Aniline-pyrazole derivatives, compositions and methods thereof

Abstract

The present invention provides novel anilino-pyrazole derivatives that are inhibitors of cyclin dependent kinase 2 (CDK2). The invention also provides pharmaceutical compositions comprising the compounds, and methods for their use in the treatment of various conditions, diseases, and conditions associated with or associated with CDK2 activity or associated with abnormal cell growth, such as tumor growth and cancer.

Description

[0001] Priority claim and related applications

[0002] This application claims the benefit of priority to U.S. Provisional Application No. 63 / 352,872, filed June 16, 2022, and U.S. Provisional Application No. 63 / 407,247, filed September 16, 2022, the entire contents of each of which are incorporated herein by reference for all purposes. Technical Field

[0003] The present invention generally relates to novel compounds and their therapeutic uses. More particularly, the present invention provides novel anilino-pyrazole derivatives that are inhibitors of cyclin-dependent kinase 2 (CDK2). The present invention also provides pharmaceutical compositions comprising the compounds, as well as methods for their use in 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 of the Invention

[0005] Many aggressive cancers overexpress and / or amplify the cyclin E gene (CCNE). Amplification of CCNE is associated with poor 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 part of the abnormal growth process of cancer cells. Growing evidence suggests that CDK2 plays a key role in tumorigenesis. Overexpression of CDK2 can cause dysregulation of the cell cycle, leading to excessive proliferation of cancer cells. Therefore, selective CDK2 inhibition may provide therapeutic benefits against 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).

[0006] Although several small molecule CDK2 inhibitors have advanced to clinical trials, the demand for CDK2 selectivity is extremely high. Due to the high similarity between the active sites of CDK2 and other CDKs, especially CDK1, identifying selective CDK2 inhibitors has been challenging. Because CDK1 is an essential cyclin-dependent kinase in the cell cycle, CDK1 inhibition can cause serious side effects. (Wood et al., 2018 Cell Chem. Biol. 26(1):121-130.e5; Brown et al., 2015 Nature Comm. 6:6769).

[0007] There is an urgent need for potent and selective CDK2 inhibitors, in particular, compounds that are useful for treating diseases and conditions associated with overexpression of CCNE and CDK2, such as various types of cancer (eg, gynecological cancers, breast cancer, and gastric cancer). Summary of the Invention

[0008] The present invention provides novel CDK2 inhibitors that have been shown to exhibit favorable efficacy and selectivity profiles compared to known CDK2 inhibitors. The novel compounds selectively target, bind to, and inhibit CDK2 activity, and cause cell cycle arrest, induce apoptosis, and inhibit tumor cell proliferation. The compounds are also orally administrable and have pharmacokinetic profiles suitable for development into orally administered therapeutics for the treatment of cancers (e.g., breast, ovarian, gastric, or lung cancers).

[0009] In one aspect, the present invention generally relates to a compound having structural formula I:

[0010]

[0011] or a pharmaceutically acceptable form or isotopic derivative thereof,

[0012] in

[0013] Ring A is a 4- to 7-membered (e.g., 4-, 5-, 6-, or 7-membered) carbocyclic ring;

[0014] R 1 and R 2 Each of R is 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 join together with the nitrogen atom to which they are bound to form a 4- to 7-membered (e.g., 4-, 5-, 6-, or 7-membered) unsubstituted or substituted heterocyclic ring;

[0015] Each R 3 are independently selected from the group consisting of halogen, OH, CN, unsubstituted or substituted C1-6 Alkyl, unsubstituted or substituted C 1-6 Alkoxy, NO2, NRR', or two R 3 together with the carbon atoms to which they are attached, form a 3- to 5-membered (e.g., 3-, 4-, or 5-membered) unsubstituted or substituted carbocyclic ring;

[0016] R 4 It is H, halogen, C 1-4 Alkyl, CN, NRR' or C(O)NRR';

[0017] R 5 yes

[0018]

[0019] in

[0020] 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)2-, -C(O)-, -S(O)2NR-, -S(O)2NRC(O)-, -C(O)NR-, -OC(O)NR-, or -C(O)NRC(O)- group;

[0021] Y 1 and Y 2 Each of them is CR 6 or N and Y 3 and Y 4 Each of C, CR 6 or N; the constraint is Y 1 、Y 2 、Y 3 and Y 4 No more than one of them is N, and Y 3 or Y 4 is C and is R 5 positions where bonding to the rest of the compound is possible;

[0022] Each R 6 are independently selected from the group consisting of halogen, OH, CN, unsubstituted or substituted C 1-6 Alkyl, unsubstituted or substituted C 1-4 Alkoxy and C(O)NRR';

[0023] Each R 7 are independently selected from the group consisting of halogen, OR, CN, unsubstituted or substituted C 1-6 Alkyl and unsubstituted or substituted C 1-4 Alkoxy, or two R 7together 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 carbocyclic or heterocyclic ring;

[0024] Each of R and R' is independently selected from H, unsubstituted or substituted C 1-6 alkyl or an unsubstituted or substituted 4- to 6-membered (e.g., 4-, 5-, or 6-membered) carbocyclic ring, or wherein R and R' are attached to the same N atom and together form an unsubstituted or substituted 4- to 6-membered (e.g., 4-, 5-, or 6-membered) heterocyclic ring;

[0025] i is 0, 1, 2, 3, 4, or 5; and

[0026] k is 0, 1, 2, 3, 4 or 5.

[0027] In another aspect, the present invention generally relates to a pharmaceutical composition comprising a compound disclosed herein and a pharmaceutically acceptable excipient, carrier, or diluent.

[0028] In another aspect, the present invention generally relates to a unit dosage form comprising a pharmaceutical composition disclosed herein.

[0029] In another aspect, the present invention generally relates to a method for treating or ameliorating cancer or a related disease or condition, comprising administering to a subject in need thereof a therapeutically effective amount of a compound disclosed herein.

[0030] In another aspect, the present invention generally relates to the use of a compound disclosed herein and a pharmaceutically acceptable excipient, carrier, or diluent for the preparation of a medicament for treating a disease or condition.

[0031] definition

[0032] Unless defined otherwise, 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 organic chemistry principles as well as specific functional moieties and reactivities are described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 2006.

[0033] As used herein, "at least" a particular value is to be understood to mean that value and all values ​​greater than that value.

[0034] When used to define compositions and methods, the term "comprising" is intended to mean that the compositions and methods include the elements described, but do not exclude other elements. When used to define compositions and methods, the term "consisting essentially of shall mean that the compositions and methods include the elements described and exclude other elements that are of any importance to the compositions and methods. For example, "consisting essentially of" refers to the use of pharmacologically active agents that are clearly described and excludes pharmacologically active agents that are not clearly described. The term "consisting essentially of" does not exclude pharmacologically inactive or inert agents, such as pharmaceutically acceptable excipients, carriers, or diluents. When used to define compositions and methods, the term "consisting of" shall mean excluding trace elements and substantial method steps of other ingredients. Embodiments defined by each of these transition terms are within the scope of the present invention.

[0035] Unless expressly stated or obvious from the context, as used herein, the term "about" should be understood as within the normal tolerance range in the art, for example, within 2 standard deviations of the mean. Approximately 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 the context clearly indicates otherwise, all numerical values ​​provided herein may be modified by the term about.

[0036]

[0026] In this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

[0037] As used herein, the terms "administration" or "administering" a disclosed compound encompasses delivering a compound as described herein, or a prodrug or other pharmaceutically acceptable form thereof, to a subject using any suitable formulation or route of administration as discussed herein.

[0038] As used herein, the term "co-administration" refers to the simultaneous presence of two pharmacological agents in a subject's body (eg, in the blood). The two pharmacological agents can be administered simultaneously or sequentially.

[0039] Unless otherwise indicated, the terms "disease," "disorder," and "condition" are used interchangeably.

[0040] 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 achieve the intended application, including but not limited to disease treatment as described below.

[0041] In some embodiments, the amount is an amount effective to prevent the progression of an inflammatory disease or condition or to achieve a reduction in an inflammatory disease or condition. In some embodiments, the amount is an amount effective to prevent the progression of an immune system condition or to achieve a reduction in an immune system condition. In some embodiments, the amount is an amount effective to prevent the progression of an autoimmune disease or condition or to achieve a reduction in an autoimmune disease or condition. In some embodiments, the amount is an amount effective to prevent the progression of a cardiovascular disease or condition or to achieve a reduction in a cardiovascular disease or condition. In some embodiments, the amount is an amount effective for: detectably killing cancer cells or inhibiting the growth or spread of cancer cells; the size or number of tumors; or other measures of the level, stage, progression, or severity of cancer. In some embodiments, the amount is an amount effective to prevent the progression of PPD, depression, insomnia, sleep apnea, restless legs syndrome and narcolepsy, mood disorders, depression, schizophrenia, bipolar disorder, obsessive-compulsive disorder and other anxiety disorders, behavioral and pharmacological syndromes of dementia, or neurodegenerative diseases or to achieve a reduction in the disease. In some embodiments, the amount is an amount effective to prevent the progression of Parkinson's disease (PD) or to achieve a reduction in Parkinson's disease. In some embodiments, the amount is an amount effective to prevent the progression of Alzheimer's disease (AD) or to achieve a reduction in Alzheimer's disease.

[0042] The therapeutically effective amount may vary depending on the intended application or subject and disease condition being treated (e.g., desired biological endpoint), the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the weight and age of the patient, and can be readily determined by one of ordinary skill in the art. Such amounts can be administered as a single dose or according to a regimen. The term also applies to doses that will induce a specific response in target cells (e.g., reduce cell migration). The specific dose will vary depending on, for example, the specific compound selected, the species of the subject and their age / existing health condition or risk of health condition, the dosing regimen to be followed, the severity of the disease, whether to be administered in combination with other agents, the timing of administration, the tissue to be administered, and the physiological delivery system that carries the dose.

[0043] As used herein, the terms "unsubstituted or substituted" and "optionally substituted" are used interchangeably and mean that a given chemical moiety (e.g., an alkyl group) is capable of (but not required to be) bonded to other substituents (e.g., heteroatoms). For example, an optionally substituted alkyl group can be a fully saturated alkyl chain (i.e., a pure hydrocarbon). Alternatively, the same optionally substituted alkyl group can have substituents other than hydrogen. For example, it can be bonded to a halogen atom, a hydroxyl group, or any other substituent described herein at any position along the chain. Thus, the term "optionally substituted" means that a given chemical moiety has the potential to contain other functional groups, but does not necessarily have any other functional groups. Suitable substituents for use in the optional substitution of the described groups include, but are not limited to, halogen, oxo, CN, -COOH, -CH2CN, -O-C1-C6 alkyl, C1-C6 alkyl, -OC1-C6 alkenyl, -OC1-C6 alkynyl, -C1-C6 alkenyl, -C1-C6 alkynyl, -OH, -OP(O)(OH)2, -OC(O)C1-C6 alkyl, -C(O)C1-C6 alkyl, -OC(O)OC1-C6 alkyl, NH2, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, -NHC(O)C1-C6 alkyl, -C(O)NHC1-C6 alkyl, -S(O)2-C1-C6 alkyl, -S(O)NHC1-C6 alkyl and S(O)N(C1-C6 alkyl)2.

[0044] 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.

[0045] In certain embodiments, the pharmaceutically acceptable form is a pharmaceutically acceptable salt. As used herein, the term "pharmaceutically acceptable salt" refers to salts that are suitable for use in contact with a subject's tissue without undue toxicity, irritation, allergic reaction, etc., within the scope of reasonable medical judgment and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail 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 with inorganic acids (such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid), or with organic acids (such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid), or by using other methods used in the art (such as ion exchange). Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, besylate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, Salts include, but are not limited to, hydroxybenzoate, benzoic acid ...

[0046] The salts can be prepared in situ during the isolation and purification of the disclosed compounds, or separately, such as by reacting the free base or free acid of the parent compound with a suitable base or acid, respectively. Pharmaceutically acceptable salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (C 1-4alkyl) 4 salts. Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, iron, zinc, copper, manganese, aluminum and the like. Where appropriate, other pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium and amine cations formed using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates and aryl sulfonates. 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, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine and ethanolamine. In some embodiments, pharmaceutically acceptable base addition salts can be selected from ammonium, potassium, sodium, calcium and magnesium salts.

[0047] 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 hydrolyzes in vivo and includes esters that are easily decomposed in the human body to leave the parent compound or its salt. Such esters can serve 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 acid, phosphoric acid, phosphinic acid, sulfinic acid, sulfonic acid, and boric acid. Examples of esters include formates, acetates, propionates, butyrates, acrylates, and ethylsuccinate. The esters can be formed with the hydroxyl or carboxylic acid groups of the parent compound.

[0048] 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 also includes a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces. The solvate may be of 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 can, for example, include 1 to about 100, or 1 to about 10, or 1 to about 2, about 3, or about 4 solvent or water molecules. It should be understood that the term "compound" as used herein encompasses the compound and solvates of the compound, as well as mixtures thereof.

[0049] In certain embodiments, pharmaceutically acceptable form is a prodrug. As used herein, the term "prodrug (prodrug)" (or "pro-drug (pro-drug)") refers to a compound that is converted in vivo to produce a disclosed compound or a pharmaceutically acceptable form of the compound. When administered to a subject, a prodrug can be inactive, but is, for example, converted into an active compound in vivo by hydrolysis (for example, hydrolysis in the blood). In some cases, compared to the parent compound, the prodrug has improved physical and / or delivery characteristics. Prodrugs can increase the bioavailability of the compound when administered to a subject (for example, by allowing enhanced absorption in the blood after oral administration), or enhance delivery to a biological compartment of interest (for example, brain or lymphatic system) relative to the parent compound. Exemplary prodrugs include derivatives of the disclosed compound, with enhanced water solubility or active transport by intestinal membrane relative to the parent compound.

[0050] Prodrug compounds often provide advantages in 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)). A discussion of prodrugs is provided in Higuchi, T. et al., "Pro-drugs as Novel Delivery Systems", ACSSymposium 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 entireties. Exemplary advantages of a prodrug may include, but are not limited to, its physical properties, such as enhanced water solubility compared to the parent compound when administered parenterally at physiological pH, or it may enhance absorption from the digestive tract, or it may enhance drug stability during long-term storage.

[0051] 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, vehicle, solvent, or encapsulating material, that participates in carrying or transporting the subject agent from one organ or part of the body to another organ or part of the body. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials that can serve as pharmaceutically acceptable carriers include: sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols such as propylene glycol; polyols such as glycerol, sorbitol, mannitol, and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethanol; phosphate buffered saline; and other nontoxic, compatible substances used in pharmaceutical formulations. Wetting agents, emulsifiers and lubricants, such as sodium lauryl sulfate, magnesium stearate and polyethylene oxide-polypropylene oxide copolymers, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition.

[0052] As used herein, the term "subject" refers to any animal (e.g., mammal), including but not limited to humans, non-human primates, rodents, etc., that is to be the recipient of a particular treatment. Generally, the terms "subject" and "patient" with respect to human subjects are used interchangeably herein.

[0053] As used herein, the term "treatment" or "treating" a disease or condition refers to a method of alleviating, delaying or improving such an illness before or after the disease or condition occurs. Treatment can be performed for one or more effects or symptoms of the disease and / or underlying pathology. Treatment is intended to obtain beneficial or desired results, including but not limited to therapeutic benefit and / or preventive benefit. "Therapeutic benefit" means eradicating or improving the underlying condition being treated. In addition, therapeutic benefit is achieved by eradicating or improving one or more physiological symptoms associated with the underlying condition so that an improvement is observed in the patient (although the patient may still have the underlying condition). For preventive benefit, pharmaceutical compounds and / or compositions can be administered to patients at risk of developing a particular disease or to patients reporting one or more physiological symptoms of a disease (although they may not have been diagnosed with the disease). Treatment can be any alleviation of the disease or the symptoms of the disease and can be, but is not limited to, complete ablation. Such reduction or prevention is at least 5%, 10%, 20%, 40%, 50%, 60%, 80%, 90%, 95% or 100% as compared to an equivalent untreated control as measured by any standard technique.

[0054] As used herein, the term "therapeutic effect" refers to a therapeutic benefit and / or a prophylactic benefit as described herein. A prophylactic effect includes delaying or eliminating the appearance of a disease or disorder; delaying or eliminating the onset of symptoms of a disease or disorder; slowing, stopping, or reversing the progression of a disease or disorder; or any combination thereof.

[0055] The compounds of the present invention are preferably isolated and purified after their preparation to obtain compositions containing an amount equal to or greater than 95% ("substantially pure") by weight, which are then used or formulated as described herein. In certain embodiments, the purity of the compounds of the present invention exceeds 99%.

[0056] Also contemplated herein are solvates and polymorphs of the compounds of the invention. Solvates of the compounds of the invention include, for example, hydrates.

[0057] As used herein, the term "isolated" or "substantially isolated" molecules (such as polypeptides or polynucleotides) are molecules that have been manipulated to exist at a higher concentration than in nature or have been removed from their native environment. For example, a subject antibody is isolated, purified, substantially isolated, or substantially purified when at least 10%, or 20%, or 40%, or 50%, or 70%, or 90% of the non-subject antibody materials with which the subject antibody is associated in nature 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 of its natural state is "isolated." In addition, for the purposes of the present invention, recombinant DNA molecules contained in a vector are considered isolated. Isolated RNA molecules include in vivo or in vitro RNA replication products of DNA and RNA molecules. Isolated nucleic acid molecules also include molecules produced synthetically. In addition, vector molecules contained in recombinant host cells are also isolated. Therefore, not all "isolated" molecules require "purification."

[0058] As used herein, the term "purified" when used with respect to a molecule means that the concentration of the purified molecule is increased compared to molecules with which it is associated in its natural environment or in the environment in which it is produced, found, or synthesized. Naturally associated molecules include proteins, nucleic acids, lipids, and sugars, but generally exclude water, buffers, and reagents that are added to maintain integrity or facilitate purification of the purified molecule. According to this definition, a substance can 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 when considered relative to the contaminants of the substance.

[0059] Definitions of specific functional groups and chemical terms are described in more detail below. When a range of values ​​is listed, it is intended to encompass every value and sub-range within the range. For example, "C 1-6 "Alkyl" is intended to encompass 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.

[0060] As used herein, the term "alkyl" refers to a group consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to ten carbon atoms (e.g., C 1-10Whenever it appears herein, a numerical range such as "1 to 10" refers to each integer in the given range; for example, "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 and including 10 carbon atoms, but the definition of the present invention also covers the presence of the term "alkyl" where no numerical range is specified. In some embodiments, "alkyl" can be C 1-6 (e.g., C1, C2, C3, C4, C5, or C6) alkyl. 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 alkyl groups include, but are not limited to, -methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl, and -n-hexyl; while saturated branched-chain alkyl groups 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 group is attached to the parent molecule by a single bond. Unless stated otherwise in the specification, an alkyl group is optionally substituted with one or more substituents which independently 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, thiol, thio, alkylthio, arylthio, thiocarbonyl, nitro, oxo, phosphate, phosphonate, phosphinate, silanyl, sulfinyl, sulfonyl, sulfonamido, sulfinyl, 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) t N(R x )2(wherein t is 1 or 2), -P(=O)(R x )(R x ) or -OP(=O)(OR x )2, where each R x and alkyl. In one embodiment, the substituted alkyl radicals are selected from the group consisting of fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 3-fluoropropyl, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, benzyl, and phenethyl.

[0061] Unless otherwise specifically defined, the term "aromatic" or "aryl" refers to a cyclic aromatic hydrocarbon group having 1 to 2 aromatic rings, including monocyclic or bicyclic groups such as phenyl, biphenyl or naphthyl. In the case of containing two aromatic rings (bicyclic, etc.), the aromatic rings of the aryl group can be joined (e.g., biphenyl) or fused (e.g., naphthyl) at a single point. The aryl group can optionally be substituted with one or more substituents (e.g., 1 to 5 substituents) at any point of attachment. Exemplary substituents include, but are not limited to, H, halogen, -O-Ci-C6 alkyl, C1-C6 alkyl, -Ci-C6 alkenyl, -OC1-C6 alkynyl, -Ci-C6 alkenyl, -Ci-C6 alkynyl, -OH, -OP(O)(OH)2, -OC(O)Ci-C6 alkyl, -C(O)Ci-C6 alkyl, -OC(O)OC1-C6 alkyl, NH2, NH(Ci-C6 alkyl), N(Ci-C6 alkyl)2, -S(O)2-Ci-C6 alkyl, -S(O)NHCi-C6 alkyl, and S(O)N(Ci-C6 alkyl). The substituents themselves may be optionally substituted. In addition, when containing two fused rings, the aryl groups defined herein may have an unsaturated or partially saturated ring fused to a fully saturated ring. Exemplary ring systems of these aryl groups include indanyl, indenyl, tetrahydronaphthyl, and tetrahydrobenzoannulyl.

[0062] The term "halogen" or "halo" refers to fluorine (F), chlorine (Cl), bromine (Br) and iodine (I).

[0063] 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; having 6, 10 or 14 p electrons in common in the cyclic array; and having, in addition to carbon atoms, one to three heteroatoms per ring selected from the group consisting of N, O and S. Examples of heteroaryl groups include acridinyl, azcinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, 6,7-dihydro-5H-pyrrolo[1,2-a]imidazole, furanyl, furazolinyl, imidazolinyl, imidazolyl, 1H-indole, oxazolyl, indolyl, indolyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, 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, phenanthridine phenyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiyl, phenoxazinyl, phthalazinyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridoxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, Tetrahydroisoquinolyl, tetrahydroquinolyl, 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, thienyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl and xanthenyl. "Heteroaryl" also refers to a bicyclic ring system having, in addition to carbon atoms, one to three heteroatoms per ring selected from the group consisting of N, O and S, wherein one of the ring systems may be saturated or partially saturated.

[0064] Heteroaryl can be substituted with 0, 1, 2, 3 or 4 substituents independently selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonyl, alkylcarbonylalkyl, alkylcarbonyloxy, alkylthio, alkylthioalkyl, alkynyl, carboxyl, carboxylalkyl, cyano, cyanoalkyl, formyl, haloalkoxy, haloalkyl, halogen, hydroxyl, hydroxyalkyl, sulfhydryl, nitro, -NZ1Z2 and (NZ1Z2)carbonyl. As used herein, the term "NZ1Z2" means two groups, i.e., Z1 and Z2, attached to the parent molecular moiety via 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 and acetylmethylamino.

[0065] As used herein, the term "alkoxy" refers to an -O-alkyl group.

[0066] As used herein, the terms "cycloalkyl" and "carbocyclyl" each refer to a monocyclic or polycyclic group containing only carbon and hydrogen, and may be saturated or partially unsaturated. Unless otherwise specified in this specification, the terms are intended to include substituted and unsubstituted cycloalkyls. Partially unsaturated cycloalkyls may be referred to as "cycloalkenyls" when the carbocyclic ring contains at least one double bond, or as "cycloalkynyls" when the carbocyclic ring contains at least one triple bond. Cycloalkyls include groups with 3 to 13 ring atoms (i.e., C 3-13 Cycloalkyl). Whenever a numerical range such as "3 to 10" appears herein, it refers to each integer in the given range; for example, "3 to 13 carbon atoms" means that the cycloalkyl group can be composed of 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, etc., up to and including 13 carbon atoms. The term "cycloalkyl" also includes bridged and spiro-fused ring structures that do not contain heteroatoms. The term also includes monocyclic or fused-ring polycyclic (i.e., rings that share adjacent pairs of ring atoms) groups. Polycyclic aromatic groups include bicyclic, tricyclic, tetracyclic, etc. In some embodiments, "cycloalkyl" can be C 3-8 In some embodiments, "cycloalkyl" can be C 3-5 Cycloalkyl. Illustrative examples of cycloalkyl include, but are not limited to, the following moieties: C 3-6 Carbocyclic 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 carbocyclic groups include norbornyl (C7). 3-8 Examples of the carbocyclic group include the aforementioned C 3-7Carbocyclic groups and cycloheptyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, etc. 3-13 Examples of the carbocyclic group include the aforementioned C 3-8 Unless otherwise stated in the specification, cycloalkyl can be optionally substituted with one or more substituents independently including: 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, sulfhydryl, sulfhydryl, alkylsulfanyl, arylsulfanyl, thiocarbonyl, nitro, oxo, phosphate, phosphonate, phosphinate, silanyl, sulfinyl, sulfonyl, sulfonamido, sulfinyl, 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(wherein t is 1 or 2), -P(=O)(R a )(R a ) or -OP(=O)(OR a )2, where each R aIn some embodiments, the cycloalkenyl radical is a cycloalkyl radical having 3 to 13 ring atoms, such as 5 to 8 ring atoms. In some embodiments, the cycloalkynyl radical is a cycloalkyl radical having 5 to 13 ring atoms. In some embodiments, the cycloalkenyl radical is a cycloalkyl radical having 3 to 13 ring atoms, such as 5 to 8 ring atoms. In some embodiments, the cycloalkynyl radical is a cycloalkyl radical having 5 to 13 ring atoms.

[0067] As used herein, the term "heterocycloalkyl" refers to a cycloalkyl group having one or more backbone chain atoms selected from atoms (e.g., O, N, S, P, or combinations thereof) other than carbon. Unless otherwise indicated in this specification, the term is intended to include substituted and unsubstituted heterocycloalkyl groups. Illustrative examples of heterocycloalkyl groups include 2-hydroxy-aziridine-1-yl, 3-oxo-1-oxetanes-2-yl, 2,2-dimethyl-tetrahydrofuran-3-yl, 3-carboxyl-morpholin-4-yl, 1-cyclopropyl-4-methyl-piperazine-2-yl, 2-pyrrolinyl, 3-pyrrolinyl, dihydro-2H-pyranyl, 1,2,3,4-tetrahydropyridine, 3,4-dihydro-2H-[1,4]oxazine, etc.

[0068] As used herein, the terms "heterocycle," "heterocyclic," or "heterocyclo" refer to fully saturated or partially unsaturated cyclic groups, such as 3- to 7-membered monocyclic, 7- to 12-membered bicyclic, or 10- to 15-membered spirocyclic or tricyclic ring systems, having at least one heteroatom (selected from the group consisting of N, O, and S) in at least one ring, wherein 0, 1, 2, or 3 atoms in each ring may be substituted with substituents. Each ring of the heterocyclic group containing heteroatoms may have 1, 2, 3, or 4 heteroatoms selected from nitrogen atoms, oxygen atoms, and / or sulfur atoms, wherein the nitrogen and sulfur heteroatoms may be optionally oxidized and the nitrogen heteroatoms may be optionally quaternized. The heterocyclic group may be attached at any heteroatom or carbon atom of the ring or ring system. The heterocyclic group is optionally substituted. Examples of heterocyclic groups include, but are not limited to, epoxy, azetidinyl, aziridinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, pyrrolidonyl, piperidinyl, piperazinyl, imidazolidinyl, imidazopyridinyl, thiazolidinyl, dithianyl, trithianyl, dioxolanyl, oxazolidinyl, oxazolidinonyl, decahydroquinolinyl, piperidinonyl, 4-piperidinonyl, quinuclidinyl, thiomorpholinyl, thiomorpholinyl 1,1 dioxide, morpholinyl, azepanyl, oxazepanyl, azabicyclohexyl, azabicycloheptyl, azabicyclooctyl, azabicyclononyl ( For example, octahydroindolizinyl), azaspiroheptyl, dihydro-1H,3H,5H-oxazolo[3,4-c]oxazolyl, tetrahydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine], hexahydro-1H-pyrrolazinyl, hexahydro-1H-pyrrolo[2,1-c][1,4]oxazinyl, octahydroindolizinyl, oxazaspirononyl, oxazaspiroctanyl, diazaspirononyl, oxazabicycloheptyl, hexahydropyrrolazinyl 4(1H)-oxide, tetrahydro-2H-thiopyranyl 1-oxide and tetrahydro-2H-thiopyranyl 1,1-dioxide. DETAILED DESCRIPTION

[0069] 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. These novel compounds have been shown to exhibit favorable efficacy and selectivity profiles compared to known CDK2 inhibitors, such as PF-07104091. These compounds exhibit excellent DMPK profiles and are suitable for development into orally administered therapeutics for the treatment of cancers, such as breast, ovarian, gastric, or lung cancers.

