Anilino-pyrazole derivatives, compositions and methods thereof

Abstract

The invention provides novel anilino-pyrazole derivatives as a cyclin-dependent kinase 2 (CDK2) inhibitors. The invention also provides pharmaceutical compositions comprising the compounds and methods thereof for treating various conditions, diseases and disorders associated with or related to CDK2 activities, or associated with abnormal cell growth, such as tumor growth and cancer.

Description

ANILINO-PYRAZOLE DERIVATIVES, COMPOSITIONS AND METHODS THEREOF Cross-Reference to Related Application

[0001] This application claims priority to U.S. Application No. 63 / 610,519, filed on December 15, 2023, the disclosures of which are hereby incorporated by reference in their entirety.Technical Fields of the Invention

[0002] The invention generally relates to novel compounds and therapeutic uses thereof. More particularly, the invention provides novel anilino-pyrazole derivatives as a cyclin-dependent kinase 2 (CDK2) inhibitors. The invention also provides pharmaceutical compositions comprising the compounds and methods thereof for treating various conditions, diseases and disorders associated with or related to CDK2 activities, or associated with abnormal cell growth, such as tumor growth and cancer.Background of the Invention

[0003] A broad range of aggressive cancers overexpress and / or amplify 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): el5498.) CDK2, a.k.ci. 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 processes of cancer cells. There is increasing evidence that CDK2 plays a critical role in tumorigenesis. Over expression of CDK2 causes abnormal regulation of cell-cycle, leading to hyperproliferation in cancer cells. Selective CDK2 inhibition thus may provide a therapeutic benefit 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 P harm. & Ther. 82 (2-3):279-284.)

[0004] Although several small-molecule CDK2 inhibitors have progressed to clinical trials, CDK2-selectivity is highly desired. Identifying selective CDK2inhibitors has been challenging due to the extreme similarity between the active sites of CDK2 and other CDKs, especially CDK1. Since CDK1 is an essential cyclin dependent kinase in the cell cycle, inhibition of CDK1 can lead to severe side effects. (Wood, et al. 2018 Cell Chem. Biol. 26(1): 121— 130.e5; Brown, et al. 2015 Nature Comm. 6: 6769.)

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

[0006] The invention provides novel CDK2 inhibitors that have been shown to exhibit favorable potency and selectivity profdes over known CDK2 inhibitors. The novel compounds selectively target, bind to and inhibit the activity of CDK2 and lead to cell cycle arrest, the induction of apoptosis, and the inhibition of tumor cell proliferation. The compounds are also orally available with pharmacokinetic profiles suitable for development into an orally administered therapeutic agent for treating cancer, e.g., breast cancer, ovarian cancer, gastric cancer or lung cancer.

[0007] In one aspect, the invention generally relates to a compound having the structural Formula (I):or a pharmaceutically acceptable form or an isotope derivative thereof, whereinRing A is a 5- to 7-membered heterocyclic ring comprising an O; each of R1and R2is independently selected from the group consisting of H, unsubstituted or substituted Ci-Ce alkyl, and C3-C6 unsubstituted or substituted carbocyclic ring; or R1and R2, together with the N atom they are bound to, are joined to form a 4- to 7-membered, unsubstituted or substituted heterocyclic ring; each R3is independently selected from the group consisting of halogen, OH, CN, unsubstituted or substituted CM alkyl, unsubstituted or substituted C1-6 alkoxy, NO2, NRR’, or two R3’S, along with the carbon atom(s) they are bound to, form a 3 - to 5 -membered unsubstituted or substituted carbocyclic ring;R4is H, halogen, CM alkyl, CN, NRR’, or C(O)NRR’;R5iswhereinRing B is a 4- to 7-membered carbocyclic or heterocyclic ring optionally comprising 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; each of Y1and Y2is CR6or N, and each of Y3and Y4is C, CR6or N; provided that not more than one of Y1, Y2, Y3and Y4is N, and either Y3or Y4is C and being the positions where R5may be bonded to the rest of the compound; each R6is independently selected from the group consisting of halogen, OH, CN, unsubstituted or substituted Ci-6 alkyl, unsubstituted or substituted C1-4 alkoxy, and C(O)NRR’; each R7is independently selected from the group consisting of halogen, OR, CN, unsubstituted or substituted C1-6 alkyl, and unsubstituted or substituted C1-4 alkoxy, or two R7’s, along with the carbon atom(s) they are bound to, 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 unsubstituted or substituted 4- to 6-membered carbocyclic ring, or where R and R’ are attached to the same N atom, together form an unsubstituted or substituted 4- to 6-membered heterocyclic ring; i is 0, 1, 2, 3 or 4; and is 0, 1, 2, 3, 4 or 5.

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

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

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

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

[0012] 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 principles of organic chemistry, as well as specific functional moieties and reactivity, are described in “Organic Chemistry”, Thomas Sorrell, University Science Books, Sausalito: 2006.

[0013] As used herein, “at least” a specific value is understood to be that value and all values greater than that value.

[0014] The term “comprising”, when used to define compositions and methods, is intended to mean that the compositions and methods include the recited elements, but do not exclude other elements. The term “consisting essentially of’, when used to define compositions and methods, shall mean that the compositions and methods include the recited elements and exclude other elements of any essential significance to the compositions and methods. For example, “consisting essentially of’ refers to administration of the pharmacologically active agents expressly recited and excludes pharmacologically active agents not expressly recited. The term consisting essentially of does not exclude pharmacologically inactive or inert agents, e.g., pharmaceutically acceptable excipients, carriers or diluents. The term “consisting of’, when used to define compositions and methods, shall mean excluding trace elements of other ingredients and substantial method steps. Embodiments defined by each of these transition terms are within the scope of this invention.

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

[0016] In this specification and the appended claims, the singular forms "a," "an," and "the" include plural reference, unless the context clearly dictates otherwise.

[0017] As used herein, the terms “administration” of or “administering” a disclosed compound encompasses the delivery to a subject of a compound as described herein, or a prodrug or other pharmaceutically acceptable form thereof, using any suitable formulation or route of administration, as discussed herein.

[0018] As used herein, the term “co-administer” refers to the presence of two pharmacological agents in a subject’s body (e.g., in the blood) at the same time. The two pharmacological agents can be administered concurrently or sequentially.

[0019] The terms “disease”, “disorder” and “condition” are used interchangeably unless indicated otherwise.

[0020] As used herein, the terms "effective amount" or "therapeutically effective amount" refer to that amount of a compound or pharmaceutical composition described herein that is sufficient to affect the intended application including, but not limited to, disease treatment, as illustrated below.

[0021] In some embodiments, the amount is that effective for stop the progression or effect reduction of an inflammatory disease or disorder. In some embodiments, the amount is that effective for stop the progression or effect reduction of an immune system disorders. In some embodiments, the amount is that effective to stop the progression or effect reduction of an autoimmune disease or disorder. In some embodiments, the amount is that effective for stop the progression or effect reduction of a cardiovascular disease or disorder. In some embodiments, the amount is that effective for detectable killing or inhibition of the growth or spread of cancer cells; the size or number of tumors; or other measure of the level, stage, progression or severity of the cancer. In some embodiments, the amount is that effective for stop the progression or effect reduction of PPD, depression, insomnia, sleep apnea, restless legs syndrome, and narcolepsy, emotional disorders, depression, schizophrenia, bipolar disorder, obsessive-compulsive disorder, and other anxiety disorders, behavioral and pharmacological syndrome of dementia, or neurodegenerative diseases. In some embodiments, the amount is that effective for stop the progression or effect reduction of Parkinson's disease (PD). In some embodiments, the amount is that effective for stop the progression or effect reduction of Alzheimer's disease (AD).

[0022] The therapeutically effective amount can vary depending upon the intended application, or the subject and disease condition being treated, e.g., the desired biological endpoint, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the weight and age of the patient, which can readily be determined by one of ordinary skill in the art. Such amount may be administered as a single dosage or according to a regimen. The term also applies to a dose that will induce a particular response in target cells, e.g., reduction of cell migration. The specific dose will vary depending on, for example, the particular compounds chosen, the species of subject and their age / existing health conditions or risk for health conditions, the dosing regimen to be followed, the severity of the disease, whether it isadministered in combination with other agents, timing of administration, the tissue to which it is administered, and the physical delivery system in which it is carried.

[0023] As used herein, the terms “unsubstituted or substituted” and “optionally substituted” are used interchangeably and refer to where a given chemical moiety (e.g., an alkyl group) can (but is not required to) be bonded to other substituents (e.g., heteroatoms). For instance, an alkyl group that is optionally substituted can be a fully saturated alkyl chain (i.e. a pure hydrocarbon). Alternatively, the same optionally substituted alkyl group can have substituents different from hydrogen. For instance, it can, at any point along the chain be bounded to a halogen atom, a hydroxyl group, or any other substituent described herein. 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 further functional groups. Suitable substituents used in the optional substitution of the described groups include, without limitation, halogen, oxo, CN, -COOH, - CH2CN, -O-Ci-C6alkyl, Ci-C6alkyl, -OCi-C6alkenyl, -OCi-C6alkynyl, -Ci-C6alkenyl, -Ci-C6alkynyl, -OH, -OP(O)(OH)2, -OC(O)Ci-C6alkyl, -C(O)Ci-C6alkyl, -OC(O)OCi-C6alkyl, NH2, NH(CI-C6alkyl), N(CI-C6alkyl)2, -NHC(O)CI-C6alkyl, -C(O)NHCI-C6alkyl, -S(O)2-Ci-C6alkyl, -S(O)NHCI-C6alkyl, and S(O)N(CI-C6alkyl)2.

[0024] As used herein, a “pharmaceutically acceptable form” of a disclosed compound includes, but is not limited to, pharmaceutically acceptable salts, esters, hydrates, solvates, isomers, prodrugs, and isotopically labeled derivatives of disclosed compounds. In one embodiment, a "pharmaceutically acceptable form" includes, but is not limited to, pharmaceutically acceptable salts, esters, isomers, prodrugs and isotopically labeled derivatives of disclosed compounds. In some embodiments, a "pharmaceutically acceptable form" includes, but is not limited to, pharmaceutically acceptable salts, esters, stereoisomers, prodrugs and isotopically labeled derivatives of disclosed compounds.

[0025] In certain embodiments, the pharmaceutically acceptable form is a pharmaceutically acceptable salt. As used herein, the term "pharmaceutically acceptable salt" refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of subjects without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences (1977) 66: 1-19. Pharmaceutically acceptable salts of the compounds provided herein include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group 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, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3 -phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluene sulfonate, undecanoate, valerate salts, and the like. In some embodiments, organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, lactic acid, trifluoracetic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like.

[0026] 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 a 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+(Ci-4alkyl)4 salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and aryl sulfonate. 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, the pharmaceutically acceptable base addition salt can be chosen from ammonium, potassium, sodium, calcium, and magnesium salts.

[0027] In certain embodiments, the pharmaceutically acceptable form is a pharmaceutically acceptable ester. As used herein, the term "pharmaceutically acceptable ester" refers to esters that hydrolyze in vivo and include those that break down readily in the human body to leave the parent compound or a salt thereof. Such esters can act as a prodrug as defined herein. Pharmaceutically acceptable esters include, but are not limited to, alkyl, alkenyl, alkynyl, aryl, aralkyl, andcycloalkyl esters of acidic groups, including, but not limited to, carboxylic acids, phosphoric acids, phosphinic acids, sulfinic acids, sulfonic acids and boronic acids. Examples of esters include formates, acetates, propionates, butyrates, acrylates and ethylsuccinates. The esters can be formed with a hydroxy or carboxylic acid group of the parent compound.

[0028] In certain embodiments, the pharmaceutically acceptable form is a “solvate” (e.g., a hydrate). As used herein, the term “solvate” refers to compounds that further include a stoichiometric or non-stoichiometric amount of solvent bound by non-covalent intermolecular forces. The solvate can be of a disclosed compound or a pharmaceutically acceptable salt thereof. Where the solvent is water, the solvate is a "hydrate". Pharmaceutically acceptable solvates and hydrates are complexes that, for example, can 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 will be understood that the term "compound" as used herein encompasses the compound and solvates of the compound, as well as mixtures thereof.

[0029] In certain embodiments, the pharmaceutically acceptable form is a prodrug. As used herein, the term “prodrug” (or “pro-drug”) refers to compounds that are transformed in vivo to yield a disclosed compound or a pharmaceutically acceptable form of the compound. A prodrug can be inactive when administered to a subject, but is converted in vivo to an active compound, for example, by hydrolysis (e.g., hydrolysis in blood). In certain cases, a prodrug has improved physical and / or delivery properties over the parent compound. Prodrugs can increase the bioavailability of the compound when administered to a subject (e.g., by permitting enhanced absorption into the blood following oral administration) or which enhance delivery to a biological compartment of interest (e.g., the brain or lymphatic system) relative to the parent compound. Exemplary prodrugs include derivatives of a disclosed compound with enhanced aqueous solubility or active transport through the gut membrane, relative to the parent compound.

[0030] The prodrug compound often offers advantages of solubility, tissue compatibility or delayed release in a mammalian organism (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," A.C.S. Symposium Series, Vol. 14, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated in full by reference herein. Exemplary advantages of a prodrug can include, but are not limited to, its physical properties, such as enhanced water solubility for parenteral administration at physiological pH compared to the parent compound, or it can enhance absorption from the digestive tract, or it can enhance drug stability for long-term storage.

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

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

[0033] As used herein, the terms “treatment” or “treating” a disease or disorder refers to a method of reducing, delaying or ameliorating such a condition before or after it has occurred. Treatment may be directed at one or more effects or symptoms of a disease and / or the underlying pathology. Treatment is aimed to obtain beneficial or desired results including, but not limited to, therapeutic benefit and / or a prophylactic benefit. By therapeutic benefit is meant eradication or amelioration of the underlying disorder being treated. Also, a therapeutic benefit is achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the patient, notwithstanding that the patient can still be afflicted with the underlying disorder. For prophylactic benefit, the pharmaceutical compounds and / or compositions can be administered to a patient at risk of developing a particular disease, or to a patient reporting one or more of the physiologicalsymptoms of a disease, even though a diagnosis of this disease may not have been made. The treatment can be any reduction and can be, but is not limited to, the complete ablation of the disease or the symptoms of the disease. As compared with an equivalent untreated control, such reduction or degree of prevention is at least 5%, 10%, 20%, 40%, 50%, 60%, 80%, 90%, 95%, or 100% as measured by any standard technique.

[0034] 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 condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, halting, or reversing the progression of a disease or condition, or any combination thereof.

[0035] Compounds of the present invention are, subsequent to their preparation, preferably isolated and purified to obtain a composition containing an amount by weight equal to or greater than 95% (“substantially pure”), which is then used or formulated as described herein. In certain embodiments, the compounds of the present invention are more than 99% pure.

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

[0037] As used herein, the term an “isolated” or “substantially isolated” molecule (such as a polypeptide or polynucleotide) is one that has been manipulated to exist in a higher concentration than in nature or has been removed from its 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 non-subject-antibody materials with which it is associated in nature have been removed. For example, a polynucleotide or a 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." Further, recombinant DNA molecules contained in a vector are considered isolated for the purposes of the present invention. Isolated RNA molecules include in vivo or in vitro RNA replication products of DNA and RNA molecules. Isolated nucleic acid molecules further include synthetically produced molecules.Additionally, vector molecules contained in recombinant host cells are also isolated. Thus, not all “isolated” molecules need be “purified.”

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

[0039] 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 each value and subrange within the range. By way of example, “Ci-6 alkyl” is intended to encompass, Ci, C2, C3, C4, C5, Ce, C1-4, C1-3, C1-2, C2-5, C2 , C3-6, C3-5 and C4-6 alkyl groups.

[0040] As used herein, the term “alkyl” refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to ten carbon atoms (e.g., C1-10 alkyl). Whenever it appears herein, a numerical range such as “1 to 10” refers to each integer in the given range; e.g., “1 to 10 carbon atoms” means that the alkyl group can consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 10 carbon atoms, although the present definition also covers the occurrence of the term "alkyl" where no numerical range is designated. In some embodiments, “alkyl” can be a C 1-6 (e.g., Ci, C2, C3, C4, C5 or Ce) alkyl group. In some embodiments, alkyl groups have 1 to 10, 1 to 8, 1 to 6, or 1 to 3 carbon atoms. Representative saturated straight chain alkyls include, but are not limited to, -methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl, and -n-hexyl; while saturated branched alkyls include, but are not limited to, -isopropyl, -sec-butyl, -isobutyl, -tert-butyl, -isopentyl, 2- methylbutyl, 3 -methylbutyl, 2-methylpentyl, 3 -methylpentyl, 4-methylpentyl, 2-methylhexyl, 3- methylhexyl, 4-methylhexyl, 5 -methylhexyl, 2,3 -dimethylbutyl, and the like. The alkyl is attached to the parent molecule by a single bond. Unless stated otherwise in the specification, an alkyl group is optionally substituted by one or more of 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, mercapto, thio, alkylthio, arylthio, thiocarbonyl, nitro, oxo, phosphate, phosphonate, phosphinate, silyl, sulfinyl, sulfonyl, sulfonamidyl, sulfoxyl, sulfonate, urea, -Si(Rx)3 , -ORX, -SRX, -OC(O)-RX, -N(RX)2, - C(O)RX, -C(O)ORX, -OC(O)N(RX)2, -C(O)N(RX)2, -N(RX)C(O)ORX, -N(RX)C(O)RX, - N(RX)C(O)N(RX)2, -N(RX)C(NRX)N(RX)2, -N(Rx)S(O)tN(Rx)2(where t is 1 or 2), -P(=O)(RX)(RX), or -O-P(=O)(ORX)2 wherein each Rxis independently hydrogen, alkyl, haloalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl, and each of these moieties can be optionally substituted as defined herein. In a non-limiting embodiment, a substituted alkyl can be selected from fluoromethyl, difluoromethyl,trifluoromethyl, 2-fluoroethyl, 3-fluoropropyl, hydroxymethyl, 2-hydroxyethyl, 3 -hydroxypropyl, benzyl, and phenethyl.

