, 109.20 μmol, 1.00 eq, TFA), phenyl N-(3-chloro-2,6-difluoro-phenyl)carbamate (34.07 mg, 120.12 μmol, 1.10 eq), TEA (22.10 mg, 218.40 μmol, 30.27 μL2.00 eq) in DCM (3.00 mL) was degassed and purged with N 2 for 3 times, and then the mixture was stirred at 30° C. for 16 hour under N 2 atmosphere. LCMS showed the starting material was consumed completely, desired product was major. The mixture was poured into water (10 mL) and extracted with DCM (5 mL*3). The combined organic phase was washed with brine (10 mL), dried with anhydrous Na 2 SO 4 , filtered and concentrated in vacuum. The residue was purified by Prep-HPLC (FA) to afford the title compound (25.00 mg, 56.58 μmol, 51.82% yield, 100% purity) as a white solid.

Compounds 137, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, and 151 were prepared in an analogous method to Compound 138.

Compound 137_E1: (S*)—N-(3-chloro-2,4,5-trifluorophenyl)-4-(hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS: 460/462 [M+1]. 1 H NMR (400 MHz, CHLOROFORM-d) δ 7.95-8.05 (m, 1H), 6.64-6.70 (m, 1H), 4.74 (d, J=3.01 Hz, 2H), 4.50-4.63 (m, 2H), 4.37-4.48 (m, 1H), 3.72-3.94 (m, 4H), 3.33 (s, 3H), 2.88 (s, 2H).

* pure but unknown stereochemistry

Compound 138_E1: (S*)—N-(3-chloro-2,6-difluorophenyl)-4-(hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS: 442/444 [M+1]. 1 H NMR (400 MHz, CHLOROFORM-d) δ 7.17-7.25 (m, 1H), 6.91 (br d, J=1.83 Hz, 1H), 6.08-6.16 (m, 1H), 4.79 (s, 2H), 4.56 (br d, J=12.59 Hz, 2H), 4.43 (s, 1H), 3.73-3.97 (m, 4H), 3.32 (s, 3H), 2.88 (t, J=5.69 Hz, 1H), 2.84-2.92 (m, 1H).

* pure but unknown stereochemistry

Compound 139_E1: (S*)—N-(5-chloro-2-fluorophenyl)-4-(hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS: 424/426 [M+1]. 1 H NMR (400 MHz, CHLOROFORM-d) δ 8.14-8.19 (m, 1H), 6.90-7.04 (m, 2H), 6.68-6.73 (m, 1H), 4.74 (s, 2H), 4.55 (br d, J=13.18 Hz, 2H), 4.37-4.47 (m, 1H), 3.71-3.95 (m, 4H), 3.33 (s, 3H), 2.88 (t, J=5.77 Hz, 2H).

* pure but unknown stereochemistry

Compound 140_E1: (S*)—N-(5-bromo-2,3-difluorophenyl)-4-(hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS: 486/488 [M+1]. 1 H NMR (400 MHz, CHLOROFORM-d) δ 8.10 (br s, 1H), 6.97-7.05 (m, 1H), 6.69-6.76 (m, 1H), 4.75 (s, 2H), 4.55 (br d, J=13.45 Hz, 2H), 4.43 (s, 1H), 3.72-3.95 (m, 4H), 3.33 (s, 3H), 2.88 (t, J=5.75 Hz, 2H), 1.53-1.64 (m, 1H).

* pure but unknown stereochemistry

Compound 141_E1: (S*)—N-(5-bromo-2-fluorophenyl)-4-(hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS: 468/470 [M+1]. 1 H NMR (400 MHz, CHLOROFORM-d) δ 8.29-8.34 (m, 1H), 7.06-7.13 (m, 1H), 6.91-6.98 (m, 1H), 6.66-6.72 (m, 1H), 4.74 (s, 2H), 4.51-4.62 (m, 2H), 4.37-4.46 (m, 1H), 3.72-3.96 (m, 4H), 3.33 (s, 3H), 2.88 (s, 2H).

* pure but unknown stereochemistry

Compound 142_E1: (S*)—N-(2,4-difluoro-3-methylphenyl)-4-(hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS: 422 [M+1]. 1 H NMR (400 MHz, CHLOROFORM-d) δ 7.69-7.79 (m, 1H), 6.77-6.86 (m, 1H), 6.48-6.55 (m, 1H), 4.74 (s, 2H), 4.51-4.61 (m, 2H), 4.36-4.46 (m, 1H), 3.73-3.93 (m, 4H), 3.33 (s, 3H), 2.83-2.90 (m, 2H), 2.21 (s, 3H).

* pure but unknown stereochemistry

Compound 143_E1: (S*)—N-(2,4-difluoro-5-methylphenyl)-4-(hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS: 422 [M+1]. 1 H NMR (400 MHz, CHLOROFORM-d) δ 7.75-7.81 (m, 1H), 6.76-6.84 (m, 1H), 6.49 (br d, J=2.51 Hz, 1H), 4.73 (s, 2H), 4.50-4.62 (m, 2H), 4.37-4.47 (m, 1H), 3.86 (br d, J=14.81 Hz, 4H), 3.32 (s, 3H), 2.87 (t, J=5.71 Hz, 2H), 2.22 (s, 3H), 2.00-2.15 (m, 1H).

* pure but unknown stereochemistry

Compound 144_E1: (S*)-4-(hydroxymethyl)-2-methyl-1-oxo-N-(2,4,5-trifluoro-3-methylphenyl)-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS: 440 [M+1]. 1 H NMR (400 MHz, CHLOROFORM-d) δ 7.78-7.89 (m, 1H), 6.57-6.63 (m, 1H), 4.73 (s, 2H), 4.51-4.62 (m, 2H), 4.37-4.47 (m, 1H), 3.71-3.94 (m, 4H), 3.33 (s, 3H), 2.87 (s, 2H), 2.24 (t, J=1.90 Hz, 2H), 2.20-2.28 (m, 1H).

* pure but unknown stereochemistry

Compound 145_E1: (S*)—N-(5-cyano-2-fluorophenyl)-4-(hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS: 415 [M+1]. 1 H NMR (400 MHz, CHLOROFORM-d) δ 8.29-8.36 (m, 1H), 7.41-7.46 (m, 1H), 7.35-7.40 (m, 1H), 6.91-6.95 (m, 1H), 4.77 (s, 2H), 4.50-4.64 (m, 2H), 4.37-4.48 (m, 1H), 3.72-3.96 (m, 4H), 3.33 (s, 3H), 2.89 (t, J=5.75 Hz, 2H), 1.84-1.92 (m, 1H).

›PREPARATIVE EXAMPLES · 48 of 53

* pure but unknown stereochemistry

Compound 146_E1: (S*)—N-(3-cyano-2-fluorophenyl)-4-(hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS: 415 [M+1]. 1 H NMR (400 MHz, CHLOROFORM-d) δ 8.32-8.38 (m, 1H), 7.24-7.27 (m, 1H), 7.18-7.24 (m, 1H), 6.70-6.83 (m, 1H), 4.77 (s, 2H), 4.50-4.63 (m, 2H), 4.37-4.47 (m, 1H), 3.73-3.97 (m, 4H), 3.33 (s, 3H), 2.89 (t, J=5.75 Hz, 2H).

* pure but unknown stereochemistry

Compound 147_E1: (S*)—N-(2,4-difluoro-5-(trifluoromethyl)phenyl)-4-(hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS: 476 [M+1]. 1 H NMR (400 MHz, CHLOROFORM-d) δ 8.35-8.42 (m, 1H), 6.95-7.05 (m, 1H), 6.59-6.67 (m, 1H), 4.75 (s, 2H), 4.56 (br d, J=12.23 Hz, 2H), 4.36-4.47 (m, 1H), 3.72-3.97 (m, 4H), 3.33 (s, 3H), 2.88 (t, J=5.75 Hz, 2H).

* pure but unknown stereochemistry

Compound 148_E1: (S*)—N-(2-fluoro-5-(trifluoromethyl)phenyl)-4-(hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS: 458 [M+1]. 1 H NMR (400 MHz, CHLOROFORM-d) δ 8.47 (dd, J=2.01, 7.28 Hz, 1H), 7.24-7.27 (m, 1H), 7.14-7.21 (m, 1H), 6.80 (br d, J=3.76 Hz, 1H), 4.76 (s, 2H), 4.51-4.62 (m, 2H), 4.38-4.47 (m, 1H), 3.72-3.97 (m, 4H), 3.33 (s, 3H), 2.85-2.93 (m, 2H).

* pure but unknown stereochemistry

Compound 149_E1: (S*)—N-(2,4-difluoro-3-(trifluoromethyl)phenyl)-4-(hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS: 476 [M+1]. 1 H NMR (400 MHz, CHLOROFORM-d) δ 8.17-8.26 (m, 1H), 6.95-7.03 (m, 1H), 6.62-6.68 (m, 1H), 4.75 (d, J=2.13 Hz, 2H), 4.56 (br d, J=12.93 Hz, 2H), 4.43 (s, 1H), 3.73-3.94 (m, 4H), 3.33 (s, 3H), 2.88 (s, 2H).

* pure but unknown stereochemistry

Compound 150_E1: (S*)—N-(2-bromo-5-fluoropyridin-4-yl)-4-(hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS: 469/471 [M+1]. 1 H NMR (400 MHz, CHLOROFORM-d) δ 8.38-8.43 (m, 1H), 8.14 (d, J=2.13 Hz, 1H), 6.94-7.00 (m, 1H), 4.75 (d, J=3.26 Hz, 2H), 4.51-4.63 (m, 2H), 4.43 (br d, J=9.16 Hz, 1H), 3.72-3.96 (m, 4H), 3.33 (s, 3H), 2.89 (t, J=5.83 Hz, 2H).

* pure but unknown stereochemistry

Compound 151_E1: (S*)-4-(hydroxymethyl)-2-methyl-1-oxo-N-(2,3,4,5-tetrafluorophenyl)-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS: 444 [M+1]. 1 H NMR (400 MHz, CHLOROFORM-d) δ 7.80-7.90 (m, 1H), 6.65 (br s, 1H), 4.74 (d, J=3.14 Hz, 2H), 4.51-4.62 (m, 2H), 4.38-4.48 (m, 1H), 3.85 (br d, J=5.65 Hz, 4H), 3.33 (s, 3H), 2.88 (t, J=5.83 Hz, 2H).

* pure but unknown stereochemistry

Compound 152_D1: (4S*,9R)—N10-(3-chloro-2,4-difluorophenyl)-N4-(2,2-difluoroethyl)-N4,2,9-trimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-4,10(2H)-dicarboxamide

Step 1. (9R)-10-tert-butoxycarbonyl-2,9-dimethyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-4-carboxylic acid. To a solution of tert-butyl (9R)-4-(hydroxymethyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxylate (Intermediate 18, 500.00 mg, 1.36 mmol, 1.00 eq, diastereomer separated by SFC) and NMO (1.19 g, 10.20 mmol, 1.08 mL, 7.50 eq) in MeCN (10.00 mL) was added TPAP (119.49 mg, 340.00 μmol, 0.25 eq). The mixture was stirred at 30° C. for 12 hr. LCMS showed the starting material was consumed completely, desired product was major. The mixture was poured into water (20 mL) and washed with tert-butyl methyl ether (10 mL), the aqueous layer was acidified by 0.5 N HCl to pH 3, extracted with DCM (20 mL*2), the organic layer was washed with brine (10 mL), dried over anhydrous Na 2 SO 4 and concentrated in vacuum to give the title compound (520.00 mg, crude) as a black brown solid. LCMS: 381[M+1].

Step 2. tert-butyl (9R)-4-[2,2-di fluoroethyl(methyl)carbamoyl]-2,9-dimethyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxylate. To a mixture of (9R)-10-tert-butoxycarbonyl-2,9-dimethyl-1-oxo-5,8,9,11-tetra hydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-4-carboxylic acid (250.00 mg, 657.22 μmol, 1.00 eq), 2,2-difluoro-N-methyl-ethanamine (172.91 mg, 1.31 mmol, 2.00 eq, HCl), 3-picoline (183.62 mg, 1.97 mmol, 191.27 μL3.00 eq) in MeCN (5.00 mL) was added MsCl (112.93 mg, 985.83 μmol, 76.30 μL1.50 eq) dropwise at 0° C. under N 2 , and then the mixture was stirred at 30° C. for 2 hour under N 2 atmosphere. LCMS showed the starting material was consumed completely, desired product was major. The mixture was poured into water (10 mL) and stirred at 5 min. The aqueous phase was extracted with DCM (5 mL*3). The combined organic phase was washed with brine (20 mL), dried with anhydrous Na 2 SO 4 , filtered and concentrated in vacuum. The residue was purified by column chromatography (SiO 2 , Petroleum ether/Ethyl acetate=100/1 to 1/2) to give the title compound (244.00 mg, 517.37 μmol, 78.72% yield, 97% purity) as a white solid. LCMS: 458[M+1].

Step 3. (9R)—N-(2,2-difluoroethyl)-N,2,9-trimethyl-1-oxo-4,5,8,9,10,11-hexahydropyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-4-carboxamide. A solution of tert-butyl (9R)-4-[2,2-difluoroethyl(methyl)carbamoyl]-2,9-dimethyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxylate (180.00 mg, 393.47 μmol, 1.00 eq) in DCM (2.00 mL) was added TFA (1.85 g, 16.21 mmol, 1.20 mL, 41.19 eq), and then the mixture was stirred at 30° C. for 1 hour. TLC showed the starting material was consumed completely, a new spot appeared. The mixture was concentrated in vacuum to give the title compound (185.47 mg, 393.46 μmol, 100.00% yield, TFA) as a yellow oil, which was used directly for next step.

Step 4. (9R)—N10-(3-chloro-2,4-difluoro-phenyl)-N4-(2,2-difluoro ethyl)-N4,2,9-trimethyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-4,10-dicarboxamide. To a mixture of (9R)—N-(2,2-difluoroethyl)-N,2,9-trimethyl-1-oxo-4,5,8,9,10,11-hexahydropyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-4-carboxamide (60.00 mg, 127.29 μmol, 1.00 eq, TFA), phenyl N-(3-chloro-2,4-difluoro-phenyl)carbamate (43.33 mg, 152.75 μmol, 1.20 eq), TEA (25.76 mg, 254.58 μmol, 35.29 μL2.00 eq) in DCM (3.00 mL) was degassed and purged with N 2 for 3 times, and then the mixture was stirred at 30° C. for 16 hour under N 2 atmosphere. LCMS showed the starting material was consumed completely, desired product was major. The mixture was poured into water (10 mL) and extracted with DCM (5 mL*3). The combined organic phase was washed with brine (10 mL), dried with anhydrous Na 2 SO 4 , filtered and concentrated in vacuum. The residue was purified by Prep-HPLC (FA) to give the title compound (51.00 mg, 86.73 μmol, 68.13% yield, 93% purity) as a white solid. LCMS: 547/548[M+1]. 1 H NMR (400 MHz, CHLOROFORM-d) δ 7.87 (br d, J=5.50 Hz, 1H), 6.92-7.00 (m, 1H), 6.56 (br s, 1H), 6.04 (s, 1H), 4.94-5.16 (m, 4H), 4.59-4.70 (m, 1H), 4.42 (d, J=15.53 Hz, 1H), 3.94-4.10 (m, 1H), 3.60 (br dd, J=4.34, 13.02 Hz, 1H), 3.15-3.35 (m, 6H), 3.05-3.13 (m, 1H), 2.62-2.74 (m, 1H), 1.19 (d, J=6.85 Hz, 3H).