[0070] In one aspect, the present invention generally relates to a compound having structural formula I:

[0071]

[0072] or a pharmaceutically acceptable form or isotopic derivative thereof,

[0073] in

[0074] Ring A is a 4- to 7-membered (e.g., 4-, 5-, 6-, or 7-membered) carbocyclic ring;

[0075] R 1 and R 2 Each of R is 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 join together with the nitrogen atom to which they are bound to form a 4- to 7-membered (e.g., 4-, 5-, 6-, or 7-membered) unsubstituted or substituted heterocyclic ring;

[0076] Each R 3 are independently selected from the group consisting of 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 atoms to which they are attached, form a 3- to 5-membered (e.g., 3-, 4-, or 5-membered) unsubstituted or substituted carbocyclic ring;

[0077] R 4 It is H, halogen, C 1-4 Alkyl, CN, NRR' or C(O)NRR';

[0078] R 5 yes

[0079]

[0080] in

[0081] 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)2-, -C(O)-, -S(O)2NR-, -S(O)2NRC(O)-, -C(O)NR-, -OC(O)NR-, or -C(O)NRC(O)- group;

[0082] Y 1 and Y 2 Each of them is CR 6 or N and Y 3 and Y 4 Each of C, CR 6 or N; the constraint is Y 1 、Y 2 、Y 3 and Y 4 No more than one of them is N, and Y3 or Y 4 is C and is R 5 positions where bonding to the rest of the compound is possible;

[0083] Each R 6 are independently selected from the group consisting of halogen, OH, CN, unsubstituted or substituted C 1-6 Alkyl, unsubstituted or substituted C 1-4 Alkoxy and C(O)NRR';

[0084] Each R 7 are independently selected from the group consisting of halogen, OR, CN, unsubstituted or substituted C 1-6 Alkyl and unsubstituted or substituted C 1-4 Alkoxy, or 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 carbocyclic or heterocyclic ring;

[0085] Each of R and R' is independently selected from H, unsubstituted or substituted C 1-6 alkyl or an unsubstituted or substituted 4- to 6-membered (e.g., 4-, 5-, or 6-membered) carbocyclic ring, or wherein R and R' are attached to the same N atom and together form an unsubstituted or substituted 4- to 6-membered (e.g., 4-, 5-, or 6-membered) heterocyclic ring;

[0086] i is 0, 1, 2, 3, 4, or 5; and

[0087] k is 0, 1, 2, 3, 4 or 5.

[0088] In certain embodiments of (I), Y 1 、Y 2 、Y 3 and Y 4 Neither N nor R 5 yes

[0089]

[0090] in

[0091] Each R 6 are independently selected from the group consisting of halogen, OH, CN, unsubstituted or substituted C 1-6 Alkyl, unsubstituted or substituted C 1-4 Alkoxy and C(O)NRR';

[0092] α and β refer to R 5 A position at which it can be bonded to the rest of the compound; and

[0093] j is 0, 1, 2, or 3.

[0094] In certain embodiments, R 5 Attached to the rest of the compound at the β position:

[0095]

[0096] In certain embodiments, R 5 Attached to the rest of the compound at the alpha position:

[0097]

[0098] In certain embodiments of (I), Y 1 、Y 2 、Y 3 and Y 4 At least one of is N.

[0099] In certain embodiments of (I), Y 1 、Y 2 、Y 3 and Y 4 Only one of them is N.

[0100] In certain embodiments of (I), Y 3 is C and R 5 In Y 3 is connected to the rest of the compound at position:

[0101]

[0102] In certain embodiments, R 5 Selected from:

[0103]

[0104] In certain embodiments of (I), Y 4 is C and R 5 In Y 4 is connected to the rest of the compound at position:

[0105]

[0106] In certain embodiments, R 5 Selected from:

[0107]

[0108] Ring B may be selected from:

[0109]

[0110] in

[0111] X 1 、X 2 、X 3 、X 4 and X 5 Each of is independently selected from S(O)2, C(O), NH, CH2 and O, subject to the following conditions:

[0112] Two adjacent Xs 1 、X 2 、X 3 、X 4 or X 5 are not independently selected from S(O)2 and C(O); and

[0113] Two adjacent Xs 1 、X 2 、X 3 、X 4 or X 5 are not individually selected from NH and O.

[0114] 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).

[0115] 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).

[0116] 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

[0117] One or two H in CH2 are replaced by F;

[0118] One H is replaced by CN and the other H is unsubstituted; or

[0119] One H is replaced by CN and the other H is replaced by OR.

[0120] In certain embodiments, R 5 Selected from:

[0121]

[0122] In certain embodiments, R 5 Selected from:

[0123]

[0124] In certain embodiments, R 5 Selected from:

[0125]

[0126] In certain embodiments, R 5 Selected from:

[0127]

[0128] In certain embodiments, R 5 Selected from:

[0129]

[0130] In certain embodiments, R 5 Selected from:

[0131]

[0132] In certain embodiments, R 5 Selected from:

[0133]

[0134] In certain embodiments, R 5 Selected from:

[0135]

[0136] In certain embodiments, R 5 Selected from:

[0137]

[0138] In certain embodiments, R 5 Selected from:

[0139]

[0140] In certain embodiments, both R 7 Together with the carbon atoms to which they are attached, they form a 3- to 6-membered (eg, 3-, 4-, 5-, or 6-membered) unsubstituted or substituted carbocyclic ring.

[0141] In certain embodiments, both R 7 Together with the carbon atoms to which they are attached, they form a 3- to 6-membered (e.g., 3-, 4-, 5-, or 6-membered) unsubstituted or substituted heterocyclic ring containing one or more ring heteroatoms selected from O, S, and N.

[0142] In certain embodiments, R 5 Selected from:

[0143] Table 1

[0144]

[0145] In certain embodiments, R 5 Selected from:

[0146] Table 2

[0147]

[0148] In certain embodiments, R 5 Selected from:

[0149] Table 3

[0150]

[0151]

[0152] In certain embodiments of Tables 1-3, Y 1 It's N, Y 2 is CH and Y 4 In certain embodiments of Tables 1-3, Y 1 It's CH, Y 2 is N and Y 4 In certain embodiments of Tables 1-3, Y 1 It's CH, Y 2 is CH and Y 4 is N. In certain embodiments of Tables 1-3, Y 1 、Y 2 and Y 4 In certain embodiments, each of R 5 Selected from:

[0153] Table 4

[0154]

[0155] In certain embodiments, R 5 Selected from:

[0156] Table 5

[0157]

[0158]

[0159] In certain embodiments, R 5 Selected from:

[0160] Table 6

[0161]

[0162]

[0163] In certain embodiments of Tables 4-6, Y 1 It's N, Y 2 is CH and Y 3 In certain embodiments of Tables 4-6, Y 1 It's CH, Y 2 is N and Y 3 In certain embodiments of Tables 4-6, Y 1 It's CH, Y 2 is CH and Y 3 is N. In certain embodiments of Tables 4-6, Y 1 、Y 2 and Y 3 Each of is CH. 5 In certain embodiments, R is H.

[0164] In R 5 In certain embodiments, R is unsubstituted or substituted C 1-6 alkyl.

[0165] In certain embodiments, R is methyl.

[0166] In certain embodiments, R 1 is H and R 2 It is an unsubstituted or substituted straight-chain or branched C1-C6 alkyl group.

[0167] In certain embodiments, R 1 and R 2 Each of the groups is independently an unsubstituted or substituted linear or branched C1-C6 alkyl group.

[0168] In certain embodiments, R 1 and R 2 Together with the nitrogen atom to which they are attached, they join to form a 4- to 7-membered (eg, 4-, 5-, 6-, or 7-membered) unsubstituted or substituted heterocyclic ring.

[0169] In certain embodiments, Ring A is a 4- to 7-membered (eg, 4-, 5-, 6-, or 7-membered) carbocyclic ring.

[0170] In certain embodiments, Ring A is selected from:

[0171]

[0172] In certain embodiments, Ring A is selected from:

[0173]

[0174] In certain embodiments, Ring A is a 5-membered carbocyclic ring.

[0175] In certain embodiments, Ring A is:

[0176]

[0177] In certain embodiments, i is 0.

[0178] In certain embodiments, the compounds of the present invention have the following structural formula:

[0179]

[0180] in (I a ), in certain embodiments, Y 1 It's N, Y 2 is CH and Y 4 It is CH. a ), in certain embodiments, Y 1 It's CH, Y 2 is N and Y 4 It is CH. a ), in certain embodiments, Y 1 It's CH, Y 2 is CH and Y 4 is N. In certain embodiments, the compounds of the present invention have the following structural formula:

[0181]

[0182] in (I b ), in certain embodiments, Y 1 It's N, Y 2 is CH and Y 3 It is CH. b ), in certain embodiments, Y 1 It's CH, Y 2 is N and Y 3 It is CH.

[0183] in (I b ), in certain embodiments, Y 1 It's CH, Y 2 is CH and Y 3 It's N.

[0184] in (I a ) and (I b ), in certain embodiments, Ring B is a 5-membered carbocyclic ring.

[0185] in (I a ) and (I b ), in certain embodiments, Ring B is a 5-membered heterocycle.

[0186] in (I a ) and (I b ), in certain embodiments of the invention, Ring B is a 6-membered carbocyclic ring.

[0187] in (I a ) and (I b ), in certain embodiments of the invention, Ring B is a 6-membered heterocycle.

[0188] in (I a ) and (I b ), in certain embodiments, Ring B comprises a -S(O)2NH- group.

[0189] in (I a ) and (I b ), in certain embodiments, Ring B comprises a -S(O)2- group.

[0190] in (I a ) and (I b ), in certain embodiments of the invention, Ring B comprises a -C(O)NH- group.

[0191] in (I a ) and (I b ), in certain embodiments, Ring B comprises a CH2 group.

[0192] in (I a ) and (I b In certain embodiments of the present invention, Ring B comprises a C(CN)R" group, wherein R" is H, OH, C 1-4 Alkyl or OC 1-4 alkyl.

[0193] in (I a ) and (I b ), in certain embodiments, j is 0.

[0194] in (I a ) and (I b ), in certain embodiments, j is 1.

[0195] in (I a ) and (I b ), k is 0.

[0196] in (I a ) and (I b ), in certain embodiments, k is 1.

[0197] in (I a ) and (I b ), in certain embodiments, k is 2.

[0198] in (I a ) and (Ib ), in certain embodiments, R 7 is unsubstituted or substituted C 1-6 alkyl.

[0199] Exemplary compounds of the present invention include:

[0200]

[0201]

[0202]

[0203]

[0204]

[0205]

[0206]

[0207]

[0208]

[0209]

[0210]

[0211] Exemplary compounds of the present invention include:

[0212]

[0213]

[0214]

[0215]

[0216]

[0217]

[0218]

[0219]

[0220] Exemplary compounds of the present invention include:

[0221]

[0222]

[0223]

[0224]

[0225]

[0226]

[0227]

[0228] Exemplary compounds of the present invention include:

[0229]

[0230]

[0231]

[0232]

[0233]

[0234]

[0235] Compounds of the invention include deuterated forms of the disclosed compounds, eg, having one or more deuterium atoms in the place of hydrogen.

[0236] In certain embodiments, the compounds have a deuterium atom in place of hydrogen.

[0237] In another aspect, the present invention generally relates to a pharmaceutical composition comprising a compound disclosed herein and a pharmaceutically acceptable excipient, carrier, or diluent.

[0238] In certain embodiments, the pharmaceutical composition is suitable for oral administration.

[0239] In another aspect, the present invention generally relates to a unit dosage form comprising a pharmaceutical composition disclosed herein.

[0240] In certain embodiments, the invention is in the form of a tablet. In certain embodiments, the invention is in the form of a capsule.

[0241] In another aspect, the present invention generally relates to a method for treating or ameliorating cancer or a related disease or condition, comprising administering to a subject in need thereof a therapeutically effective amount of a compound disclosed herein.

[0242] In certain embodiments, the subject being treated is also administered one or more of chemotherapy, radiation therapy, targeted therapy, immunotherapy, and hormone therapy.

[0243] In certain embodiments, the methods result in one or more of: inhibiting cancer cell proliferation; inhibiting cancer cell invasiveness; inducing apoptosis of cancer cells; inhibiting cancer cell metastasis; and inhibiting angiogenesis.

[0244] 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 an amount of a compound of the present invention or a pharmaceutically acceptable salt thereof effective to inhibit cell proliferation.

[0245] In certain embodiments, the present invention relates to a method of inhibiting the invasiveness of cancer cells in a subject, comprising administering to the subject an amount of a compound of the present invention or a pharmaceutically acceptable salt thereof effective to inhibit the invasiveness of the cells.

[0246] In certain embodiments, the present invention relates to a method of inducing apoptosis in cancer cells in a subject, comprising administering to the subject an amount of a compound of the present invention or a pharmaceutically acceptable salt thereof effective to induce apoptosis.

[0247] In certain embodiments, the present invention relates to a method of inhibiting cancer cell metastasis in a subject, comprising administering to the subject an amount of a compound of the present invention or a pharmaceutically acceptable salt thereof effective in inhibiting cell metastasis.

[0248] In certain embodiments, the present invention relates to a method of inhibiting angiogenesis in a subject, comprising administering to the subject an angiogenesis-effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof.

[0249] Examples of diseases or conditions that can 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.

[0250] In certain embodiments, a 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, renal cancer (including RCC), liver cancer (including HCC), pancreatic cancer, stomach (stomach / gastric) cancer, or thyroid cancer.

[0251] 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 stomach cancer.

[0252] In certain embodiments, compounds of Formula I are administered to treat breast cancer, including, 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.

[0253] In certain embodiments, the breast cancer is endocrine-resistant breast cancer, trastuzumab-resistant breast cancer, or breast cancer that displays primary or acquired resistance to CDK4 / CDK6 inhibition.

[0254] In certain embodiments, the breast cancer is advanced or metastatic breast cancer.

[0255] In certain embodiments, the breast cancer is characterized by amplification or overexpression of CCNE1 and / or CCNE2.

[0256] In certain embodiments, the abnormal cell growth is a cancer characterized by amplification or overexpression of CCNE1 and / or CCNE2.

[0257] 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.

[0258] In certain embodiments, the cancer is selected from the group consisting of breast cancer and ovarian cancer.

[0259] In certain such embodiments, the cancer is breast or ovarian cancer characterized by amplification or overexpression of CCNE1 and / or CCNE2.

[0260] 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.

[0261] In another aspect, the present invention generally relates to the use of a compound disclosed herein and a pharmaceutically acceptable excipient, carrier, or diluent for the preparation of a medicament for treating a disease or condition.

[0262] 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 phosphates), 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 silicon dioxide, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based materials, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene block polymers, polyethylene glycol, and lanolin.

[0263] The 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 herein are administered transdermally (e.g., using a transdermal patch). Other formulations can be conveniently presented in unit dosage forms (e.g., 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).

[0264] Such preparation methods include the step of bringing the molecule to be administered into association with an ingredient such as a carrier which constitutes one or more accessory ingredients. In general, the compositions are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers, liposomes or finely powdered solid carriers or both, and then, if necessary, shaping the product.

[0265] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the compound or derivative thereof described herein is mixed with at least one inert conventional excipient (or carrier) such as sodium citrate or dicalcium phosphate or (i) fillers or extenders, for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid, (ii) binders, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia, (iii) humectants, for example, glycerol, (iv) disintegrants, for example, agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate, (v) solution retarders, for example, paraffin, (vi) absorption accelerators, for example, quaternary ammonium compounds, (vii) wetting agents, for example, cetyl alcohol and glyceryl monostearate, (viii) adsorbents, for example, kaolin and bentonite, and (ix) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also include a buffer. Similar types of solid compositions may also be used as fillers in soft and hard-filled gelatin capsules using excipients such as lactose (milk sugar) and high molecular weight polyethylene glycol. Solid dosage forms such as tablets, dragees, capsules, pills and granules may be prepared with coatings and shells, such as enteric coatings and other coatings and shells known in the art.

[0266] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs. In addition to the active compound, the liquid dosage form can also contain inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, such as ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oil (especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol and sorbitan fatty acid esters, or mixtures of these substances. In addition to such inert diluents, the composition can also include other agents, such as wetting agents, emulsifiers, suspending agents, sweeteners, flavorings or aromatics.

[0267] The amount of active compound administered will depend on the subject being treated, the severity of the condition or disorder, the route of administration, the configuration of the compound, and the judgment of the prescribing physician. In some cases, dosage levels below the lower limit of the aforementioned range may be more appropriate, while in other cases, larger doses may be used without producing any harmful side effects, such larger doses generally being divided into several smaller doses for administration throughout the day.

[0268] Any suitable route of administration may be used, such as oral, intramuscular, intravenous, transdermal, subcutaneous, sublingual, parenteral, nasal, pulmonary, inhalation, buccal, intraperitoneal, rectal, intrapleural, and intrathecal administration. The most suitable means 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 therapy being used, as well as the nature of the active compound.

[0269] In certain preferred embodiments, the compound is administered orally. Pharmaceutical compositions of the present invention suitable for oral administration may be in the form of discrete units, such as capsules, sachets, or tablets, each containing a predetermined amount of active ingredient; in powder or granular form; in the form of a solution or suspension in an aqueous liquid or a non-aqueous liquid; or in the form of an oil-in-water liquid emulsion or a water-in-oil liquid emulsion; or packaged in liposomes and presented in the form of a bolus, etc. Soft gelatin capsules may be suitable for containing such suspensions, which may advantageously increase the absorption rate of the compound.

[0270] Tablets can be made by compression or molding (optionally with one or more accessory ingredients). Compressed tablets can be prepared by compressing an active ingredient in a free-flowing form (such as a powder or granules) in a suitable machine (optionally mixed with a binder, lubricant, inert diluent, preservative, surfactant or dispersant). Molded tablets can be made by molding a mixture of a powdered compound moistened with an inert liquid diluent in a suitable machine. The tablets can be optionally coated or scored and can be formulated so as to provide a slow or controlled release of the active ingredient therein. Methods for preparing such slow or controlled release compositions of pharmaceutical active ingredients (such as those herein and other compounds known in the art) are known in the art and are described in several issued U.S. patents and references cited therein, some of which include but are not limited to U.S. Patent Nos. 4,369,172 and 4,842,866. Coatings can be used to deliver the compound to the intestine (see, e.g., U.S. Pat. Nos. 6,638,534, 5,217,720, 6,569,457, 6,461,631, 6,528,080, 6,800,663, and references cited therein). Suitable formulations of the compounds of the invention are in the form of enteric granules in which the enteric layer comprises hydroxypropylmethylcellulose acetate succinate.

[0271] In the case of tablets for oral use, common carriers include lactose and corn starch. Lubricants such as magnesium stearate are also typically added. For oral administration in capsule form, suitable diluents include lactose and dried corn starch. When aqueous suspensions are administered orally, the active ingredient is combined with an emulsifier and a suspending agent. If necessary, certain sweeteners and / or flavorings and / or coloring agents may be added.

[0272] Compositions suitable for topical administration include lozenges, which comprise the ingredient in a flavored basis, usually sucrose and acacia or tragacanth, and pastilles, which comprise the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and acacia.

[0273] Compositions suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions, which may contain antioxidants, buffers, antibacterial agents, and solutes that make the preparation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions, which may include suspending agents and thickening agents. The preparations may be presented in unit dose or multidose containers, such as sealed ampoules and vials, and may be stored under freeze-dried (lyophilized) conditions, requiring only the addition of a sterile liquid carrier, such as water for injection, just before use. Ready-to-use injection solutions and suspensions may be prepared from sterile powders, granules, and tablets.

[0274] Such injection solutions can be in the form of, for example, sterile injectable aqueous or oily suspensions. Such suspensions can be prepared using suitable dispersants or wetting agents (such as Tween 80) and suspending agents according to techniques known in the art. Sterile injectable preparations can also be sterile injectable solutions or suspensions in non-toxic parenterally acceptable diluents or solvents, for example, in the form of solutions in 1,3-butanediol. Acceptable vehicles and solvents that can be used are mannitol, water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally used as solvents or suspending media. For this purpose, any mild fixed oil can be used, including synthetic monoglycerides or diglycerides. Fatty acids (such as oleic acid and its glyceride derivatives) are suitable for preparing injectables, as are natural pharmaceutically acceptable oils (such as olive oil or castor oil), especially their polyoxyethylated forms. These oil solutions or suspensions can also contain long-chain alcohol diluents or dispersants.

[0275] The compounds of the present invention can also be administered in the form of liposomes. As is known in the art, liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by monolayer or multilayer hydrated liquid crystals dispersed in an aqueous medium. Any non-toxic, physiologically acceptable and metabolizable lipid capable of forming liposomes can be used. In addition to the compounds of the present invention, the compositions of the present invention in the form of liposomes may also contain stabilizers, preservatives, excipients, etc. Preferred lipids are 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, Vol. XIV, Academic Press, New York, NY (1976), p. 33 et seq.

[0276] The pharmaceutical compositions of the present invention can be administered in the form of suppositories for rectal administration. These compositions can be prepared by mixing the compounds of the present invention with suitable non-irritating excipients that are solid at room temperature but liquid at rectal temperature and will therefore melt in the rectum to release the active ingredient. Such materials include, but are not limited to, cocoa butter, beeswax, and polyethylene glycol.

[0277] The pharmaceutical compositions of the present invention can be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well known in the art of pharmaceutical formulation and can be prepared as solutions in normal saline using benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and / or other solubilizing or dispersing agents known in the art.

[0278] Topical application of the pharmaceutical composition of the present invention is particularly suitable when the desired treatment involves an area or organ that can be easily reached by topical application. For topical application to the skin, the pharmaceutical composition should be formulated with a suitable ointment containing an active ingredient suspended or dissolved in a carrier. Carriers for topical application 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 with a suitable lotion or cream containing an 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 composition of the present invention can also be topically applied to the lower intestinal tract via a rectal suppository formulation or in the form of a suitable enema formulation. The present invention also includes topical transdermal patches and iontophoresis administration.

[0279] The treatment methods disclosed herein can be used in combination or together with other therapies.In certain embodiments, one or more of chemotherapy, radiation therapy, targeted therapy, immunotherapy, and hormone therapy are also administered to the treated subject.

[0280] Exemplary additional therapeutically active agents include, but are not limited to, small organic molecules, such as pharmaceutical compounds (e.g., compounds approved by the US Food and Drug Administration (FDA) as provided in the Code of Federal Regulations (CFR)), peptides, proteins, carbohydrates, monosaccharides, oligosaccharides, polysaccharides, nucleoproteins, mucins, lipoproteins, synthetic polypeptides or proteins, small molecules linked to proteins, glycoproteins, steroids, nucleic acids, DNA, RNA, nucleotides, nucleosides, oligonucleotides, antisense oligonucleotides, lipids, hormones, vitamins, and cells.

[0281] In certain embodiments, compounds of the invention may be administered in combination with an endocrine therapy, eg, an agent such as letrozole, fulvestrant, tamoxifen, exemestane, or anastrozole.

[0282] In some embodiments, the compounds of this invention can be used in combination with chemotherapeutic agents, such as docetaxel, paclitaxel, cisplatin, carboplatin, capecitabine, gemcitabine or vinorelbine. In other embodiments, the compounds of this invention can be used in combination with anti-HER2 agents, such as trastuzumab or pertuzumab.

[0283] 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.

[0284] In certain embodiments, the method further comprises administering a chemotherapeutic agent to the subject.

[0285] 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.

[0286] As used herein, the term "chemotherapeutic agent" refers to a compound useful in the treatment of cancer. Examples of chemotherapeutic agents include erlotinib ( Genentech / OSIPharm.), Bortezomib ( Millennium Ph arm.), Fulvestrant ( AstraZeneca), sunitinib (Sutent) (SU11248, Pfizer), letrozole ( Novartis), Imatinib mesylate ( Novartis), PTK787 / ZK222584 (Novartis), Oxaliplatin ( Sanofi), 5-FU (5-fluorouracil), leucovorin, rapamycin (Sirolimus, Wyeth), Lapatinib ( GSK572016, Glaxo Smith Kline), Lonafarnib (SCH 66336), Sorafenib (BAY43-9006, Bayer Labs) and Gefitinib (IRE AstraZeneca), AG1478, AG1571 (SU 5271; Sugen), alkylating agents (such as thiotepa and Cyclophosphamide; alkyl sulfonates such as busulfan, improsulfan, and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethyleneimines and methylmelamines, including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and trishydroxymethylmelamine; polyacetyl groups (especially bullatacin and bullatacinone); bullatacinone); camptothecin (including the synthetic analogue topotecan); bryostatin; callystatin; CC-1065 (including its synthetic analogues adozelesin, carzelesin, and bizelesin); cryptophycin (particularly cryptophycin 1 and cryptophycin 8); dolastatin; duocarmycin n) (including synthetic analogs KW-2189 and CB1-TM1); eleutherobin; pancratistatin; sarcodictyin; spongistatin; nitrogen mustards such as chlorambucil, chlornaphazine, chlorophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterin e, prednimustine, trofosfamide, uracil mustard; nitrosoureas such as carmustine, chlorozotocin, chlorambucil, chlorophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterin e, prednimustine, trofosfamide, uracil mustard; orozotocin), fotemustine, lomustine, nimustine and ranimnustine; antibiotics such as enediyne antibiotics (e.g. calicheamicins, especially gamma calicheamicin and omega calicheamicin (Angew Chem. Intl.Ed. Engl. (1994) 33: 183-186); dynemicins, including dynemicin A; bisphosphonates, such as clodronate; esperamicin; and new tumor suppressor protein chromophores and related chromophores (enediyne antibiotic chromophores), aclacinomycins, actinomycins, authramycins, azaserines, bleomycins, actinomycin C, carabicin, caminomycin, carzinophilin, chromomycins, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, (doxorubicin), morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolinyl-doxorubicin and deoxydoxorubicin), epirubicin, esonibicin, idarubicin, marcellomycin, mitomycins (such as mitomycin C), mycophenolic acid, nogalamycin, olivomycins, peplomycin, porfiromycin, puromycin, quelamycin, rodorubicin, strepto nigrin), streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; antimetabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs such as denopterin, methotrexate, pteropterin, trimet rexate; purine analogs such as fludarabine, 6-mercaptopurine, thiamniprine, thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur; mofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine; androgens such as calusterone, dromostanolone propionate, epitiostanol, mepitiostane, testol actone; antiadreners such as aminoglutethimide, mitotane, trilostane; folic acid supplements such as folinic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil;amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elformithine; elliptinium acetate; epothilone; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidainine; maytansinoids, such as maytansine and ansamit ocin; mitoguazone; mitoxantrone; mopidanmol; nitraerine; pentostatin; phenamet; pirarubicin; losoxantrone; podophyllinic acid; 2-ethylhydrazide; procarbazine; Polysaccharide complex (JHS Natural Products, Eugene, Oreg.); razoxane; rhizoxin; sizofuran; spirogermanium; tenuazonic acid; triaziquone; 2,2',2"-trichlorotriethylamine; trichothecenes (especially T-2 toxin, verracurin A, roridin A, and anguidine); urethane; vindesine; dacarbazine; mannomus mustard tine); mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside ("Ara-C"); cyclophosphamide; thiotepa; taxoids, such as (paclitaxel; Bristol-Myers Squibb Oncology, Princeton, NJ), A (without Cremophor), albumin-engineered nanoparticle formulation of paclitaxel (American Pharmaceutical Partners, Schaumberg, 111.), and (doxetaxel; Rhone-Poulenc Rorer, Antón y, France); chloranmbucil; (gemcitabine); 6-thioguanine; mercaptopurine; methotrexate; platinum analogs such as cisplatin and carboplatin; vinblastine; etoposide (VP-16); ifosfamide; mitoxantrone; vincristine; Vinorelbine; novantrone; teniposide; edatrexate; daunomycin; aminopterin; capecitabine Ibandronate; CPT-11; the topoisomerase inhibitor RFS2000; difluoromethylornithine (DMFO); a retinoid, such as retinoic acid; and pharmaceutically acceptable salts, acids, and derivatives of any of the foregoing.

