Anilinopyrazole derivatives, compositions and methods thereof

Abstract

The present invention provides novel anilinopyrazole derivatives as cyclin-dependent kinase 2 (CDK2) inhibitors. The present invention further provides pharmaceutical compositions containing such compounds and methods for treating various conditions, diseases and disorders associated with or related to CDK2 activity or associated with abnormal cell growth, such as tumor growth and cancer.

Description

[Technical Field]

[0001] Priority claims and related applications This application claims priority to U.S. Provisional Application Nos. 63 / 352,872, filed June 16, 2022, and 63 / 407,247, filed September 16, 2022, the entire contents of which are incorporated herein by reference for all purposes.

[0002] The present invention relates generally to novel compounds and their therapeutic uses. More specifically, the present invention provides novel anilinopyrazole derivatives as cyclin-dependent kinase 2 (CDK2) inhibitors. The present invention further provides pharmaceutical compositions comprising the compounds and methods for treating various conditions, diseases, and disorders associated with or related to CDK2 activity or associated with abnormal cell growth, such as tumor growth and cancer. [Background technology]

[0003] The cyclin E gene (CCNE) is overexpressed and / or amplified in a wide range of malignant cancers. CCNE amplification is associated with decreased survival in cancer patients (McDonald et al. 2017 Cell 170(3):577-592; Etemadmoghadam et al. 2010 PLoS One 2010;5(11):e15498). CDK2, also known as cell division protein kinase 2, is a member of the cyclin-dependent kinase family of serine / threonine protein kinases. CDK2 is an essential component of the abnormal growth process of cancer cells. Increasing evidence indicates that CDK2 plays an important role in tumorigenesis. Overexpression of CDK2 causes aberrant regulation of the cell cycle, leading to hyperproliferation of cancer cells. Therefore, selective CDK2 inhibition may offer therapeutic benefits for certain cancers. (Tadesse,et al.2019 J Med.Chem.62(9):4233-4251;Chohan,et al.2015 Curr.Med.Chem.22(2):237-63;Meijer,et al.1999 Pharm.& Ther.82(2-3):279-284.)

[0004] Although several small-molecule CDK2 inhibitors have advanced to clinical trials, CDK2 selectivity is highly desirable. Because the active sites of CDK2 and other CDKs, particularly CDK1, are highly similar, identifying selective CDK2 inhibitors has been challenging. Because CDK1 is a cyclin-dependent kinase essential for the cell cycle, inhibiting CDK1 can cause severe side effects. (Wood, et al. 2018 Cell Chem. Biol. 26(1):121-130.e5; Brown, et al. 2015 Nature Comm. 6:6769.)

[0005] There is an urgent need for potent and selective CDK2 inhibitors, particularly compounds useful in the treatment of diseases and conditions associated with overexpression of CCNE and CDK2, such as various types of cancer (e.g., gynecological, breast, and gastric cancers). Summary of the Invention

[0006] The present invention provides novel CDK2 inhibitors that have been shown to exhibit more favorable potency and selectivity profiles than known CDK2 inhibitors. The novel compounds selectively target, bind to, and inhibit the activity of CDK2, resulting in cell cycle arrest, induction of apoptosis, and inhibition of tumor cell proliferation. These compounds are orally bioavailable and have pharmacokinetic profiles suitable for development as orally administered therapeutic agents for the treatment of cancers such as breast cancer, ovarian cancer, gastric cancer, and lung cancer.

[0007] In one aspect, the present invention generally provides a compound having structural formula I: [ka] or a pharmaceutically acceptable form or isotopic derivative thereof, During the ceremony, Ring A is a 4- to 7-membered (e.g., 4-, 5-, 6-, or 7-membered) carbocyclic ring; R 1 and R 2 are each independently selected from the group consisting of H, unsubstituted or substituted C1-C6 alkyl, and C3-C6 unsubstituted or substituted carbocycle, or R 1 and R 2 are joined together with the N atom to which they are attached to form a 4- to 7-membered (e.g., 4-, 5-, 6-, or 7-membered) unsubstituted or substituted heterocycle; Each R 3 are independently selected from the group consisting of halogen, OH, CN, unsubstituted or substituted C1-6 alkyl, unsubstituted or substituted C1-6 alkoxy, NO2, NRR', or two R 3 together with the carbon atom(s) to which they are attached form a 3- to 5-membered (e.g., 3-, 4-, or 5-membered) unsubstituted or substituted carbocyclic ring; R 4 is H, halogen, C1-4 alkyl, CN, NRR' or C(O)NRR'; R 5 teeth, [ka] and During the ceremony, Ring B is a 4- to 7-membered (e.g., 4-, 5-, 6-, or 7-membered) carbocyclic or heterocyclic ring optionally containing a -S(O)-, -C(O)-, -S(O)NR-, -S(O)NRC(O)-, -C(O)NR-, -OC(O)NR-, or -C(O)NRC(O)- group; Y 1 and Y 2 are CR 6 or N and Y 3 and Y 4 are C and CR, respectively. 6 or N, where Y 1 , Y 2 , Y 3 and Y 4 At most one of the following is N, and Y 3 or Y 4 Either C or R 5 is a position at which the compound can be attached to the remainder of the compound, Each R 6 is halogen, OH, CN, unsubstituted or substituted C 1~6 Alkyl, unsubstituted or substituted C 1~4 independently selected from the group consisting of alkoxy and C(O)NRR′; Each R 7 is halogen, OR, CN, unsubstituted or substituted C 1~6 Alkyl and unsubstituted or substituted C 1~4 or two R independently selected from the group consisting of alkoxy 7 together with the carbon atom(s) to which they are attached form a 3- to 6-membered (e.g., 3-, 4-, 5-, or 6-membered) unsubstituted or substituted carbocyclic or heterocyclic ring; R and R' are each independently H, unsubstituted or substituted C 1~6 alkyl, or an unsubstituted or substituted 4- to 6-membered (e.g., 4-, 5-, or 6-membered) carbocycle, or R and R', together with the same N atom, are joined to form an unsubstituted or substituted 4- to 6-membered (e.g., 4-, 5-, or 6-membered) heterocycle; i is 0, 1, 2, 3, 4 or 5; k is 0, 1, 2, 3, 4 or 5.

[0008] In another aspect, the invention generally relates to pharmaceutical compositions comprising a compound disclosed herein and a pharmaceutically acceptable excipient, carrier, or diluent.

[0009] In yet another aspect, the invention generally relates to unit dosage forms comprising the pharmaceutical compositions disclosed herein.

[0010] In yet another aspect, the invention generally relates to methods of treating or ameliorating cancer or a related disease or disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a compound disclosed herein.

[0011] In yet another aspect, the invention generally relates to the use of a compound disclosed herein and a pharmaceutically acceptable excipient, carrier, or diluent in the preparation of a medicament for treating a disease or disorder.

[0012] definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. General principles of organic chemistry and specific functional groups and reactivities are described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 2006.

[0013] As used herein, "at least" a particular value means that value and all values ​​greater than that value.

[0014] The term "comprising," when used to define compositions and methods, is intended to mean that the composition and method include the recited elements but do not exclude other elements. The term "consisting essentially of," when used to define compositions and methods, means that the composition and method include the recited elements and exclude other elements that are essential to the composition and method. For example, "consisting essentially of" refers to the administration of explicitly recited pharmacologically active agents and excludes pharmacologically active agents not explicitly recited. The term "consisting essentially of" does not exclude pharmacologically inactive or inactive agents, such as pharmaceutically acceptable excipients, carriers, or diluents. The term "consisting of," when used to define compositions and methods, means excluding trace elements and substantial method steps of other components. Embodiments defined by these transitional phrases are within the scope of the present invention.

[0015] Unless otherwise specified or clear from the context, the term "about" used herein is understood to mean within a normal range of tolerance in the art, for example, within 2 standard deviations of the mean value. "About" can be understood as within 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, 0.05%, or 0.01% of the stated value. Unless otherwise specified from the context, all numerical values ​​provided herein can be modified by the term "about."

[0016] As used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise.

[0017] As used herein, the term "administration" or "administering" of the disclosed compounds encompasses delivering a compound described herein, or a prodrug or other pharmaceutically acceptable form thereof, to a subject using any suitable formulation or route of administration discussed herein.

[0018] As used herein, the term "co-administration" means that two agents are present in the subject's body (e.g., in the blood) at the same time. The two agents can be administered simultaneously or sequentially.

[0019] The terms "disease," "disorder," and "condition" are used interchangeably unless otherwise specified.

[0020] As used herein, the term "effective amount" or "therapeutically effective amount" refers to an amount of a compound or pharmaceutical composition described herein sufficient to affect its intended use, including but not limited to, the treatment of a disease, as set forth below.

[0021] In some embodiments, the amount is effective to prevent the progression or reduce the effects of an inflammatory disease or disorder. In some embodiments, the amount is effective to prevent the progression or reduce the effects of an immune system disorder. In some embodiments, the amount is effective to prevent the progression or reduce the effects of an autoimmune disease or disorder. In some embodiments, the amount is effective to prevent the progression or reduce the effects of a cardiovascular disease or disorder. In some embodiments, the amount is effective to detectably kill or inhibit the growth or spread of cancer cells, tumor size or number, or other measure of the level, stage, progression, or severity of cancer. In some embodiments, the amount is effective to prevent the progression or reduce the effects of PPD, depression, insomnia, sleep apnea, restless legs syndrome, and narcolepsy, affective disorders, depression, schizophrenia, bipolar disorder, obsessive-compulsive disorder, other anxiety disorders, behavioral and pharmacological symptoms of dementia, or neurodegenerative diseases. In some embodiments, the amount is effective to prevent progression or alleviate symptoms of Parkinson's disease (PD), hi some embodiments, the amount is effective to prevent progression or alleviate symptoms of Alzheimer's disease (AD).

[0022] The therapeutically effective amount may vary depending on the intended use or the subject and disease symptoms being treated, such as the desired biological endpoint, the pharmacokinetics of the compound, the disease being treated, the method of administration, and the patient's weight and age, and can be easily determined by one skilled in the art. Such an amount can be administered as a single dose or according to a dosing regimen. The term also applies to a dose that induces a specific response in target cells, such as a reduction in cell migration. Specific dosage amounts will vary depending, for example, on the specific compound selected, the subject's species and its age / pre-existing health conditions or risk of health conditions, the dosing regimen to be followed, the severity of the disease, whether or not it is co-administered with other drugs, the timing of administration, the tissue to which it is administered, and the physical delivery system by which it is delivered.

[0023] As used herein, the terms "unsubstituted or substituted" and "optionally substituted" are used interchangeably and refer to where a given chemical moiety (e.g., an alkyl group) can, but need not, be attached to other substituents (e.g., heteroatoms). For example, an optionally substituted alkyl group can be a fully saturated alkyl chain (i.e., pure hydrocarbon). Alternatively, the same optionally substituted alkyl group can have substituents other than hydrogen. For example, it can be attached at any position along the chain to a halogen atom, a hydroxyl group, or other substituents described herein. Thus, the term "optionally substituted" means that a given chemical moiety can include other functional groups, but does not necessarily have to have further functional groups. Suitable substituents used for the optional substitution of the described groups include, but are not limited to, halogen, oxo, CN, -COOH, -CHCN, -O-Ci-C alkyl, Ci-C alkyl, -O-Ci-C alkenyl, -O-Ci-C alkynyl, -Ci-C alkenyl, -Ci-C alkynyl, -OH, -O-P(O)(OH), -OC(O)Ci-C alkyl, -C(O)Ci-C alkyl, -OC(O)O-Ci-C alkyl, NH, NH(Ci-C alkyl), N(Ci-C alkyl), -NHC(O)Ci-C alkyl, -C(O)NHCi-C alkyl, -S(O)-Ci-C alkyl, -S(O)NHCi-C alkyl and S(O)N(Ci-C alkyl).

[0024] As used herein, "pharmaceutically acceptable forms" of the disclosed compounds include, but are not limited to, pharmaceutically acceptable salts, esters, hydrates, solvates, isomers, prodrugs, and isotopically labeled derivatives of the disclosed compounds. In one embodiment, "pharmaceutically acceptable forms" include, but are not limited to, pharmaceutically acceptable salts, esters, isomers, prodrugs, and isotopically labeled derivatives of the disclosed compounds. In some embodiments, "pharmaceutically acceptable forms" include, but are not limited to, pharmaceutically acceptable salts, esters, stereoisomers, prodrugs, and isotopically labeled derivatives of the disclosed compounds.

[0025] In certain embodiments, the pharmaceutically acceptable form is a pharmaceutically acceptable salt. As used herein, the term "pharmaceutically acceptable salt" refers to a salt that is, within the scope of sound medical judgment, suitable for use in contact with the tissues of a subject without undue toxicity, irritation, allergic reaction, etc., and that is commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. provide a detailed description of pharmaceutically acceptable salts in J. Pharmaceutical Sciences (1977) 66:1-19. Pharmaceutically acceptable salts of the compounds provided herein include salts derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts of amino groups formed using inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, and malonic acid, or other methods used in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, besylic acid, benzoic acid, bisulfate, boric acid, butyric acid, camphoric acid, camphorsulfonic acid, citric acid, cyclopentanepropionic acid, digluconic acid, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxyethanesulfonate, and lactobionic acid. Salts include, but are not limited to, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like.In some embodiments, organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, lactic acid, trifluoroacetic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like.

[0026] Salts can be prepared in situ during the isolation and purification of the disclosed compounds, or separately by reacting the free base or free acid of the parent compound with an appropriate base or acid, respectively. Pharmaceutically acceptable salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (C 1~4 Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Additionally, pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations formed, where appropriate, using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, aryl sulfonates, and the like. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines (including naturally occurring substituted amines), cyclic amines, basic ion exchange resins, and the like, including, for example, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. In some embodiments, the pharmaceutically acceptable base addition salt may be selected from ammonium, potassium, sodium, calcium, and magnesium salts.

[0027] In certain embodiments, the pharmaceutically acceptable form is a pharmaceutically acceptable ester. As used herein, the term "pharmaceutically acceptable ester" refers to an ester that is hydrolyzed in vivo and includes esters that are readily decomposed in the human body to leave the parent compound or a salt thereof. Such esters can act as prodrugs, as defined herein. Pharmaceutically acceptable esters include, but are not limited to, alkyl, alkenyl, alkynyl, aryl, aralkyl, and cycloalkyl esters of acidic groups (including, but not limited to, carboxylic acids, phosphoric acids, phosphinic acids, sulfinic acids, sulfonic acids, and boronic acids). Examples of esters include formates, acetates, propionates, butyrates, acrylates, and ethylsuccinates. Esters can be formed at hydroxy or carboxylic acid groups of the parent compound.

[0028] In certain embodiments, the pharmaceutically acceptable form is a "solvate" (e.g., a hydrate). As used herein, the term "solvate" refers to a compound that further comprises a stoichiometric or non-stoichiometric amount of solvent bound by non-covalent intermolecular forces. The solvate may be a disclosed compound or a pharmaceutically acceptable salt thereof. When the solvent is water, the solvate is a "hydrate." Pharmaceutically acceptable solvates and hydrates are complexes that may contain, for example, 1 to about 100, or 1 to about 10, or 1 to about 2, about 3, or about 4 solvent or water molecules. It will be understood that the term "compound" as used herein encompasses the compound, solvates of the compound, and mixtures thereof.

[0029] In certain embodiments, the pharmaceutically acceptable form is a prodrug. As used herein, the term "prodrug" (or "pro-drug") refers to a compound that is converted in vivo to produce a disclosed compound or a pharmaceutically acceptable form of that compound. A prodrug is inactive when administered to a subject but is converted to an active compound in vivo, for example, by hydrolysis (e.g., hydrolysis in the blood). In certain cases, a prodrug has improved physical and / or delivery properties compared to the parent compound. A prodrug can increase the bioavailability of the compound when administered to a subject (e.g., by increasing absorption into the blood after oral administration) or can enhance delivery to a biological compartment of interest (e.g., the brain or lymphatic system) compared to the parent compound. Exemplary prodrugs include derivatives of the disclosed compounds that have improved water solubility or active transport across intestinal membranes compared to the parent compound.

[0030] Prodrug compounds often have advantages such as solubility, tissue compatibility, or delayed release in mammalian organisms (see, e.g., Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24 (Elsevier, Amsterdam)). Discussions of prodrugs are found in Higuchi, T., et al., "Prodrugs as Novel Delivery Systems," ACS Symposium Series, Vol. 14, and Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference in their entirety. Exemplary advantages of prodrugs include, but are not limited to, physical properties such as improved water solubility for parenteral administration at physiological pH, or improved absorption from the gastrointestinal tract, or improved stability of the drug for long-term storage compared to the parent compound.

[0031] As used herein, the term "pharmaceutically acceptable excipient, carrier, or diluent" refers to a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material, that is involved in carrying or transporting a pharmaceutical agent of interest from one organ or part of the body to another. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Examples of substances which can function as pharmaceutically acceptable carriers include sugars (e.g., lactose, glucose, and sucrose), starches (e.g., corn starch and potato starch), cellulose and its derivatives (e.g., sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate), powdered tragacanth, malt, gelatin, talc, excipients (e.g., cocoa butter and suppository waxes), oils (e.g., peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil), glycols (e.g., propylene glycol), polyols (e.g., glycerin, sorbitol, mannitol, and polyethylene glycol), esters (e.g., ethyl oleate and ethyl laurate), agar, buffers (e.g., magnesium hydroxide and aluminum hydroxide), alginic acid, pyrogen-free water, isotonic saline, Ringer's solution, ethyl alcohol, phosphate buffer solutions, and other non-toxic compatible substances used in pharmaceutical formulations. Wetting agents, emulsifiers, lubricants, such as sodium lauryl sulfate, magnesium stearate, polyethylene oxide-polypropylene oxide copolymers, as well as coloring agents, release agents, coating agents, sweetening agents, flavoring agents, perfuming agents, preservatives, and antioxidants may also be present in the composition.

[0032] As used herein, the term "subject" refers to any animal (e.g., mammal) that is the object of a particular treatment, including, but not limited to, humans, non-human primates, rodents, etc. Typically, the terms "subject" and "patient" are used interchangeably herein in reference to a human subject.

[0033] As used herein, the terms "treatment of" or "treating" a disease or disorder refer to a method of alleviating, delaying, or ameliorating symptoms before or after the onset of such symptoms. Treatment may be directed at one or more effects or symptoms of the disease and / or underlying medical condition. Treatment is intended to obtain a beneficial or desired result, including, but not limited to, a therapeutic benefit and / or a prophylactic benefit. A therapeutic benefit refers to the eradication or amelioration of the underlying disease being treated. A therapeutic effect is also achieved by eradicating or ameliorating one or more physiological symptoms associated with the underlying disease, and an improvement in the patient's condition is observed, even though the patient may still be affected by the underlying disease. For prophylactic benefit, pharmaceutical compounds and / or compositions can be administered to patients at risk of developing a particular disease or to patients who report one or more physiological symptoms of the disease, even though they have not been diagnosed with the disease. Treatment can be any alleviation, including, but not limited to, the complete elimination of the disease or symptoms of the disease. When compared to comparable untreated controls, the degree of such reduction or prevention is at least 5%, 10%, 20%, 40%, 50%, 60%, 80%, 90%, 95% or 100% as measured by standard techniques.

[0034] As used herein, the term "therapeutic benefit" refers to a therapeutic benefit and / or a prophylactic benefit as described herein. A prophylactic benefit includes delaying or eliminating the onset of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, halting, or reversing the progression of a disease or condition, or any combination thereof.

[0035] After preparation, the compounds of the invention are preferably isolated and purified to provide compositions containing 95% or more by weight ("substantially pure"), which can then be used or formulated as described herein. In certain embodiments, the compounds of the invention are greater than 99% pure.

[0036] Solvates and polymorphs of the compounds of the invention are also contemplated herein. Solvates of the compounds of the invention include, for example, hydrates.

[0037] As used herein, the term "isolated" or "substantially isolated" molecule (e.g., a polypeptide or polynucleotide) refers to a molecule that has been engineered to exist in greater concentrations than found in nature or that has been removed from its original environment. For example, a subject antibody is isolated, purified, substantially isolated, or substantially purified if at least 10%, 20%, 40%, 50%, 70%, or 90% of the materials, other than the subject antibody, that are naturally associated with it have been removed. For example, a polynucleotide or polypeptide naturally present in a living animal is not "isolated," but the same polynucleotide or polypeptide separated from the coexisting materials in its natural state is "isolated." Furthermore, recombinant DNA molecules contained in a vector are considered isolated for purposes of the present invention. Isolated RNA molecules include the products of in vivo or in vitro RNA replication of DNA and RNA molecules. Isolated nucleic acid molecules further include molecules produced synthetically. Furthermore, vector molecules contained in a recombinant host cell are also isolated. Therefore, not all "isolated" molecules need to be "purified."

[0038] As used herein, the term "purified," when used in reference to a molecule, means that the concentration of the purified molecule is increased relative to the associated molecule in its natural environment or the environment in which it was produced, discovered, or synthesized. Naturally associated molecules include proteins, nucleic acids, lipids, and sugars, but generally do not include water, buffers, or reagents added to maintain the integrity of the purified molecule or to facilitate purification. By this definition, when considered relative to its contaminants, the material may be 5% or more, 10% or more, 20% or more, 30% or more, 40% or more, 50% or more, 60% or more, 70% or more, 80% or more, 90% or more, 95% or more, 98% or more, 99% or more, or 100% pure.

[0039] Definitions of specific functional groups and chemical terms are discussed in more detail below. When a range of values ​​is listed, it is intended that the range include each value and subrange. For example, "C 1~6 "Alkyl" refers to C1, C2, C3, C4, C5, C6, C 1~4 , C 1~3 , C 1~2 , C 2~5 , C 2~4 , C 3~6 , C 3~5 and C 4~6 Alkyl groups are intended to be included.

[0040] As used herein, the term "alkyl" refers to a straight or branched hydrocarbon chain radical, consisting solely of carbon and hydrogen atoms, containing no unsaturation, and having from 1 to 10 carbon atoms (e.g., C 1~10 As used herein, numerical ranges such as "1 to 10" refer to each integer within the given range, e.g., "1 to 10 carbon atoms" means that the alkyl group can consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to 10 carbon atoms, although this definition also covers uses of the term "alkyl" when no numerical range is specified. In some embodiments, "alkyl" refers to C 1~6It can be a (e.g., C1, C2, C3, C4, C5, or C6) alkyl group. In some embodiments, the alkyl group has 1 to 10, 1 to 8, 1 to 6, or 1 to 3 carbon atoms. Representative saturated straight chain alkyls include, but are not limited to, -methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl, and -n-hexyl, while saturated branched alkyls include, but are not limited to, -isopropyl, -sec-butyl, -isobutyl, -tert-butyl, -isopentyl, 2-methylbutyl, 3-methylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylbutyl, and the like. The alkyl is attached to the parent molecule by a single bond. Unless stated otherwise in the specification, an alkyl group is any of the following: acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylaryl, cycloalkyl, aralkyl, aryl, aryloxy, amino, amido, amidino, imino, azide, carbonate, carbamate, carbonyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, hydroxy, cyano, halo, haloalkoxy, haloalkyl, ester, ether, mercapto, thio, alkylthio, arylthio, thiocarbonyl, nitro, oxo, phosphate, phosphonate, phosphinate, silyl, sulfinyl, sulfonyl, sulfonamidyl, sulfoxyl, sulfonate, urea, -Si(R x )3, -OR x , -SR x , -OC(O)-R x , -N(R x )2, -C(O)R x , -C(O)OR x , -OC(O)N(R x )2, -C(O)N(R x )2, -N(R x )C(O)OR x , -N(R x )C(O)R x , -N(R x )C(O)N(R x )2, -N(R x )C(NR x)N(R x )2, -N(R x )S(O)tN(R x )2(t is 1 or 2), -P(=O)(R x )(R x ) or -OP(=O)(OR x Optionally substituted by one or more substituents, including 2, wherein R x are each independently hydrogen, alkyl, haloalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl, each of which moieties can be optionally substituted as defined herein. In a non-limiting embodiment, the substituted alkyl can be selected from fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 3-fluoropropyl, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, benzyl, and phenethyl.

[0041] Unless otherwise specifically defined, the terms "aromatic" or "aryl" refer to cyclic, aromatic hydrocarbon groups having one to two aromatic rings, including monocyclic or bicyclic groups such as phenyl, biphenyl, naphthyl, etc. When containing two aromatic rings (e.g., bicyclic), the aromatic rings of the aryl group can be attached at a single point (e.g., biphenyl) or fused (e.g., naphthyl). Aryl groups can be optionally substituted at any point of attachment with one or more substituents, e.g., 1 to 5 substituents. Exemplary substituents include, but are not limited to, H, halogen, —O—Ci-C alkyl, Ci-C alkyl, —Ci-C alkenyl, —O—Ci-C alkynyl, —Ci-C alkenyl, —Ci-C alkynyl, —OH, —O—P(O)(OH), —OC(O)Ci-C alkyl, —C(O)Ci-C alkyl, —OC(O)O—Ci-C alkyl, NH, NH(Ci-C alkyl), N(Ci-C alkyl), —S(O)—Ci-C alkyl, —S(O)NHCi-C alkyl, and S(O)N(Ci-C alkyl). The substituents themselves can be optionally substituted. Furthermore, when containing two fused rings, aryl groups as defined herein can have a fully unsaturated ring and a fused unsaturated or partially saturated ring. Exemplary ring systems of these aryl groups include indanyl, indenyl, tetrahydronaphthalenyl, and tetrahydrobenzoannulenyl.

[0042] The term "halogen" or "halo" refers to fluorine (F), chlorine (Cl), bromine (Br), and iodine (I).

[0043] As used herein, the term "heteroaryl" or "heteroaromatic" refers to a group having 5 to 14 ring atoms, preferably 5, 6, 9, or 10 ring atoms, with 6, 10, or 14 p-electrons shared in a cyclic arrangement, and, in addition to carbon atoms, 1 to 3 heteroatoms per ring selected from the group consisting of N, O, and S.Exemplary heteroaryl groups are acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, 6,7-dihydro-5H-pyrrolo[1,2-a]imidazole, furanyl, furazanyl, imidazolinyl, imidazolyl , 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl , oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinucinyl Includes lysinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienoxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl and xanthenyl."Heteroaryl" also refers to bicyclic ring systems having, in addition to carbon atoms, from 1 to 3 heteroatoms per ring selected from the group consisting of N, O, and S, wherein one ring system can be saturated or partially saturated.

[0044] Heteroaryl groups can be substituted with 0, 1, 2, 3, or 4 substituents independently selected from alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonyl, alkylcarbonylalkyl, alkylcarbonyloxy, alkylthio, alkylthioalkyl, alkynyl, carboxy, carboxyalkyl, cyano, cyanoalkyl, formyl, haloalkoxy, haloalkyl, halogen, hydroxy, hydroxyalkyl, mercapto, nitro, -NZ1Z2, and (NZ1Z2)carbonyl. As used herein, the term "NZ1Z2" refers to two groups, Z1 and Z2, appended to the parent molecular moiety through a nitrogen atom. Z1 and Z2 are each independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, and formyl. Representative examples of NZ1Z2 include, but are not limited to, amino, methylamino, acetylamino, acetylmethylamino, and the like.

[0045] As used herein, the term "alkoxy" refers to an --O-alkyl radical.

[0046] As used herein, the terms "cycloalkyl" and "carbocyclyl" refer to monocyclic or polycyclic radicals, respectively, that contain only carbon and hydrogen and are saturated or partially unsaturated. Unless otherwise noted in the specification, the term is intended to include both substituted and unsubstituted cycloalkyl groups. Partially unsaturated cycloalkyl groups are referred to as "cycloalkenyls" if the carbocyclic ring contains at least one double bond and "cycloalkynyls" if the carbocyclic ring contains at least one triple bond. Cycloalkyl groups are groups having 3 to 13 ring atoms (i.e., C 3~13As used herein, numerical ranges such as "3 to 10" refer to each integer within the given range; for example, "3 to 13 carbon atoms" means that the cycloalkyl group can consist of 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, etc., up to 13 carbon atoms. The term "cycloalkyl" further includes bridged and spiro-fused ring structures that do not contain heteroatoms. The term further includes monocyclic or fused-ring polycyclic (i.e., rings that share adjacent pairs of ring atoms) groups. Polycyclic aryl groups include bicyclic, tricyclic, tetracyclic, etc. In some embodiments, "cycloalkyl" refers to C 3~8 In some embodiments, "cycloalkyl" is a C 3~5 Illustrative examples of cycloalkyl groups include, but are not limited to, the following moieties: C 3~6 Carbocyclyl groups include, but are not limited to, cyclopropyl (C3), cyclobutyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), and the like. 3~7 Examples of carbocyclyl groups include norbornyl (C7). 3~8 Examples of carbocyclyl groups are those listed above. 3~7 In addition to carbocyclyl groups, these include cycloheptyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl, etc. 3~13 Examples of carbocyclyl groups are those listed above. 3~8In addition to carbocyclyl groups, cycloalkyl groups include octahydro-1H indenyl, decahydronaphthalenyl, spiro[4.5]decanyl, and the like. Unless stated otherwise in the specification, cycloalkyl groups include acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylaryl, cycloalkyl, aralkyl, aryl, aryloxy, amino, amido, amidino, imino, azide, carbonate, carbamate, carbonyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, hydroxy, cyano, halo, haloalkoxy, haloalkyl, ester, ether, mercapto, thio, alkylthio, arylthio, thiocarbonyl, nitro, oxo, phosphate, phosphonate, phosphinate, silyl, sulfinyl, sulfonyl, sulfonamidyl, sulfoxyl, sulfonate, urea, -Si(R a )3, -OR a , -SR a , -OC(O)-R a , -N(R a )2, -C(O)R a , -C(O)OR a , -OC(O)N(R a )2, -C(O)N(R a )2, -N(R a )C(O)OR a , -N(R a )C(O)R a , -N(R a )C(O)N(R a )2, -N(R a )C(NR a )N(R a )2, -N(R a )S(O) t N(R a )2(t is 1 or 2), -P(=O)(R a )(R a ) or -OP(=O)(OR a )2, wherein R aare each independently hydrogen, alkyl, haloalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl, each of which moieties can be optionally substituted as defined herein. The terms "cycloalkenyl" and "cycloalkynyl" mirror the description of "cycloalkyl" above, where the prefix "alk" is replaced with "alken" or "alkyn," respectively, and the parent "alkenyl" or "alkynyl" terms are as defined herein. For example, a cycloalkenyl group can have 3 to 13 ring atoms, e.g., 5 to 8 ring atoms. In some embodiments, a cycloalkynyl group can have 5 to 13 ring atoms.

[0047] As used herein, the term "heterocycloalkyl" refers to a cycloalkyl radical having one or more skeletal atoms other than carbon, e.g., O, N, S, P, or combinations thereof. Unless stated otherwise in the specification, this term is intended to include both substituted and unsubstituted heterocycloalkyl groups. Illustrative examples of heterocycloalkyl include 2-hydroxy-aziridin-1-yl, 3-oxo-1-oxacyclobutan-2-yl, 2,2-dimethyl-tetrahydrofuran-3-yl, 3-carboxy-morpholin-4-yl, 1-cyclopropyl-4-methyl-piperazin-2-yl, 2-pyrrolinyl, 3-pyrrolinyl, dihydro-2H-pyranyl, 1,2,3,4-tetrahydropyridine, 3,4-dihydro-2H-[1,4]oxazine, and the like.

[0048] As used herein, the terms "heterocyclic compound," "heterocyclic," or "heterocycle" refer to a fully saturated or partially unsaturated cyclic group, e.g., a 3- to 7-membered monocyclic, a 7- to 12-membered bicyclic, or a 10- to 15-membered spirocyclic or tricyclic ring system, having at least one heteroatom (selected from the group consisting of N, O, and S) in at least one ring, and 0, 1, 2, or 3 atoms in each ring may be substituted by substituents. Each ring of a heteroatom-containing heterocyclic group may have 1, 2, 3, or 4 heteroatoms selected from nitrogen, oxygen, and / or sulfur atoms, and the nitrogen and sulfur heteroatoms may be optionally oxidized, and the nitrogen heteroatom may be optionally quaternized. The heterocyclic group may be bonded to any heteroatom or carbon atom in the ring or ring system. The heterocyclic group is optionally substituted. Examples of heterocyclic groups include epoxy, azetidinyl, aziridinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, pyrrolidinonyl, piperidinyl, piperazinyl, imidazolidinyl, imidazopyridinyl, thiazolidinyl, dithianyl, trithianyl, dioxolanyl, oxazolidinyl, oxazolidinonyl, decahydroquinolinyl, piperidonyl, 4-piperidinonyl, quinuclidinyl, thiomorpholinyl, thiomorpholinyl 1,1 dioxide, morpholinyl, azepanyl, oxazepanyl, azabicyclohexanyl, azabicycloheptanyl, azabicyclooctanyl, azabicyclononanyl (e.g., octahydroindolizinyl), and the like. oxazolyl), azaspiroheptanyl, dihydro-1H,3H,5H-oxazolo[3,4-c]oxazolyl, tetrahydro-1′H,3′H-spiro[cyclopropane-1,2′-pyrrolidine], hexahydro-1H-pyrrolidinyl, hexahydro-1H-pyrrolo[2,1-c][1,4]oxazinyl, octahydroindolizinyl, oxaazaspirononanyl, oxaazaspirooctanyl, diazaspirononanyl, oxazabioctoheptanyl, hexahydropyrrolidinyl 4(1H)-oxide, tetrahydro-2H-thiopyranyl 1-oxide, and tetrahydro-2H-thiopyranyl 1,1-dioxide. DETAILED DESCRIPTION OF THE INVENTION

[0049] The present invention is based, in part, on the discovery of novel CDK2 inhibitors that selectively target, bind to, and inhibit the activity of CDK2. The novel compounds have been shown to exhibit more favorable potency and selectivity profiles than known CDK2 inhibitors, such as PF-07104091. These compounds exhibit excellent DMPK profiles that make them suitable for development as orally administered therapeutics for the treatment of cancers such as breast, ovarian, gastric, and lung cancers.

[0050] In one aspect, the present invention generally provides a compound having structural formula I: [ka] or a pharmaceutically acceptable form or isotopic derivative thereof, During the ceremony, Ring A is a 4- to 7-membered (e.g., 4-, 5-, 6-, or 7-membered) carbocyclic ring; R 1 and R 2 are each independently selected from the group consisting of H, unsubstituted or substituted C1-C6 alkyl, and C3-C6 unsubstituted or substituted carbocycle, or R 1 and R 2 are joined together with the N atom to which they are attached to form a 4- to 7-membered (e.g., 4-, 5-, 6-, or 7-membered) unsubstituted or substituted heterocycle; Each R 3 is halogen, OH, CN, unsubstituted or substituted C 1~6 Alkyl, unsubstituted or substituted C 1~6 alkoxy, NO2, NRR', or two R 3 together with the carbon atom(s) to which they are attached form a 3- to 5-membered (e.g., 3-, 4-, or 5-membered) unsubstituted or substituted carbocyclic ring; R 4 is H, halogen, C1-4 alkyl, CN, NRR' or C(O)NRR'; R 5 teeth, [ka] and During the ceremony, Ring B is a 4- to 7-membered (e.g., 4-, 5-, 6-, or 7-membered) carbocyclic or heterocyclic ring optionally containing a -S(O)-, -C(O)-, -S(O)NR-, -S(O)NRC(O)-, -C(O)NR-, -OC(O)NR-, or -C(O)NRC(O)- group; Y 1 and Y 2 are CR 6 or N and Y 3 and Y 4 are C and CR, respectively. 6 or N, where Y 1 , Y 2 , Y 3 and Y 4 At most one of the following is N, and Y 3 or Y 4 is C and R 5 is a position at which the compound can be attached to the remainder of the compound, Each R 6 is halogen, OH, CN, unsubstituted or substituted C 1~6 Alkyl, unsubstituted or substituted C 1~4 independently selected from the group consisting of alkoxy and C(O)NRR′; Each R 7 is halogen, OR, CN, unsubstituted or substituted C 1~6 Alkyl and unsubstituted or substituted C 1~4 or two R independently selected from the group consisting of alkoxy 7 together with the carbon atom(s) to which they are attached form a 3- to 6-membered (e.g., 3-, 4-, 5-, or 6-membered) unsubstituted or substituted carbocyclic or heterocyclic ring; R and R' are each independently H, unsubstituted or substituted C 1~6 alkyl, or an unsubstituted or substituted 4- to 6-membered (e.g., 4-, 5-, or 6-membered) carbocycle, or R and R', together with the same N atom, are joined to form an unsubstituted or substituted 4- to 6-membered (e.g., 4-, 5-, or 6-membered) heterocycle; i is 0, 1, 2, 3, 4 or 5; k is 0, 1, 2, 3, 4 or 5.

[0051] In certain embodiments of (I), Y 1 , Y 2 , Y 3 and Y 4 None of the above are N, but R 5 teeth, [ka] and During the ceremony, Each R 6 is halogen, OH, CN, unsubstituted or substituted C 1~6 Alkyl, unsubstituted or substituted C 1~4 independently selected from the group consisting of alkoxy and C(O)NRR′; α and β are R 5 refers to the position at which the may be attached to the remainder of the compound, j is 0, 1, 2 or 3.

[0052] In certain embodiments, R 5 is connected to the rest of the compound at the β position: [ka]

[0053] In certain embodiments, R 5 is connected to the rest of the compound at the α position: [ka]

[0054] In certain embodiments of (I), Y 1 , Y 2 , Y 3 and Y 4 At least one of them is N.

[0055] In certain embodiments of (I), Y 1 , Y 2 , Y 3 and Y4 Only one of them is N.

[0056] In certain embodiments of (I), Y 3 is C and R 5 Y 3 It is connected to the rest of the compound at the position: [ka]

[0057] In certain embodiments, R 5 teeth, [ka] is selected from.

[0058] In certain embodiments of (I), Y 4 is C and R 5 Y 4 It is connected to the rest of the compound at the position: [ka]

[0059] In certain embodiments, R 5 teeth, [ka] is selected from.

[0060] Ring B is [ka] is selected from During the ceremony, X 1 , X 2 , X 3 , X 4 and X 5 are each independently selected from S(O)2, C(O), NH, CH2, and O, with the proviso that: Two adjacent Xs 1 , X2 , X 3 , X 4 or X 5 are not selected from S(O) and C(O), Two adjacent Xs 1 , X 2 , X 3 , X 4 or X 5 are not selected from NH and O, respectively.

[0061] In certain embodiments, one or both of X1 and X2 are selected from S(O)2 and C(O), and none of X3, X4, and X5 is S(O)2 or C(O).

[0062] In certain embodiments, neither X1 nor X2 is S(O)2 or C(O), and one of X3, X4, and X5 is S(O)2 or C(O).

[0063] In certain embodiments, none of X1, X2, X3, X4, and X5 is S(O)2 or C(O), and at least one of X1, X2, X3, X4, and X5 is CH2, wherein: One or both H in CH2 is replaced by F, one H is replaced by CN and the other H is unsubstituted, or One H is replaced by CN and the other H is replaced by OR.

[0064] In certain embodiments, R 5 teeth, [ka] is selected from.

[0065] In certain embodiments, R 5 teeth, [ka] is selected from.

[0066] In certain embodiments, R 5 teeth, [ka] is selected from.

[0067] In certain embodiments, R 5 teeth, [ka] is selected from.

[0068] In certain embodiments, R 5 teeth, [ka] is selected from.

[0069] In certain embodiments, R 5 teeth, [ka] is selected from.

[0070] In certain embodiments, R 5 teeth, [ka] is selected from.

[0071] In certain embodiments, R 5 teeth, [ka] is selected from.

[0072] In certain embodiments, R 5 teeth, [ka] is selected from.

[0073] In certain embodiments, R 5 teeth, [ka] is selected from.

[0074] In certain embodiments, two R 7 together with the carbon atoms to which they are attached form a 3- to 6-membered (eg, 3-, 4-, 5-, or 6-membered) unsubstituted or substituted carbocyclic ring.

[0075] In certain embodiments, two R 7 together with the carbon atoms to which they are attached form a 3- to 6-membered (e.g., 3-, 4-, 5-, or 6-membered) unsubstituted or substituted heterocycle containing one or more ring heteroatoms selected from O, S, and N.

[0076] In certain embodiments, R 5 is selected from: [Table 1]

[0077] In certain embodiments, R 5 is selected from: [Table 2]

[0078] In certain embodiments, R 5 is selected from: [Table 3-1] [Table 3-2]

[0079] In certain embodiments of Tables 1-3, Y 1 N, Y 2 CH, Y 4 is CH.

[0080] In certain embodiments of Tables 1-3, Y 1 CH, Y 2 N, Y 4 is CH.

[0081] In certain embodiments of Tables 1-3, Y 1 CH, Y 2 CH, Y 4 is N.

[0082] In certain embodiments of Tables 1-3, Y 1 , Y 2 and 4 are CH, respectively.

[0083] In certain embodiments, R 5 is selected from: [Table 4]

[0084] In certain embodiments, R 5 is selected from: [Table 5]

[0085] In certain embodiments, R 5 is selected from: [Table 6-1] [Table 6-2]

[0086] In certain embodiments of Tables 4-6, Y 1 N, Y 2 CH, Y 3 is CH.

[0087] In certain embodiments of Tables 4-6, Y1 CH, Y 2 N, Y 3 is CH.

[0088] In certain embodiments of Tables 4-6, Y 1 CH, Y 2 CH, Y 3 is N.

[0089] In certain embodiments of Tables 4-6, Y 1 , Y 2 and Y 3 are CH, respectively.

[0090] R 5 In certain embodiments, R is H.

[0091] R 5 In certain embodiments, R is unsubstituted or substituted C 1~6 It is alkyl.

[0092] In certain embodiments, R is methyl.

[0093] In certain embodiments, R 1 is H and R 2 is unsubstituted or substituted straight-chain or branched C1-C6 alkyl.

[0094] In certain embodiments, R 1 and R 2 are each independently unsubstituted or substituted straight or branched C1-C6 alkyl.

[0095] In certain embodiments, R 1 and R 2 are joined together with the N atom to which they are attached to form a 4- to 7-membered (eg, 4-, 5-, 6-, or 7-membered) unsubstituted or substituted heterocycle.

[0096] In certain embodiments, ring A is a 4-7 membered (eg, 4-, 5-, 6-, or 7-membered) carbocyclic ring.

[0097] In certain embodiments, ring A is [ka] is selected from.

[0098] In certain embodiments, ring A is [ka] is selected from.

[0099] In certain embodiments, ring A is a 5-membered carbocyclic ring.

[0100] In certain embodiments, ring A is [ka] is.

[0101] In certain embodiments, i is 0.

[0102] In certain embodiments, the compounds of the invention have the following structural formula: [ka]

[0103] (I a In certain embodiments of 1 N, Y 2 CH, Y 4 is CH.

[0104] (I a In certain embodiments of 1 CH, Y 2 N, Y 4 is CH.

[0105] (I a In certain embodiments of 1 CH, Y 2 CH, Y 4 is N.

[0106] In certain embodiments, the compounds of the present invention have the following structural formula: [ka]

[0107] (I b In certain embodiments of 1 N, Y 2 CH, Y 3 is CH.

[0108] (I b In certain embodiments of 1 CH, Y 2 N, Y 3 is CH.

[0109] (I b In certain embodiments of 1 CH, Y 2 CH, Y 3 is N.

[0110] (I a ) and (I b In certain embodiments of ), ring B is a 5-membered carbocyclic ring.

[0111] (I a ) and (I b In certain embodiments of ), ring B is a 5-membered heterocycle.

[0112] (I a ) and (I b In certain embodiments of ), ring B is a 6-membered carbocyclic ring.

[0113] (I a ) and (I b In certain embodiments of ), ring B is a 6-membered heterocycle.

[0114] (I a ) and (I bIn certain embodiments of , ring B comprises a -S(O)2NH- group.

[0115] (Ia) and (I b In certain embodiments of ), ring B comprises a -S(O)2- group.

[0116] (Ia) and (I b In certain embodiments of ), ring B comprises a -C(O)NH- group.

[0117] (Ia) and (I b In certain embodiments of , ring B comprises a CH2 group.

[0118] (I a ) and (I b In certain embodiments of ), ring B comprises a C(CN)R″ group, where R″ is H, OH, C 1~4 Alkyl or OC 1~4 It is alkyl.

[0119] (I a ) and (I b In certain embodiments of ), j is 0.

[0120] (I a ) and (I b In certain embodiments of ), j is 1.

[0121] (I a ) and (I b In certain embodiments of ), k is 0.

[0122] (I a ) and (I b In certain embodiments of ), k is 1.

[0123] (I a ) and (I b In certain embodiments of ), k is 2.

[0124] (I a ) and (I bIn certain embodiments of 7 is unsubstituted or substituted C 1~6 It is alkyl.

[0125] Exemplary compounds of the present invention are [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] Includes.

[0126] Exemplary compounds of the present invention are [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] Includes.

[0127] Exemplary compounds of the present invention are [ka] [ka] [ka] [ka] [ka] [ka] [ka] Includes.

[0128] Exemplary compounds of the present invention are [ka] [ka] [ka] [ka] [ka] [ka] Includes.

[0129] The compounds of the invention include deuterated versions of the disclosed compounds, for example, versions having one or more deuterium atoms in place of hydrogen.

[0130] In certain embodiments, the compound has one deuterium atom in place of a hydrogen atom.

[0131] In another aspect, the invention generally relates to pharmaceutical compositions comprising a compound disclosed herein and a pharmaceutically acceptable excipient, carrier, or diluent.

[0132] In certain embodiments, the pharmaceutical compositions are suitable for oral administration.

[0133] In yet another aspect, the invention generally relates to unit dosage forms comprising the pharmaceutical compositions disclosed herein.

[0134] In certain embodiments, it is in the form of a tablet, hi certain embodiments, it is in the form of a capsule.

[0135] In yet another aspect, the invention generally relates to methods of treating or ameliorating cancer or a related disease or disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a compound disclosed herein.

[0136] In certain embodiments, the subject is further administered one or more of chemotherapy, radiation therapy, targeted therapy, immunotherapy, and hormonal therapy.

[0137] In certain embodiments, the method results in one or more of inhibiting cancer cell proliferation, inhibiting cancer cell invasion, inducing cancer cell apoptosis, inhibiting cancer cell metastasis, and inhibiting angiogenesis.

[0138] In certain embodiments, the present invention relates to a method of inhibiting the proliferation of cancer cells in a subject, comprising administering to the subject a compound of the present invention, or a pharmaceutically acceptable salt thereof, in an amount effective to inhibit cell proliferation.