[0041] Unless otherwise specifically defined, the term “aromatic” or “aryl” refers to cyclic, aromatic hydrocarbon groups that have 1 to 2 aromatic rings, including monocyclic or bicyclic groups such as phenyl, biphenyl or naphthyl. Where containing two aromatic rings (bicyclic, etc.), the aromatic rings of the aryl group may be joined at a single point (e.g., biphenyl), or fused (e.g., naphthyl). The aryl group may be optionally substituted by 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-Ce alkyl, Ci-Ce alkyl, -Ci-Ce alkenyl, -OCi-Ce alkynyl, -Ci-Ce alkenyl, -Ci-Ce alkynyl, -OH, -OP(O)(OH)2, -OC(O)Ci-C6alkyl, -C(O)Ci-C6alkyl, -OC(O)OCi-C6alkyl, NH2, NH(CI-C6alkyl), N(CI-C6alkyl)2, -S(O)2-Ci-C6alkyl, -S(O)NHCi-C6alkyl, and S(O)N(CI-C6alkyl)2. The substituents can themselves be optionally substituted. Furthermore, when containing two fused rings the aryl groups herein defined may have an unsaturated or partially saturated ring fused with a fully unsaturated ring. Exemplary ring systems of these aryl groups include indanyl, indenyl, tetrahydronaphthalenyl, and tetrahydrobenzoannulenyl.

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

[0043] As used herein, the terms “heteroaryl” or “hetero-aromatic” refer to groups having 5 to 14 ring atoms, preferably 5, 6, 9, or 10 ring atoms; having 6, 10, or 14 p electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to three heteroatoms per ring selected from the group consisting of N, O, and S. Examples of heteroaryl groups include acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, 6,7- dihydro-5H-pyrrolo[l,2- a]imidazole, furanyl, furazanyl, imidazolinyl, imidazolyl, IH-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5- oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, 6H-l,2,5-thiadiazinyl,1.2.3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3- triazolyl,1.2.4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, and xanthenyl. “Heteroaryl” also refers to bicyclic ring systems having, in addition to carbon atoms, from one to three heteroatoms per ring selected from the group consisting of N, O, and S in which one ring system may be saturated or partially saturated.

[0044] Heteroaryl groups may be substituted with 0, 1, 2, 3, or 4 substituents independently selected from alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonyl, alkylcarbonylalkyl, alkylcarbonyloxy, alkylthio, alkylthioalkyl, alkynyl, carboxy, carboxyalkyl, cyano, cyanoalkyl, formyl, haloalkoxy, haloalkyl, halogen, hydroxy, hydroxyalkyl, mercapto, nitro, -NZ1Z2, and (NZiZ2)carbonyl. The term "NZ1Z2" as used herein, means two groups, Zi and Z2, which are appended to the parent molecular moiety through a nitrogen atom. Zi 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 acetyhn ethylamino.

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

[0046] As used herein, the terms “cycloalkyl” and “carbocyclyl” each refers to a monocyclic or polycyclic radical that contains only carbon and hydrogen, and can be saturated or partially unsaturated. Unless stated otherwise in the specification, the term is intended to include both substituted and unsubstituted cycloalkyl groups. Partially unsaturated cycloalkyl groups can be termed "cycloalkenyl" if the carbocycle contains at least one double bond, or "cycloalkynyl" if the carbocycle contains at least one triple bond. Cycloalkyl groups include groups having from 3 to 13 ring atoms (i.e., C3-13 cycloalkyl). Whenever it appears herein, a numerical range such as "3 to 10" refers to each integer in the given range; e.g., "3 to 13 carbon atoms" means that the cycloalkyl group can consist of 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, etc., up to and including 13 carbon atoms. The term "cycloalkyl" also includes bridged and spiro-fused cyclic structures containing no heteroatoms. The term also includes monocyclic or fused-ring polycyclic (i.e., rings which share adjacent pairs of ring atoms) groups. Polycyclic aryl groups include bicycles, tricycles, tetracycles, and the like. In some embodiments, “cycloalkyl” can be a C3-8 cycloalkyl radical. In some embodiments, “cycloalkyl” can be a C3-5 cycloalkyl radical.Illustrative examples of cycloalkyl groups include, but are not limited to the following moieties: C3-6 carbocyclyl groups include, without limitation, cyclopropyl (C3), cyclobutyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (Ce), cyclohexenyl (Ce), cyclohexadienyl (Ce) and the like. Examples of C3-7 carbocyclyl groups include norbomyl (C7). Examples of C3-8 carbocyclylgroups include the aforementioned C3-7 carbocyclyl groups as well as cycloheptyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (Cs), bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl, and the like. Examples of C3-13 carbocyclyl groups include the aforementioned C3-8 carbocyclyl groups as well as octahydro- 1H indenyl, decahydronaphthalenyl, spiro[4.5]decanyl and the like. Unless stated otherwise in the specification, a cycloalkyl group can be optionally substituted by 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, mercapto, thio, alkylthio, arylthio, thiocarbonyl, nitro, oxo, phosphate, phosphonate, phosphinate, silyl, sulfinyl, sulfonyl, sulfonamidyl, sulfoxyl, sulfonate, urea, -Si(Ra)3 , -ORa, -SRa, -OC(O)-Ra, -N(Ra)2, - C(O)Ra, -C(O)ORa, -OC(O)N(Ra)2, -C(O)N(Ra)2, -N(Ra)C(O)ORa, -N(Ra)C(O)Ra, - N(Ra)C(O)N(Ra)2, -N(Ra)C(NRa)N(Ra)2, -N(Ra)S(O)tN(Ra)2(where t is 1 or 2), -P(=O)(Ra)(Ra), or -O-P(=O)(ORa)2where each Rais independently hydrogen, alkyl, haloalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl, and each of these moieties can be optionally substituted as defined herein. The terms “cycloalkenyl" and "cycloalkynyl" mirror the above description of "cycloalkyl" wherein the prefix "alk" is replaced with "alken" or "alkyn" respectively, and the parent "alkenyl" or "alkynyl" terms are as described herein. For example, a cycloalkenyl group can have 3 to 13 ring atoms, such as 5 to 8 ring atoms. In some embodiments, a cycloalkynyl group can have 5 to 13 ring atoms.

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

[0048] As used herein, the terms “heterocycle”, “heterocyclic” or “heterocyclo” refer to fully saturated or partially unsaturated cyclic groups, for example, 3- to 7-membered monocyclic, 7 to 12 membered bicyclic, or 10 to 15 membered spirocyclic or tricyclic ring systems, which have 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 of each ring may be substituted by a substituent. Each ring of theheterocyclic group containing a heteroatom may have 1, 2, 3 or 4 heteroatoms selected from nitrogen atoms, oxygen atoms and / or sulfur atoms, where the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatoms may optionally be quatemized. The heterocyclic group may be attached at any heteroatom or carbon atom of the ring or ring system. A heterocyclic group is optionally substituted. Examples of heterocyclic groups include, but not limited to, epoxy, azetidinyl, aziridinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, pyrrolidinonyl, piperidinyl, piperazinyl, imidazolidinyl, imidazopyridinyl, thiazolidinyl, dithianyl, trithianyl, dioxolanyl, oxazolidinyl, oxazolidinonyl, decahydroquinolinyl, piperidonyl, 4- piperidinonyl, quinuclidinyl, thiomorpholinyl, thiomorpholinyl 1,1 dioxide, morpholinyl, azepanyl, oxazepanyl, azabicyclohexanyls, azabicycloheptanyl, azabicyclooctanyls, azabicyclononanyls (e.g., octahydroindolizinyl), azaspiroheptanyls, dihydro- 1H,3H,5H- oxazolo[3,4-c]oxazolyl, tetrahydro- 1'H, 3 'H- spiro[cyclopropane-l,2'-pyrrolizine], hexahydro-lH- pyrrolizinyl, hexahydro- IH-pyrrolo [2,1- c][l,4]oxazinyl, octahydroindolizinyl, oxaazaspirononanyls, oxaazaspirooctanyls, diazaspirononanyls, oxaazabiocycloheptanyls, hexahydropyrrolizinyl 4(lH)-oxide, tetrahydro- 2H-thiopyranyl 1 -oxide and tetrahydro-2H- thiopyranyl 1 , 1 -dioxide .Detailed Description of the Invention

[0049] The invention is based in part on the discovery of novel CDK2 inhibitors that selectively target, bind to and inhibit the activity of CDK2. The novel compound have been shown to exhibit favorable potency and selectivity profiles over known CDK2 inhibitors, such as PF- 07104091. The compounds exhibit superior DMPK profiles suitable for development into an orally administered therapeutic agent for treating cancer, e.g., breast cancer, ovarian cancer, gastric cancer or lung cancer.

[0050] In one aspect, the invention generally relates to a compound having the structural Formula (I):or a pharmaceutically acceptable form or an isotope derivative thereof,whereinRing A is a 5- to 7-membered heterocyclic ring comprising an 0; each of R1and R2is independently selected from the group consisting of H, unsubstituted or substituted Ci-Ce alkyl, and C3-C6 unsubstituted or substituted carbocyclic ring; or R1and R2, together with the N atom they are bound to, are joined to form a 4- to 7-membered, unsubstituted or substituted heterocyclic ring; each R3is independently selected from the group consisting of halogen, OH, CN, unsubstituted or substituted C1-6 alkyl, unsubstituted or substituted C1-6 alkoxy, NO2, NRR’, or two R3’s, along with the carbon atom(s) they are bound to, form a 3 - to 5 -membered unsubstituted or substituted carbocyclic ring;R4is H, halogen, C1-4 alkyl, CN, NRR’, or C(O)NRR’;R5iswhereinRing B is a 4- to 7-membered carbocyclic or heterocyclic ring optionally comprising 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; each of Y1and Y2is CR6or N, and each of Y3and Y4is C, CR6or N; provided that not more than one of Y1, Y2, Y3and Y4is N, and either Y3or Y4is C and being the positions where R5may be bonded to the rest of the compound; each R6is independently selected from the group consisting of halogen, OH, CN, unsubstituted or substituted C1-6 alkyl, unsubstituted or substituted C1-4 alkoxy, and C(O)NRR’; each R7is independently selected from the group consisting of halogen, OR, CN, unsubstituted or substituted C1-6 alkyl, and unsubstituted or substituted C1-4 alkoxy, or two R7’s, along with the carbon atom(s) they are bound to, 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 unsubstituted or substituted 4- to 6-membered carbocyclic ring, or where R and R’ are attached to the same N atom, together form an unsubstituted or substituted 4- to 6-membered heterocyclic ring; i is 0, 1, 2, 3 or 4; andA is 0, 1, 2, 3, 4 or 5.

[0051] In certain embodiments of (I), Ring A is:wherein * herein refers to bonding to pyrazolyl ring of Formula (I).

[0052] In certain embodiments of (I), Ring A is selected from:

[0053] In certain embodiments, i is 0 and Ring A is selected from:

[0054] In certain embodiments of (I), none of Y1, Y2, Y3and Y4is N and R5iswherein each R6is independently selected from the group consisting of halogen, OH, CN, unsubstituted or substituted Ci-6 alkyl, unsubstituted or substituted Ci-4 alkoxy, and C(O)NRR’; a and P refer to positions where R5may be bonded to the rest of the compound; and j is 0, 1, 2 or 3.

[0055] In certain embodiments, R5is connected to the rest of the compound at the position:

[0056] In certain embodiments, R5is connected to the rest of the compound at the a position:

[0057] In certain embodiments of (I), at least one of Y1, Y2, Y3and Y4is N.

[0058] In certain embodiments of (I), only one of Y1, Y2, Y3and Y4is N.

[0059] In certain embodiments of (I), Y3is C and R5is connected to the rest of the compound at the Y3position:

[0060] In certain embodiments, R5is selected from:

[0061] In certain embodiments of (I), Y4is C and R5is connected to the rest of the compound at the Y4position:

[0062] In certain embodiments, R5is selected from:wherein each of X1, X2, X3, X4and X5is independently selected from S(O)2, C(O), NH, CH2 and O, provided that two neighboring X1, X2, X3, X4or X5are not each selected from S(O)2 and C(O); and two neighboring X1, X2, X3, X4or X5are not each selected from NH and O.

[0064] In certain embodiments, one or both of Xi and X2 is selected from S(O)2 and C(O); and none of X3, X4 and X5 is S(O)2 or C(O).

[0065] In certain embodiments, neither of Xi and X2 is S(O)2 or C(O); and one of X3, X4 and X5is S(O)2or C(O).

[0066] In certain embodiments, none of Xi, X2, X3, X4 and X5 is S(O)2 or C(O); and at least one of Xi, X2, X3, X4 and X5 is CH2, wherein one or both H’s in the CH2 are substituted with F; one of H’s is substituted with CN and the other H is unsubstituted; or one of H’s is substituted with CN and the other H is substituted with OR.

[0067] In certain embodiments, R5is selected from:

[0068] In certain embodiments, R5is selected from:

[0069] In certain embodiments, R5is selected from:

[0070]

[0071] In certain embodiments, R5is selected from:

[0072] In certain embodiments, R5is selected from:

[0073]

[0074] In certain embodiments, R5is selected from:

[0075] In certain embodiments, R5is selected from:

[0076] In certain embodiments, R5is selected from:

[0077] In certain embodiments, two R7’s, along with the carbon atom they are bound to, form a 3- to 6-membered (e.g., 3-, 4-, 5- or 6-membered) unsubstituted or substituted carbocyclic ring.

[0078] In certain embodiments, two R7’s, along with the carbon atom they are bound to, form a 3- to 6-membered (e.g., 3-, 4-, 5- or 6-membered) unsubstituted or substituted heterocyclic ring comprising one or more ring heteroatoms selected from O, S and N.

[0079] In certain embodiments, R5is selected from:Table 1

[0080] In certain embodiments, R5is selected from:Table 2

[0081] In certain embodiments, R5is selected from:Table 3

[0082] In certain embodiments of Tables 1-3, Y1is N, Y2is CH and Y4is CH.

[0083] In certain embodiments of Tables 1-3, Y1is CH, Y2is N and Y4is CH.

[0084] In certain embodiments of Tables 1-3, Y1is CH, Y2is CH and Y4is N.

[0085] In certain embodiments of Tables 1-3, each ofY1, Y2and Y4is CH.

[0086] In certain embodiments, R5is selected from:Table 4

[0087] In certain embodiments, R5is selected from:Table 5

[0088] In certain embodiments, R5is selected from:Table 6

[0089] In certain embodiments of Tables 4-6, Y1is N, Y2is CH and Y3is CH.

[0090] In certain embodiments of Tables 4-6, Y1is CH, Y2is N and Y3is CH.

[0091] In certain embodiments of Tables 4-6, Y1is CH, Y2is CH and Y3is N.

[0092] In certain embodiments of Tables 4-6, each ofY1, Y2and Y3is CH.

[0093] In certain embodiments of R5, R is H.

[0094] In certain embodiments of R5, R is an unsubstituted or substituted Ci-6 alkyl.

[0095] In certain embodiments, R is methyl.

[0096] In certain embodiments, R1is H and R2is an unsubstituted or substituted linear or branched Ci-Ce alkyl.

[0097] In certain embodiments, each of R1and R2is independently an unsubstituted or substituted linear or branched Ci-Ce alkyl.

[0098] In certain embodiments, R1and R2, together with the N atom they are bound to, are joined to form a 4- to 7-membered (e.g., 4-, 5-, 6- or 7-membered), unsubstituted or substituted heterocyclic ring.

[0099] In certain embodiments, compounds of the invention have the structural formula:

[0100] In certain embodiments, compounds of the invention have the structural formula selected from:

[0101] In certain embodiments of (Ia), Y1is N, Y2is CH and Y4is CH.

[0102] In certain embodiments of (Ia), Y1is CH, Y2is N and Y4is CH.

[0103] In certain embodiments of (Ia), Y1is CH, Y2is CH and Y4is N.

[0104] In certain embodiments, compounds of the invention have the structural formula:

[0105] In certain embodiments, compounds of the invention have the structural formula selected from:

[0106] In certain embodiments of (Ib), Y1is N, Y2is CH and Y4is CH.

[0107] In certain embodiments of (Ib), Y1is CH, Y2is N and Y4is CH.

[0108] In certain embodiments of (Ib), Y1is CH, Y2is CH and Y4is N.

[0109] In certain embodiments of (Ia) and (Ib), Ring B is 5-membered carbocyclic ring.

[0110] In certain embodiments of (Ia) and (Ib), Ring B is 5 -membered heterocyclic ring

[0111] In certain embodiments of (Ia) and (Ib), Ring B is 6-membered carbocyclic ring.

[0112] In certain embodiments of (Ia) and (Ib), Ring B is 6-membered heterocyclic ring.

[0113] In certain embodiments of (Ia) and (Ib), Ring B comprises a -S(O)2NH- group.

[0114] In certain embodiments of (Ia) and (Ib), Ring B comprises a -S(O)2- group.

[0115] In certain embodiments of (Ia) and (Ib), Ring B comprises a -C(O)NH- group.

[0116] In certain embodiments of (Ia) and (Ib), Ring B comprises a CH2 group.

[0117] In certain embodiments of (Ia) and (Ib), Ring B comprises a C(CN)R” group, whereinR” is H, OH, C1-4 alkyl or O-C1-4 alkyl.

[0118] In certain embodiments of (Ia) and (Ib), j is 0.

[0119] In certain embodiments of (Ia) and (Ib), j is 1.

[0120] In certain embodiments of (Ia) and (Ib), k is 0.

