WO2016109684A2

WO2016109684A2 - Derivatives and methods of treating hepatitis b infections

Info

Publication number: WO2016109684A2
Application number: PCT/US2015/068091
Authority: WO
Inventors: George D. Hartman; Scott Kuduk
Original assignee: Novira Therapeutics LLC
Current assignee: Novira Therapeutics LLC
Priority date: 2014-12-30
Filing date: 2015-12-30
Publication date: 2016-07-07
Anticipated expiration: 2017-06-30
Also published as: US9550779B2; US10189835B2; US10544141B2; US9518057B2; US20180127415A1; US9527845B2; US10077264B2; AU2015373996A1; US20170121329A1; US10556904B2; EP3240787A4; US20200181142A1; US20190031653A1; US20160185779A1; US20190077800A1; RU2017126995A3; AU2020233640A1; US10538519B2; US20170121328A1; EP3240787A2

Abstract

Provided herein are compounds 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.

Description

DERIVATIVES

AND METHODS OF TREATING HEPATITIS B INFECTIONS

RELATE D APPLICATIONS

This application claims priority to U. S. Provisional Application No. 62/097,835, filed December 30, 2014, and U. S. Provi sional Application No. 62/163, 150, filed May 18, 2015. The contents of these provi sional applications are incorporated herein by reference in their entirety.

BACKGROUND

Chronic hepatiti s B virus (HBV) infection is a significant global health problem, affecting over 5% of the world population (ov er 350 million people worldwide and 1 .25 million indiv iduals 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 prov ide a cure and are limited to only two classes of agents (interferon alpha and nucleoside anal ogues/i nhi bi tors of the viral polymerase); drug resistance, low efficacy, and toierability 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 achiev e with a single antiv iral agent. However, persistent suppression of HBV DNA slows liv er 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 prev enting the dev elopment of cirrhosis and hepatocellular carcinoma.

There i s a need in the art for therapeutic agents that can increase the suppression of virus production and that can treat, ameliorate and/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, improv ed prognosis, diminished progression of the disease and enhanced seroconv ersion rates. Provided herein are compounds useful for the treatment of HBV infection in a subject thereof, having the structure:

or a pharmaceutically acceptable salt thereof.

In one aspect, provided herein is a compound of Formul a I:

I,

or a pharmaceutically acceptable salt thereof.

In an embodiment, the compound of Formula I is a compound of Formula

I I,

or a pharmaceutical ly acceptable salt thereof. In another embodiment, the compound of Formula I is a compound of Formula

R⁴

III,

or a pharmaceutically acceptable salt thereof.

In another embodiment, the compound of Formula I is a compound of Formula IV :

IV ,

or a pharmaceutical ly acceptable salt thereof.

In another aspect, provided herein are pharmaceutical compositions comprising a compound of Formula I, II, II I, or IV, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier.

In one aspect, provided herein is a method of treating an HBV infection in an individual in need thereof, compri sing administering to the individual a therapeutically effective amount of a compound of Formula I, II, III, or IV, or a pharmaceutically acceptable salt thereof.

In another aspect, provided herein is a method of eradicating an HBV infection in an individual in need thereof, compri sing administering to the individual a therapeutically effective amount of a compound of Formula I, II, III, or IV, or a pharmaceutically acceptable salt thereof.

In another aspect, provided herein is a method of reducing the viral load associated with an HBV infection in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a compound of Formula I, I I, 111, or IV, or a pharmaceutically acceptable salt thereof. In another aspect, 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 compound of Formula I, II, III, or IV, or a

pharmaceutically acceptable salt thereof.

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

In another aspect, prov ided herein is a method of reducing an adverse physiological impact of an HBV infection in an indiv idual in need thereof, comprising administering to the indiv idual a therapeutically effectiv e amount of a compound of Formula I, II, III, or IV, or a pharmaceutically acceptable salt thereof.

In another aspect, prov ided herein is a method of inducing remission of hepatic injury from an HBV infection in an indiv idual in need thereof, comprising administering to the indiv idual a therapeutically effectiv e amount of a compound of Formula I, I I, 111, or IV, or a pharmaceutically acceptable salt thereof.

In another aspect, prov ided herein is a method of reducing the physiological impact of long-term antiviral therapy for HBV infection in an indiv idual in need thereof, comprising administering to the indiv idual a therapeutical ly effective amount of a compound of Formula I, II, III, or IV, or a pharmaceutically acceptable salt thereof.

In another aspect, prov ided herein is a method of prophylactically treating an HBV infection in an indiv idual in need thereof, wherein the indiv idual is afflicted with a latent HBV infection, comprising administering to the i ndiv idual a therapeutically effectiv e amount of a compound of Formula I, I I, III, or IV, or a pharmaceutically acceptabl e salt thereof.

In an embodiment, the methods prov ided herein can further comprise administering to the individual at least one additional therapeutic agent selected from the group consi sting of an HBV polymerase inhibitor, immunomodulatory agents, pegylated interferon, viral entry inhibitor, viral maturation inhibitor, literature-described capsid assembly modulator, rev erse transcriptase inhibitor, a cyciophilin/TNF inhibitor, a TLR-agonist, an HBV vaccine, agents of distinct or unknown mechanism, and a combination thereof. In a further embodiment, the methods provided herein allow 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 req ired to achieve similar results in prophylactically treating an HBV infection in an individual in need thereof.

In another embodiment, the methods provided herein reduce 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, di stinct capsid assembly modulator, antiviral compounds of distinct or unknown mechanism, and any combination thereof.

In another embodiment, the methods provided herein cause a lower incidence of viral mutation and/or viral resi stance than the admini stering of a compound selected from the group consisting of an HBV polymerase inhibitor, interferon, viral entry inhibitor, viral maturation inhibitor, di stinct capsid assembly modulator, antiviral compounds of distinct or unknown mechanism, and combination thereof.

In another embodiment, the methods provided herein further comprise admini stering to the individual at least one HBV vaccine, a nucleoside HBV inhibitor, an interferon or any combination thereof.

In an 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 indiv idual a therapeutical ly effective amount of a compound of Formula 1, I I, III, or IV, or a pharmaceutically acceptable salt thereof, alone or in combination with a reverse transcriptase inhibitor; and further administering to the individual a therapeutical ly effective amount of HBV vaccine.

In an embodiment, the methods provided herein further compri se monitoring the H BV viral load of the subject, wherein the method is carried out for a period of ti me such that the HBV virus is undetectable.

DETAI LE D DESCRIPTION

Provided herein are compounds, e.g., the compounds of Formulas I, II, III, or IV, or pharmaceutically acceptable salts thereof, that are useful in the treatment and prevention of HBV infection in subject. In a non-limiting aspect, these compounds may modulate or disrupt HBV assembly and other HBV core protein functions necessary for HBV replication or the generation of infectious particles, may inhibit the production of infectious virus particles or infection or may interact ith HBV capsid to afford defective viral particles with greatly reduced infectivity or replication capacity. In other words, the compounds provided herein may act as capsid assembly modulators. The compounds provided herein have potent antiviral activity, exhibit favorable metabolic properties, tissue distribution, safety and pharmaceutical profiles, and are suitable for use in humans.

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

The crucial function of HBV capsid proteins imposes stringent evolutionary constraints on the viral capsid protein sequence, leading to the observed low sequence variability and high conserv ation. Consistently, mutations in HBV capsid that disrupt its assembly are lethal, and mutations that perturb capsid stability severely attenuate viral replication. The high functional constraints on the multi-functional HBV core/capsid protein is consi stent with a high sequence conserv ation, as many mutations are deleterious to function. Indeed, the core/capsid protein sequences are >90% identical across HBV genotypes and show only a small number of polymorphic residues. Resi stance selection to HBV core/capsid protein binding compounds may therefore be difficult to select without large impacts on v irus replication fitness.

Reports describing compounds that bind vi al capsids and inhibit replication of HIV, rhinovirus and HBV provide strong pharmacological proof of concept for v iral capsid proteins as antiv iral drug targets.

In one aspect, the compounds provided herein are useful in HBV treatment by di srupting, accelerating, reducing, delaying and/or inhibiting normal vi al capsid assembly and/or disassembly of immature or mature particles, thereby inducing aberrant capsid morphology and leading to antiv iral effects such as di sruption of virion assembly and/or disassembly, virion maturation, virus egress and/or infection of target cells. In one embodiment, a disruptor of capsid assembly interacts with mature or immature viral capsid to perturb the stability of the capsid, thus affecting assembly and/or disassembly. In another embodiment, a di sruptor of capsid assembly perturbs protein folding and/or salt bridges required for stability, function and/or normal morphology of the viral capsi d, thereby disrupting and/or accelerating capsid assembly and/or disassembly. In yet another embodiment, the compounds of the inv ention bind capsid and alter metabolism of cellular polyproteins and precursors, leading to abnormal accumulation of protein monomers and/or oligomers and/or abnormal particles, which causes cellular toxicity and death of infected cells. In another embodiment, the compounds provided herein cause failure of the formation of capsids of optimal stability, affecting efficient uncoating and/or disassembly of viruses (e.g., during infectivity).

In one embodiment, the compounds provided herein di srupt and/or accelerate capsid assembly and/or disassembly when the capsid protein is immature. In another embodiment, the compounds provided herein disrupt and/or accelerate capsid assembly and/or disassembly when the capsid protein is mature. In yet another embodiment, the compounds provided herein di srupt and/or accelerate capsid assembly and/or disassembly during viral infectivity. In yet another embodiment, the disruption and/or acceleration of capsid assembly and/or disassembly attenuates HBV viral infectivity and/or reduces viral load. In yet another embodiment, disruption, acceleration, inhibition, delay and/or reduction of capsid assembly and/or disassembly eradicates the virus from the host organism. In yet another embodiment, eradication of the HBV from a host advantageously obviates the need for chronic long-term therapy and/or reduces the duration of long-term therapy.

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.

In another embodiment, the compounds proided herein can be used in methods of modulating (e.g., inhibiting or di srupting) the activity, stability, function, and viral replication properties of HBV cccDNA. In yet another embodiment, the compounds of the invention can be used in methods of diminishing or preventing the formation of HBV cccDNA.

In another embodiment, the the compounds prov ided herein can be used in methods of modulating (e.g., inhibiting or disrupting) the activity of HBV cccDNA. In yet another embodiment, the compounds of the inv ention can be used in methods of diminishing the formation of HBV cccDNA.

In another embodiment, the the compounds prov ided herein can be used in methods of modulating, inhibiting, or disrupting the generation or release of HBV RNA particles from within the infected cell . In a further embodiment, the total burden (or concentration) of HBV RNA particles is modulated. In a preferred embodiment, the total burden of HBV RNA is diminished. Definitions

Listed below are definitions of various terms used to describe this invention. These definitions apply to the tenns 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 tenns used herein generally have the same meaning as commonly understood by one of ordinary skil l in the art to which thi s 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 wi ll vary to some extent on the context in hich 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 and/or hinders folding and the like) with the major capsid assembly protein (CA), thereby disrupting capsid assembly or di sassembly. 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 and/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 compound of the invention (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 speci ically tailored or modified, based on knowledge obtained from the field of pharm acogen om i c s .

As used herein, the term "prevent^" or "prevention^" means no disorder or di sease development if none had occurred, or no further di sorder or disease development if there had already been development of the di sorder or disease. Also considered is the ability of one to prevent some or all of the symptoms associated with the di sorder 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 prov ide the desired biological result. That result may be reduction and/or al leviation 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 di luent, 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 i nteracting 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 conv erting 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 conv entional 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, i sopropanol , or acetonitrile are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publi shing Company, Easton, Pa., 1985, p. 14 1 8 and Journal of Pharmaceutical Science, 66, 2 (1977), each of which is incorporated herein by reference in its entirety.

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 w ithin 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 cell lose, 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 ; polvols, 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; i sotonic 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., CYCValkyl means one to six carbon atoms) and includes strai ht, branched chain. Examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, neopentyl, and hexyl. Other examples of Ci-Ce-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., CVCValkenvl ) include, but are not limited to, for example, ethenyl, propenyl, prop- l -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 "haioalkyl" refers to alkl radicals wherein any one or more of the alkyl carbon atoms is substituted with halo as defined above. Haioalkyl embraces monohaloalkyl, dihaloalkyl, and polyhaioalkyl radicals. The term "haioalkyl" includes, but is not limited to, fluorom ethyl, dilluoromethyl , trifl orom ethyl, 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. Cycloal kyl groups include groups having 3 to 10 ring atoms iC^.C in-cycloalkyl ), groups having 3 to 8 ring atoms (CYCVcycloalkyl ), groups having 3 to 7 ring atoms (CYC— cycioalkyl ), and groups having 3 to 6 ring atoms ( C ;.Cv,-cycloalkyl ). Illustrative examples of cy cioalkyl groups include, but are not limited to, the following moieties:

Monocyclic cycioalkyl s include, but are not limited to, cyclopropyl , cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl . Di cyclic cycloalkyls include, but are not limited to, tetrahydronaphthyl , indanyl, and tetrahydropentalene. Polycyclic cycloalkyls include adamantine and norbornane. The term cycioalkyl includes "unsaturated nonaromatic carbocyclyl" or "nonaromatic unsaturated carbocyclyf^" groups, both of which refer to a nonaromatic carbocycle as defined herein, which contains at least one carbon carbon double bond or one carbon carbon triple bond.

As used herein, the term "heterocycloalkyf^" 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., CVCx-heterocyclyl indicates the number of carbon atoms contained in the heterocyclic group without including the number of heteroatoms. For example, a CVCVheterocycl y 1 will include an additional one to four heteroatoms. In another embodiment, the hetet ocycloalkyl 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.

An example of a 3-membered heterocycly l group includes, and is not limited to, aziridine. Examples of 4-membered heterocyclyl 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 heterocycl oalkyl groups include, and are not limited to, piperidine, morpholine and piperazine.

Other non-limiting examples of heterocycl oal kyl groups are:

Examples of heterocycl es include monocyclic groups such as aziridine, oxirane, thiirane, azetidine, oxetane, thietane, pyrrolidine, pyrrol ine, 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-di hydropyran, tetrahydropyran, 1 ,4-dioxane, 1 ,3-dioxane, homopiperazine, homopiperidine, 1 ,3-dioxepane, 4,7-dihydro- 1 ,3-dioxepin, and

hexamethyl eneoxi de .

As used herein, the term "aromatic^" refers to a carbocycle or heterocycl e with one or more polyunsaturated rings and having aromatic character, i.e., having (4n + 2) delocalized π (pi) electrons, where n i s 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 bi phenyl, or may be fused, such as naphthalene. Examples of aryl groups include phenyl, anthracyl, and naphthyl . Preferred examples are phenyl (e.g., (Varyl ) and bi phenyl (e.g., C₁₂-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., C₆- Ci2-aryl). In some embodiments, aryl groups have six carbon atoms (e.g., CVaryl ).

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., Ci-tVheteroaryl indicates the number of carbon atoms contained in the heteroaiyl group without including the number of heteroatoms. For example, a C |-CV heteroaryl will include an additional one to four heteroatoms. A polvcyclic heteroaryl may- include one or more rings that are partially saturated. Non-limiting examples of heteroaryls include:

Additional non-limiting examples of heteroaryl groups include pyridyl, pyrazinyl pyrimidinyl (including, e.g., 2- and 4-pyrimidinyl), pyndazinyl, thienyl, furyl, pyrrolyl (including, e.g., 2-pyrrolyl), imidazolyl, thiazolyl, oxazolyl, pyrazolyl (including, e.g., 3 5-pyrazolyl), isothiazolyl, 1,2,3-tnazolyl, 1,2,4-triazolyl, 1,3,4-triazolyL tetrazolyl, 1.2.3-thiadia/olyl. 1,2,3-oxadiazolyl, 1.3.4-thiadia/olyl and 1,3,4-oxadiazolyl.

Non-limiting examples of polvcyclic heterocycles and heteroaryls include indolyl (including, e.g., 3-, 4-, 5-, 6- and 7-indoh I ), mdolinyl, quiiioiyl, tetrahydroquinolyl, isoquinolyl (including, e.g., 1- and 5-isoquinolyl),

cinnolinyl, quinoxalinyl (including, e.g., 2- and 5-quinoxaiinyl), quinazolinyl, phthalazinyl,

1,8-naphthyridinyl, 1,4-benzodioxan.yl, coumarin, dihydrocoumarin, 1,5-naphthyridinyl, benzofuryl (including, e.g., 3-, 4-, 5-, 6- and 7-benzofuryi), 2,3-dihydi benzofuryl, 1,2-benzisoxazolyl, benzothienyl (including, e.g., 3-, 4-, 5-, 6-, and 7-benzothienyl), benz.oxaz.olyl, benzothiazolyl (including, e.g., 2-benzothiazolyl and 5-benzothiazolyl), purinyl, benzimidazolyl (including, e.g., 2-benzimidazolyl), benzotriazolyl, thioxanthmvl, carbazolyl, carbolinyl. acridmyi, pyrrolizidmyl, and qumolizidinyl.

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

Provided herein are compounds useful for the treatment of HBV infection in a subject m thereof, having the structure:

or pharmaceutically acceptable salts thereof.

In one aspect, provided herein is a compound of Formula la

or a pharmaceutically acceptable salt thereof,

wherein

W' and W are each independently selected from N, NR^a, and CR^a, wherein one of W¹ and W is NR^a;

X is N or CR^b;

Y is selected from a bond, -C(O)-, and -SO₂-;

Z is selected from -(CR⁵R⁶)_m- - CR⁵R⁶)_mO-, -(CR⁵R⁶)_mCR⁵=CR⁵--, -(CR⁵R⁶)_m-C₃- Ce-cycloalkylene-, and -(CR⁵R⁶)_m-NR⁷-:

R¹ is selected from C₆-Ci₂-aryi, Ci-C₉-heteroaryl, (VCVcycloalkyl, C₂-C₈- heterocyclyl, OR^c, C -CVaikyl, C(0)OR^c, C(0)R^c, C(0)NR^dR^e, NR^dC(0)R^c, OC(0)R^c, halo, and CVCx-alkenyl, wherein alkyl, aryi, heteroaryl, cycloalkyl, heterocyclyl, and alkenyl are optionally substituted with 1, 2, 3, or 4 groups each independently selected from -OH, halo, Ci-Ce-aikyl, Ci-CVha!oalkyl, -O-C i-CValkyl, and Ci-Ce-aikyl-OH;

R is, at each occurrence, independently selected from H, -OH, halo, Ci-C₆-alkyl, C|- Ce-haloalkyl, -O-Ci-Ce-alkyl, and Ci-C„-alkyl-OH; R is, at each occurrence, independently selected from H, -OH, halo, C CValkyl, Cj - Ce-haloalkyl, -Q-Ci-Ce-alkyl, and Ci-Ce-alkyl-OH;

R⁴ is selected from Ci-C₆-alkyl, (CR⁸R⁹)_p-C₃-C₈-cycloaikyi, (CR⁸R⁹)_P-C₂-C₈- heterocyclyl, (CR⁸R⁹)_p-C₆-C₁₂-aryl, and (CR⁸R⁹)_p-Ci-C9-heteroaryl, wherein alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with 1, 2, 3, or 4 groups, each independently selected from -OH, halo, CN, Ci-C₆-aikyl, C | -G,-haloalkyl, -O- Ci-Ce-alkyl, C(0)N(R^f)₂, C(0)OR^f, OCH₂C(0)OR^f, S0₂R^f, G-CValkyl-OH, and C₃-C₈- cycloalkyl;

R⁵ is, at each occurrence, independently selected from H, -OH, halo, Ci-C₆-alkyl, CV C₆-haloalkyl, -0-C C₆-alkyl, and G-CValkyl-OH;

alternatively, R⁴ and R⁵ are optionally joined to form a ring;

R" is, at each occurrence, independently selected from H, OH, halo, Ci-Ce-alkyl, C _\- Ce-haloalkyl, -0-Ci-C₆-alkyl, and

R is selected from H, G-CValkyl, and Ci-C₆-alkyl-OH;

R⁸ is, at each occurrence, independently selected from H, -OH, halo, C i-CValkyl, C | -

CVhaloalkyl, -0-Ci-C₆-alkyl, and Ci-C₆-alkyl-OH;

R⁹ is, at each occurrence, independently selected from H, -OH, halo, C i-CValkyl, C _\- Ce-haloalkyl, O-d-CV.-alkyl , and d-C₆-alkyl-OH;

R^a is selected from H, C i-CValkyl, and C | -CValkyl-OH;

R^b is selected from H and C i-CValkyl;

R^c is selected from H, C i-CValkyl, CVCValkyl-OH, C₃-C₈-cycloalkyl, CVCV heterocyclyl, C₆-Ci₂-aryl, and Cj-Cg-heteroaryl;

R^d is selected from H, C i-CVal kyl , and C^" i-CVal kyl-OH;

R^e is selected from H, C i-CValkyl, C i-CValkyl-OH, CVCVcycloalkyl, C₂-C₈- heterocyclyl, C₆-Ci₂-aiyl, CVCVheteroaryl, and 0-(VC(,-alkyl ;

alteniatively, R^d and R^e are optionally joined to form a heterocyclic ring;

f

R is, at each occurrence, independently selected from H and C i-CValkyl;

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

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

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

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

I,

or a pharmaceutically acceptable salt thereof,

wherein

W¹ and W are each independently selected from N, NR^a, and CR^a, wherein one of W and W is NR^a;

X is N or CR^b;

Y is selected from a bond, -C(0)-, and -S0₂-;

Z is selected from -(CR⁵R⁶)_m- -(CR⁵R⁶)_fflO- -(CR⁵R⁶)_fflCR⁵=CR⁵-, -(CR⁵R⁶)_ffi-C₃- CVcycloalkylene , and -(CR⁵R⁶)_m- R⁷-;

R¹ is selected from CVCVcycloalkyl, C₂-C₈-heterocyclyl, -OR^c, CVCValkyl, halo, and CVCValkenyl, wherein alkyl, cycloalkyl, heterocyclyl, and alkenvl are optionally substituted with 1, 2, 3, or 4 groups each independently selected from OH, halo, C 1 -C_fl- alkyl, C i-CVhaloa! ky! , -0-CVCValkyl , and CVCVal kyl -OH;

R is, at each occurrence, independently selected from H, -OH, halo, Ci-C₆-alkyl, CV

CVha!oalkyl, -O-Ci-Ce-alkyl, and CVCValkyl-OH;

R³ is, at each occurrence, independently selected from H, -OH, halo, CVCValkyl, CV G.-haloalkyl , -0-Cj -C₆-alkyl, and C | -C(,-alkyl-OH,

R⁴ is selected from C ,-C₍,-alkyl, (CR⁸R⁹)_p-C₃-C₈-cycloalkyl, (CR⁸R⁹)_P-C₂-C₈- heterocyclyl, ( C R^XR ⁴ )_P-CVC 1 2-aryl , and ( CR^XR'' )_p-C 1 -Cj-heteroary 1 , wherein alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with 1, 2, 3, or 4 groups, each independently selected from OH, halo, CN, CVCValkyl, CVCVhaloalkyl, O- CrCe-alkyl, C(0)N(R^f)₂, C(0)OR^f, -OCH₂C(0)OR^f, ^»S0₂R^f, and Ci-C₆-alkyl-OH;

R⁵ is, at each occurrence, independently selected from H, -OH, halo, CVCValkyl, CV CVha!oalkyl, -0-Ci-C₆-alkyl, and d-C-alkyl-OH;

altematively, R⁴ and R are optional ly joined to form a heterocyclic ring;

R⁶ is, at each occurrence, independently selected from H, -OH, halo, CVCValkyl, CV CVhaloalkyl , O-d-CV.-alkyl , and d-Ce-alkyl-OH; R is selected from H, C i-CValkyl, and Ci-Ce-alkyl-OH;

R⁸ is, at each occurrence, independently selected from H, Oil, halo, C i-CValkyl, Ci- C₆-haloaikyl, -0-C | -C_f,-alkyl, and Ci-C₆-alkyl-OH;

R⁹ is, at each occurrence, independently selected from H, OH, halo, Ci-C₆-alkyl, C Ce-haloalkyl, -0-Ci-C₆-alkyl, and C i -Cv.-alkyl-OH;

R^a is selected from H, Ci-C₆-alkyl, and Ci-C₆-alkyl-OH;

R^b is selected from H and C i-CValkyl;

R^c is selected from H, C i-CValkyl, C|-G,-alky!-OH, Cs-Cg-cycloalkyl, C₂-Cg- heterocyclvl, C₆-Ci₂-aryl, and Ci-C₉-heteroaryl;

R is, at each occurrence, independently selected from H and Cj-C₆-alkyl;

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

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

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

In an embodiment of the compound of Formula I

I,

or a pharmaceutically acceptable salt thereof,

W¹ and W are each independently selected from N, NR^d, and CR^d, wherein one of W and W is NR^a;

X is N or CR^b;

Y is selected from a bond, -C(O)-, and -S0₂-;

Z is selected from -(CR⁵R⁶)_m-, -(CR⁵R⁶)_mO~, -(CR⁵R⁶)_mCR⁵=CR⁵~, -(CR⁵R⁶)_m-C₃- C(,-cycloalkylene -, and -(CR⁵R⁶)_m-NR '-;

R¹ is selected from C -Cg-cycloalkyl, C -Cx-heterocyclyl, Ci-C₆-alkyl, and C₂-C₈- alkenyl, wherein alkyl, cycloalkyl, heterocyclyl, and alkenyl are optionally substituted with 1, 2, 3, or 4 groups each independently selected from -OH, halo, CVCValkv , Ci-CVhaloalkv , -O-Ci-Ce-aikyl, and C C₆-alkyl~OH;

R² is, at each occurrence, independently selected from H, -OH, halo, Ci-C₆-alkyl, Ci- G-haloalkyl, ~-0-Ci-C₆-alkyl, and d-CValkyl-OH;

R³ is, at each occurrence, independently selected from H, Oil, halo, Ci-Ce-alkyl, Ci- CVhaloalkyl, 0-C|-G,-alkyl, and Ci-C₆-alkyl-OH;

R⁴ is selected from C ,-C_t -alkyl, (CR⁸R⁹)_p-C₃-C₈-cycloalkyl, (CR⁸R⁹)_P-C₂-C₈- heterocyclyl, (CR⁸R⁹)_p-C₆-Ci₂-aryl, and (CR⁸R⁹)_p-Ci-C9-heteroaryl, wherein alkyl, cycioalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with 1, 2, 3, or 4 groups, each independently selected from -OH, halo, CN, Ci-CValkyl, Ci-Ce-haloalkyl, -O- Ci-Ce-alkyl, C(0)N(R^f)₂, C(0)OR^f, -OCH₂C(0)OR , -S0₂R , and Ci-C₆-alkyl-OH;

R⁵ is, at each occurrence, independently selected from H, -OH, halo, Ci-C₆-alkyl, Ci- C₆-haloalkyl, -0-C C₆-alkyl, and C,-G,-alkyl-OH;

alternatively, R⁴ and R⁵ are optionally joined to form a ring;

R" is, at each occurrence, independently selected from H, OH, halo, Ci-Ce-alkyl, C_\- Ce-haloalkyl, -0-Ci-C₆-alkyl, and d-d-alkyl-OH;

R is selected from H, d-CValkyl, and Ci-C₆-alkyl-OH;

R⁸ is, at each occurrence, independently selected from H, -OH, halo, Ci-G,-alkyl, C|-

Ce-haloalkyl, -0-Ci-C₆-alkyl, and Ci-C₆-alkyl-OH;

R⁹ is, at each occurrence, independently selected from H, -OH, halo, Ci-CValkyl, C_\- Ce-haloalkyl, 0-(VG,-alkyl, and d-Ce-alkyl-OH;

R^a is selected from H, Ci-Ce-alkyl, and C |-CValkyl-OH;

R^b is selected from H and Ci-Ce-alkyl;

R is, at each occurrence, independently selected from H and C i-CValkyl;

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

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

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

In another embodiment of the compound of Formula I, W ¹ is R^a and W is N or CR '.

In a further embodiment, W ¹ is NH.

In another embodiment of the compound of Formula I, W¹ is N or CR^a and W is NR^a. In another embodiment of the compound of Formula I, X is .

In an embodiment of the compound of Formula I, Y is -C(O)- or -S0₂- In a further embodiment of the compound of Formula I, Z is -(CR⁵R°)_m-

-(CR⁵R⁶)_mO- or -(CR⁵R⁶)_m- R⁷-.

In an embodiment of the compound of Formula I,

m is 0 or 1;

R⁵ is H, -OH, or C C₆-alkyl; R⁶ is H or Ci-Ce-alkyl; and

R is H or Ci-C(,-alkyl.

In another embodiment of the compound of Formula I, R¹ is CVCx-cycloalkyl, C₂-C₈- heterocyclyl, Ci-C₆-alkyl, or C₂-C₈-alkenyl, wherein alkyl, cycloalkvl, heterocyclyl, and alkenyl are optionally substituted with 1, 2, 3, or 4 groups each independently selected from - OH, halo, C|-C(,-alkyl, Ci-C₆-haioalkyl, -0-Ci-C₆-alkyl, and Ci-C₆-alkyl-OH.

In another embodiment of the compound of Formula I, R¹ is (VCVcycloalkyl or C₂- Cg-heterocyclyl, wherein cycloalkyl and heterocyclyl are optionally substituted with 1, 2, 3, or 4 groups each independently selected from -OH, halo, Ci-C₆-alkyl, Ci-Ce-hafoalkyl, -O- Ci-C₆-alkyl, and C ,-C₍,-alkyl-OH.

In another embodiment of the compound of Formula I, R¹ is CVG.-cycloalkyl or C₂- Cs-heterocyclyl, wherein cycloalkyl and heterocyclyl are optionally substituted with 1 or 2 groups each independently selected from -OH, halo, Cj-C₆-alkyl, C|-C₍,-haloalkyL -C |-C- alkyl, and CVCValkyl-OH.

In an embodiment of the compound of Formula I, each R² is independently selected from H or Ci-CValkyl . In a further embodiment of the compound of Formula I, R² is H.

In an embodiment of the compound of Formula I, R³ is H.

In an embodiment of the compound of Formula I, R⁴ is (CR⁸R⁹)_p-C₃-C₈-cycloalkyl, < C R )p-CVCYheterocycl yl , (CR⁸R⁹)_p-C₆-Ci₂-aryl, or < C Il )„-C i -CVheteroary I , wherein cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with 1, 2, 3, or 4 groups each independently selected from -OH, halo, CN, C CValkyl, Ci-C₆-haloalkyl, O- CrC₆-aiky{, C(0)N(R^f)₂, C(0)OR^f, -OCH₂C(0)OR^f, -S0₂R^f, and Ci-C₆-alkyl-OH.

In another embodiment of the compound of Formula I, R⁴ is (CR⁸R⁹)_p-C6-Ci₂-aryl, or (CR^XR ')_P-C I -C)-heteroaryl, wherein aryl, and heteroaryl are optionally substituted with 1, 2, 3, or 4 groups, each independently selected from -OH, halo, CN, Ci-C₆-alkyl, Ci-C₆- haloalkyl, -0-C C₆-alkyL C(0)N(R^f)₂, C(0)OR^f, -OCH₂C(0)OR^f, -S0₂R^f, and C C₆-aikyl- OH.

In another embodiment of the compound of Formula I,

p is 0 or 1;

R⁸ is H, -OH, or C C₆-alkyl; and

R' is H or Ci-CValkyl .

In an embodiment of the compound of Formula I, n is 1.

In another embodiment of the compound of Formula I,

X is N; Y is -C(O)-;

Z is NR. ; and

R is H or Ci-4-alkyl.

In a further embodiment of the compound of Formula I,

X is N;

Y is -C(Q)-;

Z is NR⁷;

R is H or Cj-4-alkyl; and

n is 1.

Also provided herein is a compound of Formula I, having the structure of Formula II (also referred to as "a compound of Formula IF):

R⁴

II,

or a pharmaceutically acceptable salt thereof.

In an embodiment of the compound of Formula 11, Y is C(O) or -S0₂-.

In an embodiment of the compound of Formula II, Z is -(CR⁵R⁶)_m-, -(CR⁵R⁶)_ffiO- or -(CR⁵R⁶)_m-NR⁷-.

In an embodiment of the the compound of Formula II,

m is 0 or 1 ;

R⁵ is II, -OH, or C C₆-alkyl;

R⁶ is I I or Ci-C(,-alkyl; and

R is H or Ci-C₆-alkyl.

In an embodiment of the compound of Formula II, R¹ is CVCVcycloalkyl, C₂-C₈- heterocyclyl, Ci-C₆-aiky{, and C₂-C₈-aikeiiyl, wherein alkyi, cvcloalkyl, heterocyclyl, and alkenyl are optionally substituted with 1, 2, 3, or 4 groups each independently selected from - OH, halo, Ci-CValkyl, C ,-G,-haloalkyl, -0-Ci-C₆-alkyl, and Ci-C₆-alkyl-OH.

In another embodiment of the compound of Formula II, R¹ is CVCVcycloalkyl or C₂- Cg-heterocyclyl, wherein cvcloalkyl and heterocyclyl are optionally substituted with 1, 2, 3, or 4 groups each independently selected from OH, halo, CVCValkyl, C | -CVhaloalkyl, O-

Ci-Ce-alkyl, and CVCVal kyl -OH.

In another embodiment of the compound of Formula II, R¹ is CVCVcycloalkyl or C -

C -heterocyclyl, wherein cycloalkyl and heterocyclyl are optionally substituted with 1 or 2 groups each independently selected from OH, halo, CVCValkyl, Ci-Ce-haloalkyl, -O-Ci-Ce- alkyl, and CVCe-alkyl-OH.

In another embodiment of the compound of Formula II, R ¹ i s selected from OH, -Br, methyl, ethyl, ethenyl, propyl, propenyl, isopropyl, butyl, t-butyl, butenyl , pentanyl, 2- methylpentan-2-yl, cyclopropyl, cyclobutyl , cyclopentyl, cyclopentenyl, cyclohexyl , cyclohexenyl, tetrahydrofuranyi, tetraliydropyranyi , dihydropyranyl, pyrrol idinyl,

bicyclo[3. 1 OJhexanyl, wherein methyl , ethyl, ethenyl, propyl, propenyl , isopropyl, butyl, t- biityl, butenyl, pentanyl, and 2-methylpentan-2-yl are optionally substituted with 1 or 2 groups independently sel ected from OH, and halo, or wherein cyclopropyl, cyclobutyl , cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, tetrahydrofuranyi, tetraliydropyranyi, dihydropyranyl, pyrrol idinyl, and bicyclo[3.1. OJhexanyl are optionally substituted with 1 or 2 groups independently selected from OH, halo, CVCValkyl, CVCVhaloalkyi, O-CVCV alkyl, and CVCValkyl -OH.

In another embodiment of the compound of Formula II, R ¹ is selected from methyl, ethyl, ethenyl, propyl, propenyl, isopropyl, butyl, t-butyl, butenyl, pentanyl, 2-methylpentan- 2-yl , cyclopropyl , cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cycl ohexenyl , tetrahydrofuranyi, tetraliydropyranyi, dihydropyranyl, pyrrol idinyl, bicyclo[3.1. OJhexanyl, any of which are optionally substituted with 1 or 2 groups independently selected from OH and halo.