[0139] In certain embodiments, the present invention relates to a method of inhibiting cancer cell invasion in a subject, comprising administering to the subject a compound of the present invention, or a pharmaceutically acceptable salt thereof, in an amount effective to inhibit cell invasion.

[0140] In certain embodiments, the present invention relates to a method of inducing apoptosis in cancer cells in a subject, comprising administering to the subject a compound of the present invention, or a pharmaceutically acceptable salt thereof, in an amount effective to induce apoptosis.

[0141] In certain embodiments, the present invention relates to a method of inhibiting metastasis of cancer cells in a subject, comprising administering to the subject a compound of the present invention, or a pharmaceutically acceptable salt thereof, in an amount effective to inhibit cell metastasis.

[0142] In certain embodiments, the present invention relates to a method of inhibiting angiogenesis in a subject, comprising administering to the subject a compound of the present invention, or a pharmaceutically acceptable salt thereof, in an amount effective to inhibit angiogenesis.

[0143] Examples of diseases or disorders that may be treated or alleviated by the compositions or methods of the present invention include, but are not limited to, tumors, cancers, inflammatory diseases, autoimmune diseases, and the like.

[0144] In certain embodiments, the compound of Formula I is administered to treat one or more of breast cancer, ovarian cancer, bladder cancer, uterine cancer, prostate cancer, lung cancer (including NSCLC, SCLC, squamous cell carcinoma or adenocarcinoma), esophageal cancer, head and neck cancer, colorectal cancer, kidney cancer (including RCC), liver cancer (including HCC), pancreatic cancer, gastric (i.e., of the stomach region) cancer, or thyroid cancer.

[0145] In certain embodiments, the cancer is breast cancer, ovarian cancer, bladder cancer, uterine cancer, prostate cancer, lung cancer, esophageal cancer, liver cancer, pancreatic cancer, or gastric cancer.

[0146] In certain embodiments, a compound of Formula I is administered to treat breast cancer, such as, for example, ER-positive / HR-positive, HER2-negative breast cancer, ER-positive / HR-positive, HER2-positive breast cancer, triple-negative breast cancer (TNBC), or inflammatory breast cancer.

[0147] In certain embodiments, the breast cancer is endocrine-resistant breast cancer, trastuzumab-resistant breast cancer, or breast cancer that exhibits primary or acquired resistance to CDK4 / CDK6 inhibition.

[0148] In certain embodiments, the breast cancer is advanced or metastatic breast cancer.

[0149] In certain embodiments, the breast cancer is characterized by amplification or overexpression of CCNE1 and / or CCNE2.

[0150] In certain embodiments, the abnormal cell growth is a cancer characterized by amplification or overexpression of CCNE1 and / or CCNE2.

[0151] In certain embodiments of the methods provided herein, the subject is identified as having a cancer characterized by amplification or overexpression of CCNE1 and / or CCNE2.

[0152] In certain embodiments, the cancer is selected from the group consisting of breast cancer and ovarian cancer.

[0153] In certain embodiments, the cancer is breast or ovarian cancer characterized by amplification or overexpression of CCNE1 and / or CCNE2.

[0154] In certain embodiments, the cancer is (a) breast cancer or ovarian cancer, (b) characterized by amplification or overexpression of cyclin E1 (CCNE1) or cyclin E2 (CCNE2), or (c) both (a) and (b). In some embodiments, the cancer is ovarian cancer.

[0155] In yet another aspect, the invention generally relates to the use of a compound disclosed herein and a pharmaceutically acceptable excipient, carrier, or diluent in the preparation of a medicament for treating a disease or disorder.

[0156] Pharmaceutically acceptable carriers, adjuvants, and vehicles that can be used in the pharmaceutical compositions of the present invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphoric acid, glycine, sorbic acid, potassium sorbate, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene polyoxypropylene block polymers, polyethylene glycol, and wool fat.

[0157] Pharmaceutical compositions of the present invention include those suitable for oral, rectal, nasal, topical (including buccal and sublingual), vaginal, or parenteral (including subcutaneous, intramuscular, intravenous, and intradermal) administration. In certain embodiments, the compounds of the formulae described herein are administered transdermally (e.g., using a transdermal patch). Other formulations are conveniently provided in unit dosage forms, for example, tablets and sustained-release capsules, and liposomes, and can be prepared by any method well known in the art of pharmacy. See, for example, Remington's Pharmaceutical Sciences, Mack Publishing Company, Philadelphia, PA (17th ed. 1985).

[0158] Such preparatory methods include the step of bringing into association the molecule to be administered with ingredients such as the carrier which constitutes one or more accessory ingredients. In general, the compositions are prepared by uniformly and intimately bringing into association the active ingredients with liquid carriers, liposomes, or finely divided solid carriers, or both, and then, if necessary, shaping the product.

[0159] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the compounds described herein or their derivatives are incorporated into at least one inert conventional excipient (or carrier) such as sodium citrate or dicalcium phosphate, or (i) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol, and silicic acid; (ii) binders, such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia; (iii) humectants, such as glycerol; and (iv) disintegrants, such as agar, calcium carbonate, and the like. The formulation may be mixed with (v) a starch such as potato starch, potato starch, or tapioca starch, alginic acid, certain complex silicates, sodium carbonate, (v) a solution retarder such as paraffin, (vi) an absorption accelerator such as a quaternary ammonium compound, (vii) a wetting agent such as cetyl alcohol or glycerol monostearate, (viii) an adsorbent such as kaolin or bentonite, and (ix) a lubricant such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets, and pills, the dosage form may also contain buffering agents. Solid compositions of a similar type may also be used as fillers for soft and hard-filled gelatin capsules using excipients such as lactose or milk sugar and high molecular weight polyethylene glycols. Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings and others well known in the art.

[0160] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs.In addition to the active compound, liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizers, and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitan, or mixtures of these substances.In addition to such inert diluents, the composition may also contain additional agents, such as wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, and perfumes.

[0161] The amount of the active compound administered will vary depending on the subject being treated, the severity of the disorder or condition, the route of administration, the disposition of the compound, and the discretion of the prescribing physician. In some cases, dosage levels below the lower limit of the aforementioned range may be more than sufficient, while in other cases, higher doses may be used without causing adverse side effects, and such higher doses are typically administered in several small doses throughout the day.

[0162] Any suitable route of administration can be used, for example, oral, intramuscular, intravenous, transdermal, subcutaneous, sublingual, parenteral, nasal, pulmonary, inhalation, buccal, intraperitoneal, rectal, intrapleural, and intrathecal. The most suitable method of administration for a particular patient will depend on the nature and severity of the disease or condition being treated, or the nature of the treatment being used, and the nature of the active compound.

[0163] In certain preferred embodiments, the compounds are administered orally. Pharmaceutical compositions of the present invention suitable for oral administration can be provided as discrete units such as capsules, sachets, or tablets, each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or suspension in an aqueous or non-aqueous liquid; as an oil-in-water or water-in-oil liquid emulsion; or as a bolus, encapsulated in liposomes, or the like. Soft gelatin capsules are useful for containing such suspensions, which can advantageously increase the rate of absorption of the compound.

[0164] Tablets may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by mixing the active ingredient in a free-flowing form, such as a powder or granules, with an optional binder, lubricant, inert diluent, preservative, surfactant, or dispersing agent, and compressing the mixture in a suitable machine. Molded tablets may be made by molding a mixture of the powdered compound moistened with an inert liquid diluent in a suitable machine. Tablets may optionally be coated or scored and may be formulated to provide sustained or controlled release of the active ingredient therein. Methods for formulating sustained- or controlled-release compositions of pharmaceutical active ingredients, such as those described herein and other compounds known in the art, are known in the art and are described in several issued U.S. patents, some of which include, but are not limited to, U.S. Patent Application Nos. 4,369,172 and 4,842,866, and the references cited therein. Coatings can be used to deliver compounds to the intestine (see, e.g., U.S. Patent Nos. 6,638,534, 5,217,720, 6,569,457, 6,461,631, 6,528,080, 6,800,663, and references cited therein). A useful formulation of the compounds of the invention is in the form of enteric coated pellets, in which the enteric layer comprises hydroxypropyl methylcellulose acetate succinate.

[0165] For oral tablets, commonly used carriers include lactose and corn starch. Lubricants such as magnesium stearate are also typically added. For oral administration in capsule form, useful diluents include lactose and dried corn starch. For oral administration of aqueous suspension, active ingredients are combined with emulsifiers and suspending agents. If necessary, certain sweeteners and / or flavorings and / or coloring agents can also be added.

[0166] Compositions suitable for topical administration include lozenges, which typically contain the ingredient in a flavored base such as sucrose and acacia or tragacanth, and pastilles, which contain the active ingredient in an inert base such as gelatin and glycerin, or sucrose and acacia.

[0167] Compositions suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain antioxidants, buffers, bactericides, and solutes that render the preparation isotonic with the subject's blood, as well as aqueous and non-aqueous sterile suspensions which may contain suspending agents and thickening agents. The preparations may be presented in unit-dose or multi-dose containers such as sealed ampoules or vials and may be stored in a freeze-dried (lyophilized) state, requiring only the addition of a sterile liquid carrier such as water for injection immediately before use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules, and tablets.

[0168] Such injections may be in the form of, for example, a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to techniques known in the art using suitable dispersing or wetting agents (e.g., Tween 80, etc.) and suspending agents. Sterile injectable preparations may be sterile injectable solutions or suspensions in a non-toxic, parenterally acceptable diluent or solvent, such as a solution in 1,3-butanediol. Acceptable vehicles and solvents that can be used include mannitol, water, Ringer's solution, and isotonic sodium chloride solution. Additionally, sterile, fixed oils are commonly used as solvents or suspending media. For this purpose, any bland fixed oil may be used, including synthetic mono- or diglycerides. Fatty acids, such as oleic acid and its glyceride derivatives, are useful in the preparation of injections, as are natural pharmaceutically acceptable oils, such as olive oil and castor oil, especially their polyoxyethylated versions. These oil solutions or suspensions may also contain long-chain alcohol diluents or dispersants.

[0169] The compounds of the present invention can also be administered in the form of liposomes. As is well known in the art, liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by mono- or multi-lamellar hydrated liquid crystals dispersed in an aqueous medium. Any non-toxic, physiologically acceptable, and metabolizable lipid capable of forming liposomes can be used. The liposome-formed compositions of the present invention may contain stabilizers, preservatives, excipients, etc., in addition to the compounds of the present invention. Preferred lipids are both natural and synthetic phospholipids and phosphatidylcholines (lecithins). Methods for forming liposomes are known in the art. See, for example, Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, NY (1976), p. 33 et seq.

[0170] The pharmaceutical composition of the present invention can be administered in the form of suppositories for rectal administration.These compositions can be prepared by mixing the compound of the present invention with suitable non-irritating excipients that are solid at room temperature but liquid at rectal temperature, and therefore melt in the rectum to release active ingredient.Such materials include but are not limited to cocoa butter, beeswax, polyethylene glycol, etc.

[0171] The pharmaceutical compositions of the invention may be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well known in the art of pharmaceutical formulation and may be prepared as solutions in saline using benzyl alcohol or other suitable preservatives, absorption enhancers to enhance bioavailability, fluorocarbons, and / or other solubilizing or dispersing agents well known in the art.

[0172] Topical administration of the pharmaceutical compositions of the present invention is particularly useful when the desired treatment involves areas or organs easily accessible by topical application. When applied topically to the skin, the pharmaceutical composition should be formulated in a suitable ointment containing the active ingredient suspended or dissolved in a carrier. Carriers for topical administration of the compounds of the present invention include, but are not limited to, mineral oil, liquid petroleum, white petroleum, propylene glycol, polyoxyethylene polyoxypropylene compounds, emulsifying wax, and water. Alternatively, the pharmaceutical composition can be formulated in a suitable lotion or cream containing the active compound suspended or dissolved in a carrier. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, and water. The pharmaceutical compositions of the present invention can also be applied topically to the lower intestinal tract in the form of a rectal suppository or a suitable enema. Topical transdermal patches and iontophoretic administration are also encompassed by the present invention.

[0173] The treatments disclosed herein can be used in combination with or in addition to other treatments, hi certain embodiments, the subject is further administered one or more of chemotherapy, radiation therapy, targeted therapy, immunotherapy, and hormone therapy.

[0174] Exemplary additional therapeutically active agents include, but are not limited to, drug compounds (e.g., compounds approved by the U.S. Food and Drug Administration (FDA) as defined in the Code of Federal Regulations (CFR)), peptides, proteins, carbohydrates, monosaccharides, oligosaccharides, polysaccharides, nucleoproteins, mucoproteins, lipoproteins, synthetic polypeptides or proteins, small molecules bound to proteins, glycoproteins, steroids, nucleic acids, DNA, RNA, nucleotides, nucleosides, oligonucleotides, antisense oligonucleotides, lipids, hormones, vitamins, and small organic molecules.

[0175] In certain embodiments, compounds of the invention may be administered in combination with endocrine therapy, for example, agents such as letrozole, fulvestrant, tamoxifen, exemestane, or anastrozole.

[0176] In some embodiments, compounds of the invention may be administered in combination with chemotherapeutic agents such as docetaxel, paclitaxel, cisplatin, carboplatin, capecitabine, gemcitabine, or vinorelbine. In another embodiment, compounds of the invention may be administered in combination with anti-HER2 agents such as trastuzumab or pertuzumab.

[0177] In certain embodiments, the methods disclosed herein are combined with one or more of immune checkpoint blockade, T cell co-signaling, and tumor-targeted antibody therapy.

[0178] In certain embodiments, the method further comprises administering to the subject a chemotherapeutic agent.

[0179] In certain embodiments, the method further comprises administering radiation therapy to the subject. In certain embodiments, the method further comprises administering targeted therapy to the subject. In certain embodiments, the method further comprises administering immunotherapy to the subject. In certain embodiments, the method further comprises administering hormone therapy to the subject.

[0180] As used herein, the term "chemotherapeutic agent" refers to a chemical compound useful in the treatment of cancer. Examples of chemotherapeutic agents include erlotinib (TARCEVA®, Genentech / OSI Pharm.), bortezomib (VELCADE®, Millennium Pharm.), fulvestrant (FASLODEX®, AstraZeneca), Sutent (SU11248, Pfizer), letrozole (FEMARA®, Novartis), imatinib mesylate (GLEEVEC®, Novartis), PTK787 / ZK 222584 (Novartis), oxaliplatin (Eloxatin®, Sanofi), 5-FU (5-fluorouracil), leucovorin, rapamycin (Sirolimus, RAPAMUNE®, Wyeth), lapatinib (TYKERB®, GSK572016, GlaxoSmithKline), lonafarnib (SCH 66336), sorafenib (BAY43-9006, Bayer Labs), and gefitinib (IRESSA®, AstraZeneca), AG1478, AG1571 (SU 5271, Sugen), alkylating agents such as thiotepa and CYTOXAN® cyclophosphamide, alkylsulfonates such as busulfan, improsulfan, and piposulfan, aziridines such as benzodopa, carboquone, metrdopa, and uredopa, ethylenimines and methylmelamines (including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and trimethylmelamine), acetogenins (especially bullatacin and bullatasinone), camptothecin (including the synthetic analogue topotecan), bryostatin, kallistatin, CC-1065 (including its adozelesin, carzelesin and bizelesin synthetic analogues), cryptophycins (especially cryptophycin 1 and cryptophycin 8), dolastatin, duocarmycin (including the synthetic analogues KW-2189 and CB1-TM1), eleutherobin, pancratistatin, sarcodictin, spongistatin, nitrogen mustards such as chlorambucil, chlornaphazine, chlorophosphamide,estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, nobembine, phenesterine, prednimustine, trofosfamide, uracil mustard, nitrosoureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, ranimustine, antibiotics such as enediyne antibiotics (e.g., calicheamicin, particularly calicheamicin gamma 1l and calicheamicin omega 1l (Angew Chem. Intl. Ed. Engl. (1994) 33:183-186), dynemicins (including dynemicin A), bisphosphonates such as clodronate, esperamicin, neocarzinostatin chromophores and related enediyne antibiotic chromophores), aclacinomycin, actinomycin, autramycin, azaserine, bleomycin, cactinomycin, carabicin, caminomycin, carzinophilin, Chromomycin, dactinomycin, daunorubicin, detrubicin, 6-diazo-5-oxo-L-norleucine, Adriamycin® (doxorubicin), morpholino-doxorubicin, cyanomorpholinodoxorubicin, 2-pyrrolinodoxorubicin and deoxydoxorubicin), epirubicin, ethonubicin, idarubicin, marcellomycin, mitomycins such as mitomycin C, mycophenolic acid, noga ramycin, olivomycin, peplomycin, porfiromycin, puromycin, chelamycin, rhodrubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin, antimetabolites such as methotrexate and 5-fluorouracil (5-FU), folic acid analogues such as denopterin, methotrexate, pteropterin, trimetrexate, purine analogues such as fludarabine, 6-mercaptopurine, thiamnipurine, thioguanine, pyrimidine analogues such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine, androgens such as calstalon, dromostanolone propionate, epithiostanol, mepitiostane, testolactone, antiadrenal drugs such as aminoglutethimide, mitotane, trilostane,Folic acid supplements such as furoic acid, aceglatone, aldophosphamide glycosides, aminolevulinic acid, eniluracil, amsacrine, bestravcil, bisantrene, edatraxate, defamin, demecolcine, diazicon, elformitin, elliptinium acetate, epothilone, etoglucide, gallium nitrate, hydroxyurea, lentinan, lonidanine, maytansinoids such as maytansine and ansamitocins, mitoguazone, mitoxantrone, mopidamol, nitralin, pentostatin, fenamet, pirarubicin, losoxantrone, podophyllic acid, 2-ethylhydrazide, procarbazine, PSK® polysaccharide complex (JHS Natural Products, Eugene, Oreg.), razoxane, rhizoxin, schizofuran, spirogermanium, tenuazonic acid, reazicon, 2,2',2"-trichlorotriethylamine, trichothecenes (especially T-2 toxin, veracrine A, roridin A, and anguidine), urethane, vindesine, dacarbazine, mannomustine, mitobronitol, mitolactol, pipobroman, gacytosine, arabinoside ("Ara-C"), cyclophosphamide, thiotepa, taxoids such as TAXOL® (paclitaxel, Bristol-Myers Squibb Oncology, Princeton, NJ), ABRAXANE® (Cremophor-free), albumin-modified paclitaxel nanoparticle formulations (American Pharmaceutical Partners, Schaumberg, 111.), and TAXOTERE® (docetaxel, Rhone-Poulenc Rorer, Antony, France), chlorambucil, GEMZAR® (gemcitabine), 6-thioguanine, mercaptopurine, methotrexate, platinum analogues such as cisplatin and carboplatin, vinblastine, etoposide (VP-16), ifosfamide, mitoxantrone, vincristine, NAVELBINE® (vinorelbine), novantrone, teniposide, edatrexate, daunomycin, aminopterin, capecitabine (XELODA®), ibandronate, CPT-11, the topoisomerase inhibitor RFS 2000,Difluoromethylornithine (DMFO), retinoids such as retinoic acid, and pharmaceutically acceptable salts, acids, and derivatives of any of the above.

[0181] Examples of second (or more) agents or therapies include immunotherapies (e.g., PD-1 inhibitors (pembrolizumab, nivolumab, cemiplimab), PD-L1 inhibitors (atezolizumab, avelumab, durvalumab), CTLA4 antagonists, cell signaling inhibitors (e.g., imatinib, gefitinib, bortezomib, erlotinib, sorafenib, sunitinib, dasatinib, vorinostat, lapatinib, temsirolimus, nilotinib, everolimus, pazopanib, trastuzumab, bevacizumab, cetuximab, ranibizumab, pegaptanib, panitumumab, etc.), mitotic inhibitors (e.g., pak These include, but are not limited to, cyclosporine, ritaxel, vincristine, vinblastine, etc.), alkylating agents (e.g., cisplatin, cyclophosphamide, clomabucil, carmustine, etc.), antimetabolites (e.g., methotrexate, 5-FU, etc.), intercalating anticancer agents (e.g., actinomycin, anthracyclines, bleomycin, mitomycin C, etc.), topoisomerase inhibitors (e.g., irinotecan, topotecan, teniposide, etc.), immunotherapeutic agents (e.g., interleukins, interferons, etc.), and antihormonal agents (e.g., tamoxifen, raloxifene, etc.).

[0182] Certain compounds of the present invention may exist in particular geometric or stereoisomeric forms. The present invention is intended to include within its scope all such compounds, including cis and trans isomers, R and S enantiomers, diastereomers, (D)-isomers, (L)-isomers, racemic mixtures thereof, and other mixtures thereof. Additional asymmetric carbon atoms may be present in a substituent, such as an alkyl group. The present invention is intended to include all such isomers, as well as mixtures thereof.

[0183] The present invention can utilize isomer mixtures containing any of a variety of isomer ratios. For example, when only two isomers are combined, the present invention contemplates mixtures containing isomer ratios of 50:50, 60:40, 70:30, 80:20, 90:10, 95:5, 96:4, 97:3, 98:2, 99:1, or 100:0. Those skilled in the art will readily recognize that similar ratios are contemplated for more complex isomer mixtures.

[0184] For example, if a specific enantiomer of a compound of the invention is desired, it can be prepared by asymmetric synthesis or by derivatization with a chiral auxiliary, whereupon the resulting diastereomeric mixture is separated and the auxiliary cleaved to yield the pure desired enantiomer. Alternatively, if the molecule contains a basic functional group such as amino, or an acidic functional group such as carboxyl, diastereomeric salts can be formed with a suitable optically active acid or base, and the diastereomers thus formed can then be resolved by fractional crystallization or chromatographic methods well known in the art, followed by recovery of the pure enantiomer.

[0185] Isotopically labeled compounds are also within the scope of the present disclosure.As used herein, "isotopically labeled compounds" refers to compounds disclosed herein, including pharmaceutical salts and prodrugs thereof, in which one or more atoms are replaced with an atom having an atomic mass or mass number different from the atomic mass or mass number normally found in nature.Examples of isotopes that can be incorporated into compounds disclosed herein include: 2 H, 3 H, 13 C. 14 C. 15 N, 18 O. 17 O. 31 P, 32 P, 35 S, 18 F, 36 Includes isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as Cl.

[0186] By isotopically labeling the compounds disclosed herein, the compounds may be useful in drug and / or substrate tissue distribution assays. 3 H) and carbon-14 labeling ( 14 C) compounds are particularly preferred because they are easy to prepare and detect. 2 Substitution with heavier isotopes, such as H, may be preferable in some circumstances because increased metabolic stability may confer certain therapeutic advantages, such as increased in vivo half-life or reduced dosage. The isotopically labeled compounds disclosed herein (including pharmaceutical salts, esters, and prodrugs thereof) may be prepared by any means known in the art.

[0187] Furthermore, the normally abundant hydrogen ( 1 Substitution of hydrogen (H) with heavier isotopes, such as deuterium, can confer certain therapeutic advantages, such as improved absorption, distribution, metabolism, and excretion (ADME) properties, producing drugs with improved efficacy, safety, and tolerability. 12 C 13 Substitution with C may also be advantageous (see WO2007 / 005643, WO2007 / 005644, WO2007 / 016361, and WO2007 / 016431).

[0188] Stereoisomers (e.g., cis and trans isomers) and all optical isomers (e.g., R and S enantiomers) of the compounds disclosed herein, as well as racemates, diastereomers and other mixtures of such isomers, are within the scope of the disclosed invention.

[0189] After preparation, the compounds of the invention are preferably isolated and purified to provide compositions containing 95% or more by weight ("substantially pure"), which can then be used or formulated as described herein. In certain embodiments, the compounds of the invention are greater than 99% pure.

[0190] Solvates and polymorphs of the compounds of the invention are also contemplated herein. Solvates of the compounds of the invention include, for example, hydrates.

[0191] Any suitable route of administration can be used, e.g., parenteral, intravenous, subcutaneous, intramuscular, intracerebroventricular, internal, intraperitoneal, direct, or oral administration. The most suitable method of administration for a particular patient will depend on the nature and severity of the disease or condition being treated, or the nature of the treatment being used, and the nature of the active ingredient.

[0192] Compositions for parenteral injection include pharmaceutically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions, or emulsions, as well as sterile powders for reconstitution into sterile injectable solutions or dispersions immediately before use. Examples of suitable aqueous and non-aqueous carriers, diluents, solvents, or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, etc.), carboxymethylcellulose and suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by maintaining the required particle size in the case of dispersions, and by the use of surfactants.

[0193] These compositions may also contain auxiliary agents such as preservatives, wetting agents, emulsifying agents, dispersing agents, etc. Prevention of microbial action can be ensured by the addition of various antibacterial and antifungal agents, for example, paragen, chlorobutanol, phenol sorbic acid, etc. It may also be desirable to include isotonic agents such as sugars, sodium chloride, etc. Prolonged absorption of injectable pharmaceutical forms can be brought about by the inclusion of agents that delay absorption, such as aluminum monostearate and gelatin.

[0194] The compounds of the present invention can also be administered in the form of liposomes. As is well known in the art, liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by mono- or multi-lamellar hydrated liquid crystals dispersed in an aqueous medium. Any non-toxic, physiologically acceptable, and metabolizable lipid capable of forming liposomes can be used. The liposome-formed compositions of the present invention may contain stabilizers, preservatives, excipients, etc., in addition to the compounds of the present invention. Preferred lipids are both natural and synthetic phospholipids and phosphatidylcholines (lecithins). Methods for forming liposomes are known in the art. See, for example, Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, NY (1976), p. 33 et seq.

[0195] The total daily dose of the compositions of the present invention to a human or other mammalian host, when administered in single or divided doses, can be, for example, 0.0001 to 300 mg / kg body weight, more typically 1 to 300 mg / kg body weight per day, or 0.0001 to 300 mg / kg body weight twice daily.

[0196] The materials, compositions, and components disclosed herein can be used in, used in combination with, used in the preparation of, or are products of, the disclosed methods and compositions. When combinations, subsets, interactions, groups, etc. of these materials are disclosed, it is understood that although specific reference to each of the various individual and collective combinations and permutations of these compounds may not be explicitly disclosed, each is specifically contemplated and described herein. For example, when a method is disclosed and contemplated, and numerous modifications that can be made to numerous molecules included in the method are discussed, each and every combination and permutation of the method and possible modifications is specifically contemplated unless specifically indicated to the contrary. Likewise, subsets or combinations of these are also specifically contemplated and disclosed. This concept applies to all aspects of the present disclosure, including, but not limited to, method steps using the disclosed compositions. Thus, when various additional steps can be performed, it is understood that each of these additional steps can be performed with any particular method step or combination of method steps of the disclosed methods, and that each such combination or subset of combinations is specifically contemplated and should be considered disclosed.

[0197] Example The following examples are presented to illustrate the present invention and are not intended to limit the scope or spirit of the invention.

[0198] The compounds of the present invention (including those specifically disclosed hereinabove and below) can be prepared as shown in the following schemes. Although the present invention has been described in detail with preferred embodiments, those skilled in the art should understand that any modifications, variations and equivalent substitutions made to the present invention within the scope of the present invention should be protected by the present invention. [Table 7] [Table 8]

[0199] LC-MS method: Shimadzu LCMS2020, reversed-phase column (Shim-Pack Scepter C18, 33 x 3.0 mm, 3 μm), eluent: A: HO / MeCN / FA = 90 / 10 / 0.05, B: MeCN, detection: MS, ELS, UV (100 μL split to MS with in-line UV detector), MS ionization: electrospray (positive and negative ions). ES-API = electrospray atmospheric pressure ionization.

[0200] HPLC purification method: Instruments: Shimadzu FRC-40, Shimadzu LH-40, Shimadzu LC-8A, GX-281. Columns: YMC-Triart C18, 250*20mm, 5um, Welch Ultimate XB-C18, 250*21.2mm, 5um. Detection wavelengths: 220, 254nM. Flow rate: 15ml / min - 20ml / min. Run time: 8min. Column temperature: 25℃.

[0201] Compound synthesis Basic Step 1 [ka] Basic Step 2 [ka] Synthesis of common intermediate 1: 1-(tert-butyl)-3-((1S,3R)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1H-pyrazol-5-amine [ka] Step A. Methyl 1,4-dioxaspiro[4.4]nonane-7-carboxylate. To a stirred solution of methyl 3-oxocyclopentanecarboxylate (70 g, 492.9 mmol) in toluene (600 mL) was added ethane-1,2-diol (61.1 g, 985.8 mmol), molecular sieves (15 g), and TsOH (8.5 g, 49.3 mmol) at room temperature. After stirring overnight at 110 °C, the cooled mixture was concentrated. The residue was purified by chromatography (silica gel, 0–20%, EtOAc in PE) to give methyl 1,4-dioxaspiro[4.4]nonane-7-carboxylate (34.8 g, 187.1 mmol, 31%) as a colorless oil.

[0202] Step B. 3-{1,4-Dioxaspiro[4.4]nonan-7-yl}-3-oxopropanenitrile. To a stirred solution of n-BuLi (90 mL, 224.5 mmol, 2.5 M in hexane) in THF (200 mL) was added dropwise at −60 °C. After stirring at −70 °C for 1 h, a solution of methyl 1,4-dioxaspiro[4.4]nonane-7-carboxylate (34.8 g, 187.1 mmol) in THF (50 mL) was added dropwise at −60 °C. After stirring at −70 °C for 2 h, the reaction mixture was quenched with water (100 mL), adjusted to pH 7 with 1 N aqueous HCl, and extracted with ethyl acetate (50 mL). The combined organic layers were washed with brine (30 mL), dried over NaSO, and concentrated under reduced pressure to give crude 3-{1,4-dioxaspiro[4.4]nonan-7-yl}-3-oxopropanenitrile (32.8 g, 168.2 mmol, 90%) as a yellow oil, which was used directly in the next step.

[0203] Step C. 1-tert-butyl-3-{1,4-dioxaspiro[4.4]nonan-7-yl}-1H-pyrazol-5-amine. To a stirred solution of sodium hydroxide (13.5 g, 336.4 mmol) in EtOH (300 mL) was added tert-butylhydrazine (31.3 g, 252.3 mmol) at room temperature. After stirring at room temperature for 1 h, 3-{1,4-dioxaspiro[4.4]nonan-7-yl}-3-oxopropanenitrile (32.8 g, 168.2 mmol) was added. After stirring at 80 °C overnight, the mixture was filtered. The filtrate was poured into water, the pH was adjusted to 6–7 with 1 M aqueous HCl, and extracted with EtOAc (80 mL × 2). The combined organic phase was washed with water and brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by chromatography (silica gel, 0-50%, EtOAc in PE) to give 1-tert-butyl-3-{1,4-dioxaspiro[4.4]nonan-7-yl}-1H-pyrazol-5-amine (30 g, 113 mmol, 67%) as a yellow oil. LCMS: m / z 266 [M+H] + .

[0204] Step DN-(1-tert-butyl-3-{1,4-dioxaspiro[4.4]nonan-7-yl}-1H-pyrazol-5-yl)carbamate benzyl. To a stirred solution of 1-tert-butyl-3-{1,4-dioxaspiro[4.4]nonan-7-yl}-1H-pyrazol-5-amine (30 g, 113 mmol) in MeCN (350 mL) was added NaHCO (47.5 g, 565.3 mmol) and Cbz-Cl (29 g, 169.6 mmol) at 0 °C. After stirring overnight at room temperature, the mixture was filtered. The filtrate was concentrated and purified by chromatography (silica gel, 0-40%, EtOAc in PE) to give N-(1-tert-butyl-3-{1,4-dioxaspiro[4.4]nonan-7-yl}-1H-pyrazol-5-yl)benzylcarbamate (28 g, 70 mmol, 62%) as a yellow oil. LCMS: m / z 400 [M+H] + .

[0205] Step E—[1-tert-Butyl-3-(3-oxocyclopentyl)-1H-pyrazol-5-yl]carbamate benzyl. To a stirred solution of N-(1-tert-butyl-3-{1,4-dioxaspiro[4.4]nonan-7-yl}-1H-pyrazol-5-yl)carbamate benzyl (28 g, 70 mmol) in acetone (150 mL) was added HO (150 mL) and TsOH (6 g, 35 mmol) at room temperature. After stirring at 60 °C overnight, the cooled mixture was poured into water (150 mL) and extracted with EtOAc (50 mL × 2). The combined organic phase was washed with brine, dried over NaSO, filtered, and concentrated. The residue was purified by chromatography (silica gel, 0-50%, EtOAc in PE) to give N-[1-tert-butyl-3-(3-oxocyclopentyl)-1H-pyrazol-5-yl]carbamate benzyl (21 g, 59 mmol, 84%) as a white solid. LCMS: m / z 356 [M+H] - . 1 H NMR (400MHz, DMSO)δ 9.07(s, 1H), 7.36-7.25(m, 5H), 5.97(s, 1H), 5.06(s, 2H), 3.30-3.23(m, 1H), 2.43- 2.33(m, 1H), 2.27-2.20(m, 1H), 2.19-2.10(m, 3H), 1.90-1.81(m, 1H), 1.42(s, 9H).

[0206] Step F: N-[1-tert-butyl-3-(3-hydroxycyclopentyl)-1H-pyrazol-5-yl]carbamate benzyl. To a stirred solution of N-[1-tert-butyl-3-(3-oxocyclopentyl)-1H-pyrazol-5-yl]carbamate benzyl (10 g, 28.134 mmol) in THF (100 mL) was slowly added LiBH(Et) (56 mL, 56 mmol, 1 M in THF) at −65 °C. After stirring at −65 °C for 1.5 h, NaHCO (aqueous, 40 mL) was added to the mixture at −30 °C (the mixture slowly turned into a glassy solid), followed by the addition of HO (19 g, 562 mmol) slowly from −10 °C to room temperature (the glassy solid slowly returned to a normal mixture and became easily stirrable). After stirring for an additional 1.5 h at room temperature, the mixture was slowly poured into saturated NaSO (aqueous, 100 mL) and extracted with EtOAc (30 mL × 2). The combined organic phases were washed with brine, dried over NaSO, filtered, and concentrated. TLC (DCM:MeOH = 10:1) showed a less polar spot, which was the desired cis product. The residue was purified by chromatography (silica gel, 0-3%, MeOH in DCM) to give the cis isomer of N-[1-tert-butyl-3-(3-hydroxycyclopentyl)-1H-pyrazol-5-yl]carbamate benzyl (6.6 g, 18.5 mmol, 65%, less polar spot) as a white solid. LCMS: m / z 358 [M+H] + . 1 H NMR (400MHz, DMSO)δ 9.07(s, 1H), 7.49-7.21(m, 5H), 5.93(s, 1H), 5.12(s, 2H), 4.59(d, J=4.4Hz, 1H), 4.15(dd, J=10.4, 4.5Hz, 1H) , 2.96-2.77(m, 1H), 2.30-2.10(m, 1H), 1.90-1.81(m, 1H), 1.78-1.65(m, 2H), 1.63-1.55(m, 1H), 1.48(s, 9H).

[0207] Step GN-{1-tert-butyl-3-[(1S,3R)-3-hydroxycyclopentyl]-1H-pyrazol-5-yl}carbamate benzyl. N-[1-tert-butyl-3-(3-hydroxycyclopentyl)-1H-pyrazol-5-yl]carbamate benzyl (6.6 g, 18.5 mmol) was purified by preparative SFC to give N-{1-tert-butyl-3-[(1S,3R)-3-hydroxycyclopentyl]-1H-pyrazol-5-yl}carbamate benzyl (3.1 g, 8.6 mmol, 46.7%) as a white solid. LCMS: m / z 358 [M+H] + .

[0208] Step H. (1-(tert-butyl)-3-((1S,3R)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)carbamate benzyl. To a solution of N-{1-tert-butyl-3-[(1S,3R)-3-hydroxycyclopentyl]-1H-pyrazol-5-yl}carbamate benzyl (6.2 g, 17.3 mmol) in DCM (100 mL) was added DMAP (0.21 g, 1.73 mmol), 1H-imidazole (2.36 g, 34.7 mmol), and TBSCl (2.61 g, 17.3 mmol) at room temperature. The reaction mixture was stirred at room temperature overnight. The reaction was concentrated in vacuo. The residue was purified by silica gel column chromatography (eluted with EA in PE [gradient: 0-50%]) to obtain the title compound N-{1-tert-butyl-3-[(1S,3R)-3-[(tert-butyldimethylsilyl)oxy]cyclopentyl]-1H-pyrazol-5-yl}carbamate benzyl (7 g, 14.8 mmol, 85.7%) as a colorless oil. LCMS: m / z 472 [M+H] + .

[0209] Step I. 1-(tert-Butyl)-3-((1S,3R)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1H-pyrazol-5-amine. To a solution of N-{1-tert-butyl-3-[(1S,3R)-3-[(tert-butyldimethylsilyl)oxy]cyclopentyl]-1H-pyrazol-5-yl}carbamate benzyl (7 g, 14.8 mmol) in THF (50 mL) and ethyl acetate (50 mL) was added 10% Pd / C (0.20 g, 1.86 mmol) at room temperature. The reaction mixture was stirred at room temperature under H using a H balloon for 3 h. The reaction mixture was filtered and concentrated to give the title compound 1-tert-butyl-3-[(1S,3R)-3-[(tert-butyldimethylsilyl)oxy]cyclopentyl]-1H-pyrazol-5-amine (4.8 g, 14.2 mmol, 96%) as a colorless oil. LCMS: m / z 338 [M+H] + . 1 H NMR (400MHz, CDCl3)δ 5.47(s, 1H), 4.32-4.08(m, 1H), 3.47(s, 2H), 2.98-2.80(m, 1H), 2.34-2.19(m, 1H), 1.98-1.89(m, 1H) ), 1.85-1.75(m, 2H), 1.72-1.64(m, 1H), 1.63-1.59(m, 10H), 0.90-0.88(m, 9H), 0.05(d, J=2Hz, 6H).

[0210] Synthesis of common intermediate 2: (1R,3S)-3-[5-amino-1-(2-methylprop-2-yl)pyrazol-3-yl]cyclopentyl(prop-2-ylamino)methanoate [ka] Step A: {[2-(2-methylprop-2-yl)-5-[(1S,3R)-3-{[(prop-2-ylamino)carbonyl]oxy}cyclopentyl]pyrazol-3-yl]amino}methanoate benzyl. To a solution of ({5-[(1S,3R)-3-hydroxycyclopentyl]-2-(2-methylprop-2-yl)pyrazol-3-yl}amino)methanoate benzyl (1.0 g, 2.8 mmol) in THF (20 mL) was added t-BuOK (4.2 mL, 1 M in THF) at 0 °C, and the reaction was stirred at 0 °C for 30 minutes. A solution of 2-isocyanatopropane (290 mg, 3.6 mmol) in 5 mL of THF was added dropwise to the reaction at 0 °C. The reaction mixture was allowed to warm to room temperature and stirred for 1 hour, and TLC and LCMS indicated the reaction was complete. The reaction mixture was poured into ice water and extracted with EA (30 mL*3). The combined organic layer was separated, washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography eluting with methanol in dichloromethane (gradient: 0-3%) to afford the title compound {[2-(2-methylprop-2-yl)-5-[(1S,3R)-3-{[(prop-2-ylamino)carbonyl]oxy}cyclopentyl]pyrazol-3-yl]amino}methanoate benzyl (1.2 g, 2.7 mmol, 96.9%) as a white solid. LCMS: m / z 443 [M+H] + . 1 H NMR (400MHz, DMSO)δ 9.07(s, 1H), 7.45-7.33(m, 5H), 6.92(d, J=7.6Hz, 1H), 5.93(s, 1H), 5.11(s, 2H), 4.97(s, 1H), 3.60-3.50(m, 1H) , 3.01-2.88(m, 1H), 2.40-2.29(m, 1H), 1.98-1.77(m, 2H), 1.75-1.56(m, 3H), 1.47(s, 9H), 1.02(d, J=6.4Hz, 6H).

[0211] Step B: (1R,3S)-3-[5-amino-1-(2-methylprop-2-yl)pyrazol-3-yl]cyclopentyl(prop-2-ylamino)methanoate. A suspension of {[2-(2-methylprop-2-yl)-5-[(1S,3R)-3-{[(prop-2-ylamino)carbonyl]oxy}cyclopentyl]pyrazol-3-yl]amino}methanoate benzyl (1.2 g, 2.7 mmol) and 10% Pd / C (290 mg) in THF (10 mL) and EA (10 mL) was stirred at room temperature under a H atmosphere using a balloon for 18 hours. The reaction mixture was filtered and concentrated. The residue was purified by silica gel column chromatography (eluting with methanol in dichloroform (gradient: 0-6%)) to obtain the title compound (1R,3S)-3-[5-amino-1-(2-methylprop-2-yl)pyrazol-3-yl]cyclopentyl(prop-2-ylamino)methanoate (700 mg, 2.2 mmol, 83.7%) as a syrupy solid. LCMS: m / z 309 [M+H] + . 1 H NMR (400MHz, DMSO)δ 6.88(d, J=7.6Hz, 1H), 5.22(s, 1H), 4.94(s, 1H), 4.70(s, 2H), 3.62-3.53(m, 1H), 2.84-2.75(m, 1 H), 2.34-2.24(m, 1H), 1.86-1.76(m, 2H), 1.68-1.53(m, 3H), 1.48(s, 9H), 1.03(d, J=6.4Hz, 6H).

[0212] Synthesis of common intermediate 3: 1-(tert-butyl)-3-((1s,4s)-4-((tert-butyldiphenylsilyl)oxy)cyclohexyl)-1H-pyrazol-5-amine [ka] Step A: (1s,4s)-4-((tert-butyldiphenylsilyl)oxy)cyclohexane-1-carboxylate methyl ester. To a solution of (1s,4s)-4-hydroxycyclohexane-1-carboxylate methyl ester (5 g, 31.6 mmol) in DCM (30 mL) was added DMAP (0.39 g, 3.16 mmol), imidazole (6.46 g, 94.8 mmol), and TBDPSCl (9.83 mL, 37.9 mmol), and the reaction was stirred at room temperature overnight. The reaction was concentrated in vacuo. The residue was purified by silica gel column chromatography (eluted with EA in PE [gradient: 0 to 50%]) to give the title compound (1s,4s)-4-[(tert-butyldiphenylsilyl)oxy]cyclohexane-1-carboxylate methyl ester (10.1 g, 25.4 mmol, 80.4%) as a colorless oil. LCMS:ESI m / z 397[M+H] + .

[0213] Step B: 3-((1s,4s)-4-((tert-butyldiphenylsilyl)oxy)cyclohexyl)-3-oxopropanenitrile. A solution of n-BuLi (20.0 mL, 50.0 mmol) in THF (60 mL) was cooled to −65° C. ACN (1.48 g, 31.5 mmol) was added dropwise at −65° C. The reaction mixture was stirred at −65° C. for 1 h. A solution of (1s,4s)-4-((tert-butyldiphenylsilyl)oxy)cyclohexane-1-carboxylate methyl (5.00 g, 12.6 mmol) in THF (10 mL) was added dropwise at −65° C. The resulting mixture was stirred at −65° C. for 1 h. After TLC showed completion, the reaction mixture was quenched with water (50 mL), adjusted to pH=7 with 1 N HCl, and extracted with EA (50 mL*3). The combined organic layers were washed with brine (30 mL), dried over NaSO and concentrated under reduced pressure to give 3-((1s,4s)-4-((tert-butyldiphenylsilyl)oxy)cyclohexyl)-3-oxopropanenitrile (5.10 g, 12.6 mmol, 99.8%) as an oil, which was used directly in the next step.

[0214] Step C: 1-(tert-butyl)-3-((1s,4s)-4-((tert-butyldiphenylsilyl)oxy)cyclohexyl)-1H-pyrazol-5-amine. To a solution of N-tert-butylhydroxylamine (1.91 g, 21.4 mmol) in EtOH (50 mL) was added NaOH (0.6 g, 15.1 mmol). The reaction mixture was stirred at room temperature for 1 hour, followed by the addition of 3-((1s,4s)-4-((tert-butyldiphenylsilyl)oxy)cyclohexyl)-3-oxopropanenitrile (5.10 g, 12.6 mmol). The ensuing mixture was stirred at 80° C. overnight. LCMS indicated the reaction was complete. The cooled reaction mixture was filtered and concentrated. The residue was purified by FC on silica gel (eluted with PE / EA 1:1) to give a yellow solid 1-(tert-butyl)-3-((1s,4s)-4-((tert-butyldiphenylsilyl)oxy)cyclohexyl)-1H-pyrazol-5-amine (4.20 g, 8.83 mmol, 70%). LC-MS: ESI m / z 476.75 [M+H] + . 1 H NMR (400MHz, DMSO)δ 7.65-7.57(m, 4H), 7.48-7.39(m, 6H), 5.25(s, 1H), 4.71(s, 2H), 4.00(brs, 1H), 2.40-2.31(m, 1H), 1 .89-1.78(m, 2H), 1.67-1.59(m, 2H), 1.58-1.49(m, 2H), 1.49(s, 9H), 1.45-1.37(m, 2H), 1.04(s, 9H).

[0215] Synthesis of common intermediate 4: (1s,3s)-3-(5-amino-1-(tert-butyl)-1H-pyrazol-3-yl)cyclobutyl isopropylcarbamate [ka] Step A: (1s,3s)-3-((tert-butyldiphenylsilyl)oxy)cyclobutane-1-carboxylate methyl ester. To a solution of (1s,3s)-3-hydroxycyclobutane-1-carboxylate methyl ester (5 g, 31.6 mmol) in DCM (30 mL) was added DMAP (0.39 g, 3.16 mmol), imidazole (6.46 g, 94.8 mmol), and TBDPSCl (9.83 mL, 37.9 mmol), and the reaction was stirred at room temperature overnight. The reaction was concentrated in vacuo. The residue was purified by silica gel column chromatography (eluted with EA in PE [gradient: 0 to 50%]) to give the title compound (1s,3s)-3-((tert-butyldiphenylsilyl)oxy)cyclobutane-1-carboxylate methyl ester (14 g, 25.4 mmol, 80.4%) as a colorless oil. LCMS:ESI m / z 369.35[M+H] + .

[0216] Step B: 3-((1s,3s)-3-((tert-butyldiphenylsilyl)oxy)cyclobutyl)-3-oxopropanenitrile. To a stirred slurry of n-BuLi (10.0 mL, 25.2 mmol) in dry THF (150 mL) containing CHCN (1.98 mL, 37.8 mmol) at −45° C. under N was added (1s,3s)-3-((tert-butyldiphenylsilyl)oxy)cyclobutane-1-carboxylate methyl methyl (5 g, 12.6 mmol). The reaction mixture was stirred at −45° C. for 2 h. The reaction was diluted with HO and the aqueous layer was extracted with EA. The EA layers were combined and washed with saturated NaCl solution. The EA layer was dried over NaSO, filtered, and concentrated in vacuo. The compound 3-((1s,3s)-3-((tert-butyldiphenylsilyl)oxy)cyclobutyl)-3-oxopropanenitrile (5 g, 8.62 mmol, 68%) was obtained as a yellow solid and used in the next step without further purification. LCMS: ESI m / z 378.20 [M+H] + .