[0121] In certain embodiments of (Ia) and (Ib), k is 1.

[0122] In certain embodiments of (Ia) and (Ib), k is 2.

[0123] In certain embodiments of (Ia) and (Ib), R7is an unsubstituted or substituted C1-6 alkyl.

[0124] Exemplary compounds of the invention include:

[0125] Exemplary compounds of the invention include:

[0126] Exemplary compounds of the invention include:

[0127] Exemplary compounds of the invention include:

[0128] Compounds of the invention include deuterated versions of the disclosed compounds, for example, having one or more deuterium atoms in place of hydrogen.

[0129] In certain embodiments, the compound has one deuterium atom in place of a hydrogen atom.

[0130] In another aspect, the invention generally relates to a pharmaceutical composition comprising a compound disclosed herein and a pharmaceutically acceptable excipient, carrier, or diluent.

[0131] In certain embodiments, the pharmaceutical composition is suitable for oral administration.

[0132] In yet another aspect, the invention generally relates to a unit dosage form comprising a pharmaceutical composition disclosed herein.

[0133] In certain embodiments, is in the form of atablet. In certain embodiments, is in the form of a capsule.

[0134] In yet another aspect, the invention generally relates to a method for treating or reducing cancer, or a related disease or disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a compound disclosed herein.

[0135] In certain embodiments, the subject being treated is further administered one or more of chemotherapy, radiotherapy, targeted therapy, immunotherapy and hormonal therapy.

[0136] In certain embodiments, the method leads to one or more of: inhibiting cancer cell proliferation; inhibiting cancer cell invasiveness; inducing apoptosis of cancer cells; inhibiting cancer cell metastasis; and inhibiting angiogenesis.

[0137] In certain embodiments, the invention relates to a method of inhibiting cancer cell proliferation in a subject, comprising administering to the subject a compound of the invention, or a pharmaceutically acceptable salt thereof, in an amount effective to inhibit cell proliferation.

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

[0139] In certain embodiments, the invention relates to a method of inducing apoptosis in cancer cells in a subject, comprising administering to the subject a compound of the invention, or a pharmaceutically acceptable salt thereof, in an amount effective to induce apoptosis.

[0140] In certain embodiments, the invention relates to a method of inhibiting cancer cell metastasis in a subject, comprising administering to the subject a compound of the invention, or a pharmaceutically acceptable salt thereof, in an amount effective to inhibit cell metastasis.

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

[0142] Examples of diseases or disorders that may be treated or reduced by compositions or methods of the invention include, but are not limited to, tumors, cancers, inflammatory diseases, autoimmune diseases, and the like.

[0143] In certain embodiments, the compound of Formula I is administered to treat one or more of breast cancer, ovarian cancer, bladder cancer, uterine cancer, prostate cancer, lung cancer (including NSCLC, SCLC, squamous cell carcinoma or adenocarcinoma), esophageal cancer, head and neck cancer, colorectal cancer, kidney cancer (including RCC), liver cancer (including HCC), pancreatic cancer, stomach (i.e., gastric) cancer or thyroid cancer.

[0144] 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.

[0145] In certain embodiments, the compound of Formula I is administered to treat breast cancer, including, e.g., 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.

[0146] In certain embodiments, the breast cancer is endocrine resistant breast cancer, trastuzumab resistant breast cancer, or breast cancer demonstrating primary or acquired resistance to CDK4 / CDK6 inhibition.

[0147] In certain embodiments, the breast cancer is advanced or metastatic breast cancer.

[0148] In certain embodiments, the breast cancer is characterized by amplification or overexpression of CCNE1 and / or CCNE2.

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

[0150] 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.

[0151] In certain embodiments, the cancer is selected from the group consisting of breast cancer and ovarian cancer.

[0152] In certain such embodiments, the cancer is breast cancer or ovarian cancer characterized by amplification or overexpression of CCNE1 and / or CCNE2.

[0153] In certain embodiments, the cancer is (a) breast cancer or ovarian cancer; (b) characterized by amplification or overexpression of cyclin El (CCNE1) or cyclin E2 (CCNE2); or (c) both (a) and (b). In some embodiments, the cancer is ovarian cancer.

[0154] In yet another aspect, the invention generally relates to use of a compound disclosed herein, and a pharmaceutically acceptable excipient, carrier, or diluent, in preparation of a medicament for treating a disease or disorder.

[0155] Pharmaceutically acceptable carriers, adjuvants and vehicles that may be used in the pharmaceutical compositions of this 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 silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.

[0156] The pharmaceutical compositions of the invention include those suitable for oral, rectal, nasal, topical (including buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous and intradermal) administration. In certainembodiments, the compound of the formulae herein is administered transdermally (e.g., using a transdermal patch). Other formulations may conveniently be presented in unit dosage form, e.g., tablets and sustained release capsules, and in liposomes, and may be prepared by any methods well known in the art of pharmacy. See, for example, Remington’s Pharmaceutical Sciences, Mack Publishing Company, Philadelphia, PA (17th ed. 1985).

[0157] Such preparative methods include the step of bringing into association with the molecule to be administered ingredients such as the carrier that constitutes one or more accessory ingredients. In general, the compositions are prepared by uniformly and intimately bringing into association the active ingredients with liquid carriers, liposomes or finely divided solid carriers or both, and then if necessary, shaping the product.

[0158] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the compounds described herein or derivatives thereof are admixed with at least one inert customary excipient (or carrier) such as sodium citrate or dicalcium phosphate or (i) fillers or extenders, as for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid, (ii) binders, as for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia, (iii) humectants, as for example, glycerol, (iv) disintegrating agents, as for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate, (v) solution retarders, as for example, paraffin, (vi) absorption accelerators, as for example, quaternary ammonium compounds, (vii) wetting agents, as for example, cetyl alcohol, and glycerol monostearate, (viii) adsorbents, as for example, kaolin and bentonite, and (ix) lubricants, as 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 forms may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard- filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethyleneglycols, and the like. Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings and others known in the art.

[0159] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizing agents, and emulsifiers, such as for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3- butyleneglycol, dimethylformamide, oils, in particular, cottonseed oil, groundnut oil, com germoil, olive oil, castor oil, sesame oil, glycerol, tetrahydrofurfuryl alcohol, polyethyleneglycols, and fatty acid esters of sorbitan, or mixtures of these substances, and the like. Besides such inert diluents, the composition can also include additional agents, such as wetting, emulsifying, suspending, sweetening, flavoring, or perfuming agents.

[0160] The amount of the active compound administered will be dependent on the subject being treated, the severity of the disorder or condition, the route of administration, the disposition of the compound and the discretion of the prescribing physician. In some instances, dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be used without causing any harmful side effect, with such larger doses typically divided into several smaller doses for administration throughout the day.

[0161] Any appropriate route of administration can be employed, for example, oral, intramuscular, intravenous, transdermal, subcutaneous, sublingual, parenteral, nasal, pulmonary, inhalational, buccal, intraperitoneal, rectal, intrapleural, and intrathecal administration. 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 and on the nature of the active compound.

[0162] In certain preferred embodiments, the compound is administered orally.Pharmaceutical compositions of the present invention suitable for oral administration may be presented as discrete units such as capsules, sachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion, or packed in liposomes and as a bolus, etc. Soft gelatin capsules can be useful for containing such suspensions, which may beneficially increase the rate of compound absorption.

[0163] A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surface-active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets optionally may be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein. Methods of formulating such slow or controlled release compositions of pharmaceutically active ingredients, such as those herein and other compounds known in the art, are known in the art and described in several issued US Patents, some of which include, but are not limited to, US Patent Nos. 4,369,172; and 4,842,866, and references cited therein. Coatings can be used for delivery ofcompounds to the intestine (see, e.g., U.S. Patent Nos. 6,638,534, 5,217,720, and 6,569,457, 6,461,631, 6,528,080, 6,800,663, and references cited therein). A useful formulation for the compounds of this invention is the form of enteric pellets of which the enteric layer comprises hydroxypropylmethylcellulose acetate succinate.

[0164] In the case of tablets for oral use, carriers that are commonly used include lactose and com starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried cornstarch. When aqueous suspensions are administered orally, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening and / or flavoring and / or coloring agents may be added.

[0165] Compositions suitable for topical administration include lozenges comprising the ingredients in a flavored basis, usually sucrose and acacia or tragacanth; and pastilles comprising the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and acacia.

[0166] Compositions suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. The formulations may be presented in unit-dose or multi-dose containers, for example, sealed ampules and vials, and may be stored in a freeze dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets.

[0167] Such injection solutions may be in the form, for example, of a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to techniques known in the art using suitable dispersing or wetting agents (such as, for example, Tween 80) and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3 -butanediol. Among the acceptable vehicles and solvents that may be employed are mannitol, water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono- or diglycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically acceptable oils, such as olive oil or castor oil, especially in theirpoly oxyethylated versions. These oil solutions or suspensions may also contain a long -chain alcohol diluent or dispersant.

[0168] Compounds of the present invention may 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 mono- or multi-lamellar hydrated liquid crystals that are dispersed in an aqueous medium. Any non-toxic, physiologically acceptable and metabolizable lipid capable of forming liposomes can be used. The present compositions in liposome form can contain, in addition to a compound of the present invention, stabilizers, preservatives, excipients, and the like. The preferred lipids are the phospholipids and the phosphatidyl cholines (lecithins), both natural and synthetic. Methods to form liposomes are known in the art. See, for example, Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, N.Y. (1976), p. 33 et seq.

[0169] The pharmaceutical compositions of this invention may be administered in the form of suppositories for rectal administration. These compositions can be prepared by mixing a compound of this invention with a suitable non-irritating excipient which is solid at room temperature but liquid at the rectal temperature and therefore will melt in the rectum to release the active components. Such materials include, but are not limited to, cocoa butter, beeswax and polyethylene glycols.

[0170] The pharmaceutical compositions of this invention may be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and / or other solubilizing or dispersing agents known in the art.

[0171] Topical administration of the pharmaceutical compositions of this invention is especially useful when the desired treatment involves areas or organs readily accessible by topical application. For application topically to the skin, the pharmaceutical composition should be formulated with a suitable ointment containing the active components suspended or dissolved in a carrier. Carriers for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid petroleum, white petroleum, propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifying wax and water. Alternatively, the pharmaceutical composition can be formulated with a suitable lotion or cream containing the active compound suspended or dissolved in a carrier. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water. The pharmaceutical compositions of this invention may also betopically applied to the lower intestinal tract by rectal suppository formulation or in a suitable enema formulation. Topically-transdermal patches and iontophoretic administration are also included in this invention.

[0172] Methods of treatment disclosed herein may be employed in combination with or in addition to other therapies. In certain embodiments, the subject being treated is further administered one or more of chemotherapy, radiotherapy, taigeted therapy, immunotherapy, and hormonal therapy.

[0173] Exemplary additional therapeutically active agents include, but are not limited to, small organic molecules such as drug compounds, e.g., compounds approved by the U.S. Food and Drug Administration (FDA) as provided in the Code of Federal Regulations (CFR), peptides, proteins, carbohydrates, monosaccharides, oligosaccharides, polysaccharides, nucleoproteins, mucoproteins, lipoproteins, synthetic polypeptides or proteins, small molecules linked to proteins, glycoproteins, steroids, nucleic acids, DNAs, RNAs, nucleotides, nucleosides, oligonucleotides, antisense oligonucleotides, lipids, hormones, vitamins and cells.

[0174] In certain embodiments, a compound of the invention may be administered in combination with endocrine therapy, e.g., agents such as letrozole, fulvestrant, tamoxifen, exemestane, or anastrozole.

[0175] In some embodiments, a compound of the invention may be administered in combination with a chemotherapeutic agent, e.g., docetaxel, paclitaxel, cisplatin, carboplatin, capecitabine, gemcitabine or vinorelbine. In other embodiments, a compound of the invention may be administered in combination with an anti-HER2 agent, e.g., trastuzumab or pertuzumab.

[0176] In certain embodiments, the method disclosed herein is in combination with one or more of immune check point blockade, co-signaling of T cells, and tumor targeting antibody therapies.

[0177] In certain embodiments, the method further comprises administering a chemotherapeutic agent to the subject.

[0178] In certain embodiments, the method further comprises administering a radiotherapy to the subject. In certain embodiments, the method further comprises administering a targeted therapy to the subject. In certain embodiments, the method further comprises administering an immunotherapy to the subject. In certain embodiments, the method further comprises administering hormonal therapy to the subject.

[0179] As used herein, the term "chemotherapeutic agent" refers to a chemical compound useful in the treatment of cancer. Examples of chemotherapeutic agents include Erlotinib (TARCEVA®, Genentech / OSI Pharm.), Bortezomib (VELCADE®, Millennium Pharm.),Fulvestrant (FASLODEX®, AstraZeneca), Sutent (SU11248, Pfizer), Letrozole (FEMARA®, Novartis), Imatinib mesylate (GLEEVEC®, Novartis), PTK787 / ZK 222584 (Novartis), Oxaliplatin (Eloxatin®, Sanofi), 5-FU (5 -fluorouracil), Leucovorin, Rapamycin (Sirolimus, RAPAMUNE®, Wyeth), Lapatinib (TYKERB®, GSK572016, Glaxo Smith Kline), Lonafamib (SCH 66336), Sorafenib (BAY43-9006, Bayer Labs), and Gefitinib (IRESSA®, AstraZeneca), AG1478, AG1571 (SU 5271; Sugen), alkylating agents such as thiotepa and CYTOXAN® cyclosphosphamide; alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide and trimethylomelamine; acetogenins (especially bullatacin and bullatacinone); a camptothecin (including the synthetic analog topotecan); bryostatin; callystatin; CC-1065 (including its adozelesin, carzelesin and bizelesin synthetic analogs); cryptophycins (particularly cryptophycin 1 and cryptophycin 8); dolastatin; duocarmycin (including the synthetic analogs, KW-2189 and CB1-TM1); eleutherobin; pancratistatin; a sarcodictyin; spongistatin; nitrogen mustards such as chlorambucil, chlomaphazine, chlorophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimnustine; antibiotics such as the enediyne antibiotics (e.g., calicheamicin, especially calicheamicin gammall and calicheamicin omegall (Angew Chem. Inti. Ed. Engl. (1994) 33: 183-186); dynemicin, including dynemicin A; bisphosphonates, such as clodronate; an esperamicin; as well as neocarzinostatin chromophore and related chromoprotein enediyne antibiotic chromophores), aclacinomysins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, carabicin, caminomycin, carzinophilin, chromomycinis, dactinomycin, daunorubicin, detorubicin, 6- diazo-5-oxo-L-norleucine, ADRIAMY CIN® (doxorubicin), morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2- pyrrolino-doxorubicin and deoxydoxorubicin), epirubicin, esonibicin, idarubicin, marcellomycin, mitomycins such as mitomycin C, mycophenolic acid, nogalamycin, olivomycins, peplomycin, porfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; anti-metabolites such as methotrexate and 5 -fluorouracil (5-FU); folic acid analogs such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogs such as fludarabine, 6- mercaptopurine, thiamniprine, thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine; androgens such as calusterone, dromostanolone propionate, epitiostanol, mepitiostane, testolactone; anti-adrenals such as aminoglutethimide, mitotane, trilostane; folicacid replenisher such as frolinic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil; amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elformithine; elliptinium acetate; an epothilone; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidainine; maytansinoids such as maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidanmol; nitraerine; pentostatin; phenamet; pirarubicin; losoxantrone; podophyllinic acid; 2-ethylhydrazide; procarbazine; PSK® 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); urethan; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside ("Ara-C"); cyclophosphamide; thiotepa; taxoids, e.g., TAXOL® (paclitaxel; Bristol-Myers Squibb Oncology, Princeton, N.J.), ABRAXANE® (Cremophor-free), albumin-engineered nanoparticle formulations of paclitaxel (American Pharmaceutical Partners, Schaumberg, 111.), and TAXOTERE® (doxetaxel; Rhone- Poulenc Rorer, Antony, France); chloranmbucil; GEMZAR® (gemcitabine); 6-thioguanine; mercaptopurine; methotrexate; platinum analogs such as cisplatin and carboplatin; vinblastine; etoposide (VP- 16); ifosfamide; mitoxantrone; vincristine; NAVELBINE® (vinorelbine); novantrone; teniposide; edatrexate; daunomycin; aminopterin; capecitabine (XELODA®); ibandronate; CPT-11; topoisomerase inhibitor RFS 2000; difluoromethylomithine (DMFO); retinoids such as retinoic acid; and pharmaceutically acceptable salts, acids and derivatives of any of the above.

[0180] Examples of the second (or further) agent or therapy may include, but are not limited to, immunotherapies (e.g. PD-1 inhibitors (pembrolizumab, nivolumab, cemiplimab), PD-L1 inhibitors (atezolizumab, avelumab, durvalumab), CTLA4 antagonist, cell signal transduction inhibitors (e.g., imatinib, gefitinib, bortezomib, erlotinib, sorafenib, sunitinib, dasatinib, vorinostat, lapatinib, temsirolimus, nilotinib, everolimus, pazopanib, trastuzumab, bevacizumab, cetuximab, ranibizumab, pegaptanib, panitumumab and the like), mitosis inhibitors (e.g., paclitaxel, vincristine, vinblastine and the like), alkylating agents (e.g., cisplatin, cyclophosphamide, chromabucil, carmustine and the like), anti-metabolites (e.g., methotrexate, 5- FU and the like), intercalating anticancer agents, (e.g., actinomycin, anthracycline, bleomycin, mitomycin-C and the like), topoisomerase inhibitors (e.g., irinotecan, topotecan, teniposide and the like), immunotherapy agents (e.g., interleukin, interferon and the like) and antihormonal agents (e.g., tamoxifen, raloxifene and the like).