›PREPARATIVE EXAMPLES · 49 of 53

* pure but unknown stereochemistry

Compound 152_D2: (4R*,9R)—N10-(3-chloro-2,4-difluorophenyl)-N4-(2,2-difluoroethyl)-N4,2,9-trimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-4,10(2H)-dicarboxamide

Compound 152_D2 was prepared in an analogous manner to Compound 152_D1 using the opposite enantiomer of Intermediate 18.

LCMS: 547/548[M+1]. 1 H NMR (400 MHz, CHLOROFORM-d) δ 7.83-7.93 (m, 1H), 6.91-7.02 (m, 1H), 6.46-6.55 (m, 1H), 5.86-6.21 (m, 1H), 5.03 (s, 3H), 4.78-4.87 (m, 1H), 4.51-4.71 (m, 2H), 3.95-4.11 (m, 1H), 3.52-3.67 (m, 1H), 3.16-3.33 (m, 6H), 3.00-3.09 (m, 1H), 2.70-2.78 (m, 1H), 1.21-1.27 (m, 3H).

* pure but unknown stereochemistry

Compounds 153, 154, and 155 were prepared in an analogous manner to Compound 152.

Compound 153_D1: (4S*,9R)—N10-(3-cyano-2,4-difluorophenyl)-N4-(2,2-difluoroethyl)-N4,2,9-trimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-4,10(2H)-dicarboxamide

LCMS: 538[M+1]. 1 H NMR (400 MHz, CHLOROFORM-d) δ 8.22-8.32 (m, 1H), 6.99-7.06 (m, 1H), 6.61-6.68 (m, 1H), 6.04 (s, 1H), 4.94-5.16 (m, 4H), 4.59-4.70 (m, 1H), 4.39-4.47 (m, 1H), 3.93-4.08 (m, 1H), 3.52-3.70 (m, 1H), 3.15-3.34 (m, 6H), 3.04-3.13 (m, 1H), 2.66-2.74 (m, 1H), 1.20 (d, J=6.85 Hz, 3H).

* pure but unknown stereochemistry

Compound 153_D2: (4R*,9R)—N10-(3-cyano-2,4-difluorophenyl)-N4-(2,2-difluoroethyl)-N4,2,9-trimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-4,10(2H)-dicarboxamide

LCMS: 538[M+1]. 1 H NMR (400 MHz, CHLOROFORM-d) δ 8.24-8.37 (m, 1H), 6.97-7.09 (m, 1H), 6.50-6.62 (m, 1H), 6.04 (s, 1H), 5.03 (s, 3H), 4.53-4.87 (m, 3H), 3.95-4.12 (m, 1H), 3.53-3.69 (m, 1H), 3.16-3.33 (m, 6H), 2.99-3.09 (m, 1H), 2.70-2.79 (m, 1H), 1.24 (d, J=6.85 Hz, 3H).

* pure but unknown stereochemistry

Compound 154_D1: (4S*,9R)—N10-(5-chloro-2,4-difluorophenyl)-N4-(2,2-difluoroethyl)-N4,2,9-trimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-4,10(2H)-dicarboxamide

LCMS: 547/548[M+1]. 1 H NMR (400 MHz, CHLOROFORM-d) δ 8.19 (s, 1H), 6.92-6.99 (m, 1H), 6.56-6.61 (m, 1H), 5.87-6.21 (m, 1H), 4.93-5.17 (m, 4H), 4.60-4.70 (m, 1H), 4.41 (d, J=15.65 Hz, 1H), 3.94-4.18 (m, 1H), 3.51-3.73 (m, 1H), 3.14-3.34 (m, 6H), 3.06 (br d, J=5.75 Hz, 1H), 2.72 (s, 1H), 1.19 (d, J=6.85 Hz, 3H).

* pure but unknown stereochemistry

Compound 154_D2: (4R*,9R)—N10-(5-chloro-2,4-difluorophenyl)-N4-(2,2-difluoroethyl)-N4,2,9-trimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-4,10(2H)-dicarboxamide

LCMS: 547/548[M+1]. 1 H NMR (400 MHz, CHLOROFORM-d) δ 8.16-8.23 (m, 1H), 6.91-6.99 (m, 1H), 6.48-6.55 (m, 1H), 5.87-6.22 (m, 1H), 5.03 (s, 3H), 4.76-4.84 (m, 1H), 4.51-4.72 (m, 2H), 3.95-4.11 (m, 1H), 3.51-3.68 (m, 1H), 3.15-3.34 (m, 6H), 2.98-3.09 (m, 1H), 2.70-2.78 (m, 1H), 1.23 (d, J=6.90 Hz, 3H).

* pure but unknown stereochemistry

Compound 155_D1: (4S*,9R)—N10-(3-cyano-4-fluorophenyl)-N4-(2,2-difluoroethyl)-N4,2,9-trimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-4,10(2H)-dicarboxamide

LCMS: 520[M+1]. 1 H NMR (400 MHz, CHLOROFORM-d) δ 7.78-7.83 (m, 1H), 7.58-7.65 (m, 1H), 7.14 (s, 1H), 6.84 (s, 1H), 5.85-6.26 (m, 1H), 4.89-5.23 (m, 4H), 4.60-4.72 (m, 1H), 4.39 (d, J=15.65 Hz, 1H), 3.95-4.14 (m, 1H), 3.52-3.75 (m, 1H), 3.15-3.35 (m, 6H), 3.02-3.11 (m, 1H), 2.71 (s, 1H), 1.13-1.22 (m, 3H).

* pure but unknown stereochemistry

Compound 155_D2: (4R*,9R)—N10-(3-cyano-4-fluorophenyl)-N4-(2,2-difluoroethyl)-N4,2,9-trimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-4,10(2H)-dicarboxamide

LCMS: 520[M+1]. 1 H NMR (400 MHz, CHLOROFORM-d) δ 7.76 (s, 1H), 7.54-7.61 (m, 1H), 7.11-7.19 (m, 1H), 6.56-6.62 (m, 1H), 5.88-6.21 (m, 1H), 5.04 (s, 3H), 4.74-4.82 (m, 1H), 4.51-4.70 (m, 2H), 3.93-4.15 (m, 1H), 3.52-3.72 (m, 1H), 3.15-3.35 (m, 6H), 2.97-3.09 (m, 1H), 2.76 (s, 1H), 1.22 (d, J=6.90 Hz, 3H).

* pure but unknown stereochemistry

Compound 156_D1: (4S*,9R)—N10-(3-cyano-2,4-difluorophenyl)-N4,2,9-trimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-4,10(2H)-dicarboxamide

Compound 156 was prepared in an analogous manner to Compound 110.

LCMS: 474[M+1]. 1 H NMR (400 MHz, CHLOROFORM-d) δ 8.25-8.36 (m, 1H), 6.98-7.08 (m, 1H), 6.57-6.64 (m, 1H), 6.00-6.11 (m, 1H), 4.95-5.07 (m, 2H), 4.91 (s, 2H), 4.65-4.72 (m, 1H), 4.51-4.57 (m, 1H), 3.35 (s, 3H), 2.99-3.08 (m, 1H), 2.85 (d, J=4.89 Hz, 3H), 2.68-2.77 (m, 1H), 1.23 (d, J=6.85 Hz, 2H), 1.19-1.26 (m, 1H).

* pure but unknown stereochemistry

Compound 156_D2: (4R*,9R)—N10-(3-cyano-2,4-difluorophenyl)-N4,2,9-trimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-4,10(2H)-dicarboxamide

LCMS: 474[M+1]. 1 H NMR (400 MHz, CHLOROFORM-d) δ 8.24-8.34 (m, 1H), 6.99-7.06 (m, 1H), 6.62-6.68 (m, 1H), 6.09-6.20 (m, 1H), 5.02-5.11 (m, 1H), 4.86-4.99 (m, 3H), 4.68-4.77 (m, 1H), 4.46 (d, J=15.89 Hz, 1H), 3.35 (s, 3H), 2.99-3.09 (m, 1H), 2.89 (d, J=4.89 Hz, 3H), 2.69-2.78 (m, 1H), 1.20 (d, J=6.85 Hz, 3H).

* pure but unknown stereochemistry

Compound 157_D1: (4S*,9R)—N-[2-fluoro-5-(trifluoromethyl)phenyl]-4-(hydroxymethyl)-2,9-dimethyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxamide

Step 1. (9R)-4-(hydroxymethyl)-2,9-dimethyl-4,5,8,9,10,11-hexahydropyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepin-1-one. A solution of tert-butyl (9R)-4-(hydroxymethyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxylate (Intermediate 18, 40.00 mg, 109.17 μmol, 1.00 eq) in DCM (2.00 mL) was added TFA (1.54 g, 13.51 mmol, 1.00 mL, 123.72 eq), and then the mixture was stirred at 20° C. for 1 hour. TLC showed the starting material was consumed completely, a new spot appeared. The mixture was concentrated in vacuum to afford the title compound (41.52 mg, 109.17 μmol, 100.00% yield, TFA) as a yellow oil, which was used directly for next step.

Step 2. (4S*,9R)—N-[2-fluoro-5-(trifluoromethyl)phenyl]-4-(hydroxymethyl)-2,9-dimethyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxamide. A mixture of (9R)-4-(hydroxymethyl)-2,9-dimethyl-4,5,8,9,10,11-hexahydropyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepin-1-one (41.00 mg, 107.80 μmol, 1.00 eq, TFA), phenylN-[2-fluoro-5-(trifluoromethyl)phenyl]carbamate (35.48 mg, 118.58 μmol, 1.10 eq), TEA (21.82 mg, 215.61 μmol, 29.89 μL2.00 eq) in DCM (5.00 mL) was degassed and purged with N 2 for 3 times, and then the mixture was stirred at 30° C. for 16 hour under N 2 atmosphere. LCMS showed the starting material was consumed completely, desired product was major. The mixture was poured into water (10 mL) and extracted with DCM (5 mL*3). The combined organic phase was washed with brine (10 mL), dried with anhydrous Na 2 SO 4 , filtered and concentrated in vacuum. The residue was purified by Prep-HPLC (FA) to afford the title compound (35.00 mg, 73.50 μmol, 68.19% yield, 99% purity) as a white solid. LCMS: 472 [M+1]. 1 H NMR (400 MHz, CHLOROFORM-d) δ 8.48 (dd, J=1.90, 7.27 Hz, 1H), 7.24-7.27 (m, 1H), 7.17 (s, 1H), 6.73-6.81 (m, 1H), 5.05-5.17 (m, 1H), 4.87 (s, 1H), 4.52-4.64 (m, 3H), 4.46 (s, 1H), 3.81-3.88 (m, 1H), 3.71-3.80 (m, 1H), 3.34 (s, 3H), 3.01-3.11 (m, 1H), 2.71 (d, J=15.89 Hz, 1H), 1.22 (d, J=6.85 Hz, 3H).

›PREPARATIVE EXAMPLES · 50 of 53

* pure but unknown stereochemistry

Compound 157_D2: (4R*,9R)—N-[2-fluoro-5-(trifluoromethyl)phenyl]-4-(hydroxymethyl)-2,9-dimethyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxamide

1 H NMR (400 MHz, CHLOROFORM-d) δ 8.46-8.52 (m, 1H), 8.46-8.52 (m, 1H), 7.24-7.27 (m, 1H), 7.14-7.22 (m, 1H), 6.75-6.82 (m, 1H), 5.06-5.19 (m, 1H), 4.92 (s, 1H), 4.48-4.62 (m, 3H), 4.35-4.44 (m, 1H), 3.86-3.94 (m, 1H), 3.75-3.82 (m, 1H), 3.34 (s, 3H), 3.02-3.11 (m, 1H), 3.02-3.11 (m, 1H), 2.65-2.78 (m, 1H), 1.21 (d, J=6.85 Hz, 2H), 1.19-1.24 (m, 1H).

* pure but unknown stereochemistry

Compound 158: N10-(3-chloro-2,4-difluorophenyl)-N4-(2,2-difluoroethyl)-N4,2-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-4,10(2H)-dicarboxamide

Step 1. N-(2,2-difluoroethyl)-N,2-dimethyl-1-oxo-4,5,8,9,10,11-hexahydropyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-4-carboxamide

To a solution of tert-butyl 4-[2,2-difluoroethyl(methyl)carbamoyl]-2-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxylate (150.00 mg, 338.26 μmol, 1.00 eq) in DCM (4.00 mL) was added TFA (3.08 g, 27.01 mmol, 2.00 mL, 79.86 eq) at 0° C. The mixture was stirred at 25° C. for 1 h. The mixture was concentrated under reduced pressure to afford the title compound (154.70 mg, 338.25 μmol, 100.00% yield, TFA) as yellow oil, the crude product was used directly for the next step. LCMS: 344 [M+1]

Step 2. N10-(3-chloro-2,4-difluoro-phenyl)-N4-(2,2-difluoroethyl)-N4,2-dimethyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-4,10-dicarboxamide

To a solution of N-(2,2-difluoroethyl)-N,2-dimethyl-1-oxo-4,5,8,9,10,11-hexahydropyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-4-carboxamide (50.00 mg, 109.33 μmol, 1.00 eq, TFA) in DCM (3.00 mL) was added phenyl N-(3-chloro-2,4-difluoro-phenyl)carbamate (46.52 mg, 164.00 μmol, 1.50 eq) and Et3N (55.32 mg, 546.65 μmol, 75.78 μL 5.00 eq). The mixture was stirred at 25° C. for 16 h. The mixture was adjusted to neutral condition (pH˜6) with FA and concentrated in vacuo. The resulting residue was purified by prep-HPLC(FA) to afforded N10-(3-chloro-2,4-difluoro-phenyl)-N4-(2,2-difluoroethyl)-N4,2-dimethyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d] [1,2,5]oxadiazepine-4,10-dicarboxamide (40.00 mg, 74.31 μmol, 67.97% yield, 99% purity) as white solid. LCMS [M+1]: 533/535. 1 H NMR (400 MHz, CHLOROFORM-d) δ7.86-7.88 (m, 1H), 6.90-7.03 (m, 1H), 6.57 (br s, 1H), 5.85-6.22 (m, 1H), 4.94-5.12 (m, 2H), 4.58-4.84 (m, 3H), 3.76-4.13 (m, 3H), 3.50-3.69 (m, 1H), 3.13-3.37 (m, 6H), 2.80-2.98 (m, 2H).