[0217] Step C: 1-(tert-butyl)-3-((1s,3s)-3-((tert-butyldiphenylsilyl)oxy)cyclobutyl)-1H-pyrazol-5-amine. To a solution of 3-((1s,3s)-3-((tert-butyldiphenylsilyl)oxy)cyclobutyl)-3-oxopropanenitrile (5 g, 12.3 mmol) in EtOH (100 mL) was added tert-butylhydrazine (2.17 g, 24.6 mmol) and NaHCO (2.07 g, 24.6 mmol), and the reaction mixture was stirred at 80 °C for 18 h. The residue was purified by silica gel column chromatography (eluted with EA in PE [gradient: 0-50%]) to give 1-(tert-butyl)-3-((1s,3s)-3-((tert-butyldiphenylsilyl)oxy)cyclobutyl)-1H-pyrazol-5-amine (2.1 g, 3.73 mmol, 30%) as a white solid. LCMS: ESI m / z 448.3 [M+H]

[0218] Step D: (1-(tert-butyl)-3-((1s,3s)-3-((tert-butyldiphenylsilyl)oxy)cyclobutyl)-1H-pyrazol-5-yl)carbamate benzyl. To a solution of 1-(tert-butyl)-3-((1s,3s)-3-((tert-butyldiphenylsilyl)oxy)cyclobutyl)-1H-pyrazol-5-amine (1.50 g, 3.35 mmol) in ACN (15 mL) was added CbzCl (0.57 g, 3.35 mmol) and NaHCO (0.28 g, 3.35 mmol) over 30 min at 0 °C. The mixture was stirred at room temperature overnight. TLC (PE / EA = 5:1) showed that the starting material was consumed and a new spot was observed. The reaction mixture was diluted with 50 mL of water and extracted with EA (50 mL × 3). The organic phase was washed with brine, dried over Na2SO4, and concentrated. The residue was purified by silica gel chromatography (15 g column) using 0-20% EtOAc / hexanes to give (1-(tert-butyl)-3-((1s,3s)-3-((tert-butyldiphenylsilyl)oxy)cyclobutyl)-1H-pyrazol-5-yl)carbamate benzyl (1.2 g, 2.06 mmol, 61%) as a yellow oil. LCMS: 582 [M+H]+ .

[0219] Step E: (1-(tert-butyl)-3-((1s,3s)-3-hydroxycyclobutyl)-1H-pyrazol-5-yl)carbamate benzyl. A solution of (1-(tert-butyl)-3-((1s,3s)-3-((tert-butyldiphenylsilyl)oxy)cyclobutyl)-1H-pyrazol-5-yl)carbamate benzyl (1.2 g, 2.06 mmol) in HCOOH (10 mL) was stirred at 50 °C for 5 h. The cooled reaction was rotary evaporated. The residue was dissolved in MeOH (5 mL) and HO (5 mL), and LiOH (0.4 g, 10.3 mmol) was added. The subsequent mixture was stirred at room temperature for 1 h. TLC (PE / EA = 1:1) showed that the starting material was consumed and a new spot was observed. The reaction mixture was diluted with 50 mL of water and extracted with EA (50 mL × 3). The organic phase was washed with brine, dried over Na2SO4, and concentrated. The residue was purified by silica gel chromatography (15 g column) using 0-50% EtOAc / hexanes to afford (1-(tert-butyl)-3-((1s,3s)-3-hydroxycyclobutyl)-1H-pyrazol-5-yl)benzylcarbamate (670 mg, 1.95 mmol, 95%) as a colorless oil. LCMS: 344 [M+H] + . 1 H NMR (400MHz, DMSO)δ 9.12(s, 2H), 7.46-7.28(m, 5H), 5.96(s, 1H), 5.12(s, 2H), 5.02(d, J=6.8Hz, 1H), 4.01-3.92(m, 1 H), 3.17(d, J=5.2Hz, 1H), 2.81-2.60(m, 1H), 2.51-2.42(m, 1H), 1.95-1.80(m, 2H), 1.47(s, 9H).

[0220] Step F: (1s,3s)-3-(5-(((benzyloxy)carbonyl)amino)-1-(tert-butyl)-1H-pyrazol-3-yl)cyclobutyl isopropylcarbamate. To a solution of (1-(tert-butyl)-3-((1s,3s)-3-hydroxycyclobutyl)-1H-pyrazol-5-yl)carbamate benzyl (670 mg, 1.95 mmol) in THF (10 mL) was added potassium 2-methylpropan-2-olate (328 mg, 2.92 mmol) and 1-oxo-N-(prop-2-yl)methanimine (249 mg, 2.92 mmol) at 0 °C over 30 min. The reaction mixture was stirred at room temperature for 1 h. TLC (PE / EA=1:1) showed that the starting material was consumed and a new spot was observed. The reaction mixture was diluted with 50 mL of water and extracted with EA (50 mL × 3). The organic phase was washed with brine, dried over Na2SO4, and concentrated. The residue was purified by silica gel chromatography (15.0 g column) (using 0-50% EtOAc / hexane) to give (1s,3s)-3-(5-(((benzyloxy)carbonyl)amino)-1-(tert-butyl)-1H-pyrazol-3-yl)cyclobutyl isopropylcarbamate (530 mg, 1.24 mmol, 63.4%) as a white solid. LCMS: 429 [M+H] + . 1 H NMR (400MHz, DMSO)δ 9.11(s, 1H), 7.47-7.28(m, 5H), 7.04(d, J=7.2Hz, 1H), 5.99(s, 1H), 5.13(s, 2H), 4.81-4.72(m, 1H), 3.61-3.53 (m, 1H), 2.99-2.91(m, 1H), 2.67-2.53(m, 2H), 2.13-1.93(m, 2H), 1.49(d, J=4.4Hz, 9H), 1.04(d, J=6.4Hz, 6H).

[0221] Step G: (1s,3s)-3-(5-amino-1-(tert-butyl)-1H-pyrazol-3-yl)cyclobutyl isopropylcarbamate. To a solution of (1s,3s)-3-(5-(((benzyloxy)carbonyl)amino)-1-(tert-butyl)-1H-pyrazol-3-yl)cyclobutyl isopropylcarbamate (530 mg, 1.23 mmol) in THF (2.5 mL) and EA (2.5 mL) was added Pd / C (100 mg, 0.940 mmol) under H protection. The mixture was stirred at room temperature for 1 h. TLC (PE / EA = 1:1) showed that the starting material was consumed and a new spot was observed. The reaction mixture was diluted with 50 mL of water and extracted with EA (50 mL × 3). The organic phase was washed with brine, dried over Na2SO4 and concentrated to give (1s,3s)-3-(5-amino-1-(tert-butyl)-1H-pyrazol-3-yl)cyclobutyl isopropylcarbamate (350 mg, 1.19 mmol, 96%) as a colorless oil. LCMS: 295 [M+H] + . 1 H NMR (400MHz, CDCl3)δ 5.50(s, 1H), 4.97-4.84(m, 1H), 4.49(s, 1H), 3.84-3.76(m, 1H), 3.48(s, 1H), 3.02-2 .87(m, 1H), 2.79-2.62(m, 2H), 2.18-2.03(m, 2H), 1.61(s, 9H), 1.15(d, J=6.4Hz, 6H).

[0222] Example 1: (1R,3S)-3-(3-((1-methyl-3-oxo-2,3-dihydro-1H-indazol-6-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate [ka] Step A: 6-Bromo-2-(4-methoxybenzyl)-1-methyl-1,2-dihydro-3H-indazol-3-one. To a solution of 6-bromo-1-methyl-2,3-dihydro-1H-indazol-3-one (0.5 g, 2.20 mmol) in DMF (10 mL) was added NaH (0.26 g, 6.60 mmol, 60% in mineral oil), and the reaction was stirred at room temperature for 30 min. Then, 1-(chloromethyl)-4-methoxybenzene (0.360 mL, 2.642 mmol) was added. The reaction was stirred at room temperature for an additional 2 h. The reaction was diluted with EA and saturated NH4Cl solution. The organic layer was separated, washed with brine, and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluting with ethyl acetate in petroleum ether (1 / 2)). The organic layer was collected, concentrated in vacuo, and dried to give the title compound 6-bromo-2-[(4-methoxyphenyl)methyl]-1-methyl-2,3-dihydro-1H-indazol-3-one (300 mg, 0.864 mmol, 39.2%) as a yellow solid. LCMS: ESI m / z 347,349 [M+H] + .

[0223] Step B: 6-((1-(tert-butyl)-3-((1S,3R)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)amino)-2-(4-methoxybenzyl)-1-methyl-1,2-dihydro-3H-indazol-3-one. To a solution of 1-tert-butyl-3-[(1S,3R)-3-[(tert-butyldimethylsilyl)oxy]cyclopentyl]-1H-pyrazol-5-amine (320.85 mg, 0.950 mmol) in dioxane (5 mL) was added 6-bromo-2-[(4-methoxyphenyl)methyl]-1-methyl-2,3-dihydro-1H-indazol-3-one (300 mg, 0.864 mmol), [5-(diphenylphosphanyl)-9,9-dimethyl-9H-xanthen-4-yl]diphenylphosphane (99.99 mg, 0.173 mmol), sodium 2-methylpropane-2-olate (1.72 mL, 1.72 mmol), and Pd(dba) (79.1 mg, 0.086 mmol) and the reaction was stirred at 90 °C under N for 18 h. The reaction was diluted with EA and water. The organic layer was separated, washed with brine, and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluting with ethyl acetate in petroleum ether (3 / 1)). The organic layer was collected, concentrated in vacuo, and dried to give the title compound 6-({1-tert-butyl-3-[(1S,3R)-3-[(tert-butyldimethylsilyl)oxy]cyclopentyl]-1H-pyrazol-5-yl}amino)-2-[(4-methoxyphenyl)methyl]-1-methyl-2,3-dihydro-1H-indazol-3-one (200 mg, 0.331 mmol, 38.3%) as a yellow oil. LCMS: ESI m / z 604 [M+H] + .

[0224] Step C: 6-((1-(tert-butyl)-3-((1S,3R)-3-hydroxycyclopentyl)-1H-pyrazol-5-yl)amino)-2-(4-methoxybenzyl)-1-methyl-1,2-dihydro-3H-indazol-3-one. To a flask containing 6-({1-tert-butyl-3-[(1S,3R)-3-[(tert-butyldimethylsilyl)oxy]cyclopentyl]-1H-pyrazol-5-yl}amino)-2-[(4-methoxyphenyl)methyl]-1-methyl-2,3-dihydro-1H-indazol-3-one (200 mg, 0.331 mmol) was added formic acid (10 mL). The mixture was stirred at room temperature for 18 hours. The mixture was concentrated under vacuum to give a residue, which was purified by silica gel column chromatography (eluted with (DCM / MeOH=3:1)) to give the title compound 6-({1-tert-butyl-3-[(1S,3R)-3-hydroxycyclopentyl]-1H-pyrazol-5-yl}amino)-2-[(4-methoxyphenyl)methyl]-1-methyl-2,3-dihydro-1H-indazol-3-one (100 mg, 0.204 mmol, 61.7%) as a yellow oil. LC / MS(ESI)(m / z): 490 [M+H] + .

[0225] Step D: (1R,3S)-3-(1-(tert-butyl)-5-((2-(4-methoxybenzyl)-1-methyl-3-oxo-2,3-dihydro-1H-indazol-6-yl)amino)-1H-pyrazol-3-yl)cyclopentyl(4-nitrophenyl)carbonate. To a flask containing 6-({1-tert-butyl-3-[(1S,3R)-3-hydroxycyclopentyl]-1H-pyrazol-5-yl}amino)-2-[(4-methoxyphenyl)methyl]-1-methyl-2,3-dihydro-1H-indazol-3-one (100 mg, 0.204 mmol), THF (10 mL) and DCM (10 mL) were added, followed by 4-nitrophenyl chloroformate (82.33 mg, 0.408 mmol) and pyridine (0.050 mL, 0.613 mmol). The mixture was stirred at room temperature for 2 hours. The mixture was concentrated under vacuum to give a residue, which was purified by silica gel column chromatography (eluted with (PE / EA=1:3)) to give the title compound (1R,3S)-3-[1-tert-butyl-5-({2-[(4-methoxyphenyl)methyl]-1-methyl-3-oxo-2,3-dihydro-1H-indazol-6-yl}amino)-1H-pyrazol-3-yl]cyclopentyl 4-nitrophenyl carbonate (100 mg, 0.153 mmol, 74.8%) as a yellow oil. LCMS: ESI m / z 655 [M+H] + .

[0226] Step E: (1R,3S)-3-(5-((1-Methyl-3-oxo-2,3-dihydro-1H-indazol-6-yl)amino)-1H-pyrazol-3-yl)cyclopentyl(4-nitrophenyl)carbonate. To a flask containing (1R,3S)-3-[1-tert-butyl-5-({2-[(4-methoxyphenyl)methyl]-1-methyl-3-oxo-2,3-dihydro-1H-indazol-6-yl}amino)-1H-pyrazol-3-yl]cyclopentyl 4-nitrophenyl carbonate (100 mg, 0.153 mmol) was added formic acid (5 mL). The mixture was stirred at 80° C. for 18 hours. After completion, the solvent was removed in vacuo to give (1R,3S)-3-{5-[(1-methyl-3-oxo-2,3-dihydro-1H-indazol-6-yl)amino]-1H-pyrazol-3-yl}cyclopentyl 4-nitrophenyl carbonate (70 mg, 0.146 mmol, 96%) as a yellow oil, which was used in the next step without further purification. LCMS: ESI m / z 479 [M+H] + .

[0227] Step F: (1R,3S)-3-(3-((1-methyl-3-oxo-2,3-dihydro-1H-indazol-6-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate. To a solution of (1R,3S)-3-{5-[(1-methyl-3-oxo-2,3-dihydro-1H-indazol-6-yl)amino]-1H-pyrazol-3-yl}cyclopentyl 4-nitrophenyl carbonate (70 mg, 0.146 mmol) in propan-2-amine (5 mL) was added, and the reaction mixture was stirred at room temperature for 2 hours. The solvent was removed in vacuo to give a residue that was purified by preparative HPLC (C18, FA conditions, 56% ACN) to give (1R,3S)-3-{5-[(1-methyl-3-oxo-2,3-dihydro-1H-indazol-6-yl)amino]-1H-pyrazol-3-yl}cyclopentyl N-(propan-2-yl)carbamate (3.7 mg) as a white solid. LCMS: ESI m / z 399 [M+H] + . 1H NMR (400MHz, DMSO-d6)δ 8.59(s, 1H), 7.48(s, 1H), 7.34(d, J=8.4Hz, 1H), 6.95(d, J=7.6Hz, 1H), 6.73(d, J=8.4Hz, 1H), 5.66(s, 1H), 4.99(s, 1H), 3.62 -3.50(m, 1H), 3.47(s, 3H), 3.13-2.99(m, 1H), 2.55-2.42(m, 1H), 2.10-1.83(m, 2H), 1.79-1.52(m, 3H), 1.03(d, J=6.4Hz, 6H).

[0228] Example 2: (1R,3S)-3-(3-((1,1-dioxide-3,4-dihydro-2H-benzo[e][1,2]thiazin-6-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate [ka] Step A. Methyl 2-(5-bromo-2-(chlorosulfonyl)phenyl)acetate. A mixture of methyl 2-(3-bromophenyl)acetate (3 g, 13.1 mmol) in HSO3Cl (1.31 g, 13.1 mmol) was stirred at room temperature overnight. The mixture was slowly poured into ice-water (50 ml) and extracted with EtOAc (20 mL*3). The combined organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated to give crude methyl 2-[5-bromo-2-(chlorosulfonyl)phenyl]acetate (1.8 g, 5.52 mmol, 42.2%) as a yellow oil. LCMS: m / z 327 [M+H] + .

[0229] Step B. Methyl 2-(5-bromo-2-(N-(4-methoxybenzyl)sulfamoyl)phenyl)acetate. To a stirred mixture of methyl 2-[5-bromo-2-(chlorosulfonyl)phenyl]acetate (1.8 g, 5.49 mmol) in DCM (15 mL) was added (4-methoxyphenyl)methanamine (0.75 g, 5.49 mmol) and TEA (1.11 g, 10.9 mmol) slowly at 0 °C. After stirring at room temperature for 2 h, the mixture was poured into water (30 mL) and extracted with DCM (20 mL × 2). The combined organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by chromatography (silica gel, 0-35%, EtOAc in PE) to give methyl 2-(5-bromo-2-{[(4-methoxyphenyl)methyl]sulfamoyl}phenyl)acetate (800 mg, 1.86 mmol, 33.9%) as a brown solid. LCMS: m / z 429 [M+H] + .

[0230] Step C. 4-Bromo-2-(2-hydroxyethyl)-N-(4-methoxybenzyl)benzenesulfonamide. To a stirred mixture of methyl 2-(5-bromo-2-{[(4-methoxyphenyl)methyl]sulfamoyl}phenyl)acetate (800 mg, 1.86 mmol) in THF (10 mL) / MeOH (2 mL) was added NaBH (189 mg, 5.60 mmol) slowly at 0 °C. After stirring at room temperature for 1 h, the mixture was poured into ice-water (30 mL) and extracted with EtOAc (20 mL). The combined organic phase was washed with brine, dried over NaSO, filtered, and concentrated to give crude 4-bromo-2-(2-hydroxyethyl)-N-[(4-methoxyphenyl)methyl]benzene-1-sulfonamide (700 mg, 1.74 mmol, 93.6%) as a yellow solid. LCMS: m / z 401 [M+H] + .

[0231] Step D. 6-Bromo-2-(4-methoxybenzyl)-3,4-dihydro-2H-benzo[e][1,2]thiazine 1,1-dioxide. To a stirred mixture of 4-bromo-2-(2-hydroxyethyl)-N-[(4-methoxyphenyl)methyl]benzene-1-sulfonamide (700 mg, 1.74 mmol) in THF (20 mL) was added DIAD (0.693 mL, 3.49 mmol) and PPh (917 mg, 3.49 mmol) at room temperature. After stirring overnight at room temperature, the mixture was poured into water (30 mL) and extracted with EtOAc (20 mL*2). The combined organic phase was washed with brine, dried over NaSO, filtered, and concentrated. The residue was purified by chromatography (silica gel, 0-50%, EtOAc in PE) to give 6-bromo-2-[(4-methoxyphenyl)methyl]-3,4-dihydro-2H-1λ^6,2-benzothiazine-1,1-dione (400 mg, 1.04 mmol, 59.8%) as a yellow solid. LCMS: m / z 383 [M+H] + .

[0232] Step E. 6-((1-(tert-butyl)-3-((1S,3R)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)amino)-2-(4-methoxybenzyl)-3,4-dihydro-2H-benzo[e][1,2]thiazine 1,1-dioxide. To a stirred mixture of 6-bromo-2-[(4-methoxyphenyl)methyl]-3,4-dihydro-2H-1λ^6,2-benzothiazine-1,1-dione (400 mg, 1.04 mmol) in dioxane (15 mL) was added 1-tert-butyl-3-[(1S,3R)-3-[(tert-butyldimethylsilyl)oxy]cyclopentyl]-1H-pyrazol-5-amine (353 mg, 1.04 mmol), RuPhos Pd G2 (81.2 mg, 0.105 mmol), RuPhos (97.6 mg, 0.209 mmol), and Cs2CO3 (852 mg, 2.61 mmol) at room temperature. After stirring at 100 °C overnight, the mixture was poured into water (30 mL) and extracted with EtOAc (20 mL). The combined organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by chromatography (silica gel, 0-60%, EtOAc in PE) to give 6-({1-tert-butyl-3-[(1S,3R)-3-[(tert-butyldimethylsilyl)oxy]cyclopentyl]-1H-pyrazol-5-yl}amino)-2-[(4-methoxyphenyl)methyl]-3,4-dihydro-2H-1λ^6,2-benzothiazine-1,1-dione (400 mg, 0.626 mmol, 60%) as a brown solid. LCMS: m / z 640 [M+H] + .

[0233] Step F. 6-((1-(tert-butyl)-3-((1S,3R)-3-hydroxycyclopentyl)-1H-pyrazol-5-yl)amino)-2-(4-methoxybenzyl)-3,4-dihydro-2H-benzo[e][1,2]thiazine 1,1-dioxide. A mixture of 6-({1-tert-butyl-3-[(1S,3R)-3-[(tert-butyldimethylsilyl)oxy]cyclopentyl]-1H-pyrazol-5-yl}amino)-2-[(4-methoxyphenyl)methyl]-3,4-dihydro-2H-1λ^6,2-benzothiazine-1,1-dione (400 mg, 0.626 mmol) in HCOOH (10 mL) was stirred at room temperature for 1 hour and then concentrated under reduced pressure. The residue was treated with a mixture of LiOH (0.174 mL, 6.26 mmol) in EtOH (5 mL) / HO (5 mL). The resulting mixture was stirred at room temperature for 2 h, and the mixture was concentrated under reduced pressure. The mixture was poured into water (30 mL) and extracted with EtOAc (20 mL*2). The combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by chromatography (silica gel, 0–8%, MeOH in DCM) to give 6-({1-tert-butyl-3-[(1S,3R)-3-hydroxycyclopentyl]-1H-pyrazol-5-yl}amino)-2-[(4-methoxyphenyl)methyl]-3,4-dihydro-2H-1λ^6,2-benzothiazine-1,1-dione (300 mg, 0.572 mmol, 91.3%) as a white solid. LCMS: m / z 526 [M+H] + .

[0234] Step G. (1R,3S)-3-(1-(tert-butyl)-5-((2-(4-methoxybenzyl)-1,1-dioxide-3,4-dihydro-2H-benzo[e][1,2]thiazin-6-yl)amino)-1H-pyrazol-3-yl)cyclopentyl(4-nitrophenyl)carbonate. To a stirred solution of 6-({1-tert-butyl-3-[(1S,3R)-3-hydroxycyclopentyl]-1H-pyrazol-5-yl}amino)-2-[(4-methoxyphenyl)methyl]-3,4-dihydro-2H-1λ^6,2-benzothiazine-1,1-dione (180 mg, 0.343 mmol) in DCM (5 mL) / THF (5 mL) was added 4-nitrophenyl chloroformate (138 mg, 0.686 mmol), pyridine (0.083 mL, 1.02 mmol), and DMAP (12.5 mg, 0.103 mmol) at room temperature. After stirring at room temperature for 3 h, the mixture was poured into water (30 mL) and extracted with EtOAc (20 mL × 3). The combined organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by chromatography (silica gel, 0-10%, MeOH in DCM) to give (1R,3S)-3-[1-tert-butyl-5-({2-[(4-methoxyphenyl)methyl]-1,1-dioxo-3,4-dihydro-2H-1λ^6,2-benzothiazin-6-yl}amino)-1H-pyrazol-3-yl]cyclopentyl 4-nitrophenyl carbonate (100 mg, 0.145 mmol, 42.2%) as a yellow solid. LCMS: m / z 691 [M+H] + .

[0235] Step H. (1R,3S)-3-(5-((1,1-dioxide-3,4-dihydro-2H-benzo[e][1,2]thiazin-6-yl)amino)-1H-pyrazol-3-yl)cyclopentyl(4-nitrophenyl)carbonate. A mixture of (1R,3S)-3-[1-tert-butyl-5-({2-[(4-methoxyphenyl)methyl]-1,1-dioxo-3,4-dihydro-2H-1λ^6,2-benzothiazin-6-yl}amino)-1H-pyrazol-3-yl]cyclopentyl 4-nitrophenyl carbonate (100 mg, 0.145 mmol) in HCOOH (5 mL) was stirred at 100 °C overnight and then concentrated under reduced pressure to give crude (1R,3S)-3-{5-[(1,1-dioxo-3,4-dihydro-2H-1λ^6,2-benzothiazin-6-yl)amino]-1H-pyrazol-3-yl}cyclopentyl 4-nitrophenyl carbonate (70 mg, 0.136 mmol, 94.0%) as a brown oil. LCMS: m / z 515 [M+H] + .

[0236] Step I. (1R,3S)-3-(3-((1,1-Dioxide-3,4-dihydro-2H-benzo[e][1,2]thiazin-6-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate. To a stirred solution of (1R,3S)-3-{5-[(1,1-dioxo-3,4-dihydro-2H-1λ^6,2-benzothiazin-6-yl)amino]-1H-pyrazol-3-yl}cyclopentyl 4-nitrophenyl carbonate (70 mg, 0.136 mmol) in THF (5 mL), DIPEA (35.1 mg, 0.272 mmol) and propan-2-amine (0.058 mL, 0.680 mmol) were slowly added, and the reaction mixture was stirred at room temperature for 2 h. The reaction was concentrated. The residue was purified by preparative HPLC (C18, 40-90% MeCN in HO containing 0.1% HCOOH) to give (1R,3S)-3-{3-[(1,1-dioxo-3,4-dihydro-2H-1λ^6,2-benzothiazin-6-yl)amino]-1H-pyrazol-5-yl}cyclopentyl N-(propan-2-yl)carbamate (22.8 mg, 0.053 mmol, 38.9%) as a white solid. LCMS: m / z 434 [M+H] + . 1 H NMR (400MHz, DMSO)δ 8.82(s, 1H), 7.48(d, J=8.4Hz, 1H), 7.26-7.14(m, 2H), 7.15(brs, 1H), 6.95(d, J =7.2Hz, 1H), 5.69(s, 1H), 4.99(brs, 1H), 3.65-3.50(m, 1H), 3.50(d, J=4.8Hz, 2H) ), 3.11-2.99(m, 1H), 2.81(t, J=6.0Hz, 2H), 2.49-2.33(m, 1H), 2.12-1.98(m, 1H) , 1.94-1.85(m, 1H), 1.83-1.67(m, 2H), 1.65-1.54(m, 1H), 1.03(d, J=6.4Hz, 6H).

[0237] Example 3: (1R,3S)-3-(3-((1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate [ka] Step A: 4-Bromo-N-(tert-butyl)-2-methylbenzenesulfonamide. To a solution of 4-bromo-2-methylbenzene-1-sulfonyl chloride (5 g, 18.5 mmol) in DCM (20 mL) was added triethylamine (7.73 mL, 55.6 mmol) and 2-methylpropan-2-amine (3.93 mL, 37.1 mmol), and the reaction was stirred at room temperature overnight. The reaction was concentrated in vacuo. The residue was purified by silica gel column chromatography (eluting with a gradient of 0-50%) to afford the title compound, 4-bromo-N-tert-butyl-2-methylbenzene-1-sulfonamide (5 g, 16.3 mmol, 88.0%), as a white solid. LCMS: ESI m / z 306 [M+H] + . 1 H NMR (400MHz, DMSO) δ 7.75 (d, J=8.4Hz, 1H), 7.65-7.49 (m, 3H), 2.54 (s, 3H), 1.06 (s, 9H).

[0238] Step B: 4-Bromo-2-(bromomethyl)-N-(tert-butyl)benzenesulfonamide. To a solution of 4-bromo-N-tert-butyl-2-methylbenzene-1-sulfonamide (5 g, 16.3 mmol) in CHCl3 (10 mL) was added AIBN (268 mg, 1.63 mmol), DIEA (0.448 mL, 2.71 mmol), and NBS (2.91 g, 16.3 mmol), and the reaction was stirred at 60 °C overnight. The reaction was concentrated. The residue was purified by silica gel column chromatography (eluted with a gradient of 0 to 30%) to afford the title compound, 4-bromo-2-(bromomethyl)-N-tert-butylbenzene-1-sulfonamide (1.9 g, 4.9 mmol, 30.2%), as a white solid. LCMS: ESI m / z 384 [M+H] + . 1 H NMR (400MHz, DMSO) δ 7.91-7.86 (m, 2H), 7.82 (d, J=8.4Hz, 1H), 7.74-7.68 (m, 1H), 5.03 (s, 2H), 1.13 (s, 9H).

[0239] Step C: 5-Bromo-2-(tert-butyl)-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide. To a solution of 4-bromo-2-(bromomethyl)-N-tert-butylbenzene-1-sulfonamide (1.4 g, 3.63 mmol) in MeOH (20 mL) and HO (5 mL) was added NaOH (0.44 g, 10.9 mmol), and the reaction was stirred at room temperature for 3 h. The reaction was concentrated in vacuo. The residue was purified by silica gel column chromatography (eluting with EA in PE [gradient: 0 to 80%]) to afford the title compound, 5-bromo-2-tert-butyl-2,3-dihydro-1λ^6,2-benzothiazole-1,1-dione (900 mg, 2.95 mmol, 81.4%) as a white solid. LCMS: ESI m / z 304 [M+H] + . 1 H NMR (400MHz, DMSO) δ 7.83(d, J=0.8Hz, 1H), 7.77(dt, J=14.4, 4.8Hz, 2H), 4.55(s, 2H), 1.46(s, 9H).

[0240] Step D: 5-Bromo-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide. To a solution of 5-bromo-2-tert-butyl-2,3-dihydro-1λ^6,2-benzothiazole-1,1-dione (900 mg, 2.95 mmol) in HCOOH (10 mL) was added and the reaction was stirred at room temperature for 1 h. The reaction was concentrated, and MeOH (10 mL), LiOH (496 mg, 11.8 mmol) were added and stirred at room temperature for 30 min. The reaction was diluted with HO and the aqueous layer was extracted with EA. The EA layers were combined and washed with saturated NaCl solution. The EA layer was dried over NaSO, filtered, and concentrated. The residue was purified by silica gel column chromatography (eluting with a gradient of 0 to 100%) to obtain the title compound 5-bromo-2,3-dihydro-1λ^6,2-benzothiazole-1,1-dione (600 mg, 2.41 mmol, 81.7%) as a white solid. LCMS: ESI m / z 248 [M+H] + . 1 H NMR (400MHz, DMSO) δ 7.92 (s, 1H), 7.85-7.73 (m, 3H), 4.40 (s, 2H).

[0241] Step E: 5-Bromo-2-(4-methoxybenzyl)-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide. To a solution of 5-bromo-2,3-dihydro-1λ^6,2-benzothiazole-1,1-dione (500 mg, 2.01 mmol) in DMF (10 mL) was added 1-(chloromethyl)-4-methoxybenzene (0.412 mL, 3.023 mmol) and Cs2CO3 (1.97 g, 6.04 mmol), and the reaction was stirred at room temperature overnight. The reaction was diluted with HO. The aqueous layer was extracted with EA. The EA layers were combined and washed with saturated NaCl solution. The EA layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (eluting with a gradient of 0-30%) to obtain the title compound 5-bromo-2-[(4-methoxyphenyl)methyl]-2,3-dihydro-1λ^6,2-benzothiazole-1,1-dione (350 mg, 0.950 mmol, 47.1%) as a white solid. LCMS: ESI m / z 368 [M+H] + . 1 H NMR (400MHz, DMSO) δ 7.90-7.82(m, 2H), 7.80(dd, J=8.4, 1.6Hz, 1H), 7.42-7.32(m, 2H), 6.99-6.91(m, 2H), 4.33(s, 2H), 4.27(s, 2H), 3.76(s, 3H).

[0242] Step F: 5-((1-(tert-butyl)-3-((1S,3R)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)amino)-2-(4-methoxybenzyl)-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide. To a solution of 5-bromo-2-[(4-methoxyphenyl)methyl]-2,3-dihydro-1λ^6,2-benzothiazole-1,1-dione (350 mg, 0.950 mmol) in dioxane (10 mL) was added 1-tert-butyl-3-[(1S,3R)-3-[(tert-butyldimethylsilyl)oxy]cyclopentyl]-1H-pyrazol-5-amine (353 mg, 1.04 mmol), Pd2(dba)3 (87.1 mg, 95.1 μmol), Xantphos (110 mg, 0.190 mmol), and Cs2CO3 (619 mg, 1.90 mmol). The reaction was stirred at 100 °C for 6 h. The reaction was diluted with EA and water. The organic layer was separated, washed with saturated NaCl solution, and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluting with ethyl acetate in petroleum ether (gradient: 0-50%)) to give the title compound 5-({1-tert-butyl-3-[(1S,3R)-3-[(tert-butyldimethylsilyl)oxy]cyclopentyl]-1H-pyrazol-5-yl}amino)-2-[(4-methoxyphenyl)methyl]-2,3-dihydro-1λ^6,2-benzothiazole-1,1-dione (500 mg, 0.800 mmol, 84.2%) as a white solid. LCMS: ESI m / z 625 [M+H] + .

[0243] Step G: 5-((1-(tert-butyl)-3-((1S,3R)-3-hydroxycyclopentyl)-1H-pyrazol-5-yl)amino)-2-(4-methoxybenzyl)-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide. A solution of 5-({1-tert-butyl-3-[(1S,3R)-3-[(tert-butyldimethylsilyl)oxy]cyclopentyl]-1H-pyrazol-5-yl}amino)-2-[(4-methoxyphenyl)methyl]-2,3-dihydro-1λ^6,2-benzothiazole-1,1-dione (500 mg, 0.800 mmol) in HCOOH (10 mL) was stirred at room temperature for 1 h. LCMS showed the reaction was complete. The solvent was removed in vacuo. The residue was purified by silica gel chromatography (eluting with 50% ethyl acetate in petroleum ether) to give 5-({1-tert-butyl-3-[(1S,3R)-3-hydroxycyclopentyl]-1H-pyrazol-5-yl}amino)-2-[(4-methoxyphenyl)methyl]-2,3-dihydro-1λ^6,2-benzothiazole-1,1-dione (400 mg, 0.697 mmol, 87.1%) as a yellow solid. LCMS: ESI m / z 511 [M+H] + .

[0244] Step H: (1R,3S)-3-(1-(tert-butyl)-5-((2-(4-methoxybenzyl)-1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-3-yl)cyclopentyl(4-nitrophenyl)carbonate. To a solution of 5-({1-tert-butyl-3-[(1S,3R)-3-hydroxycyclopentyl]-1H-pyrazol-5-yl}amino)-2-[(4-methoxyphenyl)methyl]-2,3-dihydro-1λ^6,2-benzothiazole-1,1-dione (400 mg, 0.783 mmol) in THF / DCM (1:1) (12 mL) was added pyridine (0.190 mL, 2.35 mmol), DMAP (9.57 mg, 78.1 μmmol), and 4-nitrophenyl chloroformate (316 mg, 1.57 mmol). The mixture was stirred at room temperature for 4 h. The solvent was removed in vacuo. The residue was dissolved in ethyl acetate (5 mL*3), washed with saturated aqueous NaCl, dried over sodium sulfate, filtered, concentrated, and purified by silica gel chromatography (eluted with 50% ethyl acetate in petroleum ether) to give (1R,3S)-3-[1-tert-butyl-5-({2-[(4-methoxyphenyl)methyl]-1,1-dioxo-2,3-dihydro-1λ^6,2-benzothiazol-5-yl}amino)-1H-pyrazol-3-yl]cyclopentyl 4-nitrophenyl carbonate (300 mg, 0.444 mmol, 56.7%) as a yellow solid. LCMS: ESI m / z 676 [M+H] + .

[0245] Step I: (1R,3S)-3-(5-((1,1-Dioxide-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-3-yl)cyclopentyl(4-nitrophenyl)carbonate. A solution of (1R,3S)-3-[1-tert-butyl-5-({2-[(4-methoxyphenyl)methyl]-1,1-dioxo-2,3-dihydro-1λ^6,2-benzothiazol-5-yl}amino)-1H-pyrazol-3-yl]cyclopentyl 4-nitrophenylcarbonate (300 mg, 0.444 mmol) in HCOOH (8 mL) was stirred at 90° C. overnight. LCMS indicated the reaction was complete. The residue was concentrated to give (1R,3S)-3-{5-[(1,1-dioxo-2,3-dihydro-1λ^6,2-benzothiazol-5-yl)amino]-1H-pyrazol-3-yl}cyclopentyl 4-nitrophenyl carbonate (150 mg, 0.300 mmol, 67.6%) as a yellow oil. LCMS: ESI m / z 500 [M+H] + .

[0246] Step J: (1R,3S)-3-(3-((1,1-Dioxide-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate. A solution of (1R,3S)-3-{5-[(1,1-dioxo-2,3-dihydro-1λ^6,2-benzothiazol-5-yl)amino]-1H-pyrazol-3-yl}cyclopentyl 4-nitrophenyl carbonate (150 mg, 0.300 mmol) in propan-2-amine (10 mL, 117 mmol) was stirred at room temperature for 3 hours. The mixture was concentrated in vacuo. The residue was purified by preparative HPLC to give (1R,3S)-3-{3-[(1,1-dioxo-2,3-dihydro-1λ^6,2-benzothiazol-5-yl)amino]-1H-pyrazol-5-yl}cyclopentyl N-(propan-2-yl)carbamate (30 mg, 72.2 μmmol, 23.8%) as a yellow solid. LCMS: ESI m / z 420 [M+H] + . 1H NMR (400 MHz, DMSO) δ 9.02(s, 1H), 7.53(d, J=8.4Hz, 1H), 7.45(s, 1H), 7.30(dd, J=8.6, 1.8Hz, 1 H), 6.95(d, J=7.6Hz, 1H), 5.72(s, 1H), 4.99(brs, 1H), 4.29(s, 1H), 3.62-3 .48(m, 1H), 3.15-2.96(m, 1H), 2.48-2.40(m, 1H), 2.08-1.94(m, 1H), 1.93 -1.81(m, 1H), 1.78-1.66(m, 2H), 1.65-1.52(m, 1H), 1.03(d, J=6.4Hz, 6H).

[0247] Example 4: (1R,3S)-3-(3-((1,3-dioxoisoindolin-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate [ka] Step A: 5-((1-(tert-butyl)-3-((1S,3R)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)amino)isoindoline-1,3-dione. To a solution of 1-tert-butyl-3-[(1S,3R)-3-[(tert-butyldimethylsilyl)oxy]cyclopentyl]-1H-pyrazol-5-amine (300 mg, 0.889 mmol) in dioxane (2 mL) was added 5-bromo-2,3-dihydro-1H-isoindole-1,3-dione (200 mg, 0.889 mmol), Xantphos (102 mg, 0.178 mmol), sodium 2-methylpropane-2-olate (1.77 mL, 1.778 mmol), and Pd(dba) (8.4 mg, 0.089 mmol). The reaction was stirred at 100 °C under N for 1 h using a MW column. The cooled reaction mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography (eluting with EA in PE [gradient: 0–100%]). The organic layer was collected, concentrated in vacuo, and dried to give the title compound 5-({1-tert-butyl-3-[(1S,3R)-3-[(tert-butyldimethylsilyl)oxy]cyclopentyl]-1H-pyrazol-5-yl}amino)-2,3-dihydro-1H-isoindole-1,3-dione (240 mg, 0.497 mmol, 55.9%) as a white solid. LCMS: ESI m / z 483 [M+H] + .

[0248] Step B: 5-((1-(tert-butyl)-3-((1S,3R)-3-hydroxycyclopentyl)-1H-pyrazol-5-yl)amino)isoindoline-1,3-dione. A solution of 5-({1-tert-butyl-3-[(1S,3R)-3-[(tert-butyldimethylsilyl)oxy]cyclopentyl]-1H-pyrazol-5-yl}amino)-2,3-dihydro-1H-isoindole-1,3-dione (240 mg, 0.497 mmol) in HCOOH (3 mL) was stirred at room temperature for 1 h. The reaction was concentrated, and MeOH (3 mL) and LiOH (41.7 mg, 0.994 mmol) were added. The following reaction mixture was stirred at room temperature for 30 min. The reaction was diluted with HO. The aqueous layer was extracted with EA. The EA layers were combined and washed with saturated NaCl solution. The EA layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography ([gradient: 0 to 100%]) to obtain the title compound 5-({1-tert-butyl-3-[(1S,3R)-3-hydroxycyclopentyl]-1H-pyrazol-5-yl}amino)-2,3-dihydro-1H-isoindole-1,3-dione (50 mg, 0.136 mmol, 27.2%) as a white solid. LCMS: ESI m / z 387 [M+H] + .

[0249] Step C: (1R,3S)-3-(1-(tert-butyl)-5-((1,3-dioxoisoindolin-5-yl)amino)-1H-pyrazol-3-yl)cyclopentyl(4-nitrophenyl)carbonate. To a solution of 5-({1-tert-butyl-3-[(1S,3R)-3-hydroxycyclopentyl]-1H-pyrazol-5-yl}amino)-2,3-dihydro-1H-isoindole-1,3-dione (50 mg, 0.136 mmol) in DCM (2 mL) was added 4-nitrophenyl chloroformate (41 mg, 0.204 mmol), DMAP (1.66 mg, 0.014 mmol), and pyridine (0.022 mL, 0.271 mmol). The reaction was stirred at 40° C. for 3 hours. The reaction was concentrated in vacuo. The residue was purified by silica gel column chromatography (eluting with EA in PE [gradient: 0-100%]) to obtain the title compound (1R,3S)-3-{1-tert-butyl-5-[(1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl)amino]-1H-pyrazol-3-yl}cyclopentyl 4-nitrophenyl carbonate (27 mg, 0.051 mmol, 37.2%) as a white solid. LCMS: ESI m / z 534 [M+H] + .

[0250] Step D: (1R,3S)-3-(5-((1,3-dioxoisoindolin-5-yl)amino)-1H-pyrazol-3-yl)cyclopentyl(4-nitrophenyl)carbonate. A solution of (1R,3S)-3-{1-tert-butyl-5-[(1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl)amino]-1H-pyrazol-3-yl}cyclopentyl 4-nitrophenylcarbonate (27 mg, 0.051 mmol) in HCOOH (3 mL) was stirred at 100° C. overnight. The cooled reaction mixture was concentrated in vacuo to give the title compound (1R,3S)-3-{5-[(1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl)amino]-1H-pyrazol-3-yl}cyclopentyl 4-nitrophenyl carbonate (20 mg, 0.042 mmol, 82.8%) as a white solid. LCMS: ESI m / z 478 [M+H]+ .

[0251] Step E: (1R,3S)-3-(3-((1,3-dioxoisoindolin-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate. A solution of (1R,3S)-3-{5-[(1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl)amino]-1H-pyrazol-3-yl}cyclopentyl 4-nitrophenyl carbonate (20 mg, 0.042 mmol) in propan-2-amine (2 mL) was stirred at room temperature for 2 hours. The reaction was concentrated in vacuo. The residue was purified by preparative HPLC to give the title compound 5-({3-[(1S,3R)-3-{[(propan-2-yl)amino]oxy}cyclopentyl]-1H-pyrazol-5-yl}amino)-2,3-dihydro-1H-isoindole-1,3-dione (3.2 mg, 0.009 mmol, 20.7%) as a yellow solid. LCMS: ESI m / z 398 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 12.01(s, 1H), 10.86(s, 1H), 9.34(s, 1H), 7.87(s, 1H), 7.56(dd, J=29. 2, 8.4Hz, 2H), 6.95(d, J=7.2Hz, 1H), 5.72(s, 1H), 5.01(s, 1H), 3.75-3. 53(m, 1H), 3.12-3.04(m, 1H), 2.09-2.00(m, 1H), 1.96-1.86(m, 1H), 1. 82-1.64(m, 2H), 1.64-1.53(m, 1H), 1.24(s, 1H), 1.04(d, J=6.4Hz, 6H).

[0252] Example 5: (1R,3S)-3-(5-((1,1-dioxide-3-oxo-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate [ka] Step A: 5-((1-(tert-butyl)-3-((1S,3R)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)amino)benzo[d]isothiazol-3(2H)-one 1,1-dioxide. To a solution of 1-tert-butyl-3-[(1S,3R)-3-[(tert-butyldimethylsilyl)oxy]cyclopentyl]-1H-pyrazol-5-amine (500 mg, 1.48 mmol) in dioxane (2 mL) was added 5-bromo-2,3-dihydro-1λ^6,2-benzothiazole-1,1,3-trione (582 mg, 2.22 mmol), Xantphos (171 mg, 0.296 mmol), Cs2CO3 (482 mg, 1.481 mmol), and Pd2(dba)3 (135 mg, 0.148 mmol). The reaction mixture was stirred under N2 at 100 °C for 16 h. The cooled reaction mixture was diluted with EA and water. The organic layer was separated, washed with brine, dried over Na2SO4, and concentrated. The residue was purified by silica gel column chromatography (eluted with ethyl acetate in petroleum ether (3 / 1)). The organic layer was collected, concentrated under vacuum, and dried to give the title compound 5-({1-tert-butyl-3-[(1S,3R)-3-[(tert-butyldimethylsilyl)oxy]cyclopentyl]-1H-pyrazol-5-yl}amino)-2,3-dihydro-1λ^6,2-benzothiazole-1,1,3-trione (500 mg, 0.964 mmol, 65.0%) as a yellow solid. LCMS: ESI 519 [M+H] + .

[0253] Step B: 5-((1-(tert-butyl)-3-((1S,3R)-3-hydroxycyclopentyl)-1H-pyrazol-5-yl)amino)benzo[d]isothiazol-3(2H)-one 1,1-dioxide. A solution of 5-({1-tert-butyl-3-[(1S,3R)-3-[(tert-butyldimethylsilyl)oxy]cyclopentyl]-1H-pyrazol-5-yl}amino)-2,3-dihydro-1λ^6,2-benzothiazole-1,1,3-trione (500 mg, 0.964 mmol) in HCOOH (5 mL) was stirred at room temperature for 1 h. The reaction was concentrated, and MeOH (50 mL), LiOH (161 mg, 3.85 mmol) were added and stirred at room temperature for 30 min. The reaction was diluted with HO. The aqueous layer was extracted with EA. The EA layers were combined and washed with brine. The EA layer was dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (eluted with a gradient of 0 to 100%) to obtain the title compound 5-({1-tert-butyl-3-[(1S,3R)-3-hydroxycyclopentyl]-1H-pyrazol-5-yl}amino)-2,3-dihydro-1λ^6,2-benzothiazole-1,1,3-trione (300 mg, 0.742 mmol, 76.9%) as a white solid. LCMS: ESI m / z 405 [M+H] + .