[0181] Certain compounds of the present invention may exist in particular geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis- and / ram-isomers. R- and .S'-cnantiomcrs. diastereomers, (D)-isomers, (L)-isomers, the racemic mixtures thereof, and other mixtures thereof, as falling within the scope of the invention. Additional asymmetric carbon atoms may be present in a substituent such as an alkyl group. All such isomers, as well as mixtures thereof, are intended to be included in this invention.

[0182] Isomeric mixtures containing any of a variety of isomer ratios may be utilized in accordance with the present invention. For example, where only two isomers are combined, mixtures containing 50:50, 60:40, 70:30, 80:20, 90: 10, 95:5, 96:4, 97:3, 98:2, 99: 1, or 100:0 isomer ratios are contemplated by the present invention. Those of ordinary skill in the art will readily appreciate that analogous ratios are contemplated for more complex isomer mixtures.

[0183] If, for instance, a particular enantiomer of a compound of the present invention is desired, it may be prepared by asymmetric synthesis, or by derivation with a chiral auxiliary, where the resulting diastereomeric mixture is separated and the auxiliary group cleaved to provide the pure desired enantiomers. Alternatively, where the molecule contains a basic functional group, such as amino, or an acidic functional group, such as carboxyl, diastereomeric salts are formed with an appropriate optically-active acid or base, followed by resolution of the diastereomers thus formed by fractional crystallization or chromatographic methods well known in the art, and subsequent recovery of the pure enantiomers.

[0184] Isotopically-labeled compounds are also within the scope of the present disclosure. As used herein, an "isotopically-labeled compound" refers to a presently disclosed compound 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 compounds presently disclosed include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as2H,3H,13C,14C,15N,18O,170,31P,32P,35S,18F, and36C1, respectively.

[0185] By isotopically-labeling the presently disclosed compounds, the compounds may be useful in drug and / or substrate tissue distribution assays. Tritiated (3H) and carbon-14 (14C) labeled compounds are particularly preferred fortheir ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (2H) can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances. Isotopically labeled compounds presently disclosed, including pharmaceutical salts, esters, and prodrugs thereof, can be prepared by any means known in the art.

[0186] Further, substitution of normally abundant hydrogen (1H) with heavier isotopes such as deuterium can afford certain therapeutic advantages, e.g., resulting from improved absorption, distribution, metabolism and / or excretion (ADME) properties, creating drugs with improved efficacy, safety, and / or tolerability. Benefits may also be obtained from replacement of normally abundant12C with13C. (See, WO 2007 / 005643, WO 2007 / 005644, WO 2007 / 016361, and WO 2007 / 016431.)

[0187] Stereoisomers (e.g., cis and trans isomers) and all optical isomers of a presently disclosed compound (e.g., R and S enantiomers), as well as racemic, diastereomeric and other mixtures of such isomers are within the scope of the present disclosure.

[0188] Compounds of the present invention are, subsequent to their preparation, preferably isolated and purified to obtain a composition containing an amount by weight equal to or greater than 95% (“substantially pure”), which is then used or formulated as described herein. In certain embodiments, the compounds of the present invention are more than 99% pure.

[0189] Solvates and polymorphs of the compounds of the invention are also contemplated herein. Solvates of the compounds of the present invention include, for example, hydrates.

[0190] Any appropriate route of administration can be employed, for example, parenteral, intravenous, subcutaneous, intramuscular, intraventricular, intracorporeal, intraperitoneal, rectal, or oral administration. 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 and on the nature of the active compound.

[0191] Compositions for parenteral injection comprise pharmaceutically-acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, as well as sterile powders for reconstitution into sterile injectable solutions or dispersions just prior to use. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), carboxymethylcellulose and suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters such as ethyl oleate. Proper fluidity may be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

[0192] These compositions can also contain adjuvants such as preservatives, wetting agents, emulsifying agents, and dispersing agents. Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paragen, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents such as sugars, sodium chloride, and the like. Prolonged absorption of the injectablepharmaceutical form may be brought about by the inclusion of agents which delay absorption, such as aluminum monostearate and gelatin.

[0193] Compounds of the present invention may 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 mono- or multi-lamellar hydrated liquid crystals that are dispersed in an aqueous medium. Any non-toxic, physiologically-acceptable and metabolizable lipid capable of forming liposomes can be used. The present compositions in liposome form can contain, in addition to a compound of the present invention, stabilizers, preservatives, excipients, and the like. The preferred lipids are the phospholipids and the phosphatidyl cholines (lecithins), both natural and synthetic. Methods to form liposomes are known in the art. See, for example, Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, N.Y. (1976), p. 33 et seq.

[0194] Total daily dose of the compositions of the invention to be administered to a human or other mammal host in single or divided doses may be in amounts, for example, from 0.0001 to 300 mg / kg body weight daily and more usually 1 to 300 mg / kg body weight. The dose, from 0.0001 to 300 mg / kg body, may be given twice a day.

[0195] Materials, compositions, and components disclosed herein can be used for, can be used in conjunction with, can be used in preparation for, or are products of the disclosed methods and compositions. It is understood that when combinations, subsets, interactions, groups, etc. of these materials are disclosed that while specific reference of each various individual and collective combinations and permutations of these compounds may not be explicitly disclosed, each is specifically contemplated and described herein. For example, if a method is disclosed and discussed and a number of modifications that can be made to a number of molecules including in the method are discussed, each and every combination and permutation of the method, and the modifications that are possible are specifically contemplated unless specifically indicated to the contrary. Likewise, any subset or combination of these is also specifically contemplated and disclosed. This concept applies to all aspects of this disclosure including, but not limited to, steps in methods using the disclosed compositions. Thus, if there are a variety of additional steps that can be performed, it is understood that each of these additional steps can be performed with any specific method steps or combination of method steps of the disclosed methods, and that each such combination or subset of combinations is specifically contemplated and should be considered disclosed.Examples

[0196] The following examples are given for the purpose of illustrating the invention, but not for limiting the scope or spirit of the invention.

[0197] Compounds of the invention, including those specifically disclosed herein above and herein below, may be prepared as described in the following schemes. Although the present invention has been described in detail with preferred embodiments, those of ordinary skill in the art should understand that modifications, variations, and equivalent replacements made to the present invention within the scope of the present invention belong to the protection of the present invention.AbbreviationsAbbreviation NameDCM Dichloromethane m-CPBA meta-Chloroperoxybenzoic acidDMSO Dimethyl sulfoxideEDTA Ethylenediaminetetraacetic acidEA or EtOAc Ethyl acetateHPLC High-performance liquid chromatographyLCMS Liquid chromatography-mass spectrometryO / N OvernightPBS Phosphate-buffered salinePd2(dba)3 Tris(dibenzylideneacetone)dipalladiumPE Petroleum etherPMB p-MethoxybenzylRT or rt Room temperatureSFC Supercritical fluid chromatographyPCC Pyridinium chlorochromateTHF TetrahydrofuranTLC Thin-layer chromatography(9,9-Dimethyl-9H-xanthene-4,5-Xantphos diyl)bis(diphenylphosphane)MaterialsName SourceCDKl / cyclinB BPSCDK2 / CycA2 CamaCDK2 / CycEl CamaPeptide 18 GLEDTA GibcoHEPES, pH7.5 GibcoBrij-35 solution SigmaMgC12 SigmaDTT SigmaEGTA Sigma96 well plate Coming384well plate ComingEXPERIMENTAL PROCEDURES:Synthesis of Common Intermediate Racemic cis 5-(3-amino-l-(tert-butyl)-lH-pyrazol-5-yl)tetrahydrofuran-3-yl isopropylcarbamate (Literature compound)EXPERIMENTAL PROCEDURES:1) Preparation of methyl 3-nitro-lH-pyrazole-5-carboxylate1 2

[0198] To a solution of 3-nitro-lH-pyrazole-5-carboxylic acid (Compound 1, 5.0 g, 31.83 mmol) in Methanol (50 mL) was added thionyl dichloride (9.85 g, 82.76 mmol) at 0°C. The resulting mixture was stirred at 65°C for 16 h. The solvent was removed under reduced pressure and the residue was diluted with H2O (100 mL). The pH value was adjusted to 8 by saturated aqueous NaHCO? solution. Then, the aqueous phase was extracted with EA (3 x 120 mL) and the organic layer was washed with water (2 x 30 mL), brine (2 x 30 mL), dried over anhydrous Na2SC>4, filtered and concentrated in vacuum to afford methyl 3-nitro-lH-pyrazole-5-carboxylate(Compound 2. LCMS m / z = 170.3 [M-H] ", 4.8 g, Yield: 88.1%), which was used as such for the next step without further purification.2) Preparation of methyl l-(tert-butyl)-3-nitro-lH-pyrazole-5-carboxylate2 3

[0199] To methyl 3-nitro-lH-pyrazole-5-carboxylate (20.0 g, 116.88 mmol) in tert-butanol (32.40 g, 437.13 mmol) and Toluene (160mL) was added Sulfuric acid (14.72 g, 150.08 mmol). Then the mixture was stirred at 70°C for 16 h. The reaction mixture was diluted with water (100 mL) and extracted with EA (3 x 150 mL). The combined organic layers were washed with brine (100 mL) dried over Na2SC>4, filtered and concentrated under reduced pressure to give a residue. Which was purified with silica gel column chromatography (eluted with 0~7% EtOAc in PE) to afford methyl l-(tert-butyl)-3-nitro-lH-pyrazole-5-carboxylate (Compound 3. LCMS m / z = 250.0 [M+23]+, 13 g, Yield: 49%).3) Preparation of (l-(tert-butyl)-3-nitro-lH-pyrazol-5-yl)methanol3 4

[0200] To a solution of Compound 3 (0.9 g, 3.96 mmol) in THF (10 mL) was added Lithium borohydride (0.26 g, 11.88 mmol) at 0°C and stirred at 25 °C for 16 h. The reaction mixture was diluted with water (20 mL) and extracted with EA (3 x 30 mL). The combined organic layers were washed with brine (20 mL) dried over Na2SC>4 filtered and concentrated under reduced pressure to give (l-(tert-butyl)-3-nitro-lH-pyrazol-5-yl)methanol (Compound 4. LCMS m / z = 222.0 [M+23]+, 0.4 g, Yield: 50.7%).4) Preparation of l-(tert-butyl)-3-nitro-lH-pyrazole-5-carbaldehyde4 5

[0201] To a solution of Compound 4 (80 g, 401.59 mmol) in DCM (800 mL) was added Manganese (IV) oxide (523.71 g, 6023.0 mmol) and stirred at 25 °C for 16 h. Reaction solution was filtered, the filtrate was dried over anhydrous magnesium sulfate and concentrated to afford l-(tert-butyl)-3-nitro-lH-pyrazole-5-carbaldehyde (Compound 5, 60 g, Yield: 75.8%). 'H NMR (400 MHz, CDC13) 5 9.93 (s, 1H), 7.32 (s, 1H), 7.58 (s, 1H), 1.76 (s, 9H).5) Preparation of l-(l-(tert-butyl)-3-nitro-lH-pyrazol-5-yl)but-3-en-l-ol

[0202] To a solution of Compound 5 (59.0 g, 299.20 mmol) in DCM (400 mL) and Water (100 mL) was added TBAI (11.05 g, 29.92 mmol) and potassium, trifluoro(prop-2-enyl)boranuide (88.55 g, 598.4 mmol) at 25 °C and stirring for 16 h. The reaction mixture was diluted with water (400 mL) and extracted with DCM (3 x 700 mL). The combined organic layers were washed with brine (200 mL) dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure to afford l-(l-(tert-butyl)-3-nitro-lH-pyrazol-5-yl)but-3-en-l-ol (Compound 6. LCMS m / z = 262.2 [M+23]+, 96.1 g, Yield: 134.3%, crude)6) Preparation of l-(l-(tert-butyl)-3-nitro-lH-pyrazol-5-yl)-2-(oxiran-2-yl)ethan-l-ol

[0203] To a solution of Compound 6 (86 g, 359.43 mmol) in DCM (800 mL) was added m- CPBA (218.92 g, 1.08 mol) at 25 °C and stirred for 16 h. The reaction mixture was quenched by the addition of the saturated aqueous NaHCCL solution. The organic layer was separated, and aqueous layer was extracted with EA (3 x 1000 mL). The mixture was evaporated to get the crude product, which was chromatographed on silica gel (eluted with 0-20% EtOAc in PE) to afford 1- (l-(tert-butyl)-3-nitro-lH-pyrazol-5-yl)-2-(oxiran-2-yl)ethan-l-ol (Compound 7. LCMS m / z = 278.2 [M+23]+, 30.1 g, Yield: 32.8%) as a yellow oil.7) Preparation of 5-(l-(tert-butyl)-3-nitro-lH-pyrazol-5-yl)tetrahydrofuran-3-ol

[0204] To a solution of Compound 7 (16 g, 62.67 mmol) in Dioxane (90 mL) was added Cone. H2SO4 (3.69 g, 37.61 mmol) at 25 °C and stirred at 50°C for 16 h. The reaction mixture was diluted with water (200 mL) and extracted with EA (3 x 400 mL). The combined organic layers were washed with brine (2 x 200 mL) dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure to give crude material, which was chromatographed on silica gel (eluted with 0-50% EtOAc in PE) to give 5-(l-(tert-butyl)-3-nitro-lH-pyrazol-5-yl)tetrahydrofuran-3-ol (Compound 8. LCMS m / z = 200.0 [M-55]+, 6.9 g, Yield: 43.1%) as a yellow oil.8) Preparation of 5-(l-(tert-butyl)-3-nitro-lH-pyrazol-5-yl)dihydrofuran-3(2H)-one

[0205] To solution of Compound 8 (5.5 g, 21.55 mmol) in DCM (55 mL) was added DMP (6.85 g, 16.16 mmol) at 25 °C and stirred for 16 h. The reaction suspension was filtered through a Celite pad, and the filtrate was concentrated to give the crude material, which was chromatographed on silica gel (eluted with 0-20% EtOAc in PE) to afford the 5-(l-(tert-butyl)-3- nitro-lH-pyrazol-5-yl)dihydrofuran-3(2H)-one (Compound 9. LCMS m / z = 276.2 [M+23]+. 3.2 g, Yield: 58.6%) as a white solid.9) Preparation of Racemic cis 5-(l-(tert-butyl)-3-nitro-lH-pyrazol-5-yl)tetrahydrofuran-3-ol9 10

[0206] To a solution of Compound 9 (2.0 g, 7.90 mmol) in THF (20 mL) was added IN LiBHEt3 solution in THF (8.7 mL, IN) at -60°C. Then the mixture was stirred at -60°C for 3 hours. The reaction mixture was diluted with water (30 mL) and extracted with EA (3 x 40 mL). The combined organic layers were washed with brine (10 mL) dried over anhydrous Na2SC>4,filtered and concentrated under reduced pressure to crude material, which was chromatographed on silica gel (eluted with 0-50% EtOAc in PE) to afford Racemic cis 5-(l-(tert-butyl)-3-nitro-lH- pyrazol-5-yl)tetrahydrofuran-3-ol (Compound 10. LCMS m / z = 256.2 [M+l]+, 1.79 g, Yield: 88.7%) as a yellow oil.10) Preparation of 4-nitrophenyl isopropylcarbamate

[0207] To solution of 4-nitrophenyl carbonochloridate (20.00 g, 338.35 mmol) in THF (150 mL) was added propan-2-amine (20 g, 338.35 mmol) and TEA (68.48 g, 676.7 mmol) in THF (50 mL) at 0°C. The reaction mixture was stirred at 25 °C for 24 h, The reaction mixture was concentrated under reduced pressure. The residue was partitioned between ethyl acetate (300 mL) and H2O (50 mL). The aqueous layer was extracted by EA (3 x 150 mL). Then combined organic layers were washed with water, followed by brine solution. The organic layer was dried over anhydrous MgSC>4 and evaporated to afford the crude material, which was chromatographed on silica gel (eluted with 0-20% EtOAc in PE) to afford 4-nitrophenyl isopropylcarbamate (Compound 11. LCMS m / z = 225.0 [M+l]+. 14.00 g, Yield: 18.4 %) as a white solid.11) Preparation of Racemic cis 5-(l-(tert-butyl)-3-nitro-lH-pyrazol-5-yl)tetrahydrofuran-3-yl isopropylcarbamate

[0208] To a solution of Compound 10 (2 g, 7.83 mmol) in THF (20.00 mL) was added NaH (0.47 g, 11.75 mmol) at 0°C and stirred for 30 min, then was added Compound 11 (2.6 g, 11.60 mmol) and stirred at 50°C for 16h. The reaction mixture was diluted with water (20 mL) and extracted with EA (3 x 90 mL). The combined organic layers were washed with brine (2 x 50mL), dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure to get residue, which was chromatographed on silica gel (eluted with 0-50% EtOAc in PE) to give the Racemic cis 5-(l-(tert-butyl)-3-nitro-lH-pyrazol-5-yl)tetrahydrofuran-3-yl isopropylcarbamate (Compound 12. LCMS m / z = 363.2 [M+23]+. 2.00 g, Yield: 75.1%) as a white solid.12) Preparation of Common Intermediate Racemic cis 5-(3-amino-l-(tert-butyl)-lH-pyrazol- 5-yl)tetrahydrofuran-3-yl isopropylcarbamate

[0209] To solution of Compound 12 (3 g, 8.81 mmol) in methanol (30 mL) was added 10% Pd / C (937.56 mg, 8.81 mmol). The resulting suspension was degassed with vacuum and back filled with EE gas, this cycle was repeated 3 times and stirred under H2 gas pressure of 1 atmosphere at 25 °C forl6 h. The mixture was filtered through a Celite pad, and the filtrate was concentrated to get the residue, which was chromatographed on silica gel (eluted with 0-30% EtOAc in PE) to give Racemic cis 5-(3-amino-l-(tert-butyl)-lH-pyrazol-5-yl)tetrahydrofuran-3-yl isopropylcarbamate (Common Intermediate. LCMS m / z = 311.2 [M+l]+. 2.45 g, Yield: 89.7%) as a yellow oil.General Procedure for analog synthesis:General Prep-HPLC purification condition:

[0210] Prep-HPLC(Waters 3767) Column: XBridge XBridge C18, 19*250mm, 10 um ; Mobile Phase A: 10mmol / L NH4HCO3 / H2O, B: ACN ; flow rate: 20ml / min.General Prep-chiral-SFC separation condition:

[0211] Column: DAICELCHIRALPAK®AS, Column size : 250*25 mm 10 pm. Mobile Phase A: Supercritical CO2. Mobile Phase B: EtOH or IPA (+0.1% 7.0mol / l Ammonia in MEOH). A:B=60:40. Wavelength : 214 rim. Flow: 120 ml / min. Column temp: RT. Back Pressure: 100 bar. Cycle time: 7 min.Example 1 and 2: Synthesis of (3S,5S)-5-(3-((l,l-dioxido-2,3-dihydrobenzo[d]isothiazol-5- yl)amino)-lH-pyrazol-5-yl)tetrahydrofuran-3-yl isopropylcarbamate and (3R,5R)-5-(3-((l,l- dioxido-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-lH-pyrazol-5-yl)tetrahydrofuran-3-yl isopropylcarbamateExample 1 Example 2Step A, Synthesis of Racemic cis 5-(l-(tert-butyl)-3-((l,l-dioxido-2,3- dihydrobenzo[d]isothiazol-5-yl)amino)-lH-pyrazol-5-yl)tetrahydrofuran-3-yl

[0212] To a solution of Common intermediate (435 mg, 1.40 mmol) and 5-bromo-2,3- dihydrobenzo[d]isothiazole 1,1-dioxide (347 mg, 1.4 mmol) in toluene (8 mb) was added Pd2(dba)? (64.10 mg, 0.07 mmol), Xantphos (40.50 mg, 0.07 mmol) and CS2CO3 (912.30 mg, 2.8 mmol) at 25 °C and stirred at 100°C for 16 h. The reaction mixture was diluted with water (30 mb) and extracted with EA (3 x 80 mb). The combined organic layers were washed with brine (2 x 20 mb) dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure to get the residue, which was purified by column chromatography on silica gel (eluted with 0-50% EtOAc in PE) to afford racemic cis 5-(l-(tert-butyl)-3-((l,l-dioxido-2,3- dihydrobenzo[d]isothiazol-5-yl)amino)-lH-pyrazol-5-yl)tetrahydrofuran-3-yl isopropylcarbamate (LCMS m / z = 478.2 [M+l]+. 325 mg, Yield: 48.57%) as a yellow solid.Step B, Preparation of 5-(3-((l,l-dioxido-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-lH- pyrazol-5-yl)tetrahydrofuran-3-yl isopropylcarbamate

[0213] A solution of racemic cis 5-(l-(tert-butyl)-3-((l,l-dioxido-2,3- dihydrobenzo[d]isothiazol-5-yl)amino)-lH-pyrazol-5-yl)tetrahydrofuran-3-yl isopropylcarbamate (310 mg, 0.65 mmol) in formic acid (6 mL) was stirred at 80°C for 5 h, Reaction mixture was concentrated under reduced pressure to afford the residue, which was chromatographed on silica gel (eluted with 0-30% MeOH in DCM) to afford cis and trans mixtures of 5-(3-((l,l-dioxido- 2,3 -dihydrobenzo [d] isothiazol-5-yl)amino)- lH-pyrazol-5 -yl)tetrahydrofuran-3 -yl isopropylcarbamate (LCMS m / z = 422.2 [M+l]+. 180 mg, Yield: 65.7%) as a yellow solid.Step C, HPLC separation to obtain racemic cis 5-(3-((l,l-dioxido-2,3- dihydrobenzo[d]isothiazol-5-yl)amino)-lH-pyrazol-5-yl)tetrahydrofuran-3-yl isopropylcarbamate and racemic trans 5-(3-((l,l-dioxido-2,3-dihydrobenzo[d]isothiazol-5- yl)amino)-lH-pyrazol-5-yl)tetrahydrofuran-3-yl isopropylcarbamate

[0214] The cis and trans mixtures of 5-(3-((l,l-dioxido-2,3-dihydrobenzo[d]isothiazol-5- yl)amino)-lH-pyrazol-5-yl)tetrahydrofuran-3-yl isopropylcarbamate (180 mg, 0.43 mmol) was purified by Prep-HPLC to get racemic cis 5-(3-((l,l-dioxido-2,3-dihydrobenzo[d]isothiazol-5- yl)amino)-lH-pyrazol-5-yl)tetrahydrofuran-3-yl isopropylcarbamate (25 mg, Yield: 14%) and racemic trans 5-(3-(( 1, 1 -dioxido-2, 3 -dihydrobenzo [d]isothiazol-5-yl)amino)- lH-pyrazol-5- yl)tetrahydrofuran-3-yl isopropylcarbamate (21 mg, Yield: 11.6%).Step D, SFC separation of racemic cis 5-(3-((l,l-dioxido-2,3-dihydrobenzo[d]isothiazol-5- yl)amino)-lH-pyrazol-5-yl)tetrahydrofuran-3-yl isopropylcarbamate to obtain (3S,5S)-5-(3- ((l,l-dioxido-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-lH-pyrazol-5-yl)tetrahydrofuran-3- yl isopropylcarbamate and (3R,5R)-5-(3-((l,l-dioxido-2,3-dihydrobenzo[d]isothiazol-5- yl)amino)-lH-pyrazol-5-yl)tetrahydrofuran-3-yl isopropylcarbamate

[0215] Racemic cis 5-(3-((l,l-dioxido-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-lH- pyrazol-5-yl)tetrahydrofuran-3-yl isopropylcarbamate (25 mg, 0.06 mmol) was purified by SFC to afford fraction 1, which was arbitrarily assigned as example 1, (3S,5S)-5-(3-((l,l-dioxido-2,3- dihydrobenzo[d]isothiazol-5-yl)amino)-lH-pyrazol-5-yl)tetrahydrofuran-3-yl isopropylcarbamate (9.26 mg, Yield: 36.7%). LCMS m / z = 422.2 [M+H]+. 'HNMR (400 MHz, MeOD-d4) 57.53- 7.50 (d, J= 8.6 Hz, 1H), 7.32 (s, 1H), 7.22-7.20 (d, J= 8.0 Hz, 1H), 5.97 (s, 1H), 5.23 (s, 1H), 4.98-4.85 (d, 1H), 4.35 (s, 2H), 4.06-4.04 (d, J= 10.0 Hz, 1H), 3.96 - 3.95 (d, J= 4.0 Hz, 1H), 3.68 - 3.67 (m, 1H), 2.76 - 2.69 (m, 1H), 2.27 - 2.03 (m, 1H), 1.30 (s, 1H), 1.12-0.90 (t, J= 6.4 Hz, 6H).

[0216] Fraction 2, which was arbitrarily assigned as example 2, (3R,5R)-5-(3-((l,l-dioxido- 2,3 -dihydrobenzo [d] isothiazol-5-yl)amino)- lH-pyrazol-5 -yl)tetrahydrofuran-3 -yl isopropylcarbamate (12.07 mg, Yield: 48.3%). LCMS m / z = 422.2 [M+H]+. 'HNMR (400 MHz, MeOD-d4) 57.52-7.50 (d, J= 8.6 Hz, 1H), 7.32 (s, 1H), 7.22-7.20 (d, J= 8.0 Hz, 1H), 5.97 (s, 1H), 5.23 (s, 1H), 4.98-4.85 (d, 1H), 4.35 (s, 2H), 4.06-4.04 (d, J= 10.0 Hz, 1H), 3.96 - 3.95 (d, J= 4.0 Hz, 1H), 3.68 - 3.67 (m, 1H), 2.72 - 2.70 (m, 1H), 2.19 - 2.10 (m, 1H), 1.30 (s, 1H), 1.12-0.90 (t, J = 6.4 Hz, 6H).Example 3 and 4: SFC separation of racemic trans 5-(3-((l,l-dioxido-2,3- dihydrobenzo[d]isothiazol-5-yl)amino)-lH-pyrazol-5-yl)tetrahydrofuran-3-yl isopropylcarbamate to obtain (3R,5S)-5-(3-((l,l-dioxido-2,3-dihydrobenzo[d]isothiazol-5- yl)amino)-lH-pyrazol-5-yl)tetrahydrofuran-3-yl isopropylcarbamate and (3S,5R)-5-(3-((l,l- dioxido-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-lH-pyrazol-5-yl)tetrahydrofuran-3-yl isopropylcarbamate

[0217] The racemic trans 5-(3-((l,l-dioxido-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-lH- pyrazol-5-yl)tetrahydrofuran-3-yl isopropylcarbamate (21 mg, 0.05 mmol) was separated by SFC to get fraction 1, which was arbitrarily assigned as example 3, (3S,5R)-5-(3-((l,l-dioxido-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-lH-pyrazol-5-yl)tetrahydrofuran-3-yl isopropylcarbamate (8.1 mg, Yield: 38%). LCMS m / z = 422.2 [M+H]+. 'HNMR (400 MHz, MeOD-d4) 5 7.52-7.50 (d, J= 8.6 Hz, 1H), 7.30 (s, 1H), 7.21-7.19 (d, J= 8.0 Hz, 1H), 5.99 (s, 1H), 5.30 (s, 1H), 5.13- 5.09 (m, 1H),4.58 (s, 1H), 4.35 (s, 2H), 4.24-4.20 (m, 1H), 3.78 - 3.75 (d, J= 12.0 Hz, 1H), 3.73 - 3.70 (m, 1H), 2.24 - 2.39 (m, 1H), 2.28 - 2.21 (m, 1H), 1.40 (s, 1H), 1.15-1.13 (d, J= 8.0 Hz, 6H).

[0218] Fraction 2, which was arbitrarily assigned as example 4, (3R,5S)-5-(3-((l,l-dioxido- 2,3 -dihydrobenzo [d] isothiazol-5-yl)amino)- lH-pyrazol-5 -yl)tetrahydrofuran-3 -yl isopropylcarbamate (6.88 mg, Yield: 32.00%). LCMS m / z = 422.2 [M+H]+'HNMR (400 MHz, MeOD-d4) 5 7.52-7.50 (d, J= 8.6 Hz, 1H), 7.30 (s, 1H), 7.21 (brS, 1H), 5.98 (s, 1H), 5.30 (s, 1H), 5.12-5.09 (m, 1H),4.58 (s, 1H), 4.35 (s, 2H), 4.24-4.20 (m, 1H), 3.78 - 3.75 (d, J= 12.0 Hz, 1H), 3.73 - 3.70 (m, 1H), 2.44 - 2.39 (m, 1H), 2.28 - 2.21 (m, 1H), 1.40 (s, 1H), 1.15-1.13 (d, J= 8.0 Hz, 6H).Example 5 and 6: Synthesis of (3S,5S)-5-(3-((l,l-dioxido-2,3-dihydrobenzo[b]thiophen-5- yl)amino)-lH-pyrazol-5-yl)tetrahydrofuran-3-yl isopropylcarbamate and (3R,5R)-5-(3-((l,l- dioxido-2,3-dihydrobenzo[b]thiophen-5-yl)amino)-lH-pyrazol-5-yl)tetrahydrofuran-3-yl isopropylcarbamateExample 5 Example 6Step A, Synthesis of racemic cis and trans mixtures of 5-(3-((l,l-dioxido-2,3- dihydrobenzo[b]thiophen-5-yl)amino)-lH-pyrazol-5-yl)tetrahydrofuran-3-yl isopropylcarbamate

[0219] Racemic cis and trans mixtures of 5-(3-((l,l-dioxido-2,3-dihydrobenzo[b]thiophen-5- yl)amino)-lH-pyrazol-5-yl)tetrahydrofuran-3-yl isopropylcarbamate (230 mg) were synthesized through the general procedure using 5-bromo-2,3-dihydrobenzo[b]thiophene 1,1-dioxide and common intermediate. LCMS m / z = 421.2 [M+l]+Step B, HPLC separation to obtain racemic cis 5-(3-((l,l-dioxido-2,3- dihydrobenzo[b]thiophen-5-yl)amino)-lH-pyrazol-5-yl)tetrahydrofuran-3-yl isopropylcarbamate and racemic trans 5-(3-((l,l-dioxido-2,3-dihydrobenzo[b]thiophen-5- yl)amino)-lH-pyrazol-5-yl)tetrahydrofuran-3-yl isopropylcarbamate

[0220] Prep-HPLC separation of the cis and trans racemic mixtures gave 80 mg (34.5%) of racemic cis 5-(3-((l,l-dioxido-2,3-dihydrobenzo[b]thiophen-5-yl)amino)-lH-pyrazol-5- yl)tetrahydrofuran-3-yl isopropylcarbamate and 43 mg (18.2%) of racemic trans 5 -(3 -((1,1- dioxido-2, 3 -dihydrobenzo [b]thiophen-5 -yl)amino)- lH-pyrazol-5 -yl)tetrahydrofuran-3 -yl isopropylcarbamate .Step C, SFC separation to of racemic cis 5-(3-((l,l-dioxido-2,3-dihydrobenzo[b]thiophen-5- yl)amino)-lH-pyrazol-5-yl)tetrahydrofuran-3-yl isopropylcarbamate to obtain (3S,5S)-5-(3- ((l,l-dioxido-2,3-dihydrobenzo[b]thiophen-5-yl)amino)-lH-pyrazol-5-yl)tetrahydrofuran-3- yl isopropylcarbamate and (3R,5R)-5-(3-((l,l-dioxido-2,3-dihydrobenzo[b]thiophen-5- yl)amino)-lH-pyrazol-5-yl)tetrahydrofuran-3-yl isopropylcarbamate

[0221] Racemic cis 5 -(3 -((1,1 -dioxido-2, 3 -dihydrobenzo [b]thiophen-5-yl)amino)-lH-pyrazol-5-yl)tetrahydrofuran-3-yl isopropylcarbamate (80 mg) was purified by SFC to afford fraction 1, which was arbitrarily assigned as example 5, ((3S,5S)-5-(3-((l,l-dioxido-2,3- dihydrobenzo[b]thiophen-5-yl)amino)-lH-pyrazol-5-yl)tetrahydrofuran-3-yl isopropylcarbamate (15.2 mg, Yield: 19%). LCMS m / z = 421.2 [M+H]+, 'HNMR (400 MHz, CDCh) 57.68 (d, J= 8.0 Hz, lH), 7.17 (s, 1H), 7.11-7.09 (d, J= 8.0 Hz, 1H), 5.96 (s, lH), 5.36 (s, lH), 5.13 (s, 1H), 4.94 (s, 1H), 4.18-4.15 (d, J= 12.0 Hz 1H), 3.97 (s, 1H), 3.77 (s, 1H), 3.50-3.46 (t, J= 6.8 Hz, 2H), 3.33-3.29 (t, J= 6.8 Hz, 2H), 2.74 - 2.70 (m, 1H), 1.16 - 1.11 (m, 6H). fraction 2 (20.2 mg, Yield: 25.3%)., which was arbitrarily assigned as example 6, (3R,5R)-5-(3- ((1,1 -dioxido-2, 3 -dihydrobenzo [b]thiophen-5 -yl)amino)- lH-pyrazol-5 -yl)tetrahydrofuran-3 -yl isopropylcarbamate. LCMS m / z = 421.2 [M+H]+, 'HNMR (400 MHz, CDCh) 5 7.68 (d, J= 8.0 Hz, lH), 7.17 (s, 1H), 7.11-7.09 (d, J = 8.0 Hz, 1H), 5.96 (s, 1H), 5.36 (s, lH), 5.13 (s, lH), 4.94 (s,1H), 4.18-4.15 (d, J= 12.0 Hz 1H), 3.97 (s, 1H), 3.77 (s, 1H), 3.50-3.46 (t, J= 6.8 Hz, 2H), 3.33- 3.29 (t, J= 6.8 Hz, 2H), 2.74 - 2.70 (m, 1H), 1.16 - 1.11 (m, 6H).Example 7 and 8: Preparation of (3S,5R)-5-(3-((l,l-dioxido-2,3-dihydrobenzo[b]thiophen-5- yl)amino)-lH-pyrazol-5-yl)tetrahydrofuran-3-yl isopropylcarbamate and (3R,5S)-5-(3-((l,l- dioxido-2,3-dihydrobenzo[b]thiophen-5-yl)amino)-lH-pyrazol-5-yl)tetrahydrofuran-3-yl isopropylcarbamateExample 7 Example 8SFC separation to of racemic trans 5-(3-((l,l-dioxido-2,3-dihydrobenzo[b]thiophen-5- yl)amino)-lH-pyrazol-5-yl)tetrahydrofuran-3-yl isopropylcarbamate to obtain (3S,5R)-5-(3- ((l,l-dioxido-2,3-dihydrobenzo[b]thiophen-5-yl)amino)-lH-pyrazol-5-yl)tetrahydrofuran-3- yl isopropylcarbamate and (3R,5S)-5-(3-((l,l-dioxido-2,3-dihydrobenzo[b]thiophen-5- yl)amino)-lH-pyrazol-5-yl)tetrahydrofuran-3-yl isopropylcarbamate