[0287] Examples of second (or additional) agents or therapies can include, but are not limited to, 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), and sirolimus. b), everolimus, pazopanib, trastuzumab, bevacizumab, cetuximab, ranibizumab, pegaptanib, panitumumab, etc.), mitotic inhibitors (e.g., paclitaxel, vincristine, vinblastine, etc.), alkylating agents (e.g., cisplatin, cyclophosphamide, benzylpenicillin, etc.), The present invention also includes but is not limited to: (acid mustard, carmustine, etc.), antimetabolites (e.g., methotrexate, 5-FU, etc.), intercalating anticancer agents (e.g., actinomycin, anthracycline, bleomycin, mitomycin-C, etc.), topoisomerase inhibitors (e.g., irinotecan, topotecan, teniposide, etc.), immunotherapy agents (e.g., interleukins, interferons, etc.) and antihormonal agents (e.g., tamoxifen, raloxifene, etc.).

[0288] Certain compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention encompasses all such compounds within the scope of the present invention, including cis and trans isomers, R- and S-enantiomers, diastereomers, (D)-isomers, (L)-isomers, their racemic mixtures, and other mixtures thereof. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. The present invention is intended to include all such isomers and mixtures thereof.

[0289] Mixtures of isomers containing any of a variety of isomer ratios can be used according to the present invention. For example, when only two isomers are combined, 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 are encompassed by the present invention. One of ordinary skill in the art will readily appreciate that similar ratios are contemplated for more complex isomer mixtures.

[0290] 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, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide the pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), diastereomeric salts are formed with appropriate optically active acids or bases, followed by resolution of the diastereomers thus formed by fractional crystallization or chromatographic methods well known in the art, and then the pure enantiomers are recovered.

[0291] Isotopically labeled compounds are also within the scope of the present disclosure. As used herein, "isotopically labeled compound" refers to the presently disclosed compounds, including pharmaceutical salts and prodrugs thereof, each as described herein, in which one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into the presently disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as 2 H. 3 H. 13 C. 14 C. 15 N. 18 O. 17 O. 31 P. 32 P. 35 S. 18 F and 36 Cl.

[0292] By isotopically labeling the presently disclosed compounds, the compounds may be suitable for drug and / or substrate tissue distribution assays. 3 H) and carbon-14 ( 14 Compounds labeled with heavier isotopes, such as deuterium ( 2H)) substitutions may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and may therefore be preferred in certain circumstances. The presently disclosed isotopically labeled compounds (including pharmaceutical salts, esters, and prodrugs thereof) may be prepared by any means known in the art.

[0293] In addition, heavier isotopes such as deuterium are substituted for the normal abundance of hydrogen ( 1 H) Certain therapeutic advantages may be obtained, for example, due to improved absorption, distribution, metabolism and / or excretion (ADME) properties, thereby resulting in a drug with improved efficacy, safety and / or tolerability. 13 C replaces the normal abundance 12 C and obtain benefits. (See WO 2007 / 005643, WO 2007 / 005644, WO 2007 / 016361 and WO 2007 / 016431).

[0294] Stereoisomers (eg, cis and trans isomers) and all optical isomers (eg, R and S enantiomers) of the presently disclosed compounds, as well as racemates, diastereoisomers, and other mixtures of such isomers, are within the scope of the present disclosure.

[0295] The compounds of the present invention are preferably isolated and purified after their preparation to obtain compositions containing an amount equal to or greater than 95% ("substantially pure") by weight, which are then used or formulated as described herein. In certain embodiments, the purity of the compounds of the present invention exceeds 99%.

[0296] Also contemplated herein are solvates and polymorphs of the compounds of the invention. Solvates of the compounds of the invention include, for example, hydrates.

[0297] Any suitable route of administration may be used, for example, parenteral, intravenous, subcutaneous, intramuscular, intraventricular, intracorporeal, intraperitoneal, rectal or oral administration. The most suitable means 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 therapy being used, as well as the nature of the active compound.

[0298] The composition for parenteral injection comprises pharmaceutically acceptable sterile aqueous or non-aqueous solution, dispersion, suspension or emulsion, and for reconstitution into the sterile powder of sterile injectable solution or dispersion before use.The example of applicable aqueous and non-aqueous carrier, diluent, solvent or vehicle comprises water, ethanol, polyol (such as glycerol, propylene glycol, Polyethylene Glycol etc.), carboxymethyl cellulose and its applicable mixture, vegetable oil (such as olive oil) and such as the injectable organic ester of ethyl oleate.Can for example, by using the coating material such as lecithin, in the case of dispersion, by maintaining required particle diameter and by using surfactant to maintain suitable fluidity.

[0299] These compositions may also contain adjuvants, such as preservatives, wetting agents, emulsifiers, and dispersants. Protection against the action of microorganisms may be ensured by including various antibacterial and antifungal agents (e.g., parabens, chlorobutanol, phenol, sorbic acid, etc.). It may also be necessary to include isotonic agents, such as sugars, sodium chloride, etc. Prolonged absorption of injectable pharmaceutical forms may be achieved by including agents that delay absorption (e.g., aluminum monostearate and gelatin).

[0300] The compounds of the present invention can also be administered in the form of liposomes. As is known in the art, liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by monolayer or multilayer hydrated liquid crystals dispersed in an aqueous medium. Any non-toxic, physiologically acceptable and metabolizable lipid capable of forming liposomes can be used. In addition to the compounds of the present invention, the compositions of the present invention in the form of liposomes may also contain stabilizers, preservatives, excipients, etc. Preferred lipids are 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, Vol. XIV, Academic Press, New York, NY (1976), p. 33 et seq.

[0301] The total daily dose of the composition of the present invention administered to a human or other mammalian host in single or divided doses may be, for example, 0.0001 to 300 mg / kg body weight and more typically 1 to 300 mg / kg body weight per day. Doses of 0.0001 to 300 mg / kg body weight may be provided twice a day.

[0302] The materials, compositions, and components disclosed herein can be used in the disclosed methods and compositions, can be used in combination with the disclosed methods and compositions, can be used to prepare the disclosed methods and compositions, or are products of the disclosed methods and compositions. It should be understood that when a combination, subset, interaction, group, etc. of these materials is disclosed, but a specific mention of each of the various individual and collective combinations and arrangements of these compounds may not be explicitly disclosed, each is specifically encompassed and described herein. For example, unless specifically indicated to the contrary, if a method is disclosed and discussed and a variety of modifications that may be made to the various molecules included in the method are discussed, each combination and arrangement of the method and possible modifications are specifically encompassed. Similarly, any subset or combination of them is also specifically encompassed and disclosed. This concept applies to all aspects of the present disclosure, including but not limited to steps in the method using the disclosed compositions. Therefore, if there are multiple additional steps that may be performed, it should be understood that each of these additional steps can be performed together with any specific method step or combination of method steps of the disclosed method, and each such combination or subset of combinations is specifically encompassed and should be considered disclosed.

[0303] Example

[0304] The following examples are provided for the purpose of illustrating the present invention, but are not intended to limit the scope or spirit of the present invention.

[0305] The compounds of the present invention, including those specifically disclosed above and below, can be prepared as described in the following schemes. Although the present invention has been described in detail by preferred embodiments, it will be understood by those skilled in the art that modifications, variations, and equivalent substitutions of the present invention within the scope of the present invention fall within the scope of the present invention.

[0306] abbreviation

[0307]

[0308]

[0309] LC-MS method:

[0310] Shimadzu LCMS2020, reversed-phase column (Shim-Pack Scepter C18, 33×3.0 mm, 3 μm), eluted with the following: A: H2O / MeCN / FA = 90 / 10 / 0.05; B: MeCN; detection: MS, ELS, UV (100 μL split to MS and tandem UV detector); MS ionization method: electrospray (cationic and anionic). ES-API = electrospray-atmospheric pressure ionization.

[0311] HPLC purification method:

[0312] Instruments: Shimadzu FRC-40; Shimadzu LH-40; Shimadzu LC-8A; GX-281. Columns: YMC-Triart C18, 250 x 20 mm, 5 μm; Welch Ultimate XB-C18, 250 x 21.2 mm, 5 μm. Detection wavelengths: 220, 254 nm. Flow rate: 15 ml / min-20 ml / min; Run time: 8 min; Column temperature: 25°C.

[0313] Compound synthesis

[0314] General Procedure 1

[0315]

[0316] General Procedure 2

[0317]

[0318] Synthesis of Common Intermediate 1: 1-(tert-Butyl)-3-((1S,3R)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1H-pyrazol-5-amine

[0319]

[0320] Step A.1,4-dioxaspiro [4.4] nonane -7- methyl formate. At rt, ethane -1,2- diol (61.1g, 985.8mmol), molecular sieves (15g) and TsOH (8.5g, 49.3mmol) are added to a solution of 3-oxocyclopentane -1- methyl formate (70g, 492.9mmol) in toluene (600mL) of stirring. After stirring O / N at 110 ° C, the cooled mixture is concentrated. The residue is purified by chromatography (silica gel, 0-20%, EtOAc / PE) to obtain 1,4-dioxaspiro [4.4] nonane -7- methyl formate (34.8g, 187.1mmol, 31%) as a colorless oil.

[0321] Step B.3-{1,4-dioxaspiro[4.4]nonane-7-yl}-3-oxopropionitrile. To a stirred solution of n-BuLi (90 mL, 224.5 mmol, 2.5 M in hexane) in THF (200 mL) was added MeCN (15.3 g, 374.2 mmol) dropwise at -60 ° C. After stirring at -70 ° C for 1 hour, a solution of 1,4-dioxaspiro[4.4]nonane-7-carboxylic acid methyl ester (34.8 g, 187.1 mmol) in THF (50 mL) was added dropwise at -60 ° C. After stirring at -70 ° C for 2 hours, the reaction mixture was quenched with water (100 mL), adjusted to pH = 7 with 1N HCl aqueous solution, and extracted with ethyl acetate (50 mL * 3). The combined organic layers were washed with brine (30 mL), dried over Na 2 SO 4 and concentrated under reduced pressure to give crude 3-{1,4-dioxaspiro[4.4]nonan-7-yl}-3-oxopropionitrile (32.8 g, 168.2 mmol, 90%) as a yellow oil, which was used directly in the next step.

[0322] Step C.1-tert-butyl-3-{1,4-dioxaspiro[4.4]nonyl-7-yl}-1H-pyrazole-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 rt. After stirring at rt for 1 hour, 3-{1,4-dioxaspiro[4.4]nonyl-7-yl}-3-oxopropionitrile (32.8 g, 168.2 mmol) was added. After stirring O / N at 80 ° C, the mixture was filtered. The filtrate was poured into water, the pH was adjusted to 6-7 with 1M HCl aqueous solution 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 / 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] + .

[0323] Step D N-(1-tert-butyl-3-{1,4-dioxaspiro[4.4]nonan-7-yl}-1H-pyrazol-5-yl)carbamic acid benzyl ester. 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 O / N at rt, the mixture was filtered. The filtrate was concentrated and purified by chromatography (silica gel, 0-40%, EtOAc / PE) to give benzyl N-(1-tert-butyl-3-{1,4-dioxaspiro[4.4]nonan-7-yl}-1H-pyrazol-5-yl)carbamate (28 g, 70 mmol, 62%) as a yellow oil. LCMS: m / z 400 [M+H] + .

[0324] Step E N-[1-tert-butyl-3-(3-oxocyclopentyl)-1H-pyrazol-5-yl] benzyl carbamate. To a stirred solution of N-(1-tert-butyl-3-{1,4-dioxaspiro[4.4]nonyl-7-yl}-1H-pyrazol-5-yl)benzyl carbamate (28 g, 70 mmol) in acetone (150 mL) was added HO (150 mL) and TsOH (6 g, 35 mmol) at rt. After stirring O / N at 60 ° C, 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 Na SO , filtered and concentrated. The residue was purified by chromatography (silica gel, 0-50%, EtOAc / PE) to give benzyl N-[1-tert-butyl-3-(3-oxocyclopentyl)-1H-pyrazol-5-yl]carbamate (21 g, 59 mmol, 84%) as a white solid. LCMS: m / z 356 [M+H] - . 1H NMR(400MHz,DMSO)δ9.07(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).

[0325] Step F Benzyl N-[1-tert-butyl-3-(3-hydroxycyclopentyl)-1H-pyrazol-5-yl]carbamate. To a stirred solution of benzyl N-[1-tert-butyl-3-(3-oxocyclopentyl)-1H-pyrazol-5-yl]carbamate (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 hours, NaHCO (aq., 40 mL) was added to the mixture at -30°C (the mixture slowly turned into a glassy solid), followed by H2O2 (19 g, 562 mmol) being slowly added to the mixture at -10°C to rt (the glassy solid slowly turned back into a normal mixture that could be easily stirred). After stirring for another 1.5 hours at rt, the subsequent mixture is slowly poured into saturated Na2S2O3 (aqueous solution, 100mL) and extracted with EtOAc (30mL×2). The combined organic phase is washed with salt water, dried over Na2SO4, filtered and concentrated. TLC (DCM:MeOH=10:1) shows low polarity points, which are required cis products. By chromatography (silica gel, 0-3%, MeOH / DCM) purification of the residue, the cis isomer (6.6g, 18.5mmol, 65%, low polarity points) of N-[1-tert-butyl-3-(3-hydroxycyclopentyl)-1H-pyrazole-5-yl] benzyl carbamate is obtained as a white solid. LCMS: m / z 358[M+H]+. 1H NMR (400MHz, DMSO) δ9.07 (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).

[0326] Step G N-[1-tert-butyl-3-[(1S,3R)-3-hydroxycyclopentyl]-1H-pyrazol-5-yl}benzyl carbamate. Benzyl N-[1-tert-butyl-3-(3-hydroxycyclopentyl)-1H-pyrazol-5-yl]carbamate (6.6 g, 18.5 mmol) was purified by preparative SFC to give benzyl N-{1-tert-butyl-3-[(1S,3R)-3-hydroxycyclopentyl]-1H-pyrazol-5-yl}carbamate (3.1 g, 8.6 mmol, 46.7%) as a white solid. LCMS: m / z 358 [M+H] + .

[0327] Step H. Benzyl (1-(tert-butyl)-3-((1S,3R)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)carbamate. To a solution of benzyl N-{1-tert-butyl-3-[(1S,3R)-3-hydroxycyclopentyl]-1H-pyrazol-5-yl}carbamate (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 rt. The reaction mixture was stirred at room temperature O / N. The reaction was concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with EA / PE [gradient: 0-50%] to give the title compound, N-{1-tert-butyl-3-[(1S,3R)-3-[(tert-butyldimethylsilyl)oxy]cyclopentyl]-1H-pyrazol-5-yl}carbamic acid benzyl ester (7 g, 14.8 mmol, 85.7%) as a colorless oil. LCMS: m / z 472 [M+H] + .

[0328] Step I. 1-(tert-Butyl)-3-((1S,3R)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1H-pyrazol-5-amine. To a solution of benzyl N-{1-tert-butyl-3-[(1S,3R)-3-[(tert-butyldimethylsilyl)oxy]cyclopentyl]-1H-pyrazol-5-yl}carbamate (7 g, 14.8 mmol) in THF (50 mL) and ethyl acetate (50 mL) was added Pd / C 10% (0.20 g, 1.86 mmol) at rt. The reaction mixture was stirred under H using a H balloon at rt 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 HNMR(400MHz, CDCl3)δ5.47(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).

[0329] Synthesis of Common Intermediate 2: (1R,3S)-3-[5-amino-1-(2-methylpropan-2-yl)pyrazol-3-yl]cyclopentyl (propan-2-ylamino)formate

[0330]

[0331] Step A: Benzyl {[2-(2-methylpropan-2-yl)-5-[(1S,3R)-3-{[(propyl-2-ylamino)carbonyl]oxy}cyclopentyl]pyrazol-3-yl]amino}carboxylate To a solution of benzyl ({5-[(1S,3R)-3-hydroxycyclopentyl]-2-(2-methylpropan-2-yl)pyrazol-3-yl}amino)carboxylate (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, TLC and LCMS indicated the reaction was complete. The reactant 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 eluted with methanol / dichloromethane (gradient: 0-3%) to give the title compound {[2-(2-methylprop-2-yl)-5-[(1S, 3R)-3-{[(propyl-2-amino)carbonyl]oxy}cyclopentyl]pyrazol-3-yl]amino}benzyl carboxylate (1.2 g, 2.7 mmol, 96.9%) as a white solid. LCMS: m / z 443 [M + H] + . 1 H NMR (400MHz, DMSO) δ9.07 (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).

[0332]

[0266] Step B: (1R,3S)-3-[5-amino-1-(2-methylpropan-2-yl)pyrazol-3-yl]cyclopentyl(propan-2-ylamino)formate A suspension of benzyl {[2-(2-methylpropan-2-yl)-5-[(1S,3R)-3-{[(propan-2-ylamino)carbonyl]oxy}cyclopentyl]pyrazol-3-yl]amino}carboxylate (1.2 g, 2.7 mmol) and Pd / C 10% (290 mg) in THF (10 mL) and EA (10 mL) was stirred at room temperature under an atmosphere of H for 18 h using a balloon. The reaction mixture was filtered and concentrated. The residue was purified by silica gel column chromatography eluting with methanol / dichloroform (gradient: 0-6%) to give the title compound, (1R,3S)-3-[5-amino-1-(2-methylpropan-2-yl)pyrazol-3-yl]cyclopentyl (propan-2-ylamino)carboxylate (700 mg, 2.2 mmol, 83.7%), as a syrupy solid. LCMS: m / z 309 [M+H] + . 1 H NMR (400MHz, DMSO) δ6.88 (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,1H),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).

[0333] Synthesis of Common Intermediate 3: 1-(tert-Butyl)-3-((1s,4s)-4-((tert-butyldiphenylsilyl)oxy)cyclohexyl)-1H-pyrazol-5-amine

[0334]

[0335] Step A: (1s, 4s) -4- ((tert-butyldiphenylsilyl) oxy) cyclohexane -1- carboxylic acid methyl ester To a solution of (1s, 4s) -4-hydroxycyclohexane -1- carboxylic acid methyl ester (5g, 31.6mmol) in DCM (30mL) was added DMAP (0.39g, 3.16mmol), imidazole (6.46g, 94.8mmol) and TBDPSCl (9.83mL, 37.9mmol) and the reactants were stirred at room temperature overnight. The reactants were concentrated in vacuo. The residue was purified by silica gel column chromatography eluted with EA / PE [gradient: 0-50%] to give the title compound (1s, 4s) -4- [(tert-butyldiphenylsilyl) oxy] cyclohexane -1- carboxylic acid methyl ester (10.1g, 25.4mmol, 80.4%) as a colorless oil. LCMS:ESI m / z 397[M+H] +

[0336] Step B: 3-((1s,4s)-4-((tert-butyldiphenylsilyl)oxy)cyclohexyl)-3-oxopropionitrile 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 hour. A solution of (1s,4s)-4-((tert-butyldiphenylsilyl)oxy)cyclohexane-1-carboxylic acid methyl ester (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 hour. After TLC showed completion, the reaction mixture was quenched with water (50 mL), adjusted to pH = 7 with 1N HCl, and extracted with EA (50 mL * 3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4 and concentrated under reduced pressure to give 3-((1s,4s)-4-((tert-butyldiphenylsilyl)oxy)cyclohexyl)-3-oxopropionitrile (5.10 g, 12.6 mmol, 99.8%) as an oil, which was used directly in the next step.

[0337] Step C: 1-(tert-butyl)-3-((1s,4s)-4-((tert-butyldiphenylsilyl)oxy)cyclohexyl)-1H-pyrazole-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-oxopropionitrile (5.10 g, 12.6 mmol). The subsequent mixture was stirred at 80 ° C overnight. LCMS showed that the reaction was complete. The cooled reaction mixture was filtered and concentrated. The residue was purified by FC on silica gel eluting with PE / EA 1:1 to give 1-(tert-butyl)-3-((1s,4s)-4-((tert-butyldiphenylsilyl)oxy)cyclohexyl)-1H-pyrazol-5-amine (4.20 g, 8.83 mmol, 70%) as a yellow solid. LC-MS: ESI m / z 476.75 [M+H] + . 1 H NMR (400MHz, DMSO) δ7.65-7.57(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).

[0338] Synthesis of common intermediate 4: (1s,3s)-3-(5-amino-1-(tert-butyl)-1H-pyrazol-3-yl)cyclobutyl isopropylcarbamate

[0339]

[0340] Step A: (1s, 3s) -3- ((tert-butyldiphenylsilyl) oxy) cyclobutane -1- carboxylic acid methyl ester To a solution of (1s, 3s) -3-hydroxycyclobutane -1- carboxylic acid 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 / PE [gradient: 0-50%] to give the title compound (1s, 3s) -3- ((tert-butyldiphenylsilyl) oxy) cyclobutane -1- carboxylic acid methyl ester (14 g, 25.4 mmol, 80.4%) as a colorless oil. LCMS:ESI m / z 369.35[M+H] +

[0341] Step B: To a stirred slurry of n-BuLi (10.0 mL, 25.2 mmol) in anhydrous THF (150 mL) containing CHCN (1.98 mL, 37.8 mmol) at -45 °C under N2 was added methyl (1s,3s)-3-((tert-butyldiphenylsilyl)oxy)cyclobutyl)-3-oxopropionitrile (5 g, 12.6 mmol). The reaction mixture was stirred at -45 °C for 2 hours. The reaction was diluted with H2O. 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 in vacuo. The compound 3-((1s,3s)-3-((tert-butyldiphenylsilyl)oxy)cyclobutyl)-3-oxopropionitrile (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] +

[0342] 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-oxopropionitrile (5 g, 12.3 mmol) in EtOH (100 mL) were added tert-butylhydrazine (2.17 g, 24.6 mmol) and NaHCO3 (2.07 g, 24.6 mmol) and the reaction mixture was stirred at 80°C for 18 hours. The residue was purified using silica gel column chromatography eluting with EA / 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]

[0343] Step D: Benzyl (1-(tert-butyl)-3-((1s,3s)-3-((tert-butyldiphenylsilyl)oxy)cyclobutyl)-1H-pyrazol-5-yl)carbamate 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 3 (0.28 g, 3.35 mmol) at 0° C. over 30 minutes. 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 Na 2 SO 4 and concentrated. The residue was purified by silica gel chromatography (15 g column) using 0-20% EtOAc / hexanes to give benzyl (1-(tert-butyl)-3-((1s,3s)-3-((tert-butyldiphenylsilyl)oxy)cyclobutyl)-1H-pyrazol-5-yl)carbamate (1.2 g, 2.06 mmol, 61%) as a yellow oil. LCMS: 582 [M+H] + .

[0344] Step E: Benzyl (1-(tert-butyl)-3-((1s,3s)-3-hydroxycyclobutyl)-1H-pyrazol-5-yl)carbamate A solution of benzyl (1-(tert-butyl)-3-((1s,3s)-3-((tert-butyldiphenylsilyl)oxy)cyclobutyl)-1H-pyrazol-5-yl)carbamate (1.2 g, 2.06 mmol) in HCOOH (10 mL) was stirred at 50 ° C for 5 hours. The cooled reaction liquid was rotated to dryness. The residue was dissolved in MeOH (5 mL) and H2O (5 mL) and LiOH (0.4 g, 10.3 mmol) was added. The resulting mixture was stirred at room temperature for 1 hour. TLC (PE / EA=1:1) showed that the starting material was exhausted 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 give benzyl (1-(tert-butyl)-3-((1s,3s)-3-hydroxycyclobutyl)-1H-pyrazol-5-yl)carbamate (670 mg, 1.95 mmol, 95%) as a colorless oil. LCMS: 344 [M+H] + . 1 H NMR (400MHz, DMSO) δ9.12 (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,1H),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).

[0345] Step F: (1s,3s)-3-(5-(((benzyloxy)carbonyl)amino)-1-(tert-butyl)-1H-pyrazol-3-yl)cyclobutyl isopropylcarbamate To a solution of benzyl (1-(tert-butyl)-3-((1s,3s)-3-hydroxycyclobutyl)-1H-pyrazol-5-yl)carbamate (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-(propan-2-yl)methanimine (249 mg, 2.92 mmol) at 0° C. over 30 minutes. The reaction mixture was stirred at room temperature for 1 hour. 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 Na 2 SO 4 and concentrated. The residue was purified by silica gel chromatography (15.0 g column) using 0-50% EtOAc / hexanes 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 HNMR(400MHz,DMSO)δ9.11(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).

[0346] Step G: (1s,3s)-3-(5-amino-1-(tert-butyl)-1H-pyrazol-3-yl)cyclobutyl isopropylcarbamate Under H protection, 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). The mixture was stirred at room temperature for 1 hour. 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) δ5.50(s,1H),4.97-4.84(m,1H),4.49(s,1H),3.84-3.76(m,1H),3.48(s,1 H),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).

[0347] Example 1: (1R,3S)-3-(3-((1-methyl-3-oxo-2,3-dihydro-1H-indazol-6-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate

[0348]

[0349] 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 minutes. Subsequently, 1-(chloromethyl)-4-methoxybenzene (0.360 mL, 2.642 mmol) was added. The reaction was stirred at room temperature for another 2 hours. 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 / 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] +

[0350] 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-methoxybenzyl)-1-methyl-1,2-dihydro-3H-indazol-3-one. -[(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-methylpropan-2-ol (1.72 mL, 1.72 mmol) and Pd2(dba)3 (79.1 mg, 0.086 mmol) were added and the reaction was stirred at 90 ° C. under N2 for 18 hours. 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 eluted with ethyl acetate / 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] +

[0351] 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 rt for 18 hours. The mixture was concentrated in vacuo to give a residue, which was purified using silica gel column chromatography eluting 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] + .

[0352] 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) was added THF (10 mL) and DCM (10 mL) followed by 4-nitrophenyl chloroformate (82.33 mg, 0.408 mmol) and pyridine (0.050 mL, 0.613 mmol). The mixture was stirred at rt for 2 hours. The mixture was concentrated in vacuo 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] +

[0353] 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] +

[0354] Step F: 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 (1R,3S)-3-(3-((1-methyl-3-oxo-2,3-dihydro-1H-indazol-6-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate (70 mg, 0.146 mmol) in propan-2-amine (5 mL) was stirred at rt 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] + . 1 HNMR (400MHz, DMSO-d6) δ8.59(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).