In an embodiment of the compound of Formula II, each R² i s independently selected from H or CVCValkyl . In a further embodiment of the compound of Formula II, R² is H

In an embodiment of the compound of Formula II R³ i s H

In an embodiment of the compound of Fomiula II, R⁴ is ( C R^XR ' )_p-C -,-CVcy cl oal kyl , (CR⁸R⁹)_p-C₂-C₃-heterocyclyl, (CR^sR⁹)_p-C₆-Ci₂-aiyl, or ( C R^XR'' )„-C i -C-heteroary 1 , wherein cycloal kyl , heterocyclyl , aryl, and heteroaryl are optionally substituted with 1, 2, 3, or 4 groups, each independently selected from OH, halo, CN, CVCValkyl, CVCVhaloalkyi, O- CVCValkyl, C(0)N(R^f)₂, C(0)OR^f, -OCH₂C(0)OR , -S0₂R , and C | -CValkyl-OH.

In an embodiment of the compound of Formula 11, R⁴ is (CR⁸R⁹)_p-CVCi₂-aryl, or (CR^XR ')_P-C I -Crheteroaryl, and wherein aryl and heteroaryl are optionally substituted with 1, 2, 3, or 4 groups, each independently selected from OH, halo, CN, CVCValkyl, CVCV haloalkyl, - 0-C ,-CValkyl, C(0)N(R )₂, C(0)OR^f, -OCH₂C(0)OR^f, -S0₂R^f, and G-CValkyl- OH.

In an embodiment of the compound of Fomiula II,

Y is -C(0)-;

Z is -(CR⁵R⁶)m-, -(CR⁵R⁶)_mO- or -(CR⁵R⁶)_m-NR⁷-;

R¹ is GVCg-cycloalkyl, CVCVheterocyclyl, -OH, CVCe-alkyl, halo, and CVCV alkenyl, wherein alkyi, cycloalkyl, heterocvciyl, and alkenyl are optionally substituted with 1 , 2, 3, or 4 groups each independently selected from -OH, halo, CVCValkyl, G-CVhaloalkyl, -O-d-Ce-alkyl, and d-Cg-alkyl-OH;

R^~ and R³ are H;

R⁴ is ( C R ^x R )_p-C(,-C ₁₂-aiy 1 , or (CR⁸R⁹)_p-Ci-C9-heteroaryl, and wherein aryl and heteroaryl are optionally substituted with 1, 2, 3, or 4 groups, each independently selected from -OH, halo, CN, Ci-C₆-alkyl, G-CVhaloal kyl , -0-Ci-C₆-alkyl, C(0)N(R^f)₂, C(0)OR^f, -OCH₂C(0)OR^f, -S0₂R^f, and G-CValkyl-OH;

R⁵ is H, -OH, or G-CValkyl;

R" is H or Ci-Ce-alkyl;

R is H or C i-CValkyl;

R⁸ is, at each occurrence, independently selected from H, -OH, halo, and Ci-C₆-alkyl; R⁹ is, at each occurrence, independently selected from H, OH, halo, and CVCValkyl; R^c is Ci-Ce-alkyl;

R is, at each occurrence, independently selected from H and C i-CValkyl;

m is 1, or 2;

n is 1 ; and

p is 0, 1, or 2.

In an embodiment of this embodiment, R¹ is CVCVcycloalkyl, C₂-C₈-heterocyclyl, Ci-C₆-alkyl, and C₂-C₈-alkenyl, wherein alkyl, cycloalkyl, heterocvciyl, and alkenyl are optionally substituted with 1 or 2 groups each independently selected from -OH, halo, CVCValkyl. G-CVhaloalkyl, -0-Ci-C₆-alkyl, and i-CValkyl -OH.

In an embodiment of this embodiment, R⁴ is (CR⁸R⁹)_p-CVCi₂-aryi, or (CR⁸R⁹)_P-Cr Cg-heteroaryl, and wherein aryl and heteroaryl are optionally substituted with 1, 2, or 3 groups, each independently selected from -OH, halo, CN, Ci-Ce-alkyl, Ci-Ce-haloalkyl, -O- Ci-Ce-alkyl, and Ci-C₆-alkyl-OH.

In an embodiment of the compound of Formula II,

p is 0 or 1 ; R⁸ is independently selected from H, OH, and CVCValkyl; and

R⁹ is independently selected from H and CVCValkyl .

In an embodiment of the compound of Formula II, n is 1.

In an embodiment of the compound of Formula II,

Y is -C(O)-;

Z is NR⁷; and

R is H or Ci-4-alkyl.

In an embodiment of the compound of Formula II,

Y is -C(O)-;

Z is NR⁷;

R is I I or C i-i-alkyl; and

n is 1.

Also provided herein is a compound of Formula I, having the structure of Formula III (also referred to compound of Formula III^" ):

or a pharmaceutically acceptable salt thereof, wherein

Y is -C(O)- or -SO?-;

R¹ is Cr s-cycloal kyl , (VCYheterocyclyl, -OH, Ci-C₆-alkyl, halo, and C₂-C₈- alkenyl, wherein alkyl, cycloalkvl, heterocyclyl, and alkenyl are optionally substituted with 1, 2, 3, or 4 groups each independently selected from OH, halo,

C i-Ci,-haloalkyl, -0-Ci-C₆-alkyl, and C |-C -alkyl-OH;

R² is, at each occurrence, independently selected from H, OH, halo, Cj-C₆-alkyl, C | - C₆-haloaikyl, -0-Ci-C₆-alkyl, and C i -CValkyl-OH;

R^J is selected from H, -OH, halo, Ci-Ce-alkyl, C i-C„-haloalkyl, -0-C | -G,-alkyl, and Ci-Ce-alkyl-OH;

R⁴ is selected from (CR^XR ')_P-C I -Crheteroaryl, (CR⁸R⁹)_p-C₆-Ci₂-aryl, and C₃-C₃- cycloal kyl herein heteroaryl, aryl, and cycloalkvl are optionally substituted with 1 , 2, or 3 groups, each independently selected from OH, halo, CN, CVCValkyl, CVCVhaloalkyl, O- Ci-CValkyl, CVCValkyl -OH, and CVC cycloalkyl.

R is selected from H, Ci-Ce-alkyl, and CVCValkyl -OH;

R⁸ is, at each occurrence, independently selected from H, OH, halo, CVCValkyl, CV CVhaloalkyl, -O-Ci-CValkyl, and

R⁹ is, at each occurrence, independently selected from H and CVCValkyl; and p is O, l, 2, 3, or 4.

In an embodiment of the Compound of Formula III,

R⁴

III,

or a pharmaceutically acceptable salt thereof,

Y is -C(O)- or -SO,-;

R¹ is CVCVcycloalkyl, CVCVheterocyclyl, CVCValkyl, and CVCValkenyl, wherein alkyl, cycloalkyl, heterocyclyl, and alkenyl are optionally substituted with 1, 2, 3, or 4 groups each independently selected from -OH, halo, CVCValkyl, CVCVhaloalkyl, -O-CV Valkyl, and C-CValkyl-OH;

R² is, at each occurrence, independently selected from H, -OH, halo, CVCValkyl, C'r Ce-haloalkyl, -0-Ci-C₆-alkyl, and Ci-C₆-alkyl-OH;

R³ is selected from H, -OH, halo, Ci-Ce-alkyl, CVCVhaloalkyl, -O-CVCValkyl, and CrC₆-alkyl-OH;

R⁴ is selected from ( CR^XR )_P-C i -Orheteroaryl and (CR^XR'')_P-CV i aryl, wherein heteroaryl and aryl are optionally substituted with 1, 2, or 3 groups, each independently selected from OH, halo, CN, CVCValkyl, CVCVhaloalkyl, O-CVCValkyl, and CVCe- alkyl-OH;

R is selected from H, CVCValkyl, and Ci-C₆-alkyl-OH;

R⁸ is, at each occurrence, independently selected from H, -OH, halo, CVCValkyl, CV

Ce-haloalkyl, -0-Ci-C₆-alkyl, and CVCValkyl -OH;

R⁹ is, at each occurrence, independently selected from H and CVCValkyl; and p is 0, 1, 2, 3, or 4.

In an embodiment of the compound of Formula III, Y is -C(O)-. In an embodiment of the compound of Formula III, R ¹ is CVCVcycloalkyl, C₂-C₈- heterocyclyl, -OH, Ci-Ce-alkyl, halo, and C₂-C₈-alkenyl, wherein alkyl, cycloalkyl, heterocyclyl, and alkenyl are optionally substituted with 1 or 2 groups each independently selected from -OH, halo, CVCValkyl, CVCVhaloalkyl, -0-Ci-C₆-aikyl, and Ci-C₆-alkyl-OH.

In an embodiment of the compound of Formula III, R ¹ is Cs-Cs-cycloalkyl, CVCV heterocyclyl, Ci-C₆-alkyl, and C:>-Cx-alkenyl , wherein alkyl, cycloalkyl, heterocyclyl, and alkenyl are optionally substituted with 1 or 2 groups each independently selected from -OH, halo, CVCValkyl, C^' i-CVha!oalkyl, -O-Ci-Ce-alkyl, and CVG.-alkyl-OH;

In an embodiment of the compound of Formula III, R ¹ is CVCVcycloalkyl or C₂-C₈- heterocyclyl, wherein cycloalkyl and heterocyclyl are optionally substituted with 1 or 2 groups each independently selected from -OH, halo, CVCValkyl, CVCVhaloalkyl, O-CVCV alkyl, and G-CValkyl-OH

In another embodiment of the compound of Formula III, R¹ is C₃-C₆-cycloalkyl or C₂- Cj-heterocyclyi, wherein cycloalkyl and heterocyclyl are optionally substituted with 1 or 2 groups each independently selected from -OH, halo, CVCValkyl, CVC-haloalkyl, -O-CVCV alkyl, and CVCValkyl -OH.

In another embodiment of the compound of Formula III, R ¹ is selected from -OH, - Br, methyl, ethyl, ethenyl, propyl, propenyl, isopropyl, butyl, t-butyl, butenyl, pentanyl, 2- methylpentan-2-yl, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyciohexenyl, tetrahydrofuranvl, tetrahydropyranvl , di hvdropyranyl, pyrrol idinyl,

bicyclo[3.1.0]hexanyl, wherein methyl, ethyl, ethenyl, propyl, propenyl, isopropyl, butyl, t- butyl, butenyl, pentanyl, and 2-methylpentan-2-yl are optionally substituted with 1 or 2 groups independently selected from -OH, and halo, or wherein cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyciohexenyl, tetrahydrofuranvl, tetrahydropyranvl, di hvdropyranyl, pyrrol idinyl, and bicyclo[3.1.0]hexanyl are optionally substituted with 1 or 2 groups independently selected from -OH, halo, CVCValkyl, CVCVhaloalkyl, -O-CVCV al kyl , and CVCValkyl -OH.

In another embodiment of the compound of Formula III, R' is selected from methyl, ethyl, ethenyl, propyl, propenyl, isopropyl, butyl, t-butyl, butenyl, pentanyl, 2-methylpentan- 2-yl, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyciohexenyl, tetrahydrofuranvl, tetrahydropyranvl, dihvdropyranyl, pyrrol idinyl, bicyclo[3.1.0]hexanyl, any of which are optionally substituted with 1 or 2 groups independently selected from OH and halo.

In an embodiment of the compound of Formula III, each R² is independently selected from H or C i-CValkyl . In a further embodiment of the compound of Formula III, R² is H.

In an embodiment of the compound of Formula III, R³ is H.

In an embodiment of the compound of Formula III, R is H or CrC₄-alkyl. In a further embodiment, R i s H or -CH₃. In yet another embodiment, R is I I.

In an embodiment of the compound of Formula 111, R⁴ is (CR⁸R⁹)_p-Ci-C5-heteroaryl or (CR^xR^l')_p-C_t,-aryl, or CVCVcycloalkyl, wherein heteroaryl, aryl and cycloalkyl are optionally substituted with 1, 2, or 3 groups, each i ndependently selected from -OH, halo, CN, and C i -CValkyl ,

R⁸ is H or Ci-C₆-alkyl;

R⁹ is I I or Ci-Ce-alkyl; and

p i s 0 or 1 .

In an embodiment of the compound of Formula III, R⁴ is (CR⁸R⁹)_p-Ci-Cs-heteroaryl or (CR^sR⁹)_p-C₁,-aryl, wherein heteroaryl and aryl are optionally substituted with 1, 2, or 3 groups, each independently selected from OH, halo, CN, and C i-CValkyl;

R⁸ is H or Ci-Ce-alkyl;

R⁹ is I I or i-CValkyl; and

p is 0 or 1 .

In an embodiment of the compound of Formula III, R⁴ i s Ci-C₅-heteroaryl or CVaryl, wherein heteroaryl and aryl are optionally substituted with 1, 2, or 3 groups, each independently selected from -OH, halo, CN, and Ci-Ce-alkyl. In a particular embodiment of the compound of For ⁴ is

Also provided herein is a compound of Formula I, having the structure of Formula IV

(also referred to as "a compound of Formula IV"):

IV ,

or a pharmaceutically acceptable salt thereof wherein,

Y i s C(O) or -S0₂-; and

m is 0, 1 , or 2.

In an embodiment of the compound of Formula IV, Y is -C(O)-.

In an embodiment of the compound of Formula IV, R¹ is CVCYcycloalkyl, C₂-CV heterocycl l, -OH, CVCValkyl, halo, and C₂-C₈-alkenyl, wherein alkyl, cycloalkyl , heterocyclvi, and alkenyl are optionally substituted with 1 or 2 groups each independently selected from OH, halo, CYCValkyl, C | -CVhaloalkyl, 0-C i-CValkyl, and d-CValkyl-OH.

In an embodiment of the compound of Formula IV, R¹ is Cs-Cs-cycloalkyl, C₂-C₈- heterocyclyl, CVCr.-alkyl, and CVC alkenyl, wherein alkyl, cycloalkyl, heterocyclvi, and al kenyl are optional ly substituted with 1 or 2 groups each independently selected from OH, halo, Ci-Ce-alkyl, C i-CVhaloalkyl, -O-Ci-Ce-alkyl, and Ci-Ce-alkyl-OH;

In an embodiment of the compound of Formula IV, each R^" is independently selected from I I or C CValkyl . In a further embodiment of the compound of Formula IV, R² is H

In an embodiment of the compound of Formula IV, R³ i s H

In another embodiment of the compound of Formula IV, m is 1, R⁵ is H or Ci-C₆- alkyl, R⁶ is H or Ci-Ce-alkyl, and wherein R⁵ and R⁴ are optionally joined to form a ring. In another embodiment of the compound of Formula IV, m is 1 ; R⁵ is Ci-Ce-a!kyl; R⁶ is I I or Ci-Ce-alkyl; and R⁵ and R⁴ are optionally joined to form a ring. For example, in an embodiment.

is

In another embodiment of the compound of Formula IV, R⁴ is C i -CValky! or (CR⁸R⁹)_p-C₆-Ci2-aiyl, wherein alkyl and aryl are optionally substituted with 1, 2, or 3, groups, each independently selected from -OH, halo, CN, Ci-Ce-alkyl, Ci-Ce-haloalkyl, -O- Ci-Ce-alkyl, C(0)N(R )₂, C(0)OR^f, -OCH₂C(0)OR^f, S0₂R^f, and Ci-C₆-alkyl-OH.

In furth

Certain embodiments of Formulas I- IV, including pharmaceutically acceptable salts thereof, are shown below in Table 1. All compounds of Formula I, II, 111, and IV as well as pharmaceutically acceptable salts thereof, and the compounds of Table 1, as well as pharmaceutically acceptable salts thereof, are considered to be "compounds of the invention." Table 1.

33







In yet another embodiment of Formula 1 prov ided herein, the compound of Formula 111, or a pharmaceutically acceptable salt thereof, is selected from compounds shown in Table 2 and pharmaceutically acceptable salts thereof

Table 2.

40

41

42

44

and pharmaceutically acceptable salts thereof.

The compounds of the invention 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 i s to be understood that the compounds described herein encompass racemic, optically-active, regioisomeric and stereoi somer^ 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 recrystal lization 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 therapeutic 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 and/or separation of a mixture of enantiomers and/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 .

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

Compounds described herein al so 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 L ³H, ^UC, ¹³C, ¹⁴C, ³⁶C1, ¹⁸F, ¹²³I, ¹²⁵I, ¹³N, ¹⁵N, ¹⁵0, ¹⁷0, ¹⁸0, ³²P, and ³⁵S. In one embodiment, isotopically-labeled compounds are useful in drug and/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 ^UC, ¹⁸F, ^L,0 and ^L,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 chem i 1 umi nescent labels.

The compounds described herein, and other rel ated 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, 19 1 ), 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.

In one embodiment, reactive functional groups, such as hydroxy], amino, imino, thio or carboxy groups, are protected in order to avoid their unwanted participation in reactions. Protecting groups are used to block some or all of the reactive moieties and prevent such groups from participating in chemical reactions until the protective group is removed. In another embodiment, each protective group i s removable by a different means. Protective groups that are cleaved under totally disparate reaction conditions fulfill the requirement of differential removal .

Methods of the Invention

The invention provides a method of treating an HBV infection in an individual in need thereof, comprising administering to the individual a therapeutical ly effective amount of a compound of the invention.

The invention al so provides a method of eradicating an HBV infection in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a compound of the invention.

The invention also provides 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 compound of the invention.

The invention further prov ides a method of reducing reoccurrence of an HBV infection in an individual in need thereof, comprising admini stering to the indiv idual a therapeutically effectiv e amount of a compound of the invention.

In another aspect, prov ided herein is a method of inhibiting and/or reducing the formation or presence of HBV DNA-containing particles and/or HBV RNA-containing particles in an indiv idual in need thereof, comprisi ng admini stering to the i ndiv idual a therapeutically effectiv e amount of a compound of the inv ention.

The inv ention also provides a method of reducing an adverse physiological impact of an HBV infection in an i ndiv idual in need thereof, comprising admini stering to the indiv idual a therapeutically effectiv e amount of a compound of the invention. The invention further provides a method of reducing, slowing, or inhibiting an HBV infection in an individual in need thereof, comprising admini stering to the individual a therapeutically effective amount of a compound of the invention.

The invention al so provides a method of inducing remission of hepatic injury from an HBV infection in an individual in need thereof, compri sing administering to the individual a therapeutically effectiv e amount of a compound of the invention.

The invention further provides a method of reducing the physiological impact of long- term antiviral therapy for HBV infection in an individual in need thereof, comprising admini stering to the individual a therapeutically effective amount of a compound of the invention.

The invention further provides a method of prophylactical ly treating an HBV infection in an individual in need thereof, wherein the individual is afflicted with a latent HBV infection, comprisi ng administering to the indiv idual a therapeutically effective amount of a compound of the invention.

In one embodiment, the methods described herein further comprise administering at least one additional therapeutic agent selected from the group consisting of

nucl eoti de/ nucl eosi de analogs, entry inhibitors, fusion inhibitors, and any combination of these or other antiviral mechanisms. In another embodiment, the compound of the invention and the at least one additional therapeutic agent are co-formulated. In yet another

embodiment, the compound of the invention and the at least one additional therapeutic agent are co-administered.

In one embodiment, the individual i s refractory to other therapeutic classes of HBV drugs (e.g, HBV polymerase inhibitors, interferons, viral entry inhibitors, v ital maturation inhibitors, 1 i terature-descri bed capsid assembly modulators, antiviral compounds of distinct or unknown mechanism, and the like, or combinations thereof)- In another embodiment, the method of the inv ention reduces viral load in an indiv idual 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 admini stering of a compound of the inv ention, or a pharmaceutically acceptable salt thereof, allows for administering of the at least one additional therapeutic agent at a low er dose or frequency as compared to the admini stering 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 compound of the invention, 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 method of the invention 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 method of the invention causes a lower incidence of viral mutation and/or viral resi stance compared to other classes of HBV drugs, thereby allowing for long term therapy and minimizing the need for changes in treatment regi mens.

In one embodiment, the administering of a compound the invention, or a

pharmaceutically acceptable salt thereof, C3.USCS £1 lower incidence of viral mutation and/or viral resi stance 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 di stinct or unknown mechanism, and combination thereof.

In one embodiment, the method of the invention increases the seroconversion rate beyond that of current treatment regimens.

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

In one embodiment, the method of the invention 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 compounds of the invention.

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

In another embodiment, the method of the invention further comprises monitoring the HBV viral load of the subject, and wherein the method i s carried out for a period of time such 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 I, 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 pharmaceutical ly 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 III, 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 IV, 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 admini stering to the individual a therapeutically effective amount of a compound of Table 1, or a pharmaceutically acceptable salt thereof.

In another embodiment, prov ided 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 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 compounds of the present inv ention are intended to be useful in combination with one or more additional compounds useful for treating HBV infection. These additional compounds may comprise compounds of the present inv ention or compounds known to treat, prev ent, 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 inhibitor, i m m un om odul atory agents, a TLR-agonist, and other agents with di stinct or unknown mechanisms that affect the HBV life cycle and/or affect the consequences of HBV infection. In non-limiting examples, the compounds of the invention may be used in combination with one or more drugs (or a salt thereof) selected from the group consisting of

HBV reverse transcriptase inhibitors, and DNA and RNA polymerase inhibitors, including but not limited to: lamivudine (3TC, Zeffix, Heptovir, Epivir, and Epivir-FIBV), entecavir (Baraclude, Entav ir), adefov ir dipiv oxil (Hepsara, Preveon, bis-POM PMEA), tenofov ir disoproxil lumarate (Vi ead, TDF or PMPA );

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

viral entry inhibitors;

v iral maturation inhibitors;

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

4109;

rev erse transcriptase inhibitor;

an i m m u nom odul atory agent such as a TLR-agonist; and

agents of distinct or unknown mechanism, such as but not limited to AT-6 1 ((E)-N-(l- chloro- -oxo- 1 -phenyl -3 -(piperi din- 1 -yl)prop- 1 -en-2-yl )benzamide), A T- 130 ((E)-N-( 1 - bromo- 1

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 the famly of highly homologous species-speci ic proteins that inhibit viral replication and cellular proliferation, and modulate immune response. Human interferons are grouped into three classes; Type I, which include interferon-alpha (IFN-a), interferon-beta ( lFN-β), and interferon-omega (IF -ω), Type 11, which includes i nterferon -gam m a ( IFN-y), and Type III, which includes i nterferon-1 ambda ( IFN-λ). Recombinant forms of interferons that hav e been dev eloped and are commercially av ailable 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 include pegylated interferons and glycosylated interferons. Exampl es of interferons also include, but are not limited to, interferon-alpha-2a, interferon-alpha-2b, interferon-alpha-n 1 , interferon-beta- l a, interferon- beta- 1 b, interferon-lamda- 1 , interferon-lamda-2, and interferon-lamda-3. Examples of pegylated interferons incl ude pegylated i nterferon-al pha-2a and pegylated interferson alpha- 2b. Accordingly, in one embodiment, the compounds of Formula I, II, III, or IV, can be administered in combination with an interferon selected from the group consi ting of interferon alpha ( IFN-ot), interferon beta ( IFN-β), interferon lambda ( IF -λ), and interferon gamma (IFN-γ). In one specific embodiment, the interferon i s interferon-alpha-2a, i n terferon -al ph a-2b , or interferon-alpha-n I . 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 and/or DNA and/or RNA polymerase inhibitor is Zidovudine, Didanosine, Zalcitabine, ddA, Stavudine, Lamiv udine, Abacavir, Emtricitabine, Entecav ir, Apricitabine, Atevi rapine, ribavirin, acyclovir, famciclovir, val acyclovir, ganciclov ir, val ganciclovir, Tenofovir, Adefov ir, PMPA, cidofov ir, Efav irenz, Nevi rapine, Delav irdine, or Etrav irine.

In an embodiment, the additional therapeutic agent is an i m m un om odul atory agent that induces a natural, limited immune response leading to induction of immune responses against unrelated viruses. In other words, the i m m unom od ul atory agent can effect maturation of antigen presenting cell s, proliferation of T-cells and cytokine release (e.g., IL- 12, IL- 1 8, IFN-alpha, -beta, and -gamma and TNF-alpha among others),

In a further embodiment, the additional therapeutic agent i s 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 agoni t 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 Jamino J methyl (phenyl ]acetate).

In any of the methods prov ided herein, the method may further comprise

administering to the indiv idual 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 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 indiv idual a therapeutical ly effective amount of a compound of the invention alone or in combination with a reverse transcriptase inhibitor; and further admini stering to the individual a therapeutically effective amount of HBV vaccine. The reverse transcriptase inhibitor may be one of Zidov udine, Didanosine, Zalcitabine, ddA, Stav udine, Lamiv udine, Abacav ir, Emtricitabine, Entecavir, Apricitabine, A tev i rapine, ribavirin, acyclovir, famciclovir, val acyclov ir, ganciclov ir, valganciclovir, Tenofov ir, Adefovir, PMPA, cidofov ir, Efavirenz, evi rapine, Delavirdine, or Etravirine.

For any combination therapy described herein, synergistic effect may be calculated, for example, using suitable methods such as the Sigmoid-E_max equation (Hoi ford & Scheiner, 19981, Clin. Pharmacokinet. 6: 429-453), the equation of Loewe additiv ity (Loewe & Muischnek, 1926, Arch. Exp. Pathol Pharmacol . 1 14: 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 abov e are the concentrati on-elYect curve, isobologram curv e and combination index curv e, respectively.

In an embodiment of any of the methods of administering combination therapies prov ided herein, the method can further compri se monitoring the H BV viral load of the subject, wherein the method is carried out for a period of time such that the HBV virus is undetectable

Administration/Dosage/Formulations

In another aspect, prov ided herein is pharmaceutical composition comprising a compound of the inv ention, 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 inv ention 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 material s used in combination with the compound, the age, sex, weight, condition, general health and prior medi cal hi story of the patient bei ng treated, and like factors well, known in the medical arts.

A medical doctor, e.g., physician or veterinarian, having ordinary skil l in the art may readily determine and prescribe the effective amount of the pharmaceutical composition required. For example, the physician or veterinari an could start doses of the compounds of the invention employed in the pharmaceutical composition at levels lower than that required in order to achi eve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.

In particular embodiments, it i s 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 therapeutic 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 therapeutic compound and the particular therapeutic effect to be achieved, and (b) the limitations inherent in the art of compounding/formul ating such a therapeutic compound for the treatment of HBV infection in a patient.

In one embodiment, the compositions of the invention are formulated using one or more pharmaceutical ly acceptable excipients or carriers. In one embodiment, the

pharmaceutical compositions of the invention comprise a therapeutically effective amount of a compound of the invention and a pharmaceutically acceptable carrier.

In some embodiments, the dose of a compound of the inv ention is from about 1 mg to about 2,500 mg. In some embodiments, a dose of a compound of the invention 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.

In one embodiment, the present invention is directed to a packaged pharmaceutical composition comprising a container holding a therapeutically effective amount of a compound of the invention, 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), ( intranasal and (trans)rectal ), intravesical, intrapulmonary, intraduodenal, intragastrical, intrathecal, subcutaneous, intramuscular, intradermal, intra-arterial, intrav enous, 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 admini stration 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, parti cularly 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 consi sting 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 compounds of the invention may be formulated for injection or infusion, for example, intravenous, intramuscular or subcutaneous injection or infusion, or for admini stration in a bolus dose and/or continuous infusion. Suspensions, solutions or emulsions in an oily or aqueous vehicle, optionally containing other formulatory agents such as suspending, stabilizing and/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 speci ic procedures, embodiments, claims, and examples described herein. Such equivalents were considered to be within the scope of thi s 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 di sclosure of the present invention as set forth herein.

EXAMPLES

The invention is now described with reference to the following Examples. These Examples are provided for the purpose of i llustration only, and the invention i s not limited to these Examples, but rather encompasses all variations that are evident as a result of the teachings provided herein. Example 1: Procedure for the Preparation of Compounds 040 and 239

3

040

Step 1 : Preparation of Compound 2

Cool the three-necked round bottom flask to -78 C, LiAlH4 (192.75 mg, 5.08 mmol,

3.00 eq) was added under N₂, then a solution of 05-tert-butyl 03-ethyl 1 ,4,6,7- tetrahydropyrazolo[4,3-c]pyridine-3,5-dicarboxylate (500.00 mg, 1.69 mmol, 1.00 eq) in THF (5.00 mL) was added dropvvise, after addition the reaction mixture was warmed to 0 C and stirred at 0 °C for 5 hours. LCMS showed starting material was consumed completely and one main peak with desired MS was detected. The reaction was quenched with water (10 mL) and then extracted with EA (30 mL*3), the combined organic phase was dried over anhydrous Na₂S0₄, filtered and concentrated in vacuum. Compound tert-butyl 3- (hydroxymethv )- 1 ,4,6,7- tetrahydropyrazolo[4,3-c]pyridine -5-carboxylate (350.00 mg, crude) was obtained as yellow oil. The crude product was used into next step directly without further purification. LCMS: 254 [M+l],

Step 2: Preparation of Compound 3

To a mixture of tert-butyl 3-(hydroxymethyl)-l,4,6,7-tetrahydropyrazolo[4,3-c] pyridine-5-carboxylate (350.00 mg, 1.38 mmol, 1.00 eq) in dioxane (5.00 mL) was added HCl/dioxane (3.00 mL) in one portion, the reaction mixture was stirred at 20 °C for one hour, solid was precipitate out. TLC (Petroleum ether : Ethyl acetate=0: 1) showed the reaction was completed. The solution was concentrated on a water bath under reduced pressure using a rotary evaporator. 4,5,6,7- tetrah ydro- 1 H-pyrazol o[4, 3 -c] pyri di n-3 -y I methanol (165.00 mg, crude) was obtained as yellow solid. The crude product was used into next step directly without further purification.

Preparation of Compound 040

To a mixture of 4,5,6,7-tetrahydro-lH-pyrazolo[4,3-c]pyridin-3-ylmethanol (100.00 mg, 527.31 umol, 1.00 eq) and HATU (201.60 mg, 530.19 umol, 1.00 eq) in DCM (5.00 ml,) was added DIPEA ( 102.78 mg, 795.29 umol, 1 .50 eq) and 2- phenoxyacetic acid (80.23 mg,

527.31 umol, 1.00 eq) in one portion, the mixture was sti red at 20 °C for one hour. The desired compound was detected by LCMS. The mixture was extracted with DCM (10 mL*3) and water (10 niL), the organic phase was dried over anhydrous Na₂S0₄, filtered and concentrated in vacuum. Further purification by pre-HPLC(FA) to afford Compound 040

(40.00 mg, 139.22 umol, 26.26% yield) as yellow oil. LCMS: 288 [M+l].

Preparation of Compound 239

To a solution of 4,5,6,7-tetrahydro- 1 H-pyrazolo[4,3-c]pyridin-3-ylmethano! (85.00 mg, 448.22 umol, 1.00 eq, HC1) in DCM (5.00 ml.) was added TEA (136.07 mg, 1.34 mmol, 3.00 eq) at 0 C, followed by l -chloro-3-isocyanato-benzene (75.72 mg, 493.04 umol, 1.10 eq) , the reaction mixture was stirred at 0 °C for 30 minutes. LCMS showed compound 3 was consumed completely and one main peak with desired MS was detected. The mixture was extracted with DCM (15 mL*3 ) and water (15 ml,), the organic phase was dried with anhydrous a₂S0₄, filtered and concentrated in vacuum. Further purification by prep-

HPLC(FA) to afford Compound 239 (41.00 mg, 127.24 umol, 28.39% yield, 95.2% purity) as hite solid.

Ή NMR (400MHz, METHANOL-d ) 7.52 - 7.53 (t, J=2.01 Hz, 1 H) 7.2 1 - 7.28 (m, 2 H) 6.99 - 7.01 (m, 1 H) 4.61 (s, 4 H) 3.79 - 3.82 (t, J=5.77 Hz, 2 H) 2,79 - 2.82 (t, J=5.71 Hz, 2 H). LCMS: 307 [M+l].

xample 2: Procedure for the Preparation of Compounds 041 and 238

Step 1 : Preparation of Compound 2

Cooled the three-necked round bottom flask in an ice bath to 0 °C, MeMgBr (3 M,

2.82 mL, 5.00 eg) was added under N₂, then a solution of 5-tert-butyl -ethyl 1,4,6,7- tetrahydropyrazolo[4,3-c]pyridine-3,5-dicarboxylate (500.00 mg, 1.69 mmol, 1.00 eq) in THF (10.00 mL) was added dropvvise under N₂, after addition the reaction mixture was warmed to 20 °C and stirred at 20 °C for 3 hours. LCMS showed starting material was consumed completely and one main peak with desired MS was detected. The reaction was quenched with aqueous solution of H₄CI (15 mL) and then extracted with EA (20 mL*3), the combined organic phase was dried over anhydrous Na₂S0₄, filtered and concentrated in vacuum. Tert-butyl 3-(l -hydroxy- 1 -methyl-ethyl)-!, 4,6,7-tetrahydropyrazolo[4,3-c]pyridine- 5-carboxylae (350.00 mg, crude) was obtained as yellow oil. The crude product was used into next step directly without further purification. LCMS: 282 [M+l],

Step 2: Preparation of Compound 3

To a solution of tert-buty l 3-( 1 -hydroxy- 1 -methyl-ethyl )- 1 ,4,6,7-tetrahydropyrazolo [4,3-c]pyridine-5-carboxylate (350.00 mg, 1.24 mmol, 1.00 eq) in dioxane (5.00 mL) was added HCl/dioxane (3.00 mL) in one portion, the reaction mixture was stirred at 20 °C for one hour, solid was precipitate out. TLC (Petroleum ether : Ethyl acetate=0: l) showed the reaction was completed. The mixture was evaporated on a water bath under reduced pressure using a rotary evaporator. 2-(4,5,6,7- tetrahydro-lH-pyrazolo[4,3-c]pyridin-3-yl)propan-2-ol (200.00 mg, crude) was obtained as yellow solid. The crude product was used into next step directly without further purification. Preparation of Compound 041

To a mixture of 2-(4,5,6,7-tetrahydro-l H-pyrazolo[4,3-c]pyridin-3-yl)propan-2-ol (100.00 mg, 551.79 umol, 1.00 eq) and HATU (314.71 mg, 827.68 umol, 1.50 eq) in DCM (5.00 niL) was added DIPEA (71.31 mg, 551.79 umol, 1.00 eq) and 2- phenoxyacetic acid (83.95 mg, 551 .79 umol, 1.00 eq) in one portion, the reaction mixture was stirred at 20 °C for one hour. The desired product was detected by LCMS. The reaction mixture was extracted with DCM (15 mL*3) and water (15 ml.), the organic phase was dried ov er anhydrous Na₂S0₄, filtered and concentrated in vacuum. Further purification by prep-HPLC(FA ) to afford Compound 041 (40.00 mg, 125.57 umol, 22.76% yield, 99% purity ) as yellow oi l . ¹ H NMR (400MHz, METHANOLS) 7.24 - 7.30 (m, 2 H) 6.94 - 6.99 (m, 3 H) 4.86 (s, 2 H)

4.73 (s, 2 H) 3.80 - 3.89 (m, 2 H) 2.72 - 2.83 (m, 2 H) 1.53 (s, 6 H). LCMS : 316 [M+l].