[0254] Step C: (1R,3S)-3-(1-(tert-butyl)-5-((1,1-dioxide-3-oxo-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-3-yl)cyclopentyl(4-nitrophenyl)carbonate. To a solution of 5-({1-tert-butyl-3-[(1S,3R)-3-hydroxycyclopentyl]-1H-pyrazol-5-yl}amino)-2,3-dihydro-1λ^6,2-benzothiazole-1,1,3-trione (300 mg) in THF (10 mL) and DCM (10 mL) was added 4-nitrophenyl chloroformate (568 mg, 2.82 mmol) and pyridine (0.456 mL, 5.64 mmol). The reaction was stirred at 50° C. for 30 minutes. The reaction was concentrated in vacuo. The residue was purified by silica gel column chromatography (eluting with EA in PE [gradient: 80-100%]) to obtain the title compound (1R,3S)-3-{1-tert-butyl-5-[(1,1,3-trioxo-2,3-dihydro-1λ^6,2-benzothiazol-5-yl)amino]-1H-pyrazol-3-yl}cyclopentyl 4-nitrophenyl carbonate (200 mg, 0.351 mmol, 18.7%) as a white solid. LCMS: ESI m / z 570 [M+H] + .

[0255] Step D: (1R,3S)-3-(5-((1,1-Dioxide-3-oxo-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-3-yl)cyclopentyl(4-nitrophenyl)carbonate. A solution of (1R,3S)-3-{1-tert-butyl-5-[(1,1,3-trioxo-2,3-dihydro-1λ^6,2-benzothiazol-5-yl)amino]-1H-pyrazol-3-yl}cyclopentyl 4-nitrophenylcarbonate (200 mg) in HCOOH (5 mL) was stirred at 80 °C overnight. The reaction was concentrated in vacuo to afford the title compound 4-nitrophenyl (1R,3S)-3-(5-((1,1-dioxide-3-oxo-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-3-yl)cyclopentyl (4-nitrophenyl)carbonate (100 mg) as a white solid, which was used in the next step without further purification. LCMS: ESI m / z 514 [M+H] + .

[0256] Step E: (1R,3S)-3-(5-((1,1-Dioxide-3-oxo-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate. To a solution of 4-nitrophenyl (1R,3S)-3-{5-[(1,1,3-trioxo-2,3-dihydro-1λ^6,2-benzothiazol-5-yl)amino]-1H-pyrazol-3-yl}cyclopentyl carbonate (100 mg, 0.195 mmol) in THF (2 mL) was added propan-2-amine (0.167 mL, 1.95 mmol) and the reaction was stirred at 50° C. for 2 h. The reaction was concentrated in vacuo. The residue was purified by preparative HPLC (0.1% TFA) to give the title compound (1R,3S)-3-{5-[(1,1,3-trioxo-2,3-dihydro-1λ^6,2-benzothiazol-5-yl)amino]-1H-pyrazol-3-yl}cyclopentyl N-(propan-2-yl)carbamate (10.4 mg) as a white solid. LCMS: ESI m / z 434 [M+H] + . 1H NMR (400MHz, DMSO-d6)δ 12.05(s, 1H), 9.46(s, 1H), 8.03(d, J=2.0Hz, 1H), 7.86(d, J=8.8Hz, 1H), 7.65(dd, J=8.8, 2.0Hz, 1H), 6.9 5(d, J=7.6Hz, 1H), 5.72(s, 1H), 5.00(s, 1H), 3.11-3.04(m, 1H), 2.13-1.55(m, 6H), 1.03(d, J=8.0Hz, 6H).

[0257] Example 6: (1R,3S)-3-(3-((1,1-dioxide-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-7-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate [ka] Step A: 4-Bromo-2-fluoro-N-(2-hydroxyethyl)benzenesulfonamide. To a solution of 2-aminoethan-1-ol (2.2 mL, 36.6 mmol) and KCO (5.05 g, 36.5 mmol) in THF (200 mL) and HO (50 mL) was added 4-bromo-2-fluorobenzene-1-sulfonyl chloride (10 g, 36.6 mmol) in portions. The mixture was stirred at room temperature for 2 h and diluted with EA and aqueous NaCl. The organic layer was separated, washed with brine, and concentrated in vacuo to give the title compound S-(4-bromo-2-fluorophenyl)-2-hydroxyethane-1-sulfonamide (10 g, 33.5 mmol, 91.7%) as a white solid.

[0258] Step B: 7-Bromo-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepine 1,1-dioxide. To a solution of S-(4-bromo-2-fluorophenyl)-2-hydroxyethane-1-sulfonamide (5 g, 16.8 mmol) in DMF (50 mL) was added NaH (1.48 g, 0.370 mmol, 60% in mineral oil) at 0 °C. The reaction was stirred at room temperature overnight. The reaction was diluted with EA and HO and adjusted to pH = 6 with 1 M HCl. The organic layer was separated, washed with brine, and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluting with EA in PE [gradient: 0-50%]) to obtain the title compound 7-bromo-3,4-dihydro-2H-5,1λ^6,2-benzoxathiazepine-1,1-dione (1.3 g, 4.67 mmol, 27.9%) as a colorless oil. LCMS: ESI m / z 280 [M+2+H] + .

[0259] Step C: 7-Bromo-2-(4-methoxybenzyl)-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepine 1,1-dioxide. To a solution of 7-bromo-3,4-dihydro-2H-5,1λ^6,2-benzoxathiazepine-1,1-dione (690 mg, 2.48 mmol) and CsCO (1.62 g, 4.96 mmol) in DMF (10 mL) was added 1-(chloromethyl)-4-methoxybenzene (0.5 mL, 3.72 mmol) at 0 °C. The reaction was stirred at 80 °C for 3 h. The reaction was diluted with EA and HO. The organic layer was separated, washed with brine, and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluting with EA in PE [gradient: 0-50%]) to give the title compound 7-bromo-2-[(4-methoxyphenyl)methyl]-3,4-dihydro-2H-5,1λ^6,2-benzoxathiazepine-1,1-dione (900 mg, 2.26 mmol, 91.1%) as a colorless oil.

[0260] Step D: 7-((1-(tert-butyl)-3-((1S,3R)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)amino)-2-(4-methoxybenzyl)-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepine 1,1-dioxide. To a solution of 7-bromo-2-[(4-methoxyphenyl)methyl]-3,4-dihydro-2H-5,1λ^6,2-benzoxathiazepine-1,1-dione (650 mg, 1.63 mmol) in dioxane (15 mL) was added 1-tert-butyl-3-[(3R)-3-[(tert-butyldimethylsilyl)oxy]cyclopentyl]-1H-pyrazol-5-amine (551 mg, 1.63 mmol), Pd2(dba)3 (149 mg, 0.163 mmol), Xantphos (189 mg, 0.326 mmol), and Cs2CO3 (1.60 g, 4.90 mmol). The reaction was stirred under N2 at 100 °C overnight. The reaction was concentrated in vacuo. The residue was purified by silica gel column chromatography (eluting with EA in PE [gradient: 0-50%]) to obtain the compound 7-({1-tert-butyl-3-[(3R)-3-[(tert-butyldimethylsilyl)oxy]cyclopentyl]-1H-pyrazol-5-yl}amino)-2-[(4-methoxyphenyl)methyl]-3,4-dihydro-2H-5,1λ^6,2-benzoxathiazepine-1,1-dione (900 mg, 1.37 mmol, 84.2%) as a brown solid. LCMS: ESI m / z 655 [M+H] + .

[0261] Step E: 7-((1-(tert-butyl)-3-((1S,3R)-3-hydroxycyclopentyl)-1H-pyrazol-5-yl)amino)-2-(4-methoxybenzyl)-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepine 1,1-dioxide. A solution of 7-[(1-tert-butyl-3-{3-[(tert-butyldimethylsilyl)oxy]cyclopentyl}-1H-pyrazol-5-yl)amino]-2-[(4-methoxyphenyl)methyl]-3,4-dihydro-2H-5,1λ^6,2-benzoxathiazepine-1,1-dione (900 mg, 1.37 mmol) in HCOOH (6 mL) was stirred at room temperature for 1 h. The reaction was concentrated, and MeOH (10 mL) and LiOH (2 mL, 4.12 mmol) were added and stirred at room temperature for 30 min. The reaction mixture was diluted with HO, and the aqueous layer was extracted with EA. The combined EA layers were washed with saturated NaCl solution. The EA layers were dried over NaSO, filtered, and concentrated. The residue was purified by silica gel column chromatography (eluted with a gradient of 0 to 100%) to give the title compound 7-{[1-tert-butyl-3-(3-hydroxycyclopentyl)-1H-pyrazol-5-yl]amino}-2-[(4-methoxyphenyl)methyl]-3,4-dihydro-2H-5,1λ^6,2-benzoxathiazepine-1,1-dione (700 mg, 1.30 mmol, 94.2%) as a white solid.

[0262] Step F: (1R,3S)-3-(1-(tert-butyl)-5-((2-(4-methoxybenzyl)-1,1-dioxide-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-7-yl)amino)-1H-pyrazol-3-yl)cyclopentyl(4-nitrophenyl)carbonate. To a solution of 7-{[1-tert-butyl-3-(3-hydroxycyclopentyl)-1H-pyrazol-5-yl]amino}-2-[(4-methoxyphenyl)methyl]-3,4-dihydro-2H-5,1λ^6,2-benzoxathiazepine-1,1-dione (400 mg, 0.740 mmol) in THF (5 mL) and DCM (5 mL) was added Py (117 mg, 1.48 mmol), DMAP (0.900 mg, 7 μmol), and 4-nitrophenyl chloroformate (194 mg, 0.962 mmol). The reaction was stirred at room temperature for 3 hours. The reaction was concentrated in vacuo. The residue was purified by silica gel column chromatography (eluting with EA in PE [gradient: 0-100%]) to obtain the title compound 3-[1-tert-butyl-5-({2-[(4-methoxyphenyl)methyl]-1,1-dioxo-3,4-dihydro-2H-5,1λ^6,2-benzoxathiazepin-7-yl}amino)-1H-pyrazol-3-yl]cyclopentyl 4-nitrophenyl carbonate (450 mg, 0.638 mmol, 86.2%) as a white solid. LCMS: ESI m / z 706 [M+H] + .

[0263] Step G: (1R,3S)-3-(5-((1,1-Dioxide-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-7-yl)amino)-1H-pyrazol-3-yl)cyclopentyl(4-nitrophenyl)carbonate. A solution of 7-{[1-tert-butyl-3-(3-hydroxycyclopentyl)-1H-pyrazol-5-yl]amino}-2-[(4-methoxyphenyl)methyl]-3,4-dihydro-2H-5,1λ^6,2-benzoxathiazepine-1,1-dione (400 mg, 0.740 mmol) in HCOOH (10 mL) was stirred at 100 °C overnight. The cooled reaction mixture was concentrated in vacuo to give the title compound 3-{5-[(1,1-dioxo-3,4-dihydro-2H-5,1λ^6,2-benzoxathiazepin-7-yl)amino]-1H-pyrazol-3-yl}cyclopentyl 4-nitrophenyl carbonate (250 mg, 0.472 mmol, 83.3%) as a brown solid.

[0264] Step H: (1R,3S)-3-(3-((1,1-dioxide-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-7-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate. A solution of 3-{5-[(1,1-dioxo-3,4-dihydro-2H-5,1λ^6,2-benzoxathiazepin-7-yl)amino]-1H-pyrazol-3-yl}cyclopentyl 4-nitrophenyl carbonate (250 mg, 0.472 mmol) in isopropylamine (5 mL) was stirred at 50° C. for 2 hours. The reaction was concentrated in vacuo. The residue was purified by preparative HPLC to give the title compound 3-{5-[(1,1-dioxo-3,4-dihydro-2H-5,1λ^6,2-benzoxathiazepin-7-yl)amino]-1H-pyrazol-3-yl}cyclopentyl N-(propan-2-yl)carbamate (100 mg, 0.222 mmol, 47.1%) as a white solid. LCMS: ESI m / z 450 [M+H] + .

[0265] 1H NMR (400MHz, DMSO)δ 11.89(s, 1H), 8.94(s, 1H), 7.49(d, J=8.8Hz, 1H), 7.35(s, 1H), 7.23(s, 1H), 7.02(d, J=8.8Hz, 1H), 6.95(s, 1H), 5.67(s, 1H), 5.00(s, 1H), 4.04(s, 2H), 3.57(s, 1H), 3.37(s, 2H), 3.05(s, 1H), 2.48-2.37(m, 1H) ), 2.25-1.80(m, 2H), 1.71(s, 2H), 1.60(s, 1H), 1.03(d, J=4.8Hz, 6H).

[0266] Example 7: (1s,4s)-4-{3-[(1,1-dioxo-2,3-dihydro-1λ^6,2-benzothiazol-5-yl)amino]-1H-pyrazol-5-yl}cyclohexyl N-(propan-2-yl)carbamate [ka] Step A: 4-Bromo-N-(tert-butyl)-2-methylbenzenesulfonamide. To a solution of 4-bromo-2-methylbenzene-1-sulfonyl chloride (5 g, 18.5 mmol) in DCM (20 mL) was added triethylamine (7.73 mL, 55.6 mmol) and 2-methylpropan-2-amine (3.93 mL, 37.1 mmol). The reaction was stirred at room temperature overnight. The reaction was concentrated in vacuo. The residue was purified by silica gel column chromatography (eluting with a gradient of 0-50%) to afford the title compound, 4-bromo-N-tert-butyl-2-methylbenzene-1-sulfonamide (5 g, 16.3 mmol, 88.0%) as a white solid. LCMS: ESI m / z 306 [M+H] + . 1 H NMR (400MHz, DMSO) δ 7.75 (d, J=8.4Hz, 1H), 7.65-7.49 (m, 3H), 2.54 (s, 3H), 1.06 (s, 9H).

[0267] Step B: 4-Bromo-2-(bromomethyl)-N-(tert-butyl)benzenesulfonamide. To a solution of 4-bromo-N-tert-butyl-2-methylbenzene-1-sulfonamide (5 g, 16.3 mmol) in CHCl3 (10 mL) was added AIBN (268 mg, 1.63 mmol), DIEA (0.448 mL, 2.71 mmol), and NBS (2.91 g, 16.3 mmol). The reaction was stirred at 60 °C overnight. The reaction was concentrated. The residue was purified by silica gel column chromatography (eluted with a gradient of 0 to 30%) to afford the title compound, 4-bromo-2-(bromomethyl)-N-tert-butylbenzene-1-sulfonamide (1.9 g, 4.9 mmol, 30.2%), as a white solid. LCMS: ESI m / z 384 [M+H] + .

[0268] Step C: 5-Bromo-2-(tert-butyl)-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide. To a solution of 4-bromo-2-(bromomethyl)-N-tert-butylbenzene-1-sulfonamide (1.4 g, 3.63 mmol) in MeOH (20 mL) and HO (5 mL) was added NaOH (0.44 g, 10.9 mmol), and the reaction was stirred at room temperature for 3 h. The reaction was concentrated in vacuo. The residue was purified by silica gel column chromatography (eluting with EA in PE [gradient: 0 to 80%]) to afford the title compound, 5-bromo-2-tert-butyl-2,3-dihydro-1λ^6,2-benzothiazole-1,1-dione (900 mg, 2.95 mmol, 81.4%) as a white solid. LCMS: ESI m / z 304 [M+H] + . 1 H NMR (400MHz, DMSO) δ 7.83(d, J=0.8Hz, 1H), 7.85-7.63(m, 2H), 4.55(s, 2H), 1.46(s, 9H).

[0269] Step D: 5-Bromo-2,3-dihydro-1λ^6,2-benzothiazole-1,1-dione. A solution of 5-bromo-2-tert-butyl-2,3-dihydro-1λ^6,2-benzothiazole-1,1-dione (3 g, 9.86 mmol) in TFA (50 mL) was stirred at 60 °C for 3 h. The reaction mixture was concentrated. The pH of the residue was adjusted to 7–8 with 1 N aqueous NaOH (3 mL). The subsequent mixture was diluted with EA and water. The organic layer was separated, washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluted with ethyl acetate in petroleum ether (gradient: 0–50%)) to afford the title compound 5-bromo-2,3-dihydro-1λ^6,2-benzothiazole-1,1-dione (2.1 g, 8.46 mmol, 85.8%) as a white solid. LCMS:ESI m / z 248.10[M+H] + .

[0270] Step E: 5-Bromo-2-[(4-methoxyphenyl)methyl]-2,3-dihydro-1λ^6,2-benzothiazole-1,1-dione. To a solution of 5-bromo-2,3-dihydro-1λ^6,2-benzothiazole-1,1-dione (2.1 g, 8.46 mmol) in DMF (20 mL) was added 4-methoxybenzyl chloride (1.99 g, 12.7 mmol) and Cs2CO3 (5.52 g, 16.9 mmol). The reaction was stirred at 35 °C overnight. The reaction mixture was diluted with EA and water. The organic layer was separated, washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluting with ethyl acetate in petroleum ether (gradient: 0-20%)) to give the title compound 5-bromo-2-[(4-methoxyphenyl)methyl]-2,3-dihydro-1λ^6,2-benzothiazole-1,1-dione (2.45 g, 6.65 mmol, 78.6%) as a white solid. LCMS: ESI m / z 368.25 [M+H] + .

[0271] Step F: 5-({1-tert-butyl-3-[(1s,4s)-4-[(tert-butyldiphenylsilyl)oxy]cyclohexyl]-1H-pyrazol-5-yl}amino)-2-[(4-methoxyphenyl)methyl]-2,3-dihydro-1λ^6,2-benzothiazole-1,1-dione. To a solution of 5-bromo-2-[(4-methoxyphenyl)methyl]-2,3-dihydro-1λ^6,2-benzothiazole-1,1-dione (500 mg, 1.36 mmol) in dioxane (10 mL) was added 1-tert-butyl-3-[(1s,4s)-4-[(tert-butyldiphenylsilyl)oxy]cyclohexyl]-1H-pyrazol-5-amine (775 mg, 1.63 mmol), Cs2CO3 (1.32 g, 4.07 mmol), Pd2(dba)3 (124 mg, 0.136 mmol), and Xantphos (157 mg, 0.272 mmol). The reaction was stirred under N2 at 100 °C for 6 h. The reaction was diluted with EA and water. The organic layer was separated, washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluting with ethyl acetate in petroleum ether (gradient: 0-50%)) to give the title compound 5-({1-tert-butyl-3-[(1s,4s)-4-[(tert-butyldiphenylsilyl)oxy]cyclohexyl]-1H-pyrazol-5-yl}amino)-2-[(4-methoxyphenyl)methyl]-2,3-dihydro-1λ^6,2-benzothiazole-1,1-dione (700 mg, 0.917 mmol, 67.6%) as a white solid. LCMS: ESI m / z 763.09 [M+H] + .

[0272] Step G: 5-({1-tert-butyl-3-[(1s,4s)-4-hydroxycyclohexyl]-1H-pyrazol-5-yl}amino)-2-[(4-methoxyphenyl)methyl]-2,3-dihydro-1λ^6,2-benzothiazole-1,1-dione. To a solution of 5-({1-tert-butyl-3-[(1s,4s)-4-[(tert-butyldiphenylsilyl)oxy]cyclohexyl]-1H-pyrazol-5-yl}amino)-2-[(4-methoxyphenyl)methyl]-2,3-dihydro-1λ^6,2-benzothiazole-1,1-dione (700 mg, 0.917 mmol) in TBAF (20 mL, 1 M in THF) was added and the reaction was stirred overnight at room temperature. The reaction was diluted with EA and water. The organic layer was separated, washed with saturated NaCl solution, and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluting with ethyl acetate in petroleum ether (gradient: 0-30%)) to give the title compound 5-({1-tert-butyl-3-[(1s,4s)-4-hydroxycyclohexyl]-1H-pyrazol-5-yl}amino)-2-[(4-methoxyphenyl)methyl]-2,3-dihydro-1λ^6,2-benzothiazole-1,1-dione (400 mg, 0.762 mmol, 83.1%) as a white solid. LCMS: ESI m / z 524.69 [M+H] + .

[0273] Step H: 4-Nitrophenyl(1s,4s)-4-[1-tert-butyl-5-({2-[(4-methoxyphenyl)methyl]-1,1-dioxo-2,3-dihydro-1λ^6,2-benzothiazol-5-yl}amino)-1H-pyrazol-3-yl]cyclohexyl carbonate. To a solution of 5-({1-tert-butyl-3-[(1s,4s)-4-hydroxycyclohexyl]-1H-pyrazol-5-yl}amino)-2-[(4-methoxyphenyl)methyl]-2,3-dihydro-1λ^6,2-benzothiazole-1,1-dione (400 mg, 0.762 mmol) in THF (5 mL) and DCM (5 mL) was added 4-nitrophenyl chloroformate (230 mg, 1.14 mmol), DMAP (9.31 mg, 0.076 mmol), and Py (0.123 mL, 1.53 mmol). The reaction was stirred at room temperature under N2 for 3 h. The reaction was diluted with EA and water. The organic layer was separated, washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluting with ethyl acetate in petroleum ether (gradient: 0-50%)) to give the title compound 4-nitrophenyl (1s,4s)-4-[1-tert-butyl-5-({2-[(4-methoxyphenyl)methyl]-1,1-dioxo-2,3-dihydro-1λ^6,2-benzothiazol-5-yl}amino)-1H-pyrazol-3-yl]cyclohexyl carbonate (250 mg, 0.362 mmol, 47.5%) as a white solid. LCMS: ESI m / z 689.79 [M+H] + .

[0274] Step I: 4-Nitrophenyl (1s,4s)-4-{5-[(1,1-dioxo-2,3-dihydro-1λ^6,2-benzothiazol-5-yl)amino]-1H-pyrazol-3-yl}cyclohexyl carbonate. A solution of 4-nitrophenyl (1s,4s)-4-[1-tert-butyl-5-({2-[(4-methoxyphenyl)methyl]-1,1-dioxo-2,3-dihydro-1λ^6,2-benzothiazol-5-yl}amino)-1H-pyrazol-3-yl]cyclohexyl carbonate (70 mg, 0.101 mmol) in formic acid (5 mL) was stirred at 100 °C overnight. The reaction was concentrated in vacuo to give the title compound 4-nitrophenyl(1s,4s)-4-{5-[(1,1-dioxo-2,3-dihydro-1λ^6,2-benzothiazol-5-yl)amino]-1H-pyrazol-3-yl}cyclohexyl carbonate (50 mg, 0.097 mmol, 96.0%) as a brown solid. LCMS: ESI m / z 513.53 [M+H] + .

[0275] Step J: (1s,4s)-4-{3-[(1,1-dioxo-2,3-dihydro-1λ^6,2-benzothiazol-5-yl)amino]-1H-pyrazol-5-yl}cyclohexyl N-(propan-2-yl)carbamate. To a solution of 4-nitrophenyl (1s,4s)-4-{5-[(1,1-dioxo-2,3-dihydro-1λ^6,2-benzothiazol-5-yl)amino]-1H-pyrazol-3-yl}cyclohexyl carbonate (50 mg, 0.097 mmol) in isopropylamine (3 mL). The reaction was stirred at room temperature for 1 hour. The reaction was purified by preparative HPLC (C18, 0-50% acetonitrile in HO) to afford the title compound (1s,4s)-4-{3-[(1,1-dioxo-2,3-dihydro-1λ^6,2-benzothiazol-5-yl)amino]-1H-pyrazol-5-yl}cyclohexyl N-(propan-2-yl)carbamate (14.5 mg, 0.033 mmol, 34.4%) as a white solid. LCMS: ESI m / z 433.53 [M+H] +. 1H NMR (400MHz, DMSO)δ 11.89(s, 1H), 9.01(s, 1H), 7.57-7.26(m, 4H), 6.88(s, 1H), 5.68(s, 1H), 4.75(s, 1H) ), 4.29(s, 2H), 3.60(s, 1H), 2.68(s, 1H), 1.85-1.59(m, 8H), 1.05(d, J=5.2Hz, 6H).

[0276] Example 8: (1R,3S)-3-(3-((1-oxoisoindolin-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate [ka] Step A: 5-Bromo-2-(4-methoxybenzyl)isoindolin-1-one. To a solution of methyl 4-bromo-2-(bromomethyl)benzoate (4.50 g, 14.6 mmol) in tetrahydrofuran (100 mL) was added (4-methoxyphenyl)methanamine (2.20 g, 16.0 mmol). The mixture was stirred at 80 °C for 2 h. The cooled mixture was concentrated in vacuo. The residue was purified by flash column chromatography (using 0-50% ethyl acetate in petroleum ether) to give 5-bromo-2-[(4-methoxyphenyl)methyl]-2,3-dihydro-1H-isoindol-1-one (2 g, 6.02 mmol, 41.2%) as a white solid. LCMS: ESI 332.4, 334.4 [M+H] + . 1 H NMR (400 MHz, methyl sulfoxide-d6) δ 7.81 (s, 1H), 7.72-7.61 (m, 2H), 7.25-7.17 (m, 2H), 6.95-6.86 (m, 2H), 4.64 (s, 2H), 4.32 (s, 2H), 3.73 (s, 3H).

[0277] Step B: 5-((1-(tert-butyl)-3-((1S,3R)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)amino)-2-(4-methoxybenzyl)isoindolin-1-one. To a solution of 1-tert-butyl-3-[(1S,3R)-3-[(tert-butyldimethylsilyl)oxy]cyclopentyl]-1H-pyrazol-5-amine (500 mg, 1.48 mmol) in dioxane (5 mL) was added 5-bromo-2-[(4-methoxyphenyl)methyl]-2,3-dihydro-1H-isoindol-1-one (737 mg, 2.22 mmol), [5-(diphenylphosphanyl)-9,9-dimethyl-9H-xanthen-4-yl]diphenylphosphane (171 mg, 0.296 mmol), sodium 2-methylpropane-2-oleate (2.96 mL, 2.96 mmol), and Pd(dba) (135 mg, 0.148 mmol). The reaction was stirred under N at 90 °C for 18 h. The reaction was diluted with EA and water. The organic layer was separated, further washed with brine, and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluting with ethyl acetate in petroleum ether (3 / 1)). The organic layer was collected, concentrated in vacuo, and dried to give the title compound 5-({1-tert-butyl-3-[(1S,3R)-3-[(tert-butyldimethylsilyl)oxy]cyclopentyl]-1H-pyrazol-5-yl}amino)-2-[(4-methoxyphenyl)methyl]-2,3-dihydro-1H-isoindol-1-one (500 mg, 57% yield) as a yellow solid. LCMS: ESI m / z 589 [M+H] + .

[0278] Step C: 5-((1-(tert-butyl)-3-((1S,3R)-3-hydroxycyclopentyl)-1H-pyrazol-5-yl)amino)-2-(4-methoxybenzyl)isoindolin-1-one. To a solution of 5-({1-tert-butyl-3-[(1S,3R)-3-[(tert-butyldimethylsilyl)oxy]cyclopentyl]-1H-pyrazol-5-yl}amino)-2-[(4-methoxyphenyl)methyl]-2,3-dihydro-1H-isoindol-1-one (500 mg, 0.85 mmol) in HCOOH (5 mL) was added and the reaction was stirred at room temperature for 1 h. The reaction was concentrated, and MeOH (5 mL) and LiOH (142 mg, 3.39 mmol) were added and stirred at room temperature for 30 min. The reaction was diluted with water and the aqueous layer was extracted with EA. The combined EA layers were washed with saturated NaCl solution. The EA layers were dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (eluted with a gradient of 0 to 100%) to give the title compound 5-({1-tert-butyl-3-[(1S,3R)-3-hydroxycyclopentyl]-1H-pyrazol-5-yl}amino)-2-[(4-methoxyphenyl)methyl]-2,3-dihydro-1H-isoindol-1-one (300 mg, 74% yield) as a yellow oil. LCMS: ESI m / z 475 [M+H] + .

[0279] Step D: (3S,5S)-1-Acetyl-5-(1-(tert-butyl)-5-(3-(methoxymethyl)-1-methyl-1H-pyrazole-5-carboxamido)-1H-pyrazol-3-yl)pyrrolidin-3-yl(4-nitrophenyl)carbonate. To a solution of 5-({1-tert-butyl-3-[(1S,3R)-3-hydroxycyclopentyl]-1H-pyrazol-5-yl}amino)-2-[(4-methoxyphenyl)methyl]-2,3-dihydro-1H-isoindol-1-one (300 mg, 0.632 mmol) in THF (10 mL) and DCM (10 mL) was added 4-nitrophenyl chloroformate (191 mg, 0.948 mmol), pyridine (0.153 mL, 1.896 mmol). The reaction was stirred at 30° C. for 30 minutes. The reaction was concentrated in vacuo. The residue was purified by silica gel column chromatography (eluted with EA in PE [gradient: 0-100%]) to give the title compound (1R,3S)-3-[1-tert-butyl-5-({2-[(4-methoxyphenyl)methyl]-1-oxo-2,3-dihydro-1H-isoindol-5-yl}amino)-1H-pyrazol-3-yl]cyclopentyl 4-nitrophenyl carbonate (300 mg, 75% yield) as a white solid. LCMS: ESI m / z 640 [M+H] - .

[0280] Step E: 4-Nitrophenyl((1R,3S)-3-(3-((1-oxoisoindolin-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl)carbonate. A solution of (1R,3S)-3-[1-tert-butyl-5-({2-[(4-methoxyphenyl)methyl]-1-oxo-2,3-dihydro-1H-isoindol-5-yl}amino)-1H-pyrazol-3-yl]cyclopentyl 4-nitrophenyl carbonate (300 mg, 0.469 mmol) in HCOOH (5 mL) was stirred at 100° C. overnight. The reaction was concentrated in vacuo to give the title compound 4-nitrophenyl(1R,3S)-3-{5-[(1-oxo-2,3-dihydro-1H-isoindol-5-yl)amino]-1H-pyrazol-3-yl}cyclopentyl carbonate (300 mg, crude) as a white solid, which was used in the next step without further purification. LCMS: ESI m / z 464 [M+H] + .

[0281] Step F: (1R,3S)-3-(3-((1-oxoisoindolin-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate. To a solution of 4-nitrophenyl (1R,3S)-3-{5-[(1-oxo-2,3-dihydro-1H-isoindol-5-yl)amino]-1H-pyrazol-3-yl}cyclopentyl carbonate (300 mg, 0.647 mmol) in THF (2 mL) was added propan-2-amine (0.555 mL, 6.47 mmol). The reaction was stirred at 50° C. for 2 hours. The reaction was concentrated in vacuo. The residue was purified by preparative HPLC (0.1% TFA) to give the title compound (1R,3S)-3-{5-[(1-oxo-2,3-dihydro-1H-isoindol-5-yl)amino]-1H-pyrazol-3-yl}cyclopentyl N-(propan-2-yl)carbamate (4.8 mg, 1.9% yield) as a white solid. LCMS: ESI m / z 384 [M+H] + . 1H NMR (400MHz, DMSO-d6)δ 8.78(brs,1H), 8.03(s, 1H), 7.54(s, 1H), 7.43(d, J=8.4Hz, 1H), 7.24(d, J=8.4Hz, 1H), 6.94(d, J=7.6Hz, 1H), 5.70(s, 1H), 5.00(s, 1H), 4.26(s, 2H), 3.11-3.03(m, 1H), 2.11-1.52(m, 6H), 1.03(d, J=6.4Hz, 6H).

[0282] Example 9: (1R,3S)-3-(3-((1,1-dioxide-2,3-dihydrobenzo[b]thiophen-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate [ka] Step A: 5-Bromo-1λ^6-benzothiophene-1,1-dione. To a solution of 5-bromo-1-benzothiophene (1 g, 4.69 mmol) in DCM (8 mL) was added HO (2 mL, 19.6 mmol, 30% in HO) and TFA (2 mL, 26.92 mmol). The mixture was stirred at 20 °C for 5 h. The reaction mixture was diluted with water and extracted with DCM (30 mL × 3). The organic phase was washed with aqueous NaSO, dried over NaSO, and concentrated. The residue was purified by silica gel chromatography (10 g column) using 0–30% EtOAc / hexane to give 5-bromo-1λ^6-benzothiophene-1,1-dione (700 mg, 2.85 mmol, 60.8%) as a brown oil.

[0283] Step B: 5-Bromo-2,3-dihydro-1λ^6-benzothiophene-1,1-dione. To a solution of 5-bromo-1λ^6-benzothiophene-1,1-dione (700 mg, 2.85 mmol) in MeOH (30 mL) was added NaBH4 (221 mg, 5.71 mmol), and the mixture was stirred at 20 °C for 2 h. HO (0.5 mL) was added to quench the reaction. The resulting mixture was concentrated, and the residue was purified by silica gel chromatography (10 g column) using 0–30% EtOAc / hexanes to afford 5-bromo-2,3-dihydro-1λ^6-benzothiophene-1,1-dione (540 mg, 2.18 mmol, 76.5%) as a brown oil. 1 H NMR (400MHz, DMSO) δ 7.84(s, 1H), 7.72(s, 2H), 3.66-3.54(m, 2H), 3.42-3.28(m, 2H).

[0284] Step C: 5-({1-tert-butyl-3-[(1S,3R)-3-[(tert-butyldimethylsilyl)oxy]cyclopentyl]-1H-pyrazol-5-yl}amino)-2,3-dihydro-1λ^6-benzothiophene-1,1-dione. To a solution of 5-bromo-2,3-dihydro-1λ^6-benzothiophene-1,1-dione (100 mg, 0.40 mmol) and 1-tert-butyl-3-[(1S,3R)-3-[(tert-butyldimethylsilyl)oxy]cyclopentyl]-1H-pyrazol-5-amine (150 mg, 0.44 mmol) in dioxane (5 mL) was added CsCO (263 mg, 0.81 mmol), Pd(dba) (37.0 mg, 0.04 mmol), and Xantphos (23.4 mg, 0.04 mmol). The reaction mixture was stirred at 100 °C under N for 5 h. The mixture was purified by silica gel chromatography (2 g column) using 0–50% EtOAc / hexanes. The product-containing fractions were concentrated to give 5-({1-tert-butyl-3-[(1S,3R)-3-[(tert-butyldimethylsilyl)oxy]cyclopentyl]-1H-pyrazol-5-yl}amino)-2,3-dihydro-1λ^6-benzothiophene-1,1-dione (160 mg, 0.32 mmol, 78.5%) as a brown solid. LCMS: ESI m / z 504.3 [M+H] + .

[0285] Step D: 5-({1-tert-butyl-3-[(1S,3R)-3-hydroxycyclopentyl]-1H-pyrazol-5-yl}amino)-2,3-dihydro-1λ^6-benzothiophene-1,1-dione. A solution of 5-({1-tert-butyl-3-[(1S,3R)-3-[(tert-butyldimethylsilyl)oxy]cyclopentyl]-1H-pyrazol-5-yl}amino)-2,3-dihydro-1λ^6-benzothiophene-1,1-dione (160 mg, 0.32 mmol) in formic acid (4 mL) was stirred at 20° C. for 30 min. The mixture was concentrated in vacuo to remove formic acid and give the crude product. To the crude product was added MeOH (3 mL) and LiOH (100 mg), which was stirred at 20° C. for 30 min. The mixture was concentrated in vacuo, poured into EA (30 mL), and extracted with water. The organic layer was concentrated to give 5-({1-tert-butyl-3-[(1S,3R)-3-hydroxycyclopentyl]-1H-pyrazol-5-yl}amino)-2,3-dihydro-1λ^6-benzothiophene-1,1-dione (120 mg, 0.31 mmol, 97.0%) as a brown solid. LCMS: ESI m / z 390.1 [M+H] + .

[0286] Step E: (1R,3S)-3-{1-tert-butyl-5-[(1,1-dioxo-2,3-dihydro-1λ^6-benzothiophen-5-yl)amino]-1H-pyrazol-3-yl}cyclopentyl 4-nitrobenzoate. To a solution of 5-({1-tert-butyl-3-[(1S,3R)-3-hydroxycyclopentyl]-1H-pyrazol-5-yl}amino)-2,3-dihydro-1λ^6-benzothiophene-1,1-dione (120 mg, 0.31 mmol) in DCM (2 mL) and THF (2 mL) was added 4-nitrophenyl chloroformate (93.14 mg, 0.46 mmol), pyridine (0.05 mL, 0.62 mmol), and DMAP (3.76 mg, 0.03 mmol). The mixture was stirred at 20 °C for 1 h. The mixture was concentrated, and the residue was purified by silica gel chromatography (2 g column) (0–50% EtOAc / hexanes) to afford (1R,3S)-3-{1-tert-butyl-5-[(1,1-dioxo-2,3-dihydro-1λ^6-benzothiophen-5-yl)amino]-1H-pyrazol-3-yl}cyclopentyl 4-nitrobenzoate (130 mg, 0.24 mmol, 78.3%) as a brown solid. LCMS: ESI m / z 555.2 [M+H] + .

[0287] Step F: (1R,3S)-3-{5-[(1,1-dioxo-2,3-dihydro-1λ^6-benzothiophen-5-yl)amino]-1H-pyrazol-3-yl}cyclopentyl 4-nitrophenyl carbonate. A solution of (1R,3S)-3-{1-tert-butyl-5-[(1,1-dioxo-2,3-dihydro-1λ^6-benzothiophen-5-yl)amino]-1H-pyrazol-3-yl}cyclopentyl 4-nitrophenyl carbonate (130 mg, 0.23 mmol) in formic acid (4 mL) was stirred at 100° C. for 12 h. The cooled mixture was concentrated in vacuo to give (1R,3S)-3-{5-[(1,1-dioxo-2,3-dihydro-1λ^6-benzothiophen-5-yl)amino]-1H-pyrazol-3-yl}cyclopentyl 4-nitrophenyl carbonate (110 mg, 0.2 mmol, 84.7%) as a brown solid. The crude product was used in the next step without purification. LCMS: ESI m / z 499.1 [M+H] + .

[0288] Step G: (1R,3S)-3-(3-((1,1-Dioxide-2,3-dihydrobenzo[b]thiophen-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate. To a solution of (1R,3S)-3-{5-[(1,1-dioxo-2,3-dihydro-1λ^6-benzothiophen-5-yl)amino]-1H-pyrazol-3-yl}cyclopentyl 4-nitrophenyl carbonate (110 mg, 0.2 mmol) in THF (5 mL) was added ethyldiisopropylamine (0.11 mL, 0.66 mmol). Then propan-2-amine (0.09 mL, 1.10 mmol) was added dropwise. The reaction mixture was stirred at 20 °C for 2 h. The mixture was concentrated and the residue was purified by preparative TLC (EA) to give (1R,3S)-3-(3-((1,1-dioxide-2,3-dihydrobenzo[b]thiophen-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate (14.7 mg, 0.035 mmol, 16%) as a white solid. LCMS: ESI m / z 419.1 [M+H] + . 1H NMR (400MHz, DMSO)δ 11.92(s, 1H), 8.99(s, 1H), 7.52-7.40(m, 2H), 7.29(d, J=8.4Hz, 1H), 6.95(d, J=7. 2Hz, 1H), 5.71(s, 1H), 5.00(brs, 1H), 3.64-3.52(m, 1H), 3.48(t, J=6.8Hz, 2H), 3.2 4(t, J=6.8Hz, 2H), 3.12-3.01(m, 1H), 2.49-2.42(m, 1H), 2.03(dd, J=15.6, 7.6Hz, 1 H), 1.94-1.82(m, 1H), 1.78-1.64(m, 2H), 1.63-1.52(m, 1H), 1.04(d, J=6.4Hz, 6H).

[0289] Example 10: (1R,3S)-3-(5-((3-methyl-1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate [ka] Step A: 5-Bromo-3-methylbenzo[d]isothiazole 1,1-dioxide. A solution of 5-bromo-2,3-dihydro-1λ^6,2-benzothiazole-1,1,3-trione (500 mg, 1.91 mmol) in THF (0.1 M) was treated with MeMgBr (5.7 mL, 5.72 mmol, 1 M in THF) at 0 °C. The mixture was stirred overnight at room temperature, quenched with water, and extracted with EtOAc (100 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (PE / EA = 2:1) to give the pure product, 5-bromo-3-methyl-1λ^6,2-benzothiazole-1,1-dione (400 mg, 1.54 mmol, 80.6%), as a white solid. LCMS: ESI 259.9, 261.9 [M+H] + .

[0290] Step B: 5-Bromo-3-methyl-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide. To a solution of 5-bromo-3-methyl-1λ^6,2-benzothiazole-1,1-dione (400 mg, 1.54 mmol) in THF (20 mL) was added NaBH4 (104 mg, 3.07 mmol), and the reaction mixture was then stirred at 25 °C for 5 h. Upon completion, the reaction mixture was quenched with 2 mL of NH4Cl (aq). The reaction was diluted with EA and water. The organic layer was separated, washed with brine, and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluting with PE / EA = 1:3). The organic layer was collected, concentrated in vacuo, and dried to give the title compound 5-bromo-3-methyl-2,3-dihydro-1λ^6,2-benzothiazole-1,1-dione (350 mg, 1.33 mmol, 86.8%) as a colorless oil. LCMS: ESI m / z 261.9, 263.9 [M+H] + .

[0291] Step C: 5-((1-(tert-butyl)-3-((1S,3R)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)amino)-3-methyl-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide. To a solution of 1-tert-butyl-3-[(1S,3R)-3-[(tert-butyldimethylsilyl)oxy]cyclopentyl]-1H-pyrazol-5-amine (350 mg, 1.04 mmol) in dioxane (2 mL) was added 5-bromo-3-methyl-2,3-dihydro-1λ^6,2-benzothiazole-1,1-dione (300 mg, 1.14 mmol), [5-(diphenylphosphanyl)-9,9-dimethyl-9H-xanthen-4-yl]diphenylphosphane (120 mg, 0.207 mmol), Cs2CO3 (675 mg, 2.074 mmol), and Pd2(dba)3 (95 mg, 0.104 mmol). The reaction mixture was stirred at 90 °C for 18 h. The reaction mixture was diluted with EA and water. The organic layer was separated, washed with brine, and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluted with ethyl acetate in petroleum ether (3 / 1)) to give the title compound 5-({1-tert-butyl-3-[(1S,3R)-3-[(tert-butyldimethylsilyl)oxy]cyclopentyl]-1H-pyrazol-5-yl}amino)-3-methyl-2,3-dihydro-1λ^6,2-benzothiazole-1,1-dione (200 mg, 0.386 mmol, 37.2%) as a yellow solid. LCMS: ESI m / z 519.2 [M+H] + .

[0292] Step D: 5-((1-(tert-butyl)-3-((1S,3R)-3-hydroxycyclopentyl)-1H-pyrazol-5-yl)amino)-3-methyl-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide. A solution of 5-({1-tert-butyl-3-[(1S,3R)-3-[(tert-butyldimethylsilyl)oxy]cyclopentyl]-1H-pyrazol-5-yl}amino)-3-methyl-2,3-dihydro-1λ^6,2-benzothiazole-1,1-dione (200 mg, 0.386 mmol) in HCOOH (50 mL) was stirred at room temperature for 1 h. The reaction was concentrated, and MeOH (50 mL), LiOH (64.7 mg, 1.54 mmol) were added and stirred at room temperature for 30 min. The reaction was diluted with HO. The subsequent mixture was extracted with EA. The combined EA layers were washed with saturated NaCl solution. The EA layers were dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (eluted with a gradient of 80-100%) to obtain the title compound 5-({1-tert-butyl-3-[(1S,3R)-3-hydroxycyclopentyl]-1H-pyrazol-5-yl}amino)-3-methyl-2,3-dihydro-1λ^6,2-benzothiazole-1,1-dione (120 mg, 0.297 mmol, 76.9%) as a white solid. LCMS: ESI m / z 405 [M+H] + .

[0293] Step E: (1R,3S)-3-(1-(tert-butyl)-5-((3-methyl-1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-3-yl)cyclopentyl(4-nitrophenyl)carbonate. To a solution of 5-({1-tert-butyl-3-[(1S,3R)-3-hydroxycyclopentyl]-1H-pyrazol-5-yl}amino)-3-methyl-2,3-dihydro-1λ^6,2-benzothiazole-1,1-dione (120 mg, 0.297 mmol) in THF (10 mL) and DCM (10 mL) was added 4-nitrophenyl chloroformate (89.7 mg, 0.445 mmol), pyridine (0.072 mL, 0.890 mmol). The reaction was stirred at 50 °C for 30 min. The reaction mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography (eluting with EA in PE [gradient: 70-90%]) to give the title compound (1R,3S)-3-{1-tert-butyl-5-[(3-methyl-1,1-dioxo-2,3-dihydro-1λ^6,2-benzothiazol-5-yl)amino]-1H-pyrazol-3-yl}cyclopentyl 4-nitrophenyl carbonate (100 mg, 0.176 mmol, 59.2%) as a white solid. LCMS: ESI m / z 570.1 [M+H] + .

[0294] Step F: (1R,3S)-3-(5-((3-Methyl-1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-3-yl)cyclopentyl(4-nitrophenyl)carbonate. A solution of (1R,3S)-3-{1-tert-butyl-5-[(3-methyl-1,1-dioxo-2,3-dihydro-1λ^6,2-benzothiazol-5-yl)amino]-1H-pyrazol-3-yl}cyclopentyl 4-nitrophenylcarbonate (100 mg, 0.176 mmol) in HCOOH (5 mL) was stirred at 80 °C overnight. The reaction was concentrated in vacuo to afford the title compound (1R,3S)-3-{5-[(3-methyl-1,1-dioxo-2,3-dihydro-1λ^6,2-benzothiazol-5-yl)amino]-1H-pyrazol-3-yl}cyclopentyl 4-nitrophenyl carbonate (80 mg, 0.156 mmol, 88.9%) as a white solid, which was used in the next step without further purification. LCMS: ESI m / z 514 [M+H] + .

[0295] Step G: (1R,3S)-3-(5-((3-Methyl-1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate. To a solution of (1R,3S)-3-{5-[(3-methyl-1,1-dioxo-2,3-dihydro-1λ^6,2-benzothiazol-5-yl)amino]-1H-pyrazol-3-yl}cyclopentyl 4-nitrophenyl carbonate (80 mg, 0.156 mmol) in THF (2 mL) was added propan-2-amine (0.133 mL, 1.558 mmol) and the reaction was stirred at 50° C. for 2 h. The reaction was concentrated in vacuo. The residue was purified by preparative HPLC (FA conditions) to give the title compound (1R,3S)-3-{5-[(3-methyl-1,1-dioxo-2,3-dihydro-1λ^6,2-benzothiazol-5-yl)amino]-1H-pyrazol-3-yl}cyclopentyl N-(propan-2-yl)carbamate (2.4 mg, 3.55%) as a white solid. LCMS: ESI m / z 434 [M+H] + .1 H NMR (400MHz, DMSO-d6)δ 11.92(s, 1H), 9.01(s, 1H), 7.57(d, J=4.4Hz, 1H), 7.50(d, J=8.8Hz, 2H), 7.32(d, J=8.8Hz, 1H), 6.94(d, J=7.6Hz, 1H), 5.69(s, 1H), 5.06-4.94(m, 1H), 4.67-4.54(m , 1H), 3.65-3.53(m, 1H), 3.13-2.98(m, 1H), 2.48-2.40(m, 1H), 2.06-1.97(m, 1H) , 1.95-1.82(m, 1H), 1.79-1.53(m, 3H), 1.39(d, J=6.4Hz, 3H), 1.03(d, J=8Hz, 6H).