[0355] Example 2: (1R,3S)-3-(3-((1,1-dioxo-3,4-dihydro-2H-benzo[e][1,2]thiazin-6-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate

[0356]

[0357] Step A. 2-(5-bromo-2-(chlorosulfonyl)phenyl)acetic acid methyl ester A mixture of 2-(3-bromophenyl)acetic acid methyl ester (3 g, 13.1 mmol) in HSO Cl (1.31 g, 13.1 mmol) was stirred overnight at rt. 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 Na SO , filtered and concentrated to give the crude material 2-[5-bromo-2-(chlorosulfonyl)phenyl]acetic acid methyl ester (1.8 g, 5.52 mmol, 42.2%) as a yellow oil. LCMS: m / z 327[M+H] + .

[0358] Step B. 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) at 0° C., (4-methoxyphenyl)methanamine (0.75 g, 5.49 mmol) and TEA (1.11 g, 10.9 mmol) were slowly added. After stirring at rt for 2 hours, the mixture was poured into water (30 mL) and extracted with DCM (20 mL*2). The combined organic phases were washed with brine, dried over Na SO , filtered and concentrated. The residue was purified by chromatography (silica gel, 0-35%, EtOAc / 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] + .

[0359] 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 slowly added NaBH4 (189 mg, 5.60 mmol) at 0°C. After stirring at rt for 1 hour, the mixture was poured into ice water (30 mL) and extracted with EtOAc (20 mL*2). The combined organic phases were washed with brine, dried over Na2SO4, filtered and concentrated to give the crude material 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] + .

[0360] Step D. 1,1-dioxidation of 6-bromo-2-(4-methoxybenzyl)-3,4-dihydro-2H-benzo[e][1,2]thiazine 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 rt. After stirring overnight at rt, 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 NaSO, filtered and concentrated. The residue was purified by chromatography (silica gel, 0-50%, EtOAc / 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] + .

[0361] Step E. 1,1-Dioxido 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 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). After stirring at 100 ° C overnight, 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 Na2SO4, filtered and concentrated. The residue was purified by chromatography (silica gel, 0-60%, EtOAc / 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] + .

[0362] Step F. 1,1-Dioxido 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 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 RT for 1 hour and then concentrated under reduced pressure. The residue was treated with a mixture of LiOH (0.174mL, 6.26mmol) in EtOH (5mL) / H2O (5mL). The resulting mixture was stirred at rt for 2 hours and the mixture was concentrated under reduced pressure. The mixture was poured into water (30mL) and extracted with EtOAc (20mL*2). The combined organic phase was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by chromatography (silica gel, 0-8%, MeOH / DCM) to obtain 6- ({1- tert-butyl -3- [(1S, 3R) -3- hydroxycyclopentyl] -1H- pyrazole-5-yl} amino) -2- [(4- methoxyphenyl) methyl] -3,4- dihydro -2H-1λ^6,2- benzothiazine -1,1- dione (300mg, 0.572mmol, 91.3%) as a white solid. LCMS: m / z 526 [M+H] + .

[0363] Step G. (1R,3S)-3-(1-(tert-butyl)-5-((2-(4-methoxybenzyl)-1,1-dioxo-3,4-dihydro-2H-benzo[e][1,2]thiazin-6-yl)amino)-1H-pyrazol-3-yl)cyclopentyl (4-nitrophenyl) carbonate was added to a stirred 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) was added to a solution of DCM (5 mL) / THF (5 mL) with 4-nitrophenyl chloroformate (138 mg, 0.686 mmol), pyridine (0.083 mL, 1.02 mmol) and DMAP (12.5 mg, 0.103 mmol). After stirring at rt for 3 hours, the mixture was poured into water (30 ml) and extracted with EtOAc (20 ml * 3). The combined organic phases were washed with brine, dried over NaSO, filtered and concentrated. The residue was purified by chromatography (silica gel, 0-10%, MeOH / 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] + .

[0364] Step H. (1R,3S)-3-(5-((1,1-dioxo-3,4-dihydro-2H-benzo[e][1,2]thiazin-6-yl)amino)-1H-pyrazol-3-yl)cyclopentyl carbonate (4-nitrophenyl) A mixture of 4-nitrophenyl cyclopentyl ester (100 mg, 0.145 mmol) in HCOOH (5 mL) was stirred at 100 ° C. overnight and then concentrated under reduced pressure to give (1R,3S)-3-{5-[(1,1-dioxo-3,4-dihydro-2H-1λ^6,2-benzothiazin-6-yl)amino]-1H-pyrazol-3-yl}cyclopentyl ester 4-nitrophenyl ester (70 mg, 0.136 mmol, 94.0%) as a brown oil. LCMS: m / z 515 [M+H] + .

[0365] To a stirred solution of (1R,3S)-3-{5-[(1,1-dioxo-3,4-dihydro-2H-benzo[e][1,2]thiazin-6-yl)amino]-1H-pyrazol-3-yl}cyclopentyl isopropylcarbamate (70 mg, 0.136 mmol) in THF (5 mL) was slowly added DIPEA (35.1 mg, 0.272 mmol) and propan-2-amine (0.058 mL, 0.680 mmol), and the reaction mixture was stirred at room temperature for 2 hours. The reaction was concentrated. The residue was purified by preparative HPLC (C18, 40-90% MeCN / HO containing 0.1% HCOOH) to afford (1R,3S)-3-{3-[(1,1-dioxo-3,4-dihydro-2H-1,6,2-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) δ8.82 (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).

[0366] Example 3: (1R,3S)-3-(3-((1,1-dioxo-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate

[0367]

[0368] 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), 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 eluted with [gradient: 0-50%] to give 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) δ7.75 (d, J = 8.4Hz, 1H), 7.65-7.49 (m, 3H), 2.54 (s, 3H), 1.06 (s, 9H).

[0369] To a solution of 4-bromo-N-tert-butyl-2-methylbenzene-1-sulfonamide (5 g, 16.3 mmol) in CHCl 3 (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 [gradient: 0-30%] to give 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) δ7.91-7.86 (m, 2H), 7.82 (d, J = 8.4Hz, 1H), 7.74-7.68 (m, 1H), 5.03 (s, 2H), 1.13 (s, 9H).

[0370] Step C: 1,1-dioxidation of 5-bromo-2-(tert-butyl)-2,3-dihydrobenzo[d]isothiazole To a solution of 4-bromo-2-(bromomethyl)-N-tert-butylbenzene-1-sulfonamide (1.4 g, 3.63 mmol) in MeOH (20 mL) and H2O (5 mL) was added NaOH (0.44 g, 10.9 mmol) and 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 eluted with EA / PE [gradient: 0-80%] to give 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) δ7.83 (d, J = 0.8 Hz, 1H), 7.77 (dt, J = 14.4, 4.8 Hz, 2H), 4.55 (s, 2H), 1.46 (s, 9H).

[0371] Step D: 1,1-dioxidation 5-bromo-2,3-dihydrobenzo [d] isothiazole 5-bromo-2-tert-butyl-2,3-dihydro-1λ,6,2-benzothiazole-1,1-dione (900mg, 2.95mmol) in HCOOH (10mL) and the reactant was stirred at room temperature for 1 hour. The reaction was concentrated and MeOH (10mL) and LiOH (496mg, 11.8mmol) were added and the reactant was stirred at room temperature for 30 minutes. The reactant was diluted with H2O. The aqueous layer was extracted with EA. The EA layer was 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 [Gradient: 0-100%] to give 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) δ7.92 (s, 1H), 7.85-7.73 (m, 3H), 4.40 (s, 2H).

[0372] Step E: 5-Bromo-2-(4-methoxybenzyl)-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide To a solution of 5-bromo-2,3-dihydro-1,6,2-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 CsCO (1.97 g, 6.04 mmol) and the reaction was stirred at room temperature overnight. The reaction was diluted with H2O. 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 [Gradient: 0-30%] to give 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) δ7.90-7.82(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).

[0373] Step F: 1,1-Dioxide 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 to 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 hours. 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 using silica gel column chromatography eluting with ethyl acetate / 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] +

[0374] Step G: 1,1-dioxido 5-((1-(tert-butyl)-3-((1S,3R)-3-hydroxycyclopentyl)-1H-pyrazol-5-yl)amino)-2-(4-methoxybenzyl)-2,3-dihydrobenzo[d]isothiazole 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-1,6,2-benzothiazole-1,1-dione (500 mg, 0.800 mmol) in HCOOH (10 mL) was stirred at rt for 1 hour. 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 / 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] +

[0375] Step H: Reaction of (1R,3S)-3-(1-(tert-butyl)-5-((2-(4-methoxybenzyl)-1,1-dioxo-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-3-yl)cyclopentyl (4-nitrophenyl) carbonate to 5-({1-tert-butyl-3-[(1S,3R)-3-hydroxycyclopentyl]-1H-pyrazol-5-yl}amino)-2-[(4- To a solution of [4-(2 ...2-(2-2-(2-2-(2-(2-(2-(2-(2-2-(2-2-(2-2-(2-2-(2-2-(2-2- The residue was dissolved in ethyl acetate (5 mL*3), washed with saturated aqueous NaCl solution, dried over sodium sulfate, filtered, concentrated and purified by silica gel chromatography (eluted with 50% ethyl acetate / 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]+

[0376] Step I: (1R,3S)-3-(5-((1,1-dioxo-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-nitrophenyl carbonate (300 mg, 0.444 mmol) in HCOOH (8 mL) was stirred at 90° C. overnight. The reaction was detected to be complete by LCMS. 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] +

[0377] A solution of (1R,3S)-3-{5-[(1,1-dioxo-2,3-dihydro-1,6,2-benzothiazol-5-yl)amino]-1H-pyrazol-3-yl}cyclopentyl isopropylcarbamate (150 mg, 0.300 mmol) in propan-2-amine (10 mL, 117 mmol) was stirred at rt 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-1,6,2-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 (400MHz, DMSO) δ9.02 (s, 1H), 7.53 (d, J = 8.4Hz, 1H), 7.45 (s, 1H), 7.30 (dd, J=8.6,1.8Hz,1H),6.95(d,J=7.6Hz,1H),5.72(s,1H),4.99(brs,1H),4.29(s,1 H),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).

[0378] Example 4: (1R,3S)-3-(3-((1,3-dioxoisoindolin-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate

[0379]

[0380] 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), Xant-PHOS (102 mg, 0.178 mmol), sodium 2-methylpropan-2-ol (1.77 mL, 1.778 mmol) and Pd2(dba)3 (81.4 mg, 0.089 mmol). The reactant was stirred at 100 ° C. under N2 for 1 hour using MW. The cooled reaction mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography eluted with EA / 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] +

[0381] 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 hour. The reaction was concentrated and MeOH (3 mL) and LiOH (41.7 mg, 0.994 mmol) were added. The subsequent reaction mixture was stirred at room temperature for 30 minutes. The reaction was diluted with H2O. 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 [gradient: 0-100%] to give 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] +

[0382] 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), 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 / PE [gradient: 0-100%] to give 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] +

[0383] Step D: (1R,3S)-3-(5-((1,3-dioxoisoindol-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-nitrophenyl carbonate (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] +

[0384] 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 RT 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(400MHz,DMSO)δ12.01(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).

[0385] Example 5: (1R,3S)-3-(5-((1,1-dioxo-3-oxo-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate

[0386]

[0387] Step A: 1,1-Dioxido-5-((1-(tert-butyl)-3-((1S,3R)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)amino)benzo[d]isothiazol-3(2H)-one to 1-tert-butyl-3-[(1S,3R)-3-[(tert-butyldimethylsilyl)oxy]cyclopentyl]-1H-pyrazol-5-amine (500 mg, 1.48 mL) To a solution of 5-bromo-2,3-dihydro-1λ-6,2-benzothiazole-1,1,3-trione (582 mg, 2.22 mmol), Xant-PHOS (171 mg, 0.296 mmol), Cs2CO3 (482 mg, 1.481 mmol) and Pd2(dba)3 (135 mg, 0.148 mmol) in dioxane (2 mL) was added. The reaction mixture was stirred at 100 ° C under N2 for 16 hours. 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 / 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)-2,3-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] +

[0388] Step B: 1,1-dioxido 5-((1-(tert-butyl)-3-((1S,3R)-3-hydroxycyclopentyl)-1H-pyrazol-5-yl)amino)benzo[d]isothiazol-3(2H)-one A solution of 5-({1-tert-butyl-3-[(1S,3R)-3-[(tert-butyldimethylsilyl)oxy]cyclopentyl]-1H-pyrazol-5-yl}amino)-2,3-dihydro-1λ,2-benzothiazole-1,1,3-trione (500 mg, 0.964 mmol) in HCOOH (5 mL) was stirred at room temperature for 1 hour. The reaction was concentrated and MeOH (50 mL) and LiOH (161 mg, 3.85 mmol) were added and stirred at room temperature for 30 minutes. The reaction was diluted with H2O. 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 eluting with [gradient: 0-100%] to give 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] -

[0389] Step C: (1R,3S)-3-(1-(tert-butyl)-5-((1,1-dioxo-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-1,6,2-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 / PE [gradient: 80-100%] to give the title compound (1R,3S)-3-{1-tert-butyl-5-[(1,1,3-trioxo-2,3-dihydro-1,6,2-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] +

[0390] Step D: (1R,3S)-3-(5-((1,1-dioxo-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-nitrophenyl carbonate (200 mg) in HCOOH (5 mL) was stirred at 80°C overnight. The reaction was concentrated in vacuo to give the title compound, 4-nitrophenyl (1R,3S)-3-(5-((1,1-dioxo-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] +

[0391] To a solution of (1R,3S)-3-{5-[(1,1,3-trioxo-2,3-dihydro-1,6,2-benzothiazol-5-yl)amino]-1H-pyrazol-3-yl}cyclopentyl 4-nitrophenyl 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 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-[(1,1,3-trioxo-2,3-dihydro-1,6,2-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] + . 1 HNMR (400MHz, DMSO-d6) δ12.05(s,1H),9.46(s,1H),8.03(d,J=2.0Hz,1H),7.86(d,J=8.8Hz,1H),7.65(dd,J=8.8,2.0 Hz,1H),6.95(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).

[0392] Example 6: (1R,3S)-3-(3-((1,1-dioxo-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-7-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate

[0393]

[0394] Step A: 4-bromo-2-fluoro-N-(2-hydroxyethyl)benzenesulfonamide To a solution of 2-aminoethan-1-ol (2.2 mL, 36.6 mmol), KCO (5.05 g, 36.5 mmol) in THF (200 mL) and HO (50 mL) was added portionwise 4-bromo-2-fluorobenzene-1-sulfonyl chloride (10 g, 36.6 mmol). The mixture was stirred at rt for 2 hours, then diluted with EA and NaCl aqueous solution. 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-sulfonamido (10 g, 33.5 mmol, 91.7%) as a white solid.

[0395] 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-sulfonamido (5 g, 16.8 mmol) in DMF (50 mL) at 0° C. was added NaH (1.48 g, 0.370 mmol, 60% in mineral oil). The reaction was stirred at room temperature overnight. The reaction was diluted with EA and H 2 O 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 / PE [gradient: 0-50%] to give the title compound 7-bromo-3,4-dihydro-2H-5,1λ^6,2-benzoxazolidinone-1,1-dione (1.3 g, 4.67 mmol, 27.9%) as a colorless oil. LCMS: ESI m / z 280 [M+2+H] +

[0396] 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-benzooxathiazepine-1,1-dione (690 mg, 2.48 mmol) and CsCO (1.62 g, 4.96 mmol) in DMF (10 mL) at 0° C. was added 1-(chloromethyl)-4-methoxybenzene (0.5 mL, 3.72 mmol). The reaction was stirred at 80° C. for 3 h. The reaction was diluted with EA and H O. The organic layer was separated, washed with brine, and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with EA / 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.

[0397] Step D: 1,1-Dioxidation of 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 to 7-bromo-2-[(4-methoxyphenyl)methyl]-3,4-dihydro-2H-5,1λ^6,2-benzooxathiazepine-1,1-dione (65 To a solution of 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) was added. The reaction was stirred at 100° C. under N2 overnight. The reaction was concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with EA / PE [gradient: 0-50%] to give 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] +

[0398] 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 rt for 1 hour. The reaction was concentrated and MeOH (10 mL) and LiOH (2 mL, 4.12 mmol) were added, and the reaction was stirred at rt for 30 minutes. The reaction was diluted with H2O and the aqueous layer was extracted with EA. The EA layer was combined and washed with a saturated NaCl solution. The EA layer was dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography eluted with [gradient: 0-100%] to obtain 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-benzoxazol-1,1-dione (700 mg, 1.30 mmol, 94.2%) as a white solid.

[0399] Step F: Reaction of (1R,3S)-3-(1-(tert-butyl)-5-((2-(4-methoxybenzyl)-1,1-dioxo-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-7-yl)amino)-1H-pyrazol-3-yl)cyclopentyl (4-nitrophenyl) carbonate to 7-{[1-tert-butyl-3-(3-hydroxycyclopentyl)-1H-pyrazol-5-yl]amino}-2-[(4 To a solution of [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 rt for 3 hours. The reaction was concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with EA / PE [gradient: 0-100%] to give 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] +

[0400] Step G: (1R,3S)-3-(5-((1,1-dioxo-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-benzoxathiazepin-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.

[0401] Step H: (1R,3S)-3-(3-((1,1-dioxo-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-7-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate

[0277] A solution of 3-{5-[(1,1-dioxo-3,4-dihydro-2H-5,1λ^6,2-benzooxathiazepin-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] +

[0402] 1 H NMR (400MHz, DMSO) δ11.89 (s, 1H), 8.94 (s, 1H), 7.49 (d, J = 8.8Hz, 1H), 7.3 5(s,1H),7.23(s,1H),7.02(d,J=8.8Hz,1H),6.95(s,1H),5.67(s,1H),5.0 0(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).

[0403] Example 7: N-(Propan-2-yl)carbamic acid (1s,4s)-4-{3-[(1,1-dioxo-2,3-dihydro

[0404] -1λ^6,2-benzothiazol-5-yl)amino]-1H-pyrazol-5-yl}cyclohexyl ester

[0405]

[0406] 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), 2-methylpropan-2-amine (3.93 mL, 37.1 mmol). The reactants were stirred at room temperature overnight. The reactants were concentrated in vacuo. The residue was purified by silica gel column chromatography eluted with [gradient: 0-50%] to give 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) δ7.75 (d, J = 8.4Hz, 1H), 7.65-7.49 (m, 3H), 2.54 (s, 3H), 1.06 (s, 9H).

[0407] 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 CHCl 3 (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 [gradient: 0-30%] to give 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] + .

[0408] Step C: 1,1-dioxidation of 5-bromo-2-(tert-butyl)-2,3-dihydrobenzo[d]isothiazole To a solution of 4-bromo-2-(bromomethyl)-N-tert-butylbenzene-1-sulfonamide (1.4 g, 3.63 mmol) in MeOH (20 mL) and H2O (5 mL) was added NaOH (0.44 g, 10.9 mmol) and 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 eluted with EA / PE [gradient: 0-80%] to give 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] + . 1H NMR (400MHz, DMSO) δ7.83 (d, J = 0.8Hz, 1H), 7.85-7.63 (m, 2H), 4.55 (s, 2H), 1.46 (s, 9H).

[0409] 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 hours. The reaction mixture was concentrated. The pH value of the residue was adjusted to 7-8 with 1N NaOH aqueous solution (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 / petroleum ether (gradient: 0-50%) to give 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] +

[0410] 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 CsCO (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 NaSO and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with ethyl acetate / 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] +

[0411] 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 was reacted with 5-bromo-2-[(4-methoxyphenyl)methyl]-2,3-dihydro-1λ^6,2-benzothiazole-1,1-dione (500 mg, 1.36 mm To a solution of 1-tert-butyl-3-[(1s,4s)-4-[(tert-butyldiphenylsilyl)oxy]cyclohexyl]-1H-pyrazol-5-amine (775 mg, 1.63 mmol), CsCO (1.32 g, 4.07 mmol), Pd(dba) (124 mg, 0.136 mmol), and Xant-PHOS (157 mg, 0.272 mmol) was added 1-tert-butyl-3-[(1s,4s)-4-[(tert-butyldiphenylsilyl)oxy]cyclohexyl]-1H-pyrazol-5-amine (775 mg, 1.63 mmol), CsCO (1.32 g, 4.07 mmol), Pd(dba) (124 mg, 0.136 mmol), and Xant-PHOS (157 mg, 0.272 mmol). The reaction was stirred at 100° C. under N for 6 hours. The reaction was diluted with EA and water. The organic layer was separated, washed with brine, dried over NaSO, and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with ethyl acetate / 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] +

[0412] Step G: 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 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) and 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 using silica gel column chromatography eluting with ethyl acetate / 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] +

[0413] 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 5-({1-tert-butyl-3-[(1s,4s)-4-hydroxycyclohexyl]-1H-pyrazol-5-yl}amino)-2-[(4 To a solution of]-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 reactants were stirred at room temperature under N2 for 3 hours. The reactants were diluted with EA and water. The organic layer was separated, washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified using silica gel column chromatography eluted with ethyl acetate / 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] +

[0414] 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] +

[0415] Step J: A solution of (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 and 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) was added. The reaction was stirred at room temperature for 1 hour. The reaction was purified by preparative HPLC (C18, 0-50% acetonitrile / HO) to give the title compound, (1s,4s)-4-{3-[(1,1-dioxo-2,3-dihydro-1,6,2-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] + . 1 H NMR(400MHz,DMSO)δ11.89(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).

[0416] Example 8: (1R,3S)-3-(3-((1-oxoisoindolin-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate

[0417]

[0418] 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)methylamine (2.20 g, 16.0 mmol). The mixture was stirred at 80 ° C for 2 hours. The cooled mixture was concentrated in vacuo. The residue was purified by flash column chromatography with 0-50% ethyl acetate / petroleum ether to give 5-bromo-2-[(4-methoxyphenyl)methyl]-2,3-dihydro-1H-isoindolin-1-one (2 g, 6.02 mmol, 41.2%) as a white solid. LCMS: ESI 332.4, 334.4 [M+H] + . 1H NMR (400 MHz, dimethyl 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).

[0419] 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-methylpropan-2-ol (2.96 mL, 2.96 mmol) and Pd2(dba)3 (135 mg, 0.148 mmol) were added. The reaction was stirred at 90°C under N2 for 18 hours. 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 / 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] +

[0420] Step C: A solution of 5-((1-(tert-butyl)-3-((1S,3R)-3-hydroxycyclopentyl)-1H-pyrazol-5-yl)amino)-2-(4-methoxybenzyl)isoindolin-1-one 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-isoindolin-1-one (500 mg, 0.85 mmol) in HCOOH (5 mL) was stirred at room temperature for 1 hour. The reaction was concentrated and MeOH (5 mL) and LiOH (142 mg, 3.39 mmol) were added and stirred at room temperature for 30 minutes. The reaction was diluted with water. 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 [gradient: 0-100%] 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] +

[0421] 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 eluting with EA / 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] -

[0422] 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] +

[0423] 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 as a white solid (4.8 mg, 1.9% yield). LCMS: ESI m / z 384 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.78(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).

[0424] Example 9: (1R,3S)-3-(3-((1,1-dioxo-2,3-dihydrobenzo[b]thiophen-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate

[0425]

[0426] 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 H2O2 (2 mL, 19.6 mmol, 30% in H2O) and TFA (2 mL, 26.92 mmol). The mixture was stirred at 20 ° C for 5 hours. The reaction mixture was diluted with water and extracted with DCM (30 mL×3). The organic phase was washed with an aqueous solution of Na2S2O3, dried over Na2SO4 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.

[0427] 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 hours. H2O (0.5 mL) was added to quench. The subsequent mixture was concentrated and the residue was purified by silica gel chromatography (10 g column) using 0-30% EtOAc / hexane to give 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) δ7.84(s,1H),7.72(s,2H),3.66-3.54(m,2H),3.42-3.28(m,2H).

[0428] 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) were added Cs2CO3 (263 mg, 0.81 mmol), Pd2(dba)3 (37.0 mg, 0.04 mmol) and Xant-PHOS (23.4 mg, 0.04 mmol). The reaction mixture was stirred at 100 ° C. under N2 for 5 hours. The mixture was purified by silica gel chromatography (2 g column) using 0-50% EtOAc / hexane. The eluted fraction containing the product was 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] +

[0429] 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 to give a crude material, to which MeOH (3 mL) and LiOH (100 mg) were added and stirred at 20° C. for 30 min. The mixture was concentrated in vacuo and poured into EA (30 mL), 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] +

[0430] To a solution of 5-({1-tert-butyl-3-[(1S,3R)-3-hydroxycyclopentyl]-1H-pyrazol-5-yl}amino)-2,3-dihydro-1λ^-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 hour. The mixture was concentrated and the residue was purified by silica gel chromatography (2 g column) using 0-50% EtOAc / hexanes to give (1R,3S)-3-{1-tert-butyl-5-[(1,1-dioxo-2,3-dihydro-1,6-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] +

[0431] 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 hours. The cooled mixture was concentrated in vacuo to afford (1R,3S)-3-{5-[(1,1-dioxo-2,3-dihydro-1,6-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] +

[0432] To a solution of (1R,3S)-3-{5-[(1,1-dioxo-2,3-dihydro-1,6-benzothiophen-5-yl)amino]-1H-pyrazol-3-yl}cyclopentyl isopropylcarbamate (110 mg, 0.2 mmol) in THF (5 mL) was added ethyldiisopropylamine (0.11 mL, 0.66 mmol). Propan-2-amine (0.09 mL, 1.10 mmol) was then added dropwise. The reaction mixture was stirred at 20 °C for 2 hours. The mixture was concentrated and the residue was purified by preparative TLC (EA) to give (1R,3S)-3-(3-((1,1-dioxo-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] + . 1 H NMR (400MHz, DMSO) δ11.92(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),3.24(t,J=6.8Hz,2H),3.12-3.01(m,1H),2.49-2.42(m,1H),2.03(dd,J=15.6,7.6 Hz, 1H), 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).

[0433] Example 10: (1R,3S)-3-(5-((3-methyl-1,1-dioxo-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate

[0434]

[0435] Step A: 1,1-dioxidized 5-bromo-3-methylbenzo [d] isothiazole 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 rt, then 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 flash silica gel column 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] +

[0436] Step B: 1,1-dioxidation of 5-bromo-3-methyl-2,3-dihydrobenzo[d]isothiazole 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 stirred at 25 ° C for 5 hours. After completion, the reaction mixture was quenched with 2 mL of NH4Cl (aqueous solution). The reactant 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 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] +

[0437] Step C: 1,1-Dioxidized 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 was added to 1-tert-butyl-3-[(1S,3R)-3-[(tert-butyldimethylsilyl)oxy]cyclopentyl]-1H-pyrazol-5-amine (350 mg, 1.04 mmol) in dioxane (2 mL) and stirred for 1 hr. ) was added to a solution of 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 hours. The reaction was diluted with EA and water. The organic layer was separated, washed with brine and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with ethyl acetate / 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] +

[0438] Step D: 1,1-dioxidation of 5-((1-(tert-butyl)-3-((1S,3R)-3-hydroxycyclopentyl)-1H-pyrazol-5-yl)amino)-3-methyl-2,3-dihydrobenzo[d]isothiazole 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 hour. The reaction was concentrated and MeOH (50 mL) and LiOH (64.7 mg, 1.54 mmol) were added and the reaction was stirred at room temperature for 30 minutes. The reaction was diluted with H2O. The subsequent mixture 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 eluted with [gradient: 80-100%] to give 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] +

[0439] Step E: (1R,3S)-3-(1-(tert-Butyl)-5-((3-methyl-1,1-dioxo-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 minutes. The reaction was concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with EA / 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] +

[0440] Step F: (1R,3S)-3-(5-((3-methyl-1,1-dioxo-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-nitrophenyl carbonate (100 mg, 0.176 mmol) in HCOOH (5 mL) was stirred at 80 °C overnight. The reaction was concentrated in vacuo 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 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] + .