Preparation of Compound 238

To a solution of 2-(4,5,6,7-tetrahydro- lH-pyrazolo[4,3-c]pyridin-3-yl)propan-2-ol (85.00 mg, 390.45 umol, 1 .00 eq, HC1) in DCM (5.00 ml.) was added TEA (1 18.53 mg, 1 .17 mmol, 3.00 eq) at 0 °C, followed by l -chloro-3-isocyanato-benzene (65.96mg, 429.49 umol, 1.10 eq) , the reaction mixture was stirred at 0 °C for 30 minutes. LCMS (EW 1 3 0- 1 80- PIC) showed the desired compound was obtained. The mixture was extracted with DCM ( 1 5 mL*3) and water (15 mL), the organic phase was dried over with anhydrous Na₂S0₄, filtered and concentrated in vacuum. Further purification by prep-HPLC(FA) to afford Compound 238(48.00 mg, 142.94 umol, 36.61% yield, 99.7% purity) as white solid. Ή NMR (400MHz, METHANOL-cU) 7.51 - 7.52 (t, J=2.01 Hz, 1 H) 7.23 - 7.28 (m, 2 H) 6.99 - 7.01 (m, 1 H) 4.68 (s, 2 H) 3.77 - 3.80 (t, J=5.84 Hz, 2 H) 2.77 - 2.80 (t, J=5.77 Hz, 2 H) 1.55 (s, 6 H). LCMS: 335 [M+l ].

Example 3: Proccedure for the Preparation of Compound 042 and 324

324

Step 1 : Preparation of Compound 2

To a solution of tert-butyl 3-(hydiOxymethyl)-l,4,6,7-tetrahydropyrazolo[4,3-c] pyridine-5-carboxylate (200.00 mg, 789.58 umol, 1.00 eq) in DCM (5.00 mL) was added DAST (152.73 mg, 947.50 umol, 1.20 eq) drop vise at -78 °C, the reaction mixture was stirred at -78 °C for 5 hours. TLC (Ethyl acetate. Methanol ^::: 20. 1 ) showed the starting material was consumed completely, The desired product was detected by LCMS. The reaction was quenched with saturated aqueous of NaHC0₃ (10 mL) and extracted with DCM (15 mL*3), the combined organic phase was dried over anhydrous Na₂S0₄, filtered and concentrated in vacuum. Compound tert-butyl 3-(fluoromethyl)-l, 4,6,7- tetrahydropyrazolo[4,3-c] pyri di ne-5-carboxyl ate (180.00 mg, crude) was obtained as yellow oil. The crude product was used into next step directly without further purification. LCMS: 256 [M+l].

Step 2: Preparation of Compound 3

To a solution of tert-butyl 3-(fluoromethyl)-l,4,6,7-tetrahydropyrazolo[4,3-c]pyridine -5-carboxylate (180.00 mg, 705.08 umol, 1.00 eq) in dioxane (5.00 mL) was added

HCI/dioxane (3.00 mL) in one portion, the reaction mixture was stirred at 10 °C for one hour, solid was precipitate out. TLC (Ethyl acetate: Methanol =20: 1) showed the reaction was completed. The solution was removed on a water bath under reduced pressure using a rotary evaporator. 3 -( fl uorom ethyl )-4, 5 ,6,7 -tetrahy dro -lH-pyrazolo[4,3-c]pyridine (120.00 mg, crude, HCI) was obtained as light yellow solid. The crude product was used into next step directly without further purification.

Preparation of Compound 042

To a mixture of 2-phenoxyacetic acid (63.52 mg, 417.47 umol, 1.00 eq) and HATU (158.74 mg, 417.47 umol, 1.00 eq) in DCM (5.00 mL) was added DIPEA (80.93 mg, 626.21 umol, 1.50 eq) and 3-(fluoromethyl)-4,5,6,7-tetrahydro-lH-pyrazolo[4,3- cjpyridine (80.00 mg, 417.47 umol, 1.00 eq, HC1) in one portion, the reaction mixture was stirred at 10 C for one hour. LCMS (EW 1350-204-P 1 A) showed the desired compound was obtained. The mixture was extracted with DCM (15 mL*3) and water (15 mL), the organic phase was dried with anhydrous Na₂S0₄, filtered and concentrated in vacuum. Further purification by pre- HPLC(FA) to afford Compound 042 (20.00 mg, 65.68 umol, 15.73% yield, 95% purity) as yellow solid.

Ή NMR (400MHz, METHANOL-d₄) 7.24 - 7.30 (m, 2 H) 6.94 - 6.99 (m, 3 H) 5.29 - 5.43 (m, 2 H) 4.90 (br. s., 2 H) 4.66 - 4.68 (m, 2 H) 3.84 - 3.93 (m, 2 H) 2.75 - 2.88 (m, 2 H). LCMS: 290 [M+l].

Preparation of Compound 324

To a smixture of 3-(fluoromethyl)-4,5,6,7 etrahydro-lH-pyrazoio[4,3-c]pyridine (40.00 mg, 208.74 umol, 1.00 eq, HC1) in DCM (5.00 mL) was added TEA (63.37 mg, 626.22 umol, 3.00 eq) at 0 °C, followed by l-chloro-3-isocyanato-benzene (32.06 mg, 208.74 umol, 1.00 eq) , the reaction mixture was stirred at 0 °C for 30 minutes. The desired product was detected by LCMS. The mixture was extracted with DCM (15 mL*3) and water (15 mL), the organic phase was dried with anhydrous Na₂S0₄, filtered and concentrated in vacuum. Further purification b pre-HPLC(FA) to afford Compound 24 (23.00 mg, 72.48 umol, 34.72% yield, 97.3% purity) as white solid. Ή NMR (400MHz, METHANOL-d,) 7.52 - 7.53 (t, J=2.01 Hz, 1 H) 7.21 - 7.29 (m, 2 H) 7.01 - 7.02 (m, 1 H) 5.31 - 5.43 (m, 2 H) 4.62 (s, 2 H) 3.81 - 3.84 (t, J=5.77 Hz, 2 H) 2.82 - 2.85 (t, J=5.71 Hz, 2 H). LCMS: 309 [M+l].

Example 4: Procedure for the Preparation of Compound 241

Step 1 : Preparation of Compound 302

To a mixture of ethyl 4-oxopiperidine-3-carboxylate (10,00 g, 48.16 mmol, 1.00 eq, HC1) and TEA (19.49 g, 192.64 mmol, 4.00 eq) in DCM (150.00 mL) was added l -chloro-3- i socyanato-benzen e (7.40 g, 48.16 mmol, 1.00 eq) dropwise at 0 °C under N₂. The mixture was stirred at 0 °C for 30 min, then heated to 15 °C and stirred for 4 hours. TLC showed the reaction was completed. The mixture was poured into water (100 mL) and stirred for 5 min. The aqueous phase was extracted with DCM ( 100 mL*2). The combined organic phase was washed with saturated brine (50 mL*2), dried over anhydrous a.->S0 , filtered and concentrated in vacuum. The residue was purified by silica gel chromatography (Petroleum ether/Ethyl acetate=4/l) to afford ethyl l-[(3-chlorophenyl)carbamoyl]-4-oxo-piperidine-3- carboxylate( 15 60 g, 47.31 mmol, 98.25% yield, 98.5% purity) as yellow solid. 1H NMR (400 MHz, METHANOLS) 7.44-7.60 (m, 1H), 7.17-7.35 (m, 2H), 6.95-7.08 (m, 1H), 4.28 (d, J 7. ! 5 Hz, 1H), 4.18 (s, 2H), 3.90-4.03 (m, 1H), 3.68 (s, 2H), 2.56-2.64 (m, 1H), 2.40- 2.51 (m, 1H), 1.29-1.38 (m, 2H), 1 .2 1 - 1 .28 (m, 1H). LCMS: 325 [M+ l ],

Step. 2: Preparation of Compound 241

To a mixture of ethyl l-[(3-chloiOphenyl)carbamoyl]-4-oxo-piperidine-3-carboxylate (2.00 g, 6.16 mmol, 1.00 eq) in EtOH (20.00 mL) was added N₂H₄-H₂0 (501.10 mg, 8.01 mmol, 1 .30 eq) in one portion under N₂. The mixture was stirred at 80 °C for 3

hours. LCMS showed the reaction was completed. The mixture was concentrated in vacuum to afford N-(3-chlorophenyl)-3-hydroxy-l,4,6,7-tetrahydropyrazolo[4,3-c] pyridine-5- carboxamide (1.78 g, 6.02 mmol, 97.78% yield, 99.05% purity) as white solid. Ή NMR (400 MHz, METHANOL-d₄) 7.49-7.60 (m, 1H), 7.20-7.33 (m, 2H), 6.99-7.04 (m, H i ), 4.35 (s, 2H), 3.78 (s, 2H), 2.65-2.76 (m, 2H). LCMS: 293 [M+l]. Example 5: Procedure or the Preparation of Compound 337

5 337

To a mixture of [5-[(3-chloropheiiyl)carbamoyl]-l,4,6,7-tetrahydiOpyrazolo[4,3-c] pyridin-3-yl] tri 11 uoromethanesul fonate (400.00 mg, 941.66 umol, 1.00 eq) and cyclohexen- 1 -ylboronic acid (237.22 mg, 1.88 mmol, 2.00 eq) in dioxane (15.00 mL) was added Pd(dppf)Cl₂ (68.90 nig, 94.17 umol, 0.10 eq), DPPF (52.20 mg, 94.17 umol, 0.10 eq) and K₃PO₄ (599.66 rag, 2,82 mmol, 3.00 eq) in one portion under N₂. The reaction vessel was sealed and heated in microwave at 130 °C for 2 hr. LCMS showed the reaction was completed. The mixture 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?S0₄, filtered and concentrated in

vacuum . The residue was purified by prep-HPLC(FA) to afford Ni -( 3 -chl oropheny I )-3 - (cyclohexen- 1 -yl )- 1 ,4,6,7-tetrahydro pyrazolo[4,3-c]pyridine-5-carboxamide (195.00 mg, 510.93 umol, 54.26% yield, 93.5% purity) as white solid. Ή NMR (400 MHz,

METHANOL^) D7.52-7.56 (m, 1H), 7.22-7.35 (m, 2H), 7.00-7.06 (m, IH), 6.04-6.10 (m, IH), 4.64 (s, 3H), 3.79-3.89 (m, 2H), 2.82 (s, 2H), 2.39-2.49 (m, 2H), 2.23-2.33 (m, 2H), 1.66-1.87 (m, 4H). LCMS: 357 [M+l].

Example 6: Preparation o f Compounds 338

Step 1 : Preparation of Compound 2

To a mixture of 2-(cyclopenten-l-yl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (200.00 mg, 1.03 mmol, 1.00 eq) in H₂0 (5.00 mL) was added KHF₂ (241.45 mg, 3.09 mmol, 3.00 eq) in one portion under N₂. The reaction stirred at 20 C for 13 h. TLC showed the reaction was completed. The mixture was concentrated in vacuum to afford potassium cyclopent- 1 - en- 1 -yltri fl uoroborate (445.00 mg, crude) as yellow solid.

Step 2: Preparation of Compound 338

To a mixture of [5-[(3-chlorophenyl)carbamoyl]-l,4,6,7-tetrahydropyrazolo[4,3-c] pyridin-3-yl] tri tl uorom eth anesul fon ate (50.00 mg, 117.71 umol, 1.00 eq) and potassium cyclopent- 1 -en- 1 -yltri fluoroborate (40.97 mg, 2 5.42 umol, 2.00 eq) in dioxane (3.00 mL) was added Pd(dppf)Cl₂ (8.61 mg, 1 1 .77 umol, 0.10 e ), DPPF (6.53 mg, 1 1.77 umol, 0.10 eq) and K₃PO₄ (74.96 nig, 353.12 uniol, 3.00 eq) in one portion under Nk The mixture was stirred at 145 °C for 1.5 hour. LCMS showed the starting material was consumed completely and the desired compound was detected. The mixture was poured into water (10 niL) and stirred for 2 min. The aqueous phase was extracted with ethyl acetate (10 mL*2) The combined organic phase was washed with saturated brine (10 ml.* 2 ), dried with anhydrous Na₂S0₄, filtered and concentrated in vacuum. The residue was purified by prep-HPLC(FA) to afford N-( 3 -chl orophenyl )-3 -(cycl openten- 1 -yl )- 1 ,4,6,7-tetrahydropyrazol o[4,3 -c] pyridine-5-carboxamide (10.23 mg, 28. 1 1 umol, 23.88% yield, 94.2% purity) as white solid. LCMS: 343 [M+l ].

Example 7: Preparation o f Compound 264

Step 1 : Preparation of Compound 3

To a mixture of tert-butyl 3-(trifluoromethylsulfonyloxy)-l ,4,6,7-tetrahydropyrazolo [4,3-c]pyridine-5-carboxylate (300.00 mg, 807.91 umol, 1.00 eq) and cycl openten- 1 - y 1 boron ic acid (135.64 mg, 1.21 mmol, 1.50 eq) in dioxane (2.00 m l.) and H₂0 (200.00 uL) was added XPHOS-PD-G, (63.57 mg, 80.79 umol, 0.10 eq), K₃P0₄ (342.99 mg, 1.62 mmol, 2.00 eq) in one portion under ₂. The mixture was stirred at 1 10 °C for 10 hour. TLC (Ethyl acetate:Petroleum ether=2: 1) showed the reaction was completed and the desired product was detected. The mixture was poured into water (20 mL) and stirred for 2 min. The aqueous phase was extracted with ethyl acetate (20 niL*2). The combined organic phase was washed with brine (20 mL*2), dried with anhydrous Na₂S0₄, filtered and concentrated in vacuum. The residue was purified by silica gel chromatography (Petroleum ether/Ethyl acetate=2/l) to afford tert-butyl 3~(cyclopenten-l~yl)-l,4,6,7-tetrahydropyrazolo[4,3~c]pyridine-5- carboxylate (Compound 3) (200.00 mg, 691 .16 umol, 85.55% yield) as white solid. Step 2: Preparation of Compound 4

To a solution of tert-butyl 3-(cyclopenten-l-yi)-l,4,6,7-tetrahydropyrazoio[4,3-c] pyridine-5-carboxylate (50.00 mg, 172.79 umol, 1.00 eq) in MeOH (5.00 mL) was added Pd/C (10%, 5 mg) under N₂. The suspension was degassed under vacuum and purged with Hi several times. The mixture was stirred under H₂ (15 psi ) at 20 °C for 12 hours. I MS showed the starting material was consumed completely. The reaction mixture was filtered and the filter was concentrated to give tert-butyl 3 -cyclopentyl- 1,4,6,7- tetrahydropyrazolo[4,3-c]pyridine-5-carboxylate (Compound 4) (44.00 mg, 151.00 umol, 87.39% yield) as yellow solid. LCMS: 292 [M+1 ],

Step 3 : Preparation of Compound 5

To a mixture of tert-butyl 3 -cy cl opentyl - 1 ,4,6, 7-tetrahy dropyrazol o[4,3 -cjpyri di ne-5- carboxylate (44.00 mg, 151.00 umol, 1.00 eq) in dioxane (2.00 mL) was added HCl/dioxane (4 M, 4.00 mL, 105.96 eq) in one portion at 1 5 °C under ₂. The mixture was stirred at 15 C for 2 hours. TLC (Ethyl acetate:Petroleum ether=2: 1) showed the reaction was completed. The mixture was concentrated in vacuum to afford 3 -cy cl opentyl -4,5,6,7- tetrahydro-lH-pyrazolo[4,3-c]pyridine (34.39 mg, 151.01 umol, 100.00%) yield, HC1) as yellow solid.

Step 4: Preapration of Compound 264

To a mixture of 3-cyclopeiityl-4,5,6,7-tetrahydro-lH-pyrazolo[4,3-c]pyridine (34.00 mg, 149.30 umol, 1.00 eq, HC1) and TEA (30.22 mg, 298.60 umol, 2.00 eq) in DCM (3.00 mL) was added l -chloro-3-isocyanato-benzene (22.93 mg, 149.30 umol, 1.00 eq) in one portion at 0 °C under N₂. The mixture was stirred at 15 C for 0.5 hours. LCMS showed the reaction was completed. The mixture was poured into water (10 ml.) and stirred for I min. The aqueous phase was extracted with DCM (10 mL*2). The combined organic phase was washed with brine (10 mL*2), dried with anhydrous Na₂S0₄, filtered and concentrated in vacuum. The residue was purified by prep-HPLC(FA) to afford -( -chl orophenyl )-3 - cyclopentyl - 1 ,4,6,7-tetrahydro pyrazolo[4,3-c]pyridine-5-carboxamide (26.00 mg, 73.44 umol, 49.19% yield, 97.4% purity) as white solid. 1H NMR (400 MHz, METHANOLS)□ 7.49-7.56 (m, 1H), 7.27-7.33 (m, 1 H), 7.20-7.26 (m, 1H), 6.97-7.04 (m, 1H), 4.55 (s, 2H), 3.80 (s, 2H), 3.00-3.15 (m, 1H), 2.72-2.83 (m, 2H), 1.98-2.16 (m, 2H), 1.70 (br. s., 6H). LCMS: 345 [M+1]. xample 8: Preparation of Compounds 274 and 275

Step 1 : Preaparation of Compound 2

To a solution of Compound 1 (400.00 mg, 1.90 mmol, 1.00 eq) in H₂0 (4 mL) was added a solution of potassium fluoride hydrofluoride (446.12 mg, 5.71 mmol, 3.00 eq) in H₂0 (4 mL) at 0 °C under N₂, and the mixture was stirred at 18 °C for 16 hrs. The reaction mixture was concentrated under reduced pressure to afford the desired product, Compound 2, (847.00 mg, crude) as yellow solid, which was used directly for the next step.

Preparation of Compound 274

A mixture of Compound 3 (30.00 mg, 70.62 umol, 1.00 eq). Compound 2 (20. 13 mg, 105.94 umol, 1.50 eq), K₃PO₄ (29.98 mg, 141.25 umol, 2,00 eq), DPPF (3.92 mg, 7.06 umol, 0.10 eq), KBr (840.38 ug, 7.06 umol, 0.10 eq) and Pd(dppf)Cl₂ (2.58 mg, 3.53 umol, 0.05 eq) in dioxane (3.00 mL) was heated to 145 °C in microwave for I hr. The reaction mixture was diluted with brine (60 mL), and extracted ith EA (80 mL ). The organic layer was concentrated under reduced pressure to give a brown residue. The residue was purified by prep-HPLC (FA) to afford desire product (10.00 mg, 27.20 umol, 38.52% yield, 97.6% purity) as yellow solid. 1H NMR (400 MHz, METHANOL-d₄) δ = 7.54 (t, J = 2.01 Hz, IH), 7.30 - 7.35 (m, H), 7.21 - 7.28 (m, 1H), 7.04 (d, J = 0.88 Hz, 1H), 6.07 (s, 1H), 4.66 (s, 2H), 4.35 (q, J = 2.64 Hz, 2H), 3.93 (t, J = 5.52 Hz, 2H), 3.84 (t, J = 5.77 Hz, 2H), 2.84 (s, 2H), 2.56 (d, J = 1 .76 Hz, 2H). LCMS: 359/361 [M+ ],

Preparation of Compound 275

A mixture of Compound 274 (30.00 mg, 83.61 umol, 1.00 eq), Lid (3.54 mg, 83.61 umol, 1.00 eq) and Pd/C (5.00 mg) in EA (8.00 mL) was heated to 50 °C under H₂ (50 Psi) for 16 hrs. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give a yellow residue. The residue was purified by prep-HPLC (FA) to give impure product. The impure product was purified by prep-TLC to afford desire product (5.00 mg, 13.59 umol, 16.26% yield, 98.1% purity) as yellow solid. 1H NMR (400 MHz,

METHANOLS) δ = 7.55 (s, 1H), 7.20 - 7.37 (m, 2H), 7.03 (d, J= 7.53 Hz, IH), 4.61 (s, 2H), 4.05 (d, J = 11.17 Hz, 2H), 3.82 (t, J = 5.52 Hz, 2H), 3.57 (t, ./ 1 1.48 Hz, 2H), 2.98 (s, IH), 2.81 (t, J= 5.52 Hz, 2H), 1.80 - 1.94 (m, 4H). LCMS: 361/363 [M+l],

Example 9: Preparation of Compounds 267, 336, 388, and 441

Step 1 : Preparation of Compound 336

A mixture of Compound 1 (100.00 mg, 235.42 umol, 1.00 eq), potassium

trifluoroiprop- 1 -en-2-yl )borate (52.26 mg, 353.13 umol, 1.50 eq), K₃P0₄ (99.95 mg, 470.84 umol, 2.00 eq) and Pd(dppf)Cl₂ (17.23 mg, 23.54 umol, 0.10 eq) in dioxane (3.00 mL) was heated to 140 °C in microwave for 1 hr. The reaction mixture was diluted with brine (60 mL), and extracted with EA (80 mL). The organic layer was dried over Na₂S0₄, filtered and concentrated under reduced pressure to give a brown residue. The residue was purified by prep-HPLC (FA) to afford desire product (14.00 mg, 43.63 umol, 18.53% yield, 98.73% purity) as yellow solid. LCMS: 31 7/319 [M+l]. 1H NMR (400 MHz, DMSO-d₆) δ = 12.34 - 12.75 (m, IH), 8.85 (s, IH), 7.64 (s, IH), 7.42 (d, J=8.16 Hz, IH), 7.26 (t, J= 8.09 Hz, IH), 6.99 (d, J= 9.16 Hz, IH), 5.17 (s, 2H), 4.57 (s, 2H), 3.73 (t, J= 5.52 Hz, 2H), 2.71 (s, 2H), 2.09 (s, 3H). Preparation of Compound 267

A mixture of Compound 1 (40.00 nig, 126.27 umol, 1 .00 eq), Li CI (5.35 nig, 126.27 umol, 1.00 eq) and Pd/C (5.00 mg) in EA (8.00 mL) was heated to 65 C under H₂ ( 1 5 Psi ) for 16 hrs. LCMS showed no reaction . The mixture was stirred at 50 °C under H₂ (50 Psi) for 1 6 hrs. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give a yellow residue. The residue was purified by prep-HPLC (FA) to afford the desired product, Compound 267 (15.00 mg, 45.12 umol, 35.73% yield, 95.90% purity) as white solid. LCMS: 3 19/321 [M+l].

1H MR (400 MHz, METHANOL^) δ = 7.55 (t, J= 1.94 Hz, IH), 7.21 - 7.37 (m, 2H), 7.04 (d, J = 8.66 Hz, 1H), 4.62 (s, 2H), 3.85 (t, J = 5.96 Hz, 2H), 3.04 - 3.17 (m, 1H), 2.86 (s, 2H), 1.35 (d, ./ 7.03 FIz, 6H).

Preparation of Compound 388

To a solution of Compound 1 (50.00 mg, 157.84 umol, 1 .00 eq) in TH (3.00 mL) was added BH₃-Me₂S (10 M, 63.14 uL, 4.00 eq) at 0 C under N₂, and the mixture was stirred at 15 C for 16 hrs. A solution of NaOH (25.25 mg, 631.36 umol, 4.00 eq) in FLO (1.00 mL) and H 0₂ (81.34 mg, 789.20 umol, 5.00 eq) was added into the mixture at 0 °C, and the reaction mixture was stirred at 15 °C for another 2 hrs. The reaction mixture was diluted with Na₂S0₃ (Saturated, 60 mL), and extracted with EA (80 mL). The organic layer was concentrated under reduced pressure to give a yellow residue. The residue was purified by Prep-FIPLC(FA) to afford N-(3-chlorophenyl)-3-(2-hydroxy-l-methyl-ethyl)-l, 4,6,7- tetrahydropyrazolo[4,3-c]pyridine-5-carboxamide (15.00 mg, 43.28 umol, 27.42% yield, 96.6% purity) as white solid. LCMS: 335/337 [M+l], 1H NMR (400 MHz, METHANOL- d₄) δ = 7.54 (t, J= 1.88 Hz, 1H), 7.29 - 7.35 (m, H), 7.21 - 7.28 (m, 1H), 7.02 (d, J= 7.91 Hz, IH), 4.60 (d, J = 2.64 Hz, 2H), 3.62 - 3.92 (m, 4H), 2.98 - 3.1 1 (m, I H), 2.81 (s, 2H), 1 .32 (d, J = 7.15 Hz, 3H).

Preparation of Compound 441

To a solution of Compound 1 (35.00 mg, 1 10.49 umol, 1.00 eq) in DCM (4.00 mL) was added ZnEt₂ (1 M, 552.43 uL, 5.00 eq) at 0 °C under N₂, followed by

ch 1 oro( i odo )m eth an e (1 16.93 mg, 662,92 umol, 6.00 eq) after 0.5 h, and the mixture was stirred at 18 °C for 16 hrs. The mixture was quenched with HQ (2M) to pH = 6 and extracted with EA (60 mL). The organic layer was dried over Na₂S0₄, filtered and concentrated under reduced pressure to give yellow residue. The residue was purified with EW645-4 16-P 1 by prep-HPLC (FA) to afford desired product. Compound 44 1 , (9.00 mg, 26.77 umol, 24.23% yield, 98.4% purity) as yellow solid. LCMS: 331 333 [M+l ]. Ή NMR (400 MHz, METHANOLS) δ = 7.55 (s, IH), 7.29 - 7.35 (m, 1H), 7.22 - 7.29 (m, IH), 7.03 (d, ./ 7.65 Hz, IH), 4.62 (s, 211), 3.81 (t, J = 5.65 Hz, 2H), 2.79 (t, ./ 5.52 Hz, 2H), 1.40 (s, 3H), 0.93 (s, 2H), 0.73 (s, 2H). Example 10: Preparation of Compound 547

547

Step 1 : Preparation of Compound 3

To a solution of 2-chl oro-3 -fl uoro-pyri di n-4-am i n e (100.00 mg, 682.36 umol, 1.00 eq) and pyridine (161.92 mg, 2.05 mmol, 3.00 eq) in DCM (5.00 mL) was added phenyl carbonochloridate ( 160.26 mg, 1.02 mmol, 1 .50 eq) at 0 °C under N₂, and the mixture was stirred at 18 °C for 0.5 hr. The reaction mixture was diluted with DCM (50 mL) and washed with brine (40 mL, three times). The organic layer was concentrated under reduced pressure to afford desired product, Compound 3, (180.00 mg, crude) as yellow oil, which was used directly for the next step.

Step 2: Preparation of Compound 6

A mixture of Compound 4 (1.00 g, 3.31 mmol, 1.00 eq), Compound 5 (734.59 mg, 4.97 mmol, 1 .50 eq), K₃P0₄ (1 .41 g, 6.62 mmol, 2.00 eq) and Pd(dppf)Cl₂ (121.10 mg, 165.50 umol, 0.05 eq) in dioxane (20.00 mL) was heated to 120 °C in microwave for 1 hr. The reaction mixture was diluted with brine (80 mL) and extracted with EA (100 mL). The organic layer was dried over Na₂S0₄, filtered and concentrated under reduced pressure to give a brown residue. The residue was purified by silicagel column to afford desire product (580.00 mg, 2.20 mmol, 66.47% yield) as yellow solid. LCMS: 264 [M M J .

Step 3 : Preparation of Compound 7

To a solution of Compound 6 (315.00 mg, 1.20 mmol, 1.00 eq) in DCM (1 .00 mL) was added TFA ( 1 .53 g, 13.42 mmol, 1 1 . 1 8 eq) under N₂, and the mixture was stirred at 1 8 °C under N₂ for 1 hr. The reaction mixture was concentrated under reduced pressure to afford 3-isopropeny{-4,5,6,7-tetraliydro-lH-pyrazoio[4,3-c]pyridine (330.00 mg, 1.19 mmol, 99.19% yield, TFA) as yellow oil, which was used directly for the next step.

Step 4: Preparation of Compound 547

To a solution of 3 -i sopropen yl -4,5,6, 7-tetrah ydro- 1 H-py razol o[4, 3 -c jpyri di ne (55.09 mg, 337.50 umol, 2.00 eg) and Et₃N (68.30 mg, 675.00 umol, 4.00 eg) in DCM (4.00 mL) was added phenyl N-(2-chl oro-3 -tl uoro-4-py ri dyl )carbam ate (45.00 mg, 168.75 umol, 1.00 eg), and the mixture was stirred at 18 °C for 16 hrs. The reaction mixture was diluted with brine (40 mL) and extracted with DCM (50 mL). The organic layer was concentrated under reduced pressure to give a yellow residue. The residue was purified by prep-HPLC (FA) to afford the desired product, Compound 547, (20.00 mg, 57.66 umol, 34.17% yield, 96.8% purity) as yellow solid. LCMS: 336/338 [M+l]. ^lH NMR (400 MHz, METHANOL- d₄) δ = 7.22 (s, 1H), 7.12 - 7.19 (m, 2H), 6.84 - 6.91 (m, 1H), 5.26 (s, 2H), 4.66 (s, 2H), 3.84 (t, ./ 5.77 FIz, 2H), 2.84 (t, J = 5.71 Hz, 2FI), 2.32 (s, 3FI), 2.16 (s, 3H). Example 11: Preparation o f Compound 548

To a solution of -bromo-2-fl uoro-ani 1 i ne (25.00 mg, 131.57 umol, 1.00 eg) and Et₃N (66.57 mg, 657.85 umol, 5.00 eg) in DCM (4.00 mL) was added TRIPFIO S GENE (19.52 mg, 65.79 umol, 0.50 eg) at 0 C under N₂, and the mixture was stirred at 18 °C for 0.5 hr. A solution of Compound I (42,95 mg, 263.14 umol, 2.00 eg) and Et₃N (56.66 mg, 559.95 umol, 3.00 eg) in DCM (4.00 mL) was added, and the reaction mixture was stirred at 18 °C for 0.5 h. The reaction mixture was diluted with brine (40 mL) and extracted with DCM (50 mL). The organic layer was concentrated under reduced pressure to give a yellow residue. The residue was purified by prep-HPLC (FA) to afford desire product, Compound 548, (26.00 mg, 67.87 umol, 51.59% yield, 99.00% purity) as yellow solid. LCMS: 379/381 [M+l]. Ή NMR (400 MHz, METHANOLS) δ = 7.32 - 7.51 (m, 2H), 7.07 (dt, J= 1.32, 8. 13 Hz, 1H), 5.25 (s, 2FI), 4.68 (s, 2FL), 3.86 (t, ./ 5.83 FIz, 2H), 2.85 (t, J = 5.77 Hz, 2FI), 2.16 (s, 3FI). xample 12: Preparatio of Compound 549

549

To a solution of 3 -methyl aniline (20.00 mg, 86.65 umol, 1.00 eq) and Et₃N (94.44 mg, 933.25 umol, 5.00 eq) in DCM (4.00 mL) was added TRIPHOSGENE (27.69 mg, 93.33 umol, 0.50 eq) at 0 °C under N₂, and the mixture was stirred at 18 °C for 0.5 hr. A solution of 3 -i sopropenyi -4, 5, 6,7-tetrahydro- 1 H-pyrazol o[4, 3-c] pyri di ne (54.84 mg, 335.97 umol, 1.80 eq) and Et₃N (56.66 mg, 559.95 umol, 3.00 eq) in DCM (4.00 mL) was added, and the reaction mixture was stirred at 1 8 °C for 0.5 h . The reaction mixture was diluted with brine (40 mL), and extracted with DCM (50 mL). The organic layer was concentrated under reduced pressure to give a yellow residue. The residue was purified by prep-HPLC (FA) to afford 3-isopropenyl-N-(m-tolyl)-l,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxamide (23.00 mg, 76.29 umol, 40.87% yield, 98.30% purity) as yellow solid. LCMS: 297 [M i l], Ή NMR (400 MHz, METHANOLS ) δ = 7.22 (s, IH), 7.12 - 7.19 (m, 2H), 6.84 - 6.91 (m, 1 H), 5.26 (s, 2H), 4.66 (s, 2H), 3.84 (t, J = 5.77 Hz, 2H), 2.84 (t, J = 5.71 Hz, 2H), 2.32 (s, 3H), 2.16 (s, 3H).

Example 13: Preparation of Compounds 260

260 Step 1 : Preparation of Compound 2

To a mixture of ethyl 3-aminopropanoate (50.00 g, 320.55 mmol, 1.00 eq, HCl salt) in

MeOH (150.00 niL) was added NaOH (13 g, 320.55 mmol, 1.00 eq). The mixture was heated to 70°C. Acrylonitrile (21.8 g, 410.1 mmol, 1.26 eq) was added dropwise into the above mixture. And the mixture was stirred at 70°C for 4h. It was cooled 25 C, Boc₂0

(6.39 g, 29.30 mmol, 0.90 eq) was added. Then the mixture was stirred at 25°C for 16h.

TLC showed the reaction completed. The mixture was filtered, the filtrate was wahsed with water (500 rtiL), extracted with EtOAc (500 mL*3), the filtrate was dried over Na?S0₄ and concentrated to give Compound 2A (6.70 g, 24.79 mmol, 76.15% yield), which was used directly. Ή NMR (400 MHz, CHLOROF ORM-d) δ= 3.71 (s, 3H), 3.50-3.63 (m, 4H), 2.56-

2.70 (m, 4H), 1.49 (s, 9H).

Step 2: Preparation of Compound 3

To a mixture of ethyl 3-[tert-butoxycarbonyl(2-cyanoethyl)amino]piOpanoate (70.00 g, 258.95 mmol, 1.00 eq) in PhMe (150.00 mL) was added NaH (10.46 g, 261.54 mmol, 1.01 eq) in three portions. The mixture was stirred at 1 10°C for 4h. TLC showed the reaction completed. The reaction was quenched with aqueous saturate NH₄C1 (200 ml. ), the aqueous was acidified with HCl (2N) to pH=6, then the mixture was extracted with EtOAc (150 mL*3),the organic layer was washed with brine ( 100 mL), dried over Na₂S0₄ and concentrated to give Compound 3 which was used directly. Ή NMR (400 MHz,

CHLOROFORM-d) δ==4.40 (br. s., 1H), 4.16-4.26 (m, 1H), 3.58 (brs., 2H), 3.41 (d, J=7.28

Hz, 1H), 2.67 (d, J=14.31 Hz, 1H), 2.53 (dd, J=5.77, 9.54 Hz, 1H), 1.52 (s, 9H).

Step 3 : Preparation of Compound 4

To a mixture of tert-butyl 3-cyano-4-oxo-piperidine- 1 -carboxylate (20.00 g, 89.18 mmol, 1.00 eq) in EtOH (200.00 mL) was added NH₂NH₂.H₂0 (8.93 g, 178.36 mmol, 2.00 eq ) in one portion. The mixture was stirred at 80°C for 2 h. TLC showed the reaction worked well. The mixture was concentrated to give Compound 4 (19.70 g, 82.67 mmol, 92.70% yield).