[0296] Example 11: (1s,4s)-4-{3-[(1,1-dioxo-3,4-dihydro-2H-1λ^6,2-benzothiazin-6-yl)amino]-1H-pyrazol-5-yl}cyclohexyl N-(propan-2-yl)carbamate [ka] Step A. Methyl 2-(5-bromo-2-(chlorosulfonyl)phenyl)acetate. A reaction mixture of methyl 2-(3-bromophenyl)acetate (10 g, 43.8 mmol) in HSO3Cl (5.10 g, 43.8 mmol) was stirred at room temperature overnight. The reaction mixture was slowly poured into ice water and extracted with EtOAc. The combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated to give crude methyl 2-[5-bromo-2-(chlorosulfonyl)phenyl]acetate (3 g, 9.2 mmol, 21%) as a yellow oil. LCMS: m / z 327 [M+H] + .

[0297] Step B. Methyl 2-(5-bromo-2-(N-(4-methoxybenzyl)sulfamoyl)phenyl)acetate. To a stirred mixture of methyl 2-[5-bromo-2-(chlorosulfonyl)phenyl]acetate (3 g, 9.2 mmol) in DCM (30 mL) at 0 °C, (4-methoxyphenyl)methanamine (1.26 g, 9.2 mmol) and TEA (1.86 g, 18.4 mmol) were slowly added. After stirring overnight at room temperature, the mixture was poured into water and extracted with DCM. The combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by chromatography (silica gel, 0–35%, EtOAc in PE) to give methyl 2-(5-bromo-2-{[(4-methoxyphenyl)methyl]sulfamoyl}phenyl)acetate (2 g, 4.65 mmol, 33.9%) as a brown solid. LCMS: m / z 429 [M+H] + .

[0298] Step C. 4-Bromo-2-(2-hydroxyethyl)-N-(4-methoxybenzyl)benzenesulfonamide. To a stirred mixture of methyl 2-(5-bromo-2-{[(4-methoxyphenyl)methyl]sulfamoyl}phenyl)acetate (2.5 g, 5.84 mmol) in THF (30 mL) was slowly added lithium(1+) ion boronide (5.84 mL, 11.6 mmol) at 0 °C. After stirring overnight at room temperature, the mixture was poured into ice water and extracted with EtOAc. The combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo, and the residue was purified by flash chromatography to give 4-bromo-2-(2-hydroxyethyl)-N-[(4-methoxyphenyl)methyl]benzene-1-sulfonamide (1.5 g, 3.75 mmol, 64.2%) as a colorless oil. LCMS: m / z 401 [M+H] + .

[0299] Step D. 6-Bromo-2-(4-methoxybenzyl)-3,4-dihydro-2H-benzo[e][1,2]thiazine 1,1-dioxide. To a stirred mixture of 4-bromo-2-(2-hydroxyethyl)-N-[(4-methoxyphenyl)methyl]benzene-1-sulfonamide (700 mg, 1.749 mmol) in THF (10 mL) was added triphenylphosphane (917 mg, 3.49 mmol) and (E)-N-{[(propan-2-yloxy)carbonyl]imino}(propan-2-yloxy)formamide (0.69 mL, 3.49 mmol) at room temperature. After stirring overnight at room temperature, the mixture was poured into water and extracted with EtOAc. The combined organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by chromatography to give 6-bromo-2-[(4-methoxyphenyl)methyl]-3,4-dihydro-2H-1λ^6,2-benzothiazine-1,1-dione (300 mg, 0.785 mmol, 44.9%) as a white solid. LCMS: m / z 383 [M+H] + .

[0300] Step E. 6-({1-tert-butyl-3-[(1s,4s)-4-[(tert-butyldiphenylsilyl)oxy]cyclohexyl]-1H-pyrazol-5-yl}amino)-2-[(4-methoxyphenyl)methyl]-3,4-dihydro-2H-1λ^6,2-benzothiazine-1,1-dione. To a stirred mixture of 6-bromo-2-[(4-methoxyphenyl)methyl]-3,4-dihydro-2H-1λ^6,2-benzothiazine-1,1-dione (600 mg, 1.570 mmol) in dioxane (10 mL) was added 1-tert-butyl-3-[(1s,4s)-4-[(tert-butyldiphenylsilyl)oxy]cyclohexyl]-1H-pyrazol-5-amine (746 mg, 1.570 mmol), CsCO (1.28 g, 3.92 mmol), RuPhos (146 mg, 0.314 mmol), and 2-(2-aminophenyl)benzen-1-ide, chloropalladium ylium, {2-[2,6-bis(propan-2-yloxy)phenyl]phenyl}dicyclohexylphosphane (122 mg, 0.157 mmol) at room temperature. After stirring at 100°C overnight, the mixture was poured into water and extracted with EtOAc. The combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by chromatography to give 6-({1-tert-butyl-3-[(1s,4s)-4-[(tert-butyldiphenylsilyl)oxy]cyclohexyl]-1H-pyrazol-5-yl}amino)-2-[(4-methoxyphenyl)methyl]-3,4-dihydro-2H-1λ^6,2-benzothiazine-1,1-dione (600 mg, 0.772 mmol, 49.2%) as a colorless oil. LCMS: m / z 777 [M+H] + .

[0301] Step F. 6-({1-tert-butyl-3-[(1s,4s)-4-hydroxycyclohexyl]-1H-pyrazol-5-yl}amino)-2-[(4-methoxyphenyl)methyl]-3,4-dihydro-2H-1λ^6,2-benzothiazine-1,1-dione. To a mixture of 6-({1-tert-butyl-3-[(1s,4s)-4-[(tert-butyldiphenylsilyl)oxy]cyclohexyl]-1H-pyrazol-5-yl}amino)-2-[(4-methoxyphenyl)methyl]-3,4-dihydro-2H-1λ^6,2-benzothiazine-1,1-dione (450 mg, 0.579 mmol) in THF (10 mL) was added pyridine hydrogen fluoride (5 mL). The reaction mixture was stirred at 25 °C overnight. The mixture was adjusted to pH 8 with NaHCO3 (aq) and extracted. The organic layer was separated, washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluted with ethyl acetate in petroleum ether) to give the title compound 6-({1-tert-butyl-3-[(1s,4s)-4-hydroxycyclohexyl]-1H-pyrazol-5-yl}amino)-2-[(4-methoxyphenyl)methyl]-3,4-dihydro-2H-1λ^6,2-benzothiazine-1,1-dione (130 mg, 0.241 mmol, 41.6%) as a colorless oil. LCMS: m / z 539 [M+H] + .

[0302] Step G. 4-Nitrophenyl(1s,4s)-4-[1-tert-butyl-5-({2-[(4-methoxyphenyl)methyl]-1,1-dioxo-3,4-dihydro-2H-1λ^6,2-benzothiazin-6-yl}amino)-1H-pyrazol-3-yl]cyclohexyl carbonate. To a stirred solution of 6-({1-tert-butyl-3-[(1s,4s)-4-hydroxycyclohexyl]-1H-pyrazol-5-yl}amino)-2-[(4-methoxyphenyl)methyl]-3,4-dihydro-2H-1λ^6,2-benzothiazine-1,1-dione (130 mg, 0.241 mmol) in DCM (2 mL) / THF (2 mL) was added 4-nitrophenyl chloroformate (145 mg, 0.724 mmol), Py (0.039 mL, 0.483 mmol), and DMAP (2.95 mg, 0.024 mmol) at room temperature. After stirring at room temperature for 3 h, the mixture was poured into water (30 mL) and extracted with EtOAc. The combined organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by chromatography (silica gel, 0-10%, MeOH in DCM) to give 4-nitrophenyl(1s,4s)-4-[1-tert-butyl-5-({2-[(4-methoxyphenyl)methyl]-1,1-dioxo-3,4-dihydro-2H-1λ^6,2-benzothiazin-6-yl}amino)-1H-pyrazol-3-yl]cyclohexyl carbonate (70 mg, 0.099 mmol, 41.2%) as a brown solid. LCMS: m / z 704 [M+H] + .

[0303] Step H. 4-Nitrophenyl(1s,4s)-4-{5-[(1,1-dioxo-3,4-dihydro-2H-1λ^6,2-benzothiazin-6-yl)amino]-1H-pyrazol-3-yl}cyclohexyl carbonate. A mixture of 4-nitrophenyl(1s,4s)-4-[1-tert-butyl-5-({2-[(4-methoxyphenyl)methyl]-1,1-dioxo-3,4-dihydro-2H-1λ^6,2-benzothiazin-6-yl}amino)-1H-pyrazol-3-yl]cyclohexyl carbonate (70 mg, 0.099 mmol) in formic acid (3 mL) was stirred at 100° C. overnight and then concentrated under reduced pressure to give crude 4-nitrophenyl(1s,4s)-4-{5-[(1,1-dioxo-3,4-dihydro-2H-1λ^6,2-benzothiazin-6-yl)amino]-1H-pyrazol-3-yl}cyclohexyl carbonate (60 mg, 0.097 mmol, 97.2%) as a brown oil. LCMS: m / z 528 [M+H] + .

[0304] Step I. (1s,4s)-4-{3-[(1,1-dioxo-3,4-dihydro-2H-1λ^6,2-benzothiazin-6-yl)amino]-1H-pyrazol-5-yl}cyclohexyl N-(propan-2-yl)carbamate. To a stirred solution of 4-nitrophenyl (1s,4s)-4-{5-[(1,1-dioxo-3,4-dihydro-2H-1λ^6,2-benzothiazin-6-yl)amino]-1H-pyrazol-3-yl}cyclohexyl carbonate (60 mg, 0.114 mmol) in THF (3 mL) was added propan-2-amine (0.019 mL, 0.227 mmol). The reaction mixture was stirred at room temperature for 2 hours. The reaction was concentrated. The residue was purified by preparative HPLC to give (1s,4s)-4-{3-[(1,1-dioxo-3,4-dihydro-2H-1λ^6,2-benzothiazin-6-yl)amino]-1H-pyrazol-5-yl}cyclohexyl N-(propan-2-yl)carbamate (46.4 mg, 0.104 mmol, 91.1%) as a brown solid. LCMS: m / z 448 [M+H] + . 1H NMR (400MHz, DMSO)δ 11.86(s, 1H), 8.80(s, 1H), 7.47(d, J=8.8Hz, 1H), 7.34-7.19(m, 2H), 7.14(s, 1H), 6.88(d, J=7.2Hz, 1H), 5.64(s, 1H), 4.75(s, 1H), 3.65-3. 55(m, 1H), 3.50(dd, J=12.8, 6.4Hz, 2H), 2.83-2.77(m, 2H), 2.73-2.65(m, 1H), 1.82-1.75(m, 4H), 1.75-1.62(m, 4H), 1.05(d, J=6.4Hz, 6H).

[0305] Example 12: (1R,3S)-3-{3-[(4-methyl-1,1-dioxo-3,4-dihydro-2H-1λ^6,2,4-benzothiadiazin-6-yl)amino]-1H-pyrazol-5-yl}cyclopentyl N-(propan-2-yl)carbamate [ka] Step A: 4-Bromo-2-nitrobenzene-1-sulfonic acid. To a solution of 4-bromo-1-fluoro-2-nitrobenzene (2.80 mL, 22.7 mmol) in EtOH (60 mL) was added dropwise a suspension of NaSO (2.72 mL, 56.8 mmol) in EtOH (100 mL) and HO (125 mL). The reaction was stirred at 70 °C overnight. The cooled reaction mixture was acidified to pH 2 with HCl (2N). The reaction was diluted with EA and water. The organic layer was separated, washed with saturated NaCl solution, and concentrated in vacuo to give the title compound 4-bromo-2-nitrobenzene-1-sulfonic acid (12.4 g, 44.0 mmol, 100%) as a white solid. LCMS: ESI m / z 282.07 [M+H] + .

[0306] Step B: 4-Bromo-2-nitrobenzene-1-sulfonamide. To a solution of 4-bromo-2-nitrobenzene-1-sulfonic acid (10 g, 35.5 mmol) in SOCl2 (20 mL) was added DMF (0.5 mL). The reaction was stirred at 90 °C for 2 h. The cooled reaction mixture was concentrated in vacuo. The residue was azeotroped with chloroform. The residue was dissolved in tetrahydrofuran. The resulting solution was added dropwise to NH4OH (40 mL) at 0 °C. The reaction mixture was stirred at room temperature for 1 h and then acidified to pH 7 with HCl (2N). The resulting mixture was diluted with EA and water. The organic layer was separated, washed with brine, and concentrated in vacuo to give the title compound 4-bromo-2-nitrobenzene-1-sulfonamide (4.57 g, 16.3 mmol, 45.9%) as a white solid. LCMS: ESI m / z 281.09 [M+H] + .

[0307] Step C: 2-Amino-4-bromobenzene-1-sulfonamide. To a solution of 4-bromo-2-nitrobenzene-1-sulfonamide (4.57 g, 16.3 mmol) in EtOH (10 mL) and HO (10 mL) was added NH4Cl (4.35 g, 81.3 mmol) and Fe (4.54 g, 81.3 mmol). The reaction was stirred at 70 °C for 2 h. The cooled reaction mixture was filtered. The filtrate was concentrated. The residue was purified by silica gel column chromatography (eluting with methanol in dichloroform (gradient: 0 to 10%)) to afford the title compound, 2-amino-4-bromobenzene-1-sulfonamide (3.02 g, 12.0 mmol, 74.0%), as a white solid. LCMS: ESI m / z 251.0 [M+H] + .

[0308] Step D: 6-Bromo-4H-1λ^6,2,4-benzothiadiazine-1,1-dione. A reaction mixture of 2-amino-4-bromobenzene-1-sulfonamide (400 mg, 1.593 mmol) in (diethoxymethoxy)ethane (10 mL) was stirred at 70° C. for 1 hour. The reaction mixture was cooled to room temperature and then filtered. The filter cake was washed with MTBE and dried under vacuum to give the title compound 6-bromo-4H-1λ^6,2,4-benzothiadiazine-1,1-dione (350 mg, 1.34 mmol, 84.2%) as a white solid. LCMS: ESI m / z 261.10 [M+H] + .

[0309] Step E: 6-Bromo-4-methyl-4H-1λ^6,2,4-benzothiadiazine-1,1-dione. To a solution of 6-bromo-4H-1λ^6,2,4-benzothiadiazine-1,1-dione (1.2 g, 4.60 mmol) in DMF (5 mL) was added CHCl (0.98 g, 6.89 mmol) and CsCO (2.99 g, 9.19 mmol). The reaction was stirred at 80 °C overnight. The reaction was diluted with EA and water. The organic layer was separated, washed with brine, and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluting with ethyl acetate in petroleum ether (gradient: 0 to 80%)) to afford the title compound, 6-bromo-4-methyl-4H-1λ^6,2,4-benzothiadiazine-1,1-dione (370 mg, 1.35 mmol, 29.3%), as a white solid. LCMS:ESI m / z 275.13[M+H] + .

[0310] Step F: 6-Bromo-4-methyl-3,4-dihydro-2H-1λ^6,2,4-benzothiadiazine-1,1-dione. To a solution of 6-bromo-4-methyl-4H-1λ^6,2,4-benzothiadiazine-1,1-dione (370 mg, 1.35 mmol) in isopropyl alcohol (20 mL) was added NaBH4 (182 mg, 5.38 mmol). The reaction was stirred overnight at room temperature. The reaction was diluted with EA and water. The organic layer was separated, washed with brine, and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluting with ethyl acetate in petroleum ether (gradient: 0–50%)) to afford the title compound, 6-bromo-4-methyl-3,4-dihydro-2H-1λ^6,2,4-benzothiadiazine-1,1-dione (340 mg, 1.27 mmol, 91.2%), as a white solid. LCMS:ESI m / z 277.14[M+H] + .

[0311] Step G: 6-({1-tert-butyl-3-[(1S,3R)-3-[(tert-butyldimethylsilyl)oxy]cyclopentyl]-1H-pyrazol-5-yl}amino)-4-methyl-3,4-dihydro-2H-1λ^6,2,4-benzothiadiazine-1,1-dione. To a solution of 6-bromo-4-methyl-3,4-dihydro-2H-1λ^6,2,4-benzothiadiazine-1,1-dione (340 mg, 1.23 mmol) in dioxane (10 mL) was added 1-tert-butyl-3-[(1S,3R)-3-[(tert-butyldimethylsilyl)oxy]cyclopentyl]-1H-pyrazol-5-amine (414 mg, 1.23 mmol), Cs2CO3 (1.20 g, 3.68 mmol), Pd2(dba)3 (112 mg, 0.123 mmol), and Xantphos (142 mg, 0.245 mmol). The reaction was stirred under N2 at 100 °C for 3 h. The cooled reaction mixture was diluted with EA and water. The organic layer was separated, washed with brine, and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluting with methanol in DCM (gradient: 0-10%)) to give the title compound 6-({1-tert-butyl-3-[(1S,3R)-3-[(tert-butyldimethylsilyl)oxy]cyclopentyl]-1H-pyrazol-5-yl}amino)-4-methyl-3,4-dihydro-2H-1λ^6,2,4-benzothiadiazine-1,1-dione (320 mg, 0.599 mmol, 48.9%) as a yellow oil. LCMS: ESI m / z 533.82 [M+H] + .

[0312] Step H: 6-({1-tert-butyl-3-[(1S,3R)-3-hydroxycyclopentyl]-1H-pyrazol-5-yl}amino)-4-methyl-3,4-dihydro-2H-1λ^6,2,4-benzothiadiazine-1,1-dione. A solution of 6-({1-tert-butyl-3-[(1S,3R)-3-[(tert-butyldimethylsilyl)oxy]cyclopentyl]-1H-pyrazol-5-yl}amino)-4-methyl-3,4-dihydro-2H-1λ^6,2,4-benzothiadiazine-1,1-dione (320 mg, 0.599 mmol) in formic acid (5 mL) was stirred at room temperature for 1 h. It was then concentrated in vacuo. The residue was dissolved in methanol and the pH was adjusted to 12-13 with LiOH (2 M in HO). The reaction was diluted with EA and water. The organic layer was separated, washed with brine, and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluting with methanol in dichloroform (gradient: 0-10%)) to give the title compound 6-({1-tert-butyl-3-[(1S,3R)-3-hydroxycyclopentyl]-1H-pyrazol-5-yl}amino)-4-methyl-3,4-dihydro-2H-1λ^6,2,4-benzothiadiazine-1,1-dione (90 mg, 0.215 mmol, 35.8%) as a yellow oil. LCMS: ESI m / z 419.55 [M+H] + .

[0313] Step I: (1R,3S)-3-{1-tert-butyl-5-[(4-methyl-1,1-dioxo-3,4-dihydro-2H-1λ^6,2,4-benzothiadiazin-6-yl)amino]-1H-pyrazol-3-yl}cyclopentyl 4-nitrophenyl carbonate. To a solution of 6-({1-tert-butyl-3-[(1S,3R)-3-hydroxycyclopentyl]-1H-pyrazol-5-yl}amino)-4-methyl-3,4-dihydro-2H-1λ^6,2,4-benzothiadiazine-1,1-dione (90 mg, 0.215 mmol) in THF (5 mL) and DCM (5 mL) was added 4-nitrophenyl chloroformate (64.7 mg, 0.322 mmol), DMAP (2.62 mg, 0.021 mmol), and Py (33.9 mg, 0.429 mmol). The reaction was stirred at room temperature for 3 h. The reaction was diluted with EA and water. The organic layer was separated, washed with saturated NaCl solution, and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluting with ethyl acetate in petroleum ether (gradient: 0-50%)) to give the title compound (1R,3S)-3-{1-tert-butyl-5-[(4-methyl-1,1-dioxo-3,4-dihydro-2H-1λ^6,2,4-benzothiadiazin-6-yl)amino]-1H-pyrazol-3-yl}cyclopentyl 4-nitrophenyl carbonate (40 mg, 0.068 mmol, 31.9%) as a brown solid. LCMS: ESI m / z 584.65 [M+H] + .

[0314] Step J: (1R,3S)-3-{5-[(4-methyl-1,1-dioxo-3,4-dihydro-2H-1λ^6,2,4-benzothiadiazin-6-yl)amino]-1H-pyrazol-3-yl}cyclopentyl 4-nitrophenyl carbonate. To a solution of (1R,3S)-3-{1-tert-butyl-5-[(4-methyl-1,1-dioxo-3,4-dihydro-2H-1λ^6,2,4-benzothiadiazin-6-yl)amino]-1H-pyrazol-3-yl}cyclopentyl 4-nitrophenyl carbonate (40 mg, 0.068 mmol) in formic acid (5 mL). The reaction was stirred at 100 °C overnight. The reaction was concentrated in vacuo to afford the title compound (1R,3S)-3-{5-[(4-methyl-1,1-dioxo-3,4-dihydro-2H-1λ^6,2,4-benzothiadiazin-6-yl)amino]-1H-pyrazol-3-yl}cyclopentyl 4-nitrophenyl carbonate (30 mg, 0.057 mmol, 82.9%) as a brown solid. LCMS: ESI m / z 528.55 [M+H] + .

[0315] Step K: (1R,3S)-3-{5-[(4-methyl-1,1-dioxo-4H-1λ^6,2,4-benzothiadiazin-6-yl)amino]-1H-pyrazol-3-yl}cyclopentyl N-(propan-2-yl)carbamate. To a solution of (1R,3S)-3-{5-[(4-methyl-1,1-dioxo-4H-1λ^6,2,4-benzothiadiazin-6-yl)amino]-1H-pyrazol-3-yl}cyclopentyl 4-nitrophenyl carbonate (40 mg, 0.076 mmol) in propan-2-amine (5 mL, 58.4 mmol), the reaction was stirred at room temperature for 1 hour. The reaction was concentrated in vacuo to afford the title compound (1R,3S)-3-{5-[(4-methyl-1,1-dioxo-4H-1λ^6,2,4-benzothiadiazin-6-yl)amino]-1H-pyrazol-3-yl}cyclopentyl N-(propan-2-yl)carbamate (30 mg, 0.067 mmol, 88.4%) as a yellow oil. LCMS: ESI m / z 446.53 [M+H] + .

[0316] Step L: (1R,3S)-3-{3-[(4-methyl-1,1-dioxo-3,4-dihydro-2H-1λ^6,2,4-benzothiadiazin-6-yl)amino]-1H-pyrazol-5-yl}cyclopentyl N-(propan-2-yl)carbamate. To a solution of (1R,3S)-3-{5-[(4-methyl-1,1-dioxo-4H-1λ^6,2,4-benzothiadiazin-6-yl)amino]-1H-pyrazol-3-yl}cyclopentyl N-(propan-2-yl)carbamate (20 mg, 0.045 mmol) in isopropyl alcohol (5 mL) was added NaBH4 (6.06 mg, 0.179 mmol). The reaction was stirred at room temperature for 1 hour. The reaction was concentrated in vacuo. The residue was purified by preparative HPLC (C18, 0-50% acetonitrile in HO) to give the title compound (1R,3S)-3-{3-[(4-methyl-1,1-dioxo-3,4-dihydro-2H-1λ^6,2,4-benzothiadiazin-6-yl)amino]-1H-pyrazol-5-yl}cyclopentyl N-(propan-2-yl)carbamate (2.8 mg, 0.006 mmol, 14.0%) as a white solid. LCMS: E1 m / z 448.55 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 11.88(s, 1H), 8.69(s, 1H), 7.76(t, J=7.6Hz, 1H), 7.30(d, J=8.4Hz, 1H) , 6.95(s, 2H), 6.64(d, J=8.4Hz, 1H), 5.66(s, 1H), 5.00(s, 1H), 4.60(d, J =8.0Hz, 2H), 3.63-3.53(m, 1H), 3.11-3.01(m, 1H), 2.88(s, 3H), 2.08-1 .88(m, 2H), 1.85-1.66(m, 2H), 1.65-1.55(m, 1H), 1.04(d, J=6.4Hz, 6H).

[0317] Example 13: (1R,3S)-3-(3-((3,3-dimethyl-1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate [ka] Step A: 1-(Benzylsulfanyl)-4-bromo-2-(propan-2-yl)benzene. To a solution of 4-bromo-1-iodo-2-(propan-2-yl)benzene (4 g, 12.3 mmol) in toluene (100 mL) was added Xantphos (0.71 g, 1.23 mmol), DIEA ethyldiisopropylamine (4.06 mL, 24.6 mmol), Pd(dba) (1.13 g, 1.23 mmol), and phenylmethanethiol (1.53 g, 1.44 mL, 12.3 mmol). The mixture was stirred at 100 °C under N for 12 h. The cooled reaction mixture was concentrated, and the residue was purified by silica gel chromatography (20 g column) using 0–5% EtOAc / hexanes to give 1-(benzylsulfanyl)-4-bromo-2-(propan-2-yl)benzene (2.66 g, 8.27 mmol, 67.3%) as a brown oil.

[0318] Step B: 4-Bromo-2-(propan-2-yl)benzene-1-sulfonyl chloride. To a solution of 1-(benzylsulfanyl)-4-bromo-2-(propan-2-yl)benzene (2.67 g, 8.31 mmol) in HOAc (15 mL) and water (7.5 mL) was added NCS (3.33 g, 24.9 mmol). The mixture was stirred at 20 °C for 30 min. The reaction mixture was diluted with 50 mL of water and extracted with EA (50 mL × 3). The organic phase was washed with brine, dried over Na2SO4, and concentrated. The residue was purified by silica gel chromatography (15 g column) using 0–5% EtOAc / hexane to give 4-bromo-2-(propan-2-yl)benzene-1-sulfonyl chloride (2.4 g, 8.06 mmol, 97.0%) as a white solid. 1 H NMR (400MHz, DMSO) δ 7.90(d, J=12.0Hz, 1H), 7.71(s, 1H), 7.52(t, J=4.0Hz, 1H), 4.05-3.98(m, 1H), 1.35(d, J=8.0Hz, 6H).

[0319] Step C: 4-Bromo-2-(propan-2-yl)benzenesulfonamide acetate. To a solution of 4-bromo-2-(propan-2-yl)benzene-1-sulfonyl chloride (2.4 g, 8.06 mmol) in DCM (30 mL) was added pyridine (1.95 mL, 24.1 mmol) and aminoacetate (0.61 g, 8.06 mmol). The reaction mixture was stirred at 20 °C for 1 h. The reaction mixture was diluted with water and extracted with DCM (50 mL × 3). The organic phase was washed with brine, dried over Na2SO4, and concentrated. The residue was purified by silica gel chromatography (10 g column) (0–30% EtOAc / hexanes) to give 4-bromo-2-(propan-2-yl)benzenesulfonamide acetate (900 mg, 2.67 mmol, 33.2%) as a brown oil. LCMS:ESI m / z 338.0[M+H] + .

[0320] Step D: 5-Bromo-3,3-dimethyl-2,3-dihydro-1λ^6,2-benzothiazole-1,1-dione. A solution of 4-bromo-2-(propan-2-yl)benzenesulfonamide acetate (500 mg, 1.48 mmol) in DMSO (5 mL) was stirred at 130 °C under N2 for 3 h. The cooled reaction mixture was diluted with water (50 mL) and extracted with EA (50 mL × 3). The organic phase was washed with brine, dried over Na2SO4, and concentrated. The residue was purified by silica gel chromatography (5 g column) using 0–50% EtOAc / hexane to give 5-bromo-3,3-dimethyl-2,3-dihydro-1λ^6,2-benzothiazole-1,1-dione (270 mg, 0.978 mmol, 65.7%) as a clear oil. LCMS:ESI m / z 277.9[M+H] + .

[0321] Step E: ({1-tert-butyl-3-[(1S,3R)-3-[(tert-butyldimethylsilyl)oxy]cyclopentyl]-1H-pyrazol-5-yl}amino)-3,3-dimethyl-2,3-dihydro-1λ^6,2-benzothiazole-1,1-dione. To a solution of 5-bromo-3,3-dimethyl-2,3-dihydro-1λ^6,2-benzothiazole-1,1-dione (270 mg, 0.978 mmol) and 1-tert-butyl-3-[(1S,3R)-3-[(tert-butyldimethylsilyl)oxy]cyclopentyl]-1H-pyrazol-5-amine (330 mg, 0.978 mmol) in dioxane (5 mL) was added CsCO (637 mg, 1.95 mmol), Xantphos (56.5 mg, 0.098 mmol), and Pd(dba) (89.5 mg, 0.098 mmol). The reaction mixture was stirred at 100 °C under N for 5 h. The reaction mixture was concentrated, and the residue was purified by silica gel chromatography (5 g column) (0–50% EtOAc / hexanes) to give 5-({1-tert-butyl-3-[(1S,3R)-3-[(tert-butyldimethylsilyl)oxy]cyclopentyl]-1H-pyrazol-5-yl}amino)-3,3-dimethyl-2,3-dihydro-1λ^6,2-benzothiazole-1,1-dione (500 mg, 0.938 mmol, 95.9%) as a brown oil. LCMS: ESI m / z 533.4 [M+H] + .

[0322] Step F: 5-({1-tert-butyl-3-[(1S,3R)-3-hydroxycyclopentyl]-1H-pyrazol-5-yl}amino)-3,3-dimethyl-2,3-dihydro-1λ^6,2-benzothiazole-1,1-dione. A solution of 5-({1-tert-butyl-3-[(1S,3R)-3-[(tert-butyldimethylsilyl)oxy]cyclopentyl]-1H-pyrazol-5-yl}amino)-3,3-dimethyl-2,3-dihydro-1λ^6,2-benzothiazole-1,1-dione (500 mg, 0.938 mmol) in formic acid (7 mL) was stirred at 20 °C for 30 min. The mixture was concentrated in vacuo to give 5-({1-tert-butyl-3-[(1S,3R)-3-hydroxycyclopentyl]-1H-pyrazol-5-yl}amino)-3,3-dimethyl-2,3-dihydro-1λ^6,2-benzothiazole-1,1-dione (370 mg, 0.884 mmol, 94.2%) as a brown oil, which was used in the next step without purification. LCMS: ESI m / z 419.2 [M+H] + .

[0323] Step G: (1R,3S)-3-{1-tert-butyl-5-[(3,3-dimethyl-1,1-dioxo-2,3-dihydro-1λ^6,2-benzothiazol-5-yl)amino]-1H-pyrazol-3-yl}cyclopentyl 4-nitrophenyl carbonate. To a solution of 5-({1-tert-butyl-3-[(1S,3R)-3-hydroxycyclopentyl]-1H-pyrazol-5-yl}amino)-3,3-dimethyl-2,3-dihydro-1λ^6,2-benzothiazole-1,1-dione (370 mg, 0.884 mmol) and 4-nitrophenyl chloroformate (267 mg, 1.32 mmol) in THF (5 mL) and DCM (5 mL) was added pyridine (0.143 mL, 1.76 mmol) and DMAP (21.6 mg, 0.177 mmol). The reaction mixture was stirred at room temperature for 1 h. The mixture was concentrated, and the residue was purified by silica gel chromatography (2 g column) (0–50% EtOAc / hexanes) to afford (1R,3S)-3-{1-tert-butyl-5-[(3,3-dimethyl-1,1-dioxo-2,3-dihydro-1λ^6,2-benzothiazol-5-yl)amino]-1H-pyrazol-3-yl}cyclopentyl 4-nitrophenyl carbonate (380 mg, 0.651 mmol, 73.6%) as a brown solid. LCMS: ESI m / z 584.2 [M+H] + .

[0324] Step H: (1R,3S)-3-{5-[(3,3-dimethyl-1,1-dioxo-2,3-dihydro-1λ^6,2-benzothiazol-5-yl)amino]-1H-pyrazol-3-yl}cyclopentyl 4-nitrophenyl carbonate. A solution of (1R,3S)-3-{1-tert-butyl-5-[(3,3-dimethyl-1,1-dioxo-2,3-dihydro-1λ^6,2-benzothiazol-5-yl)amino]-1H-pyrazol-3-yl}cyclopentyl 4-nitrophenyl carbonate (380 mg, 0.651 mmol) in formic acid (10 mL) was stirred at 100 °C for 10 h. The cooled mixture was concentrated in vacuo to give (1R,3S)-3-{5-[(3,3-dimethyl-1,1-dioxo-2,3-dihydro-1λ^6,2-benzothiazol-5-yl)amino]-1H-pyrazol-3-yl}cyclopentyl 4-nitrophenyl carbonate (340 mg, 0.644 mmol, 98.9%) as a brown solid, which was used in the next step without purification. LCMS: ESI m / z 528.2 [M+H] + .

[0325] Step I: (1R,3S)-3-(3-((3,3-Dimethyl-1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate. To a solution of (1R,3S)-3-{5-[(3,3-dimethyl-1,1-dioxo-2,3-dihydro-1λ^6,2-benzothiazol-5-yl)amino]-1H-pyrazol-3-yl}cyclopentyl 4-nitrophenyl carbonate (150 mg, 0.284 mmol) in THF (10 mL) was added DIEA (0.141 mL, 0.853 mmol) and propan-2-amine (25.2 mg, 0.037 mL, 0.426 mmol). The mixture was stirred at 20 °C for 30 min and then concentrated. The residue was purified by preparative TLC (EA) to give (1R,3S)-3-(3-((3,3-dimethyl-1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate (46.1 mg, 0.103 mmol, 36.2%) as a white solid. LCMS: ESI m / z 448.2 [M+H] + . 1 H NMR (400MHz, DMSO)δ 11.98(s, 1H), 9.03(s, 1H), 7.53(d, J=1.6Hz, 2H), 7.48(d, J=8.8Hz, 1H), 7.31(dd, J= 8.8, 1.6Hz, 1H), 6.94(d, J=7.6Hz, 1H), 5.69(s, 1H), 5.00(s, 1H), 3.58(dd, J=13.2, 6. 4Hz, 1H), 3.13-2.99(m, 1H), 2.49-2.44(m, 1H), 2.02(dd, J=15.6, 7.6Hz, 1H), 1.96-1 .83(m, 1H), 1.78-1.70(m, 2H), 1.68-1.59(m, 1H), 1.47(s, 6H), 1.03(d, J=6.4Hz, 6H).

[0326] Step J: Aminoacetate. To a solution of [(tert-butoxy)carbonyl]aminoacetate (1.1 g, 6.27 mmol) in DCM (4 mL) was added trifluoromethanesulfonic acid (0.558 mL, 6.28 mmol), and the reaction mixture was stirred at 20° C. for 1 h. The reaction mixture was concentrated in vacuo to give the aminoacetate (500 mg, 5.99 mmol, 95.4%) as a brown solid, which was used in the next step without purification.

[0327] Example 14: (1R,3S)-3-(3-((1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-4-fluoro-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate [ka] Step A: 5-((1-(tert-butyl)-3-((1S,3R)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)amino)-2-(4-methoxybenzyl)-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide. To a solution of 1-tert-butyl-3-[(1S,3R)-3-[(tert-butyldimethylsilyl)oxy]cyclopentyl]-1H-pyrazol-5-amine (300 mg, 0.889 mmol) in dioxane (2 mL) was added 5-bromo-2-[(4-methoxyphenyl)methyl]-2,3-dihydro-1λ^6,2-benzothiazole-1,1-dione (392 mg, 1.06 mmol), [5-(diphenylphosphanyl)-9,9-dimethyl-9H-xanthen-4-yl]diphenylphosphane (103 mg, 0.178 mmol), CsCO (290 mg, 0.889 mmol), and Pd(dba) (81.3 mg, 0.089 mmol) and the reaction was stirred under N at 90 °C for 18 h. The reaction was diluted with EA and water. The organic layer was separated, further washed with brine, and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluting with ethyl acetate in petroleum ether (3 / 1)). The organic layer was collected, concentrated in vacuo, and dried to give the title compound 5-({1-tert-butyl-3-[(1S,3R)-3-[(tert-butyldimethylsilyl)oxy]cyclopentyl]-1H-pyrazol-5-yl}amino)-2-[(4-methoxyphenyl)methyl]-2,3-dihydro-1λ^6,2-benzothiazole-1,1-dione (500 mg, 0.8 mmol, 90%) as a yellow oil. LC-MS (ESI): m / z 625.3 [M+H] + .

[0328] Step B: 5-((1-(tert-butyl)-4-fluoro-3-((1S,3R)-3-hydroxycyclopentyl)-1H-pyrazol-5-yl)amino)-2-(4-methoxybenzyl)-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide. To a solution of 5-({1-tert-butyl-3-[(1S,3R)-3-[(tert-butyldimethylsilyl)oxy]cyclopentyl]-1H-pyrazol-5-yl}amino)-2-[(4-methoxyphenyl)methyl]-2,3-dihydro-1λ^6,2-benzothiazole-1,1-dione (300 mg, 0.48 mmol) in acetonitrile (10 mL) was added Selectfluor (170 mg, 0.48 mmol). The reaction mixture was stirred at 60 °C for 1 h. After completion, the solvent was removed under vacuum to give a residue, which was purified by flash column (PE / EA=5:1) to give the title 5-({1-tert-butyl-4-fluoro-3-[(1S,3R)-3-hydroxycyclopentyl]-1H-pyrazol-5-yl}amino)-2-[(4-methoxyphenyl)methyl]-2,3-dihydro-1λ^6,2-benzothiazole-1,1-dione (40 mg, 0.076 mmol, 15.8%) as a yellow solid. LC-MS (ESI): m / z 529.2 [M+H] + .

[0329] Step C: (1R,3S)-3-(1-(tert-butyl)-4-fluoro-5-((2-(4-methoxybenzyl)-1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-3-yl)cyclopentyl(4-nitrophenyl)carbonate. To a solution of 5-({1-tert-butyl-4-fluoro-3-[(1S,3R)-3-hydroxycyclopentyl]-1H-pyrazol-5-yl}amino)-2-[(4-methoxyphenyl)methyl]-2,3-dihydro-1λ^6,2-benzothiazole-1,1-dione (40 mg, 0.076 mmol) in pyridine (5 mL) was added 4-nitrophenyl chloroformate (23 mg, 0.113 mmol) and the reaction was stirred at 50° C. for 3 hours. The reaction was concentrated in vacuo. The residue was purified by silica gel column chromatography (eluting with EA in PE [gradient: 0-100%]) to obtain the title compound (1R,3S)-3-[1-tert-butyl-4-fluoro-5-({2-[(4-methoxyphenyl)methyl]-1,1-dioxo-2,3-dihydro-1λ^6,2-benzothiazol-5-yl}amino)-1H-pyrazol-3-yl]cyclopentyl 4-nitrophenyl carbonate (40 mg, 0.06 mmol, 80.0%) as a white solid. LC-MS (ESI): m / z 694.2 [M+H] + .

[0330] Step D: (1R,3S)-3-(5-((1,1-Dioxide-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-4-fluoro-1H-pyrazol-3-yl)cyclopentyl(4-nitrophenyl)carbonate. A solution of (1R,3S)-3-[1-tert-butyl-4-fluoro-5-({2-[(4-methoxyphenyl)methyl]-1,1-dioxo-2,3-dihydro-1λ^6,2-benzothiazol-5-yl}amino)-1H-pyrazol-3-yl]cyclopentyl 4-nitrophenylcarbonate (40 mg, 0.06 mmol) in HCOOH (10 mL) was stirred at 100 °C overnight. The reaction was concentrated in vacuo to give the title compound (1R,3S)-3-{5-[(1,1-dioxo-2,3-dihydro-1λ^6,2-benzothiazol-5-yl)amino]-4-fluoro-1H-pyrazol-3-yl}cyclopentyl 4-nitrophenyl carbonate (30 mg, 0.06 mmol, crude) as a white solid. LC-MS (ESI): m / z 518 [M+H] + .

[0331] Step E: (1R,3S)-3-(3-((1,1-Dioxide-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-4-fluoro-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate. To a solution of (1R,3S)-3-{5-[(1,1-dioxo-2,3-dihydro-1λ^6,2-benzothiazol-5-yl)amino]-4-fluoro-1H-pyrazol-3-yl}cyclopentyl 4-nitrophenyl carbonate (30 mg, 0.06 mmol) in THF (2 mL) was added propan-2-amine (300 mg, 5.08 mmol) and the reaction was stirred at 25 °C for 2 h. The reaction was concentrated in vacuo. The residue was purified by preparative HPLC (FA conditions) to give the title compound (1R,3S)-3-{5-[(1,1-dioxo-2,3-dihydro-1λ^6,2-benzothiazol-5-yl)amino]-4-fluoro-1H-pyrazol-3-yl}cyclopentyl N-(propan-2-yl)carbamate (1.2 mg, 4.0%) as a white solid. LC-MS (ESI): m / z 438.2 [M+H] + .1 H NMR (400 MHz, methanol-d₄) δ 7.51 (d, J = 8.4 Hz, 1H), 7.17 (s, 2H), 5.10 (s, 1H), 4.34 (s, 2H), 3.79-3.62 (m, 1H), 3.25-3.15 (m, 1H), 2.61-2.52 (m, 1H), 2.23-1.80 (m, 5H), 1.31 (d, J = 6.4 Hz, 1H), 1.11 (d, J = 6.4 Hz, 6H).

[0332] Example 15: (1R,3S)-3-{5-[(3-methoxy-1,1-dioxo-2,3-dihydro-1λ6-benzothiophen-5-yl)amino]-2H-pyrazol-3-yl}cyclopentyl(prop-2-ylamino)methanoate [ka] Step A: 5-Bromo-1λ6-benzothiophene-1,1-dione. To a stirred solution of 5-bromobenzothiophene (2 g, 9.39 mmol) in DCM (16 mL) was added HO (4 mL, 39.2 mmol, 30% in HO) and TFA (4 mL, 53.8 mmol) at room temperature. After stirring for 5 h at room temperature, the mixture was poured into aqueous NaSO and extracted with DCM (30 mL × 2). The combined organic phases were washed with brine, dried over NaSO, filtered, and concentrated. The residue was purified by chromatography (silica gel, 0–40%, EA in PE) to give 5-bromo-1λ6-benzothiophene-1,1-dione (1.7 g, 6.94 mmol, 73.9%) as a white solid.

[0333] Step B: 5-{[2-(2-methylprop-2-yl)-5-[(1S,3R)-3-{[(2-methylprop-2-yl)diphenylsilyl]oxy}cyclopentyl]pyrazol-3-yl]amino}-1λ6-benzothiophene-1,1-dione. To a solution of 5-[(1S,3R)-3-{[dimethyl(2-methylprop-2-yl)silyl]oxy}cyclopentyl]-2-(2-methylprop-2-yl)pyrazol-3-amine (300 mg, 0.889 mmol), 5-bromo-1λ-benzothiophene-1,1-dione (191 mg, 0.779 mmol), Pd(dba) (59.4 mg, 0.065 mmol), Xantphos (75.1 mg, 0.130 mmol), and CsCO (529 mg, 1.62 mmol) were added. The reaction was purged with N and stirred at 100 °C under N for 1.5 h. The reaction was diluted with EA and water. The organic layer was separated, washed with brine, and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluting with ethyl acetate in petroleum ether (2 / 1)). The organic layer was collected, concentrated in vacuo, and dried to give the title compound 5-{[2-(2-methylprop-2-yl)-5-[(1S,3R)-3-{[(2-methylprop-2-yl)diphenylsilyl]oxy}cyclopentyl]pyrazol-3-yl]amino}-1λ6-benzothiophene-1,1-dione (350 mg, 0.559 mmol, 86.2%) as a yellow oil. LCMS: ESI m / z 626 [M+H] + .

[0334] Step C: 5-({5-[(1S,3R)-3-hydroxycyclopentyl]-2-(2-methylprop-2-yl)pyrazol-3-yl}amino)-3-methoxy-2,3-dihydro-1λ 6 -benzothiophene-1,1-dione. 5-{[2-(2-methylprop-2-yl)-5-[(1S,3R)-3-{[(2-methylprop-2-yl)diphenylsilyl]oxy}cyclopentyl]pyrazol-3-yl]amino}-1λ in HCOOH (4 mL) 6A mixture of 1,1-benzothiophene-1,1-dione (350 mg, 0.559 mmol) and LiOH-H2O (0.062 mL, 2.24 mmol) was stirred at room temperature overnight and then concentrated under reduced pressure. The residue was treated with a mixture of LiOH-H2O (0.062 mL, 2.24 mmol) in MeOH (2 mL) / H2O (2 mL). The resulting mixture was stirred at room temperature for 1 hour and then concentrated under reduced pressure. The subsequent mixture was poured into water and extracted with EtOAc. The combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by chromatography (silica gel, 0-80%, EA in PE) to give 5-({5-[(1S,3R)-3-hydroxycyclopentyl]-2-(2-methylprop-2-yl)pyrazol-3-yl}amino)-3-methoxy-2,3-dihydro-1λ 6 -benzothiophene-1,1-dione (220 mg, 0.524 mmol, 93.8%) was obtained as a white solid. LCMS: m / z 420 [M+H] + . 1 H NMR (400MHz, DMSO)δ 8.24(s, 1H), 7.53(d, J=8.8Hz, 1H), 6.80(dd, J=8.8, 2.0Hz, 1H), 6.71(d, J=2.0Hz, 1H), 5.99(s, 1H), 5.07(dd, J=6.8, 3.6Hz, 1H), 4.56(d, J=4.4Hz, 1H), 4.19-4.13(m, 1H), 3.87 (dd, J=13.6, 6.8Hz, 1H), 3.47(dd, J=13.6, 3.6Hz, 1H), 3.35(s, 3H), 2.99-2.89(m, 1H), 2 .25-2.18(m, 1H), 1.90-1.83(m, 1H), 1.77-1.68(m, 2H), 1.65-1.50(m, 1H), 1.50(s, 9H).

[0335] Step D: (1R,3S)-3-{5-[(3-methoxy-1,1-dioxo-2,3-dihydro-1λ 65-({5-[(1S,3R)-3-hydroxycyclopentyl]-2-(2-methylprop-2-yl)pyrazol-3-yl}amino)-3-methoxy-2,3-dihydro-1λ in THF (3 mL) and DCM (3 mL). 6 To a solution of 1R,3S)-benzothiophene-1,1-dione (220 mg, 0.524 mmol), 4-nitrophenyl chloromethanoate (317 mg, 1.58 mmol), DMAP (6.41 mg, 0.052 mmol), and Py (0.127 mL, 1.57 mmol) were added, and the reaction was stirred at room temperature for 2 hours. The reaction was concentrated in vacuo. The residue was purified by silica gel column chromatography (eluting with EA in PE [gradient: 0-50%]) to give the title compound (1R,3S)-3-{5-[(3-methoxy-1,1-dioxo-2,3-dihydro-1λ]. 6 -benzothiophen-5-yl)amino]-1-(2-methylprop-2-yl)pyrazol-3-yl}cyclopentyl[(4-nitrophenyl)oxy]methanoate (210 mg, 0.359 mmol, 68.5%) was obtained as a white solid. LCMS: ESI 585 [M+H] + .