[0441] Step G: (1R,3S)-3-(5-((3-methyl-1,1-dioxo-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-1,6,2-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 hours. 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-1,6,2-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] + . 1H NMR (400MHz, DMSO-d6) δ11.92(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).

[0442] 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

[0443]

[0444] Step A. 2-(5-bromo-2-(chlorosulfonyl)phenyl)acetic acid methyl ester The reaction mixture of 2-(3-bromophenyl)acetic acid methyl ester (10 g, 43.8 mmol) in HSO Cl (5.10 g, 43.8 mmol) was stirred overnight at rt. The reaction mixture was slowly poured into ice water and extracted with EtOAc. The combined organic phase was washed with brine, dried over Na SO , filtered and concentrated to give the crude material 2-[5-bromo-2-(chlorosulfonyl)phenyl]acetic acid methyl ester (3 g, 9.2 mmol, 21%) as a yellow oil. LCMS: m / z 327 [M+H] + .

[0445] Step B. 2-(5-bromo-2-(N-(4-methoxybenzyl)sulfamoyl)phenyl)acetic acid methyl ester At 0 ° C, to a stirred mixture of 2-[5-bromo-2-(chlorosulfonyl)phenyl]acetic acid methyl ester (3 g, 9.2 mmol) in DCM (30 mL) was slowly added (4-methoxyphenyl)methylamine (1.26 g, 9.2 mmol) and TEA (1.86 g, 18.4 mmol). After stirring overnight at rt, 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 / PE) to give 2-(5-bromo-2-{[(4-methoxyphenyl)methyl]sulfamoyl}phenyl)acetic acid methyl ester (2 g, 4.65 mmol, 33.9%) as a brown solid. LCMS: m / z 429[M+H] + .

[0446] 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 borohydride (1+) ion (5.84 mL, 11.6 mmol) at 0°C. After stirring overnight at rt, 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 afford 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] + .

[0447] 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) at rt was added triphenylphosphine (917 mg, 3.49 mmol) and (E)-N-{[(propan-2-yloxy)carbonyl]imino}(propan-2-yloxy)formamide (0.69 mL, 3.49 mmol). After stirring overnight at rt, 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 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] + .

[0448] 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 was added to a stirred solution 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) at rt. To the mixture in 1% 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)phenyl-1-yl; chloropalladium; {2-[2,6-bis(propan-2-yloxy)phenyl]phenyl}dicyclohexylphosphane (122 mg, 0.157 mmol) were added. 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 NaSO, 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] + .

[0449] 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 hydrofluoride (5 mL). The reaction mixture was stirred at 25° C. overnight. The pH of the mixture was adjusted to 8 with NaHCO 3 (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 eluting with ethyl acetate / 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] + .

[0450] 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 was added to a stirred 6-({1-tert-butyl-3-[(1s,4s)-4-hydroxycyclohexyl]-1H-pyrazol-5-yl}amino)-2-[ To a solution of [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). After stirring at rt for 3 hours, the mixture was poured into water (30 ml) 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, 0-10%, MeOH / 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] + .

[0451] 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. 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. A mixture of 4-nitrophenyl (1s,4s)-4-{5-[(1,1-dioxo-3,4-dihydro-2H-1,6,2-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-1,6,2-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] + .

[0452] 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] + . 1 H NMR (400MHz, DMSO) δ11.86 (s, 1H), 8.80 (s, 1H), 7.47 (d, J = 8.8Hz, 1H), 7.3 4-7.19(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).

[0453] 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

[0454]

[0455] 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 Na2SO3 (2.72 mL, 56.8 mmol) in EtOH (100 mL) and H2O (125 mL). The reactants were stirred at 70 ° C overnight. The cooled reaction mixture was acidified to pH 2 with HCl (2N). The reactants were 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] + .

[0456] 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 reactant was stirred at 90 ° C for 2 hours. The cooled reaction mixture was concentrated in vacuo. The residue was azeotroped with chloroform. The residue was dissolved in tetrahydrofuran. At 0 ° C, the subsequent solution was added dropwise to NH4OH (40 mL). The reaction mixture was stirred at rt for 1 hour and then acidified to pH 7 with HCl (2N). The subsequent 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] +

[0457] 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 H2O (10 mL) was added NH4Cl (4.35 g, 81.3 mmol) and Fe (4.54 g, 81.3 mmol). The reactants were stirred at 70 ° C for 2 hours. The cooled reaction mixture was filtered. The filtrate was concentrated. The residue was purified by silica gel column chromatography eluted with methanol / dichloroform (gradient: 0-10%) to give 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] +

[0458] Step D: 6-bromo-4H-1λ^6,2,4-benzothiadiazine-1,1-dione The 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 rt and then filtered. The filter cake was washed with MTBE and dried in vacuo 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] +

[0459] 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 CH3I (0.98 g, 6.89 mmol) and Cs2CO3 (2.99 g, 9.19 mmol). The reactants were stirred at 80 ° C overnight. The reactants were 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 / petroleum ether (gradient: 0-80%) to give 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] +

[0460] 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 isopropanol (20 mL) was added NaBH4 (182 mg, 5.38 mmol). The reactants were stirred at room temperature overnight. The reactants were 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 / petroleum ether (gradient: 0-50%) to give 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] +

[0461] 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 was reacted with 6-bromo-4-methyl-3,4-dihydro-2H-1λ^6,2,4-benzothiadiazine-1,1-dione (340 mg, 1.23 mmol) in distilled water. To a solution in oxane (10 mL) was added 1-tert-butyl-3-[(1S,3R)-3-[(tert-butyldimethylsilyl)oxy]cyclopentyl]-1H-pyrazol-5-amine (414 mg, 1.23 mmol), CsCO (1.20 g, 3.68 mmol), Pd(dba) (112 mg, 0.123 mmol) and Xant-PHOS (142 mg, 0.245 mmol). The reaction was stirred at 100 ° C under N for 3 hours. 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 / 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] +

[0462] 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 hour. It was then concentrated in vacuo. The residue was dissolved in methanol and the pH was adjusted to 12-13 with LiOH (2M in H2O). 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 eluted with methanol / 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] +

[0463] 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 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) were 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 reactants were stirred at room temperature for 3 hours. The reactants were 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 / 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] +

[0464] 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 (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 give 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] +

[0465] Step K: 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 and (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 give 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] +

[0466] 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 isopropanol (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 / 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: ESI m / z 448.55 [M+H] + . 1HNMR (400MHz, DMSO) δ11.88(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).

[0467] Example 13: (1R,3S)-3-(3-((3,3-dimethyl-1,1-dioxo-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate

[0468]

[0469] To a solution of 4-bromo-1-iodo-2-(propan-2-yl)benzene (4 g, 12.3 mmol) in toluene (100 mL) was added Xant-PHOS (0.71 g, 1.23 mmol), DIEAethyldiisopropylamine (4.06 mL, 24.6 mmol), Pd2(dba)3 (1.13 g, 1.23 mmol) and phenylmethylmercaptan (1.53 g, 1.44 mL, 12.3 mmol). The mixture was stirred at 100° C. under N2 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 afford 1-(benzylthio)-4-bromo-2-(propan-2-yl)benzene (2.66 g, 8.27 mmol, 67.3%) as a brown oil.

[0470] Step B: 4-bromo-2-(propan-2-yl)benzene-1-sulfonyl chloride To a solution of 1-(benzylthio)-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 minutes. 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) δ7.90 (d, J = 12.0 Hz, 1H), 7.71 (s, 1H), 7.52 (t, J = 4.0 Hz, 1H), 4.05-3.98 (m, 1H), 1.35 (d, J = 8.0 Hz, 6H).

[0471] Step C: 4-bromo-2-(propan-2-yl)benzenesulfonamido 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 hour. 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) using 0-30% EtOAc / hexane to give 4-bromo-2-(propan-2-yl)benzenesulfonamido acetate (900 mg, 2.67 mmol, 33.2%) as a brown oil. LCMS: ESI m / z 338.0 [M+H] + .

[0472] 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)benzenesulfonamido acetate (500 mg, 1.48 mmol) in DMSO (5 mL) was stirred at 130 ° C under N2 for 3 hours. 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] + .

[0473] 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) was reacted with 5-bromo-3,3-dimethyl-2,3-dihydro-1λ^6,2-benzothiazole-1,1-dione (270 mg, 0.978 mmol) and 1-tert-butyl- To a solution of 3-[(1S,3R)-3-[(tert-butyldimethylsilyl)oxy]cyclopentyl]-1H-pyrazol-5-amine (330 mg, 0.978 mmol) in dioxane (5 mL) were added Cs2CO3 (637 mg, 1.95 mmol), Xant-PHOS (56.5 mg, 0.098 mmol) and Pd2(dba)3 (89.5 mg, 0.098 mmol). The reaction mixture was stirred at 100° C. under N2 for 5 hours. The reaction mixture was concentrated and the residue was purified by silica gel chromatography (5 g column) using 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] + .

[0474] 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 minutes. 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] + .

[0475] 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-benzothiazol-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) were added pyridine (0.143 mL, 1.76 mmol) and DMAP (21.6 mg, 0.177 mmol). The reaction mixture was stirred at rt for 1 hour. The mixture was concentrated and the residue was purified by silica gel chromatography (2 g column) using 0-50% EtOAc / hexane to give (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] + .

[0476] 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 hours. The cooled mixture was concentrated in vacuo to give (1R,3S)-3-{5-[(3,3-dimethyl-1,1-dioxo-2,3-dihydro-1,6,2-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] + .

[0477] To a solution of (1R,3S)-3-{5-[(3,3-dimethyl-1,1-dioxo-2,3-dihydro-1,6,2-benzothiazol-5-yl)amino]-1H-pyrazol-3-yl}cyclopentyl isopropylcarbamate (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 minutes and then concentrated. The residue was purified by preparative TLC (EA) to give (1R,3S)-3-(3-((3,3-dimethyl-1,1-dioxo-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] + . 1H NMR (400MHz, DMSO) δ11.98(s,1H),9.03(s,1H),7.53(d,J=1.6Hz,2H),7.48(d,J=8.8Hz,1 H),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).

[0478] 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 for 1 hour at 20° C. 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.

[0479] Example 14. (1R,3S)-3-(3-((1,1-dioxo-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-4-fluoro-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate

[0480]

[0481] Step A: 1,1-dioxido 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 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-methoxybenzyl)-2,3-dihydrobenzo[d]isothiazole. -[(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), Cs2CO3 (290 mg, 0.889 mmol) and Pd2(dba)3 (81.3 mg, 0.089 mmol) were added and the reaction was stirred at 90°C under N2 for 18 hours. The reaction was diluted with EA and water. The organic layer was separated, washed with brine and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with ethyl acetate / petroleum ether (3 / 1), and the organic layer was collected, concentrated, and dried in vacuo 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] + .

[0482] 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 hour. After completion, the solvent was removed in vacuo to give a residue, which was purified by flash column (PE / EA=5:1) to give the title compound 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] + .

[0483] Step C: (1R,3S)-3-(1-(tert-butyl)-4-fluoro-5-((2-(4-methoxybenzyl)-1,1-dioxo-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 using silica gel column chromatography eluting with EA / PE [gradient: 0-100%] to give 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] + .

[0484] Step D: (1R,3S)-3-(5-((1,1-dioxo-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-nitrophenyl carbonate (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] + .

[0485] To a solution of (1R,3S)-3-{5-[(1,1-dioxo-2,3-dihydro-1,6,2-benzothiazol-5-yl)amino]-4-fluoro-1H-pyrazol-3-yl}cyclopentyl isopropylcarbamate (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 hours. 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-1,6,2-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).

[0486] Example 15: (1R,3S)-3-{5-[(3-methoxy-1,1-dioxo-2,3-dihydro-1λ6-benzothiophen-5-yl)amino]-2H-pyrazol-3-yl}cyclopentyl (propan-2-ylamino)formate

[0487]

[0488] 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 H2O2 (4 mL, 39.2 mmol, 30% in H2O) and TFA (4 mL, 53.8 mmol) at rt. After stirring for 5 hours at rt, the mixture was poured into an aqueous Na2S2O3 solution and extracted with DCM (30 mL x 2). The combined organic phases were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by chromatography (silica gel, 0-40%, EA / PE) to give 5-bromo-1λ6-benzothiophene-1,1-dione (1.7 g, 6.94 mmol, 73.9%) as a white solid.

[0489] Step B: 5-{[2-(2-methylpropan-2-yl)-5-[(1S,3R)-3-{[(2-methylpropan-2-yl)diphenylsilanyl]oxy}cyclopentyl]pyrazol-3-yl]amino}-1λ6-benzothiophene-1,1-dione To a solution of 5-[(1S,3R)-3-{[dimethyl(2-methylpropan-2-yl)silanyl]oxy}cyclopentyl]-2-(2-methylpropan-2-yl)pyrazol-3-amine (300 mg, 0.889 mmol) was added 5-bromo-1λ6-benzothiophene-1,1-dione (191 mg, 0.779 mmol), Pd2(dba)3 (59.4 mg, 0.065 mmol), Xantphos (75.1 mg, 0.130 mmol) and Cs2CO3 (529 mg, 1.62 mmol). The reactant was purged with N2 and stirred at 100 ° C under N2 for 1.5 hours. The reactant 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 / 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]pyrazole-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] +.

[0490] Step C: 5-({5-[(1S,3R)-3-hydroxycyclopentyl]-2-(2-methylpropan-2-yl)pyrazol-3-yl}amino)-3-methoxy-2,3-dihydro-1λ 6 -Benzothiophene-1,1-dione 5-{[2-(2-methylpropan-2-yl)-5-[(1S,3R)-3-{[(2-methylpropan-2-yl)diphenylsilanyl]oxy}cyclopentyl]pyrazol-3-yl]amino}-1λ 6 -benzothiophene -1,1- dione (350mg, 0.559mmol) in HCOOH (4mL) was stirred overnight at RT and then concentrated under reduced pressure. The residue was treated with a mixture of LiOH-H2O (0.062mL, 2.24mmol) in MeOH (2mL) / H2O (2mL). The resulting mixture was stirred for 1 hour at rt and then concentrated under reduced pressure. The subsequent 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 (silica gel, 0-80%, EA / PE) to obtain 5- ({5- [(1S, 3R) -3- hydroxycyclopentyl] -2- (2- methylprop- 2-yl) pyrazole-3-yl} amino) -3- methoxy -2,3- dihydro -1λ as a white solid. 6 -Benzothiophene-1,1-dione (220 mg, 0.524 mmol, 93.8%). LCMS: m / z 420 [M+H] + . 1 H NMR (400MHz, DMSO) δ8.24(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,1 H),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).

[0491] Step D: [(4-nitrophenyl)oxy]carboxylic acid (1R,3S)-3-{5-[(3-methoxy-1,1-dioxo-2,3-dihydro-1λ 65-({5-[(1S,3R)-3-hydroxycyclopentyl]-2-(2-methylpropan-2-yl)pyrazol-3-yl}amino)-3-methoxy-2,3-dihydro-1λ 6 To a solution of -benzothiophene-1,1-dione (220 mg, 0.524 mmol) in THF (3 mL) and DCM (3 mL) was added 4-nitrophenyl chloroformate (317 mg, 1.58 mmol), DMAP (6.41 mg, 0.052 mmol) and Py (0.127 mL, 1.57 mmol) and the reactants were stirred at rt for 2 hours. The reactants were concentrated in vacuo. The residue was purified by silica gel column chromatography eluted with EA / PE [gradient: 0-50%] to give the title compound [(4-nitrophenyl)oxy]formic acid (1R, 3S)-3-{5-[(3-methoxy-1,1-dioxo-2,3-dihydro-1λ]-4-nitrophenyl]formate as a white solid. 6 -benzothiophen-5-yl)amino]-1-(2-methylpropan-2-yl)pyrazol-3-yl}cyclopentyl ester (210 mg, 0.359 mmol, 68.5%). LCMS: ESI 585 [M+H] +

[0492] Step E: [(4-nitrophenyl)oxy]carboxylic acid (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]carboxylic acid (1R,3S)-3-{5-[(3-methoxy-1,1-dioxo-2,3-dihydro-1λ 6 A solution of [(4-nitrophenyl)oxy]-1-(5-[(3-methoxy-1,1-dioxo-2,3-dihydro-1-[(4-nitrophenyl)oxy]carboxylic acid]-1-(2-methyl-1-[(4-nitrophenyl)oxy)-1-[(1R,3S)-3-{ ... 6 -benzothiophen-5-yl)amino]-1H-pyrazol-3-yl}cyclopentyl ester (88 mg, 0.166 mmol, 97.4%) was used in the next step without further purification. LCMS: ESI m / z 529 [M+H] +

[0493] Step F: (1R,3S)-3-{5-[(3-methoxy-1,1-dioxo-2,3-dihydro-1λ-propan-2-ylamino)carboxylic acid6 -benzothiophen-5-yl)amino]-2H-pyrazol-3-yl}cyclopentyl ester

[0494] [(4-nitrophenyl)oxy]carboxylic acid (1R,3S)-3-{5-[(3-methoxy-1,1-dioxo-2,3-dihydro-1λ 6 To a solution of]-1H-pyrazol-3-yl}cyclopentyl ester (88 mg, 0.166 mmol) in THF (2 mL) was added isopropylamine (0.043 mL, 0.499 mmol) and DIPEA (64.6 mg, 0.499 mmol). After stirring at rt for 30 minutes, the mixture was concentrated. The residue was purified by preparative HPLC (C18, 20-95% MeCN / HO containing 0.1% HCOOH) to give (1R,3S)-3-{5-[(3-methoxy-1,1-dioxo-2,3-dihydro-1λ-propan-2-ylamino)carboxylic acid as a white solid. 6 -benzothiophen-5-yl)amino]-2H-pyrazol-3-yl}cyclopentyl ester (37.6 mg, 0.084 mmol, 50.4%). LCMS: ESI m / z 449.2 [M+H] + . 1H NMR (400MHz, DMSO) δ11.96(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).

[0495] Example 16: (1s,4s)-4-{5-[(1,1-dioxo-2,3-dihydro-1λ6-benzothiophen-5-yl)amino]-2H-pyrazol-3-yl}cyclohexyl(2-propanylamino)formate

[0496]

[0497] 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 hours. The reactant 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 / 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] + .

[0498] Step B: 5-({5-[(1s,4s)-4-{[(2-methylpropan-2-yl)diphenylsilanyl]oxy}cyclohexyl]-2-(2-methylpropan-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-methylpropan-2-yl)diphenylsilyl]oxy}cyclohexyl]-2-(2-methylpropan-2-yl)pyrazol-3-amine (385 mg, 0.809 mmol), CsCO (791 mg, 2.43 mmol), Pd(dba) (74.1 mg, 0.081 mmol) and Xant-PHOS (93.7 mg, 0.162 mmol). The reaction was stirred at 100° C. under N for 3 hours. 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 using silica gel column chromatography eluting with ethyl acetate / petroleum ether (gradient: 0-30%) to give the title compound 5-({5-[(1s,4s)-4-{[(2-methylpropan-2-yl)diphenylsilanyl]oxy}cyclohexyl]-2-(2-methylpropan-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] + .

[0499] Step C: 5-({5-[(1s,4s)-4-hydroxycyclohexyl]-2-(2-methylpropan-2-yl)pyrazol-3-yl}amino)-2,3-dihydro-1λ6-benzothiophene-1,1-dione A solution of 5-({5-[(1s,4s)-4-{[(2-methylpropan-2-yl)diphenylsilanyl]oxy}cyclohexyl]-2-(2-methylpropan-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 / dichloroform (gradient: 0-10%) to give the title compound 5-({5-[(1s,4s)-4-hydroxycyclohexyl]-2-(2-methylpropan-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] + .

[0500] To a solution of 5-({5-[(1s,4s)-4-hydroxycyclohexyl]-2-(2-methylpropan-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 chloroformate (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 reactant 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 eluted with ethyl acetate / petroleum ether (gradient: 0-30%) to give the title compound [(4-nitrophenyl)oxy]formic acid (1s, 4s)-4-{5-[(1,1-dioxo-2,3-dihydro-1λ6-benzothiophene-5-yl)amino]-1-(2-methylprop-2-yl)pyrazol-3-yl}cyclohexyl ester (120 mg, 0.211 mmol, 47.3%) as a yellow solid. LCMS: m / z 568.64[M+H] + .

[0501] 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 (propan-2-ylamino)formate A solution of (1s,4s)-4-{5-[(1,1-dioxo-2,3-dihydro-1λ6-benzothiophen-5-yl)amino]-1-(2-methylpropan-2-yl)pyrazol-3-yl}cyclohexyl [(4-nitrophenyl)oxy]formate (60 mg, 0.106 mmol) in formic acid (5 mL) was stirred at 100°C overnight. The reaction was concentrated in vacuo 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[(4-nitrophenyl)oxy]carboxylate (50 mg, 0.098 mmol, 92.5%) as a yellow oil. LCMS: m / z 512.54 [M+H] + .

[0502] Step F: (1s,4s)-4-{5-[(1,1-dioxo-2,3-dihydro-1λ6-benzothiophen-5-yl)amino]-2H-pyrazol-3-yl}cyclohexyl(propan-2-ylamino)formate 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]formate (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 / 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(propan-2-ylamino)carboxylate (20.9 mg, 0.048 mmol, 49.5%) as a white solid. LCMS: m / z 432.54 [M+H] + . 1H NMR (400MHz, DMSO) δ11.90(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).

[0503] Example 17: (1R,3S)-3-(3-((1,1-dioxo-2,3-dihydrobenzo[d]isothiazol-6-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate

[0504]

[0505] 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 hour. The reaction was detected to be complete by LCMS. 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] + .

[0506] To a solution of 5-bromo-2-methylbenzenesulfonamide (3.30 g, 13.2 mmol) in CCl (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 hours. The reaction was detected to be complete by TLC. The reaction mixture was dissolved in EA (50 mL), washed with H O (20 mL) and brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (eluting with 0-30% EA / PE) to obtain 5-bromo-2-(bromomethyl)benzenesulfonamide (2.90 g, 8.81 mmol, 67.6%) as a white solid.

[0507] 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 H2O (11.3 mL) was added NaOH (0.710 g, 17.6 mmol) and the mixture was stirred at room temperature for 3 hours. The reaction was detected to be complete by LCMS. The reaction mixture was concentrated in vacuo and purified by silica gel chromatography (eluting with 0-50% EA / 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] + .

[0508] 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. The reaction was detected to be complete by LCMS. The reaction mixture was dissolved in EA (50 mL), washed with H2O (10 mL) and brine, dried over sodium sulfate, filtered, concentrated, and purified by silica gel chromatography (eluting with 0-80% EA / PE) to give 1,1-dioxidized 6-bromo-2-(4-methoxybenzyl)-2,3-dihydrobenzo[d]isothiazole (250 mg, 0.679 mmol, 37.4%) as a pale yellow solid. LCMS: ESI m / z 368.25 [M+H] + .

[0509] 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 6-bromo-2-(4-methoxybenzyl)-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide (250 mg, 0.679 mmol) in dioxane ( To a solution in 4% 4-[(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(dba) (29.8 mg, 0.0320 mmol) and Xantphos (37.6 mg, 0.065 mmol) were added. The reaction mixture was stirred at 100° C. under N atmosphere for 1 hour. The reaction was detected to be complete by LCMS. The cooled reaction mixture was dissolved in EA (50 mL), washed with H2O (20 mL) and brine, dried over sodium sulfate, filtered, concentrated, and purified by silica gel chromatography (eluting with 0-80% EA / 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] + .

[0510] 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

[0268] 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 by TLC. The solvent was removed in vacuo. EtOH (2 mL), H2O (2 mL) and lithium hydroxide monohydrate (25.2 mg, 0.601 mmol) were then added to reach an alkaline pH. The reaction mixture was stirred at room temperature for 1 hour. LCMS showed that the reaction was complete. The reaction mixture was dissolved in EA (50 mL), washed with H2O (10 mL) and brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (eluting with 0-80% EA / PE) to give 1,1-dioxido 6-((1-(tert-butyl)-3-((1S,3R)-3-hydroxycyclopentyl)-1H-pyrazol-5-yl)amino)-2-(4-methoxybenzyl)-2,3-dihydrobenzo[d]isothiazole (100 mg, 0.196 mmol, 97.8%) as a light yellow oil. LCMS: ESI m / z 511.65 [M+H] + .

[0511] Step G: (1R,3S)-3-(1-(tert-butyl)-5-((2-(4-methoxybenzyl)-1,1-dioxo-2,3-dihydrobenzo[d]isothiazol-6-yl)amino)-1H-pyrazol-3-yl)cyclopentyl (4-nitrophenyl) carbonate A suspension of 2-(4-methoxybenzyl)-2,3-dihydrobenzo[d]isothiazole (100 mg, 0.196 mmol), DMAP (2.39 mg, 0.0200 mmol), Py (0.0480 mL, 0.588 mmol), and 4-nitrophenyl chloroformate (198 mg, 0.980 mmol) in DCM (2 mL) and THF (2 mL) was stirred at room temperature for 3 hours. The solvent was removed in vacuo. The residue was dissolved in EA (50 mL), washed with H2O (5 mL) and brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (eluting with 0-80% EA / PE) to give (1R,3S)-3-(1-(tert-butyl)-5-((2-(4-methoxybenzyl)-1,1-dioxo-2,3-dihydrobenzo[d]isothiazol-6-yl)amino)-1H-pyrazol-3-yl)cyclopentyl (4-nitrophenyl) carbonate as a pale yellow oil (100 mg, 0.148 mmol, 75.6%). LCMS: ESI m / z 676.76 [M+H] + .

[0512] A solution of (1R,3S)-3-(1-(tert-butyl)-5-((2-(4-methoxybenzyl)-1,1-dioxo-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-dioxo-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] + .

[0513] To a suspension of (1R,3S)-3-(5-((1,1-dioxo-2,3-dihydrobenzo[d]isothiazol-6-yl)amino)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate (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 H2O (10 mL) and brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (eluting with 12% MeOH / DCM) and preparative HPLC (C18, 15-95% MeCN / H2O containing 0.1% FA) to give (1R,3S)-3-(3-((1,1-dioxo-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)δ8.90(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).

[0514] Example 18: (1R,3S)-3-(3-((4-methyl-1,1-dioxo-3-oxo-3,4-dihydro-2H-benzo[e][1,2,4]thiadiazin-6-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate

[0515]

[0516] 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 reactants were stirred at 100 ° C. for 18 hours in a sealed tube. TLC and LCMS indicated that the reaction was complete. The cooled reaction mixture was concentrated and the residue was purified by silica gel column chromatography eluted with ethyl acetate / petroleum ether (gradient: 0-30%) to give 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] -

[0517] Step B: 4-({5-[(1S,3R)-3-{[dimethyl(2-methylprop-2-yl)silanyl]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)silanyl]oxy}cyclopentyl]-2-(2-methylprop-2-yl)pyrazol-3-amine (268 mg, 0.8 mmol), Xantphos (68 mg, 0.12 mmol) and Cs2CO3 (774 mg, 2.4 mmol) in 1,4-dioxane (10 mL) was added Pd2(dba)3 (72 mg, 0.08 mmol). The reactants were stirred at 100 ° C under N2 atmosphere for 5 hours. TLC and LCMS indicated that the reaction was complete. The cooled reaction mixture was poured into ice water, the pH was adjusted to 5-6 with 1N HCl, extracted with EA (20 mL * 3), the combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by silica column purification eluting 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] +

[0518] Step C: 6-({5-[(1S,3R)-3-{[dimethyl(2-methylprop-2-yl)silanyl]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)silanyl]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 mixture was stirred for 30 min. Triphosgene (244 mg, 0.8 mmol) was added to the reactants and the reactants were stirred at room temperature overnight. The reactants were poured into ice water and the pH was adjusted to 5-6 with 1N HCl, extracted with EA, washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography eluted with methanol / 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] + .