Compounds 159, 160, and 161 were prepared in an analogous manner to 158.

Compound 159: N10-(5-chloro-2,4-difluorophenyl)-N4-(2,2-difluoroethyl)-N4,2-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-4,10(2H)-dicarboxamide

LCMS [M+1]:533/535. 1 H NMR (400 MHz, CHLOROFORM-d) δ 8.17 (t, J=8.07 Hz, 1H), 6.95 (dd, J=8.44, 10.64 Hz, 1H), 6.59 (br d, J=2.81 Hz, 1H), 5.85-6.20 (m, 1H), 4.93-5.09 (m, 2H), 4.58-4.83 (m, 3H), 3.80-4.12 (m, 3H), 3.59 (br dd, J=4.28, 13.08 Hz, 1H), 3.12-3.34 (m, 6H), 2.82-2.96 (m, 2H).

Compound 160: N10-(3-cyano-4-fluorophenyl)-N4-(2,2-difluoroethyl)-N4,2-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-4,10(2H)-dicarboxamide

LCMS [M+1]: 506. 1 H NMR (400 MHz, CHLOROFORM-d) δ 7.77 (dd, J=2.76, 5.40 Hz, 1H), 7.54-7.63 (m, 1H), 7.14 (t, J=8.72 Hz, 1H), 6.71 (s, 1H), 5.86-6.22 (m, 1H), 4.95-5.10 (m, 2H), 4.73-4.84 (m, 1H), 4.57-4.69 (m, 2H), 3.78-4.09 (m, 3H), 3.47-3.68 (m, 1H), 3.14-3.36 (m, 6H), 2.81-2.95 (m, 2H).

Compound 161: N10-(3-cyano-2,4-difluorophenyl)-N4-(2,2-difluoroethyl)-N4,2-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-4,10(2H)-dicarboxamide

LCMS [M+1]: 524. 1 H NMR (400 MHz, CHLOROFORM-d) δ 8.28 (dt, J=5.90, 9.10 Hz, 1H), 7.02 (ddd, J=1.69, 8.00, 9.51 Hz, 1H), 6.63 (d, J=2.51 Hz, 1H), 5.83-6.20 (m, 1H), 4.95-5.10 (m, 2H), 4.58-4.85 (m, 3H), 3.79-4.09 (m, 3H), 3.52-3.69 (m, 1H), 3.13-3.34 (m, 6H), 2.79-2.97 (m, 2H).

Compound 162: -(acetamidomethyl)-N-(3-chloro-4-fluoro-phenyl)-2-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxamide

A mixture of 4-(aminomethyl)-N-(3-chloro-4-fluoro-phenyl)-2-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxamide (Compound 113, 80.00 mg, 189.20 μmol, 1.00 eq), TEA (95.72 mg, 946.00 μmol, 131.12 μL5.00 eq) in DCM (3.00 mL) was added acetyl acetate (77.26 mg, 756.80 μmol, 70.88 μL4.00 eq) dropwise at 0° C. under N 2 , and then the mixture was stirred at 30° C. for 2 hour under N 2 atmosphere. LCMS showed the starting material was consumed completely, desired product was major. The mixture was poured into ice-water (10 mL) and stirred at 5 min. The aqueous phase was extracted with DCM (5 mL*2). The combined organic phase was washed with brine (20 mL), dried with anhydrous Na 2 SO 4 , filtered and concentrated in vacuum. The residue was purified by Prep-HPLC (FA) to give 4the title compound (48.00 mg, 102.22 μmol, 54.03% yield, 99% purity) as a white solid. LCMS: 465/467 [M+1]. 1 H NMR (400 MHz, Acetone) δ 8.33-8.39 (m, 1H), 7.82-7.88 (m, 1H), 7.43-7.49 (m, 1H), 7.32-7.41 (m, 1H), 7.16 (t, J=9.10 Hz, 1H), 4.55-4.69 (m, 4H), 4.36 (s, 1H), 3.83 (s, 2H), 3.52-3.62 (m, 1H), 3.35-3.44 (m, 1H), 3.24 (s, 3H), 2.74-2.78 (m, 2H), 1.90 (s, 3H).

Compounds 163, 164, 165, and 166 were prepared by an analogous method.

Compound 163: N-(3-chloro-4-fluorophenyl)-2-methyl-1-oxo-4-((2,2,2-trifluoroacetamido)methyl)-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS: 519/520 [M+1]. 1 H NMR (400 MHz, CHLOROFORM-d) δ 7.55-7.60 (m, 1H), 7.17-7.23 (m, 1H), 7.07 (s, 1H), 6.60-6.69 (m, 1H), 6.47-6.51 (m, 1H), 4.64-4.79 (m, 3H), 4.56-4.63 (m, 1H), 4.44-4.51 (m, 1H), 3.76-3.94 (m, 2H), 3.66 (s, 2H), 3.31 (s, 3H), 2.81-2.91 (m, 2H).

›PREPARATIVE EXAMPLES · 51 of 53

Compound 164: N-(3-chloro-4-fluorophenyl)-2-methyl-1-oxo-4-(((trifluoromethyl)sulfonamido)methyl)-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS: 555/556 [M+1]. 1 H NMR (400 MHz, CHLOROFORM-d) δ 7.54-7.60 (m, 1H), 7.17-7.24 (m, 1H), 7.06 (s, 1H), 6.58 (s, 1H), 4.67 (s, 4H), 4.43-4.49 (m, 1H), 3.76-3.95 (m, 2H), 3.39-3.51 (m, 2H), 3.31 (s, 3H), 2.81-2.89 (m, 2H), 2.81-2.89 (m, 2H).

Compound 165: N-(3-chloro-4-fluorophenyl)-2-methyl-4-(methylsulfonamidomethyl)-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS: 501/502 [M+1]. 1 H NMR (400 MHz, CHLOROFORM-d) δ 7.57-7.62 (m, 1H), 7.21-7.26 (m, 1H), 7.02-7.09 (m, 1H), 6.79-6.84 (m, 1H), 5.16-5.25 (m, 1H), 4.69 (s, 3H), 4.51-4.58 (m, 1H), 4.38-4.45 (m, 1H), 3.76-3.95 (m, 2H), 3.35-3.45 (m, 1H), 3.23-3.33 (m, 1H), 3.19 (s, 3H), 3.03 (s, 3H), 2.85 (br s, 2H).

Compound 166: methyl((10-((3-chloro-4-fluorophenyl)carbamoyl)-2-methyl-1-oxo-1,2,4,5,8,9,10,11-octahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepin-4-yl)methyl)carbamate

LCMS: 481/482 [M+1]. 1 H NMR (400 MHz, CHLOROFORM-d) δ 7.55-7.61 (m, 1H), 7.17-7.23 (m, 1H), 7.03-7.09 (m, 1H), 6.53-6.59 (m, 1H), 4.95-5.06 (m, 1H), 4.50-4.76 (m, 4H), 4.38 (br dd, J=4.39, 14.05 Hz, 1H), 3.79-3.94 (m, 2H), 3.72 (s, 3H), 3.39-3.49 (m, 2H), 3.30 (s, 3H), 2.85 (s, 2H).

Compound 167_E1: (S*)-4-(acetamidomethyl)-N-(3-cyano-2,4-difluorophenyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

Step 1. tert-butyl 4-(aminomethyl)-2-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxylate. To a solution of tert-butyl 4-(azidomethyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxylate (Intermediate 28, 850.00 mg, 2.25 mmol, 1.00 eq) in THF (12.00 mL) and H 2 O (2.00 mL) was added PPh 3 (1.18 g, 4.50 mmol, 2.00 eq). The mixture was stirred at 25° C. for 16 hr. LCMS showed the reactant consumed completely. The mixture was poured into water (20 mL) and extracted with ethyl acetate (20 mL*3), the organic layer was washed with brine (20 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuum. The crude was purified by column chromatography to afford the title compound (790.00 mg, 2.25 mmol, 99.92% yield) as white solid.

Step 2. tert-butyl 4-(acetamidomethyl)-2-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxylate. To a solution of tert-butyl 4-(aminomethyl)-2-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxylate (720.00 mg, 2.05 mmol, 1.00 eq) in DCM (10.00 mL) was added TEA (622.00 mg, 6.15 mmol, 852.05 μL3.00 eq) and Ac 2 O (251.01 mg, 2.46 mmol, 230.29 μL1.20 eq). The mixture was stirred at 25° C. for 2 hr. TLC showed the reaction completed. The mixture was poured into water (20 mL), extracted with DCM (20 mL*3), the organic layer was washed with HCl (20 mL, 1N), brine (20 mL), dried over anhydrous Na 2 SO 4 and concentrated in vacuum to afford the title compound (770.00 mg, 1.96 mmol, 95.66% yield) as white solid

Step 3. N-[(2-methyl-1-oxo-4,5,8,9,10,11-hexahydropyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepin-4-yl)methyl]acetamide. To a solution of tert-butyl 4-(acetamidomethyl)-2-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxylate (450.00 mg, 1.14 mmol, 1.00 eq) in DCM (4.00 mL) was added TFA (3.08 g, 27.02 mmol, 2.00 mL, 23.70 eq) at 0° C. The mixture was stirred at 25° C. for 1 h. The mixture was concentrated under reduced pressure to afford the title compound (464.00 mg, 1.14 mmol, 99.92% yield, TFA) as yellow oil, which was used directly for the next step.

Step 4. (S*)-4-(acetamidomethyl)-N-(3-cyano-2,4-difluorophenyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide To a solution of (3R)-10-(2,2-difluoroethyl)-3-methyl-2,3,4,7,8,9-hexahydro-1H-pyrido[2,3]pyrazolo[2,4-b][1,4]diazepin-11-one (55.00 mg, 138.08 μmol, 1.00 eq, TFA) and Et3N (69.86 mg, 690.40 μmol, 95.70 μL5.00 eq) in DCM (2.00 mL) was added phenyl N-(3-chloro-4-fluoro-phenyl)carbamate (36.68 mg, 138.08 μmol, 1.00 eq), the mixture was stirred at 25° C. for 16 h. The mixture was adjusted to neutral condition (pH˜6) with FA and directly evaporated to give the residue. The residue was purified by prep-HPLC (FA) to afford the title compound (31.70 mg, 69.33 μmol, 50.21% yield, 99.7% purity) as white solid. LCMS: 474 [M+1]. LCMS: 474 [M+1]. 1 H NMR (400 MHz, CHLOROFORM-d) δ 8.28 (dt, J=5.77, 9.10 Hz, 1H), 6.96-7.07 (m, 1H), 6.62 (d, J=2.64 Hz, 1H), 5.74 (br s, 1H), 4.68-4.82 (m, 2H), 4.59-4.66 (m, 1H), 4.50-4.56 (m, 1H), 4.36-4.57 (m, 1H), 3.76-3.96 (m, 2H), 3.42-3.59 (m, 2H), 3.31 (s, 3H), 2.81-2.92 (m, 2H), 2.02 (s, 3H).

* pure but unknown stereochemistry

Compounds 168, 169, 170, 171, 172, 173, 174, and 175 were prepared by an analogous manner to Compound 167.

Compound 168_E1: (S*)-4-(acetamidomethyl)-N-(3-cyano-4-fluorophenyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS: 456 [M+1]. 1 H NMR (400 MHz, CHLOROFORM-d) δ 7.77 (dd, J=2.76, 5.40 Hz, 1H), 7.59 (ddd, J=2.82, 4.49, 9.13 Hz, 1H), 7.10-7.19 (m, 1H), 6.69 (s, 1H), 5.75 (br s, 1H), 4.68-4.78 (m, 2H), 4.59-4.67 (m, 1H), 4.36-4.57 (m, 2H), 3.82-3.92 (m, 2H), 3.43-3.58 (m, 2H), 3.31 (s, 3H), 2.82-2.91 (m, 2H), 2.02 (s, 3H).

* pure but unknown stereochemistry

Compound 169_E1: (S*)-4-(acetamidomethyl)-N-(3-chloro-2,4-difluorophenyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS: 483/485 [M+1]. 1 H NMR (400 MHz, CHLOROFORM-d) δ 7.87 (dt, J=5.58, 8.94 Hz, 1H), 6.90-7.02 (m, 1H), 6.56 (d, J=2.76 Hz, 1H), 5.77 (br s, 1H), 4.68-4.81 (m, 2H), 4.62 (quin,

J=5.46 Hz, 1H), 4.35-4.56 (m, 2H), 3.76-3.95 (m, 2H), 3.42-3.57 (m, 2H), 3.30 (s, 3H), 2.79-2.92 (m, 2H), 2.01 (s, 3H).

›PREPARATIVE EXAMPLES · 52 of 53

* pure but unknown stereochemistry

Compound 170_E1: (S*)-4-(acetamidomethyl)-N-(3-bromo-2,4-difluorophenyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS: 527/529[M+1]. 1 H NMR (400 MHz, CHLOROFORM-d) δ 7.94 (dt, J=5.65, 8.97 Hz, 1H), 6.94 (ddd, J=2.07, 7.72, 9.41 Hz, 1H), 6.56 (d, J=3.01 Hz, 1H), 5.73 (br s, 1H), 4.70-4.80 (m, 2H), 4.58-4.67 (m, 1H), 4.34-4.57 (m, 2H), 3.74-3.97 (m, 2H), 3.43-3.60 (m, 2H), 3.30 (s, 3H), 2.81-2.93 (m, 2H), 2.01 (s, 3H).

* pure but unknown stereochemistry

Compound 171_E1: (S*)-4-(acetamidomethyl)-N-(3-bromo-4-fluorophenyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS: 509/511 [M+1]. 1 H NMR (400 MHz, CHLOROFORM-d) δ 7.71 (dd, J=2.64, 6.02 Hz, 1H), 7.24-7.27 (m, 1H), 7.00-7.10 (m, 1H), 6.52 (s, 1H), 5.75 (br s, 1H), 4.67-4.78 (m, 2H), 4.59-4.66 (m, 1H), 4.35-4.57 (m, 2H), 3.76-3.94 (m, 2H), 3.44-3.61 (m, 2H), 3.30 (s, 3H), 2.80-2.91 (m, 2H), 2.01 (s, 3H).