[0336] Step E: (1R,3S)-3-{5-[(3-methoxy-1,1-dioxo-2,3-dihydro-1λ 6 -benzothiophen-5-yl)amino]-1H-pyrazol-3-yl}cyclopentyl[(4-nitrophenyl)oxy]methanoate. (1R,3S)-3-{5-[(3-methoxy-1,1-dioxo-2,3-dihydro-1λ]HCOOH (2 mL) 6 A solution of [(1R,3S)-3-{5-[(3-methoxy-1,1-dioxo-2,3-dihydro-1λ-benzothiophen-5-yl)amino]-1-(2-methylprop-2-yl)pyrazol-3-yl}cyclopentyl[(4-nitrophenyl)oxy]methanoate (100 mg, 0.171 mmol) was stirred overnight at 100° C. The reaction was concentrated in vacuo to afford the title compound (1R,3S)-3-{5-[(3-methoxy-1,1-dioxo-2,3-dihydro-1λ-benzothiophen-5-yl)amino]-1-(2-methylprop-2-yl)pyrazol-3-yl}cyclopentyl[(4-nitrophenyl)oxy]methanoate (100 mg, 0.171 mmol).6 -benzothiophen-5-yl)amino]-1H-pyrazol-3-yl}cyclopentyl[(4-nitrophenyl)oxy]methanoate (88 mg, 0.166 mmol, 97.4%) was obtained as a yellow oil, which was used in the next step without further purification. LCMS: ESI m / z 529 [M+H] + .

[0337] Step F: (1R,3S)-3-{5-[(3-methoxy-1,1-dioxo-2,3-dihydro-1λ 6 -benzothiophen-5-yl)amino]-2H-pyrazol-3-yl}cyclopentyl(prop-2-ylamino)methanoate. (1R,3S)-3-{5-[(3-methoxy-1,1-dioxo-2,3-dihydro-1λ] 6 To a solution of {(4-nitrophenyl)oxy]-1H-pyrazol-3-yl}cyclopentyl[(4-nitrophenyl)oxy]methanoate (88 mg, 0.166 mmol) was added isopropylamine (0.043 mL, 0.499 mmol) and DIPEA (64.6 mg, 0.499 mmol) at room temperature. After stirring at room temperature for 30 minutes, the mixture was concentrated. The residue was purified by preparative HPLC (C18, 20-95% MeCN / HO, 0.1% HCOOH) to give (1R,3S)-3-{5-[(3-methoxy-1,1-dioxo-2,3-dihydro-1λ]-benzothiophen-5-yl)amino]-1H-pyrazol-3-yl}cyclopentyl[(4-nitrophenyl)oxy]methanoate (88 mg, 0.166 mmol). 6 -benzothiophen-5-yl)amino]-2H-pyrazol-3-yl}cyclopentyl(prop-2-ylamino)methanoate (37.6 mg, 0.084 mmol, 50.4%) was obtained as a white solid. LCMS: ESI m / z 449.2 [M+H] + . 1H NMR (400MHz, DMSO)δ 11.96(s, 1H), 9.10(s, 1H), 7.70(s, 1H), 7.53(d, J=8.4Hz, 1H), 7.39(d, J=8.4Hz, 1H), 6.94(d, J =7.6Hz, 1H), 5.68(s, 1H), 5.10(dd, J=6.8, 3.6Hz, 1H), 5.00(s, 1H), 3.88(dd, J=13.6, 6.8Hz, 1H) , 3.63-3.55(m, 1H), 3.48(dd, J=13.6, 3.6Hz, 1H), 3.39(s, 3H), 3.10-3.00(m, 1H), 2.48-2.42(m , 1H), 2.02(dd, J=15.2, 7.6Hz, 1H), 1.96-1.85(m, 1H), 1.76-1.53(m, 3H), 1.03(d, J=6.4Hz, 6H).

[0338] Example 16: (1s,4s)-4-{5-[(1,1-dioxo-2,3-dihydro-1λ6-benzothiophen-5-yl)amino]-2H-pyrazol-3-yl}cyclohexyl(prop-2-ylamino)methanoate [ka] Step A: 5-Bromo-2,3-dihydro-1λ6-benzothiophene-1,1-dione. To a solution of 5-bromo-1λ6-benzothiophene-1,1-dione (1.1 g, 4.49 mmol) in MeOH (50 mL) was added NaBH4 (0.30 g, 8.98 mmol). The reaction mixture was stirred at room temperature for 3 h. The reaction mixture was diluted with EA and water. The organic layer was separated, washed with brine, and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluted with ethyl acetate in petroleum ether (gradient: 0-30%)) to give the title compound 5-bromo-2,3-dihydro-1λ6-benzothiophene-1,1-dione (1.1 g, 4.45 mmol, 99.2%) as a white solid. LCMS: m / z 247.11 [M+H] + .

[0339] Step B: 5-({5-[(1s,4s)-4-{[(2-methylprop-2-yl)diphenylsilyl]oxy}cyclohexyl]-2-(2-methylprop-2-yl)pyrazol-3-yl}amino)-2,3-dihydro-1λ6-benzothiophene-1,1-dione. To a solution of 5-bromo-2,3-dihydro-1λ6-benzothiophene-1,1-dione (200 mg, 0.809 mmol) in dioxane (10 mL) was added 5-[(1s,4s)-4-{[(2-methylprop-2-yl)diphenylsilyl]oxy}cyclohexyl]-2-(2-methylprop-2-yl)pyrazol-3-amine (385 mg, 0.809 mmol), CsCO (791 mg, 2.43 mmol), Pd 2( dba)3 (74.1 mg, 0.081 mmol) and Xantphos (93.7 mg, 0.162 mmol) were added. The reaction was stirred under N2 at 100 °C for 3 h. The cooled reaction was diluted with EA and water. The organic layer was separated, washed with brine, and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluting with ethyl acetate in petroleum ether (gradient: 0-30%)) to afford the title compound 5-({5-[(1s,4s)-4-{[(2-methylprop-2-yl)diphenylsilyl]oxy}cyclohexyl]-2-(2-methylprop-2-yl)pyrazol-3-yl}amino)-2,3-dihydro-1λ6-benzothiophene-1,1-dione (240 mg, 0.374 mmol, 46.2%) as a yellow solid. LCMS: m / z 641.95 [M+H] + .

[0340] Step C: 5-({5-[(1s,4s)-4-hydroxycyclohexyl]-2-(2-methylprop-2-yl)pyrazol-3-yl}amino)-2,3-dihydro-1λ6-benzothiophene-1,1-dione. A solution of 5-({5-[(1s,4s)-4-{[(2-methylprop-2-yl)diphenylsilyl]oxy}cyclohexyl]-2-(2-methylprop-2-yl)pyrazol-3-yl}amino)-2,3-dihydro-1λ6-benzothiophene-1,1-dione (240 mg, 0.374 mmol) in TBAF (5 mL, 1 M in THF) was stirred at 70 °C overnight. The cooled reaction was diluted with EA and water. The organic layer was separated, washed with brine, and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluting with methanol in dichloroform (gradient: 0-10%)) to obtain the title compound 5-({5-[(1s,4s)-4-hydroxycyclohexyl]-2-(2-methylprop-2-yl)pyrazol-3-yl}amino)-2,3-dihydro-1λ6-benzothiophene-1,1-dione (150 mg, 0.372 mmol, 99.4%) as a yellow oil. LCMS: m / z 403.0 [M+H] + .

[0341] Step D: (1s,4s)-4-{5-[(1,1-dioxo-2,3-dihydro-1λ6-benzothiophen-5-yl)amino]-1-(2-methylprop-2-yl)pyrazol-3-yl}cyclohexyl[(4-nitrophenyl)oxy]methanoate. To a solution of 5-({5-[(1s,4s)-4-hydroxycyclohexyl]-2-(2-methylprop-2-yl)pyrazol-3-yl}amino)-2,3-dihydro-1λ6-benzothiophene-1,1-dione (180 mg, 0.446 mmol) in THF (5 mL) and DCM (5 mL) was added 4-nitrophenyl chloromethanoate (135 mg, 0.669 mmol), DMAP (5.45 mg, 0.045 mmol), and Py (70.6 mg, 0.892 mmol). The reaction was stirred at room temperature overnight. The reaction was diluted with EA and water. The organic layer was separated, washed with saturated NaCl solution, and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluting with ethyl acetate in petroleum ether (gradient: 0-30%)) to obtain the title compound (1s,4s)-4-{5-[(1,1-dioxo-2,3-dihydro-1λ6-benzothiophen-5-yl)amino]-1-(2-methylprop-2-yl)pyrazol-3-yl}cyclohexyl[(4-nitrophenyl)oxy]methanoate (120 mg, 0.211 mmol, 47.3%) as a yellow solid. LCMS: m / z 568.64 [M+H] + .

[0342] Step E: (1R,3S)-3-{5-[(4-methyl-1,1-dioxo-4H-1λ6-benzo[2,1-e][1,2,4]thiadiazin-6-yl)amino]-2H-pyrazol-3-yl}cyclopentyl(prop-2-ylamino)methanoate. A solution of (1s,4s)-4-{5-[(1,1-dioxo-2,3-dihydro-1λ6-benzothiophen-5-yl)amino]-1-(2-methylprop-2-yl)pyrazol-3-yl}cyclohexyl[(4-nitrophenyl)oxy]methanoate (60 mg, 0.106 mmol) in formic acid (5 mL) was stirred at 100 °C overnight. The reaction was concentrated in vacuo to afford the title compound (1s,4s)-4-{5-[(1,1-dioxo-2,3-dihydro-1λ6-benzothiophen-5-yl)amino]-2H-pyrazol-3-yl}cyclohexyl[(4-nitrophenyl)oxy]methanoate (50 mg, 0.098 mmol, 92.5%) as a yellow oil. LCMS: m / z 512.54 [M+H] + .

[0343] Step F: (1s,4s)-4-{5-[(1,1-dioxo-2,3-dihydro-1λ6-benzothiophen-5-yl)amino]-2H-pyrazol-3-yl}cyclohexyl(prop-2-ylamino)methanoate. A solution of (1s,4s)-4-{5-[(1,1-dioxo-2,3-dihydro-1λ6-benzothiophen-5-yl)amino]-2H-pyrazol-3-yl}cyclohexyl[(4-nitrophenyl)oxy]methanoate (50 mg, 0.098 mmol) in propan-2-amine (3 mL, 35.0 mmol) was stirred at room temperature for 1 hour. The reaction was concentrated in vacuo. The residue was purified by preparative HPLC (C18, 0-70% acetonitrile in HO) to give the title compound (1s,4s)-4-{5-[(1,1-dioxo-2,3-dihydro-1λ6-benzothiophen-5-yl)amino]-2H-pyrazol-3-yl}cyclohexyl(prop-2-ylamino)methanoate (20.9 mg, 0.048 mmol, 49.5%) as a white solid. LCMS: m / z 432.54 [M+H] + . 1H NMR (400MHz, DMSO)δ 11.90(s, 1H), 9.00(s, 1H), 7.47(d, J=8.8Hz, 2H), 7.29(d, J=9.2Hz, 1H), 6.88(s, 1H), 5.67(s, 1H), 4.75(s, 1H), 3.63-3.50(m , 1H), 3.47(t, J=6.8Hz, 2H), 3.24(t, J=6.8Hz, 2H), 2.68(s, 1H), 1.83-1.75(m, 4H), 1.75-1.58(m, 4H), 1.05(d, J=6.4Hz, 6H).

[0344] Example 17: (1R,3S)-3-(3-((1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-6-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate [ka] Step A: 5-Bromo-2-methylbenzenesulfonamide. To a solution of 5-bromo-2-methylbenzenesulfonyl chloride (3.70 g, 13.7 mmol) in THF (50 mL) was added NH3·MeOH (2 mol / L, 108 mL, 216 mmol), and the mixture was stirred at room temperature for 1 h. LCMS showed the reaction was complete. The reaction mixture was concentrated to give 5-bromo-2-methylbenzenesulfonamide (3.30 g, 13.2 mmol, 96.0%) as a white solid. LCMS: ESI m / z 251.12 [M+H] + .

[0345] Step B: 5-Bromo-2-(bromomethyl)benzenesulfonamide. To a solution of 5-bromo-2-methylbenzenesulfonamide (3.30 g, 13.2 mmol) in CCl4 (40 mL) was added NBS (3.52 g, 19.7 mmol) and BPO (1.60 g, 6.60 mmol), and the mixture was stirred at 80 °C for 2 h. The reaction was complete as detected by TLC. The reaction mixture was dissolved in EA (50 mL), washed with HO (20 mL) and brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (eluted with 0–30% EA in PE) to give 5-bromo-2-(bromomethyl)benzenesulfonamide (2.90 g, 8.81 mmol, 67.6%) as a white solid.

[0346] Step C: 6-Bromo-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide. To a solution of 5-bromo-2-(bromomethyl)benzenesulfonamide (2.90 g, 8.81 mmol) in MeOH (45 mL) and HO (11.3 mL) was added NaOH (0.710 g, 17.6 mmol), and the mixture was stirred at room temperature for 3 h. LCMS indicated the reaction was complete. The reaction mixture was concentrated in vacuo and purified by silica gel chromatography (eluting with 0–50% EA in PE) to give 6-bromo-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide (880 mg, 3.55 mmol, 40.2%) as a white solid. LCMS: ESI m / z 248.10 [M+H] + .

[0347] Step D: 6-Bromo-2-(4-methoxybenzyl)-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide. To a solution of 6-bromo-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide (450 mg, 1.81 mmol) in DMF (10 mL) was added PMBCl (426 mg, 2.72 mmol) and CsCO (1.18 mg, 3.63 mmol), and the mixture was stirred at room temperature for 3 hours. LCMS showed the reaction was complete. The reaction mixture was dissolved in EA (50 mL), washed with HO (10 mL) and brine, dried over sodium sulfate, filtered, concentrated, and purified by silica gel chromatography (eluted with 0-80% EA in PE) to give 6-bromo-2-(4-methoxybenzyl)-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide (250 mg, 0.679 mmol, 37.4%) as a pale yellow solid. LCMS: ESI m / z 368.25 [M+H] + .

[0348] Step E: 6-((1-(tert-butyl)-3-((1S,3R)-3-((tert-butyldiphenylsilyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)amino)-2-(4-methoxybenzyl)-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide. To a solution of 6-bromo-2-(4-methoxybenzyl)-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide (250 mg, 0.679 mmol) in dioxane (8 mL) was added 1-(tert-butyl)-3-((1S,3R)-3-((tert-butyldiphenylsilyl)oxy)cyclopentyl)-1H-pyrazol-5-amine (150 mg, 0.325 mmol), CsCO (317 mg, 0.975 mmol), Pd(dpa) (29.8 mg, 0.0320 mmol), and Xantphos (37.6 mg, 0.065 mmol). The reaction mixture was stirred at 100 °C under a N atmosphere for 1 h. LCMS indicated the reaction was complete. The cooled reaction mixture was dissolved in EA (50 mL), washed with HO (20 mL) and brine, dried over sodium sulfate, filtered, concentrated, and purified by silica gel chromatography (eluting with 0-80% EA in PE) to give 6-((1-(tert-butyl)-3-((1S,3R)-3-((tert-butyldiphenylsilyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)amino)-2-(4-methoxybenzyl)-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide (150 mg, 0.200 mmol, 61.6%) as a white solid. LCMS: ESI m / z 749.06 [M+H] + .

[0349] Step F: 6-((1-(tert-butyl)-3-((1S,3R)-3-hydroxycyclopentyl)-1H-pyrazol-5-yl)amino)-2-(4-methoxybenzyl)-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide. A solution of 6-((1-(tert-butyl)-3-((1S,3R)-3-((tert-butyldiphenylsilyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)amino)-2-(4-methoxybenzyl)-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide (150 mg, 0.200 mmol) in formic acid (2 mL) was stirred at 50° C. for 5 hours. The reaction was complete as detected by TLC. The solvent was removed in vacuo. Next, EtOH (2 mL), HO (2 mL), and lithium hydroxide monohydrate (25.2 mg, 0.601 mmol) were added to adjust the pH to alkaline. The reaction mixture was stirred at room temperature for 1 h. LCMS indicated the reaction was complete. The reaction mixture was dissolved in EA (50 mL), washed with HO (10 mL) and brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (eluted with 0–80% EA in PE) to give 6-((1-(tert-butyl)-3-((1S,3R)-3-hydroxycyclopentyl)-1H-pyrazol-5-yl)amino)-2-(4-methoxybenzyl)-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide (100 mg, 0.196 mmol, 97.8%) as a pale yellow oil. LCMS:ESI m / z 511.65[M+H] + .

[0350] Step G: (1R,3S)-3-(1-(tert-butyl)-5-((2-(4-methoxybenzyl)-1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-6-yl)amino)-1H-pyrazol-3-yl)cyclopentyl(4-nitrophenyl)carbonate. A suspension of 6-((1-(tert-butyl)-3-((1S,3R)-3-hydroxycyclopentyl)-1H-pyrazol-5-yl)amino)-2-(4-methoxybenzyl)-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide (100 mg, 0.196 mmol), DMAP (2.39 mg, 0.0200 mmol), Py (0.0480 mL, 0.588 mmol), and 4-nitrophenyl chloromethanoate (198 mg, 0.980 mmol) in DCM (2 mL) and THF (2 mL) was stirred at room temperature for 3 h. The solvent was removed in vacuo. The residue was dissolved in EA (50 mL), washed with HO (5 mL) and brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (eluting with 0-80% EA in PE) to give (1R,3S)-3-(1-(tert-butyl)-5-((2-(4-methoxybenzyl)-1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-6-yl)amino)-1H-pyrazol-3-yl)cyclopentyl(4-nitrophenyl)carbonate (100 mg, 0.148 mmol, 75.6%) as a pale yellow oil. LCMS: ESI m / z 676.76 [M+H] + .

[0351] Step H: (1R,3S)-3-(5-((1,1-Dioxide-2,3-dihydrobenzo[d]isothiazol-6-yl)amino)-1H-pyrazol-3-yl)cyclopentyl(4-nitrophenyl)carbonate. A solution of (1R,3S)-3-(1-(tert-butyl)-5-((2-(4-methoxybenzyl)-1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-6-yl)amino)-1H-pyrazol-3-yl)cyclopentyl(4-nitrophenyl)carbonate (100 mg, 0.148 mmol) was dissolved in formic acid (2 mL) and stirred at 100° C. overnight. LCMS showed the reaction was complete. The cooled reaction mixture was concentrated to give (1R,3S)-3-(5-((1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-6-yl)amino)-1H-pyrazol-3-yl)cyclopentyl(4-nitrophenyl)carbonate (70.0 mg, 0.140 mmol, 94.7%) as a yellow oil. LCMS: ESI m / z 500.50 [M+H] + .

[0352] Step I: (1R,3S)-3-(3-((1,1-Dioxide-2,3-dihydrobenzo[d]isothiazol-6-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate. To a turbid solution of (1R,3S)-3-(5-((1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-6-yl)amino)-1H-pyrazol-3-yl)cyclopentyl(4-nitrophenyl)carbonate (70.0 mg, 0.140 mmol) in THF (2 mL) was added propan-2-amine (0.0360 mL, 0.420 mmol) and DIEA (0.0690 mL, 0.420 mmol). The reaction mixture was stirred at room temperature for 2 hours. LCMS showed the reaction was complete. The reaction mixture was dissolved in EA (50 mL), washed with HO (10 mL) and brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (eluted with 12% MeOH in DCM) and preparative HPLC (C18, 15-95% MeCN in HO containing 0.1% FA) to afford (1R,3S)-3-(3-((1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-6-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate (2.00 mg, 0.00500 mmol, 3.40%) as a white solid. LCMS: ESI m / z 420.50 [M+H] + . 1 H NMR (400MHz, DMSO) δ 8.90(s, 1H), 7.97(s, 1H), 7.62(br s, 1H), 7.39(d, J=8.4Hz, 1H), 7.31(d, J=8.4Hz, 1H), 6.95(d, J=6.8Hz, 1H), 5.65(s, 1H), 5.00(s, 1H), 4.27 (s, 2H), 3.11-3.05(m, 1H), 2.48-2.40(m, 1H), 2.04-1.89(m, 2H), 1.77-1.53(m, 3H), 1.04(d, J=6.0Hz, 6H).

[0353] Example 18: (1R,3S)-3-(3-((4-methyl-1,1-dioxide-3-oxo-3,4-dihydro-2H-benzo[e][1,2,4]thiadiazin-6-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate [ka] Step A: 4-Bromo-2-(methylamino)benzene-1-sulfonamide. To a solution of 4-bromo-2-fluorobenzene-1-sulfonamide (300 mg, 1.2 mmol) in 1,4-dioxane (4 mL) was added CH3NH2 (3 mL, 2 M in THF). The reaction was stirred in a sealed tube at 100 °C for 18 h. TLC and LCMS indicated the reaction was complete. The cooled reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (eluting with ethyl acetate in petroleum ether (gradient: 0 to 30%)) to afford the title compound, 4-bromo-2-(methylamino)benzene-1-sulfonamide (260 mg, 1.0 mmol, 83.0%) as a yellow solid. LCMS m / z: 266 [M+H] - .

[0354] Step B: 4-({5-[(1S,3R)-3-{[dimethyl(2-methylprop-2-yl)silyl]oxy}cyclopentyl]-2-(2-methylprop-2-yl)pyrazol-3-yl}amino)-2-(methylamino)benzene-1-sulfonamide. To a solution of 4-bromo-2-(methylamino)benzene-1-sulfonamide (210 mg, 0.792 mmol), 5-[(1S,3R)-3-{[dimethyl(2-methylprop-2-yl)silyl]oxy}cyclopentyl]-2-(2-methylprop-2-yl)pyrazol-3-amine (268 mg, 0.8 mmol), Xantphos (68 mg, 0.12 mmol), and CsCO (774 mg, 2.4 mmol) in 1,4-dioxane (10 mL) was added Pd(dba) (72 mg, 0.08 mmol). The reaction was stirred at 100 °C under a N atmosphere for 5 h. TLC and LCMS indicated the reaction was complete. The cooled reaction mixture was poured into ice water, the pH adjusted to 5-6 with 1N HCl, and extracted with EA (20 mL*3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified on a silica column (eluted with PE:EA (gradient: 0-50%)) to give the desired product 4-({5-[(1S,3R)-3-{[dimethyl(2-methylprop-2-yl)silyl]oxy}cyclopentyl]-2-(2-methylprop-2-yl)pyrazol-3-yl}amino)-2-(methylamino)benzene-1-sulfonamide (130 mg, 0.25 mmol, 31%) as a yellow solid. LCMS m / z: 522 [M+H] +

[0355] Step C: 6-({5-[(1S,3R)-3-{[dimethyl(2-methylprop-2-yl)silyl]oxy}cyclopentyl]-2-(2-methylprop-2-yl)pyrazol-3-yl}amino)-4-methyl-3-oxo-3,4-dihydro-2H-1λ6-benzo[2,1-e][1,2,4]thiadiazine-1,1-dione. To a solution of 4-({5-[(1S,3R)-3-{[dimethyl(2-methylprop-2-yl)silyl]oxy}cyclopentyl]-2-(2-methylprop-2-yl)pyrazol-3-yl}amino)-2-(methylamino)benzene-1-sulfonamide (430 mg, 0.8 mmol) in DMF (10 mL) was added NaH (165 mg, 4.1 mmol, 60% in mineral oil) at 0 °C and the reaction was stirred for 30 min. Triphosgene (244 mg, 0.8 mmol) was added to the reaction and the reaction was stirred at room temperature overnight. The reaction was poured into ice water, the pH was adjusted to 5-6 with 1 N HCl, extracted with EA, and the organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (eluting with methanol in dichloroform (gradient: 0-10%)) to give the title compound 6-({5-[(1S,3R)-3-{[dimethyl(2-methylprop-2-yl)silyl]oxy}cyclopentyl]-2-(2-methylprop-2-yl)pyrazol-3-yl}amino)-4-methyl-3-oxo-3,4-dihydro-2H-1λ6-benzo[2,1-e][1,2,4]thiadiazine-1,1-dione (280 mg, 0.5 mmol, 62%) as a gray solid. LCMS m / z: 548 [M+H] + .

[0356] Step D: 6-({5-[(1S,3R)-3-hydroxycyclopentyl]-2-(2-methylprop-2-yl)pyrazol-3-yl}amino)-4-methyl-3-oxo-3,4-dihydro-2H-1λ6-benzo[2,1-e][1,2,4]thiadiazine-1,1-dione. A solution of 4-methyl-6-{[2-(2-methylprop-2-yl)-5-[(1S,3R)-3-{[(2-methylprop-2-yl)diphenylsilyl]oxy}cyclopentyl]pyrazol-3-yl]amino}-3-oxo-3,4-dihydro-2H-1λ6-benzo[2,1-e][1,2,4]thiadiazine-1,1-dione (300 mg, 0.45 mmol) in HCOOH (4 mL) was stirred at room temperature for 18 h. The reaction was concentrated, and the residue was dissolved in 10 mL of THF and HO (1:1). LiOH was added and stirred for an additional 30 minutes. The pH of the reaction was adjusted to 5-6 with 1N HCl and extracted with EA. The combined organic layers were separated, washed with brine, dried over NaSO, filtered, and concentrated. The residue was purified by silica gel column chromatography (eluting with methanol in dichloroform (gradient: 0-10%)) to afford the title compound 6-({5-[(1S,3R)-3-hydroxycyclopentyl]-2-(2-methylprop-2-yl)pyrazol-3-yl}amino)-4-methyl-3-oxo-3,4-dihydro-2H-1λ6-benzo[2,1-e][1,2,4]thiadiazine-1,1-dione (180 mg, 0.4 mmol, 93%) as a gray solid. LCMS m / z: 434 [M+H] + .

[0357] Step E: (1R,3S)-3-[1-(2-methylprop-2-yl)-5-[(4-methyl-1,1,3-trioxo-3,4-dihydro-2H-1λ6-benzo[2,1-e][1,2,4]thiadiazin-6-yl)amino]pyrazol-3-yl]cyclopentyl[(4-nitrophenyl)oxy]methanoate. To a solution of 6-({5-[(1S,3R)-3-hydroxycyclopentyl]-2-(2-methylprop-2-yl)pyrazol-3-yl}amino)-4-methyl-3-oxo-3,4-dihydro-2H-1λ6-benzo[2,1-e][1,2,4]thiadiazine-1,1-dione (200 mg, 0.46 mmol) and DMAP (6 mg, 0.05 mmol) in pyridine (4 mL) was added 4-nitrophenyl chloroformate (139 mg, 0.7 mmol) and the reaction was stirred at 60° C. for 18 hours. TLC and LCMS indicated the reaction was complete. The cooled reaction mixture was concentrated. The residue was dissolved in EA, washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (eluting with methanol in dichloroform (gradient: 0-10%)) to give the title compound (1R,3S)-3-[1-(2-methylprop-2-yl)-5-[(4-methyl-1,1,3-trioxo-3,4-dihydro-2H-1λ6-benzo[2,1-e][1,2,4]thiadiazin-6-yl)amino]pyrazol-3-yl]cyclopentyl[(4-nitrophenyl)oxy]methanoate (80 mg, 0.13 mmol, 29%) as a gray solid. LCMS m / z: 599 [M+H] + .

[0358] Step F: (1R,3S)-3-{5-[(4-methyl-1,1,3-trioxo-3,4-dihydro-2H-1λ6-benzo[2,1-e][1,2,4]thiadiazin-6-yl)amino]-1H-pyrazol-3-yl}cyclopentyl[(4-nitrophenyl)oxy]methanoate. A solution of (1R,3S)-3-[1-(2-methylprop-2-yl)-5-[(4-methyl-1,1,3-trioxo-3,4-dihydro-2H-1λ6-benzo[2,1-e][1,2,4]thiadiazin-6-yl)amino]pyrazol-3-yl]cyclopentyl[(4-nitrophenyl)oxy]methanoate (80 mg, 0.13 mmol) in HCOOH (5 mL) was stirred at 100 °C for 16 h under a N atmosphere. LCMS showed normal. The reaction solution was concentrated to give (1R,3S)-3-{5-[(4-methyl-1,1,3-trioxo-3,4-dihydro-2H-1λ6-benzo[2,1-e][1,2,4]thiadiazin-6-yl)amino]-1H-pyrazol-3-yl}cyclopentyl[(4-nitrophenyl)oxy]methanoate (60 mg, 0.11 mmol, 83%) as a yellow solid, which was used directly in the next step without purification. LCMS m / z: 543 [M+H] +

[0359] Step G: (1R,3S)-3-{5-[(4-methyl-1,1,3-trioxo-3,4-dihydro-2H-1λ6-benzo[2,1-e][1,2,4]thiadiazin-6-yl)amino]-1H-pyrazol-3-yl}cyclopentyl(prop-2-ylamino)methanoate. To a solution of (1R,3S)-3-{5-[(4-methyl-1,1,3-trioxo-3,4-dihydro-2H-1λ6-benzo[2,1-e][1,2,4]thiadiazin-6-yl)amino]-1H-pyrazol-3-yl}cyclopentyl[(4-nitrophenyl)oxy]methanoate (100 mg, 0.18 mmol) in THF (3 mL) was added isopropylamine (3 mL). The reaction was stirred at room temperature for 1 hour. The reaction mixture was concentrated, and the residue was purified by preparative HPLC to give the title compound (1R,3S)-3-{5-[(4-methyl-1,1,3-trioxo-3,4-dihydro-2H-1λ6-benzo[2,1-e][1,2,4]thiadiazin-6-yl)amino]-1H-pyrazol-3-yl}cyclopentyl(prop-2-ylamino)methanoate (10.4 mg, 0.02 mmol, 12%) as an off-white solid. LCMS m / z: 463 [M+H] + . 1 H NMR (400MHz, DMSO)δ 11.99(s, 1H), 8.91(s, 1H), 7.49(d, J=8.4Hz, 1H), 7.41(s, 1H), 7.31-6.92(m, 4H), 5.74(s, 1H), 5.05(s, 1H), 3.64(d, J=6.4Hz, 1H), 3.33(s, 3H), 3.15-3.05(m, 1H), 2.52-2.44(m, 1H), 2.10-2.05(m, 1H), 2.01-1.90(m, 1H), 1.80-1.65(m, 3H), 1.09(d, J=6.4Hz, 6H).

[0360] Example 19: (1R,3S)-3-(3-((1,1-dioxide-2,3-dihydrobenzo[b]thiophen-6-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate [ka] Step A: 6-Bromobenzo[b]thiophene 1,1-dioxide. To a solution of 6-bromobenzothiophene (2.0 g, 9.39 mmol) in DCM (15 mL) was added HO (4 mL, 39.2 mmol, 30% in HO) and TFA (4 mL, 53.8 mmol). The mixture was stirred at 20 °C for 5 h. The mixture was purified by silica gel chromatography (20 g column) using 0–30% EtOAc / hexanes. The product-containing fractions were concentrated to give 6-bromobenzo[b]thiophene 1,1-dioxide (2.1 g, 8.57 mmol, 91%) as a white solid.

[0361] Step B: 6-Bromo-2,3-dihydrobenzo[b]thiophene 1,1-dioxide. 6-Bromo-1λ in MeOH (30 mL) 6 To a solution of 2,3-benzothiophene-1,1-dione (1.0 g, 4.08 mmol) was added NaBH4 (300 mg, 8.98 mmol), and the mixture was stirred at 20 °C for 2 h and then concentrated. The residue was purified by silica gel chromatography (10 g column) using 0–40% EtOAc / hexanes. The product-containing fractions were concentrated to give 6-bromo-2,3-dihydrobenzo[b]thiophene-1,1-dioxide (900 mg, 3.64 mmol, 89%) as a white solid.

[0362] Step C: 6-((1-(tert-butyl)-3-((1S,3R)-3-((tert-butyldiphenylsilyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)amino)-2,3-dihydrobenzo[b]thiophene 1,1-dioxide. 6-Bromo-2,3-dihydro-1λ in 1,4-dioxane (8 mL) 6To a solution of 1,1-benzothiophene-1,1-dione (300 mg, 1.214 mmol) and 2-(2-methylprop-2-yl)-5-[(1S,3R)-3-{[(2-methylprop-2-yl)diphenylsilyl]oxy}cyclopentyl]pyrazol-3-amine (616 mg, 1.34 mmol) was added CsCO (791 mg, 2.43 mmol). Next, Pd(dba) (111 mg, 0.121 mmol) and Xantphos (140 mg, 0.24 mmol) were added to the mixture, and the mixture was stirred at 100 °C under N for 5 h. The mixture was purified by silica gel chromatography (2 g column) using 0–50% EtOAc / hexanes. The product-containing fractions were concentrated to give 6-((1-(tert-butyl)-3-((1S,3R)-3-((tert-butyldiphenylsilyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)amino)-2,3-dihydrobenzo[b]thiophene 1,1-dioxide (530 mg, 0.84 mmol, 69%) as a brown solid. LCMS: ESI m / z 628.4 [M+H] + .

[0363] Step D: 6-((1-(tert-butyl)-3-((1S,3R)-3-hydroxycyclopentyl)-1H-pyrazol-5-yl)amino)-2,3-dihydrobenzo[b]thiophene 1,1-dioxide. 6-{[2-(2-methylprop-2-yl)-5-[(1S,3R)-3-{[(2-methylprop-2-yl)diphenylsilyl]oxy}cyclopentyl]pyrazol-3-yl]amino}-2,3-dihydro-1λ in formic acid (4 mL). 6A solution of 1-benzothiophene-1,1-dione (520 mg, 0.83 mmol) was stirred at 20° C. for 30 min. The mixture was concentrated in vacuo to remove formic acid and give the crude product. MeOH (3 mL) and LiOH (100 mg) were added to the crude product, which was stirred at 20° C. for 30 min. The reaction mixture was concentrated in vacuo, poured into EA (30 mL), and extracted with water. The organic layer was concentrated to give 6-((1-(tert-butyl)-3-((1S,3R)-3-hydroxycyclopentyl)-1H-pyrazol-5-yl)amino)-2,3-dihydrobenzo[b]thiophene 1,1-dioxide (270 mg, 0.69 mmol, 84%) as a brown solid. LCMS: ESI m / z 390.2 [M+H] + .

[0364] Step E: (1R,3S)-3-(1-(tert-butyl)-5-((1,1-dioxide-2,3-dihydrobenzo[b]thiophen-6-yl)amino)-1H-pyrazol-3-yl)cyclopentyl(4-nitrophenyl)carbonate. 6-({5-[(1S,3R)-3-hydroxycyclopentyl]-2-(2-methylprop-2-yl)pyrazol-3-yl}amino)-2,3-dihydro-1λ in DCM (3 mL) and THF (3 mL). 6 To a solution of 1R,3S)-benzothiophene-1,1-dione (270 mg, 0.69 mmol) was added 4-nitrophenyl chloromethanoate (210 mg, 1.04 mmol). Pyridine (0.11 mL, 1.39 mmol) and DMAP (17 mg, 0.14 mmol) were then added. The reaction mixture was stirred at 20 °C for 1 h. The mixture was purified by silica gel chromatography (2 g column) using 0–50% EtOAc / hexanes. The product-containing fractions were concentrated to give (1R,3S)-3-(1-(tert-butyl)-5-((1,1-dioxide-2,3-dihydrobenzo[b]thiophen-6-yl)amino)-1H-pyrazol-3-yl)cyclopentyl(4-nitrophenyl)carbonate (160 mg, 0.29 mmol, 42%) as a brown solid. LCMS:ESI m / z 555.2[M+H] + .

[0365] Step F: (1R,3S)-3-(1-(tert-butyl)-3-((1,1-dioxide-2,3-dihydrobenzo[b]thiophen-6-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate. (1R,3S)-3-{5-[(1,1-dioxo-2,3-dihydro-1λ]]cyclopentyl isopropylcarbamate in THF (5 mL). 6 To a solution of {1R,3S)-3-(1-(tert-butyl)-3-((1,1-dioxide-2,3-dihydrobenzo[b]thiophen-6-yl)amino)-1-(2-methylprop-2-yl)pyrazol-3-yl}cyclopentyl[(4-nitrophenyl)oxy]methanoate (100 mg, 0.18 mmol) was added DIEA (0.045 mL, 0.27 mmol). Next, propan-2-amine (0.09 mL, 1.10 mmol) was added dropwise to the mixture, and the mixture was stirred at 20 °C for 2 hours and then concentrated. The residue was purified by silica gel chromatography to give (1R,3S)-3-(1-(tert-butyl)-3-((1,1-dioxide-2,3-dihydrobenzo[b]thiophen-6-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate (70 mg, 0.15 mmol, 82%) as a yellow oil. LCMS:ESI m / z 475.2[M+H] + .

[0366] Step G: (1R,3S)-3-(3-((1,1-dioxide-2,3-dihydrobenzo[b]thiophen-6-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate. (1R,3S)-3-{5-[(1,1-dioxo-2,3-dihydro-1λ] 6A solution of (1R,3S)-3-(3-((1,1-dioxide-2,3-dihydrobenzo[b]thiophen-6-yl)amino)-2-(2-methylprop-2-yl)pyrazol-3-yl}cyclopentyl(prop-2-ylamino)methanoate (70 mg, 0.15 mmol) was stirred at 100° C. for 12 hours. The reaction mixture was concentrated, and the residue was purified by preparative HPLC to give (1R,3S)-3-(3-((1,1-dioxide-2,3-dihydrobenzo[b]thiophen-6-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate (16.3 mg, 0.04 mmol, 26%) as a white solid. LCMS: ESI m / z 419.2 [M+H] + . 1 H NMR (400MHz, DMSO)δ 11.81(s, 1H), 8.81(s, 1H), 7.94(s, 1H), 7.38(d, J=8.4Hz, 1H), 7.28(d, J=8.4Hz, 1H) , 6.95(d, J=9.6Hz, 1H), 5.61(s, 1H), 5.07-4.93(m, 1H), 3.64-3.55(m, 1H), 3.52(t, J= 6.8Hz, 2H), 3.20(t, J=6.8Hz, 2H), 3.12-2.99(m, 1H), 2.48-2.40(m, 1H), 2.07-1.97(m , 1H), 1.97-1.84(m, 1H), 1.80-1.66(m, 2H), 1.66-1.53(m, 1H), 1.03(d, J=6.4Hz, 6H).

[0367] Example 20: (1R,3S)-3-{5-[(3-oxo-2,3-dihydro-1H-isoindol-5-yl)amino]-2H-pyrazol-3-yl}cyclopentyl(prop-2-ylamino)methanoate [ka] Step A: 5-Bromo-2-(bromomethyl)benzoate. To a solution of methyl 5-bromo-2-methylbenzoate (3 g, 13.1 mmol) in CCl4 (30 mL) was added NBS (3.50 g, 19.6 mmol) and BPO (1.59 g, 6.55 mmol). The reaction mixture was stirred at 80 °C for 6 h. The cooled reaction mixture was poured into water and extracted with EtOAc. The combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography (using 0–10% ethyl acetate in petroleum ether) to give crude methyl 5-bromo-2-(bromomethyl)benzoate (3 g, 9.74 mmol, 74.4%) as a white solid.

[0368] Step B: 6-Bromo-2-[(4-methoxyphenyl)methyl]-2,3-dihydro-1H-isoindol-1-one. To a solution of methyl 5-bromo-2-(bromomethyl)benzoate (3 g, 9.74 mmol) in THF (30 mL) was added (4-methoxyphenyl)methanamine (1.40 mL, 10.7 mmol). The reaction mixture was stirred at 80 °C for 2 h. The cooled reaction mixture was poured into water and extracted with EtOAc. The combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography (using 0-50% ethyl acetate in petroleum ether) to give 6-bromo-2-[(4-methoxyphenyl)methyl]-2,3-dihydro-1H-isoindol-1-one (2 g, 6.02 mmol, 61.8%) as a white solid. LCMS: ESI m / z 332 [M+H] + .

[0369] Step C: 2-[(4-methoxyphenyl)methyl]-6-{[2-(2-methylprop-2-yl)-5-[(1S,3R)-3-{[(2-methylprop-2-yl)diphenylsilyl]oxy}cyclopentyl]pyrazol-3-yl]amino}-2,3-dihydro-1H-isoindol-1-one. To a solution of 6-bromo-2-[(4-methoxyphenyl)methyl]-2,3-dihydro-1H-isoindol-1-one (258 mg, 0.779 mmol) in dioxane (10 mL) was added 2-(2-methylprop-2-yl)-5-[(1S,3R)-3-{[(2-methylprop-2-yl)diphenylsilyl]oxy}cyclopentyl]pyrazol-3-amine (300 mg, 0.650 mmol), CsCO (529 mg, 1.62 mmol), Xantphos (75.2 mg, 0.130 mmol), and Xantphos Pd G (62.6 mg, 0.065 mmol), and the reaction was purged with N and stirred overnight at 100 °C under N. The cooled reaction mixture was diluted with EA and water. The organic layer was separated, washed with brine, and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluting with ethyl acetate in petroleum ether (2 / 1)). The organic layer was collected, concentrated under vacuum, and dried to give the title compound 2-[(4-methoxyphenyl)methyl]-6-{[2-(2-methylprop-2-yl)-5-[(1S,3R)-3-{[(2-methylprop-2-yl)diphenylsilyl]oxy}cyclopentyl]pyrazol-3-yl]amino}-2,3-dihydro-1H-isoindol-1-one (420 mg, 0.589 mmol, 90.7%) as a yellow oil. LCMS: ESI m / z 713 [M+H] + .

[0370] Step D: 6-({5-[(1S,3R)-3-Hydroxycyclopentyl]-2-(2-methylprop-2-yl)pyrazol-3-yl}amino)-2-[(4-methoxyphenyl)methyl]-2,3-dihydro-1H-isoindol-1-one. A mixture of 2-[(4-methoxyphenyl)methyl]-6-{[2-(2-methylprop-2-yl)-5-[(1S,3R)-3-{[(2-methylprop-2-yl)diphenylsilyl]oxy}cyclopentyl]pyrazol-3-yl]amino}-2,3-dihydro-1H-isoindol-1-one (420 mg, 0.589 mmol) in HCOOH (6 mL) was stirred at room temperature overnight and then concentrated under reduced pressure. The residue was treated with a mixture of LiOH-HO (0.065 mL, 2.36 mmol) in MeOH (3 mL) / HO (3 mL). The resulting mixture was stirred at room temperature for 1 h and then concentrated under reduced pressure. The resulting mixture was poured into water and extracted with EtOAc. The combined organic phases were washed with brine, dried over NaSO, filtered, and concentrated. The residue was purified by chromatography (silica gel, 0-70%, EA in PE) to give 6-({5-[(1S,3R)-3-hydroxycyclopentyl]-2-(2-methylprop-2-yl)pyrazol-3-yl}amino)-2-[(4-methoxyphenyl)methyl]-2,3-dihydro-1H-isoindol-1-one (210 mg, 0.442 mmol, 75.1%) as a white solid. LCMS: ESI m / z 475 [M+H] + .

[0371] Step E: (1R,3S)-3-[5-({2-[(4-methoxyphenyl)methyl]-3-oxo-2,3-dihydro-1H-isoindol-5-yl}amino)-1-(2-methylprop-2-yl)pyrazol-3-yl]cyclopentyl[(4-nitrophenyl)oxy]methanoate. To a solution of 6-({5-[(1S,3R)-3-hydroxycyclopentyl]-2-(2-methylprop-2-yl)pyrazol-3-yl}amino)-2-[(4-methoxyphenyl)methyl]-2,3-dihydro-1H-isoindol-1-one (210 mg, 0.442 mmol) in THF (2.5 mL) and DCM (2.5 mL) was added 4-nitrophenyl chloromethanoate (267 mg, 1.33 mmol), DMAP (5.40 mg, 0.044 mmol), and Py (0.107 mL, 1.326 mmol), and the reaction was stirred at room temperature for 2 hours. The reaction was concentrated in vacuo. The residue was purified by silica gel column chromatography (eluting with EA in PE [gradient: 0-50%]) to obtain the title compound (1R,3S)-3-[5-({2-[(4-methoxyphenyl)methyl]-3-oxo-2,3-dihydro-1H-isoindol-5-yl}amino)-1-(2-methylprop-2-yl)pyrazol-3-yl]cyclopentyl[(4-nitrophenyl)oxy]methanoate (160 mg, 0.250 mmol, 56.5%) as a white solid. LCMS: ESI 640 [M+H] + .

[0372] Step F: (1R,3S)-3-[1-(2-methylprop-2-yl)-5-[(3-oxo-2,3-dihydro-1H-isoindol-5-yl)amino]pyrazol-3-yl]cyclopentyl[(4-nitrophenyl)oxy]methanoate. A solution of (1R,3S)-3-[5-({2-[(4-methoxyphenyl)methyl]-3-oxo-2,3-dihydro-1H-isoindol-5-yl}amino)-1-(2-methylprop-2-yl)pyrazol-3-yl]cyclopentyl[(4-nitrophenyl)oxy]methanoate (60 mg, 0.09 mmol) in HCOOH (4 mL) and TfOH (0.4 mL) was stirred at 80 °C for 2 hours under a N atmosphere. LCMS showed that the desired product was detected in 50%. The reaction was concentrated to give the crude desired product (1R,3S)-3-[1-(2-methylprop-2-yl)-5-[(3-oxo-2,3-dihydro-1H-isoindol-5-yl)amino]pyrazol-3-yl]cyclopentyl[(4-nitrophenyl)oxy]methanoate (60 mg, 0.08 mmol, approx. 50% purity, 61% yield) as a gray solid, which was used directly in the next step without purification. LCMS: ESI 520 [M+H] + .

[0373] Step G: (1R,3S)-3-[1-(2-methylprop-2-yl)-5-[(3-oxo-2,3-dihydro-1H-isoindol-5-yl)amino]pyrazol-3-yl]cyclopentyl(prop-2-ylamino)methanoate. To a solution of ((1R,3S)-3-[1-(2-methylprop-2-yl)-5-[(3-oxo-2,3-dihydro-1H-isoindol-5-yl)amino]pyrazol-3-yl]cyclopentyl[(4-nitrophenyl)oxy]methanoate (80 mg, 0.125 mmol) in THF (3 mL) was added isopropylamine (3 mL). The reaction solution was stirred at room temperature for 1 hour. LCMS indicated the reaction was complete. The mixture was concentrated and purified by silica gel column chromatography (eluting with EA in PE [gradient: 0-100%]) to give (1R,3S)-3-[1-(2-methylprop-2-yl)-5-[(3-oxo-2,3-dihydro-1H-isoindol-5-yl)amino]pyrazol-3-yl]cyclopentyl(prop-2-ylamino)methanoate (40 mg, 0.09 mmol, 72.8%) as a yellow solid. LCMS: ESI 440 [M+H] + .