Step 4: Preparation of Compound 5

To a suspension of Compound 4 (40.00 g, 0.47 mol, 1.00 eq) and CuBr₂ (44 g, 0.58 mol, 1.20 eq) in 500 mL of acetonitrile was added t-BuONO (20.2 g, 0.58 mol, 1.20 eq) dropwise at 0°C. The contents were allowed to stir at 50°C for 4 h. TLC showed the reaction completed. Then it was quenched with HCl (1M, 300 mL), extracted with EtOAc (200 mL*3 ), the organic layer was washed with brine (300 mL), dried over Na₂S0₄ and concentrated to give Compound 5 (1 1.00 g, 36.40 mmol, 21.69% yi eld). 1H MR (400 MHz, CHLOROFORM-d) 6 4.33 (brs, 2H), 3.72 (brs, 2H), 2.83 (t, J=5.27 Hz, 2H), 1 .50 (s, 9H). Step 5 : Preparation of Compound 6

To a mixture of Compound 5 (1 1.00 g, 36.40 mmol, 1 .00 eq) in DCM (10.00 mL)was added HCl/dioxane (4 M, 20.02 ml.) in one portion at 0°C. The mixture was stirred at 0°C for 1 h. The mixture was concentrated to give Compound 5 (HCI )

Preparation of Compound 260

To a mixture of 3-bromo-4,5,6,7-tetrahydro-lH-pyrazolo[4,3-c]pyridine (10.50 g, 38.19 mmol, 1.00 eq, 2HC1) in MeOH (350.00 ml.) was added K₂C0₃ (13.20 g, 95.48 mmol, 2.50 eq). Then the mixture was filtered, the filtrate was used directly. And l-chloro-3- isocyanato-benzene (5.86 g, 38.19 mmol, 1.00 eq) was added slowly into above filtrate at 25°C. The reaction was stirred at 25°C for lh. LCMS showed the reaction worked well . The mixture was concentrated. The residue was rinsed with a mixed solution of PE/EA (10/1, 20 mL). The mixture was filtered and the cake was collected to give Compound 260 (1 1.00 g, 30.93 mmol, 80.99% yield). 1H NMR (400 MHz, DMSO-d6) δ= 12.95 (brs, 1H), 8.88 (s, H), 7.64 (s, I H), 7.41 (d, J=8.03 Hz, 1 H), 7.26 (t, J=8.16 Hz, 1H), 6.99 (d, J=7.78 Hz, IH), 4.34 (s, 2H), 3.72 (brs, 2H), 2.72 (brs, 2H). LCMS: 355 [M+l].

Example 14: Preparation of Compound 515

515

Step 1 : Preparation of Compound 3

To a solution of tert-butyl 4-oxopiperidine- 1 -carboxylate (1.00 g, 5.02 mmol, 1.00 eq) in THF (15.00 mL) was added LiHMDS (1 M, 6.53 mL, 1.30 eq) portion-wise at -60 °C under N₂. The mixture was stirred at -60 °C for 30 min, 2,2-dimethylpropanoyl chloride (786.91 mg, 6.53 mmol, 1.30 eq) in THF (2.00 mL) was added dropwise at -60 °C. The mixture was stirred at 10 °C for 2 hr. TLC showed the reaction was completed. The mixture was quenched by saturated NH₄CI (20 mL) and extrated with EA (50 mL*2). The combined organic phase was dried with anhydrous Na₂S0₄, filtered and concentrated in vacuum to afford tert-butyl 3-(2,2-dimethylpropanoyl)-4-oxo-piperidine-l-carboxylate (1.20 g, crude) as yellow oil.

Step 2: Preparation of Compound 4

To a solution of tert-butyl 3-(2,2-dimethylpropanoyl)-4-oxo-piperidine-l-carboxylate (1.20 g, 4.23 mmol, 1.00 eq) in EtOH (10.00 mL) was added NH₂NH₂.H₂0 (498.24 mg, 8.46 mmol, 2.00 eq) in one portion. The mixture was heated to 110 °C and stirred for 5 hours. LCMS showed the reaction was completed. The mixture was concentrated in vacumm. The residue was purified by prep-HPLC (FA) to afford tert-butyl -3 -tert-butyl- 1, 4,6,7- tetrah ydropyrazol o[4, 3 -c] pyri di ne-5-carboxy 1 ate( 300.00 mg, 1.07 mmol, 25.39% yield) as white solid. 1H NMR (400MHz, CHLOROFORM-d) 6 4.56 (brs, 2 H), 3.69 (brs, 2 PI), 2.70 - 2.81 (m, 2 H), 1.50 (s, 10 H), 1.35 (s, 9 H).

Step 3 : Preparation of Compound 5

To a solution of tert-butyl 3-tert-butyl-l,4,6,7-tetrahydropyrazolo[4,3-c]pyridine -5- carboxylate (80.00 mg, 286.35 umol, 1.00 eq) in dioxane (3.00 mL) was added HCl/dioxane (4 M, 3.00 mL, 41.91 eq) in one portion. The mixture was stirred at 10 °C for 30 min. TLC showed the reaction was completed. The mixture was concentrated in vacumm to afford 3- tert-butyl-4,5,6,7-tetrahydro-lH-pyrazolo [4,3 -cjpyri dine (65.00 mg, 257.75 umol, 90.01% yield, 2HC1) as white solid.

Step 4: Preparation of Compound 515

To a solution of 3-tert-butyl-4,5,6,7-tetrahydro-l H-pyrazolo[4,3-c]pyridine (65.00 mg, 257.75 umol, 1.00 eq, 2HC1) in DCM (10.00 mL) was added TEA (52.16 mg, 515.50 umol, 2.00 eq) followed by a solution of l-chloro-3-isocyanato-benzene (39.58 mg, 257.75 umol, 1.00 eq) in DCM (1.00 mL) dropwise at -10 °C. The mixture was stirred at -10 °C for 20 min. LCMS showed the reaction was completed. The mixture was quenched with H₂0 (10 mL) and extracted with DCM (20 mL*2). The combined organic phase was dried with anhydrous Na₂S0₄, filtered and concentrated in vacuum. The residue was purified by pre-HPLC (FA) to afford 3-tert-butyl-N-(3-chlorophenyl )- 1 ,4,6,7-tetrahydropyrazolo[4,3- c]pyri di ne-5 -carboxami de (35.00 mg, 102.21 umol, 39.66% yield, 97.2% purity) as yellow solid. 1H NMR (400MHz, METHANOL-d4)6= 7.54 (t, ,1 = 2.0 Hz, 1 H), 7.34 - 7.30 (m, IH), 7.22 - 7.28 (ra, 1 H), 7.01 - 7.05 (m, 1 H), 4.69 (s, 2 H), 3.80 (t, ./ 5.8 Hz, 2 H), 2.81 (t, J 5.8 Hz, 2 H), 1.38 (s, 9 H). Example 15: Preparation of Compound 554

Step 1 : Preparation of Compound 2

To a solution of LiHMDS (1 M, 7.53 mL, 1.50 eq) was added dropwise tert-butyl 4- oxopi peri dine- 1 -carboxylate (1.00 g, 5.02 mmol, 1.00 eq) in THF (4.00 mL) at -70 °C for 30 min, then cyclobutanecarbonyl chloride (892,76 mg, 7.53 mmol, 1.50 eq) in THF (4.00 mL) was added dropwise at -70 °C. The mixture was stirred at 16 °C for 3 hr. The reaction was quenched with sat. NH₄CI (20 mL) and then extracted with EA (20 mL*2). The combined organic phase was washed with brine (15 mL), dried over anhydrous Na₂S0₄, filtered and concentrated in vacuo to give tert-butyl 3 -(cy cl obutan ecarbonyl )-4-oxo- piperi dine- 1 -carboxylate (1.50 g, crude) as a yellow solid. LCMS: I 82[M + l - I OOj .

Step 2: Preparation of Compound 3

A solution of tert-butyl 3 -(cyclobutanecarbonyl )-4-oxo-piperidine- 1 -carboxyl ate (7.50 g, 5.33 mmol, 1.00 eq), N₂H₄.H₂0 (320.18 mg, 6.40 mmol, 1.20 eq) in EtOH (10.00 mL) was heated to 80 C for 3 hr. The solution was concentrated. The residue was purified by column chromatography (Si0₂, PE/E A= 1 0/ 1 to 3/1) to give tert-butyl 3-cyclobutyl- 1 ,4,6,7- tetrahydropyrazolo[4,3-c]pyridine-5-carboxylate (700.00 mg, 1.51 mmol, 28.41% yield, 60% purity) as a light yellow solid. LCMS: 278[M+1],

Step 3 : Preparation of Compound 4

To a solution of tert-butyl 3 -cycl obutyl - 1 ,4,6,7-tetrahy dropyrazol o[4,3 -c] pyridine- 5- carboxylate (245.00 mg, 883.33 umol, 1.00 eq) in dioxane (3.00 mL) was added HCl/dioxane (4 M, 3.00 mL, 13.58 eq), the solution was stirred at 16 °C for 2 hr. The reaction was concentrated to give 3-cyclobutyl-4,5,6,7-tetrahydro-lH-pyrazolo[4,3- c] py ri di ne; hy droch I ori de (200.00 mg, caide) as a white solid. LCMS: 178ΓΜ+1],

Step 4: Preparation of Compound 554

To a solution of 3-cyclobutyl-4,5,6,7-tetrahydro-l H-pyrazolo[4,3-c]pyridine hydrochloride (90.00 mg, 421.13 umol, 1.00 eq), TEA (127.84 mg, 1.26 mmol, 3.00 eq) in DCM (8.00 mL) was added dropwise I -chloro-3-i socvanato-benzene (64.67 mg, 421.13 umol, 1.00 eq) in DCM (lmL) at -10 °C and stirred for 30 min. The solution was washed with water (lOmL), the organic phase was dried over anhydrous Na₂S0₄, filtered and concentrated in vacuum. The residue was purified by prep-HPLC ( basic ) to give N-(3- chl oropheny 1 )- -cy cl obutyl - 1 ,4,6,7-tetrahydropyrazol o[4,3 -c] pyri dine -5-carboxamide (40.00 mg, 120.19 umol, 28.54% yield, 99.4% purity) as a white solid. Ή NMR (400 MHz, METHANOL-^) ppm 7.52 (t, ./ 2.01 Hz, 1 H), 7.28 - 7.32 (m, 1 H), 7.21 - 7.26 (m, 1 H), 6.99 - 7.03 (m, 1 H), 4.55 (brs, 2 H), 3.79 (t, .1 = 5.77 Hz, 2 H), 3.58 (brs, 1 H), 2.78 (t, .1 = 5.65 Hz, 2 H), 2.24 - 2.40 (m, 4 H), 2.03 - 2.15 (m, 1 H), 1.93 (d, J= 7.03 Hz, 1 H). LCMS: 331 ΓΜ+1],

Example 16: Preparation of Compound 455

455

Step 1 : Preparation of Compound 2

To a mixture of tert-butyl 3-amino-l,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carbo xylate (150.00 mg, 629.49 umol, 1.00 eq) and 1,4-dibromobutane (135.91 mg, 629.49 umol, 1.00 eq) in MeCN (10.00 mL) was added Cs₂C0₃ (410.20 mg, 1.26 mmol, 2.00 eq). The mixture was stirred at 50 C for I hr. TLC (Petroleum ether/Ethyl acetate=0/l) showed the starting material 1 was consumed completely, and a major new spot detected. The solvent was evaporated, the residue was washed with water (20 mL), extracted with Ethyl acetate (20 mL*2), the combined organic layer was dried over anhydrous Na?S0₄, concentrated. The residue was purified by chromatography (silica gel, eluting with Petroleum ether/Ethyl acetate=l/l to 0/1) to afford tert-butyl-3-pyrrolidin- 1 -yl- 1 ,4,6,7-tetrahydropyrazolo[4,3- c] py ri di ne-5 -carboxyl ate (45.00 mg, 153.91 umol, 24.45% yield) as light yellow oil. Ή NMR (400 MHz, CDC1₃) δ 4.46 (br. s., 2 H), 3.59 (brs, 2 H), 3.28 (t, .1 = 6.27 Hz, 4 H), 2.57 (br. s., 2 H), 1.87 (br. s., 4 H), 1.38 - 1.45 (m, 9 H). LCMS: 293 [M+\\ .

Step 2: Preparation of Compound 3

To a solution of tert-butyl 3-pyrrolidin-l-y{-l,4,6,7-tetrahydropyrazolo[4,3-c]pyridine -5-carboxylate (45.00 mg, 153.91 umol, 1 .00 eq) in dioxane (1.00 ml.) was added

HCl/dioxane (4 M, 3.00 mL, 77.97 eq). The mixture was stirred at 15 °C for 1 hr. Then white solid was formed, the solvent was evaporated to afford 3-pyrro!idin- 1 -yl-4,5,6,7-tetrahvdro- I H-pyrazol o[4, -c]py ri di ne (38.00 mg, crude, HC1) as white solid, which was not purified and used directly in the next step.

Step 3 : Preparation of Compound 455

To a solution of 3-pyiTolidin-l-yi-4,5,6,7-tetrahydro-lH-pyrazolo[4,3-c]pyridine (38.00 mg, 166.14 umol, 1.00 eq, HC1) in DCM (3.00 mL) was added TEA (33.62 mg, 332.28 umol, 2.00 eq) and I -chloro-3-isocyanato-benzene (25.51 mg, 166.14 umol, 1.00 eq). The mixture was stirred at 1 5 °C for 1 hr. LCMS showed the material 3 was consumed completely, and a main peak with desired MS detected. The solvent was evaporated, the residue was washed with water (10 mL), extracted with ethyl acetate (10 niL*3 ), the combined organic layer was dried over anhydrous Na₂S0₄, concentrated to afford a residue. The residue was purified by prep-HPLC (FA) to afford -(3 -chl orophenyl )-3 - pyrrolidin- 1 -yl- 1 ,4,6,7-tetrahydropyrazolo[4,3-c] pyridine-5-carboxamide (23.94 mg, 60.77 umol, 36.58% yield, 99.47% purity, F A salt) as white solid. 1H NMR (400 MHz, MeOD) δ 8.17 (brs, 1 H), 7.54 (brs, 1 H), 7.22 - 7.34 (m, 2 H), 7.03 (d, J = 7.53 Hz, 1 H), 4.66 (s, 2 H), 3.80 (t, J = 5.27 Hz, 2 H), 3.38 (brs, 4 H), 2.75 (brs, 2 FI), 1 .99 (brs, 4 FT). LCMS: 346/348 [MM ].

Example 17: Preparation of Compound 546

Step 1 : Preparation of Compound 3

To a mixture of tert-butyl 3~(trifluoromethylsulfonyloxy)-L4,6,7-tetrahydropyrazolo [4,3-c]pyridine-5-carboxyiate (300.00 mg, 807.91 umol, 1.00 eq) and cyclopenten- 1 - ylboronic acid (135.64 mg, 1 .2 1 mmol, 1 .50 eq) i n dioxane (2.00 niL) and Ι¾0 (200.00 uL) was added XPHGS-PD-G2 (63.57 mg, 80.79 umol, 0.10 eq), K3PO4 (342.99 mg, 1 .62 mmol, 2.00 eq) in one portion under Nk The mixture was stirred at 1 10 °C for 10 hour. TLC (Ethyl acetate: Petroleum ether^:::2: 1 ) showed the reaction was completed and the desired product was detected. The mixture was poured into water (20 raL) 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 Na₂S0₄, filtered and concentrated in vacuum. The residue was purified by silica gel chromatography (Petroleum ether/Ethyl acetate=2/l) to afford tert-butyl 3-(cyclopenten-l -yl)-l,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5- carboxylate (200.00 mg, 691.16 umol, 85.55% yield) as white solid. LCMS: 290 [M+l], Step 2 : Preparation of Compound 4

To a mixture of tert-butyl 3-(cyclopenten-l-yl)-l,4,6,7-tetrahydropyrazolo[4,3-c] pyridine-5-carboxylate (50.00 mg, 172.79 umol, 1.00 eq) in DCM (8.00 mL ) was added diethylzinc (1 M, 863.95 uL, 5.00 eq) at 0°C under Nk Then ch 1 oro( i odo )m eth an e (182.86 mg, 1.04 mmol, 6.00 eq) was added to the mixture and stirred at 20 °C for 12 hours. LCMS showed the reaction was completed. The mixture was poured into water (10 raL) and stirred for 2 min. The aqueous phase was extracted with DCM (10 mL*2). The combined organic phase was washed with brine (10 mL*2), dried with anhydrous Na₂S0 i, filtered and concentrated in vacuum. The residue was purified by prep-HPLC(FA) to afford tert-butyl 3- (l-bicyclo[3. 1.0] hexanyl)-l ,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylate (20.00 mg, 65.92 umol, 38.15% yield) as yellow solid. LCMS: 304 [M+l]. Step 3 : Preparation of Compound 5

To a mixture of tert-butyl 3-( I -bicyclo[3. 1 .Ojhexanyl )- 1 ,4,6,7-tetrahydropyrazolo [4,3-c]pyridine-5-carboxylate (20.00 mg, 65.92 umol, 1.00 eq) in dioxane (1.00 niL ) was added HCl/dioxane (4 M, 2.00 mL, 121.36 eq) in one portion under N₂. The mixture was stirred at 18 °C for 1 hour. TLC (Petroleum ether : Ethyl acetate=2: l) showed the reaction was completed. The mixture was concentrated in vacuum to afford 3-( I - bicyclo[3.1 .0]hexanyl)-4,5,6,7-tetrahydro-l H-pyrazolo[4,3-c]pyridine ( 15.80 mg, 65.90 umol, 100.00% yield, HC1) as yellow solid.

Step 4: Preparation of Compound 546

To a mixture of 3-( 1 -bicyclo[3 1 .Ojhexanyl )-4,5,6,7-tetrahydro- 1 H-pyrazolo[4,3-c] pyridine (15.80 mg, 65.90 umol, 1.00 eq, HQ) and TEA (20.01 mg, 197.70 umol, 3.00 eq) in DCM (2.00 mL) was added 1 -chloro-3-isocyanato-benzene (9.1 1 mg, 59.31 umol, 0.90 eq) in one portion at 1 5 C under N₂. The mixture was stirred at 15 °C for 30 min. LCMS showed the reaction was completed. The mixture was poured into water (10 mL) and stirred for 2 min. The aqueous phase was extracted with DCM (10 mL*2). The combined organic phase was washed with brine (10 mL*2), dried with anhydrous Na_.>S() i, filtered and concentrated in vacuum. The residue was purified by prep-HPLC(FA) to afford 3-( I - bicycio[3.1.0]hexanyl)-N-(3- chlorophenyl)-l ,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5- carboxamide (10.00 mg, 26.90 umol, 40.82% yield, 96.0% purity) as white solid. Ή NMR (400 MHz, METHANOL^) 7.50-7.54 (m, 1H), 7.27-7.32 (m, 1 H), 7.20-7.26 (m, 1H), 6.98- 7.04 (m, 1H), 4.57 (s, 2H), 3.78 (t, J=5.77 Hz, 2H), 2.77 (t, J=5.71 Hz, 2H), 2.05-2.13 (m, 1H), 1 .90-2.03 (m, 2H), 1.65-1.87 (m, 3H), 1 .28-1 .43 (m, 1H), 0.79-0.88 (m, 2H). LCMS: 357 [M+l]. Example 18: Preparation of Compound 644

Step 1 : Preparation of Compound 2

To a mixture of I -tert-butyl 3 -ethyl 4-oxopiperidine-l,3-dicarboxylate (10.00 g, 36.86 niniol, 1.00 eq) in EtOH (130.00 mL) was added N₂H₄-H₂0 (2.77 g, 44.23 mmol, 1.20 eq) in one portion under N₂. The reaction was stirred at 85 °C for 2 hr. TLC (Petroleum ether: ethyl acetate=T : 1 ) showed the reaction was completed. The mixture was concentrated in vacuum to afford tert-butyl 3 -hydroxy- 1 , 4,6,7- tetrahydropyrazolo[4,3-c]pyridine-5-carboxylate (8.82 g, 36.86 mmol, 100.00% yield) as white solid. I MS: 240 [M+l].

Step 2: Preparation of Compound 3

To a mixture of tert-butyl-3-hydroxy-l,4,6,7-tetrahydropyrazolo[4,3-c]

pyridine-5-carboxylate (8.82 g, 36.86 mmol, 1.00 eq) in Py (100.00 mL) was added 1, 1, 1- tri 11 uoro- -ph enyl - -(tri tl uorom ethyl sul fony 1 )m ethanesul fonami de at 10 °C. The reaction mixture was stirred at 10 C for 12 hours. The mixture was concentrated in vacuum. The residue was diluted with ethyl acetate (150 mL) and poured into 0.5N HCl (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?S0₄, filtered and concentrated in vacuum . The residue was purified by si lica gel chromatography (Petroleum ether/Ethyl acetate=5/l) to afford tert-butyl 3 -( tri 11 uorom ethyl sul Ion y 1 ox y )- 1 ,4,6,7- tetrahydropyrazolo[4,3-c]pyridine-5-carboxylate (9.16 g, 23.19 mmol, 62.91% yield, 94% purity) as yellow solid. LCMS: 372 [M+l].

Step 3 : Preparation of Compound 5

To a mixture of tert-butyl 3 -(tri 11 uoromethy 1 sul fonyl oxy )- l,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylate (900.00 mg, 2.42 mmol, 1 .00 eq) and 2-allyl-4,4,5,5 -tetramethyl- 1 ,3,2-dioxaborolane (610.92 mg, 3.64 mmol, 1.50 eq) in dioxane (1.00 mL)/H₂0 (100.00 uL) was added XPHOS-PD-G2 (190.70 mg, 242.37 umol, 0.10 eq) under N₂, followed by K₃PO₄ (1 .03 g, 4.85 mmol, 2.00 eq). The reaction mixture was stirred at 1 10 C for 16 hours. The mixture was extracted with EA (10 mL*3) and water (5 mL), the organic phase was dried with anhydrous Na₂SO}, filtered and concentrated in vacuum. The residue was purified by silica gel chromatography (Petroleum ether/Ethyl acetate=10/l to 1/1) to afford Compound 5 (400.00 mg, 1.52 mmol, 62,77% yield) was obtained as yellow oil.

Step 4: Preparation of Compound 6

To a solution of tert-butyl -3 -al 1 yl - 1 ,4,6, 7-tetrahydropy azol o[ 4,3 -c Jpyri di ne- 5-carboxylate (147.06 mg, 1 89.88 umol, 1.00 eq) in MeOH (20.00 mL) was added

Pd/C (10%, 0.1 g) under N₂. The suspension was degassed under vacuum and purged with H; several times. The mixture was stirred under ¾ (20 psi) at 15 °C for 16 hours. The mixture was filtrated. The filtrates was concentrated in vacumm to afford tert-butyl 3-propyl- l,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5- carboxylate (110.00 mg, crude) as colorless oil. Preparation of Compound 644

Tert-butyl 3-piOpyl-l,4,6 7-tetraliydropyrazolo[4,3-cjpyridine-5-carboxylate (80.00 mg, 301.49 umol, 1.00 eq) was dissolved in DCM (1.00 mL) and TFA (1.60 g, 14.03 mmol, 46.52 eq). The mixture was stirred at 10 °C for 0.5 hr. The mixture was concentrated in vacumm. The residue was dissolved in DCM (5.00 mL) and added TEA (122.03 mg, 1.21 mmol, 4.00 eq) followed by a solution of l-chloro-3-isocyanato-benzene (46.30 mg, 301.49 umol, 1.00 eq) in DCM (300.00 uL) dropwise at 0 °C. The reaction mixture was stirred at 0 °C for 10 min. The mixture was extracted with DCM (10 mL*2) and H₂0 (10 mL). The organic layer was concentrated in vacumm. The residue was purified by prep-HPLC (FA) to afford N-(3-chlorophenyl)-3-propyl-l,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5- carboxamide (37.00 mg, 112.69 umol, 37.38% yield, 97.1% punt}') as white solid. Ή NMR (400MHz, METHANQL-d4) δ - 7.55 (t, .1 = 1.9 Hz, 1 H), 7.30 - 7.35 (m, 1 H), 7.22 - 7.28 (m. 1 H), 7.03 (d, J= 7.8 Hz, 1 H), 4.54 (s, 2 H), 3.82 (t J= 5.8 Hz, 2 H). 2.80 (t, J= 5.8 Hz, 2 H), 2.62 (t, J = 7.5 Hz, 2 H), 1.63 - 1.75 (m, 2 H), 0.99 (t, J = 7.3 Hz, 3 H). LCMS:

319/321 [M+1]. Example 19: Preparation of Compound 642

Step 1 : Preparation of Compound 2

To a solution of 5-tert-buty 1-3-ethy 1- 1 ,4,6,7-tetrahydropyrazolo[4,3-c]

pyridine- 3.5 -di carbox late (50.00 g, 169.30 mmol, 1.00 eq) in dioxane (200.00 mL) was added HCl/dioxane (4 M, 300.00 mL, 7.09 eq) at 15 °C. The reaction mixture was stirred at 15 °C for one hour. Precipitate formed. Evaporated the solution on a water bath under reduced pressure using a rotary evaporator to afford ethyl 4,5,6, 7-tetrahydro- 1 H- py razol o[4,3 -c jpyri di ne-3 -carboxyl ate (37.00 g, 59.70 mraol, 94.33% yield, HC1) as yellow solid. The crude product was used in next step directly without further purification.

Step 2 : Preparation of Compound 3

To a mixture of ethyl 4,5,6,7-tetrahydro-l H-pyrazolo[4,3-c]pyridine-

3-carboxylate (37.00 g, 159.70 mmol, 1.00 eq, HC1) in DCM (300.00 mL) was added TEA (48.48 g, 479.11 mmol, 3.00 eq) at -10 °C, followed by 1 -chloro-3-i socyanato-benzene (19.62 g, 127.76 mmol, 0.80 eq). The reaction mixture was stirred at -10 °C for another 30 minutes. TLC (Petroleum ether: Ethyl acetate=0: l ) indicated 5% of compound 2 was remained, and one major new spot with lower polarity was detected. The mixture was extracted with DCM (800 mL*3) and water (300 mL*2), the organic phase was dried with anhydrous Na₂S0₄, filtered and concentrated in vacuum to afford ethyl-5-[(3- chlorophenyl )carbamoyl]- l,4,6,7-tetrahydi pyrazolo[4,3-c]pyridine-3-carboxylate (52.00 g, crude) as yellow solid. The crude product was used in next step directly without further purification.

Step 3 : Preparation of Compound 4

To a solution of ethyl 5-[(3-chlorophenyl)carbamoyl]-l, 4,6,7- tetrahydropyrazolo [4,3 -c] pyri di ne-3 -carboxyl ate (30.00 g, 86.01 mmol, 1.00 eq) in THF (300.00 mL) was added a solution of NaOH (6.88 g, 172.02 mmol, 2.00 eq) in ¾0 (60.00 mL) , the reaction mixture was warmed to 40 °C and stirred at 40 °C for 16 hours. TLC (Petroleum ether: Ethyl acetate=0: 1) showed the reaction was completed. The pH of the reaction mixture was adjusted to around 5 by adding diluted hydrochloride acid (1 N), then extracted with EA (500 mL*4) and water (300 mL). The organic phase was dried over anhydrous Na₂S0₄, filtered and concentrated in vacuum to afford 5-[(3- chiorophenyl)carbamoyl]-l,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-3-carboxylic acid (23.00 g, crude) as light yellow solid. The crude product was used in next step directly without further purification. ^lH NMR (400 MHz, METHANOL-d4) 1 1.48 (t, J-1.94 Hz, 1 H) 1 1.23 - 11.28 (m, 1 H) 11.14 - 11.21 (m, 1 H) 10.92 - 10.98 (m, 1 H) 8.71 (s, 2 H) 7.78 ( t, ,7 = 5.71 Hz, 2 H) 6.80 (t, ./ 5.65 Hz, 2 H). LCMS: 321/323 [M i l],

Step 4: Preparation of Compound 6

To a mixture of 5-[(3-chlorophenyl)carbamoyl]-l,4,6,7- tetrahydropyrazolo[4,3-c] pyri di ne-3 -carboxyl i c acid (10.00 g, 31.18 mmol, 1.00 eq) and HATU ( 1 1 .86 g, 3 1 . 18 mmol, 1.00 eq) in DMF (150.00 mL) was added DIPEA (6.04 g, 46.77 mmol, 1.50 eq), followed by -methoxymethanamine (4.56 g, 46.77 mmol, 1.50 eq. HQ), the reaction mixture was stirred at 15 °C for 16 hours. TLC (Ethyl acetate: Methanol ^::::20: 1 ) indicated compound 4 was consumed completely, and one major new spot with lower polarity was detected. The mixture was extracted with EA (500 niL*3) and water (300 mL*3), the organic phase was dried with anhydrous Na₂SQ₄, filtered and concentrated in vacuum . Further purification by silica gel chromatography (100-200 mesh silica gel, Ethyl acetate: Methanol = 100: 1 to 20: 1) to afford N⁵-(3-chlorophenyl)-N³-methoxy-N³-methyl- 1 ,4,6,7-tetrahydropyrazolo [4,3-c]pyridine-3,5-dicarboxamide (8.00 g, 17.59 mmol, 56.42% yield, 80% purity) as yellow solid. Ή NMR (400 MHz, M ETH ANOL-d4 ) 11.48 (t, J= 1.94 Hz, 1 H) 11.23 - 1 1 .28 (m, 1 H) 11.14 - 11.21 (m, 1 H) 10.92 - 10.98 (m, 1 H) 8.71 is, 2 H) 7.78 (t, J= 5.71 Hz, 2 H) 6.80 (t, J = 5.65 Hz, 2 H). LCMS: 364/366 [M+1].

Step 5: Preparation of Compound 7

To a solution of N⁵-(3-ch{orophenyl)-N³-methoxy-N³-methyl- 6,7-dihydro-lH- pyrazolo[4,3-c]pyridine-3,5(4H)-dicarboxamide (200.00 nig, 549.75 umol, 1.00 eq) in THF (5.00 niL) was added propylmagnesium bromide (1 M, 5.50 niL, 10.00 eq) at -10 °C. The reaction mixture was stirred at 10 °C for 3 hr. The mixture was added into saturated NH₄C1 (10 ml.) and extracted with EA (10 mL*2). The combined organic layer was dried over Na₂S0₄, and concentrated. The residue was purified by column

chromatography (PE : E A=30%~60%) to afford 3-butanoyl-N-(3-chlorophenyl )- 1 ,4,6,7- tetrahydropyrazolo[4,3-c]pyridine-5-carboxamide (85.00 mg, 245.09 umol, 44.58% yield) as white solid.

Preparation of Compound 642

To a solution of 3-butanoyl-N-(3-chlorophenyl)-l,4,6,7-tetraHydropyrazolo

[4,3-c] pyridine-5-carboxamide (40.00 mg, 115.34 umol, 1.00 eq) in DCM (4.00 m L) was added DAST (74.37 mg, 461.36 umol, 4.00 eq) at -10 °C. The mixture was stirred at 10 °C for 2 hr. The mixture was extracted with DCM (10 mL*2) and H₂0 (10 mL). The combined organic layer was dried over Na₂S0₄, and filtrated and concentrated in vacumm. The residue was purified by prep-HPLC (FA) to afford N-(3-chlorophenyl)-3-(l, l- difluorobutyl )- 1 ,4,6,7-tetrahydropyrazolo [4,3-c]pyridine-5-carboxamide (11.00 mg, 29.68 umol, 25.73% yield, 99.5% purity) as white solid. 1H NMR (400MHz, METHANOL-d4) δ 7.54 (t, J= 1.9 Hz, 1 H), 7.29 - 7.33 (m, 1 H), 7.22 - 7.28 (m, 1 H), 7.03 (d, J= 7.9 Hz, 1 H), 4.65 (s, 2 H), 3.83 (t, J= 5.7 Hz, 2 H), 2.87 (t, J= 5.6 Hz, 2 H), 2.16 - 2.34 (m, 2 H), 1.54 (qd, J= 7.5, 15.4 Hz, 2 H), 1.00 (t, J= 7.5 Hz, 3 H). LCMS: 369/371 [M+1]. Example 20: Preparation of Compound 696

^ 695 696

Preparation of Compound 695

To a solution of EtMgBr (1 M, 4. 12 niL, 5.00 eq) was added a solution of N⁵-(3- chlorophenyl)-N³-methoxy-N³-methyl-l,4,6,7 etrahydropyrazolo[4,3-c]pyridine-3,5-- dicarboxamide (300.00 mg, 824.63 umol, 1.00 eq) in THF (5.00 ml.) at -10 °C. The mixture was stirred at 15 °C for 3 hr. TLC (PE:EA = 0: 1) showed starting material was remained. EtMgBr (1 M, 4.12 ml., 5.00 eq) was added at -10 °C. The mixture was stirred at 15 °C for 2 hr. The mixture was quenched by saturated with NH₄C1 (10 mL ) and extracted with EA (20 mL*2). The combined organic layer was dried over

filtrated, and concentrated in vacumni. The residue was purified by prep-TLC (PE:EA=0: 1) to afford N- (3-chlorophenyl )- 3-propanoyl-l,4,6,7-tetrahydi pyrazoio[4,3-c]pyridine-5-carboxamide (100.00 mg, 287.88 umol, 34.91% yield, 95.8% purity) as white solid. Ή NMIl (400MHz, METHANOL-d4) δ = 7.54 (t, J = 1.9 Hz, 1 H), 7.29 - 7.33 (m, 1 H), 7.22 - 7.27 (m, 1 H), 7.02 (d, J = 7.9 Hz, 1 H), 4.76 (s, 2 H), 3.82 (t, J = 5.6 Hz, 2 H), 3.03 (q, J = 7.4 Hz, 2 H), 2.87 (t, J = 5.7 Hz, 2 H), 1.12 - 1.23 (m, 3 H). LCMS: 333/335[M+l].

Preparation of Compound 696

To a solution of N-(3-chlorophenyl )-3-propanoyl- 1 ,4,6,7-tetrahydropyrazolo

[4,3-c] pyridine-5-carboxamide (60.00 mg, 180.30 umol, 1.00 eq) in DCM (3.00 mL) was added DAST (145.31 mg, 901.50 umol, 1 19.1 1 uL, 5.00 eq) at -40 °C. The mixture was stirred at 15 C for 2 hr. The mixture was extracted with DCM (10 mL*2). The organic layer was washed with saturated aHCO, (10 mL), dried over Na₂SO.t, filtrated, and concentrated in vacumm. The residue was purified by prep-HPLC (FA) to afford N-(3- chlorophenyl )-3-( 1 , 1 -ditiuoropropv )- 1 ,4,6,7-tetra hy dropy razol o[ 4, 3 -c ] py ri di n e-5 - carboxamide (23.00 mg, 64.76 umol, 35.92% yield, 99.9% purity) as white solid. Ή NMR (400MHz, METHANOL-d4) 6 7.54 (t, J = 1 .9 Hz, 1 H), 7.29 - 7.33 (m, 1 H), 7.22 - 7.28 (m, 1 H), 7.00 - 7.05 (m, 1 H), 4.66 (s, 2 H), 3.83 (t, J= 5.7 Hz, 2 H), 2.87 (t, J = 5.6 Hz, 2 H), 2.21 - 2.38 (m, 2 H), 1 .06 (t, J 7.5 Hz, 3 H). LCMS: 355/357ΓΜ+1]. Example 21. Preparation of Compound 604

Steps 1 and 2: Preparation of Compounds 2 and 4

2,2-dimethylbut-3-enoic acid (200,00 nig, 1 .75 mmol, 1.00 eq) was dissolved in SOQ₂ (208.46 mg, 1.75 mmol, 127.1 1 uL, 1.00 eq) and heated to 8 C for 1 hr. The mixture was concentrated in vacumm to get 2, 2-di m eth yl b ut-3 -en oy 1 chloride (190.46 mg), compound 2.