[0222] Racemic trans 5-(3-((l,l-dioxido-2,3-dihydrobenzo[b]thiophen-5-yl)amino)-lH- pyrazol-5-yl)tetrahydrofuran-3-yl isopropylcarbamate (43 mg) was purified by SFC to afford fraction 1 (15.7 mg, Yield: 36.6%), which was arbitrarily assigned as example 7, ((3S,5R)-5-(3- ((1,1 -dioxido-2,3 -dihydrobenzo [b]thiophen-5 -yl)amino)- lH-pyrazol-5 -yl)tetrahydrofuran-3 -yl isopropylcarbamate (15.2 mg, Yield: 19%). LCMS m / z = 421.2 [M+H]+. 'H NMR (400 MHz, CDC13) 57.58-7.55 (d, J= 12.0 Hz, 1H), 7.20 (s, 1H), 7.06-7.02 (d, J= 8.0 Hz, 1H), 6.39(s, 1H), 5.89 (s, 1H), 5.36 (s, 1H), 5.18-5.14 (t, J= 8.0 Hz, ,1H), 4.62-4.54 (m, 1H), 4.22-4.16 (m, 1H), 3.99-3.96 (d, J= 12.0 Hz,lH), 3.48-3.40 (t, J= 6.8 Hz, 2H), 3.33-3.28 (t, J= 6.8 Hz, 2H), 2.50 - 2.48 (d, J= 8.0 Hz, 1H), 2.22-2.18 (m, 1H), 1.19 - 1.17 (d, J= 8.0 Hz, 6H). fraction 2 (14.3 mg, Yield: 33.3%)), which was arbitrarily assigned as example 8, ((3R,5S)-5-(3- ((1,1 -dioxido-2,3 -dihydrobenzo [b]thiophen-5 -yl)amino)- lH-pyrazol-5 -yl)tetrahydrofuran-3 -yl isopropylcarbamate. LCMS m / z = 421.2 [M+H]+. 'H NMR (400 MHz, CDCh) 5 7.58-7.56 (d, J = 12.0 Hz, 1H), 7.21 (s, 1H), 7.06-7.00 (m, 1H), 6.37 (s, 1H), 5.89 (s, 1H), 5.36 (s, 1H), 5.18-5.14(t, J= 8.0 Hz, ,1H), 4.62-4.54 (m, 1H), 4.22-4.16 (m, 1H), 3.99-3.96 (d, J= 12.0 Hz,lH), 3.48-3.40 (t, J= 6.8 Hz, 2H), 3.33-3.28 (t, J= 6.8 Hz, 2H), 2.50 - 2.48 (d, J= 8.0 Hz, 1H), 2.22-2.18 (t, J = 8.0 Hz, 1H).1.19 - 1.17 (d, J= 8.0 Hz, 6H).Example 9 and 10: Synthesis of (3S,5S)-5-(3-((l,l-dioxido-2,3-dihydrobenzo[b]thiophen-4- yl)amino)-lH-pyrazol-5-yl)tetrahydrofuran-3-yl isopropylcarbamate and (3R,5R)-5-(3-((l,l- dioxido-2,3-dihydrobenzo[b]thiophen-4-yl)amino)-lH-pyrazol-5-yl)tetrahydrofuran-3-yl isopropylcarbamateExample 9 Example 10Step A, Synthesis of racemic cis and trans mixtures of 5-(3-((l,l-dioxido-2,3- dihydrobenzo[b]thiophen-4-yl)amino)-lH-pyrazol-5-yl)tetrahydrofuran-3-yl isopropylcarbamate

[0223] Racemic cis and trans mixtures of 5-(3-((l,l-dioxido-2,3-dihydrobenzo[b]thiophen-4- yl)amino)-lH-pyrazol-5-yl)tetrahydrofuran-3-yl isopropylcarbamate (180 mg) were synthesized through the general procedure using 4-bromo-2,3-dihydrobenzo[b]thiophene 1,1-dioxide and common intermediate. LCMS m / z = 421.2 [M+l]+Step B, HPLC separation to obtain racemic cis 5-(3-((l,l-dioxido-2,3- dihydrobenzo[b]thiophen-4-yl)amino)-lH-pyrazol-5-yl)tetrahydrofuran-3-yl isopropylcarbamate and racemic trans 5-(3-((l,l-dioxido-2,3-dihydrobenzo[b]thiophen-4- yl)amino)-lH-pyrazol-5-yl)tetrahydrofuran-3-yl isopropylcarbamate

[0224] Prep-HPLC separation of the cis and trans racemic mixtures gave 29 mg (16.3%) of racemic cis 5-(3-((l,l-dioxido-2,3-dihydrobenzo[b]thiophen-4-yl)amino)-lH-pyrazol-5- yl)tetrahydrofuran-3-yl isopropylcarbamate and 21.0 mg, (11.63%) of racemic trans 5-(3-((l,l- dioxido-2, 3 -dihydrobenzo [b]thiophen-4-yl)amino)- lH-pyrazol-5 -yl)tetrahydrofuran-3 -yl isopropylcarbamate .Step C, SFC separation to of racemic cis 5-(3-((l,l-dioxido-2,3-dihydrobenzo[b]thiophen-4- yl)amino)-lH-pyrazol-5-yl)tetrahydrofuran-3-yl isopropylcarbamate to obtain (3S,5S)-5-(3- ((l,l-dioxido-2,3-dihydrobenzo[b]thiophen-4-yl)amino)-lH-pyrazol-5-yl)tetrahydrofuran-3- yl isopropylcarbamate and (3R,5R)-5-(3-((l,l-dioxido-2,3-dihydrobenzo[b]thiophen-4- yl)amino)-lH-pyrazol-5-yl)tetrahydrofuran-3-yl isopropylcarbamate

[0225] Racemic cis 5 -(3 -((1,1 -dioxido-2, 3 -dihydrobenzo [b]thiophen-4-yl)amino)-lH-pyrazol-5-yl)tetrahydrofuran-3-yl isopropylcarbamate (29 mg) was purified by SFC to afford fraction 1, which was arbitrarily assigned as example 9, (3S,5S)-5-(3-((l,l-dioxido-2,3- dihydrobenzo[b]thiophen-4-yl)amino)-lH-pyrazol-5-yl)tetrahydrofuran-3-yl isopropylcarbamate (13.8 mg, Yield: 48%). LCMS m / z = 421.2 [M+H]+, 'HNMR (400 MHz, CDC13) 57.60- 7.57 (d, J= 8.0 Hz, 1H), 7.40-7.36 (t, J= 8.0 Hz, 1H), 7.25 (s, 1H), 5.92 (s, 1H), 5.89 (s, 1H), 5.34 (s, 1H), 5.08 (brs, 1H), 4.69 (s, 1H), 4.14 (d, J= 12 Hz, 1H), 3.95-3.89 (m, 1H), 3.85 - 3.71 (m, 1H), 3.54-3.50 (m, 2H), 3.22-3.19 (m, 2H), 2.73-2.70 (m, 1H), 2.22 - 2.16 (m, 1H), 2.11 - 2.00 (m, 1H), 1.29-1.10 (m, 6H).

[0226] Fraction 2 (13 mg, Yield: 45%)), which was arbitrarily assigned as example 10. LCMS m / z = 421.2 [M+H]+, 'HNMR (400 MHz, CDCh) 57.61-7.59 (d, J= 8.0 Hz, 1H), 7.41- 7.37 (t, J =8.0 Hz, 1H), 7.25 (s, 1H), 5.93 (s, 1H), 5.89 (s, 1H), 5.34 (s, 1H), 5.09-5.07 (d, J =8.0 Hz, 1H), 4.69 (s, 1H), 4.16-4.13 (d, J= 12.0 Hz 1H), 3.95-3.89 (m, 1H), 3.85 - 3.71 (m, 1H), 3.55-3.51 (t, J =8.0 Hz, 2H), 3.22-3.19 (t, J= 8.0 Hz, 2H), 2.70 - 2.68 (m, 1H), 2.21 - 2.16 (d, J= 16 Hz,lH), 1.28 - 1.11 (m, 6H).Example 11 and 12: Synthesis of (3S,5R)-5-(3-((l,l-dioxido-2,3-dihydrobenzo[b]thiophen-4- yl)amino)-lH-pyrazol-5-yl)tetrahydrofuran-3-yl isopropylcarbamate and (3R,5S)-5-(3-((l,l- dioxido-2,3-dihydrobenzo[b]thiophen-4-yl)amino)-lH-pyrazol-5-yl)tetrahydrofuran-3-yl isopropylcarbamateExample 11 Example 12SFC separation to of racemic trans 5-(3-((l,l-dioxido-2,3-dihydrobenzo[b]thiophen-4- yl)amino)-lH-pyrazol-5-yl)tetrahydrofuran-3-yl isopropylcarbamate to obtain (3S,5R)-5-(3- ((l,l-dioxido-2,3-dihydrobenzo[b]thiophen-4-yl)amino)-lH-pyrazol-5-yl)tetrahydrofuran-3- yl isopropylcarbamate and (3R,5S)-5-(3-((l,l-dioxido-2,3-dihydrobenzo[b]thiophen-4- yl)amino)-lH-pyrazol-5-yl)tetrahydrofuran-3-yl isopropylcarbamate

[0227] Racemic cis 5 -(3 -((1,1 -dioxido-2, 3 -dihydrobenzo [b]thiophen-4-yl)amino)-lH-pyrazol- 5-yl)tetrahydrofuran-3-yl isopropylcarbamate (21 mg) was purified by SFC to afford fraction 1, which was arbitrarily assigned as example 11, (3S,5R)-5-(3-((l,l-dioxido-2,3- dihydrobenzo[b]thiophen-4-yl)amino)-lH-pyrazol-5-yl)tetrahydrofuran-3-yl isopropylcarbamate (9 mg, Yield: 40%). LCMS m / z = 421.2 [M+H]+, 'HNMR (400 MHz, CDCh) 57.59-7.57 (d, J = 8.0 Hz, 1H), 7.41-7.37 (t, = 8.0 Hz, 1H), 7.28 (s, 1H), 5.92(s, 1H), 5.36 (s, 1H), 5.18-5.08 (m, 1H), 4.58 (s, 1H), 4.18(d, J=4.0 Hz. 1H), 3.99-3.96 (m, 1H), 3.54-3.51 (t, J= 6.8 Hz, 2H), 3.22- 3.19 (t, J= 6.9 Hz, 2H), 2.51-2.47 (m, 1H), 2.24-2.14 (m, 1H), 1.19 - 1.17 (d, J= 8.0 Hz, 6H). Fraction 2 (10 mg, Yield: 49%)), which was arbitrarily assigned as example 12. (3R,5S)-5-(3-((l,l- dioxido-2, 3 -dihydrobenzo [b]thiophen-4-yl)amino)- lH-pyrazol-5 -yl)tetrahydrofuran-3 -ylisopropylcarbamate (9 mg, Yield: 40%). LCMS m / z = 421.2 [M+H]+, 'H NMR (400 MHz, CDCh) 5 7.58-7.56 (d, J= 8.0 Hz, 1H), 7.41-7.37 (m, 1H), 7.28 (s, 1H), 5.93 (s, 1H), 5.36 (s, 1H), 5.19- 5.08 (m, 1H), 4.58 (s, 1H), 4.18(d, J=4.0 Hz, 1H), 3.99-3.96 (m,lH), 3.54-3.51 (t, J= 6.8 Hz. 2H), 3.22-3.19 (t, J= 6.9 Hz, 2H), 2.51-2.47 (m, 1H), 2.24-2.14 (m, 1H), 1.19 - 1.17 (d, J= 8.0 Hz, 6H).Example 13 and 14: Synthesis of (3S,5S)-5-(3-((l,l-dioxido-2,3-dihydrobenzo[d]isothiazol-4- yl)amino)-lH-pyrazol-5-yl)tetrahydrofuran-3-yl isopropylcarbamate and (3R,5R)-5-(3-((l,l- dioxido-2,3-dihydrobenzo[d]isothiazol-4-yl)amino)-lH-pyrazol-5-yl)tetrahydrofuran-3-yl isopropylcarbamateExample 13 Example 14Synthetic procedure for example 13 and example 14:Step A, Preparation of 3-bromo-2-methylbenzenesulfonyl chloride1 2

[0228] To a solution of 3-bromo-2-methylaniline (Complound 1, 3.3 ImL, 26.9 mmol) in MeCN (100 mL) at 0 °C was added con.HCl (21.0 mL) followed by AcOH (21.0 mb, 366 mmol) and a solution of NaNO2 (2.20 g, 31.9 mmol) in H2O (6 mL) at 0 oC. The reaction mixture was purged with SO2 gas for 15 min and a solution of CuC12 (4.55 g, 45.5 mmol) in H2O (6 mL) was added dropwise at 0 °C. The reaction mixture was allowed to warm to room temperature and stirred for 16 hrs. TLC showed the reaction had been completed. The reaction mixture was concentrated, diluted with 100 mL of water and extracted with 300 mL of EA. The organic extracts were washed with 100 mL of sat. aqueous sodium bicarbonate solution, 100 mL of brine, dried over sodium sulfate and concentrated to afford 3 -bromo-2 -methylbenzenesulfonyl chloride (Compound 2, 5.0 g, 18.6 mmol, 69.0%) as a yellow oil.1H NMR (400 MHz, DMSO-de) 5 7.79- 7.77 (d, J = 8.0 Hz, 1H), 7.57-7.55 (d, J = 8.0 Hz, 1H), 7.08 (dd, J = 8.0 Hz, 8.0 Hz, 1H), 2.61 (s, 3H).Step B, Preparation of 3-bromo-N-(tert-butyl)-2-methylbenzenesulfonamide cr2 3

[0229] To a solution of Compound 2 (5.0 g, 1.6 mmol) in DCM (100 mL) at 0 °C was added TEA (3.86 mL, 27.8 mmol), followed by tert-butylamine (2.91 mL, 27.8 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 16 h. The mixture was diluted with 100 mL of water and extracted with 300 mL of DCM. The organic extracts were washed with 100 mL of water, 100 mL of brine, dried over sodium sulfate and concentrated to afford 3- bromo-N-(tert-butyl)-2-methylbenzenesulfonamide (Compound 3, 2.4 g, 7.8 mmol, 42.3%) as a yellow solid.1H NMR (400 MHz, DMSO-d6) 5 7.95-7.93 (d, J = 8.0 Hz, 1H), 7.87-7.85 (d, J = 8.0 Hz, 1H), 7.65 (s, 1H), 7.34-7.30 (dd, J = 8.0 Hz, 8.0 Hz, 1H), 2.66 (s, 3H), 1.11 (s, 9H).Step C, Preparation of 3-bromo-2-(bromomethyl)-N-(tert-butyl)benzenesulfonamide

[0230] To a solution of Compound 3 (2.5 g, 7.8 mmol) in CC14 (20 mL) was added NBS (2.8 g, 15.7 mmol) followed by BPO (0.38 g, 1.6 mmol). The mixture was then heated at 80 °C for 16 hrs. The reaction mixture was allowed to cool to room temperature, diluted with 50 mL of water and extracted with 150 mL of DCM. The combined organic extracts were washed with 50 mL of water, 50 mL of brine, dried over sodium sulfate and concentrated. The residue was purified by silica gel chromatography (eluting with 0—15% EA in PE) to afford 3-bromo-2-(bromomethyl)-N- (tert-butyl)benzenesulfonamide (Compound 4, 2.1 g, 5.5 mmol, 70%) as a yellow solid. 'H NMR (400 MHz, DMSO-d6) 5 7.98-7.94 (m, 2H), 7.48-7.44 (m, 1H), 5.06 (s, 2H), 1.17-1.16 (d, J = 4 Hz, 9H).Step D, Preparation of 4-bromo-2-(tert-butyl)-2,3-dihydrobenzo[d]isothiazole 1,1-dioxideK2CO3, TBAI, MeCN, 50 °C, 2 hrs

[0231] To a solution of 3-bromo-2-(bromomethyl)-N-(tert-butyl)benzenesulfonamide (Compound 4, 2.7 g, 7.0 mmol) in MeCN (27 mL) was added K2CO3 (1.9 g, 14.0 mmol) followed by TBAI (0.52 g, 1.4 mmol). The reaction mixture was heated to 50 °C for 2 hrs. The reaction mixture was allowed to cool to room temperature and concentrated. The residue was resuspended in 30 mL of water and extracted with 90 mL of EtOAc. The combined organic extracts were washed with 30 mL of water, 30 mL of brine, dried over sodium sulfate and concentrated. The residue was purified by silica gel chromatography (eluting with 0-15% EtOAc in PE) to afford 4-bromo-2-(tert-butyl)-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide (Compound 5, 700 mg, 2.3 mmol, 33%) as a faint yellow solid. 'H NMR (400 MHz, CDC13) 5 7.72 (dd, J = 7.6, 5.2 Hz, 2H), 7.42 (t, J = 7.6 Hz, 1H), 4.34 (s, 2H), 1.59 (s, 9H).Step E, Preparation of racemic cis-5-(3-((l,l-dioxido-2,3-dihydrobenzo[d]isothiazol-4- yl)amino)-lH-pyrazol-5-yl)tetrahydrofuran-3-yl isopropylcarbamate

[0232] To a solution of common intermediate (500 mg, 1.61 mmol) and 4-bromo-2-(tert- butyl)-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide (490 mg, 1.61 mmol) in 1,4-dioxane (10 mL) was added Pd2(dba)s (74 mg, 0.081 mmol), xantphos (47 mg, 0.081 mmol) and CS2CO3 (1049 mg, 3.22 mmol) at 25°C under N2. Then the mixture was stirred at 100°C for 16 hours under N2. LCMS (368-129-01) indicated the starting material was consumed completely. After cooling down to room temperature, the reaction mixture was quenched with H2O (20 mL) and then extracted with EtOAc (20 mL x 3). The combined organic phases were washed with brine (20 mL), dried over anhydrous Na2SC>4, filtered and evaporated under reduced pressure to give the residue. The residue was purified with silica gel column chromatography (eluted with 50% EtOAc in PE) to give the racemic cis-5-(3-((l,l-dioxido-2,3-dihydrobenzo[d]isothiazol-4-yl)amino)-lH- pyrazol-5-yl)tetrahydrofuran-3-yl isopropylcarbamate (Compound 6, 500 mg, purity 95%, yield 55%) as a grown solid. LCMS: m / z = 534.4 [M+H]+.Step F, Preparation of racemic cis-5-(3-((l,l-dioxido-2,3-dihydrobenzo[d]isothiazol-4- yl)amino)-lH-pyrazol-5-yl)tetrahydrofuran-3-yl isopropylcarbamate