[0374] Step H: (1R,3S)-3-{5-[(3-oxo-2,3-dihydro-1H-isoindol-5-yl)amino]-2H-pyrazol-3-yl}cyclopentyl(prop-2-ylamino)methanoate. A solution of (1R,3S)-3-[1-(2-methylprop-2-yl)-5-[(3-oxo-2,3-dihydro-1H-isoindol-5-yl)amino]pyrazol-3-yl]cyclopentyl(prop-2-ylamino)methanoate (40 mg, 0.09 mmol) in HCOOH (4 mL) was stirred at 100° C. for 16 h. The cooled reaction mixture was concentrated. The residue was purified by preparative HPLC to give the title compound (1R,3S)-3-{5-[(3-oxo-2,3-dihydro-1H-isoindol-5-yl)amino]-2H-pyrazol-3-yl}cyclopentyl(prop-2-ylamino)methanoate (1.3 mg, 0.003 mmol, 3.7%) as a white solid. LCMS: ESI 384 [M+H]+ . 1 H NMR (400 MHz, DMSO) δ 11.73(s, 1H), 8.50(s, 1H), 8.36(s, 1H), 7.79(s, 1H), 7.42(d, J=8.2Hz, 1H), 7.33(d, J=8.2Hz, 1H), 6.94(s, 1H), 5.63(s, 1H), 5.01(s, 1H), 4.24( s, 2H), 3.63-3.55(m, 1H), 3.11-3.03(m, 1H), 2.51-2.43(m, 1H), 2.08-1 .97(m, 1H), 1.97-1.84(m, 1H), 1.84-1.61(m, 3H), 1.04(d, J=6.4Hz, 6H).

[0375] Example 21: (1R,3S)-3-{5-[(3,3-dimethyl-1,1-dioxo-2,3-dihydro-1λ 6 -benzothiophen-5-yl)amino]-2H-pyrazol-3-yl}cyclopentyl(prop-2-ylamino)methanoate [ka] Step A: 1-[(4-Bromophenyl)sulfanyl]-2-methylpropan-2-ol. To a solution of compound 4-bromobenzene-1-thiol (10 g, 52.9 mmol) in DMF (100 mL) was added 2,2-dimethyloxirane (5.19 mL, 58.2 mmol) and K2CO3 (10.9 g, 79.3 mmol). The resulting reaction solution was stirred at 20 °C for 0.5 h. The reaction was quenched by the addition of saturated sodium chloride solution (500 mL) and extracted with ethyl acetate (300 mL × 3). The combined organic phase was washed with saturated sodium chloride solution (100 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (petroleum ether / ethyl acetate=100-0%) to obtain the compound 1-[(4-bromophenyl)sulfanyl]-2-methylpropan-2-ol (10 g, 38.288 mmol, 72.39%) as a colorless oil. 1H NMR (400MHz, DMSO) δ 7.46(d, J=8.4Hz, 2H), 7.30(d, J=8.4Hz, 2H), 4.68(s, 1H), 3.04(s, 2H), 1.19(s, 6H).

[0376] Step B: 5-Bromo-3,3-dimethyl-2,3-dihydrobenzothiophene. To a suspension of aluminum chloride (7.66 g, 57.432 mmol) in carbon disulfide (100 mL) was added a solution of 1-[(4-bromophenyl)sulfanyl]-2-methylpropan-2-ol (5 g, 19.144 mmol) in 100 mL of carbon disulfide solution at -10 °C. The resulting reaction solution was stirred at 50 °C for 0.5 h and then cooled to 0 °C. 1N dilute hydrochloric acid was added to the reaction mixture, which was then extracted with ethyl acetate. The combined organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by separation using column chromatography (petroleum ether / ethyl acetate=100-0%) to obtain the compound 5-bromo-3,3-dimethyl-2,3-dihydrobenzothiophene (1.2 g, 4.935 mmol, 25.78%) as a yellow oil. 1 H NMR (400MHz, CDCl3) δ 7.24 (dd, J=8.0, 2.0Hz, 1H), 7.16 (d, J=2.0Hz, 1H), 7.06 (d, J=8.0Hz, 1H), 3.20 (s, 2H), 1.39 (d, J=4.4Hz, 6H).

[0377] Step C: 5-Bromo-3,3-dimethyl-2,3-dihydro-1λ 4-benzothiophen-1-one. To a solution of 5-bromo-3,3-dimethyl-2,3-dihydrobenzothiophene (1 g, 4.1 mmol) in 1,2-dichloroethane (10 mL) was slowly added acetic acid (0.825 mL, 14.4 mmol) and H2O2 (1 mL, 30 wt% in H2O, 9.8 mmol). The reaction mixture was stirred at 40 °C for 3.5 h. Ice water was added to the reaction mixture, followed by Na2SO3 (aq). The resulting mixture was extracted with ethyl acetate, washed twice with aqueous sodium carbonate, washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by flash chromatography to give 5-bromo-3,3-dimethyl-2,3-dihydro-1λ. 4 -benzothiophen-1-one (500 mg, 1.929 mmol, 46.91%) was obtained as a white solid. LCMS: ESI m / z 259 [M+H] + .

[0378] Step D: 5-Bromo-3,3-dimethyl-2,3-dihydro-1λ 6 -benzothiophene-1,1-dione. 5-Bromo-3,3-dimethyl-2,3-dihydro-1λ in DCM (10 mL) 4 To a solution of 500 mg of benzothiophen-1-one (1.929 mmol), 85% 3-chlorobenzene-1-carboperoxy acid (832 mg, 4.82 mmol) was added at 0°C. The reaction mixture was stirred at 5-15°C for 3 hours. The reaction mixture was purified by silica gel column chromatography to obtain the title compound, 5-bromo-3,3-dimethyl-2,3-dihydro-1λ. 6 -benzothiophene-1,1-dione (300 mg, 1.09 mmol, 56.5%) was obtained as a white solid. LCMS: ESI m / z 275 [M+H] + .

[0379] Step E: 3,3-dimethyl-5-{[2-(2-methylprop-2-yl)-5-[(1S,3R)-3-{[(2-methylprop-2-yl)diphenylsilyl]oxy}cyclopentyl]pyrazol-3-yl]amino}-2,3-dihydro-1λ 6-benzothiophene-1,1-dione. 5-Bromo-3,3-dimethyl-2,3-dihydro-1λ in dioxane (10 mL) 6 To a solution of 1,1-benzothiophene-1,1-dione (300 mg, 1.090 mmol), 2-(2-methylprop-2-yl)-5-[(1S,3R)-3-{[(2-methylprop-2-yl)diphenylsilyl]oxy}cyclopentyl]pyrazol-3-amine (503 mg, 1.09 mmol), CsCO (710.47 mg, 2.18 mmol), Xantphos (126 mg, 0.218 mmol), and Pd(dba) (99.8 mg, 0.109 mmol) were added. The reaction mixture was stirred overnight at 100 °C under N. The cooled reaction mixture was diluted with EA and water. The organic layer was separated, washed with brine, and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluted with ethyl acetate in petroleum ether) to give the title compound 3,3-dimethyl-5-{[2-(2-methylprop-2-yl)-5-[(1S,3R)-3-{[(2-methylprop-2-yl)diphenylsilyl]oxy}cyclopentyl]pyrazol-3-yl]amino}-2,3-dihydro-1λ 6 -benzothiophene-1,1-dione (500 mg, 0.762 mmol, 69.9%) was obtained as a yellow oil. LCMS: ESI m / z 656 [M+H] + .

[0380] Step F: 5-({5-[(1S,3R)-3-hydroxycyclopentyl]-2-(2-methylprop-2-yl)pyrazol-3-yl}amino)-3,3-dimethyl-2,3-dihydro-1λ 6 -benzothiophene-1,1-dione. 3,3-Dimethyl-5-{[2-(2-methylprop-2-yl)-5-[(1S,3R)-3-{[(2-methylprop-2-yl)diphenylsilyl]oxy}cyclopentyl]pyrazol-3-yl]amino}-2,3-dihydro-1λ in formic acid (3 mL) 6A mixture of 5-benzothiophene-1,1-dione (500 mg, 0.762 mmol) and 5-(2-benzothiophene-1,1-dione) was stirred at room temperature for 1 hour and then concentrated under reduced pressure. The residue was treated with a mixture of lithium hydroxide hydrate (31.98 mg, 0.762 mmol) in MeOH (3.00 mL) / HO (0.30 mL). The resulting mixture was stirred at room temperature for 2 hours, and the mixture was concentrated under reduced pressure. The mixture was poured into water and extracted with EtOAc. The combined organic phases were washed with brine, dried over NaSO, filtered, and concentrated. The residue was purified by chromatography to give 5-({5-[(1S,3R)-3-hydroxycyclopentyl]-2-(2-methylprop-2-yl)pyrazol-3-yl}amino)-3,3-dimethyl-2,3-dihydro-1λ 6 -benzothiophene-1,1-dione (280 mg, 0.671 mmol, 87.97%) was obtained as a colorless oil. LCMS: ESI m / z 418 [M+H] + .

[0381] Step G: (1R,3S)-3-{5-[(3,3-dimethyl-1,1-dioxo-2,3-dihydro-1λ 6 5-({5-[(1S,3R)-3-hydroxycyclopentyl]-2-(2-methylprop-2-yl)pyrazol-3-yl}amino)-3,3-dimethyl-2,3-dihydro-1λ in DCM (5 mL) and THF (5 mL). 6 To a solution of 1R,3S)-benzothiophene-1,1-dione (300 mg, 0.718 mmol), 4-nitrophenyl chloromethanoate (289 mg, 1.44 mmol), Py (0.174 mL, 2.15 mmol), and DMAP (8.78 mg, 0.072 mmol) were added. The reaction mixture was stirred at 25 °C for 2 h. The reaction solution was diluted with EA, washed with water and brine, dried over anhydrous NaSO, and concentrated in vacuo. The residue was purified by flash chromatography to give (1R,3S)-3-{5-[(3,3-dimethyl-1,1-dioxo-2,3-dihydro-1λ] 6{-benzothiophen-5-yl)amino}-1-(2-methylprop-2-yl)pyrazol-3-yl}cyclopentyl[(4-nitrophenyl)oxy]methanoate (350 mg, 0.601 mmol, 83.6%) was obtained as a yellow solid. LCMS: ESI m / z 583 [M+H] - .

[0382] Step H: (1R,3S)-3-{5-[(3,3-dimethyl-1,1-dioxo-2,3-dihydro-1λ 6 -benzothiophen-5-yl)amino]-1H-pyrazol-3-yl}cyclopentyl[(4-nitrophenyl)oxy]methanoate. (1R,3S)-3-{5-[(3,3-dimethyl-1,1-dioxo-2,3-dihydro-1λ] in formic acid (5 mL). 6 To a solution of (1R,3S)-3-{5-[(3,3-dimethyl-1,1-dioxo-2,3-dihydro-1λ-benzothiophen-5-yl)amino]-1-(2-methylprop-2-yl)pyrazol-3-yl}cyclopentyl[(4-nitrophenyl)oxy]methanoate (350 mg, 0.601 mmol) was added at 25°C. The reaction mixture was stirred at 100°C overnight. FA was removed under vacuum, and ... 6 -benzothiophen-5-yl)amino]-1H-pyrazol-3-yl}cyclopentyl[(4-nitrophenyl)oxy]methanoate (280 mg, 0.532 mmol, 88.5%) was obtained as a yellow oil. LCMS: ESI m / z 527 [M+H] + .

[0383] Step I: (1R,3S)-3-{5-[(3,3-dimethyl-1,1-dioxo-2,3-dihydro-1λ 6 -benzothiophen-5-yl)amino]-2H-pyrazol-3-yl}cyclopentyl(prop-2-ylamino)methanoate. (1R,3S)-3-{5-[(3,3-dimethyl-1,1-dioxo-2,3-dihydro-1λ-benzothiophen-5-yl)amino]-2H-pyrazol-3-yl}cyclopentyl(prop-2-ylamino)methanoate. 6To a solution of {(4-nitrophenyl)oxy]-1H-pyrazol-3-yl}cyclopentyl[(4-nitrophenyl)oxy]methanoate (280 mg, 0.532 mmol) was added propan-2-amine (0.091 mL, 1.064 mmol), and the reaction was stirred at room temperature for 1 hour. The reaction mixture was concentrated in vacuo. The residue was purified by preparative HPLC to give the title compound (1R,3S)-3-{5-[(3,3-dimethyl-1,1-dioxo-2,3-dihydro-1λ]. 6 -benzothiophen-5-yl)amino]-2H-pyrazol-3-yl}cyclopentyl(prop-2-ylamino)methanoate (83.5 mg, 0.187 mmol, 35.2%) was obtained as a white solid. LCMS: ESI m / z 447 [M+H] + . 1 H NMR (400MHz, DMSO)δ 9.03(s, 1H), 7.57(s, 1H), 7.45(d, J=8.8Hz, 1H), 7.31(dd, J=8.8, 1.6Hz, 1H), 6.94(d, J=7.6Hz, 1H), 5.69(s, 1H), 5.00(s, 1H) , 3.39(s, 2H), 3.13-3.02(m, 1H), 2.51-2.43(m, 1H), 2.07-1.83(m, 2H), 1.76-1.54(m, 3H), 1.42(s, 6H), 1.03(d, J=6.4Hz, 6H).

[0384] Example 22: (1R,3S)-3-(3-((2,2-dioxide-1,3-dihydrobenzo[c]thiophen-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate [ka] Step A: 5-((1-(tert-butyl)-3-((1S,3R)-3-((tert-butyldiphenylsilyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)amino)-1,3-dihydrobenzo[c]thiophene 2,2-dioxide. To a solution of 5-bromo-1,3-dihydrobenzo[c]thiophene 2,2-dioxide (460 mg, 1.86 mmol) in dioxane (15 mL) was added 1-(tert-butyl)-3-((1S,3R)-3-((tert-butyldiphenylsilyl)oxy)cyclopentyl)-1H-pyrazol-5-amine (250 mg, 0.541 mmol), CsCO (529 mg, 1.62 mmol), Pd(dba) (49.6 mg, 0.0540 mmol), and Xantphos (62.7 mg, 0.108 mmol). The reaction mixture was stirred at 100 °C under a N atmosphere for 2 h. LCMS indicated the reaction was complete. The cooled reaction mixture was dissolved in EA (10 mL*3), washed with HO (20 mL) and brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (eluted with 0-50% EA in PE) to give 5-((1-(tert-butyl)-3-((1S,3R)-3-((tert-butyldiphenylsilyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)amino)-1,3-dihydrobenzo[c]thiophene 2,2-dioxide (300 mg, 0.478 mmol, 88.2%) as a white solid. LCMS: ESI m / z 628.92 [M+H] + .

[0385] Step B: 5-((1-(tert-butyl)-3-((1S,3R)-3-hydroxycyclopentyl)-1H-pyrazol-5-yl)amino)-1,3-dihydrobenzo[c]thiophene 2,2-dioxide. A solution of 5-((1-(tert-butyl)-3-((1S,3R)-3-((tert-butyldiphenylsilyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)amino)-1,3-dihydrobenzo[c]thiophene 2,2-dioxide (300 mg, 0.478 mmol) in formic acid (5 mL) was stirred at room temperature for 5 h. LCMS showed the reaction was complete. The solvent was removed in vacuo. Then, EtOH (3 mL), HO (3 mL), and lithium hydroxide hydrate (120 mg, 2.87 mmol) were added to make the pH alkaline. The mixture was stirred at room temperature for 1 hour. LCMS showed the reaction was complete. The reaction mixture was dissolved in EA (50 mL), washed with HO (10 mL) and brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (eluted with 0-50% EA in PE) to give 5-((1-(tert-butyl)-3-((1S,3R)-3-hydroxycyclopentyl)-1H-pyrazol-5-yl)amino)-1,3-dihydrobenzo[c]thiophene 2,2-dioxide (260 mg, 0.668 mmol, 69.9%) as a yellow solid. LCMS: ESI m / z 390.51 [M+H] + .

[0386] Step C: (1R,3S)-3-(1-(tert-butyl)-5-((2,2-dioxide-1,3-dihydrobenzo[c]thiophen-5-yl)amino)-1H-pyrazol-3-yl)cyclopentyl(4-nitrophenyl)carbonate. A suspension of 5-((1-(tert-butyl)-3-((1S,3R)-3-hydroxycyclopentyl)-1H-pyrazol-5-yl)amino)-1,3-dihydrobenzo[c]thiophene 2,2-dioxide (120 mg, 0.308 mmol), DMAP (3.76 mg, 0.0310 mmol), Py (0.0750 mL, 0.924 mmol), and 4-nitrophenyl chloromethanoate (310 mg, 1.54 mmol) in DCM (3 mL) and THF (3 mL) was stirred at room temperature for 3 h. The solvent was removed in vacuo. The residue was dissolved in EA (50 mL), washed with HO (50 mL) and brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (eluting with 0-50% EA in PE) to give (1R,3S)-3-(1-(tert-butyl)-5-((2,2-dioxide-1,3-dihydrobenzo[c]thiophen-5-yl)amino)-1H-pyrazol-3-yl)cyclopentyl(4-nitrophenyl)carbonate (120 mg, 0.216 mmol, 70.2%) as a yellow solid. LCMS: ESI m / z 555.62 [M+H] + .

[0387] Step D: (1R,3S)-3-(5-((2,2-dioxide-1,3-dihydrobenzo[c]thiophen-5-yl)amino)-1H-pyrazol-3-yl)cyclopentyl(4-nitrophenyl)carbonate. A solution of (1R,3S)-3-(1-(tert-butyl)-5-((2,2-dioxide-1,3-dihydrobenzo[c]thiophen-5-yl)amino)-1H-pyrazol-3-yl)cyclopentyl(4-nitrophenyl)carbonate (120 mg, 0.216 mmol) in formic acid (2 mL) was stirred at 100° C. overnight. LCMS showed the reaction was complete. The cooled reaction mixture was concentrated to give crude (1R,3S)-3-(5-((2,2-dioxide-1,3-dihydrobenzo[c]thiophen-5-yl)amino)-1H-pyrazol-3-yl)cyclopentyl(4-nitrophenyl)carbonate (105 mg, 0.211 mmol, 97.4%) as a yellow oil. LCMS: ESI m / z 499.51 [M+H] + .

[0388] Step E: (1R,3S)-3-(3-((2,2-Dioxide-1,3-dihydrobenzo[c]thiophen-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate. A suspension of (1R,3S)-3-(5-((2,2-dioxide-1,3-dihydrobenzo[c]thiophen-5-yl)amino)-1H-pyrazol-3-yl)cyclopentyl(4-nitrophenyl)carbonate (105 mg, 0.211 mmol), propan-2-amine (0.0540 mL, 0.632 mmol), and DIEA (0.104 mL, 0.632 mmol) in THF (2 mL) was stirred at room temperature for 3 hours. LCMS showed the reaction was complete. The reaction was dissolved in EA (50 mL), washed with HO (10 mL) and brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (eluting with 0-12% MeOH in DCM) and preparative HPLC (C18, 15-95% MeCN in HO with 0.1% NHOH) to afford (1R,3S)-3-(3-((2,2-dioxide-1,3-dihydrobenzo[c]thiophen-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate (21.8 mg, 0.0520 mmol, 24.7%) as a white solid. LCMS: 419.51 [M+H] + . 1 H NMR (400MHz, DMSO)δ 11.74(s, 1H), 8.48(s, 1H), 7.42(s, 1H), 7.23(d, J=7.6Hz, 1H), 7.15(d, J=7.6Hz, 1H), 6.95(s, 1H), 5.64(s, 1H), 5.00(s, 1H), 4.4 2(s, 2H), 4.33(s, 2H), 3.58(s, 1H), 3.05(s, 1H), 2.50-2.42(m, 1H), 2.06-1.88(m, 2H), 1.79-1.56(m, 3H), 1.04(d, J=6.0Hz, 6H).

[0389] Example 23: Racemic cis 3-(5-((2-methyl-1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate [ka] Step A: 4-Bromo-2,N-dimethylbenzenesulfonamide. To a solution of 4-bromo-2-methylbenzenesulfonyl chloride (5 g, 18.6 mmol) in DCM (20 mL) was added methanamine-THF (5 mL, 10 mmol, 2 M in THF) and EtN (7.74 mL, 55.6 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo, dissolved in EA (50 mL), washed with HO (20 mL) and brine, dried over sodium sulfate, and concentrated. The residue was purified by silica gel chromatography (eluted with 0-50% EA in PE) to give 4-bromo-2,N-dimethylbenzenesulfonamide (2.3 g, 8.71 mmol, 46.9%) as a white solid. LCMS: ESI m / z 266 [M+H] + .

[0390] Step B: 4-Bromo-2-(bromomethyl)-N-methylbenzenesulfonamide. To a solution of 4-bromo-2,N-dimethylbenzenesulfonamide (1.8 g, 6.82 mmol) in tetrachloromethane (15 mL) was added BPO (0.33 g, 1.36 mmol) and NBS (1.33 g, 7.50 mmol) at room temperature. The reaction mixture was stirred at 80 °C overnight. The cooled reaction mixture was concentrated. The resulting mixture was poured into water and extracted with EtOAc. The combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (eluted with EA in PE [gradient: 0 to 30%]) to afford the title compound 4-bromo-2-(bromomethyl)-N-methylbenzenesulfonamide (970 mg, 2.83 mmol, 41.5%) as a white solid. LCMS: ESI 343 [M+H] - .

[0391] Step C: 5-Bromo-2-methyl-2,3-dihydro-1λ6-benzo[2,1-d][1,2]thiazole-1,1-dione. To a solution of 4-bromo-2-(bromomethyl)-N-methylbenzenesulfonamide (970 mg, 2.83 mmol) in HO (2 mL) and MeOH (8 mL) was added NaOH (226 mg, 5.66 mmol). The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated in vacuo. The subsequent mixture was poured into water and extracted with EtOAc. The combined organic phase was washed with brine, dried over NaSO, filtered, and concentrated. The residue was purified by silica gel column chromatography (eluting with EA in PE [gradient: 0-30%]) to obtain the title compound 5-bromo-2-methyl-2,3-dihydro-1λ6-benzo[2,1-d][1,2]thiazole-1,1-dione (390 mg, 1.49 mmol, 52.6%) as a white solid. LCMS: ESI 262 [M+H] - .

[0392] Step D: Racemic cis 3-(5-((2-methyl-1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate. To a solution of 5-bromo-2-methyl-2,3-dihydro-1λ6-benzo[2,1-d][1,2]thiazole-1,1-dione (16.2 mg, 0.062 mmol) in dioxane (6 mL) was added racemic cis-ethyl 5-amino-3-(3-((isopropylcarbamoyl)oxy)cyclopentyl)-1H-pyrazole-1-carboxylate (10 mg, 0.031 mmol), Xantphos (3.59 mg, 0.006 mmol), Pd(dba) (2.84 mg, 0.003 mmol), and CsCO (25.2 mg, 0.077 mmol). The reaction mixture was stirred under a N atmosphere at 100 °C for 1.5 h. LCMS indicated the reaction was complete. The cooled reaction mixture was filtered. The filtrate was concentrated. The residue was purified by preparative HPLC (C18, 10-95% MeCN in HO containing 0.1% HCOOH) to give racemic cis 3-(5-((2-methyl-1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate (2 mg, 0.005 mmol, 14.8%) as a white solid. LCMS: ESI m / z 434.2 [M+H] + . 1 H NMR (400MHz, DMSO)δ 11.93(s, 1H), 9.06(s, 1H), 7.59(d, J=8.4Hz, 1H), 7.50(s, 1H), 7.34(d, J=8.4H) z, 1H), 6.95(d, J=7.2Hz, 1H), 5.71(s, 1H), 5.00(s, 1H), 4.29(s, 2H), 3.64-3.55 (m, 1H), 3.10-3.02(m, 1H), 2.74(s, 3H), 2.50-2.43(m, 1H), 2.06-1.97(m, 1H), 1.96-1.86(m, 1H), 1.79-1.69(m, 2H), 1.68-1.58(m, 1H), 1.03(d, J=6.4Hz, 6H).

[0393] Example 24: Racemic cis 3-{5-[(1,1-dioxo-2,3-dihydro-1λ6-benzothiophen-5-yl)amino]-4-methyl-1H-pyrazol-3-yl}cyclopentyl(prop-2-ylamino)methanoate [ka] Step A: Racemic cis {[5-(3-hydroxycyclopentyl)-4-iodo-2-(2-methylprop-2-yl)pyrazol-3-yl]amino}methanoate benzyl. To a solution of racemic cis (1-(tert-butyl)-3-(3-hydroxycyclopentyl)-1H-pyrazol-5-yl)carbamate benzyl (4 g, 11.2 mmol) in acetonitrile (50 mL) was added 1-iodotetrahydropyrrole-2,5-dione (2.52 g, 11.2 mmol), and the reaction was stirred at room temperature for 1 hour. The reaction was diluted with DCM (100 mL) and water (200 mL). The organic layer was separated, washed with brine, dried over Na2SO4, and concentrated. The residue was purified by silica gel column chromatography (eluting with ethyl acetate (1% to 20%) in petroleum ether) to obtain the title compound cis{[5-(3-hydroxycyclopentyl)-4-iodo-2-(2-methylprop-2-yl)pyrazol-3-yl]amino}methanoate benzyl (5.2 g, 10.7 mmol, 96.1%) as a yellow solid. LCMS: 484.1 [M+H] + .

[0394] Step B: Racemic cis{[4-iodo-2-(2-methylprop-2-yl)-5-(3-{[(2-methylprop-2-yl)diphenylsilyl]oxy}cyclopentyl)pyrazol-3-yl]amino}methanoate benzyl. To a solution of cis{[5-(3-hydroxycyclopentyl)-4-iodo-2-(2-methylprop-2-yl)pyrazol-3-yl]amino}methanoate benzyl (5.2 g, 10.7 mmol) in DCM (60 mL) was added DMAP (1.31 g, 10.7 mmol), 1H-imidazole (2.20 g, 32.2 mmol), and TBDPS chloride (3.34 g, 12.9 mmol) at 0 °C. The reaction was stirred at room temperature for 18 h. The reaction solution was dissolved in EtOAc (100 mL), washed with HO (200 mL) and brine, dried over sodium sulfate, and concentrated. The residue was purified by silica gel chromatography (eluted with 60% ethyl acetate in petroleum ether) to give {[4-iodo-2-(2-methylprop-2-yl)-5-(3-{[(2-methylprop-2-yl)diphenylsilyl]oxy}cyclopentyl)pyrazol-3-yl]amino}methanoate benzyl (5.0 g, 6.93 mmol, 64.4%) as a white oil. LCMS: ESI m / z 720.0 [MH] - .

[0395] Step C: Racemic cis 4-methyl-2-(2-methylprop-2-yl)-5-(3-{[(2-methylprop-2-yl)diphenylsilyl]oxy}cyclopentyl)pyrazol-3-amine. To a mixture of cis{[4-iodo-2-(2-methylprop-2-yl)-5-(3-{[(2-methylprop-2-yl)diphenylsilyl]oxy}cyclopentyl)pyrazol-3-yl]amino}methanoate benzyl (800 mg, 1.11 mmol) and 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (2.53 mL, 8.86 mmol) in DMF (10 mL) was added K2CO3 (459 mg, 3.33 mmol) and Pd(dppf)Cl2 (81.1 mg, 0.111 mmol). The reaction was stirred at 110°C for 3 hours. The cooled reaction mixture was diluted with water and extracted with EA (50 mL*3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated. The residue was purified by silica gel column chromatography (eluted with PE / EA (100 / 1 to 12 / 1)) to give the title compound cis 4-methyl-2-(2-methylprop-2-yl)-5-(3-{[(2-methylprop-2-yl)diphenylsilyl]oxy}cyclopentyl)pyrazol-3-amine (140 mg, 0.294 mmol, 26.5%) as a pink oil. LCMS: 476.3 [M+H] + .

[0396] Step D: Racemic cis 5-((1-(tert-butyl)-3-(3-((tert-butyldiphenylsilyl)oxy)cyclopentyl)-4-methyl-1H-pyrazol-5-yl)amino)-2,3-dihydrobenzo[b]thiophene 1,1-dioxide. To a stirred mixture of cis 4-methyl-2-(2-methylprop-2-yl)-5-(3-{[(2-methylprop-2-yl)diphenylsilyl]oxy}cyclopentyl)pyrazol-3-amine (140 mg, 0.294 mmol) in dioxane (10 mL) was added 5-bromo-2,3-dihydro-1λ-benzothiophene-1,1-dione (109.08 mg, 0.441 mmol), Xantphos (34.05 mg, 0.059 mmol), CsCO (191 mg, 0.589 mmol), and Pd(dba) (26.9 mg, 0.029 mmol). The reaction mixture was stirred at 120 °C under N for 3 h. The cooled reaction mixture was diluted with water and extracted with EA (20 mL*3). The combined organic layers were washed with white brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluted with PE / EA (100 / 1 to 3 / 1)) to give the title compound racemic cis 5-((1-(tert-butyl)-3-(3-((tert-butyldiphenylsilyl)oxy)cyclopentyl)-4-methyl-1H-pyrazol-5-yl)amino)-2,3-dihydrobenzo[b]thiophene 1,1-dioxide (110 mg, 0.171 mmol, 58.2%) as a yellow-green oil. LCMS: 642.5 [M+H] + .

[0397] Step E: Racemic cis 5-{[5-(3-hydroxycyclopentyl)-4-methyl-2-(2-methylprop-2-yl)pyrazol-3-yl]amino}-2,3-dihydro-1λ6-benzothiophene-1,1-dione. A solution of cis 5-((1-(tert-butyl)-3-(3-((tert-butyldiphenylsilyl)oxy)cyclopentyl)-4-methyl-1H-pyrazol-5-yl)amino)-2,3-dihydrobenzo[b]thiophene-1,1-dioxide (150 mg, 0.234 mmol) in HCOOH (5 mL) was stirred at 40 °C for 18 h. The reaction mixture was concentrated. The residue was dissolved in methanol, and the pH was adjusted to 12-13 with 2 N aqueous lithium hydroxide solution. The reaction mixture was stirred at room temperature for 30 min and then diluted with EA and water. The organic layer was separated, washed with brine, and concentrated. The residue was purified by silica gel column chromatography (eluted with PE / EA (100 / 1 to 1 / 100)) to obtain the title compound cis 5-{[5-(3-hydroxycyclopentyl)-4-methyl-2-(2-methylprop-2-yl)pyrazol-3-yl]amino}-2,3-dihydro-1λ6-benzothiophene-1,1-dione (90 mg, 0.223 mmol, 95.4%) as a yellow oil. LCMS: 404.3 [M+H] + .

[0398] Step F: Racemic cis 3-{5-[(1,1-dioxo-2,3-dihydro-1λ6-benzothiophen-5-yl)amino]-4-methyl-1-(2-methylprop-2-yl)pyrazol-3-yl}cyclopentyl[(4-nitrophenyl)oxy]methanoate. A suspension of cis 5-{[5-(3-hydroxycyclopentyl)-4-methyl-2-(2-methylprop-2-yl)pyrazol-3-yl]amino}-2,3-dihydro-1λ6-benzothiophene-1,1-dione (90 mg, 0.223 mmol), pyridine (0.054 mL, 0.669 mmol), DMAP (2.72 mg, 0.022 mmol), and 4-nitrophenyl chloromethanoate (89.9 mg, 0.446 mmol) in THF (5 mL) and DCM (5 mL) was stirred at 50 °C overnight. The solvent was removed in vacuo. The residue was dissolved in ethyl acetate (50 mL), washed with brine (100 mL), dried over sodium sulfate, and concentrated. The residue was purified by silica gel chromatography (eluting with 100% ethyl acetate in petroleum ether) to give cis 3-{5-[(1,1-dioxo-2,3-dihydro-1λ6-benzothiophen-5-yl)amino]-4-methyl-1-(2-methylprop-2-yl)pyrazol-3-yl}cyclopentyl[(4-nitrophenyl)oxy]methanoate (50 mg, 0.088 mmol, 39.4%) as a white solid. LCMS: 569.3 [M+H] + .

[0399] Step G: Racemic cis 3-{5-[(1,1-dioxo-2,3-dihydro-1λ6-benzothiophen-5-yl)amino]-4-methyl-1H-pyrazol-3-yl}cyclopentyl[(4-nitrophenyl)oxy]methanoate. A solution of cis 3-{5-[(1,1-dioxo-2,3-dihydro-1λ6-benzothiophen-5-yl)amino]-4-methyl-1-(2-methylprop-2-yl)pyrazol-3-yl}cyclopentyl[(4-nitrophenyl)oxy]methanoate (50 mg, 0.088 mmol) in HCOOH (5 mL) was stirred at 100° C. for 18 h. The cooled reaction mixture was concentrated in vacuo to give the title compound cis 3-{5-[(1,1-dioxo-2,3-dihydro-1λ6-benzothiophen-5-yl)amino]-4-methyl-1H-pyrazol-3-yl}cyclopentyl[(4-nitrophenyl)oxy]methanoate (50 mg, 0.073 mmol, 83.2%) as a yellow oil. LCMS: 513.2 [M+H] + .

[0400] Step H: Racemic cis 3-{5-[(1,1-dioxo-2,3-dihydro-1λ6-benzothiophen-5-yl)amino]-4-methyl-1H-pyrazol-3-yl}cyclopentyl(prop-2-ylamino)methanoate. A solution of cis 3-{5-[(1,1-dioxo-2,3-dihydro-1λ6-benzothiophen-5-yl)amino]-4-methyl-1H-pyrazol-3-yl}cyclopentyl[(4-nitrophenyl)oxy]methanoate (50 mg, 0.073 mmol) in propan-2-amine (5 mL, 58.366 mmol) was stirred at room temperature for 2 hours. The reaction mixture was concentrated. The residue was purified by preparative HPLC (C18, 5% to 95% MeCN in HO containing 0.1% HCOOH) to give cis 3-{5-[(1,1-dioxo-2,3-dihydro-1λ6-benzothiophen-5-yl)amino]-4-methyl-1H-pyrazol-3-yl}cyclopentyl(prop-2-ylamino)methanoate (18.9 mg, 0.044 mmol, 59.7%) as a white solid. LCMS: 433 [M+H] + . 1H NMR (400MHz, DMSO)δ 11.82(s, 1H), 8.34(s, 1H), 7.45(d, J=8.4Hz, 1H), 7.29-7.19(m, 2H), 6.97(d, J=8.4Hz, 1H), 4.99(s, 1H), 3.65-3.55(m, 1H), 3.46(t, J=6.8Hz) , 2H), 3.21(t, J=6.8Hz, 2H), 3.15-3.02(m, 1H), 2.44-2.35(m, 1H), 2.0 3-1.91(m, 2H), 1.88(s, 3H), 1.83-1.63(m, 3H), 1.04(d, J=6.4Hz, 6H).

[0401] Example 25: (1R,3S)-3-{5-[(1-oxo-2,3-dihydro-1H-inden-5-yl)amino]-2H-pyrazol-3-yl}cyclopentyl(prop-2-ylamino)methanoate [ka] Step A: 5-({5-[(1S,3R)-3-{[dimethyl(2-methylprop-2-yl)silyl]oxy}cyclopentyl]-2-(2-methylprop-2-yl)pyrazol-3-yl}amino)-2,3-dihydro-1H-inden-1-one. To a solution of 5-bromo-2,3-dihydro-1H-inden-1-one (0.169 mL, 0.948 mmol) in dioxane (10 mL) was added 5-[(1S,3R)-3-{[dimethyl(2-methylprop-2-yl)silyl]oxy}cyclopentyl]-2-(2-methylprop-2-yl)pyrazol-3-amine (319 mg, 0.948 mmol), CsCO (617 mg, 1.89 mmol), Xantphos (109 mg, 0.190 mmol), and Pd(dba) (86.7 mg, 0.095 mmol). The reaction mixture was stirred under N at 120 °C for 3 h. The cooled reaction mixture was diluted with EA and water. The organic layer was separated, washed with brine, and concentrated. The residue was purified by silica gel column chromatography (eluted with ethyl acetate in petroleum ether) to give the title compound 5-({5-[(1S,3R)-3-{[dimethyl(2-methylprop-2-yl)silyl]oxy}cyclopentyl]-2-(2-methylprop-2-yl)pyrazol-3-yl}amino)-2,3-dihydro-1H-inden-1-one (200 mg, 0.428 mmol, 45.1%) as a yellow oil. LCMS: ESI m / z 468 [M+H] + .

[0402] Step B: 5-({5-[(1S,3R)-3-Hydroxycyclopentyl]-2-(2-methylprop-2-yl)pyrazol-3-yl}amino)-2,3-dihydro-1H-inden-1-one. A mixture of 5-({5-[(1S,3R)-3-{[dimethyl(2-methylprop-2-yl)silyl]oxy}cyclopentyl]-2-(2-methylprop-2-yl)pyrazol-3-yl}amino)-2,3-dihydro-1H-inden-1-one (150 mg, 0.321 mmol) in formic acid (6 mL) was stirred at room temperature for 1 hour and then concentrated under reduced pressure. The residue was treated with a mixture of lithium hydroxide hydrate (26.9 mg, 0.642 mmol) in MeOH (9 mL) / HO (3 mL). The resulting mixture was stirred at room temperature for 2 hours, and the mixture was concentrated under reduced pressure. The residue was poured into water and extracted with EtOAc. The combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by chromatography to give 5-({5-[(1S,3R)-3-hydroxycyclopentyl]-2-(2-methylprop-2-yl)pyrazol-3-yl}amino)-2,3-dihydro-1H-inden-1-one (80 mg, 0.226 mmol, 70.5%) as a colorless oil. LCMS: ESI m / z 354 [M+H] + .

[0403] Step C: (1R,3S)-3-[1-(2-methylprop-2-yl)-5-[(1-oxo-2,3-dihydro-1H-inden-5-yl)amino]pyrazol-3-yl]cyclopentyl[(4-nitrophenyl)oxy]methanoate. To a solution of 5-({5-[(1S,3R)-3-hydroxycyclopentyl]-2-(2-methylprop-2-yl)pyrazol-3-yl}amino)-2,3-dihydro-1H-inden-1-one (100 mg, 0.283 mmol) in DCM (3 mL) and THF (3 mL) was added 4-nitrophenyl chloromethanoate (114 mg, 0.566 mmol), Py (0.046 mL, 0.566 mmol), and DMAP (3.46 mg, 0.028 mmol). The reaction mixture was stirred at 25° C. for 2 hours. The reaction solution was diluted with EA, washed with water and brine, dried over anhydrous NaSO, and concentrated. The residue was purified by flash chromatography to give (1R,3S)-3-[1-(2-methylprop-2-yl)-5-[(1-oxo-2,3-dihydro-1H-inden-5-yl)amino]pyrazol-3-yl]cyclopentyl[(4-nitrophenyl)oxy]methanoate (100 mg, 0.193 mmol, 68.1%) as a yellow solid. LCMS: ESI m / z 519 [M+H] - .

[0404] Step D: (1R,3S)-3-{5-[(1-oxo-2,3-dihydro-1H-inden-5-yl)amino]-1H-pyrazol-3-yl}cyclopentyl[(4-nitrophenyl)oxy]methanoate. A solution of (1R,3S)-3-[1-(2-methylprop-2-yl)-5-[(1-oxo-2,3-dihydro-1H-inden-5-yl)amino]pyrazol-3-yl]cyclopentyl[(4-nitrophenyl)oxy]methanoate (100 mg, 0.193 mmol) in formic acid (5 mL) was stirred at 100° C. overnight. The cooled reaction mixture was concentrated to give (1R,3S)-3-{5-[(1-oxo-2,3-dihydro-1H-inden-5-yl)amino]-1H-pyrazol-3-yl}cyclopentyl[(4-nitrophenyl)oxy]methanoate (70 mg, 0.151 mmol, 78.5%) as a yellow oil. LCMS: ESI m / z 463 [M+H] + .

[0405] Step E: (1R,3S)-3-{5-[(1-oxo-2,3-dihydro-1H-inden-5-yl)amino]-2H-pyrazol-3-yl}cyclopentyl(prop-2-ylamino)methanoate. To a solution of (1R,3S)-3-{5-[(1-oxo-2,3-dihydro-1H-inden-5-yl)amino]-1H-pyrazol-3-yl}cyclopentyl[(4-nitrophenyl)oxy]methanoate (70 mg, 0.151 mmol) in THF (5 mL) was added propan-2-amine (0.026 mL, 0.303 mmol). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated in vacuo. The residue was purified by preparative HPLC to give the title compound (1R,3S)-3-{5-[(1-oxo-2,3-dihydro-1H-inden-5-yl)amino]-2H-pyrazol-3-yl}cyclopentyl(prop-2-ylamino)methanoate (53 mg, 0.139 mmol, 91.5%) as a white solid. LCMS: ESI m / z 383 [M+H] + . 1H NMR (400MHz, DMSO)δ 11.94(s, H), 9.07(s, 1H), 7.53(s, 1H), 7.43(d, J=8.4Hz, 1H), 7.17(d, J=8.4Hz, 1H), 6.95(d, J=7.2Hz, 1H), 5.73(d, J=1.6Hz, 1H), 5.00(s, 1H), 3.63-3.53(m, 1H) ), 3.13-3.01(m, 1H), 3.00-2.93(m, 2H), 2.48-2.42(m, 1H), 2.008-1.97(m, 1H), 1.96-1.86(m, 1H), 1.81-1.68(m, 2H), 1.68-1.58(m, 1H), 1.03(d, J=6.4Hz, 6H).

[0406] Example 26: (1R,3S)-3-(3-((1,1-dioxidothiochroman-6-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate [ka] Step A: 6-Bromo-3,4-dihydro-2H-1-benzothiin-4-ol. To a solution of 6-bromo-3,4-dihydro-2H-1-benzothiin-4-one (1 g, 4.11 mmol) in MeOH (5 mL) was added NaBH4 (0.28 g, 8.23 ​​mmol). The reaction mixture was stirred at room temperature for 1 h. The reaction was diluted with EA and water. The organic layer was separated, washed with brine, and concentrated in vacuo to give the title compound 6-bromo-3,4-dihydro-2H-1-benzothiin-4-ol (900 mg, 3.67 mmol, 89.3%) as a brown oil. LCMS: m / z 245.13 [M+H] + .

[0407] Step B: 6-Bromo-3,4-dihydro-2H-1-benzothiin. To a solution of 6-bromo-3,4-dihydro-2H-1-benzothiin-4-ol (900 mg, 3.67 mmol) in TFA (10 mL) was added EtSiH (2.97 mL, 18.4 mmol). The reaction mixture was stirred at 60 °C overnight. The cooled reaction mixture was diluted with EA and water. The organic layer was separated, washed with brine, and concentrated. The residue was purified by silica gel column chromatography (eluted with ethyl acetate in petroleum ether (gradient: 0 to 1%)) to give the title compound 6-bromo-3,4-dihydro-2H-1-benzothiin (840 mg, 3.67 mmol, 99.9%) as a colorless oil. LCMS: m / z 229.13 [M+H] + .

[0408] Step C: 6-Bromothiochroman 1,1-dioxide. To a solution of 6-bromo-3,4-dihydro-2H-1-benzothiin (900 mg, 3.93 mmol) in 1,2-dichloroethane (10 mL) was added 3-chloroperoxybenzoic acid (2.39 g, 11.8 mmol). The reaction was stirred at 60 °C overnight. The reaction was diluted with EA and water. The organic layer was separated, washed with saturated NaHCO3 solution, and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluted with ethyl acetate in petroleum ether (gradient: 0 to 30%)) to give the title compound 6-bromothiochroman 1,1-dioxide (780 mg, 2.99 mmol, 76.1%) as a pink solid. LCMS: m / z 261.13 [M+H] + .

[0409] Step D: 6-((1-(tert-butyl)-3-((1S,3R)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)amino)thiochroman 1,1-dioxide. To a stirred solution of 6-bromothiochroman 1,1-dioxide (300 mg, 1.15 mmol) in dioxane (10 mL) was added 5-[(1S,3R)-3-{[dimethyl(2-methylprop-2-yl)silyl]oxy}cyclopentyl]-2-(2-methylprop-2-yl)pyrazol-3-amine (388 mg, 1.15 mmol), Pd(dba) (105 mg, 0.115 mmol), Xantphos (133 mg, 0.230 mmol), and CsCO (1.12 g, 3.48 mmol). The reaction was stirred under N2 at 100 °C for 4 h. The cooled reaction mixture was diluted with EA and water. The organic layer was separated, washed with brine, and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluting with ethyl acetate in petroleum ether (gradient: 0-30%)) to give the title compound 6-((1-(tert-butyl)-3-((1S,3R)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)amino)thiochroman 1,1-dioxide (400 mg, 0.772 mmol, 67.2%) as a yellow solid. LCMS: m / z 517.80 [M+H] + .

[0410] Step E: 6-((1-(tert-butyl)-3-((1S,3R)-3-hydroxycyclopentyl)-1H-pyrazol-5-yl)amino)thiochroman 1,1-dioxide. A solution of 6-((1-(tert-butyl)-3-((1S,3R)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)amino)thiochroman 1,1-dioxide (150 mg, 0.240 mmol) in formic acid (5 mL) was stirred at room temperature for 1 h and then concentrated in vacuo. The residue was dissolved in methanol, and the pH value was adjusted to 12-13 with 2 N aqueous lithium hydroxide solution. The reaction was stirred at room temperature for 30 min and then diluted with EA and water. The organic layer was separated, washed with brine, and concentrated. The residue was purified by silica gel column chromatography (eluting with ethyl acetate in petroleum ether (gradient: 0-50%)) to give the title compound 6-((1-(tert-butyl)-3-((1S,3R)-3-hydroxycyclopentyl)-1H-pyrazol-5-yl)amino)thiochroman 1,1-dioxide (90 mg, 0.176 mmol, 73.4%) as a yellow solid. LCMS: m / z 510.65 [M+H] + .

[0411] Step F: (1R,3S)-3-(1-(tert-butyl)-5-((1,1-dioxidethiochroman-6-yl)amino)-1H-pyrazol-3-yl)cyclopentyl(4-nitrophenyl)carbonate. To a stirred solution of 6-((1-(tert-butyl)-3-((1S,3R)-3-hydroxycyclopentyl)-1H-pyrazol-5-yl)amino)thiochroman 1,1-dioxide (300 mg, 0.743 mmol) in THF (5 mL) and DCM (5 mL) was added 4-nitrophenyl chloromethanoate (225 mg, 1.12 mmol), DMAP (9.08 mg, 0.074 mmol), and Py (118 mg, 1.49 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with DCM and water. The organic layer was separated, washed with brine, and concentrated. The residue was purified by silica gel column chromatography (eluting with ethyl acetate in petroleum ether (gradient: 0-30%)) to obtain the title compound (1R,3S)-3-(1-(tert-butyl)-5-((1,1-dioxidothiochroman-6-yl)amino)-1H-pyrazol-3-yl)cyclopentyl(4-nitrophenyl)carbonate (330 mg, 0.580 mmol, 78.1%) as a yellow solid. LCMS: m / z 568.64 [M+H] + .