A solution of tert-butyl 4-oxopiperidine-l -carboxyl ate (278.95 mg, 1.40 mmol, 0.80 eq) in THF (3.00 mL) was added into Li HM DS (1 M, 1.75 mL, 1 .00 eq) dropwise at -70 °C under N₂. The mixture was stirred at -70 °C for 0.5 hr. A solution of 2,2-dimethylbut-3- enoyl chloride (190.46 mg, obtained above) in THF (2.00 mL) was added dropwise at -70 °C. The mixture was stirred at 15 C for 16 hr. The mixture was quenched by NH₄C1 (10 mL) and extracted with EA (10 mL*2). The combined organic layer was dried over Na₂SC«4, filtrated. The filtrates was concentrated in vacumm to afford tert-butyl 3-(2,2-dimethylbut-3- enoyl )-4-oxo-piperidine- 1 -carboxylate (450.00 mg, crude) as brown oil .

Step 3 : Preparation of Compound 5

To a solution of tert-butyl 3-(2,2-dimethylbut-3-enoyl)-4-oxo-piperidine-l - carboxylate (300.00 mg, 1.02 mmol, 1.00 eq) in EtOH (2.00 mL) was added NH₂N 1 L. H 0 (204.24 mg, 2.04 mmol, 198.29 uL, 50% purity, 2.00 eq). The mixture was heated to 90 C for 2 hr. The mixture was concentrated. The residue was extracted with EA (10 m L*2 ) and H₂0 (10 mL). The combined organic layer was dried

filtrated, and

concentrated. The residue was purified by prep-HPLC (FA) to afford tert-butyl 3 -( 1 , 1 - dimethylpropyl)- 1,4,6,7- tetrahydropyrazolo[4,3-c]pyridine-5-carboxylate (10.00 mg, 34.08 umol, 3.34% yield) as colorless oil. 1H NMR (400MHz, CHLOROFORM-d) δ 4.52 (brs, H), 3.69 (brs, H), 2.76 (brs, 2 H), 1.64 (q, .1 = 7.4 Hz, 2 H), 1.45 - 1.53 (m, 16 H), 1.32 (s, 6 H), 0.80 (t, J == 7.5 Hz, 3 H).

Preparation of Compound 604

Tert-butyl 3-(l, l -dimethylpropyl)- l ,4,6,7-tetrahydropyrazolo[4,3-c]

pyridine-5-carboxy!ate (10.00 mg, 34.08 umol, 1.00 eq) was dissolved in HCl/dioxane (4 M, 3.00 mL, 352.1 1 eq) and stirred at 15 °C for 1 hr. The mixture was concentrated and dissolved in DCM (5.00 mL) added phenyl N-(3-chlorophenyl)carbamate (8.44 mg, 34.08 umol, 1.00 eq) followed by TEA (17.24 mg, 170.40 umol, 23.62 uL, 5.00 eq). The mixture was stirred at 1 5 °C for 1 6 hr. LCMS showed the reaction was completed. The mixture was concentrated in vacumm. The residue was purified by prep-HPLC (FA) to afford N-(3- chiorophenyl)-3 -(1, 1 -dim ethyl propyl )- 1,4,6, 7-tetrahydropyrazolo

[4,3-c]pyridine-5-carboxamide (4.80 mg, 12.90 umol, 37.85% yield, 93.2% purity).

1H MR (400MHz, METHANOL-d4) δ 7.53 (s, 1 H), 7.29 - 7.34 (m, 1 H), 7.22 - 7.28 (m, 1 H), 7.03 (d, J = 7.0 Hz, 1 H), 4.65 (s, 2 H), 3.80 (t, J= 5.8 Hz, 2 H), 2.82 (t, J = 5.7 Hz, 2 H), 1.70 (q, J = 7.4 Hz, 2 H), 1.35 (s, 6 H), 0.79 (t, J = 7.4 Hz, 3 H).

LCMS: 347/349ΓΜ+1 ],

Example 22. Preparation of Compound 694

Step 1 : Preparation of Compound 2

To a solution of 1 -methyl cycl obutanecarboxy 1 i c acid (2.00 g, 17.52 mniol, 1.00 eq) in DCM (20.00 mL) was added GDI (3.12 g, 19.27 mmol, 1.10 eq) under N₂. The mixture was stirred at 15 °C for 1 hr. The mixture was extracted with EA (20 mL). The organic layer was dried over Na₂S0₄, filtrated, and concentrated in vacumm . The residue was used in the next step directly to afford imidazol- 1 -yl-( 1 -methylcyclobutyl )methanone (2.60 g, 15.83 mmol, 90.38% yield) as brown oil. Step 2: Preparation of Compound 4

To a solution of LiHMDS (1 M, 21.92 mL, 1.20 eq) in THF (10.00 ml.) was added a solution of tert-butyl 4-oxopiperidine-l-carboxylate (2.55 g, 12.79 mmol, 0.70 eq) in THF (15.00 mL) under N₂ at -65 °C. The mixture was stirred at -65 °C for 0.5 hr. A solution of imidazol-l-yl-(l-methylcyclobutyl)methanone (3.00 g, 1 8.27 mmol, 1.00 eq) in THF ( I 5.00 mL) was added at -65 °C dropwise. The solution was stirred at 15 °C for 16 hr. The mixture was quenched by saturated NH₄C1 (20 raL) and extracted with EA (20 niL*2). The combined organic layer was dried over Na₂S0₄ and concentrated to afford tert-butyl 3-(l- methylcyclobutanecarbonyl )-4- oxo-piperidine-l-carboxylate (759.10 nig, 2.57 mmol, 14.07% yield) as colorless oil.

Step 3 : Preparation of Compound 5

To a solution of tert-butyl-3-( 1 -methylcyclobutanecarbonyl )-4-oxo- piperidine- 1 - carboxylate (760.00 mg, 2.57 mmol, 1.00 eq) in EtOH (20.00 mL) was added NH₂NH₂-H₂0 (515.23 mg, 5.15 mmol, 500.22 uL, 50% purity, 2.00 eq). The mixture was heated to 90 C for 2 hr. The mixture was concentrated in vacumm. The residue was purified by flash chromatography (PE:EA=50%~1 00%) to afford tert-butyl 3-( 1 - methylcyclobutyl)-l,4,6,7-tetrahydropyrazolo[4,3-c] pyridine-5-carboxylate (500.00 mg, 1.72 mmol, 66.77%) yield) as colorless oil.

Step 4: Preparation of Compound 694

Tert-butyl 3-( 1 -methylcyclobutyl )- 1 ,4,6,7-tetrahydropyrazolo[4,3-cJpyridine-5- carboxylate (60.00 mg, 205. 1 umol, 1.00 eq) was dissolved in HCl/Dioxane (4 M) and stirred at 15 °C for 1 hr. The mixture was concentrated in vacumm. The residue was dissolved in DCM (3.00 mL), then TEA (62.51 mg, 617.73 umol, 85.63 uL, 3.00 eq) and 1 - chloro-3-isocyanato-benzene (31.62 mg, 205.91 umol, 24.90 uL, 1.00 eq) was added at -10 °C. The mixture was stirred at -10 °C for 30 min. The mixture was concentrated in vacumm. The residue was purified by prep-HPLC (FA) to afford N-(3-chlorophenyl)-3-(l- m ethyl cyclobutyl )- 1 ,4,6,7-tetrahydropyrazolo [4,3-c]pyridine-5-carboxamide (42.00 mg, 1 1 5.7 1 umol, 56.19% yield, 95.0% purity) as white solid. Ή NMR (400MHz, METHANOL- d4) δ 7.53 (t, J 2.0 Hz, 1 H), 7.29 - 7.33 (m, 1 H), 7.22 - 7.28 (m, 1 H), 7.00 - 7.05 (m, 1 H), 4.57 (s, 2 H), 3.81 (t, J = 5.8 Hz, 2 H), 2.81 (t, .1 = 5.8 Hz, 2 H), 2.46 - 2.56 (m, 2 H), 2.04 - 2.23 (m, 3 H), 1.89 - 2.00 (m, 1 H), 1.52 (s, 3 H). LCMS: 345/347[M+l], xample 23: Preparation of Compounds 508 (E and Z) and 0509

509

Step 1 : Preparation of Compound 2

To a cooled the three-necked round bottom flask in an ice bath at 0 °C, was added NaH (880.40 mg, 22.01 mrnol, 1.30 eg) under N₂, then a solution of 5-tert-butyl 3 -ethyl l,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-3,5-dicarboxylate (5.00 g, 16.93 mmol, 1.00 eq) in DMF (70.00 niL) was added dropwise. The reaction mixture was stirred at 0 °C for 30 minutes. PMBCI (2.92 g, 18.62 mmol, 1.10 eq) was added dropwise, the reaction mixture was warmed to 10 °C and stirred at 10 °C for another 16 hours. TLC showed starting material was consumed completed and two major new spots with lower polarity was detected. The reaction was added to water (60 niL) and then extracted with EA (100 mL*3), the combined organic phase was dried over anhydrous Na₂S0₄, filtered and concentrated in vacuum. The residue was purified by silica gel chromatography to afford 5-tert-butyl 3- ethyl- l -[(4-methoxyphenyl )methyl]-6,7-dihydro-4H- pyrazolo[4,3-c]pyridine-3,5-dicarboxylate (4.30 g, 7.24 mmol, 42.79% yield, 70% purity) as yellow oil. LCMS: 416 [M+l].

Step 2: Preparation of Compound 3

Cooled the three-necked round bottom flask to -50 °C, LiAlH₄ (511.50 mg, 13.48 mmol, 2.00 eq) was added under N₂, then a solution of 5-tert-butyl 3 -ethyl l-[(4- methoxyphenyl)methyl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-3,5-dicarboxylate (4.00 g, 6.74 mmol, 1.00 eq) in THF (50.00 mL) was added dropwise, after addition the reaction mixture was warmed to 0 °C and stirred at 0 C for 2 hours. TLC showed the reaction was completed, two major new spot with larger polarity was detected. The reaction mixture was quenched with water (5 mL) and filtered. The filtrate was washed with DCM (80 mL*3). The organic phase was dried with anhydrous Na₂S0₄, filtered and concentrated in vacuum. Tert-butyl 3-(hydroxymethyl)-l-[(4-methoxyphenyl)methyl]-6,7-dihydro-4H-pyrazolo[4,3- c]pyridine-5-carboxylate (2.30 g, crude) was obtained as yellow oil. The crude product was used in the next step directly without further purification. LCMS: 374 [M+l].

Step 3 : Preparation of Compound 4

To a solution of tert-butyl-3-(hydroxym ethyl)- l-[(4-methoxyphenyl)

methyl] -6, 7- dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate (1.40 g, 3.75 mmol, 1.00 eq) in DCM (25.00 mL) was added Mn0₂ (6.52 g, 75.00 mmol, 20.00 eq) in three portions. The reaction mixture was warmed to 60 °C and stirred at 60 °C for 16 hours. LCMS showed starting material was consumed completely and one main peak with desired M S was detected. The mixture was filtered to remove MnO?. The filtrate was extracted with DCM (30 mL*3) and water (20 mL). The organic phase was dried with anhydrous Na₂S0₄, filtered and concentrated in vacuum. The residue was purified by silica gel chromatography to afford tert-buty1-3-formyl-l -[(4-methoxy^henyl)methyl]-6,7-dihydro-4H-pyTazolo[4,3-c]pyridine-5- carboxylate (750.00 mg, 2.02 mmol, 53.85% yield) as yellow oil.

LCMS: 372 [M+l],

Step 4: Preparation of Compound 5

To a mixture of triphenyl(propyl)phosphonium;bromide (1.24 g, 3.23 mmol, 4.00 eq) in THF (1.00 mL) was added t-BuOK (362.52 mg, 3.23 mmol, 4.00 eq) under N₂ at 0 °C, the reaction mixture was stirred at 0 °C for one hour, then a solution of tertbutyl-3-forrnyl- 1 -[(4- methoxyphenyl)methyl]-6,7-dihydro-4H-pyrazolo[4,3-c] pyridine-5-carboxylate (300.00 mg, 807.69 umol, 1.00 eq) in THF (2.00 niL ) was added dropwise under N₂, the mixture was wanned to 10 °C and stirred at 10 C for 16 hours. LCMS showed compound 4 was consumed completely and one main peak with desired MS was detected. The mixture was extracted with EtOAc (10 mL*3) and water (5 ml.). The organic phase was dried with anhydrous filtered and concentrated in vacuum. The residue was purified by silica gel chromatography to afford tert-butyl-3-[but-l-enyl]-l- [(4-methoxyphenyl )methyl ]-6,7- dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate (200.00 mg, 503.13 umol, 62.29% yield) as yellow oil. LCMS: 398 [ X I 1 1.

Step 5 : Preparation of Compound 6

Tert-butyl-3~[but- 1 -enyl j- 1 ~[(4-methoxyphenyl)methyl]-6,7-dihydro-4H~pyrazolo

[4,3- c]pyridine-5-carboxylate (50.00 mg, 125.78 umol, 1.00 eq) was dissolved in TFA (2.00 niL). The mixture was heated to 80 °C for 16 hours. LCMS showed the reaction was completed. The mixture was concentrated in vacuum to afford 3-[but-l -enyl]-4,5,6,7- tetrahydro- 1 H-pyrazolo[4,3-c]pyridine (20.00 mg, 1 12.83 umol, 89.71% yield) as brown oil. The residue was used in the next step directly. LCMS: 178 [M+l].

Preparation of Compound 508 (E and Z)

To a solution of 3-[but-l-enyl]-4,5,6,7-tetrahydro- lH-pyrazolo[4,3-c]

pyridine (20.00 mg, 1 12.83 umol, 1.00 eq) in DCM (3.00 ml.) was added TEA (34.25 mg, 338.49 umol, 3.00 eq) at 0 °C, followed by 1 -chloro-3-isocyanato-benzene (17.33 mg, 1 12.83 umol, 1.00 eq), the reaction mixture was stirred at 0 °C for 30 minutes. LCMS showed compound 6 was consumed completely and one main peak with desired MS was detected. The mixture was extracted with DCM (10 mL*3) and water (5 ml.), the organic phase was dried with anhydrous a₂SO.i, filtered and concentrated in vacuum. Purification by prep- HPLC (FA) gave both E-isomer and Z-isomer.

3-[(E)-but-l -enyl]-N-(3-chlorophenyl)-l,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5- carboxamide (2.00 mg, 5.92 umol, 5.25% yield, 98.0% purity) was obtained as white solid. 1H MR (400 MHz, METHANGL-d4) 7.52 (brs, 1 H), 7.29 (brs, 1 H), 7.23 - 7.25 (d, 1 H), 7.00 - 7.02 (d, 1 H), 6.33 - 6.37 (m, J = 16 Hz, 1 H), 6. 1 7 - 6.21 (m, 1 H), 4.61 (brs, 2 H), 3.81 (brs, 2 H), 2.79 (brs, 2 H), 2.27 (brs, 2 H), 1. 12 (brs, 3 FI). LCMS: 331/333 [M+l ].

3-[(Z)-but-l-enyl]-N-(3-chlorophenyl)-l,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5- carboxamide (16.00 mg, 47.83 umol, 42.39% yield, 98.9% purity) was obtained as white solid. 1H MR (400 MHz, METHANOL-d4) 7.52 (brs, 1 H), 7.28 - 7.30 (m, 1 H), 7.20 - 7.24 (m, 1 H), 6.99 - 7.00 (d, 1 H), 6. 15 - 6.18 (d, J = 12 Hz, 1 H), 5.79 - 5.80 (d, 1 H), 4.49 (brs, 2 H), 3.81 (brs, 2 H), 2.8 1 (brs, 2 H), 2.32 (brs, 2 H), 1.03 - 1.05 (m, 3 H). LCMS: 331/333 [M+l].

Step 7: Preparation of Compound 7

To a solution of tert-butyl-3-[but- 1 -enyl ]- 1 -[(4-methoxyphenyl )

methyl ]-6,7-dihydro -4H-pyrazol o[4, 3 -c] pyri di ne-5-carboxyl ate (50.00 nig, 125.78 umol, 1.00 eq) in CH₃OH (10.00 ml.) was added Pd/C (10.00 mg) under N₂, the suspension was degassed under vacuum and purged with H₂ three times, the mixture was stirred under H₂ ( 15 psi) at 15 C for 16 hours. LCMS showed starting material was consumed completely and one main peak with desired MS was detected. The reaction mixture was filtered and the filter was concentrated. Compound tert-butyl-3-butyl-l -[(4~methoxyphenyl)methyl]~6,7-dihydro- 4H-pyrazoio[4,3-c]pyridine-5-carboxyiate (45.00 mg, 1 12.63 umol, 89.54% yield) was obtained as yellow oil . The crude product was used in the next step directly without further purification. LCMS: 400 [M+l ].

Step 8: Preparation of Compound 8

Tert-butyl-3~butyl-l-[(4~methoxyphenyl)methyl]~6,7-dihydro-4H-pyrazolo[4,3~c] pyridine-5-carboxylate (45.00 mg, 1 12.63 umol, 1.00 eq) was dissolved in TFA (3.00 m L), the reaction mixture was warmed to 75 °C and stirred at 75 °C for 16 hours. LCMS showed that the Boc was removed and the PMB preserved. The reaction mixture was warmed to 80 C and stirred at 80 C for another 16 hours. Several new peaks were shown on LCMS and 50% of desired compound was detected. Removed the solvent on a rotary evaporator to afford 3-butyl-4,5,6,7-tetrahydro- 1 H-pyrazolo [4,3-c]pyridine(18.00 mg, crude) as black brown oil. The crude product was used in the next step without further purification. LCMS: 180 [M+l].

Preparation of Compound 509

To a solution of 3-butyl-4,5,6,7-tetrahydro-l H-pyrazolo[4,3-c]pyridine (18.00 mg,

100.41 umol, 1.00 eq) in DCM (5.00 111 L) was added TEA (30.48 mg, 301.23 umol, 3.00 eq) at 0 °C, followed by I -chloro-3-isocyanato-benzene (15.42 mg, 100.41 umol, 1.00 eq). The reaction mixture was stirred at 0 C for 30 minutes. LCMS showed compound 8 was consumed completely and one main peak with desired MS was detected. The mixture was extracted with DCM (10 mL*3 ) and water (10 niL ), the organic phase was dried with anhydrous filtered and concentrated in vacuum. Further purification by prep- HPLC(FA ) afforded Compound 509 (20.00 mg, 58.89 umol, 58.65% yield, 98%) purity) as white solid. 1H NMR (400MHz, METHANOL-d₄) 7.52 - 7.53 (t, J= 1.94 Hz, 1 H), 7.29 (m, 1 H), 7.21 - 7.25 (m, 1 H), 6.99 - 7.01 (m, 1 H), 4.51 (s, 2 H), 3.78 - 3.81 (t, J= 5.83 Hz, 2 H), 2.76 - 2.79 (t, J= 5.77 Hz, 2 H), 2.60 - 2.64 (t, J= 7.65 Hz, 2 H), 1.59 - 1.65 (q, J= 7.65 Hz, 2 H), 1.34 - 1.40 (dq, J = 14.98, 7.39 Hz, 2 H), 0.93 - 0.97 (t, ./ 7.34 Hz, 3 H). LCMS: 333/335 [M+l].

Example 24: Preparation of Compounds 693 and 734

734

Step 1 : Preparation of Compound 2

To a solution of cyclopent-3-ene- 1 -carboxylic acid (6.00 g, 53.51 mmol, 1.00 eq) in DCM (20.00 ml.) was added catalytic amount of DMF. (COCl)₂ (10.19 g, 80.26 mmol, 1.50 eq) was added dropwise at 0 °C. The reaction mixture was stirred at 0 °C for one hour. TLC monitored that starting material was consumed completely by quenching with MeOH. The reaction mixture was concemtrated in vacuo on a rotary evaporator. The residue was purified by distillation (bp 120-125°C 50 mm Hg) to give cyclopent-3-ene- 1 -carbonyl chloride (4.10 g, 31.40 mmol, 58.68% yield) as colorless oil.

Step 2: Preparation of Compound 4

A three-necked round bottom flask was cooled to -78 °C, a solution of tert-butyl 4- oxopiperidine- 1 -carboxylate (3.82 g, 19.15 mmol, 1.00 eq) in THF (15.00 niL) was added dropwise to Li HMDS (1 M, 22.98 raL, 1.20 eq) under N₂. The reaction mixture was stirred at -78 °C for one hour under N₂. Then, cyclopent-3-ene- 1 -carbonyl chloride (2.50 g, 1 . 15 mmol, 1 .00 eq) was added dropwise. After addition the reaction mixture was warmed to 25 C and stirred at 25 °C for another 2 hours. TLC showed starting material was consumed completely. Several new peaks were shown on LCMS and 20% of desired compound was detected. The reaction mixture was added to saturated aqueous NH₄C1 (40 niL) and then extracted with EA (80 mL*3). The combined organic phase was dried over anhydrous Na₂S0₄, filtered and concentrated in vacuum to afford tert-butyl 3-(cyclopent-3-ene- 1 - carbonyl )-4-oxo-piperidine- 1 -carboxylate (4.20 g, crude) as yellow oil. The crude product was used in the next step directly without further purification. LCMS: 294 [M+l ],

Step 3 : Preparation of Compound 5

To a solution of tert-butyl-3-(cyclopent-3-ene- 1 -carbonyl )-4-oxo-pi peri din e- 1 -carboxylate (7.00 g, 23.86 mmol, 1.00 eq) in EtOH (15.00 niL) was added NH₂NH₂ H₂0 (2.1 1 g, 35.79 mmol, 1.50 eq). The reaction mixture was warmed to 60 °C and stirred at 60 °C for 2 hours. TLC indicated starting material was consumed completely and many new spots formed. The mixture was extracted with EA (50 mL*3) and water (20 mL*2), the organic phase was dried with anhydrous a₂S0₄, filtered and concentrated in vacuum. The residue was purified by silica gel chromatography to give tert-butyl 3-cyclopent-3-en- 1 -yl- 1 ,4,6,7- tetrahydropyrazolo[4,3-c]pyridine-5-carboxylate (4.50 g, 12.44 mmol, 52.14% yield, 80% purity) as yellow solid. LCMS: 290 [M+l].

Step 4: Preparation of Compound 6

To a solution of tert-butyl-3-cyclopent-3-en- 1 -yl- 1 ,4,6,7-tetrahydropyrazolo

[4,3-c] pyri di ne-5-carboxyl ate (500.00 nig, 1.73 mmol, 1.00 eq) in dioxane (3.00 ml .) was added HCl/dioxane (4 M, 10.00 niL, 23. 12 eq). The reaction mixture was stirred at 25 °C for 30 minutes. TLC showed starting material was consumed completely. The reaction mixture was filtered and the filtrate was washed with dioxane (15 niL*3) to give 3-cyclopent-3-en-l- yl-4,5,6,7-tetrahydro- 1 H-pyrazolo [4,3-c]pyridine (320.00 mg, 1.42 mmol, 81.95%

yield,HCl) as light yellow solid. The crude product was used in the next step directly without further purification.

1H MR (400MHz, METHANOL-d₄) 5.82 - 5.86 (s, 2 H), 4.30 (s, 2 H), 3.72 - 3.75 (tt, ./ 9.22, 6.02 Hz, 1 H), 3.60 - 3.63 (t, J= 6.34 Hz, 2 H), 3.18 - 3.20 (t, .1 = 6.27 Hz, 2 H), 2.90 - 2.96 (m, 2 H), 2.50 - 2.55 (m, 2 H).

Preparation of Compound 693

To a mixture of 3-cyclopent-3-en-l-yl-4,5,6,7-tetrahydro-lH-pyrazolo[4,3-c] pyridine (120.00 mg, 531.63 umol, 1 .00 eq, HC1) in DCM (2.00 ml.) was added TEA (161.39 mg, 1.59 mmol, 3.00 eq) at 0 °C, followed by l-chloro-3-isocyanato-benzene (48.99 mg, 318.98 umol, 0.60 eq), the reaction mixture was stirred at 0 °C for 30 minutes. LCMS showed compound 6 was consumed completely and one main peak with desired MS was detected. The mixture was extracted with DCM (10 mL*3) and water (10 mL), the organic phase was dried with anhydrous Na₂S0₄, filtered and concentrated in vacuum. The residue was purified by prep-HPLC (FA) to afford Compound 693 (35.00 nig, 97.70 umol, 18.38% yield, 95.7% purity) as white solid. 1H NMR (400 MHz, METHANOL-d4) 7.51 - 7.52 (t, J= 1.94 Hz, 1 H), 7.28 - 7.30 (m, I H), 7.20 - 7.25 (m, 1 H), 6.99 - 7.01 (d, ./ 7.78 Hz, 1 H), 5.78 - 5.82 (m, 2 H), 4.51 (s, 2 H), 3.77 - 3.80 (t, J= 5.77 Hz, 2 H), 3.51 - 3.57 (m, 1 H), 2.76 - 2.81 (dt, J= 1 1.51, 5.85 Hz, 4 H), 2.50 - 2.54 (dd, J= 14.12, 7.47 Hz, 2 H). LCMS: 343/345 [ XI i |. Preparation of Compound 734

To a solution of N-(3-chlorophenyl)-3-cyclopent-3-en-l-yl-l,4,6,7- tetrahydropyrazoio[4,3-c]pyridine-5-carboxamide (80.00 nig, 233.36 umol, 1.00 eq) in DCM (2.00 mL) was added Et₂Zn (1 M, 1 . 17 mL, 5.00 eq) dropwise at 0 °C. The mixture was stirred at 0 °C for 30 min. A solution of C1CH₂I (246.99 mg, 1.40 mmol, 6.00 eq) in DCM (500.00 uL) was added dropwise at 0 °C. The mixture was stirred at 1 °C for 1 hr. LCMS showed the reaction was completed. The mixture was quenched by saturted H₄C1 (10 mL) and extracted with EA (10 mL*2). The combined organic layer was dried over Na₂S0₄, filtrated and concentrated in vacumrn. The residue was purified by prep-HPLC (FA) to afford 3-(3-bicyclo[3.1.0]hexanyl)-N-(3-chlorophenyl)-l,4,6,7-tetrahydropyrazolo[4,3- c ] p y ri d i n e- 5 -ca rb ox a m i de (12.00 mg, 31.07 umol, 13.31% yield, 92.4% purity) as white solid. ^lH NMR (400MHz, METHANOL-d4) 6 = 7.54 (t, J = 1.9 Hz, 1 II), 7.30 - 7.34 (m, 1 H), 7.22 - 7.28 (m, 1 H), 7.00 - 7.05 (m, 1 H), 4.54 (s, 2 H), 3.77 - 3.83 (m, 2 H), 3.47 - 3.58 (m, 1 FI), 2.78 (t, ./ 5.7 FIz, 2 H), 2.10 - 2.42 (m, 2 FI), 1.93 (dd, J = 5.2, 13.5 Hz, 2 II), 1.38 - 1 .47 (m, 2 H), 0.58 - 0.66 (m, 1 H), 0.16 - 0.46 (m, 1 H). LCMS: 357/359ΓΜ+1].

Exam le 25: Preparation of Compound 827

627

Step 1 : Preparation of Compound 2

To a solution of methyl cyclopentanecarboxylate (6.40 g, 49.93 mmol, 1.00 eq) in THF (40.00 ml.) was added LDA (2 M, 29.96 mL, 1.20 eg) at 0 °C under N₂, followed by Mel (8.50 g, 59.92 mmol, 3.73 mL, 1 .20 eq) after 0.5 h. The mixture was stirred at 25 °C for 1 .5 h. TLC showed two major new spots. The mixture was quenched with NH₄C1 (saturated, 120 raL) and extracted with EA (120 mL). The organic layer was dried over a₂S0₄, filtered and concentrated under reduced pressure to afford methyl 1 - methyl cyclopentanecarboxylate (7.20 g, crude), which was used directly for the next step. Step 2: Preparation of Compound 3

To a solution of methyl I -methyl cyclopentanecarboxylate (3.60 g, 25.32 mmol, 1.00 eq) in MeOH (30.00 mL )/l LO (6.00 mL) was added NaOH ( 1.52 g, 37.98 mmol, 1.50 eq). The reaction mixture was warmed to 70 °C and stirred at 70 C for 2 hours. TLC indicated starting material was consumed completely. The reaction mixture was extracted with DCM (20 mL) and water (10 mL*2). The pH of the aqueous phase was adjusted to around 6 by adding diluted hydrochloride acid (1 N, 5 mL), then extracted with DCM (20 mL*4). The organic phase was dried over anhydrous a₂S0₄, filtered and concentrated in vacuum. The residue was purified by silica gel chromatography to afford 1-m ethyl cyclopentanecarboxylic acid (2.10 g, 16.38 mmol, 64.71% yield) as yellow oil. 1H NMR (400 MHz, DMSO-£¾) 1 1.92 (brs, 1 H), 1.97 - 2.01 (m, 2 H), 1.58 - 1.61 (m, 4 H), 1.34 - 1.38 (m, 2 H), 1.14 (s, 3 H). Step 3 : Preparation of Compound 4

To a solution of 1 -methyl cyclopentanecarboxylic acid (400.00 nig, 3.12 mmol, 1.00 eq) in DCM (10.00 mL) was added CDI (556.65 mg, 3.43 mmol, 1.10 eq) at 0 °C under N », the reaction mixture was warmed to 30 °C and stirred at 30 °C for one hour. TLC showed the reaction was completed. The mixture was extracted with DCM ( 10 ml_*3) and water (10 mL*2). The organic phase was dried with anhydrous Na₂S0₄, filtered and concentrated in vacuum to afford imidazol- 1 -yl-( 1 -methyl cyclopentyl )methanone (510.00 mg, crude) as yellow oil. The crude product was used in the next step without further purification.

Step 4: Preparation of Compound 6

At -78 °C, to Li HMDS (1 M, 4.01 mL, 1.40 eq) was added a solution of tert-butyi 4- oxopiperidine- 1 -carboxylate (456.12 mg, 2.29 mmol, 0.80 eq) in THF (10.00 mL) dropwise under N₂. The reaction mixture was stirred at -78 °C for one hour under N₂. A solution of imidazol- 1 -yl-( 1 -methylcyclopentyl )methanone (510.00 mg, 2.86 mmol, 1.00 eq) in THF (10.00 mL) was added dropwise. After addition, the reaction mixture was warmed to 30 °C and stirred at 30 °C for another 2 hours. TLC showed compound 5 was consumed completely. The reaction mixture was added to saturated aqueous of NH₄C1 (30 mL) and then extracted with EA (50 mL*3), the combined organic phase was dried over anhydrous a₂S0₄, filtered and concentrated in vacuum to afford tert-butyi 3-( 1 - methylcyclopentanecarbonyi) -4-oxo-piperidine- 1 -carboxylate (730.00 mg, crude) as yellow oil. The crude product was used in the next step directly without purification.

Step 5: Preparation of Compound 7

To a solution of tert-butyi 3 -(1 -methyl cycl ope tanecarbonyl)-4-oxo- pi peri dine- 1 - carboxylate (500.00 mg, 1.62 mmol, 1.00 eq) in EtOH (10.00 mL) was added ΝΗ?ΝΗ₂Ή₂0 (124.03 mg, 2.11 mmol, 120.42 uL, 85% purity, 1.30 eq), the reaction mixture was warmed to 60 °C and stirred at 60 °C for 30 minutes. Several new peaks were shown on LCMS and 25% of the desired compound was detected. The mixture was extracted with EA (20 mL*3) and water (20 mL), the organic phase was washed with water (20 mL), dried with anhydrous Na₂SC«4, filtered and concentrated in vacuum. The residue was purified by silica gel chromatography, further purification by prep-TLC to afford tert-butyi -3 -( 1 - methylcyclopentyl) -l,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylate (31.00 mg, 101.50 umol, 6.27% yield) as yellow oil. LCMS: 306 [M+l].

Step 6: Preparation of Compound 8

To a solution of tert-butyi 3-( 1 -methylcyclopentyl )- 1 ,4,6,7- tetrahydropyrazolo[4,3-c] pyridine-5-carboxylate (31.00 mg, 81.20 umol, 1.00 eq) in dioxane (1.00 ml.) was added HCl/dioxane (4 M, 1.00 mL, 49.26 eq). The reaction mixture was stirred at 30 °C for 3 hours. TLC showed starting material was consumed completely.

Evaporated the solution on a water bath under reduced pressure using a rotary evaporator to afford 3-( I -methylcyclopentvi )- 4,5,6,7-tetrahydro- 1 H-pyrazol o[4,3-c] pyridine (13.00 mg, 53.77 umol, 66.22% yield, HCI) as yellow oil. The crude product was used in the next step directly without further purification.

Preparation of Compound 827

To a mixture of 3-( 1 -methylcyclopentvi )-4,5,6,7-tetrahydro- 1 H- pyrazolo[4,3-c] pyridine (13.00 mg, 43.02 umol, 1.00 eq, HCI) in DCM (5.00 mL) was added TEA (13.06 mg, 129.05 umol, 17.89 uL, 3.00 eq), followed by phenyl N-(3- c h 1 orop h en y 1 ) c a rb a m ate ( 10.65 mg, 43.02 umol, 1.00 eq). The reaction mixture was stirred at 30 °C for 5 hours. EC MS showed the starting material was consumed completely and one main peak with desired MS was detected. The mixture was extracted with DCM ( 1 5 niL*3) and water (10 mL). The organic phase was dried with anhydrous Na₂S0₄, filtered and concentrated in vacuum . The residue was purified by prep-HP LC (FA ) to afford Compound 827 (5.16 mg, 14. 14 umol, 32.86% yield, 98.32% purity) as white solid. Ή NMR (400 MHz, METHANOL-d4) 7.51 - 7.52 (t, J= 2.01 Hz, 1 H), 7.28 (m, 1 H), 7.21 - 7.25 (m, 1 H), 7.00 - 7.02 (m, 1 H), 4.62 (s, 2 H), 3.77 - 3.80 (t, J = 5.83 Hz, 2 H), 2.77 - 2.80 (t, J= 5.77 Hz, 2 H), 2.01 - 2.03 (t, ./ 7.09 Hz, 2 H), 1.73 - 1.81 (m, 6 H), 1.29 (s, 3 H). LCMS: 359/361 [M+l ],

Example 26: Preparation o f Compound 700

Steps I and 2: Preparation of Compounds 2 and 4 To a solution of tert-butyl 4-o\opiperidine- 1 -carboxylate (2.59 g, 12.98 mmol, 1.00 eq) in THF (20.00 mL) was added GDI (2.32 g, 14.28 mmol, 1 . 10 eq) under N₂. The mixture was stirred at 1 C for I hr. The mixture was extracted with DCM (20 mL ) and H₂0 (10 mL). The organic layer was dried over Na₂S0₄, filtrated and concentrated in vacumm to gave a crude (IH-imidazo!-l-y!) (1 -( tri lluoromethyl )cycl opropyl )methanone.