* pure but unknown stereochemistry

Compound 172_E1: (S*)-4-(acetamidomethyl)-N-(2,4-difluoro-3-(trifluoromethyl)phenyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS: 517 [M+1]. 1 H NMR (400 MHz, CHLOROFORM-d) δ 8.22 (dt, J=5.40, 8.91 Hz, 1H), 6.94-7.05 (m, 1H), 6.64 (br d, J=3.64 Hz, 1H), 5.75 (br s, 1H), 4.75 (d, J=1.51 Hz, 2H), 4.58-4.67 (m, 1H), 4.35-4.57 (m, 2H), 3.76-3.96 (m, 2H), 3.42-3.60 (m, 2H), 3.30 (s, 3H), 2.81-2.95 (m, 2H), 2.01 (s, 3H).

* pure but unknown stereochemistry

Compound 173_E1: (S*)-4-(acetamidomethyl)-N-(5-chloro-2,4-difluorophenyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS:483/485 [M+1]. 1 H NMR (400 MHz, CHLOROFORM-d) δ 8.18 (t, J=8.03 Hz, 1H), 6.95 (dd, J=8.47, 10.60 Hz, 1H), 6.56 (d, J=3.14 Hz, 1H), 5.74 (br s, 1H), 4.69-4.77 (m, 2H), 4.59-4.66 (m, 1H), 4.35-4.56 (m, 2H), 3.74-3.96 (m, 2H), 3.43-3.58 (m, 2H), 3.30 (s, 3H), 2.82-2.92 (m, 2H), 2.01 (s, 3H).

* pure but unknown stereochemistry

Compound 174_E1: (S*)-4-(acetamidomethyl)-N-(5-bromo-2,4-difluorophenyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS: 527/529 [M+1]. 1 H NMR (400 MHz, CHLOROFORM-d) δ 8.27-8.36 (m, 1H), 6.94 (dd, J=7.91, 10.79 Hz, 1H), 6.56 (br d, J=3.14 Hz, 1H), 5.76 (br s, 1H), 4.73 (s, 2H), 4.62 (quin, J=5.43 Hz, 1H), 4.35-4.56 (m, 2H), 3.74-3.97 (m, 2H), 3.42-3.57 (m, 2H), 3.30 (s, 3H), 2.80-2.93 (m, 2H), 2.01 (s, 3H).

* pure but unknown stereochemistry

Compound 175_E1: (S*)-4-(acetamidomethyl)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS: 499 [M+1]. 1 H NMR (400 MHz, CHLOROFORM-d) δ 7.67 (dd, J=2.76, 6.02 Hz, 1H), 7.54-7.62 (m, 1H), 7.13 (t, J=9.41 Hz, 1H), 6.66 (s, 1H), 5.76 (br s, 1H), 4.70-4.78 (m, 2H), 4.58-4.68 (m, 1H), 4.36-4.57 (m, 2H), 3.79-3.94 (m, 2H), 3.45-3.57 (m, 2H), 3.30 (s, 3H), 2.80-2.92 (m, 2H), 2.01 (s, 3H).

* pure but unknown stereochemistry

Compound 176_D1: (4S*,9R)-4-(acetamidomethyl)-N-(3-cyano-4-fluorophenyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

Step 1. tert-butyl(9R)-4-(aminomethyl)-2,9-dimethyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxylate. A mixture of tert-butyl (9R)-4-(azidomethyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxylate (Intermediate 29, 1.06 g, 2.71 mmol, 1.00 eq), PPh 3 (1.42 g, 5.42 mmol, 2.00 eq) in THF (12.00 mL) and H 2 O (2.00 mL) was degassed and purged with N 2 for 3 times, and then the mixture was stirred at 30° C. for 16 hour under N 2 atmosphere. LCMS showed the starting material was consumed completely, desired product was major. The mixture was concentrated in vacuum. The residue was purified by column chromatography (SiO 2 , Petroleum ether/Ethyl acetate=100/1 to 0:1) to give the title compound (827.00 mg, 2.20 mmol, 81.00% yield, 97% purity) as a white solid. LCMS: 366 [M+1]

Step 2. Preparation of tert-butyl (9R)-4-(acetamidomethyl)-2,9-dimethyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxylate. A mixture of tert-butyl(9R)-4-(aminomethyl)-2,9-dimethyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxylate (250.00 mg, 684.13 μmol, 1.00 eq), TEA (346.13 mg, 3.42 mmol, 474.16 μL5.00 eq) in DCM (5.00 mL) was added Ac 2 O (279.37 mg, 2.74 mmol, 256.30 μL4.00 eq) dropwise at 0° C. under N 2 , and then the mixture was stirred at 30° C. for 2 hour under N 2 atmosphere. LCMS showed the starting material was consumed completely, desired product was major. The mixture was poured into water (10 mL) and stirred at 5 min. The aqueous phase was extracted with DCM (5 mL*3). The combined organic phase was washed with brine (10 mL), dried with anhydrous Na 2 SO 4 , filtered and concentrated in vacuum to give the title compound (270.00 mg, crude) as a white solid. LCMS: 408 [M+1].

Step 3. (4S*,9R)-4-(acetamidomethyl)-N-(3-cyano-4-fluorophenyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide A solution of tert-butyl(9R)-4-(acetamidomethyl)-2,9-dimethyl-1-oxo-5,8,9,11-tetra hydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxylate (140.00 mg, 343.59 μmol, 1.00 eq) in DCM (2.00 mL) was added TFA (1.54 g, 13.51 mmol, 1.00 mL, 39.31 eq), and then the mixture was stirred at 30° C. for 1 hour. TLC showed the starting material was consumed completely and a new spot formed. The mixture was concentrated in vacuum to give N-[[(9R)-2,9-dimethyl-1-oxo-4,5,8,9,10,11-hexahydropyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepin-4-yl]methyl]acetamide (144.78 mg, 343.59 μmol, 100.00% yield, TFA) as a yellow oil, which was used directly for next step.

›PREPARATIVE EXAMPLES · 53 of 53

Step 4. (4S*,9R)-4-(acetamidomethyl)-N-(3-cyano-4-fluorophenyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide. A mixture of N-[[(9R)-2,9-dimethyl-1-oxo-4,5,8,9,10,11-hexahydropyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepin-4-yl]methyl]acetamide (70.00 mg, 166.12 μmol, 1.00 eq, TFA), phenyl N-(3-cyano-4-fluoro-phenyl)carbamate (42.57 mg, 166.12 μmol, 1.00 eq), TEA (50.43 mg, 498.36 μmol, 69.08 μL3.00 eq) in DCM (3.00 mL) was degassed and purged with N 2 for 3 times, and then the mixture was stirred at 30° C. for 16 hour under N 2 atmosphere. LCMS showed the starting material was consumed completely, desired product was major. The mixture was poured into water (10 mL) and stirred at 5 min. The aqueous phase was extracted with DCM (5 mL*3). The combined organic phase was washed with brine (10 mL), dried with anhydrous Na 2 SO 4 , filtered and concentrated in vacuum. The residue was purified by Prep-HPLC (FA) to give the title compound (30.00 mg, 61.98 μmol, 37.31% yield, 97% purity) as a white solid. LCMS: 470 [M+1] 1 H NMR (400 MHz, CHLOROFORM-d) δ 8.04 (s, 1H), 7.77 (dd, J=2.76, 5.40 Hz, 1H), 7.56-7.63 (m, 1H), 7.14 (s, 1H), 6.67 (s, 1H), 5.74-5.86 (m, 1H), 5.06-5.22 (m, 1H), 4.77-4.87 (m, 1H), 4.62-4.70 (m, 1H), 4.49-4.59 (m, 2H), 4.39-4.47 (m, 1H), 3.50 (s, 2H), 3.31 (s, 3H), 2.97-3.07 (m, 1H), 2.66-2.75 (m, 1H), 2.01 (s, 3H), 1.20 (d, J=7.03 Hz, 3H).

* pure but unknown stereochemistry

Compound 176_D2: (4R*,9R)-4-(acetamidomethyl)-N-(3-cyano-4-fluorophenyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS

›Tables in the description — 4

TABLE 6

Term	Acronym
Acetonitrile	ACN or MeCN
Aqueous	aq
Atmosphere	atm
tert-Butylcarbamoyl	Boc
Boron-dipyrromethene	BODIPY
Benzyl	Bn
Broad	br
Capside assembly	CA
Carboxybenzyl	CBz
Diatomaceous Earth	Celite ®
1,1′-Carbonyldiimidazole	CDI
Doublet of doublets	dd
Diethylaminosulfur trifluoride	DAST
Di-tert-butyl azodicarboxylate	DBAD
1,8-Diazabicyclo[5.4.0]undec-7-ene	DBU
Dichloroethane	DCE
Dichloromethane	DCM
Bis(2-methoxyethyl)aminosulfur trifluoride	Deoxo-Fluor ®
Diethyl azodicarboxylate	DEAD
Diisopropyl azodicarboxylate	DIAD
Diisopropylethylamine	DIPEA, DIEA,
	or Hunig's base
4-Dimethylaminopyridine	DMAP
1,2-Dimethoxyethane	DME
N,N-Dimethylformamide	DMF
Dimethyl sulfide	DMS
Dimethylsulfoxide	DMSO
Deoxyribonucleic Acid	DNA
1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide	EDCI, EDAC,
	or EDC
Diethyl ether	Ether, Et 2 O
Ethyl Acetate	EtOAc, or EA
Ethanol	EtOH
Electrospray ionization	ESI
Normal-phase silica gel chromatography	FCC
Grams	g
Hours	h or hr
(1-[Bis(dimethylamino)methylene]-1H-1,2,3-	HATU
triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate)
Hepatitis B Virus	HBV
Acetic acid	HOAc
1-Hydroxy-7-azabenzotriazole	HOAt
Hydroxybenzotriazole	HOBt
High-pressure liquid chromatography	HPLC
Hertz	Hz
Isopropyl alcohol	iPrOH, IPA
Potassium tert-butoxide	KOtBu
Lithium aluminum hydride	LAH
Liquid chromatography and mass spectrometry	LCMS
Lithium diisopropylamide	LDA
Lithium bis(trimethylsilyl)amide	LHMDS
Molar	M
multiplet	m
Mass to charge ratio	m/z
meta-Chloroperoxybenzoic acid	mCPBA
Methyl Iodide	MeI
Methanol	MeOH
Milligrams	mg
Megahertz	MHz
Minute	min
Milliliter	mL
Microliter	uL
Millimole	mmol
Micromole	μmol
Mass spectrometry	MS
Mesityl chloride	MsCl
Normal	N
Sodium acetate	NaOAc
Sodium tert-butoxide	NaOt-Bu
N-Methylmorpholine N-oxide	NMO
Nuclear magnetic resonance	NMR
CF3SO3-or triflate	OTf
Polymerase chain reaction	PCR
Petroleum ether	PE
Palladium (II) acetate	Pd(OAc) 2
Palladium(II)bis(triphenylphosphine) dichloride	Pd(PPh 3 ) 2 Cl 2
Tetrakis(triphenylphosphine)palladium(0)	Pd(PPh 3 ) 4
[1,1′-Bis(di-tert-butylphosphino)ferrocene]	PdCl 2 (dtbpf) or
dichloropalladium(II)	Pd(dtbpf) 2 Cl 2
[1,1′-Bis(diphenylphosphino)ferrocene]	PdCl 2 (dppf) or
dichloropalladium(II)	Pd(dppf) 2 Cl 2
9-(2-Phosphonyl-methoxypropyly)adenine	PMPA
Parts per million	ppm
Precipitate	ppt
Polytetrafluoroethylene	PTFE
Pyridine	Py
Benzotriazol-1-yl-oxytripyrrolidinophosphonium	PyBOP
hexafluorophosphate
Retention time	R t
Ribonucleic Acid	RNA
Room temperature	rt
singlet	s
Saturated	sat
1-Chloromethyl-4-fluoro-1,4-	Selectfluor ®
diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate)
[2-(Trimethylsilyl)ethoxy]methyl acetal	SEM
Supercritical Fluid Chromatography	SFC
Temperature	T
triplet	t
Propylphosphonic anhydride	T 3 P
Tert-Butyl alcohol	tBuOH, t-BuOH
Tetra-n-butylammonium fluoride	TBAF
Tetra-n-butylammonium iodide	TBAI
Tert-butyldiphenylsilyl chloride	TBDP SCl
Triethylamine	TEA
Trifluoroacetic acid	TFA
Tetrahydrofuran	THF
Thin layer chromatography	TLC
Toll-like receptor	TLR
Tumor necrosis factor	TNF
Tetrapropylammonium perruthenate	TPAP
Volume in milliliters of solvent per gram of substrate	V, or volumes
(Diethylamino)difluorosulfonium tetrafluoroborate	XtalFluor ®

TABLE 7 — Activity in BDNA-assay (EC 50 ) *Pure but unknown enantiomer or diastereomer.