[0519] Step D: 6-({5-[(1S,3R)-3-hydroxycyclopentyl]-2-(2-methylpropan-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-methylpropan-2-yl)-5-[(1S,3R)-3-{[(2-methylpropan-2-yl)diphenylsilanyl]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 hours. The reaction was concentrated and the residue was dissolved in 10 ml of THF and H2O (1:1). LiOH was added and stirred for another 30 minutes. The pH of the reactant was adjusted to 5-6 with 1N HCl and extracted with EA. The combined organic layer was separated, washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography eluted with methanol / dichloroform (gradient: 0-10%) to give 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] + .

[0520] Step E: [(4-nitrophenyl)oxy]carboxylic acid (1R,3S)-3-[1-(2-methylpropan-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 ester to 6-(5-[(1S,3R)-3-hydroxycyclopentyl]-2-(2-methylpropan-2-yl)pyrazol-3-yl) cyclopentyl ester To a solution of 4-nitrophenyl chloroformate (139 mg, 0.7 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 / dichloroform (gradient: 0-10%) to give the title compound (1R,3S)-3-[1-(2-methylpropan-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]carboxylate as a gray solid (80 mg, 0.13 mmol, 29%). LCMS m / z: 599 [M+H] + .

[0521]

[0266] 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]carboxylate

[0267] A solution of (1R,3S)-3-[1-(2-methylpropan-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]carboxylate (80 mg, 0.13 mmol) in HCOOH (5 mL) was stirred at 100°C under N2 atmosphere for 16 hours. LCMS showed completion. 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]carboxylate as a yellow solid (60 mg, 0.11 mmol, 83%), which was used in the next step without purification. LCMS m / z: 543 [M+H] + .

[0522] 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 (propan-2-ylamino)formate 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]formate (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 (propan-2-ylamino)carboxylate (10.4 mg, 0.02 mmol, 12%) as an off-white solid. LCMS m / z: 463 [M+H] + . 1H NMR (400MHz, DMSO) δ11.99(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).

[0523] Example 19: (1R,3S)-3-(3-((1,1-dioxo-2,3-dihydrobenzo[b]thiophen-6-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate

[0524]

[0525] To a solution of 6-bromobenzothiophene (2.0 g, 9.39 mmol) in DCM (15 mL) was added H2O2 (4 mL, 39.2 mmol, 30% in H2O) and TFA (4 mL, 53.8 mmol). The mixture was stirred at 20 ° C for 5 hours. The mixture was purified by silica gel chromatography (20 g column) using 0-30% EtOAc / hexane. The fractions containing the product were concentrated to give 1,1-6-bromobenzo[b]thiophene (2.1 g, 8.57 mmol, 91%) as a white solid.

[0526] Step B: 1,1-Dioxidation of 6-bromo-2,3-dihydrobenzo[b]thiophene to 6-bromo-1λ 6 To a solution of 6-bromo-2,3-dihydrobenzo[b]thiophene-1,1-dione (1.0 g, 4.08 mmol) in MeOH (30 mL) was added NaBH4 (300 mg, 8.98 mmol) and the mixture was stirred at 20°C for 2 hours and then concentrated. The residue was purified by silica gel chromatography (10 g column) using 0-40% EtOAc / hexane. The fractions containing the product were concentrated to give 6-bromo-2,3-dihydrobenzo[b]thiophene-1,1-dioxide (900 mg, 3.64 mmol, 89%) as a white solid.

[0527] Step C: 1,1-Dioxidation of 6-((1-(tert-butyl)-3-((1S,3R)-3-((tert-butyldiphenylsilyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)amino)-2,3-dihydrobenzo[b]thiophene to 6-bromo-2,3-dihydro-1λ 6 To a solution of -benzothiophene-1,1-dione (300 mg, 1.214 mmol) and 2-(2-methylpropan-2-yl)-5-[(1S,3R)-3-{[(2-methylpropan-2-yl)diphenylsilyl]oxy}cyclopentyl]pyrazol-3-amine (616 mg, 1.34 mmol) in 1,4-dioxane (8 mL) was added CsCO (791 mg, 2.43 mmol). Pd(dba) (111 mg, 0.121 mmol) and Xantphos (140 mg, 0.24 mmol) were then added to the mixture and stirred at 100° C. under N for 5 hours. The mixture was purified by silica gel chromatography (2 g column) using 0-50% EtOAc / hexanes. The fractions containing the product 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) as a brown solid (530 mg, 0.84 mmol, 69%). LCMS: ESI m / z 628.4 [M+H] +

[0528] Step D: 1,1-dioxidation of 6-((1-(tert-butyl)-3-((1S,3R)-3-hydroxycyclopentyl)-1H-pyrazol-5-yl)amino)-2,3-dihydrobenzo[b]thiophene to 6-{[2-(2-methylpropan-2-yl)-5-[(1S,3R)-3-{[(2-methylpropan-2-yl)diphenylsilyl]oxy}cyclopentyl]pyrazol-3-yl]amino}-2,3-dihydro-1λ 6 -benzothiophene-1,1-dione (520 mg, 0.83 mmol) in formic acid (4 mL) was stirred at 20 ° C for 30 minutes. The mixture was concentrated in vacuo to remove formic acid to give a crude material, to which MeOH (3 mL) and LiOH (100 mg) were added and stirred at 20 ° C for 30 minutes. The reaction mixture was concentrated in vacuo and poured into EA (30 mL) and extracted with water. The organic layer was concentrated to give 1,1-dioxido 6- ((1- (tert-butyl) -3- ((1S, 3R) -3-hydroxycyclopentyl) -1H- pyrazole-5-yl) amino) -2,3-dihydrobenzo [b] thiophene (270 mg, 0.69 mmol, 84%) as a brown solid. LCMS: ESI m / z 390.2 [M + H] +

[0529] Step E: Reaction of (1R,3S)-3-(1-(tert-butyl)-5-((1,1-dioxo-2,3-dihydrobenzo[b]thiophen-6-yl)amino)-1H-pyrazol-3-yl)cyclopentyl (4-nitrophenyl) carbonate to 6-({5-[(1S,3R)-3-hydroxycyclopentyl]-2-(2-methylpropan-2-yl)pyrazol-3-yl}amino)-2,3-dihydro-1λ 6 To a solution of -benzothiophene-1,1-dione (270 mg, 0.69 mmol) in DCM (3 mL) and THF (3 mL) was added 4-nitrophenyl chloroformate (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 hour. The mixture was purified by silica gel chromatography (2 g column) using 0-50% EtOAc / hexane. The fraction containing the product was concentrated to give (1R,3S)-3-(1-(tert-butyl)-5-((1,1-dioxo-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] +

[0530] Step F: (1R,3S)-3-(1-(tert-butyl)-3-((1,1-dioxo-2,3-dihydrobenzo[b]thiophen-6-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate to (1R,3S)-3-{5-[(1,1-dioxo-2,3-dihydro-1λ-[4-nitrophenyl)oxy]carboxylic acid 6 To a solution of (1R,3S)-3-(1-(tert-butyl)-3-((1,1-dioxo-2,3-dihydrobenzo[b]thiophen-6-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate (70 mg, 0.15 mmol, 82%) was added DIEA (0.045 mL, 0.27 mmol). Propan-2-amine (0.09 mL, 1.10 mmol) was then 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-dioxo-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] +

[0531] Step G: (1R,3S)-3-(3-((1,1-dioxo-2,3-dihydrobenzo[b]thiophen-6-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate 6 A solution of (1R,3S)-3-(3-((1,1-dioxo-2,3-dihydrobenzo[b]thiophen-6-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate (70 mg, 0.15 mmol) in formic acid (4 mL) 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-dioxo-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) δ11.81(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).

[0532] Example 20: (1R,3S)-3-{5-[(3-oxo-2,3-dihydro-1H-isoindol-5-yl)amino]-2H-pyrazol-3-yl}cyclopentyl (propan-2-ylamino)formate

[0533]

[0534] To a solution of 5-bromo-2-methylbenzoic acid methyl ester (3g, 13.1mmol) in CCl4 (30mL) was added NBS (3.50g, 19.6mmol) and BPO (1.59g, 6.55mmol). The reaction mixture was stirred at 80°C for 6 hours. The cooled reaction mixture was poured into water and extracted with EtOAc. The combined organic phases were washed with salt water, dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography with 0-10% ethyl acetate / petroleum ether to obtain the crude material 5-bromo-2-(bromomethyl)benzoic acid methyl ester (3g, 9.74mmol, 74.4%) as a white solid.

[0535] Step B: 6-bromo-2-[(4-methoxyphenyl)methyl]-2,3-dihydro-1H-isoindole-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)methylamine (1.40 mL, 10.7 mmol). The reaction mixture was stirred at 80 ° C for 2 hours. The cooled reaction 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 flash column chromatography with 0-50% ethyl acetate / petroleum ether to give 6-bromo-2-[(4-methoxyphenyl)methyl]-2,3-dihydro-1H-isoindole-1-one (2 g, 6.02 mmol, 61.8%) as a white solid. LCMS: ESI m / z 332 [M + H] +

[0536] Step C: 2-[(4-methoxyphenyl)methyl]-6-{[2-(2-methylpropan-2-yl)-5-[(1S,3R)-3-{[(2-methylpropan-2-yl)diphenylsilanyl]oxy}cyclopentyl]pyrazol-3-yl]amino}-2,3-dihydro-1H-isoindol-1-one to 6-bromo-2-[(4-methoxyphenyl)methyl]-2,3-dihydro-1H-isoindol-1-one (258 mg, 0.779 mM) To a solution of 2-(2-methylprop-2-yl)-5-[(1S,3R)-3-{[(2-methylprop-2-yl)diphenylsilyl]oxy}cyclopentyl]pyrazole-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) was added and the reactants were purged with N and stirred at 100 ° C under N overnight. 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 / petroleum ether (2 / 1). The organic layer was collected, concentrated in vacuo, and dried to give the title compound 2-[(4-methoxyphenyl)methyl]-6-{[2-(2-methylpropan-2-yl)-5-[(1S,3R)-3-{[(2-methylpropan-2-yl)diphenylsilanyl]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] + .

[0537] Step D: 6-({5-[(1S,3R)-3-hydroxycyclopentyl]-2-(2-methylpropan-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-methylpropan-2-yl)-5-[(1S,3R)-3-{[(2-methylpropan-2-yl)diphenylsilanyl]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 RT overnight and then concentrated under reduced pressure. The residue was treated with a mixture of LiOH-H2O (0.065mL, 2.36mmol) in MeOH (3mL) / H2O (3mL). The resulting mixture was stirred at rt for 1 hour and then concentrated under reduced pressure. The subsequent 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 (silica gel, 0-70%, EA / PE) to obtain 6- ({5- [(1S, 3R) -3- hydroxycyclopentyl] -2- (2- methylprop- 2-yl) pyrazole-3-yl} amino) -2- [(4- methoxyphenyl) methyl] -2,3- dihydro -1H- isoindole -1- one (210mg, 0.442mmol, 75.1%) as a white solid. LCMS: ESI m / z 475 [M+H] + .

[0538] Step E: (1R,3S)-3-[5-({2-[(4-methoxyphenyl)methyl]-3-oxo-2,3-dihydro-1H-isoindol-5-yl}amino)-1-(2-methylpropan-2-yl)pyrazol-3-yl]cyclopentyl[(4-nitrophenyl)oxy]formate to 6-({5-[(1S,3R)-3-hydroxycyclopentyl]-2-(2-methylpropan-2-yl)pyrazol-3-yl}amino)-2-[(4-methoxyphenyl)oxy]formate To a solution of [4-nitrophenyl)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 chloroformate (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 rt for 2 hours. The reaction was concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with EA / PE [gradient: 0-50%] to give the title compound (1R,3S)-3-[5-({2-[(4-methoxyphenyl)methyl]-3-oxo-2,3-dihydro-1H-isoindol-5-yl}amino)-1-(2-methylpropan-2-yl)pyrazol-3-yl]cyclopentyl [(4-nitrophenyl)oxy]carboxylate (160 mg, 0.250 mmol, 56.5%) as a white solid. LCMS: ESI 640 [M+H] +

[0539]

[0266] A solution of (1R,3S)-3-[5-({2-[(4-methoxyphenyl)methyl]-3-oxo-2,3-dihydro-1H-isoindol-5-yl}amino)-1-(2-methylpropan-2-yl)pyrazol-3-yl]cyclopentyl [(4-nitrophenyl)oxy]carboxylate (60 mg, 0.09 mmol) in HCOOH (4 mL) and TfOH (0.4 mL) was stirred at 80°C under N2 atmosphere for 2 hours. LCMS showed 50% of the desired product was found. The reaction was concentrated to give the desired crude product, (1R,3S)-3-[1-(2-methylpropan-2-yl)-5-[(3-oxo-2,3-dihydro-1H-isoindol-5-yl)amino]pyrazol-3-yl]cyclopentyl [(4-nitrophenyl)oxy]carboxylate (60 mg, 0.08 mmol, approximately 50% purity, 61% yield), as a gray solid. This was used in the next step without purification. LCMS: ESI 520 [M+H] +

[0540] Step G: To a solution of (1R,3S)-3-[1-(2-methylpropan-2-yl)-5-[(3-oxo-2,3-dihydro-1H-isoindol-5-yl)amino]pyrazol-3-yl]cyclopentyl [(4-nitrophenyl)oxy]carboxylate (80 mg, 0.125 mmol) in THF (3 mL) was added ... Isopropylamine (3 mL) was added. The reaction solution was stirred at room temperature for 1 hour. LCMS showed that the reaction was complete. The reaction mixture was concentrated and purified by silica gel column chromatography eluted with EA / 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 (40 mg, 0.09 mmol, 72.8%) of (propan-2-ylamino)formic acid as a yellow solid. LCMS: ESI 440 [M+H] +

[0541] Step H: (1R,3S)-3-{5-[(3-oxo-2,3-dihydro-1H-isoindol-5-yl)amino]-2H-pyrazol-3-yl}cyclopentyl (propan-2-ylamino)carboxylate A solution of (1R,3S)-3-[1-(2-methylpropan-2-yl)-5-[(3-oxo-2,3-dihydro-1H-isoindol-5-yl)amino]pyrazol-3-yl]cyclopentyl (propan-2-ylamino)carboxylate (40 mg, 0.09 mmol) in HCOOH (4 mL) was stirred at 100° C. for 16 hours. 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 (propan-2-ylamino)carboxylate (1.3 mg, 0.003 mmol, 3.7%) as a white solid. LCMS: ESI 384 [M+H] + . 1HNMR(400MHz,DMSO)δ11.73(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).

[0542] Example 21: (1R,3S)-3-{5-[(3,3-dimethyl-1,1-dioxo-2,3-dihydro-1λ-propan-2-ylamino)formic acid 6 -benzothiophen-5-yl)amino]-2H-pyrazol-3-yl}cyclopentyl ester

[0543]

[0544] Step A: 1-[(4-bromophenyl)thio]-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 hours. The reactants were quenched by adding saturated sodium chloride solution (500 mL) and then extracted with ethyl acetate (300 mL×3). The organic phases were combined and washed with saturated sodium chloride solution (100 mL×3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (petroleum ether / ethyl acetate=100-0%) to give compound 1-[(4-bromophenyl)thio]-2-methylpropan-2-ol (10 g, 38.288 mmol, 72.39%) as a colorless oil. 1 H NMR (400MHz, DMSO) δ7.46 (d, J = 8.4 Hz, 2H), 7.30 (d, J = 8.4 Hz, 2H), 4.68 (s, 1H), 3.04 (s, 2H), 1.19 (s, 6H).

[0545] Step B: 5-Bromo-3,3-dimethyl-2,3-dihydrobenzothiophene was added to a suspension of aluminum chloride (7.66 g, 57.432 mmol) in carbon disulfide (100 mL) at -10°C. A solution of 1-[(4-bromophenyl)thio]-2-methylpropan-2-ol (5 g, 19.144 mmol) in 100 mL of carbon disulfide solution was added. The resulting reaction solution was stirred at 50°C for 0.5 hours and then cooled to 0°C. 1N dilute hydrochloric acid was added to the reaction system, followed by extraction with ethyl acetate. The organic phases were combined and washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was separated and purified by column chromatography (petroleum ether / ethyl acetate=100-0%) to give 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) δ7.24 (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).

[0546] Step C: 5-Bromo-3,3-dimethyl-2,3-dihydro-1λ 4 -benzothiophene-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 hours. Ice water was added to the reaction mixture and then Na2S2O3 (aqueous solution) was added. The subsequent mixture was extracted with ethyl acetate, washed twice with aqueous sodium carbonate solution, washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash chromatography to obtain 5-bromo-3,3-dimethyl-2,3-dihydro-1λ as a white solid. 4 -Benzothiophene-1-one (500 mg, 1.929 mmol, 46.91%). LCMS: ESI m / z 259 [M+H] + .

[0547] Step D: 5-Bromo-3,3-dimethyl-2,3-dihydro-1λ 6 -benzothiophene-1,1-dione to 5-bromo-3,3-dimethyl-2,3-dihydro-1λ at 0 °C 4To a solution of 5-benzothiophene-1-one (500 mg, 1.929 mmol) in DCM (10 mL) was added 85% 3-chlorobenzene-1-peroxycarboxylic acid (832 mg, 4.82 mmol). The reaction mixture was stirred at 5-15 ° C for 3 hours. The reaction mixture was purified by silica gel column chromatography to give the title compound 5-bromo-3,3-dimethyl-2,3-dihydro-1λ as a white solid. 6 -Benzothiophene-1,1-dione (300 mg, 1.09 mmol, 56.5%). LCMS: ESI m / z 275 [M+H] + .

[0548] Step E: 3,3-dimethyl-5-{[2-(2-methylpropan-2-yl)-5-[(1S,3R)-3-{[(2-methylpropan-2-yl)diphenylsilanyl]oxy}cyclopentyl]pyrazol-3-yl]amino}-2,3-dihydro-1λ 6 -benzothiophene-1,1-dione to 5-bromo-3,3-dimethyl-2,3-dihydro-1λ 6 To a solution of -benzothiophene-1,1-dione (300 mg, 1.090 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 (503 mg, 1.09 mmol), Cs2CO3 (710.47 mg, 2.18 mmol), Xant-PHOS (126 mg, 0.218 mmol) and Pd2(dba)3 (99.8 mg, 0.109 mmol). The reaction mixture was stirred at 100 ° C. under N2 overnight. 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 using silica gel column chromatography eluting with ethyl acetate / petroleum ether to give the title compound 3,3-dimethyl-5-{[2-(2-methylpropan-2-yl)-5-[(1S,3R)-3-{[(2-methylpropan-2-yl)diphenylsilanyl]oxy}cyclopentyl]pyrazol-3-yl]amino}-2,3-dihydro-1λ as a yellow oil. 6 -Benzothiophene-1,1-dione (500 mg, 0.762 mmol, 69.9%). LCMS: ESI m / z 656 [M+H] + .

[0549] Step F: 5-({5-[(1S,3R)-3-hydroxycyclopentyl]-2-(2-methylpropan-2-yl)pyrazol-3-yl}amino)-3,3-dimethyl-2,3-dihydro-1λ 6-benzothiophene-1,1-dione 3,3-dimethyl-5-{[2-(2-methylpropan-2-yl)-5-[(1S,3R)-3-{[(2-methylpropan-2-yl)diphenylsilyl]oxy}cyclopentyl]pyrazol-3-yl]amino}-2,3-dihydro-1λ 6 -benzothiophene -1,1- dione (500mg, 0.762mmol) in formic acid (3mL) was stirred at RT for 1 hour and then concentrated under reduced pressure. The residue was treated with a mixture of hydrated lithium hydroxide (31.98mg, 0.762mmol) in MeOH (3.00mL) / H2O (0.30mL). The resulting mixture was stirred at rt for 2 hours and the mixture was concentrated under reduced pressure. 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 obtain 5- ({5- [(1S, 3R) -3- hydroxycyclopentyl] -2- (2- methylprop- 2-yl) pyrazole-3-yl} amino) -3,3- dimethyl -2,3- dihydro-1λ as a colorless oil. 6 -Benzothiophene-1,1-dione (280 mg, 0.671 mmol, 87.97%). LCMS: ESI m / z 418 [M+H] + .

[0550] Step G: [(4-nitrophenyl)oxy]carboxylic acid (1R,3S)-3-{5-[(3,3-dimethyl-1,1-dioxo-2,3-dihydro-1λ 6 5-({5-[(1S,3R)-3-hydroxycyclopentyl]-2-(2-methylpropan-2-yl)pyrazol-3-yl}amino)-3,3-dimethyl-2,3-dihydro-1λ 6 -benzothiophene-1,1-dione (300 mg, 0.718 mmol) in DCM (5 mL) and THF (5 mL) was added 4-nitrophenyl chloroformate (289 mg, 1.44 mmol), Py (0.174 mL, 2.15 mmol) and DMAP (8.78 mg, 0.072 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 Na2SO4, concentrated in vacuo and the residue was purified by flash chromatography to give [(4-nitrophenyl)oxy]formic acid (1R, 3S)-3-{5-[(3,3-dimethyl-1,1-dioxo-2,3-dihydro-1λ]-[(4-nitrophenyl)oxy]formic acid as a yellow solid. 6[-benzothiophen-5-yl)amino]-1-(2-methylpropan-2-yl)pyrazol-3-yl}cyclopentyl ester (350 mg, 0.601 mmol, 83.6%). LCMS: ESI m / z 583 [M+H] - .

[0551] Step H: [(4-nitrophenyl)oxy]carboxylic acid (1R,3S)-3-{5-[(3,3-dimethyl-1,1-dioxo-2,3-dihydro-1λ 6 -benzothiophen-5-yl)amino]-1H-pyrazol-3-yl}cyclopentyl ester at 25 ° C [(4-nitrophenyl)oxy] carboxylic acid (1R,3S)-3-{5-[(3,3-dimethyl-1,1-dioxo-2,3-dihydro-1λ 6 A solution of [(4-nitrophenyl)oxy]carboxylic acid (1R,3S)-3-{5-[(3,3-dimethyl-1,1-dioxo-2,3-dihydro-1λ-[(4-nitrophenyl)oxy]carboxylic acid) was prepared. 6 -benzothiophen-5-yl)amino]-1H-pyrazol-3-yl}cyclopentyl ester (280 mg, 0.532 mmol, 88.5%). LCMS: ESI m / z 527 [M+H] + .

[0552] Step I: (1R,3S)-3-{5-[(3,3-dimethyl-1,1-dioxo-2,3-dihydro-1λ-propan-2-ylamino)carboxylic acid 6 -benzothiophen-5-yl)amino]-2H-pyrazol-3-yl}cyclopentyl ester to (1R,3S)-3-{5-[(3,3-dimethyl-1,1-dioxo-2,3-dihydro-1λ-[(4-nitrophenyl)oxy]carboxylic acid 6 To a solution of]-1H-pyrazole-3-yl}cyclopentyl ester (280 mg, 0.532 mmol) in THF (5 mL) was added propan-2-amine (0.091 mL, 1.064 mmol) and the reactant was stirred at rt for 1 hour. The reaction mixture was concentrated in vacuo. The residue was purified by preparative HPLC to give the title compound (propan-2-ylamino) formic acid (1R, 3S)-3-{5-[(3,3-dimethyl-1,1-dioxo-2,3-dihydro-1λ) as a white solid. 6-benzothiophen-5-yl)amino]-2H-pyrazol-3-yl}cyclopentyl ester (83.5 mg, 0.187 mmol, 35.2%). LCMS: ESI m / z 447 [M+H] + . 1 H NMR (400MHz, DMSO) δ9.03(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).

[0553] Example 22: (1R,3S)-3-(3-((2,2-dioxo-1,3-dihydrobenzo[c]thiophen-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate

[0554]

[0555] 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), Cs2CO3 (529 mg, 1.62 mmol), Pd2(dba)3 (49.6 mg, 0.0540 mmol) and Xantphos (62.7 mg, 0.108 mmol). The reaction mixture was stirred at 100 ° C. under N2 atmosphere for 2 hours. The reaction was detected to be complete by LCMS. The cooled reaction mixture was dissolved in EA (10 mL * 3), washed with H2O (20 mL) and brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (eluted with 0-50% EA / PE) to give 2,2-dioxidized 5-((1-(tert-butyl)-3-((1S,3R)-3-((tert-butyldiphenylsilyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)amino)-1,3-dihydrobenzo[c]thiophene (300 mg, 0.478 mmol, 88.2%) as a white solid. LCMS:ESI m / z 628.92[M+H] + .

[0556] 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 hours. The reaction was detected as complete by LCMS. The solvent was removed in vacuo. EtOH (3 mL), HO (3 mL) and lithium hydroxide monohydrate (120 mg, 2.87 mmol) were then added to reach a basic pH. 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 H2O (10 mL) and brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (eluting with 0-50% EA / PE) to give 2,2-dioxidized 5-((1-(tert-butyl)-3-((1S,3R)-3-hydroxycyclopentyl)-1H-pyrazol-5-yl)amino)-1,3-dihydrobenzo[c]thiophene (260 mg, 0.668 mmol, 69.9%) as a yellow solid. LCMS: ESI m / z 390.51 [M+H] + .

[0557]

[0266] Step C: (1R,3S)-3-(1-(tert-Butyl)-5-((2,2-dioxo-1,3-dihydrobenzo[c]thiophen-5-yl)amino)-1H-pyrazol-3-yl)cyclopentyl (4-nitrophenyl) carbonate

[0267] 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 chloroformate (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 H2O (50 mL) and brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (eluting with 0-50% EA / PE) to give (1R,3S)-3-(1-(tert-butyl)-5-((2,2-dioxo-1,3-dihydrobenzo[c]thiophen-5-yl)amino)-1H-pyrazol-3-yl)cyclopentyl (4-nitrophenyl) carbonate as a yellow solid (120 mg, 0.216 mmol, 70.2%). LCMS: ESI m / z 555.62 [M+H] + .

[0558] A solution of (1R,3S)-3-(1-(tert-butyl)-5-((2,2-dioxo-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-dioxo-1,3-dihydrobenzo[c]thiophen-5-yl)amino)-1H-pyrazol-3-yl)cyclopentyl (4-nitrophenyl) carbonate as a yellow oil (105 mg, 0.211 mmol, 97.4%). LCMS: ESI m / z 499.51 [M+H] + .