[0233] To racemic cis-5-(3-((l,l-dioxido-2,3-dihydrobenzo[d]isothiazol-4-yl)amino)-lH- pyrazol-5-yl)tetrahydrofuran-3-yl isopropylcarbamate (Compound 6, 600 mg, 1.12 mmol) was added CF3SO3H (2 mL) at 25°C. Then the mixture was stirred at 25°C for 4 hours. LCMS (368- 130-01) indicated the starting material was consumed completely. After cooling down to room temperature, the reaction mixture was adjusted pH to 8 with 2M ice NaHCCL aq, and thenextracted with EtOAc (30 mL x 3). The combined organic phases were washed with brine (40 mb), dried over anhydrous Na2SC>4, filtered and evaporated under reduced pressure to give the residue. The residue was purified with silica gel column chromatography (eluted with 10% MeOH in DCM) to give the product racemic cis-5-(3-((l,l-dioxido-2,3-dihydrobenzo[d]isothiazol-4- yl)amino)-lH-pyrazol-5-yl)tetrahydrofuran-3-yl isopropylcarbamate (Compound 7, 270 mg, purity 98%, yield 57%) as a light-yellow solid. LCMS: m / z=422.2 [M+H]+.Step G, SFC separation to of racemic cis-5-(3-((l,l-dioxido-2,3-dihydrobenzo[d]isothiazol-4- yl)amino)-lH-pyrazol-5-yl)tetrahydrofuran-3-yl isopropylcarbamate to obtain (3S,5S)- 5-(3- ((l,l-dioxido-2,3-dihydrobenzo[d]isothiazol-4-yl)amino)-lH-pyrazol-5-yl)tetrahydrofuran-3- yl isopropylcarbamate and (3R,5R)- 5-(3-((l,l-dioxido-2,3-dihydrobenzo[d]isothiazol-4- yl)amino)-lH-pyrazol-5-yl)tetrahydrofuran-3-yl isopropylcarbamate

[0234] Racemic cis-5-(3-((l,l-dioxido-2,3-dihydrobenzo[d]isothiazol-4-yl)amino)-lH- pyrazol-5-yl)tetrahydrofuran-3-yl isopropylcarbamate (270 mg) was purified by SFC. Fraction 1, which was arbitrarily assigned as example 13, (3S,5S)-5-(3-((l,l-dioxido-2,3- dihydrobenzo[d]isothiazol-4-yl)amino)-lH-pyrazol-5-yl)tetrahydrofuran-3-yl isopropylcarbamate (90 mg, Yield: 33%). LCMS m / z = 422.2 [M+H]+. 'H NMR (400 MHz, DMSO-d6) 5 8.14 (s, 1H), 7.88 (s, 1H), 7.40 (t, J= 7.2 Hz, 1H), 7.10 (d, J= 7.2 Hz, 2H), 5.94 (s, 1H), 5.16 (brs, 1H), 4.84 (brs, 1H), 4.29 (s, 2H), 3.85 (s, 2H), 3.60-3.50 (m, 2H), 2.72-2.65 (m, 2H), 1.98-1.90 (m, 1H), 1.03 (brs, 6H).

[0235] Fraction 2, which was arbitrarily assigned as example 14, (3R,5R)-5-(3-((l,l-dioxido- 2,3 -dihydrobenzo [d] isothiazol-4-yl)amino)- lH-pyrazol-5 -yl)tetrahydrofuran-3 -yl isopropylcarbamate (90 mg, Yield: 33%). LCMS m / z = 422.2 [M+H]+. 'H NMR (400 MHz, DMSO-d6) 5 8.21 (brs, 1H), 7.87 (s, 1H), 7.40 (t, J= 7.2 Hz, 1H), 7.10 (d, J= 7.2 Hz, 2H), 5.94 (s, 1H), 5.17 (s, 1H), 4.88-4.80 (m, 1H), 4.29 (s, 2H), 3.85 (s, 2H), 3.60-3.50 (m, 2H), 2.72 - 2.63 (m, 2H), 1.98-1.90 (m, 1H), 1.04 (s, 6H).Example 15: Synthesis of racemic cis-5-(3-((2,2-dioxido-l,3-dihydrobenzo[c]thiophen-5- yl)amino)-lH-pyrazol-5-yl)tetrahydrofuran-3-yl isopropylcarbamateExample 15Step A, Synthesis of racemic cis and trans mixtures of 5-(3-((2,2-dioxido-l,3- dihydrobenzo[c]thiophen-5-yl)amino)-lH-pyrazol-5-yl)tetrahydrofuran-3-yl isopropylcarbamate

[0236] Racemic cis and trans mixtures of 5-(3-((2,2-dioxido-l,3-dihydrobenzo[c]thiophen-5- yl)amino)-lH-pyrazol-5-yl)tetrahydrofuran-3-yl isopropylcarbamate (380 mg) were synthesized through the general procedure using 5 -bromo- 1,3 -dihydrobenzo [c]thiophene 2,2-dioxide and common intermediate. LCMS m / z = 421.2 [M+l]+Step B, HPLC separation to obtain example 15, racemic cis 5-(3-((2,2-dioxido-l,3- dihydrobenzo[c]thiophen-5-yl)amino)-lH-pyrazol-5-yl)tetrahydrofuran-3-yl isopropylcarbamate and racemic trans 5-(3-((2,2-dioxido-l,3-dihydrobenzo[c]thiophen-5- yl)amino)-lH-pyrazol-5-yl)tetrahydrofuran-3-yl isopropylcarbamate

[0237] Prep-HPLC separation of the cis and trans racemic mixtures of 5-(3-((2,2-dioxido-l,3- dihydrobenzo[c]thiophen-5-yl)amino)-lH-pyrazol-5-yl)tetrahydrofuran-3-yl isopropylcarbamate (380 mg) gave 17 mg of example 15, racemic cis 5-(3-((l,l-dioxido-2,3- dihydrobenzo[b]thiophen-4-yl)amino)-lH-pyrazol-5-yl)tetrahydrofuran-3-yl isopropylcarbamate. LCMS: m / z = 421.2 [M+H]+. 'H NMR (400 MHz, CDCh) 5 7.18 (d, J= 7.2 Hz, 2H), 7.07 (d, J= 7.6 Hz, 1H), 5.91 (s, 1H), 5.36 (s, 1H), 5.10 (s, 1H), 4.32-4.28 (m, 4H), 4.18-4.11 (m, 1H), 3.99- 3.94 (m, 1H), 3.80-3.73 (m, 1H), 2.72-2.64 (m, 1H), 2.24-2.18 (m, 1H), 1.15 - 1.12 (m, 6H).

[0238] The separation also gave 43 mg of racemic trans 5-(3-((2,2-dioxido-l,3- dihydrobenzo[c]thiophen-5-yl)amino)-lH-pyrazol-5-yl)tetrahydrofuran-3-yl isopropylcarbamate. This will be used for generation of example 16 and 17.Example 16 and 17: Synthesis of (3R,5S)-5-(3-((2,2-dioxido-l,3-dihydrobenzo[c]thiophen-5- yl)amino)-lH-pyrazol-5-yl)tetrahydrofuran-3-yl isopropylcarbamate and (3S,5R)-5-(3-((2,2- dioxido-l,3-dihydrobenzo[c]thiophen-5-yl)amino)-lH-pyrazol-5-yl)tetrahydrofuran-3-yl isopropylcarbamateExample 16 Example 17SFC separation to of racemic trans 5-(3-((2,2-dioxido-l,3-dihydrobenzo[c]thiophen-5- yl)amino)-lH-pyrazol-5-yl)tetrahydrofuran-3-yl isopropylcarbamate to obtain example 16, (3R,5S)-5-(3-((2,2-dioxido-l,3-dihydrobenzo[c]thiophen-5-yl)amino)-lH-pyrazol-5- yl)tetrahydrofuran-3-yl isopropylcarbamate and example 17, (3S,5R)-5-(3-((2,2-dioxido-l,3- dihydrobenzo[c]thiophen-5-yl)amino)-lH-pyrazol-5-yl)tetrahydrofuran-3-yl isopropylcarbamate

[0239] Racemic trans 5-(3-((2,2-dioxido-l,3-dihydrobenzo[c]thiophen-5-yl)amino)-lH- pyrazol-5-yl)tetrahydrofuran-3-yl isopropylcarbamate 43 mg was purified by SFC to afford fraction 1, which was arbitrarily assigned as example 16, (3R,5S)-5-(3-((2,2-dioxido-l,3- dihydrobenzo[c]thiophen-5-yl)amino)-lH-pyrazol-5-yl)tetrahydrofuran-3-yl isopropylcarbamate (9 mg). LCMS m / z = 421.2 [M+H]+.1HNMR (400 MHz, CDCh) 57.16-7.10 (m, 2H), 7.03- 7.00 (m, 1H), 6.40-6.32 (m, 1H), 5.92-5.84 (m, 1H), 5.36 (brs, 1H), 5.17 (brs, 1H), 4.58 (brs, 1H), 4.35-4.25 (m, 4H), 4.26-4.19 (m, 1H), 4.15-4.11(m, 1H), 3.96-3.86 (m, 1H), 3.85-3.77 (m, 1H), 2.52-2.42 (m, 1H), 2.20 (s, 1H), 1.19-1.17 (d, J= 8.0 Hz, 6H).

[0240] Fraction 2, which was arbitrarily assigned as example 17, (3S,5R)-5-(3-((2,2-dioxido- 1 ,3 -dihydrobenzo [c]thiophen-5 -yl)amino)- lH-pyrazol-5-yl)tetrahydrofuran-3 -yl isopropylcarbamate (9 mg). LCMS m / z = 421.2 [M+H]+. 'HNMR (400 MHz, CDCh) 57.17-7.10 (m, 2H), 7.03-7.00 (m, 1H), 6.40-6.32 (m, 1H), 5.92-5.84 (m, 1H), 5.36 (brs, 1H), 5.16 (brs, 1H), 4.59 (brs, 1H), 4.35-4.25 (m, 4H), 4.26-4.19 (m, 1H), 4.15-4.11(m, 1H), 3.96-3.86 (m, 1H), 3.85-3.77 (m, 1H), 2.52-2.42 (m, 1H), 2.20 (s, 1H), 1.19-1.17 (d, J= 8.0 Hz, 6H).Synthesis of Example 18 (3S,5S)-5-(3-((2,2-dioxido-l,3-dihydrobenzo[c]isothiazol-5- yl)amino)-lH-pyrazol-5-yl)tetrahydrofuran-3-yl isopropylcarbamateand and Example 19 (3R,5R)-5-(3-((2,2-dioxido-l,3-dihydrobenzo[c]isothiazol-5-yl)amino)-lH-pyrazol-5- yl)tetrahydrofuran-3-yl isopropylcarbamateExample 18 Example 19Synthetic scheme of Example 18 and Example 19Step A, preparation of sodium (2-nitrophenyl)methanesulf onatetetrabutylammonium bromide1

[0241] To a mixture of tetrabutylammonium bromide (0.75 g, 2.31 mmol) in water (20 mb) was added Na2SC>3 (3.79 g, 30.1 mmol), l-(bromomethyl)-2-nitrobenzene (5.0 g, 23.1 mmol) in methanol (4.0 mL) dropwise at 90 °C under N2 1 atm atmosphere. The resulting mixture was concentrated under vacuum to afford sodium (2-nitrophenyl)methanesulfonate (Compound 2, 10.0 g, crude) as a yellow solid.Step B, Preparation of sodium (2-aminophenyl)methanesulfonate2 3

[0242] To a mixture of sodium (2-nitrophenyl)methanesulfonate (Compound 2 , 5.0 g, 20.9 mmol) in methanol (5.0 mL) was added Pd / C (1.45 g, 13.6 mmol). The mixture was stirred at 25 °C for 16h under H2. The reaction mixture was filtered through ce lite-bed and washed with MeOH. The resulting mixture was concentrated under vacuum, to afford sodium (2- aminophenyl)methanesulfonate (compound 3, 4.0 g, crude) as a yellow oil.Step C, preparation of l,3-dihydrobenzo[c]isothiazole 2,2-dioxide

[0243] A solution of sodium (2-aminophenyl)methanesulfonate (2.5 g, 13.4 mmol) in POCI3 (28 mL) was stirred for 2 h at 120°C under N2 atmosphere. The reaction mixture was concentrated under reduce pressure and diluted with DCM (300 mL). The mixture was washed with water (100 mL). The organic phase was dried over sodium sulfate, filtered and concentrated to dryness under reduce pressure. The crude residue was purified by silica gel column (PE : EA = 3: 1) to afford l,3-dihydrobenzo[c]isothiazole 2,2-dioxide (compound 4, 600 mg, 26.4 %) as a white soild. LC-MS (EST) m / z: 168.2 (M-H)'. 'H NMR (400 MHz, DMSO -6) 5 10.46 (s, 1H), 7.26 (dd, J= 7.6 Hz, 2H), 6.97 (t, J= 7.6 Hz, 1H), 6.82 (d, J= 8.0 Hz, 1H), 4.52 (s, 2H).Step D, preparation of 5-bromo-l,3-dihydrobenzo[c]isothiazole 2,2-dioxide4 5

[0244] To a solution of Bn (380 mg, 2.47 mmol) in AcOH (6 mL) was added 1,3- dihydrobenzofc] isothiazole 2,2-dioxide (500 mg, 2.95 mmol) in AcOH (6 mL) dropwise at 25 °C. After stirring for 20 min at rt, the reaction mixture was concentrated under reduced pressure and diluted with DCM (200 mL). The mixture was washed with water (100 mL). The organic phase was dried over sodium sulfate, filtered and concentrated to dryness under reduce pressure. The crude residue was purified by silica gel column (PE: EA = 3: 1) to afford 5-bromo-l,3- dihydrobenzofc] isothiazole 2,2-dioxide (compound 5, 420 mg, 57.2%) as a yellow oil. LC-MS(ESF) m / z: 246.0 (M-H)’. 'H NMR (400 MHz, DMSO -6) 5 10.69 (brs, 1H), 7.46 (s, 1H), 7.41 (d, J= 8.4 Hz, 1H), 6.75 (d, J= 8.4 Hz, 1H), 4.52 (s, 2H).Step E, preparation of 5-bromo-l-(4-methoxybenzyl)-l,3-dihydrobenzo[c]isothiazole 2,2- dioxide

[0245] To a solution of 5-bromo-l,3-dihydrobenzo[c]isothiazole 2,2-dioxide (Compound 5,900 mg, 3.63 mmol), 4-Methoxybenzyl chloride (PMBCI , 682 mg, 4.36 mmol), K2CO3 (1.50 g, 10.9 mmol) and KI (121 mg, 0.73 mmol) in acetonitrile (12 m ) was stirred at 70 °C for 1 h. The reaction mixture was concentrated under reduced pressure and diluted with DCM (200 m ) and washed with water (200 mb). The organic phase was dried over sodium sulfate, filtered, and concentrated to dryness under reduce pressure. The crude residue was purified by silica gel column (PE: EA = 5: 1) to afford 5 -bromo- l-(4-methoxybenzyl)- 1,3 -dihydrobenzo [c]isothiazole 2,2-dioxide (compound 6, 1 .30 g, 97.3 %) as a white solid.1H NMR (400 MHz, CDCh) 5 7.44 - 7.11 (m, 4H), 6.89 (d, J= 8.6 Hz, 2H), 6.43 (d, J= 8.6 Hz, 1H), 4.77 - 4.62 (m, 2H), 4.40 (d, J = 6.4 Hz, 2H), 3.80 (d, J= 6.4 Hz, 3H).Step F, preparation of racemic cis-5-(l-(tert-butyl)-3-((l-(4-methoxybenzyl)-2,2-dioxido-l,3- dihydrobenzo[c]isothiazol-5-yl)amino)-lH-pyrazol-5-yl)tetrahydrofuran-3-yl isopropylcarbamate

[0246] To a solution of common intermediate (466 mg, 1.50 mmol), 5-bromo-l-(4- methoxybenzyl)-l,3-dihydrobenzo[c]isothiazole 2,2-dioxide (622 mg, 1.80 mmol), BrettPhos-G3- Pd (204 mg, 0.22 mmol) and CS2CO3 (977 mg, 3 mmol) in 1,4-dioxane (10 mb) was stirred at 100 °C under N2 atmosphere for 8 h. The reaction mixture was concentrated to dryness under reduced pressure. The residue was diluted with DCM (100 mb) and washed with water (50 mb). The organic phase was dried over sodium sulfate, then concentrated under reduced pressure. The crude residue was purified by silica gel column (EA) to afford racemic cis-5-(l-(tert-butyl)-3-((l- (4-methoxybenzyl)-2,2-dioxido-l,3-dihydrobenzo[c]isothiazol-5-yl)amino)-lH-pyrazol-5- yl)tetrahydrofuran-3-yl isopropylcarbamate (compound 7, 700 mg, 78 %) as a yellow solid.LC-MS (ESI+) m / z: 598.4 (M+H)+Step G, preparation of racemic cis-5-(3-((2,2-dioxido-l,3-dihydrobenzo[c]isothiazol-5- yl)amino)-lH-pyrazol-5-yl)tetrahydrofuran-3-yl isopropylcarbamate