Compound		DNA EC 50
ID	Compound Name	(nM)
001	N-(3-bromophenyl)-4-(hydroxymethyl)-2-methyl-1-oxo-	A
	1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
002	4-(hydroxymethyl)-2-methyl-1-oxo-N-(m-tolyl)-	A
	1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
003	N-(2-chloro-3-fluoropyridin-4-yl)-4-(hydroxymethyl)-2-	B
	methyl-1-oxo-1,4,5,8,9,11-
	hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
004	N-(3-bromo-2-fluorophenyl)-4-(hydroxymethyl)-2-	A
	methyl-1-oxo-1,4,5,8,9,11-
	hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
005	N-(3,4-difluorophenyl)-4-(hydroxymethyl)-2-methyl-1-	A
	oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
006	4-(hydroxymethyl)-2-methyl-1-oxo-N-(3,4,5-	A
	trifluorophenyl)-1,4,5,8,9,11-
	hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
007	N-(3-chloro-2,4-difluorophenyl)-4-(hydroxymethyl)-2-	A
	methyl-1-oxo-1,4,5,8,9,11-
	hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
008	4-(hydroxymethyl)-2-methyl-1-oxo-N-(3-	A
	(trifluoromethyl)phenyl)-1,4,5,8,9,11-hexahydropyrido
	[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
009	N-(3-ethylphenyl)-4-(hydroxymethyl)-2-methyl-1-oxo-	A
	1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
010	N-(3-bromo-2,4-difluorophenyl)-4-(hydroxymethyl)-2-	A
	methyl-1-oxo-1,4,5,8,9,11-
	hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
011_E1	(S*)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-4-	A
	(hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11-
	hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
011_E2	(R*)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-4-	A
	(hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11-
	hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
012	N-(3,4-dichlorophenyl)-4-(hydroxymethyl)-2-methyl-1-	A
	oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
013	N-(5-chloro-2,4-difluorophenyl)-4-(hydroxymethyl)-2-	A
	methyl-1-oxo-1,4,5,8,9,11-
	hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
014	N-(5-bromo-2,4-difluorophenyl)-4-(hydroxymethyl)-2-	A
	methyl-1-oxo-1,4,5,8,9,11-
	hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
015	N-(3-bromo-4,5-difluorophenyl)-4-(hydroxymethyl)-2-	A
	methyl-1-oxo-1,4,5,8,9,11-
	hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
016	N-(2,5-dimethylphenyl)-4-(hydroxymethyl)-2-methyl-1-	A
	oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1d]-
	[1,2,5]oxadiazepine-10(2H)-carboxamide
017	N-(5-bromo-2-methylphenyl)-4-(hydroxymethyl)-2-	A
	methyl-1-oxo-1,4,5,8,9,11-
	hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
018	N-(5-bromo-4-fluoro-2-methylphenyl)-4-	A
	(hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11-
	hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
019	4-(hydroxymethyl)-2-methyl-N-(3-methylcyclohexyl)-1-	C
	oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
020	4-(hydroxymethyl)-N-(3-iodophenyl)-2-methyl-1-oxo-	A
	1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
021	N-(3-(difluoromethyl)phenyl)-4-(hydroxymethyl)-2-	A
	methyl-1-oxo-1,4,5,8,9,11-
	hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
022	N-(3-chloro-4-fluoro-5-(trifluoromethyl)phenyl)-4-	A
	(hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11-
	hexahydropyrido[4′,3′:3,4]pyrazolo[5,1d]-
	[1,2,5]oxadiazepine-10(2H)-carboxamide
023	N-(2,3-dichloro-4-fluorophenyl)-4-(hydroxymethyl)-2-	A
	methyl-1-oxo-1,4,5,8,9,11-
	hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
024	N-(3,4-dichloro-2-fluorophenyl)-4-(hydroxymethyl)-2-	A
	methyl-1-oxo-1,4,5,8,9,11-
	hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]
	oxadiazepine-10(2H)-carboxamide
025	N-(4-chloro-3-(trifluoromethyl)phenyl)-4-	A
	(hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11-
	hexahydropyrido[4′,3′:3,4]pyrazolo[5,1d]-
	[1,2,5]oxadiazepine-10(2H)-carboxamide
026	N-(3-chloro-4-methylphenyl)-4-(hydroxymethyl)-2-	A
	methyl-1-oxo-1,4,5,8,9,11-
	hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
027	N-(4,5-dichloro-2-fluorophenyl)-4-(hydroxymethyl)-2-	A
	methyl-1-oxo-1,4,5,8,9,11-
	hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
028_E1	(S*)-N-(3-chloro-4,5-difluorophenyl)-4-	A
	(hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11-
	hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
029	4-(hydroxymethyl)-2-methyl-1-oxo-N-(3-(pentafluoro-16-	A
	sulfanyl)phenyl)-1,4,5,8,9,11-
	hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
030	N-(3-chlorophenyl)-4-(hydroxymethyl)-2-methyl-1-oxo-	A
	1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
031_E1	(S*)-N-(3-chloro-4-fluorophenyl)-4-(hydroxymethyl)-2-	A
	methyl-1-oxo-1,4,5,8,9,11-
	hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
031_E2	(R*)-N-(3-chloro-4-fluorophenyl)-4-	A
	(hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11-
	hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
032_E1	(S*)-N-(3-bromo-4-fluorophenyl)-4-(hydroxymethyl)-2-	A
	methyl-1-oxo-1,4,5,8,9,11-
	hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
033_E1	(S*)-N-(2-bromo-3-fluoropyridin-4-yl)-4-	A
	(hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11-
	hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
034_E1	(S*)-N-(3-cyano-4-fluorophenyl)-4-(hydroxymethyl)-2-	A
	methyl-1-oxo-1,4,5,8,9,11-
	hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
035_E1	(S*)-N-(4-fluoro-3-methylphenyl)-4-(hydroxymethyl)-2-	A
	methyl-1-oxo-1,4,5,8,9,11-
	hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
036	4-(fluoromethyl)-2-methyl-1-oxo-N-(3-	A
	(trifluoromethyl)phenyl)-1,4,5,8,9,11-
	hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]
	oxadiazepine-10(2H)-carboxamide
037_E1	(S*)-N-(3-chlorophenyl)-4-(fluoromethyl)-2-methyl-1-	A
	oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
038_E1	(S*)-N-(3-chloro-4-fluorophenyl)-4-(fluoromethyl)-2-	A
	methyl-1-oxo-1,4,5,8,9,11-
	hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
039_E1	(S*)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-4-	A
	(fluoromethyl)-2-methyl-1-oxo-1,4,5,8,9,11-
	hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
040_E1	(S*)-N-(3-bromo-4-fluorophenyl)-4-(fluoromethyl)-2-	A
	methyl-1-oxo-1,4,5,8,9,11-
	hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
041_E1	(S*)-N-(2-bromo-3-fluoropyridin-4-yl)-4-(fluoromethyl)-	A
	2-methyl-1-oxo-1,4,5,8,9,11-
	hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
042_E1	(S*)-N-(3-cyano-4-fluorophenyl)-4-(fluoromethyl)-2-	A
	methyl-1-oxo-1,4,5,8,9,11-
	hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
043_E1	(S*)-N-(4-fluoro-3-methylphenyl)-4-(fluoromethyl)-2-	A
	methyl-1-oxo-1,4,5,8,9,11-
	hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
044_E1	(S*)-N-(3-chloro-4,5-difluorophenyl)-4-(fluoromethyl)-	A
	2-methyl-1-oxo-1,4,5,8,9,11-
	hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
045	N-(3-chloro-4-fluorophenyl)-4-(hydroxymethyl)-N,2-	B
	dimethyl-1-oxo-1,4,5,8,9,11-
	hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
046	N-(3-chlorophenyl)-4-(hydroxymethyl)-2,8,8-trimethyl-	B
	1-oxo-1,4,5,8,9,11-
	hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
047	N-(3-chlorophenyl)-4-(hydroxymethyl)-2,8-dimethyl-1-	B
	oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
048	N-(3-chloro-4-fluoro-phenyl)-2-methyl-4-	A
	(methylsulfanylmethyl)-1-oxo-5,8,9,11-tetrahydro-4H-
	pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-
	carboxamide
049_E1	(S)-N-(3-chloro-4-fluorophenyl)-2-methyl-4-(((S)-	B
	methylsulfinyl)methyl)-1-oxo-1,4,5,8,9,11-
	hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
049_E2	(S)-N-(3-chloro-4-fluorophenyl)-2-methyl-4-(((R)-	A
	methylsulfinyl)methyl)-1-oxo-1,4,5,8,9,11-
	hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
049_E3	(R)-N-(3-chloro-4-fluorophenyl)-2-methyl-4-(((R)-	A
	methylsulfinyl)methyl)-1-oxo-1,4,5,8,9,11-
	hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
049_E4	(R)-N-(3-chloro-4-fluorophenyl)-2-methyl-4-(((S)-	B
	methylsulfinyl)methyl)-1-oxo-1,4,5,8,9,11-
	hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
050	N-(3-chloro-4-fluorophenyl)-2-methyl-4-	A
	((methylsulfonyl)methyl)-1-oxo-1,4,5,8,9,11-
	hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
051	(10-((3-chloro-4-fluorophenyl)carbamoyl)-2-methyl-1-	A
	oxo-1,2,4,5,8,9,10,11-
	octahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepin-4-yl)methyl methyl carbonate
052	(10-((3-chloro-4-fluorophenyl)carbamoyl)-2-methyl-1-	A
	oxo-1,2,4,5,8,9,10,11-
	octahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepin-4-yl)methyl acetate
053	(10-((3-chloro-4-fluorophenyl)carbamoyl)-2-methyl-1-	A
	oxo-1,2,4,5,8,9,10,11-
	octahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepin-4-yl)methyl isopropyl carbonate
054	tert-butyl((10-((3-chloro-4-fluorophenyl)carbamoyl)-2-	A
	methyl-1-oxo-1,2,4,5,8,9,10,11-
	octahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepin-4-yl)methyl) carbonate
055	(10-((3-chloro-4-fluorophenyl)carbamoyl)-2-methyl-1-	A
	oxo-1,2,4,5,8,9,10,11-
	octahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepin-4-yl)methyl pivalate
056	(10-((3-chloro-4-fluorophenyl)carbamoyl)-2-methyl-1-	A
	oxo-1,2,4,5,8,9,10,11-
	octahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepin-4-yl)methyl ethyl carbonate
057	(104(3-chloro-4-fluorophenyl)carbamoyl)-2-methyl-1-	A
	oxo-1,2,4,5,8,9,10,11-
	octahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepin-4-yl)methyl carbamate
058	N-(3-chloro-4-fluoro-phenyl)-4-	A
	[(dimethylamino)methyl]-2-methyl-1-oxo-5,8,9,11-
	tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d]
	[1,2,5]oxadiazepine-10-carboxamide
059	[10-[(3-chloro-4-fluoro-phenyl)carbamoyl]-2-methyl-1-	A
	oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d]
	[1,2,5]oxadiazepin-4-yl]methyl N,N-
	dimethylcarbamate
060_E1	(S*)-N-(3-chloro-4-fluorophenyl)-2-ethyl-4-	A
	(hydroxymethyl)-1-oxo-1,4,5,8,9,11-
	hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
060_E2	(R*)-N-(3-chloro-4-fluorophenyl)-2-ethyl-4-	A
	(hydroxymethyl)-1-oxo-1,4,5,8,9,11-
	hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
061	N-(3-chloro-4-fluoro-phenyl)-2,5-dimethyl-1-oxo-	A
	5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d]
	[1,2,5]oxadiazepine-10-carboxamide
062	N-(3-chloro-4-fluorophenyl)-2,4-dimethyl-1-oxo-	A
	1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
063	N-(3-chlorophenyl)-2,4-dimethyl-1-oxo-1,4,5,8,9,11-	A
	hexahydropyrido[4′,3′:3,4]pyrazole[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
064	N-(3-chloro-4-fluoro-phenyl)-2,4,4-trimethyl-1-oxo-	A
	5,8,9,11-tetrahydro pyrido[2,3]pyrazolo[2,4-d]
	[1,2,5]oxadiazepine-10-carboxamide
065	N-(3-chloro-4-fluoro-phenyl)-4-(methoxymethyl)-2-	A
	methyl-1-oxo-5,8,9,11-tetrahydro-4H-
	pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-
	carboxamide
066	N-(3-chloro-4-fluoro-phenyl)-2-methyl-1-oxo-5,8,9,11-	A
	tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-c]
	[1,2,5]oxadiazepine-10-carboxamide
067	2-allyl-N-(3-chloro-4-fluoro-phenyl)-1-oxo-5,8,9,11-	A
	tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-c]
	[1,2,5]oxadiazepine-10-carboxamide
068	N-(3-chloro-4-fluoro-phenyl)-1-oxo-2-propyl-5,8,9,11-	A
	tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-c]
	[1,2,5]oxadiazepine-10-carboxamide
069_E1	(4S,9S)-N-(3-chloro-4-fluorophenyl)-4-	A
	(hydroxymethyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-
	hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
069_E2	(4R,9S)-N-(3-chloro-4-fluorophenyl)-4-	A
	(hydroxymethyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-
	hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
069_E3	(4R,9R)-N-(3-chloro-4-fluorophenyl)-4-	B
	(hydroxymethyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-
	hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
069_E4	(4S,9R)-N-(3-chloro-4-fluorophenyl)-4-	A
	(hydroxymethyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-
	hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
070	N-(3-chloro-4-fluoro-phenyl)-4-(hydroxymethyl)-2,9-	A
	dimethyl-1-oxo-5,8,9,11-tetrahydro-4H-
	pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-
	carboxamide
071	methyl 10-[(3-chloro-4-fluoro-phenyl)carbamoyl]-2-	D
	methyl-1-oxo-5,8,9,11-tetrahydro-4H-
	pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-
	carboxylate
072	N10-(3-chloro-4-fluoro-phenyl)-2-methyl-1-oxo-	A
	5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d]
	[1,2,5]oxadiazepine-4,10-dicarboxamide
073	N10-(3-chloro-4-fluoro-phenyl)-N4,2-dimethyl-1-oxo-	A
	5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d]
	[1,2,5]oxadiazepine-4,10-dicarboxamide
074	N10-(3-chloro-4-fluoro-phenyl)-N4,N4,2-trimethyl-1-	A
	oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d]
	[1,2,5]oxadiazepine-4,10-dicarboxamide
075	(9R)-N-(3-chloro-4-fluoro-phenyl)-2,9-dimethyl-1-oxo-	A
	5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-c]
	[1,2,5]oxadiazepine-10-carboxamide
076	(R)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-2,9-dimethyl-	A
	1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo
	[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide
077	(R)-N-(3-bromo-4-fluorophenyl)-2,9-dimethyl-1-oxo-	A
	1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
078	(R)-N-(2-bromo-3-fluoropyridin-4-yl)-2,9-dimethyl-1-	A
	oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
079	(R)-N-(3-cyano-4-fluorophenyl)-2,9-dimethyl-1-oxo-	A
	1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
080	(R)-N-(4-fluoro-3-methylphenyl)-2,9-dimethyl-1-oxo-	A
	1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
081	(R)-N-(3-chloro-4,5-difluorophenyl)-2,9-dimethyl-1-oxo-	A
	1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
082_E1	(4S*,9R)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-4-	A
	(hydroxymethyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-
	hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
082_E2	(4R*,9R)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-4-	A
	(hydroxymethyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-
	hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
083_E1	(4S*,9R)-N-(4-fluoro-3-methylphenyl)-4-	A
	(hydroxymethyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-
	hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
083_E2	(4R*,9R)-N-(4-fluoro-3-methylphenyl)-4-	A
	(hydroxymethyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-
	hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
084_E1	(4S*,9R)-N-(3-cyano-4-fluorophenyl)-4-	A
	(hydroxymethyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-
	hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
084_E2	(4R*,9R)-N-(3-cyano-4-fluorophenyl)-4-	A
	(hydroxymethyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-
	hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
085_E1	(4S*,9R)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-4-	A
	(fluoromethyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-
	hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
085_E2	(4R*,9R)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-4-	A
	(fluoromethyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-
	hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
086_E1	(4S*,9R)-N-(4-fluoro-3-methylphenyl)-4-(fluoromethyl)-	A
	2,9-dimethyl-1-oxo-1,4,5,8,9,11-
	hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
086_E2	(4R*,9R)-N-(4-fluoro-3-methylphenyl)-4-(fluoromethyl)-	A
	2,9-dimethyl-1-oxo-1,4,5,8,9,11-
	hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
087_E1	(4S*,9R)-N-(3-cyano-4-fluorophenyl)-4-(fluoromethyl)-	A
	2,9-dimethyl-1-oxo-1,4,5,8,9,11-
	hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
087_E2	(4R*,9R)-N-(3-cyano-4-fluorophenyl)-4-(fluoromethyl)-	A
	2,9-dimethyl-1-oxo-1,4,5,8,9,11-
	hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
088_E1	(4S*,9R)-N-(3-chloro-4-fluorophenyl)-4-(fluoromethyl)-	A
	2,9-dimethyl-1-oxo-1,4,5,8,9,11-
	hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
088_E2	(4R*,9R)-N-(3-chloro-4-fluorophenyl)-4-(fluoromethyl)-	A
	2,9-dimethyl-1-oxo-1,4,5,8,9,11-
	hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
089_E1	(4S*,9R)-N-(5-bromo-2,4-difluorophenyl)-4-	A
	(hydroxymethyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-
	hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
089_E2	(4R*,9R)-N-(5-bromo-2,4-difluorophenyl)-4-	A
	(hydroxymethyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-
	hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
090_E1	(4S*,9R)-N-(5-chloro-2,4-difluorophenyl)-4-	A
	(hydroxymethyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-
	hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
090_E2	(4R*,9R)-N-(5-chloro-2,4-difluorophenyl)-4-	A
	(hydroxymethyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-
	hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
091_E1	(4S*,9R)-N-(3-chloro-2,4-difluorophenyl)-4-	A
	(hydroxymethyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-
	hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
091_E2	(4R*,9R)-N-(3-chloro-2,4-difluorophenyl)-4-	A
	(hydroxymethyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-
	hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
092_E1	(4S*,9R)-N-(3-bromo-2,4-difluorophenyl)-4-	A
	(hydroxymethyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-
	hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
092_E2	(4R*,9R)-N-(3-bromo-2,4-difluorophenyl)-4-	A
	(hydroxymethyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-
	hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
093_D1	(4S*,9R)-N-(3-chloro-4-fluorophenyl)-4-	A
	((dimethylamino)methyl)-2,9-dimethyl-1-oxo-
	1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
093_D2	(4R*,9R)-N-(3-chloro-4-fluorophenyl)-4-	A
	((dimethylamino)methyl)-2,9-dimethyl-1-oxo-
	1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
094_D1	(4S*,9R)-N-(3-bromo-4-fluorophenyl)-4-	A
	((dimethylamino)methyl)-2,9-dimethyl-1-oxo-
	1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
094_D2	(4R*,9R)-N-(3-bromo-4-fluorophenyl)-4-	A
	((dimethylamino)methyl)-2,9-dimethyl-1-oxo-
	1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
095_D1	(4S*,9R)-N-(2-bromo-3-fluoropyridin-4-yl)-4-	B
	((dimethylamino)methyl)-2,9-dimethyl-1-oxo-
	1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
095_D2	(4R*,9R)-N-(2-bromo-3-fluoropyridin-4-yl)-4-	B
	((dimethylamino)methyl)-2,9-dimethyl-1-oxo-
	1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
096_D1	(4S*,9R)-N-(3-cyano-4-fluorophenyl)-4-	B
	((dimethylamino)methyl)-2,9-dimethyl-1-oxo-
	1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
096_D2	(4R*,9R)-N-(3-cyano-4-fluorophenyl)-4-	A
	((dimethylamino)methyl)-2,9-dimethyl-1-oxo-
	1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1d]-
	[1,2,5]oxadiazepine-10(2H)-carboxamide
097_D1	(4S*,9R)-4-((dimethylamino)methyl)-N-(4-fluoro-3-	A
	methylphenyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-
	hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
097_D2	(4R*,9R)-4-((dimethylamino)methyl)-N-(4-fluoro-3-	A
	methylphenyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-
	hexahydropyrido[4′,3′:3,4]pyrazolo[5,1d]-
	[1,2,5]oxadiazepine-10(2H)-carboxamide
098_D1	(4S*,9R)-4-((dimethylamino)methyl)-N-(4-fluoro-3-	A
	(trifluoromethyl)phenyl)-2,9-dimethyl-1-oxo-
	1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
098_D2	(4R*,9R)-4-((dimethylamino)methyl)-N-(4-fluoro-3-	A
	(trifluoromethyl)phenyl)-2,9-dimethyl-1-oxo-
	1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
099_D1	(4S*,9R)-N-(5-chloro-2,4-difluorophenyl)-4-	B
	((dimethylamino)methyl)-2,9-dimethyl-1-oxo-
	1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
099_D2	(4R*,9R)-N-(5-chloro-2,4-difluorophenyl)-4-	B
	((dimethylamino)methyl)-2,9-dimethyl-1-oxo-
	1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
100_D1	(4S*,9R)-N-(5-bromo-2,4-difluorophenyl)-4-	B
	((dimethylamino)methyl)-2,9-dimethyl-1-oxo-
	1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
100_D2	(4R*,9R)-N-(5-bromo-2,4-difluorophenyl)-4-	A
	((dimethylamino)methyl)-2,9-dimethyl-1-oxo-
	1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
101	N-(3-chloro-4-fluoro-phenyl)-4-(ethoxymethyl)-2-	A
	methyl-1-oxo-5,8,9,11-tetrahydro-4H-
	pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-
	carboxamide
102	4-(allyloxymethyl)-N-(3-chloro-4-fluoro-phenyl)-2-	A
	methyl-1-oxo-5,8,9,11-tetrahydro-4H-
	pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-
	carboxamide
103	N-(3-chloro-4-fluoro-phenyl)-2-methyl-1-oxo-4-	A
	(propoxymethyl)-5,8,9,11-tetrahydro-4H-
	pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-
	carboxamide
104	N-(3-chloro-4-fluoro-phenyl)-4-	A
	(cyclopropylmethoxymethyl)-2-methyl-1-oxo-5,8,9,11-
	tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d]
	[1,2,5]oxadiazepine-10-carboxamide
105	N-(3-chloro-4-fluoro-phenyl)-4-(2,2-	A
	difluoroethoxymethyl)-2-methyl-1-oxo-5,8,9,11-
	tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d]
	[1,2,5]oxadiazepine-10-carboxamide
106	N-(3-chloro-4-fluoro-phenyl)-2-methyl-1-oxo-4-(2,2,2-	A
	trifluoroethoxymethyl)-5,8,9,11-tetrahydro-4H-
	pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-
	carboxamide
107	N-(3-chloro-4-fluoro-phenyl)-4-(hydroxymethyl)-1-oxo-	A
	2-(trideuteriomethyl)-5,8,9,11-tetrahydro-4H-
	pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-
	carboxamide
108_D1	(4S*,9R)-N-(5-bromo-2,4-difluorophenyl)-4-((2,2-	B
	difluoroethoxy)methyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-
	hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]
	oxadiazepine-10(2H)-carboxamide
108_D2	(4R*,9R)-N-(5-bromo-2,4-difluorophenyl)-4-((2,2-	A
	difluoroethoxy)methyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-
	hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
109_D1	(4S,9S)-N-(3-chloro-4-fluorophenyl)-9-ethyl-4-	B
	(hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11-
	hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
109_D2	(4S,9R)-N-(3-chloro-4-fluorophenyl)-9-ethyl-4-	B
	(hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11-
	hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
109_D3	(4R,9R)-N-(3-chloro-4-fluorophenyl)-9-ethyl-4-	C
	(hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11-
	hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
109_D4	(4R,9S)-N-(3-chloro-4-fluorophenyl)-9-ethyl-4-	B
	(hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11-
	hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
110_D1	(4S*,9R)-N10-(3-chloro-2,4-difluorophenyl)-N4,2,9-	C
	trimethyl-1-oxo-1,4,5,8,9,11-
	hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-4,10(2H)-dicarboxamide
110_D2	(4R*,9R)-N10-(3-chloro-2,4-difluorophenyl)-N4,2,9-	A
	trimethyl-1-oxo-1,4,5,8,9,11-
	hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-4,10(2H)-dicarboxamide
111_D1	(4S*,9R)-N10-(5-chloro-2,4-difluorophenyl)-N4,2,9-	D
	trimethyl-1-oxo-1,4,5,8,9,11-
	hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-4,10(2H)-dicarboxamide
111_D2	(4R*,9R)-N10-(5-chloro-2,4-difluorophenyl)-N4,2,9-	A
	trimethyl-1-oxo-1,4,5,8,9,11-
	hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-4,10(2H)-dicarboxamide
112_D1	(4S*,9R)-N10-(3-cyano-4-fluorophenyl)-N4,2,9-	D
	trimethyl-1-oxo-1,4,5,8,9,11-
	hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-4,10(2H)-dicarboxamide
112_D2	(4R*,9R)-N10-(3-cyano-4-fluorophenyl)-N4,2,9-	A
	trimethyl-1-oxo-1,4,5,8,9,11-
	hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-4,10(2H)-dicarboxamide
113	4-(aminomethyl)-N-(3-chloro-4-fluoro-phenyl)-2-methyl-	A
	1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d]
	[1,2,5]oxadiazepine-10-carboxamide
114_E1	(S*)-4-(aminomethyl)-N-(3-cyano-4-fluoro-phenyl)-2-	A
	methyl-1-oxo-5,8,9,11-tetrahydro-4H-
	pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-
	carboxamide
115_D1	(4S*,9R)-4-(aminomethyl)-N-(3-cyano-4-fluorophenyl)-	A
	2,9-dimethyl-1-oxo-1,4,5,8,9,11-
	hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
115_D2	(4R*,9R)-4-(aminomethyl)-N-(3-cyano-4-fluorophenyl)-	N/A
	2,9-dimethyl-1-oxo-1,4,5,8,9,11-
	hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
116_D1	(4S*,9R)-4-(aminomethyl)-N-(4-fluoro-3-	A
	(trifluoromethyl)phenyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-
	hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
116_D2	(4R*,9R)-4-(aminomethyl)-N-(4-fluoro-3-	A
	(trifluoromethyl)phenyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-
	hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
117_D1	(4S*,9R)-4-(aminomethyl)-N-(3-bromo-4-fluorophenyl)-	A
	2,9-dimethyl-1-oxo-1,4,5,8,9,11-
	hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
117_D2	(4R*,9R)-4-(aminomethyl)-N-(3-bromo-4-fluorophenyl)-	A
	2,9-dimethyl-1-oxo-1,4,5,8,9,11-
	hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