[0412] Step G: (1R,3S)-3-(5-((1,1-dioxidothiochroman-6-yl)amino)-1H-pyrazol-3-yl)cyclopentyl(4-nitrophenyl)carbonate. A solution of (1R,3S)-3-(1-(tert-butyl)-5-((1,1-dioxidothiochroman-6-yl)amino)-1H-pyrazol-3-yl)cyclopentyl(4-nitrophenyl)carbonate (150 mg, 0.264 mmol) in formic acid (5 mL) was stirred at 100° C. overnight. The reaction mixture was concentrated to give the title compound (1R,3S)-3-(5-((1,1-dioxidothiochroman-6-yl)amino)-1H-pyrazol-3-yl)cyclopentyl(4-nitrophenyl)carbonate (130 mg, 0.254 mmol, 96.2%) as a brown oil. LCMS: m / z 512.54 [M+H] + .

[0413] Step H: (1R,3S)-3-(3-((1,1-dioxidothiochroman-6-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate. A solution of (1R,3S)-3-(5-((1,1-dioxidothiochroman-6-yl)amino)-1H-pyrazol-3-yl)cyclopentyl(4-nitrophenyl)carbonate (150 mg, 0.293 mmol) in propan-2-amine (17.3 mg, 0.293 mmol) was stirred at room temperature for 1 hour. The reaction was concentrated in vacuo. The residue was purified by preparative HPLC (C18, 0-70% acetonitrile in HO) to give the title compound (1R,3S)-3-(3-((1,1-dioxidothiochroman-6-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate (31.1 mg, 0.072 mmol, 24.5%) as a white solid. LCMS: m / z 432.54 [M+H] + . 1 H NMR (400MHz, DMSO)δ 11.88(s, 1H), 8.85(s, 1H), 7.54(d, J=8.8Hz, 1H), 7.27(d, J=8.0Hz, 2H), 6.91( dd, J=26.8, 8.0Hz, 1H), 5.67(s, 1H), 4.99(s, 1H), 3.62-3.52(m, 1H), 3.42-3.34 (m, 2H), 3.12-2.98(m, 1H), 2.89(t, J=6.4Hz, 2H), 2.48-2.40(m, 1H), 2.27(dt, J =12.0, 5.6Hz, 2H), 2.02-1.82(m, 2H), 1.75-1.54(m, 3H), 1.03(d, J=6.4Hz, 6H).

[0414] Example 27: (1s,4s)-4-{5-[(1,1-dioxo-2,3-dihydro-1λ 6 -benzo[b]thiophen-6-yl)amino]-2H-pyrazol-3-yl}cyclohexyl(prop-2-ylamino)methanoate [ka] Step A. 6-({5-[(1s,4s)-4-{[(2-methylprop-2-yl)diphenylsilyl]oxy}cyclohexyl]-1-(2-methylprop-2-yl)pyrazol-3-yl}amino)-2,3-dihydro-1λ 6 -benzo[b]thiophene-1,1-dione. 6-Bromo-2,3-dihydro-1λ in dioxane (2 mL) 6 To a stirred solution of 1,1-benzo[2,1-b]thiophene-1,1-dione (104 mg, 0.42 mmol) at room temperature was added 5-[(1s,4s)-4-{[(2-methylprop-2-yl)diphenylsilyl]oxy}cyclohexyl]-1-(2-methylprop-2-yl)pyrazol-3-amine (200 mg, 0.42 mmol), Pd(dba) (38 mg, 0.04 mmol), Xantphos (49 mg, 0.08 mmol), and CsCO (342 mg, 1.1 mmol). The reaction mixture was stirred at 100 °C under N for 2 h. The cooled reaction mixture was poured into water (30 mL) and extracted with EtOAc (20 mL * 2). The combined organic phase was washed with brine, dried over NaSO, filtered, and concentrated. The residue was purified by chromatography (silica gel, 0–60%, EtOAc in PE) to give 6-({5-[(1s,4s)-4-{[(2-methylprop-2-yl)diphenylsilyl]oxy}cyclohexyl]-1-(2-methylprop-2-yl)pyrazol-3-yl}amino)-2,3-dihydro-1λ 6 -benzothiophene-1,1-dione (250 mg, 0.39 mmol, 92%) was obtained as a yellow solid. LCMS: m / z 642 [M+H] + .

[0415] Step B. 6-({5-[(1s,4s)-4-hydroxycyclohexyl]-1-(2-methylprop-2-yl)pyrazol-3-yl}amino)-2,3-dihydro-1λ 6-benzo[b]thiophene-1,1-dione. 6-({5-[(1s,4s)-4-{[(2-methylprop-2-yl)diphenylsilyl]oxy}cyclohexyl]-1-(2-methylprop-2-yl)pyrazol-3-yl}amino)-2,3-dihydro-1λ in HCOOH (5 mL). 6 A mixture of 1,1-benzothiophene-1,1-dione (260 mg, 0.41 mmol) and 1,1-benzothiophene-1,1-dione was stirred at room temperature overnight. The reaction mixture was concentrated. Next, EtOH (1 mL) / HO (3 mL) and LiOH (15 mg, 3.2 mmol) were added. The resulting mixture was stirred at room temperature for 2 hours, diluted with water (15 mL), and extracted with EtOAc (10 mL*2). The combined organic phase was washed with brine, dried over NaSO, filtered, and concentrated. The residue was purified by chromatography (silica gel, 0-10%, MeOH in DCM) to give 6-({5-[(1s,4s)-4-hydroxycyclohexyl]-1-(2-methylprop-2-yl)pyrazol-3-yl}amino)-2,3-dihydro-1λ 6 -benzothiophene-1,1-dione (130 mg, 0.32 mmol, 79%) was obtained as a yellow solid. LCMS: m / z 404 [M+H] + .

[0416] Step C. (1s,4s)-4-{5-[(1,1-dioxo-2,3-dihydro-1λ 6 -benzo[b]thiophen-6-yl)amino]-2-(2-methylprop-2-yl)pyrazol-3-yl}cyclohexyl[(4-nitrophenyl)oxy]methanoate. 6-({5-[(1s,4s)-4-hydroxycyclohexyl]-1-(2-methylprop-2-yl)pyrazol-3-yl}amino)-2,3-dihydro-1λ in DCM (3 mL) / THF (3 mL). 6To a stirred solution of 1s,4s)-benzothiophene-1,1-dione (130 mg, 0.32 mmol) at room temperature, 4-nitrophenyl chloromethanoate (324 mg, 1.6 mmol), DMAP (13 mg, 0.11 mmol), and pyridine (2 mL, 24 mmol) were slowly added. After stirring overnight at room temperature, the cooled mixture was poured into water (30 mL) and extracted with EtOAc (20 mL*2). The combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by chromatography (silica gel, 0-10%, MeOH in DCM) to give (1s,4s)-4-{5-[(1,1-dioxo-2,3-dihydro-1λ]-4-(4-chloro-5-(1,1-dioxo-2,3-dihydro-1λ) ... 6 -benzothiophen-6-yl)amino]-2-(2-methylprop-2-yl)pyrazol-3-yl}cyclohexyl[(4-nitrophenyl)oxy]methanoate (170 mg, 0.3 mmol, 92%) was obtained as a yellow solid. LCMS: m / z 569 [M+H] + .

[0417] Step D. (1s,4s)-4-{5-[(1,1-dioxo-2,3-dihydro-1λ 6 -benzo[b]thiophen-6-yl)amino]-2-(2-methylprop-2-yl)pyrazol-3-yl}cyclohexyl(prop-2-ylamino)methanoate. (1s,4s)-4-{5-[(1,1-dioxo-2,3-dihydro-1λ 6 To a stirred solution of {(4-nitrophenyl)oxy}-2-(2-benzothiophen-6-yl)amino}-2-(2-methylprop-2-yl)pyrazol-3-yl}cyclohexyl[(4-nitrophenyl)oxy]methanoate (170 mg, 0.3 mmol) was slowly added DIPEA (0.5 mL, 0.2 mmol) and propan-2-amine (0.5 mL, 3 mmol) at room temperature. After stirring at room temperature for 1 h, the cooled mixture was poured into water (30 mL) and extracted with EtOAc (20 mL*2). The combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by chromatography (silica gel, 0–10%, MeOH in DCM) to give (1s,4s)-4-{5-[(1,1-dioxo-2,3-dihydro-1λ 6-benzothiophen-6-yl)amino]-2-(2-methylprop-2-yl)pyrazol-3-yl}cyclohexyl(prop-2-ylamino)methanoate (130 mg, 0.27 mmol, 89%) was obtained as a yellow oil. LCMS: m / z 489 [M+H] + .

[0418] Step E. (1s,4s)-4-{5-[(1,1-dioxo-2,3-dihydro-1λ 6 -benzo[b]thiophen-6-yl)amino]-2H-pyrazol-3-yl}cyclohexyl(prop-2-ylamino)methanoate. (1s,4s)-4-{5-[(1,1-dioxo-2,3-dihydro-1λ-benzo[b]thiophen-6-yl)amino]-2H-pyrazol-3-yl}cyclohexyl(prop-2-ylamino)methanoate. 6 A mixture of (1s,4s)-4-{5-[(1,1-dioxo-2,3-dihydro-1λ-benzothiophen-6-yl)amino]-2-(2-methylprop-2-yl)pyrazol-3-yl}cyclohexyl(prop-2-ylamino)methanoate (120 mg, 0.25 mmol) and (1s,4s)-4-{5-[(1,1-dioxo-2,3-dihydro-1λ-benzothiophen-6-yl)amino]-2-(2-methylprop-2-yl)pyrazol-3-yl}cyclohexyl(prop-2-ylamino)methanoate (120 mg, 0.25 mmol) was stirred at 100 °C for 5 h. The reaction mixture was concentrated. The residue was purified by preparative HPLC (C18, 40-90% MeCN in HO containing 0.1% TFA) and then by preparative TLC (DCM:MeOH = 10:1) to give (1s,4s)-4-{5-[(1,1-dioxo-2,3-dihydro-1λ-benzothiophen-6-yl)amino]-2-(2-methylprop-2-yl)pyrazol-3-yl}cyclohexyl(prop-2-ylamino)methanoate (120 mg, 0.25 mmol) and ( ... 6 -benzothiophen-6-yl)amino]-2H-pyrazol-3-yl}cyclohexyl(prop-2-ylamino)methanoate (18 mg, 0.042 mmol, 17%) was obtained as a white solid. LCMS: m / z 433.2 [M+H] + . 1 H NMR (400MHz, DMSO)δ 11.89(s, 1H), 8.88(s, 1H), 8.02(s, 1H), 7.43(dd, J=8.4, 1.6Hz, 1H), 7.35(d, J=8.4Hz, 1H), 6.96(d, J=7.2Hz, 1H), 5.65(s, 1H), 4.81(s, 1H), 3 .71-3.61(m, 1H), 3.58(dd, J=8.8, 4.8Hz, 2H), 3.26(t, J=6.8Hz, 2H), 2.74(s, 1H), 1.96-1.80(m, 4H), 1.80-1.60(m, 4H), 1.11(d, J=6.4Hz, 6H).

[0419] Example 28: (1s,3s)-3-(3-((2,2-dioxide-1,3-dihydrobenzo[c]thiophen-5-yl)amino)-1H-pyrazol-5-yl)cyclobutyl isopropylcarbamate [ka] Step A: 5-((1-(tert-butyl)-3-((1s,3s)-3-((tert-butyldiphenylsilyl)oxy)cyclobutyl)-1H-pyrazol-5-yl)amino)-1,3-dihydrobenzo[c]thiophene 2,2-dioxide. To a solution of 5-bromo-1,3-dihydrobenzo[c]thiophene 2,2-dioxide (450 mg, 1.82 mmol) in dioxane (15 mL) was added 1-(tert-butyl)-3-((1s,3s)-3-((tert-butyldiphenylsilyl)oxy)cyclobutyl)-1H-pyrazol-5-amine (200 mg, 0.447 mmol), CsCO (437 mg, 1.34 mmol), Pd(dba) (40.9 mg, 0.0450 mmol), and Xantphos (51.7 mg, 0.089 mmol). The reaction mixture was stirred at 100 °C under a N atmosphere for 1 h. LCMS detected the reaction was complete. The cooled reaction mixture was dissolved in EA (10 mL*3), washed with HO (20 mL) and brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (eluting with 0-50% EA in PE) to give 5-((1-(tert-butyl)-3-((1s,3s)-3-((tert-butyldiphenylsilyl)oxy)cyclobutyl)-1H-pyrazol-5-yl)amino)-1,3-dihydrobenzo[c]thiophene 2,2-dioxide (250 mg, 0.407 mmol, 91.2%) as a yellow solid. LCMS: ESI m / z 614.89 [M+H] + .

[0420] Step B: 5-((1-(tert-butyl)-3-((1s,3s)-3-hydroxycyclobutyl)-1H-pyrazol-5-yl)amino)-1,3-dihydrobenzo[c]thiophene 2,2-dioxide. A solution of 5-((1-(tert-butyl)-3-((1s,3s)-3-((tert-butyldiphenylsilyl)oxy)cyclobutyl)-1H-pyrazol-5-yl)amino)-1,3-dihydrobenzo[c]thiophene 2,2-dioxide (245 mg, 0.399 mmol) in formic acid (4 mL) was stirred at room temperature overnight. LCMS showed the reaction was complete. The solvent was removed in vacuo. Then, EtOH (2.5 mL), HO (2.5 mL), and lithium hydroxide monohydrate (50.2 mg, 1.20 mmol) were added to make the pH alkaline. The mixture was stirred at room temperature for 1 hour. LCMS showed the reaction was complete. The residue was dissolved in EA (5 mL*3), washed with HO (10 mL) and brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (eluted with 0-12% MeOH in DCM) to give 5-((1-(tert-butyl)-3-((1s,3s)-3-hydroxycyclobutyl)-1H-pyrazol-5-yl)amino)-1,3-dihydrobenzo[c]thiophene 2,2-dioxide (130 mg, 0.346 mmol, 86.8%) as a white solid. LCMS: ESI m / z 376.49 [M+H] + .

[0421] Step C: (1s,3s)-3-(1-(tert-butyl)-5-((2,2-dioxide-1,3-dihydrobenzo[c]thiophen-5-yl)amino)-1H-pyrazol-3-yl)cyclobutyl(4-nitrophenyl)carbonate. A suspension of 5-((1-(tert-butyl)-3-((1s,3s)-3-hydroxycyclobutyl)-1H-pyrazol-5-yl)amino)-1,3-dihydrobenzo[c]thiophene 2,2-dioxide (130 mg, 0.346 mmol), DMAP (4.23 mg, 0.0350 mmol), Py (0.0840 mL, 1.04 mmol), and 4-nitrophenyl chloromethanoate (349 mg, 1.73 mmol) in DCM (3 mL) and THF (3 mL) was stirred at room temperature for 3 h. The reaction was complete by LCMS. The solvent was removed under vacuum. The residue was dissolved in EA (5 mL*3), washed with HO (5 mL) and brine, dried over sodium sulfate, filtered, concentrated, and purified by silica gel chromatography (eluted with 0-12% MeOH in DCM) to give (1s,3s)-3-(1-(tert-butyl)-5-((2,2-dioxido-1,3-dihydrobenzo[c]thiophen-5-yl)amino)-1H-pyrazol-3-yl)cyclobutyl(4-nitrophenyl)carbonate (170 mg, 0.314 mmol, 90.8%) as a white solid. LCMS: ESI m / z 541.59 [M+H] + .

[0422] Step D: (1s,3s)-3-(5-((2,2-dioxide-1,3-dihydrobenzo[c]thiophen-5-yl)amino)-1H-pyrazol-3-yl)cyclobutyl(4-nitrophenyl)carbonate. A solution of (1s,3s)-3-(1-(tert-butyl)-5-((2,2-dioxide-1,3-dihydrobenzo[c]thiophen-5-yl)amino)-1H-pyrazol-3-yl)cyclobutyl(4-nitrophenyl)carbonate (170 mg, 0.314 mmol) in formic acid (4 mL) was stirred at 100° C. overnight. LCMS showed the reaction was complete. The cooled reaction mixture was concentrated to give crude (1s,3s)-3-(5-((2,2-dioxido-1,3-dihydrobenzo[c]thiophen-5-yl)amino)-1H-pyrazol-3-yl)cyclobutyl(4-nitrophenyl)carbonate (150 mg, 0.310 mmol, 98.4%) as a yellow oil. LCMS: ESI m / z 485.48 [M+H] + .

[0423] Step E: (1s,3s)-3-(3-((2,2-Dioxide-1,3-dihydrobenzo[c]thiophen-5-yl)amino)-1H-pyrazol-5-yl)cyclobutyl isopropylcarbamate. To a suspension of (1s,3s)-3-(5-((2,2-dioxide-1,3-dihydrobenzo[c]thiophen-5-yl)amino)-1H-pyrazol-3-yl)cyclobutyl(4-nitrophenyl)carbonate (150 mg, 0.310 mmol) in THF (4 mL) was added propan-2-amine (0.133 mL, 1.55 mmol) and DIEA (0.154 mL, 0.929 mmol). The reaction mixture was stirred at room temperature for 3 hours. LCMS showed the reaction was complete. The residue was dissolved in EA (5 mL*3), washed with HO (10 mL) and brine, dried over sodium sulfate, filtered, concentrated, and purified by silica gel chromatography (eluted with 0-12% MeOH in DCM) and preparative HPLC (C18, 15-95% MeCN in HO with 0.1% FA) to give (1s,3s)-3-(3-((2,2-dioxide-1,3-dihydrobenzo[c]thiophen-5-yl)amino)-1H-pyrazol-5-yl)cyclobutyl isopropylcarbamate (17.8 mg, 0.0440 mmol, 14.2%) as a white solid. LCMS: ESI m / z 405.49 [M+H] + . 1 H NMR (400MHz, DMSO)δ 8.55(s, 1H), 7.36(s, 1H), 7.21-7.13(m, 2H), 7.06(t, J=9.6Hz, 1H), 5.71(s, 1H), 4.79(dd, J=14.8, 7.6Hz, 1H), 4.41(s, 2H) , 4.33(s, 2H), 3.54-3.52(m, 1H), 3.12-3.00(m, 1H), 2.69-2.55(m, 2H), 2.08(dd, J=17.6, 9.2Hz, 2H), 1.04(d, J=6.4Hz, 6H).

[0424] Example 29: (1R,3S)-3-{5-[(1-cyano-2,3-dihydro-1H-inden-5-yl)amino]-2H-pyrazol-3-yl}cyclopentyl(prop-2-ylamino)methanoate [ka] Step A: 5-({5-[(1S,3R)-3-{[dimethyl(2-methylprop-2-yl)silyl]oxy}cyclopentyl]-2-(2-methylprop-2-yl)pyrazol-3-yl}amino)-2,3-dihydro-1H-indene-1-carbonitrile. To a solution of 5-bromo-2,3-dihydro-1H-indene-1-carbonitrile (200 mg, 0.901 mmol) in dioxane (10 mL) was added 5-[(1S,3R)-3-{[dimethyl(2-methylprop-2-yl)silyl]oxy}cyclopentyl]-2-(2-methylprop-2-yl)pyrazol-3-amine (304 mg, 0.901 mmol), CsCO (586 mg, 1.80 mmol), Xantphos (104 mg, 0.180 mmol), and Pd(dba) (82.5 mg, 0.090 mmol). The reaction mixture was stirred under N at 120 °C for 3 h. The cooled reaction mixture was diluted with EA and water. The organic layer was separated, washed with brine, and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluted with ethyl acetate in petroleum ether) to give the title compound 5-({5-[(1S,3R)-3-{[dimethyl(2-methylprop-2-yl)silyl]oxy}cyclopentyl]-2-(2-methylprop-2-yl)pyrazol-3-yl}amino)-2,3-dihydro-1H-indene-1-carbonitrile (190 mg, 0.397 mmol, 44.0%) as a yellow oil. LCMS: ESI m / z 479 [M+H] + .

[0425] Step B: 5-({5-[(1S,3R)-3-Hydroxycyclopentyl]-2-(2-methylprop-2-yl)pyrazol-3-yl}amino)-2,3-dihydro-1H-indene-1-carbonitrile. A mixture of 5-({5-[(1S,3R)-3-{[dimethyl(2-methylprop-2-yl)silyl]oxy}cyclopentyl]-2-(2-methylprop-2-yl)pyrazol-3-yl}amino)-2,3-dihydro-1H-indene-1-carbonitrile (140 mg, 0.292 mmol) in formic acid (5 mL) was stirred at room temperature for 1 hour and then concentrated under reduced pressure. The residue was treated with a mixture of lithium hydroxide hydrate (24.5 mg, 0.584 mmol) in MeOH (5 mL) / HO (1 mL). The resulting mixture was stirred at room temperature for 1 hour and then concentrated under reduced pressure. The residue was poured into water and extracted with EtOAc. The combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by chromatography to give 5-({5-[(1S,3R)-3-hydroxycyclopentyl]-2-(2-methylprop-2-yl)pyrazol-3-yl}amino)-2,3-dihydro-1H-indene-1-carbonitrile (65 mg, 0.178 mmol, 60.9%) as a colorless oil. LCMS: ESI m / z 365 [M+H] + .

[0426] Step C: (1R,3S)-3-{5-[(1-cyano-2,3-dihydro-1H-inden-5-yl)amino]-1-(2-methylprop-2-yl)pyrazol-3-yl}cyclopentyl[(4-nitrophenyl)oxy]methanoate. To a solution of 5-({5-[(1S,3R)-3-hydroxycyclopentyl]-2-(2-methylprop-2-yl)pyrazol-3-yl}amino)-2,3-dihydro-1H-indene-1-carbonitrile (80 mg, 0.219 mmol) in DCM (2 mL) and THF (2 mL) was added 4-nitrophenyl chloromethanoate (176 mg, 0.878 mmol), Py (0.053 mL, 0.657 mmol), and DMAP (2.68 mg, 0.022 mmol). The reaction mixture was stirred at 25° C. for 2 hours. The reaction solution was diluted with EA, washed with water and brine, dried over anhydrous NaSO, and concentrated. The residue was purified by flash chromatography to give (1R,3S)-3-{5-[(1-cyano-2,3-dihydro-1H-inden-5-yl)amino]-1-(2-methylprop-2-yl)pyrazol-3-yl}cyclopentyl[(4-nitrophenyl)oxy]methanoate (40 mg, 0.076 mmol, 34.41%) as a yellow oil. LCMS: ESI m / z 530 [M+H] + .

[0427] Step D: (1R,3S)-3-{5-[(1-cyano-2,3-dihydro-1H-inden-5-yl)amino]-1H-pyrazol-3-yl}cyclopentyl[(4-nitrophenyl)oxy]methanoate. A solution of (1R,3S)-3-{5-[(1-cyano-2,3-dihydro-1H-inden-5-yl)amino]-1-(2-methylprop-2-yl)pyrazol-3-yl}cyclopentyl[(4-nitrophenyl)oxy]methanoate (40 mg, 0.076 mmol) in formic acid (5 mL) was stirred at 100° C. for 48 hours. The cooled reaction mixture was concentrated to give (1R,3S)-3-{5-[(1-cyano-2,3-dihydro-1H-inden-5-yl)amino]-1H-pyrazol-3-yl}cyclopentyl[(4-nitrophenyl)oxy]methanoate (25 mg, 0.053 mmol, 69.9%) as a yellow oil. LCMS: ESI m / z 474 [M+H] + .

[0428] Step E: (1R,3S)-3-{5-[(1-cyano-2,3-dihydro-1H-inden-5-yl)amino]-2H-pyrazol-3-yl}cyclopentyl(prop-2-ylamino)methanoate. To a solution of (1R,3S)-3-{5-[(1-cyano-2,3-dihydro-1H-inden-5-yl)amino]-1H-pyrazol-3-yl}cyclopentyl[(4-nitrophenyl)oxy]methanoate (25 mg, 0.053 mmol) in THF (3 mL) was added propan-2-amine (0.014 mL, 0.158 mmol), and the reaction was stirred at room temperature for 1 hour. The reaction was concentrated in vacuo. The residue was purified by preparative HPLC to give the title compound (1R,3S)-3-{5-[(1-cyano-2,3-dihydro-1H-inden-5-yl)amino]-2H-pyrazol-3-yl}cyclopentyl(prop-2-ylamino)methanoate (1.5 mg, 0.004 mmol, 7.22%) as a white solid. LCMS: ESI m / z 394 [M+H] + . 1H NMR (400MHz, DMSO)δ 11.68(s, 1H), 8.34(s, 1H), 7.33(s, 1H), 7.15(s, 2H), 6.95(d, J=6.8Hz, 1H) , 5.61(s, 1H), 4.98(s, 1H), 4.26(t, J=7.6Hz, 1H), 3.64-3.53(m, 1H), 3.08- 2.98(m, 1H), 2.98-2.77(m, 2H), 2.49-2.41(m, 2H), 2.27-2.13(m, 1H), 2.05 -1.95(m, 1H), 1.94-1.83(m, 1H), 1.75-1.52(m, 3H), 1.03(d, J=6.4Hz, 6H).

[0429] Example 30: (1R,3S)-3-{5-[(2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)amino]-1H-pyrazol-3-yl}cyclopentyl(prop-2-ylamino)methanoate [ka] Step A: 6-Bromo-1-[(4-methoxyphenyl)methyl]-1,2,3,4-tetrahydroquinolin-2-one. To a solution of 6-bromo-1,2,3,4-tetrahydroquinolin-2-one (1000 mg, 4.42 mmol) in DMF (10 mL) was added CsCO (2.88 g, 8.84 mmol), 1-(chloromethyl)-4-methoxybenzene (0.9 mL, 6.63 mmol), and the reaction mixture was stirred at 50 °C for 2 h. The cooled reaction mixture was diluted with HO and extracted with EA. The organic layer was washed with brine, dried over NaSO, filtered, and concentrated. The residue was purified by silica gel column chromatography (eluting with EA in PE [gradient: 0-50%]) to obtain the title compound 6-bromo-1-[(4-methoxyphenyl)methyl]-1,2,3,4-tetrahydroquinolin-2-one (1.17 g, 3.37 mmol, 76.4%) as a white solid. LCMS: ESI m / z 348 [M+H] + .

[0430] Step B: 6-({5-[(1S,3R)-3-hydroxycyclopentyl]-2-(2-methylprop-2-yl)pyrazol-3-yl}amino)-1-[(4-methoxyphenyl)methyl]-1,2,3,4-tetrahydroquinolin-2-one. To a solution of (1R,3S)-3-[5-amino-1-(2-methylprop-2-yl)pyrazol-3-yl]cyclopentan-1-ol (500 mg, 2.24 mmol) in dioxane (10 mL) was added CsCO (1.45 g, 4.48 mmol), 6-bromo-1-[(4-methoxyphenyl)methyl]-1,2,3,4-tetrahydroquinolin-2-one (1.16 g, 3.36 mmol), Pd(dba) (205 mg, 0.22 mmol), and Xantphos (259 mg, 0.45 mmol). The reaction mixture was stirred overnight at 100 °C under N. The cooled reaction mixture was diluted with HO and extracted with EA. The organic phase was washed with brine, dried over NaSO, filtered, and concentrated. The residue was purified by silica gel column chromatography (eluting with EA in PE [gradient: 0-100%]) to give the title compound 6-({5-[(1S,3R)-3-hydroxycyclopentyl]-2-(2-methylprop-2-yl)pyrazol-3-yl}amino)-1-[(4-methoxyphenyl)methyl]-1,2,3,4-tetrahydroquinolin-2-one (200 mg, 0.41 mmol, 18.2%) as a white solid. LCMS: ESI m / z 489 [M+H] + .

[0431] Step C: (1R,3S)-3-[5-({1-[(4-methoxyphenyl)methyl]-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl}amino)-1-(2-methylprop-2-yl)pyrazol-3-yl]cyclopentyl[(4-nitrophenyl)oxy]methanoate. To a solution of 6-({5-[(1S,3R)-3-hydroxycyclopentyl]-2-(2-methylprop-2-yl)pyrazol-3-yl}amino)-1-[(4-methoxyphenyl)methyl]-1,2,3,4-tetrahydroquinolin-2-one (150 mg, 0.307 mmol) in DCM (5 mL) was added 4-nitrophenyl chloromethanoate (92.8 mg, 0.460 mmol), pyridine (0.050 mL, 0.614 mmol), and DMAP (3.75 mg, 0.031 mmol). The reaction mixture was stirred at 40° C. for 4 hours and then concentrated. The residue was purified by silica gel column chromatography (eluting with EA in PE [gradient: 0-100%]) to obtain the compound (1R,3S)-3-[5-({1-[(4-methoxyphenyl)methyl]-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl}amino)-1-(2-methylprop-2-yl)pyrazol-3-yl]cyclopentyl[(4-nitrophenyl)oxy]methanoate (125 mg, 0.191 mmol, 62.2%) as a white solid. LCMS: ESI m / z 654 [M+H] + .

[0432] Step D: (1R,3S)-3-{5-[(2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)amino]-1H-pyrazol-3-yl}cyclopentyl[(4-nitrophenyl)oxy]methanoate. A solution of (1R,3S)-3-[5-({1-[(4-methoxyphenyl)methyl]-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl}amino)-1-(2-methylprop-2-yl)pyrazol-3-yl]cy...

Claims

1. Compounds having structural formula I, 【Chemistry 1】 or a pharmaceutically acceptable form thereof or an isotope derivative thereof, During the ceremony, Ring A is a 4- to 7-membered carbon ring. R 1 and R 2 These are H and C, which are independent of each other. 1 ~C 6 Alkyl and C 3 ~C 6 Selected from the group consisting of carbon rings, or R 1 and R 2 These combine with the N atoms to which they are bonded to form a 4- to 7-membered heterocycle. Each R 3 is independently selected from the group consisting of halogen, OH, CN, C 1 to 6 alkyl, C 1 to 6 alkoxy, NO 2 , NRR', or two Rs 3 together with the carbon atom(s) to which they are attached form a 3- to 5-membered carbocyclic ring R 4 H, halogen, C 1 ~ 4 Alkyl, CN, NRR' or C(O)NRR', R 5 teeth, 【Chemistry 2】 And, During the ceremony, Ring B is -S(O) 2 -, -C(O)-, -S(O) 2 NR-, -S(O) 2 A 4- to 7-membered carbon ring or heterocycle optionally containing an NRC(O)-, -C(O)NR-, -OC(O)NR-, or -C(O)NRC(O)- group, α and β are R 5 This refers to a position where it can be bonded to the rest of the compound. j is 0, 1, 2, or 3. Y 1 and Y 2 These are CR 6 Or N, Y 3 CR 6 or N, where Y 1 , Y 2 , and Y 3 One or fewer of these is N, Each R 6 These are halogens, OH, CN, and C 1 ~ 6 Alkyl, C 1 ~ 4 Independently selected from the group consisting of alkoxys and C(O)NRR', Each R 7 These are halogen, OR, CN, C 1 ~ 6 Alkyl and C 1 ~ 4 Independently selected from the group consisting of alkoxys, or two R 7 These, together with the carbon atoms (or more) to which they are bonded, form a 3- to 6-membered carbon ring or heterocycle. R and R' are independent of H and C, respectively. 1 ~ 6 Selected from alkyl groups or 4-6 membered carbon rings, or R and R' are bonded together with the same N atom to form a 4-6 membered heterocycle. i is 0, 1, 2, 3, 4, or 5. k is 0, 1, 2, 3, 4, or 5. At each occurrence, C 1 to C 6 alkyl, C 3 to C 6 carbocyclic ring, 4- to 7-membered heterocyclic ring, C 1 to 6 alkoxy, 3- to 5-membered carbocyclic ring, C 1 to 4 alkoxy, 3- to 6-membered carbocyclic or heterocyclic ring, 4- to 6-membered carbocyclic ring, and 4- to 6-membered heterocyclic ring are each optionally and independently halogen, oxo, CN, -COOH, -CH 2 CN, -O-C 1 to C 6 alkyl, C 1 to C 6 alkyl, -OC 1 to C 6 alkenyl, -OC 1 to C 6 alkynyl, -C 1 to C 6 alkenyl, -C 1 to C 6 alkynyl, -OH, -OP(O)(OH) 2 ,-OC(O)C 1 to C 6 alkyl, -C(O)C 1 to C 6 alkyl, -OC(O)OC 1 to C 6 alkyl, NH 2 , NH(C 1 to C 6 alkyl), N(C 1 to C 6 alkyl) 2 , -NHC(O)C 1 to C 6 alkyl, -C(O)NHC 1 to C 6 alkyl, -S(O) 2 -C 1 to C 6 alkyl, -S(O)NHC 1 to C 6 alkyl and S(O)N(C 1 to C 6 alkyl) 2 A compound having the structural formula I, or a pharmaceutically acceptable form thereof, or an isotope derivative thereof, substituted with a group selected from the above.

2. Y 1 , Y 2 , and Y 3 The compound according to claim 1, or a pharmaceutically acceptable form thereof or isotope derivative thereof, wherein only one of the elements is N.

3. R 5 teeth, 【Transformation 3】 A compound according to claim 1, or a pharmaceutically acceptable form thereof, or an isotope derivative, selected from the above.

4. Ring B is, 【Chemistry 4】 Selected from, During the ceremony, X 1 、 X 2 、 X 3 、 X 4 and X 5 are each independently S(O) 2 、 C(O), NH, CH 2 and O, provided that Two adjacent X 1 , X 2 , X 3 , X 4 or X 5 These are S(O) respectively 2 Not selected from C(O), Two adjacent X 1 , X 2 , X 3 , X 4 or X 5 Each of the following compounds is not selected from NH and O, and is a compound according to any one of claims 1 to 3, or a pharmaceutically acceptable form thereof or an isotope derivative thereof.

5. R 5 teeth, 【Transformation 5】 Selected from, In the formula, X 1 ~X 5 The compound according to claim 1, or a pharmaceutically acceptable form thereof, or an isotope derivative thereof, as defined in claim 4.

6. Two R's 7 These atoms, together with the carbon atoms to which they are bonded, form a 3-6 membered carbon ring, or a 3-6 membered heterocycle containing one or more ring heteroatoms selected from O, S, and N, and the 3-6 membered carbon ring and the 3-6 membered heterocycle can each be optionally a halogen, oxo, CN, -COOH, or -CH 2 CN, -O-C 1 ~C 6 Alkyl, C 1 ~C 6 Alkyl, -OC 1 ~C 6 Alkenyl, -OC 1 ~C 6 Alkinyl, -C 1 ~C 6 Alkenyl, -C 1 ~C 6 Alkinyl, -OH, -OP(O)(OH) 2 , -OC(OC)C 1 ~C 6 Alkyl, -C(O)C 1 ~C 6 Alkyl, -OC(O)OC 1 ~C 6 Alkyl, NH 2 NH(C 1 ~C 6 Alkyl), N (C 1 ~C 6 Alkyl) 2 ,-NHC(O)C 1 ~C 6 Alkyl, -C(O)NHC 1 ~C 6 Alkyl, -S(O) 2 -C 1 ~C 6 Alkyl, -S(O)NHC 1 ~C 6 Alkyl and S(O)N(C) 1 ~C 6 Alkyl) 2 The compound according to claim 5, or a pharmaceutically acceptable form thereof, or an isotope derivative thereof, which is substituted with a group selected from the above.

7. R 5 teeth, 【Transformation 6】 【Transformation 7】 【Transformation 8】 Selected from, In the formula, Y 1 , Y 2 and Y 4 The compound according to claim 1, or a pharmaceutically acceptable form thereof, or an isotope derivative thereof, wherein each is CH.

8. R 5 teeth, 【Chemistry 9】 【Chemistry 10】 【Chemistry 11】 A compound according to claim 1, or a pharmaceutically acceptable form thereof, or an isotope derivative, selected from the above.

9. (1) Y 1 N, Y 2 CH, Y 3 (2) Y 1 CH, Y 2 N, Y 3 ga CH (3) Y 1 CH, Y 2 CH, Y 3 (4) Y 1 , Y 2 and Y 3 The compound according to claim 8, or a pharmaceutically acceptable form thereof or an isotope derivative thereof, wherein each of the members is CH.

10. (1) R 1 H is R 2 However, optionally, halogen, oxo, CN, -COOH, -CH 2 CN, -O-C 1 ~C 6 Alkyl, C 1 ~C 6 Alkyl, -OC 1 ~C 6 Alkenyl, -OC 1 ~C 6 Alkinyl, -C 1 ~C 6 Alkenyl, -C 1 ~C 6 Alkinyl, -OH, -OP(O)(OH) 2 , -OC(OC)C 1 ~C 6 Alkyl, -C(O)C 1 ~C 6 Alkyl, -OC(O)OC 1 ~C 6 Alkyl, NH 2 NH(C 1 ~C 6 Alkyl), N (C 1 ~C 6 Alkyl) 2 ,-NHC(O)C 1 ~C 6 Alkyl, -C(O)NHC 1 ~C 6 Alkyl, -S(O) 2 -C 1 ~C 6 Alkyl, -S(O)NHC 1 ~C 6 Alkyl and S(O)N(C) 1 ~C 6 Alkyl) 2 Linear or branched C, substituted with a group selected from the above. 1 ~C 6 It is alkyl. (2) R 1 and R 2 Each of these can be selected independently and arbitrarily as follows: halogen, oxo, CN, -COOH, -CH 2 CN, -O-C 1 ~C 6 Alkyl, C 1 ~C 6 Alkyl, -OC 1 ~C 6 Alkenyl, -OC 1 ~C 6 Alkinyl, -C 1 ~C 6 Alkenyl, -C 1 ~C 6 Alkinyl, -OH, -OP(O)(OH) 2 , -OC(OC)C 1 ~C 6 Alkyl, -C(O)C 1 ~C 6 Alkyl, -OC(O)OC 1 ~C 6 Alkyl, NH 2 NH(C 1 ~C 6 Alkyl), N (C 1 ~C 6 Alkyl) 2 ,-NHC(O)C 1 ~C 6 Alkyl, -C(O)NHC 1 ~C 6 Alkyl, -S(O) 2 -C 1 ~C 6 Alkyl, -S(O)NHC 1 ~C 6 Alkyl and S(O)N(C) 1 ~C 6 Alkyl) 2 Linear or branched C, substituted with a group selected from the above. 1 ~C 6 Alkyl, or (3) Caution 1 and R 2 These bonds with the N atom to which they are bonded, and optionally form halogens, oxo, CN, -COOH, and -CH 2 CN, -O-C 1 ~C 6 Alkyl, C 1 ~C 6 Alkyl, -OC 1 ~C 6 Alkenyl, -OC 1 ~C 6 Alkinyl, -C 1 ~C 6 Alkenyl, -C 1 ~C 6 Alkinyl, -OH, -OP(O)(OH) 2 , -OC(OC)C 1 ~C 6 Alkyl, -C(O)C 1 ~C 6 Alkyl, -OC(O)OC 1 ~C 6 Alkyl, NH 2 NH(C 1 ~C 6 Alkyl), N (C 1 ~C 6 Alkyl) 2 ,-NHC(O)C 1 ~C 6 Alkyl, -C(O)NHC 1 ~C 6 Alkyl, -S(O) 2 -C 1 ~C 6 Alkyl, -S(O)NHC 1 ~C 6 Alkyl and S(O)N(C) 1 ~C 6 Alkyl) 2 The compound according to claim 1, or a pharmaceutically acceptable form thereof or an isotope derivative thereof, which forms a 4- to 7-membered heterocycle substituted with a group selected from the above.

11. Ring A is, 【Chemistry 12】 A compound according to claim 1, or a pharmaceutically acceptable form thereof, or an isotope derivative, selected from the above.

12. Ring A is, 【Chemistry 13】 A compound according to claim 11, or a pharmaceutically acceptable form thereof, or an isotope derivative, selected from the above.

13. The compound according to claim 1, or a pharmaceutically acceptable form thereof or an isotope derivative thereof, wherein ring A is a five-membered carbon ring.

14. Ring A is, 【Chemistry 14】 The compound according to claim 13, or a pharmaceutically acceptable form thereof, or an isotope derivative thereof.

15. A compound according to any one of claims 11 to 14, or a pharmaceutically acceptable form thereof or an isotope derivative thereof, wherein i is 0.

16. A compound according to claim 1, having the following structural formula, or a pharmaceutically acceptable form thereof, or an isotope derivative thereof. 【Chemistry 15】

17. (1) Y 1 N, Y 2 CH, Y 3 (2) Y 1 CH, Y 2 N, Y 3 (3) Y 1 CH, Y 2 CH, Y 3 The compound according to claim 16, or a pharmaceutically acceptable form thereof or an isotope derivative thereof, wherein is N.

18. The compound according to claim 16 or 17, or a pharmaceutically acceptable form thereof or an isotope derivative thereof, wherein ring B is (1) a five-membered or six-membered carbon ring, or a five-membered or six-membered heterocycle.

19. Ring B is (1)-S(O) 2 NH- group, (2)-S(O) 2 - group, (3) -C(O)NH- group, (4) CH 2 (5) A group comprising a C(CN)R" group, where R" is H, OH, or C 1 ~ 4 Alkyl or O-C 1 ~ 4 The compound according to claim 18, or a pharmaceutically acceptable form thereof or an isotope derivative thereof, which is alkyl.

20. The compound according to claim 16, or a pharmaceutically acceptable form thereof or an isotope derivative thereof, wherein k is 0, 1, or 2.

21. R 7 However, optionally, halogen, oxo, CN, -COOH, -CH 2 CN, -O-C 1 ~C 6 Alkyl, C 1 ~C 6 Alkyl, -OC 1 ~C 6 Alkenyl, -OC 1 ~C 6 Alkinyl, -C 1 ~C 6 Alkenyl, -C 1 ~C 6 Alkinyl, -OH, -OP(O)(OH) 2 , -OC(OC)C 1 ~C 6 Alkyl, -C(O)C 1 ~C 6 Alkyl, -OC(O)OC 1 ~C 6 Alkyl, NH 2 NH(C 1 ~C 6 Alkyl), N (C 1 ~C 6 Alkyl) 2 ,-NHC(O)C 1 ~C 6 Alkyl, -C(O)NHC 1 ~C 6 Alkyl, -S(O) 2 -C 1 ~C 6 Alkyl, -S(O)NHC 1 ~C 6 Alkyl and S(O)N(C) 1 ~C 6 Alkyl) 2 Substituted with a group selected from C 1 ~ 6 The compound according to claim 20, or a pharmaceutically acceptable form thereof or an isotope derivative thereof, which is alkyl.

22. The aforementioned compound is as follows: 【Chemistry 16】 【Chemistry 17】 [Chemistry 18] 【Chemistry 19】 【Chemistry 20】 【Chemistry 21】 【Chemistry 22】 【Chemistry 23】 【Chemistry 24】 【Chemistry 25】 【Chemistry 26】 【Chemistry 27】 【Chemistry 28】 【Chemistry 29】 【Transformation 30】 【Chemistry 31】 【Chemistry 32】 【Transformation 33】 【Transformation 34】 【Chemistry 35】 【Transformation 36】 【Chemistry 37】 【Transformation 38】 【Chemistry 39】 【Chemistry 40】 A compound according to claim 1, or a pharmaceutically acceptable form thereof, or an isotope derivative, selected from the above.

23. The aforementioned compound, 【Chemistry 41】 The compound according to claim 1, or a pharmaceutically acceptable form thereof, or a pharmaceutically acceptable form thereof or an isotope derivative.

24. The aforementioned compound, 【Chemistry 42】 The compound according to claim 1, or a pharmaceutically acceptable form thereof, or a pharmaceutically acceptable form thereof or an isotope derivative.

25. The aforementioned compound, 【Chemistry 43】 The compound according to claim 1, or a pharmaceutically acceptable form thereof, or a pharmaceutically acceptable form thereof or an isotope derivative.

26. The aforementioned compound, 【Chemistry 44】 The compound according to claim 1, or a pharmaceutically acceptable form thereof, or a pharmaceutically acceptable form thereof or an isotope derivative.

27. The aforementioned compound, 【Chemistry 45】 The compound according to claim 1, or a pharmaceutically acceptable form thereof, or a pharmaceutically acceptable form thereof or an isotope derivative.

28. The aforementioned compound, 【Chemistry 46】 The compound according to claim 1, or a pharmaceutically acceptable form thereof, or a pharmaceutically acceptable form thereof or an isotope derivative.

29. The aforementioned compound, 【Chemistry 47】 The compound according to claim 1, or a pharmaceutically acceptable form thereof, or a pharmaceutically acceptable form thereof or an isotope derivative.

30. The aforementioned compound, 【Chemistry 48】 The compound according to claim 1, or a pharmaceutically acceptable form thereof, or a pharmaceutically acceptable form thereof or an isotope derivative.

31. The aforementioned compound, 【Chemistry 49】 The compound according to claim 1, or a pharmaceutically acceptable form thereof, or a pharmaceutically acceptable form thereof or an isotope derivative.

32. The aforementioned compound, [Transformation 50] The compound according to claim 1, or a pharmaceutically acceptable form thereof, or a pharmaceutically acceptable form thereof or an isotope derivative.

33. The aforementioned compound, 【Chemistry 51】 The compound according to claim 1, or a pharmaceutically acceptable form thereof, or a pharmaceutically acceptable form thereof or an isotope derivative.

34. The aforementioned compound, 【Chemistry 52】 The compound according to claim 1, or a pharmaceutically acceptable form thereof, or a pharmaceutically acceptable form thereof or an isotope derivative.

35. The aforementioned compound, 【Chemistry 53】 The compound according to claim 1, or a pharmaceutically acceptable form thereof, or a pharmaceutically acceptable form thereof or an isotope derivative.

36. The aforementioned compound, 【Chemistry 54】 The compound according to claim 1, or a pharmaceutically acceptable form thereof, or a pharmaceutically acceptable form thereof or an isotope derivative.

37. The aforementioned compound, 【Transformation 55】 The compound according to claim 1, or a pharmaceutically acceptable form thereof, or a pharmaceutically acceptable form thereof or an isotope derivative.

38. A compound according to any one of claims 1 and 22 to 37, or a pharmaceutically acceptable form thereof or an isotope derivative thereof, having one or more deuterium atoms instead of hydrogen.

39. A pharmaceutical composition comprising a compound according to any one of claims 1 and 22 to 38, or a pharmaceutically acceptable form thereof or an isotope derivative thereof, and a pharmaceutically acceptable excipient, carrier, or diluent.

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