A solution of tert-butyl 4-oxopiperidine-l -carboxyl ate (2.59 g, 12.98 mmol , 1 .00 eq) in THF ( 15.00 mL) was added to LiHMDS (1 M, 16.87 mL, 1 .30 eq) dropwise at -70 °C under N₂. The mixture was stirred at -70 °C for 0.5 hr. ( l H-imidazol- l -yl )( 1 - ( tri lluoromethyl jcyclopropyl )methanone prepared above was dissolved in THF (5.00 mL) and added to reaction mixture at -70 °C. Then the resulting mixture was stirred at 15 °C for 16 hr. The mixture was quenched by saturated N H jCl (20 mL) and extracted with EA (50 mL*2). The combined organic layer was dried over Na₂S0₄, filtrated. The filtrates was concentrated in vacumm to afford tert-butyl 4-oxo-3-[l-

(tri lluoromethyl )cyclopropanecarbonyl]piperidine- 1 - carboxylate (3.30 g, crude) as brown oil.

Step 3 : Preparation of Compound 5

To a solution of tert-butyl 4-oxo-3-[ 1 -(trifluoromethyl Jcyclopropanecarbonyl] pi pen di ne- 1 -carboxyl ate (3.30 g, 9.84 mmol, 1.00 eq) in EtOH (30.00 mL) was added ΝΗ₂ΝΗ₂·Η₂0 (985.18 mg, 19.68 mmol, 956.49 uL, 2.00 eq). The solution was heated at 90 °C for 16 hr. The mixture was concentrated in vacumm and extracted with EA (20

mL*2). The combined organic layer was dried over Na₂S0₄. The residue was purified by prep-HPLC (FA) to afford tert-butyl 3-[ 1 -(tri lluoromethyl )cyclopropyl]- 1 ,4,6,7- tetrahydropyrazolo[4,3-c]pyridine-5-carboxylate (200.00 mg, 603.63 umol, 6.13% yield) as brown oil.

Step 4: Preparation of Compound 6

Tert-butyl3-[ l-(trifluoromethyi)cyclopropyi]-l,4,6,7-tetrahydropyrazolo[4,3- c]py ri di ne-5 -carboxyl ate (50.00 mg, 150.91 umol, 1.00 eq) was treated with HCl/dioxane (4 M, 7.73 uL, 1.00 eq). The mixture was stirred at 1 5 °C for 1 hr. TLC (PE:EA=0: 1) showed the reaction was completed. The mixture was concentrated in vacumm to afford 3-[ l - ( tri fl uorom ethyl )cycl opropyl ] -4, 5 , 6, 7-tetrahydro- 1 H-pyrazolo

[4,3-c]pyridine (45.00 mg, 147.96 umol, 98.04% yield, 2HC1) as brown solid.

Preparation of Compound 700

To a solution of 3 - [ 1 -( tri 11 uorom ethyl )cy cl opropyl ] -4,5,6, 7-tetrah y d ro- l H-pyrazolo [4,3 -c]pyri dine (45.90 mg, 150.92 umol, 1.00 eq, 2HC1) in DCM (8.00 mL) was added phenyl N-(3-chlorophenyl)carbamate (37.38 mg, 150.92 umol, 1.00 eq) and TEA (61.09 mg, 603.68 umol, 83.68 uL, 4.00 eq). The mixture was stirred at 15 °C for 16 hr. The mixture was concentrated in vacumm. The residue was purified by prep-HPLC (FA) to afford N-(3-chlorophenyl )-3-[ 1 -(trifluoromethyl )

cyclopropyl] - 1 ,4,6, 7-tetrahy dropyrazol o[4,3 -c]py ri di ne-5-carboxam i de (25.00 mg, 63.93 umol, 42,36% yield, 98.4% purity) as white solid. ^lH NMR (400MHz, METHANOL-d4) δ 7.54 (t, J = 2.0 Hz, 1 H), 7.29 - 7.34 (m, 1 H), 7.22 - 7.28 (m, 1 H), 7.00 - 7.05 (m, 1 H), 4.61 (brs, 3 H), 3.83 (t, J = 5.8 Hz, 2 H), 2.84 (t, J = 5.5 Hz, 2 H), 1.37 (brs, 2 H), 1.18 (brs, 2 H). LCMS: 385/387[M+l]

Example 27: Preparation of Compound 446

446 Step 1 : Preparation of Compound 2

A mixture of tetrahydrofuran-3 -carboxy 1 i c acid (8.00 g, 68.90 mmol, 1.00 eq) in SOCl₂ (80.00 mL) was stirred at 60 °C for 1 hour. TLC showed the reaction was completed. The mixture was concentrated in vacuum to give tetrahydrofuran-3 - carbonyl chloride (8.90 g, 66. 14 mmol, 96.00%) yield) as light yellow oil, which was used directly for next step.

Step 2: Preparation of Compound 4

To a mixture of LiHMDS (1 M, 65.25 mL, 1.30 eq) in THF (100 mL) at -60°C under N₂, then tert-butyl 4-oxopiperidine- 1 -carboxylate (10.00 g, 50. 19 mmol, 1.00 eq) in THF (25 mL ) was added portion-wise at -60°C under N₂. The mixture was stirred at -60°C for 30 min. Then tetrahydrofuran-3 -carbonyl chloride (8.78 g, 65.25 mmol, 1 .30 eq) in TH (25 m L ) was added dropwise at -60°C. The mixture was stirred at 15°C for 2.5 hr under N₂ atmosphere. TLC and I MS showed the reaction was completed. The mixture was quenched by saturated NH₄C1 (200 mL ) and extracted with EA (50 mL*3). The combined organic phase was dried over anhydrous Na₂S0₄, filtered and concentrated in vacuum to give tert-butyl4- oxo-3-(tetrahydrofuran-3-carbonyl)piperidine-l -carboxylate (15.60 g, crude) as a yellow oil. LCMS: 298 [M+l],

Step 3 : Preparation of Compound 5

A mixture of tert-butyl 4-oxo-3~(tetrahydrofuran-3-carbonyl)piperidine-l - carboxylate (15.50 g, 52.13 mmol, 1.00 eq) , ΝΗ₂ΝΗ₂·Η₂0 (6.14 g, 104.25 mmol, 2.00 eq) in EtOH (150.00 mL) was degassed and purged with N₂ for 3 times, and then the mixture was stirred at 80 °C for 3 hour under N₂ atmosphere. LCMS and TLC showed the reaction was completed. The mixture was poured into HCl (0.5N 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 (200 mL*2), dried with anhydrous Na₂S0₄, filtered and concentrated in vacuum. The residue was purified by column chromatography (Si02, Petroleum ether/Ethyl acetate=100/l to 1/1) to give tert-butyl 3-tetrahydrofuran-3-yl-l , 4,6,7- tetrahydropyrazolo[4,3-c]pyridine-5-carboxylate (6.00 g, 20.45 mmol, 39.23% yield) as a yellow oil. 1H NMR (400 MHz, CHLOROFORM-d) ppm 4.42 (brs, 2 H), 4.03 (dt, J = 5.46, 8. 19 Hz, 2 H), 3.82 - 3.94 (m, 2 H), 3.69 (brs, 2 H), 3.39 - 3.48 (m, 1 H), 2.73 (t, J = 5.71 Hz, 2 H), 2.27 - 2.39 (m, 1 H), 2.05 - 2.15 (m, 1 H), 1.45 - 1.53 (m, 1 1 l i ) LCMS: 294 [M+l].

Step 4: Preparation of Compound 6

A mixture of tert-butyl-3-tetrahydrofuran-3-yl-l, 4,6,7- tetrahydropyrazolo[4,3-c] pyridine-5-carboxylate (6.00 g, 20.45 mmol, 1.00 eq) in dioxane (20.00 mL) was added HCl/dioxane (4 M, 40.00 mL, 7.82 eq) , and then the mixture was stirred at 15 °C for 1 hour. TLC showed the reaction was completed. The mixture was concentrated in vacuum to give 3-tetrahydrofuran-3- yl-4,5,6,7-tetrahydro-lH-pyrazolo[4,3-c]pyridine (4.50 g, 19.59 mmol, 95.79% yield, HCl) as a yellow solid. 1H NMR (300 MHz, METHANOL-d₄) ppm 4.38 (s, I H), 4.09 (dt, ./ 4.62, 8.52 Hz, 1 H), 3.96 - 4.03 (m, 1 H), 3.86 - 3.94 (m, 1 H), 3.78 - 3.85 (m, 1 H), 3.70 (d, J = 2.07 Hz, 1 H), 3.58 - 3.64 (m, 2 H), 3.31 (td, J = 1.67, 3.25 Hz, 1 H), 3.20 (t, J= 6.3 1 Hz, 2 H), 2,48 (dd, J = AAA, 8.48 Hz, 1 H), 2.06 (dd, J = 5.46, 7.54 Hz, 1 H). Preparation of Compound 446

A mixture of 3-tetrahydrofuran-3-yl-4,5,6,7-tetrahydro-lH-pyrazolo [4,3-c]pyridine (80.00 mg, 348.27 umol, 1.00 eq, HCI), TEA (70.48 mg, 696.53 umol, 2.00 eq), l-chloro-3- i socyanato-benzen e (48.13 mg, 313.44 umol, 0.90 eq) in DCM (5.00 ml .) was degassed and purged with N₂ for 3 times, and then the mixture was stirred at 1 5 °C for I hour under N₂ atmosphere. LCMS showed the reaction was completed. The mixture was poured into water (10 m L ) 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*2), dried with anhydrous a₂S0₄, filtered and concentrated in vacuum. The residue was purified by prep-HPLC (FA) to give N-(3-chlorophenyl )-3-tetrahydrofuran-3-yl- 1 ,4,6,7-tetrahydropyrazolo[4,3-c] pyridine-5-carboxamide (30.00 mg, 85.38 umol, 24.51% yield, 98.7% purity) as a white solid. 1H MR (400 MHz, METHANOL-d₄) ppm 7.52 (t, J= 1.94 Hz, 1 H), 7.27 - 7.32 (m, 1 H), 7.20 - 7.26 (m, 1 H), 7.00 (td, ./ 0.93, 7.81 Hz, 1 H), 4.56 (s, 2 H), 4.00 - 4.1 1 (m, 2 H), 3.87 (q, ./ = 7.95 Hz, 1 H), 3.75 - 3.82 (m, 3 H), 3.50 (t, J = 7.91 Hz, 1 H), 2.79 (t, J = 5.71 Hz, 2 H), 2.30 - 2.40 (m, 1 H), 2.04 - 2.17 (m, 1 H). LCMS: 347/349 [ X I i |.

Example 28: Procedure for preparation of Compounds 660, 661, 662, 663, 664, 665, 666, 667, 668, and 669

660, 661 , 662, 663,

664, 665, 666, 667,

668, 669

Step 1 : Preparation of Compound 3

At -78 °C, to LiHMDS (1 M, 24.10 niL, 1.20 eq) was added a solution of ten-butyl 4- oxopiperidine- 1 -carboxylate (4.00 g, 20.08 mmol, 1.00 eq) in THF (50.00 mL) dropwise under N₂. The reaction mixture was stirred at -78 °C for one hour under N₂.

Cyclobutanecarbonyl chloride (2.38 g, 20.08 mmol, 1.00 eq) was added dropwise. After addition, the reaction mixture was warmed to 20 °C and stirred at 20 °C for another 2 hours. Several new peaks were shown on LCMS and 20% of desired compound was detected. The reaction mixture was added to aqueous solution of NH₄C1 (100 mL) and then neutralised by dilute hydrochloric acid (1 N), the aqueous layer was extracted with EA (200 mL*3), the combined organic phase was dried over anhydrous Na?S0₄, filtered and concentrated in vacuum to afford tert-butyl 3-(cyclobutanecarbonyl )-4-o\o-piperidine- 1 -carboxylate (5.00 g, crude) as yellow oil. The crude product was used in the next step directly without

purification.

Step 2: Preparation of Compound 4

To a solution of tert-butyl 3-(cyclobutanecarbonyl)-4-oxo- piperidine- 1 -carboxylate (5.00 g, 1 7.77 mmol, 1.00 eq) in EtOH (50.00 mL) was added

NH₂NH₂ H₂Q (2.09 g, 35.54 mmol, 2.00 eq) drop wise, the reaction mixture was warmed to 60 °C and stirred at 60 °C for 2 hours. LCM S showed starting material was consumed completely. Several new peaks were shown on LCMS and 50% of desired compound was detected. Removed the solvent on a rotary evaporator, the mixture was extracted with EA (80 mL*3) and water (50 mL*2). The organic phase was dried with anhydrous Na₂S0₄, filtered and concentrated in vacuum . The residue was purified by si lica gel chromatography to afford tert-butyl 3-cyclobutyl- l,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylate (3.20 g, 9.23 mmol, 51.94% yield, 80%) purity) as yellow oil.

Step 3 : Preparation of Compound 5

To a solution of tert-butyl-3-cyclobutyl- l ,4,6,7-tetrahydropyrazolo[4,3-c]

pyridine-5-carboxylate (2.70 g, 9.73 mmol, 1.00 eq) in dioxane (10.00 mL) was added HCl/dioxane (4 M, 25.00 mL, 10.28 eq) at 30 °C. The reaction mixture was stirred at 30 °C for one hour. Precipitate formed. TLC showed starting material was consumed completely. The reaction mixture was filtered and the filtrate cake was washed with dioxane (15 mL*2) to afford 3-cyclobutyl-4,5,6,7-tetrahydro -l H-pyrazolo[4,3-c] pyridine (2.00 g, 9.36 mmol, 96.18%> yield, HC1) as light yellow solid. The crude product was used in the next step directly without further purification. 1H MR (400 MHz, METHANOL-^) 4.35 (s, 2 H), 3.78 (m, ./ = 9.03 Hz, 1 H), 3.62 - 3.66 (m, 2 H), 3.16 - 3.28 (m, 2 H), 2.39 - 2.53 (m, 2 H), 2.28 - 2.39 (m, 2 H), 2.12 - 2.26 (m, 1 H), 1 .93 - 2.06 (m, 1 H). Gen ral procedure for preparation of Compounds 660 through 669

5 660 - 669

To a solution of amine (1 eq) and TEA (10 eq. ) in 1.5 niL of dry THE, a solution of triphosgene (0.45 eq) in 0.5 ml, dry THE was added. The resulting mixture was stirred at 0°C for 4 hr and TLC showed amine was consumed completely. Then a mixture of compound 5 (1 eq) in 1 ml, of dry THE was added. The reaction mixture was allowed to warm to 30°C for 8 hr. LC-MS showed the reaction was completed. The solution was concentrated under reduced pressure to give a residue. The residue was purified by pre- HPLC (FA or Base) to afford the desired products.

General procedure II:

5 660-669

To a stirred solution of amine (1.2 eq) and phenyl carbonochloridate (1.2 eq) in 2 ml, of dry DCM was added a solution of Py (3 eq). The mixture was stirred at 0 °C for 4 hr and TLC showed amine was consumed completely. The mixture was quenched with water (15 ml,) and extracted with DCM ( 1 5m L). The combined organic phase was dried with a₂S0₄ and concentrated in vacuum. The residue was dissolved in DM SO (3mL). Compound 5 (1 eq), TEA (3 eq.) was added and stirred at 40°C for 8 hr. LC-MS showed reaction was completed. The solution was purified by pre-HPLC (FA or Base) to afford the desired product.

Example 29: Procedure for Preparation o f Compounds 648, 649, 650, 651, 652, 653, 654, 655, 656, and 657

648-0657

Step 1 : Preparation of Compound 3

A mixture of tert-butyl 4-oxopi peri dine- 1 -carboxylate (20.00 g, 100.38 mmol, 1.00 eq), (15.73 g, 130.49 mmol, 1.30 eq) in THF (20 mL) was added to Li HMDS (1 M, 130.49 mL, 1.30 eq) portion-wise at -60 °C under N₂. The mixture was stirred at -60 °C for 30 min. 2,2-dimethylpropanoyl chloride (15.73 g, 130.49 mmol, 1.30 eq) in THF (20 mL) was added dropwise at -60°C. The mixture was stirred at 15 °C for 2.5 hr. TLC showed the reaction was completed. The mixture was quenched by saturated NH₄C1 (80 mL) and extracted with EA (50 mL*3). The combined organic phase was dried with anhydrous Na₂S0₄, filtered and concentrated in vacuum to give tert-butyl 3 -(2,2-dimethylpropanoyl )- 4-oxo-piperidine-l- carboxylat e (33.29 g, crude) as a yellow oil, which was used directly for next step.

Step 2: Preparation of Compound 4

A mixture of tert-butyl 3-(2,2-dimethylpropanoyl)-4-oxo-piperidine-

1 -carboxylate (33.29 g, 1 17.48 mmol, 1.00 eq), Ν₂Η₄·Η₂0 (11.76 g, 234.96 mmol, 2.00 eq) in EtOH (350.00 mL) was degassed and purged with N₂ for 3 times, and then the mixture was stirred at 80 °C for 16 hour under N₂ atmosphere. LCMS showed the reaction was completed. The mixture was poured into FICl (0.5 N, 500 mL) and stirred at 5 min. The aqueous phase was extracted with ethyl acetate (200 niL*3). The combined organic phase was washed with brine (500 mL*2), dried with anhydrous Na₂S0₄, filtered and concentrated in vacuum. The residue was purified by column chromatography (Si0₂, Petroleum ether/Ethyl acetate=100/l to 1/1) and checked by LCMS and HPLC, the desired product was

impurity. The impure desired product was puri ied by Prep-HPLC (FA) to give tert-butyl 3- tert-butyl- 1 ,4,6,7-tetrahydropyr azol o[4, -c]py ri di ne-5-carbox yl ate (4.00 g, 14.32 mmol. 12.19% yield) as a white solid. 1H NMR (400 MHz, METHANOL-d₄) ppm 4.54 (s, 2 H), 3.66 (s, 2 H), 2.68 (s, 2 H), 1.46 - 1.50 (m, 9 H), 1.32 (s, 9 H). LCMS: 280 [M+l].

Step 3 : Preparation of Compound 5

A mixture of tert-butyl3-tert-butyl-l,4,6,7-tetrahydropyrazolo[4,3-c]

pyridinee-5- carboxylate (4.00 g, 14.32 mmol, 1.00 eq) in dioxane (30.00 mL) was added HCl/dioxane (4 M, 30.00 mL, 8.38 eq), and then the mixture was stirred at 15 °C for 2 hour. TLC showed the reaction was completed. The mixture was concentrated in vacuum to give 3- tert-butyl -4,5,6,7 -tetrahydro- 1 H-pyrazol o

[4,3 -c] pyridine (2.60 g, 12.05 mmol, 84.17% yield, HC1) as a yellow solid. Ή NMR (400 MHz, METHANOL^) ppm 4.50 (s, 2 H), 3.59 - 3.65 (m, 2 H), 3.21 (s, 2 H), 1.43 (s, 9 H). General procedure for preparation of Compounds 648 through 0657

General procedure I:

648 - 0657

To a solution of amine (1 eq) and TEA (10 eq) in 1.5 mL of dry THF, a solution of triphosgene (0.45 eq) in 0.5 mL dry THF was added. The resulting mixture was stirred at 0°C for 4 hr and TLC showed amine was consumed completely. Then Compound 5 (1 eq) in 1 mL of dry THF was added. The reaction mixture was allowed to warm to 30°C for 8 hr. LC-MS showed the reaction was completed. The solution was concentrated under reduced pressure to give a residue. The residue was purified by pre-HPLC (FA or Base) to afford the desired products.

General procedure II:

648 - 06

To a stirred solution of amine (1.2 eq) and phenyl carbonochloridate ( 1 .2 eq ) in 2 mL of dry DCM was added a solution of Py (3 eq.). The mixture was stirred at 0°C for 4 hr and TLC showed amine was consumed completely. The mixture was quenched with water (15 niL) and extracted with DCM (15mL). The combined organic phase was dried with a^SCl_t and concentrated in vacuum. The residue was di ssolved in DMSO (3mL). Compound 5 (1 eq), TEA (3 eq) was added and stirred at 40°C for 8 hr. LC-MS showed reaction was completed. The solution was purified by pre-HPLC (F A or Base) to afford the desired product.

Example 30: Preparation of Compounds 782, 783, 784, 785, 786, 787, 788, 789, 790, 791, and 792

782 - 792

Step 1 : Preparation of Compound 3

To a solution of ethyl B-hydroxycyclohexanecarboxylate (10.00 g, 58.07 mmol, 1.00 eq) in DCM (100.00 mL ) was added 4-bromobenzenesulfonyl chloride (22.26 g, 87. 1 1 mmol, 1.50 eq) under N₂. The mixture was stirred at 15 °C for 16 hr. TLC (PE:EA =3 : 1) showed the reaction was nearly completed. The mixture was extracted wih DCM (200 mL) and saturated NaHCO; (80 mL). The organic layer was washed with IN HCl (50 mL), dried over Na₂S0₄, filtrated, and concentrated. The residue was purified by flash chromatography (PE:EA= 0%~10%) to afford ethyl 3 -(4-bromophen yl )sul fony 1 oxycy cl ohex anecarboxyl ate (20.00 g, 51.11 mmol, 88.02% yield) as colorless oil.

Step 2: Preparation of Compound 4

To a solution of ethyl 3-(4-bromophenyl)sulfonyloxycyclohexane

carboxylate (20.00 g, 51.11 mmol, 1.00 eq) in t-BuOH (200.00 mL) was added a solution of t-BuOK (7.46 g, 66.44 mmol, 1.30 eq) in t-BuOH (60.00 mL) dropwise under Nk The mixture was stirred at 90 °C for 1.0 hr. TLC (PE:EA = 20: 1) showed the reaction was completed. The mixture was extracted with DCM (200 mL*3) and H₂0 (100 mL). The combined organic layer was washed saturated NaCl (80 mL), dried over Na₂S0₄, filiated, and concentrated in vacumm. The residue was purified by column chromatography (PE:EA 0%~1%) to afford ethyl bicyclo[3.1.0] hexane- 1 -carboxylate (4.80 g, 31.13 mmol, 60.90% yield) as colorless oil.

Step 3 : Preparation of Compound 5

To a solution of ethyl bicyclo[3. 1 .Ojhexane- 1 -carboxylate (2.00 g, 12.97 mmol, 1.00 eq) in MeOH (20.00 m l. ) was added a solution of NaOH (778.16 mg, 19.45 mmol, 1 .50 eq) in H₂0 (8.00 mL). The mixture was stirred at 70 °C for 3 hr. The mixture was concentrated in vacumm. pH of the residue was adjusted to 6 and the mixture was extracted with DCM (50 mL*3). The organic layer was dried over Na₂S0₄, filtrated and concentrated. The residue was used in the next step directly to afford bicyclo[3.1.0]hexane-l -carboxylic acid (1 .40 g, crude) as brown oil .

Step 4: Preparation of Compound 6

To a solution of bicyclo[3.1.0]hexane-l-carboxylic acid (2.40 g, 19.02 mmol, 1.00 eq) in DCM (24.00 mL) was added di(imidazol- 1 -y )methanone (3.39 g, 20.92 mmol, 1.10 eq). The mixture was stirred at 1 5 °C for 3 hr. The mixture was extracted with DCM (80 mL*2) and H₂0 (50 mL). The combined organic layer was dried over Na₂S0₄, filtrated and concentrated. The residue was used in the next step directly to afford 1 - bicyclo[3.1.0]hexanyl(imidazol-l-yl)-methanone (2.40 g, 13.62 mmol, 71.61% yield) as brown oil.

Step 5 : Preparation of Compound 8

To a solution of LiHMDS (1 M, 16.34 mL, 1.20 eq) in THF (5.00 ml,) was added a solution of tert-butyl 4-oxopi peri dine- 1 -carboxylate (2.71 g, 13.62 mmol, 1.00 eq) in THF (20.00 mL) under N₂ at -65°C. The mixture was stirred at -65 °C for 0.5 hr. A solution of I - bicyclo[3.1.0]hexanyl(imidazol-l-yl)methanone (2.40 g, 13.62 mmol, 1.00 eq) in THF (20.00 mL) was added at -65 C dropwise. The solution was stirred at 1 5 C for 16 hr. The reaction was quenched by saturated NH₄C1 (30 mL) and extracted with EA (50 mL*3). The combined organic layer was dried over Na₂S0₄, filtrated and concentrated in vacumm. The residue was purified by column chromatography (PE:EA : 10%~100%) to afford tert-butyl 3- (bicyclo[3. 1 .0]hexane- l -carbonyl )-4-oxo-piperidine- l -carboxylate (2.30 g, 4.94 mmol, 36.26% yield, 66% purity) as colorless oil.

Step 6: Preparation of Compound 9

To a solution of tert-butyl-3-(bicyclo[3.1. Ojhexane- l-carbonyl)-4-oxo- piperidine-1 - carboxylate (2.30 g, 7.48 mmol, 1.00 eq) in EtOH (1 5.00 mL) was added NH₂NH₂*H₂0 (1.50 g, 14.97 mmol, 1.45 mL, 50% purity, 2.00 eq). The mixture was heated to 90 °C for 3 hr. The mixture was concentrated in vacumm . The residue was extracted with EtOAc (50 mL*3) and H₂0 (50 mL). The organic layer was dried over Na₂S0₄, filtrated, and concentrated in vaciimm. The residue was purified by column chromatography

(PE:EA=20%~100%) to afford tert-butyl-3-(l -bicyclo[3.1.0]hexanyl)-l,4,6,7- tetrahydropyrazolo[4,3-c]pyridine-5- carboxylate (1.90 g, 6.26 mmol, 83.69% yield) as brown oil.

Step 7: Preparation of Compound 10

Tert-butyl-3-( I -bicyclo[3. 1 .Ojhexanyl )- 1 ,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5- carboxylate (1.30 g, 4.28 mmol, 1.00 eq) was dissolved in HCl/dioxane (4 M, 20.00 mL, 18.69 eq) and stirred at 1 °C for I hr. The mixture was filtrated. The solid was collected and dried to afford 3-( I -bicyclo[3. 1 .Ojhexanyl )-4,5,6,7-tetrahydro- 1 H-pyrazolo[4,3- cjpyridine (950.00 mg, crude, 2HC1) as yellow solid. 1H MR (400MHz, METHANOL-d4) δ 4.40 (brs, 2 H), 3.53 - 3.69 (m, 1 H), 3.21 (brs, 1 H), 2.12 - 2.21 (m, 1 H), 1.87 - 2.08 (m, 4 H), 1 .76 - 1.86 (m, 1 H), 1.43 (d, ./ 1 1.2 Hz, I H), 1.13 (brs, 1 H), 1.03 (brs, 1 H).

General procedure for preparation of Compounds 648 through 657

782 - 792

To a solution of amine (1.00 eq) in DCM (2.00 mL) were added TEA (2.00 eq) and phenyl carbonochloridate (1.00 eq). The mixture was stirred at 25°C for 2 hr. To a solution of compound 10 (60.00 mg, 1.00 eq, HC1) and TEA (2.00 eq) in DCM (2.00 mL) were added above reaction mixture. The mixture was stirred at 25 °C for 20 hr. LC-MS showed the reaction was completed. The reaction mixture was concentrated in vacuo. The resiude was purified by prep-HPLC (FA) to afford the desired product.

Example 31: Preparation o f Compound 440

440 Step 1 : Preparation of Compound 2

A mixture of 3-bromo-N-(3-chlorophenyl)-l ,4,6,7-tetrahydropyrazolo[4,3-c] pyridine-5-carboxamide (1.07 g, 3.00 mniol, 1.00 eq), potassium trifluoro(vinyl)borate (602.78 nig, 4.50 mmol, 1.50 eq), Pd₂(dba)₃ (137.36 mg, 150.00 umol, 0.05 eq), XPhos (143.02 mg, 300.00 umol, 0.10 eq) and Na₂C0₃ (699.53 mg, 6.60 mmol, 2.20 eq) in dioxane (40.00 mL) and H?0 (6.00 mL) was degassed and purged with N₂ for 3 times, and then the mixture was stirred at 100 °C for 8 hours under N₂ atmosphere. TLC indicated the reactant was consumed, and a major new spot formed. The reaction mixture was concentrated, extracted with EA (30 mL) and water (10 mL). The aqueous layer was extracted with EA (20 mL*2). The combined organic layer was washed with brine, dried over a^SC^, and concentrated in vacuo. The residue was purified by column chromatography (Si02,

Petroleum ether/Ethyl acetate=3/l to 1 : 1 , then DCM: MeOH 50: 1 to 20: 1) to afford -(3- chlorophenyi)-3-viny{-l,4,6,7-tetrahydropyrazoio[4,3-c]pyridine-5- carboxamide (435.97 mg, 1.44 mmoi, 48.00% yield) as yellow solid.

Preparation of Compound 440

A mixture of N-(3 -chlorophenyl)-3 -vinyl- 1 ,4,6,7-tetrahydropyrazolo

[4,3-c]pyridine -5-carboxamide (100.00 mg, 330.29 umol, 1.00 eq) in DCM (2.00 mL) was degassed and purged with N₂ for 3 times, and then ZnEt₂ (1 M, 1.65 mL, 5.00 eq) was added dropwise at 0 °C. The mixture was stirred for 30 min. C hi oro( i odo )m eth ane (291.28 mg, 1.65 mmoi, 5.00 eq) was added. The mixture was stirred at 1 C for 1 hr under N₂ atmosphere. LCMS showed material was consumed completely. The mixture was poured into saturated NH₄CI (10 mL), extracted with ethyl acetate (15 mL*2), the combined organic layer was dried over anhydrous Na₂S0₄, concentrated. The residue was purified by prep-HPLC (FA) to afford N-(3-chlorophenyl)-3-cyclopropyl-l,4,6,7-tetrahydropyrazolo[4,3-c]pyridine- 5- carboxamide (7.87 mg, 24.40 umol, 7.39% yield, 98.21% purity) as white solid. ¹ H NMR (400 MHz, MeOD) δ 7.54 (s, 1 H), 7.20 - 7.35 (m, 2 H), 7.02 (d, J= 7.72 Hz, 1 H), 4.57 (s, 2 H), 3.80 (s, 2 H), 2.77 (t, J = 5.65 Hz, 2 H), 1.84 (brs, 1 H), 0.94 (d, J = 6.59 Hz, 2 H), 0.81 (d, J=3.77 Hz, 2 H). LCMS: 317/319 [M+l].

xample 32: Preparation of Compounds 742 and 743

743

Step 1 : Preparation of Compound 3

To a solution of tert-butyl 3-bromo-l-(2-trimethylsilylethoxymethyl)- 6,7-dihydro -4H-pyrazolo[4,3-c]pyridine-5-carboxylate (200.00 mg, 462.50 umol, 1.00 eq) and cyclopent-2-en- 1 -one (56.96 mg, 693.75 umol, 1.50 eq) in DMF (2.00 niL) were added N-cyclohexyl-N-methylcyclohexanamine (135.52 mg, 693.75 umol, 1 .50 eq) and Ad₂nBuP Biphenyl (9.28 mg, 13.88 umol, 0.03 eq). The mixture was stirred at 100 °C for 16 hr under 2 protection. LCMS showed starting material remained and desired product and multiply peaks were detected. The mixture was poured into water (10 niL), extracted with ethyl acetate (10 mL*3), the combined organic layer was dried over anhydrous Na₂S0₄, concentrated. The residue was purified by chromatography ( silica gel, eluting with Petroleum ether/Ethyl acetate=50: l, 10: 1) to afford tert-butyl 3-(3-o\ocyclopenten- 1 -yl )- 1 -(2-trimethyl

silylethoxymethyl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate (55.00 mg, 126.84 umol, 27.42% yield) as colorless oil. LCMS: 434 [M+l].

Step 2: Preparation of Compound 4

To a solution of tert-butyl 3-(3-oxocyclopenten- 1 -yl )- 1 - (2-trimethylsilylethoxymethyl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate (300.00 mg, 691.85 umol, 1.00 eq) in DCM (4.00 niL) was added DIBAL-H (146.54 mg, 1.04 mmol, 1.50 eq) at -78 °C under N₂ protection. The mixture was stirred at 25 °C for 16 hr. TLC (Petroleum ether/ethyl acetate=3 : l) showed material was consumed completely, and a major new spot detected. The mixture was poured into water (10 mL), extracted with ethyl acetate 10 mL*3). The combined organic layer was dried over anhydrous Na₂S0₄,

concentrated. The residue was purified by chromatography (silica gel, eluting with

Petroleum ether/ethyl acetate=10: l, 5 : 1 , 3 : 1 ) to afford tert-butyl 3-(3-hydroxycyclopenten-l-

(180.00 mg, 413.19 umol, 59.72% yield) as colorless oil .

Step 3 : Preparation of Compound 5

To a solution of tert-butyl 3-(3~hydroxycyclopenten-l-yl)- l-(2 rimethylsilyiethoxymethyl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate (120.00 mg, 275.46 umol, 1.00 eq) in MeOH (10.00 mL) was added Pd-C (10%, 25 mg) under N₂. The suspension was degassed under vacuum and purged with H₂ several times. The mixture was stirred under H₂ (45 psi ) at 50°C for 16 hours. LCMS showed the material was consumed completely, and major desired MS detected. The reaction mixture was filtered and the filtrate was concentrated to afford tert-butyl 3-( 3-hydroxycyclopentyl )- 1 -(2- trimethylsilylethoxymethyl)- 6, 7-di hydro-4H-py razol o[4,3 -cjpyri di ne-5-carboxyl ate (100.00 mg, 228.49 umol, 82.95% yield) as colorless oil, which was used directly in the next step. LCMS: 438 [M+l].

Step 4: Preparation of Compound 6

A mixture of tert-butyl 3-(3-hydroxycyclopentyl )- 1 -(2-trimethylsilylethoxy methyl )- 6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate (180.00 mg, 41 1.29 umol, 1.00 eq) in HCl/dioxane (4 M, 5.00 mL, 48.63 eq) was stirred at 25 °C for 2 hr. Precipitate was formed. The mixture was evaporated to afford 3-(4,5,6,7- tetrahydro- lH-pyrazolo[4,3- c] py ri di n-3 -yl )cycl opentanol (100.00 mg, 410.29 umol, 99.76% yield, HCl ) as white solid, without further purification and used directly in the next step.