118	N10-(3-chloro-2,4-difluorophenyl)-N4,2-dimethyl-1-oxo-	A
	1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-4,10(2H)-dicarboxamide
119	N10-(5-chloro-2,4-difluorophenyl)-N4,2-dimethyl-1-oxo-	B
	1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-4,10(2H)-dicarboxamide
120	N10-(3-cyano-4-fluorophenyl)-N4,2-dimethyl-1-oxo-	B
	1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-4,10(2H)-dicarboxamide
121_D1	(4S*,9R)-N-(3-chloro-4-fluorophenyl)-4-((2,2-	A
	difluoroethoxy)methyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-
	hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
121_D2	(4R*,9R)-N-(3-chloro-4-fluorophenyl)-4-((2,2-	A
	difluoroethoxy)methyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-
	hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
122_D1	(4S*,9R)-N-(3-bromo-4-fluorophenyl)-4-((2,2-	A
	difluoroethoxy)methyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-
	hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
122_D2	(4R*,9R)-N-(3-bromo-4-fluorophenyl)-4-((2,2-	A
	difluoroethoxy)methyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-
	hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
123_D1	(4S*,9R)-N-(2-bromo-3-fluoropyridin-4-yl)-4-((2,2-	B
	difluoroethoxy)methyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-
	hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
123_D2	(4R*,9R)-N-(2-bromo-3-fluoropyridin-4-yl)-4-((2,2-	A
	difluoroethoxy)methyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-
	hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
124_D1	(4S*,9R)-N-(3-cyano-4-fluorophenyl)-4-((2,2-	A
	difluoroethoxy)methyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-
	hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-
	d][1,2,5]oxadiazepine-10(2H)-carboxamide
124_D2	(4R*,9R)-N-(3-cyano-4-fluorophenyl)-4-((2,2-	A
	difluoroethoxy)methyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-
	hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
125_D1	(4S*,9R)-442,2-difluoroethoxy)methyl)-N-(4-fluoro-3-	A
	methylphenyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-
	hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
125_D2	(4R*,9R)-44(2,2-difluoroethoxy)methyl)-N-(4-fluoro-3-	A
	methylphenyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-
	hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
126_D1	(4S*,9R)-442,2-difluoroethoxy)methyl)-N-(4-fluoro-3-	B
	(trifluoromethyl)phenyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-
	hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
126_D2	(4R*,9R)-442,2-difluoroethoxy)methyl)-N-(4-fluoro-3-	A
	(trifluoromethyl)phenyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-
	hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
127_D1	(4S*,9R)-N-(5-chloro-2,4-difluorophenyl)-442,2-	B
	difluoroethoxy)methyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-
	hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
127_D2	(4R*,9R)-N-(5-chloro-2,4-difluorophenyl)-4-((2,2-	A
	difluoroethoxy)methyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-
	hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
128	N-(3-chloro-4-fluoro-phenyl)-2-methyl-1-oxo-4-	A
	(trifluoromethoxymethyl)-5,8,9,11-tetrahydro-4H-
	pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-
	carboxamide
129	N-(3-chloro-4-fluorophenyl)-4-	A
	(ethylsulfonamidomethyl)-2-methyl-1-oxo-1,4,5,8,9,11-
	hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
130	N-(3-chloro-4-fluorophenyl)-2-methyl-1-oxo-4-(((2,2,2-	A
	trifluoroethyl)sulfonamido)methyl)-1,4,5,8,9,11-
	hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
131	N-(3-chloro-4-fluorophenyl)-4-(3,3-difluoroazetidine-1-	A
	carbonyl)-2-methyl-1-oxo-1,4,5,8,9,11-
	hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
132	N-(3-chloro-4-fluorophenyl)-4-(3 3-difluoropyrrolidine-	A
	1-carbonyl)-2-methyl-1-oxo-1,4,5,8,9,11-
	hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
133	N10-(3-chloro-4-fluorophenyl)-N4,2-dimethyl-1-oxo-N4-	A
	(2,2,2-trifluoroethyl)-1,4,5,8,9,11-
	hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-4,10(2H)-dicarboxamide
134	N10-(3-chloro-4-fluorophenyl)-N4-(2,2-difluoroethyl)-	A
	N4,2-dimethyl-1-oxo-1,4,5,8,9,11-
	hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-4,10(2H)-dicarboxamide
135	N10-(3-chloro-4-fluorophenyl)-2-methyl-1-oxo-N4-	A
	(2,2,2-trifluoroethyl)-1,4,5,8,9,11-
	hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-4,10(2H)-dicarboxamide
136	N10-(3-chloro-4-fluorophenyl)-N4-(2,2-difluoroethyl)-2-	A
	methyl-1-oxo-1,4,5,8,9,11-
	hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-4,10(2H)-dicarboxamide
137_E1	(S*)-N-(3-chloro-2,4,5-trifluorophenyl)-4-	A
	(hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11-
	hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
138_E1	(S*)-N-(3-chloro-2,6-difluorophenyl)-4-	B
	(hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11-
	hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
139_E1	(S*)-N-(5-chloro-2-fluorophenyl)-4-(hydroxymethyl)-2-	A
	methyl-1-oxo-1,4,5,8,9,11-
	hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
140_E1	(S*)-N-(5-bromo-2,3-difluorophenyl)-4-	A
	(hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11-
	hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
141_E1	(S*)-N-(5-bromo-2-fluorophenyl)-4-(hydroxymethyl)-2-	A
	methyl-1-oxo-1,4,5,8,9,11-
	hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
142_E1	(S*)-N-(2,4-difluoro-3-methylphenyl)-4-	A
	(hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11-
	hexahydropyrido[4′,3′:3,4]pyrazolo[5,1d]-
	[1,2,5]oxadiazepine-10(2H)-carboxamide
143_E1	(S*)-N-(2,4-difluoro-5-methylphenyl)-4-	A
	(hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11-
	hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
144_E1	(S*)-4-(hydroxymethyl)-2-methyl-1-oxo-N-(2,4,5-	A
	trifluoro-3-methylphenyl)-1,4,5,8,9,11-
	hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]
	oxadiazepine-10(2H)-carboxamide
145_E1	(S*)-N-(5-cyano-2-fluorophenyl)-4-(hydroxymethyl)-2-	D
	methyl-1-oxo-1,4,5,8,9,11-
	hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
146_E1	(S*)-N-(3-cyano-2-fluorophenyl)-4-(hydroxymethyl)-2-	A
	methyl-1-oxo-1,4,5,8,9,11-
	hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
147_E1	(S*)-N-(2,4-difluoro-5-(trifluoromethyl)phenyl)-4-	A
	(hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11-
	hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
148_E1	(S*)-N-(2-fluoro-5-(trifluoromethyl)phenyl)-4-	B
	(hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11-
	hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
149_E1	(S*)-N-(2,4-difluoro-3-(trifluoromethyl)phenyl)-4-	A
	(hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11-
	hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
150_E1	(S*)-N-(2-bromo-5-fluoropyridin-4-yl)-4-	A
	(hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11-
	hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
151_E1	(S*)-4-(hydroxymethyl)-2-methyl-1-oxo-N-(2,3,4,5-	A
	tetrafluorophenyl)-1,4,5,8,9,11-
	hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
152_D1	(4S*,9R)-N10-(3-chloro-2,4-difluorophenyl)-N4-(2,2-	A
	difluoroethyl)-N4,2,9-trimethyl-1-oxo-1,4,5,8,9,11-
	hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-4,10(2H)-dicarboxamide
152_D2	(4R*,9R)-N10-(3-chloro-2,4-difluorophenyl)-N4-(2,2-	A
	difluoroethyl)-N4,2,9-trimethyl-1-oxo-1,4,5,8,9,11-
	hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-4,10(2H)-dicarboxamide
153_D1	(4S*,9R)-N10-(3-cyano-2,4-difluorophenyl)-N4-(2,2-	B
	difluoroethyl)-N4,2,9-trimethyl-1-oxo-1,4,5,8,9,11-
	hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-4,10(2H)-dicarboxamide
153_D2	(4R*,9R)-N10-(3-cyano-2,4-difluorophenyl)-N4-(2,2-	A
	difluoroethyl)-N4,2,9-trimethyl-1-oxo-1,4,5,8,9,11-
	hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-4,10(2H)-dicarboxamide
154_D1	(4S*,9R)-N10-(5-chloro-2,4-difluorophenyl)-N4-(2,2-	C
	difluoroethyl)-N4,2,9-trimethyl-1-oxo-1,4,5,8,9,11-
	hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-4,10(2H)-dicarboxamide
154_D2	(4R*,9R)-N10-(5-chloro-2,4-difluorophenyl)-N4-(2,2-	A
	difluoroethyl)-N4,2,9-trimethyl-1-oxo-1,4,5,8,9,11-
	hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-4,10(2H)-dicarboxamide
155_D1	(4S*,9R)-N10-(3-cyano-4-fluorophenyl)-N4-(2,2-	C
	difluoroethyl)-N4,2,9-trimethyl-1-oxo-1,4,5,8,9,11-
	hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-4,10(2H)-dicarboxamide
155_D2	(4R*,9R)-N10-(3-cyano-4-fluorophenyl)-N4-(2,2-	A
	difluoroethyl)-N4,2,9-trimethyl-1-oxo-1,4,5,8,9,11-
	hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-4,10(2H)-dicarboxamide
156_D1	(4S*,9R)-N10-(3-cyano-2,4-difluorophenyl)-N4,2,9-	D
	trimethyl-1-oxo-1,4,5,8,9,11-
	hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-4,10(2H)-dicarboxamide
156_D2	(4R*,9R)-N10-(3-cyano-2,4-difluorophenyl)-N4,2,9-	A
	trimethyl-1-oxo-1,4,5,8,9,11-
	hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-4,10(2H)-dicarboxamide
157_D1	(4S*,9R)-N-[2-fluoro-5-(trifluoromethyl)phenyl]-4-	A
	(hydroxymethyl)-2,9-dimethyl-1-oxo-5,8,9,11-
	tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d]
	[1,2,5]oxadiazepine-10-carboxamide
157_D2	(4R*,9R)-N-[2-fluoro-5-(trifluoromethyl)phenyl]-4-	A
	(hydroxymethyl)-2,9-dimethyl-1-oxo-5,8,9,11-
	tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d]
	[1,2,5]oxadiazepine-10-carboxamide
158	N10-(3-chloro-2,4-difluorophenyl)-N4-(2,2-	A
	difluoroethyl)-N4,2-dimethyl-1-oxo-1,4,5,8,9,11-
	hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-4,10(2H)-dicarboxamide
159	N10-(5-chloro-2,4-difluorophenyl)-N4-(2,2-	A
	difluoroethyl)-N4,2-dimethyl-1-oxo-1,4,5,8,9,11-
	hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-4,10(2H)-dicarboxamide
160	N10-(3-cyano-4-fluorophenyl)-N4-(2,2-difluoroethyl)-	A
	N4,2-dimethyl-1-oxo-1,4,5,8,9,11-
	hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-4,10(2H)-dicarboxamide
161	N10-(3-cyano-2,4-difluorophenyl)-N4-(2,2-	A
	difluoroethyl)-N4,2-dimethyl-1-oxo-1,4,5,8,9,11-
	hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-4,10(2H)-dicarboxamide
162	4-(acetamidomethyl)-N-(3-chloro-4-fluorophenyl)-2-	A
	methyl-1-oxo-1,4,5,8,9,11-
	hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
163	N-(3-chloro-4-fluorophenyl)-2-methyl-1-oxo-4-((2,2,2-	A
	trifluoroacetamido)methyl)-1,4,5,8,9,11-
	hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
164	N-(3-chloro-4-fluorophenyl)-2-methyl-1-oxo-4-	B
	(((trifluoromethyl)sulfonamido)methyl)-1,4,5,8,9,11-
	hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
165	N-(3-chloro-4-fluorophenyl)-2-methyl-4-	A
	(methylsulfonamidomethyl)-1-oxo-1,4,5,8,9,11-
	hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
166	methyl ((10-((3-chloro-4-fluorophenyl)carbamoyl)-2-	A
	methyl-1-oxo-1,2,4,5,8,9,10,11-
	octahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepin-4-yl)methyl)carbamate
167_E1	(S*)-4-(acetamidomethyl)-N-(3-cyano-2,4-	A
	difluorophenyl)-2-methyl-1-oxo-1,4,5,8,9,11-
	hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
168_E1	(S*)-4-(acetamidomethyl)-N-(3-cyano-4-fluorophenyl)-2-	A
	methyl-1-oxo-1,4,5,8,9,11-
	hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
169_E1	(S*)-4-(acetamidomethyl)-N-(3-chloro-2,4-	A
	difluorophenyl)-2-methyl-1-oxo-1,4,5,8,9,11-
	hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
170_E1	(S*)-4-(acetamidomethyl)-N-(3-bromo-2,4-	A
	difluorophenyl)-2-methyl-1-oxo-1,4,5,8,9,11-
	hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
171_E1	(S*)-4-(acetamidomethyl)-N-(3-bromo-4-fluorophenyl)-	A
	2-methyl-1-oxo-1,4,5,8,9,11-
	hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
172_E1	(S*)-4-(acetamidomethyl)-N-(2,4-difluoro-3-	A
	(trifluoromethyl)phenyl)-2-methyl-1-oxo-1,4,5,8,9,11-
	hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
173_E1	(S*)-4-(acetamidomethyl)-N-(5-chloro-2,4-	A
	difluorophenyl)-2-methyl-1-oxo-1,4,5,8,9,11-
	hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
174_E1	(S*)-4-(acetamidomethyl)-N-(5-bromo-2,4-	A
	difluorophenyl)-2-methyl-1-oxo-1,4,5,8,9,11-
	hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
175_E1	(S*)-4-(acetamidomethyl)-N-(4-fluoro-3-	A
	(trifluoromethyl)phenyl)-2-methyl-1-oxo-1,4,5,8,9,11-
	hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
176_D1	(4S*,9R)-4-(acetamidomethyl)-N-(3-cyano-4-	B
	fluorophenyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-
	hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
176_D2	(4R*,9R)-4-(acetamidomethyl)-N-(3-cyano-4-	A
	fluorophenyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-
	hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
177_D1	(4S*,9R)-4-(acetamidomethyl)-N-(4-fluoro-3-	A
	(trifluoromethyl)phenyl)-2,9-dimethyl-1-oxo-
	1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
177_D2	(4R*,9R)-4-(acetamidomethyl)-N-(4-fluoro-3-	A
	(trifluoromethyl)phenyl)-2,9-dimethyl-1-oxo-
	1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
178_D1	(4S*,9R)-N-(3-cyano-4-fluorophenyl)-2,9-dimethyl-4-	B
	(methylsulfonamidomethyl)-1-oxo-1,4,5,8,9,11-
	hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-
	10(2H)-carboxamide
178_D2	(4R*,9R)-N-(3-cyano-4-fluorophenyl)-2,9-dimethyl-4-	A
	(methylsulfonamidomethyl)-1-oxo-1,4,5,8,9,11-
	hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
179_D1	(4S*,9R)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-2,9-	A
	dimethyl-4-(methylsulfonamidomethyl)-1-oxo-
	1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
179_D2	(4R*,9R)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-2,9-	A
	dimethyl-4-(methylsulfonamidomethyl)-1-oxo-
	1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
180_D1	methyl (((4S*,9R)-10-((3-cyano-4-	A
	fluorophenyl)carbamoyl)-2,9-dimethyl-1-oxo-
	1,2,4,5,8,9,10,11-octahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepin-4-yl)methyl)carbamate
180_D2	methyl (((4R*,9R)-10-((3-cyano-4-	A
	fluorophenyl)carbamoyl)-2,9-dimethyl-1-oxo-
	1,2,4,5,8,9,10,11-octahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepin-4-yl)methyl)carbamate
181_D1	methyl (((4S*,9R)-10-((4-fluoro-3-	A
	(trifluoromethyl)phenyl)carbamoyl)-2,9-dimethyl-1-oxo-
	1,2,4,5,8,9,10,11-octahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepin-4-yl)methyl)carbamate
181_D2	methyl (((4R*,9R)-10-((4-fluoro-3-	A
	(trifluoromethyl)phenyl)carbamoyl)-2,9-dimethyl-1-oxo-
	1,2,4,5,8,9,10,11-octahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepin-4-yl)methyl)carbamate
182_D1	(4S*,9R)-4-(((2,2-difluoroethyl)amino)methyl)-N-(4-	A
	fluoro-3-(trifluoromethyl)phenyl)-2,9-dimethyl-1-oxo-
	1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
182_D2	(4R*,9R)-4-(((2,2-difluoroethyl)amino)methyl)-N-(4-	A
	fluoro-3-(trifluoromethyl)phenyl)-2,9-dimethyl-1-oxo-
	1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
183_D1	(4S*,9R)-N-(3-cyano-4-fluorophenyl)-4-(((2,2-	A
	difluoroethyl)amino)methyl)-2,9-dimethyl-1-oxo-
	1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
183_D2	(4R*,9R)-N-(3-cyano-4-fluorophenyl)-4-(((2,2-	A
	difluoroethyl)amino)methyl)-2,9-dimethyl-1-oxo-
	1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
184_D1	(4S*,9R)-N-(3-bromo-4-fluorophenyl)-4-(((2,2-	A
	difluoroethyl)amino)methyl)-2,9-dimethyl-1-oxo-
	1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
184_D2	(4R*,9R)-N-(3-bromo-4-fluorophenyl)-4-(((2,2-	A
	difluoroethyl)amino)methyl)-2,9-dimethyl-1-oxo-
	1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
185_D1	(4S*,9R)-4-(((2,2-difluoroethyl)amino)methyl)-N-(4-	A
	fluoro-3-methylphenyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-
	hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
185_D2	(4R*,9R)-44(2,2-difluoroethyl)amino)methyl)-N-(4-	A
	fluoro-3-methylphenyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-
	hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
186_E1	(S*)-N-(3-cyano-2,4-difluorophenyl)-4-(((2,2-	A
	difluoroethyl)amino)methyl)-2-methyl-1-oxo-
	1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
187_E1	(S*)-N-(3-cyano-4-fluorophenyl)-4-(((2,2-	A
	difluoroethyl)amino)methyl)-2-methyl-1-oxo-
	1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
188_E1	(S*)-N-(3-chloro-2,4-difluorophenyl)-4-(((2,2-	A
	difluoroethyl)amino)methyl)-2-methyl-1-oxo-
	1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
189_E1	(S*)-N-(3-bromo-2,4-difluorophenyl)-4-(((2,2-	A
	difluoroethyl)amino)methyl)-2-methyl-1-oxo-
	1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
190_E1	(S*)-N-(3-bromo-4-fluorophenyl)-4-(((2,2-	A
	difluoroethyl)amino)methyl)-2-methyl-1-oxo-
	1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
191_E1	(S*)-N-(2,4-difluoro-3-(trifluoromethyl)phenyl)-4-(((2,2-	A
	difluoroethyl)amino)methyl)-2-methyl-1-oxo-
	1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
192_E1	(S*)-N-(5-chloro-2,4-difluorophenyl)-4-(((2,2-	A
	difluoroethyl)amino)methyl)-2-methyl-1-oxo-
	1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
193_E1	(S*)-N-(5-bromo-2,4-difluorophenyl)-4-(((2,2-	A
	difluoroethyl)amino)methyl)-2-methyl-1-oxo-
	1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
194_E1	(S*)-44(2,2-difluoroethyl)amino)methyl)-N-(4-fluoro-3-	A
	(trifluoromethyl)phenyl)-2-methyl-1-oxo-1,4,5,8,9,11-
	hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
195	N10-(3-cyano-2,4-difluorophenyl)-N4,2-dimethyl-1-oxo-	A
	1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-4,10(2H)-dicarboxamide
196	N-(3-chloro-4-fluoro-phenyl)-2-methyl-1-oxo-4-[(2-	N/A
	oxopyrrolidin-1-yl)methyl]-5,8,9,11-tetrahydro-4H-
	pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-
	carboxamide
197	N-(3-chloro-4-fluorophenyl)-2-methyl-1-oxo-4-	A
	(propionamidomethyl)-1,4,5,8,9,11-
	hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
198	N-(3-chloro-4-fluorophenyl)-4-	A
	(cyclopropanecarboxamidomethyl)-2-methyl-1-oxo-
	1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
199	N-(3-chloro-4-fluorophenyl)-2-methyl-1-oxo-4-((3,3,3-	A
	trifluoropropanamido)methyl)-1,4,5,8,9,11-
	hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
200	N-(3-chloro-4-fluorophenyl)-4-(isobutyramidomethyl)-2-	A
	methyl-1-oxo-1,4,5,8,9,11-
	hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
201	N-(3-chloro-4-fluorophenyl)-2-methyl-1-oxo-4-	A
	(pivalamidomethyl)-1,4,5,8,9,11-
	hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
202	ethyl ((10-((3-chloro-4-fluorophenyl)carbamoyl)-2-	A
	methyl-1-oxo-1,2,4,5,8,9,10,11-
	octahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepin-4-yl)methyl)carbamate
203	cyclopropyl ((1043-chloro-4-fluorophenyl)carbamoyl)-	A
	2-methyl-1-oxo-1,2,4,5,8,9,10,11-
	octahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepin-4-yl)methyl)carbamate
204	N-(3-chloro-4-fluorophenyl)-4-((3,3-	A
	dimethylureido)methyl)-2-methyl-1-oxo-1,4,5,8,9,11-
	hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
205	N-(3-chloro-4-fluorophenyl)-4-((2-	A
	cyanoacetamido)methyl)-2-methyl-1-oxo-1,4,5,8,9,11-
	hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
206	N-(3-chloro-4-fluorophenyl)-4-((2-	A
	hydroxyacetamido)methyl)-2-methyl-1-oxo-1,4,5,8,9,11-
	hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
207	2,2,2-trifluoroethyl ((10-((3-chloro-4-	A
	fluorophenyl)carbamoyl)-2-methyl-1-oxo-
	1,2,4,5,8,9,10,11-octahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepin-4-yl)methyl)carbamate
208	N-(3-chloro-4-fluorophenyl)-4-	A
	(ethylsulfonamidomethyl)-2-methyl-1-oxo-1,4,5,8,9,11-
	hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
209	N-(3-chloro-4-fluoro-phenyl)-4-(hydroxymethyl)-2-	C
	methyl-1-oxo-4,5,8,9,10,11-hexahydro-
	[1,2,5]oxadiazepino[5,4-b+indazole-10-carboxamide
210	(4S*,9R)-N-(3-cyano-4-fluorophenyl)-2,9-dimethyl-1-	A
	oxo-442,2,2-trifluoroethoxy)methyl)-1,4,5,8,9,11-
	hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
211	(S*)-N-(3-cyano-4-fluorophenyl)-442,2-	A
	difluoroethoxy)methyl)-2-methyl-1-oxo-1,4,5,8,9,11-
	hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
212	(S*)-4((2,2-difluoroethoxy)methyl)-N-(4-fluoro-3-	A
	(trifluoromethyl)phenyl)-2-methyl-1-oxo-1,4,5,8,9,11-
	hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
213	(R)-N-(3-cyano-4-fluorophenyl)-2,4,4,9-tetramethyl-1-	A
	oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
214	(R)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-2,4,4,9-	A
	tetramethyl-1-oxo-1,4,5,8,9,11-
	hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]oxadiazepine-10(2H)-carboxamide
216	N-(3-chloro-4-fluorophenyl)-2-methyl-1-oxo-	B
	1,2,3,4,5,8,9,11-octahydro-10H-
	pyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]triazepine-10-
	carboxamide
217	N-(3-chloro-4-fluorophenyl)-2,3-dimethyl-1-oxo-	A
	1,2,3,4,5,8,9,11-octahydro-10H-
	pyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]triazepine-10-
	carboxamide
218	(R)-3-allyl-N-(3-cyano-4-fluorophenyl)-2,9-dimethyl-1-	A
	oxo-1,2,3,4,5,8,9,11-octahydro-10H-
	pyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]triazepine-10-
	carboxamide
219	(R)-N-(3-cyano-4-fluorophenyl)-3-(2,2-difluoroethyl)-	A
	2,9-dimethyl-1-oxo-1,2,3,4,5,8,9,11-octahydro-10H-
	pyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]triazepine-10-
	carboxamide
220	(R)-N-(3-cyano-4-fluorophenyl)-3-(2-hydroxyethyl)-2,9-	B
	dimethyl-1-oxo-1,2,3,4,5,8,9,11-octahydro-10H-
	pyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]triazepine-10-
	carboxamide
221	(R)-N-(3-cyano-4-fluorophenyl)-2,9-dimethyl-1-oxo-3-	A
	propyl-1,2,3,4,5,8,9,11-octahydro-10H-
	pyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]triazepine-10-
	carboxamide
222	(R)-N-(3-cyano-4-fluorophenyl)-3-(3-hydroxypropyl)-	B
	2,9-dimethyl-1-oxo-1,2,3,4,5,8,9,11-octahydro-10H-
	pyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]triazepine-10-
	carboxamide
223	(9R)-N-(3-cyano-4-fluorophenyl)-3-(2-hydroxypropyl)-	B
	2,9-dimethyl-1-oxo-1,2,3,4,5,8,9,11-octahydro-10H-
	pyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]triazepine-10-
	carboxamide
224	(R)-N-(3-cyano-4-fluorophenyl)-2,3,9-trimethyl-1-oxo-	A
	1,2,3,4,5,8,9,11-octahydro-10H-
	pyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]triazepine-10-
	carboxamide
225	(R)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-2,3,9-	A
	trimethyl-1-oxo-1,2,3,4,5,8,9,11-octahydro-10H-
	pyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]triazepine-10-
	carboxamide
226	N-(3-chloro-4-fluorophenyl)-4-hydroxy-2-methyl-1-oxo-	D
	4-(trifluoromethyl)-1,2,3,4,5,8,9,11-octahydro-10H-
	pyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]triazepine-10-
	carboxamide
227	N-(3-chloro-4-fluorophenyl)-4-(hydroxymethyl)-2-	A
	methyl-1-oxo-1,2,5,8,9,11-hexahydro-10H-
	pyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]triazepine-10-
	carboxamide
228	N-(3-cyano-4-fluorophenyl)-4-(hydroxymethyl)-2-	A
	methyl-1-oxo-1,2,5,8,9,11-hexahydro-10H-
	pyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]triazepine-10-
	carboxamide
229	N-(3-chloro-4-fluorophenyl)-4-(1-hydroxypropyl)-2-	B
	methyl-1-oxo-1,2,5,8,9,11-hexahydro-10H-
	pyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]triazepine-10-
	carboxamide
230	N-(3-chloro-4-fluorophenyl)-4-(1-hydroxyethyl)-2-	A
	methyl-1-oxo-1,2,5,8,9,11-hexahydro-10H-
	pyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]triazepine-10-
	carboxamide
231	N-(3-chloro-4-fluorophenyl)-4-	B
	(cyclopropyl(hydroxy)methyl)-2-methyl-1-oxo-
	1,2,5,8,9,11-hexahydro-10H-
	pyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]triazepine-10-
	carboxamide
232	N-(3-chloro-4-fluorophenyl)-2,4-dimethyl-1-oxo-	A
	1,2,5,8,9,11-hexahydro-10H-
	pyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]triazepine-10-
	carboxamide
233	(R)-N-(3-cyano-4-fluorophenyl)-4-(hydroxymethyl)-2,9-	A
	dimethyl-1-oxo-1,2,5,8,9,11-hexahydro-10H-
	pyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]triazepine-10-
	carboxamide
234	(R)-N-(3-bromo-4-fluorophenyl)-4-(hydroxymethyl)-2,9-	A
	dimethyl-1-oxo-1,2,5,8,9,11-hexahydro-10H-
	pyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]triazepine-10-
	carboxamide
235	(R)-N-(3-chloro-4-fluorophenyl)-4-(hydroxymethyl)-2,9-	A
	dimethyl-1-oxo-1,2,5,8,9,11-hexahydro-10H-
	pyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]triazepine-10-
	carboxamide
236	(R)-N-(3-bromo-4-fluorophenyl)-4-((2,2-	A
	difluoroethoxy)methyl)-2,9-dimethyl-1-oxo-1,2,5,8,9,11-
	hexahydro-10H-pyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]triazepine-10-carboxamide
237	(R)-N-(3-cyano-4-fluorophenyl)-4-((2,2-	A
	difluoroethoxy)methyl)-2,9-dimethyl-1-oxo-1,2,5,8,9,11-
	hexahydro-10H-pyrido[4′,3′:3,4]pyrazolo[5,1-d]
	[1,2,5]triazepine-10-carboxamide
238	(R)-4-((2,2-difluoroethoxy)methyl)-N-(4-fluoro-3-	B
	(trifluoromethyl)phenyl)-2,9-dimethyl-1-oxo-
	1,2,5,8,9,11-hexahydro-10H-
	pyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]triazepine-10-
	carboxamide