[0559] A suspension of (1R,3S)-3-(5-((2,2-dioxo-1,3-dihydrobenzo[c]thiophen-5-yl)amino)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate (4-nitrophenyl) carbonate (105 mg, 0.211 mmol) in THF (2 mL) and propan-2-amine (0.0540 mL, 0.632 mmol) and DIEA (0.104 mL, 0.632 mmol) was stirred at room temperature for 3 hours. LCMS showed the reaction was complete. The reactants were dissolved in EA (50 mL), washed with H2O (10 mL) and brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (eluting with 0-12% MeOH / DCM) and preparative HPLC (C18, 15-95% MeCN / H2O with 0.1% NH4OH) to afford (1R,3S)-3-(3-((2,2-dioxo-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) δ11.74(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),4.42(s,2H),4.33(s,2H),3.58(s,1H),3.05(s,1H),2.50-2.4 2(m,1H),2.06-1.88(m,2H),1.79-1.56(m,3H),1.04(d,J=6.0Hz,6H).

[0560] Example 23: Racemic cis-3-(5-((2-methyl-1,1-dioxo-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate

[0561]

[0562] 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 methylamine-THF (5 mL, 10 mmol, 2 M in THF) and Et3N (7.74 mL, 55.6 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo and dissolved in EA (50 mL), washed with H2O (20 mL) and brine, dried over sodium sulfate and concentrated. The residue was purified by silica gel chromatography (eluting with 0-50% EA / 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] +

[0563] 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 rt. The reaction mixture was stirred at 80 ° C overnight. The cooled reaction mixture was concentrated. The subsequent 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 silica gel column chromatography eluted with EA / PE [gradient: 0-30%] to give 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] - .

[0564] 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 H o (2 mL) and MeOH (8 mL) was added NaOH (226 mg, 5.66 mmol). The reaction mixture was stirred at rt 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 Na sO , filtered and concentrated. The residue was purified by silica gel column chromatography eluting with EA / PE [gradient: 0-30%] to give 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]- .

[0565] Step D: Racemic cis-3-(5-((2-methyl-1,1-dioxo-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate was reacted with 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). To the solution 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), Pd2(dba)3 (2.84 mg, 0.003 mmol) and Cs2CO3 (25.2 mg, 0.077 mmol). The reaction mixture was stirred at 100°C under N2 atmosphere for 1.5 hours. The reaction was complete as determined by LCMS. The cooled reaction mixture was filtered. The filtrate was concentrated. The residue was purified by preparative HPLC (C18, 10-95% MeCN / HO containing 0.1% HCOOH) to give racemic cis-3-(5-((2-methyl-1,1-dioxo-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-3-yl)cyclopentylisopropylcarbamate (2 mg, 0.005 mmol, 14.8%) as a white solid. LCMS: ESI m / z 434.2 [M+H] + . 1 H NMR (400MHz, DMSO) δ11.93 (s, 1H), 9.06 (s, 1H), 7.59 (d, J = 8.4Hz, 1H), 7.50 (s, 1H), 7.34(d,J=8.4Hz,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).

[0566] Example 24: Racemic cis-(propan-2-ylamino)carboxylic acid 3-{5-[(1,1-dioxo-2,3-dihydro-1λ6-benzothiophen-5-yl)amino]-4-methyl-1H-pyrazol-3-yl}cyclopentyl ester

[0567]

[0568] Step A: Racemic cis-{[5-(3-hydroxycyclopentyl)-4-iodo-2-(2-methylpropan-2-yl)pyrazol-3-yl]amino}carboxylic acid benzyl ester To a solution of racemic cis-(1-(tert-butyl)-3-(3-hydroxycyclopentyl)-1H-pyrazol-5-yl)carbamate (4 g, 11.2 mmol) in acetonitrile (50 mL) was added 1-iodopyrrole-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 / petroleum ether (1% to 20%) to give the title compound, cis-{[5-(3-hydroxycyclopentyl)-4-iodo-2-(2-methylpropan-2-yl)pyrazol-3-yl]amino}carboxylic acid benzyl ester (5.2 g, 10.7 mmol, 96.1%), as a yellow solid. LCMS: 484.1 [M+H] + .

[0569] Step B: Racemic cis-{[4-iodo-2-(2-methylpropan-2-yl)-5-(3-{[(2-methylpropan-2-yl)diphenylsilanyl]oxy}cyclopentyl)pyrazol-3-yl]amino}carboxylic acid benzyl ester To a solution of cis-{[5-(3-hydroxycyclopentyl)-4-iodo-2-(2-methylpropan-2-yl)pyrazol-3-yl]amino}carboxylic acid benzyl ester (5.2 g, 10.7 mmol) in DCM (60 mL) at 0° C. 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). The reaction was stirred at room temperature for 18 hours. The reaction solution was dissolved in EtOAc (100 mL), washed with H O (200 mL) and brine, dried over sodium sulfate and concentrated. The residue was purified by silica gel chromatography (eluting with 60% ethyl acetate / petroleum ether) to give benzyl {[4-iodo-2-(2-methylpropan-2-yl)-5-(3-{[(2-methylpropan-2-yl)diphenylsilanyl]oxy}cyclopentyl)pyrazol-3-yl]amino}carboxylate (5.0 g, 6.93 mmol, 64.4%) as a white oil. LCMS: ESI m / z 720.0 [MH] - .

[0570] Step C: Racemic cis-4-methyl-2-(2-methylpropan-2-yl)-5-(3-{[(2-methylpropan-2-yl)diphenylsilanyl]oxy}cyclopentyl)pyrazol-3-amine To a mixture of cis-benzyl{[4-iodo-2-(2-methylpropan-2-yl)-5-(3-{[(2-methylpropan-2-yl)diphenylsilanyl]oxy}cyclopentyl)pyrazol-3-yl]amino}carboxylate (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 KCO (459 mg, 3.33 mmol) and Pd(dppf)Cl (81.1 mg, 0.111 mmol). The reaction was stirred at 110° C. for 3 h. 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)pyrazole-3-amine (140 mg, 0.294 mmol, 26.5%) as a pink oil. LCMS: 476.3 [M+H] +

[0571] Step D: Racemic cis 1,1-dioxido 5-((1-(tert-butyl)-3-(3-((tert-butyldiphenylsilyl)oxy)cyclopentyl)-4-methyl-1H-pyrazol-5-yl)amino)-2,3-dihydrobenzo[b]thiophene was added to a stirred mixture of cis 4-methyl-2-(2-methylpropan-2-yl)-5-(3-{[(2-methylpropan-2-yl)diphenylsilyl]oxy}cyclopentyl)pyrazol-3-amine (140 mg, To a mixture of 5-bromo-2,3-dihydro-1λ6-benzothiophene-1,1-dione (109.08 mg, 0.441 mmol), xant-PHOS (34.05 mg, 0.059 mmol), Cs2CO3 (191 mg, 0.589 mmol) and Pd2(dba)3 (26.9 mg, 0.029 mmol) in dioxane (10 mL) was added. The reaction mixture was stirred at 120 ° C under N2 for 3 hours. The cooled reaction mixture was diluted with water and extracted with EA (20 mL * 3). The combined organic layers were washed with brine and dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with PE / EA (100 / 1 to 3 / 1) to give the title compound, racemic cis-1,1-dioxido-5-((1-(tert-butyl)-3-(3-((tert-butyldiphenylsilyl)oxy)cyclopentyl)-4-methyl-1H-pyrazol-5-yl)amino)-2,3-dihydrobenzo[b]thiophene (110 mg, 0.171 mmol, 58.2%), as a yellow-green oil. LCMS: 642.5 [M+H] +

[0572] Step E: racemic cis 5-{[5-(3-hydroxycyclopentyl)-4-methyl-2-(2-methylpropane-2-yl)pyrazol-3-yl]amino}-2,3-dihydro-1λ6-benzothiophene-1,1-dione A solution of cis 1,1-dioxidized 5-((1-(tert-butyl)-3-(3-((tert-butyldiphenylsilyl)oxy)cyclopentyl)-4-methyl-1H-pyrazol-5-yl)amino)-2,3-dihydrobenzo[b]thiophene (150 mg, 0.234 mmol) in HCOOH (5 mL) was stirred at 40 ° C for 18 hours. The reaction mixture was concentrated. The residue was dissolved in methanol and the pH was adjusted to 12-13 with 2N lithium hydroxide aqueous solution. The reaction mixture was stirred at rt for 30 minutes 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 PE / EA (100 / 1 to 1 / 100) to give the title compound, cis-5-{[5-(3-hydroxycyclopentyl)-4-methyl-2-(2-methylpropan-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] +

[0573] Step F: Racemic cis 3-{5-[(1,1-dioxo-2,3-dihydro-1λ6-benzothiophen-5-yl)amino]-4-methyl-1-(2-methylpropan-2-yl)pyrazol-3-yl}cyclopentyl[(4-nitrophenyl)oxy]carboxylate A suspension of cis 5-{[5-(3-hydroxycyclopentyl)-4-methyl-2-(2-methylpropan-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 chloroformate (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 (eluted with 100% ethyl acetate / petroleum ether) to give cis-[(4-nitrophenyl)oxy]carboxylic acid 3-{5-[(1,1-dioxo-2,3-dihydro-1λ6-benzothiophen-5-yl)amino]-4-methyl-1-(2-methylprop-2-yl)pyrazol-3-yl}cyclopentyl ester (50 mg, 0.088 mmol, 39.4%) as a white solid. LCMS: 569.3 [M+H] + .

[0574] Step G: Racemic cis-[(4-nitrophenyl)oxy]carboxylic acid 3-{5-[(1,1-dioxo-2,3-dihydro-1λ6-benzothiophen-5-yl)amino]-4-methyl-1H-pyrazol-3-yl}cyclopentyl cis-[(4-nitrophenyl)oxy]carboxylic acid 3-{5-[(1,1-dioxo-2,3-dihydro-1λ6-benzothiophen-5-yl)amino]-4-methyl-1-(2-methylpropan-2-yl)pyrazol-3-yl}cyclopentyl ester (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, 3-{5-[(1,1-dioxo-2,3-dihydro-1λ6-benzothiophen-5-yl)amino]-4-methyl-1H-pyrazol-3-yl}cyclopentyl cis[(4-nitrophenyl)oxy]carboxylate (50 mg, 0.073 mmol, 83.2%) as a yellow oil. LCMS: 513.2 [M+H] +

[0575] Step H: Racemic cis-(propan-2-ylamino)carboxylic acid 3-{5-[(1,1-dioxo-2,3-dihydro-1λ6-benzothiophen-5-yl)amino]-4-methyl-1H-pyrazol-3-yl}cyclopentyl cis-[(4-nitrophenyl)oxy]carboxylic acid 3-{5-[(1,1-dioxo-2,3-dihydro-1λ6-benzothiophen-5-yl)amino]-4-methyl-1H-pyrazol-3-yl}cyclopentyl ester (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%-95% MeCN / HO containing 0.1% HCOOH) to give 3-{5-[(1,1-dioxo-2,3-dihydro-1λ6-benzothiophen-5-yl)amino]-4-methyl-1H-pyrazol-3-yl}cyclopentyl cis(propan-2-ylamino)carboxylate (18.9 mg, 0.044 mmol, 59.7%) as a white solid. LCMS: 433 [M+H] + . 1HNMR(400MHz,DMSO)δ11.82(s,1H),8.34(s,1H),7.45(d,J=8.4Hz,1H),7.2 9-7.19(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 ), 2.03-1.91 (m, 2H), 1.88 (s, 3H), 1.83-1.63 (m, 3H), 1.04 (d, J = 6.4Hz, 6H).

[0576] Example 25: (1R,3S)-3-{5-[(1-oxo-2,3-dihydro-1H-inden-5-yl)amino]-2H-pyrazol-3-yl}cyclopentyl (propan-2-ylamino)formate

[0577]

[0578] Step A: 5-({5-[(1S,3R)-3-{[dimethyl(2-methylprop-2-yl)silanyl]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), Cs2CO3 (617 mg, 1.89 mmol), Xant-PHOS (109 mg, 0.190 mmol) and Pd2(dba)3 (86.7 mg, 0.095 mmol). The reaction mixture was stirred at 120°C under N2 for 3 hours. 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 eluting with ethyl acetate / petroleum ether to give the title compound 5-({5-[(1S,3R)-3-{[dimethyl(2-methylprop-2-yl)silanyl]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] + .

[0579] Step B: 5-({5-[(1S,3R)-3-hydroxycyclopentyl]-2-(2-methylpropan-2-yl)pyrazol-3-yl}amino)-2,3-dihydro-1H-inden-1-one A mixture of 5-({5-[(1S,3R)-3-{[dimethyl(2-methylpropan-2-yl)silanyl]oxy}cyclopentyl]-2-(2-methylpropan-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 RT for 1 hour and then concentrated under reduced pressure. The residue was treated with a mixture of hydrated lithium hydroxide (26.9 mg, 0.642 mmol) in MeOH (9 mL) / HO (3 mL). The resulting mixture was stirred at rt for 2 hours and the mixture was concentrated under reduced pressure. The residue 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 5-({5-[(1S, 3R)-3-hydroxycyclopentyl]-2-(2-methylprop-2-yl)pyrazol-3-yl}amino)-2,3-dihydro-1H-indene-1-one (80 mg, 0.226 mmol, 70.5%) as a colorless oil. LCMS: ESI m / z 354[M+H] + .

[0580] To a solution of 5-({5-[(1S,3R)-3-hydroxycyclopentyl]-2-(2-methylpropan-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 chloroformate (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 h. The reaction solution was diluted with EA, washed with water and brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by flash chromatography to give (1R,3S)-3-[1-(2-methylpropan-2-yl)-5-[(1-oxo-2,3-dihydro-1H-inden-5-yl)amino]pyrazol-3-yl]cyclopentyl[(4-nitrophenyl)oxy]carboxylate (100 mg, 0.193 mmol, 68.1%) as a yellow solid. LCMS: ESI m / z 519 [M+H] - .

[0581] Step D: (1R,3S)-3-{5-[(1-oxo-2,3-dihydro-1H-inden-5-yl)amino]-1H-pyrazol-3-yl}cyclopentyl [(4-nitrophenyl)oxy]carboxylate A solution of (1R,3S)-3-[1-(2-methylpropan-2-yl)-5-[(1-oxo-2,3-dihydro-1H-inden-5-yl)amino]pyrazol-3-yl]cyclopentyl [(4-nitrophenyl)oxy]carboxylate (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]carboxylate (70 mg, 0.151 mmol, 78.5%) as a yellow oil. LCMS: ESI m / z 463 [M+H] + .

[0582] Step E: (1R,3S)-3-{5-[(1-oxo-2,3-dihydro-1H-inden-5-yl)amino]-2H-pyrazol-3-yl}cyclopentyl (propan-2-ylamino)formate 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]formate (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 rt 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-oxo-2,3-dihydro-1H-inden-5-yl)amino]-2H-pyrazol-3-yl}cyclopentyl (propan-2-ylamino)carboxylate (53 mg, 0.139 mmol, 91.5%) as a white solid. LCMS: ESI m / z 383 [M+H] + . 1H NMR (400MHz, DMSO) δ11.94(s,1H),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).

[0583] Example 26: (1R,3S)-3-(3-((1,1-dioxothiochroman-6-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate

[0584]

[0585] Step A: 6-bromo-3,4-dihydro-2H-1-benzothiazin-4-ol To a solution of 6-bromo-3,4-dihydro-2H-1-benzothiazin-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 hour. The reactant 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-benzothiazin-4-ol (900 mg, 3.67 mmol, 89.3%) as a brown oil. LCMS: m / z 245.13 [M+H] + .

[0586] Step B: 6-bromo-3,4-dihydro-2H-1-benzothiazine To a solution of 6-bromo-3,4-dihydro-2H-1-benzothiazine-4-ol (900 mg, 3.67 mmol) in TFA (10 mL) was added Et3SiH (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 / petroleum ether (gradient: 0-1%) to give the title compound 6-bromo-3,4-dihydro-2H-1-benzothiazine (840 mg, 3.67 mmol, 99.9%) as a colorless oil. LCMS: m / z 229.13 [M + H] + .

[0587] Step C: 1,1-dioxidized 6-bromothiochroman To a solution of 6-bromo-3,4-dihydro-2H-1-benzothiazine (900 mg, 3.93 mmol) in 1,2-dichloroethane (10 mL) was added 3-chloroperoxybenzoic acid (2.39 g, 11.8 mmol). The reactants were stirred at 60 ° C overnight. The reactants were 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 / petroleum ether (gradient: 0-30%) to give the title compound 1,1-dioxidized 6-bromothiochroman (780 mg, 2.99 mmol, 76.1%) as a pink solid. LCMS: m / z 261.13 [M + H] + .

[0588] 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), Pd2(dba)3 (105 mg, 0.115 mmol), Xant-PHOS (133 mg, 0.230 mmol) and Cs2CO3 (1.12 g, 3.48 mmol). The reactant was stirred at 100 ° C under N2 for 4 hours. The cooled reaction mixture was diluted with EA and water. The organic layer was separated, washed with saturated brine and concentrated in vacuo. The residue was purified by silica gel column chromatography eluted with ethyl acetate / petroleum ether (gradient: 0-30%) to give the title compound 1,1-dioxido 6- ((1- (tert-butyl) -3- ((1S, 3R) -3- ((tert-butyldimethylsilyl) oxy) cyclopentyl) -1H- pyrazol-5-yl) amino) thiochroman (400mg, 0.772mmol, 67.2%) as a yellow solid. LCMS: m / z 517.80 [M + H] + .

[0589] Step E: 1,1-dioxidized 6-((1-(tert-butyl)-3-((1S,3R)-3-hydroxycyclopentyl)-1H-pyrazol-5-yl)amino)thiochroman A solution of 1,1-dioxidized 6-((1-(tert-butyl)-3-((1S,3R)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)amino)thiochroman (150 mg, 0.240 mmol) in formic acid (5 mL) was stirred at room temperature for 1 hour and then concentrated in vacuo. The residue was dissolved in methanol and the pH was adjusted to 12-13 with 2N aqueous lithium hydroxide solution. The reaction was stirred at rt for 30 minutes and then diluted with EA and water. The organic layer was separated, washed with brine and concentrated. The residue was purified using silica gel column chromatography eluting with ethyl acetate / petroleum ether (gradient: 0-50%) to give the title compound, 1,1-dioxido6-((1-(tert-butyl)-3-((1S,3R)-3-hydroxycyclopentyl)-1H-pyrazol-5-yl)amino)thiochroman (90 mg, 0.176 mmol, 73.4%) as a yellow solid. LCMS: m / z 510.65 [M+H] + .

[0590] Step F: (1R, 3S) -3- (tert-butyl) -5- ((1,1- dioxothiochroman-6-yl) amino) -1H- pyrazol-3-yl) cyclopentyl (4-nitrophenyl) carbonate To a stirred solution of 1,1-dioxido 6- ((1- (tert-butyl) -3- ((1S, 3R) -3-hydroxycyclopentyl) -1H- pyrazol-5-yl) amino) thiochroman (300 mg, 0.743 mmol) in THF (5 mL) and DCM (5 mL) was added 4-nitrophenyl chloroformate (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 using silica gel column chromatography eluting with ethyl acetate / petroleum ether (gradient: 0-30%) to give the title compound, (1R,3S)-3-(1-(tert-butyl)-5-((1,1-dioxothiochroman-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] + .

[0591] Step G: (1R,3S)-3-(5-((1,1-dioxothiochroman-6-yl)amino)-1H-pyrazol-3-yl)cyclopentyl (4-nitrophenyl) carbonate A solution of (1R,3S)-3-(1-(tert-butyl)-5-((1,1-dioxothiochroman-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-dioxothiochroman-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] + .

[0592] A solution of (1R,3S)-3-(5-((1,1-dioxothiochroman-6-yl)amino)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate (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 / H2O) to give the title compound, (1R,3S)-3-(3-((1,1-dioxothiochroman-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 HNMR (400MHz, DMSO) δ11.88(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).

[0593] Example 27: (Propan-2-ylamino)formic acid (1s,4s)-4-{5-[(1,1-dioxo-2,3-dihydro-1λ 6 -Benzo[b]thiophen-6-yl)amino]-2H-pyrazol-3-yl}cyclohexyl ester

[0594]

[0595] Step A. 6-({5-[(1s,4s)-4-{[(2-methylpropan-2-yl)diphenylsilanyl]oxy}cyclohexyl]-1-(2-methylpropan-2-yl)pyrazol-3-yl}amino)-2,3-dihydro-1λ 6 -benzo[b]thiophene-1,1-dione was added to stirred 6-bromo-2,3-dihydro-1λ 6 To a solution of 1-benzo[2,1-b]thiophene-1,1-dione (104 mg, 0.42 mmol) in dioxane (2 mL) 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), Xant-PHOS (49 mg, 0.08 mmol), and CsCO (342 mg, 1.1 mmol). The reaction mixture was stirred at 100° C. under N for 2 hours. The cooled reaction mixture was poured into water (30 mL) and extracted with EtOAc (20 mL*2). The combined organic phases were washed with brine, dried over NaSO, filtered, and concentrated. The residue was purified by chromatography (silica gel, 0-60%, EtOAc / PE) to give 6-({5-[(1s,4s)-4-{[(2-methylpropan-2-yl)diphenylsilanyl]oxy}cyclohexyl]-1-(2-methylpropan-2-yl)pyrazol-3-yl}amino)-2,3-dihydro-1λ as a yellow solid 6 -Benzothiophene-1,1-dione (250 mg, 0.39 mmol, 92%). LCMS: m / z 642 [M+H] + .

[0596] Step B. 6-({5-[(1s,4s)-4-hydroxycyclohexyl]-1-(2-methylpropan-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-1λ6 -benzothiophene -1,1- dione (260mg, 0.41mmol) in HCOOH (5mL) was stirred overnight at rt. The reaction mixture was concentrated. EtOH (1mL) / H was then added O (3mL) and LiOH (15mg, 3.2mmol). The subsequent mixture was stirred for 2 hours at rt and then diluted with water (15mL), extracted with EtOAc (10mL*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 / DCM) to obtain 6- ({ 5- [(1s, 4s) -4- hydroxycyclohexyl] -1- (2- methylprop- 2-yl) pyrazole-3-yl} amino) -2,3- dihydro-1λ as a yellow solid. 6 -Benzothiophene-1,1-dione (130 mg, 0.32 mmol, 79%). LCMS: m / z 404 [M+H] + .

[0597] Step C. [(4-nitrophenyl)oxy]carboxylic acid (1s,4s)-4-{5-[(1,1-dioxo-2,3-dihydro-1λ 6 6-({5-[(1s,4s)-4-hydroxycyclohexyl]-1-(2-methylpropan-2-yl)pyrazol-3-yl}amino)-2,3-dihydro-1λ-benzo[b]thiophen-6-yl)amino]-2-(2-methylpropan-2-yl)pyrazol-3-yl}cyclohexyl ester was added to a stirred 1% ethanol solution at rt. 6 -Benzothiophene-1,1-dione (130mg, 0.32mmol) was slowly added to a solution of 4-nitrophenyl chloroformate (324mg, 1.6mmol), DMAP (13mg, 0.11mmol) and pyridine (2mL, 24mmol) in DCM (3mL) / THF (3mL). After stirring overnight at rt, the cooled mixture was poured into water (30mL) and extracted with EtOAc (20mL*2). The combined organic phase was washed with salt water, dried over Na2SO4, filtered and concentrated. The residue was purified by chromatography (silica gel, 0-10%, MeOH / DCM) to obtain [(4-nitrophenyl) oxy] formic acid (1s, 4s)-4-{5-[(1,1-dioxo-2,3-dihydro-1λ]-1-ol as a yellow solid. 6 [-benzothiophen-6-yl)amino]-2-(2-methylpropan-2-yl)pyrazol-3-yl}cyclohexyl ester (170 mg, 0.3 mmol, 92%). LCMS: m / z 569 [M+H] + .

[0598] Step D. (Propan-2-ylamino)carboxylic acid (1s,4s)-4-{5-[(1,1-dioxo-2,3-dihydro-1λ 6 [(4-nitrophenyl)oxy]carboxylic acid (1s,4s)-4-{5-[(1,1-dioxo-2,3-dihydro-1λ-[4-nitrophenyl)oxy]carboxylic acid]-2-(2-methylprop-2-yl)pyrazol-3-yl}cyclohexyl ester was added to a stirred solution of [(4-nitrophenyl)oxy]carboxylic acid (1s,4s)-4-{5-[(1,1-dioxo-2,3-dihydro-1λ-[ ... 6 To a solution of]-2-(2-methylprop-2-yl)pyrazole-3-yl}cyclohexyl ester (170 mg, 0.3 mmol) in THF (10 mL) was slowly added DIPEA (0.5 mL, 0.2 mmol) and propan-2-amine (0.5 mL, 3 mmol). After stirring at rt for 1 hour, the cooled mixture was poured into water (30 mL) and extracted with EtOAc (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, 0-10%, MeOH / DCM) to obtain (propan-2-ylamino) formic acid (1s, 4s)-4-{5-[(1,1-dioxo-2,3-dihydro-1λ 6 [M+H] + .

[0599] Step E. (Propan-2-ylamino)carboxylic acid (1s,4s)-4-{5-[(1,1-dioxo-2,3-dihydro-1λ 6 -benzo[b]thiophen-6-yl)amino]-2H-pyrazol-3-yl}cyclohexyl ester (1s,4s)-4-{5-[(1,1-dioxo-2,3-dihydro-1λ 6 A mixture of 1-benzothiophen-6-yl)amino]-2-(2-methylpropan-2-yl)pyrazol-3-yl}cyclohexyl ester (120 mg, 0.25 mmol) in HCOOH (3 mL) was stirred at 100 ° C for 5 hours. The reaction mixture was concentrated. The residue was purified by preparative HPLC (C18, 40-90% MeCN / 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-yl)-2-(1-benzothiophen-6-yl)amino]-2-(2-methylpropan-2-yl)pyrazol-3-yl}cyclohexyl ester as a white solid. 6-benzothiophen-6-yl)amino]-2H-pyrazol-3-yl}cyclohexyl ester (18 mg, 0.042 mmol, 17%). LCMS: m / z 433.2 [M+H] + . 1 H NMR (400MHz, DMSO) δ11.89(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).

[0600] Example 28: (1s,3s)-3-(3-((2,2-dioxo-1,3-dihydrobenzo[c]thiophen-5-yl)amino)-1H-pyrazol-5-yl)cyclobutyl isopropylcarbamate

[0601]

[0602] 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), Cs2CO3 (437 mg, 1.34 mmol), Pd2(dba)3 (40.9 mg, 0.0450 mmol) and Xantphos (51.7 mg, 0.089 mmol). The reaction mixture was stirred at 100 ° C. under N2 atmosphere for 1 hour. The reaction was detected to be complete by LCMS. The cooled reaction mixture was dissolved in EA (10mL*3), washed with H2O (20mL) and brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (eluting with 0-50% EA / PE) to give 2,2-dioxidated 5-((1-(tert-butyl)-3-((1s, 3s)-3-((tert-butyldiphenylsilyl)oxy)cyclobutyl)-1H-pyrazol-5-yl)amino)-1,3-dihydrobenzo[c]thiophene (250 mg, 0.407 mmol, 91.2%) as a yellow solid. LCMS:ESI m / z 614.89[M+H] + .

[0603] 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. The reaction was detected as complete by LCMS. The solvent was removed in vacuo. EtOH (2.5 mL), HO (2.5 mL) and lithium hydroxide monohydrate (50.2 mg, 1.20 mmol) were then added to reach a basic pH. 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 H2O (10 mL) and brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (eluted with 0-12% MeOH / DCM) to give 2,2-dioxidated 5- ((1- (tert-butyl) -3- ((1s, 3s) -3-hydroxycyclobutyl) -1H- pyrazol-5-yl) amino) -1,3-dihydrobenzo [c] thiophene (130 mg, 0.346 mmol, 86.8%) as a white solid. LCMS: ESI m / z 376.49 [M + H] + .