Preparation of Compound 742

To a solution of 3-(4,5,6,7-tetrahydro- 1 H-pyrazolo[4,3-c]pyridin- 3 -yl)cycl opentanol (100.00 mg, 410.29 umol, 1.00 eq, HCl) in DCM (5.00 mL) were added TEA (83.03 mg, 820.58 umol, I 13.74 uL, 2.00 eq) and phenyl N-(3-chlorophenyl)carbamate (101.62 mg, 410.29 umol, 1.00 eq). The mixture was stirred at 25 °C for 2 hr. LCMS showed material was consumed completely, and major desired MS detected. The solvent was evaporated. The residue was purified by prep-HPLC(FA) to afford N-(3 -chl oropheny 1 )- -( 3 - hydroxycyciopentyl)-l,4,6,7-tetrahydropyrazolo[4,3-c] pyridine-5-carboxamide (57.00 mg, 155.04 umol, 37.79% yield, 98. 15% purity) as white solid. 1H NMR (400 MHz, MeOD) δ 7.54 (s, 1 H), 7.31 (s, 1 H), 7.20 - 7.28 (m, 1 H), 7.02 (d, J= 7.78 Hz, 1 H), 4.54 - 4.71 (m, 2 H), 4.39 (brs, 1 H), 3.72 - 3.93 (m, 3 H), 3.03 (ddd, .1 = 11.67, 7.65, 4.27 Hz, 1 H), 2.81 (t, J = 5.65 Hz, 2 H), 1.91 - 2.22 (m, 4 H), 1.69 - 1.87 (ra, 2 H). LCMS: 361/363 [M+l].

Preparation of Compound 743

To a solution of N-(3-chlorophenyl)-3-(3-hydroxycyclopentyl)-l , 4,6,7- tetrahydropyrazolo[4,3-c]pyridine-5-carboxamide (50.00 mg, 138.57 umol, 1.00 eq) in DCM (3.00 ml.) was added DAST (33.50 mg, 207.86 umol, 27.46 uL, 1.50 eq) at -78°C, The mixture was stirred at 25 °C for 16 hr. LCMS showed the material was consumed

completely, and major desired MS detected. The reaction was quenched by water (10 mL), extracted with DCM (10 mL*2). The combined organic layer was dried over anhydrous Na₂S0₄, concentrated, the residue was purified by prep-HPLC (FA) to afford N-(3- chlorophenyl)-3-(3-fluorocyciopentyl) -l,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5- carboxamide (6.02 mg, 16.06 umol, 11.59% yield, 96.8% purity) as white solid. LCMS: 363/365 [M+l]. Example 33: Preparation of Compounds535 and 744

Preparation of Compound 535

A mixture of tert-butyl 3-(3~hydroxycyclopenten-l-yl)-l-(2- trimethylsilylethoxymethyl)-6,7-dihydro-4Fl )yrazolo[4,3-c]pyridine-5-carboxylate (60.00 mg, 137.73 umol, 1.00 eq) in HCI/dioxane (4 M, 4.00 mL, 116.17 e ) was stirred at 25 C for 2 hr. The the solvent was evaporated, and diluted in DCM (3.00 mL), TEA (27.87 mg, 275.46 umol, 38.18 uL, 2.00 eq) and phenyl N-(3-chlorophenyl)carbamate (34.11 mg, 137.73 umol, 1.00 eq) were added, the mixture was stirred at 25 °C for 16 hr. LCMS showed the material was consumed completely, and major desired MS detected. The solvent was evaporated. The residue was purified by prep-HPLC (FA) to afford N-( -chl orophenyl )-3 -( - hydroxycyciopenten-l-yi) -l,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxamide (7.44 mg, 20.21 umol, 14.67% yield, 97.46% purity) as white solid. LCMS: 359/361 [M+l],

Preparation of Compound 744

To a solution of N-(3-chlorophenyl)-3-(3-hydroxycyclopenten-l-y{)-l, 4,6,7- tetrahydropyrazolo[4,3-c]pyridine-5-carboxamide (50.00 mg, 139.35 umol, 1.00 eq) in DCM (5.00 mL) was added DAST (44.92 mg, 278.70 umol, 36.82 uL, 2.00 eq) at - 78 °C under N, protection. The mixture was stirred at 25 °C for 16 hr. LCMS showed the material was consumed completely, and major desired MS detected. The mixture was poured into water (10 mL), extracted with ethyl acetate (10 mL*2 ). the combined organic layer was dried over anhydrous concentrated. The residue was purified by prep-HPLC (FA) to afford N- (3-chlorophenyl)-3-( 3-fluorocyclopenten- l -vl H _^

carboxamide (15.00 mg, 41.03 umoi, 29.45% yield, 98.7% purity) as white solid. LCMS: 361/363 [M+l].

Example 34: Preparation of Compound 704

Step 1: Preparation of Compound 2

To a solution of 4-methoxypyridine (16.10 g, 147.53 mmol, 1.00 eq) in THF (200.00 mL) was added CTLMgBr (3 M, 59.50 mL, 1.21 eq) at -10 °C over a period of 20 min under N_2j during which the temperature was maintained below 5 °C. The reaction mixture was warmed to 25 °C for 30 mm. A solution of CbzCl (30.20 g, 177.04 mmol, 1.20 eq) in THF (80.00 mL) was added dropwise at -10 °C under 2. during which the temperature was maintained below 25°C. The reaction mixture was stirred at 25 °C for 3hr. TLC

(PE:EA=3: 1) showed the starting material was dissapeared. A HC1 solution (3N, 300 mL) was added into the reaction dropwise at -10 °C. The mixtire was extracted with EA (200 mL*2). The combined organic layer was washed 5 % NaHCC (500 mL) and dried over Na₂S0₄, filtrated. The filtrate was concentrated in vacuum. The residue was purified by column chromatography (PE:EA=10: 1,5: 1) to afford benzyl 2-methyl-4-oxo- 2,3-dihydropyridine-l-carboxylate (14.50 g, 59.12 mmol, 40.07% yield) as brown oil. Hi NMR (400 MHz, CDCI3) δ 7.67 (d, J = 7.9 Hz, 1 H), 7.35 - 7.27 (m, 5 H), 5.28 - 5.22 (m, 1 H), 5.20 (d, J= 4.0 Hz, 2H), 4.70 - 4.61 (m, 1 H), 2.78 (dd, J = 6.8, 16.4 Hz, 1H), 2.24 (d, J = 16.4 Hz, 1H), 1.19 (d, J 6.8 Hz, 3H). Step 2: Preparation of Compound 3

To a solution of benzyl 2-methyl-4-oxo-2,3-dihydropyridine-l-carboxylate (1.00 g, 4.08 mmol, 1.00 eg) in THF (10.00 niL) was added lithium trisec-butylboranuide (1 M, 4.90 mL, 1.20 eg) at -78 °C under N₂ protection. The reaction mixture was stirred for 1 hr. Then a solution of cyclobutanecarbonyl chloride (628.84 nig, 5.30 mmol, 604.65 uL, 1.30 eg) in THF (1 mL) was added at -78 C. The mixture was stirred 20 °C for 16 hr. LCMS showed material was consumed completely, and several new peaks were detected. The mixture was poured into saturated H₄CI (20 mL), extracted with ethyl acetate (15 niL*2), the combined organic layer was dried over anhydrous Na₂S0₄, concentrated to afford benzyl 5- (cyclobutanecarbonyl)-2-methyl~4-oxo-piperidine- l-carboxylate (1.30 g, crude) as light yellow oil, which was not purified and used directly in the next step. LCMS: 352 [M+23], Step 3 : Preparation of Compound 4

To a solution of benzyl

1-carboxylate (1.00 g, 3.04 mmol, 1.00 eg) in EtOH (10.00 mL) was added N₂H₄-H₂0 (1.22 g, 6.08 mmol, 1.18 mL, 2.00 eg). The mixture was stirred at 80 °C for 1 hr. TLC (petroleum ether/ethyl acetate=l : 1 ) showed a major new spot. The mixture was concentrated. The residue was extracted with ethyl acetate (10 mL*2). The combined organic layer was dried over anhydrous Na₂S0₄, and concentrated. The residue was purified by chromatography (silical gel, eluting with petroleum ether/ethyl acetate=10: 1, 1 : 1) to afford impure product (230 nig with 30 % purity, colorless oil) which was purified by prep-HPLC (FA) to afford benzyl 3-cyclobutyl-6-methyl- l ,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylate (30.00 mg, 92.19 umol, 3.03% yield) as colorless oil. 1H MR (400 MHz, CDC1₃) δ 7.38 (d, J=3.96 Hz, 5 H), 5.19 (s, 2 H), 4.58 - 4.65 (m, 1 H), 4.14 (brs, 1 H), 3.56 (s, 1 H), 2.90 (dd, J = 15.82, 5.84 Hz, 1 H), 2.56 (d, J = 15.82 Hz, 1 H), 2.32 (brs, 4 H), 2.02 - 2.15 (m, 1 H), 1.84 - 1.99 (m, 1 H), 1.15 (d, J = 6.97 Hz, 3 H). LCMS: 326 [M+l],

Step 4: Preparation of Compound 5

To a solution of benzyl 3-cyclobutyl-6-methyl-l , 4,6,7- tetrahydropyrazolo[4,3-c]pyridine-5-carboxylate (60.00 mg, 184.39 umol, 1.00 eg) in MeOH (5.00 mL) was added Pd/C (6.00 mg, 10%) under N₂. The suspension was degassed under vacuum and purged with H₂ several times. The mixture was stirred under H₂ (50psi) at 25 °C for 16 hours. TLC (Petroleum ether/ethyl acetate=l : l) showed the material was consumed completely. The reaction mixture was filtered and the filtrate was concentrated to afford 3- cyclobutyl-6-methyl-4,5,6,7~tetrahydro-lH~pyrazolo[4,3-c] pyridine (18.00 mg, 94.1 1 umol, 51 .04% yield) as colorless oil . Preparation of Compound 704

To a solution of 3-cyclobutyl-6-methyl-4,5,6,7-tetrahydro-lH-pyrazolo[4,3-c] pyridine (18.00 mg, 94.1 1 umol, 1.00 eq) and phenyl N-( 3 -chl oropheny 1 )carbamate (27.97 mg, 1 12.93 umol, 1.20 eq) in DCM (4.00 mL) was added TEA (19.05 mg, 188.22 umol, 26. 1 0 uL, 2.00 eq). The mixture was stirred at 25 °C for 4 hr. LCMS showed the material was consumed completely, major was desired MS detected. The mixture was concentrated in vacuo. The residue was purified by prep-HPLC (FA) to afford N-(3-chlorophenyl)-3- cyclobutyl-6-methyl-l, 4,6,7- tetrahydropyrazolo[4,3-c]pyridine-5-carboxamide (29.98 mg, 81.35 umol, 86.44% yield, 93.57% purity) as white solid. Ή NMR (400 MHz, MeOD) δ 7.54 (s, 1 H), 7.19 - 7.36 (m, 2 H), 7.03 (d, J = 7.78 Hz, 1 H), 4.91 (brs, 2 H), 4.2 1 (d, J = 15.3 1 Hz, 1 H), 3.61 (s, 1 FI), 2.98 (d, J 5.77 Hz, 1 H), 2.62 (d, ./ 15.81 Hz, 1 FI), 2.28 - 2.43 (m, 4 H), 2.04 - 2.16 (m, 1 H), 1.97 (brs, 1 H), 1.20 (d, J= 6.78 Hz, 3 H). LCMS:

345/347 [M+l]. Example 35: Preparation of ^'Compounds^'/ ⁷04 and 7⁷56, 757, 758, 759, 760, 761, 762, 763, 764, and 765

704 and 756 - 766

A B C D E F

Step 1 : Preparation of Compounds 2A and 2B

To a solution of tert-butyl 2-m ethyl -4-oxo-pi peri dine- 1 -carboxyl ate (1 ,00 g, 4.69 mmol, 1.00 eq) in THF (10.00 mL) was added Li HMDS (1 M, 9.38 mL, 2.00 eq) at -78 °C. The mixture was stirred for 1 hr. Then cyclobutanecarbonyl chloride (834.07 nig, 7.04 mmol, 801 .99 uL, 1.50 eq) was added, and the mixture was stirred at 25 °C for 15 hr. TLC (Petroleum ether/ethyl acetate=5: l) showed material was consumed completely and a major new spot detected. The mixture was poured into saturated NH₄C1 (20 mL), extracted with ethyl acetate (20 mL*2). The combined organic layer was dried over anhydrous Na₂S0₄, concentrated to afford a mixture of tert-butyl3-(cyclobutanecarbonyl)-2-methyl-4-oxo- pi peri dine- 1 - carboxylate and tert-butyl 5-(cyclobiitanecarbonyl )-2-methyl-4-oxo-piperidine- 1 -carboxyl ate (1.10 g, crude) as light yellow oil.

Step 2: Preparation of Compounds 3A and 3B

2A 2B 3B

To a mixture of tert-butyl 3-(cyclobutanecarbonyl )-2-methyl -4-oxo- pi peri dine- 1 - carboxylate (1.10 g, 3.72 mmol, 1.00 eq) and tert-butyl 5- ( cyclobutanecarbonyl )-2-methyl-4-oxo-piperidine- l -carboxylate (1.10 g, 3.72 mmol, 1.00 eq) in EtOH (15.00 mL) was added hydrazine (238.45 mg, 7.44 mmol, 267.92 uL, 2.00 eq). The mixture was stirred at 80 C for I hr. TLC (Petroleum ether/ethyl acetate= 1 : 1 ) showed material was consumed completely, and a major new spot detected. The solvent was evaporated. The residue was washed with water (20 mL), extracted with ethyl acetate (30 mL*2). The combined organic layer was dried over anhydrous Na₂S0₄, and concentrated. The residue was purified by chromatography (silical gel, eluting with Petroleum ether/ethyl acetate=10: l, 3 : 1, 1 : 1 ) to afford a mixture of tert-butyl 3-cyclobutyl-4-methyl-l, 4,6,7- tetrahydro pyrazolo[4,3-c]pyridine-5-carboxylate and tert-butyl 3 -cy cl obutyl -6-m ethyl - l ,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carbo\ylate (680.00 mg, 2.33 mmol, 62.63% yield) as white solid. The mixture (200 mg) was purified by chiral SFC to afford

two fractions, fraction 1 (86 mg, white solid, Rt = 1 .855, 1.922 min) and fraction 2 (82 mg white solid, Rt = 2.251,2.357 min).

The separation method:

Instrument: SFC 80

Column: AD-lOum.

Mobile phase: A for C0₂ and B for Ethanol (0. 1 % Ammonia)

Gradient: B 40%

Flow rate: 70m L /min

Back pressure: lOObar

Column temperature: 35°C

Wavelength: 220nm

The fraction 1 (2.5 g) was further purified by chiral SFC to afford the first enantiomer of tert-butyi3-cyclobutyl-4-methyl-l ,4,6,7-tetrahydropyrazoio[4,3-c] pyridine-5- carboxylate 3A E 1 (: .10 g, 3.78 mmol, 44.06% yield, Rt = 1.128 min) as white solid and the first enantiomer of tert-butyl 3- cyclobutyl-6-methyl-l,4,6,7-tetrahydropyrazolo[4,3- c ] py ri d i n e- 5 -ca rb ox y 1 at e 3B E 1 (1.20 g, 4.12 mmol, 48.02% yield, Rt = 1.536 min) as white solid.

3A_E1 : Ή NMR (400 MHz, CDC1₃) δ 4.93 - 5.20 (m, 1 H), 4.09 - 4.40 (m, 1 H), 3.43 (q, J 8.72 Hz, 1 H), 2.98 (brs, 1 H), 2.51 - 2.74 (m, 2 H), 2.08 - 2.34 (m, 4 H), 1.95 - 2.04 (m, 1 H), 1.85 (d, J = 7.28 Hz, 1 H), 1.41 (s, 9 H), 1 .18 - 1.26 (m, 3 H). 3B_E1 : ^lB NMR (400 MHz, CDC1₃) δ 4.73 (brs, 2 H), 3.90 (d, J= 15.56 Hz, 1 H), 3.39 - 3.51 (m, 1 H), 2.86 (dd, J = 15.69, 5.90 Hz, 1 H), 2.46 (d, J = 15.56 Hz, 1 H), 2, 1 1 - 2.33 (m, 4 H), 1.93 - 2.07 (m, 1 H), 1.78 - 1.90 (m, 1 H), 1.37 - 1.49 (m, 9 H), 1.05 (d, J = 7.03 Hz, 3 H).

The separation method:

Instrument: SFC 80

Column: AS-lOum.

Mobile phase: A for CO 2 and B for Ethanol (0.1 % Ammonia)

Gradient: B 40%

Flow rate: 70m L /min

Back pressure: lOObar Column temperature: 35°C

Wavelength: 220nm

The fraction 2 (2,5 g) was further purified by chiral SFC to afford the second enantiomer of tert-butyl3-cyclobutyl-4-methyl- l ,4,6,7-tetrahydropyrazolo [4,3-c]pyridine-5- carboxylate 3A_E2 (1.10 g, 3.78 mmol, 44.06% yield, Rt ^:::: 1.587) as white solid and the second enantiomer of tert-butyl 3 -cycl obutyl -6-methyl - 1 ,4,6, 7-tetrahydropyrazol o[4,3 - c J py ri di n e- 5 -ca rb o y 1 a t e 3 B E 2 (1.20 g, 4.12 mmol, 48.02% yield, Rt = 1.841 min) as white solid. 3A_E2: 1H NMR (400 MHz, CDC1₃) δ 4.91 - 5.22 (m, 1 H), 4.06 - 4.39 (m, 1 H), 3.36 - 3.50 (m, 1 H), 2.98 (brs, 1 H), 2.59 (brs, 2 H), 2.09 - 2.34 (m, 4 H), 1.93 - 2.06 (m, 1 H), 1.85 (d, J = 7.28 Hz, 1 H), 1 .31 - 1 .46 (m, 9 H), 1 .22 (d, J= 6.53 Hz, 3 H). 3B E2: 1H MR (400 MHz, CDC1₃) δ 4.73 (brs, 2 H), 3.90 (d, J= 15.56 Hz, 1 H), 3.45 (t, J = 8.78 Hz, 1 H), 2.86 (dd, J = 15.69, 5.90 Hz, 1 H), 2.46 (d, ./ 15.81 Hz, 1 H), 2.12 - 2.34 (m, 4 H), 1.96 - 2.04 (m, 1 H), 1.78 - 1.90 (m, 1 H), 1.42 (s, 9 H), 1.05 (d, J=6.78 Hz, 3 H).

The separation method:

Instrument: SFC 80

Column: AD-lOum.

Mobile phase: A for CO: and B for Ethanol (0.1 % Ammonia)

Gradient: B 40%

Flow rate: 70m L /min

Back pressure: lOObar

Column temperature: 35°C

Wavelength: 220nm.

Step 3 : Preparation of Compound 4B E I /E2

3B E1 4B E1

3B E2 4B E2

A mixture of tert-butyl 3-cyclobutyl-6-methyi-l,4,6,7-tetrahydropyrazolo [4,3- c]pyridine-5 -carboxylate 3B E 1 (1.20 g, 4.12 mmol, 1.00 eq) in HCl/dioxane (4 M, 10.00 mL, 9.71 eq) was stirred at 25 °C for 2 hr. White solid was formed. The solvent was evaporated to afford 3 -cycl obutyl -6-methyl -4, ,6, 7-tetrahydro - 1 H-pyrazolo[4,3-c]pyridine 4 B E I (930.00 mg, 4.08 mmol, 99.12% yield, HC1) as white solid. Preparation of Compounds 704, and 757 through 765

704 and 757 - 765

General Procedure

To a solution of amine (1.0 eq) and phenyl carbonochloridate (1.0 eq) in DCM (1.00 rnL) was added TEA (3 eq), the reaction mixture was stirred at 30 °C for 30 minutes. TLC indicated amine was consumed completely. The mixture was added to a mixture of compound 4B (1.00 eq, HC1 salt) in DCM (1.00 ml_) and TEA (3 eq ). The reaction mixture was stirred at 30 C for 16 hours. LCMS showed reaction was completed. The mixture was extracted with DCM (10 mL*3) and water (10 niL), the organic phase was dried with anhydrous Na₂S0₄, filtered and concentrated in vacuum. The residue was purified by prep-

HPLC (FA) to give the desired product as white solid.

Structure Comp. ID Analytical Data

LCMS(M+l):345/347; Ή NMR (400 MHz, METHANOL-d4) d ppm 7.54 (t, ./ 1.88 Hz, 1 H), 7.31 (s, 1 H), 7.22 - 7.28 (m, 1 H), 7.03 (d, J = 7.78 Hz, 1 H), 4.84 (brs, 2 H), 4.21 (d,

704 (El) ./ 15.06 Hz, 1 H), 3.61 (t, ./ 8.78 Hz, 1 H),

3.00 (dd, .1 = 15.69, 5.90 Hz, 1 H), 2.62 (d, J ----- 15.81 Hz, 1 H), 2.27 - 2.43 (m, 4 H), 2.10

(d, J = 9.03 Hz, 1 H), 1.95 (dd, J= 7.53, 3.26

Hz, 1 H), 1.20 (d, J= 6.78 Hz, 3 H).

LCMS(M+l):345/347; Ή NMR (400 MHz, METHANOL-d4) d ppm 7.54 (t, J = 1.88 Hz, 1 H), 7.21 - 7.37 (m, 2 H), 7.03 (d, J = 7.78 Hz, 1 H), 4.84 (brs, 2 H), 4.21 (d, J= 15.06

704 (E2) Hz, 1 H), 3.61 (t, ./ 8.91 Hz, 1 H), 3.00 (dd,

J= 15.81, 5.77 Hz, 1 H), 2.62 (d, J = 15.81 Hz, 1 H), 2.26 - 2.46 (m, 4 H), 2.10 (d, J = 9.29 Hz, 1 H), 1.95 (dd, J = 7.53, 3.51 Hz, 1 H), 1.20 (d, J= 6.78 Hz, 3 H).

HCI dioxane

861

Step 1 : Preparation of Compound 2

A mixture of tetrahydrofuran-2-carboxylic acid (2.00 g, 17.23 mmol, 1.65 mL, 1.00 eq) in SOCK (10.25 g, 86.13 mmol, 6.25 mL, 5.00 eq) was stirred at 90 °C for 3 hours. The mixture was concentrated in reduced pressure to afford tetrahydrofiiran-2-carbonyl chloride (2.32 g, 17.24 mmol, 100.00% yield) as yellow oil.

Step 2 : Preparation of Compound 4

To a mixture of tert -butyl 4-o\opiperidine- 1 -carboxylate (3.44 g, 17.24 mmol, 1 .00 eq) in THF (20 mL) was added Li HMDS (1 M, 25.86 mL, 1.50 eq) dropwise at -78 °C under N.<. The mixture was stirred at -78 °C for 30 min, then tetrahydrofuran-2-carbonyl chloride (2.32 g, 1 7.24 mmol, 1.00 eq) in THF (20 mL) was added to the mixture. The mixture was heated to 25 °C and stirred for 2.5 hours. LCMS showed the reaction was completed. The mixture was quenched with aq. NH₄C1 (30 mL). The aqueous phase was extracted with ethyl acetate (40 mL*2). The combined organic phase was washed with brine (40 mL*2 ), dried with anhydrous a₂SO.), filtered and concentrated in vacuum to afford tert- butyl 4-ox o- -(tetrahydrofuran-2-carbonyl )pi peri di ne- 1 -carboxy 1 ate (6.00 g, crude) as yellow oil. LCMS: 298 [M+l].

Step 3 : Preparation of Compound 5

To a mixture of tert-butyl 4-oxo-3-(tetrahydrofuran-2-carbonyi)piperidine- 1 -carboxy late (6.00 g, 20.18 mmol, 1.00 eq) in MeOH (100.00 mL) was added Ν₂Η₄Ή₂0 (1.19 g, 20.18 mmol, 1 .15 mL, 85% purity, 1 .00 eq) in one portion under N₂. The mixture was stirred at 30 C for 12 hours. LCMS showed the reaction was completed, and desired product was detected. The mixture was concentrated in reduced pressure. The residue was poured into water (50 mL) and stirred for 2 min. The aqueous phase was extracted with ethyl acetate (50 mL*2). The combined organic phase was washed with brine (50 mL*2), dried w ith anhydrous Na₂SO filtered and concentrated in vacuum . The residue was purified by silica gel chromatography (Petroleum ether/Ethyl acetate=T/l) to afford tert-butyl 3- tetrahydrofuran-2-yl-l,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5- carboxylate (1.80 g, 3.31 mmol, 16.42% yield, 54% purity) as yellow solid.

LCMS: 294 [M+l],

Step 4: Preparation of Compound 6

To a mixture of tert-butyl 3-tetrahydrofuran-2-yl-l ,4,6,7-tetrahydropyrazolo

[4,3 -c] pyri di ne-5-carboxyl ate (80.00 nig, 272,70 umol, 1.00 eq) in dioxane (1.00 mL) was added HCl/dioxane (4 M, 4.00 mL, 58.67 eq) in one portion at 25 C under N₂. The mixture was stirred at 25 °C for 2 hours. TLC (Petroleum ether : Ethyl acetate=T : 1) showed the reaction was completed. The mixture was concentrated in vacuum to afford 3- tetrahydrofuran-2-yl-4,5,6,7-tetrahydro-lH-pyrazolo[4,3-c] pyridine (62,64 mg, 272.69 umol, 100.00% yield, HC1) as yellow solid.

Preparation of Compound 861

To a mixture of 3-tetrahydrofuran-2-yl-4,5,6,7-tetrahydro-lH-pyrazolo

[4,3-c] pyridine (62.64 mg, 272.69 umol, 1.00 eq, HC1) and phenyl N-(3-chlorophenyl) carbamate (67.54 mg, 272.69 umol, 1.00 eq) in DCM (8.00 mL) was added TEA (82.78 mg, 818.07 umol, 113.40 uL, 3.00 eq) in one portion at 30 °C under N₂. The mixture was stirred at 30 °C for 12 hours. LCMS showed the reaction was completed. The mixture 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 a₂S0₄, filtered and concentrated in vacuum. The residue was purified by prep- HPLC(FA) to afford N-(3-chlorophenyl)-3-tetrahydrofuran-2-yl-

1,4,6,7-tetrahydropyrazolo [4,3 -c] pyri di n e-5 -carbox amide (31.66 mg, 91.29 umol, 33.48% yield, 100% purity) as white solid. 1H NMR (400 MHz, METHANOL-d4) δ 7.51 (t, J=1.95 Hz, 1H), 7.23 (s, 2H), 6.97-7.04 (m, lH), 4.92-4.96 (m, 1H), 4.58 (s, 2H), 3.99-4.08 (m, 1H), 3.73-3.92 (m, 3H), 2.74-2.87 (m, 2H), 2.23-2.37 (m, 1H), 1.95-2.13 (m, 3H). LCMS: 347

[M i l ] .

Example 37: Preparation of Compounds 927, 928, 929, 930, 93 J, 932, 933, and 934

927, 928, 929, 930, 931 , 932, 933,

934 (R&S)

Step 1 : Preparation of Compound 2

To a solution of methyl cyclopentanecarboxylate (10.00 g, 78.02 mmol, 1.00 eq) in MeOH (100.00 mL) was added a solution of NaOH (6.24 g, 156.04 mmol, 2.00 eq) in H₂0 (40.00 mL), the reaction mixture was stirred at 25 °C for 2 hours. TLC indicated starting material was consumed completely, and one major new spot with larger polarity was detected. The pH of the reaction mixture was adjusted to around 6 by adding diluted hydrochloride acid (6 N, 40 mL), then extracted with EA (200 mL*4), the organic phase was dried over anhydrous Na^SO , filtered and concentrated in vacuum to afford

cycl open taneca rbo y 1 i c acid (8.80 g, 77.10 mmol, 98.82% yield) as yellow oil. The crude product was used in the next step directly without further purification. Ή NMR (400 MHz, DMSO-d6) δ ppm 1 1.90 (br. s., 1 H) 2.56 - 2.67 (m, 1 H) 1.73 - 1.82 (m, 2 H) 1.46 - 1.71 (m, 6 H).

Step 2: Preparation of Compound 3

To a solution of cyclopentanecarboxylic acid (8.80 g, 77.10 mmol , 8.38 ml., 1.00 eq) in DCM (60.00 niL) was added DMF (563.52 nig, 7.7 1 mmol, 593.18 uL, 0.10 eq), followed by (COCl)₂ (19.57 g, 154.20 mmol, 13.50 ml.., 2.00 eq) dropwise at 0 °C, the reaction mixture was warmed to 25 °C and stirred at 25 C for 2 hours. TLC indicated starting material was consumed completely (treating with MeOH and monitoring the ester).

Removed the solvent on a rotary evaporator to afford cyclopentanecarbonyl chloride (9.80 g, 73.91 mmol, 95.87% yield) as yellow oil . The crude product was used in the next step directly without purification.

Step 3 : Preparation of Compound 4

To a mixture of N-methoxymethanamine (7.21 g, 73.91 mmol, 1.00 eq, HQ) in DCM (100.00 niL) was added TEA (22.44 g, 221.73 mmol, 30.74 niL, 3.00 eq) at 0 °C, followed by cyclopentanecarbonyl chloride (9.80 g, 73.91 mmol, 8.99 ml., 1 .00 eq), the reaction mixture was stirred at 25 °C for 2 hou s. One main peak with desired MS was detected by LCMS. The mixture was extracted with DCM (500 mL*2) and water (400 mL*2), the organic phase was dried with anhydrous Na₂S0₄, filtered and concentrated in vacuum. The residue was purified by silica gel chromatography to afford N -m ethox y-N-m eth y 1 - cyclopentanecarboxamide (10.80 g, 68.70 mmol, 92.95% yield) as yellow oil. ¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 3.67 (s, 3 H) 3. 16 (s, 3 H) 2.98 - 3.13 (m, 1 H) 1.67 - 1.87 (m, 6 H) 1.47 - 1 .62(m, 2 H).

Step 4: Preparation of Compound 5

Cooled the three-necked round bottom flask to -78 °C, bromo( vinyl )magnesium (1 M, 25.44 niL, 2.00 eq) was added to a solution of N-methoxy- -methyl - cyclopentane carboxamide (2.00 g, 12.72 mmol, 1.00 eq) in THF (25.00 ml,) dropwise under N₂, the reaction mixture was stirred at -78 °C for one hour, then warmed to 25 °C and stirred at 25 °C for another 30 minutes. TLC indicated starting material was consumed completely, and one major new spot with lower polarity was detected. The reaction mixture was added to diluted hydrochloride acid (2N, 100 niL) dropwise and then extracted with EA (150 mL*3 ), the combined organic phase was dried over anhydrous Na₂S0₄, filtered and concentrated in vacuum to afford 1 -cyclopentylprop-2-en- 1 -one (1.30 g, 10.47 mmol, 82.30% yield) as yellow oil. The crude product was used in the next step directly without purification. ¹ I I

NMR (400 MHz, CHLOROFORM-d) d ppm 6.33 - 6.46 (m, 1 H) 6.19 - 6.27 (m, 1 H) 5.73 - 5.79 (m, 1 H) 3.08 - 3.18 (m, 1 II) 1.74 - 1.84 (m, 4 H) 1.56 - 1 .69 (m, 4 H).

Preparation of Compound (S)-7

To a mixture of ethyl (3 S)-3-aminobutanoate (1.76 g, 10.47 mmol, 1.00 eq, HCl) in THF (10.00 rnL) was added TEA ( 3. 1 8 g, 31.41 mmol, 4.36 mL, 3.00 eq), followed by a solution of I -cyclopentylprop-2-en- 1 -one (1.30 g, 10.47 mmol, 1.00 eq) in THF (10.00 m l.), the reaction mixture was stirred at 25 C for 16 hours. TLC showed the reaction was completed. To the mixture was added (Boc)₂0 (2.29 g, 10.47 mmol, 2.41 ml., 1.00 eq) , the mixture was stirred at 25 °C for 2 hours, 60% of desired compound was detected by LCMS. The reaction mixture was extracted with EA (100 ml.) and diluted hydrochloride acid (IN, 80 m l.* 2), the organic phase was dried with anhydrous Na₂S0₄, filtered and concentrated in vacuum. The residue was purified by silica gel chromatography to afford ethyl (3 S)-3-[tert- butoxycarbonyl-(3- cycl opentyl -3 -o o-propyl )am i no Jbutanoate (1.90 g, 5.35 mmol, 51.05% yield) as light yellow oil. Ή NMR (400 MHz, CHLOROFORM-d) δ ppm 4. 10 - 4.49 (m, 1 H) 4.02 - 4.09 (m, 2 H) 3.20 - 3.45 (m, 2 H) 2.60 - 2.86 (m, 3 H) 2.32 - 2.57 (m, 2 IT) 1.49 - 1.78 (m, 8 H) 1.40 (s, 9 H) 1.14 - 1.2 1 (m, 6 H).

Preparation of Compound (R)-7

To a solution of ethyl ( 3 R )-3 -ami nobutanoate ( 1 .62 g, 9.66 mmol, 1.00 eq, HCl) in THF (10.00 mL) was added TEA (2.93 g, 28.99 mmol, 4.02 ml,, 3.00 eq) , followed by a solution of I -cyclopentylprop-2-en- 1 -one (1.20 g, 9.66 mmol, 1.00 eq) in THF (10.00 mL), the reaction mixture was stirred at 25 °C for 16 hours. TLC showed the reaction was completed. To the mixture was (Boc)₂0 (2.11 g, 9.66 mmol, 2.22 mL, 1.00 eq), the mixture was stirred at 25 C for 2 hours, 65% of desired compound was detected by LCMS. The reaction mixture was dissolved with EA (100 mL) and washed with diluted HCl (IN, 80 mL* 2), the organic phase was dried with anhydrous ^"Na₂S0₄, filtered and concentrated in vacuum. The residue was purified by silica gel chromatography to afford ethyl (3R)-3-[tert- butoxycarbonyl -( 3 -cycl open ty 1 -3 -ox o-propy 1 )am i n o] bu tanoate (2.10 g, 5.91 mmol, 61 .16% yield) as yellow oil.

Preparation of Compound (S)-8

To a solution of ethyl ( 3 S )-3 -[ tert-butoxycarbon \ -( 3 -cycl openty 1 -3 - oxo-propyl ) amino]butanoate (1.70 g, 4.78 mmol, 1.00 eq) in THF (20.00 mL) was added t- BuOK (1.18 g, 10.52 mmol, 2.20 eq) at -40 °C under ₂, the reaction mixture was warmed to 0 C and stirred at 0 °C for one hour. TLC indicated starting material was consumed completely, and one major new spot with lower polarity was detected. The reaction was quenched with aqueous solution of NH₄C1 (70 mL) and then extracted with EA (100 mL*3), the combined organic phase was dried over anhydrous Na₂S04, filtered and concentrated in vacuum to afford tert-butyl (2S)-5-(cyclopentanecarbonyl )-2- methyl-4-oxo-piperidine- 1 - carbox late ( 1 .38 g, crude) as yellow oil. The crude product was used in the next step directly without purification.