TABLE 8 — Crystal data and structure refinement.

Empirical formula	C23 H29 I N4 O6
Formula weight	584.40
Temperature	173(2) K
Wavelength	1.54178 A
Crystal system, space group	Monoclinic, P 21
Unit cell dimensions	a = 5.2409(7) A alpha = 90 deg.
	b = 19.141(2) A beta = 99.804(6) deg.
	c = 12.9592(15) A gamma = 90 deg.
Volume	1281.0(3) A{circumflex over ( )}3
Z, Calculated density	2, 1.515 Mg/m{circumflex over ( )}3
Absorption coefficient	10.196 mm{circumflex over ( )}−1
F(000)	592
Crystal size	0.25 × 0.10 × 0.08 mm
Theta range for data collection	3.46 to 67.23 deg.
Limiting indices	−5 <= h <= 6, −22 <= k <= 22,
	−15 <= l <= 15
Reflections collected/unique	9564/4208 [R(int) = 0.0479]
Completeness to theta = 67.23	97.4%
Absorption correction	Semi-empirical from equivalents
Max. and min. transmission	0.3182 and 0.1437
Refinement method	Full-matrix least-squares on F{circumflex over ( )}2
Data/restraints/parameters	4208/1/311
Goodness-of-fit on F{circumflex over ( )}2	1.087
Final R indices [I > 2sigma(I)]	R1 = 0.0456, wR2 = 0.1152
R indices (all data)	R1 = 0.0523, wR2 = 0.1222
Absolute structure parameter	0.078(9)
Largest diff. peak and hole	0.931 and −0.569 e.AA{circumflex over ( )}−3