[0247] To a solution of racemic cis-5-(l-(tert-butyl)-3-((l-(4-methoxybenzyl)-2,2-dioxido- 1 , 3 -dihydrobenzo [c]i sothiazol-5 -y l)amino) - 1 H-py razol-5 -yl)tetrahydrofuran-3 -yl isopropylcarbamate (compound 7, 350 mg, 0.59 mmol) in DCM (10 mL) was added CF3SO3H (3177 mg, 21.17 mmol) in DCM (10 mL) dropwise at 25 °C. The resulting mixture was stirred for 1 h at 25 °C. The reaction mixture was concentrated to dryness under reduced pressure. The residue was diluted with DCM (100 mL) and washed with saturated NaHCCL solution (50 mL). The organic layer was separated and concentrated to dryness. The crude residue was purified by silica gel column (DCM : MeOH = 10: 1) to afford racemic cis-5-(3-((2,2-dioxido-l,3- dihydrobenzo[c]isothiazol-5-yl)amino)-lH-pyrazol-5-yl)tetrahydrofuran-3-yl isopropylcarbamate (compound 8, 70 mg, 28 %) as a white solid, LCMS m / z = 422.1 [M+H]+.Step H, SFC separation to of racemic cis-5-(3-((2,2-dioxido-l,3-dihydrobenzo[c]isothiazol-5- yl)amino)-lH-pyrazol-5-yl)tetrahydrofuran-3-yl isopropylcarbamate to obtain (3S,5S)-5-(3- ((2,2-dioxido-l,3-dihydrobenzo[c]isothiazol-5-yl)amino)-lH-pyrazol-5-yl)tetrahydrofuran-3- yl isopropylcarbamate and (3R,5R)-5-(3-((2,2-dioxido-l,3-dihydrobenzo[c]isothiazol-5- yl)amino)-lH-pyrazol-5-yl)tetrahydrofuran-3-yl isopropylcarbamate

[0248] SFC separation of racemic cis-5-(3-((2,2-dioxido-l,3-dihydrobenzo[c]isothiazol-5- yl)amino)-lH-pyrazol-5-yl)tetrahydrofuran-3-yl isopropylcarbamate gave fraction 1 (9.2 mg, 13%) , which was assigned as example 18, (3S,5S)-5-(3-((2,2-dioxido-l,3- dihydrobenzo[c]isothiazol-5-yl)amino)-lH-pyrazol-5-yl)tetrahydrofuran-3-yl isopropylcarbamate. LCMS m / z = 422.1 [M+H]+. 'HNMR (400 MHz, MeOD-d4) 5 7.24 (s, 1H), 7.05 (d, J= 8.0 Hz, 1H), 6.77 (d, J= 12.0 Hz, 1H), 5.86 (s, 1H), 5.22 (brs, 1H), 5.00-4.95 (m, 1H), 4.34 (s, 2H), 4.03 (d, J= 8.0 Hz, 1H), 3.92 (dd, J= 8.0 Hz, 4.0Hz, 1H), 5.16 (brs, 1H), 4.59 (brs, 1H), 4.35-4.25 (m,4H), 4.26-4.19 (m, 1H), 4.15-4.11(m, 1H), 3.71-3.61 (m, 1H), 2.75-3.55 (m, 1H), 2.12-2.08 (m, 1H), 2.20 (s, 1H), 1.15-1.02 (m, 6H).

[0249] Fraction 2 (5 mg, 7%), which was assigned as example 19, (3R,5R)-5-(3-((2,2- dioxido- 1 ,3 -dihydrobenzo [c]isothiazol-5 -yl)amino)- lH-pyrazol-5 -yl)tetrahydrofuran-3 -yl isopropylcarbamate. LCMS m / z = 422.1 [M+H]+.1H NMR (400 MHz, MeOD-d4) 5 7.24 (s, 1H), 7.05 (d, J= 8.0 Hz, 1H), 6.77 (d, J= 12.0 Hz, 1H), 5.86 (s, 1H), 5.22 (brs, 1H), 5.00-4.95 (m, 1H), 4.34 (s, 2H), 4.03 (d, J = 8.0 Hz, 1H), 3.92 (dd, J= 8.0 Hz, 4.0Hz, 1H), 5.16 (brs, 1H), 4.59 (brs, 1H), 4.35-4.25 (m, 4H), 4.26-4.19 (m, 1H), 4.15-4.11(m, 1H), 3.71-3.61 (m, 1H), 2.75- 3.55 (m, 1H), 2.12-2.08 (m, 1H), 2.20 (s, 1H), 1.15-1.02 (m, 6H).Biological StudiesIn vitro kinase TR-FRET assays: CDK2 / CycA2, CDK2 / CycEl, CDKl / cyclinB and GSK30

[0250] The test compounds were prepared as 10 mM stock solution in 100% DMSO. The stock solution was then serially diluted 3 -fold in 100% DMSO to 10 concentrations. 200 nL of each diluted compound solution was transferred to 384-well plate in duplicate. To each well, 5uL of enzyme and ATP mixture solution containing enzyme CDK2 / CycA2, CDK2 / CycEl, CDKl / cyclinB, or GSK3[3 (final concentrations 3nM, 0.6 nM, 0.3nM, 0.6nM, respectively) and ATP (final concentrations 27 pM, 82 pM, 56 pM, 7.6 pM, respectively) in the assay buffer (50mM HEPES, pH7.5, lOmM MgCh, ImM DTT, 0.01% BSA, 0.01% Triton X-100). For negative control, 5uL of assay buffer was added instead. The plate was incubated at room temperature for lOmin. 5uL of peptide solution containing ULight-4E-BP 1 peptide (final concentrations 50 nM) in the assay buffer was subsequently added into each well to initiate the reaction. By incubation at room temperature for 1 hour, lOuL of 2 nM Eu-anti-phospho-4E BP1 antibody was then added for detection. After one hour incubation at room temperature, all samples were subjected to read the TR-FRET signal on Envision with excitation at 340nm and emission fluorescence at 615 nm and 665 nm. IC50 values were then calculated by plotting dose-response curves and then using the XLfit application in Excel software.Table 1. Biochemical Data (TR-FRET)

[0251] In Table 1, a compound described herein may have an IC50 of CDK1 cyclinB, CDK2 cyclinA2, CDK2 cyclinEl or GSK3p. “A” refers to an IC50 less than 50 nM; “B” refers to an IC50 from 50 nM to 0.5 pM; “C” refers to an IC50 from 0.5 pM to 1 uM; and “D” refers to an IC50 greater than 1 pM.

[0252] Although the present invention has been described in detail with preferred embodiments, those of ordinary skill in the art should understand that modifications, variations, and equivalent replacements made to the present invention within the scope of the present invention belong to the protection of the present invention.

[0253] Applicant’s disclosure is described herein in preferred embodiments with reference to the Figures, in which like numbers represent the same or similar elements. Reference throughout this specification to “one embodiment,” “an embodiment,” or similar language means that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment of the present invention. Thus, appearances of the phrases “in one embodiment,” “in an embodiment,” and similar language throughout this specification may, but do not necessarily, all refer to the same embodiment.

[0254] The described features, structures, or characteristics of Applicant’s disclosure may be combined in any suitable manner in one or more embodiments. In the description, herein, numerous specific details are recited to provide a thorough understanding of embodiments of the invention. One skilled in the relevant art will recognize, however, that Applicant’s composition and / or method may be practiced without one or more of the specific details, or with other methods, components, materials, and so forth. In other instances, well-known structures, materials, or operations are not shown or described in detail to avoid obscuring aspects of the disclosure.

[0255] 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. Although any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present disclosure, the preferred methods and materials are now described. Methods recited herein may be carried out in any order that is logically possible, in addition to a particular order disclosed.Incorporation by Reference

[0256] References and citations to other documents, such as patents, patent applications, patent publications, journals, books, papers, web contents, have been made in this disclosure. All such documents are hereby incorporated herein by reference in their entirety for all purposes. Any material, or portion thereof, that is said to be incorporated by reference herein, but which conflicts with existing definitions, statements, or other disclosure material explicitly set forth herein is only incorporated to the extent that no conflict arises between that incorporated material and the present disclosure material. In the event of a conflict, the conflict is to be resolved in favor of the present disclosure as the preferred disclosure.Equivalents

[0257] The representative examples are intended to help illustrate the invention, and are not intended to, nor should they be construed to, limit the scope of the invention. Indeed, various modifications of the invention and many further embodiments thereof, in addition to those shown and described herein, will become apparent to those skilled in the art from the full contents of this document, including the examples and the references to the scientific and patent literature included herein. The examples contain important additional information, exemplification and guidance that can be adapted to the practice of this invention in its various embodiments and equivalents thereof.

Claims

What is claimed is:CLAIMS1. A compound having the structural Formula (I):or a pharmaceutically acceptable form or an isotope derivative thereof, whereinRing A is a 5- to 7-membered heterocyclic ring comprising an O; each of R1and R2is independently selected from the group consisting of H, unsubstituted or substituted Ci-Ce alkyl, and C3-C6 unsubstituted or substituted carbocyclic ring; or R1and R2, together with the N atom they are bound to, are joined to form a 4- to 7- membered, unsubstituted or substituted heterocyclic ring; each R3is independently selected from the group consisting of halogen, OH, CN, unsubstituted or substituted CM alkyl, unsubstituted or substituted C1-6 alkoxy, NO2, NRR’, or two R3’s, along with the carbon atom(s) they are bound to, form a 3 - to 5- membered unsubstituted or substituted carbocyclic ring;R4is H, halogen, CM alkyl, CN, NRR’, or C(O)NRR’;R5iswhereinRing B is a 4- to 7-membered carbocyclic or heterocyclic ring optionally comprising 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; each of Y1and Y2is CR6or N, and each of Y3and Y4is C, CR6or N; provided that not more than one of Y1, Y2, Y3and Y4is N, and either Y3or Y4is C and being the positions where R5may be bonded to the rest of the compound;each R6is independently selected from the group consisting of halogen, OH, CN, unsubstituted or substituted Ci-6 alkyl, unsubstituted or substituted C1-4 alkoxy, and C(O)NRR’; each R7is independently selected from the group consisting of halogen, OR, CN, unsubstituted or substituted C1-6 alkyl, and unsubstituted or substituted C1-4 alkoxy, or two R7’S, along with the carbon atom(s) they are bound to, 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 unsubstituted or substituted 4- to 6-membered carbocyclic ring, or where R and R’ are attached to the same N atom, together form an unsubstituted or substituted 4- to 6- membered heterocyclic ring; i is 0, 1, 2, 3 or 4; andA is 0, 1, 2, 3, 4 or 5.

2. The compound of claim 1, wherein Ring A is:wherein * herein refers to bonding to pyrazolyl ring of Formula (I).

3. The compound of claim 1 or 2, wherein Ring A is selected from:

4. The compound of claim 3, wherein i is 0 and Ring A is selected from:

5. The compound of any one of claims 1-4, wherein R5iswhereineach R6is independently selected from the group consisting of halogen, OH, CN, unsubstituted or substituted Ci-6 alkyl, unsubstituted or substituted C1-4 alkoxy, and C(O)NRR’; a and P refer to positions where R5may be bonded to the rest of the compound; and j is 0, 1, 2 or 3.

6. The compound of claim 5, wherein R5is connected to the rest of the compound at the position:

7. The compound of claim 5, wherein R5is connected to the rest of the compound at the a position:

8. The compound of any one of claims 1-4, wherein at least one of Y1, Y2, Y3and Y4is N.

9. The compound of claim 8, wherein only one of Y1, Y2, Y3and Y4is N.

10. The compound of claim 8 or 9, wherein Y3is C and R5is connected to the rest of the11. The compound of any one of claims 8-10, wherein R5is selected from:

12. The compound of claim 8 or 9, wherein Y4is C and R5is connected to the rest of the compound at the Y4position:

14. The compound of any one of claims 1-13, wherein Ring B is selected from:wherein each of X1, X2, X3, X4and X5is independently selected from S(O)2, C(O), NH, CH2 and O, provided that two neighboring X1, X2, X3, X4or X5are not each selected from S(O)2 and C(O); and two neighboring X1, X2, X3, X4or X5are not each selected from NH and O.

15. The compound of claim 14, wherein one or both of Xi and X2 is selected from S(O)2 and C(O); and none of X3, X4 and X5 is S(O)2 or C(O).

16. The compound of claim 14, wherein neither of Xi and X2 is S(O)2 or C(O); and one of X3, X4 and X5 is S(O)2 or C(O).

17. The compound of claim 14, wherein none of Xi, X2, X3, X4 and X5 is S(O)2 or C(O); and at least one of Xi, X2, X3, X4 and X5 is CH2, wherein one or both H’s in the CH2 are substituted with F; one of H’s is substituted with CN and the other H is unsubstituted; or one of H’s is substituted with CN and the other H is substituted with OR.

18. The compound of any one of claim 1-4 or 6, wherein R5is selected from:

19. The compound of any one of claims 1-4 or 7, wherein R5is selected from:

20. The compound of claim 1-4 or 10, wherein R5is selected from:21.

22. The compound of claim 1-4 or 10, wherein R5is selected from:

23. The compound of any one of claims 1-4 or 10, wherein R5is selected from:

24. The compound of any one of claims 1-4 or 12, wherein R5is selected from:

25. The compound of any one of claims 1-4 or 12, wherein R5is selected from:

26. The compound of any one of claims 1-4 or 12, wherein R5is selected from:

27. The compound of any one of claims 1-4 or 12, wherein R5is selected from:

28. The compound of any one of claims 14-27, wherein two R7’s, along with the carbon atom they are bound to, form a 3- to 6-membered unsubstituted or substituted carbocyclic ring.

29. The compound of any one of claims 14-27, wherein two R7’s, along with the carbon atom they are bound to, form a 3- to 6-membered unsubstituted or substituted heterocyclic ring comprising one or more ring heteroatoms selected from O, S and N.

30. The compound of any one of claims 1-4, wherein R5is selected from:

31. The compound of any one of claims 1-4, wherein R5is selected from:

32. The compound of any one of claims 1-4, wherein R5is selected from:

33. The compound of any one of claims 10 and 30-32, wherein Y1is N, Y2is CH and Y4is CH.

34. The compound of any one of claims 10 and 30-32, wherein Y1is CH, Y2is N and Y4is CH.

35. The compound of any one of claims 10 and 30-32, wherein Y1is CH, Y2is CH and Y4is N.

36. The compound of any one of claims 10 and 30-32, wherein each of Y1, Y2and Y4is CH.

37. The compound of any one of claims 1-4, wherein R5is selected from:

38. The compound of any one of claims 1-4, wherein R5is selected from:

39. The compound of any one of claims 1-4, wherein R5is selected from:

40. The compound of any one of claims 12 and 37-39, wherein Y1is N, Y2is CH and Y3isCH.

41. The compound of any one of claims 12 and 37-39, wherein Y1is CH, Y2is N and Y3isCH.

42. The compound of any one of claims 12 and 37-39, wherein Y1is CH, Y2is CH and Y3isN.

43. The compound of any one of claims 12 and 37-39, wherein each of Y1, Y2and Y3is CH.

44. The compound of any one of claims 1-43, wherein R1is H and R2is an unsubstituted or substituted linear or branched Ci-Ce alkyl.

45. The compound of any one of claims 1-43, wherein each of R1and R2is independently an unsubstituted or substituted linear or branched Ci-Ce alkyl.

46. The compound of any one of claims 1-43, wherein R1and R2, together with the N atom they are bound to, are joined to form a 4- to 7-membered, unsubstituted or substituted heterocyclic ring.

47. The compound of any one of claims 1-46, wherein Ring A is a 4- to 6-membered carbocyclic ring.

50. The compound of any one of claims 1-4, having the structural formula:

51. The compound of claim 50, having a structural formula selected from:

52. The compound of claim 50 or 51, wherein Y1is N, Y2is CH and Y4is CH.

53. The compound of claim 50 or 51, wherein Y1is CH, Y2is N and Y4is CH.

54. The compound of claim 50 or 51, wherein Y1is CH, Y2is CH and Y4is N.

55. The compound of any one of claims 1-4, having the structural formula:

56. The compound of claim 55, having a structural formula selected from:

57. The compound of claim 55 or 56, wherein Y1is N, Y2is CH and Y3is CH.

58. The compound of claim 55 or 56, wherein Y1is CH, Y2is N and Y3is CH.

59. The compound of claim 55 or 56, wherein Y1is CH, Y2is CH and Y3is N.

60. The compound of any one of claims 50-59, wherein Ring B is 5 -membered carbocyclic ring.

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

62. The compound of any one of claims 50-59, wherein Ring B is 6-membered carbocyclic ring.

63. The compound of any one of claims 50-59, wherein Ring B is 6-membered heterocyclic ring.

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

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

66. The compound of any one of claims 50-63, wherein Ring B comprises a -C(O)NH- group.

67. The compound of any one of claims 50-63, wherein Ring B comprises a CH2 group.

68. The compound of any one of claims 50-63, wherein Ring B comprises a C(CN)R” group, wherein R” is H, OH, C1-4 alkyl or O-C1-4 alkyl.

69. The compound of any one of claims 50-68, wherein j is 0.

70. The compound of any one of claims 50-68, wherein j is 1.

71. The compound of any one of claims 50-68, wherein k is 0.

72. The compound of any one of claims 50-68, wherein k is 1.

73. The compound of any one of claims 50-68, wherein k is 2.

74. The compound of claim 72 or 73, wherein R7is an unsubstituted C1-6 alkyl.

75. The compound of claim 72 or 73, wherein R7is a substituted C1-6 alkyl.

76. A compound selected from:

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

78. The compound of any of claims 1-76, having one 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, being suitable for oral administration.

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

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

83. A method for treating or reducing cancer, or a related disease or disorder, 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, gastric cancer and thyroid cancer.

85. The method of claim 83 or 84, wherein the subject being treated is further administered one or more of chemotherapy, radiotherapy, targeted therapy, immunotherapy and hormonal therapy.

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

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, gastric cancer and thyroid cancer.

89. A method for making a compound of any one claims 1-78.

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