Preparation of Compound (R)-8

(R)-7 (R)-

To a solution of ethyl ( 3 R )-3 -[tert-butox ycarbonyl -(3 -cycl openty 1 -3 - oxo-propyl) amino]butanoate (1.90 g, 5.35 mmol, 1.00 eq) in THF (20.00 mL) was added t- BuOK ( 1.32 g, 11.77 mmol, 2.20 eq) at -40 °C under N₂, the reaction mixture was warmed to 0 °C and stirred at 0 °C for one hour. TLC indicated starting material was consumed completely, and one major new spot with lower polarity was detected. The reaction was quenched with aqueous solution of NH₄CI (80 mL) and then extracted with EA (100 mL*3), the combined organic phase was dried over anhydrous Na₂S0₄, filtered and concentrated in vacuum to afford tert-butyl (2R)-5-(cyclopentanecarbonyl )-2-methyl-4-oxo-piperidine- 1 - carboxylate (1.53 g, caide) as yellow oil. The crude product was used in the next step directly without purification.

Preparation of Compound (S)-9

To a solution of tert-butyl (2S)-5-(cyclopentanecarbonvl )-2-methyl-4-oxo- piperidine- 1 -carboxylate (1.38 g, 4.46 mmol, 1.00 eq) in EtOH (20.00 mL) was added NH₂ H₂ H₂0 (525.36 mg, 8.92 mmol, 510.06 uL, 85% purity, 2.00 eq) , the reaction mixture was warmed to 50 °C and stirred at 50 °C for one hour. TLC indicated starting material was consumed completely, and one major new spot with larger polarity was detected. The mixture was extracted with EA (180 mL*2) and water (80 niL*3), the organic phase was dried with anhydrous Na₂S0₄, filtered and concentrated in vacuum. The residue was purified by silica gel chromatography to afford tert-butyl (6S)-3-cyclopentyl-6-m ethyl- 1,4,6,7- tetrahydropyrazolo[4,3-c] pyridine-5-carboxylate (1.30 g, 4.21 mmol, 94.48% yield, 99% purity) as yellow solid.

Preparation of Compound (R)-9

To a solution of tert-butyl ( 2 R )- 5 -( cy cl opentan ecarbony 1 )-2-m ethyl -4-ox o- pi eridine- I -carboxylate (1.53 g, 4.95 mmol, 1.00 eq) in EtOH (20.00 mL) was added NH₂NH₂ H₂0 (582.47 mg, 9.90 mmol, 565.50 uL, 85% purity, 2.00 eq) , the reaction mixture was warmed to 50 C and stirred at 50 °C for one hour. TLC indicated starting material was consumed completely, and one major new spot with larger polarity was detected. The mixture was extracted with EA (200 mL*2) and water (100 mL*3), the organic phase was dried with anhydrous Na₂S0₄, filtered and concentrated in vacuum. The residue was purified by silica gel chromatography to afford tert-butyl (6R)-3-cyclopentyl-6-methyl-l,4,6,7- tetrahydropyrazol o[4, 3 -c] pyridine-5-carboxylate (1.40 g, 4.54 nimol, 91.68% yield, 99% purity) as yellow solid.

Preparation of Compound (S)-10

To a solution of tert-butyl (6S)-3-cyclopentyl-6-methyl- 1 ,4,6,7- tetrah y dropy razol o [4,3 -c] pyri di ne-5-carboxyl ate (1.40 g, 4.58 mmol, 1.00 eq) in dioxane (10.00 raL) was added HCl/dioxane (4 M, 20.00 m L, 17.47 eq) , the reaction mixture was stirred at 25 °C for 2 hours. TLC indicated starting material was consumed completely, and one major new spot with larger polarity was detected. Removed the solvent on a rotary evaporator to afford (6S)-3-cyclopentyl-6-methyl-4,5,6,7-tetrahydro-lH- pyrazolo[4,3- c] pyri dine (1.10 g, 4.55 mmol, 99.34% yield, HC1 ) as white solid. The product was used in the next step directly without purification. Ή MR (400 MHz, METHANOL-d4) δ ppm 4.29 - 4.50 (m, 2 H) 3.79 (td, J=10.57, 5.46 Hz, 1 H) 3.17 - 3.29 (m, 2 H) 2.87 - 3.01 (m, 1 H) 2.12 - 2.27 (m, 2 H) 1.66 - 1.90 (m, 6 H) 1.53 - 1.59 (m, 3 H).

Preparation of Compound (R)-10

₍R)-9 (R)-10

To a solution of tert-butyl (6R)-3-cyclopentyl-6-methyl- 1 ,4,6,7

tetrahy dropyrazol o [4,3-c]pyridme-5-carboxylate (1.50 g, 4.91 mmol, 1.00 eq) in dioxane (10.00 niL) was added HCl/dioxane (4 M, 20.00 mL, 16.29 eq) , the reaction mixture was stirred at 20 °C for one hour. TLC showed the reaction was completed. Evaporate the solution on a water bath under reduced pressure using a rotary evaporator to afford (6R)-3- cyclopentyl-6~methyl~4,5,6,7-tetrahydro-lH-pyrazolo[4,3-c]pyridine (1.20 g, crude, HC1) as white solid. The product was used in the next step directly without purification. General procedure for preparation of Compounds 927 through 934

(S) 10 ⁰¹ (R) 10 327 through 934

(S and )

A solution of compound 10 (40.00 mg, 157.62 umol, 1.00 eq, HC1), phenyl carbamate 11 (1.00 eq) and TEA (73.00 mg, 721.42 umol, 100.00 uL, 4.58 eq) in DCM (2.00 ml,) and MeOH (0. 1 mL) was stirred at 25 °C for 1 2 hours. LCMS showed desired product was detected. The solvent was removed. The residue was purified by prep-HPLC(FA) to afford the desired product.

Example 38: Preparation of Compounds 964, 965, 966, 967, 968, 969, 970, and 971 (D1&D2)

6 7 8

964, 965, 966, 967, 968, 969, 970, and 0971

(D1 and Da)

Step 1 : Preparation of Compound 2

To a solution of tetrahydrofuran-2-carboxylic acid (8.00 g, 68.90 mmol, 6.6 1 mL, 1.00 eq) in DCM (80.00 mL) was added DMF (503.59 mg, 6.89 mmol, 530.10 uL, 0.10 eq), followed by (COCl )₂ (17.49 g, 137.80 mmol, 12.06 mL, 2.00 eq) dropwise at 0 °C, the reaction mixture was stirred at 0 C for 2 hours. The solvent was removed on a rotary evaporator to afford tetrahydrofuran-2-carbonyl chloride (9.00 g, crude) as yellow oil. The product was used in the next step directly without purification.

Step 2 : Preparation of Compound 3

To a mixture of N-methoxymethanamine (9.79 g, 100.32 mmol, 1.50 eq, HCl ) in DCM (100.00 mL) was added TEA (20.30 g, 200.64 mmol, 27.81 mL, 3.00 eq), followed by tetrahydrofuran-2-carbonyl chloride (9.00 g, 66.88 mmol, 1.00 eq), the reaction mixture was stirred at 20 °C for 2 hours. One main peak with desired MS was detected by LCMS. The mixture was diluted with DCM (300 mL) and washed with diluted HCl (IN, 100 mL*2), the organic phase was dried with anhydrous Na₂S0₄, filtered and concentrated in vacuum. The residue was purified by silica gel chromatography to afford N-methoxy-N-methyl- tetrahydrofuran-2- carboxamide (8.80 g, 55.28 mmol, 82.66% yield) as yellow oil. Ή NMR (400 MHz, CHLOROFORM-d) d ppm 4.71 (br. s., 1 H) 3.80 - 4.00 (m, 2 H) 3.63 - 3.67 (m, H) 3.13 (s, 3 H) 2.06 -2.19 (m, 1 H) 1.79 - 1.99 (m, 3 H). Step 3 : Preparation of Compound 4

Cooled the three-necked round bottom flask to -78 °C, brom o( vi n y 1 )m agn esi um (1 M, 50.26 mL, 2.00 eq) was added to a solution of - m et h ox y- N - m et h y 1 - tetrahydrofuran-2- carboxamide (4.00 g, 25. 13 mmol, 1.00 eq) in THF (40.00 mL) dropwise under N₂, the reaction mixture as stirred at -78 °C for one hour, then warmed to 1 5 °C and stirred at 1 5 °C for another 30 minutes. TLC indicated starting material was consumed completely, and one major new spot w ith lower polarity was detected. The reaction mixture was added to diluted HQ (2N, 200 mL) dropwise and then extracted with EA (300 mL*3 ), the combined organic phase was dried over anhydrous a^SO ), filtered and concentrated in vacuum to afford I - tetralrydrofuran-2-ylprop-2-en- 1 -one (2.10 g, crude) as yellow oil. The product was used in the next step directly without purification.

Step 4: Preparation of Compound 6

To a solution of ethyl (3 S)-3-aminobutanoate (2,79 g, 16.65 mmol, 1.00 eq, HQ) in THF (20.00 mL) was added TEA (5.05 g, 49.95 mmol, 6.92 mL, 3.00 eq), followed by a solution of I -tetrahydrofuran-2-ylprop-2-en- 1 -one (2.10 g, 16.65 mmol, 1.00 eq) in THF

(20.00 mL), the reaction mixture was stirred at 15 °C for 4 hours. TLC showed the reaction was completed, (Boc)₂0 (3.63 g, 16.65 mmol, 3.83 mL, 1.00 eq) was added, the mixture was stirred at 15 °C for another 12 hours. TLC indicated many new spots formed. The reaction mixture was dissolved with EA (300 mL ) and washed with diluted HQ (IN, 100 mL*2), the organic phase was dried with anhydrous

filtered and concentrated in vacuum. The residue was purified by silica gel chromatography to afford ethyl (3 S)-3-ftert-butoxycarbonyl -(3-oxo-3-tetrahydrofuran-2-yl-propyl)amino]butanoate (3.10 g, 7.81 mmol, 46.88% yield, 90% purity) as yellow oil .

Step 5 : Preparation of Compound 7

To a solution of ethyl (3 S)-3-[tert-butoxycarbonyl-(3-oxo-3-tetrahydrofuran

-2-yl -propyl )amino]butanoate (1.40 g, 3.92 mmol, 1.00 eq) in THF (15.00 mL) was added t- BuOK (879.00 mg, 7.83 mmol, 2.00 eq) at -40 °C under N₂, the reaction mixture was stirred at -10 °C for one hour, then warmed to 10 °C and stirred at 10 °C for another one hour. TLC indicated starting material was consumed completely, and three new spots formed. The reaction mixture was quenched with aqueous solution of N Hi CI (70 mL) and then extracted with EA (150 m L*3 ), the combined organic phase was dried over anhydrous Na₂SC«4, filtered and concentrated in vacuum to afford tert-butyl (2S)-2-methyl-4-oxo-5- ( tetrahydrofuran-2- carbonyl Jpiperidine- 1 -carboxylate (750.00 mg, crude) as yellow oil. The product was used in the next step directly without purification . Step 6: Preparation of Compound 8

To a solution of tert-butyl (2S)-2-methyl-4-oxo-5-(tetrahydrofuran- 2-carbonyl ) pi peri dine- 1 -carboxylate (750.00 mg, 2.4 1 mmol, 1.00 eg) in EtOH (10.00 niL ) was added ΝΗ₂ΝΗ₂Ή₂0 (283.72 mg, 4.82 mmol, 275.46 uL, 85% purity, 2,00 eg). The reaction mixture was stirred at 10 °C for 16 hours. Several new peaks were shown on LCM S and about 50% of desired compound was detected. The reaction mixture was diluted with EA (150 mL) and washed with diluted HCl (I N, 80 mL*2), the organic phase was dried with anhydrous Na. SO.», filtered and concentrated in vacuum. The residue combined with another two batch was purified by prep-HPLC(FA) to give desired compound (800 mg, purity 90%) as yellow oil, which was further separated by SFC to get peak one (D l, 0.36 g) and peak two (D2, 0.23 g).

Compound 8 (Dl) (Peak one) Ή NMR (400 MHz, CHLOROFORM-d ) δ ppm 4.98 (t, J=6.90 Hz, I H) 4.83 (d, J= 14.05 Hz, 2 H) 3.97 - 4.05 (m, 2 II) 3.86 -3.93 (m, 1 H) 2.95 (dd, J= 1 5.69, 5.90 Hz, 1 H) 2.54 (d, J= 1 5.69 Hz, 1 H) 2.24 - 2.34 (m, 1 H) 1.95 - 2.07 (m, 3 H) 1.49 (s, 9 H) 1.13 (d, J=6.90 Hz, 3 H).

Compound 8 (D2) (Peak two) Ή NMR (400 MHz, CHLOROFORM-d) δ ppm 4.9 1 - 5.00 (m, 1 H) 4.84 (d, J=14.68 Hz, 2 H) 3.95 - 4.05 (m, 2 H) 3.86 - 3.94 (m, 1 H) 2.95 (dd, .1=15.56, 5.77 Hz, 1 H) 2.55 (d, J=15.69 Hz, 1 H) 2,25 - 2.35 (m, 1 H) 1.99 - 2.08 (m, 3 H) 1.49 (s, 9 H) 1.13 (d, J=6.90 Hz, 3 H).

SFC separation condition:

Instrument: Waters Q 80 preparative

SFCcolumn: ChiralPak AD-H, 250x30mm I D. , particle size lOum

Mobile Phase : Phase A for C02

Phase B for Ethanol (0. l 'OAmmonia)

Isocratic:25% Phase B

Flow rate:55g /min

Column Temp: room temperature

Back pressure: lOObar

UV:220nm

Cycle Time:3.3min. Preparation of Compound 9 (D l )

S I 9 D1

To a solution of tert-butyl (6S)-6-methyl-3-tetrahydrofuran-2-yi- 1 , 4,6,7- tetrahydropyrazolo[4,3-c]pyridine-5-carboxylate (360.00 nig, 1.17 mmol, 1.00 eq) in dioxane (2.00 mL) was added HCl/dioxane (4 M, 10.00 mL, 34.19 eq), the reaction mixture was stirred at 10 °C for 2 hours. TLC showed the reaction was completed. Evaporated the solution on a water bath under reduced pressure using a rotary evaporator to afford (6S)-6- methyl-3-tetrahydrofuran-2-yl -4,5,6,7- tetrahydro- 1 H-pyrazolo[4,3-c]pyridine (330.00 mg, cmde, 2HC1) as yellow solid. The product product was used in the next step directly without purification.

Preparation of Compound 9 (D2 )

8 I 9 D2

To a solution of tert-butyl (6S)-6-methyl-3-tetrahydrofuran-2-yl-l,4,6,7- tetrahydropyrazolo[4,3-c]pyridine-5-carboxylate (230.00 mg, 748.24 umol, 1.00 eq) in dioxane (2.00 mL) was added HCl/dioxane (4 M, 8.00 mL, 42.77 eq), the reaction mixture was stirred at 10 °C for 2 hours. TLC showed the reaction was completed. Evaporated the solution on a water bath under reduced pressure using a rotary evaporator to afford ( 6S)-6- m ethyl - -tetrahydrofuran -2-v -4, 5,6, 7- tetrahydro- lH-pyrazolo[4,3-c]pyri dine (170.00 mg, crude, 2HC1) as yellow solid. The product product was used in the next step directly without puri ication. General Preparation of Compounds 964 through 971 (D1&D2)

9_D1 ^or 9_D2 Compounds 964 through 0971

(D1 and D2)

A mixture of compound 9 (40 mg, 142.76 umol, 1.00 eq, 2HC1), phenyl carbamate 10 (142.76 umol, 1.00 eq) and TEA (146.00 mg, 1.44 mniol, 200.00 uL, 10.1 1 eq) in DCM (2.00 mL) was stirred at 25 °C for 16 hours. LCMS showed desired product was detected. The solvent was removed. The residue was purified by prep-HPLC(FA) to afford the desired product.

Example 39: HBV Assembly Assay

The interference of compounds from this invention with HBV capsid assembly could be measured using an in vitro assembly assay based on fluorescence quenching, which was developed according to a method described by Zlotnick and coworkers (Nature

Biotechnology 2006, 24:358). In a typical assay, a mutant HBV C I 50 protein (amino acids 1-150, C49A, C61A, C 107A, 150C) is cloned into a T7 RNA-polymerase based expression vector, expressed in E.coli and purified to homogeneity as a dimer. The purified HBV core protein is desalted and labeled with BODIPY-FL Dye.

In a non-limiting embodiment, the assembly assay is conducted in 96- well plate format. The assembly reactions are carried out in 50 mM Hepes buffer, pH 7.5 and 150 mM NaCl. The compounds are pre-incubated with the HBV CA protein for 15 min, and the assembly reactions are initiated by addition of NaCl. The reaction is allowed to continue for 1 hour at room temperature. The changes in fluorescence between DMSO treated and compound treated samples are recorded and analyzed for assembly modulation. Example 40: HBV Replication Inhibition Assay

HBV replication inhibition by the compounds of this invention could be determined in cells infected or transfected with HBV, or cells with stably integrated HBV, such as

HepG2.2. 1 5 cells ( Sells et al . 1987), In thi s example, HepG2.2. 1 5 cells were maintained in cell culture medium containing 10% fetal bovine serum (FBS), Geneticin, L-glutamine, penicillin and streptomycin. HepG2.2. 1 5 cells could be seeded in 96-well plates at a density of 40,000 cells/well and be treated with serially diluted compounds at a final DM SO concentration of 0.5% either alone or in combination by adding drugs in a checker box format. Cells were incubated with compounds for three days, after which medium was removed and fresh medium containing compounds was added to cells and incubated for another three days. At day 6, supernatant was removed and treated with DNase at 37°C for 60 minutes, followed by enzyme inactivation at 75 °C for 1 5 minutes. Encapsi dated HBV DNA was released from the virions and covalently linked HBV polymerase by incubating in lysis buffer (Affymetrix QSOO I O) containing 2.5 ng proteinase K at 50°C for 40 minutes. HBV DNA was denatured by addition of 0.2 M NaOH and detected using a branched DNA (BDNA) QuantiGene assay kit according to manufacturer recommendation (Affymetrix). HBV DNA levels could also be quantified using qPCR, based on amplification of encapsidated HBV DNA extraction with QuickExtraction Solution (Epicentre

Biotechnologies) and am pi ill cation of HBV DNA using HBV specific PGR probes that can hybridize to HBV DNA and a fluorescentlv labeled probe for quantitation. In addition, cell viabi lity of HepG2.2. 1 5 cel ls incubated with test compounds alone or in combination was determined by using CellTitre-Glo reagent according to the manufacturer protocol

(P romega). The mean background signal from wells containing only culture medium was subtracted from all other samples, and percent inhibition at each compound concentration was calculated by normalizing to signals from HepG2 2. 1 5 cells treated w ith 0.5% DM SO using equation E l .

E l : % inhibition = (DMSOave - Xi)/DMSOave x 100%

where DMSOave is the mean signal calculated from the well s that were treated w ith DM SO control (0% inhibition control ) and Xi is the signal measured from the individual wells. EC 50 values, effective concentrations that achieved 50% inhibitory effect were determined by non-linear fitting using Graphpad Prism software ( San Diego, CA) and equation E2

E2: Y = Ymin + (Ymax - Ymin) / (l+lQ(LogEC50-X) x Hi ll Slope) where Y represents percent inhibition values and X represents the logarithm of compound concentrations.

Selected compounds of the invention were assayed in the HBV replication assay (BDN A assay), as described above and a representative group of these active compounds is shown in Table 3. Table 3 shows EC₅₀ values obtained by the BDNA assay for a group of select compounds. In Table 3, "A" represents 0.01 < EC₅₀ < 0.10; "B" represents 0J 0<EC₅₀ < 0.50; and "C" represents 0.50 <EC₅₀ < 1.0; ('+' indicates >50% activity at 10 μΜ).

Activ ity in BDNA-assay (EC50)

970 Dl B

971 Dl A 971 D2 B

238 + 260 +

241 + 388 +

604 B 669 B

642 A 782 A

644 B 783 A

693 A 784 A

694 A 785 A

696 B 786 A

700 B 787 A

660 B 788 A

661 B 789 A

662 A 790 A

663 A 791 A

664 B 792 B

665 A 760 S B

440 B 760 R B

742 B 762 E1/E2 A

744 A 763 E1/E2 A

757 E1/E2 A 764 E1/E2 A

758 E1/E2 A 765 E1 /E2 A

759 E1/E2 B 667 A

666 A 668 A

The disclosures of each and ever)' patent, patent application, and publication cited herein are hereby incorporated herein by reference in their entirety.

While the invention has been disclosed with reference to specific embodiments, it is apparent that other embodiments and variations of this invention may be devised by others skilled in the art without departing from the true spirit and scope of the invention. The appended claims are intended to be construed to include all such embodiments and equivalent variations.

Claims

1 , A compound having the structure of Formula III:

R⁴

III,

or a pharmaceutically acceptable salt thereof, wherein

Y is -C(0>- or -SO₂-;

R¹ is C -C^'x-cycloalkyl, CV Cx-heterocy cl yl , -OH, Ci-C₆-alkyl, halo, and C₂-C₈- alkenyl, wherein alkyl, cycloalkyl, heterocyclyl, and alkenyl are optionally substituted with 1, 2, 3, or 4 groups each independently selected from OH, halo, CVCValkyl, Cj-Ce-haioalkyl, -O-Ci-Ce-alkyl, and Ci-C₆-alkyl-OH;

R is, at each occurrence, independently selected from H, -OH, halo, Ci-C₆-alkyl, C | - C₆-haloalkyl, -0-Ci-C₆-alkyl, and Ci-C₆-alkyi-OH;

\V is selected from H, -OH, halo, Ci-Ce-alkyl, i-CVhaloalkyl, -O-Ci-Ce-alkyl, and Ci-Ce-alkyl-OH;

R⁴ is selected from (CR^xR'^,)_p-Ci-C.»-heteroaryl and (CR⁸R⁹)_p-C₆-Ci₂-aryl, wherein heteroaryl and aryl are optionally substituted with 1, 2, or 3 groups, each independently selected from -OH, halo, CN, Ci-Ce-alkyl, Ci-Ce-haloalkyl, -O-Ci-Ce-alkyl, and Ci-Ce- alkyl-OH.

R is selected from H, C |-Ci,-alkyl, and CVCValkyl-OH,

R⁸ is, at each occurrence, independently selected from H, -OH, halo, Ci-C₆-alkyl, C | - CVha!oalkyl, -O-Ci-Ce-alkyl, and Ci-C„-alkyl-OH;

R⁹ is, at each occurrence, independently selected from H and Ci-Ce-alkyf; and p is O, 1, 2, 3, or 4.

2. The compound of claim 1, wherein Y is -C(O)-.

3. The compound of claim 1 or 2, wherein R¹ is Cs-Cg-cycloalkyl or C₂-C₈-heterocyclyi, wherein cycloalkyl and heterocvclyl are optionally substituted with 1 or 2 groups each independently selected from OH, halo, C i-CValkyl, d-CVhaloalkyl, -Q-Ci-Ce-alkyl, and C-CValkyl-OH.

4. The compound of any one of claims 1 -3, wherein R¹ is (VG,-cycloalkyl or (VCV heterocyclyl, wherein cycloalkyl and heterocvclyl are optional ly substituted with 1 or 2 groups each independently selected from OH, halo, G-CV-alkyl, Ci-Ce-haloalkyl, -O-Ci-C alkyl, and C^' i-CValkyl-OH.

5. The compound of any one of claims 1 -4, wherein each R² is independently selected from H or Ci-C4-alkyl and R³ is H.

6. The compound of any one of claims 1 -5, wherein R⁴ is is Ci-Cj-heteroaryl or 0,-aryl wherein heteroaryl and aryl are optionally substituted with 1 , 2, or 3 groups, each independently selected from -OH, halo, CN, and C CValky! .

The compound of any one of claim 1-7, wherein R is H. The compound of any one of claims 1-8, selected from

155

656

157

159

10. A compound of Formula I

I,

or a pharmaceutically acceptable salt thereof,

wherein

W¹ and W are each independently selected from N, R^a, and CR ¹, wherein one of W and W is NR^:i;

X is N or CR^b;

Y is selected from a bond, -C(O)-, and -S0₂-;

Z is selected from -(CR⁵R⁶)_m-, -(CR⁵R⁶)_mQ-, -(CR⁵R⁶)_mCR⁵==CR⁵-, -(CR⁵R⁶)_m-C₃- (Vcycloalkylene , and (CR R" )„,- R ; R¹ is selected from CVCVcycloalkyl, CVCVheterocyclyl, OR^c, CVCValkyl, halo, and CVCValkenyl, wherein alkyl, cycloalkyl, heterocyclyl, and alkenvl are optionally substituted with 1, 2, 3, or 4 groups each independently selected from OH, halo, CVCV al kyl , CVCVhaloal kyl , -0-CVCValkyl , and

R² is, at each occurrence, independently selected from H, -OH, halo, CVCValkyl, CV

C₆-haloalkyl, -0-Ci-C₆-alkyl, and Ci-C₆-alkyl-OH;

R³ is, at each occurrence, independently selected from H, -OH, halo, CVCValkyl, CV Ce-haloalkyl, -O-CVCValky! , and CVCValkyl-OH,

R⁴ is selected from C ,-C₍,-alkyl, (CR⁸R⁹)_p-C₃-C₈-cycloalkyl, (CR⁸R⁹)_P-C₂-C₈- heterocyclyl, (CR⁸R⁹)_p-C₆-Ci₂-aryl, and ( CR^XR⁹ )_P-C i -CVheteroaryl , wherein alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with 1, 2, 3, or 4 groups, each independently selected from OH, halo, CN, CVCValkyl, CVCVhaloalkyl, O- CrCe-alkyl, C(0)N(R^f)₂, C(0)OR^f, -QCH₂C(Q)OR^f, -SQ₂R^f, and Ci-C₆-alkyl-OH;

R⁵ is, at each occurrence, independently selected from H, -OH, halo, CVCValkyl, CV CVha!oalkyl, -0-Ci-C₆-alkyl, and G-CValkyl-OH;

alternatively, R⁴ and R are optional ly joined to form a heterocyclic ring;

R⁶ is, at each occurrence, independently selected from H, -OH, halo, CVCValkyl, CV CVhaloalkyl , O-d-CV.-alkyl , and d-Ce-alkyl-OH;

R is selected from H, CVCValkyl, and CVCValkyl-OH;

R⁸ is, at each occurrence, independently selected from H, OH, halo, Ci-Ce-alkyl, CV

CVhaloalkyl, 0-C | -CValkyl, and CVCValkyl-OH;

R⁹ is, at each occurrence, independently selected from H, -OH, halo, CVCValkyl, CV Ce-haloalkyl, -0-Ci-C₆-alkyl, and Ci-C₆-alkyl-OH;

R^a is selected from H, CVCValkyl, and CVCValkyl -OH;

R^b is selected from H and CVCValkyl;

R^c is selected from H, CVCValkyl, CVCValkyl -OH, CVCVcycloa!kyl, C₂-C₈- heterocyclyl, C₆-Ci₂-aryl, and CVCVheteroaryl;

R^f is, at each occurrence, independently selected from H and CVCValkyl;

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

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

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

1 1. The compound of claim 10, wherein W ¹ is NR^a and W is or CR^d.

12. The compound of claim 10, wherein W ' is N or CR'¹ and W is NR^a.

13. The compound of any one of claims 10- 12, wherein X is N. 14. The compound of any one of claims 10-13, wherein Y is -C(0)- or -S0₂-

15. The compound of any one of claims 10- 14, wherein Z is-(CR⁵R⁶)_m-,

-(CR⁵R⁶)_mO- or -(CR⁵R⁶)_m- R⁷-. 16. The compound of any one of claims 10-15, wherein

m is 0 or 1;

R⁵ is H, OH, or Ci-C₆-alkyl;

R⁶ is H or Ci-C(,-alkyl; and

R is H or Ci-CValkyl.

17. The compound of any one of claims 10-16, wherein R¹ is C₃-C₈-cycloalkyl, C₂-C₈- heterocyclyl, Ci-C₆-alkyl, or CVCValkenyl, wherein alkyl, cycloalkyl, heterocyclyl, and alkenyl are optionally substituted with 1, 2, 3, or 4 groups each independently selected from - OH, halo, Ci-CValkyl, Ci-C₆-haloalkyl, -0-Ci-C₆-alkyl, and Ci-C₆-aikyl-OH.

18. The compound of any one of claims 10-17, wherein each R² is independently selected from H or Ci-C alkyl and R^J is H.

19. The compound of any one of claims 10-18, wherein R⁴ is ( CR^XR ' )_P-C <-CVcycl oal kyl , (CR⁸R⁹)_p-C₂-C₈-heterocyciyl, (CR⁸R⁹)_p-C₆-C₁₂-aryl, or wherein cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with 1, 2, 3, or 4 groups, each independently selected from -OH, halo, CN, CVCValky , G-CVhaloalkyl, -O- Ci-Ce-alkyl, C(0)N(R^f)₂, C(0)OR , -OCH₂C(0)OR^f, -S0₂R^f, and Ci-C₆-alkyl-OH. 20. The compound of any one of claims 10-19, wherein R⁴ is (CR⁸R⁹)_p-C₆-Ci₂-aryl or (C R^XR'* )p-C i -C)-heteroaryl , wherein aryl and heteroaryl are optionally substituted with 1, 2, 3, or 4 groups, each independently selected from -OH, halo, CN, C i-CValkyl, (VG,- haloalkyl, -0-C ,-G,-alkyl. C(0)N(R )₂, C(0)OR^f, -OCH₂C(0)OR^f, -S0₂R^f, and C C₆-alkyl- OH.

21 . The compound of any one of claims 10-20, wherein

p is 0 or 1 ;

R⁸ is H, -OH, or Ci-C₆-alkyl; and

R⁹ is H or Ci-C₆-alkyl .

22. The compound of any one of claims 10-21 , wherein n is 1.

23. The compound of any one of claims 10-22, wherein

X is N;

Y is -C(Q)-;

Z is NR ; and

R i s H or Ci-4-alkyl .

24. The compound of any one of claims 10-23, wherein

X is N;

Y is -C(O)-;

Z is NR⁷;

R is H or Ci-4-alkyl; and

n is 1 .

25. The compound of any one of claims 10-24, having the structure of Fonnul a II:

II,

or a pharmaceutically acceptable salt thereof. 26. The compound of claim 25, wherein Y is -C(O)- or -S0₂-

27. The compound of claim 25 or 26, wherein Z is < CR⁵R'V , -(CR⁵R⁶)_mO- or -

(CR⁵R⁶)_m-NR⁷-.

28. The compound of any one of claims 25-27, wherein

m is 0 or 1 ;

R⁵ is H, -OH, or CVCValkyl;

R" is H or C-CValkyl; and

R is H or CVCValkyl . 29. The compound of any one of claims 25-28, wherein R¹ is CVCVcycloalkyl, C₂-C - heterocyclyl, Ci-CValkyl, or C₂-C₈-alkenyl, wherein alkyl, cycloalkyl, heterocyclyl, and alkenyl are optionally substituted with 1, 2, 3, or 4 groups each independently selected from - OH, halo, C CValkyl, d-CVhaloalkyl, -0-Cj-C₆-alkyl, and Ci-C₆-alkyl-OH. 30. The compound of any one of claims 25-29, wherein each R^" is independently selected from H or CVCValkyl and R³ is H.

31. The compound of any one of claims 25-30, wherein R⁴ is (CR^R ^_p-CVCVcycloalkyl, (CR⁸R⁹)p-C₂-C₈-heterocyclyl, (CR^sR⁹)_p-C₆-Ci₂-aiyl, or < C Il )„-C i -CVheteroary I , wherein cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with 1, 2, 3, or 4 groups, each independently selected from OH, halo, CN, CVCValkyl, CVCVhaloalkyl, O- CrC₆-aiky{, C(0)N(R^f)₂, C(0)OR^f, -OCH₂C(0)OR^f, -S0₂R^f, and Ci-C₆-alkyl-OH.

32. The compound of any one of claims 25-31, wherein R⁴ is (C^'R^XR ')_P-CVC I ₂-aryl, or ( C" R^SR^'' )_p-C i -Crheteroaryl , and wherein aryl and heteroaryl are optionally substituted with 1,

2, 3, or 4 groups, each independently selected from -OH, halo, CN, CVCValkyl, CVCV haloalkyl, -O-CVCValkyl, C(0)N(R^f)₂, C(0)OR^f, -OCH₂C(0)OR^f, -S0₂R^f, and Ci-C₆-alkyl- OH. 33. The compound of any one of claims 25-32, wherein

p is 0 or 1;

R⁸ is independently selected from H, Oi l, or CVC alkyl ; and

R⁹ is independently selected from H or CVCValkyl.

34. The compound of any one of claims 25-33, wherein n is 1.

The compound of any one of claims 25-34, wherein

Y is -C(0)-;

Z is NR⁷; and

R is H or C i - -alkyl .

The compound of any one of claims 25-35, wherein

Y is --C(O) -;

Z is NR⁷;

R is H or C i -i-alkyl; and

n is 1.

37. The compound of claim 10 or 25, wherein the compound is selected from

167

171

38. A pharmaceutical composition comprising a compound of any one of claims 1 -37, a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier.

39. 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 according to any one of claims 1-37.

40. A method of inhibiting or reducing the formation or presence of HBV DNA- containing particles or HBV RN A-containing particles in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a compound according to any one of claims 1-37.

41. The method of claim 39 or 40 further comprising administering to the individual at least one additional therapeutic agent selected from the group consi sting of an HB V polymerase inhibitor, immunomodulatory agents, pegylated interferon, viral entry inhibitor, viral maturation inhibitor, literature-described cap si d assembly modulator, reverse

transcriptase inhibitor, a cyclophilin/TNF inhibitor, a TLR-agonist, an HBV vaccine, and agents of distinct or unknown mechanism, and a combination thereof.

42, The method of claim 41, wherein the therapeutic agent is a reverse transcriptase inhibitor, and is at least one of Zidovudine, Didanosine, Zalcitabine, ddA, Stavudine, Lamivudine, Abacavir, Emtricitabine, Entecavir, Apricitabme, Atevi rapine, ribavirin, acyclovir, famciclovir, val acyclovir, ganciclovir, valganciclovir, Tenofovir, Adefovir, PMPA, cidofovir, Efavirenz, evi rapine, Delavirdine, and Etravirine.

43. The method of claim 41, wherein the therapeutic agent is a TLR agonist, and wherein the TLR agonist is a TLR- 7 agonist selected from the group consisting of SM360320 (9- benzyl-8-hydiOxy-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).

44. The method of claim 41 , wherein the therapeutic agent is an interferon selected from the group consisting of interferon alpha (IFN-a), interferon beta ( IFN-β), interferon lambda (IFN-λ), and interferon gamma ( IFN-γ).

45. The method of cl aim 44, wherein the interferon is i nterferon -al ph a-2a, interferon- alpha-2b, or interferon-al pha-n 1 . 46. The method of claim 45, wherein the interferon-alpha-2a or interferon-alpha-2b is pegylated.

47. The method of any one of claims 39-46, further comprising administering to the individual at least one HBV vaccine, a nucleoside HBV inhibitor, an interferon or any combination thereof.

48. The method of claim 47, wherein the HBV vaccine is selected from the group consisting of RECOMBIVAX HB, ENGERIX-B, ELOVAC B, GENEVAC-B, and SHAN VAC B.