TABLE 9 — Atomic coordinates and equivalent isotropic displacement parameters.

	x	y	z	U(eq)
I(1)	2937(1)	5453(1)	−515(1)	50(1)
O(1)	8677(10)	4897(2)	4622(4)	48(1)
O(2)	8496(10)	3521(2)	6400(4)	46(1)
O(3)	12572(11)	2866(3)	7830(5)	57(1)
O(4)	−1079(9)	6970(2)	3889(4)	46(1)
N(1)	6070(10)	4702(3)	7026(4)	37(1)
N(2)	4327(11)	5136(3)	7358(4)	40(1)
N(3)	2310(10)	6353(3)	4757(4)	38(1)
N(4)	9283(13)	3932(3)	5604(5)	49(1)
C(1)	9483(14)	3805(4)	7432(6)	46(2)
C(2)	7211(14)	4172(3)	7782(5)	43(1)
C(3)	3569(11)	5571(3)	6568(4)	35(1)
C(4)	1694(12)	6154(3)	6567(5)	39(1)
C(5)	2121(14)	6704(3)	5762(5)	40(1)
C(6)	4451(13)	5851(3)	4740(5)	40(1)
C(7)	4851(9)	5429(4)	5724(4)	34(1)
C(8)	6436(12)	4862(3)	6034(5)	35(1)
C(9)	8225(13)	4557(3)	5371(5)	37(1)
C(10)	10442(15)	3215(4)	8132(6)	50(2)
C(11)	11166(16)	3614(4)	5079(6)	52(2)
C(12)	712(12)	6552(3)	3879(5)	36(1)
C(13)	1240(12)	6265(3)	2862(5)	35(1)
C(14)	3170(15)	6560(4)	2406(6)	49(2)
C(15)	3618(15)	6325(4)	1444(6)	50(2)
C(16)	2130(14)	5808(4)	930(5)	44(2)
C(17)	236(14)	5506(6)	1390(5)	51(2)
C(18)	−282(15)	5735(4)	2335(6)	49(2)
C(19)	4496(15)	7147(4)	6121(7)	54(2)
O(1′)	−1840(30)	3792(6)	473(10)	152(4)
O(2′)	−3660(40)	3365(8)	1631(11)	175(6)
C(1′)	−640(100)	2470(14)	770(30)	340(30)
C(2′)	−2150(90)	3320(20)	969(15)	340(30)
C(3′)	−4410(30)	4042(6)	1973(13)	110(4)
C(4′)	−5960(40)	3988(9)	2697(16)	138(6)

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11 codes

IPC · International Patent Classification

Section A — Human necessities

A61K45/06
A61P31/12
A61K31/55
A61P31/20
A61K31/553
A61K31/551

Section C — Chemistry; metallurgy

C07D487/04
C07D471/04
C07D498/14
C07D498/04
C07D471/14

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