[0604]

[0266] 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 chloroformate (349 mg, 1.73 mmol) in DCM (3 mL) and THF (3 mL) was stirred at room temperature for 3 h. LCMS showed the reaction was complete. The solvent was removed in vacuo. The residue was dissolved in EA (5 mL * 3), washed with H2O (5 mL) and brine, dried over sodium sulfate, filtered, concentrated and purified by silica gel chromatography (eluted with 0-12% MeOH / DCM) to give (1s, 3s)-3-(1-(tert-butyl)-5-((2,2-dioxo-1,3-dihydrobenzo [c] thiophen-5-yl)amino)-1H-pyrazol-3-yl)cyclobutyl carbonate (4-nitrophenyl) (170 mg, 0.314 mmol, 90.8%) as a white solid. LCMS: ESI m / z 541.59 [M + H] + .

[0605] A solution of (1s,3s)-3-(1-(tert-butyl)-5-((2,2-dioxo-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-dioxo-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] + .

[0606] To a suspension of (1s,3s)-3-(5-((2,2-dioxo-1,3-dihydrobenzo[c]thiophen-5-yl)amino)-1H-pyrazol-3-yl)cyclobutyl isopropylcarbamate (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 H2O (10 mL) and brine, dried over sodium sulfate, filtered, concentrated and purified by silica gel chromatography (eluted with 0-12% MeOH / DCM) and preparative HPLC (C18, 15-95% MeCN / H2O containing 0.1% FA) to give (1s,3s)-3-(3-((2,2-dioxo-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 HNMR(400MHz,DMSO)δ8.55(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).

[0607] Example 29: (1R,3S)-3-{5-[(1-cyano-2,3-dihydro-1H-inden-5-yl)amino]-2H-pyrazol-3-yl}cyclopentyl (propan-2-ylamino)formate

[0608]

[0609] Step A: 5-({5-[(1S,3R)-3-{[dimethyl(2-methylprop-2-yl)silanyl]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 To the reaction mixture was added 4-[[(2-[(2-[(2-[(2-methyl-3-( ... The residue was purified by silica gel column chromatography eluting with ethyl acetate / petroleum ether to give the title compound 5-({5-[(1S,3R)-3-{[dimethyl(2-methylprop-2-yl)silanyl]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] + .

[0610] Step B: 5-({5-[(1S,3R)-3-hydroxycyclopentyl]-2-(2-methylpropan-2-yl)pyrazol-3-yl}amino)-2,3-dihydro-1H-indene-1-carbonitrile A mixture of 5-({5-[(1S,3R)-3-{[dimethyl(2-methylpropan-2-yl)silanyl]oxy}cyclopentyl]-2-(2-methylpropan-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 rt for 1 hour and then concentrated under reduced pressure. The residue was treated with a mixture of hydrated lithium hydroxide (24.5 mg, 0.584 mmol) in MeOH (5 mL) / HO (1 mL). The resulting mixture was stirred at rt for 1 hour and then concentrated under reduced pressure. The residue 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 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] + .

[0611] To a solution of 5-({5-[(1S,3R)-3-hydroxycyclopentyl]-2-(2-methylpropan-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 chloroformate (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 h. The reaction solution was diluted with EA, washed with water and brine, dried over anhydrous Na2SO4 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-methylpropan-2-yl)pyrazol-3-yl}cyclopentyl[(4-nitrophenyl)oxy]carboxylate (40 mg, 0.076 mmol, 34.41%) as a yellow oil. LCMS: ESI m / z 530 [M+H] + .

[0612] Step D: (1R,3S)-3-{5-[(1-cyano-2,3-dihydro-1H-inden-5-yl)amino]-1H-pyrazol-3-yl}cyclopentyl [(4-nitrophenyl)oxy]carboxylate A solution of (1R,3S)-3-{5-[(1-cyano-2,3-dihydro-1H-inden-5-yl)amino]-1-(2-methylpropan-2-yl)pyrazol-3-yl}cyclopentyl [(4-nitrophenyl)oxy]carboxylate (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]carboxylate (25 mg, 0.053 mmol, 69.9%) as a yellow oil. LCMS: ESI m / z 474 [M+H] + .

[0613] Step E: (1R,3S)-3-{5-[(1-cyano-2,3-dihydro-1H-inden-5-yl)amino]-2H-pyrazol-3-yl}cyclopentyl (propan-2-ylamino)formate 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]formate (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 rt 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 (propan-2-ylamino)carboxylate (1.5 mg, 0.004 mmol, 7.22%) as a white solid. LCMS: ESI m / z 394 [M+H] + . 1H NMR(400MHz,DMSO)δ11.68(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).

[0614] Example 30: (1R,3S)-3-{5-[(2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)amino]-1H-pyrazol-3-yl}cyclopentyl (propan-2-ylamino)formate

[0615]

[0616] 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 hours. The cooled reaction mixture was diluted with H O and extracted with EA. The organic layer was washed with brine, dried over Na SO , filtered and concentrated. The residue was purified by silica gel column chromatography eluting with EA / PE [gradient: 0-50%] to give 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] + .

[0617] Step B: 6-({5-[(1S,3R)-3-hydroxycyclopentyl]-2-(2-methylpropan-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-methylpropan-2-yl)pyrazol-3-yl]cyclopentan-1-ol (500 mg, 2.24 mmol) in dioxane (10 mL) was added Cs2CO3 (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), Pd2(dba)3 (205 mg, 0.22 mmol) and Xant-PHOS (259 mg, 0.45 mmol). The reaction mixture was stirred at 100 ° C under N2 overnight. The cooled reaction mixture was diluted with H2O and extracted with EA. The organic phase was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography eluted with EA / 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] + .

[0618] Step C: (1R,3S)-3-[5-({1-[(4-methoxyphenyl)methyl]-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl}amino)-1-(2-methylpropan-2-yl)pyrazol-3-yl]cyclopentyl [(4-nitrophenyl)oxy]formate To a solution of 6-({5-[(1S,3R)-3-hydroxycyclopentyl]-2-(2-methylpropan-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) were added 4-nitrophenyl chloroformate (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 / PE [gradient: 0-100%] to give (1R,3S)-3-[5-({1-[(4-methoxyphenyl)methyl]-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl}amino)-1-(2-methylpropan-2-yl)pyrazol-3-yl]cyclopentyl[(4-nitrophenyl)oxy]carboxylate (125 mg, 0.191 mmol, 62.2%) as a white solid. LCMS: ESI m / z 654 [M+H] + .

[0619] Step D: (1R,3S)-3-{5-[(2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)amino]-1H-pyrazol-3-yl}cyclopentyl [(4-nitrophenyl)oxy]carboxylate A solution of (1R,3S)-3-[5-({1-[(4-methoxyphenyl)methyl]-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl}amino)-1-(2-methylpropan-2-yl)pyrazol-3-yl]cyclopentyl [(4-nitrophenyl)oxy]carboxylate (125 mg, 0.191 mmol) in HCOOH (3 mL) was stirred at 100 °C overnight. The cooled reaction mixture was concentrated in vacuo to give (1R,3S)-3-{5-[(2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)amino]-1H-pyrazol-3-yl}cyclopentyl [(4-nitrophenyl)oxy]carboxylate (100 mg crude material) as a white solid. LCMS: ESI m / z 478 [M+H] + .

[0620] Step E: (1R,3S)-3-{5-[(2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)amino]-1H-pyrazol-3-yl}cyclopentyl (propan-2-ylamino)formate A solution of (1R,3S)-3-{5-[(2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)amino]-1H-pyrazol-3-yl}cyclopentyl [(4-nitrophenyl)oxy]formate (125 mg, 0.262 mmol) in propan-2-amine (3 mL) was stirred at RT for 4 hours. The reaction mixture was concentrated. The residue was purified by preparative HPLC to give the title compound (1R,3S)-3-{5-[(2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)amino]-1H-pyrazol-3-yl}cyclopentyl (propan-2-ylamino)carboxylate (2 mg, 0.075 mmol, 2.88%) as a white solid. LCMS: ESI m / z 398 [M+H] + . 1 H NMR (400MHz, DMSO) δ9.86 (s, 1H), 8.12 (s, 1H), 7.24 (s, 1H), 7.14 (d, J = 8.4Hz, 1H ),7.02(s,1H),6.75(d,J=8.4Hz,1H),5.64(s,1H),5.07(s,1H),3.15-3.05(m,2H ),2.86(t,J=7.2Hz,2H),2.55-2.50(m,1H),2.49-2.44(m,2H),2.11-2.05(m,1H) ,2.04-1.94(m,1H),1.85-1.70(m,2H),1.70-1.61(m,1H),1.11(d,J=6.4Hz,6H).

[0621] Example 31: (1R,3S)-3-{5-[(3-cyano-2,3-dihydro-1H-inden-5-yl)amino]-2H-pyrazol-3-yl}cyclopentyl (propan-2-ylamino)formate

[0622]

[0623] Step A: 6-({5-[(1S,3R)-3-{[dimethyl(2-methylprop-2-yl)silanyl]oxy}cyclopentyl]-2-(2-methylprop-2-yl)pyrazol-3-yl}amino)-2,3-dihydro-1H-indene-1-carbonitrile To a stirred mixture of (1R,3S)-3-[5-amino-1-(2-methylprop-2-yl)pyrazol-3-yl]cyclopentan-1-ol (20 mg, 0.09 mmol) in dioxane (15 mL) were added 5-bromo-1-methyl-2,3-dihydro-1H-indol-2-one (26.3 mg, 0.116 mmol), Xanthan Gum, and the like. Phos (103mg, 0.178mmol), Cs2CO3 (579mg, 1.78mmol) and Pd2(dba)3 (81.38mg, 0.089mmol). The reaction mixture was stirred at 100°C under N2 for 18 hours. The reaction was detected to be complete by LCMS. The residue was dissolved in EA (5mL*2), washed with H2O (10mL) and brine, dried over sodium sulfate and concentrated. The residue was purified by silica gel chromatography (eluted with 50% ethyl acetate / petroleum ether) to obtain 6- ({5- [(1S, 3R) -3- { [dimethyl (2- methylprop- 2-yl) silyl] oxy} cyclopentyl] -2- (2- methylprop- 2-yl) pyrazole-3-yl} amino) -2,3- dihydro -1H- indene -1- carbonitrile (340mg, 0.497mmol, 55.9%) as a yellow oil. LCMS:ESI m / z 479.6[M+H] + .

[0624] Step B: 6-({5-[(1S,3R)-3-hydroxycyclopentyl]-2-(2-methylprop-2-yl)pyrazol-3-yl}amino)-2,3-dihydro-1H-indene-1-carbonitrile A solution of 6-({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 (340 mg, 0.497 mmol) in HCOOH (5 mL) was stirred at rt for 2 hours. The reaction mixture was concentrated in vacuo. The residue was dissolved with methanol and the pH was adjusted to 12-13 with 2N lithium hydroxide aqueous solution. The reaction mixture was stirred at rt for 1 hour and then 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 eluting with MeOH and 1% NH4OH in DCM (gradient: 0-10%) to give the title compound 6-({5-[(1S,3R)-3-hydroxycyclopentyl]-2-(2-methylpropan-2-yl)pyrazol-3-yl}amino)-2,3-dihydro-1H-indene-1-carbonitrile (150 mg, 0.412 mmol, 82.8%) as a yellow oil. LCMS: 365.2 [M+H] + .

[0625] Step C: (1R,3S)-3-{5-[(3-cyano-2,3-dihydro-1H-inden-5-yl)amino]-1-(2-methylpropan-2-yl)pyrazol-3-yl}cyclopentyl[(4-nitrophenyl)oxy]formate A suspension of 6-({5-[(1S,3R)-3-hydroxycyclopentyl]-2-(2-methylpropan-2-yl)pyrazol-3-yl}amino)-2,3-dihydro-1H-indene-1-carbonitrile (100 mg, 0.274 mmol), pyridine (6 mL, 74.2 mmol), DMAP (3.35 mg, 0.027 mmol) and 4-nitrophenyl chloroformate (277 mg, 1.372 mmol) in THF (3 mL) and DCM (3 mL) was stirred at rt overnight. The solvent was removed in vacuo. The residue was dissolved in ethyl acetate (50 mL * 2), washed with brine, dried over sodium sulfate and concentrated. The residue was purified by silica gel chromatography (eluted with 100% ethyl acetate / petroleum ether) to give (1R, 3S)-3-{5-[(3-cyano-2,3-dihydro-1H-inden-5-yl)amino]-1-(2-methylpropan-2-yl)pyrazol-3-yl}cyclopentyl [(4-nitrophenyl)oxy]carboxylate (65 mg, 0.123 mmol, 44.7%) as a white solid. LCMS: 530.4 [M + H] + .

[0626] Step D: (1R,3S)-3-{5-[(3-cyano-2,3-dihydro-1H-inden-5-yl)amino]-1H-pyrazol-3-yl}cyclopentyl [(4-nitrophenyl)oxy]carboxylate A solution of (1R,3S)-3-{5-[(3-cyano-2,3-dihydro-1H-inden-5-yl)amino]-1-(2-methylpropan-2-yl)pyrazol-3-yl}cyclopentyl [(4-nitrophenyl)oxy]carboxylate (80 mg, 0.151 mmol) in HCOOH (8 mL) was stirred at 100 °C for 18 hours. The reaction was concentrated in vacuo to give the title compound (1R,3S)-3-{5-[(3-cyano-2,3-dihydro-1H-inden-5-yl)amino]-1H-pyrazol-3-yl}cyclopentyl [(4-nitrophenyl)oxy]carboxylate (50 mg, 0.106 mmol, 69.9%). LCMS: 474.3 [M+H] +

[0627] Step E: (1R,3S)-3-{5-[(3-cyano-2,3-dihydro-1H-inden-5-yl)amino]-2H-pyrazol-3-yl}cyclopentyl (propan-2-ylamino)formate A solution of (1R,3S)-3-{5-[(3-cyano-2,3-dihydro-1H-inden-5-yl)amino]-1H-pyrazol-3-yl}cyclopentyl [(4-nitrophenyl)oxy]formate (50 mg, 0.106 mmol) in propan-2-amine (1.81 mL, 21.1 mmol) was stirred at room temperature for 1 hour. The reaction mixture was concentrated and the residue was purified by preparative HPLC (C18, 5%-95% MeCN / HO containing 0.1% HCOOH) to give (1R,3S)-3-{5-[(3-cyano-2,3-dihydro-1H-inden-5-yl)amino]-2H-pyrazol-3-yl}cyclopentyl (propan-2-ylamino)carboxylate (6 mg, 0.015 mmol, 14.4%) as a white solid. LCMS: m / z 394.1 [M+H] + . 1H NMR(400MHz,MeOD)δ7.27(d,J=8.4Hz,2H),7.12(d,J=8.4Hz,1H),5.10(s,1H), 4.28(t,J=8.0Hz,1H),3.72-3.62(m,1H),3.25-3.15(m,1H),3.08-2.99(m,1H), 2.94(dt,J=16.0,8.0Hz,1H),2.66-2.51(m,2H),2.31(dq,J=12.8,8.0Hz,1H),2 .23-2.13(m,1H),2.00-1.84(m,3H),1.31(d,J=18.4Hz,2H),1.15-1.02(m,6H).

[0628] Example 32: (1R,3S)-3-(3-((2,2-difluoro-2,3-dihydro-1H-inden-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate

[0629]

[0630] Step A: 5-Bromo-2,2-difluoro-2,3-dihydro-1H-indene To a solution of 5-bromo-2,3-dihydro-1H-indene-2-one (500 mg, 2.37 mmol) in DCM (5 mL) was added diethyl(trifluoro-λ) 4 -sulfur)amine (1.6mL, 11.85mmol). The reaction mixture was stirred at rt overnight. The reaction mixture was diluted with DCM and water. The organic layer was separated, washed with brine and concentrated in vacuo. The residue was purified using silica gel column chromatography (eluted with 10% ethyl acetate / petroleum ether) to give the title compound 5-bromo-2,2-difluoro-2,3-dihydro-1H-indene (150mg, 0.65mmol, 27.2%) as a colorless oil. LCMS: 233 / 235[M+H] + .

[0631] S...

Claims

1. A compound having structural formula I: or a pharmaceutically acceptable form or isotopic derivative thereof, in Ring A is a 4- to 7-membered carbon ring; R 1 and R 2 Each of R is 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 Join together with the N atom to which they are bound to form a 4- to 7-membered unsubstituted or substituted heterocyclic ring; Each R 3 are independently selected from the group consisting of 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 atoms to which they are attached, they form a 3- to 5-membered unsubstituted or substituted carbocyclic ring; R 4 H, halogen, C 1-4 Alkyl, CN, NRR' or C(O)NRR'; R 5 yes in Ring B is a 4- to 7-membered carbocyclic or heterocyclic ring optionally containing a -S(O)2-, -C(O)-, -S(O)2NR-, -S(O)2NRC(O)-, -C(O)NR-, -OC(O)NR- or -C(O)NRC(O)- group; Y 1 and Y 2 Each of them is CR 6 or N and Y 3 and Y 4 Each of them is C, CR 6 or N; the restriction is Y 1 , Y 2 , Y 3 and Y 4 No more than one of them is N, and Y 3 or Y 4 is C and is R 5 a position at which bonding to the rest of the compound is possible; Each R 6 are independently selected from the group consisting of halogen, OH, CN, unsubstituted or substituted C 1-6 Alkyl, unsubstituted or substituted C 1-4 Alkoxy and C(O)NRR'; Each R 7 are independently selected from the group consisting of halogen, OR, CN, unsubstituted or substituted C 1-6 Alkyl and unsubstituted or substituted C 1-4 Alkoxy, or two R 7 Together with the carbon atoms to which they are attached, they form a 3- to 6-membered unsubstituted or substituted carbocyclic or heterocyclic ring; Each of R and R' is independently selected from H, unsubstituted or substituted C 1-6 alkyl or an unsubstituted or substituted 4- to 6-membered carbocyclic ring, or wherein R and R' are attached to the same N atom and together form an unsubstituted or substituted 4- to 6-membered heterocyclic ring; i is 0, 1, 2, 3, 4 or 5; and k is 0, 1, 2, 3, 4 or 5.

2. The compound of claim 1, wherein R 5 yes in Each R 6 are independently selected from the group consisting of halogen, OH, CN, unsubstituted or substituted C 1-6 Alkyl, unsubstituted or substituted C 1-4 Alkoxy and C(O)NRR'; α and β refer to R 5 a position at which it may be bonded to the rest of the compound; and j is 0, 1, 2, or 3.

3. The compound as claimed in claim 2, wherein R 5 is linked to the remainder of the compound at the β position:

4. The compound as claimed in claim 2, wherein R 5 is attached to the rest of the compound at the alpha position:

5. The compound of claim 1, wherein Y 1 , Y 2 , Y 3 and Y 4 At least one of is N.

6. The compound of claim 5, wherein Y 1 , Y 2 , Y 3 and Y 4 Only one of them is N.

7. The compound of claim 5 or 6, wherein Y 3 is C and R 5 In the Y 3 is connected to the rest of the compound at position:

8. A compound as described in any one of claims 5 to 7, wherein R 5 Selected from:

9. The compound of claim 5 or 6, wherein Y 4 is C and R 5 In the Y 4 is connected to the rest of the compound at position:

10. The compound of claim 5, 6 or 8, wherein R 5 Selected from:

11. The compound of any one of claims 1 to 10, wherein Ring B is selected from: in X 1 , X 2 , X 3 , X 4 and X 5 Each of is independently selected from S(O)2, C(O), NH, CH2 and O, subject to the following conditions: Two adjacent Xs 1 , X 2 , X 3 , X 4 or X 5 are not independently selected from S(O)2 and C(O); and Two adjacent Xs 1 , X 2 , X 3 , X 4 or X 5 are not each selected from NH and O.

12. The compound of claim 11, wherein one or both of X1 and X2 are selected from S(O)2 and C(O); and X3, X4 and X5 are not S(O)2 or C(O).

13. The compound of claim 11, wherein 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).

14. The compound of claim 11, wherein X1, X2, X3, X4 and X5 are not S(O)2 or C(O); and At least one of X1, X2, X3, X4 and X5 is CH2, wherein one or two H in CH2 are substituted by F; One H is replaced by CN and the other H is not replaced; or One H is replaced by CN and the other H is replaced by OR.

15. The compound of claim 1 or 3, wherein R 5 Selected from:

16. The compound of claim 1 or 4, wherein R 5 Selected from:

17. The compound of claim 1 or 7, wherein R 5 Selected from:

18. The compound of claim 1 or 7, wherein R 5 Selected from:

19. The compound of claim 1 or 7, wherein R 5 Selected from:

20. The compound of claim 1 or 7, wherein R 5 Selected from:

21. The compound of claim 1 or 9, wherein R 5 Selected from:

22. The compound of claim 1 or 9, wherein R 5 Selected from:

23. The compound of claim 1 or 9, wherein R 5 Selected from:

24. The compound of claim 1 or 9, wherein R 5 Selected from:

25. A compound as described in any one of claims 11-24, wherein two R 7 Together with the carbon atoms to which they are attached, they form a 3- to 6-membered unsubstituted or substituted carbocyclic ring.

26. A compound as described in any one of claims 11-24, wherein two R 7 Together with the carbon atoms to which they are attached they form a 3- to 6-membered unsubstituted or substituted heterocyclic ring containing one or more ring heteroatoms selected from O, S and N.

27. The compound of claim 1, wherein R 5 Selected from:

28. The compound of claim 1, wherein R 5 Selected from:

29. The compound of claim 1, wherein R 5 Selected from:

30. A compound as described in any one of claims 7 and 27-29, wherein Y 1 Yes N, Y 2 is CH and Y 4 It is CH.

31. A compound as described in any one of claims 7 and 27-29, wherein Y 1 It is CH, Y 2 is N and Y 4 It is CH.

32. A compound as described in any one of claims 7 and 27-29, wherein Y 1 It is CH, Y 2 is CH and Y 4 It is N.

33. A compound as described in any one of claims 7 and 27-29, wherein Y 1 , Y 2 and Y 4 Each of is CH.

34. The compound of claim 1, wherein R 5 Selected from:

35. The compound of claim 1, wherein R 5 Selected from:

36. The compound of claim 1, wherein R 5 Selected from:

37. A compound as described in any one of claims 9 and 34-36, wherein Y 1 Yes N, Y 2 is CH and Y 3 It is CH.

38. A compound as described in any one of claims 9 and 34-36, wherein Y 1 It is CH, Y 2 is N and Y 3 It is CH.

39. A compound as described in any one of claims 9 and 34-36, wherein Y 1 It is CH, Y 2 is CH and Y 3 It is N.

40. A compound as described in any one of claims 9 and 34-36, wherein Y 1 , Y 2 and Y 3 Each of is CH.

41. A compound as described in any one of claims 1-40, wherein R 1 is H and R 2 It is an unsubstituted or substituted straight chain or branched chain C1-C6 alkyl group.

42. A compound as described in any one of claims 1-40, wherein R 1 and R 2 Each of is independently an unsubstituted or substituted straight or branched C1-C6 alkyl group.

43. A compound as described in any one of claims 1-40, wherein R 1 and R 2 Together with the N atom to which they are bound, they join to form a 4- to 7-membered unsubstituted or substituted heterocyclic ring.

44. The compound of any one of claims 1-43, wherein Ring A is a 4- to 6-membered carbocyclic ring.

45. The compound of any one of claims 1-44, wherein Ring A is selected from:

46. ​​The compound of claim 45, wherein Ring A is selected from:

47. The compound of any one of claims 1-44, wherein Ring A is a 5-membered carbocyclic ring.

48. The compound of claim 47, wherein Ring A is:

49. A compound as described in any one of claims 45-48, wherein i is 0.

50. The compound of claim 1, having the following structural formula:

51. The compound of claim 50, wherein Y 1 Yes N, Y 2 is CH and Y 4 It is CH.

52. The compound of claim 50, wherein Y 1 It is CH, Y 2 is N and Y 4 It is CH.

53. The compound of claim 50, wherein Y 1 It is CH, Y 2 is CH and Y 4 It is N.

54. The compound of claim 1, having the following structural formula:

55. The compound of claim 54, wherein Y 1 Yes N, Y 2 is CH and Y 3 It is CH.

56. The compound of claim 54, wherein Y 1 It is CH, Y 2 is N and Y 3 It is CH.

57. The compound of claim 54, wherein Y 1 It is CH, Y 2 is CH and Y 3 It is N.

58. The compound of any one of claims 50-57, wherein Ring B is a 5-membered carbocyclic ring.

59. The compound of any one of claims 50-57, wherein Ring B is a 5-membered heterocyclic ring.

60. The compound of any one of claims 50-57, wherein Ring B is a 6-membered carbocyclic ring.

61. The compound of any one of claims 50-57, wherein Ring B is a 6-membered heterocycle.

62. The compound of any one of claims 50-61, wherein Ring B comprises a -S(O)2NH- group.

63. The compound of any one of claims 50-61, wherein Ring B comprises a -S(O)2- group.

64. The compound of any one of claims 50-61, wherein Ring B comprises a -C(O)NH- group.

65. The compound of any one of claims 50-61, wherein Ring B comprises a CH2 group.

66. A compound as described in any one of claims 50-61, wherein ring B contains a C(CN)R" group, wherein R" is H, OH, C 1-4 Alkyl or OC 1-4 alkyl.

67. A compound as described in any one of claims 50-66, wherein j is 0.

68. A compound as described in any one of claims 50-66, wherein j is 1.

69. The compound of any one of claims 50-66, wherein k is 0.

70. The compound of any one of claims 50-66, wherein k is 1.

71. A compound as described in any one of claims 50-66, wherein k is 2.

72. The compound of claim 70 or 71, wherein R 7 is unsubstituted or substituted C 1-6 alkyl.

73. A compound selected from:

74. A compound selected from:

75. A compound selected from:

76. A compound selected from:

77. The compound of any one of claims 1-76, having one or more deuterium atoms in place of hydrogen.

78. The compound of any one of claims 1-76, having a deuterium atom in place of a hydrogen atom.

79. A pharmaceutical composition comprising a compound according to any one of claims 1-78 and a pharmaceutically acceptable excipient, carrier or diluent.

80. The pharmaceutical composition of claim 79, which is suitable for oral administration.

81. A unit dosage form comprising the pharmaceutical composition according to claim 79 or 80.

82. The unit dosage form of claim 81, which is in the form of a tablet or a capsule.

83. A method for treating or ameliorating cancer or a related disease or condition, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any one of claims 1-78.

84. The method of claim 83, wherein the cancer is selected from breast cancer, ovarian cancer, bladder cancer, uterine cancer, prostate cancer, lung cancer, esophageal cancer, head and neck cancer, colorectal cancer, kidney cancer, liver cancer, pancreatic cancer, stomach cancer, and thyroid cancer.

85. The method of claim 83 or 84, wherein one or more of chemotherapy, radiation therapy, targeted therapy, immunotherapy, and hormone therapy is also administered to the subject being treated.

86. Use of a compound according to any one of claims 1-78 and a pharmaceutically acceptable excipient, carrier or diluent for the preparation of a medicament for treating a disease or condition.

87. The use of claim 86, wherein the disease or disorder is cancer.

88. The use of claim 87, wherein the cancer is selected from breast cancer, ovarian cancer, bladder cancer, uterine cancer, prostate cancer, lung cancer, esophageal cancer, head and neck cancer, colorectal cancer, kidney cancer, liver cancer, pancreatic cancer, stomach cancer and thyroid cancer.

89. A process for preparing a compound as described in any one of claims 1-78.

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